CHE601 Organic Reaction Mechanism

YASHWANTRAO CHAVAN M AHARASHTRA O PEN U NIVERSITY
SCHOOL OF SCIENCES
(F ORMERLY S CHOOL OF A RCHITECTURE , S CIENCE & T ECHNOLOGY )
V154: M.Sc. Chemistry

2023 {As per NEP 2020}
Pattern
CHE601
ORGANIC REACTION
MECHANISM
(4 Credits)
Semester –III
Email: director.ast@ycmou.ac.in
Website: www.ycmou.ac.in
Phone: +91-253-2231473
CHE511: Organic Chemistry-II Page 1

Yashwantrao Chavan CHE601
Maharashtra Open Organic Reacton Mechanism

University
Brief Contents
Vice Chancellor’s Message ................................................................................. 3
Foreword By The Director ................................................................................. 4
Credit 01 ................................................................................................................. 5
Credit 01 -Unit 01: Methods Of Determining Reaction Mechanisms .. 6
Credit 01-Unit 02: Types Of Reactions ...................................................... 19
Credit 01-Unit 03: Energy Of Activation .................................................. 42
Credit 01-Unit 04: Non-Kinetic Methods ................................................. 56
Credit 02 ............................................................................................................... 80
Credit 02-Unit 01: Oxidation Methods ...................................................... 81
Credit 02-Unit 02: Oxidation Involving ................................................... 123
Credit 02-Unit 03: Reduction Methods ................................................... 149
Credit 02-Unit 04: Reductions Of Conjugated Systems ...................... 190
Credit 03 .............................................................................................................. 203

Credit 03-Unit 01: Reactive Intermediates: Carbenes And Nitrenes204
Credit 03 -Unit 02: Study Of Reactions ................................................... 225
Credit 03 -Unit 03: Molecular Recognition ............................................ 242
Credit 03 -Unit 04: Supramolecular Reactivity And Catalysis .......... 290
Credit 04.............................................................................................................. 315

Credit 04 -Unit 01: Types Of Free Radical Reactions ........................... 316
Credit 04 -Unit 02: Neighboring Group Assistance .............................. 331
Credit 04 -Unit 03: Allylic Hydrogenation (Nbs) .................................. 355
Credit 04 -Unit 04: Coupling Of Alkynes And Arylation ..................... 373
FEEDBACK SHEET FOR THE STUDENT ..................................................... 389
CHE601: Organic Reaction Mechanism Page 1

CHE601: Organic Reaction Mechanism
Yashwantrao Chavan Maharashtra Open University
Vice-Chancellor: Prof. Dr. P. G. Patil
School of Architecture, Science and Technology
Director of the School: Dr. Sunanda More
Programme Advisory Committee
Dr Sunanda More Dr. Chetana Kamlaskar
Director, Associate Professor, School of Architecture,
School of Architecture, Science & Science & Technology, YCMOU, Nashik
Technology, YCMOU, Nashik
Prof. Dr. S. D. Delekar, Prof. Dr.Nandkishor N. Dr. Arvind Vinayak Nagawade
Professor, Deptt of Chemistry,
Karade, Vice Principal & Head Deptt
Shivaji University
Kolhapur - 416004 Deptt of Chemistry, of Chemistry, Ahmednagar
RashtrasantTukadoji Maharaj College Ahmednagar,
Nagpur University, Dist: Ahmednagar, 414001
Nagpur 440033
Dr. Tukaram. S. Thopate, Prof. ShamraoGolekar Dr.Borhade Ashok Vishram
Vice Principal and Head Deptt
Associate Professor and Head Associate Prof., Deptt of
of Chemistry, New Arts,
Commerce Science College, Deptt of Chemistry Jamkhed
Chemistry, H.P.T. Arts &
Parner, Taluka Parner, Dist: College Jamkhed,
Ahmednagar 414302 Dist: Ahmednagar 413201 R.Y.K. Science College,
Nashik 422001
Dr. Amol Kategaonkar Dr. Bharat More
Associate Prof. in Chemistry,
Academic Coordinator, School of
KSKW College, Cidco,
Architecture, Science and Technology,
Nashik 422008
YCMOU, Nashik-422 222
Development Team
Instructional Course Coordinators Book Writer Book Editor
Technology Editor
Dr Sunanda More 1.Dr. Bharat More Mr. Roshan Abhiman Mr. Atul S. Patil
Director, Jadhav Assistant Professor,
2. Mr.Ghanshyam Patil
School of Assistant Professor , Dept. of Chemistry,
Academic Coordinator, KVPS’s Kisan ACS
Architecture, Dept. of Chemistry,
School of College, Parola Dist-
AST, YCMOU, Nashik- JET’s Z.B.Patil College
Science &
Technology, Jalgaon
422 222 ,Dhule- 424002 .
YCMOU, Nashik
This work by YCMOU is licensed under a Creative Commons Attribution-on

Commercial-ShareAlike 4.0 International License.
 Book Publication: 16-Feb.-2023 Publication No: 2620
 Publisher: Mr. B.P. Patil, Registrar(I/C), YCMOU, Nashik- 422 222, MS
ISBN: 978-93-95855-76-1
 This SLM V142: M.Sc. Chemistry {2022 Pattern}, dtd. 16/02/2023
Book used
V154: M.Sc. Chemistry {2023 Pattern}, dtd. 31/08/2023
in

V ICE C HANCELLOR ’ S M ESSAGE
Dear Students,
Greetings!!!
I offer cordial welcome to all of you for the Master’s degree programme of Yashwantrao
Chavan Maharashtra Open University.
As a post graduate student, you must have autonomy to learn, have information and knowledge
regarding different dimensions in the field of Chemistry and at the same time intellectual development is
necessary for application of knowledge wisely. The process of learning includes appropriate thinking,
understanding important points, describing these points on the basis of experience and observation,
explaining them to others by speaking or writing about them. The science of Education today accepts
the principle that it is possible to achieve excellence and knowledge in this regard.
The syllabus of this course has been structured in this book in such a way, to give you autonomy to
study easily without stirring from home. During the counseling sessions, scheduled at your respective study
centre, all your doubts will be clarified about the course and you will get guidance from some qualified
and experienced counsellors/ professors. This guidance will not only be based on lectures, but it will also
include various techniques such as question-answers, doubt clarification. We expect your active
participation in the contact sessions at the study centre. Our emphasis is on ‘self study’. If a student
learns how to study, he will become independent in learning throughout life. This course book has been
written with the objective of helping in self-study and giving you autonomy to learn at your convenience.
During this academic year, you have to give assignments, complete laboratory activities, field visits
and the Project work wherever required. You have to opt for specialization as per programme structure.
You will get experience and joy in personally doing above activities. This will enable you to assess your
own progress and thereby achieve a larger educational objective.
We wish that you will enjoy the courses of Yashwantrao Chavan Maharashtra Open University,
emerge successful and very soon become a knowledgeable and honorable Master’s degree holder of
this university.
I congratulate “Development Team” for the development of this excellent high quality “Self-
Learning Material (SLM)” for the students. I hope and believe that this SLM will be immensely useful
for all students of this program.
Best Wishes!
- Prof. Dr. P. G. Patil
Vice-Chancellor, YCMOU

F OREWORD B Y T HE D IRECTOR
Dear Students,
Greetings!!!
This book aims at acquainting the students with conceptual and applied fundamentals
about Chemistry required at degree level. The book has been specially designed for
Science students. It has a comprehensive coverage of concepts and its application of
Chemistry in practical life. The book contains numerous examples to build
understanding and skills. The book is written with self- instructional format. Each
chapter is prepared with articulated structure to make the contents not only easy to
understand but also interesting to learn. Each chapter begins with learning objectives
which are stated using Action Verbs as per the Bloom’s Taxonomy. Each Unit is started
with introduction to arouse or stimulate curiosity of learner about the content/ topic.
Thereafter the unit contains explanation of concepts supported by tables, figures,
exhibits and solved illustrations wherever necessary for better effectiveness and
understanding. This book is written in simple language, using spoken style and short
sentences. Topics of each unit of the book presents from simple to complex in logical
sequence. This book is appropriate for low achiever students with lower intellectual
capacity and coversthe syllabus of the course. Exercises given in the chapter include
conceptual questions and practical questions so as to create a ladder in the minds of
students to grasp each and every aspect of a particular concept. I thank the students who
have been a constant motivation for us. I am grateful to the writers, editors and the
School faculty associated in this SLM development of the Programme.
Best Wishes to all of you!!!
- Dr. Sunanda More

Director,
School of Arch., Science &Technology,
YCMOU

C REDIT 01

CREDIT 01 -UNIT 01: METHODS OF DETERMINING REACTION
MECHANISMS
LEARNING OBJECTIVES
After successful completion of this unit, you will be able to
 Understand what a reaction mechanism is
 Understand the relationship between rate equations and reaction mechanisms
 This will explain how reactions can be ‘zero’ order
 Learn to identify possible reaction mechanisms from suit able rate data.
 How can we determine the reaction mechanism?
 To gain an understanding of reaction mechanisms, including the concepts of
elementary steps and molecularity.
 To become familiar with reaction potential energy diagrams.
 To gain an understanding of rate-determining steps in multistep reactions.
INTRODUCTION
In chemistry, a reaction mechanism is the step by step sequence of elementary
reactions by which overall chemical change occurs.
A chemical mechanism is a theoretical conjecture that tries to describe in detail what
takes place at each stage of an overall chemical reaction. The detailed steps of a
reaction are not observable in most cases. The conjectured mechanism is chosen
because it is thermodynamically feasible, and has experimental support in isolated
intermediates (see next section) or other quantitative and qualitative characteristics of
the reaction. It also describes each reactive intermediate, activated complex,
and transition state, and which bonds are broken (and in what order), and which bonds
are formed (and in what order). A complete mechanism must also explain the reason for
the reactants and catalyst used, the stereochemistry observed in reactants and
products, all products formed and the amount of each.
01-01: KINETIC METHODS
Chemical kinetics is that branch of chemistry which deals with the study of the rate of
chemical reactions and the mechanism by which they occur. In other words, it deals
with how fast and through what mechanism a particular chemical reaction occurs.
The chemical reactions can be classified into the following categories on the
basis of their speeds:
(a)Instantaneous or fast reactions which proceed at a very fast speed and it are
practically impossible to measure the speed of such reactions. Typical examples of fast
reactions include (i) several ionic reactions, i.e., neutralisation of acids and bases, (ii)
organic substitution reactions, (iii) reactions of biological importance and (iv)

explosive reactions of oxygen with hydrogen and hydrocarbons. The rates of such
reactions can be measured by using special methods.
(b)Extremely slow reactions which proceed at a very slow speed and the speed
is so slow that it is again not possible to measure the speed of such reactions.
(c) Reactions which proceed at a measurable speed. Reactions involving
organic substances belong to this category, e.g., inversion of cane sugar, saponification
of ethyl acetate etc.
Reactions belonging to the above third category, viz., (c) are utilised in the study
of chemical kinetics.
SOLVED PROBLEMS:
1) Problem 1:
For the reaction N 2 + 3H 2 → 2NH 3 , the rate of change of concentration for hydrogen is
–0.3 × 10 –4 Ms –1 . Calculate the rate of change of concentration of ammonia?
Solution: N 2 + 3H 2 → 2NH 3
2) Problem 2:
In an experiment to study the reaction
A + 2B → C + 2D, the initial rate –d[A]/dt at t = 0 was found to be 2.6 × 10–2 Ms–1. What is the
value of -d[B]/dt at t = 0 in Ms–1 ?
Solution: A + 2B → C + 2D
= 5.2 × 10–2 Ms–1
SHORT ANSWER QUESTIONS:

Que.1: Define order of reaction.

Answer: ‘The order of reaction is given by the number of concentration terms of atoms or
molecules which determine the rate law’.
Que.2: Give the examples of Instantaneous or fast reactions.
Answer: examples of fast reactions include (i) several ionic reactions, i.e., neutralisation of acids
and bases, (ii) organic substitution reactions, (iii) reactions of biological importance and (iv)
explosive reactions of oxygen with hydrogen and hydrocarbons.
01-02: ORDER OF REACTION:
In chemical kinetics, the reactions are generally classified in terms of their
order. Order of a reaction is defined as follows:
‘The order of reaction is given by the number of atoms or molecules whose
concentration changes during a chemical reaction’.
Or
‘The order of reaction is given by the number of concentration terms of atoms or
molecules which determine the rate law’.
A reaction is said to be of first order, if its rate, r (or dx/dt) is given by the
following expression,
The reaction is of second order and third order if its rate is given by
expressions (1) and (2), respectively.
The subscripts A, B and C stand for various reactants A, B and C, respectively.

When the rate of a reaction is given by
Where k is a constant, the reaction orders of the individual constituents are n 1 ,

n 2 , n 3 , etc., and the order of the reaction as a whole, n, is given by
So, order of reaction may also be defined as, ‘the sum of the powers to which
the concentration (or pressure) terms of the reactants are raised in order to express the
reaction rate.
SOLVED PROBLEMS:
1) Problem 3:
What is the molecularity of the following reaction?
2NO2 (g) → 2NO (g) + O2 (g)

Solution: The molecularity of this reaction is two i.e. bimolecular. Because, in this reaction, two
molecules take part in the reaction.
2) Problem 4:
Consider a complex reaction, in general,
2A+3B → X+Y
Suppose that the reaction occurs through the following steps:
(i) A+B M+N

(ii) B+M BM
(iii) BM+A X+Z
(iv) B + N+ Z Y
Which step is the rate determining step?
Solution: The mechanism of the above reaction takes place in four steps. Step (i) is the rate
determining step. Because the slowest step in the reaction mechanism which involves many steps
is called rate determining step.
Que.3: What is molecularity?

Answer: Molecularity of a reaction is defined as the number of atoms or molecules which collide
together at one and the same time for the reaction to occur.
Que.4: Define the term elementary reaction.
Answer: A reactioin that takes place in a single step and cannot be broken down further into
simpler chemical reaction is called as elementary reaction.
01-03: MOLECULARITY:
Many chemical reactions are not kinetically simple; they proceed through a
number of steps between initial reactants and final products. Each of the individual
steps is called an elementary reaction. Complex reactions are made up of a sequence of
elementary reactions.
In the earlier literature, the terms unimolecular, bimolecular and trimolecular
were used to express reactions of the first, second and third orders. We now apply the
concept of molecularity only to elementary reactions. The molecularity shows how
many molecules of reactants are involved in the elementary reaction. For example,
consider the reaction NO + O 3 = NO 2 + O 2 . When an NO molecule strikes an O 3
molecule with sufficient kinetic energy, it can capture an O atom, thus completing the
reaction. This elementary reaction involves two molecules and it is, therefore, called a
bimolecular reaction.

At the molecular level, a chemical reaction is a rearrangement of the chemical
bonds of reactant molecules to form the chemical bonds of product molecules. It is
necessary to change the energy state of a reactant molecule to allow the original bonds
to change over to the new bonds. Consider the reaction,
HCl + Br 2 = HBr + BrCl
One H—Cl bond and one Br—Br bond are changed into one H—Br bond and
one Br —Cl bond.
The transition state between reactants and products is called the activated
complex.
The molecularity of a reaction can be defined as the ‘number of molecules of

reactants that are used to form the activated complex.’ The word molecule is used in its
general sense to include atoms and ions also. In other words, molecularity of a reaction
is defined as the number of atoms or molecules which collide together at one and the
same time for the reaction to occur.
In the examples of NO + O 3 and HCl + Br 2 , the complex is formed from two

molecules and the reactions are bimolecular. Clearly, the molecularity of a reaction
must be a whole number, and in fact, is always found to be one, two or occasionally
three. Experimental measurements show that the rate law for the reaction of NO with O 3
is
This reaction is, therefore, second order. All bimolecular reactions are second
order, but the converse is not true; many second order reactions are not bimolecular.
Similarly, chemical reactions that are unimolecular are either isomerisations o r

decompositions. The isomerisation of cyclopropane to propene in the gas phase is one
of the most carefully studied unimolecular reactions.
Experimental results show that the rate law for the above reaction is,

This reaction is, therefore, first order. All the unimolecular reactions are first
order, but the converse is not true, some first order reactions are not unimolecular.
Differences between Order of Reaction and Molecularity
(1) For simple reactions. Earlier, no distinction was made between molecularity and
order of a reaction. Reactions of first, second and third orders were called unimolecular,
bimolecular, trimolecular reactions. This practice is, however, not followed now.
In several reactions, the order of reaction is different from molecularity,
particularly when one of the reactants is in large excess, e.g., inversion of cane sugar,
hydrolysis of methyl acetate etc.
Both the reactions are bimolecular but the order of reaction is 1, as it is found
from experimental data that the rate of reaction is directly proportional to concentration
of cane sugar in the first case and that of ester in the second case. This is explained due
to the fact that water is present in large excess and its concentration does not change
during the course of the reaction.
Moreover, molecularity of any process can only be small positive integers, while
order of reaction can have zero as well as fractional values.
We thus conclude that in elementary reactions, the molecularity of the reaction
is given by the number of molecules of the reactant or reactants appearing in the
stoichiometric equation for the reaction, while the order of reaction is given by the
number of concentration terms of the reactant or reactants on which the rate of reaction
depends.
Table-1. Differences between order of reaction and molecularity

Molecularity Order of reaction
1. It is equal to the number of 1. It is equal to the sum of the
molecules which take part in a powers of the molar
single step chemical reaction concentrations of the reactants in
the rate expression.
2. It is a theoretical concept which 2. It is an experimentally determined

depends on the rate determining quantity which is obtained from
step in the reaction mechanism. the rate for the overall reaction.
3. It is always a whole number. 3. It may be whole number, zero or
fractional value.
4. It is obtained from a single 4. It cannot be obtained from a
balanced chemical equation. balanced chemical equation.
5. It reveals some basic facts about 5. It does not reveal anything about
reaction mechanism. reaction mechanism.
(2) For complex reactions. Those reactions which occur in two or more steps are
termed as complex reactions, from the point of view of chemical kinetics. Each step of
it is a simple reaction, i.e., an elementary reaction has its own molecularity depending
upon the number of molecules of the reactant or reactants taking part in that simple
reaction.
Consider a complex reaction, in general,
2A+3B → X+Y
Suppose that the reaction occurs through the following steps:
(iii) A+B M+N
(iv) B+M BM
(iii) BM+A X+Z
(iv) B + N+ Z Y
The complex reaction 2A + 3B → X + Y takes place in four steps, the rates of every
elementary reaction differs from one another. Suppose the first elementary reaction is
the slowest. The rate of the overall reaction cannot be faster than the rate of the slowest
reaction. In other words, the rate of the overall reaction will be exactly eq ual to the
rate of the slowest reaction. Thus, we can conclude that the slowest step in the sequence
ofvarious steps is the rate determining step of the overall reaction. So, step (i) is the
rate determining step.
The rate of reaction of step (i), which i s the slowest, will be given by,
The rate of the overall reaction will evidently be given by the above expression.
The order of the slowest reaction and, therefore, the order of the overall reaction will
also be 2. The molecularity of the slowest reaction, viz, step (i) is also 2. However, the
molecularity of the other succeeding steps is 2, 2 and 3. Consider the reduction of
bromic acid to hydrobromic acid by hydroiodic acid. It occurs as follows:
HBrO 3 + 6HI → HBr + 3H 2 0 + 3I 2

The reaction involves seven molecules, yet it is of second order. The order of
reaction is justified by the following mechanism:
(i) HBrO 3 + HI → HBrO 2 + HIO [Stow]
(ii) HBrO 2 + 4HI → HBr + 2H 2 0 + 2I 2 [Fast]
(iii) HIO + HI → + H 2 O +I 2 [Fast]
As the first step is slow, it means that the reaction is of second order. In
elementary steps involved in the complex reaction each has its own m olecularity. The
molecularities of steps (i), (ii) and (iii) are 2, 5 and 2, respectively.
We thus conclude that the order of a complex reaction is given by the order of
the slowest step involved in the reaction. The molecularity of such a complex reactio n
has thus no significance. Each step or reaction involved has its own value of
molecularity. It is given by the number of molecules of reactant or reactants involved in
that particular step of the overall reaction. The molecularity of the slowest step gives
the order of the overall reaction.
Q. Why reactions of the higher orders are rare?
From the balanced chemical equation of the overall reaction, we can neither
predict the order nor the molecularity of a reaction. For example, in the reaction 2A +
3B → products, neither the molecularity nor the order of reaction is 2+ 3 = 5. This also
follows from probability considerations, as the chances of five molecules to collide
simultaneously are remote. In fact, the chances for even three molecules to collide
simultaneously are not high, whereas the chances for one or two molecules to collide
simultaneously are high. This is the reason why reactions of third and higher orders are
very rare and most of the reactions are of first and second order.
Problem 1. For the decompositon of N 2 O 5 dissolved in CCl 4 which occurs as follows:
2N 2 O 5 → 4NO 2 + O 2
The following data at 303 K are obtained:
Reactant concentrations [N 2 O 5 ]
0.170 mole lit -1 0.05 mole lit -1 hr -1

(i) Write the rate equation for the reaction. What is the order of reaction?
(ii) Calculate the rate constant for the reaction at 303 K.
(iii) Calculate the decomposition at the instant when [N 2 O 5 ] is 0.54 mole lit -1 .
Solution: (i) It is observed from the data that the rate of decomposition of N 2 O 5 is
proportional to the concentration of N 2 O 5 . The rate becomes twice when the

concentration is doubled and becomes four times when the concentration is made four
times.
Mathematically, we can write
Order of reaction = 1.
(ii) The rate constant,
(iii) By substituting the values of k and [N 2 O 5 ] = 0.54 mole lit -1 in equation (i), we get,
Rate of decompositon = 0.2941 x 0.54
= 0.1588 mole lit -1 hour -1 .
SOLVED PROBLEMS:
1. Assuming an elementry reaction H2O2 + 3I– + 2H+ → 2H2O + I3–. The effect on the rate of this
reaction brought about by doubling the concentration of I– without changing the order
(1) The rate would increase by a factor of 3
(3) The rate would decrease by a factor of 1/3
Solution: Answer (2)
r = K[H2O2][I–]3[H+]2
given [I–]1 = 2I–
r2= K[H2O2][2I–]3[H+]2
⇒ 8K[H2O2][I–]3[H+]2
= 8r1
2. For the hypothetical reaction 2A → 3C, the reaction rate ‘r’ in terms of the rate of change of
the concentration is given by

Que.5: What is pseudo first order reaction?

Answer: A reaction which has higher order true rate law but experimentally found to behave as
first order is called pseudo first order reaction.
Que.6: Explain pseudo first order reaction with one example.
Answer: Explanation of pseudo first order reaction
Consider acid hydrolysis of methyl acetate,
H + (aq + CH OH(aq)
CH3COOCH3 (aq) + H2O(l)CH3COOH(aq) 3
True rate law of the reaction, )
Rate = k’[CH3COOCH3][H2O]
As water is in large excess, hence its concentration remains constant throughout the reaction.
Rate of reaction = k[CH3COOCH3]
Where k = k’[H2O]
Therefore order of this reaction one. Thus second order true rate law has been forced into first
order form. Hence the reaction is pseudo first order reaction.
01-04: PSEUDO-MOLECULAR REACTIONS

There are several reactions which obey a first order rate equation although in
reality they are bi-or tri-molecular. For example, consider the hydrolysis of methyl
acetate (ester) in presence of an acid.
According to the law of mass action, this reactio n should be of second order,
with the rate dependent on the concentration of both ester and water. Actually, however,
the rate is found to be of first order with respect to the ester and independent of water.
Reactions showing such behaviour are termed pseudo-molecular reactions(pseudo =
false).
The pseudo-unimolecular nature of this reaction is explainable by the fact that
water is present in such excess that its concentration remains practically constant
during the course of the reaction. Pseudo-molecular reactions are encountered whenever
concentrations of one or more reactants remain constant during the course of the
reaction.
SOLVED PROBLEMS 04
1) For a reaction of the type aA + bB→ products;

Sol. Answer (3)
2) A reaction involving two different reactants can never be a

(1) Second order reaction
(2) Biomolecular reaction
(3) Unimolecular reaction
(4) First order reaction
Sol. Answer (3)
Que.7: What is pseudo first order reaction?
Answer: A reaction which has higher order true rate law but experimentally found to behave as
first order is called pseudo first order reaction.
Que.8: Explain pseudo first order reaction with one example.

Answer: Explanation of pseudo first order reaction
Consider acid hydrolysis of methyl acetate,
H + (aq)
CH3COOCH3 (aq) + H2O (l) CH3COOH (aq) + CH3OH (aq)
True rate law of the reaction,
Rate = k’ [CH3COOCH3][H2O]
As water is in large excess, hence its concentration remains constant throughout the reaction.
Rate of reaction = k[CH3COOCH3]
Where k = k’[H2O]
Therefore order of this reaction one. Thus second order true rate law has been forced into first
order form. Hence the reaction is pseudo first order reaction.
CHECK POINT 01-01
1. Assuming an elementry reaction H2O2 + 3I– + 2H+ → 2H2O + I3–. The effect on the rate of this
2. For the hypothetical reaction 2A → 3C, the reaction rate ‘r’ in terms of the rate of change of
the concentration is given by

3. For a reaction of the type aA + bB→ products;
Sol. Answer (3)

4. A reaction involving two different reactants can never be a
(1) Second order reaction
(2) Biomolecular reaction
(3) Unimolecular reaction
(4) First order reaction
Sol. Answer (3)
SUMMARY
Mechanism of a reaction states the actual process by which the reaction has taken place.
Mechanism can be determined by the study of various aspects of product formation,
intermediates, catalysts, sterreochemical considerations, kinetic considerations, and
isotope labelling and isotope effect.
KEY WORDS
Product formation, intermediates, catalysts, sterreochemical conside rations, kinetic
considerations, and isotope labelling and isotope effect.
REFERENCES
PHYSICAL CHEMISTRY Vol. I Dr. J. N. Gurtu MSc., Ph.D, Former Principal Meerut
College, MEERUT.AayushiGurtu PRAGATI PRAKASHAN
MOOCS
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YOUTUBE VIDEOS
https://www.youtube.com/watch?v=7wn8kHqLvYc
https://www.youtube.com/watch?v=OxM-bIBhwWo
https://www.youtube.com/watch?v=FPOpG2QO1Sk
WIKIPEDIA
https://en.wikipedia.org/wiki/Chemical_kinetics
https://wiki2.org/en/Order_of_reaction
https://en.wikipedia.org/wiki/Molecularity
https://en.wikipedia.org/wiki/Rate_equation

OER
-------
REFERENCEB OOKS
PHYSICAL CHEMISTRY Vol. I Dr. J. N. Gurtu MSc., Ph.D, Former Principal Meerut
College, MEERUT.AayushiGurtu PRAGATI PRAKASHAN

CREDIT 01-UNIT 02: TYPES OF REACTIONS
LEARNING OBJECTIVES
 How to identify different types of chemical reactions and predict the products
likely to form.
 Identify and define chemical reactions as combination, decomposition,
displacement, or combustion reactions.
 Predict the likely products of a chemical reaction from the type of reaction,
 Write chemical equations for each type of chemical reaction,
 Suggest the different products that may form in a combination reaction.
INTRODUCTION
Chemical reaction, a process in which one or more substances, the reactants, are
converted to one or more different substances, the products. Substances are either
chemical elements or compounds. A chemical reaction rearranges the constituent atoms
of the reactants to create different substances as products.
Many chemical reactions can be classified as o ne of five basic types. Having a thorough
understanding of these types of reactions will be useful for predicting the products of
an unknown reaction. The five basic types of chemical reactions are combination,
decomposition, single-replacement, double-replacement, and combustion. Analyzing the
reactants and products of a given reaction will allow you to place it into one of these
categories. Some reactions will fit into more than one category.
02-01: FIRST ORDER REACTION
Definition of First Order Reactions
A first order reaction is that in which the reaction rate is determinedby the change of
one concentration term of reactant only.
[II] Rate Equation of First Order Reactions
Consider a first order reaction,
A  B + C
a 0 0 (Initially)
a-x x x (After time t)
Suppose the initial concentration of the reactant A be a molellitre. Let
xmole/litre of A decomposes after time t, leaving behind (a - x) molellitre of A.
Theamounts of Band C formed will be x mole/litre each.
The rate for a first order reaction is proportional to the concentration of A atany
particular time. Therefore,
Where k = rate constant or velocity constant.

Integrating equation (4), we get
-loge (a - x) = kt + I ---------------------- (3)
Where I is integration constant
When t = 0, x = 0; then
I = -loge a
Hence, equation (5) becomes
- log e (a - x) = kt - log e a
obtained with a slope of 2.303/k.

Equations (4) and (5) are known as first order rate equations. Equation (5) can also be
written as
Or x = a (1 - e -kt )
If equation (2) is integrated between proper limits, we have
From equation (9), it is possible to calculate the rate constant from any pair of
concentration measurements.
SOLVED PROBLEMS 01
Problem 1
A first order reaction completes 60% in 20 minutes. Calculate the time required for the
completion of 90% of the reaction?
Solution:

Divide equation i by ii
t = 50 minutes
Problem 2
99% of a first order reaction was completed in 32 minute. When will 99.9% of the reaction
complete?
Solution:
Divide equation (i) by (ii)
∵ log10 = 1
SHORT ANSWER QUESTIONS WITH MODEL ANSWER 01

Que.1: Define first order reaction?
Answer: A reaction whose rate depends on the single reactant concentration raised to first power
is called the first order reaction.
Que.2: Give the integrated rate equation of first order reaction.
Where a = concentration of reactant at t = 0

a  x = Concentration of reactant at time t
02-02: SECOND ORDER REACTION

Definition of Second Order Readions
A reaction is said to be of second order if its reaction rate is determined by the change
of two concentration terms of reactants.
[I] Rate Equation of Second Order Reactions
It can be represented as,
(a) Rate expression when concentrations of both reactants are equal.
Suppose,we start with equal concentrations of both the reactants, say a mole. Let x
mole of each be transformed during an interval of time t. The velocity of the reaction
will then be given by
Where 1 = integration constant.
When t = 0, x = 0, we have from equation (1 )
Substituting the value of I in equation (1), we get

Equation (14) is the rate equation for a second order reaction when concentrations of
both the reactants are equal.
(b) Rate expression when the concentrations of the reactants are not
equal
Suppose a and b represent the initial concentrations of the reactants and (a - x) and (b -
x) be their respective concentrations after time t. The reaction rate will be given by
= k (a - x) (b - x)
Splitting into partial fractions, we get
Integrating it we get
Where I = integration constant.

When t = 0, x = 0 then from equation (15), we have
Substituting the value of I in equation (1), we get,
Converting it to logarithm to the base 10,
Equations (2) and (3) are the general rate equations for a second order reaction.
SOLVED PROBLEMS 02
Problem 3
A second order reaction where a = b is 20% completed in 500 seconds. How long will it take for
the reaction to go to 60% completion?
Solution: For a second order reaction, where a = b

When the reaction is 20% complete, x = 0.2a
Suppose it takes t1seonds for the reaction to go to 60% completion.
t1 = 3000 sec.
Problem 4
A second order reaction with two reactants is started with O.1M concentrations of each reactant.
It is 20% completed in 500 seconds. How long will it take the reaction to go to 70% completion?
Solution: For a second order reaction when the concentrations are equal, we have
For 20% completion: a = 0.1, x= 0.2  0.1 = 0.02; t = 500
For 60% completion: a = 1; x = 0.6  0.1 = 0.06; t =?

Que.3: Define second order reaction.
Answer: A reaction is said to be of second order if its reaction rate is determined by the change
of two concentration terms of reactants.
Que.4: Give general rate equations for a second order reaction.

Answer:

Where a and b represent the initial concentrations of the reactants and (a - x) and (b -x) be their
respective concentrations after time t.
02-03: THIRD ORDER REACTION
[I] Definition of Third Order Reactions
A reaction is said to be of third order if its reaction rate is determined by the
change of three concentration terms of reactants.
Reactions of third and higher orders are rare, but there are in fact reactionswhich are
definitely of third and sometimes of higher order. This is due to the fact that the
probability of three modecules coming to a single point simultaneously, i.e.,probability
of trimolecular collisions is much less as compared to unimolecular or bimolecular
collisions.
[II] Rate Equation of Third Order Reactions
For a third order reaction:
A + B + C  Products
The reaction rate is given by,
Where a, b and c are the initial concentrations of reactants A, B and C and xis the
concentration of each reactant decomposed in time t.
[I] Case I. When a = b = c (Integrated rate law)
On integration, we get

When t = 0, x = 0, we then have
Substituing the value of I in equation (1), we get

[II] Case II. When a b  c (Integrated rate law)
Or 1 = p (b - x) (c - x) + q (a - x) (c - x) + z (a - x) (b - x)
Putting x = a, band c, respectively in equation (4), we get
Substituting the values of p, qand z from equations (5), (6) and (7) in equation (4) and
rearrangement, we get a differential equation which is equivalent to equation (2).
When t = 0, x = 0, we get from equation (8),

[III] Case III. When two of the molecules are identical and third is different
(Integrated rate law)
2A + B  Products
Concentration when t = 0 a b
Concentration when t = t (a - 2x) (b- x)
Breaking into partial fractions, we get
Or 1 = (px + q) (b - x) + z(a - 2x) 2

Or 1 = (qb+za 2 ) + (pb -q - 4za)x + (4z- p)x 2 -------------------------- (12)
Equating coefficients of x 2 , x and constant on both sides of equation (12), we get
4z - p = 0 or p = 4z ------------ (13)
and pb - q - 4za = 0 ------- (14)
and qb + za 2 = 1 -------------- (15)
Putting values of pand q from equations (13) and (15) in equation (14),

Equation (17) is kinetic equation for the above type of third order reaction.
[II] Opposing or Reversible Reactions

Opposing reactions result in chemical equilibrium. In many cases the equilibrium is so
much on the product side at the experimental temperature and pressure that for all
practical purposes it can be said that the reaction is complete, as in the dissociation of
N 2 O 5 . But there are other systems in which the equilibrium remains on the reactants
side, e.g., the hydrolysis of ethyl acetate in water.
The correct expression for the rate of change is given by

It means that the rate of decrease of ester is not characterised by a factor k 1 but by (k 1 -
k 2 ).
(i) When both the reactions are offirst order.
The simplest case of opposing reactions is that in which both the forward and backward
reactions are of the first order, i.e.
Where k 1 and k 2 are rate constants for forward and backward reactions.
Let the initial concentrations of A and B be a and b, respectively. If after time t,

xmole/litre of A changes into B, then, concentrations of A and B will be ( a - x)and (b +
x), respectively.
The different rate expression is thus given by
At equilibrium, the net rate is zero, i.e., d x/dt = 0, then
k 1 (a - x e ) = k 2 (b +x e ) -------------------------------------------------------------- (6)
Where x e is the value of x at equilibrium.
Substituting the value of b in equation (5), we get

Equation (7) is similar to the first order rate expression, except that the measured rate
constant is now the sum of the forward and reverse rate constants. Examples of such
reactions are mutarotation of -bromonitrocamphors, conversion of ammonium
thiocyanate into urea etc.
(ii) When a first order reaction is opposed by a second order reaction.
Consider the reaction:
The rate of reaction at any 'time t is given by
The square is completed by adding and substracting k 1 2 / 4k 2 , and the resulting square is
then divided by k 2 . Then
Where
We thus have,

Where I, is the integration constant.
When t = 0, x = 0, hence
The fractional factor may be written in the form
At t = ,coth (k 2  t)  1,
On squaring and rearranging, we get
At equilibrium x = x e , hence on substituting the value of k 2 from equation (9) in (8), and
integrating it after splitting into partial fractions, we have
Examples of this type are decomposition of phosphorous pentachloride into phosphorus

trichloride and chlorine, hydrolysis of ethyl acetate in presence of acid etc.
(iii) When a second order reaction is opposed by a first order reaction .
Consider the following reaction:

We have,
At equilibrium, k 1 (a - x e ) 2 = k 2 x e ------------- (11)
Substituting the value of k 2 from equation (11) in (10) and integrating after splitting it
into partial fractions, we have
Examples of this type are synthesis ofNH 3 by Haber's process, reaction between
ethyl alcohol and acetic acid etc.
(iv) When a second order reaction is opposed by one of the same order .
Consider the following reaction:
Thus,
Remember that k 2 / k 1 = K' and at equilibrium x = x e ' we have after splitting into partial
fractions and integrating
Where,

Examples of this type are saponification of ethyl acetate by alkali, decomposition of HI
etc,
(v) When a third order reaction is opposed by one of the second order .
Consider the following reaction,
The rate of reaction is given by
If k 1 / k 2 = K and x =Xeat equilibrium, we have
SOLVED PROBLEMS 03
Problem 5
The rate of the reaction aA + bBcC + dD is given by the following expression:
Where, k is the velocity constant. What is (i) order of reaction if A is present in excess
(ii) order of reaction if B is present in excess (iii) total order of reaction (iv)
molecularity of the reaction?
Solution: (i) Order of reaction when A is in excess = 2
(ii) Order of reaction when B is in excess = 1
(iii) Total order of reaction = 2 + 1 = 3
(iv) Molecularity of the reaction = a + b.
Problem 6
Consider the following reaction
A+B
is found to follow the following rate law:
rate = k[A] 1 [B] 2
Determine: a) the reaction order with respect to A, b) the reaction order with respect to
B, and c) the total reaction order for the equation.
Solution: a) The order of reaction with respect to A is 1.
b) The order of reaction with respect to B is 2.
c) Overall order of the reaction is 1 + 2 = 3

Que.5: Define third order reaction.
Answer: A reaction is said to be of third order if its reaction rate is determined by the change of
three concentration terms of reactants.
Que.6: Write a note on opposing reaction.

Answer: Opposing reactions result in chemical equilibrium. In many cases the equilibrium is so
much on the product side at the experimental temperature and pressure that for all practical
purposes it can be said that the reaction is complete, as in the dissociation of N2O5. But there are
other systems in which the equilibrium remains on the reactants side, e.g., the hydrolysis of ethyl
acetate in water.
02-04: CONSECUTIVE, SIMULTANEOUS OR PARALLEL REACTIONS

Chemical reactions which proceed from reactants to products through one or
more intermediate stages are called consecutive reactions. The simplest case arises
when both the consecutive reactions are of the same order, viz.,
Suppose we start with a mole of A. Let after a time t, x mole of A is left behind, giving
y mole of B and z mole of C. Therefore, x, yand zare connected as,
x+y+z=a ---------------- (1)
The rate of disappearance of A, i.e., (- dx/dt) is given by
Where k 1 = rate constant for transformation of A to B.

The rate of formation of C, i.e., (dz/dt) is given by
Where k 2 = rate constant for the formation of C from B.

The rate at which B accummulates, i.e., (dy/dt) in the system is thus the difference
between the rate of formation of B from A and the rate of transformation of B into C.
Therefore,

On integrating equation (2), and finding the proper value of integration constant,
as usual, we have
Therefore,
or x= ae -k 1 t
This shows that [A]decreases exponentially with time as in first order reactions.
To get the value of [B], i.e.y, substitute the value of x in equation (4). So,
This is a linear differential equation of the first order, whose solution is
When t = 0, y = 0. So, c = - k 1 a/(k 2 – k 1 )
Substituting the values of x and y in equation (1), we get

z=a – x – y

Some examples of consecutive reactions are
(a) Thermal decomposition of acetone
(b) Decomposition of dimethyl ether
The simplest case of consecutive reactions of the first order is that involving
radioactive series. Suppose an element A undergoes radioactive disintegration, emitting
or  particles, to give element B, which in turn gives element C, as follows:
Where k 1 , k 2 and k 3 are the velocity constants for the respective consecutive reactions.
The constant k of a reaction of first order is known as decay constant, which is the
number of atoms disintegrating per second referred to a system which has on e atom
present.
Where a, b and c are the concentrations of A, B and C at time t.

On integrating equation (7), we get
From equation (8), we get,
On integrating it, we obtain

Substituting the value of b in equation, we get
The last equation on integration gives
Where
SOLVED PROBLEMS 04
Problem 7:
For a series of competing reactions:
H + HO2→H2 + O2; H + OH2→H2O + O; H + HO2→2OH;

Westenberg and de Hass reported that k1/k2/k3 = 0.62/0.27/0.11. Find the ratio of products at time
t.
Solution: The rate equation for the reactions is
Rate = ki CH CHO2 + k2 CH·CHO2 + k3 CHCHO2 = k CH·CHO2
Where, k = k1 + k2 + k3. The given ratio of rate constants implies that 62% of the reactants will
form the products of the first reaction, 27% will form the products of the second reaction and so
on. Thus, the ratio of the products will be
(CH2 = CO)/COH/(CH2O = CO) = 0.62/0.54/0.11
Problem 8:
The acid catalysed conversion of y-hydroxy butyric acid into its lactone was studied in 0.2 N HCl
solutions at 25°C. The initial concentration of the hydroxy acid was 18.23 (measured in arbitrary
units). The concentration of lactone (expressed in the same units) is shown as a function of time
in the following table:
Time (min.) 0 21 36 50 65 80 100 
Lactone conc. 0 2.41 0.73 4.96 6.10 7.08 8.11 13.28
Calculate the equilibrium constant and first order velocity coefficient for the forward and reverse
processes.
Solution: The reaction scheme may be represented as

Where kl and k2 are the first order velocity coefficient for the forward and backward process,
respectively. Let
Thus, a graph of t versus log (xe x) should give a straight line, whose slope is given by
Figure shows such a plot made from the data as given in the following table:
Xe X = ( reading reading at time t)
Time (min.) 0 21 36 50 65 80 100
(xe x) 13.28 3.28 - 2.41= 10.87 9.55 8.32 7.18 6.20 13.28 - 8.11 =
5.17
log (xe x) 1.123 1.036 0.980 0.920 0.856 0.792 0.714
k1 + k2 = 9.48  10-3 min1

For the given data, Xe = 13.28 and a = 18.23
k1 = 2.68k2
Now k1 + k2 = 9.48  103
2.68 k2 + k2 = 9.48  103
3.68 k2 = 9.48  103
k2 = 2.58  103 min1

Hence, k1 =K. k2
= 2.68  2.58  103 = 6.90  103 min1
Que.7: What are consecutive reactions?
Answer: Chemical reactions which proceed from reactants to products through one or more
intermediate stages are called consecutive reactions.
Que.8: Give some examples of consecutive reactions?
Answer: Some examples of consecutive reactions are
(a) Thermal decomposition of acetone
(b) Decomposition of dimethyl ether
CHECK POINT 01-02

1. The rate constant is numerically the same for three reactions of first, second and third order
respectively. Which one is true for rate of three reactions, if concentration of reactant is greater
than 1M?
(1) r1 = r2 = r3 (2) r1> r2> r3

(3) r1< r2< r3 (4) All of these
Sol. Answer (3)
2. Assuming an elementry reaction H2O2 + 3I– + 2H+→ 2H2O + I3–. The effect on the rate of this
Sol. Answer (2)
3. For a reaction A + B → products, the rate of reaction was doubled when concentration of A
was doubled. When concentration of A and B both was doubled, the rate was again doubled,
order of reaction w.r.t. A and B are
(1) 1, 1 (2) 2, 0
(3) 1, 0 (4) 0, 1
Sol. Answer (3)
4. The overall order of reaction between X & Y is 3. Which of the following rate equation must
be correct, if on doubling the concentration of X, the rate of reaction gets doubled?
(1) r = K[X]2[Y]0 (2) r = K[X]1[Y]2
(3) r = K[X]1[Y]3 (4) r = K[X]2[Y]1
Sol. Answer (2)
SUMMARY
The five basic types of chemical reactions are combination, decomposition, single -
replacement, double-replacement, and combustion. Analyzing the reactants and
products of a given reaction will allow you to place it into one of these categories.
Some reactions will fit into more than one category.
Chemical reaction, a process in which one or more substances, the reactants, are
converted to one or more different substances, the products. Substances are either
chemical elements or compounds. A chemical reaction rearranges the constituent atoms
of the reactants to create different substances as products.
KEY WORDS
Combination, decomposition, single-replacement, double-replacement, combustion

REFERENCES
PHYSICAL CHEMISTRY Vol. I Dr. J. N. Gurtu MSc., Ph.D
Former Principal Meerut College, MEERUT.AayushiGurtu, PRAGATI PRAKASHAN
MOOCS
----------
YOUTUBE VIDEOS
https://www.youtube.com/watch?v=8-ova__I_QY
https://www.youtube.com/watch?v=gBgdzYzd7gc
https://www.youtube.com/watch?v=_2twQGAaNSY
https://www.youtube.com/watch?v=tp8URMlXUZQ
https://www.youtube.com/watch?v=R9S0de6jejI
WIKIPEDIA
https://en.wikipedia.org/wiki/First-order
https://en.wikipedia.org/wiki/Second-order
https://en.wikipedia.org/wiki/Rate_equation
https://en.wikipedia.org/wiki/Side_reaction
OER
------
REFERENCE BOOKS
PHYSICAL CHEMISTRY Vol. I Dr. J. N. Gurtu MSc., Ph.D
Former Principal Meerut College, MEERUT.AayushiGurtu, PRAGATI PRAKASHAN

CREDIT 01-UNIT 03: ENERGY OF ACTIVATION
LEARNING OBJECTIVES
 Understand the term activation energy
 Calculate activation energy from experimental data.
 Discuss the concept of activation energy
 To determine activation energy graphically or algebraically.
 Identify the reaction intermediates and catalysts
 Write the overall reaction.
 Determine the molecularity of each step.
INTRODUCTION
Activation energy is defined as the minimum amount of extra energy required by a
reacting molecule to get converted into product. It can also be described as the
minimum amount of energy needed to activate or energize molecules or atoms so that
they can undergo a chemical reaction or transformation.
In chemistry and physics, activation energy is the minimum amount of energy that must
be provided for compounds to result in a chemical reaction. The activation energy (E a )
of a reaction is measured in joules per mole (J/mol), kilojoules per mole (kJ/mol) or
kilocalories per mole (kcal/mol). Activation energy can be thought of as the magnitude
of the potential barrier (sometimes called the energy barrier) separating minima of the
potential energy surface pertaining to the initial and final thermodynamic state. For a
chemical reaction to proceed at a reasonable rate, the temperature of the system should
be high enough such that there exists an appreciable number of molecules with
translational energy equal to or greater than the activation energy. The term "activation
energy" was introduced in 1889 by the Swedish scientist Svante Arrhenius.
03-01: ACTIVATION ENERGY
We know that for a chemical reaction to occur, collisions between
reactantmolecules must occur. It has been postulated that only those collisions
betweenreactant molecules which are associated with a certain minimum amount of
energycan cause a chemical reaction. The minimum amount of energy which must
beassociated with molecules so that mutual collisions may result in chemical reactionis
termed as threshold energy.Molecules possessing energy less than thresholdenergy will
not react on collisions. Molecules possessing energy equal to or in excessof threshold
energy constitute only a small fraction of the total number of molecules.This explains
why a small fraction of the total number of collisions results inchemical reactions. The
number of molecules possessing energy equal to or in excessof threshold energy
increase appreciably even with a small rise in temperature. So,the rate of reaction
increases considerably even with a small increase oftemperature.

As already explained, there is a certain minimum energy (or threshold
energy)which .the colliding molecules must acquire before they are in a position to
react.Most of the molecules have much less kinetic energy than t he threshold energy.
Theexcess energy that the reactant molecules having energy less than the
thresholdenergy must acquire in order to react to give the final products is known
asactivation energy. Therefore,
Activation energy = Threshold energy - Energy possessed by the molecules initially.
In other words, passive or non-active molecules, i.e., molecules

possessingenergy less than threshold energy, can be activated by absorption of excess
energyknown as activation energy. As already stated, the reactant molecules have
toaquire a minimum amount of energy beforethey can yield products on
mutualcollisions, i.e., there is an energybarrier placed between reactantsand products.
This barrier has to be crossed before the reactants can yield products. It determines the
magnitude of threshold energy which the reactant molecules must acquire before they
can react to give products. Heat of reaction Products
Further, different reactionsrequire different amounts ofactivation energy. The

concept ofactivation energy gives us an ideawhether a given reaction is slow or fast at a
given temperature. A reaction whichhas lower activation energy will proceed at a faster
rate at a given temperature orvice versa. The differences in activation energy are mainly
responsible for observeddifference in rates of reactions. Threshold energy Activated or
transition state

The concept of activation energy as applied to chemical reactions can be
explained by plotting energy against the progress of the reaction (A + BC ⇌ AB + C) as
shown in figure. The point x representsinitial energy (E 1 ) of the reactants, (A + BC) and
represents the energy of the products (AB + C), E 2 .At the beginning of rising portion of
the curve the molecules come very close to each other, but they cannot react as they
possess energy less than the threshold energy. If, however, sufficient energy is given to
them, they can go up and reachthe summit (or cliff) z of the energy barrier. The
molecules are then said to be inan activated state and the configuration A ... B ... C is
attained. This configurationis known as activated complex or transition state or energy
cliff state which has themaximum potential energy.
In transition state, the molecules are under conditions of acute strain. Thebonds
between atoms of the reacting molecules become very feeble. The conditionnow is such
that the probability of formation of new bonds between atoms of themoleules of the
reactant is fairly strong and the transition state decomposes to givethe products of the
reaction (AB and C) or vice versa.
In the above case, the reactants are shown to possess a higher total energy
thanthe products. So, according to the law of conservation of energy, there will be
arelease of energy, i.e., heat will be evolved. The reaction is exothermic and theamount
of heat evolved gives the heat of reaction. This release of energy is shownby ∆E in
figure. Evidently ∆E =E 1 –E 2 whereE l is the normal energy of thereactants and E 2 of the
products. In this case, ∆E is negative as energy is releasedand not absorbed. An
exothermic reaction has thus lower activation energy or afaster rate of reaction.

Now, consider the reaction (A + BC⇌AB + C). Since the energy (E 1 ) ofreactants (A +
BC) is less than the energy (E 2 ) of the products (AB + C), as shown in figure, energy
will be absorbed and not released, i.e., the reaction will beendothermic. An endothermic
reaction has always greater activation energy andhence has a slower rate of reaction
than the opposing reaction.
SOLVED PROBLEMS 01
Problem 1
Predict from the following figure that the given reaction is exothermic or endothermic?
Solution: From the graph it is clear that the given reaction is exothermic i.e. heat is liberated.
Because potential energy of product is less than the potential energy of reactant.
Problem 2
From the graph explain why catalysed reactions are fast?
Solution: Catalysed reactions are faster than uncatalysedreaction, because catalyst decreases the
activation energy. Hence speed of the reaction increases.

Que.1: Define threshold energy?
Answer: The minimum amount of energy which must beassociated with molecules so that mutual
collisions may result in chemical reactionis termed as threshold energy
Que.: 2: Which molecules do not react on collision in chemical reaction?
Answer: Molecules possessing energy less than threshold energy will not react on collisions.
03-02: CONCLUSIONS DRAWN FROM ENERGY PROFILE DIAGRAM

From figures, we can draw the following conclusions:
(1) Reaction coordinate: The reaction coordinate is a measure of theapproach of the
reactant molecules towards the change. As the reactant moleculescome closer, their
structural orientations, internal vibrations, and relative internucleardistances etc.
change and even they make a transiet association. So, the reactioncoordinate is a
measure of these physical variations which involve potential energychanges of the

system. It is not possible to get any quantitative value for thereaction coordinate but it
simply gives a qualitative description of the conversionof reactants into products.
(2) In the energy profile diagram, we have
E 1 = Activation energy of reactants
E 2 = Activation energy of products
H 1 and H 2 = Enthalpies of reactants and products, respectively.
E (A + BC) and E (AB + C) = Potential energies of reactants and products,
respectively,which may be considered as H 1 and H 2 , respectively.
(3) The difference in the level between the valley of reactants and valley of,products is
equal to the heat of reaction (∆H). So,
(a) For endothermic reaction: ∆H=E 2 –E 1 =H 2 –H 1 = positive, i.e., energyequal to
All is absorbed during the chemical reaction.
(b) For exothermic reaction: ∆H = E 2 –E 1 = H 2 – H 1 = negative, i.e., energyequal
to All is evolved during the chemical reaction.
When E 2 <E 1 the reaction will be endothermic
When E 2 >E 1 the reaction will be exothermic.
(4) The difference in level between the reactant valley and the top of the hill(activated
complex) is equal to energy of activation
Energy of activation offorward reaction, i.e., energy of activation of reactants,
E 1 =E (A ..... B.....C) -E (A+ BC)
Energy of activation of reverse reaction, i.e.,energy of activation of products,
E 2 =E (A ..... B.....C) -E (AB +C)
(5) The height of the hill, i.e., energy of activation determines the reaction rate. Lower
the height of the hill or lower the value of energyof activation faster is the reaction. As
the height of the hill, i.e., energy of activation increases, the reaction rate goes on
decreasing. Therefore, thesubstances which lower the energy of activationwill increase
the reaction rate. For example, addition of catalyst lowers the energy of activation of
the reaction; the presence ofcatalyst makes the reaction faster. A catalyst gives a new
reaction path with a lowerenergy of activation.

(6) In an endothermic reaction, the energy of activation must be at least aslarge as ∆H.
(7) The wider the hump in energy profile diagram for a given height the easierit is for
the reactant molecules to form the transition state since there is now awider latitude in
nuclei positions for the activated complex.
SOLVED PROBLEMS 02
Problem 3
Bodenstein by studying the kinetics of decomposition of gaseous hydrogen iodide gave the values
of specific reaction rates to be 3.517  107 and 3.954  102 at 556 K and 781 K. Calculate the
energy of activation of the reaction.
Solution: We know that
Problem 4
For a given reaction at temperature T, the velocity constant, k is expressed as
k =A. e27000k/T
Given, R = 2 cal mole1 K1. Calculate the value of energy of activation. Comment on the results.
Solution: From Arrhenius equation
On comparison, we get

Que.3: Which terms are shown in energy profile digram?
Answer: The following terms are shown in energy profile digram
1. Reactants 2. Products 3. Potential energy 4. Reaction coordinates
5. Transition state 6. Activation energy

Que.4: Give the meaning of the following terms
E1, E2, H1 and H2
Answer: E1= Activation energy of reactants
E2= Activation energy of products
H1 and H2= Enthalpies of reactants and products, respectively.
Determination of Activation Energy

The frequency factor (A) and energy of activation (E) can be determined by two methods.
(1) First method: This is a graphical method. The quantities A and E are characteristics of the
given reaction, i.e., they have fixed values for a given reaction.
According to Arrhenius equation,
Taking logarithm of both sides, we get
The above equation represents a straight line, i.e., a plot of log k against 1/T will give a straight
line as shown in figure.
The tangent of the angle of inclination, i.e., slope of the straight line with 1/T axis is given by
The line AB is extrapolated to cut the log k axis at point C. The intercept (OC) of this line is
equal to log A, i.e., Intercept = log A ---------- (3)

Thus, knowing the slope and intercept from equations (2) and (3), we can calculate the values of
E and A, respectively.
(2) Second' method: From Arrhenius equation, we can get the following equation
We know that k has different values at different temperatures for a given reaction. Since E and A
are the characteristics of the given reaction, they do not depend on the temperatures for a given
reaction. Thus, from equation (4),
Subtracting equation (5) from equation (6), we get
So, by measuring the velocity constants k1 and k2 at two temperatures, T1 and T2,
respectively we can calculate the value of E from equation (7). When the value of E is known
we can calculate the value of A by putting the value of E in equation, k = AeE/RT.
The Arrhenius equation holds equally good for homogeneous and heterogeneous
reactions. Heterogeneous and catalytic reactions also give straight lines over a very wide range of
temperatures.
If there is a marked deviation from a straight line on plotting log k and 1/T, then it gives
an indication that the observed reaction is a composite one made up of two or more concurrent
reactions influenced by one of the reactions and it may predominate so that the slope of the curve
corresponds to the value of E proper to this reaction.
For many reactions taking place at ordinary temperatures, the energy of activation is of
the order of 20,000 cal/mole. Under such circumstances, the temperature coefficient (tc) is found
to satisfy van't Hoff rule. At 300 K, the value of tc is given by,

03-03: THERMODYNAMIC OR MATHEMATICAL TREATMENT OF
TRANSITION
State Theory (Entropy of activation)

Consider a bimolecular reaction between reactants A and B. According to
transition state theory,
A+B ⇌ x* Products
Reactants Activatedcomplex
The equilibrium constant (K*) for the formation of activated complex is
According to transition state theory, the rate of reaction is the numberof

activated complexes which pass over the potential energy barrier per unittime. This, in
turn, is equal to the concentration of activated complex multipliedby the frequency at
which the complex would decompose into products.
Mathematically,
From equations (1) and (2), we get
The activated complex would decompose only if enough vibrationalenergy is

supplied to the system, so that the atoms vibrate with certain criticalfrequency, leading
to bond breaking. Therefore,
Frequency of dissociation of activated complex = E vib 1 h ... (3)
Where, E vib = average vibrational energy at temperature Tand h = Planck'sconstant.
From equations (3) and (4) frequency of dissociation of activated

complex=RT/Nh
For conversion of reactants into products,

From equations (5) and (6),
k [A] [B] = K * [A] [B]. RT /Nh
k=K * . RT/Nh --------- (7)
Equation (7) is the mathematical statement of transition state theory.
According to thermodynamics, K can be correlated with ilG* throughthe following
relation,
∆ G* = - RTln K *
Where ∆G* = (Free energy of activated complex) - (Free energy of reactants).
∆ G* is known as standard free energy change
∆G' == ∆H * - T ∆ S *
-RTln K * = ∆ H - T∆S *
∆ ∆
∆ ∆
Where, ∆H * = standard enthalpy change, i.e., standard heat of activation,

∆S * = standard entropy change, i.e., standard entropy of activation.
Equation (9) can be applied not only to bimolecular, but also to unimolecularand
trimolecular processes. Morever, it can be applied to reactionsin solution also.
SOLVED PROBLEMS 03
Problem 5
For the hydrolysis of sulphamic acid, the velocity constant is 1.16  103 mole1 dm3 sec1 at 363
K, while Ea = 127490 J mole1. From these data find ∆G*, ∆H*, and ∆S* of the reaction at 363
K.
Solution: We know that
K* = 1.534  1016 mole1 dm3

Now ∆G* = RTlnK*
=  2.303 RT log K*
∆G* =  2.303  8.314  363  log (1.534  1016) = 109900 J mole1
Since we know
Ea = ∆H* + RT
∆H* = Ea RT
= (127490) - (8.314)  (363) = 124473 J mole1

Again,
∆G* = ∆H* - T∆S*
∆ ∆
∆
= 40.14 J mole1 K1
Problem 6
Calculate ∆H*, ∆G* and ∆S* for the second order reaction
2NO2(g)  2NO(g) + O2(g)
at 500 K. Given A = 2.0  109 secl and the energy of activation = 111 kJ mole1
Solution: For a bimolecular reaction,
Ea = ∆H* + 2RT
∆H* =Ea 2RT
= 111  2  8.314  500
= 102700 J mole1
∆H* = 102.7 KJ mole1
∆ ∵
∆S* = 71.17 J mole1 K1

Since ∆G* = ∆H*  T∆S*
= 102700  500  (71.17)
∆G* = 138300 JK mole1
Que.5: Give the equation for mathematical statement of transition state theory.
Answer: k = K*. RT/Nh
Que.6: Write the mathematical equation which shows relationship between equilibrium constant
K and standard Gibb’s free energy change (∆G*).

Answer: According to thermodynamics, K can be correlated with ∆G* through the following
relation,
∆G* = - RTln K*
Where ∆G* = (Free energy of activated complex) - (Free energy of reactants).
∆G* is known as standard free energy change.
CHECK POINT 01-03

1. The chemical reactions in which the reactants require high amount of activation energy are
generally
(1) Slow (2) Fast
(3) Instantaneous (4) Spontaneous
Sol. Answer (1)
2. For an exothermic chemical process occurring in two steps as

(i) A + B → X (slow) ; (ii) X → AB (fast)
The progress of the reaction can be best described by (X is considered as intermediate)
Sol. Answer (2)
3. A chemical process occurring in two steps, is plotted as
The correct statement is

(1) Endothermic, A + B → X (slow),
X → AB (fast)
(2) Exothermic, A + B → X (slow)
X →AB (fast)
(3) Exothermic, A + B → X (fast)

X → AB (slow)
(4) Endothermic, A + B X (fast)
X → AB (slow)
Sol. Answer (2)
4. For the chemical process energies are plotted in graph.
Which of the following is correct?

(1) It is the exothermic reaction, H = b – a
(2) Threshold energy, e = a + c
(3) (Ea)f< (Ea)b
(4) All of these
Sol. Answer (4)
SUMMARY
Activation energy is defined as the minimum amount of extra energy required by a
reacting molecule to get converted into product. It can also be described as the
minimum amount of energy needed to activate or energize molecules or atoms so that
they can undergo a chemical reaction or transformation.
The rate at which a certain reaction will progress is determined by the activation energy
of that process. When the activation energy is high, the chemical reaction will proceed
at a slower rate.
Activation energy is required for all chemical reactions, even exothermic reactions, in
order to get them started. It is necessary to have activation energy in order for reactants
to move together, overcome forces of repulsion, and begin to dissolve bonds.
KEY WORDS
Activation energy, Reactant, Product, Ttransformation, Rate, Exothermic, Endothermic
REFERENCES
PHYSICAL CHEMISTRY Vol. I ,Dr. J. N. Gurtu, AayushiGurtu, PRAGATI PRAKASHAN
MOOCS
______

YOUTUBE VIDEOS
https://www.youtube.com/watch?v=L3z63M7l2wQ
https://www.youtube.com/watch?v=ZXwkQEB1yNQ
https://www.youtube.com/watch?v=0Vznqs7IOBc
https://www.youtube.com/watch?v=UFRLtJkrsyE
WIKIPEDIA
https://en.wikipedia.org/wiki/Activation_energy
https://en.wikipedia.org/wiki/Energy_profile_(chemistry)
https://en.wikipedia.org/wiki/Transition_state_theory
OER
____
REFERENCE BOOKS
PHYSICAL CHEMISTRY Vol. I ,Dr. J. N. Gurtu, AayushiGurtu, PRAGATI PRAKASHAN

CREDIT 01-UNIT 04: NON-KINETIC METHODS
LEARNING OBJECTIVES
 To understand stereochemistry
 To understand geometry
 To understand hybridisation
 To understand kinetic evidence and study of catalysis.
 To understand methods to determine the mechanism of a particular reaction.
INTRODUCTION
A reaction mechanism must explain all observations regarding a given chemical
transformation. It should show which bonds are broken, which are formed, and the
order in which this is accomplished.
It should explain any change in stereochemistry, geometry and hybridisation.
After characterizing the product(s), the mechanism of a reaction is determined by
considering all the possibilities compatible with the experimental observations.
There are a number of commonly used methods for determining the mechanism
of areaction. These include product analysis, determination of the presence of
intermediates, isotopic labelling and isotope effects, crossover experiments,
stereochemical evidence, kinetic evidence and study of catalysis.
It should be noted that the above order is not necessarily the order of
experimentation. Furthermore, it may not be necessary to apply all the methods to
determine the mechanism of a particular reaction.
04-01: PRODUCT ANALYSIS, DETERMINATION OF THE PRESENCE OF
INTERMEDIATES , TRAPPING OF REACTION INTERMEDIATES
Product Analysis
The most fundamental basis for mechanistic speculation is the identification of the
reaction products and by-products (if any). The approximate yield must also be known
before one startsspeculating about its mechanism. Even a minor product may indicate
that a competing reaction is going on, or a proposed mechanism is inadequate or
incorrect. Some typical examples are:
(i) Hydrolysis of isomeric allyl chlorides (I) and (II) yields a mixture of 85% of
tertiary alcohol and 15% of primary alcohol. Since product composi tion remains the
same in either case, a common intermediate is suggested.

(ii) A little ethane invariably acompanies methyl chloride when methane is
chlorinated in the presence of light. Hexafluoroethane is similarly a by product when
fluorine reacts with methane. Free radical mechanism accounts for these facts readily
but an ionic mechanism cannot.
(iii) A coproduct of the reaction may throw light on the path of the reaction and
suggest a mechanism in some cases. For example, 1-bromo-2-chloroethane is formed
together with 1, 2-dibromoethane when bromine gives addition reaction with ethene in
the -presence of aqueous sodium chloride. It shows that addition of bromine does not
take place in a single step and thus mechanism is as follows:

(iv) Toluene and chlorine produce benzyl chloride in the presence of light, but o - and p-
chlorotoluene in the presence of iron or iodine at boiling temperature. The different
products from the same reactants under different conditions indicate different
mechanisms.
In fact, the former follows free radical pathway, and the latter, an ionic mechanism.
Determination of the Presence of Intermediates
One or more intermediates may be formed in complex reactions; they may often be
detected by physical methods if transient, and isolated if reasonably stable. Sometimes
intermediates may be trapped by a chemical reaction with an added compound and the
compound is known as trapping agent. Indirect methods may also suggest an
intermediate, e.g., converting a suspected intermediate into normal product under
conditions of the reaction. Kinetic studies in some cases indicate the formation of an
intermediate.
(i) Isolation: Occasionally, it is possible to isolate intermediates by stoping the
reaction before it is completed, or by using mild conditions.
(a) Isolation of three intermediates, N-bromamide (I) its anion (II) and isocyanate (III)
during the formation of a primary amine from an amide by the well known Hofmann
rearrangement is one of few such cases. These can be readily converted into a primary
amine.
Thus any proposed mechanism for this rearrangement must account for the
formation of all these intermediates.
(b) Bimolecular aromatic nucleophilic substitution reaction takes place by the
formation of
Cyclohexadienylide anion (also known as Meisenheimer complex or  complex).
In many cases salts of the postulated intermediates have been isolated from the
reaction. A typical example is the salt (I) which is formed either by the action of

potassium ethoxide on 2, 4, 6-trinitroanisole or of potassium methoxide on trinitro-
pheneol.
(c) Bimolecular aromatic electrophilic substitution reactions take place via the
formation of benzenium ion (-complex).
A few stable  complexes such as (II) and (III) have been isolated from the
reaction mixture and also prepared in the form of salts.
(ii) Detection of Intermediates:

Unstable reaction intermediates cannot be isolated but are often detected by
spectroscopic methods. For example, carbocations and carbanions are detected by
NMR; NO 2 + is detected by Raman spectroscopy, whereas free radicals and carbenes are
detected by CIDNP (chemically induced dynamic polarisation which is an NMR
technique) and by ESR (electron spin resonance) spectroscopy, which is also called as
EPR (electron paramagnetic resonancespectroscopy.)

(iii) Trapping of Reaction Intermediates :
Sometimes an intermediate may be detected, although it cannot be isolated, by
adding a "trapping" reagent to the reaction mixture. The trapping reagent is added so
that it will combine, with the intermediate to form easily identifiable product that
cannot be accounted for otherwise. For example:
(a) Trapping of carbocation: Nucleophiles are commonly employed to trap
carbocations.Direct evidence for the intermediacy of carbocation in the addition of a
halogen to alkenes is provided by the observation that when the reaction is carried out
in the presence of other nuc1eophiles, a mixture of products is obtained.
(b) Trapping of free radicals: Transient alkyl free radicals are trapped by nitroso
compounds.
Nitroso compounds react with alkyl free radicals to form long-lived nitroxides. These
nitroxides are stable.
Thus isolation and identification of nitroxides confirm the formation of R·free

radical in the reaction mixture. For example:
Formation of product (I) in the above reaction confirms that the reaction
intermediate of the
(c) Trapping of carbenes and benzynes: The trapping reagent for carbenes is alkenes.
The formation of cyclopropanes by the 1, 2 -addition of carbenes to alkanes is probably
the most characteristic reaction of carbene intermediate. This reaction is used for
trapping of carbene. Thus, the formation of cyclopropane derivative with alkene in the
reaction confirms that intermediate of the reaction is carbene. One of the most common
examples in which product formation takes place by formation of carbene as reaction
intermediate is the Reimer-Tiemann reaction.

A benzyne intermediate is trapped as anthracene adduct,triptycene :
SOLVED PROBLEMS 01
Problem 1
Why the addition of HCl to the following olefin takes place in the opposite manner as
predicted by Markonikov’s rule (i.e., the hydrogen atom of HX adds to that carbon
which has the greatest number of hydrogens?
CH 2= CH—CO 2 Et + HCl  CH 2 Cl—CH 2 —CO 2 Et
Answer: Of the two possible intermediate I and II, I i s of lower energy than II. In, II
the positive charge is adjacent to the strongly electron withdrawing carboethoxy group.
Problem 2
Predict the product of the following reaction

Que.1: How is free radical trapped?
Answer: Transient alkyl free radicals are trapped by nitroso compounds. Nitroso compounds
react with alkyl free radicals to form long-lived nitroxides. These nitroxides are stable.
Thus isolation and identification of nitroxides confirm the formation of R  free radical in
the reaction mixture. For example:

Formation of product (I) in the above reaction confirms that the reaction intermediate of
the reaction is C6H5CH2
Que.2: How will you carbine and benzyne intermediate trapped?
Answer: The trapping reagent for carbenes is alkenes. The formation of cyclopropanes by the 1,
2-addition of carbenes to alkanes is probably the most characteristic reaction of carbene
intermediate. This reaction is used for trapping of carbene. Thus the formation of cyclopropane
derivative with alkene in the reaction confirms that intermediate of the reaction is carbene.
A benzyne intermediate is trapped as anthracene adduct,triptycene
04-02: ISOTOPIC LABELLING AND ISOTOPE EFFECTS, CROSSOVER

EXPERIMENTS
Isotopic Labelling and Isotope Effects:
Isotopic Labelling: In non-kinetic studies, stable isotopes of carbon ( l3 C) hydrogen
(D), nitrogen ( 15 N),oxygen ( 18 0), and radioactive isotopes of carbon ( 14 C),
hydrogen ( 3 H), sulphur ( 35 S), iodine ( 121 I and 131
I) and bromine ( 82 Br), have been
introduced in strategical positions of reacting molecules to have an insight into
reaction mechanisms by noting which parts of reactants form which parts of products.
For example, base- catalysed hydrolysis of an ester may involve either
(i) An acyl-oxygen bond fission or (ii) an alkyl-oxygen bond fission:

What actually happens has been confirmed by hydrolysing the ester in H 2 O 18 . If
the acyl-oxygen bond breaks, the labelled oxygen will appear in the acid; otherwise it
will be in the alcohol.
The hydrolysis of ester yields an unlabelled alcohol an d a labelled acid.

This confirmed that during the course of hydrolysis acyl -oxygen bond fission occurs as
follows:
Isotope Effects: In spite of their chemical similarly, the isotopes are not exactly
identical and often the rate at which chemical reactions occur may vary with isotope. A
difference in the rate of a reaction due to a difference in the isotope present in the
reaction system is called the isotope effect.
The ground-state vibrational energy (called the zero-point vibrational energy) of a bond
depends on the mass of the bonded atoms and is lower when the reduced mass (m l x
m 2 /m l + m 2 , where m 1 and m 2 are masses of the bonded atoms) is higher. Thus, C-D, O-
D, D-N bonds, etc., have lower energies in the ground state than the corresponding C-
H, O-H, N-H bonds, etc. Consequently, a C-H bond is broken more readily than a C-D
(or C-T) bond. Therefore, whenever hydrogen is lost in the rate-determining step of a
reaction, it will show an isotope effect on replacing the hydrogen by deuterium or
tritium. Since the C-D (or C-T) bond has lower energy in the ground state than the C-H
bond, if such an isotopically substituted bond is broken in the rate-determining step,
then the rate will be lowered by the substitution and the isotope effect is called primary
isotope effect because it is of relatively larger magnitude. Most of isotope effect studies
have been carried out by using the more easily available deuterium.
The primary isotope effect has been used for the elucidation of mechanisms of
many reactions. For example, the substitution of deuterium in the methyl groups
of isopropyl bromide considerably slows down the rate of its elimination reaction
with the ethoxide ion.

The primary isotope effect is expressed in terms of the rate ratio k H /k D , thus,
for the above reaction it is
The large isotope effect clearly indicates that the rate determining step of the
reaction involves C-H bond fission and rules out the mechanisms such as one given
below:
The correct mechanism for the above reaction has been formulated as follows :
In the arenium ion mechanism, the C-H bond is not broken in the rate-
determining step.so no isotope effect should be found. Isotope effect has not actually
been observed in most of the aromatic electrophilic substitutions. For example, the rate
of nitration of C 6 D 6 , deuterio benzene (or C 6 T 6 , tritiobenzene) is the same as the rate
for benzene (C 6 H 6 ). This clearly shows that the loss of proton is not the rate -
determining step. This provides a strong evidence for the following arenium ion
mechanism:
Crossover Experiments:
Whether a rearrangement is a one-step or a two-step (inter-molecular) process
can be decided by carrying out the reaction with a mixture of two similarly constituted
but nonidentical reactants and then analysing the products. Since themigrating group
must become free in an intermolecular process, we should get a product containing
fragments of both the reactants in such a process.

One of the most familiar examples of the use of this mode of investigation is
connected with the benzidine rearrangement, a reaction in which hydrazobenzenes are
converted by acid to benzidines.
If the reaction is carried out on a mixture of 2, 2' -dimethoxyhydrazobenzene

and its diethoxy analogue onlytwo benzidines can be isolated, both of them
symmetrical1y substituted. There is no formation of unsymmetrical benzidine (III),
which would result if fragments from two different hydrazobenzenes were to combine
to give crossover product, is strong evidence that the rearrangement is intramolecular.
No crossover product (III) is formed:

Fries rearrangement, which involves migration of an acyl group of a phenyl
ester to the benzene ring is the example of intermolecular rearrangement and this
can be confirmed by crossover experiment.
The two esters (IV) and (V), rearrange under identical conditions and at
approximately the same rate to give the products (IVa) and (Va), respectively.
Rearrangement of a mixture of (IV) and (V), however not only gives (IVa) and (Va) but
also the cross products (VI) and (VII). Isolation of cross products unequivocally
confirms that the Fries rearrangement is an intermolecular rearrangement (a two-step
process). However, in certain cases crossover products have not been found; in such
cases this rearrangement is intramolecular.

SOLVED PROBLEMS 02
Problem 3
The reactions (Scheme) may follow the E2 mechanism; however, these occur at almost identical
rates. What conclusion one can draw from these rate data?
Answer: Since the rate of reaction of the undeuterated compound is almost similar to that of the
deuterated analog, indicates that the C—D bond is not cleaved in the rate-determining step.
Therefore, this reaction is not proceeding by an E2 mechanism.
Problem 4: Predict the product of the following reaction
Solution:

Que.3: What is isotope effect?
Answer: A difference in the rate of a reaction due to a difference in the isotope present in the
reaction system is called the isotope effect.
Que.4: Explain crossover experiments with suitable example?
Answer: The two esters (IV) and (V), rearrange under identical conditions and at approximately
the same rate to give the products (IVa) and (Va), respectively. Rearrangement of a mixture of
(IV) and (V), however not only gives (IVa) and (Va) but also the cross products (VI) and (VII).
Isolation of cross products unequivocally confirms that the Fries rearrangement is an
intermolecular rearrangement (a two-step process). However, in certain cases crossover products
have not been found; in such cases this rearrangement is intramolecular.
04-03: STEREOCHEMICAL EVIDENCE, KINETIC EVIDENCE, STUDY OF

CATALYSIS AND KINETIC AND THERMODYNAMIC CONTROL
Stereochemical Evidence (Studies)
If the products of a reaction are capable of existing in more than one
stereoisomeric form, the form that is obtained may give information about the
mechanism.

For example, mechanism of nucleophilic substitution reactions have been
investigated with optically active compounds.
In the above case an optically active reactant yielded a product which has no optical
activity (racemic mixture). Racemisation of the product indicates that the reaction
passed through an intermediate that has a p!anar configuration, such as a
−
carbocation, which is equally likely to be attacked by the OH on either side
producing a mixture of equal number of molecules with inversion and retention
configuration.
In the Hofmann rearrangement, if the amide used is optically active, the
resulting product (amine) is also optically active. This shows that the migrating group
does not become free from the remainder of the molecule for sufficient time to allow it
to racemise. The configuration of the resulting amine is same as that of amide, i.e.,
reaction occurs with retention of configuration indicating that breaking of bond and
formation of bond take place simultaneously on the same side of the migrating group.
cis-1,2-Dichloroethene undergoes elimination to give chloroacetylene 20 time faster

than the correspondingtrans isomer. This observation confirms the conclusion that the
E 2 reaction proceeds with greater facility when the departing groups are trans than
when they are cis.
Kinetic Evidence
Although a reaction mechanism cannot be deduced unequivocally from kinetic
studies, knowledge of the reaction order constitutes the most important step of the

investigation. When the kinetics of the reaction between methy l bromide and sodium
hydroxide are measured, the rate expression derive d from the experimental data is:
The rate of reaction depends on the concentration of both reactants, i.e., both are
involved in the rate-determining step, which supports S N 2 mechanism suggested for this
reaction.
Similarly, when the kinetics of the reaction between t-butyl bromide and sodium
hydroxide are measured, the rate expression derived from the experimental data is:
The rate of the reaction depends on the concentration of t-butyl bromide only,
i.e., only t-butyl bromide is involved in the rate-determining step, which supports S N 1
mechanism suggested for this reaction.
Thus, it is often possible to rule out several mechanisms merely by an inspection
of the rate law.
Study of Catalysis
A very important question regarding any mechanism is whether or not it is
catalysed or inhibited in any way. What is the effect of; for example, heat, light, acid
strength or solvent? For example, does the reaction require the presence of a cids, metal
or peroxides? The answers to these questions provide valuable infor mation about the
mechanism of a reaction.
Examples of reactions that do require catalysts include free -radical substitution
and hydrogenation of alkenes. In the former, heat or light is necessmy, and a metal is
necessary in the latter:

A catalyst speeds-up a reaction by providing an alternate reaction pathway that
involves but does not consume the catalyst. This a lternate route has a lower ∆G # and is
therefore a more rapid reaction. Of course, just as a mechanism must be compatible
with the products, so must it be compatible with its catalysts.
Kinetic and thermodynamic control

Where a starting material may be converted into two or more alternative products, e.g.
in electrophilic attack on an aromatic species that alread y carries a substituent, the
proportions in which the alternative products are formed are often determined by t heir
relative rate of formation: the faster a product is formed the more of it there will be in
the final product mixture; this is known as kinetic control. This is not always what is
observed however, for if one or more of thealternative reactions is reversible, or if the
products are readily interconvertible directly under the conditions of the reaction, the
composition of the final product mixture may be dictated not by the relative rates of
formation of the different products, but by the ir relative thermodynamic stabilities in
the reaction system: we are then seeing thermodynamic or equilibrium control. Thus
the nitration of methylbenzene is found to be kinetically controlled, whereas the
Friedel-Crafts alkylation of the same species is often thermodynamically controlled.
The form of control that operates may also be influenced by the reactio n condition, thus
the sulphonation of naphthalene with concentrated H 2 SO 4 at 80° is essentially
kinetically controlled, whereas at 160° it i s thermodynamically controlled.
SOLVED PROBLEMS 03
Solution:
Problem 6: What is the effect on stereochemistry of Hoffmann bromide degradation?

Solution: In the Hofmann rearrangement, if the amide used is optically active, the resulting
product (amine) is also optically active. This shows that the migrating group does not become
free from the remainder of the molecule for sufficient time to allow it to racemise. The
configuration of the resulting amine is same as that of amide, i.e., reaction occurs with retention
of configuration indicating that breaking of bond and formation of bond take place
simultaneously on the same side of the migrating group.

Que.5: Give the rate law expression for the reaction between methyl bromide and aqueous
sodium hydroxide?
Answer: Rate = k [CH3Br] [OH]
Que.6: What is the role of catalyst in chemical reaction?

Answer: A catalyst speeds-up a reaction by providing an alternate reaction pathway that involves
but does not consume the catalyst. This alternate route has a lower ∆G# and is therefore a more
rapid reaction.
04-04: LINEAR FREE ENERGY RELATIONSHIP

THE HAMMETT EQUATION:
Despite establishing such linear relationships for a wide range of reactions of m- and p-
substituted benzene derivatives, we still lack any simple form of this quantitative
relationship that can actually be used to investigate new situations: here again, it was
Hammett who supplied the answer.
Derivation of Hammett equation:
The general equation for a straight line is y = mx +c, and this can be applied to the
straight line to give,
log kX = ρ log KX + c [1]
where ρ is the slope of this straight line, c the intercept, and X is the particular m- or p-
substituent in the benzene ring of the species concerned. It is also possible to write an
exactly analogous equation that is restricted to the unsubstituted ester and acid, i.e.
where X=H:
log kH= ρ logKH+ c [2]
Subtracting [2] from [1], we obtain,

logkX - log kH = ρ (log KX — log KH) [3]
This may also be written in the form:
Substituent constant, σX :
Hammett then designated the ionisation, in water at 25°, of m- and p-substituted

benzoic acids as his standard reference reaction. He chose this reaction because
reasonably precise aqueous ionisation constant, K X , data were already available in the
literature for quite a range of differently m- and p-substituted benzoic acids. Knowing
K H and Kx for a variety of differently X-substituted benzoic acids, it is then possible to
define a quantity, σ X , as
[5] may, of course, also be written in the form, σ X =pK a(H) -pK a(x) ; so that the numerical
value of σ X for a particular substituent is obtained by simple subtraction of the pK a
value for the substituted acid (where this is known) from the pK a value for benzoic acid
itself.
Where σ x is a substituent constant, whose value will remain constant for a specific
substituent in a specific position (m- or p-), irrespective of the nature of the particular
reaction in which a benzene derivative, carrying this substituent, is involved.
Substituting [5] into [4] we then get,
ρσ
This is the usual form of what has come to be called the Hammett equation.
By using known values of K X (or p Ka ) for aqueous ionisation of m- and p-

substituted benzoic acids (or measuring K X [or p Ka ] where the value is not already
available for a particular m- or p-substituent) it is possible to calculate σ X , as required,
and a selection of values obtained in this way is shown below:

Hardly surprisingly, the value of σ X for a particular substituent is found to depend on
the location of the substituent, having a different value in the m-position from that in
the p-position.
Reaction constant, :
Having thus obtained a range of substituent constant,  x values it isnow possible to use
them to calculate the value of , the reactionconstant, in [6] for any further reactions in
which we may beinterested: this is often done graphically. Thus to evaluate p for,
say,the base-catalysed hydrolysis of m- and p-substituted ethyl 2-arylethanoates (4) we
would, from kinetic measurements (or fromthe literature if we’re lucky!), obtain k, for
the unsubstituted esterand k x for at least three different substituted esters. Knowing
thevalue of  x for each of these substituents, we can then plotlog (k x /k H ) against ox and,
from [6], the slope of the resultingstraight line will be the value of p for this reaction: it
turns out to be+0.82 for this particular hydrolysis, when carried out in aqueous ethanol
at 30°. The  values for quite a wide range of different reactions of m- and p-substituted
benzene derivatives are shown abelow
Reaction Type 
1 ArNH 2 with 2, 4-(NO 2 ) 2 C 6 H 5 Cl in EtOH (25 0 ) k -3.19
2 ArNH 2 with PhCOCl in C 6 H 6 (25 0 ) k -2.69
3 ArCH 2 Cl solvolysis in aq. Me 2 CO(69-8°) k -1.88
4 ArO - with EtI in EtOH(25 0 ) k -0.99
5 ArCO 2 H with MeOH (acid-catalysed, 25°) k -0.99
6 ArCO 2 Me hydrolysis (acid) in aq. MeOH(25°) k +0.03
7 ArCH 2 CO 2 H ionisation in H 2 O(25°) k +0.47
8 ArCH 2 Cl with I  in Me 2 CO(20°) k +0.79
9 ArCH 2 CO 2 Et hydrolysis (base) in aq. EtOH(30°) k +0.82

10 ArCO 2 H ionisation in H 2 O(25°) k +1.00
11 ArOH ionisation in H 2 O (25°) k +2.01
12 ArCN with H 2 S (base) in EtOH(60-6°) k +2.14
13 ArCO 2 Et hydrolysis (base) in aq. EtOH(25°) k +2.51
14 ArNH 3 + ionisation in H 2 O(25°) k +2.73
The standard reaction, the aqueous ionisation of m- and psubstitutedbenzoic acids at

25°, will have a p value of 1:00 as anecessary concomitant of the definition of o, in [5],
and its use in [6]. The value of the reaction constant, p, for a particular reaction , carried
out under specified conditions, remains constant no matterwhat the m - or p-substituents
present in the compounds involved.
USES OF HAMMETT PLOTS:
Having now given some consideration to the significance that can be attached to σ x and
ρ in more familiar physical terms, it is possible to go on and discuss the actual use s that
can be made of them in providing information about reactions and the pathways by
which § they take place.
TAFT EQUATION
Acting on a suggestion originally made by Ingold, Taft began bycomparing the

relative susceptibility to polar substituent effects (thep value) of the hydrolysis -under
acid-catalysed (A AC 2 ) andunder base-catalysed (B AC 2 ) conditions-of m- and p-
substitutedbenzoate esters (42).
The  value for base-catalysed hydrolysis (+2-51) is +ve andquite large,
reflecting the development of not inconsiderable vecharge at the reaction centre in the
rate-limiting stepattack on thiscentre by OH  (step 1 in the B AC 2 pathway). By
contrast, the ρvalue for acid-catalysed hydrolysis (+0-03) is very nearly zero;which
means, of course, that the rate of this hydrolysis does not varysignificantly from one
ester to another, no matter what the m- orp-substituent present.

The ρ value for this hydrolysis is so small,despite their being conside rable
redistribution of +ve charge in the slow step (step 2), because the overall rate of
reaction, ie. k obs (which is plotted to evaluate ), is determined not solely by k 2 forthis
slow step, but involves also K 1 for the preceding, reversible, step 1. These two terms all
but cancel each other out, in so far assusceptibility of the two steps to electron -
donation/-withdrawal bypolar substituents is concerned, and the overall  value for
thereaction is thus virtually zero.
If we now extend our consideration of base-catalysed (B AC 2 ), andacid-catalysed

(A AC 2 ), hydrolysis to esters in general, includingaliphatic ones (RCO 2 Et), we see that
there is a close similaritybetween the transition states (42b or 42a) for the rate -limiting
stepin each of the two pathways: they are both tetrahedral; and differonly in the second
of them having two protons more than the first.
Protons, being very small, exert comparatively little steric influence;it is

therefore a not unreasonable assumption that any steric effectstemming from the group
R is, because of the close spatial similarityof the two transition states, substantially the
same in both acid- and base-catalysed hydrolysis. It then becomes possible to write a
Hammett type equation, [1], to represent the operation of the polareffect only of
substituent R in ester hydrolysis:


As the steric effect exerted by R is essentially the same in bothmodes of hydrolysis, the
two steric terms will cancel each other out,and will thus not appear in equation [1].
Taft then gave ρ* in [1], the value 2.48, derived by subtractingthe  value for
acid-catalysed hydrolysis of benzoate esters (0.03)from the  value for base-catalysed
hydrolysis of the same esters(2.51). He took as his reference substituent R= Me, rather
thanR=H, so that k o in [1] refers to MeCO 2 Et rather than HCO 2 Et.Then by kinetic
measurements on the acid- and base-catalysedhydrolysis of a series of esters containing
R groups other than Me, itis possible -using [1] to evaluate  * R for each of these
different Rgroups with respect to Me, for which by definition  * Me ,=0 (c f . Hwith  H =0
for benzoic acid ionisation). By giving * here the value 2.48, the resulting  * R
valueswhich are a measure of thepolar effect only exerted by R—do not differ too
greatly in magnitude from the values of  x ,  + x and   x with which we are already
familiar.
The employing the more general equation (2), it is possible to use these  * R
values, in conjunction with suitable kinetic measurements of k R and k Me , to evaluate *
for otherreactions of a whole range of aliphatic compounds in addition to esters.

Using (2) in this way, straight line plots were obtained for a anumber of different
reactions of aliphatic compounds.
SOLVED PROBLEMS 04
Problem 7: What is the value  m-x for tert. butyl group?
Solution: value  m-x for tert. butyl group 0.10.
Problem 8: Write the transition state for B AC 2 mechanism and A AC 2 mechanism?
Solution:

Que.7: What is the equation for substituent constant x?
Answer:

σ
Que.8: Write BAC2 mechanism?

Answer: Mechanism of BAC2 mechanism
CHECK POINT 01-04
1. The product P of the following reaction is
2. The name of the following reaction is
(1) Curtius rearrangement (2) Hoffmann bromamide degradation

(3) Schmidt rearrangemet (4) Losen rearrangement

Answer: (2) Hoffmann bromamide degradation
3. What is full form of ESR?

(1) Electrophile state resonance (2) Electron spin resonance
(3) Excited state radical (4) Electron state radical
Answer: (2) Electron spin resonance
4. The traping reagent for carbine is ------
(1) Benzene (2) Alkane
(3) Cycloalkanes (4) Alkene
Answer: (4) Alkene
SUMMARY
A reaction mechanism must explain all observations regarding a given chemi cal
transformation. It should show which bonds are broken, which are formed, and the
order in which this is accomplished.
It should explain any change in stereochemistry, geometry and hybridisation. After

characterizing the product(s), the mechanism of a r eaction is determined by considering
all the possibilities compatible with the experimental observations.
There are a number of commonly used methods for determining the mechanism of a
reaction. These include product analysis, determination of the presence of
intermediates, isotopic labelling and isotope effects, crossover experiments,
stereochemical evidence, kinetic evidence and study of catalysis.
It should be noted that the above order is not necessarily the order of experimentation.
Furthermore, it may not be necessary to apply all the methods to determine the
mechanism of a particular reaction.
KEY WORDS
Intermediates, isotopic, labelling, isotope effects, crossover experiments,
stereochemical evidence, kinetic evidence, study of catalysis.
REFERENCES
UNDER GRADUATE ORGANIC CHEMISTRY (Volume I), Dr.Jagdamba Singh, Dr. L.D.S
Yadav, PRAGATI PRAKASIIAN, MEERUT.
PHYSICAL CHEMISTRY Vol. I Dr. J. N. Gurtu, AayushiGurtu, PRAGATI PRAKASHAN
ANSWER TO CHECK POINT 01-04
MOOCS
YOUTUBE VIDEOS
https://www.youtube.com/watch?v=vjXSXbzq-u8

https://www.youtube.com/watch?v=mVXRCC94-vw
https://www.youtube.com/watch?v=uWAQ_dX4tr0
https://www.youtube.com/watch?v=cEWpIvhrD2Y
https://www.youtube.com/watch?v=zh6cdqkbuJ0
https://www.youtube.com/watch?v=C9pjPYd-a38
https://www.youtube.com/watch?v=N2z1foIr0_M
WIKIPEDIA
https://en.wikipedia.org/wiki/Reaction_intermediate
https://en.wikipedia.org/wiki/Crossover_experiment_(chemistry)#:~:text=An%20isotopic%20lab
eling%20experiment%20is,a%20type%20of%20crossover%20experiment.
https://en.wikipedia.org/wiki/Kinetic_isotope_effect
https://en.wikipedia.org/wiki/Thermodynamic_versus_kinetic_reaction_control
https://en.wikipedia.org/wiki/Hammett_equation#:~:text=The%20Hammett%20equation%20in%
20organic,constant%20and%20a%20reaction%20constant.
OER
REFERENCE BOOKS
PHYSICAL CHEMISTRY Vol. I Dr. J. N. Gurtu, AayushiGurtu, PRAGATI PRAKASHAN

C REDIT 02

CREDIT 02-UNIT 01: OXIDATION METHODS
LEARNING OBJECTIVES
 Understand oxidation reduction reactions.
 Understand oxidation by using different Oxidising reagent
 Understand Reductionby using different Reducing reagent
INTRODUCTION
According to Classical or earlier concept oxidation is a process which involves
the addition of oxygen or any electronegative element or the removal of hydrogen or
any electropositive element.According to electronic concept oxidation is defined as the
process in which an atom or ion loses one or more electrons.
According to Classical or earlier concept reduction is a process which involves the
addition of hydrogen or any electropositive element or the removal of oxygen or any
electronegative element.According to electronic concept reduction is defined as the
process in which an atom or ion gains one or more electrons.
Oxidation and Reduction reactions are always interlinked. Because electrons are neither
created nor destroyed in a chemical reaction, oxidation and reduction always occur in
pairs, it is impossible to have one without the other. In the below reaction Magnesium
gets oxidized by losing two electrons to oxygen which gets reduced by accepting two
electrons from magnesium.
01-01: CHROMIUM (VI) OXIDE/ CHROMIUM TRIOXIDE
From among a variety of transition metal oxidants, the Cr (VI) — derived reagents are
highlyuseful. The oxidation state of Cr in these reagents is (VI), and these are powerful
oxidizingspecies. The CrO 3 based oxidants convert an alcohol to the corresponding
ketone or aldehyde (oxidation of a primary alcohol proceeds through the aldehyde to
carboxylic acid) and thegeneral mechanism is given (Scheme). The most commonly
used reagent is chromic acidH 2 CrO 4 , which is usually prepared by adding chromium VI
oxide (CrO 3 ) or sodium dichromate (Na 2 Cr 2 O 7 ) to sulphuric acid. When the oxidations
are carried out in aqueous acetone theprocess is termed Jones oxidation (or oxidation
by the Jones reagent, CrO 3 —H 2 SO 4 —H 2 O.
The mechanism starts with the formation of HCrO 4 – ions, that is, Cr(VI), from
dichromate ion in solution. In acid, these form chromate esters with alcoh ols. The esters
decompose by elimination of the Cr(IV) HCrO 3 – , which subsequently reacts with a
Cr(VI) species to yield 2  Cr(V). These Cr(V) species can oxidize alcohols in the same
way, and are thereby reduced to Cr(III) (the final metal -containing by-product). Cr(VI)
is orange and Cr(III) is green, so the progre ss of the reaction is easy to follow by colour
change.

A marked isotope effect (~ 6) was observed with propan -2-ol. Thus when
chromic acid isused in the oxidation of CH 3 CDOHCH 3 and isopropanol,
CH 3 CHOHCH 3 , the deuterated compound reacted about six times slower, so that k H /k D
is ~ 6 to prove that the rate determining step involves the cleavage of a C—H bond.
01-02: PYRIDINIUM DICHROMATE (PDC)

Pyridinium dichromate (C 5 H 5 NH + ) 2 Cr 2 O 7 is a good oxidising agent and is obtained by
the reaction of chromium trioxide with pyridine in presence of water. It oxidises
primary alcohols in dichloromethane solution to aldehydes in excellent yield.
Pyridinium dichromate also oxidises allylic alcoho ls to , - unsaturated carbonyl
compounds
01-03: PYRIDINIUM CHLOROCHROMATE (PCC)

This reagent is obtained by adding pyridine to a solution of chromium (VI) oxide in
hydrochloric acid.
PCC is a mild, highly selective reagent and is used in organic solvents such as CH 2 Cl 2 .
PCC can oxidise primary and secondary alcohols to the corresponding carbonyl
compounds.
The oxidation of primary alcohols with PCC stops at aldehyde stage because
acid chromate is not present in the reaction mixture. The acid chromate is required to

form chromate ester of aldehyde which is necessary intermediate for further oxidation
to the carboxylic acid by chromium (VI)
PCC is also useful for oxidising an allylic carbon to keto group. However, in such cases
the alcoholic group if present must be protected before oxidation.
01-04: POTASSIUM PERMANGANATE

Potassium permanganate, a derivative of heptavalent manganese is a very powerful
oxidising agent. Its reactivity depends on whether it is used in acid, neutral or basic
conditions. In acid solution,Mn(VII) is reduced to divalent manganese (II) with a net
transfer of five electrons (MnVII Mn II). However, in neutral basic medium,
manganese dioxide is usually formed, corresponding to a three electron change
(MnVIIMnIV). Potassium permanganate is normally used in aqueous sol ution. Since
all compounds are not soluble in water, the use of potassium permanganate is limited.
However, solvents which are not affected by potassium permanganate, such as acetic
acid, acetone, pyridine or t-butanol can also be employed.
It is now well known that the yields in potassium permanganate oxidations
areconsiderably improved by the use of a phase transfer catalysts (PTC) (e.g., certain
tetraalkylammoniumor phosphonium salts) and crown ethers ( e.g., dicyclohexano-18-
crown6). Even the time required for oxidation is considerably s hortened.
Following are given some of the applications of potassium permanganate oxidations.
1. Oxidation of alcohols
The oxidation of primary alcohols to is not normally carried out by potassium
permanganate, as the reaction proceed through carboxylic aci d. Primary and secondary
alcohols are oxidised to carboxylic acids and ketones, respectively, containing the same
number of carbon atoms.
For example, 2-methylpropan-1-ol is oxidized to 2-methylpropanoic acid with

KMnO 4 /Na 2 CO 3 solution in 76%.

Secondary alcohols, however, can be oxidised by KMnO 4 , in acidic or alkaline
conditionsto give the ketones.
The utility of this method lies in the fact that the product of oxidation (i.e. ketone)
shouldbe removed as the reaction proceeds by distillation.
Use of a mild oxidising agent like barium permanganate (which is quite stable
andreadily availabe) also oxidises’ primary and secondary alcohols into
carbonylcompounds. N-Bromosuccinimide is also used for the oxidation of secondary
alcohols to ketones.
2. Oxidation of alkenes
Alkenes on treatment with dilute KMnQg solution in presence of alkali give 1, 2-diols.
Inthis reaction, the purple KMnO 4 is reduced to MnO 2 , a brown solid. This change in
colour is the basis of a test for the presence of double and triple bonds known as the
Baeyer’s test for unsaturation.
The hydroxylation of alkenes with KMnO 4 is carried out by stirring alkene and
theaqueous KMnO 4 solution, either neutral or slightly alkaline at room temperature.
Forexample, oleic acid on oxidation in basic medium gives a glycol.
Similarly, oxidation of nonbornene with KMnO 4 in basic medium gives 1, 2-glycol,

while in neutral medium a dialdehyde is obtained.

Mechanism
In the above reactions, the diols obtained are cis diols. The hydroxylation of alkenes
with KMnO 4 involves the cyclic intermediate, a manganate ester. The intermediate
breaksdown in water to give cis-1,2-diol. The manganate ion is converted to MnO2
whichprecipitates. Evidence by the work of Wibergef al supports the mechanism
18 18
proposed, who used KMnO 4 labelled with O. The diol obtained is enriched with O.
Thisindicates that both oxygen atoms of the diol come from permanganate ion. For
example, But-2-ene is oxidized to cis-Butane-1, 2-diol by KMnO 4 .
The oxidation of alkenes with aqueous solution of KMnO 4 can also be effected
inpresence of PTC and crown ethers. The catalylic action of the quaternary salt (PTC)
isdue to the ability of their organic soluble cations to transfer anions (e.g. MnO 4  ) from
theaqueous into the organic phase. For example, 1-octene gives the heptanoic acid by
usinga PTC and aq. KMnO 4 .

In place of PTC, crown ethers (a group of cyclic polyethers) can also be used. The
crown ethers form permanganate complex with KMnO 4 as shown below.
The formation of the complex depends on the cavity in 18 -crown-6-molecule (the cavity
in the 18-crown-6 has a diameter of 2.7A 0 , which is just sufficient for K + ion having
diameter of 2.66 A 0 to fit. As an illustration toluene can be oxidised with KMnO 4 in
presence of crown ether.
For example, using crown ether as catalyst, a -pinene gives pinonic acid in 90%yield,
In place of phase transfer catalysts or crown ether, it is also possible to carry out
oxidations by using permanganate salts, which are soluble in organic solvent. One such
Salt is tetra-n-butylammonium permanganate.
3. Oxidation of alkynes
Alkynes can be oxidised with KMnO 4 to give a mixture of carboxylic acids.
The later degradation (oxidation) is used for structure elucidation of alkynes (compare
with the oxidation of alkenes, which give diol under mild conditions but carboxylic
areusing strong conditions). In case of alkynes, it is sometimes possible to stop the
oxidation at an intermediate stage. For example, the acetylene analogue of oleic acid on
oxidationwith KMnO 4 in neutral condition gives the corresponding diketo acid. If the
oxidation iscarried out in alkaline medium, a mixture of two acids is obtained.
4. Oxidation of aromatic side chains and aromatic ring systems

Benzene is an exceptionally stable compound and is not affected by usual oxidising
agents. It is for this reason that benzene is used as a solvent in most of the organic
reactions. If an alkyl group is present in benzene nucleus (e.g., toluene) the side chain
is oxidised to the corresponding carboxylic acid. Thus, toluene on oxidation with
alkaline KMnO 4 gives benzoic acid in 40-50% yield. However, the oxidation of toluene
with KMnO 4 in presence of PTC catalyst, viz., cetyltrimethyJammonium chloride gives
about 80% yield in a much shorter time.
The oxidation of toluene with KMnO 4 is represented below.
In a similar way isopropyl benzene on oxidation also gives benzoic acid. However ,
tertiarybutylbenzene is resistant to oxidation by KMnO 4 . This is attributed to the
absenceof H atom in the -position (benzylic position), which is susceptible to attack
byoxidising agent. There must be at least one hydrogen in the benzylic position for
thereaction to succeed.
Oxidation with KMnO 4 is a standard method for identifying the positional
isomers ofmonosubstituted alkylbenzenes. For examples, o-chlorotoluene on oxidation
gives an o-chlorobenzoicacid and mesitylene gives mesitoic acid.

It has already stated that benzene ring is resistant to the action of KMnO 4 . However, the
benzene ring can be cleaved if it is fused to a heterocyclic ring system. Thus, quinoline
and isoquinoline on oxidation with alkaline KMnO 4 give the corresponding
dicarboxylic acids, quinolinic acid and cinchomeronic acid, respectively.
SOLVED PROBLEMS 01
Problem 1
What product is formed when pent-2E-ene reacts with KMnO4/aq. KOH? What is the
product when pent-2Z-ene reacts with KMnO4/aq. KOH?
Solution: The reaction of pent-2E-ene gives pentan-2S, 3S-diol, whereas pent-2Z-ene gives
pentan-2S, 3R-diol. These diols are different diastereomers, but each is racemic.
Problem 2
What is the major product when trans-hex-3-ene reacts with KMnO4 followed by aqueous
KOH?
Solution:

For an acyclic alkene, cis- addition of the hydroxyl groups applies, but the terms cis- and trans-
do not apply to the diol product. To sort out the stereochemistry of the product, first rotate the
alkene as shown in A, such that one ethyl group is projected to the front of the page and one ethyl
group is projected to the rear, refecting the trans- geometry. If permanganate reacts from the
bottom face of the alkene as it is drawn manganate ester B is formed, with the (3R, 4R)
stereochemistry. If permanganate reacts from the top face, manganate ester C is formed, with the
(3S, 4S) stereochemistry. Structures B and C are enantiomers of a single diastereomer. When
these manganate esters react with hydroxide, the stereochemistry at carbon is retained since
hydroxide attacks manganese rather than carbon. The final products are (3R, 4R) hexanediol and
(3S, 4S)-hexanediol, in equal amounts. The cis- addition has led to a single diastereomer, but it is
racemic, reflecting the fact that the planar alkene can be attacked from two opposite faces.
SHORT ANSWER QUESTIONS 01
Que.1: What is the major product when dilute KMnO4 reacts with cyclopentene in aqueous
KOH?
Answer: The major product of this reaction is one diastereomer, the cis-1, 2-cyclopentanediol. In
other words, the two OH units are on the same side of the molecule. This oxidation is a
diastereospecifc reaction since none of the diastereomer, the trans-diol, is formed. The cis- diol is
racemic since reaction (both the 1R, 2S and the 1S, 2R stereoisomers are formed) can occur from
the “top” face of the alkene and also from the “bottom” face equally well. Note that the cis- diol
derived from cyclopentene is a meso compound since the 1R, 2S and the 1S, 2R stereoisomers are
the same compound (they are superimposable).
Que.2: Is there an intermediate in the reaction of dilute KMnO4 with cyclopentene in

aqueous KOH?
Answer: Yes! The reaction proceeds by initial formation of a cyclic manganese compound that
reacts with hydroxide to decompose the manganate ester to give the diol.

01-05: MANGANESE DIOXIDE (MNO2)
Manganese dioxide is a mild reagent and is useful for the oxidation of primary and
secondary alcohols to carbonyl compounds. This reagent is specific for the oxidation of
allylic and benzylic alcohols. The reaction takes place under mild conditions (room
temperature) and in neutral solvent (benezene, petroleum ether, chloroform, water). For
oxidation, manganese dioxide must be freshly prepared by the reaction of a manganese
(II) sulphate with KMnO 4 in alkaline solution. MnO 2 does not affect C-C double bonds
and triple bonds. Some typical oxidations are given below.
Manganese dioxide has also been used for oxidation of polyunsaturated alcohols in
vitamin A series.
Manganese dioxide has also been used to convert conjugated aldehyde to a ester in
presence of CN - . The reaction takes the following course.
Mechanism

Goldman and Henbest proposed that the oxidation of alcohols to carbonyl compounds
proceed via a radical intermediate as shown in scheme. The alcohol is absorbed on
manganese dioxide followed by formation of a co -ordination complex (1). Electron
transfer from alcohol to Mn generates a radical (2), further Mn (IV) is reduced to Mn
(III) in this process. A second electron transfer generates the carbonyl product and
Mn(OH) 2 (3). Finally loss of water molecule and carbonyl desorption results in the
formation of carbonyl product and manganese (II) oxide (4).
Although oxidation of allylic alcohols with MnO 2 stops at aldehyde stage and further
oxidation to carboxylic acid does not take place. However, in the presence of HCN the
derived aldehyde (5), is converted into cyanohydrins (6), which undergoes further
oxidation to acyl cyanide (7). Acyl cyanide (7) on a lcoholysis leads to corresponding,
-unsaturated carboxylic ester. Thus, cinnamaldehyde (5) is converted into methyl
cinnamate (8), as shown in scheme-2.
Another important feature of this transformation is that the reacti on proceeds in high
yield without cis-trans isomerisation of the , -olefinic linkage. At high temperature
or using sufficient reagent and pure solvents, active MnO 2 can oxidise even saturated
primary and secondary alcohols. Androstane-17-ol (9) in hexane with an excess of
active MnO 2 at room temperature gives pure androstane-17-one (10) in quantitative
yield.

The reagent is sensitive to steric interactions as shown below.
Oxidation of amines
The oxidation of amines by MnO 2 can lead to various products depending on the nature
of the starting material. Thus, the formation of imines, amides and diazo compounds
from amines has been described by the following examples.
N, N-Dimethylaniline on oxidation with MnO 2 in CHCl 3 at room temperature affords N-

methylformanilide in 78% yield.
In some cases tertiary amines are cleaved to carbonyl compounds. For example, N, N -
dimethylcyclohexyl amine is converted into cyclohexanone in 85% yield.
Oxidation of hydrazo compounds

MnO 2 oxidsiseshydrazobenzene to azobenzene in 97% yield.

Oxidation of sulphur compounds
Oxidation of mercaptans and dialkylsulphides with MnO 2 lead to coupled product,
disulphides and sulphoxides, respectively.
Oxidative cleavage of 1,2-diols

MnO 2 cleaves 1, 2-diols to aldehydes or ketones
Conversion of nitriles to amides

By treatment with MnO 2 , nitriles are readily converted to amides. Maximum yield of
amide is obtained when MnO 2 on silica gel is used.
Aromatisation
MnO 2 has been widely used to carry out various dehydrogenation and aromatisation
reactions.
Oxidation of phosphines
Triphenylphosphine can be converted into triphenylphosphine oxide by MnO 2 .

01-06: PERIODIC ACID (HIO4)
Periodic acid is used for the oxidative cleavage of bonds with adjacent oxidisable
groups, e.g., 1, 2-diols, α-hydroxy carbonyl compounds, 1, 2-diketones and α-amino
acids. This reaction has been used as a test for 1, 2 -diols and in the determination of the
structures of carbohydrates.
Some representative examples are given below.
Mechanism
The oxidation proceeds via a cyclic periodate ester intermediate.
The intermediate breaks down to form the two carbonyl compounds.

In conjugation with KMnO 4 or OsO 4 , periodate is used for the cleavage of
alkenes. The KMnO 4 hydroxylates the double bond to give 1, 2 -diol, which is cleaved
by periodate. The periodate also oxidises manganate back up to permanganate.

In these reactions sodium iodate is used in place of iodic acid.
01-07: LEAD TETRA-ACETATE [PB(OCOCH3)4] OR PB(OAC)4
Lead tetra-acetate Pb(OAc) 4 , is a versatile oxidising agent, which has been widely used
in organic synthesis. The reagent has also been used as a drying agent for solvents such
as benzene, pyridine, chloroform, carbon tetrachloride and ethers. Pb(OAc) 4 , is
hygroscopic and turns brown due to lead dioxide formation on exposure to air. The
reagent is very toxic and may be resorb through the skin. Because of its high toxicity
and high vapor pressure it should be handled with extreme care in a chemical fume
hood. Pb(OAc) 4 , can be readily prepared by slowly adding red lead oxide (Pb;O4) to a
mixture of acetic acid and acetic anhydride at 60 -80° C. The mixture is cooled and the
separated lead tetra-acetate filtered. It is recrystallised from acetic acid as white
needles.
For application in organic chemistry, Pb(OAc) 4 , is most often used for the oxidative
decarboxylation of carboxylic acids, oxidation of alcohol s, formation of cyclic ethers. It
is also used as a good acetoxylating and met hylating reagent.
Reaction of LTA with hydroxycompounds
(a) With monohydric alcohols
In presence of pyridine solution, Pb(OAc) 4 oxidises a variety of primary and
secondaryalcohols to the carbonyl compounds at room temperature.
However, primary and secondary alcohols containing δ C -H group give high yields of
tetrahydrofuran derivatives when treated with Pb(OAc) 4 in benzene without the
presence of pyridine.
(b) Reaction with 1,2-diols
1,2-Diols are cleaved under mild conditions with lead tetra -acetate to give aldehydes,
ketones or both depending upon the structure of the 1,2-diols. The reaction is
quantitative and rapid enough to allow titrimetric estimation of glycols. Pinacol, for
example, givestwo molecules of acetone and 1,2 -cyclohexanediol gives hexanedial.

The cleavage of diols proceeds via a cyclic intermediate.’ Since, cyclic intermediate is
formed rapidly with syn-diols, therefore, syn-diols are oxidised faster than anti-diols.
Thus, the reaction can be used not only to detect the presence of glycol groups but also
their stereochemistry. The mechanism of glycol oxidation with Pb(OAc) 4 , was proposed
by Criegee .
When three or more hydroxy groups are located on adjacent carbon atoms, then the
middle one is converted to formic acid.
Similar cleavage is undergone by other compounds that contain oxygen or nitrogen on
adjacent carbons such as α-hydroxy-ketones, 1 ,2-diketones and β-amino-alcohols.

Cyclic α-hydroxy-ketone (1) is cleaved with Pb(OAc) 4 in ethanol to give (2).
The reaction of Pb(OAc) 4 with 1,2-diols has been effectively applied in the area of
carbohydrates and sugars.
Reaction with carboxylic acids (Oxidative decarboxylation)

(a) Monocarboxylic acids
Monocarboxylic acids on oxidation with Pb(OAc) 4 in the presence of copper (II) salts
give mainly alkenes. The free radical mechanism’ is generally proposed.
Rosefuran (4) can be obtained by the oxidative decarboxylation of 3 -methyl-2-furoic

acid derivative (3) with Pb(OAc) 4 in the presence of Cu(OAc) 2 .
(b) Dicarboxylic acids

Bisdecarboxylation of compounds containing carboxyl groups on adjacent carbons can
be achieved with Pb(OAc) 4 in the presence of oxygen and pyridine.
Mechanism proposed for this reaction is given below.
Compounds containing geminal carboxyl groups (malonic acid derivatives) are

decarboxylated with Pb(OAc) 4 to give gem diacetate, which is easily hydrolyzed to
ketones.
(c) α-Substituted carboxylic acids

α-Hydroxy acids are cleaved to carbon dioxide and a carbonyl compound (aldehyde or
ketone) in acetic acid.
In contrast to hydroxy acids, α-keto acids are relatively inert to Pb(OAc) 4 unless
“hydroxyl forming substances” such as water or alcohols are present. Under such
conditions α-keto acids undergo oxidative decarboxylation to give acids.
Dehydrogenation and oxidative cyclisation

(a) Cyclisation of saturated alcohols
Treatment of saturated alcohols having a hydrogen in the δ - position with Pb(OAc) 4 in
hot benzene results in cyclisation to give tetrahydrofurans together with low yields of

tetrahydropyrans. This reaction has been extensively applied for the preparation of
simple alkyltetrahydofurans from alcohols. For example, 1 -heptanol with Pb(OAc) 4 in
boiling cyclohexane gives 2-propyltetrahydrofuran in 50% yield; small amount of 2 -
ethyltetrahydropyran is also formed.
The mechanism’ is probably as follows:
The initial intermediate is triacetoxy lead alkoxide (5). Homolysis of (5) gives the
radical (6), which undergoes hydrogen abstraction from the δ -position through a cyclic
six-membered transition state. The resulting free radical (7) produces tetrahydrofur an
via a carbonium ion (8). Homolysis of (5) can be induced thermally or photochemically
at room temperature.
The reaction can also be applied to cyclic alcohol (9) to produce bridged ether ( 10).
(b) Cyclisation of carboxylic acids

Usually treatment of carboxylic acids with Pb(OAc) 4 leads to decarboxylation, however,
when a double bond is located nearby, lactone is formed.

(c) Dehydrogenation
Lead tetra-acetate oxidation of 1° aliphatic amines results in dehydrogenation to
nitriles.
N,N'-Disubstitutedhydrazines are readily dehydrogenated to azo compounds by

Pb(OAc) 4 .
Diphenoquinone has been prepared in 45% yield by treating 4,4'-dihydroxybipheny!

With Pb(OAc) 4 in a mixture of dioxane-acetic acid (1:2). Similarly, hydroquinone is
converted into p-benzoquinone with Pb(OAc) 4 and 2,6-dihydroxynaphthalene
(naphthaquinone) is converted into 2,6-dihydronaphthalene-2,6-dione (amphi-
naphthaquinone).
Acetoxylation
Ketones, in the enol form can be acetoxylated at α -position. The yields of α-
acetoxylation product can be improved by the addition of a catalyst, boron tri fluoride.

The acetoxylation of unsymmetrical dialkyl ketones usua lly occurs at the less
substituted position. 2-Butanone, for example, gives 1-acctoxy-2-butanone with
Pb(OAc) 4
Benzene derivatives, containing electron-donating substituents and the more reactive

condensed aromatic hydrocarbons, do undergo acetoxylation on thermal reaction with
the Pb(OAc) 4
Acetoxylation of alkyl side chains in aromatic compounds can be readily achieved by :

LTA treatment.
A mixture of products is formed by the oxidation of cyclohexene with Pb(OAc) 4 in

acetic acid.

Nuclear methylation
Nuclear methylation of aromatic compounds can be achieved by refluxing the aromatic
compound with Pb(OAc) 4 and glacial acetic acid.
Mechanism
SOLVED PROBLEMS 02
Problem 3: What is the mechanism for the following reaction?
Solution: The mechanism’ is probably as follows:

Solution:

Que.3: What is the general mechanism of the reaction of periodic acid with a 1, 2-diol?
Answer: Periodic acid reacts with the 1, 2-diol to form a cyclic periodate ester, A. A concerted
rearrangement allows cleavage of the carbon–carbon bond with elimination of iodic acid and
formation of two equivalents of the carbonyl compound.
Que.4: What is the action of Pb(OAc)4 on α-Substituted carboxylic acids?

Answer:α-Hydroxy acids are cleaved to carbon dioxide and a carbonyl compound (aldehyde or
ketone) in acetic acid.
In contrast to hydroxy acids, α-keto acids are relatively inert to Pb(OAc)4 unless “hydroxyl
forming substances” such as water or alcohols are present. Under such conditions α-keto acids
undergo oxidative decarboxylation to give acids.
01-08: OSMIUM TETRAOXIDE (OSO4)

Osmium tetroxide is highly toxic and has high vapor pressure. It should be handled
withextreme care in a chemical fume hood. For application to organic chemistry, OsO 4
ismost often used for the syn-hydroxylation of alkenes. It oxidisessulfoxides to sulfones
but does not oxidise sulfides. Ketones and esters can be ohydroxylatedby treatment of
their enolate forms with osmium tetroxide-Nmethylmorpholine-N-oxide.
Hydroxylation of alkenes
Hydroxylation of alkenes with OsO 4 , to vicinal diols proceeds via the formation of
fivememberedcyclic ester of vicinal diols (osmate ester, 1) as an intermediate, which is
thenhydrolyzed to yield cis-diols. In most of the cases, the osmate ester is not isolated,
andthe reaction is usually done in the presence of tert -butyl alcohol-water mixture,

whichhydrolyses the osmate ester to the diol. The osmium starts as Os(VIII) and ends
up asOs(VI). A variety of reagents can be used to decompose the osmate ester,
includingsodium sulfite or bisulfite in aqueous ethanol, bisulfite i on in pyridine,
mannitol inalkaline solution. The reduced osmium species is normally removed by
filteration. Forexample, cyclohexene reacts with osmium tetroxide to give a cis -1,2-
cyclohexanediol.
When the reaction is carried out in the presence of pyridine, an ester complex (2),
isformed by co-ordination with two equivalents of the ligand (pyridine), and it
cansometimes be isolated. The ester is then hydrolyzed to give a cis -diol.
The chief drawback of this reaction is that OsO 4 is expensive and highly toxic.
However,cis hydroxylation can be performed more economically with a catalytic
amount ofosmium tetroxide in the presence of oxidising agent which reoxidises
hexavalent osmiumto octavalent osmium (i.e., regenerates the osmium tetroxide) to
continue the catalyticcycle. The common co - oxidants are metal chlorates” (such as
barium chlorate or sodiumchlorate), hydrogen pe roxide’ and t-butyl hydroperoxide.
This is illustrated by thefollowing examples.

The H 2 O 2 or metal chlorate oxidatively cleaves the osmium complex and regenerates
theosmium tetroxide by oxidising the reduced form of osmium resulting from
thehydroxylation.
Tertiary amine-oxide, such as N-methylmorpholine-N-oxide (NMO) (3), are
veryeffective catalyst and oxidiseOs(VI) back to Os( VIII). In these reactions, where
NMO isused as catalyst, only 1 mol % of OsO 4 is required.

Due to electrophilic nature of osmium tetroxide, the prese nce of electron-withdrawing
groups to the alkene double bond retard the hydroxylation. Thus, when more than one
double bonds are present, hydroxylation occurs at the most electron -rich double bond as
illustrated by the following example.
The overall hydroxylation is stereoselectively syn. Thus, meso 1,2 -diol is obtained from
cis 2-butene. For example, Maleic acid gives meso -tartaric acid with OsO 4 and
NaHSO 3 .
01-09: LEMIEUX-JOHNSON REAGENT (OSO4- NAIO4)

When OsO 4 is used in combination with NalO 4 , it is known as Lemieux-Johnsonreagent
and it gives the same products as is obtained in the ozonolysis procedure.Osmium
tetroxide (catalytic amount) reacts with a double bond to give an osmate ester,which
then decomposes in the presence of sodium periodate to give cleavage
products(aldehydes or ketones) of the diol along with the regenerated osmium tetroxide.
Forexample, 1-dodecene (4) is converted to undecanal (5) and cyclohexene to
hexanedial (6) by osmium tetroxide and NaIO 4 .

01-10: RUTHENIUM TETRAOXIDE (RUO4)
Ruthenium tetroxide is powerful oxidising agent (reduction potential of 0.59 v)
Oxidation aregenerally carried out in carbon tetrchloride -acetonitrile solution.
Sinceruthenium tetroxide is costly, it is equally convenient to use a catalytic amount
ofruthenium tetroxide in presence of sodium periodate, which oxidises the
reducedruthenium back to the active tetroxide.
Ruthenium tetroxide cleaves the carbon-carbon double bonds to give carboxylic

acids, aldehydes or ketones. This reagent is a good alternative to ozonolysis.
Primaryalcohols on oxidation give aldehydes and secondary alcohols give ketones.
Esterfunction, if, present is unaffected.
Ketones are stable to further oxidation but aldehydes are converted into
carboxylic acids.The alkenes are cleaved without oxidation of secondary alcohols as
seen in the following synthesis.
01-11: OXIDATION WITH PERACIDS

A number of peracids having the general formula, RCO 3 H have been used to
affectoxidation. Some common peracids are: performic acid (HCO 3 H), peracetic
acid(CH 3 CO 3 H), perbenzoic acid (C 6 H 5 CO 3 H), trifluoroperacetic acid (CF 3 CO 3 H), m-

chloroperbenzoic acid (m-ClC 6 H 4 CO 3 H) andmonoperphthalic acid (o-
HOOCC 6 H 4 CO 3 H). Performic and peracetic acids are generally prepared in situ by
theaction of hydorgen peroxide on the corresponding carboxylic acids.
Trifluoroperacetic acid is obtained from trifluoroacetic acid and H 2 O) as a 90%

solution.m-Chloroperbenzoic acid is available commercially as a crystalline solid, It
can also beprepared from m-chlorobenzoyl chloride and hydrogen peroxide.
Following are given some of the applications of peracids.
Oxidation of alkenes
Peracids react with alkenes to give stable three-membered rings containing one
oxygenatom, epoxides or oxiranes.
Mechanism
The reaction is believed to take place by transfer of oxygen atom from peracid to
thealkene. The reaction involves a one -step process without intermediates. The
expoxidation is stereospecific leading to the syn addition of t he oxygen atom.
Epoxidation
The rate of epoxidation is increased by the presence of electron withdrawing groups

inthe peroxy acid; thus, trifluoroperacetic acid is more effective than peracetic acid.
Therate of epoxidation is also increased if the alken e has electron-donating
substituents.Thus, terminal alkenes react slowly with peracids compared to alkyl
substituted alkeneslike butene-2.

The epoxidations with peroxy acids are stereoselective and take place by syn-addition
tothe double bond, which is established by X-ray analysis of the products obtained. As
thecis alkene gives only cis expoxide and trans alkene gives trans eposide, the
reactionmust be concerted i.e. the one-step mechanism retains the stereochemistry of
the starting alkenes.
In case of cyclic alkenes, which are conformationally rigid, the reagent approaches
fromthe less hindered side of the double bond. This is illustrated in the epoxidation of
norbornene.
However, unhindered olefinic bond yields a mixture of epoxides. This is be cause the
twopotential modes are not markedly different.

It has already been mentioned that alkylsubstituted alkenes react faster than the
terminalalkenes. This has been made use of in the preferential epoxidation of the
substrate havingtwo double bonds (dienes). This is illustrated by the epoxidation of p -
mentha-1,4(8)-diene.
SOLVED PROBLEMS 03
Problem 5: Predict the product of the following reaction?
Solution:
Que.6: Depict the reaction of trans-2-butene with meta-chloroperbenzoic acid followed by

the reaction of the product with CH3OH/H2SO4.
Answer: It is a stereospecific epoxidation leading to only the trans epoxide. The ring opening in
acid solution is an SN2 reaction occurring with inversion of configuration.

Que.5: What is an osmate ester?
Answer:

An osmate ester (see the figure) is the product formed when OsO4reacts with an alkene via [3+2]-
cycloaddition.
Que.6: What structural feature of peroxycarboxylic acids is important for the oxidation
of alkenes to oxiranes?
+
Answer: Peroxyacids shown have an electrophilic oxygen atom (δ ) that will react with the
electron-rich π-bond of an alkene. The electrophilic oxygen is a consequence of an induced dipole
that originates with the carbonyl oxygen. The bond polarization that leads to electrophilic oxygen
is shown with peroxyformic acid
01-12: SHARPLESS EPOXIDATION

The first of Sharpless’s reactions is an oxidation of alkenes by asymmetric
epoxidation.This new reaction makes use of titanium, as titanium tetraisopropoxide,
Ti(OiPr) 4 , to do thesame thing. Sharpless surmised that, by adding a chiral ligand to the
titanium catalyst, he might beable to make the reaction asymmetric. The ligand that
works best is diethyl tartrate, and the reactionshown below is just one of many that
demonstrate that this is a remarkably good reaction.
Transition-metal-catalysed epoxidations work only on allylic alcohols, so there

is one limitationto the method, but otherwise there are few restrictions on what can be
epoxidized enantioselectively.When this reaction was discovered in 1981 it was
by far the best asymmetric reaction known.Because of its importance, a lo t of work
went into discovering exactly how the reaction worked, andthe scheme below shows
what is believed to be the active complex, formed from two titanium atomsbridged by
two tartrate ligands. Each titanium atom retains two of its isopropoxideligands, and is
coordinated to one of the carbonyl groups of the tartrate ligand. The reaction worksbest

if the titanium and tartrate are left to stir for a while so that these dimers can form
cleanly.
When the oxidizing agent (t-BuOOH, shown in green) is added to the mixture, it
displaces one ofthe remaining isopropoxide ligands and one of the tartrate carbonyl
groups.
Now, for this oxidizing complex to react with an allylic alcohol, the alcohol
must become co-
ordinated to the titanium too, displacing a further isopropoxide ligand. Because of the
shape of thecomplex the reactive oxygen atom of the bound hydroperoxide has to be
delivered to the lower faceof the alkene (as drawn), and the epoxide is formed in high
enantiomeric excess.
Different allylic alcohols coordinate in the same way to the titanium and reliably
present the sameenantiotopic face to the bound oxidizing agent, and the preference for
oxidation with L -(+)-DET isshown in the schematic diagram below. Tartrate is ideal as
a chiral ligand because it is availablerelatively cheaply as either enantiomer. L -tartrate
is extracted from grapes; D -(–)-tartrate is rarerand more expensive—it is sometimes
called unnatural tartrate, but, in fact, it too is natural. By using D -(–)-tartrate it is, of
course, possible to produce the other enantiomer of the epoxide
equallyselectively.

Sharpless also found that this reaction works with only a catalytic amount of
titanium–tartratecomplex, because the reaction products can be displaced from the
metal centre by more of the tworeagents. The catalytic version of the asymmetric
epoxidation is well suited to industrial exploitation,and the American Company J. T.
Baker employs it to make synthetic disparlure, the pheromone ofthe gypsy moth.
Not many target molecules are themselves epoxides, but the great thing
about the epoxideproducts is that they are highly versatile —they react with
many types of nucleophiles to give1,2 -disubstituted products.
Unfortunately, the obvious starting material, allyl alcohol itself, gives and
epoxide which is hardto handle, so Sharpless who carried out this synthesis of
propranolol, used this silicon-substitutedallylic alcohol instead.
The hydroxyl group was mesylated and displaced with 1 -naphthoxide and, after
treatment withfluoride to remove the silicon, the epoxide was opened with
isopropylamine.

01-13: H 2 O 2 – NaOH (Alkaline hydrogen peroxide)
Epoxides of,  -unsaturated carbonyl compounds are best made by the action of
nucleophilicreagents such as hydrogen peroxide or tert -butyl hydroperoxide in alkaline
solution.
Reaction of alkenes with tert-butyl hydroperoxide (t-BuOOH) in the presenceof a

transition metal catalyst, for example, a vanadium(V), molybdenum(VI) ortitanium(IV)
complex, provides an excellent method for the preparation of epoxides. The
molybdenum catalysts are most effective for the epoxidation of isolateddouble bonds,
and the vanadium or titanium catalysts are most effective for allylicalcohols. Even
terminal alkenes can be epoxidized readily. For example, 1 -decenewas converted into
its epoxide with t-BuOOH and Mo (CO) 6 on heating in 1,2-dichloroethane.
The oxidation of allylic alcohols has been studied thoroughly using a variety of
catalysts. The reactivity of the vanadium-tert-butyl hydroperoxide reagentstowards the
double bond of allylic alcohols makes possible selective epoxidation. Thus, reaction of
geraniol with t-BuOOH and vanadium acetylacetonate [VO (acac) 2 ] gave the 2,3-
epoxide 33. With peroxy-acids, reaction takesplace preferentially at the other double
bond.

Vanadium catalysts have found particular advantage for stereoselective
epoxidations. Thus, the acyclic allylic alcohol 34 is oxidized with high selectivity
usingt-BuOOH and vanadium acetylacetonate, whereas with mCPBA a nearly
equalmixture of the diastereomeric epoxides was produced.
01-14: OZONOLYSIS
Ozone gives 1, 3-dipolar addition reaction with alkenes. Product of the addition
reaction is mol ozonide which undergoes rearrangement to give ozonide. The reaction
takes place in the presence of solvent at - 78°C. Ozonides are unstable compounds and
they are explosive in nature.
Ozonide converts into carbonyl compound by the addition of oxidising as well as

reducing agents.
(a) Reaction with oxidising agents.

Overall reaction can be represented as follows:
In this sequence of reactions doubly bonded carbon having no hydrogen

converts into keto groupand doubly bonded carbon having hydrogens converts into
carboxylic group, e.g.,
Reduction of ozonide: In the presence of reducing agents such as LiAlH 4 and

NaBH 4 ozonide first converts into carbonyl compounds which further undergo reduction
to give alcohols.
When reducing agent is Zn/CH 3 COOH, H 2 /Ni or triphenylphosphine, products

are carbonylcompounds. In this case carbonyl compounds do not convert into
corresponding alcohols.
Ozonolysis: Ozonolysis reaction is two step reactions. First step is formation of

ozonide.Second step is hydrolysis of ozonide, either in the presence of reducing agents
(Zn dust orCH 3 -S-CH 3 ) or in the absence of reducing agents. Thus ozonolysis is of two
types:
Reductive Ozonolysis or Reductive Work up
Addition of ozone followed by hydrolysis in the presence of reducing agent is

known asreductive ozonolysis. This type of ozonolysis is mainly used in alkenes.

In reductive ozonolysis by-product H 2 O 2 which is an oxidising agent is reduced
by reducingagent and hence carbonyl compounds do not undergo further oxidation.
In reductive ozonolysis unsubstituted or monosubstituted olefinic carbon

converts into aldehydeand disubstituted carbon converts into ketone. Thus overall
reaction can be represented as follows:
Ozonolysis reaction is used to know the number and position of double bonds in
alkenes and polyenes.
Follow the following points for the determination of structure of an alkene from
the ozonolysis products:
(i) Number of carbons in alkene and products should be the same, e.g.,
(ii) Connect both carbonyl carbons by double bond with the removal of oxygen.
(iii) If product is dicarbonyl compound and number of carbons in reactant and product
is thesame then reactant will be cycloalkene.

(iv) Number of product in polyenes = n + 1
Where, n = number of double bonds whose value may be 2, 3, 4, 5, 6, -----
Out of n + 1 products, two products will always be monocarbonyl compou nds and
remainingproducts will be dicarbonyl compounds. This result is applicable in those
polyenes whose double bondsare present in the main chain. For example:
Number of double bonds = 4

Hence number of products = 5
Out of 5 products two products will be monocarbonyl compounds
and~neremaining three willbe dicarbonyl compounds.
Oxidative Ozonolysis
Addition of ozone followed by hydrolysis in the absence of reducing agent is
known as oxidativeozonolysis. This ozonolysis is mainly carried out in alkynes.
In this ozonolysis, by product, hydrogen peroxide oxidises aldehyde into
carboxylic acid.
Thus in oxidative ozonolysis unsubstituted and monosubstituted olefinic carbon

converts intocarboxylic group (i.e., =CH ~ COOH) and disubstituted olefinic carbon
converts into keto group.

Thus if alkene is terminal then terminal carbon converts into formic acid.
Note:
(i) In oxidative ozonolysis formic acid does not undergo oxidation into CO 2 and H 2 O.
(ii) For determining structure of alkene from products of oxidative ozonolysis ketones
arewritten as such but carboxylic acids are written as corresponding aldehydes rest
process issame as in reductive ozonolysis.
SOLVED PROBLEMS 04
Problem 7: What product is formed initially when cyclohexene reacts with ozone?
Solution: In a process that is similar to the one observed with OsO4 and MnO4, ozone reacts with
alkenes, such as cyclohexene, and the π-bond of an alkene attacks one terminal oxygen, and the
other terminal oxygen of ozone in turn attacks the developing positive charge on the carbon to
form a cyclic species, a 1,2,3-trioxolane.
Problem 8: Predict the products of the following reaction?
Solution:

Que.7: What is ozonolysis?
Solution: Ozone (O3) adds to alkenes, but the initially formed product rearranges to a more stable
product called an ozonide, even at low temperatures. Subsequent treatment with an oxidizing or
reducing agent leads to net cleavage of the carbon–carbon double bond and formation of
aldehydes, ketones, or carboxylic acids. The process of cleavage of alkenes by reaction with
ozone into carbonyl derivatives is called ozonolysis.
Que.8: What is the use of ozonolysis?

Answer: Ozonolysis is used for the detection of double bond.
CHECK POINT 02-01
1. The specific use of MnO2 is ----
(1) Oxidation of primary alcohol (2) Oxidation of secondary alcohol
(3) Oxidation allylic and benzylic alcohols (4) Oxidation of tertiary alcohols
Answer: (3) Oxidation allylic and benzylic alcohols
2. Addition of MnO4 takes place as -------
(1) Syn addition (2) Trans addition
(3) Reverse direction (4) Opposite direction
Answer: (1) Syn addition
3. The product A of the following reaction is
4. Hydroxylation of alkenes with OsO4 produces ---------

(1) Anti diol (2) Geminal diol
(3) Vicinal cis diol (4) Terminal diol
Answer: (3) Vicinal diols
SUMMARY
Originally, the term oxidation was used to describe reactions where an element
combines with oxygen. For example, the oxidation of magnesium involves the chemical
reaction between magnesium metal and oxygen to form magnesium oxide.
The word reduction comes from the “to lead back” sense of the Latin stem. Th us,
everything that leads back to magnesium metal in the previously mentioned chemical
reaction implies reduction. An example of the reduction of magnesium oxide to
magnesium metal is a reaction between magnesium oxide and carbon at 2000 degrees
Celsius to form magnesium metal and carbon monoxide.
Due to the changes in oxidation states that occur without the independent transfer of
electrons, many reactions in organic chemistry can be classified as redox reactions. For
instance, the oxidation state of carbon atoms in the wood increases during the

combustion of wood with molecular oxygen, and that of oxygen atoms decreases as
carbon dioxide and water are produced. The oxygen atoms are reduced, formally
receiving electrons, while the carbon atoms are oxidised, losing electrons. Therefore,
oxygen is the oxidising agent and the reducing agent in this reaction is carbon.
KEY WORDS
Oxidation, Reduction, Oxidising agent, Reducing agent, molecular oxygen.
REFERENCES
Organic Reaction Mechanism Third Edition V.K. Ahluwalia, Rakesh Kumar Prasar
Organic Reactions and their Mechanisms Third Edition, P S KALSI, India, New Age Science
Limited.
MODERN METHODS OF ORGANIC SYNTHESISW. CARRUTHERS, Canbrige University
Press.
Organic Chemistry by Clayden Greeves, Warren &Wothers.
MOOCS
--------
YOUTUBE VIDEOS
https://www.youtube.com/watch?v=h4s-Ui4dpJ0
https://www.youtube.com/watch?v=HlgZPXHSmII
https://www.youtube.com/watch?v=yAMWJcUVElQ
https://www.youtube.com/watch?v=lP9P1TIFKww
WIKIPEDIA
https://en.wikipedia.org/wiki/Chromium_trioxide
https://en.wikipedia.org/wiki/Manganese_dioxide
https://en.wikipedia.org/wiki/Osmium_tetroxide
https://en.wikipedia.org/wiki/Sharpless_epoxidation
OER
------
BOOKS
Limited.
MODERN METHODS OF ORGANIC SYNTHESISW. CARRUTHERS, Canbrige University
Press.
Organic Chemistry by Clayden Greeves, Warren &Wothers.


CREDIT 02-UNIT 02: OXIDATION INVOLVING
LEARNING OBJECTIVES
 To understand Oxidation Reactions
 To understand Oxidation by using different Oxidising agent
INTRODUCTION
According to Classical or earlier concept oxidation is a process which involves the
addition of oxygen or any electronegative element or the removal of hydrogen or any
electropositive element.
According to electronic concept oxidation is defined as the process in which an atom or
ion loses one or more electrons.
02-01: Oxidation Involving AlkoxysulphoniumSalts
One the most popular of all oxidations of alcohols to aldehydes or ketones involvesthe
formation of intermediate alkoxysulfonium salts. A number of methods areavailable for
the formation of the alkoxysulfonium salts, which are treated witha base to give the
aldehyde or ketone. The conditions of the reaction are mild, the reactions proceed
rapidly and high yields of carbonyl compounds are generallyobtained.
One of the earliest procedures involved reaction of the alcohol with
dimethylsulfoxide (DMSO) and dicyclohexylcarbodiimide (DCC) in the presence of a
protonsource. This method has been used to oxidize a number of sensitive
compounds,such as 3’-O-acetylthymidine.
A disadvantage of the carbodiimide route is that the product has to be

separatedfrom the dicyclohexylurea formed in the reaction. To overcome this, a
numberof other reagents have been used in conjunction with dimethyl sulfoxide,
including acetic anhydride, trifluoroacetic anhydride, sulfur trioxide–pyridine complex,
thionyl chloride and oxalyl chloride. Best results are normally obtained with
oxalylchloride in what is called the Swern oxidation. By reaction with dimethyl
sulphoxide and oxalyl chloride, followed by treatme nt of the resulting alkoxysulfonium
saltwith a base, usually triethylamine, many different alcohols have been converted
intothe corresponding carbonyl compounds in high yield under mild conditions.
TheSwern oxidation is one of the best methods for oxidizin g alcohols; it is effectivefor

almost all types of primary and secondary alcohol, including sensitive substrates such
as allylic alcohols that give ,-unsaturated aldehydes. In addition, noenolization
typically takes place and therefore no loss of stereochemical integrityoccurs in the
formation of aldehydes that have an-chiral centre. Some examples are given in
Schemes
The reaction is believed to proceed by way of the activated complex, formedby

spontaneous loss of carbon dioxide and carbon monoxide from the oxysulfonium salt.
Displacement of chloride by the alcohol gives the alkoxysulfonium salt. This then
undergoes proton abstraction by the base to form the ylide,which fragments to the
aldehyde or ketone by an intramolecular concerted proce ss.
The reaction of dimethyl sulfoxide, oxalyl chloride and an alcohol is normallycarried

out at − 78 or –60 0 C, since the formation of the alkoxysulfonium saltis rapid at this low
temperature. After addition of the base triethylamine, themixture may be warmed to –
30 0 C or higher to promote proton abstraction andfragmentation. The use of

diisopropylethylamine instead of triethylamine as thebase or addition of pH 7 phosphate
buffer can, in the rare cases when it doesoccur, reduce the extent of enolization and
therefore minimize any racemization orrearrangement of ,  -double bonds.
02-02: Swern Oxidation

It involves the oxidationof alcohols to aldehydes or ketones (in the presence of
othergroups) by oxalyl chloride, dimethyl sulfoxide and a base (trimethylamine) at
lowtemperature. 1-Decanol, for example, is oxidised to decanal in a 56% yield under
Swernoxidation conditions. Swern initially used trifluroacetic acidin place of oxalyl
chlorideto activate DMSO for the oxidation of alcohols. The reacti on is carried out at
lowtemperature (below -30°C) in dichloromethvlene.
Mechanism
The first step is the reaction of dimethylsulfoxide with oxalyl chloride (1) to
givedimethylchlorosulfonium ion (2), a species in which the oxygen atom of DMSO has
been converted into a good leaving group. This is followed by the reaction of an alcohol
withthe dimethylchlorosulfonium ion to yield the new sulf onium ion (3). The base
abstractsthe acidic proton from the sulfonium ion;the resultin g carbanion (4) removes a
protonfrom the carbon adjacent to the oxygen to give al dehyde and dimethyl sulfide (5).
Applications

The trimethylsilyl group is removed with 5% HCl in methanol to get free
hydroxylgroups.
SOLVED PROBLEMS 01
Solution:
Problem 2:
What is the yield of the reaction?
Solution:

Que.1: Explain the mechanism of Swern oxidation?

Answer: The first step is the reaction of dimethylsulfoxide with oxalyl chloride (1) to give
dimethylchlorosulfonium ion (2), a species in which the oxygen atom of DMSO has been
converted into a good leaving group. This is followed by the reaction of an alcohol
withthedimethylchlorosulfonium ion to yield the new sulfonium ion (3). The base abstractsthe
acidic proton from the sulfonium ion;the resulting carbanion (4) removes a protonfrom the carbon
adjacent to the oxygen to give aldehyde and dimethyl sulfide (5).
Que.2: Which reagents are used in Swern oxidation?

Answer: Dimethyl sulphoxide and oxalyl chloride
02-03: Selenium Dioxide (SeO 2)

Selenium dioxide (SeO 2 ) is a white crystalline solid. It is soluble in solvents like
dioxane, ethanol, acetic acid, acetic anhydride and even in aqueous medium. SeO 2 is
extremelypoisonous and proper care should be taken while working with it. It is a very
selective oxidant.
Oxidation of allylic or benzylic compounds
SeO 2 is used primarily for the oxidation of allylic or benzylic C -H fragments to

thecorresponding allylic or benzylic alcohols. This reaction has very useful applications
asthe allylic alcohols can easily be oxidised further to the o,B-unsaturated
carbonylcompounds. The order of ease of oxidationis CH 2 > CH 3 > CH. The oxidation
occurs atthe more substituted end of the double bond.

-Pinene can be converted into trans-pinocarveol with selenium dioxide.
Mechanism
The reaction proceeds via an initial ene reaction of allylic compounds with S eO 2 togive
allylic seleninic acid (1), which undergoes a [2, 3]- sigmatropic shift to yield
(2).Hydrolysis of (2) affords the allylic alcohol. Overall, CH 3 has been replaced by
CH 2 OHin an allylic position.

In the presence of tert-butyl] hydroperoxide, only a catalyti amount of SeO 2 is
required,as the peroxide reoxidises the formed Se(II) to give back SeO 2 after each
‘cycle of thereaction. This eliminates the need to get rid of large amounts of selenium -
containing products, which are toxic.
In some cases, SeO 2 oxidation continues to give an aldehyde or ketone,
Theconversion of methylene to carbonyl group is especially easy when methylene group
isflanked by two aromatic rings. Thus, diphenylmethane yields benzophenone’
onoxidation with SeO 2 at 200-210°C. Similarly, tropone is obtained in a simple one
stepprocess.
The methyl group trans to the main chain will react rather than the cis, thus only one
[E-] isomer is formed. A useful application of this reaction is the oxidation of -
myrcene to give a mixture of the (E)-alcohol and the (E)-aldehyde.

In aromatic heterocycles, the methyl group in o -position with respect to nitrogen
areoxidised more easily. Thus, 8-ethyl-2-methylquinoline (3) gives selective
oxidationproduct, aldehyde derivative (4), when treated with SeO 2 . Similarly, 2,5-
dimethylpyridine-N-oxide (5) is converted into 5-methylpyridine-2-aldehyde-N-oxide
(6) on reaction with SeO 2 in the presence of pyridine.
Oxidation of alkynes
SeO 2 is also capable of oxidising alkynes to vicinal dicarbonyl compounds. SeO 2 with
asmall amount of H 2 SO 4 oxidises internal alkynes to a-diketones.
Thusdiphenylacetylene (7) is readily oxidised at 110°C in the presence of aqueous
acetic acid containing H 2 SO 4 to benzil (8) in 84%, Phenylacetylene (9) is oxidised
under similar conditions to phenylglyoxylic acid (benzoylformic acid) (10).
Oxidation of carbonyl compounds

A useful application of SeO 2 is the oxidation of the methyl or methylene groupadjacent
to the carbonyl group. Thus, aldehydes and ketones with a methyl or methylenegroup -
to the carbonyl group are oxidised to the 1,2 -dicarbonyl compounds.
Acetophenone, for example, is converted to phenylglyoxal in 70% yield by
warmingwith SeO 2 in aqueous dioxane. Similarly, cyclohexanone’ and acetone are
converted intocyclohexane-1,2-dione and methylglyoxal, respectively.

The method is used for the synthesis of benzils. For example, benzil is obtained by
theoxidation of phenylbenzyl ketone (deoxybenzoin) with selenium dioxide.
Camphor gives camphorquinone, an intermediate in the preparartion of Horner’s acid,

in about 90% yield with SeO 2 .
The oxidation of methylene group to carbonyl is easy if it is flanked by two

carbonylgroups. Selenium dioxide oxidises ethyl malonate directly t o ethyl mesoxalate
in 23%yield. Similarly, selenium dioxide oxidises pentane -2,4-dione to pentane-2,3,4-
trione.Indane-1,2,3-trione (ninhydrin) may be prepared by the action of SeO2 on
indane-1,3-dione.

Mechanism
The mechanism of SeO 2 reaction is not yet clear. Sharpless and Gorden proposed
thatreaction proceeds via the intermediate -ketoseleninic acid (11), formed by
electrophilicattack of selenious acid on the enol. -Ketoseleninic acid (11) undergoes a
Pummererlike rearrangement to afford 1,2-dicarbonyl compounds. Various steps are
shown below.
Another mechanism proposed involves a selenate ester intermediate (12), which

isformed by the reaction of the enol form of the carbonyl derivative with SeO 2 .
Oxidativerearrangement of (12), followed by loss of selenium and water affords the
dicarbonylcompound.

Dehydrogenation
SeO 2 is an oxidising agent but in certain cases it converts carbonyl compounds to ,-
unsaturatedcarbonyl compounds by removing hydrogen. For example, SeO 2 has
beenused to dehydrogenate 1,4-diketones and 1,2-diarylethane.
Another example of dehydrogenation with SeO; is found in the case of a 12 -ketobile

acid(13), where a 9,11-double bond is introduced. This is the key step in the synthesis
ofcortisone.
02-04: OPPENAUER O XIDATION

The reaction is the reverse of Meerwein–Ponndorf–Verley reduction. The
reaction involves the oxidation of asecondary alcohol with a ketone and a base to the
corresponding ketone of the alcohol.

Commonly used ketones are acetone, methyl ethyl ketone and cyclohexanone.
Commonly used bases are aluminium tert-butoxide, aluminium isoporpoxide, potassium
tert-butoxide, etc.
Thus, when a secondary alcohol in acetone or cyclohexanone is refluxed with

aluminium tert-butoxide in benzene or toluene solution, the secondary alcohol is
dehydrogenated to a ketone and the hydrogens are transferred to acetone or
cyclohexanone converting them to alcohols.
Primary alcohols may also be oxidized to aldehydes if aceton e is replaced by a

better hydrogen acceptor, e.g., p-benzoquinone. The equillibrium can be controlled by
the amount of acetone; an excess of which favours the oxidation of the alcohol.
Mechanism
The mechanism is the reverse of Meerwein–Ponndorf–Verley reaction. The alcohol and

aluminium tert-butoxide react to form aluminium derivative of the 2 alcohol. [Metal
alkoxides undergo rapid acid–base exchange with their corresponding alcohols.
The aluminium derivative then forms with acetone a cyclic transition state
which undergoes internalhydride ion transfer, resulting in the oxidation of the alcohol
to ketone.

Since the initial attack is on the alcoholic hydroxyl group, hindered alcoholic groups
react less readily. Thus, incyclohexanols, the axial hydroxyl groups are attacked less
readily.
Applications
1. The reagent is particularly useful for oxidizing unsaturated alcohols because it does
not affect thedouble bonds.
2. Primary unsaturated alcohols have been oxidized to aldehydes in the presence of

good hydrogenacceptors, e.g., p-benzoquinone. In some cases acetaldehyde or
cinnamaldehyde have been used.
The reaction is successful with low-boiling aldehydes which can be distilled off as it is
formed.

(c) The terminal CH 2 OHgroup of the unsaturated side chain in Vit A 1 is oxidized to
aldehyde group byusing aluminiumisopropoxide in the presence of acetaldehyde and
benzene and prolonged heatingat 70 0 C.
3. The ,-unsaturated alcohols undergo oxidation with migration of double bond to

form,-unsaturated ketones.This reaction finds numerous applications in steroid
chemistry.
4. Formates (but not acetates or benzoates) have been oxidized to ketones.
5. Alicyclic alcohols have been oxidized to alicyclic ketones.
Sensitive alcohols can be oxidized under mild conditions by using fluorenone which is
a stronghydrogen acceptor.
SOLVED PROBLEMS 02
Problem 3
Solve the following reactions
Solution:

Problem 4:
Predict the product of the following reactions.
Solution:

Que.3: Write oxidation reaction of allylic carbon with selenium dioxide. Also shows their
mechanism.
Answer:
Mechanism

Que.4: Mention application of Oppenauer oxidations?
Answer: Applications
1. The reagent is particularly useful for oxidizing unsaturated alcohols because it does not affect
the double bonds.
2. Primary unsaturated alcohols have been oxidized to aldehydes in the presence of good
hydrogen acceptors.
3. The ,-unsaturated alcohols undergo oxidation with migration of double bond to form ,-
unsaturated ketones.This reaction finds numerous applications in steroid chemistry.
4. Formates (but not acetates or benzoates) have been oxidized to ketones.
5. Alicyclic alcohols have been oxidized to alicyclic ketones.
02-05: Palladium-catalysed oxidation

The oxidation of ethene to ethanal by oxygen and a solution of a palladium(II)salt in
aqueous hydrochloric acid is an important industrial process (the Wackerreaction). The
palladium(II) is simultaneously reduced to the metal, but the reactionis made catalytic
by addition of copper(II) chloride in the presence of air or oxygen,whereby the
palladium is continuously re-oxidized to palladium (II).
The Wacker reaction has found most use for the oxidation of terminal alkenes to give
methyl ketones. It is believed to take place by an initial trans hydroxypalladation of the

alkene to form an unstable complex that undergoes rapid -elimination to the enol.
Hydropalladation then reductive elimination completesthe overall process that involves
transfer of hydride ion from one carbon to theother, via the palladium atom. The
hydride migration is required to explain theobservation that when the reaction is
conducted in deuterium oxide, no deuteriumis incorporated in the aldehyde produced.
Conversion of a terminal alkene to a methyl ketone is a useful tran sformation

inorganic synthesis. The reaction is typically carried out in aqueous DMF as
solvent,using palladium(II) chloride as a catalyst (commonly 10 mol%) with
copper(II)or copper(I) chloride and 1 atmosphere of oxygen. Copper(I) chloride is
normallypreferable as this avoids the formation of -chlorinated ketones. Many
differentfunctional groups are tolerated and the reaction is selective for the oxidation
ofterminal alkenes in the presence of di- or trisubstituted alkenes. For example, onlythe
terminal alkene is converted to a ketone on oxidation of the dienes.
The Wacker reaction provides a method for the preparation of 1,4 -

dicarbonylcompounds, by formation of an enolate, allylation with an allyl halide,

followed bypalladium-catalysed oxidation of the terminal alkene. The product 1,4-
dicarbonylcompounds can be treated with base to promote intramolecular aldol reaction
to give cyclopentenones. Thus, in asynthesis of pentalenene, Wacker oxi dation of the 2-
allyl ketone gave the 1,4-diketone, which was converted to the cyclopentenone.
Oxidation of 1,2-disubstituted alkenes occurs more slowly than that of

terminalalkenes and a mixture of the two regioisomeric products is normally formed.
Withcertain substrates, however, very high levels of regioselectiv ity have been
obtained.For example; oxidation of the allylic ether gave only the -alkoxy ketone. The
regioselectivity in oxidation reactions of unsymmetrical 1, 2-disubstituted alkenes can
be explained by electronic and neighbouring group effects,the latte r involving co-
ordination of a heteroatom or even an allylic hydrogen atomto the pallad ium atom in
the intermediate.
SOLVED PROBLEMS 03
Problem 5: Predict the product of the following reactions.

Solution:
Problem 6:How will you convert allylic ether to -alkoxy ketone?
Solution:

Que.5: What is the name of palladium catalyzed oxidation reaction?
Answer: Wacker reaction (oxidation)
Que.6: What is the use of Wacker reaction?
Answer: The Wacker reaction has found most use for the oxidation of terminal alkenes to give
methyl ketones.
02-06: Woodward Prevost reaction

Woodward and Prevost method involves the reaction of an olefin with iodine and
silveracetate. Under dry condition (absence of water) this method leads to a trans-1, 2-
diacetate (Scheme) from which the trans- diol is obtained by hydrolysis. Woodward
reaction iscarried out in the presence of water to yield the monoester of the cis- diol,
and the final hydrolysis gives the cis- diol (Scheme). The olefin is reacted with iodine
in the presence of silveracetate. Iodine reacts with the double bond to give an
iodonium ion which undergoesdisplacement by acetate in the SN 2 type reaction,
giving a trans-iodo-acetate. Anchimericassistance by the acetate group, together with
the powerful bonding capacity of silver ion foriodide, gives a cyclic acetoxonium ion
(I, Scheme) which gives a trans-1, 2-diacetate. Theacetoxonium ion, under wet
conditions traps water and reacts to yield a cis -hydroxyacetate.

The reaction (Prevost) is depicted (Scheme shown below) to show the
stereochemicalconsequences of the reaction more clearly with the chair conform ation of
cyclohexane system.
Thus in summary, both Woodward and Prevost reactions a 1, 2 -glycol is formed

from anolefin by reacting it with iodine and silver acetate. In the presence of an aprotic
solvent (Prevost-method) trans-1,2-glycols are formed. In the presence of water
(Woodward-method) the productis a cis-diol.

02-07: Dess- Martin oxidation and IBX oxidation
A popular oxidizing agent that affects rapid oxidati on of primary or secondary alcohols
to aldehydes or ketones is the Dess–Martin reagent. 38 This is the hypervalentiodine(V)
compound, prepared from 2-iodoxybenzoic acid (IBX). Both IBX and the Dess–Martin
reagent are potentially explosive and should behandled with care.
The conditions for the oxidation of alcohols us ing the Dess–Martin reagent are
particularly mild and simple, typically using CH 2 Cl 2 (or MeCN) as the solventat room
temperature. High yields of the carbonyl products are obtained, with noover -oxidation,
and the neutral conditions make this method suitable for sensitivesubstrates. For
example, of a selection of oxidizing agents, the Dess –Martin reagentwas the only one
found suitable for the oxidation of the alcohol. Thealcohol is thought to undergo ligand
exchange with the periodinane prior to theoxidation step. The reaction is effective for
substrates in which the carbonyl productsare sensitive to epimerization, elimination or
rearrangement. In addition, aminesand thioethers are tolerated. For exam ple, oxidation
of the alcohol with the Dess–
Martin reagent gave the ketone 49, used in a synthesis of perhydrohistrionicotoxin .

SOLVED PROBLEMS 04
Solution:
Problem 8: Show the mechanism of Woodward Prevost reaction.

Solution:

Que.7: What are the products formed in Woodward Prevost reaction under
(a) Dry condtion (b) in presence of water
Answer: Under dry condition (absence of water) this method leads to a trans-1, 2-diacetate from
which the trans- diol is obtained by hydrolysis. Woodward reaction is carried out in the presence
of water to yield the monoester of the cis- diol, and the final hydrolysis gives the cis- diol.
Que.8: From which compound Dess-Martin reagent is prepared?
Answer: Dess-Martin reagent is prepared from 2-iodoxybenzoic acid (IBX).
CHECK POINT 02-02

1. Product of the following reaction is

2. The product A and B in the following reactions is
3. The reaction in which the oxidation of a secondary alcohol with a ketone and a base to the
corresponding ketone of the alcohol. The reaction is called ------
(1) Meerwein–Ponndorf–Verley reduction (2) Oppenauer Oxidation
(3) Birch reduction (4) Clemmenson’s reduction
Answer: (2) Oppenauer Oxidation
4. Which reagent is used in Woodward Prevost reactions?
(1) Alkaline KMnO4 (2) Dil. H2SO4 and K2Cr2O7
(3) Hydrogen peroxide (4) Iodine and silver acetate
Answer: (4) Iodine and silver acetate
SUMMARY
According to Classical or earlier concept oxidation is a process which involves the
addition of oxygen or any electronegative element or the removal of hydrogen or any
electropositive element. According to electronic concept oxidation is defined as the
process in which an atom or ion loses one or more electrons.
A chemical reaction that takes place when a substance comes into contact with oxygen
or another oxidizing substance.

Oxidation reactions are important in the synthesis of organic compounds, because these
reactions create new functional groups or modify ex isting functional groups in
molecules.
KEY WORDS
Oxidation, electropositive
REFERENCES
MODERN METHODS OF ORGANIC SYNTHESIS, W. CARRUTHERS, Canbrige University
Press.
Reactions, Rearrangements and Reagents, Somorendra Nath Sanyal, Ph D, Bharati Bhawan
Publishers and Distributors.
Limited.
MOOCS
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WIKIPEDIA
https://www.youtube.com/watch?v=K7nSMvn99us
https://www.youtube.com/watch?v=Tb9cuj5rr60
https://www.youtube.com/watch?v=UqrUxx21-Rg
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OER
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REFERENCE BOOKS

MODERN METHODS OF ORGANIC SYNTHESIS, W. CARRUTHERS, Canbrige University
Press.
Limited.

CREDIT 02-UNIT 03: REDUCTION METHODS
LEARNING OBJECTIVES
 To understand Reduction Reactions
 To understand Reduction by using different Reducing agent
INTRODUCTION
There must be few organic syntheses of any complexity that do not involve
areduction at some stage. Reduction is used in the sense of addition of hydrogen toan
unsaturated group (such as a carbon–carbon double bond, a carbonyl group or
anaromatic ring) or addition of hydrogen with concomitant fission of a bond
betweentwo atoms (such as the reduction of a disulfide to a thiol or of an alkyl halide to
ahydrocarbon).
Reductions are generally effected either by catalytic hydrogenation or by a reducing

agent (such as lithium aluminium hydride). Complete reduction of an unsaturated
compound can generally be achieved without undue difficulty, but the aimis often
selective reduction of one group in a molecule in the presence of otherunsaturated
groups. The method of choice in a particular case will often depend onthe selectivity
required and on the stereochemistry of the desired product.
03-01: CATALYTIC HYDROGENATION

Of the many methods available for reduction of organic compounds, catalytic
hydrogenation is one of the most convenient. Reduction is carried out easily by
simplystirring or shaking the substrate with the catalyst in a suitable solvent (or
evenwithout a solvent if the substance being reduced is a liquid) in an atmosphere
ofhydrogen gas. An apparatus can be used that meas ures the uptake of hydrogen. Atthe
end of the reaction, the catalyst is filtered off and the product is recovered fromthe
filtrate, often in a high state of purity. The method is easily adapted for workon a micro
scale, or on a large, even industrial, scale. In many cases reaction proceeds smoothly at
or near room temperature and at atmospheric or slightly elevated pressure. In other
cases, high temperatures (100–200 0 C) and pressures (100–300atmospheres) are
necessary, requiring special high-pressure equipment.
Catalytic hydrogenation may result simply in the addition of hydrogen to one

ormore unsaturated groups in the molecule or it may be accompanied by fission of
abond between atoms. The latter process is known as hydrogenolysis.

Most of the common unsaturated groups in organic chemistry, such as
alkenes,alkynes, carbonyl groups, nitriles, nitro groups and aromatic rings can be
reducedcatalytically under appropriate conditions, although they are not all reduced
withequal ease. Certain groups, notably allylic and benzylic hydroxyl and amino
groupsand carbon–halogen single bonds readily undergo hydrogenolysis, resulting
incleavage of the bond between the carbon and the heteroatom. Much of the
usefulnessof the benzyloxycarbonyl protecting group (especially in pep tide chemistry)
is theresult of the ease by which it can be removed by hydrogenolysis over a palladium
catalyst. Hydrogenolysis of the CO bond gives toluene and an intermediatecarbamic
acid that loses carbon dioxide to give the deprotected amine product.
An alternative procedure that is sometimes advantageous is ‘catalytic

transferhydrogenation’, in which hydrogen is transferred to the substrate from
anotherorganic compound. The reduction is carried out simply by warming the
substrateand hydrogen donor (such as isopropanol or a salt of formic acid) together
inthe presence of a catalyst, usually palladium. Catalytic-transfer hydrogenation
canshow different selectivity towards functional groups from that shown in catalytic
reduction with molecular hydrogen.
Pd/C, PtO2, H2 /catalyst:
Many different catalysts have been used for catalytic hydrogenations; they aremainly
finely divided metals, metallic oxides or sulfides. The most commonly usedin the
laboratory are the platinum metals (platinum, palladium and, incr easingly,rhodium and
ruthenium) and nickel. The catalysts are not specific and may be usedfor a variety of
different reductions. The most widely used are pal ladium and platinum catalysts. They
are used either as the finely divided metal or, more commonly,sup ported on a suitable
carrier such as activated carbon, alumina or barium sulfate.
In general, supported metal catalysts, because they have a larger surface area,
aremore active than the unsupported metal, but the activity is influenced strongly bythe
support and by the method of preparation, and this provides a means of preparing
catalysts of varying activity. Platinum is often used in the form of its oxidePtO 2
(Adams’ catalyst), which is reduced to metallic platinum by hydrogen in thereaction

medium. For example, reduction of the dihydropyrrole 1 occurs with good selectivity
under these conditions.
Most platinum metal catalysts (with the exception of Adams’ catalyst) are
stableand can be kept for many years without appreciable loss of activity, but they
canbe deactivated by many substances, particularly by compounds of divalent
sulfur.Catalytic activity is sometimes increased by addition of small amounts of
platinumor palladium salts or mineral acid. The increase in the activity may simply be
theresult of neutralization of alkaline impurities in the catalyst.
03-02: SELECTIVITY OF REDUCTION

Many hydrogenations proceed satisfactorily under a wide range of conditions, butwhere
a selective reduction is wanted, conditions may be more critical.
The choice of catalyst for a hydrogenation is governed by the activity and

selectivity required. In general, the more active the catalyst the less discriminating it
isin its action, and for greatest selectivity reactions should be run with the least
activecatalyst and under the mildest possible conditions consistent with a reasonable
rateof reaction. The rate of a given hydrogenation may be increased by raising
thetemperature, by increasing the pressure or by an increase in the amount of catalyst
used, but all these factors may result in a decrease in selectivity. For example ,
hydrogenation of ethyl benzoate with copper chromite catalyst under the appropriate
conditions leads to benzyl alcohol by reduction of the ester group, while Raneynickel
gives ethyl cyclohexanecarboxylate by selective attack on the benzene ring. At higher
temperatures, however, the selective activity of the catalysts is lostand mixtures of the
two products and toluene are obtained from both reactions. Raney nickel is a porous,
finely divided nickel obtained by treating a powderednickel–aluminium alloy with
sodium hydroxide. Most unsaturated groups can bereduced with Raney nickel, but it is
most frequently used for reduction of aromaticrings and hydrogenolysis of sulfur
compounds. When freshly prepared, it contains25–100 ml adsorbed hydrogen per gram
of nickel. Raney nickel catalysts are alkaline and may be used only for hydrogenations
that are not adversely affected bybasic conditions. They are deactivated by acids.

Both the rate and, sometimes, the course of a hydrogenation may be influenced bythe
solvent used. The most common solvents are methanol, ethanol and acetic acid,although
other solvents can be used. Many hydrogenations over platinum metalcatalysts are
favoured by strong acids. For example, reduction of b-nitrostyrenein acetic acid–
sulfuric acid is rapid and gives 2-phenyl-ethylamine (90% yield),but in the absence of
sulfuric acid reduction is slow and the yield of amine ispoor.
Not all functional groups are reduced with equal ease. Table 1 shows
theapproximate order of decreasing ease of catalytic hydrogenation of a number
ofcommon groups. This order is not invariable and is influenced to some extent by
thestructure of the compound being reduced and by the catalyst employed. In
general,groups near the top of the list can be reduced selectively in the presence of
groupsnear the bottom. For example, reduction of an unsaturated ester or ketone to
asaturated ester or ketone is, in most cases, accomplished readily by hydrogenationover
palladium or platinum, but selective reduction of the carbonyl group to form
anunsaturated alcohol is difficult to achieve by catalytic hydrogenation and is
generallyeffected using a hydride reducing agent. Similarly, nitrobenzeneis easily
converted into aniline, but selective reduction to nitrocyclohexane is notpossible.
Hydrogenation of alkenes
Hydrogenation of carbon–carbon double bonds takes place easily and in most casescan
be effected under mild conditions. Only a few hi ghly hindered alkenes are resistant to
hydrogenation and even these can generally be reduced under more vigorousconditions.
Palladium and platinum are the most -frequently used catalysts. Bothare very active and
the preference is determined by the nature of other functionalgroups in the molecule
and by the degree of selectivity required (platinum usuallybrings about a more
exhaustive reduction). For example, the diene 3 is reduced byhydrogenation with
palladium on charcoal. Raney nickel may also be usedin certain cases. For example,
cinnamyl alcohol is reduced to 3-phenylpropan-1-ol with Raney nickel in ethanol at
20 0 C. Hydrogenation of alkenes is oftenaccompanied by concomitant hydrogenolysis of
sensitive benzyl ethers, such as N-CO 2 Bn (N-Cbz) groups. A few different conditions
can be employed to minimizehydrogenolysis, such as the addition of ethylenediamine
(en) and THF as solvent, as illustrated in the reduction of the alkene 4.

Rhodium and ruthenium catalysts may alternatively be used and sometimesshow
useful selective properties. Rhodium allows hydrogenation of alkenes
withoutconcomitant hydrogenolysis of an oxygen function. For example, hydrogenation
ofthe plant toxin, toxol5 over rhodium–alumina gave the dihydro compound 6with
platinum or palladium catalysts, however, extensive hydrogenolysis too k placeand a
mixture of products was formed.
The ease of reduction of an alkene decreases with the degree of substitutionof

the double bond, and this sometimes allows selective reducti on of one double bond in a
molecule which contains several. For example, limonene 7 can beconverted into p-
menthene (by reduction of the terminal alkene) in almost quantitative yield by
hydrogenation over platinum oxide if the reaction is stopped afterabsorption of one
molar equivalent of hydrogen. In contrast, the isomeric diene 8, in which both double
bonds are disubstituted, gives only the completely reduced product.
Selective reduction of carbon–carbon double bonds in compounds

containingother unsaturated groups can usually be accomplished, except in the
presenceof triple bonds, aromatic nitro groups and acyl halides. Palladium is usually the

best catalyst. For example, 2-benzylidenecyclopentanone 9 is readily convertedinto 2-
benzylcyclopentanone 10 with hydrogen and palladium in methanol;with a platinum
catalyst, benzylcyclopentanol is formed. Unsaturated nitriles andnitro compounds are
also reduced selectively at the double bond with a palladiumcatalyst.
SOLVED PROBLEMS 01
Problem 1: Write the Possible products of the following reaction.
Solution:
Problem 2: Predict the product of the following reaction.
Solution:

Que.1: Mention the different catalyst used in the hydrogenation.
Answer: Nickel, Platinum or Palladium.
Que.2: Write few words about Platinum calayst?
Answer: Most platinum metal catalysts (with the exception of Adams’ catalyst) are stable and
can be kept for many years without appreciable loss of activity, but they can be deactivated by
many substances, particularly by compounds of divalent sulfur. Catalytic activity is sometimes
increased by addition of small amounts of platinum or palladium salts or mineral acid. The

increase in the activity may simply be the result of neutralization of alkaline impurities in the
catalyst.
03-03: STEREOCHEMISTRY AND MECHANISM

Hydrogenation of an unsaturated compound takes place by adsorption of the compound
on to the surface of the catalyst, followed by transfer of hydrogen fromthe catalyst to
the side of the molecule that is adsorbed on it. Adsorption onto thecatalyst is largely
controlled by steric factors, and it is found in general that hydrogenation takes place by
cis addition of hydrogen atoms to the less-hindered side ofthe unsaturated centre.
For example, hydrogenation of the E-alkene 11 gives the racemic dihydro

compound 12 by cis addition of hydrogen, while the Z-alkene 13 gives the meso
isomer14. Hydrogenation of the pinene derivative 15 and of the ketone 17 gave
products formed by cis addition of hydrogen to the more accessible side of the double
bonds. In these examples the molecule possesses a certain degree of rigidity and it is
clear which the less hindered face of the double bond is with more-flexible molecules, it
may be more difficult to decide on which side the molecule will bemore easily adsorbed
on the catalyst and to predict the steric course of a hydrogenation. In some cases, the
affinity of a particular substituent group for the catalystsurface may induce addition of
hydrogen from its own side of the molecule. The CH 2 OH group can be effective in this
respect. Thus, predominant cis additionof hydrogen to the alkene 18 occurs when
RCH 2 OH, but trans addition whenRCO 2 Me.

The hydrogenation of substituted cyclic alkenes is anomalous in many casesin that
substantial amounts of trans-addition products are formed, particularly with palladium
catalysts. For example, the alkene 19 on hydrogenation over palladium in acetic acid
gives mainly trans-decalin, and thealkene 1,2-dimethylcyclohexene 20gives variable
mixtures of cis- and trans-1,2-dimethylcyclohexane depending on the conditions.
Similarly, in the hydrogenation of the isomeric dimethylbenzenes (xylenes) over
platinum oxide, the cis-dimethylcyclohexanes are the main products, but some trans
isomer is alwaysproduced.
The reason for the formation of the trans products is thought to be becauseof
migration of the double bond in a partially hydrogenated product on the catalyst
surface. Although catalytic hydrogenation of alkenes may be accompaniedby migration
of the double bond, no evidence of migration normally remains oncompletion of the
reduction. Sometimes, however, a tetrasubstituted double bondis formed whi ch resists
further reduction.

A satisfactory mechanism for catalytic hydrogenation must explain not only
thenormal cis-addition of hydrogen, but also that alkenes may be isomerized, thattrans -
addition products are formed in some hydrogenations, and the obs ervationthat
deuteration of an alkene often leads to products containing more or fewer thantwo
atoms of deuterium per molecule. These results can be rationalized on thebasis of a
mechanism in which transfer of hydrogen atoms from the catalyst tothe adsorbe d
substrate takes place in a stepwise manner. The process is thoughtto involve equilibria
between p-bonded forms 21 and 22 and a half hydrogenatedform 23, which can either
take up another atom of hydrogen (to give the reducedproduct 24) or revert to starting
material or to an isomeric alkene 25.
Hydrogenation of alkynes
Catalytic hydrogenation of alkynes takes place in a stepwise manner, and both

thealkene and the alkane can be isolated. Complete reduction of alkynes to the
saturatedcompound is easily accomplished over platinum, palladium or Raney nickel.
Acomplication which sometimes arises, particularly with platinum catalysts, is
thehydrogenolysis of hydroxyl groups - to the alkyne (propargylic hydroxyl groups).
More useful from a synthetic point of view is the partial hydrogenation of alkynesto Z-
alkenes. This reaction can be effected in high yield with a palladium –calciumcarbonate
catalyst that has been partially deactivated by addition of lead acetate(Lindlar’s
catalyst) or quinoline. It is aided by the fact that the more electrophilicalkynes are

absorbed on the electron-rich catalyst surface more strongly than thecorresponding
alkenes. An important feature of these reductions is their high stereoselectivity. In most
cases the product consists very largely of the thermodynamically less stable Z-alkene
and partial catalytic hydrogenation of alkynes providesone of the most convenient
routes to Z-1,2-disubstituted alkenes. Thusstearolicacid 26, on reduction over Lindlar’s
catalyst, gives oleic acid 27. Partialreduction of alkynes with Lindlar’s catalyst has
been invaluable in the synthesis ofmany natural products with Z -disubstituted double
bonds.
Hydrogenation of aromatic compounds
Reduction of aromatic rings by catalytic hydrogenation is more difficult than that

ofmost other functional groups, and selective reduction is not easy. The
commonestcatalysts are platinum and rhodium, which can be used at ordinary
temperatures, and Raney nickel or ruthenium, which requires high temperatures and
pressures.Benzene itself can be reduced to cyclohexane with platinum oxide in
aceticacid solution. Derivatives of benzene such as benzoic acid, phenol or aniline
arereduced more easily. For large scale work, the most convenient method is
0
typicallyhydrogenation over Raney nickel at 150–200 C and 100–200 atm. The
catalystrhodium, absorbed on alumina, can be used under mild conditions.
Hydrogenations of phenols, followed by oxidation of the resulting cyclohexanols are a
convenientmethod for the preparation of substituted cyclohexanones. The product
28was formed by hydrogenation at 55 atm, followed by oxidation with Jones reagent.A
small amount (10–15%) of the trans compound was also formed.
Reduction of benzene derivatives carrying oxygen or nitrogen functions in

benzylic positions is complicated by the easy hydrogenol ysis of such groups,
particularly over palladium catalysts. Preferential reduction of the benzene ring inthese
compounds is best achieved with ruthenium or rhodium catalysts, which canbe used

under mild conditions. For example, mandelic acid is readily convertedinto the
cyclohexyl derivative 29 over rhodium–alumina, whereas with palladium,
Hydrogenolysis to phenylacetic acid is the main reaction.
With polycyclic aromatic compounds, it is often possible, by varying the

conditions, to obtain either partially or completely reduced products. Naphthalene can
beconverted into the tetrahydro or decahydro co mpound over Raney nickel depending
on the temperature. With anthracene and phenanthrene, the 9,1 0-dihydro compounds
are obtained by hydrogenation over copper chromite although, in general,aromatic rings
are not reduced with this catalyst. To obtain more -fully hydrogenatedcompounds, more-
active catalysts must be used.
Hydrogenation of aldehydes and ketones
Hydrogenation of the carbonyl group of aldehydes and ketones is easier than thatof
aromatic rings, but not as easy as that of most carbon –carbon double bonds.Selective
hydrogenation of a carbonyl group in the presence of carbon –carbondouble bonds is, in
most cases, best effected with hydride reducing agents.
For aliphatic aldehydes and ketones, reduction to the alcohol can be carried
outunder mild conditions over platinum or the more -active forms of Raney
nickel.Ruthenium is also an excellent catalyst for re duction of aliphatic aldehydes
andcan be used to advantage with aqueous solutions. Palladium is not very active
forhydrogenation of aliphatic carbonyl compounds, but is effective for the reductionof
aromatic aldehydes and ketones; excellent yields of the a lcohols can be obtainedif the
reaction is interrupted after absorption of one mole of hydrogen. Prolongedreaction,
particularly at elevated temperatures or in the presence of acid, leads tohydrogenolysis
and can therefore be used as a method for the reduct ion of aromaticketones to
methylene compounds.
Asymmetric reduction of ketones by catalytic homogeneous hydrogenation

canbe carried out with very high selectivity in many cases and is described below.

Hydrogenation of nitriles, oximes and nitro compounds
Functional groups with multiple bonds to nitrogen are readily reduced by

catalytichydrogenation. Nitriles, oximes, azides and nitro compounds, for example, are
allsmoothly converted into primary amines. Reduction of nitro compounds takes
placeeasily and is generally faster than reduction of alkenes or carbonyl groups.
Raneynickel or any of the platinum metals can be used as the catalyst and the choice
isgoverned by the nature of other functional groups in the molecule. Thus 2 -phenyl-
ethylamines, important biologically active molecules and useful for the synthesis
ofisoquinolines, are conveniently obtained by catalytic reduction of ,-unsaturated
nitro compounds.
Nitriles are reduced with hydrogen and platinum or palladium at room

temperature, or with Raney nickel under pressure. Unless precautions are taken,
however,large amounts of secondary amines may be formed in a side reaction of the
aminewith the intermediate imine.
With the platinum-metal catalysts, this reaction can be suppressed by

conductingthe hydrogenation in acid solution or in acetic anhydride, which removes the
aminefrom the equilibrium as its salt or as its acetate. For reactions with Raney
nickel,where acid cannot be used, secondary amine formation is prevented by addition
ofammonia. Hydrogenation of nitriles containing other functional groups may leadto
cyclic compounds. For example, indolizidine and quinolizidine derivatives havebeen
obtained in certain cases.

Reduction of oximes to primary amines takes place under conditions simila r tothose
used for nitriles, with palladium or platinum in acid solution, or with Raneynickel
under pressure.
Wilkinson’s catalyst
Catalysts for heterogeneous hydrogenation of the types discussed above,

althoughuseful, have some disadvantages. They may sho w lack of selectivity when
more thanone unsaturated centre is present, or cause double -bond migration and, in
reactionswith deuterium, they often bring about allylic interchanges with deuterium.
This,in conjunction with double-bond migration, results in unspecific labelling with
inmany cases introduction of more than two deuterium atoms. The stereochemistryof
reduction may not be easy to predict, since it depends on chemisorption and noton
reactions between molecules. Some of these difficulties have been over come bythe
introduction of soluble catalysts, which allow hydrogenation in homogeneous solution.
A number of soluble-catalyst systems have been used, but the most common
arebased on rhodium and ruthenium complexes, such as [(Ph 3 P) 3 RhCl]
(Wilkinson’scatalyst) and [(Ph 3 P) 3 RuClH].
Wilkinson’s catalyst is an extremely efficient catalyst for the

homogeneoushydrogenation of non-conjugated alkenes and alkynes at ordinary
temperatureand pressure. Functional groups such as carbonyl, cyano, nitro an d chloro
are notreduced under these conditions. Mono- and disubstituted double bonds are
reducedmuch more rapidly than tri- or tetrasubstituted ones, permitting the partial
hydrogenation of compounds containing different kinds of double bonds. For
example,in the reduction of linalool 30, addition of hydrogen occurred selectively at
thevinyl group, giving the dihydro compound 31 in high yield, and carvone 32was
similarly converted into the ketone 33. The selectivity of the catalyst isshown further
by the reduction of b-nitrostyrene to 2-phenyl-nitroethane.

Hydrogenations take place by cis addition to the double bond. This has beenshown by
the catalysed reaction of deuterium with maleic acid to form meso -dideuterosuccinic
acid, while fumaric acid gave the racemic compound.
An important practical advantage of this catalyst in addition to its selectivity

isthat deuterium is introduced without scrambling; that is, only two deuterium atomsare
added, at the site of the original double bond. Another very valua ble featureof this
catalyst is that it does not bring about hydrogenolysis, thus allowing theselective
hydrogenation of carbon–carbon double bonds without hydrogenolysisof other
susceptible groups in the molecule. For example, benzyl cinnamate isconverted
smoothly into the dihydro compound without attack on the benzyl estergroup and allyl
phenyl sulfide is reduced to phenyl propyl sulfide.
Wilkinson’s catalyst has a strong affinity for carbon monoxide and

decarbonylates aldehydes, therefore alkene compounds containing aldehyde groups
cannotnormally be hydrogenated with this catalyst under the usual conditions. For
example, cinnamaldehyde is converted into styrene in 65% yield, and benzoyl
chloridegives chlorobenzene in 90% yield.
Addition of hydrogen to Wilkinson’s catalyst promotes oxidative addition

ofhydrogen. Dissociation of a bulky phosphine ligand and co -ordination of the alkeneis
followed by stepwise stereospecific cis transfer of the two hydrogen atoms fromthe
metal to the alkene by way of an intermediate with a carbon–metal bond.Diffusion of
the saturated substrate away from the transfer site allows the releasedcomplex to
combine with dissolved hydrogen and repeat the catalytic reductioncycle.

The ruthenium complex [(Ph 3 P) 3 RuClH], formed in situ from [(Ph 3 P) 3 RuCl 2 ]and
molecular hydrogen in the presence of a base (such as Et 3 N), is an even more-efficient
catalyst, which is specific for the hydrogenation of monosubstituted alkenes RCH=CH 2 .
Rates of reduction for other types of alkenes are slower by a factor of at least 2 × 10 3 .
Thus 1-heptene was rapidly converted into heptane but 3 -heptenewas unaffected. Some
isomerization of alkenes is observed with this catalyst butthe rate is slow compared
with the rate of hydrogenation. The catalyst allows theconv ersion of disubstituted
alkynes into Z-alkenes. Very similar behaviour is shownby the rhodium complex
[(Ph 3 P) 3 RhH(CO)].
Hydrogenations with [(Ph 3 P) 3 RuClH] and [(Ph 3 P) 3 RhH(CO)] are two-step processes
which proceed by the reversible formation of a metal –alkyl intermediate.The high
selectivity for reduction of terminal double bonds is attributed to sterichindrance by the
bulky Ph 3 P groups to the formation of the metal–alkyl intermediatewith other types of
alkenes.
SOLVED PROBLEMS 02
Problem 3: Out of the following two reactions, find out hydrogenation and hydrogenolysis
reaction?
Solution:

Problem 4: Write the reaction of hydrogenation of the following compound using palladium
in acetic acid.
Solution:

Que.3: From which side the addition of hydrogen takes place across the double bond?
Answer: The addition of hydrogen across the double takes place by cis addition to the less-
hindered side of the unsaturated centre.
Que.4: What is hydrogenolysis?
Answer: Hydrogenolysis process involves the addition of hydrogen followed by bond rupture.
03-04: BORANE AND HYDROBORATION REACTIONS

Borane, BH 3 (which exists as the gaseous dimer diborane B 2 H 6 ) is a powerfulreducing
agent and attacks a variety of unsaturated groups. It can be preparedby reaction of
boron trifluoride etherate with sodium borohydride, but for mostpurposes the
commercially available solutions as complexes with tetrahydrofuranor dimethyl sulfide
are suitable. The latter, BH 3 ·SMe 2 , has the advantage that it isstable and is soluble in
several organic solvents. The use of complexes of boranewith amines is becoming
increasingly popular and these have lower sensitivity toair and moisture.
Reaction of borane with unsaturated groups takes place readily at room

temperature and the products are isolated in high yield after hydrolysis of the
intermediateboron compound. Borane reacts rapidly with water, and reactions must be
effectedunder anhydrous conditions and preferably under inert atmosphere since
boranemay ignite in air.
Reductions with borane do not simply parallel those with sodium

borohydride.This is because sodium borohydride is a nucleophile and reacts by addition
ofhydride ion to the more-positive end of a polarized multiple bond, whereas boraneis a

Lewis acid and attacks electron-rich centres. For example, whereas sodiumborohydride
very rapidly reduces acid chlorides to primary alcohols, the reactionbeing facilitated by
the electron-withdrawing effect of the halogen, borane does notreact with acid chlorides
under the usual mild conditions. Reduction of carbonylgroups by borane takes place by
addition of the electron-deficient borane to theoxygen atom, followed by the
irreversible transfer of hydride ion from boron to carbon. The inertness of acid
chlorides can be ascribed to the decreased basicproperties of the carbonyl oxygen atom
resulting from the electron-withdrawingeffect of the halogen atom. For a similar reason
esters are reduced only slowly byborane.
A useful reaction of borane is the reduction of carboxylic acids to alcohols ,

which occurs very readily and can be achieved selectively in the presence of
otherfunctional group, including esters. For example, 4-nitrobenzoic acid is reducedto
4-nitrobenzyl alcohol in 79% yield, and the carboxylic acid 103 is reduced tothe
alcohol 104 in the presence of the less reactive ester group. A reduction of carboxylic
acid is believed to proceed by way of a triacyloxyborane, the carbonylgroups of whic h
are reduced rapidly by further reaction with borane.
Carboxylic amides and lactams are good functional groups for reduction
byborane and this provides a method for the formation of amines. Borane, beingelectron
deficient, reacts fastest with the most -nucleophilic carbonyl group. It is therefore
possible to carry out selective reduction of carboxylic amides in the presence of other
unsaturated groups such as esters. For example, the amide 105 was reduced to the
amine 106. In comparison, the reducing agent lithium aluminium hydride reduces both
the carboxylic amide and the ester groups of thecompound 105.

Reduction of aldehydes and ketones is possible with borane.
Stereoselectivereduction of ketones is possible when a heteroatom is located -or - to
the carbonylgroup. Treatment of a b-hydroxy-ketone with catecholborane results in the
selectiveformation of the syn 1,3-diol product. The borane reacts preferentially withthe
alcohol to release hydrogen gas and to form the boronic ester 107. A secondequivalent
of the borane then effects the reduction to give the syn diastereomer. Forthe preparation
of the anti diastereomer, triacetoxyborohydride can be used.
In another example, stereoselective reduction of a -phenylsulfonyl ketones

wasaccomplished to give predominantly the anti diastereomer by using borane (as
itscomplex with pyridine) together with titanium tetr achloride, but the syn diastereomer
by using lithium triethylborohydride. It is thought that chelation ofthe carbonyl and a
sulfonyl oxygen atom by the titanium (IV) in a non-polar solvent promotes subsequent
reduction by borane to give the anti-product, whereasthe non-chelating condition
(Felkin–Anh model) with cerium (III) gives the synproduct. Other diastereoselective
reductions, such as of -alkyl--keto-esters togive syn or anti a-alkyl-b-hydroxy esters,
have been reported.
The reduction of epoxides with borane is noteworthy as it gives rise to theless

substituted alcohol as the major product, in contrast to reduction with complexhydrides.
The reaction is catalysed by small amountsof sodium or lithium borohydride and high
yields of the alcohol are obtained. With1-alkylcycloalkene epoxides, the 2-
alkylcycloalkanols produced are entirely cis,and this reaction thus complements the
hydroboration–oxidation of cycloalkenes, which leads to trans products. Reaction with
borane inthe presence of boron trifluoride has also been used for the reduction of
epoxidesand for the conversion of lactones and some esters into ethers.

Reduction of unsymmetrical ketones generates a new chiral centre. Chiral
alcohols are present in a vast number of natural produ cts and biologically active
compounds and there are many reports of the enantioselective reduction of ket ones.
High selectivities have been achieved by using hydrid e reducing agents such aslithium
aluminium hydride in the presence of chiral ligands such as BINOL (2,2 ′ -binaphthol),
or chiral organoborane reagents. For example, reduction of the ketone108 with
diisopinocampheylchloroborane, (Ipc) 2 BCl, gave the chiral alcohol 109with high
enantioselectivity. The reaction proceeds by co-ordination of theketone to the borane to
give the complex 110, with the larger group R L (such asaryl) on the less-hindered side,
followed by transfer of hydride predominantly toone face of the carbonyl group.
A more-efficient method for asymmetric reduction uses the chiral inducing

agentas a catalyst. A suitable system involves the oxazab orolidine 111, which can be
prepared from the corresponding amino-alcohol and methylboronicacid, or is available
commercially in either enantiomeric form. Addition of borane to thisreagent provides
the active reducing agent 112. The oxazaborolidine 111 enhancesthe rate of reduction of
ketones with borane (or catecholborane) and can be usedas a catalyst in
substoichiometric amounts. Very high levels of enantioselectivityin the reduction are
obtained with a wide selection of ketones.

The mechanism for the reduction involves the oxazaborolidine 111 acting as
aLewis acid for the ketone, with co-ordination of the carbonyl oxygen atom to theboron
atom on the less-hinderedexo face of the bicyclic molecule. This activatesthe ketone for
reduction. The borane is activated by binding to the nitrogen atom, which also occurs
on the exo face and so is in close proximity to the carbonyl group. The ketone adopts
the least-congested conformation and transfer ofhydride then takes place to the
carbonyl group. Dissociation of the product 113 togive the boronate R 2 CHOBH 2 (which
is hydrolysed to the alcohol on work-up)releases the catalyst 111 for further reaction.
Sodium Borohydride (NaBH 4 )
Sodium borohydride is less reactive than lithiumaluminium hydride and is

therefore more discriminating (chemoselective) in its action. It reacts only slowly
withwater and most alcohols at room temperature and reductions with this reagentare
often effected in ethanol solution. At room temperature in ethanol it readilyreduces

aldehydes and ketones but it does not generally attack esters or amides andit is
normally possible to reduce aldehydes and ketones selectively with sodiumborohydride
in the presence of a variety of other functional groups. For example,ethyl acetoacetate,
which contains both an ester and a ketone functional group,on reduction with sodium
borohydride gives ethyl 3-hydroxybutanoate, the product from selective reduction of
only the keto group. In contrast, the morereactive lithium aluminium hydride gives 1,3 -
butanediol, by reduction of both carbonyl groups. To effect selective reduction of the
ester, the keto group must beprotected as its acetal, and the ester reduced with lithium
aluminium hydride. Mildacid hydrolysis then regenerates the ketone to give the keto -
alcohol.
The reducing properties of sodium borohydride are substantially modified in

thepresence of metal salts, and particularly useful in this respect are lanthanide salts.In
the presence of cerium(III) chloride, for example, sodium borohydride reduces ,-
unsaturated ketones with extremely high selectivity, such that 1,2 - and almostno 1,4-
reduction occurs to give allylic alcohols. This reagent system has thereforefound some
use for the formation of allylic alcohols from ,-unsaturated ketonesthat otherwise
lead to reduction of the carbon–carbon double bond as well. Incomparison, sodium
borohydride in alcoholic solvent effects conjugate reductionof ,-unsaturated esters or
lactones. Remarkably, sodium borohydride–CeCl 3 candiscriminate between different
ketone and aldehyde groups, effecting the selectivereduction of the less -reactive
carbonyl group. For example, ,-unsaturated ketonesare reduced selectively in the
presence of saturated ketones or aldehydes. Ketonescan be sometimes be reduced in th e
presence of an aldehyde. It is believedthat, under the reaction conditions, the more -
reactive aldehyde group is protectedas the hydrate, which is stabilized by complexation
with the cerium ion, and isregenerated during isolation of the product.

Selective reduction of aldehydes in the presence of ketones can be effectedwith
tetra-n-butylammonium triacetoxyborohydride and other reagents. Althoughlithium
aluminium hydride is used most commonly for the reduction of carboxylicesters,
sodium borohydride can provide some useful selectivity and its reactivityis enhanced in
the presence of metal salts. For example, reduction of carboxylicesters in the presence
of carboxylic amides is possible using sodium borohydrideand calcium chloride.
The use of solid-supported reagents is gaining in popularity, mostly because

oftheir ease of use and the ability to purify the product by simple filtration rather
thancolumn chromatography. For example, borohydride supported on amberlyst
wasused for the reduction of the ketone 79 to give the alcohol 80, which was
furthertransformed into the alkaloid epibatidine.
Sodium cyanoborohydride (NaBH 3 CN) and sodium triacetoxyborohydride

[NaBH (OAc) 3 ]
A number of reagents derived from sodium borohydride by replacement of one ormore

of the hydrogen atoms by other groups allow more-selective reduction thanwith sodium

borohydride itself. Among the most useful are sodium cyanoborohydride and sodium
triacetoxyborohydride.
Sodium cyanoborohydride is a weaker and more -selective reducing agent

thansodium borohydride because of the electron-withdrawing effect of the cyano
group.It has the further advantage that it is stable in acid to pH = 3 and can be
employedto effect reductions in the presence of functional groups that are sensitive to
themore-basic conditions of reduction with sodium borohydride.
Aldehydes and ketones are unaffected by sodium cyanoborohydride in

neutralsolution, but they are readily reduced to the corresponding alcohol at pH = 3 –4
byway of the protonated carbonyl group. By previous exchange of t he hydrogens ofthe
borohydride for deuterium or tritium, by reaction with D 2 O or tritiated water,an
efficient and economical route is available for deuteride or tritiide reduction
ofaldehydes and ketones.
Iminium groups are more easily reduced than carbonyl groups in acid
solution,and this has been exploited in a method for reductive amination of aldehydes
andketones by way of the iminium salts formed from the carbonyl compounds anda
primary or secondary amine, typically at pH > 5 (7.83); at this pH the carbonyl
compounds themselves are unaffected. Some examples of reductive amination using
sodium cyanoborohydride or sodium triacetoxyborohydride are given in the following
Schemes. Improvement in the yield of the amine product can sometimesbe obtained by
addition of titanium (IV) salts such as Ti(O i -Pr) 4 .

Reductive amination with formaldehyde and sodium cyanoborohydride
providesa convenient method for methylation of a secondary amine (or dimethylation of
aprimary amine). An alternative procedure uses for maldehyde together with formicacid
(HCOOH) as the source of hydride in what is termed the Eschweiler–Clarkreaction.
Deprotonation of formic acid provides the formate anion, which delivershydride to the
iminium ion with concomitant formation of carbon dioxi de.Reductive amination of an
aldehyde or ketone with ammonia or a primary aminecan sometimes be problematic, as
the product amine can undergo further reductiveamination with the starting carbonyl
compound. One method that promotes selectiveformation of pri mary amines uses the
rhodium (III) complex [RhCp*Cl 2 ] 2 as acatalyst and ammonium formate (HCOONH 4 ),
which acts as the source of the ammonia and the hydride.
Sodium triacetoxyborohydride can reduce aldehydes selectively in the

presenceof ketones. However, -and -hydroxy-ketones are reduced with this reagent.
The reduction occurs stereoselectively to give predominantly the anti diol product. The
reagent tetramethyl ammonium triacetoxy borohydride Me 4 NBH(OAc) 3 has shown
excellent selectivity for this transformation. Exchange of one of the acetoxy groups for
the alcohol is thought to preceed stereoselective intramolecular transfer of hydride.
A method for the conversion of carbonyl compounds into the corresponding

hydrocarbons involves reduction of the derived toluene -p-sulfonyl (tosyl) hydrazones
with sodium cyanoborohydride in acidic dimethylformamide (DMF). There action is
specific for aliphatic carbonyl compounds; aromatic compounds are normally
unaffected. The tosyl hydrazone need not be isolated but can be prepared and reduced
in situ. For example, the ketone 97 was reduced to the alkane 98.

With,-unsaturated carbonyl compounds, reduction of the tosyl h ydrazone
isaccompanied by migration of the double bond. Thus, cinnamaldehyde tosyl hydrazone
gives 3-phenyl-1-propene in 98% yield and the a,b-unsaturated ketone 99gives the
alkene 100. The mechanism for this reaction involves reductionof the iminium ion to
the tosylhydrazine101, elimination of p-toluenesulfinic acidand subsequent [1,5]-
sigmatropic shift of hydrogen, with loss of nitrogen, to therearranged alkene.
Lithium aluminium hydride
A number of metal hydrides have been employed as reducing agents in

organicchemistry, but the most commonly used are lithium aluminium hydride and
sodiumborohydride, both of which are commercially avai lable. These reagents are
nucleophilic and as such they normally attack polarized multiple bonds such as C =Oor
C N by transfer of hydride ion to the more-positive atom. They do not usuallyreduce
isolated carbon–carbon double or triple bonds.
With both reagents all four hydrogen atoms may be used for reduction,
beingtransferred in a stepwise manner. For reductions with lithium aluminiumhydride,
each successive transfer of hydride ion takes place more slowly than theone before, and
this has been exploited for the preparation of modified reagentsthat are less reactive and

more selective than lithium aluminium hydride itself (fore xample, by replacement of
two or three of the hydrogen atoms of the anion byalkoxy groups).
Lithium aluminium hydride is a more powerful reducing agent than

sodiumborohydride and reduces most of the commonly encountered organic functional
groups. It reacts readily with water and other compounds that contain active hydrogen
atoms and must be used under anhydrous conditions in anon -hydroxylic solvent; diethyl
ether and THF are commonly employed. Lithiumaluminium hydride has found
widespread use for the reduction of carbonyl compounds. Aldehydes, ketones, esters,
carboxylic acids and lactones can all be reducedsmoothly to the corresponding alcohols
under mild conditions. Carboxylic amidesare converted into amines or aldehydes,
depending on the conditions and on the type of N–substitution.
Some examples of the use of lithium aluminium hydrideare given in the following
Scheme.

Anexceptiontothegeneralrulethatcarbon–carbondoublebondsarenotattackedby
hydride reducing agents is found in the reduction of -aryl-,-unsaturatedcarbonyl
compounds with lithium aluminium hydride, where the carbon –carbondouble bond is
often reduced as well as the carbonyl group. Even in thesecases, however, selective
reduction of the carbonyl group can generally be achievedby working at low
temperatures or by using sodium borohydride, alane (AlH 3 ,formed from lithium
aluminium hydride and aluminium chloride) or most commonly DIBAL-H
(diisobutylaluminium hydride). This type of reduction of thedouble bond of allylic
alcohols is thought to proceed through a cyclic organoaluminium intermediate 77, for it
is found experimentally that only one of the twohydrogen atoms added to the double
bond is derived from the hydride, and acidification with a deuterated solvent leads to
the deuterated alcohol 78. A similartype of aluminium compound is thought to be
involved in the reduction of the triplebond of propargylic alcohols (R C CCH 2 OH)
with lithium aluminium hydrideto give trans alkenes.
Diisobutylaluminium hydride (DIBAL-H)
Diisobutylaluminium hydride (DIBAL-H or DIBAL, i Bu 2 AlH) is a very usefulderivative

of aluminium hydride and is available commercially as a solution in avariety of
solvents. At ordinary temperatures, esters and ketones are reduced toalcohols, nitriles
give amines and epoxides are cleaved to alcohols. However, it is particularly useful for
the preparation of aldehydes. At low temperatures, estersand lactones are reduced
directly to aldehydes (or lactols); nitriles and carboxylicamides give imines which are
readily converted into the aldehydes by hydrolysis. The lack of further reduction of the
aldehyde lies in the relative stabilityof the intermediate hemiacetal (or imine salt),
which hydrolyses to the aldehydeonly upon work -up.

Diisobutylaluminium hydride has found considerable use for the selective 1,2 -
reduction of ,-unsaturated carbonyl compounds to allylic alcohols. For example,the
ester 95 was reduced to the allylic alcohol 96. The reagent has also founduse for the
reduction of alkynes to cis-alkenes.
Section text starts here with detail elaboration of the concepts to be covered from the
syllabus.
SOLVED PROBLEMS 03
Problem 5: Solve the following reactions
Solution:

Problem 6: Predict product of the following reactions
Solution:

Que.5: How is borane is prepared?
Answer: Borane can be prepared by reaction of boron trifluoride etherate with sodium
borohydride.
Que.6: What is the use of sodium borohydride?
Answer: Sodium hydride is used for the reduction of aldehydes and ketone functional groups in
the presence of a variety of other functional groups.
03-05: Reductions with trialkylsilanes

The addition of R 3 SiH to unsaturated substrates is a useful method of reduction insome
cases, and is also an important route to complex organosilanes. Addition canbe brought
about under catalytic or ionic conditions.

Silanes will reduce a variety of functional groups in the presence of transition -
metal catalysts. Alkynes undergo cis-addition to give vinylsilanes, ketones givesilyl
ethers of the corresponding secondary alcohols and aromatic imines are readily reduced
to amines. A useful reaction is the conversion of acid chlorides orthioesters into
aldehydes, which provides an alternative to the Rosenmund reduction (hydrogenolysis
of acid chlorides with palladium on barium sulfate) or reduction with complex hydrides.
For example, reduction of octanoyl chloride gave octanal, and the thioester 128 gave
the aldehyde 129 in highyield without racemization or reduction of the ester or
carbamate carbonyl groups. It is possible, however, to reduce carboxylic esters and
lactones to thecorresponding ethers by using triethylsilane in the presence of TiCl 4 and
TMSOTf.
The reduction of a,b-unsaturated aldehydes or ketones with trialkylsilanes

hasproved a valuable reaction for the regioselective preparation of silyl enol
ethers.Wilkinson’s catalyst [(Ph 3 P) 3 RhCl] is suitable to promote the reaction and
subsequent hydrolysis provides the saturated carbonyl compound, as illustrated by the
selective reduction of the a,b-unsaturated ketone 130 in the presence of an isolated
carbon–carbon double bond. The intermediate silyl enol ether may be used for further
functionalization by reaction with other electrophiles.
An alternative to trialkylsilane reduction of ,-unsaturated aldehydes or

ketonesis the use of copper hydride complexes, such as [Ph 3 PCuH] 6 (Stryker’s
reagent). This reagent promotes efficient conjugate reduction, and can be used as a
catalystin the presence of stoichiometric reductants such as silyl hydrides (e.g.
PhMe 2 SiH). Copper hydride complexes can be prepared by reduction of various copper

(I) salts with mild reducing agents. Recently, asymmetric reduction has be en achieved
with the chiral ligand (S)-p-Tol-BINAP, with formation of the chiral ligand -
complexedcopper hydride from CuCl and the polymeric redu cing agent
polymethylhydrosiloxane (PMHS).
Polymethylhydrosiloxane (PMHS) is easy to handle and is finding increasing

popularity as a reducing agent. For example, in the presence of catalytictris
(pentafluorophenyl) borane, B(C 6 F 5 ) 3 , it is effective for the reduction of ketones(both
aromatic and aliphatic) to the corresponding methylene compounds at room
temperature.
Ionic hydrogenation with silanes can be accomplished in the presence of anacid

or Lewis acid. For example, a combination of triethylsilane and trifluoroaceticacid
(TFA) provides a non-catalytic method for hydrogenation of C=C, C=O andC=N double
bonds and for hydrogenolysis of some single bonds (such as C Bror benzylic COH).
Alkenes can be reduced to saturated hydrocarbons, but onlyif the double bond is at least
trisubstituted, allowing the possibility of selectivehydrogenation in a compound
containing different types of double bond. A usefulapplication of this chemistry is for
the reduction of aromatic ketones. For example,the ketone 131 gave the reduced
compound 132 under these conditions.This type of reduction is also effective with a
Lewis acid such as boron trifluoride.
Acetals and hemiacetals can be reduced with triethylsilane and an acid or

Lewisacid. For example, the benzylidene acetal 133 was treated with triethylsilane
andboron trifluoride etherate to give the product 134, in which the 6-benzyl ether was
formed selectively. In a synthesis of the potent anti-tumor agent phorboxazole B, the
hemiacetal 135 was reduced to a single diastereomer of the cyclic ether 136. These types
of reactions are thought to take place by co -ordinationof the Lewis acid to one of the
oxygen atoms (or its protonation when using TFA) followed by formation of an
oxonium ion, which is reduced by the silane.

03-05: REDUCTIONS WITH TRIBUTYLTIN HYDRIDE
Tin hydrides have played a highly significant role in organic synthesis in volving
radicalreactions. Tin forms strong covalent bonds to halogens, but the covalent bond
with hydrogenis very weak. This aspect has been exploited in a radical chain reaction
particularly in followingreactions:
• Reduction of haloalkanes to alkanes. During the reduction of an organohalide

moleculewith tributyltin hydride an iodine atom is more easily transferred than a
bromineatom or a chlorine atom. When one has a choice, an organoiodide or a bromide
can beselected as the substrate. The substrate react ivity also follows the expected
order,the more stable radical is generated faster in the first propagation step (allyl,
benzyl> 3° > 2° > 1° > vinyl, phenyl).
• Carbon-carbon bond formation
• Intramolecular addition—Formation of five membered rings.
Reduction of haloalkanes to alkanes (Scheme 1) is an excellent synthetic

methodfor this purpose. The mechanism starts with the homolysis of Bu 3 SnH with the
initiator AIBN.Use of AIBN is sufficient and a stronger peroxide initiator is
not needed since theSn—H bond of Bu 3 Sn—H to be cleaved is very weak and a
comparatively less reactive nitrilestabilized radical generated from A IBN would be
sufficient. The RO• radicals from peroxidesare highly reactive and will thus lead to
problems by abstracting hydrogens from other positionsas well. The organotin radical
preferentially abstracts halogen atoms from the haloalkane(except fluorine). To
generate an alkyl radical, the organotin radical, however, does not abstracta hydrogen
from the C—H bonds of the alkyl halide since the Sn—H bond thus formed wouldbe
very weak. In the next step the alkyl radical preferentially abstracts a hydrogen atom
fromthe Sn—H bond which is the weakest. Thus in the reaction (Scheme 1) one has
generateda specific radical which abstracts a halogen efficiently and undergoes a single
reaction processand is then terminated. The termination step gives only a single product
and the reactiveradical to continue the chain. This reaction can be applied to substrates
which have othergroups e.g., carbonyl which would be readily reduced by
reagents like lithium aluminiumhydride.

The method is used for C—C bond formation and the net addition of an alkyl group to
areactive double bond follow the halogen abstraction by an organotin radical. In this
reactionan organic radical and a hydrogen atom add to the C —C double bond. This is a
successfulreaction since the new C—H and Sn—I bonds are far stronger than the
previous bonds Sn—Hand C—I which are cleaved.
When this method of free radical generation is applied to an unsaturated alkyl

halidee.g., 6-bromo-1-hexene (Scheme 16.12h), the reaction can lead to two pathways.
Intramolecularaddition of carbon radical to the C =C bond produces a ring or the carbon
radical abstractsa hydrogen atom from tributyltin hydride to give a reduction product
(Scheme 3).

These two pathways i.e., substitution (reduction) and addition compete with each other.
The course of reaction can be changed by changing the concentration of tributyltin
hydride. The substitution reaction is a bimolecular process, thus high concentration of
tributyltin hydride will favour it, while a lower concentration of tributyltin hydride will
favour the ring formation.
It is known that the rates of ring-forming free radical cyclizations are 5 > 6 > 7.
It was found that reaction (I, Scheme 16.12h) gives the five -membered ring product
exclusively. Thus the regioselectivity of ring formation is not controlled by
thermodynamic considerations, but rather by kinetic control of the cyclization . It is
found that bond formation between the radical and the alkene stereoelectronically
requires an approach angle of about 110° between the free radical center and the
olefinic plane. This is because the free radical addition results via donation of the
unpaired electron on the radical into the π antibonding orbital of the olefin, which
coincidentally makes an angle of about 110° with the olefinic plane (Scheme 4).

It is easy to achieve this approach angle during cyclization via attack on that end of t he
double bond which is closest to the radical centre (favourable entropy factors) leading
to a five membered ring. For attack on the other olefinic carbon the radical shall have
to reach across the double bond to achieve the proper approach angle. This in deed
would be a higher energy path and is kinetically not favoured, thus six -membered ring
formation is not favoured.
One may appreciate that while Diels Alder reaction is one of the methods to
form fusedsix-membered rings, radical cyclization is superior to synthesize a fused ring
system containinga five membered carbocycle. The power of the method for the
synthesis of fused ring systemwith a five membered carboc ycle is presented (Scheme
5). In this case the reaction isinduced at a bridgehead position wher e radical reactions
are normally difficult since the radicalcannot achieve planar geometry. Thus when the
halogen is separated by four carbons from thedouble bond, cyclization to give a five
membered ring can occur.
03-06: MEERWEIN–PONDORFF–VERLEY (MPV REDUCTION)

The reduction of carbonyl compounds to alcohols with aluminiumisopropoxide haslong
been known under the name of the Meerwein–Pondorff–Verley reduction. The reaction
is easily effected by heating the components together in solution in isopropanol. An
equilibrium is set up and the product is obtained by using anexcess of the reagent or by
distilling off the acetone as it is formed. The reaction isthought to proceed by transfer
of hydride ion from the isopropoxide to the carbonylcompound through a six-membered
cyclic transition state.
Aldehydes and ketones are reduced to primar y and secondary alcohols

respectively, often in high yield. The reaction owes its usefulness to the fact that
carbon–carbon double bonds and many other unsaturate d groups are unaffected, thus

allowing selective reduction of carbonyl groups. For example, cinnamaldehyde is
converted into cinnamyl alcohol, o-nitrobenzaldehyde gives o-nitrobenzyl alcohol
andphenacyl bromide gives the alcohol 76.
Reductions of a similar type can be brought about by other metallic alkoxides,but

aluminium alkoxide is particularly effective beca use it is soluble in both alcohols and
hydrocarbons and, being a weak base, it shows little tendency to bringabout wasteful
condensation reactions of the carbonyl compounds. Reduction ofaldehydes by a similar
mechanism can occur by using lithium diisopropylamide(LDA). Therefore it is normally
advisable to avoid the use of LDA for attempted
enolization of aldehydes.
03-07: WOLF–KISHNER REDUCTION

The Wolff–Kishner reduction provides an excellent method for the reduction of
thecarbonyl group of many aldehydes and ketones to a methyl or methylene group
respectively. As originally described the reaction involved preparing the hydrazone or
semicarbazone from the carbonyl compound and then heating with sodium ethoxide or
other base at 200 0 C in a sealed tube. More conveniently, the Wolff –
Kishner reduction can be effected by heating a mixture of the carbonyl

compound,hydrazine hydrate and sodium or potas sium hydroxide in a high-boiling
solvent at 180–200 0 C for several hours. Use of the high-boiling solvent diethylene
glycol promotes removal of excess hydrazine and water after hydrazone formationand
reduces the time required for the reduction (Huang–Minlon modification). Forexample,
reduction of the hydrazone of the ketone 119 with sodium in diethyleneglycol gave the
product 120 (7.107). Alternatively, by using microwave irradiationthe reduction can be
carried out in minutes in the absence of a solvent.

The mechanism of the reduction is believed to involve deprotonation of thehydrazone to
give the anion 121. This is followed by the rate-limitingprotonation at the carbon atom
and deprotonation of the terminal nitrogen atom togive 122. Loss of nitrogen and
protonation of the carbanion gives the product. Inline with this mechanism, the polar
aprotic solvent DMSO increases the rate of thereaction, and with potassium tert -
butoxide in DMSO reduction can even be carriedout at room temperature.
Reduction of conjugated unsaturated aldehydes or ketones is sometimes

accompanied by a shift in the position of the double bond. In other cases
pyrazolinederivatives may be formed; these decompose yielding cyclopropanes
isomeric with the expected alkene.
With carbonyl compounds carrying a leaving group in the a -position

eliminationmay accompany reduction. Useful in this regard is the reductive opening of
,-epoxyketones to provide allylic alcohol products. For example, treatment of
theketone 123 with hydrazine and triethylamine gave the allylic alcohol 124.

Alternative procedures for deoxygenation of aldehydes and ketones include
theClemmensen reduction and the reduction of tosylhydrazones, forexample with
sodium cyanoborohydride. Another method for redu ction is desulfurization of the
corresponding thio-acetals with Raney nickel in refluxing ethanol. Hydrogenolysis is
affected by the hydrogen adsorbed on the nickel during its preparation . The reduction
can be carried out fairly easily, althoughlarge amount s of Raney nickel are required,
and other unsaturated groups in thecompound may also be reduced.
Section text starts here with detail elaboration of the concepts to be covered from the
syllabus.
SOLVED PROBLEMS 04
Problem 7: Write the products of the following reactions
Solution:

Solution:

Que.7: Which is the alternative reaction for Rosenmund reduction?
Answer: conversion of acid chlorides or thioesters into aldehydes by using trialkyl silane is an
alternative to the Rosenmund reduction.
Que.8: What is Meerwein–Pondorff–Verley reduction?
Answer: The reduction of carbonyl compounds to alcohols with aluminium isopropoxidehaslong
been known under the name of the Meerwein–Pondorff–Verley reduction.
CHECK POINT 02-03

1. Compound A and B in the following reaction is
2. What is the formula for Wilkinson's catalyst?

(1) RhCl(PPh3)3 (2) RhClPPh3
(3) CH3 CH2 RhCl (4) CH3 CH2 RhClPPH3
Answer: (1) RhCl(PPh3)3
3. Which of the following methods cannot produce aldehydes?
(1) Oxidation of primary alcohols (2) Dehydrogenation of secondary alcohols
(3) Ozonolysis of alkenes (4) Hydration of ethyne with acid
Answer: (2) Dehydrogenation of secondary alcohols

4. Which of the following carbonyl compounds can be prepared from Rosenmund reaction?
(1) Methanal (2) Acetone
(3) Butanone (4) Benzaldehyde
Answer: (4) Benzaldehyde
SUMMARY
Synthetic organic chemists have a wide range of reagents at their disposal for the
reduction or oxidation of functional groups in organic compounds. The reagent to be
used for any given transformation must be chosen carefully in order to ensure that only
the desired functional group or groups is effected: some reducing agents, for example,
will act on ketones and aldehydes but leave alkenes and carboxylic acid derivatives
untouched, while other will reduce all of these functional groups. Different redox
reagents will also transform groups to different extents: we will soon see oxidizing
agents, for example, that will transform a primary alcohol to a carboxylic acid, and
others that, given the same primary alcohol, will produce an aldehyde. Similarly,
reduction of an alkyne can produce a cis -alkene, a trans-alkene, or an alkane, depending
on the reducing agent used.
KEY WORDS
Reagent, Oxidation, Reduction
REFERENCES
MODERN METHODS ORGANIC SYNTHESIS, W. CARRUTHERS, Canbrige University
Press.
Limited.
MOOCS
______
YOUTUBE VIDEOS
https://www.youtube.com/watch?v=QSyPnyBxEBA
https://www.youtube.com/watch?v=The6GsEQeQU
https://www.youtube.com/watch?v=GPig-X7a05M
https://www.youtube.com/watch?v=isUt0sdUiNs
https://www.youtube.com/watch?v=7jZlOl3f4HM
https://www.youtube.com/watch?v=XXt2CNfS8lg

WIKIPEDIA
https://en.wikipedia.org/wiki/Hydrogenation
https://en.wikipedia.org/wiki/Asymmetric_hydrogenation
https://en.wikipedia.org/wiki/Carbonyl_reduction
https://en.wikipedia.org/wiki/Hydroboration%E2%80%93oxidation_reaction#:~:text=Hydroborat
ion%20step,-
Main%20article%3A%20hydroboration&text=In%20the%20first%20step%2C%20borane,add%2
0to%20each%20BH3.
https://en.wikipedia.org/wiki/Hydroboration
https://en.wikipedia.org/wiki/Reductions_with_hydrosilanes
OER
____
REFERENCE BOOKS
MODERN METHODS ORGANIC SYNTHESIS, W. CARRUTHERS, Canbrige University
Press.
Limited.

CREDIT 02-UNIT 04: REDUCTIONS OF CONJUGATED SYSTEMS
LEARNING OBJECTIVES
 Identify the major functional groups and types of reactions.
 conjugated system is a system of connected p -orbitals with delocalized electrons

in a molecule
 Molecules containing conjugated systems of orbitals and electrons are called

conjugated molecules.
 Conjugation is possible by means of alternating single and double bonds in

which each atom supplies a p orbital perpendicular to the plane of the molecule.
INTRODUCTION:
The term “conjugated” was invented in 1899 by the German chemist Johannes Thiele. A
conjugated system is a molecule’s system of connected p -orbitals with delocalised
electrons, which decreases the molecule’s overall energy and promotes stabi lity. It is
commonly depicted as having single and multiple bonds that alternate.
Conjugation is achieved by alternating single and double bonds, with each atom
providing a p-orbital perpendicular to the molecule’s plane. The system can be regarded
as conjugated as long as each consecutive atom in a chain has an accessible p -orbital.
However, conjugation can take place in a variety of ways.
04-01: Birch Reduction

Isolated carbon–carbon double bonds are not normally reduced by dissolving
metalreducing agents. Reduction is possible when the double bond is conjugated,
becausethe intermediate anion can be stabilized by electron delocalization. The best
reagentis a solution of an alkali metal in liquid ammonia, with or without addition of
analcohol – the so-called Birch reduction conditions. Under these conditions conjugated
alkenes, ὰ,β-unsaturated ketones and even aromatic rings can be reduced todihydro
derivatives.
Birch reductions are usually carried out with solutions of lithium or sodium
inliquid ammonia. Any added alcohol can act as a proton donor to buffer againstthe
accumulation of the strongly basic amide ion. Solutions of alkali metals inliquid
ammonia contain solvated metal cations and electrons, and part of theusefulness of
these reagents arises from the small steric requirement of the electrons.This may allow
reactions that are difficult to achieve with other reducing agentsand can lead to different
stereochemical results. Reductions are usually carriedout at th e boiling point of

ammonia (−33 0 C). As the solubility of many organiccompounds in liquid ammonia is
low at this temperature, co-solvents such as Et 2 O,THF or DME can be added to aid
solubility.
Conjugated dienes are readily reduced to the 1,4 -dihydro derivatives with
metal–ammonia reagents in the absence of added proton donors. For example, isoprene
isreduced to 2-methyl-2-butene by sodium in ammonia, by way of an intermediate
radical anion. The protons required to complete the reduction are suppliedby the
ammonia.
Reduction of ,-unsaturated ketones gives the saturated ketone or

saturatedalcohol, depending on the conditions. Thus, cyperone57 is converted to
theketone 58 with lithium in ammonia. Reduction in the presence of ethanol asproton
source, however, gave the saturated alcohol 59. In contrast, hydrogenationreduces both
double bonds.
The first step in the reduction of ,-unsaturated ketones is the formation ofthe
radical anion 60, which subsequently abstracts a proton from the ammoniaor from
added alcohol to give 61. After addition of another electron, theenolate anion 63 is
formed. In the absence of a stronger acid, this enolate remainsunprotonated and resists
addition of another electron, this would correspond to further reduction. Acidification
with ammonium chloride then leads to the saturatedketone product. The reaction of

ammonium ions with solvated electrons apparently destroys the reducing system before
further reduction of the ketone to the alcoholcan takes place.
In the presence of ‘acids’ (e.g. ethanol) sufficiently strong to protonate the

enolate anion, however, the ketone is generated in the reducing medium and is
reducedfurther to the saturated alcohol. The formation o f enolate anions such as 63
during metal–ammonia reduction of ,-unsaturated ketones is shown by their
readytrapping with electrophiles such as iodomethane.
Reduction of cyclic , -unsaturated ketones in which there are substituents

onthe - and -carbon atoms could give rise to two stereoisomeric products. In many
cases one isomer is formed predominantly, generally the more stable of the two.The
guiding principle appears to be that protonation of the intermediate anion takesplace
orthogonal to the enol double bond (axially in six -membered rings). Thus, reduction of
the enone 64 led almost exclusively to the trans-decalone65 through axial protonation.
One of the most useful synthetic applications of metal –ammonia–alcohol reducing

agents is in the reduction of benzene rings to 1,4 -dihydro derivatives. The reagents are
powerful enough to reduce benzene rings, but specific enough to add onlytwo hydrogen
atoms. Benzene itself is reduced with lithium and ethanol in liquid ammonia to 1,4-
dihydrobenzene by way of the radical anion. The presenceof an alcohol as a proton
donor is necessary in these reactions, for the initial radical anion is an insufficiently
strong base to abstract a proton from ammonia. The alcohol also acts to prevent the
accumulation of the strongly basic amide ion, which might bring about isomerization of

the 1,4-dihydro compound to the conjugated1,2-dihydro isomer (which would be further
reduced to tetrahydrobenzene).
Particularly useful synthetically is the reduction of methoxy - or amino-

substituted benzenes to dihydro compounds, which are readily hydrolyzed to
cyclohexenones. Under mild acid conditions, the first -formed ,-unsaturated ketones
are obtained, but these are readily isomerized to the conjugated,-unsaturated
compounds. This is an excellent method for preparing substituted cyclohexenones.
The Birch reduction of benzenes containing electron-donating substituents takes

place to give the 1,4-dihydro compounds in which the two new hydrogen atoms avoid
the carbon atoms to which the electron-donating substituents are attached.This
selectivity can be rationalized in terms of the relative electron densities of thecarbon
atoms in the intermediate radical anion. An electron -donating substituent destabilizes
an adjacent negative charge and therefore the site of highest electron density (and
therefore of protonation) is not a- to such substituents. It follows then, that reduction of
benzene rings substituted by electron-withdrawing carbonyl groups gives rise to 1,4-
dihydro benzoic acid derivatives, in which the intermediate anion is - to the anion-
stabilizing substituent. These intermediate carbanions can be alkylated in the a-position
to the carbonyl group. For example, 2 -heptyl-2-cyclohexenone 68 was obtained from o-
methoxy benzoic acid by way of the dianion 66. Alkylation of 66 followed by acid
hydrolysis of the enol ether led to the,-unsaturated ketone 67, which undergoes
decarboxylation to give 2-heptyl-2-cyclohexenone.

Selective reduction of a benzene ring in the presence of another reducible group
ispossible if the other group is first protected in so me way. Ketones, for example,
maybe converted to acetals or enol ethers to protect them from reduction. Conversely,
reduction of benzene rings takes place only slowly in the absence of a proton donor,and
selective reduction of an a,b-unsaturated carbonyl system can be effected.Selective
reduction of less-electron-rich aromatic rings occurs in bicyclic aromatic compounds.
Stereoselective Birch reduction is possible and a number of examples have

beenreported, particularly for selective alkylation of th e intermediate enolate anion. For
example, reduction of the chiral benzamide 69 with potassium in ammonia,followed by
alkylation with ethyl iodide gave essentially a single diastereomerof the cyclohexadiene
70, which was used in a synthesis of (+)-apovincamine.
Heterocyclic aromatic compounds can sometimes be reduced, particularly

thosewhich are electron-deficient. For example, reduction of pyridines gives 1,4 -
dihydropyridines (which are readily hydrolysed to 1,5 -dicarbonyl compounds).Partial
reduction of five-membered heteroaromatic compounds such as furans andpyrroles is
also possible if these have electron-withdrawing substituents to stabilizethe

intermediate radical anion. For example, reduction of the furan 71 occurred withhigh
selectivity to give the dihydrofuran 72, used in a synthesis of (+)-nemorensic acid.
04-02: REDUCTIVE FISSION OF ALCOHOLS

This can be achieved by the reductive elimination of the tosylate group from an alcohol tosylate
with lithium aluminium hydride (Scheme 1) and is an SN2 type of reaction.
SOLVED PROBLEMS 01
Problem 1: How will you convert 1-Methoxy-4-methyl benzene to conjugated
ketone? Explain with example.
Solution: When 1-Methoxy-4-methylbenzene is reduced by Birch reduction it gives

dihydo compound, which on acidic hydrolysis it produces ,  unsaturated ketone and
then it is isomerised to , -unsaturated ketone.
Solution:

Que.1: Why conjugated double bond reduced easily as compared to isolated double bonds
by using birch reduction?

Answer: Isolated carbon–carbon double bonds are not normally reduced by dissolving metal
reducing agents. Reduction is possible when the double bond is conjugated, because the
intermediate anion can be stabilized by electron delocalization.
Que.2: Which reagents are used in Birch reduction?
Answer: The reagent used in Birch reduction is a solution of an alkali metal in liquid ammonia.
04-03: McMurry or Pinacol coupling

Reduction of ketones with dissolving metals or low -valent transition metals
inthe absence of a proton donor leads to the formation of bimolecular products.
Thereductive coupling of two aldehydes or ketones is referred to as the McMurry
orpinacol coupling reaction and gives rise to a 1,2 -diol (a pinacol). A number of
reagents can be used, such as magnesium, magnesium amalgam, aluminium amalgam;
low valent titanium or chromium species or samarium (II) iodide.A popular reagent is
derived from reduction of titanium (III) chloride with zinc–copper couple. For example,
treatment of the dialdehyde 57 under these conditions gave the diol sarcophyto l58.
This methodology is effective for the synthesisof small - or medium-sized rings and
even for intermolecular couplings.
SOLVED PROBLEMS 02
Solution:
Problem 4: Give the mechanism for the above reaction.

Solution:

Que.3: What is McMurry or Pinacol coupling?
Answer: The reductive coupling of two aldehydes or ketones is referred to as the McMurry or
pinacol coupling reaction.
Que.4: Which reagents are used in McMurry or Pinacol coupling?
Answer: A number of reagents can be used, such as magnesium, magnesium amalgam,
aluminium amalgam, low valent titanium or chromium species or samarium (II) iodide.
04-04: Deoxygenation of Carbonyl compounds

Alternative procedures for deoxygenation of aldehydes and ketones include the
Clemmensen reduction and the reduction of tosylhydrazones, for example with sodium
cyanoborohydride. Another method for reduction is desulfurization of the
corresponding thio-acetals with Raney nickel in refluxing ethanol. Hydrogenolysis is
affected by the hydrogen adsorbed on the nickel during its preparatio n. The reduction
can be carried out fairly easily, although large amounts of Raney nickel are required,
and other unsaturated groups in the compound may also be reduced.
SOLVED PROBLEMS 03
Solution:
Problem 6: Suggest the product of the following reaction.

Solution:

Que.5: Which reagents are used in deoxygenation of carbonyl compounds other
than Clemmensen reduction and wolf-kishner reduction?
Answer: Ethane 1, 2-dithiol, Boron trifluoride and diethyl is used in deoxygenation of

carbonyl compounds.
Que.6: Explain Mozingo reaction.
Answer: A carbonyl group of a ketone can be converted into a methylene group by

desulphurization of its thioketal. The carbonyl compound an aldehyde or ketone is
reacted with ethylene dithiol in the presence of a Lewis acid to its thioacetal or ketal.
Reaction with excess Raney nickel causes hydrogenolysis of both C —S bonds. Freshly
prepared Raney nickel has enough hydrogen to reduce the thioacetal or thioketal
without added hydrogen.
04-05: Shapiro Reaction

A carbonyl compound reacts with toluene-p-sulphonyl hydrazine to give its
corresponding to sylhydrazone (Scheme 1). The reduction of tosyl hydrazones with
sodium borohydride converts the carbonyl group to a methylene group. The mechanism
(Scheme 2) probably involves the formation of a diimide as in the case of Wolff-
Kishner reduction.

The conversion of ketone p-toluene sulphonyl hydrazones to alkenes occurs on
treatment with a strong base e.g., alkyl lithium called Shapiro reaction (Scheme 3). This
reaction proceeds via the anion of a vinyl di-imide which subsequently decomposes to a
vinyl lithium reagent. This intermediate on contact with a proton source gives the
alkene (Scheme3).While dealing with unsymmetrical acyclic ketones, one has to
consider both regiochemistry and stereochemical aspects. Thus, 2 -octanone gives
exclusively 1-octene (Scheme4) and the observed region specificity is dictated by the
stereochemistry of the C=N bond ofthe starting hydrazone. There is preference for th e
removal of a proton which is syn to the arene sulphonyl group since the arrangement
allows chelation with the lithium ion (Scheme 4).
SOLVED PROBLEMS 04
Problem 7: Give the reaction scheme for Shapiro reaction.
Solution:

Solution:

Que.7: Which is the intermediate in Shapiro reaction?
Answer: Tosylhydrazone is the intermediate formed in the Shapiro reaction.
Que.8: What is Shapiro reaction?
Answer: The conversion of ketone p-toluenesulphonyl hydrazones to alkenes occurs on treatment
with a strong base e.g., alkyl lithium called Shapiro reaction.
CHECK POINT 02-04
1. The Birch reduction of benzoic acid gives:
2. Name of given reaction is

(1) Birch reaction (2) Bouveault-Blanc reaction
(3) McMurry Reaction (4) None of these
Answer: (3) McMurry Reaction
3. Given reduction is called
(1) Birch reduction (2) Bouveault-Blanc reduction

(3) McMurry Reduction (4) None of these
Answer: (1) Birch reduction
4. For Mc-Murry reaction the correct reaction condition is
(1) MnCl3/THF 3oK (2) TiCl3/THF 3oK
(3) CrCl3/THF 5oK (4) None of these
Answer: (2) TiCl3/THF 3oK
SUMMARY
Organic reductions or organic oxidations or organic redox reactions are redox reactions
that take place with organic compounds. In organic chemistry oxidations and reductions
are different from ordinary redox reactions, because many reactions carry the name but
do not actually involve electron transfer. Instead the relevant criterion for organic
oxidation is gain of oxygen and/or loss of hydrogen, respectively.
Many reactions classified as reductions also appear in other classes. For instance,
conversion of the ketone to an alcohol by lithium aluminium hydride can be considered
a reduction but the hydride is also a good nucleophile in nucleophilic substitution.
Many redox reactions in organic chemistry have coupling reaction reaction mechanism
involving free radical intermediates. True organic redox chemistry can be found in
electrochemical organic synthesis or electrosynthesis. Examples of organic reactions
that can take place in an electrochemical cel l are the Kolbe electrolysis.
KEY WORDS
Redox reaction, LAH, Oxidation, reduction, Intermediate
REFERENCES
MODERN METHODS OF ORGANIC SYNTHESIS, W. CARRUTHERS, Cambrige University
Press.
Limited.

MOOCS
_______
YOUTUBE VIDEOS
https://www.youtube.com/watch?v=NJBZheaBg-M
https://www.youtube.com/watch?v=hyaoVkxCWnY
https://www.youtube.com/watch?v=MdG4x-BVQBI
https://www.youtube.com/watch?v=_vl4Hs756Ss
WIKIPEDIA
https://en.wikipedia.org/wiki/Birch_reduction
https://en.wikipedia.org/wiki/McMurry_reaction#:~:text=Reaction%20mechanism,-
This%20reductive%20coupling&text=First%20is%20the%20formation%20of,exploits%20the%2
0oxophilicity%20of%20titanium.
https://en.wikipedia.org/wiki/Carbonyl_reduction
https://en.wikipedia.org/wiki/Clemmensen_reduction
https://en.wikipedia.org/wiki/Wolff%E2%80%93Kishner_reduction
https://en.wikipedia.org/wiki/Shapiro_reaction
OER
_____
REFERENCE BOOKS
MODERN METHODS OF ORGANIC SYNTHESIS, W. CARRUTHERS, Cambrige University
Press.
Limited.

C REDIT 03

CREDIT 03-UNIT 01: REACTIVE INTERMEDIATES: CARBENES
AND NITRENES
LEARNING OBJECTIVES
 Identify the basic structure of carbenes and nitrenes
 Know about the methods of generation of carbenes and nitrenes
 Evaluate reactivities of both carbenes and nitrenes
 Learn about important named reactions using carbenes and nitrenes to yield
products of industrial and chemical importance
01-01: CARBENES:
Methylene CH 2 can be considered as the first member of an alkene series. Methylene as
a highly reactive, transient molecule was first proposed in 1930 (Paneth technique–
removal of metallic mirrors). Its existence as a definite intermediate in certain
reactions was proved in 1959 by spectroscopic methods. Not only CH 2 but RCH, R 2 C
type of carbenes have been investigated. Carbene chemistry was one of the topics most
intensely studied during 1950-1960 and again between 1990-94. The word carbene is
used for methylene and as a general term for all similar compounds.
(A)STRUCTURE
Carbenes are highly reactive species, and practically all have lifetimes considerably < 1
s. With exceptions noted below, carbenes have been isolated only by en trapment in
matrices at low temperatures (77 K or less). Carbenes are divalent carbon compounds
with two non-bonding electrons on one carbon (In all six electrons on carbon). The
nature of bonding in carbenes has been analysed by molecular orbital calculat ions
(many approaches). Two important possibilities are:
The two nonbonded electrons of a carbene can be either paired or unpaired. If they are
paired, the species is spectrally a singlet, while, two unpaired electrons appear as a
triplet. The designations singlet state and triplet state refer to molecular electronic

states. In singlet carbene the carbon is sp2 hybridized, the non -bonding electrons have
anti-parallel spin i.e. the electrons are paired. Triplet carbene has two unpaired
electrons. The carbene centre is sp hybridized in triplet carbene. The non -bonding
electrons have parallel spins in different orbitals. The ground state energy difference
between (CH 2 )S and (CH 2 )T is calculated to be about 10 Kcal/mole.
On the basis of the above one can say singlet methylene should be diamagnetic and
triplet methylene be paramagnetic – a diradical.
Alkyl and dialkyl carbenes are generally triplets. Substituents carbene of electron pair
donor ability tend to stabilise the singlet state by electron release into the vacant
orbital.
(B) REACTIVITYOF CARBENES :

Carbenes being electron deficient molecules are generally electrophilic. Singlet carbene
is more like an electrophilic species (R3C+, CO and isocyanides). Triplet carbenes
should behave like a radical.
Both singlet and triplet carbenes are very reactive. Most of them are generated in situ.
There are no useful solvents to be used as media. They cannot be isolated but their
formation/involvement can be demonstrated by product analysis. Most reactions are
carried out in gas phase or liquid phase. Reactions involving free carbenes are highly
exothermic. All reactions of carbenes are generally fast (low activation energy).
(C) GENERATIONOFCARBENES:
Diazoalkanes are readily decomposed to carbenes by copper sal ts and other transition
metal ions. The products of the overall reaction are the same as obtained by direct
photolysis. The general evidence suggest that an adduct of the metal ion and carbene is
involved. The adduct can be represented as:

In this way the complexes can be treated as metal stabilised carbenes. A distinction is
generally made between free carbenes and metal ion complexes. These latter types are
spoken as carbenoids. For example carbene generated by photothesis of diazomethane is
a free carbene. The copper ion catalysed reaction leads to carbene coordinated to the
metal (carbenoid).
 Therearenumerousexamplesofcarbene generation:
A. Isopolarapproach–Photolysis,pyrolysis,transitionmetalioncatalysis
B. Polarapproach – αEliminations
A. ISOPOLARAPPROACH
Alkyl, aryl and acyl substituted carbenes from diazo compounds.
B. PolarApproach: Generation ofcarbenesviz. a-Elimination[1,1-E]

These (1 and 2) type of reactions are not applicable if there is β hydrogen present
because α (E2) elimination becomes the preferred reaction.
(C) Decarboxylationoftrihaloacetatesinaproticsolvents.
(D) Thermolysisorpyrolysisoftrihalomethylmercurycompounds
These mercury halides are covalent, stable at r.t.

(E)Trichloromethyl trihalosilane:
Thesemethodspermitreadyformationofcarbenes innearneutralmedia
(F) Preparationofcarbenesfromcarbonylcompounds.
Thisisausefulmethodtopreparecarbenes from readilyavailable
carbonylcompounds.
a. Analdehydeoraketoneisconvertedtoap-
toluenesulphonylhydrazone(Tosylhydrazone)
b. Thetosylhydrazone istreated witha1eq. ofbaseatlow temperature
(NaOCH 3 ) toform a salt of hydrazine.

There action consists of three steps.
c. The salt is decomposed in two ways (i)UV light(ii) heat(>130 0 C)
An aprotic solvent such asDMSO, diglymeare essential to prevent carbanion reactions
The carbene generated leads to products. This method avoids handling dangerous
diazoalkanes.
Thefirst twocompoundsare formed asaresult ofhydrogen migrationand thethird byC -

Hbond insertion of theCH 3 group.
(D) REACTIONS INVOLVING CARBENES

a) Additionto doublebonds and triplebonds
b) InsertionintoC–H bondsand otherbonds
c) Rearrangements.
The outcome of the overall reaction depends on the mode of formation, the Singlet,
triplet nature of the carbene.
EXAMPLES:
(E) BehaviourofMethylene(CH 2 )

Thechemical behaviourof‘CH 2 ’ is highlydependenton
1. There agent (precursor) from which it is generated.
2. ThewavelengthofUVlightused.
3. Whether the reactions are carried out in the liq. Phaseor gasphase.
4. Whether the reactions are carried out in the presence of inert gas like
Nitrogen, argon, CO 2 ; or gas likeO 2 .
The situation is complex and there are disagreements as to the exact

interpretation of the facts.
Methylene itself is the most indiscriminate reagent known in organic

chemistry. It shows addition to double bond, triple bond and even adds on
to benzene and insertion into C-Hbonds.
Example: Pay attention to thefollowing examples.

EXPLANATION:
ViewNo.1: Hot methylene (HighEnergy) high reactivity low selectivity; low energy,low
reactivity high selectivity.
ViewNo.2: Singlet methylene and triplet methylene.
Skell Hypothesis: Singlet carbine reacts in a single concerted step and

triplet carbine reacts in atwo-step radical pathway
These hypothesis are applicable both to addition as well as insertion reactions.
MECHANISM OF ADDITION BY SINGLET CARBENE

In this pathway, spin inversion and bond inversion are postulated. The difficulty here is
that there is no wayto predict which process is fast or slow.
General conclusions regardingreactivityofcarbenes:
 Intermolecularandintramolecularadditionsandinsertionscanoccur.However,
 Where there is a possibility of intramolecular reaction intermolecular

reactionsmaynot occur.
 Intramolecular insertion reactions one more selective. The proximity of C -H

bond to the carbine center plays a major role in determining the product
distribution.
Addition reactions are10 times fasterthan insertioninto bonds.
(D) CARBENES: ILLUSION OR REALITY

Carbenes are postulated reactive intermediates which are known to chemists. But
nocarbene was ever isolated and its properties studied till 1911. In that year, one French
chemistry Arduengo working in DuPont laboratory (USA) reported the preparation and
properties of a stable“bottle able”carbene.

This carbene derivative has an imidazole ring and two bulky adamantine rings linked
tonitrogen. It crystallises from toluene as colourless rectangular solid melting point
240-241 0 C. It is stable in the absence of oxygen and moisture. It has been fully
characterized by elemental analysis (C,H,N), IR and NHR spectra and by single-crystal
x-raydiffraction.
Several other type of stable carbenes have been prepared, and studied. Thus, th e
existenceofcarbenes is real and not a myth
Selected reactions involving carbenes and carbenoids as intermediates.

6. Synthesis of cyclopropanes: This is a useful reaction inorganic synthesis.
A good method of adding CH 2 unit to an alkene to give cyclopropane is to use CH 2 I 2 +

(Zn-Cu). This method is commonly known as Simmons -smith reaction. The active step
is believed to be I + ZnCH 2 I. Free CH 2 is not involved. Simmons-smith reaction has
charge scope, wide applicability and many functional groups can be present in the
alkene. In preparation procedures where a CH 2 is to be added to a double bond to form
cyclopropane, free methylene is not used, some other method which does not the
(reactive) methylene itself.

SOLVED PROBLEMS:
Solution:
Problem 2: Predict the major and minor product of the following reaction. Give reason.
Solution:
Ortho product is major because of intramolecular hydrogen bonding.

Que.1: Draw the orbital diagram for singlet carbine and triplet carbine.
Answer:
Que.2: Give the examples of generation of carbenes.

Answer: Examples of generation of carbine

01-02: NITRENES
(A) NITRENE: BASIC DEFINITION
Nitrenes (R-N), are the nitrogen analogues of carbenes, and most of the comments
about carbenes also applies to them. Nitrenes are too reactive for isolation under
ordinary conditions, although a binitio calculations show that nitrenes are more
stable than carbenes with an enthalpy difference of 25–26 kcal mol -1 (104.7–108.8 kJ
mol -1 ).
GENERALSTRUCTUREOFANITRENE
(R=H, alkyl). Such species a real so called azenes, imidogen, imene, azacarbene.
Nitrenes are postulated inter mediates in certain reactions (1913)
(B) SIGNIFICANT DIFFERENCES BETWEENCARBENESANDNITRENES :
(A) Electronicstates:
(B) METHODS OF GENERATION.
(1)Fromazides: The most common method of forming nitrenes is photolytic or
thermal decomposition of azides.

This is an example of α-Elimination. This method is not general and of very limited
application.
(2) Oxidation – Reduction methods:
Here, the great ability of phosphorous to combine with oxygen is the driving force for
the reaction.
Note: This is not similar to the method in carbene chemistry.
(A) GENERALISED REACTION OF NITRENES.

Examples

(C)REACTIONS INVOLVING NITRENE AS AN INTERMIDIATE : There are a few examples of
reactions which involves a nitrene as intermediate. These is

SOLVED PROBLEMS:
Problem 3: Give the generalised reactions of nitrenes
Solution:
Solution:

Que.3: How will you prepare nitrene from azide?
Answer:

Que.4: Give examples of reaction which involves a nitrene as intermediate
Answer: Curtius reaction
Hoffman-bromide reaction
01-03: CURTIUS REACTION

The Curtius Rearrangement is the thermal decomposition of carboxylic azides to
produce an isocyanate. These intermediates may be isolated, or their corresponding
reaction or hydrolysis products may be obtained. The reaction sequence - including
subsequent reaction with water which leads to amines –is named the Curtius
Reaction.This reaction is similar to the Schmidt Reaction with acids, differing in that
the acyl azide in the present case is prepared from the acyl halide and an azide salt.
SOLVED PROBLEMS:
Solution:
Problem 6: Complete the following sequence of reactions
Solution:

Que.5: Which is the starting compound used in Curtius reaction?
Answer: Acid chloride is used as starting compound in Curtius reaction.
Que.6: Which reaction is similar toCurtius reaction?
Answer: Curtius reaction is similar to the Schmidt Reaction.
01-04: HOFFMAN REACTION

The Hofmann reaction involves the conversion of carboxylic primary amides to primary
amines or their derivatives. Generally, alkaline hypohalites or a combination of
halogens and alkaline hydroxides are used in aqueous solutions. The rearrangement
generally occurs by heating. The Hofmann reaction is applicable to the preparation of a
wide variety of aliphatic, aromatic and heterocyclic amines, and is suitable for large-
scale preparative work, since it is safe and relatively inexpensive to carry out,
especially when chlorine and sodium hydroxide can beused.
Schmidt Reaction: The Schmidt reaction is the name given to a group of rea ctions
which involve the addition of hydrazoic acid to carboxylic acids, ketones and
aldehydes, alcohols and alkenes under strongly acidic conditions.
SOLVED PROBLEMS :
Problem 7: Write the product for following reaction.
Solution:
Problem 8: How can you prepare hydrazine from urea?

Solution:

Que.7: What is Hoffmann bromamide degradation?
Answer: Conversion of primary amide to primary amine is called Hoffmann bromamide
degradation.
Que.8: Which reagents are used in Hoffmann bromamide degradation?
Answer: Combination of halogens and alkaline hydroxides are used in aqueous solutions
CHECK POINT 03-01

1. The major product P in the following reaction is
2. In which of the following reaction nitrene as intermediate?

(1) Birch reduction (2) Curtius reaction
(3) Reimer Tiemann reaction (4) Wolf kishner reduction
Answer: (2) Curtius reaction
3. The name of the following reaction is
(1) Simmons-smith (2) Clemmenson’s reduction

(3) Reimer Tiemann reaction (4) Schmidt reaction
Answer: (1) Simmons-smith
4. Which reagent is used in Hoffmann bromamide degradation?
(1) Br2 + NaOH solution (2) CH2I2+ (Zn-Cu)

(3) CHCl3 + NaOH solution (4) NaOH Solution + CO2
Answer: (1) Br2 + NaOH solution
SUMMARY
In this module, we have taught you that:
 Carbenes are highly reactive species, and practically all have life times
considerably<1s. With exceptions noted below, carbenes have been isolated only
by entrapmentin matrices at low temperatures (77Kor less).
 The two nonbonded electrons of a carbene canbe either paired or unpaired.Ifthey
are paired, the species is spectrally a singlet, while, two unpaired
electronsappear as atriplet.
 The generation and reactivity of carbenes have been studied in detail with polar
and isopolar approaches having being discussed in detail.
 Reactions involving carbenes have been studied which include Addition to
double bonds and triple bonds, Insertion intoC–Hbonds and other bonds,
Rearrangements.
 Many important reactions involving carbenes as intermediates have been
thoroughly discussed.
 Nitrenes (R-N), are the nitrogen analogues of carbenes, and most of the
comments about carbenes also applies to them.
 Nitrenes differ from carbenes interms of electronic states and generalized
reactions.
 Important named reactions such as Curtius, Schmidtand Hoffman reactions have
been discussed which involve nitrene as an intremidiate.
KEY WORDS
Carbenes, Nitrenes, Curtius reaction, Schmidtand Hoffman reaction
REFERENCES
MARCH’S ADVANCED ORGANIC CHEMISTRY: REACTIONS, MECHANISMS,
AND STRUCTURE (Eighth Edition) by MICHAEL B. SMITH ( John Wiley & Sons)
Advanced Organic Chemistry: Part A: Structure and Mechanisms (Fifth Edition) by

FRANCIS A. CAREY and RICHARD J. SUNDBERG (springer)
MOOCS
_________
YOUTUBE VIDEOS
https://www.youtube.com/watch?v=Aom79kqwkbI

https://www.youtube.com/watch?v=LSJH5SwdVPw
https://www.youtube.com/watch?v=yGYOtOARsd8
https://www.youtube.com/watch?v=wthuhTEOJSc
WIKIPEDIA
https://en.wikipedia.org/wiki/Carbene
https://en.wikipedia.org/wiki/Nitrene
https://en.wikipedia.org/wiki/Curtius_rearrangement
https://en.wikipedia.org/wiki/Hofmann_rearrangement
OER
____
REFERENCE BOOKS
“Carbenes nitrenes and arynes”, byT. L. Gilchrist, ISBN: 978-1-4684-7292-9



CREDIT 03 -UNIT 02: STUDY OF REACTIONS
LEARNING OBJECTIVES
 The importance of alkene metathesis reaction

 Various routes to synthesize amides using Weinreb ketone synthesis reaction.
 Preparation of amines and their derivatives such as α -amino acids by means of
Petasis reaction
 Formation of diastereomeric mixtures of 2-nitro alcohols are formed on
treatment of primary and secondary nitroalkanes and carbonyl derivatives (more
frequently aldehydes) in presence of a base.
 Oxidation reaction used to synthesise aldehydes and ketones from primary and
secondary alcohols
02-01: ALKYENE METATHESIS

Olefin metathesis, or alkene metathesis, is an important process in petroleum refining and in
the synthesis of important compounds such as pharmaceuticals. The mechanism of olefin
metathesis is related to pericyclic reactions like Diels Alder and [2+2] reactions. In other
words, it occurs through the concerted interaction of one molecule with another.
In petroleum refining, heating alkenes over metal oxide surfaces results in the formation of
longer-chain alkenes. In particular, terminal olefins (with the double bond at the end of the
chain) are converted into internal olefins (with the double bond somewhere in the middle of
the chain).
Figure3.2.1. Olefin metathesis produces longer-chain "internal olefins" from shorter

chain "terminal olefins".
Role in addition reactions involving double bonds
Clearly, the alkenes have double bonds. In addition, so do the metal oxides. Metal atoms
inside the metal oxides are bridged together by oxygen atoms. The surface of the metal
oxides may be covered with a mixture of hydroxyl groups as well as terminal oxides (M=O
groups). The terminal oxides on the surface are the important part of the catalyst.

When metal alkylidene complexes were developed in the 1970's, it was found that th ey, too,
could catalyze this reaction.
Figure 3.2.2. Olefin metathesis produces longer-chain "internal olefins" from shorter
chain "terminal olefins"
In fact, scientists working in petroleum chemistry soon came to believe that metal oxides on
the catalyst surface were converted to alkylidenes, which then carried out the work of olefin
metathesis. The reaction, it turns out, involves a [2+2] cycloaddition of an alkene to a metal
alkylidene (to the metal-carbon double bond). This reaction results in a four-membered ring,
called a metallacyclobutane. The [2+2] cycloaddition is quickly followed by the reverse
reaction, a retro-[2+2]. The metallacyclobutane pops open to form two new double bonds.
THE CHAUVIN MECHANISM
This mechanism is called the Chauvin mechanism, after its first proponent, Yves Chauvin of
the French Petroleum Institute. Chauvin's proposal of this mechanism shortly after the
discovery of metal alkylidenes by Dick Schrock at DuPont earned him a Nobel Prize in 2005.
Chauvin and Schrock shared the prize with Bob Grubbs, who made it possible for the
reaction to be adapted easily to the synthesis of complex molecules such as pharmaceuticals.
Figure 3.2.3. The Chauvin mechanism for olefin metathesis.

Why does olefin metathesis lead to the formation of internal alkenes?
The [2+2] addition and retro-[2+2] reactions occur in equilibrium with each other. Each time
the metallacyclobutane forms, it can form two different pairs of double bonds through the
retro reaction. In the presence of terminal alkenes, one of those pairs of alkenes will
eventually include ethene. Since ethene is a gas, it is easily lost from the system, and
equilibrium shifts to the right in the equation below.

That leaves a longer-chain alkylidene on the metal, ready to be attached to another long chain
through subsequent [2+2] addition and reversion reactions.
In most cases, a [2+2] addition will not work unless photochemistry is involved, but it does
work with metal alkylidenes. The reason for this exception is thought to involve the nature of
the metal-carbon double bond. In contrast to an orbital picture for an alkene, an orbital
picture for an alkylidene pi bond suggests orbital symmetry that can easily interact with the
LUMO on an alkene. That's because a metal-carbon pipi bond likely involves a d orbital on
the metal, and the d orbital has lobes alternating in phase like a pipi antibonding orbital.
SOLVED PROBLEMS:
Problem 1: Predict the product of the following reactions

Solution:
Problem 2: Which mechanism is proposed to alkene metathesis?

Solution: The Chauvin mechanism.
Que.1: What is the use of alkene metathesis?
Answer: Alkene Metathesis is used for the synthesis of longer-chain "internal olefins" from
shorter chain "terminal olefins".
Que.2: Which cyclic intermediate is fomed in alkene metathesis?
Answer: The cyclic intermediate formed in alkene metatheis is metallacyclobutane.
02-02: WEINREB–NAHM KETONE SYNTHESIS

The Weinreb–Nahm ketone synthesis is a chemical reaction used in organic
chemistry to make carbon–carbon bonds. It was discovered in 1981 by Steven M.
Weinreb and Steven Nahm as a method to synthesize ketones. The original reaction
involved two subsequent nucleophilic acyl substitutions: the conversion of an acid
chloride with N,O-Dimethylhydroxylamine, to form a Weinreb–Nahm amide, and
subsequent treatment of this species with an organometallic reagent such as a Grignard
reagent or organolithium reagent. Nahm and Weinreb also reported the synthesis
of aldehydes by reduction of the amide with an excess of lithium aluminum hydride.
The major advantage of this method over addition of organometallic reagents to more typical
acyl compounds is that it avoids the common problem of over-addition. For these latter

reactions, two equivalents of the incoming group add to form an alcohol rather than a ketone
or aldehyde. This occurs even if the equivalents of nucleophile are closely controlled.
The Weinreb–Nahm amide has since been adopted into regular use by organic chemists
as a dependable method for the synthesis of ketones. These functional groups are
present in a large number of natural products and can be reliably reacted to form new
carbon–carbon bonds or converted into other functional groups. This method has been
used in a number of syntheses, including macrosphelides A and B, amphidinolide J, and
spirofungins A and B.
Weinreb and Nahm originally proposed the following reaction mechanism to explain the
selectivity shown in reactions of the Weinreb–Nahm amide. Their suggestion was that
the tetrahedral intermediate (A below) formed as a result of nucleophilic addition by
the organometallic reagent is stabilized by chelation from the methoxy group as
shown. This intermediate is stable only at low temperatures, requiring a low -
temperature quench.
This chelation is in contrast to the mechanism for formation of the over-addition

product wherein collapse of the tetrahedral intermediate allows a second addition. The
mechanistic conjecture on the part of Weinreb was immediately accepted by the
academic community, but it was not until 2006 that it was confirmed by spectroscopic
and kinetic analyses.
In addition to the original procedure shown above (which may have compatibility issues
for sensitive substrates), Weinreb amides can be synthesized from a variety
of acyl compounds. The vast majority of these procedures utilize the commercially
available salt N,O-dimethylhydroxylamine hydrochloride [MeO(Me)NH•HCl], which is
typically easier to handle than the free amine.
Treatment of an ester or lactone with AlMe 3 or AlMe2Cl affords the corresponding Weinreb
amide in good yields. Alternatively, non-nucleophilic Grignard reagents such as isopropyl
magnesium chloride can be used to activate the amine before addition of the ester.

A variety of peptide coupling reagents can also be used to prepare Weinreb–Nahm
amides from carboxylic acids. Various carbodiimide-, hydroxy benzotriazole-,
and triphenyl phosphine-based couplings have been reported specifically for this
purpose.
Finally, an aminocarbonylation reaction reported by Stephen Buchwald allows

conversion of aryl halides directly into aryl Weinreb–Nahm amides.
The standard conditions for the Weinreb–Nahm ketone synthesis are known to tolerate a
wide variety of functional groups elsewhere in the molecule, including alpha -halogen
substitution, N-protected amino acids, α-β unsaturation, silyl ethers,
various lactams and lactones, sulfonates, sulfinates, and phosphonate esters. A wide
variety of nucleophiles can be used in conjunction with the
amide. Lithiates and Grignard reagents are most commonly employed; examples
involving aliphatic, vinyl, aryl, and alkynyl carbon nucleophiles have been reported.

However, with highly basic or sterically hindered nucleophiles, elimination of the
methoxide moiety to release formaldehyde can occur as a significant side reaction .
Nonetheless, the Weinreb–Nahm amide figures prominently into many syntheses,

serving as an important coupling partner for various fragments. Shown below are key
steps involving Weinreb amides in the synthesis of several natural products, including
members of the immuno suppressant family of macro sphelides, and
the antibiotic family of spiro fungins.
SOLVED PROBLES:

Solution:
Problem 4: What will the product when Weinreb amide is treated with LiAlH4?
Solution: Aldehyde is obtained when Weinreb amide is treated with LiAlH4.

Que.3: What is Weinreb–Nahm ketone synthesis?
Answer: When acid chloride is treated with N, O-Dimethylhydroxylamine, to form a Weinreb–
Nahm amide, which on reaction with Grignard reagent or organolithium it produces ketone.
Weinreb–Nahm amide is reduced by LiAlH4 it produces aldehyde.
Que.4: Explain mechanism of Weinreb-Nahm ketone ynthesis?
Answer: Weinreb and Nahm originally proposed the following reaction mechanism to explain
the selectivity shown in reactions of the Weinreb–Nahm amide. Their suggestion was that
the tetrahedral intermediate (A below) formed as a result of nucleophilic addition by
the organometallic reagent is stabilized by chelation from the methoxy group as shown. This
intermediate is stable only at low temperatures, requiring a low-temperature quench.

02-03: PETASIS REACTION
The Petasis Reaction is a multicomponent reaction (MCR) that enables the preparation of
amines and their derivatives such as α-amino acids. The reaction is also referred to as the
Boronic Acid Mannich Reaction, since it proceeds via an imine with the organic ligand of the
boronic acid acting as the nucleophile, similar to the role of the enolizable ketone component
in the original Mannich Reaction.
MECHANISM OF THE P ETASIS REACTION:

As in the classical reaction that it resembles, the Petasis Reaction also involves a large
number of interdependent equilibrium steps, some of them identical to those in the Mannich
Reaction.
Little is known with certainty in connection with the key step that involves the
nucleophilic addition of the organic ligand from the boronate to the imine. One
proposal is that the transfer is actually intramolecular, and takes place via the adduct
pictured above:
Regardless of how it does take place, the fact that this addition is irreversible certa inly
imparts a clear advantage. In the classical Mannich, the reversibility of the final step limits
the number of cases where the yields are synthetically useful. By comparison, the Boronic
Acid Mannich Reaction permits a much broader scope of conversions to be carried out.
The direct reaction with glyoxylic acid merits particular mention, since it leads to interesting,
unnatural α-amino acids in a single step, while avoiding the appearance of toxic byproducts
such as seen with the Strecker Synthesis.

This reaction can be carried out with secondary amines, sterically hindered primary
amines, hydrazines or anilines in dichloromethane at room tempera ture. The range of
potential nucleophilic partners includes alkenylboronic acids, and electroneutral as well
as electron-rich (hetero-) arylboronic acids. The conversion of electron-poor boronic
acids can be effected at elevated temperatures (MW) in suitab le solvents.
Reaction Scope
One of the most attractive features of the Petasis reaction is the stability of the vinyl
boronic acids. With the advent of the Suzuki coupling, many are commercially
available.
A wide variety of functional groups including alcohols, carboxylic acids, and amines
are tolerated in the Petasis Reaction. Known substrates that are compatible with
reaction conditions include vinyl boronate esters, arylboronate esters, and
potassium organo trifluoroborates. Additionally, a variety of substituted amines can be
used other than secondary amines. Tertiary aromatic amines, hydrazines, hydroxyl
amines, sulfonamides, and indoles have all been reported.
SOLVED PROLEMS :
Problem 5: Fill in the blank

The Petasis Reaction is a -------------- reaction (MCR) that enables the preparation of amines and
their derivatives such as α-amino acids.
Solution: Multicomponent
Solution:

Que.5: What is another name of Petasis reaction?
Answer: Boronic Acid Mannich Reaction.
Que.6: What is most attractive features of the Petasis reaction?
Answer: One of the most attractive features of the Petasis reaction is the stability of the vinyl
boronic acids.
02-04: HENRY REACTION

The Henry reaction is a classic carbon–carbon bond formation reaction in organic
chemistry. Discovered in 1895 by the Belgian chemist Louis Henry (1834–1913), it is
the combination of a nitroalkane and an aldehyde or ketone in the presence of a base to
form β-nitro alcohols. [1][2][3] This type of reaction is also referred to as a nitroaldol
reaction (nitroalkane, aldehyde, and alcohol).
It is nearly analogous to the aldol reaction that had been discovered 23 years prior that
couples two carbonyl compounds to form β -hydroxy carbonyl compounds known as
"aldols" (aldehyde and alcohol). The Henry reaction is a useful technique in the area of

organic chemistry due to the synthetic utility of its corresponding products, as they can
be easily converted to other useful synthetic intermediates. These conversions include
subsequent dehydration to yield nitroalkenes, oxidation of the secondary alcohol to
yield α-nitro ketones, or reduction of the nitro group to yield β -amino alcohols.
Mechanism of Henry reaction:

The Henry reaction begins with the deprotonation o f the nitroalkane on the α-carbon
position forming a nitronate. The pKa of most nitroalkanes is approximately 17.
Although this structure is nucleophilic both at the deprotonated carbon and at the oxy -
anions of the nitro group,the observed result is of the carbon attacking the carbonyl
compound. The resulting β-nitro alkoxide is protonated by the conjugate acid of t he
base that originally deprotonated the nitroalkyl structure, giving the respective β -nitro
alcohol as product.
It is important to note that all steps of the Henry reaction are reversible. This is due to
the lack of a committed step in the reaction to for m product. It is for this reason that
research has been geared towards modifications to drive the reaction to completion.
Stereochemical Course:
The figure below illustrates one of the commonly accepted models for stereoselection
without any modification to the Henry reaction. In this model, stereoselectivity is
governed by the size of the R groups in the model (such as a carbon chain), as well as
by a transition state that minimizes dipole by orienting the nitro group and carbonyl
oxygen anti each other (on opposite sides of the molecule). The R groups play a role in
the transition state of the Henry reaction: the larger the R groups on each of the
substrates, the more they will tend to orient themselves away from each other
(commonly referred to as steric effects).

Due to the reversibility of the reaction and the tendency for easy epimerization of the
nitro-substituted carbon atom (among a number of factors), the Henry reaction will
typically produce a mixture of enantiomers or diastereomers. It is for this reason that
explanations for stereoselectivity remain scarce without some modification of the
reaction. In recent years, research focus has shifted toward modifications of the Henry
reaction to overcome this synthetic challenge. The first example of an enantioselective
nitroaldol reaction was reported in 1992 using Shibasaki catalysts. One of the most
frequently employed methods for inducing enantio - or diastereoselectivity in the Henry
reaction is the use of chiral metal catalysts, in which the nitro group and carbonyl
oxygen coordinate to a metal that is bound to a chiral organic molecule. Some metals
that have been used include zinc, cobalt, copper, magnesium, and chromium. A
depiction of this coordination is illustrated above .
One of the many features of the Henry reaction that makes it synthetically attractive is
that it utilizes only a catalytic amount of base to drive the reaction. Additionally a
variety of bases can be used including ionic bases such as alkali metal hydroxides,
alkoxides, carbonates, and sources of fluoride anion (e.g. TBAF) or nonionic organic
amine bases including TMG, DBU, DBN, and PAP. It is important to note that the base
and solvent used do not have a large influence on the overall outcome of th e reaction.
Limitations of Henry reaction
One of the main drawbacks of the Henry reaction is the potential for side reactions
throughout. Aside from the inherent reversibility of the reaction (or "retro –Henry") that
can prevent the reaction from proceeding; the β-nitro alcohol also has the potential to

undergo dehydration. For sterically hindered substrates, it is also possible for a base -
catalyzed self-condensation (Cannizzaro reaction) to occur. A general scheme of the
Cannizzaro reaction is depicted below.
02-05: COREY KIM OXIDATION

The Corey–Kim oxidation is an oxidation reaction used to
synthesise aldehydes and ketones from primary and secondary alcohols. It is named for
American chemist and Nobel Laureate Elias James Corey and Korean-American
chemist Choung Un Kim.
Although the Corey–Kim oxidation possesses the distinctive advantage over Swern
oxidation of allowing an operation above –25 °C, it is not so commonly used due to
issues with selectivity in substrates susceptible to chlorination by N-chlorosuccinimide.
Reaction mechanism:
Dimethyl sulfide (Me 2 S) is treated with N-chlorosuccinimide (NCS), resulting in
formation of an "active DMSO" species that is used for the activation of the alcohol.
Addition of triethylamine to the activated alcohol leads to its oxidation to aldehyde or
ketone and generation of dimethyl sulfide. In variance with other alcohol oxidation
using "activated DMSO," the reactive oxidizing species is not generated by reaction of
DMSO with an electrophile. Rather, it is formed by oxidation of dimethyl sulfide with
an oxidant (NCS).
Under Corey–Kim conditions allylic and benzylic alcohols have a tendency to evolve to
the corresponding allyl and benzyl chlorides unless the alcohol activation is very

quickly followed by addition of triethylamine. In fact, Corey–Kim conditions —with no
addition of triethylamine— are very efficient for the transformation of allylic and
benzylic alcohols to chlorides in presence of other alcohols.
SOLVED PROBLEMS :
Solution:
Problem 8: Give the possible products for Korey kim oxidation reaction
Solution:

Que.7: What is Corey Kim Oxidation?

Answer: The Corey–Kim oxidation is an oxidation reaction used to synthesize aldehydes and
ketones from primary and secondary alcohols.
Que.8: Which reagents are used in Corey kim oxidation?
Answer: The reagents used in Corey Kim oxidation is as follows:
Dimethyl sulfide (Me2S), N-chlorosuccinimide (NCS) and triethyl amine (Et3N).
CHECK POINT 03-02

1. The mechanism of alkene metathesis is related to ---------
(1) Paterno buchi reaction (2) Shapiro reaction
(3) Wacker reaction (4) Diels-Alder [2 + 2] reaction
Answer: (4) Diels-Alder [2 + 2] reaction
2. Which of the following intermediate is formed in alkene metathesis?
(1) Carbene (2) Carbocation
(3) Cyclobutane (4) Carbanion
Answer: (3) Cyclobutane
3. The conversion of acid chloride to ketone by using N, O-Dimethylhydroxylamineis called -----
(1) Weinreb–Nahm ketone synthesis (2) Alkene metathesis
(3) Williamson’s synthesis (4) Rosenmund reduction
Answer: (1) Weinreb–Nahm ketone synthesis
4. The Petasis reaction is also referred as -----
(1) Reimer Tiemann reaction (2) Schmidt reaction
(3) Boronic Acid Mannich reaction (4) Rosenmund reaction
Answer: (3) Boronic Acid Mannich reaction
SUMMARY
 Alkene metathesis is an innovative catalytic reaction that provides a versatile
method to build molecules through carbon-carbon bond formation.
 Alkene metathesis is a chemical reaction in which two carbon-carbon double
bonds (also known as alkenes) come together and exchange with one another,
forming new alkeneic products in the process .
 Weinreb amides (N-methoxy-N-methylamides) have many important synthetic
uses. Their reactivity can be summarized as that of a controlled -reactivity
acylating agent. They react with Grignard and organolithium reagents to give
ketones, instead of tertiary alcohols as esters do .
 The Petasis reaction is a multicomponent reaction involves the reaction between
an aldehyde, an amine and a boronic acid that enables the preparation of amines
and their derivatives such as α-amino acids
 The Henry reaction (nitroaldol addition) is one of the classical CC bond -forming

processes by which diastereomeric mixtures of 2 -nitro alcohols are formed on
treatment of primary and secondary nitroalkanes and carbonyl derivatives (more
frequently aldehydes) with a base.
 The Corey–Kim oxidation is an oxidation reaction used to synthesise aldehydes
and ketones from primary and secondary alcohols . It is named for American
chemist and Nobel Laureate Elias James Corey and Korean-American chemist
Choung Un Kim.
KEY WORDS
Alkene metathesis, Weinreb ketone synthesis, Petasis reaction, Corey–Kim oxidation
REFERENCES
AND STRUCTURE (Eighth Edition) by MICHAEL B. SMITH (John Wiley & Sons)
MOOCS
______
YOUTUBE VIDEOS
https://www.youtube.com/watch?v=DrS-75wEIJM
https://www.youtube.com/watch?v=DbZR9OUNI4c
https://www.youtube.com/watch?v=hCcqN9vMncM
https://www.youtube.com/watch?v=u77DDstg5iM
WIKIPEDIA
https://en.wikipedia.org/wiki/Henry_reaction
https://en.wikipedia.org/wiki/Olefin_metathesis
https://en.wikipedia.org/wiki/Corey%E2%80%93Kim_oxidation
https://en.wikipedia.org/wiki/Petasis_reaction
https://en.wikipedia.org/wiki/Olefin_metathesis
https://en.wikipedia.org/wiki/Weinreb_ketone_synthesis#:~:text=The%20Weinreb%E2%80%93
Nahm%20ketone%20synthesis,a%20method%20to%20synthesize%20ketones.
https://en.wikipedia.org/wiki/Petasis_reaction
https://en.wikipedia.org/wiki/Henry_reaction
OER
____
REFERENCE BOOKS

CREDIT 03 -UNIT 03: MOLECULAR RECOGNITION
LEARNING OBJECTIVES
 Learnaboutthebasicsof supramolecularchemistry.
 Knowaboutnon-covalentinteractions.
 Understandthe concepts ofself-assemblyandself-organization.
 Learnandanalysehost-guestchemistry
 Basicsofcagedmolecules
 Syntheticmethodologyofcagedmolecules
 Applicationsofcagedmolecules
 Learn about the basic knowledge of catenanes and rotaxanes
 Understand the nomenclature of rotaxanes and catenanes
 Analyze the chemical topology of rotaxanes and catenanes
 Know to determine stereochemistry of rotaxanes and catenanes
 Learn about the properties and applications of rotaxanes and catenanes
03-01: Principles of molecular associations and organizations

A) Non-covalent synthesis
INTRODUCTION:
Supramolecular chemistry is a highly interdisciplinary field of science covering the
chemical, physical, and biological features of the organized chemical species of greater
complexity than molecules themselves, which are held together and organized by means
of intermolecular (non-covalent) binding interactions. In other words, these can also
bedefined as ‘chemistry of molecular assemblies and of the intermolecular bond’.
Professor Jean-Marie Lehn won the Nobel Prize in 1987 for his work in the area of
supramolecular chemistry. Basically, supramolecular chemistry was defined in terms of
the non-covalent interactions between a‘host’ and a‘guest’molecule.
The non-covalent interactions such as electrostatic interactions, hydrogen bonding
andvan der Waals forces define the inter component bond between the molecular
individuals and populations. These non-covalent interactions are as important in
supramolecular chemistry as covalent interactions in classical organic chemistry. The
energy of these non-covalent interactions is much smaller than 200-400 kJmol -1 which
is typical for covalent chemical bonds. In addition to relatively strong ion-ion
electrostatic interactions of ca.100-350kJmol -1 and hydrogen bonding of ca.10-
120kJmol -1 , they include muc smaller London dispersion forces, ion-induced dipole and
dipole-dipole interactions that are in the range of 5-50 kJmol-1 strong. Supramolecular

chemistry covers the crystals, solutions and also the polymers in which non -covalent
interactions play such an important role.
In general, supramolecular chemistry involves the self -assembly and host-guest systems
using a variety of interactions, some of which are clearly non -covalent (e.g. hydrogen
bonds) and some of which possess a significant covalent component (e.g. metal –ligand
interactions) It also has diversified enormously and includes charge -transfer complexes,
inclusion complexes (incorporating e.g. Cram's hemicarcerands and cyclodextrins),
mono- and polylayers, micelles, vesicles, liquid crystals and cocrystals consisting of at
least two different kinds of molecules which form highly specific domains di ffering in
the objects studied and research techniques. The specificity and separateness of the
charge-transfer complexes and those of liquid crystals seem generally recognized. On
the other hand, as concerns inclusion complexes or other molecular aggregat es
consisting of only few molecules, higher molecular aggregates, and cocrystals formed
by at least two types of molecules the situation is not that clear.
NON-COVALENT INTERACTIONS:
The supramolecular chemistry generally concerns non -covalent bonding interactions
such as ion-ion interactions, ion-dipole interactions, dipole-dipole interactions,
hydrogen bonding, cation-π interactions, anion-π interactions, π-π interactions, closed
shell interactions, van der Waals forces and crystal close packing. The term ‘non-
covalent’ encompasses an enormous range of attractive and repulsive effects.
Fig. 3.3.1. Comparison between the scope of molecular and supramolecular

chemistry according to Lehn
The ion-ion interaction as in ionic cubic lattice of solid sodium chloride in which each
Na + cation is surrounded by six Cl - anions. The Na + cation is able to organize six

complementary donor atoms about itself in order to maximize non-covalent ion–ion
interactions. The ionic cubic lattice of solid sodium chloride breaks d own in
solution because of solvation effects to give species such as the labile, octahedral
Na(H 2 O) 6 + . The bond strength of ionic bonding is comparable in strength to covalent

bonding and bond energy in the range of 100–350 kJmol -1 .
Fig. 3.3.2: (a) The ionic cubic lattice of solid sodium chloride (b) showing
supramolecular ion-ion interactions by anion and an organic cation and (c)
showing the supramolecular ion-dipole interactions by metal cation and crown
ether.
The bonding of anion, such as Na + , with a polar molecule, such as water, is an example
of an ion–dipole interaction, whichrange in strength from ca. 50– 200 kJ mol -1 . This
kind of bonding is seen both in the solid state and in solution. The ion -dipole
interactionsin supramolecular structures of the complexes of alkali metal cations with
macrocyclic (large ring) ethers termed crown ethers in which the ether oxygen atoms
play the same role as the polar water molecules, although the complex is stabilized by
the chelate effect and the effects of macrocyclic pre-organization.
A hydrogen bond (H-bond) maybe regarded as a particular kind of dipole–dipole
interaction in which a hydrogen atom attached to an electronegative atom (or electron
withdrawing group) is attracted to a neighbouring dipole on an adjacent molecule or
functional group. H-bonds are commonly written D–H. And usually involve a hydrogen
atom attached to an electronegative atom such as O or N as the donor (D) and a
similarly electronegative atom, often bearing a lone pair, as the acceptor (A).The
typical range for H-bond strength is from ca. 10–120 kJ mol -1 and the typically H-
bonded O···O distances are 2.50–2.80 Å in length, though interactions in excess of 3.0
Å may also be significant. An excellent example of H-bonding in supramolecular
chemistry is the formation of carboxylic acid dimers. Figure 3.3.3(a), which results in
the shift of the ν(OH) infrared stretching frequency from about 3400cm -1 to about
2500cm -1 , accompanied by a significant broadening and intensifying of t he absorption.
H-bonds

are ubiquitous in supramolecular chemistry. In particular, H-bonds are responsible for
the overall shape ofmany proteins, recognition of substrates by numerous enzymes, and
(along with π-π stacking interactions) forthe doubl ehelix structure of DNA.
Fig. 3.3.3: Supramolecular Hydrogen bonding (H -bonding) interactions in (a)

carboxylic acid dimers (b) organic molecule and (c) & (d) guanine and cytosine
base pairs of DNA
The π-π interactions occur between aromatic rings so sometimes it is also called
aromaticπ-π stacking interactions, often in situations where one is relatively electron
rich and oneis electron poor. The typical range for π -π interactions strength is from ca.
50–500 kJmol -1 . There are two types of π-interactions: face-to-face and edge-to-face
(Figure 3.3.4). Face-to-face π-stacking interactions are responsible for the slippery feel
of graphite and its useful lubricant properties. Similar π -stacking interactions between
the aryl rings ofnucleobase pairs also help to stabilize the DNA double helix. Edge -to-
face interactions may be regarded as weak forms of hydrogen bonds between the
slightly electron deficient. Hydrogen atoms of one aromatic ring and the electron rich
π-cloud of another. Strictly they should not be referred to as π-stacking since there is no
stacking of the π-electron surfaces. Edge-to-face interactions are responsible for the
characteristic herring bone packing in the crystal structures of a range of small aromatic
hydrocarbons including benzene.
Fig. 3.3.4: Supramolecular π-π interactions in the molecular structures
Cation-π interactions: Transition metal cations such as Fe 2+ , Pt 2+ etc. are well known to
form complexes with olefinic and aromatic hydrocarbons suchas Zeise’s salt
[PtCl 3 (C 2 H 4 )] - and ferrocene [Fe(C 5 H 5 ) 2 ]. The bonding in such complexes is strong

and could by no means be considered non-covalent, since it is intimately linked with
+
the partially occupied d-orbitals of the metals. Even species such as Ag ···C 6 H 6 have a
significant covalent component. The interaction of alkaline and alkaline earthmetal
cations with C=C double bonds is, however, a much more non-covalent ‘weak’
interaction, and is suggested to play an important role in biological systems. For
example, the interaction energy of K + (Figure 3.3.5) and benzene in the gas phase is
~80 kJ mol -1 . By comparison, the association of K + with a single water molecule is
similar at 75 kJ mol -1 . The reason for this is that the K + ion is more soluble in water
than in benzene is related tothe fact that many water molecules can interact with the
potassium ion, whereas only afew bulkier benzene molecules can fit around it. The
interaction of non-metallic cations such as RNH 3 + with double bonds may be thought of
as a form of X—H ···π hydrogen bond.
Fig. 3.3.5: Cation-π interactions in molecular structures (a) ferrocene (b) Zeise’s
salt and (c) schematic representation of cation-π interactions in between K + ion and
benzene and quadrupole moment of benzene
Anion-π interactions: Cation-π interactions are favorable however the interaction of an

anion with π-electron density seems like it should be repulsive and indeed the affinity
of the aromatic ring containing cryptand figure 3.3.6(a) for halides rapidly falls off in
the order F‒ >> Cl‒ > Br‒ ~ I‒ because of anion-π repulsions in the case of the larger
halides, with all except F‒ showing a constant anion -ring centroid distance of ca. 3.7 Å.
However, there is a charge difference between an overall neutral aromatic ring and an
anion and therefore in principle the possibility exists for an electrostatic attraction.
Such short anion-π interactions have been noted for organometallic calixar ene
derivatives shown in figure 6(b) where the aromatic ring bears a significant positive
charge. Anion-π interactions have also been implicated as controlling elements in self -
assembly reactions of Ag(I) complexes with π -acidic aromatic rings.

Fig. 3.3.6: Molecular structures which are involve in anion -π interactions (a)
aromatic ring containing cryptand and (b) organ ometallic calixarene derivative
VanderWaals interactions arise from the polarization of an electron cloud by the

proximity of an adjacent nucleus, resulting in a weak electrostatic attraction. The
typicalrange for Van der Waals interactions strength is from ca. 0.50–40 kJ mol -1 . These
Vander Waals interactions are non-directional and hence possess only limited scope in
thedesign of specific hosts for selective complexation of particular guests.In general ,
vander Waals interactions provide a general attractive interaction for most ‘soft’
(polarisable) species with the interaction energy proportional to the surface area of
contact. In supramolecular chemistry, they are most important information of
‘inclusion’ compounds in which small, typically organic molecules are loosely
incorporated within crystalline lattices or molecular cavities, e.g. the inclusion of
toluene within the molecular cavity of the p-tert-butylphenol-based macrocycle, p-tert-
butylcalix [4] arene (Figure 3.3.7(a)).
Fig. 3.3.7: (a) X-ray crystal structure of a typical van der Waals inclusion complex
p- tert-butylcalix [4] arene·toluene and (b) hydrophobic van der Waals interactions
Dipole-dipole interactions: Alignment of one dipole with another can result in

significant attractive interactions from matching of either a single pair of poles on

adjacent molecules (type I) or opposing alignment of one dipole with the other (type II)
(Figure 8) with energies in the range 5–50 kJmol -1 . Organic carbonyl compounds show
this behaviour well in the solid state and calculations have suggested that type II
interactionshave an energy ~20 kJ mol -1 which is comparable to a moderately strong
hydrogen bond.The boiling point of ketones such as acetone (56 ºC), however,
demonstrates that dipole–dipole interactions of this type are relatively weak in solution.
Fig. 3.3.8: Dipole-dipoleinteractionsincarbonyls

1. Self-assembly and self-organization
Self-assembly is the spontaneous and reversible association of molecules or ions to
form discrete/extended entities at either the molecular, covalent or the supramolecular,
non-covalentlevel. Within self-assembly processes, we must distinguish molecular self-
assembly and supramolecular self-assembly. Molecular self-assembly concerns the
formation of covalent bonds as part of a special synthetic procedure. The assembly is
subject to control by the reaction stereochemistry and the conformational features of the
intermediates, e.g.the formation of amine–aldehyde condensation macrocycles (Figure
3.3.9). The formation of supramolecular self-assemblies results from the recognition-
directed spontaneous association of a well-defined and limited number of molecular
components under the intermolecular control of the non -covalent interactions such as
coordination interactions, hydrogen bonds and dipolar interactions that hold them
together. The reversibility of supramolecular self-assembly is the key to resulting
systems’ ability toshift through the available components to form the
thermodynamically most favourable structure. In other words supramolecular self-
assembly concerns the spontaneous association of either a few or many components
resulting in the generation of either discrete oligo molecular supramolecules or of
extended polymolecular assemblies such as molecular layers, films, membranes, etc.The
name tecton (fromτέκτων:builder) has been proposed for designating the components

that undergo self-assembly.
Fig. 3.3.9: (a) The Schiff base condensation and the reduction of the product to
give an amine (b) macrocycle synthesized by aldol condensation of acetone and
[Ni(en) 3 ] 2+
Self-organization could be considered as a set intersecting self-assembly, ordered self-
assembly, that would (1) contain the systems presenting a spontaneous emergence
oforder in either space or time or both; (2) cover spatial (structural) and temporal
(dynamic)order of both equilibrium structures and of non-equilibrium, dissipative
structures, incorporating non-linear chemical processes, energy flow and the arrow of
time; (3) concern only the non-covalent, supramolecular level; (4) be multicomponent
and result inthe formation of polymolecular assemblie s presenting supramolecular
organization and long-range order (with or without regularity and periodicity) by virtue
of specific interactions operating either through recognition events between the
molecular components or in a dynamic process. The higher the degree of confinement
or order (1D,2D, 3D, 4D) of self-assembled entities, the more they may be considered
as organized (molecular layers, membranes, micelles, colloids, liquid crystals,
molecular crystals) Entities. Self-organization thus involves interaction (between parts)
and integration (ofthe interactions) leading to collective behaviour, such as is found in a
phase change or inthe generation of spatial or temporal waves. The phenomenological
description of the macroscopic features of self-organizing systems must eventually find
an etiological explanation at the microscopic, molecular, and supramolecular levels.
Self-assembly and self-organization of a supramolecular architecture are both multi step
processes implying information and instructed components of one or several types. And
these may distinguished from mere templating.Templating is a synthetically most
efficient procedure involving the use of temporary or permanent "helper" species,
oforganic or inorganic nature, for the stepwise assembly of molecular or supramolecular
structure sof high complexity. Self-assembly and self-organization require molecular
components containing two or more interaction sites and thus capable of establishing
multiple connections. Self-complementary components associate with themselves
undergoing homo assembly, whereas complementary components (pleromers) associate
with one another giving hetero assembly.

2. Host-guest compounds:
In host-guest compounds generally we consider a molecule (a ‘host’) binding another
molecule (a ‘guest’) to produce a ‘host–guest’ complex or supramolecule. Commonly
thehost is a large molecule or aggregate such as an enzyme or synthetic cyclic
compound possessing a sizeable, central hole or cavity. The guest may be a monatomic
cation, a simple inorganic anion, an ion pair or a more sophisticated molecule such as a
hormone, pheromone or neuro transmitter. More formally, the host is defined as the
molecular entity possessing convergent binding sites (e.g.Lewis basic donor atoms,
hydrogen bond donors etc.). The guest possesses divergent binding sites (e.g. a
spherical, Lewis acidic metal cation or hydrogen bond accept or halide anion). In turn a
binding site is defined as a region of the host or guest capable of taking part in a non -
covalent interaction. Thehost–guest relationship has been defined by Donald Cram and
he also received the Nobel Prize with Profess or Jean-Marie Lehnand J.Pedersen for
their work in area of supramolecular chemistry.
The supramolecular host–guest chemistry generally shows the stability of a host–guest
complex in solution. The chemistry of clathrates (figure 3.3.10), or more generally,
inclusion, relates to hosts that are often stable only in the solid (crystalline) state and
dissociate on dissolution in a solvent. Gas hydrates, urea clathrates and a wide variety
of crystalline solvates fall into this category. On the other hand, molecular hosts for
ions (figure 3.3.11) such as the crown ethers, cryptands and spherands, or hosts for
neutral molecules (figure 3.3.12) such as the carcerands and cryptophanes, display
significant binding both in the solid state and in solution.
Fig. 3.3.10: Inclusion of guest molecules in cavities formed between the host
molecules in the lattice resulting in conversion of a clathrand into a clathrate

Fig. 3.3.11: Supramolecular host molecules for ions
Fig. 3.3.12: Supra molecularhostsforneutralmolecules
SOLVED PROBLEMS :
Problem 1
What is the bond range in ionic bonding?
Solution: 100 – 350 KJ mol-1
Problem 2: Show the diagram for dipole dipole interactions in carbonyl compounds.
Solution:

Que.1: Define supramolecular chemistry?
Answer: Supramolecular chemistry is a branch of science that deals with the study of the
physical, chemical, and biological properties of molecular assemblies that are bounded in a non-
covalent bond.
Que.2: Which types of interactions are considered in Supramolecular chemistry?
Answer: The supramolecular chemistry generally concerns non-covalent bonding interactions
such as ion-ion interactions, ion-dipole interactions, dipole-dipole interactions, hydrogen
bonding, cation-π interactions, anion-π interactions, π-π interactions, closed shell interactions, van
der Waals forces and crystal close packing.
03-02: Supramolecular reactivity and Catalysis

Supramolecular chemical reactivity can be predominantly utilized in accelerating or
understanding chemical reactions. There are close parallels between artificial, abiotic
supramolecular reactivity and biochemistry, for example in the st udy of enzymes and
Nature’s catalysts. Synthetic catalysts can both model natural ones and allow the design
of new different kinds of reactions. Supramolecular catalysis lies somewhere between
chemical catalysis (transition metal and organocatalysis) and b iology. Supramolecular
catalytic reactions involve binding of a welldefined substrate (reactant) to the receptor
(catalyst) and the catalytic process complete in three steps (see Figure 3.3.13)
1) Selective binding of reactant(s) based on their recognition by the receptor that may
bear reactive group(s).
2) Transformation of the bound species.
3) Release of the products and regeneration of the catalyst.
First two steps binding and transformation in this catalytic process, are the important
steps because both steps take part in the molecular recognition of the productive
substrate and require the correct molecular information in the reactive receptor.
Compared to molecular catalysis, a binding step is involved that selects the substrate
and precedes the reaction itself.
Fig.3.3.13: Schematic representation of the supramolecular catalysis process.

Supramolecular catalysis obeys the general rule stating that catalytic action consists in
stabilization of a transition state of the reaction and in the rapid release of the product
(see Figure 3.3.14). In a reaction catalyzed by the formation of a supramolecular
transition state complex, substrates are inserted into either an active site of an enzyme,
a host cavity, a layer, a micelle, a vesicle or microp ores bringing their functional groups
into a close contact for relatively long time. In addition, the incorporation can stabilize
favorable conformations of the substrates.
Functional groups in the active site or cavity such as hydrogen bonding donor or
acceptor groups can additionally exert ‘true’ catalytic action. Supramolecular catalysis
may be divided according to the type of the aggregate involved since it can be based on
a catalytic action of a macrocyclic host, that of micro emulsions, micelles or vesicles or
on the catalytic activity of mesoporous materials.
Fig.3.3.14: Transition state plots for the supramolecular catalysis process.

Catalysis by Reactive Macrocyclic Cation Receptor Molecules
The most important example for catalysis by reactive mac rocyclic cation receptors is
the deacylation of O-acetylhydroxylamine CH 3 COONH 2 in presence of the macrocyclic
polyether bearing four carbonyl groups derived from tartaric acid. The ability of [18] -
O6 macrocyclic polyethers to bind primary ammonium ions op ens the possibility to
induce chemical transformations on such substrates (see Figure 3.3.15). Activation and
orientation by binding was observed for the hydrolysis of O -acetylhydroxylamine,
which forms such a stable complex with the macrocyclic tetracarbo xylate receptor that
it remains protonated and bound even at neutral pH, despite the low pKa (ca. 2.15) of
the free species. As a consequence, its hydrolysis is accelerated and exclusively gives
acetate and hydroxylamine, whereas in the presence of K+ ions , which displace the
substrate, it yields also acetylhydroxamic acid, CH 3 CONH-OH (ca. 50%). Thus, strong
binding may be sufficient for markedly accelerating a reaction and affecting its course,
a result that also bears on enzyme-catalysed reactions. Chemical transformations may
be induced by reaction between a bound substrate and functional groups borne by the
macrocyclic receptor unit.

Fig.3.3.15: Scheme of binding of a primary ammonium group by the NH3+ to the
cavity of [18]-O6 macrocyclic polyether.
Ester cleavage processes have been most frequently investigated in enzyme model
studies. Macrocyclic polyethers fitted with side chains bearing thiol groups cleave
activated esters with marked rate enhancements and chiral discrimination between
optically active substrate. The tetraL-cysteinyl derivative of macrocycle [18] -O 6
polyether binds p-nitrophenyl (PNP) esters of amino acids and peptides, and reacts with
the bound species, releasing p-nitrophenol as shown in Figure 3.3.16. The reaction
displays (1) substrate selectivity with (2) marked rate enhancements in favor of
dipeptide ester substrates, (3) inhibition by complexable metal cations that displace the
bound substrate, (4) high chiral recognition between enantiomeric dipeptide esters, and
(5) slow but definite catalytic turnover.
Fig.3.3.16: Schematic representation of the complex of receptor [18] -O6 with the
dipeptide substrate, glycyl-glycine p-nitrophenyl ester salt.
A well-understood example as mimics for transacylases has also been addressed by
Cram, who used chiral corands as shown in Figure 5, bearing thiolate nucleophiles
situated above and below the plane of the macrocycle. Corands of this type can bind
primary ammonium cations via charge-assisted N-H···O hydrogen bonds. The host is
complementary to the organic cation because of the matching of the three -fold
symmetry of the -NH 3+ group with the pseudo-six-fold arrangement of the corand

binding sites. In the case of chiral guests, chiral recognition is observed as a
consequence of steric interactions between the substituents on the naphthenyl groups ( -
CH 2 SH in corand) and the substituents on the guest. Guest binding was accompanied by
transacylation, in which an acyl group is transferred from guest to the host thiol group
as a result of nucleophilic attack by the thiol (see Figure 3.3.17). In each case, the
resolved S-host was used, and it was found that in the intermediate the stabilisation of
the S-host/Lamino ester pair was significantly greater than the S –D diastereoisomer.
The system thus displays kinetic selectivity in the sense that the substrates of L -
handedness react more quickly than those of D -chirality because the reaction transition
state is more stable for the S–L pair. This kinetic selectivity depends strongly on the
nature of the amino acid derivative, which determines the identity of the R group on the
substrate. For small amino esters such as alanine derivatives (R = Me), the ratio
kS,L/kR,L is 1, i.e. no selectivity. The selectivity increases rapidly with the bulk of R,
however, with rate selectivity factors of 6.4 for R = Me 2 CHCH 2 , 8.2 for R = C 6 H 5 CH 2
and 9.4 for R = Me 3 CH.
Fig.3.3.17: Key features of chiral corandtransacylase mimics.
Fig.3.3.18: Scheme of transacylation step carried out by above described corand

(Ar = p - C 6 H 4 NO 2 )
Hydrogen transfer has been induced with macrocyclic receptors bearing 1,4 -
dihydropyridyl (DHP) groups. Bound pyridinium substrates are reduced by hydrogen

transfer from DHP side chains within the supramolecular species (1); the first order
intra complex reaction is inhibited and becomes bimolecular on displacement of the
bound substrate by complexable cations. Reactions with carbonyl or sulphonium
substrates have been performed with other DHP containing macrocycles, such as (2).
4. Catalysis by Reactive Anion Receptor Molecules

Generally, the anion hosts are also obey the same rules that govern the magnitude of
binding constants and host selectivity in cation hosts (primarily based on
preorganisation, complementarity, salvation and size and shap e effects), their
application is made much more diffi cult because of some of the intrinsic properties of
anions, listed below.
 Anions are relatively large and therefore require receptors of considerably
greater size than cations. For example, one of the s mallest anions, F-, is
comparable in ionic radius to K+ (1.33Å versus 1.38Å).
 Even simple inorganic anions occur in a range of shapes and geometries, e.g.
spherical (halides), linear (SCN - , N 3 - ), planar (NO 3 -, PtCl 4 2-), tetrahedral (PO 4 3- ,
SO 4 2- ), octahedral (PF 6 - , Fe(CN) 6 3- ) as well as more complicated examples as in
the case of biologically important oligophosphate anions.
 In comparison to cations of similar size, anions have high free energies of
solvation and hence anion hosts must compete more effectively with the
surrounding medium, e.g. ΔG hydration (F-) = -465 kJ mol-1, ΔG hydration(K+)
= -295 kJ mol-1.

 Many anions exist only in a relatively narrow pH window, which can cause
problems especially in the case of receptors based upon polyammon ium salts
where the host may not be fully protonated in the pH region in which the anion
is present in the desired form.
 Anions are usually coordinatively saturated and therefore bind only via weak
forces such as hydrogen bonding and van der Waals interact ions, although they
can form dative bonds.
The development of anion coordination chemistry and anion receptor molecules has
made it possible to perform molecular catalysis on anionic substrates of chemical and
biochemical interest, such as adenosine tripho sphate (ATP). ATP hydrolysis was found'
to be catalyzed by a number of protonated macrocyclic polyamines. In particular, [24] -
N6O2 (3) strongly binds ATP and markedly accelerates its hydrolysis to ADP and
inorganic phosphate over a wide pH range. The react ion presents first-order kinetics
and is catalytic with turnover. It proceeds via initial formation of a complex between
ATP and protonated (3), followed by an intracomplex reaction which may involve a
combination of acid, electrostatic, and nucleophilic c atalysis. Structure (4) represents
one possible binding mode of the ATP-(3) complex and indicates how cleavage of the
terminal phosphoryl groups might take place. A transient intermediate, identified as
phosphoramidate (5), is formed by phosphorylation of the macrocycle by ATP and is
subsequently hydrolyzed. Studies with analogues of ATP indicated that the mechanism
was dissociative in character within a preassociative scheme resulting from
receptorsubstrate binding. In this process, catalyst (3) presents p rototypical ATPase
activity; i.e., it behaves as a proto ATPase.
Multiple recognition and catalysis in ATP hydrolysis with increased ATP/ADP

selectivity has been achieved with a multifunctional anion receptor containing a
macrocyclic polyamine as anion binding site, an acridine group as stacking site and a
catalytic site for hydrolysis (structure (6)). Phosphoryl transfer is accelerated by other
types of hydrogen-bonding receptors.

5. Catalysis with Cyclophane Type Receptors
The term ‘cyclophane’ literally means any organic molecule containing a bridged
aromatic ring. By definition, cyclophane hosts (e. g. calixarenes and resorcarenes) must
contain at least one macrocyclic ring and thus must achieve closure by some means of
curvature. Cyclophane hosts commonly bind both neutral molecules and organic
cations, and there is sometimes even some ambiguity as to whether a guest is
protonated by, for example, a hydrogen bond acid host or vice versa, resulting in
charge-assisted binding. Cyclophanes may or may not contain a molecular cavity large
enough to host guest species, but in some cases cavities are unnecessary to achieve high
binding affinity as long as binding sites exhibiting stereoelectronic (steric and
electronic) complementary to the guest and are properly positioned (preorganised) on
the surface of the host. Thus cyclophanes can exhibit capsular or nesting types of
binding, or even apolar surface interactions, often leading to aggregation. Cavities are
frequently encountered however, because of the entropic and enthalpic gains associated
with spherical or three-dimensional encapsulation of the guest by a host with
convergent binding sites. A number of studies have made use of functionalized
cyclophanes for developing supramolecular catalysts and enzyme models. Their
catalytic behaviour is based on the implementation of electrostatic, hydrophobic and
metal coordination features for effecting various reactions in aqueous media.
Hydrophobic species bearing hydrocarbon chains pre sent vitamin B12 or vitamin B6
type activity. Such systems lend themselves to inclusion in membrane or micellar
media. They thus provide a link with catalysis in more or less organized media such as
membranes, vesicles, micelles, polymers. Water soluble cy clophanes showing, for
example, transaminase, acetyl transfer, pyruvate oxidase or nucleophilic substitution
activity have been described. Cyclophane catalysts offer a rich playground for
developing novel reactions and enzyme models in view of the variety of their structural
types, the large cavities they contain and the possibility to attach several functional
groups.
6. Supramolecular Metallocatalysis
Supramolecular metallocatalysts consist in principle of the combination of a
recognition subunit (such as a macrocycle, a cyclodextrin, a cyclophane, etc.) that

selects the substrate(s) and of a metal ion, bound to another subunit that is the reactive
site. Complexed metal ions presenting free coordination positions may present a variety
of substrate activation and functionalization properties. Heterotopic coreceptors such as
(7) bind simultaneously a substrate and a metal ion bringing them into proximity, thus
potentially allowing reaction between them. Approaches towards the development of
artificial metalloenzymes have been made, based on cyclodextrins or macrocycles and
involving various metal ions, such as Zn(ll), Cu(ll), Co(lll), for facilitating hydrolysis,
epoxidation, hydrogen transfer, etc. Metalloporphyrins have been used for epoxidation
and hydroxylation and a phosphine-rhodium complex for isomerization and
hydrogenation. Cytochrome P-450 model systems are represented by a porphyrin -
bridged cyclophane, macrobicyclic transition metal cyclidenes or β -cyclodextrin-linked
porphyrin complexes that may bind substrates and perform oxygenation reactions on
them. A cyclodextrin connected to a coenzyme B12 unit forms a potential enzyme -
coenzyme mimic. Recognition directed, specific DNA cleavage reagents also make use
of the reactivity features of various complexed metallic sites. The remarkable
facilitation of amide hydrolysis by dinuclear copper complexes and related processes
may open routes towards metallo cleavage of proteins. Selective metalloprocesses, in
particular asymmetric reactions utilizing externa l chiral ligands, such as hydrogenation,
epoxidation, hydroxylation, etc. are of great value for organic synthesis and are being
actively investigated. Supermolecular metallo catalysts, by combining a substrate
recognition unit with a catalytic metallic site, offer powerful entries to catalysts
presenting shape, regio and stereoselectivity.
7. Cocatalysis: Catalysis of Synthetic Reactions

A further step lies in the design of systems capable of inducing bond formation rather
than bond cleavage, thus effecting synthetic reactions as compared to degradative ones.
To this end, the presence of several binding and reactive groups is essential. Such is the
case for coreceptor molecules (7) in which subunits may cooperate for substrate binding
and transformation. They should be able to perform cocatalysis by bringing together
substrate(s) and cofactor(s) and mediating reactions between them within the
supramolecular structure (Figure 5).

Figure 5: Schematic illustration of cocatalysis processes: group transfer an d ligation
reactions occuring within the supramolecular complex formed by the binding of
substrates to the two macrocyclic subunits of a macrotricyclic coreceptor molecule.
Figure 6: Cocatalysis: pyrophosphate synthesis by phosphoryl transfer mediated b y

macrocycle (3) via the phosphorylated intermediate (5).
Processes of this type have been realized in supramolecular phosphorylation reactions.
Indeed, the same [24]-N 6 O 2 macrocycle (3) as that already used in the studies of ATP
hydrolysis was also found to mediate the synthesis of pyrophosphate from
acetylphosphate (AcP). Substrate consumption was accelerated and catalytic with
turnover following the steps: (1) substrate AcP binding by the protonated molecular
catalyst (3); (2) phosphorylation of (3) within the supramolecular complex, giving the
phosphorylated intermediate PN (5); (3) binding of the substrate HPO42 - (P); (4)
phosphoryl transfer from PN to P with formation of pyrophosphate PP (Figure 6); (5)
release of the product and of the free catalyst f or a new cycle. PP is also formed in the
hydrolysis of ATP in the presence of divalent metal ions. The fact that (3) is a ditopic
coreceptor containing two diethylenetriamine subunits is of special significance for
both PN and PP formation. These subunits may cooperate in binding AcP and activating
it for phosphoryl transfer via the ammonium sites, in providing an unprotonated

nitrogen site for PN formation and in mediating phosphoryl transfer from PN 81 to P.
Thus (3) would combine electrostatic and nucleophilic catalysis in a defined structural
arrangement suitable for PP synthesis via two successive phosphoryl transfers,
displaying kinase type activity (Figure 3.3.16). This process was extended to the
phosphorylation of various substrates, in particular t o the synthesis of ATP from ADP in
mixed solvent and in aqueous solution in the presence of Mg2+, probably via formation
of a ternary catalytic species (8). The latter abiotic ATP generating system has been
coupled to sets of ATP consuming enzymes resultin g in the production of NADH by a
combined artificial/natural enzymatic process (Figure 3.3.18).
Figure 3.3.18: Sequence of transformations catalysed by the supramolecular ATP -

generating system [(3), AcP, Mg2+, ADP] ((3) = [24] -N6O2) and the enzymes
hexokinase (HK), glucose-6-phosphate dehydrogenase (G-6-PDH) and 6-phospho-
gluconate dehydrogenase (6-P-GDH).
Templates possessing two hydrogen bonding subunits bind two substrates forming a
ternary complex in which the substrates are positioned so as to facilitate bond
formation between them. In a related way, the rate and stereoselectivity of a
bimolecular Diels-Alder reaction are substantially increased by binding both the diene
and the dienophile within the cavity of a trisporphyrin macrocycle. A macro bicyclic
thiazolium cyclophane (9) functions as a model of thiamine pyrophosphate -dependent
ligases and effects benzoin condensations. Acyl transfer is catalysed by formation of a
ternary complex between a cyclophane receptor and two substrates. Difunction al
binding and catalysis has been observed in functionalized cyclodextrins and in a
hydrogen bonding cleft. Functionalized crown ethers have been used as reagent for
peptide synthesis.
8. Biomolecular and Abiotic Catalysis
The design of supramolecular catalysts may make use of biological materials and
processes for tailoring appropriate recognition sites and achieving high rates and
selectivities of reactions. Modified enzymes obtained by chemical mutation or by
protein engineering represent biochemical app roaches to artificial catalysts. This is also
the case for the generation of catalytic proteins by induction of antibodies. Antibodies

to reactive haptensare able to facilitate the transformation of the bound species.
Generating antibodies against analogues of transition states should lead to transition
state stabilization and facilitate the process. Such catalytic antibodies or abzymes have
been produced for a variety of reaction and an active field of research has developed
along such lines. It represents an approach to substrate specific, efficient and selective
catalysis of supramolecular type which is of much basic and applied interest. The strong
affinity for the transition state (TS) of the reaction of a given substrate leads it along
the way and thus facilitates the process. In line with the remarks made at the beginning
of this chapter, the antibodies should be generated not against a transition state
analogues (TSA) itself but against a (TSA-X) isoster lacking the group(s) X, which
belong(s) to the reactive function(s) of the protein that is (are) expected to perform the
reaction. This requires designing a (TSA-X) species in which the face presenting the ( -
X) gap be ideally chosen so as to lead to the induction in the antibody of the desired
reactive functional group at the correct position.
SOLVED PROBLEMS:
Problem 3: Which are the main factors for catalytic activity?
Solution: Functional groups in the active site or cavity such as hydrogen bonding donor or
acceptor groups can additionally exert ‘true’ catalytic action.
Problem 4: Draw schematic representation of the supramolecular catalysis process?
Solution:

Que.3: Give the three steps involved in calalysis?
Answer: 1) Selective binding of reactant(s) based on their recognition by the receptor that may
2) Transformation of the bound species.
3) Release of the products and regeneration of the catalyst.
Que 4: What is Guest and Host compound?
Answer: The host is a large molecule or aggregate such as an enzyme or synthetic cyclic
compound possessing a sizeable, central hole or cavity. The guest may be a monatomic cation, a
simple inorganic anion, an ion pair or a more sophisticated molecule such as a hormone,
pheromone or neurotransmitter.

Que.5: Which general rule is obeyed by supramolecular catalysis?
Answer: Supramolecular catalysis obeys the general rule stating that catalytic action consists in
stabilization of a transition state of the reaction and in the rapid release of the product.
03-03: CRYPTS AND CROWN ETHERS

INTRODUCTION
Crypts and crown ethers constitute an important and an interesting class of complexing
ligands. Apart from metal complexes, a variety of unusual species among which
'alkalides' and' electrides' was made possible through them and they require special
mention.Thecrowns and crypts are enormously studied due to their increasing
applications varied chemical and physical processes. Their use as biochemical models
further draws greater interest towards them.
STRUCTURE OF CROWN ETHERS AND CRYPTS:

The study of crown ethers grew enormously after Pedersen’s finding of crown ethers
and their abilities to bind strongly with metal ions in 1967. When the Nobel was
conferred upon the three chemists Pederson, Cramand Lehnin 1987, the advances in
host guest and supramolecular chemistry gained special attention. The development of
this field was becauseof the remarkable properties of crown ethers. Crypts and crown
ethers have an interesting property to form complexes even with many slowly reacting
alkali metals. This property made possible things including pulling ionic substances
into organic solvents, which is very difficult as such. Ions of all sizes fit into cavity
sizes which are apt for them. Since the ionic radius of group 1 metals increase down the
group, thus, lithium, sodium and potassium aresaid to be compatible with 12 -, 15- and
18- membered rings respectively. Biological systems employ crowns and crypts widely,
especially to understand the perplexing and very efficient selectivity between Na + and
K + ions. Crown ethers (or crowns) are known as a group of macrocyclic polyethers. The
structure has ethereal oxygen atoms are separated by two methylene (CH 2 -) groups. A
classical example of crown ether is 2, 3, 11, 12-dibenzo 1, 4, 7, 10, 13, 16-
hexaoxacyclooctadeca-2, single 11-diene which is designated as dibenzo -18-Crown-6
(or simply 18-C-6 or Crown-6 as handynotations) has the structure which is depicted
given in Figure 1. The crown ether’s na medibenzo-18-Crown-6 shows that there are two
benzene rings and 18 atoms form the crown -shaped ring. The ring consists of 6 are
oxygen atoms. Thus, we can say that, when n depicts the ring size, m is the number of
etherealoxygen atoms, the crown ether can thus be abbreviated asnC-m. Crown ethers
which possess 3-20 ethereal oxygen atoms are nowknown. Apart from the cavity which
encapsulates the metal ion in it, the remaining part of the molecule Iispuckered to give
a crown-like arrangement and hence the name‘crown ethers’.

Many macropolycyclic ligands which are related to each other are also known to
us and arecalled as ‘cryptates’ (or cryptands or simply, crypts). They are more potent,
stronger and selective complexing agents for alkali metals. Crypts contain nitrogen,
oxygen and sometimes phosphorus and sulfur atoms in their core structure. They are for
the same reason considered as the 3D equivalents of crown ethers. The molecules are
cross-linked appropriately with donor atoms correctly positioned in the bridging group
in orderencapsulate metal ions in structures having cage-like formations.
A typical crypt is the molecule called Crypt -222 (222 denotes the no. of ethereal
oxygenatoms in each N-N bridge) having the basic structure given in Figure 3.3.1 9.
Cryptates (meaning hidden) are so called because they wrap around and hide the cation.
It is because of thepolyether bridges formed between the two N atoms which resemble
the seams of a football –that this class of crypts is really known as 'football li gands'.
Entire class of these ligands formscomplexes with veryhigh formation constants.
Fig. 3.3.19: A: Graphic structure of 18-Crown-6, a macrocyclic polyether; the

cavity [•] size depends on the size of the ring. Metal cation which is appropriately
size is trapped in this cavityto forming a stable complex.
B. Graphic structure depiction of a cryptand; in this structure, when oxygen atoms

occupy [•] positions it is Crypt-222; Mixed donor cryptates result when S atoms or
others occupy these.The ligands encapsulate metal ions in cage-like structures and
form highly stable complexes.
NOVELCROWN ETHERS ANDIMPORTANT P ROPERTIES

The crown ethers having other varied and uniquely interesting functions are at the
crucialstages of development. An example is the co mpound in Figure 3.3.20 changes its
colour when itcaptures an ion like sodium. There’s a possibility that it can be employed
to make iondetectors.

Fig.3.3.20: Coloured crownether
Efforts in research areas have also been made to enhance the ion -capturing ability of
crownethers. The lariat crown developed by Professor Seiji Shinkai of Kyushu
University in Japanhas a long chain as its name suggests (Figure 3.3.21). It uses this
chain to wrap around the ion,“fixing”the complexsothat theion won’t escape.
Fig.3.3.21: Lariatcrown
Taking the idea a level ahead, Professor Jean Mary Lehn in France synthesized the
double-cyclic crown ether. Professor Jean Mary Lehn and his team gave the molecule
cryptand itsname after theGreekterm crypto, which means “to hide” (Figure 3.3.22).
The two rings ofcryptand provide extra strength to hold the ion. In case regular crown
ether “surrounds” anion, a cryptand “locks it up”. This ion -capturing capability of a
cryptand can reach upto ahundredthousand time’s morethan that of 18-crown-6.

Fig.3.3.22: Crypt and capturing an ion and pictureof another cryptand
SYNTHESIS OF CROWN ETHERS AND CRYPTANDS

In an attempt to prepare alkyl phenolic ether, the first synthesis of crowns was
achieved.Instead of the expected product, the contaminating catechol present in the
reaction mixture, formation of a different product was observed by the chemists. The
isolated product wasfound to be dibenzo-18-Crown-6. Numerous other crowns were
subsequently prepared inPederson's laboratory. Later on Pederson followed the
synthesis and characterisation of a variety of crowns and crypts as well as their metal
complexes, e.g.sepulchrates, anionic crypts and inorganiccrypts.
A short note on synthesis of sepulchrates, anionic crypts and inorganic crypts :

Sepulchrates:
They are a group of multi cyclic encapsulating ligands called 'sepulchrates'
which are related closely to the football ligands.These are synthesized around a metal
ion which can not be released. Condensation of formaldehyde and ammonia on to the N
atoms of Co(en) 3 3+ (en=ethylenediamine) gives rise to a sephulchrate containing tris

(methylene) amino capson opposite faces of the coordination octahedron. Sepulchrates
are stable over large pH ranges. This makes the investigation of solution chemistry of
elements like Mo,W which are proneto hydrolysis and polymerization by changes in
pH, simpler.
Anionic Crypts: Although cationic crypts have dominated in its complexes with alkali
and few other metal cations for a long time-recently. Anionic crypts viz.,
[CIN(CH 2 CH 2 NHCH 2 CH 2 NHCH 2 CH 2 ) 3 N] - have also come into existence. Inorganic
Crypts: Inorganic crypts may also surround a metal cation completely. They are of
organic origin, just like the crowns and crypts; one such compound reported by Vogtle
and Weber is (NH 4 ) 17 Na [NaW 21 Sb 9 O 86 ].14H 2 O where the hetero polytungstate, an
inorganic crypt, completely surrounds the Na + ion. This compound is reported to have
antiviral activity.
APPLICATION AND USES OF CROWN ETHERS AND CRYPTS

Crowns and crypts find many important applications and uses. These include
preparative organic chemistry, solvent extraction, phase transfer catalysis, stabilization

of uncommon or reactive oxidation states and the promotion of other improbable
reactions.
Few classical examples are listed below:
1. The enhancement of solubility of alkali metal salts in organic media can be
assisted using crowns and crypts. This is because they contain large hydrophobic
organic ring in the ligand; e.g. KOH and KMnO 4 can be used as an alkali and an
oxidising agent, respectively in organic media also.
2. Various zintlsaIts containing alkali metal cation as well as zintl anions viz.
Te 3 2-, Sb 7 3-,Bi 4 2-,Sn 5 2-,Pb 5 2-and Sn 9 4-have been prepared with the help of
crowns and crypts in anhydrous solvent.
3. Mixed metal complexes of the alkalis can be prepared by the exploitation of
selectivityand differential stabilities of alkalides and metal complexes. For
example, a K-Na alloyreacts with the crown 18-C-6 to give [K(8-C-6)] + Na - as
the product which contains both the alkali metals, oneas cation and other as
anion.
4. Crown ethers can also act as second coordination sphere ligands e.g.
[Pt(bipy)(NH 3 ) 2 ] 2+ is known to produce a crystalline compound
[Pt(bipy)(NH 3 )(18-C-6)] 2+ with18-C-6.
SOLVED PROBLEMS:
Problem 5: How the solubility of alkali metal salts in organic media is assisted?
Solution: The enhancement of solubility of alkali metal salts in organic media can be assisted
using crowns and crypts. This is because they contain large hydrophobic organic ring in the
ligand.
Problem 6: What is the name of the following compound?
Solution:

Que.5: What are crown ethers?
Answer: Macrocyclic polyethers are called crown ethers.
Que.6: Give one example of crypt?
Answer: Crypt-222
03-04: CAGED MOLECULES

INTRODUCTION:
The dictionary meaning of the word "cage" says that it is a closed pattern
having space in the middlewhere something can be located. In the similar
pattern of definition, caged molecule in chemistry is a polycyclic compound
that contains atoms connected with one another in such a way that an enclosed
space is created where other atom or molecules can be located. According to
the definition of IUPAC, a cage compound is a ‘polycyclic compound with the
shape of a cage’. An organic cage molecule is as an organic molecule where
the backbone consists of carbon–carbon (C-C) bonds and/or other functional
groups which are found in organic molecules. There are also inorganic or
coordination caged molecules. In general, a caged molecule is a shape -
persistent macrocycles that have a defined interior space, large enough to host
other molecules, and do not crumple to a more dense or twisted structure
(Figure 3.3.23).
During 1960’s to 1980’s period, three platonic shaped hydrocarbon
molecules such as tetrahedrane, cubane and dodecahedrane (Figure 3.3.23) had
been targeted for several multistep syntheses. The caged polycyclic compounds
had drawn the interest of synthetic chemists due to their strained nature and
unusual reactivity patterns. The caged molecules were found to be useful in
different drugs, supramolecules and high-energy materials.

Figure3.3.23: Chemical structure of some caged molecules
On the basis of types of atoms involved, caged molecules are classified as homoatomic
rings andheteroatomic rings. The caged molecule having same atoms are homoatomic
rings like the white phosphorus (P) whichexists in perfect tetrahedral of P 4 .
The caged molecule having more than one type of atoms involved are called
heteroatomic cages which includes polymetal clusters, iron-molybdenum-sulfur clusters
(Fe 3 MoS 4 ) having the cubane-like framework, adamantane-like P 4 O 6 , carbosilanes etc.
The metal–organic frameworks (MOFs) are also an example of heteroatomic caged
molecules. They are crystalline polymeric coordination networks which have metal
centers and ligands that form a three dimensional archite ctures with potential inner
porosity. A variety of metal–organic caged molecules are known that encapsulate
appropriate guests on the basis of non-covalent interactions like Coulomb, vander
Waals, ion-association forces, hydrogen bonding and steric interactions.
Another important caged molecule is cyclodextrins (CDs) (Figure 3.3.24). They
are synthetic substances obtained from the enzymatic degradation of polysaccharides.
The core of their structure is consists of a stable hydrophobic cavity that can
encapsulate other molecules. The applications of CDsare foundin all sectors of industry
such as food, pharmaceutical, chemistry, chromatography, biotechnology, agriculture,
cosmetics, hygiene, medicine, textiles, and the environment. Other specialized
applications include the formulation of detergents, glues and adhesives, the industry of
fibers and paper and the sector of plastics.
Fig. 3.3.24a: Chemical structure of -Cyclodextrin

Fig.3.3.24b: Chemicalstructuresofβ-Cyclodextrin andɣ-Cyclodextrin
SYNTHESIS OF SOME CAGED COMPOUNDS

The caged compounds possessing organic molecules can be synthesized by two popular
methods.
(i) Irreversible bond formation method like cross-coupling reactions or amidation,
and
(ii) Reversible bond formation method.
IRREVERSIBLE BOND FORMATION METHOD
Using amide-bond formation: In this method of synthesis,the final cyclization step
leading to thecage compound synthesis is due to the formation of one or more amide
bonds. The Raymond group have synthesized caged molecule (1) using iron(III)cations
as a template to pre-organize three catechol (2) units that further reacts with tris(2-
aminoethyl)amine (TREN, 4) in remarkable 70% yields (Figure 3.3.25). Davis group
has synthesized another monosaccharide receptor caged molecule bycyclization of
compounds 5 and 6(Figure 3.3.26).

Fig.3.3.25: Synthesis ofcaged molecule byRaymondgroup
Fig.3.3.26: Synthesis of caged molecule by Davis group
Using nucleophilic aromatic csubstitutions: The nucleophilic substitution reactions

form stable covalent bond to give smaller [2+3] caged molecules (Scheme 3). The
caesium cation might have atemplate effect and it preorganizes the 2,6 -
dichloropyridine-3,5-dicarbonitrile (8) which further reacts with benzene-1,3,5-triol(9)
to give the caged molecule 10 (Figure 3.3.27).
Fig. 3.3.27: Synthesis of small cage molecule using nucleophilic substitution

reaction
Using the formation of carbon–carbon bonds: Using this method, caged compounds
with a fully carbon–carbon bonded backbone can be prepared. They are very important
synthetic targets due to their chemical and thermal stability and photophysical
properties.The major problem with this method is the overall yields which is quite low.
An important macrobicycle 11 was synthesized by Moore and co-workers in amultistep
Sonogashira–Hagihara approach.

REVERSIBLE BOND FORMATIONMETHOD
Another method to prepare caged compounds is the use of reversible covalent bond
formation. This isa type of self-healing processes of bond making and breaking to
achieve a thermodynamic stableproduct.
Using imine bond formation: The imine bond (>C=N-) formation takes place by the
condensation ofamines and aldehydes/ketones. This bond formation is very frequently
used in the synthesis of largecaged molecules. A large [4+4] c age was synthesized by
linking a bowl-shaped ruthenium complexpossessing three aldehyde groups with an
extended adamantane-cored triamine (Figure 3.3.28). Anotherlarge caged molecule
[12+8] was synthesized by the reaction of 4-tert-butyl-2,6-diformyl phenol and1,3,5-
triaminocyclohexane by Skowroneketal (Figure 3.3.29). It has been observed that the
entropy ofthe caged molecules contributes in the cage formation process. The higher
symmetrical cages are entropically more favoured in comparison to lower symmetric
caged molecule.
Fig.3.3.28: Synthesis ofa [4+4] cage by connection of metallamacrocycles via

imine bonds.

Fig.3.3.29: Synthesis of an octahedral [12+8] cage
STABILITYOFREACTIVECOMPOUNDS
The space inside the caged molecules is generally called cavity of a cage. This space is
an ideal spacefor any molecule to get encapsulated with appropriate size. By using
appropriate cages, the reactive speciescan be protected from the outer environment and
stabilized for a longertime.
RECOGNITION OFGUESTIONSORMOLECULES
The host-guest chemistry is known from the early days. The presence of appropriate
size and well defined cavity of caged molecule make them an ideal host for recognition
of varied guest ions or molecules. The small cations, like Li+, Na+ and K+, are usually
bound at the outside of the cage, whereas the larger cations, like Rb+ and Cs+, are
bound inside the cage (Figure 3.3.30). Zhang and co - workers reported the synthesis of
a rigid porphyrin-based cage compound, which showed high selectivity (>10 00) in
binding C70 compound over C60.
Fig.3.3.29: Synthesis of caged molecule by imine and olefin metathesis

Fig.3.3.30: Recognition of ions by caged molecules
CAGEDMOLECULESASPERMANENTPOROUSMATERIALS
The caged molecules also showed a zeolitic behavior and played the role of permanent
porous materials. The porosity behavior can be switched on and off by changing the
polymorphism of crystalline cages influenced by the solvent employed.
IONICTRANSPORT
The metal–organic polyhedral (MOP) cages are actively involved in the ionic transport
and single molecule detection behavior. They are employed for both cationic and
anionic transport. For example, Furukawa et al. synthesized a charge -neutral MOP-18,
[(Cu2)12-(5-dodecyloxy-1,3- benzenedicarboxylate) 24]. This caged compound had
overall size of 5 nm having a hydrophilic cuboctahedral core cavity with the diameter
of 13.8 Å. This was used in the preparation of synthetic ion channel that has
successfully been used to transport protons and alkali -metal ions across the lipid
membranes.
PHARMACEUTICALAPPLICATIONS
The caged compounds have been successfully applied in drug delivery to specific
locations within the human body. The metal–organic self-assemblies with proper
functionalities and appealing drug hosting and release potential are a new input to the
field. The caged molecules offer storage, carriers and controlled release. Literature is
filled with publications where the use of caged molecules in drug release studied.
03-05: Catenanes and Rotaxanes

Introduction:
In the late 1970s, emerged a new branch of chemistry, called supramolecular chemistry,
and it has managed to expand very rapidly, consecrated by the award of the Nobel Prize
in Chemistry which was conferred upon C. J. Pedersen, D. J. Cram, and J. -M. Lehn in
1987. Catenanes and rotaxanes differ from all other organic compounds synthesized to

this date in a way that molecular subunits are linked mechanically. Catenane is a
compound consisting of two or more rings that are interlocked mechan ically without
there being necessarily any chemical interaction/bond between the two. Generally,
without breaking a chemical bond, the rings cannot be separated. Catenane is derived
from the Latin catena meaning "chain". In recent times the terminology "me chanical
bond" has been coined and it is the connection between the macrocycles of a catenane.
Rotaxanes are long, fairly linear molecules consisting of a "dumbbell shaped molecule"
threaded through a macrocyclic ring, like cotton threads through the eye o f a needle.
The name is derived from the Latin for wheel (rota) and axle (axis). Same as catenanes,
rotaxanes also cannot decompose into ring and chain without breaking chemical bonds.
Hence, the bulky groups terminate the linear, chain part of the molecul e and it is too
large to fit through the cyclic fragment. Rotaxanes without such physical barriers, in
which the thread can leave the needle, are called pseudorotaxanes. Pseudorotaxanes are
necessary precursors for both rotaxanesand catenanes.
Chemical Topology of rotaxanes and catenanes

Acompound canbeusuallydescribed, unequivocally,by:
1. Theorderin whichgiven numbersofatomsarejoined
2. Thetypeofbondswhichconnectthem
3. Theconfigurationatasymmetricatomsorrigidcenters
4. Theconformation
5. Thetopology
Chemical topology deals with the structure and the property differences of compounds
which are identical with regard to the afore mentioned first three points and which in
spite of tha cannot be interconverted by conformational changes, such as rotation about
an axis or modification of bond angles. Compounds which can be suitably classified in
this manner were called as ‘Topological Isomers’ by Frisch and Wasserman. Catenane 1
and the twice threaded catenane 6 are thus topological isomers and for similar reasons
as stated above, arotaxanesis not isomeric with its molecular subunits.

Fig. 3.3.31: Consider these catenanes in the figure. Since there is no chemical bond
between the two rings Frisch et al call it as a mechanical bond whereas, Frisch and
Wasserman suggested topological bond as a name.
Nomenclature of Catenanes and Rotaxanes
The nomenclature of catenanes is decided by the number of rings, i.e.how many number
ofrings interlocked to each other, e.g. a [2]-catenane consists of two interlocked rings
(fig. 3.3.32). Analog ‘ane’ used in the end which is similar to alkanes. A catenane
mainly consists of an organic fragment; it rarely consists of hydrocarbon moieties. The
terms [n]-catenandand [n]- catenate are also used analogously with cryptand and
cryptate, for a metal center which issuitably interlocked in the ring system of a
catenane acting as a ligand. The catenand is thefree ligand that forms a catenate
complex in the presence of metal center. Rotaxanes can benamedin an analogous
manner too.
In the case of unbranched species such an umbering system is not necessary. The names
of the rings forming a branch to the main chain are numbered with subscripts and
placed together with the ring on which the branching takes place in one bracket.
Fig. 3.3.32: Nomenclature of catenanes, rotaxanes and pseudorotaxanes
In catenanes and rotaxanes containing multiple windings it is also necessary to

designate the winding number α. The quantity α represents the number of times one
macrocycle winds about the other. Catenanes which formaring with themselves as
designated as cyclocatenanes. The examples below will clarify the concept of
nomenclature.

Fig. 3.3.33: Concept of nomenclatre of catenanes and rotaxanes
Steriochemistry of Catenanes and Rotaxanes
Stereochemistry of catenanes and rotaxanes is not a very highly explored topic except
for discussion on simple structures of catenanes in particular. Rotaxanes have been very
minimally dealt with in this area of study. Here we shall discuss all the possible cases
of stereochemistry of both catenanes and rotaxanes.
Catenanes
The stereochemistry of simpler carbocyclic [2]-catenanes can be categorized as follows:
1. Catenanes bearing no substituents do not occur as antipodes (antipodes are

synonymous with enantiomers or optical isomers).
2. Catenanes having substituents in only one of the two rings are stereochemically
related to the corresponding uncatenated macrocycles.
3. Catenanes in which each subunit contains two substituents located on the same ring
atom are stereochemically related to allenes and spiro compounds. If each ring has
two substituents A and B, as shown in formula in the figure, a necessary and
sufficient condition for the occurrence of enantiomers is that A≠B.
Fig. 3.3.34: A necessary and sufficient condition for the occurrence of enantiomers
in catenanes in which each subunit contains two substituents located on the same
ring atom is that A≠B
4. Catenanes where each subunit contains two substituents located on different ring
atoms, generally exist as an enantiomeric pair. However, Doornbos pointed out that
this may not always be true. Consider catenane shown in the figure as an example.
In this catenane, each ring has the same two substit uents R on different ring atoms.
The segments of the individual rings of the catenanehave to be of such a nature that
the molecule possesses a fourfold alternating axis of symmetry. In this case the
catenane is achiral, although the component rings are dis symmetrical.
Fig. 3.3.35: In this catenane, each ring has the same two substituents R on different
ring atoms. In this case the catenane is achiral, although the com ponent rings are
dissymmetrical
5. A type of enantiomerism closely related catenane mentione d in point 3 was first
pointed by Closson, and in more generalized form by Prelog et al and later by
Cruse. Consider the following two catenanes which are cycloenantiomers. In order
that this difference be pertinent, each ring of a catenane must consist of atleast three
different segments, even though every segment may appear in both rings.

Fig.3.3.36: Consider the following two catenanes which are cycloenantiomers. In
order that this difference be pertinent, each ring of a catenane must consist of
atleast three different segments, even though every segment may appear in both
rings
6. Special cases may arise if one of the two rings of a catenane is so small, or has
substituents so large, that free rotation of one ring within the other is hindered. This
case is shown in the figure below wherein the enantiomers arise because the large
substituents A and B prevent free rotation of the rings. As shown in figure, the small
ring is fixed on right side by two bulky groups A and B in one enantiomer while in
the other enantiomer it is fixed on left side. Both stereoisomers should be separable
into antipodes.
Fig. 3.3.37: Figure depicting that both stereoisomers sho uld be separable into
antipodes
7. The [2]-catenane shown below in the figure having a winding number α=2, is not
identical with its mirror image and should therefore be optically active. This
isomerism corresponds to the mirror image relation which exists between an α - and
β- helices.

Fig. 3.3.38: figure showing that this isomerism corresponds to the mirror image
relation which exists between an α- and β- helices
Fig. 3.3.39: A possibility to differentiate the [3] -catenanes as depicted in the figure
below by means of optically active compounds, was pointe d first by Frisch and
Wasserman
Rotaxanes
The stereochemistry of rotaxanes closely resembles that of catenanes as illustratedwith
catenane mentioned above in point 3. In the figure of the rotaxanes shown
below,R≠R’and A≠B is achiral, itexhibits geometric isomerism.
Fig.3.3.40: In this figure if, R≠R’ and A≠B is achiral, it exhibits geometric
isomerism
As in the case of catenanes, rotaxanes may exist as cycloenantiomers. The

compoundsgiven below are mirror images, which only differ in the direction of the ring
segmentsequences.

Fig.3.3.41: The compounds in this figure are mirror images, which only differ in
the direction of the ring segment sequences
Properties and applications of Catenanes and Rotaxanes

Catenanes
An interesting property of many catenanes is the ability of the rings to rotate with
respect toone another. This rotational motion of one ring with respect to another can
often be detectedand measured by NMR spectroscopy, amongst other methods. If in the
finished catenane, molecular recognition motifs exist (usually those that were used to
synthesize the catenane), the catenane can have one or more thermodynamically
preferred positions of the rings with respect to each other. If incase, one recognition
site is a switch able moiety, amechanical molecular switch results. When a catenane is
synthesized by coordination of the macrocycles moieties around a metal ion, then
removal and re-insertion of the metal ion can switch the free motion of the rings on and
off. Thus, they can function as molecular switches.
Fig.3.3.42: Photochemically driven switching systems in catenanes

Catenanes have been synthesized by incorporation of many functional units, including
redox-active groups (e.g. viologen, TTF=tetrathiafulvalene) for making redox switches,
photo isomerizable groups (e.g.azobenzene) for photo switches, fluorescent groups for
fluorescent switches and chiral groups for optical switches. Many of these units have
been used to create molecular switches as described above, as well as for the
fabrication of molecular electronicdevices and molecular sensors.
Rotaxanes
Fig. 3.3.43: Modes of movement of rotaxanes and catenanes which enables them to
function as molecular switches
Rotaxane-based molecular machines have been of particular interest for their potential
uses in molecular electronics as logical molecular switching elements and also as
molecular shuttles. These molecular machines are usually based on the movement of
macrocycle on the dumbbell. The macrocycle can rotate around the axis of the dumbbell
like a wheel and axle or it can slide along its axis from one site to another as shown in
figure 13. By controlling the position of the macrocycle, it allows the rotaxane to
function as molecular switch. With each possible location of the macrocycle
corresponding to a different state. These rotaxane machines can be manipulated both by
chemical and photochemical inputs. Rotaxane based systems have also been
demonstrated as molecular muscles. In 2009, "domino effect" was reported from one
extremity to the other in a Glycorotaxane Molecular Machine. In this case, the 4C1 or
1C4 chair-like conformation of the mannopyrano side stopper can be controlled,
depending on the localization of the macrocycle. Unique pseudo -macrocycles consisting
of double-lasso molecular machines (also called rotamacrocycles) have been reported in
Chem. Sci. journal in 2012. These structures can be tightened or loosened depending on

varying the pH. A controllable jump rope movement was also observed in these new
molecular machines.
Fig.3.3.44: Rotaxanesas molecular switches

In the last few years, several examples of molecular machines and motors have
been designedand constructed. It should be noted, however, that the molecular level
machines described inthis module operate in solution, that is, in an incoherent fashion.
Apart from more or less futuristic applications, the extension of the concept of a
machine to the molecular level is ofinterest not only for the development of
nanotechnology, but also for the growth of basic research. Looking at supramolecular
chemistry from the view point of functions with references to devices of the
macroscopic world is indeed a very interesting exercise which introduces novel
concepts into Chemistry as a scientific discipline.
03-05: CALIXARENES
The calix[n]arenes are cyclic phenols bridged by –CH 2 - groups [RC 6 H 4 (OR) CH 2 ] n
(R=H in unsubstituted calixarene) that mayadopt different conformations according to
the value of n and R and R substituents. The most common calixarenes are n=4, they
represent particularly asignificantfamilyofmacrocyclic hosts in host -guest and
supramolecular chemistry.They exist in a ‘cup’ like shape with a defined upper and
lower rim and a central annulus (Fig. 3.3.45).The rigid conformation enables
calixarenes to act as host molecules as result of the preformed cavities. By functionally
modifying either the upper and/or lower rims it is possible to prepare various
derivatives with different selectivities for various guest ions and small molecules. The
term calixarene was the more pictorially and descriptively appealing term based on the
similarityof the basket shapes to the calix (Greek vase or chalice) and the arene which
denotes the presence of aryl groups.

Fig. 3.3.45: General Structure of calixarene
Fig. 3.3.46: p-tert-butyl calix [4] arene
The parent calixarenes are white crystalline materials characterized by high

melting points. They are insoluble in water and generally have low solubilities in most
organic solvents but after preparing derivatives they can be soluble in either medium.
Conformation
Host-guest chemistry of calixarene is of great interest, as the calyx arenes exhibit
complexing abilities with alkali, alkaline-earth metals and some transition metal cations
by means of functional group modification at the phenolic groups. Calix [4] arene is a
versatile supramolecular building block. The molecule possesses a well pre organized
cavity which accommodate guest such as metalions. Lower and upper rim of Calix [4]
arene unit can be modified to accommodate useful moieties for complexing cations,
anions and organic molecules. Calix [4] arene has also a very interesting property of
conformational interconversion which occurred by rotation of the aryl rings through the
methylene bridges. The possible conformations of calix [4] arene are cone, partial cone,
1,2-alternate and1,3-alternate (Fig. 3.3.47).

Fig. 3.3.47: Possible Conformations of Calix [4] arene
The cone conformation is the most favored among these four conformations due to the
very strong intramolecular hydrogen bonding between the four OH groups at the lower
rim of the calix. In particular, the easy accessibility of p-tert-butyl calix [4] arene has
made this member of the series increasingly popular with ligating side arms or podands
for the reception of guest species. For example, Nabeshima et al synthesized a calix [4]
arene framework bearing two ester units, two polyether units, two urea units, and two
bipyridine units and used it to recognize Na + efficiently. This fac is attributed to the
size of the ionophoric cavitycomposed of derived calyx [4] arene which is comparable
to the ion size of Na + , and also to the cone conformation which isfirmly constructed on
the rigid calyx [4] arene platform.
APPLICATIONOF CALIXARENE
Calixarenes are applied in enzyme mimetics, ion-selective electrodes or sensors,
selective membranes and optic sensors. Calixarenes are used in commercial applications
as sodium selectiveelectrodes for the measurement of sodium levelis in blood.
Calixarenes are often used as mobile phase additives for HPLC and chemically bonded
stationary phase for both GC and HPLC in chromatography. Particularly stress is given
on the sensitized luminescence of lanthanide ions complexes with calixarene
derivatives because these functional complexes how potential applications, such as
probes and labels for chemical and biological applications. Calix [4] arene was used as
scaffold to assemble a construct bearing four Tn-antigen unit, at upper rim, and the
immune adjuvant P3CS, at lower rim. The construct showed a cluster effect in the

production of Tn specific IgG antibodies in mice when compared to an analogous
monovalent construct. This reveals perspectives for potential applications in cancer
immune therapy.
SOLVED PROBLEMS:
Problem 7: What are the applications of Calixarene?
Solution: Calixarenes are applied in enzyme mimetics, ion-selective electrodes or sensors,

selective membranes and optic sensors. Calixarenes are used in commercial applications as
sodium selective electrodes for the measurement of sodium level is in blood. Calixarenes are
often used as mobile phase additives for HPLC and chemically bonded stationary phase for both
GC and HPLC in chromatography. Particularly stress is given on the sensitized luminescence of
lanthanide ions complexes with calixarene derivatives because these functional complexes how
potential applications, such as probes and labels for chemical and biological applications.Calix
[4] arene was used as scaffold to assemble a construct bearing four Tn-antigen unit, at upper rim,
and the immune adjuvant P3CS, at lower rim. The construct showed a cluster effect in the
production of Tn specific IgG antibodies in mice when compared to an analogous monovalent
construct. This reveals perspectives for potential applications in cancer immuno therapy.
Problem 8: Draw Possible Conformations of Calix [4] arene?

Solution:
Possible conformations of calix [4] arene

Que.7: What is a cage compound?
Answer: According to the definition of IUPAC, a cage compound is a ‘polycyclic compound
with the shape of a cage’.
Que.8: draw the structure of p-tert-butyl calyx [4] arene?
Answer:
p-tert-butyl calyx [4] arene
CHECK POINT 03-01

1. In ion-ion interaction as in ionic cubic lattice of solid sodium chloride in which each Na+ cation
is surrounded by ---------
(1) Five chloride ions (2) Six chloride ions
(3) Four chloride ions (4) Two chloride ions
Answer: (2) Six chloride ions
2. The guest possesses ---------- binding sites.
(1) Divergent (2) Monovergent
(3) Cation (4) Anion
Answer: (1) Divegent
3. Which of following statement is incorrect regarding the catalytic process
(1) Selective binding of reactant(s) based on their recognition by the receptor that may
(2) Transformation of the bound species.
(3) Release of the products and regeneration of the catalyst
(4) Decreases the speed of reaction
Answer: Decreases the speed of reaction
4. Which of the following facts about catalysts is incorrect?
(1) Catalysts reduce a reaction’s activation energy.
(2) Catalysts increase the number of reactions that can happen spontaneously

(3) Catalysts enhance the number of molecules with enough energy to break beyond the
activation energy barrier.
(4) Catalysts offer a different technique to get from reactant to product.
Answer: (2) Catalysts increase the number of reactions that can happen spontaneously
SUMMARY
In this module you have learnt that:
 Supramolecular chemistry deals with the organized chemical species of greater
complexity than molecules themselves, which are held together and organized by means
of inter molecular (non-covalent) binding interactions.
 The supramolecular chemistry generally concerns non-covalent bonding interactions
such as ion-ion interactions, ion-dipole interactions, dipole-dipole interactions,
hydrogen bonding, cation-π interactions, anion-π interactions, π-πinteractions, closed
shell interactions, Van der Waals forces and crystal close packing.
 In general, supramolecular chemistry involve the self -assemble and host-guests
ystems using a variety of interactions, some of which are clearly non -covalent
(e.g.hydrogenbonds) and some of which possess a significant covalent component (e.g.
metal–ligand interactions).
 Self-assembling systems do not involve hosts and guests but rather self-
complementary molecules or complementary partners (tectons).
 In host-guest compounds a host component with convergent binding sites and aguest
component with divergent binding sites are involved.
 Host molecules which are generally involved in supramolecular chemistry such as
the crown ethers, cryptands and spherands for ions, and hosts for neutral molecules
such as the carcerands and cryptophanes, display significant binding both in the solid
state and in solution.
 The caged molecule sexist as cage for other molecules. They exist in a closed
pattern having space in the middle where something can be located or trapped or
encapsulated.
 The caged molecules are either organic or inorganic including coordination in
nature.
 In general, a caged molecule is a shape-persistent macrocycles that have a defined
interior space, large enough to host other molecules, and do not crumple to a more
dense or twisted structure.
 The caged molecule possesses features like permanent porosity, highly selective
guest binding/encapsulation, solubility, chemical and thermal stabilityetc.
 The caged molecule can be synthesized by two popular methods like irreversible

bond formation method which includes cross-coupling reactions or amidation such as
amide-bond formation nucleophilic aromatic substitutions, the formation of carbon –
carbon bonds etc. The other method is reversible bond formation method like imine
bond formation, imine and olefin metathesis etc.
KEY WORDS
Alkene metathesis, Weinreb ketone synthesis, Petasis reaction, Corey–Kim oxidation
REFERENCES
MOOCS
______
YOUTUBE VIDEOS
https://www.youtube.com/watch?v=LR1Uc_sOqmk
https://www.youtube.com/watch?v=r2WA3cEQFjM
https://www.youtube.com/watch?v=UfawjxM0Igw
https://www.youtube.com/watch?v=bGPebd9Zaik
https://www.youtube.com/watch?v=kp6YTmblNyU
https://www.youtube.com/watch?v=IOZfaK3xFTo
https://www.youtube.com/watch?v=nf2ZgIs9NE0
https://www.youtube.com/watch?v=ALnw1rYE1UU
WIKIPEDIA
https://en.wikipedia.org/wiki/Supramolecular_chemistry
https://en.wikipedia.org/wiki/Crown_ether
https://en.wikipedia.org/wiki/Macromolecular_cages
https://en.wikipedia.org/wiki/Rotaxane
https://en.wikipedia.org/wiki/Catenane
OER
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REFERENCE BOOKS

CREDIT 03 -UNIT 04: SUPRAMOLECULAR REACTIVITY AND
CATALYSIS
LEARNING OBJECTIVES
 Basics about the self-assembly and self-organisation processes.
 Distinguish between molecular self-assembly and supramolecular self-assembly.
 Self-assembly of inorganic architectures.
 Self-assembly of organic architectures.
 Basics about the use of supramolecular entities as molecular device s
 Energy and electron transfer processes.
 Semiochemistry.
 Molecular and supramolecular devices as photonic, electronic and ionic
04-01: SELF-ASSEMBLY AND SELF -ORGANISATION

INTRODUCTION
Self-assembly is the spontaneous and reversible association of molecules or ions to
form discrete/extended entities at either the molecular, covalent or the supramolecular,
non-covalent level.Within self-assembly processes, we must distinguish molecular self-
assembly and supramolecular self-assembly. Molecular self-assembly concerns the
formation of covalent bonds as part of a special synthetic procedure. The assembly is
subject to control by the reaction stereochemistry and the conformational features of the
intermediates, e.g. the formation of amine–aldehyde condensation macrocycles (Figure
4.1). The formation of supermolecular self-assemblies results from the recognition-
directed spontaneous association of a well-defined and limited number of molecular
components under the intermolecular control of the non -covalent interactions such as
coordination interactions, hydrogen bonds and dipolar interactions that holdthem
together. The reversibility of supramolecular self -assembly is the key to resulting
systems’ ability to sift through the available components to form the thermod ynamically
most favourable structure. In other words supramolecular self -assembly concerns the
spontaneous association of either a few or many components resulting in the generation
of either discrete oligomolecular supermolecules or of extended polymolecular
assemblies such as molecular layers, films, membranes, etc. The name tecton (from
τέκτων: builder) has been proposed for designating the components that undergo self-
assembly.

Fig. 4.1: (a) The Schiff base condensation and the reduction of the product to give
an amine (b) macrocycle synthesized byaldol condensation of acetone and
[Ni(en) 3 ] 2+ .
Self-organization could be considered as a set intersecting self -assembly, ordered self-
assembly, that would (1) contain the systems presenting a spontaneous emer gence of
order in either space or time or both; (2) cover spatial (structural) and temporal
(dynamic) order of both equilibrium structures and of non-equilibrium, dissipative
structures, incorporating non-linear chemical processes, energy flow and the arrow of
time; (3) concern only the non-covalent, supramolecular level; (4) be multicomponent
and result in the formation of polymolecular assemblies presenting supramolecular
organization and long-range order (with or without regularity and periodicity) b y virtue
of specific interactions operating either through recognition events between the
molecular components or in a dynamic process. The higher the degree of confinement
or order (1D, 2D, 3D,4D) of self-assembled entities, the more they may be considere d
as organized (molecular layers, membranes, micelles, colloids, liquid crystals,
molecular crystals) entities. Self-organization thus involves interaction (between parts)
and integration (of the interactions) leading to collective behaviour, such as is found in
a phase change or in the generation of spatial or temporal waves.The phenomenological
description of the macroscopic features of self organizing systems must eventually find
an etiological explanation at the microscopic, molecular, and supramolecular levels.
Self-assembly and self-organization of a supramolecular architecture are both
multistep processes implying information and instructed components of one or several
types. And these may distinguished from meretemplating. Templating is a synthetically
most efficient procedure involving the use of temporary or permanent "helper" species,
of organic or inorganic nature, for the stepwise assembly of molecular or
supramolecular structures of high complexity. Self-assembly and self-organization
require molecular components containing two or more interaction sites and thus capable
of establishing multiple connections. Self-complementary components associate with
themselves undergoing homo assembly, where as complementary components
(pleromers) associate with one another giving hetero assembly.

Self assembly of inorganic architectures
Inorganic self-assembly and self-organization involve the spontaneous generation of
well-defined metallo-supramolecular architectures from organic ligands and
metalions.The latter serve bothas cement holding the ligands together and as centre
orienting them in a given direction. In the process, full use is being made of the
structural and coordination features of both types of components, which in addition
convey redox, photochemical or chemical functionality, depending on their nature.
The formation of any complex species from an organic ligand and a metal ion is in
principle anassembly process, which occurs spontaneously. The emphasis here lies in
the design of the ligands and the choice of the metal ions in order to produce defined
architectures in a controlled fashion from multiple subunits. Metal ions have properties
of special interest as components of supramolecular systems and linkers for self-
assembly. They provide (1) a set of coordination geometries, (2) a range of binding
strengths, from weak to very strong, and of formation and dissociation kinetics, from
labile to inert, and (3) a variety of photochemical, electrochemical and reactional
properties. In addition, and most significantly, they allow the reversible assembly -
disassembly of supramolecular architectures and represent switch able interaction sites,
for instance, by electrochemical interconversion between oxidation states of different
coordination geometries. For example, a self-assembly of double helicates is shown in
figure 4.2. In the presence of Cu (I) ions and a organic ligand (Figure 4.2(a)) containing
2,2'-bipyridine (bipy) groups, a spontaneous assembly takes place giving double-
stranded helicates, in which two ligand strands are wrapped around each other in a
double-helical fashion with Cu(I) ions holding them together. It results from the
tetrahedral-like coordination imposed by each Cu (bipy) 2+ site and from the design of
the ligands, which disfavours binding to only a single strand. In such instances, double-
helix formation requires self-recognition by the two helic and sand that leads to
preferential formation of the double-helical structures. In other words, helicate
formation amounts to a tetrahedral reading of the molecular information stored in the
bipystrands.

Figure 4.2: (a) A organic ligand containing 2,2’-bipyridine (bipy) group, (b) and (c)
are the doublehelical self-assemblyof Cu(I) ion.
Only metal ions presenting the appropriate coordination features with bipy will
form double helicates. This is also shown to be the case for Ag(I), which yields the tri-,
tetra-, and penta helicates, as confirmed by determination of the crystal structure of the
silver trihelicate in figure 4.3. Using oligo-bipyligands, the formation of triplehelicates
becomes possible through hamodification of the steric instruction by shifting the 6,6' -
disubstitution, as in figure 2(a), to a 5,5'-disubstitution (figure 4.4(a)), which should
remove the hindrance towards binding of three bipyunits to an octahedral metal centre.
Figure 4. 3: (a) Schematic representation of a trinuclear double helicate silver self-

assembly [Ag 3 (BP 3 ) 2 ] (CF 3 SO 3 ) 3 : and (b) the structural view by ORTEP plot, the
spheres represent 20% probability and (c) MOLDRAW plot with radii criteria,
giving a space filling model.

A trinuclear triple-helical complex figure 4.4is indeed formed spontaneously by self-
assembly from three 5,5'-disubstituted tris(bpy) strands and three Ni II ions.
Figure 4.4: (a) 5,5'-disubstituted tris(bpy) organic ligand; (b) trinuclear self -
assembly of triple helical NiII complex; (c) and (d) crystal structural
representation of the self-assembled trinuclear triple helical NiII complex.
The nature and the coordination geometry of the metal ions involved in the self -
assembly of helicates, in addition to, three main features that bear structural
information determining the nature and shape of the helical species formed may be
distinguished: (1) the precise structure of the binding site; it specifies in particular the
ability to coordinate metal ions with a given geometry as well as the number of strands
bound; (2) the spacer separating the binding sites; it must favour inter- over intrastrand
binding, and it influences the tightness of the helix (the pitch)t hrough the rotation of
one metal centre with respect to the next; (3) most importantly theconfiguration of the
coordination centres determines whether the structure is indeed of helical nature;
helicity implies that all metal centres have the same screw sense.
The self-assembly of the helicates and related structures involves just one type
of ligand and metal ion. Further progress in the understanding and the control of the
self-assembly and self-organization of inorganic super structures requires the
conception of systems capable of spontaneously generating well-defined architectures
from a larger set of components, comprisingat least two types of ligands and/or metal
ions. The design and choice of these components must fulfill criteria at all three levels
of molecular programming and information input that determine the out put of the
desired final species: recognition, orientation and termination.
Multi ligand multimetal self-assembly hasbeen achieved by means of a flat
ligand containing three chelating subunits, hexaphenyl hexaaza-triphenylene figure 5(a)

and bipy derived ligands. The ditopic bis-bipy component figure 5(b) is employed; two
units of figure 4.5(a) and three of 4.5(b) bind six Cu (I) ions to form the cylindrical
complex 4.5(c) (Figure 4.5). This amounts to the self -assembly of five ligands of two
different types and six metal ions, altogether eleven particles, to give the closed, cage-
like entity in one stroke.
Figure 4.5: Schemeof formation of a self-assembly of a multicomponent cylindrical

complex.
Various other inorganic super structures are also shown as self-assembly such as arack-
like arrangement schematically represented in figure 6, would be formed by the
complexation of several metal ions to rigid, linear sequences of binding sites. A ladder
super structure figure 4.6(c) may result from the complexation of linear ligands of the
type of 4.6(a) and bispyrimidine derivatives 4.6(a) or extended units 4.6(b) with
tetrahedral metal centres.
Figure 4.6: (a) and (b) are organic bispyrimidine ligands and (c) is the resulting
ladder like self-assembly constructed from these organic ligands
Self assembly of organic supramolecular structures
The self-assembly of organic supramolecular species makes use of interactions other
than metalion coordination, such as electrostatic, hydrogen bonding, van der Waals,

stacking or donor-acceptor effects as found in proteins, nucleic acids, liquid crystals
and molecular complexes. The spontaneous generation of organized structures depends
on the design of molecular components capable of self-assembling into supramolecular
entities presenting the desired architectural and functional features. The nature of the
species obtained will be determined by the information stored in the components. Thus,
the self-assembly process may be directed by molecular recognition between two or
more complementary subunits so as to form a given supramolecular architecture. If
these molecular units incorporate specific optical, electrical, magnetic, binding, etc.,
properties their ordering may induce a range of novel features. Depending on the
subunits involved the association may lead either to supermolecules or to organized
assemblies, such as membranes, molecular layers and films, mesophases, polymeric
species or solid state lattices.
The self-assembly of supramolecular structures via molecula rrecognition
between complementary hydrogen bonding components has developed into well -defined
arrangements of molecules in solution, in liquid crystals and in the solid state. The
build-up of two-dimensional and three-dimensional architectures requires the presence
in the molecular components of two or more hydrogen bonding subunits whose
disposition determines the final supramolecular architecture. When two subunits are
incorporated into a single group, it will then possess two recognition faces and may be
termed a Janus molecule, a double faced H -bonding recognitionunit. If the faces are the
same or different the unit is homotopic or heterotopic, if the unit is self-complementary
and may be termed plerotopic. Considering tridentate sites, 2,6 -diamino pyridine and
uracil are complementary single site groups figure 4.7( a), while 4.7(b) is plerotopic by
virtue of its two complementary sites. On the other hand barbituricacid (BA) and 2,4,6-
triamino pyrimidine (TAP) or-triazine (TAT) are Janus molecules containing two
identical recognition sites and these may associate either as a linear or as a cyclic
structure (figure 4.8). Each recognition it may be monodentate, bidentate or tridentate
depending on whether it contains one, two or three hydrogen bond donor (D) or
acceptor (A) centres. Of course, the stability and selectivity of the associations depend
on the nature and position of the centres.The bases of nucleic acids are well known
heterocyclic groups that interact through hydrogen bonding, usually forming base pairs
through Watson-Crick type association. In which flavinadenine dinucleotide contains
complementary adenine group and uracil site of the flavin.

Figure 4.7: (a) complementary single site groups of 2,6 -diaminopyridine and uracil
and (b) is plerotopic group
Figure 4.8: Self-assembly of either a supramolecular ribbon (righttop) or a

supramolecular macrocycle (right bottom) from barbituric acid and 2,4,6-triamino
pyrimidine units
The self-assembly of a porphyrin (or its Zn(II) complex) bearing two uracil groups by
means of two TAP units yields a supramolecular bis-porphyrin cage figure 4.9 into
which a bipy guest molecule may bind by coordination to the Zn(II) sites ina synergic
fashion.

Figure 4. 9: self-assemblyofa supramolecular bis-porphyrin cage.
SOLVED PROBLEMS:
Problem 1: What is Inorganic self-assembly and self-organization?
Solution: Inorganic self-assembly and self-organization involve the spontaneous generation of
well-defined metallo-supramolecular architectures from organic ligands and metal ions.
Problem 2: Which metal ion form dublehelicate?
Solution: Only metal ions presenting the appropriate coordination features with bipy will form
double helicates.

Que.1: What is self assembly?
Answer: Self-assembly is the spontaneous and reversible association of molecules or ions to form
discrete/extended entities at either the molecular, covalent or the supramolecular, non-covalent
level.
Que.2: What is templeting?
Answer: Templating is a synthetically most efficient procedure involving the use of temporary or
permanent "helper" species, of organic or inorganic nature, for the stepwise assembly of
molecular or supramolecular structures of high complexity.
04-02: Supramolecular Devices

Introduction
Molecular devices have been defined as structurally organized and functionally
integrated chemical systems; they are based on specific components arranged in a
suitable manner, and may be built into supramolecular architectures. Thus a
supramolecular device is a complex system made up of molecular components with
definite individual properties. These properties are intrinsic to a particular molecular

component whether it is part of the device or not. Another way of saying this is that the
interaction energy between the components of the supramolecular device must be small
compared with other energy parameters relevant to the system. Such a definition of a
supramolecular device does not exclude the ‘traditional’ concept of host and guest or
receptor and substrate. Molecular recognition events between host and guest may be a n
intrinsic part of the operation of a supramolecular device, which might, for example, be
designed to bind and then signal the presence of a guest. The function performed by a
device results from the integration of the elementary operations executed by th e
components. In other words we can say that photonic, electronic or ionic devices
depending on whether the components are respectively photoactive electroactive or
ionoactive, i.e., whether they operate with (accept or donate) photons, electrons, or
ions. This defines fields of molecular and supramolecular photonics, electronics and
ionics. Two basic types of components may be distinguished: 1) Active components:
that perform a given operation (accept, donate, transfer) on photons, electrons, ions,
etc.; 2) Structural components: that participate in the build -up of the supramolecular
architecture and in the positioning of the active components, in particular through
recognition processes; in addition, ancillary components may be introduced to modify
or perturb the properties of the other two types of components. A major requirement
would be that these components, and the devices that they bring about, perform their
function(s) at the molecular and supramolecular levels as distinct from the bulk
material.
Molecular Recognition, Information and Signals Semiochemistry

Molecular recognition events represent the basis of information processing at the
supramolecular level. They may give rise to changes in electronic, ionic, optical, and
conformational properties and thus translate themselves into the generation of a signal.
By making the use of three dimensional information storage/readout operating in
molecular recognition, in combination with substrate transformation and translocation,
one may be able to design components for devices that would be capable of processing
information and signals at the molecular and supramolecular levels.
The molecular recognition events can occur only if the correct selective binding of the
complementary active components takes place (see Figure 4.10) and this processes may
play a role in several key steps: (1) the building up of the device from its components;
(2) its incorporation into supramolecular arrays; (3) the selective operation on given
species (e.g., ions); (4) the response to external physical or chemical stimuli (light,
electrons, ions, molecules, etc.) that may regulate the operation of the device and
switch it on or off; (5) the nature of the signals generated and of the signal conversion
effected (photon-photon, photon-electron, electron-electron, electron-ion, ion-ion, etc.).

Figure 4.10: Molecular recognition-dependent photochemical molecular devices.
Recognition-dependent informed devices represent the molecular and

supramolecular entities by which molecular re cognition events may be transduced into
processes and signals, through the design of suitable components responding to external
stimuli and suitable for incorporation into the final superstructure. Recognition
expressed via a chemical transformation, in th e nature or in the rate of formation of the
products, amounts to the generation of a specific molecular signal and the resulting area
of investigation has been termed semiochemistry (from the Greek σημε ῖoν: sign, signal)
Semiochemistry is the name given to the area of supramolecular chemistry which is
broadly concerned with signalling devices. The term comes from ‘semiotics,’ meaning
the study of signs or symbols and their use or interpretation. The basic concept of a
molecular sensor is that the substrate (guest, analyte) must be attracted to a receptor
portion of the sensor (Figure 4.11). This is a straight forward molecular recognition
event, and the receptor can be any of the systems, such as crown ethers, cryptands, and
cavitands. The binding must be selective for the target substrate in the presence of a
range of other potential guest species, depending on the system and its environment. In
endo receptors the binding (information) sites are oriented into a molecular concavity;
exo receptors, with outward-directed sites, present "informed" surfaces on which
recognition may occur. The receptor must also be in communication with a signalling
unit that is responsive to the guest binding, which generates a signal in the form of an
emission of electromagnetic radiation (photochemical sensing), a current
(electrochemical sensing) or an otherwise externally measurable change (e.g. in colour
or pH).
Figure 4.11: Model representation of chemical sensor.

SOLVED PROBLEMS:
Problem 3: What is essential the condition for molecular recognition?
Solution: The molecular recognition events can occur only if the correct selective binding of the
complementary active components takes place.
Problem 4: What does recognition - dependent informed devices represent?
Solution: Recognition-dependent informed devices represent the molecular and supramolecular
entities by which molecular recognition events may be transduced into processes and signals,
through the design of suitable components responding to external stimuli and suitable for
incorporation into the final super structure.

Que.3: Define supramolecular device.
Answer: Molecular devices have been defined as structurally organized and functionally
integrated chemical systems; they are based on specific components arranged in a suitable
manner, and may be built into supramolecular architectures.
Que.4: What is molecular recognition?
Answer: Molecular recognition events represent the basis of information processing at the
supramolecular level. They may give rise to changes in electronic, ionic, optical, and
conformational properties and thus translate themselves into the generation of a signal.
04-03: Supramolecular Photochemistry

Supramolecular photochemistry in which the use of photochemically active
components as a supramolecular device and the formation of supramolecular entities
from photoactive components may be expected to pertub the ground -state and excited-
state properties of the individual species (i.e. chromophores), giving rise to nove l
properties such as energy migration, photoinduced charge separation, perturbations of
optical transitions and polarisabilities, modifi cation of ground - and excited-state redox
potentials, photoregulation of binding properties, selective photochemical re activity
etc. When a molecular chromophore is irradiated with electromagnetic radiation of a
wavelength corresponding to the energy required to promote an electron to an
accessible electronic excited state, energy is absorbed resulting in the promotion of an
electron from a ground-state molecular orbital to one of higher energy. This is known as
primary charge separation and results in a high -energy electron and a positively charged
‘hole’. The energy of the excited-state electron can either be dissipated as heat by
relaxation by the solvent (nonradiative decay), emitted radiatively (luminescence) or
used to carry out a chemical reduction (Figure 3). Luminescence involving direct
radiative decay, in which the electron returns immediately to the ground state from a
singlet excited state, is termed fluorescence. Fluorescent emissions are usually of lower

energy than the absorbed energy because the electron is promoted into a vibrationally
excited state from which it relaxes non-radiatively before fluorescing back to the
electronic ground state (Figure 4.12).
Figure 4.12: Possible radiative events following photoexcita tion. ISC: Intersystem
crossing
Phosphorescence is the process in which the electron undergoes a change of spin

state (intersystem crossing) to triplet state then the triplet excited state (long -lived) may
undergo vibrational relaxation to a lower energy level emitting a kind of luminesc ence.
Fluorescent and phosphorescent processes may be distinguished by time -resolved
spectroscopic measurements because phosphorescence takes much longer to decay than
fluorescence. The results of photoexcitation may be divided into three broad categories:
1. Re-emission of the absorbed energy as light (fluorescence or phosphorescence).
2. Chemical reaction of the excited state (secondary charge separation, isomerisation,
disassociation etc.).
3. Non-radiative vibrational quenching of the excitation by s olvent.
The process re-emission of the radiation by luminescence is of interest in sensing and
signalling applications, while chemical reactions are of interest in applications such as
molecular switches and photocatalysis. Strictly speaking absorption and re-emission
type processes are termed molecular ‘photophysics’ while light -induced chemical
reactions or chemical processes are termed ‘photochemistry’.

Supramolecular photochemistry, may involve three steps: binding of substrate and
receptor, mediating a photochemical process (such as energy, electron or proton
transfer), followed by either restoration of the initial state for a new cycle or by a
chemical reaction (Figure 4.12).
Figure 4.13: Representation of photoinduced energy transfer and electron tr ansfer

processes involved in supramolecular photochemistry. Generation of R*S, RS*,
R+S-, or R-S+ may be followed by a chemical reaction.
In principle, supramolecular photonic devices require a complex organization and
adaptation of the components in space, energy, and time, leading to the generation of
photo-signals by energy transfer (ET) or electron transfer (eT), substrate binding,
chemical reactions, etc.
Light Conversion and Energy Transfer Devices

A light conversion molecular device may be realized b y an Absorption-Energy-
TransferEmission (A-ET-E) process in which light absorption by a receptor molecule is
followed by intramolecular energy transfer to a bound substrate which then emits. An
optimum device may be designed if the light absorber or antenn a, light emitter and the
degree of coupling between them may be tuned separately. The combination of coupled
absorber and emitter thus produces a lightconversion device with optimal properties
such as maximum light collection and emission at the desired wa velength. This occurs
in the europium(III) and terbium(III) cryptates of the macrobicyclic ligand
[bipy.bipy.bipy]. UV light absorbed by the bipy groups is transferred to the lanthanoid
cation bound in the molecular cavity, and released in the form of visi ble lanthanoid
emission via an A-ET-E process, as shown in Figure 4.14. These Eu III and

Tb III complexes display a bright luminescence in aqueous solution, whereas the free ions
do not emit under the same conditions.
Figure 4.14: The A-ET-E process is shown for the Eu(III)-tris bpy cryptate.
Photoinduced Electron Transfer in Photoactive Devices

The photogeneration of charge separated states by photoinduced electron transfer (PeT)
is of interest for initiating photocatalytic reactions (e.g., natural and arti ficial
photosynthesis) and for the transfer of photosignals (e.g., through a membrane). A
schematic diagram of a simple example of such a process is shown in Figure 4.15 in
which a three component entity containing a photosensitizer PS linked to an electro n
donor D and an electron acceptor A, possessing suitable redox properties in their
ground and excited (for PS) states so that irradiation of PS leads to electron transfer
from D to A yielding the charge separated triad D+ -PS-A-.
Figure 4.15: Schematic representation of a center for photoinduced charge

separation consisting of a photosensitizer PS, a donor D and an acceptor A as well
as insulating spacer group.
An example of a photoinduced charge separation is shown Figure 4.16 in which

a macropolycyclic coreceptors containing both a photosensitive porphyrin group and
binding sites for silver(l) ions as acceptor centres. This results in quenching of the

singlet excited state of the Zn-porphyrin center by an efficient intracomplex electron
transfer, leading to charge separation and generating a porphyrinium cation of long
lifetime.
Figure 4.16: A macropolycyclic Zn-porphyrin coreceptors containing both a

photosensitive porphyrin group and binding sites for silver (I) ions as acceptor
centres.
SOLVED PROBLEMS:
Problem 5: Write the product of the following reaction.
Solution:
Problem 6: Solve the following reaction
Solution:

Que.5: Which elements aquires desired property for Light Conversion and Energy Transfer
Devices?
Answer: The desired property for Light Conversion and Energy Transfer Devices is found in
europium (III) and terbium (III) cryptates of the macrobicyclic ligand.
Que.6: What is Phosphorescence?
Answer: Phosphorescence is the process in which the electron undergoes a change of spin state
(intersystem crossing) to triplet state then the triplet excited state (long-lived) may undergo
vibrational relaxation to a lower energy level emitting a kind of luminescence.
04-04: Molecular and Supramolecular Electronic Devices

Molecular electronic devices are conceptually most resemble electronic and
computer components. If individual electronic components that may be coupled
together, such as wires, switches, rectifiers etc., can be produced, then the conceptual
basis exists to manufacturing molecule-sized (i.e. nanoscale) electronic devices with
concomitant gains in speed, efficiency, capacity and reduced use of resources. Much
attention has been given to design electronic devices that would operate at the level of
the molecular and the supermolecular. Very extensive work has been performed on
electroactive materials such as organic metals (e.g., conducting polymers and charge
transfer salts) or molecular semiconductors that may lead to devices based on organic
materials. This defines a field of molecular and supramolecular electronics concerning
the properties of single molecules, of oligomolecular associations and of polymolecular
architectures such as Langmuir-Blodgett films within and between which electron
transfer processes may occur.
Molecular electronic devices are conceptually most resemble electronic and computer
components. If individual electronic components that may be coupled together, such as
wires, switches, rectifiers etc., can be produced, then the conceptual ba sis exists to
manufacturing molecule-sized (i.e. nanoscale) electronic devices with concomitant
gains in speed, efficiency, capacity and reduced use of resources. Much attention has
been given to design electronic devices that would operate at the level of the molecular
and the supermolecular. Very extensive work has been performed on electroactive
materials such as organic metals (e.g., conducting polymers and charge transfer salts) or
molecular semiconductors that may lead to devices based on organic mate rials. This
defines a field of molecular and supramolecular electronics concerning the properties of
single molecules, of oligomolecular associations and of polymolecular architectures
such as Langmuir-Blodgett films within and between which electron trans fer processes
may occur.
Supramolecular Electrochemistry

Supramolecular electrochemistry is the resulting electrochemical effects from
redox responsive receptor-substrate binding and the molecular devices operating on
electrons are basic elements for converting molecular recognition events into electronic
signals. The redox responsive receptor molecules are based on two types of component:
substrate binding sites and electroactive groups. A number of substances have been
studied in which the redox properties of groups such as metallocenes, quinones or
paraquat are modified on substrate binding. Conversely, redox interconversion of these
groups allows the reversible switching between states of high and low affinity. The
mutual effects of redox changes and binding strength in a receptor-substrate pair thus
may make it possible to achieve electrocontrol of complexation and, conversely, to
modify redox properties by binding. As a consequence of these electrochemical effects,
molecular receptors may be used to convert the chemical information present in binding
and recognition processes into electronic signals. Multinuclear metal complexes possess
a rich electrochemistry and may serve as electron reservoirs. Thus, dinuclear Cu(I) and
Ni(II) complexes exchange two electrons in one step and four electrons in two steps,
respectively. Attachment of several redox groups such as ferrocene, viologen or Ni(ll)
cyclam to a core provides electron reservoirs that may be capable of powering
multielectron catalytic reactions. Polyoxymetallates also take up a number of electrons
(up to 32). Biological multiredoxcentres are found, for instance, in the electron transfer
protein cytochrome c3 that contains four heme groups, whose redox properties are
affected by local solvation as in synthetic porphyrins.
Electron conducting devices- Molecular Wires

The basic properties of a molecular wire are that it should connect to two components
(generally an electron acceptor and an electron donor) and conduct an electrical signal
or impulse between them. The three main classes of electron transfer processes may be
considered: (1) electron transport by redox active molecules acting as mobile carriers
through membranes; this may or may not also involve electron transfer from one carrier
to another during an encounter; (2) electron hopping between suitable redox active
groups attached to a backbone or assembled via non -covalent interactions; (3) electron
conduction along a continuous conjugation path formed by π -bonds (see Figure 4.17),
which may also involve other electron transmitting groups such as strained σ -bonds,
etc.; it represents an electron channel, and embodies specifically the idea of a molecular
wire. Thus the molecular wire concept is analogous to the channel -mediated
mechanism, since it is expected to involve a rapid current flow, but the ideal electronic
device would result solely in electron flow rather than the flow of alkali metal cations.

Figure 4.17: The triplet excitation transfer3 between the ruthenium (II) donor and
the osmium (II) acceptor in [Ru(bpy) 3 ] 2+ (ph) 7- [Os(bpy) 3 ] 2+.
The design of a molecular wire should satisfy three criteria: (1) contain an electron -
conducting chain; (2) possess terminal electroactive and polar groups for reversible
electron exchange; (3) be long enough to span a typical molecular supporting element
such as a monolayer or a bilayer membrane (see Figure 4.18).
Figure4.18: Trans membrane electron transfer processes: carrier mediated via are
dox carrier (left) or channel mediated via a molecular wire (right). Both processes
may be coupled to light by introduction of photoactive groups in the carrier or in
the wire.
Electron transfer occurred between an external reducing phase and an internal oxidizing
phase on in corporation of zwitter ionic caroviologens CV 2± compound into phospho
lipid vesicles. Using only a small amount of incorporated CV 2± (about 150 active
molecules per vesicle) an acceleration factor of 4-8 over background was obtained. This
clearly indicated that CV 2± did induce electron conduction.

Figure 4.19: Schematic representation of trans membrane electron transfer from a
reducing agent (such as sodium dithionite) to an oxidizing agent (such as potassium
ferricyanide) by a zwitter ionic caroviologen (CV 2± ) incorporated in the bi layer
membrane of a phospho lipid vesicle.
Molecular and Supramolecular Devices

The numerous receptor, reagent, and carrier molecules are potential components
of molecular and supramolecular ionic devices that are capable of handling inorganic
and organic ions via highly selective recognition, reaction, and transport processes with
coupling to external factors and regulation. Such components and the devices that they
may build up form the basis of a field ofmolecular ionics, the field of systems operating
with positively or negatively charged ionic species as support for signal and
information storage, processing, and transfer. In view of the size and mass of ions, ionic
devices may be expected to perform more slowly than electronic devices.However, ions
have a very high information content by virtue of their multiple molecular (charge, size,
shape, structure) and supramolecular (binding geometry, strength and selectivity)
features.
The molecular recognition events involved may be directly related to
information and signalprocessing by ions, as is the case in biology. Indeed, biological
signals and communication eventsare based on ionic and molecular species (sodium,
potassium, calcium, chloride, acetyl choline ions, etc.). Selective ion receptors
represent basic units for ionic transmitters or detectors; selective ion carriers
correspond to ionic transducers. These units may be fitted with triggers and switches
sensitive to external physical (light, electricity, heat, pressure) or chemical l (other
binding species, regulating sites) stimuli for connection and activation.
Binding, transport and triggering may be performed by separate species, each
having a specific function, as in multiple carrier transport systems.This allows a variety
of combinations between photo- or electroactive components and different receptors or
carriers. Light- and redox-sensitive groups incorporated into receptors and carriers

affect binding and transport properties. Co-receptors and co-carriers provide means for
regulation via co-factors, co-bound species that modulate the interaction with the
substrate. Thus, a simple ionizable group, such as a carboxylic acid function, represents
a proton switch and leads to proton-gated receptors and carriers responding to pH
changes, as seen for instance in the regulation of transport selectivity by alipophilic
carrier (Figure 4.20, (1)), containing a single cation receptor site and two ionizable
carboxylic acid groups, was found to transport selectively Ca 2+ in the dicarboxylate
form and K + when mono ionized, thus allowing pH control of the process. This striking
change in transport features as a function of pH involves pH regulation of Ca 2+ -K +
selectivity in a competitive (Ca 2+ ,K + ) symport coupled to (Ca 2+ , 2H + ) and (K + , H + )
antiport in a pH gradient, which provides a proton pump (Figure 11, (2)).
Figure 4.20: (1) A lipophilic carrier and (2) A competitive divalent/monovalent

cation symport coupled to M 2+ /2H + and M + /H + antiport in a pH gradient by a
22
macrocyclic lipophilic carrier such as (1); the state of the carrier is indicated as
diprotonated, [(CO 2 H) 2 ], or complexed,[(CO - ),M 2+ ]and [(CO 2 H)(CO 2 - ),M + ].
Ion transfer takes place through mobile carriers or ion channels (see Figure 4.20); a
rotating shuttle process may also be considered. Artificial trans membrane channels
have been much less explored than carriers, probably because of the inherently larger
molecular structures involved, despite the fact that biological transport is thought to
occur mainly via channel-type species. Various routes to the design of ion channels and
ion-responsive membrane systems have been investigated. One may imagine a variety
of ion channel types depending on the nature of the ion binding sites, on the way in

which they are arranged, on the molecular type and on the overall structural features.
Some are represented schematically in Figure4.21.
Figure 4.21: Transport processes. Carrier mediated, via a neutral species (3), of an
ion pair (4).Channelmediated (5, top), gated channel (5,bottom).
Figure 4.22: Schematic representation of different possible types of ion channel

structures (from left to right): stack, string, rack, pipe of macrocycles, helical
strand, two half-channel units, self-aggregated and macrocycle core bearing
bundles of chains.
SOLVED PROBLEMS:
Problem 7: Which two types of components on which redox responsive receptor molecules
are based?
Solution: The redox responsive receptor molecules are based on two types of component:
substrate binding sites and electroactive groups.
Problem 8: Which are three main classes of electron transfer processes in electron
conducting devices – molecular wires?
Solution: The three main classes of electron transfer processes may be considered:
(1) Electron transport by redox active molecules acting as mobile carriers through membranes;
this may or may not also involve electron transfer from one carrier to another during an encounter

(2) Electron hopping between suitable redox active groups attached to a backbone or assembled
via non-covalent interactions.
(3) Electron conduction along a continuous conjugation path formed by π-bonds, which may also
involve other electron transmitting groups such as strained σ-bonds, etc.; it represents an electron
channel, and embodies specifically the idea of a molecular wire.

Que.7: On which events biological signals and communication based?
Answer: biological signals and communication events are based on ionic and molecular species
(sodium, potassium, calcium, chloride, acetylcholine ions, etc.).
Que.8: Mention the steps involved in supramolecular photochemistry?
Answer: Supramolecular photochemistry, may involve three steps: binding of substrate and
receptor, mediating a photochemical process (such as energy, electron or proton transfer),
followed by either restoration of the initial state for a new cycle or by a chemical reaction.
CHECK POINT 03-04

1. In supramolecular photochemistry which device is used?
(1) Cation (2) Benzene
(3) Photochemically active components (4) Free radical
Answer: (3) Photochemically active components
2. Which chemical process takes much more time?
(1) Phosphorescence (2) Fluorescence
(3) Non-radiative vibrational quenching (4) Photoluminiscence
Answer: (1) Phosphorescence
3. Light Conversion and Energy Transfer Devices is based on ----
(1) Emission-Energy-Transfer technique
(2) Absorption-Energy-Transfer Emission
(3) Phosphorescence
(4) Chemiluminiscence
Answer: (2) Absorption-Energy-Transfer Emission
4. What are basic properties of molecular wire?
(1) It should connect to two components (generally an electron acceptor and an electron
donor) and conduct an electrical signal or impulse between them
(2) It should not connect to two components (generally an electron acceptor and an
electron donor) and conduct an electrical signal or impulse between them
(3) It should connect to two components (generally an electron acceptor and an electron
donor) and do not conduct an electrical signal or impulse between them
(4) It should not connect to two components (generally an electron acceptor and an
electron donor) and do not conduct an electrical signal or impulse between them

Answer: (1) It should connect to two components (generally an electron acceptor and an electron
donor) and conduct an electrical signal or impulse between them.
SUMMARY
In this module you have learnt that:
 Self-assembly is the spontaneous and reversible association of molecules or ions
(tectons) to form larger, more complex supramolecular entities according to the intrinsic
information contained in the molecules themselves.
 Fundamentally self-assembly is a convergent process in which a number of
components assemble into, ideally, a single fi nal, stable structure. Self -assembly is thus
very distinctfrom chemical emergence which is a divergent process in which complexity
evolves overtime.
 Self-assembly broadly divided into two classes 1. Self -assembly of inorganic
structures and 2. Self-assemblyof organic structures.
 Inorganic self-assembly and self-organization involve the spontaneous generation of
well-defined metallo-supramolecular architectures from organic ligands and metal ions.
 The self-assembly of organic supramolecular species makes use of interactions other
than metal ion coordination, such as electrostatic, hydrogen bonding, v an der Waals,
stackingor donor-acceptor effects as found in proteins, nucleic acids, liquid crystals and
molecular complexes.
 The understanding of the design and properties of molecular and supramolecular
devices as basis for the development of chemical in formation processing and signalling
as well as for the exploration of their relationships with related biological phenomena.
 The development of circuitry and functional materials at the nanometric scale by the
formation of photonic, electronic, ionic switc hing devices from molecular components
and their incorporation into well-defined organized assemblies.
 A supramolecular device comprises two or more components linked either covalently
or non covalently with distinct functions that are properties of the in dividual
components.
 Supramolecular sensors comprise binding, transduction and actuator components
either in a single molecule or as part of an indicator displacement assay.
 Molecules can display characteristics of electronic components such as the
conduction of energy or electrons.
KEY WORDS
Self assembly, self-organization, photonic, electronic, ionic switching devices,
supramolecular sensors

REFERENCES

MOOCS
______
YOUTUBE VIDEOS
https://www.youtube.com/watch?v=6_ALzMJ9geM
https://www.youtube.com/watch?v=saeAIk61n1s
https://www.youtube.com/watch?v=saeAIk61n1s
https://www.youtube.com/watch?v=5k9Sew8Wjww
WIKIPEDIA
https://en.wikipedia.org/wiki/Self-assembly
https://en.wikipedia.org/wiki/Supramolecular_electronics
https://en.wikipedia.org/wiki/Molecular_electronics
OER
____
REFERENCE BOOKS


C REDIT 04

CREDIT 04 -UNIT 01: Types Of Free Radical Reactions
LEARNING OBJECTIVES
After studying this module, you know
 Different types of free radical reactions and their mechanism.
INTRODUCTION:
A free radical (or radical) may be defined as a species that contains one or more
unpaired electrons. Due to the presence of unpaired electron(s) free radicals are
paramagnetic.
01-01: Types of Free Radical Reactions

Propagation reactions: These lead to other radicals, which themselves react further.
There are four main propagation reactions, of which the first two are most comm on.
Termination reactions: These gives stable products. The most common termination
reactions are simple combinations of similar or different radicals
Another termination process is disproportionation.

In disproportionation reaction an alkane and an alkene are produced from a pair of
radicals. A hydrogen atom of one radical is abstracted by another radical.
SOLVED PROBLEMS:
1)
1)

1) Give the example of propagation reaction.
Answer:
2) Give the example of termination reaction reaction.

Answer:
01-02: FREE RADICAL SUBSTITUTION MECHANISMS:

Halogenation at an alkyl carbon:
Alkenes can be chlorinated or brominated on reaction with chlorine or bromine in the
presence of visible or u.v. light or at high temperatures (250-400°C). For example:

The reaction can also be applied to alkyl chains containing many functional groups. The
chlorination reaction is not useful for preparative purposes because every alkyl carbon
in the moleule is chlorinated as well as di and polychloro compounds are formed. The
bromination is much more selective than chlorination. It is possible to brominate
tertiary and benzylic positions selectively. It should be remembered that the greater the
reactivity of species, the less is the selectivity. It should be noted that fluorine reacts
too violently involving rupture of c-c bonds, whereas iodine react too slowly and
reversibly to be of any practical interest.
Mechanism: The halogenation at an alkyl carbon is a free radical chain reac tion and
proceeds through the following mechanism.
The following is the decreasing order of reactivity of halogens F 2 > Cl 2 > Br 2 > I2 .
The most important single factor causing the order of halogen reactivity is the
decreasing strength of the H-X bond which is in the order H – F > H – Cl > H – Br > H
– I.
This is because with increasing H-X bond strength the propagation steps:
Is favoured which is the rate determining step at least in the case of methane.
The following is the decreasing order of the cas e of abstraction of different bonds of
hydrogens: Tertiary H> secondary H> primary H > methane H. This order is easily
understandable in view of the relative stabilities of the free radicals formed after the
abstraction of hydrogen.
Stereochemistry of Radical Substitution:

The alkyl radical having planar structure is attacked from both the faces with equal ease
to form racemic modification.For example
SOLVED PROBLEMS:
1)
2)

1) Explain mechanism of Halogenation at an alkyl carbon.
Answer: Mechanism: The halogenation at an alkyl carbon is a free radical chain
reaction and proceeds through the following mechanism.

2) Give the reactivity orderof halogens towards halogenation.
Answer:The following is the decreasing order of reactivity of halogens
F 2 > Cl 2 > Br 2 > I 2
01-03: Allylic Halogenation:

Alkenes can be halogenated in the allylic position by the number of reagents such as N -
bromosuccinimide (NBS), N-chlorosuccinimide (NCS), t-butyl hypochlorite, etc, of
these, NBS is the most common, when NBS is used, the reaction is known as wohl -
Ziegler reaction. Using NBS rather than bromine for allylic bromination sol ves the
problem of formation ofthe undesired addition product of alkene with bromine.
The reaction of NBS is highly regioselective and takes place at the allylic position NBS
is also a highly regioselective brominating agent at positions to an aromatic ring 
(benzylic position), to a C C triple bond, to a carbonyl group. When both double and
triple bonds are in the same molecule, the preferred posi tion is to the triple bond. For
example.
The reaction of NBS is carried out in nonpolar solvent, most often CCl 4 is used NBS is
only slightly soluble in CCl 4 , this ensures the low concentration of bromine necessary
for the success of this reaction. The reaction is catalysed by peroxides, heat or light .

Free radical mechanism at an aromatic Substrate:
Hey (1934) reported that the thermal decomposition of diazonium salts in aromatic
solvents results in the arylation of the aromatic rings. He explained these results by the
following mechanism involving the direct displacement of a hydrogen atom in the
aromatic solvent molecule by the aryl radical, i.e., the abstraction of an e ntire aryl
group of the solvent molecule by the aryl radical.
Similar results are obtained from the aryl radicals generated from other sources such as
the decomposition of benzoyl peroxide in aromatic solvents.
The above direct displacement mechanism was discarded because;

1. It involves the formation of a c-c bond at the expense of a relatively stronger C -H
bond (i.e., abstraction of an entire aryl group) which requires very high activation
energy, thus, actually this is not the case.
2. It does not explain the formation of products I and II. The following two step
mechanism which is exothermic and also explains the formation of products I and II
was proposed. This similar to the mechanism of aromatic electrophilic and
nucleophilic substitutions.

The intermediate free radical is establised by resonance. The reaction can terminate in
three ways
(i) By simple coupling
The coupling need not be ortho-ortho, other isomer can also be formed.
(ii) Disproportionation:
Under the reaction conditions dihydrobiphenyls like II are oxidised to the

corresponding Biphenyls.
(iii) By abstraction of hydrogen, if a radical R is present in the system.

SOLVED PROBLEMS:
1)
2)
SHORT QUESTION ANSWER :

1) Explain the condition of NBS reaction.
Answer: The reaction of NBS is carried out in nonpolar solvent, most often CCl4 is
used NBS is only slightly soluble in CCl 4 , this ensures the low concentration of
bromine necessary for the success of this reaction. The reaction is catalysed by
peroxides, heat or light.
2) Show free radical intermediate is establised by resonance.
Answer: The mechanism of aromatic electrophilic and nucleophilic substitutions.
The intermediate free radical is establised by resonance.
01-04: Detection and Characterization of Radicals

The distinguishing characteristic of a free radical is the presence of an unpaired
electron. Species with an unpaired electron are said to be paramagnetic. The relative
stability of the triphenyl methyl radical allows it to be studied by magnetic
susceptibility measurement, which involves weighing it both inside and outside a
magnetic field. The unpaired electron makes the radical paramagnetic, so the sample is
drawn into the magnetic field. By this technique the dissociation of hexaphenylethane

to the triphenylmethyl radical was determined to occur to the extent of 2% in a 0.1 M
sample.
A technique that has been of more value to organic chemists is that of electron
paramagnetic resonance (EPR), which is also known as electron spin resonance (ESR)
spectroscopy. This is a very sensitive method of detecting radicals, even at
concentrations of 10−7 M. ESR not only confifirms that radicals exist, but it can also
tell us quite a lot about their structure. The principle of ESR is similar to that of NMR,
except that electron spin is involved rather than nuclear spin. The electrons are
associated with the electron spin quantum number, ms, which may have the value +1∕2
or −1∕2. If electrons are paired in an orbital, then one has ms = +1∕2 and the other has
ms = −1∕2, so there is no net spin magnetic moment. If an electron is unpaired, however,
there will be a net magnetic moment of 9.284 × 10−19 erg G−1. The direction of the
magnetic moment depends on the spin quantum number, so there will be two spin states.
The two states are equal in energy in the absence of an external magnetic fifield. In the
presence of an external magnetic field (with strength H 0 ) the two spin states have
different energies, with the electron having
ms = −1∕2 being lower in energy. The energy difference between the two states,
ΔE, is:
In this equation, g is the spectroscopic splitting factor, which is the ra tio of the
magnetic moment to the angular momentum of the electron. This value is 2.002 319 for
a free electron, and does not vary greatly for unpaired elect rons in organic radicals. The
term Be is the Bohr magneton, a constant with the value of 9.2732 × 10 −21 erg G –1 .
Thus, at a field of 3400 G the energy difference is ΔE =(2.0023) × (9.2732 × 10 −21 erg
G –1 ) × (3400 G)=0.63 × 10 −16 erg, which corresponds to 0.91 cal mol–1 and to a
frequency of 9500 MHz.
There are some similarities between PMR and EPR spectroscopy. In both, the
sample is placed in a magnetic field and is irradiated with electromagnetic energy of an
appropriate frequency. An EPR spectrophotomete r records the absorption of energy
when an electron is excited from lower to the higher state. The energy separation is
very small on an absolute scale and corresponds to the energy of microwaves. The
magnetic field is swept or varied linearly, and absorpt ion of energy by the sample is
recorded as a decrease in intensity of the radio frequency energy received by a detector.
Thus, we can observe an absorption or resonance when the changing magnetic field
strength makes the energy of the electromagnetic signa l exactly equal to the energy
difference between the two spin states (Figure 4.1.2a). For experimental reasons,
however, the EPR signal is more often recorded as the first derivative of absorption,

Figure 4.1.2b, or as the second derivative, Figure 4.1.2c. The g value in above equation
has been compared to the chemical shift in PMR spectroscopy. However, the very slight
variation in g values from radical to radical means that g values seldom give chemically
useful information for most organic compounds.
A second type of structural information can be deduced from the hyperfine splitting in
EPR spectra. The splitting of the EPR signal is due to interaction of the electron spin
with the spins of nearby magnetic nuclei (e.g., 1 H, 13
C, 19
F, 31
P). This effect has been
explained by McConnell et al. in terms of spin polarization involving the unpaired
electron on carbon with the electrons in the C–H bond (Figure 4.1.3). The number of
lines is given by the equation 2nI +1, where I is the nuclear spin quantum number a nd n
is the number of equivalent interacting nuclei. Thus, the EPR signal due to the methyl
radical (shown as a second-derivative spectrum
Figure 4.1.2: Representation of EPR spectra, (a) resonance sinal, (b) first
derivative and (c) second derivative.
Figure 4.1.3: Mechanism of spin polarization for planer methyl radical
Figure 4.1.4: EPR spectrum for methyl radical

In Figure 4.1.4) is split into a four-line pattern with relative intensities of 1 : 3 : 3 : 1
because of coupling with the three methyl protons. Similarly, the unpaired electron in
the benzene radical anion is split by six equiv. protons, so the signal is septet intensities
1:6:15:20:15:6:1. In the EPR spectrum of the ethyl radical (also as a second derivative),
splitting of the signal by the two protons on the α carbon atom (a α =22.4 G) gives rise
to a three-line pattern, but each of those three lines is further split into four lines by the
β protons (a β =26.9 G). The combination of the two sets of splitting results in a 12 -line
pattern. Note that EPR spectra, unlike NMR and IR spectra, are displayed as the
derivatives of absorption rather than as absorption. Also of interest here are the
magnitudes of the two α values. The magnitude of the hyperfine coupling depends on
the density of the unpaired electron in an orbital with s character about a magnetic
nucleus. Therefore, it might seem surprising that the values of a α and a β for the ethyl
radical are approximately equal, because such a result is not consistent with a simple
model for the ethyl radical (Figure 4.1.5) in which all of the unpaired electron density
is on the α-carbon atom. Nevertheless, it is common for values of a α and a β to be
similar. However, values of aγ (e.g., the hyperfine coupling constant for splitting of the
signal of 1-propyl radical by the terminal methyl group) are much smaller, typically
less than 1 G.
The valence bond explanation for the similarity of aα and aβ values is based on the
concept of hyperconjugation, which holds that a C –H or C–C sigma (σ) bond can be
conjugated with an adjacent radical or cation center. Now the unpaired electron density
is localized on one of the hydrogen atoms of the methyl group, and by rotation about
the C–C bond all three hydrogen atoms can participate equally in the hyperconjugati on
(Figure 4.1.6).
Figure 4.1.7 shows the perturbational molecular orbital (PMO) description of radical
stabilization. The singly occupied p orbital is the SOMO (singly occupied molecular
orbital), which is higher in energy than a π -like orbital on the methyl fragment. The
HOMO (highest occupied molecular orbital) is a C–H bonding orbital localized on the
methyl group and parallel with the p orbital. The interaction of the SOMO and the
HOMO produces two new orbitals, one lower in energy than the HOMO and o ne higher
in energy than the SOMO. However, since two electrons go into the lower energy
orbital while only one goes into the higher energy orbital, the overall effect is
stabilizing. Additional insight into the structure of the ethyl radical comes from an
extended Huckel calculation.

Figure 4.1.4: Localized model for ethyl radical
Figure 4.1.5: Hyperconjugation model for ethyl radical
Figure 4.1.6: PMO description for radical stabilization; interaction of SUMO with
donar HOMO
A technique called spin trapping can also be used to study radicals. A diamagnetic
molecule that has the property of reacting rapidly with radicals to give a stable
paramagnetic species is introduced into the reaction system being studied. As radical
intermediates are generated, they are trapped by the reactive molecule to give more
stable, detectable radicals. The most useful spin traps are nitroso compounds. They
rapidly react with radicals to give stable nitro oxides. Analysis of the EPR spectrum of
the nitro oxide can provide information about the structure of the original radical.
Another technique for radical detection is chemically induced dynamic nuclear
polarization (CIDNP). The instrumentation required for such studies is a normal NMR
spectrometer. CIDNP is observed as a strong perturbation of the intensity of the NMR
signals in products formed in certain types of free radical reactions. One aspect of both
EPR and CIDNP studies is that either is capable of detecting very small amounts of
radical intermediates. CIDNP, often pronounced like ‘‘kidnap,’’ is a non Boltzmann
nuclear spin state distribution produced in thermal or photo - chemical reactions, usually
from colligation and diffusion, or disproportionation of radical pairs, and detected by
NMR spectroscopy as enhanced absorption or emission signals. CIDNP was discovered
in 1967 by Bargon and Fischer, and independently by Ward and Lawler. Early theories
were based on dynamic nuclear polarization (DNP) (hence the name). However,
subsequent experiments have found that in many cases DNP fails to explain the CIDNP

polarization phase. In 1969 an alternative explanation was proposed by Closs, and
independently by Kaptein and Oosterhoff, which relied on the ability of nuclear spin
interactions to alter the recombination probability in reactions that proceed through
radical pairs. This mechanism, known as the radical pair mechanism, is currently
accepted as the most common cause of CIDNP. However, there are exceptions, and the
DNP mechanism was found to be operational, for example , in many fluorine-containing
radicals detected as enhanced absorptive or emissive signals in the NMR spectra of the
reaction products, CIDNP has been exploited for the last 30 years to characterize
transient free radicals and their reaction mechanisms.
SOLVED PROBLEMS:
1) Hyperconjugation model for ethyl radical
2) Localized model for ethyl radical

1) How to calculate number of lines in EPR signal?
Answer: The number of lines is given by the equation 2nI +1, where I is the nuclear
spin quantum number and n is the number of equivalent interacting nuclei.
2) Why are free radicals so reactive?
Answer: Radicals contain unpaired electrons which makes them so reacti ve in that they
need so much energy to shape. As we speak about radical reactivity, “more reactive”
generally means a step towards more exothermic abstraction of the hydrogen atoms.
That makes the reaction less prone to the carbon -centric radical’s stability.
CHECK POINT 04-01 [MCQS TYPE OF QUESTIONS ]

1) Which free radical is most stable?
(a) Primary free radical (b) Secondary free radical
(c) Tertiary free radical (d) Quaternary free radical
2) Which of the following free radical is least stable?

(a) CH3 (b) CH3CHCH3

(c) CH3CH2 (d) (CH3)3C
3) Which is the correct order for halogenations reaction?

(a) F2< Br2< I2< Cl2 (b) I2< Br2< Cl2< F2
(c) Cl2< F2< Br2< I2 (d) F2< Cl2< Br2< I2
4) Which type of hydrogen abstraction takes place fast?

(a) 10 hydrogen (2) 20 hydrogen
(c) 40 hydrogen (d) 30 hydrogen
SUMMARY
 Free radicals are atoms or groups of atoms which have a single unpaired
electron. A free radical substitution reaction is one involving these radicals. Free
radicals are formed if a bond splits evenly - each atom getting one of the two
electrons.
 EPR (electron paramagnetic resonance), often also referred to as ESR (electron
spin resonance), is a spectroscopic method that allows one to obta in information
on the structure and dynamics of systems with unpaired electrons (paramagnetic
systems).
KEY WORDS
Free Radical Substitution,
REFERENCES


1) Answer: (c) Tertiary free radical
2) Answer: (a) CH3
3) Answer: (b) I2< Br2< Cl2< F2
4) Answer: (d) 30hydrogen
MOOCS

YOUTUBE VIDEOS
https://www.youtube.com/watch?v=a2ru3MSffY8&list=PLDjIJRH6sIC5XvynEWvgIDPcIU4_W
PQ4R
https://www.youtube.com/watch?v=kFhZHcwyyNk
https://www.youtube.com/watch?v=fWh6Y-VAUSo
https://www.youtube.com/watch?v=3L3KzZG8pRE
WIKIPEDIA
https://en.wikipedia.org/wiki/Free-radical_reaction
https://en.wikipedia.org/wiki/Radical_substitution#:~:text=In%20organic%20chemistry%2C%20
a%20radical,radical%20is%20created%20by%20homolysis.
https://en.wikipedia.org/wiki/Allylic_rearrangement
https://en.wikipedia.org/wiki/Electron_paramagnetic_resonance
OER
REFERENCE BOOKS


CREDIT 04 -UNIT 02: NEIGHBORING GROUP ASSISTANCE
LEARNING OBJECTIVES
After studying this module, you shall be able to
 Know what is anchimeric assistance
 Learn mechanism of anchimeric assistance
 Identify functional groups taking part in anchimeric assistance
 Evaluate outcomes of anchimeric assistance for various reactions
 Analyze how to know if anchimeric assistance is operational completion of this
unit, you will be able to
 KnowaboutNGPreaction
 Learn reaction mechanism of NGP reaction
 Identify stereochemistry of NGP reaction
 Evaluate the factors affecting the NGP reaction
 Analyse Phenoniumion, NGP by alkene, and NGP by heteroatom.
INTRODUCTION:
When a catalytic functional group or atom is part of the reacting molecule,
the catalysis is called intra-molecular catalysis. Anchimeric assistance (anchimeric
in Greek means“adjacent parts”) is a case of intra-molecular catalysis where a
suitably placed intra-molecular nucleophile assists in a substitution reaction by
enhancing rate of reaction.
02-01: MECHANISM OF ANCHIMERIC ASSISTANCE

The bimolecular mechanisms for nucleophilic substitution are termed S N 2 reactions.
S N 2 reactions follow second order rate kinetics. The geometric alignment of
transition state for S N 2 mechanism is such that the nucleophile attacks from the rear
of the leaving group, leading to inversion of configuration. However, there are some
examples of retention of configuration in S N 2 reactions, where an atom or group (Z)
close to the carbon undergoing subsitution assists inthe reaction with its available
pair of electrons. Such a group is called a neighbouring group (NG) and the
assistance provided is termed neighbouring group participation (NGP). If such
participation leads to an enhanced reaction rate, the group is said to provide
anchimeric assistance.

The mechanism for anchimeric assistance is a two step mechanism where two
consecutive S N 2 reaction leads to retention of configuration. In the first step, the
neighbouring group (Z) acts as a nucleophile, attacking the substitution centre and
expelling out the leaving group. In the next step, the external nucleophile (Y) attack
from backside displacing the neighbouring group and retaining the overall
configuration. Since the first step is slow and is rate determining, the reaction
follows first order kinetics and there is no effect of concentration of Y - onrate of
reaction. Anchimeric assistance enhances rate of reactions by several order of
magnitudes. This is because step I is the rate determining step and the neighbouring
group Z which is readily available within the substrate makes the attack much faster
as compared to attack by any external nucleophile Y for which,to react, the
substrate hasto collide with Y - . Since, Z is readily available by virtue of its position
its attack is much faster. Thermodynamically also, anchimeric assistance is favoured
as the reaction between the substrate and Y - involves a large decrease in entropy of
activation (∆S†), as the reactants are far less free in the transition state than before.
Reaction of Z involves a much smaller loss of entropy. Important atoms and groups
that can act as neighbouring groups are COO - COOR, COAr,OCOR,OR,OH,O - , NH 2 ,
NHR, NR 2 , NHCOR, SH, SR, S - , SO 2 Ph, I, Br, and Cl. The effectiveness of
halogens as neighbouring groups decreases in the order I>Br>Cl. The chloride isa
very weak neighbouring group and can be shown to act in this way only when the
solvent doesnot interfere.
Examples of Reactions Where Anchimeric Effect Is Operative:
NGP takes place by internal attack of a nucleophile leading to formation of a ring.
Upon attack ofthe external nucleophile thering can have three different fates:
1) Ring opening at the same point where the ring closure took place,

Such reactions lead to an un-rearranged product with the same configuration as the
starting material
2) Ring opening at a different point from which the ring closure took place
Such reactions lead to a rearranged product.

3) No ring opening so the overall lreaction is a Cyclization.
At times the cyclic intermediate may undergo ring opening at two points
competitively so thatsome of the product is rearranged and some remains un-
rearranged. The initial existence of the phenomena of anchimeric assistance was
observed for the reaction where, dl pair of 3-bromo-2-butanol when treated with
HBr to give dl-2,3-dibromobutane, while the erythro pair gave theme so isomer.
Interestingly, either of the two threo isomers alone also gave dl pair. This is
explained by the presence of a common bromonium ion intermediate formed as a
result of attack by the neighbouring bromine atom. This symmetrical intermediate

gives equal opportunity to the incoming nucleophile Br - to attackbothcarbonatoms
equally. How do we know if anchimeric assistance is involved in a reaction
mechanism? Experimentally to demonstrate the involvement of anchimeric
assistance in a reaction, following methods are employed;
a) Comparing the rate of the NGP reaction with the rate expected in the absence of
participation. The reactions where participation takes place, there reactions go much
faster.
b) To compare the rate constant for the intra-molecular reaction with that of the
analogous intermolecular one. This method is limited to those systems where
corresponding analogous intermolecular reactions may occur.
Here the rate of intra-molecular reactions is much faster as compared to inter-
molecular reactions.
Examination of stereochemistry of products formed. Unusual stereochemistry might

be observed such as retention of configuration in S N 2 mechanism.
Here reactions with rearranged products due to anchimeric assistance through
acyclic intermediate have been observed. The cyclic intermediate gives the external
nucleophile with equal potential to attack any of the carbon atoms, and based on
polar and stearic conditions themore stableproduct would predominateas follows;
In such cases, substitution and rearrangement products are often formed together.
SOLVED PROBLEMS:
1) The initial existence of the phenomena of anchimeric assistance was observed for
the reactionwhere, dl pair of 3-bromo-2-butanol when treated with HBr to give dl-
2,3-dibromobutane, whiletheerythropair gavethemesoisomer.

2) Ring opening at a different point from which the ring closur e took place

1) What is anchimeric assistance?
Answer: However, there are some examples of retention of configuration in S N 2
reactions, where an atomor group (Z) close tothe carbon undergoing subsitution
assists in the reaction with its available pair of electrons. Such a group is called a
neighbouring group (NG) and the assistance provided is termed neighbouring group
participation (NGP).If such participation leads to an enhanced reaction rate, the
groupis said to provide anchimeric assistance.
2) Give the example of Anchimeric effect.
Answer: Ring opening at the same point where the ring closure took place,

02-02: REACTIONS WITH OXYGEN AS NEIGHBORING GROUP
DONOR
The acetolysis of two different substrates (a) 4-methoxy-1-pentyl brosylate and, (b)
5-methoxy-2-pentyl brosylate, with a common intermediate structure gave the same
mixture of products which further confirmed participation by neighbouring group
leading toacommon intermediate.
The hydrolysis of 1,2-dichlorohydrin under alkaline conditions was found to yield

1,2-diol with retention of configuration following S N 2 mechanism. Here formation
of a cyclic intermediate takes placeas a result of anchimeric assistance .

Another example of anchimeric assistance in cyclic system with oxygen donor is the
following reaction where one starting material has syn and the other has anti
stereochemistry, however the products have the same (anti) stereochemistry.
The mechanism involves participation of acetyl group in expulsion of tosyl group

as follows;
Thus only when both the substituent are in axial position there is a greater chance of
anchimeric assistance and faster kinetics is observed. For the syn diastereomer NGP
is impossible, and substitution goes simply by intermolecular displacement of OTs
byAcOH. Therefore just oneS N 2step leads to overall inversion of configuration, and
a slower reaction rate.
REACTIONS WITH SULPHUR AS NEIGHBOURING GROUP DONOR

The hydrolysis of EtSCH 2 CH 2 Cl was found to be 10 4 times faster than
EtOCH 2 CH 2 Cl under comparable conditions owing to the sulphonium ion
intermediate mediated anchimeric assistance as shown below;
In comparison, for EtOCH 2 CH 2 Cl substrate the electronegative oxygen atom
provides no internal assistance and thus the reaction proceeds with simple S N 2
mechanism. For substrates of the type RSCH 2 CH 2 X the NGP occurs so readily that
ordinary S N 2 reactions are hard to observe.
Trans 2-thio-substituted chloro cyclohexane undergoes reaction with aqueous
solution of ethano l70000 times faster than the unsubstituted compound. However,

the cis2-thio-substituted compound reacts a little more slowly than the unsubstituted
compound. These experimental observations have been ascribed to anchimeric
assistance provided by sulphur atom present incorrect stereochemistry to assist
expulsion of the leaving group.
As shown above the thio substituent displaces the chloro group by attacking the
back side of thecarbon to which the chloro group is attached. Since back -side attack
requires both substituents to be in axial positions thus only the trans isomer which
has both of its substituents in axial positions reacts faster. Subsequent attack by
water or ethanol on the sulfonium ion is further facilitated as the positively charged
sulphur is an excellent leaving group and breaking the three-memberring releases
strain.
REACTIONS WITH NITROGEN AS NEIGHBOURING GROUP DONOR:

Amines as lone pair donor for anchimeric assistance
In the above reaction the substrate is a secondary alkyl chloride. Notice that the
product alcohol isarearrangedproduct.
In the following, the–NMe 2 is providing anchimeric assistance for hydrolysis of
ester.

A ring expansion reaction involving anchimeric assistance is as follows;
DOUBLE BOND PARTICIPATION AND REARRANGEMENTS

Properly placed π-electrons of a C=C double bond in a substrate can also function
as NG and lend anchimeric assistance
For the above reaction the product showed retention of stereochemistry and extremely
fast reaction kinetics, i.e. 10 11 times faster than that of the saturated substrate. The
ability of a carbon-carbon double bond to serve as a neighbouring group depends
strongly on its electron density. Therefore, when the electron -withdrawing CF 3 groups
are present in the substrate, thes olvolysis rateis lowered severely. Aryl groups are a
suitable NG in substitution reactions. One example has already been mentioned, another
example is as follows.

There is retention of configuration in the product acetate.This clearly indicates the
participation of phenyl group.The п electrons of the ring assist and stabilize the
developing positive charge. The intermediates, for the sake of book keeping, can be
shown as the delocalized phenoniumion.
NEIGHBOURING GROUP PARTICIPATION BY Π AND Σ BONDS

The reaction centre (carbenium centre) has direct interaction with a lone pair of
electrons of anatom or with the electrons of s - or p-bond present within the parent
molecule but these are not in conjugation with there action centre. A distinction is
sometimes made between n, s and p-participation. An increase in rate due to
Neighbouring Group Participation (NGP) is known as"anchimeric assistance".
"Synartetic acceleration" happens to be the special case of anchimericassistance and
applies to participation by electrons binding a substituent to a carbon atom in a β -
position relative to the leaving group attached to the α -carbon atom. In accordance with
the underlying model, these electrons then provide for a three -centre bond (or bridge)”,
"fastening together" (as the word "synartetic" is meansto suggest) the α and β -carbon
atoms between which the charge is divided in the intermediate bridge ion form (and in
the transition state preceding its formation).

NGP is often seen in nucleophilic substitution reactions, where in a neighbouring group
aids in the removal of the leaving group to form a reactive intermediate that leads to
product formation. The increase of reaction rate and unexpected stereo chemical
outcomes are associated in reactions involving NGP. An atom having an unshared pair
of electrons and is present on the β – positon to the leaving group can act as a
neighbouring group. Also, NGP is most often observed in solvolysis reactions where the
solvent acts as the nucleophile. For example:
During NGP, the neighbouring group (G) attacks the electr ophilic centre to eliminate
the leaving group (L). Acyclic intermediate is thus formed, which is very reactive. The
nucleophile (Nu - ) then attacks this intermediate to form the product. If the attack takes
place onthe carbon that was having the leaving group then the configuration will be
retained because the configuration on that carbon will be inverted twice. The examples
of groups, like, halides, hydroxides, ethers, thioethers, amino groups, carboxy lates,
phenyl group, π-bonds etc., have been identified to act as neighbouring groups in many
reactions. Thus, according to the IUPAC, interaction of a reaction centre with a lone
pair of electrons in anatom or electrons present in σ -bond or π-bond in organic
chemistry is known as NGP. When NGP operates, increase in the reaction of rate is
normal. It is also possible for neighbouring group’s toinfluence many reactions in
organic chemistry. For nucleophilic substitution reactions, NGP canbe defined as the
introduction of a new reaction intermediate by a substituent that bond to the reaction
centre. For such substitutions, NGP occurs primarily occurs in the form of intra-
molecular nucleophilic attack, followed by inter-molecular substitution. Some
nucleophilic aliphatic substitution reactions that are in totality intermolecular in nature
observably begin with a nucleophilic atom in the substrate which reacts intra -
molecularly with the carbon atom which bears the leaving group and finally expelling
the leaving group. The resultant intermediate latter reacts with the external nucleophile
giving the observed substitution product, which happens to be an intermolecular
rnucleophilic substitution.
For example:

The role of the nucleophilic atom present in the substr ate in the overall reaction is
known as neighbouring group participation or anchimeric assistance. The net reaction is
thus a nucleophilic substitution in which A is the substrate and B, the substitution
product. If the reaction was to take place via S N 1 mechanism, it would yield B, as
substitution product and resulting in retention of configuration at the chiral centre, and
its enantiomer (C), resulting in inversion of configuration.
If the reaction was to take place via S N 2 mechanism, it would happen with inversion of
configuration at the chiral centre, yielding C as the only substitution product. The
formation of B as the only substitution product proves to great extent in favour of the
fact that there action is not a simple intermolecular nucleophilic aliphatic substitution
that follows either S N 1 or S N 2 path. Neighbouring group participation is invoked to
explain the course of the reaction. There are some conditions forNGP reactions when it
in operation:
1. It is normal for the reaction of rate to be increased.
2. There is a strong possibility for the stereochemistry of the reaction to be
abnormal (or unexpected) as compared with a normal reaction
SOLVED PROBLEMS:
1)
2)

1) Explain Aryl group as NGP.
Answer: Aryl groups are a suitable NG in substitution reactions. One example has
already been mentioned, another example is as follows.
There is retention of configuration in the product acetate.This clearly indicates the

participation of phenyl group.The пelectrons of the ring assist and stabilize the
developing positive charge. The intermediates, for the sake of book keeping, can be
shown as the delocalized phenoniumion.
2) Give example of Oxygen as NGP.

Answer:

02-03: NEIGHBOURING GROUP PARTICIPATION BY HETEROATOM LONE
PAIRS
A fine example of NGP is when reaction of a sulphur or nitrogen mustard occurs with a
nucleophile, the rate of reaction happens to be much higher for the sulphur mustard and
a nucleophile than it would befor a primary alkyl chloride not having a heteroatom.
NGPBY ALKENE
The π orbitals of an alkene are able to stabilize a transition state by helping to
delocalize the positive charge of the carbocation. For instance the unsaturated tosylate
will react more quickly (1011 times faster for aqueous solvolysis) with a nucleophile
than the saturated tosylate.
The carbocationic intermediate produced will be stabilized by resonance when the

positive charge spreads over several atoms. This is shown in the diagram below:

Even, if the alkene is far off from the reacting centre, even then the alkene can still act
in this manner. For instance, while forming alkyl benzene sulfonate, the alkene is still
able to delocalize the carbocation.
Also an increase in the rate of the S N 2 reaction of allyl bromide with a nucleophile as
compared with the reaction of n-propyl bromide is due to the fact that the orbitals of the
π-bond overlap with those of the transition state. In the allyl system the alkene orbitals
overlap with the orbitals of a S N 2 transition state
NGP BY CYCLOPROPANE, CYCLOBUTANE OR A HOMOALLYL GROUP

If Cyclo propyl methyl chloride is made to react with ethanol and water, then a mixture
of 48% cyclo propyl methyl alcohol, 47% cyclobutanol and 5% homoallyl alcohol (but -
3-enol) is formed.This is due to the fact that the carbocationic intermidate is
delocalised on to many different carbons through a reversible ring opening.
NGPTHROUGH AN AROMATICRING
Consider the case in which the reactivity ofbenzyl halide is higher because the S N 2
transition state enjoys asimilar overlap effect to that in the allyl system.
An aromatic ring can aid in the formation of a carbo cationic intermediate called a
phenonium ion by delocalization of the positive charge.
Example: When the tosylate tends to react with acetic acid in solvolysis then, instead of
a simple SN2 reaction forming B, a 48:48:4 mixture of A, B and (C+D) was obtained.

Themechanismwhichform A and B isdepictedbelow
SOLVED PROBLEMS:
1)
2) An aromatic ring can aid in the formation of a carbocationic intermediate called a

phenonium ionbydelocalisationofthe positive charge.

1) Explain the tosylate tends to react with acetic acid in solvolysis then, instead of a
simple SN 2 reaction forming B, a 48:48:4 mixture of A, B and (C+D) was obtained.
Answer: When the tosylate tends to react with acetic acid in solvolysis then, instead of
a simple SN 2 reaction forming B, a 48:48:4 mixture of A, B and (C+D) was obtained.
2) Show alkene is still able to delocalise the carbocation.
Answer: alkene is still able to delocalisethecarbocation.

02-04: NEIGHBOURING GROUP PARTICIPATION ON SN2 REACTIONS
For nucleophilic substitution reactions, neighbouring group participation is defined as
the introduction of a new reaction intermediate by a substituent that bonds to the
reaction centre. For such substitutions, neighbouring group participation occurs
primarily in the form of intra-molecular nucleophilic attack, followed by inter-
molecular substitution.
NGP INBIMOLECULARNUCLEOPHILICSUBSTITUTION
The result of this participation is the formation of a substituted product with retention
of configuration by opposing the inversion of configuration, which is typically
associated with the S N 2 mechanism. Hence, the mechanism of the reaction is changed.
In addition to this neighboring groups can also affect the stereochemical outcome of a
reaction. If a neighbouring group affects areaction in such a way that the rate of the
reaction is increased, then that neighbouring group issaid to provide anchimeric
assistance. The background reaction is used to determine if the neighbouring group is
rate enhancing. It is usually the analogous reaction in the absence of the neighbouring
group. NGP has been observed for a wide variety of substituents.
β-Halogens (one carbon removed from the leaving group) are a very basic example of
NGP, forming cyclic halonium ions with the reacting centre. Ions of this type are known
for chlorine, bromine, and iodine. Cyclic ions of this type are formed stereospeci fically
with inversion ofconfiguration.
F ORMATIONOFACYCLICIODONIUMINTERMEDIATE
Similarly, sulfides, amines, alcohols, and ethers can be effective NGP’s. Like the
halogens, thesegroups add stereospecificity to the reaction centre. Unlike halogens,
these groups do not have tobe in the β-position in order to act as a neighbouring group,
and can therefore form cyclic intermediates of rings of varying sizes. These groups
mostly provide anchimeric assistance, in addition to the mentioned retention of
configuration of the products.

AMINES , SULFIDES , ETHERS , AND ALCOHOLS AS
PARTICIPATING NEIGHBOURING GROUPS X=LEAVING

GROUP
β-Acetoxy substituents are also known to be neighbouring participants, forming 5 -

memberedcyclic species by bonding through the carbonyl carbon. The existence of the
acetoxonium ion (2) has been supported by trapping experiments in ethanol to give 4.
These trapping experiments were important in showing that the reaction was not
preceding by a classical S N 1 mechanism. The reaction produces 3 proceeds with the
inversion of configuration, once again yielding an overall retention of configuration.
ACETOXYGROUPASA NGP
In addition to substituents with lone pairs of electrons, p -bonded systems have been
shown to be participating neighbouring groups. β-Phenyl groups form phenonium ions
by donation of p-electrons. The phenonium ion intermediate has been supported by the
stereochemistry of the final substitution products as an inverted configuration.
P HENYL GROUPASANEIGHBOURING GROUP
NGP has also been demonstrated for non-conjugated p-systems. Perhaps the most
famous example of p-bond neighbouring group participation is that of anti-7-
norbornenyl derivatives.These derivatives were believed to participate via a p -orbital
interaction. Though this interaction invokes a molecular orbital explanation (as opposed

to the nucleophilic nature of the neighbouring groups), still the retention of
configuration is observed in substitution products asseen with previous examples. In
other words, one observed only anti-substitution with respect tothe double bond.
STABILIZATION OF THE NORBORNENYL CATION THROUGH P-ORBITAL INTERACTION
Supporting evidence was provided for this type of cation versus a rapidly equilibrating
structure by Gassmanetal, who substituted one methyl group on to the double bond and
showed a significant rate increase (13.3times greater than the unsubstituted reaction)
for a similar substitution reaction. When they substituted a second methyl group onto
the double bond, the rate increase was similar to that in the first substitution (148 times
greater than the unsubstituted reaction). Hence, the stabilization of the carbocation is
dependent on both carbons in the double bond. If the structure of the carbocation were
rapidly equilibrating between the two double bonded carbons, then we would have
shown no rate increase by adding the second methyl group.
Thus, the SN2 pathway is a more favourable pathway in which displacement of

brosylate is possible for compounds like H 3 COCH 2 CH 2 CH 2 CH 2 OBs and
H 3 COCH 2 CH 2 CH 2 CH 2 CH 2 OBs. The internal displacement pathway lead to the
formation of relatively stable 5- & 6-membered cyclic oxonium salts. As the chain
length increases, the likelihood of cyclic oxonium ion formation diminishes, and rates
approach to that of the reference case where only SN 2 attack by HCOOH is possible.
02-05: NEIGHBOURING GROUP PARTICIPATION ON SN1 REACTIONS

The S N 1 pathway leading to a primary carbocation intermediate is not as favourable as
an NGP (internal displacement) pathway leading to an episulfonium ion intermediate.

02-06: NEIGHBOURING GROUPS AND REARRANGEMENTS
Case 1. The exo bicyclic tosylate undergoes solvolysis 1011 times faster than the endo
isomer.This happens because the pi bond assists the formation of the carbocation and
the assistance is much better from the backside of the tosyl group.
Case 2. The trans-tosylate undergoes solvolysis 1000 times faster than the cis isomer.
The nonbonding electrons of the carbonyl group assist the formation of the developing
charge, and again the assistance is much better from the backside of the leaving group.
Case 3. Although 1 o cations are not formed in solvolysis reactions, neighboring groups
can assist the solvolysis of a primary substrate in a synchronous step to form a
stablecarbocation. Rearrangement occurs in β-pheny substrates because the phenyl
group donates electrons, from the backside,to give a stable cyclic phenoniumion.

Case 4. The neopentyl system, another primary substrate, rearranges rapidly to give the
product. CH 3 group assists the formation of a charge in acyclic ion to give the more
stable 3 o carbocation.
Case5. This shows the uncommon case of avinyl cation that can be formed by
solvolysis because of the good leaving group triflate. The phenyl group migrates to give
a more stable benzylic-type ion.
SOLVED PROBLEMS:
1.
2.
3.
4. S N 2 type reaction: Inversion of configuration (non-NGP reaction)

5.

1
1) Explain NGP -S N reaction.
Answer: NGP - SN1 reaction
2) Explain SN 2 type reaction: Inversion of configuration (non -NGP reaction).

Answer: SN 2 type reaction: Inversion of configuration (non -NGP reaction)

1) NGP is -----------
a) Number group parts
b) Neighbouring group participation
c) No group participation
d) None
2) Configuration of NGP is
a) Inversion
b) Retention

c) Both
d) Racemisation
3) NGP proceeds via
a) S N 1
b) E 1
c) S N 2
d) 2 times S N 2
4) Rate of S N2 reaction by NGP is --------
a) Decreases
b) Same
c) Increases
d) None
SUMMARY
 Anchimeric assistance is a case of intramolecular catalysis where NGP leads
to enhancement of rate of reaction.
 Anchimeric assistance involves two steps where first step is rate determining
leading to overall first order kinetics.
 For reactions that may go by S N 2 mechanism, if anchimeric assistance is
involved, the reactions proceed with retention of configuration.
 Various functional groups may participate in NGP including COO - COOR,
COAr, OCOR, OR, OH, O - , NH 2 , NHR, NR 2 , NHCOR, SH, SR, S - ,SO 2 Ph, I,
Br, and Cl.
 Neighbouring groups with electron releasing property are more efficient.
 In NGP the intermediate has acyclic structure which may lead to normal,
rearranged or cyclic product.
 For NGP to occur proper orientation of functional groups is a necessary
requirement.
 Double bond and phenyl ring can alsofunction as NGs in S N reactions.
 NGP is a useful tool for synthetic chemists. In SN2 reactions, retention of
configuration of the reaction centre can be obtained instead of the expected
inversion of configuration.
 Also, if the neighbouring group helps stabilize the intermediate produced in
the rate determining step, rate acceleration occurs.
 In the case study, the effects of solvent polarity on the compet ition between
NGP and SN2 direct substitution were addressed. It was observed that polar

solvents increased NGP. Use of polar solvents seemed to help stabilize the
cyclic cation intermediate.Also, the strength of the nucleophile was found to
affect the reaction outcome. When strong nucleophiles were used, only direct
substitution was observed.
KEY WORDS
Anchimericassistance, NGP, polar solvents, cyclic cation intermediate,
REFERENCES
A Guidebook to Mechanism in Organic Chemistry by Peter Sykes
1) (b) Neighbouring group participation
2) (b) Retention
3) (d) 2 times S N 2
4) (c) Increases
MOOCS
YOUTUBE VIDEOS
https://www.youtube.com/watch?v=y_XSSA4l0rk
https://www.youtube.com/watch?v=V4jucqpiKO4
https://www.youtube.com/watch?v=oHzC0BCh3yc
https://www.youtube.com/watch?v=yYiYt4jdaIY
WIKIPEDIA
https://en.wikipedia.org/wiki/Neighbouring_group_participation#:~:text=In%20organic%20chem
istry%2C%20neighbouring%20group,pi%20bond%20contained%20within%20the
https://en.wikipedia.org/wiki/Chemical_reaction
https://en.wikipedia.org/wiki/Neighbouring_group_participation#:~:text=NGP%20by%20heteroa
tom%20lone%20pairs,-
In%20this%20type&text=A%20classic%20example%20of%20NGP,alkyl%20chloride%20witho
ut%20a%20heteroatom.
https://en.wikipedia.org/wiki/Neighbouring_group_participation#:~:text=For%20instance%20in
%20the%20following,those%20of%20the%20transition%20state.
OER
____
REFERENCE BOOKS

CREDIT 04 -UNIT 03: ALLYLIC HYDROGENATION (NBS)
LEARNING OBJECTIVES
After studying this module, you shall be able to
 Know what is meant by hydrogenation
 Learn about the types of hydrogenations and hydrogenation catalysts
 Identify the conditions used for hydrogenation, mechanism and stereo
chemical aspects
 Evaluate the type of catalysts to be used for a selective hydrogenation
 Be familiar about asymmetric hydrogenations
 Analyze the hydrogenation conditions for alkenes, alkynes and aromatic
rings
INTRODUCTION:
As is evident from the term “Hydrogenation”, i.e., addition of hydrogen, it involves
the treatment of a chemical compound with hydrogen where by the hydrogen
molecule adds tothe substrate. It is the most commonly reaction used for the
reduction of unsaturated compounds such as alkynes and alkenes to form saturated
compound i.e., alkanes. In addition, aromatic rings and carbon-hetero atom multiple
bonds (imines, nitriles, carbonyls etc.) are also reduced by hydrogenation.
In order to carry out a hydrogenation reaction, gaseous hydrogen (H 2 ) is used in the

presence of acatalyst. Without a catalyst, hydrogenation requires very high
temperatures since the energy barrier to the reaction is huge as the H—H bond is
very strong (bond enthalpy of 436 kJ mol -1 ).The catalyst decreases the energy of
activation by breaking the H—H bond. Hence, catalytic hydrogenation is an
important method to reduce organic compounds via hydrogenation.
Usually, transition metals such as Platinum or Palladium are used in a finely divided
state adsorbed on charcoal (Pt/C or Pd/C) and hydrogenation is done simply by
stirring or shaking thesubstrate with the catalyst in a suitable solvent, in an
atmosphere of hydrogen gas. For example,2-butene gets reduced to butane by
reaction with hydrogen in the presence of Platinum -charcoal. Hydrogenation is done
in an apparatus which is arranged so that the up takeoff H 2 can be measured.
(Fig.4.3.1)

Fig.4.3.1: Apparatus for low pressure catalytic hydrogenation
Fig. 4.3.2: Alternative setup for catalytic hydrogenation and

dehydrogenation
The method is spoken as heterogeneous hydrogenation. (There are three phases

namely a gas (H 2 ), a solid (insoluble catalyst) and a solution (substrate in a
solvent). Filtration is done to remove a heterogeneous catalyst. It can also be
recycled, which is important from an economic and greener perspective.
Hydrogenation is an important reaction industrially and the most suitable example
of its largescale industrial use is the manufacture of solid/semi-solid hydrogenated
fat (margarine) from the vegetable oils (Figure 4.3.3).

Fig. 4.3.3: Partial hydrogenation of typical plant oil to typical component
margarine.
Most of the C=Cdoublebonds are converted to single bonds and increases product
melting point. In most of the cases hydrogen gas is used for hydrogenations, but
sometimes other sources of hydrogen can also be used; these are termed transfer
hydrogenations. For example, cyclohexene in the presence of Pd/C provides
hydrogen to the substrate for its reduction and itself gets converted to benzene via
cyclohex-1,3-dieneas shown below.
Hydrogenolysis involves “lysis” of carbon–carbon or carbon–heteroatom single

bond i.e. bond gets cleaved by hydrogen. Hydrogenolysis is most commonly used in
protection/de-protection strategies in organic syntheses such as for de-benzylation.
Also, hydrogenolysis can be a major side-reaction in multi-functional compounds.
03-01: Catalysts for Hydrogenation:

Catalytic hydrogenation can be done by number of catalyst. They lie under
the two broad families of catalysts- heterogeneous catalysts and homogeneous
catalysts. Heterogeneous catalysts remain suspended in the reaction mixture (orused
in reactions where the substrate is gaseous). On the other hand, homogeneous
catalysts become soluble in the solvent of the unsaturated substrate. The

homogeneous catalyst is used for binding of unsaturated substrate and hydrogen.
The catalysts development has not only enabled the implementation of
hydrogenations at lower temperatures and pressure conditions. This has resulted in
not only the reduced costs, but the advent of symmetric hydrogenations has opened
newer possibilities for thedrug industry.
(a) Heterogeneous Catalysts

Heterogeneous catalysts are mainly finely divided metals or their oxides or sulfides.
Noble metal catalysts (platinum and/or palladium and rhodium, ruthenium and
nickel) are commonly used.These catalysts are notspecific and may be usedfora
variety of reductions. The most extensively used are palladium and platinum
catalysts either in the finely divided formor, more commonly, supported on a
suitable support such as activated carbon, alumina or bariumsulfate. In general,
supported metal catalysts are active and unsupported metal are less active dueto
their larger surface area. However, their activity is influenced strongly by the
support and bythe method of preparation, which provides a means of preparing
catalysts of varying activity.Platinum, which i s pyrophoric and difficult to handle
and optimize for a reaction, is not employeditself as a catalyst, but is often used in
the form of its oxide PtO 2 (Adams’ catalyst), which is reduced to metallic platinum
by hydrogen. Palladium is used as a5-10% w/w loading on activated charcoal and
its hydroxide supported on activated carbon can also be used..
Nickel-based metal catalysts (such as Raney nickel and Urushibara nickel) can be
an alternative but they are slow enough that they require higher temperatures and /or
pressures conditions.Raney nickel is a porous, fine -grained solid obtained by
treating a powdered nickel–aluminium alloy with sodium hydroxide and contains
25–100 mL adsorbed H 2 per g of nickel, when freshly prepared.
2Al+2NaOH+6H 2 O→2Na[Al(OH) 4 ]+3H 2
Raney nickel is alkaline and may be used only for hydrogenations that are not
adversely affectedby basic conditions. Due to its alkaline nature, Raney nickel gets
deactivated by acids. However, it is highly active and can reduce any unsaturated
substrate by optimal changes in temperature and pressure, and is usually used when
all other methods have failed.
(b) Homogeneous Catalysts

Homogeneous catalysts provide better results as compared to heterogeneous
catalysts in the formof improved, more predictable selectivity, milder conditions
and lower catalyst loadings. Further, the stereochemistry of reduction becomes
easier to predict, since it depends not on chemisorptions but on reactions between
molecules. These soluble catalysts, which allow hydrogenation in homogeneous
solution, are thus, increasingly used for asymmetric hydrogenations as their spatial
configurations can direct the addition of hydrogen molecule to one or more favored
3-dimensional arrangements.
There are a large number of homogeneous cataly sts. The most common are based
on rhodium and ruthenium complexes. For example, [(Ph 3 P) 3 RhCl]
(tris(triphenylphosphine)chlororhodium,Wilkinson’scatalyst) and [(Ph 3 P) 3 RuClH].
Another example of homogeneous catalyst is acomplex of Iridium with 1,5-cyclo
octa diene, tris-cyclohexylphosphine, and pyridine, developed by Robert H.
Crabtree (Crabtree’scatalyst). (Figure 4.3.4)
Wilkinson’s Catalyst Crabtree’sCatalyst
Fig.4.3.4: Structures of Wilkinson and Crabtree’s catalyst
03-02: SELECTIVITY OF HYDROGENATION

The selectivity of a hydrogenation catalyst becomes important in the light of
the numerous hydrogenation catalysts available with a chemist. A question arises
that what type of catalyst must be used for a particular type of hydrogenation
reaction? The answer is not simple and for heterogeneous catalysts, highly
empirical observations and modifications form the basis of their selectivity for
hydrogenation. In general, one must remember the governing principle that
moreactive the catalyst, the less discriminating it is in its action. Other parameters
to be kept in mindare:
 Therate of a given hydrogenation reaction may be increased by raising the

temperature, by increasing the pressure orby increasing the amountof
catalyst used.

 For greatest selectivity, reactions should be run with the least active catalyst
and under the mildest possible conditions consistent with a reasonable rate
of reaction.
 Sometimes, the role of solvent is important and can decide the course of
hydrogenation.
 It is important to select an appropriate catalyst and reaction conditions for
selective hydrogenation. Sometimes the catalyst itself may be more active
towards certain classes of compound than others. For example, Pt, Rh, and
Ru will selectively hydrogenate aromatic rings in the presence of benzylic
C–O bonds, while with Pd catalysts the benzylic C–O bonds are
hydrogenolysed faster.
 The functional groups present on the substrate are also important. Not all
functional groups are reduced with equalease. In general, the reactivity of
functional groups towards catalytic hydrogenation decrease in the order as
listed in Table 1. In general, groups at the top of the list can be reduced
selectively in the presence of those at thebottom. For example, reduction of
an unsaturated ketone to a saturated ketone can be accomplished readily by
hydrogenation over palladium, but the hydrogenation of unsaturated ketone
to unsaturated alcohol is not possible. Similarly, benzonitrile can be
converted into benzylamine, but selective reduction to cyclohexane
carbonitrile is not possible.
Table 4.3.1: Order of reactivity of various functional groups towards catalytic

hydrogenations

In heterogeneous hydrogenation catalysts, the activesites (the metal surface
on the support which is exposed for the reaction) are important and selectivity (or
reducing the activity of the catalyst) can also be achieved by blocking some of these
by means of “poisons” which can include halides, metal cations, amines, sulfides
and phosphines. Effect of poisoning agents is not the same for every catalyst and
their use is based solely on observation. For example partial hydrogenation of
alkynes give high yield alkenes with a palladium –calcium carbonate catalyst that
has been partially deactivated by lead acetate or quinolone (Lindlar’s catalyst).
Sometimes, the substrateitself can have a functional group which may act as
catalyst poison and can lead to selectivity or may even make the substrate less
active to catalytic hydrogenation.
SOLVED PROBLEMS:
1) Order of reactivity of various functional groups towards catalytic hydrogenations
2) Nickel-based metal catalysts (such as Raney nickel and Urushibara nickel) can
be an alternativebut they are slow enough that they require higher temperatures
and/or pressures conditions.Raney nickel is a porous, fine -grained solid obtained by
treating a powdered nickel–aluminiumalloy with sodium hydroxide and contains
25–100 mL adsorbed H 2 per g of nickel, when freshlyprepared.
2Al+2NaOH+6H 2 O→2Na[Al(OH) 4 ]+3H 2
1) Give the structure of Wilkinson’sCatalyst.
Answer:

2) Give the structure of Crabtree’s Catalyst
Answer:
03-03: HALOGENATION OF ALKENES: ASPECTS OF CARBON -CARBON

DOUBLE BOND HYDROENATIONS
Hydrogenationof alkenes takes place easilyandinmost cases canbe
effectedunder mildconditions. However, as hydrogenation is sensitive to steric
hindrance, highly hindered alkenes are resistant to hydrogenation, but even these
can generally be hydrogenated under more vigorous conditions. Pd and Pt are the
most frequently used catalysts. Both are very active and their use depends upon the
type of substrate and degree of selectivity required. In general, Pt is more active
than Pd-catalysts.
Other catalysts that can be used are Raney-Nickel (only in some cases as it is highly
reactive) and Rhodium and Ruthenium catalysts. Rh and Ru catalysts sometimes
show useful selectivity. For example, in the reaction shown below, rhodium allows
hydrogenation of alkenes with out affecting the hydrogenolysis of the ether (an
oxygen functional group).
The degree of substitution of the double bond decreases the ease of reduction of an
alkene, and this sometimes selectively reduce one double bond over other in a
molecule with more than one double bond. Out of the exocyclic and endocyclic

double bonds, exocycli cdouble bonds are easier to be reduced. For example,
limonene can be converted into p-menthene by hydrogenation over Adam’s catalyst
if the reaction is stopped after absorption of one molar equivalent of hydrogen.
The reactivity order of various functional groups towards hydrogenation reflects

that alkenes canbe selectively hydrolyze in many cases excluding when aromatic
nitro, alkynes or acyl halides are present in the same molecule with Pd be ing the
catalyst of choice. For example, in the following reaction, C=C is reduced
selectively without affecting the nitrile.
For different hydrogenation metal catalysts, an empirical generality has been

observed in their selective hydrogenations of a functional group in preference to
another which is depicted in figure 4.3.3.Similarly, when the substrate is alkene,
more is the steric hindrance; less is the reactivity (Figure4.3.4).
Fig. 4.3.3: Order of reactivity of functional groups for different metals as

catalysts
Fig 4.4.4: Order of reactivity of different alkenes
For homogeneous hydrogenation of non-conjugated alkenes, Wilkinson’s catalyst is

an extremely efficient catalyst (and also for alkynes) at ordinary temperature and
pressures. Functional groups such as –C=O, –CN, –NO 2 and –Cl are not reduced
under these conditions. Tri-or tetrasubstituted double bonds are reduced much
more sluggishly than mono- and di-substituted ones, permitting the selective
hydrogenation of compounds containing different kinds of double bonds.For
example, in the reduction of carvone, the hydrogenation occurred at the non -
conjugated double bond.

Another example is the selective reduction of β -nitrostyrene to 2-phenyl-nitroethane
by reduction of double bond without affecting the nitro group.
Another synthetically useful feature of the Wilkinson’s catalyst is that it does not
lead to hydrogenolysis of the susceptible functionalities in the molecule and hence
can be employed in multi-step synthetic strategies for selective double bond
hydrogenation without hydrogenolysis of protecting groups. Another important
aspect is that on reaction with deuterium, only two deuterium atoms are added, at
the site of the original double bond and no allylic scrambli ng is observed as with
heterogeneous catalyst.
However, one disadvantage associated with the Wilkinson’s catalyst is that

substrates containing aldehyde group undergo de-carbonylation due to strong
affinity of this catalyst towards carbon-monoxide.
The Ir-based Crabtree’s catalyst is even more reactive than Wilkinson’s catalyst and
is good for hydrogenating hindered alkenes. Also, this catalyst gives superior
directing effect for cyclic substrates as high degree of stereo-control can be
achieved in the hydrogenation of cyclic allylic and homo allylic alcohols. This
directing effect is due to a bonding interaction of the hydroxyl group with the
iridium center.

SOLVED PROBLEMS:
1)
2)

1) Give the example of hydrogenation over Adam’s catalyst.
Answer: limonene can be converted into p-menthene by hydrogenation over Adam’s
catalyst if the reaction is stopped after absorption of one molar equivalent
ofhydrogen.
2) Explain selective reduction of β-nitrostyrene to 2-phenyl-nitroethane.
Answer: example is the selective reduction of β-nitrostyrene to 2-phenyl-

nitroethane by reduction of double bond without affecting the nitro group.
03-04: Mechanism of Hydrogenation and Stereochemical aspects

(a) Mechanism of Heterogeneous catalytic hydrogenation

In the mechanism of catalytic hydrogenation, the surface of metal catalyst
absorbs hydrogen. Thealkene complexes with the metal by reversible π -complex
formation with vacant metal orbitals.After this hydrogen from the catalyst is
transferred to the side of the molecule that is adsorbed onit.The adsorption on to the
catalystis largely controlled by steric factors, and it is found in general that
hydrogenation takes place by cis addition of hydrogen atoms to the less-hindered
side of the unsaturated center and thus cis-hydrogented product is usually obtained.
However, trans product may form occasionally. The most plausible mechanism
which can explain these out comes is in which transfer of hydrogen atoms from the
catalyst to the adsorbed substrate takes place in number of steps as shown in the
figure 4.3.5.
The process involves equilibria between π-bonded forms 1 and 2 and a half
hydrogenated form 3,which can either take up another atom of hydrogen (to give the
reduced product 4) or revert to starting material or to an isomeric alkene 5.
Subsequently, the new iso-alkene is hydrogenated. In principle it may add hydrogen
from either of its diastereotopic faces and would eventually lead to trans-
hydrogenated product. Similarly, the formation of allylic deuteration products may
be explained when an alkene is reacted with D 2 in presence of Pd catalysts.
Fig.4.3.5: Mechanism of heterogeneous catalytic hydrogenation

(b) Mechanism of Homogeneous Hydrogenation
Homogeneous hydrogenations with Wilkinson’s catalyst [(Ph 3 P) 3 RhCl]also
occur cis selectivelysans the side reactions as observed with heterogeneous ones. In
this mechanism initially thereaction involves dissociation of one or two
triphenylphosphine ligands to give 14- or 12-electron complexes, respectively, and
then H 2 is added to the metal. Alkane product is rubbed out bySubsequent π -
complexation of alkene, intramolecular hydride transfer (olefin insertion), and
reductive elimination. Here we observes that PPh 3 is readily lost due to steric
crowding and that the inner catalyst cycle with a weakly coordinated solvent
molecule (resulting in a 16-electroncomplex) is about 1000 times faster than 3 PPh 3
ligands coordinated to the metal (Figure 4.3.6). TheCrab tree’s catalyst has a similar
mechanism but the substrate adds before H 2 .
Fig. 4.3.6: Mechanism of hydrogenation by Wilkinson’s catalyst; (i) H 2

addition, (ii) alkene addition, (iii) migratory insertion,(iv) reductive elimination
of the alkane and regeneration of the catalyst
(C) Asymmetric hydrogenation

Homogeneous hydrogenations are well-suited to asymmetric induction using chiral
ligands on therhodium or ruthenium metal centre. Chiral phosphines are most
common and many have beenstudied. Recently monodentate phosphine ligands such
as MonoPhos (1) have been shown to be very effective for enantioselectively
reducing the N-acyldehydro-aminoacids or their corresponding esters, to amino-acid
derivatives, for example giving N-acetylphenyl alanine in quantitative yield and
with 97% ee. The N-acyl dehydro-amino acid is thought to complex with the
rhodium metal via its alkene and N-acyl carbonyl oxygen atom, leaving co-
ordination sites for the ligand and hydrogen, which is then delivered asymmetrically
to the alkene. Thus, asymmetric hydrogenation depends on the nature of substrate

and a second functional group which can co -ordinateto the metal catalyst often
aidsto the asymmetric induction of hydrogen.
(D) Hydrogenation of Alkynes:

Alkynes are catalytically hydrogenated to alkene and further to alkane in a step -
wise manner as discussed earlier. Both alkene and alkane may be isolated. For
complete conversion of alkyne to alkane, Pt, Pd catalysts or Raney-Nickel are used.
However, if a propargylic alcohol group is present, it may occasionally undergo
hydrogenolysis, especially when Pt-catalysts are used.
As mentioned earlier, it is possible to partially hydrogenate alkynes to alkenes by

the use ofcatalyst poisons. The use of Lindlar’s catalystto get Z -alkenes is a most
important example of such transformation. More electrophilic alkynes absorb more
strongly on the electron-rich catalyst surface than the corresponding alkenes, aids
such partial hydrogenations. However, when using Lindlar’s catalyst, it is important
to prevent over-hydrogenation by carefully monitoring there action conditions and
limiting the hydrogen consumption to around 1 mol. Such selective hydrogenation
to Z-alkenes has found significant use in the synthesis of natural products and some
pharmaceutically important intermediates.

(D) Hydrogenation of Aromatic rings
Aromatic rings are among the hardest to be hydrogenated and even with
precious metal catalysts, require higher temperatures and pressures. But, once a
benzene ring starts to hydrogenate, there is nothing like partial hydrogenation, and
it hydrogenates to cyclohexane. This is because when benzene has been converted
to cyclohexadiene (first hydrogenation and the hardest, endothermic step), it is
associated with the loss of resonance energy and the subsequent hydrogenations are
exothermic and faster than the first one. Pt and Rh catalysts are common and used at
ordinary temperatures whereas Raney-Nickel or Ru-catalysts require higher
temperatures and pressures and Raney-Nickel isused for large scale hydrogenations
involving heating at 150 ᴼC at high pressures (100-200 atm). Rh over Alumina is
another prominent catalyst used and requires milder conditions than others. Also, it
does notcause hydrogenolysis of the sensitive C—O bonds present in the molecule.
Hydrogenation of polycyclic aromatic rings such as naphthalenes and phenanthrenes

are also performed and by varying the reaction conditions, partially hydrogenated or
fully hydrogenated products may be obtained. For example, Raney -Nickel may be
used to obtain tetrahydro or decahydro-naphthalene by varying the reaction
conditions. Similarly, 9,10-dihydro phenathrenesor anthracenes can be obtained by

reduction over copper-chromite and to fully reduce them, more active catalysts are
required .
SOLVED PROBLEMS:
1)
2)

1) Complete the following reaction
Answer:
2) Complete the following reaction
Answer:

1) Which of the following is an allylic bromide?
a) 1-bromopropene
b) 2-bromopropene
c) 3-bromopropene
d) All of the above
2) Which of the following is a conjugated diene?
a) Benzene
b) 1,2-pentadiene
c) 1,3-pentadiene
d) 1,4-pentadiene
3) Which of the following has the lowest heat of hydrogenation?
a) 1,2-hexadiene
b) (E)-1,4-hexadiene
c) (Z)-1,4-hexadiene
d) (E)-1,3-hexadiene
e) (Z)-1,3-hexadiene
4) How many constitutional isomers would be expected as products in the NBS allylic
bromination of 1-methylcyclohexene?
a) 1
b) 2
c) 3
d) 4
e) 5
SUMMARY
 Hydrogenation involves the treatment of a chemical compound with
hydrogen and H 2 is added to a multiple bond.
 Hydrogenolysis (hemolytic fission of a bond by action of hydrogen) is an
associated reaction and can bean unwanted side reaction in hydrogenation
reactions.
 Hydrogenation requires use of a catalyst (homogeneous or heterogeneous) as
the un-catalysed reaction requires very high temperatures and pressures.
 Different catalysts have different chemo-selectivities and their selection
depends upon empirical observations and variations of reaction conditions.
 Catalyst poisons are added to decrease the activity of a catalyst and there by
bringing more selectivity, Lindlar catalyst to form alkene from alkynes being
the most prominent example.

 The most plausible mechanism of heterogeneous hydrogenation is
chemisorption of H 2 and unsaturated substrate over the catalyst surface and
cis-addition of hydrogen atoms tothe less-hindered side of the unsaturated
centre a stepwise manner.
 Homogeneous hydrogenations involve a cycle of oxidative addition of H 2 to
the metal, subsequent π-complexation of alkene, intramolecular hydride
transfer (olefin insertion), and reductive elimination to give the product.
 Asymmetric hydrogenations are also possible in homogeneous
hydrogenations by use of chiral ligands.
 Alkenes, alkynes and aromatic rings can be successfully hydrogenated by the
variety of hydrogenation catalysts available to any feasible level of chemo-
selectivity.
KEY WORDS
Hydrogenation, Catalyst, Homogeneous, Hydrogenolysis, Selectivity
REFERENCES
1) (c) 3-bromopropene
2) (c) 1,3-pentadiene
3) (d) (E)-1,3-hexadiene
4) (e) 5
MOOCS
YOUTUBE VIDEOS
https://www.youtube.com/watch?v=fWh6Y-VAUSo
https://www.youtube.com/watch?v=Hx7eHHYmLT0
https://www.youtube.com/watch?v=y2LaS1gdhIk
https://www.youtube.com/watch?v=The6GsEQeQU
WIKIPEDIA
https://en.wikipedia.org/wiki/Hydrogenation
https://en.wikipedia.org/wiki/Hydrogenation#:~:text=Hydrogenation%20is%20a%20chemical%2
0reaction,as%20nickel%2C%20palladium%20or%20platinum.
https://en.wikipedia.org/wiki/Hydrohalogenation
https://en.wikipedia.org/wiki/Asymmetric_hydrogenation
https://en.wikipedia.org/wiki/Wilkinson%27s_catalyst
OER
____
REFERENCE BOOKS

CREDIT 04 -UNIT 04: COUPLING OF ALKYNES AND
ARYLATION
LEARNING OBJECTIVES
After studying this module, you know
 Different types of free radical reactions and their mechanism.
INTRODUCTION:
Compounds containing -N=N- group are known as diazo compounds. Their general
structure is R-N=N-R’.Here R and R’ are preferably arene groups and the azo group is
thus stabilised by becoming part of extended delocalised system. They are prepared by
coupling reaction between a diazonium salt and a coupling reagent.
04-01: DIAZO COMPOUNDS&DIAZONIUM SALT:

Compounds containing -N=N- group are known as diazo compounds. Their
general structure is R-N=N-R’.Here R and R’ are preferably arene grou ps and the azo
group is thus stabilised by becoming part of extended delocalised system. They are
prepared by coupling reaction between a diazonium salt and a coupling reagent.
Diazonium salts are prepared by adding cold solution of sodium nitrite (NaNO2)
to arylamine solution in dilute acid below 5oC temperature. This process is called
diazotisation. The diazonium salts are prepared fresh and used immediately.
The hydrochloric acid reacts with sodium nitrite to form unstable nitrous acid.
The nitrous acid formed in situ reacts with the arylamine to form diazonium ion.
MECHANISM OF DIAZOTIZATION:
Step 1: Formation or generation of NO + (nitrosonium ion) or dinitrogentrioxide: The
nitrosonium ion formation takes place as follows where water is removed from nitrous
acid

Step 2: Attack of NO+ (nitrosonium ion) or N 2 O 3 on the amine
Step 3: Loss of proton
Step 4: Tautomerisation
Step 5: Loss of water and formation or generation of diazonium ion
STABILITY OF DIAZONIUM ION

The aromatic diazonium salts are relatively more stable than aliphatic diazonium salts,
as the electron rich benzene ring stabilises the -N + ≡N group. If the temperature rises
above 5 ℃, the benzenediazonium chloride decomposes to form phenol and nitrogen
gas is given off. The aromatic groups present stabilise the diazonium ion through
donating electrons via delocalisation in comparison to aliphatic groups, as sh own
below.
SOLVED PROBLEMS:
1)

2)

1) Explain Stability of diazonium ion.
Answer: Stability of diazonium ion:
The aromatic diazonium salts are relatively more stable than aliphatic diazonium salts,
as the electron rich benzene ring stabilises the -N + ≡N group. If the temperature rises
above 5, the benzenediazonium chloride decomposes to form phenol and nitrogen gas is
given off. The aromatic groups present stabilise the diazonium ion through donating
electrons via delocalisation in comparison to aliphatic groups, as shown below.
2) How to form benzene diazonium cation?

Answer:
04-02: COUPLING REACTION

If the benzenediazonium chloride is reacted with another compound containing a
benzene ring, called a coupling agent (such as phenol or aromatic amine), an azo
compound is produced. The diazonium salt acts as an electrophile in a coupling
reaction. Many of the products of coupling reactions are important dyes. A coloured
precipitate of azo compound is formed immediately on reaction of diazonium salt with
amines or phenols.
Examples of coupling reactions:
a) Benzene diazonium salt and alkaline phenol gives a yellow orange azo compound
b) Benzene diazonium salt and alkaline naphthalen -2-ol gives a red azo compound

c) Benzene diazonium salt and phenylamine gives a yellow azo compound.
d) Mechanism of coupling reaction:

The mechanism involves an initial attack of coupling agent (phenols or anilines) on an
electrophilic diazonium ion, followed by loss of a proton. The product is normally a
trans-diazo compound rather than cis.
SOLVED PROBLEMS:
1)
2)

1) What happen if Benzenediazonium salt and phenylamine react together?
Answer: Benzenediazonium salt and phenylamine gives a yellow azo compound.

2) Explain the mechanism of coupling reaction:
Answer: Mechanism of coupling reaction:
The mechanism involves an initial attack of coupling agent (phenols or anilines) on an
electrophilic diazonium ion, followed by loss of a proton. The product is normally a
trans-diazo compound rather than cis.
04-03: SANDMEYER REACTION

The Sandmeyer reaction is a chemical reaction used to synthesize aryl halides from aryl
diazonium salts using copper salts as reagents or catalysts. It is an example of a radical -
nucleophilic aromatic substitution. The Sandmeyer reaction provides a method through
which one can perform unique transformations on benzene, such as halogenation,
cyanation, trifluoro methylation, and hydroxylation.
The reaction was discovered in 1884 by Swiss chemist Traugott Sandmeyer,

when he attempted to synthesize phenylacetylene from benzenediazonium chloride and
cuprous acetylide. Instead, the main product he isolated was phenyl chloride. In modern
times, the Sandmeyer reaction refers to any method for substitution of an aromatic
amino group via preparation of its diazonium salt followed by its displacement with a
nucleophile in the presence of catalytic copper(I) salts. (Due to the low cost of copper
salts, a stoichiometric amount is often employed for better reactivity even when
catalysis is possible.) The most commonly employed Sandmeyer reactions are the
chlorination, bromination, cyanation, and hydroxylation reactions using CuCl, CuBr,
CuCN, and Cu2O, respectively. More recently, trifluoromethylation of diazonium salt s
has been developed and is referred to as a 'Sandmeyer -type' reaction.
Diazonium salts also react with boronates, iodide, thiols, water,
hypophosphorous acid and others, and fluorination can be carried out using
tetrafluoroborate anions (Balz–Schiemann reaction). However, since these processes do
not require a metal catalyst, they are not usually referred to as Sandmeyer reactions. In
numerous variants that have been developed, other transition metal salts, including
copper(II), iron(III) and cobalt(III) have also been employed.Due to its wide synthetic
applicability, the Sandmeyer reaction, along with other transformations of diazonium
compounds, is complementary to electrophilic aromatic substitution.

Reaction conditions and mechanism:
The nitrous acid is typically prepared in situ from sodium nitrite and acid.
Following two protonation steps, one equivalent of water is lost to form the
nitrosonium ion. The nitrosonium ion then acts as an electrophile in a reaction with an
aromatic (or heterocyclic) amine, such as aniline, to form a diazonium salt, proceeding
through a nitrosamine intermediate. Typical reaction conditions are as follows:
Chlorination: ArN 2 +Cl–, CuCl, HCl (36% aq.), 50 – 100 °C; bromination: ArN2+HSO 4 –
, CuBr, HBr (48% aq.), 50 – 100 °C; cyanation: ArN 2 +Cl–, CuCN, KCN, H 2 O, benzene,
0 °C; hydroxylation: Cu 2 O, Cu(NO 3 ) 2 , H 2 O, 25 °C.
The Sandmeyer reaction is an example of a radical-nucleophilic aromatic

substitution (SRNAr). The radica mechanism of the Sandmeyer reaction is supported by
the detection of biarylbyproducts. The substitution of the aromatic diazo group with a
halogen or pseudohalogenis initiated by a one-electron transfer mechanism catalyzed by
copper (I) to form an aryl radical with loss of nitrogen gas. The substituted arene is
possibly formed by direct transfer of Cl, Br, CN, or OH from a copper (II) species to
the aryl radical to produce the substituted arene and regenerate the copper (I) catalyst.
In an alternative proposal, a transient copper(III) intermediate, formed from coupling of
the aryl radical with the copper(II) species, undergoes rapid redu ctive elimination to
afford the product and regenerate copper(I).However, evidence for such an
organocopper intermediate is weak and mostly circumstantial,and the exact pathway
may depend on the substrate and reaction conditions. These possibilities are sh own
below
Step 1: Formation of nitrosonium ion
Step 2: Formation of benzene diazonium ion

Single electron transfer
SOLVED PROBLEMS:
1)

2)

1) What is Sandmeyer reaction with example?
Answer: Sandmeyer reaction is a type of substitution reaction that is widely used in the
production of aryl halides from aryl diazonium salts. Copper salts like chloride,
bromide or iodide ions are used as catalysts in this reaction. Notably, Sandmeyer
reaction can be used to perform unique transformations on benzene.The transformations
include hydroxylation, trifluoromethylation, cyanation, and halogenation.
2) Give the applications of Sandmeyer Reaction.

Answer: Applications of Sandmeyer Reaction:
Today, a lot of variations of the Sandmeyer reaction have been developed. As a result of
these developments, the reaction has multiple synthetic applications. The different
adaptations help in the synthesis of aryl thioethers, aryl fluorides (the Schiemann
reaction), phenols, and aryl nitriles.
The common uses of the Sandmeyer reaction are:
 It is used in hydroxylation to convert aryl amines to phenols leading to the
formation of an aryl diazonium salt.
 To create aryl compounds during the process of trifluoromethylation. The
compounds inherit unique chemical properties with a wide variety of practical
applications.
 Sandmeyer reaction is used for the formation of benzonitriles through the
process of cyanation. The reaction is also found during the synthesis of
neoamphimedine, a chemical compound that targets topoisomerase II as an anti -
cancer drug.
 To create aryl halides. Some of the solvents used in this process are
diiodomethane to synthesize aryl iodides, bromoform to synthesize aryl
bromides, chloroform to synthesize aryl chlorides.
04-04: SYNTHETIC APPLICATIONS

Variations on the Sandmeyer reaction have been developed to fit multiple synthetic
applications. These reactions typically proceed through the formation of an aryl
diazonium salt followed by a reaction with a copper (I) salt to yield a substituted arene
according to the scheme below.Some examples of the synthetic applications of the
Sandmeyer reaction are provided below.

A. Halogenation:
One of the most important uses of the Sandmeyer reaction is the formation of aryl
halides. The solvent of choice for the synthesis of aryl iodides is diiodomethane, while
for the synthesis of aryl bromides, bromoform is used. For the synthesis of aryl
chlorides, chloroform is the solvent of choice. The synthesis of (+)-curcuphenol, a
bioactive compound that displays antifungal and anticancer activity, employs the
Sandmeyer reaction to substitute an amine group by a bromo group.
One bromination protocol employs a Cu(I)/Cu(II) mixture with additional

amounts of the bidentate ligand phenanthroline and phase-transfer catalyst dibenzo-18-
crown-6 to convert an aryl diazonium tetrafluoroborate salt to an aryl bromide.
The Balz–Schiemann reaction uses tetrafluoroborate and delivers the halide-substituted

product, fluorobenzene, which is not obtained by the use of copper fluorides. This
reaction displays motifs characteristic of the Sandmeyer reaction.
B. Cyanation
Another use of the Sandmeyer reaction is for cyanationwhich allows for the formation
of benzonitriles, an important class of organic compounds. A key intermediate in the

synthesis of the anti-psychotic drug, Fluanxol, is synthesized by a cyanation through
the Sandmeyer reaction.
The Sandmeyer reaction has also been employed in the synthesis of neoamphimedine, a
compound that is suggested to target topoisomerase II as an anti-cancer drug.
C. Trifluoromethylation
It has been demonstrated that Sandmeyer-type reactions can be used to generate
aryl compounds functionalized by trifluoromethyl substituent groups. This process of
trifluoromethylation provides unique chemical properties with a wide variety of
practical applications. Particularly, pharmaceuticals with CF3 groups have enhanced
metabolic stability, lipophilicity, and bioavailability. Sandmeyer-type
trifluoromethylation reactions feature mild reaction conditions and greater functional
group tolerance relative to earlier methods of trifluoromethylation.An example of a
Sandmeyer-type trifluoromethylation reaction is presented below.
D. Hydroxylation:
The Sandmeyer reaction can also be used to convert aryl amines to phenols
proceeding through the formation of an aryl diazonium salt as shown below.

In the presence of copper catalyst, this reaction takes place readily at room
temperature. The procedure reported by Cohen and coworkers calls for cuprous oxide
together with an excess of cupric nitrate in neutral water. This is in contrast to the
classical procedure (known by the German name Verkochung, Verkochung), which calls
for boiling the diazonium salt in aqueous acid, a process that is believed to involve the
aryl cation instead of radical and is known to generate other nucleophilic addition side
products in addition to the desired hydroxylation product.
04-05: HUNSDIECKER REACTION :

The decarboxylation of silver salts of carboxylic acids to alkyl bromides by treating
with bromine is known as Hunsdiecker reaction. The alkyl bromide contains one carbon
less than those in carboxylic acid.
This reaction is also known as Borodin -Hunsdiecker reaction.
 Very good yields are obtained with alkyl groups containing 2 to 18 carbons. This
reaction works with linear as well as branched chains. However the reaction
seldom works with alkyl groups containing unsaturation. This reaction is usually
carried out in carbon tetrachloride solvent.
 Although bromine is used often, the reaction is also possible with ch lorine and
iodine.
 When iodine is used, the ratio between the silver carboxylate and iodine is very
important and determines the products.
 A 1:1 ratio of silver salt and iodine gives the alkyl halide. However, an ester,
RCOOR is formed when the reaction is carried out with a 2:1 ratio of silver
carboxylate and iodine. This is called as Simonini reaction.
 Incase of aromatic carboxylates, the Hunsdiecker reaction is possible when the
aromatic ring contains electron-withdrawing groups. Otherwise, if the aromatic
system contains electron-donating groups, the bromine will substitute one of the
hydrogen on the aromatic ring rather than promoting the Hunsdiecker reaction.
However the use of NBS instead of bromine will give the desired

Hunsdieckerproduct. This reagent is especially useful since it produces bromine
free radicals slowly.
 The silver carboxylate used as the starting material must be sufficiently pure and
dry. It can be prepared from the corresponding carboxylic acid by treating it with
silver oxide, Ag2O.
Christol-Firth Modification: It is possible to perform the Hunsdiecker reaction
conveniently on the free carboxylic acid instead of the silver salt, which otherwise
requires purification. In this modification the free carboxylic acid is treated with a
mixture of mercuric oxide, HgO and bromine in CCl4. There is no need to isolate an
intermediate salt.
Mechanism of Hunsdiecker reaction:

(a) Initiation: Initially the bromine reacts with the silver carboxylate to give an
unstable acyl hypobromite. The driving force of this step is the precipitation of the
extremely poorly soluble and stable AgBr. The acyl hypobromite decomposes by
homolytic cleavage of relatively weak O-Br bond to furnish an acyl free radical.
(c) Propagation: The acyl free radical undergoes decarboxylation to furnish an alkyl
free radical, which reacts with acyl hypobromite to give the final product alkyl
bromide along with the formation of a new acyl free radical.
The following facts support the above proposed free radical mechanism for
Hunsdiecker reaction.
 No rearrangement of alkyl groups
 The formation of side products like R-R.
 If the alkyl group, R is chiral, it loses its optical activity during this reaction.
SOLVED PROBLEMS:
1) The silver salt of propionic acid is converted to ethyl bromide when treated with

bromine in tetrachloromethane.
2)In the following reaction, the use of NBS (N -Bromosuccinimide) reduces the chances
of electrophilic substitution on benzene ring.

1) Explain the conversion of Bicyclo [1.1.1] pentane-1,3-dicarboxylic acid to the
Corresponding dibromide.
Answer: The Christol-Firth Modification is used in the preparation of [1.1.1 ]
propellane (tricycle [1.1.1.01,3]pentane). The conversion of Bicyclo [1.1.1] pentane-
1,3-dicarboxylic acid to the corresponding dibromide is achieved by using mercuric
oxide and bromine in carbon tetrachloride as shown below.
2) Explain Hunsdiecker reaction.

Answer: The decarboxylation of silver salts of carboxylic acids to alkyl bromides by
treating with bromine is known as Hunsdiecker reaction. The alkyl bromide contains
one carbon less than those in carboxylic acid.
This reaction is also known as Borodin -Hunsdiecker reaction.

1) Which of the following is(are) example(s) of Sandmeyer reaction?
a) C6H5N2+Cl⁻ → C6H5Cl
b) C6H5N2+Cl⁻ → C6H5OH
c) C6H5N2+Cl⁻ → C6H5CN
d) C6H5N2+Cl⁻ → C6H5NH2
2) In order to convert aniline into chlorobenzene, the reagents needed are-
(a) CuCl
(b) NaNO2/HCl and CuCl

(c) Cl2/CCl4
(d) Cl2/AlCl3
3) Which of the following cannot be prepared by Sandmeyer's reaction?
(a) Chlorobenzene
(b) Bromobenzene
(c) Iodobenzene
(d) Fluorobenzene
4) The coupling reaction is a type of _________ reaction.
a) Electrophilic addition
b) Electrophilic substitution
c) Nucleophilic addition
d) Nucleophilic substitution
SUMMARY
 The diazotization reaction mechanism begins with the reaction of nitrous acid
with the other acid to give water and nitrosonium ion. Thus, the required
nitrosonium ion is formed. This is now reacted with the aromatic ring to which
the NH 2 group is attached.
 Diazonium Salts find application in the dye and pigment industries and are used to
produce dyed fabrics. They are useful in the synthesis of a large variety of organic
compounds, especially aryl derivatives. Direct halogenation is not a suitable method for
preparing aryl iodides and fluorides.
 Sandmeyer reaction is used for the formation of benzonitriles through the
process of cyanation. The reaction is also found during the synthesis of
neoamphimedine, a chemical compound that targets topoisomerase II as an anti -
cancer drug.
 Hunsdiecker Reaction is Important Because of Various Reasons. In certain cases, it can
selectively produce two different types of alkyl halides from the same benzene
compound. This reaction enables chemists to synthesise complex organic compounds
through an efficient methodology with a high atom economy and low cost.
KEY WORDS
Diazotization reaction, nitrosonium ion, Sandmeyer reaction,Hunsdiecker Reaction, alkyl
halides.
REFERENCES
1) (a) C6H5N2+Cl⁻ → C6H5Cl

2) (b) NaNO2/HCl and CuCl
3) (c) Iodobenzene and (d) Fluorobenzene
4) Answer: (b)
Explanation: During a coupling reaction, the diazonium cation which has a positive charge on the
terminal nitrogen acts as the electrophile, and the electron rich compounds act as nucleophiles.
MOOCS
______
YOUTUBE VIDEOS
https://www.youtube.com/watch?v=f7btfysVaC4
https://www.youtube.com/watch?v=5yi5eyi12us
https://www.youtube.com/watch?v=upnp9tdA5u0
https://www.youtube.com/watch?v=AgJblxTMJhc
WIKIPEDIA
https://en.wikipedia.org/wiki/Diazonium_compound
https://en.wikipedia.org/wiki/Diazo
https://en.wikipedia.org/wiki/Coupling_reaction
https://en.wikipedia.org/wiki/Sandmeyer_reaction
https://en.wikipedia.org/wiki/Sandmeyer_reaction#:~:text=Another%20use%20of%20the%20San
dmeyer,cyanation%20through%20the%20Sandmeyer%20reaction.
OER
____
REFERENCE BOOKS

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YASHWANTRAO CHAVAN M AHARASHTRA O PEN U NIVERSITY

V154: M.Sc. Chemistry

CHE511: Organic Chemistry-II Page 1

Maharashtra Open Organic Reacton Mechanism

Vice Chancellor’s Message ................................................................................. 3

Foreword By The Director ................................................................................. 4

Credit 03 .............................................................................................................. 203

Credit 04.............................................................................................................. 315

FEEDBACK SHEET FOR THE STUDENT ..................................................... 389

CHE601: Organic Reaction Mechanism Page 1

This work by YCMOU is licensed under a Creative Commons Attribution-on

CHE601: Organic Reaction Mechanism Page 2

CHE601: Organic Reaction Mechanism Page 3

- Dr. Sunanda More

CHE601: Organic Reaction Mechanism Page 4

CHE601: Organic Reaction Mechanism Page 5

CHE601: Organic Reaction Mechanism Page 6

= 5.2 × 10–2 Ms–1

SHORT ANSWER QUESTIONS:

CHE601: Organic Reaction Mechanism Page 7

The subscripts A, B and C stand for various reactants A, B and C, respectively.

Where k is a constant, the reaction orders of the individual constituents are n 1 ,

CHE601: Organic Reaction Mechanism Page 8

(i) A+B M+N

SHORT ANSWER QUESTIONS:

Que.3: What is molecularity?

CHE601: Organic Reaction Mechanism Page 9

HCl + Br 2 = HBr + BrCl

The molecularity of a reaction can be defined as the ‘number of molecules of

In the examples of NO + O 3 and HCl + Br 2 , the complex is formed from two

Similarly, chemical reactions that are unimolecular are either isomerisations o r

CHE601: Organic Reaction Mechanism Page 10

Table-1. Differences between order of reaction and molecularity

CHE601: Organic Reaction Mechanism Page 11

(iii) A+B M+N

(iii) BM+A X+Z

CHE601: Organic Reaction Mechanism Page 12

0.170 mole lit -1 0.05 mole lit -1 hr -1

CHE601: Organic Reaction Mechanism Page 13

(ii) The rate constant,

Solution: Answer (2)

SHORT ANSWER QUESTIONS:

CHE601: Organic Reaction Mechanism Page 14

True rate law of the reaction, )

01-04: PSEUDO-MOLECULAR REACTIONS

CHE601: Organic Reaction Mechanism Page 15

2) A reaction involving two different reactants can never be a

Que.8: Explain pseudo first order reaction with one example.

Solution: Answer (2)

CHE601: Organic Reaction Mechanism Page 16

Sol. Answer (3)

CHE601: Organic Reaction Mechanism Page 17

CHE601: Organic Reaction Mechanism Page 18

Where k = rate constant or velocity constant.

CHE601: Organic Reaction Mechanism Page 19

obtained with a slope of 2.303/k.

CHE601: Organic Reaction Mechanism Page 20

Divide equation (i) by (ii)

SHORT ANSWER QUESTIONS WITH MODEL ANSWER 01

Que.2: Give the integrated rate equation of first order reaction.