Chapter 4

Major Organic Reactions

There are four general types of organic reactions:
Substitution, Elimination, Addition and rearrangement reaction

4.1 Substitution Reactions

 Substitution reactions occur when two reactants exchange parts to
give new products
 In nucleophilic substitution reactions, the C–L bond of the
substrate undergoes heterolysis, and the lone-pair electrons of the
nucleophile is used to form a new bond to the carbon atom.
 A leaving group is substituted by a nucleophile

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General equations for nucleophilic substitution reactions:

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When does the C–X bond break?
1) Does it break at the same time that the new bond between the
nucleophile and the carbon forms?

 Concerted process
2) Does the C–X bond break first? And then

And then

 Stepwise process 3
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 Nucleophile(Nu:-)
 reacts at the electron deficient carbon
 any molecule with an unshared electron pair
 nucleus lover
 Eg. OH-, Br-
Leaving Group (R-L)
 is a substituent that can leave as a relatively stable entity.
 It can leave as an anion or a neutral species

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There are two kinds of substitution reactions, called SN1 and SN2.

SN2 reactions
 SN2 stands for Substitution, Nucleophilic, bimolecular(„2nd order‟).
 Bimolecular (or 2nd order) means that the rate of an SN2 reaction is
directly proportional to the molar concentration of two reacting
molecules, the „substrate‟ and the nucleophile.

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Mechanism for the SN2 Reaction

 In the transition state of this reaction bonds are partially formed

and broken
 Both chloromethane and hydroxide are involved in the transition
state and this explains why the reaction is 2nd order
 SN2 reaction is a one-step displacement mechanism
=> CONCERTED PROCESS
 Involves a single transition state
 There is no intermediate 6
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 The Stereochemistry of SN2 Reactions
 Backside attack of nucleophile results in an inversion of
configuration.

 In cyclic systems a cis compound results trans product

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 SN1 Reaction
 Substitution, nucleophilic, 1st order (unimolecular)
 The rate depends only on the concentration of the substrate
 Only the substrate (not the nucleophile) is involved in the
transition state.

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Mechanism for the SN1 Reaction

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Carbocations
 has only 6 electrons, is sp2 hybridized and has an empty p orbital
 The more highly substituted a carbocation is, the more stable it is
 The more stable a carbocation is, the easier it is to form

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The Stereochemistry of SN1 Reactions
 When the leaving group leaves from a stereogenic center of an
optically active compound in an SN1 reaction, racemization will
occur
 This is because an achiral carbocation intermediate is formed
 Racemization: transformation of an optically active compound to a
racemic mixture

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ASSIGNMENT 2
Factors Affecting the Rate of SN1 and SN2 Reactions
 The Structure of the Substrate
 The Concentration and Strength of Nucleophile for SN2 rxns
 The effect of solvent
 The Nature of the Leaving Group

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Applications of substitution reactions
i) Alcohols

 But it is not often employed in synthesis

 It is more common to convert alcohols into alkyl halides

 This method is too slow to be convenient for synthesizing alkyl

chlorides (Cl¯ is too weak a nucleophile) 14
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Alkyl Halides from the Rxn of Alcohols with PBr3 and SOCl2
 These reagents only react with 10 and 20 alcohols in SN2 reactions
 the reagent converts the hydroxyl to an excellent leaving group.

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 Reaction of thionyl chloride to give alkyl chlorides
 Often an amine is added to react with HCl formed in the reaction

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ii) Ether
 Williamson ether synthesis:- SN2

 Use the more substituted alcohol & the less substituted alkyl
halide, otherwise elimination takes place and olefine forms

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iii) Carboxylic acids
 It cannot be prepared directly by nucleophilic substitution
1) Prepare nitrile

2) Hydrolysis of the nitrile

 With 3° alkyl halides, elimination is predominant rxn and olefine is

the major product

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 iv) Alkynes, alkenes, and alkanes

The preparation of alkynes provides a route to alkenes and alkanes

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 v) Amines
 If an alkyl halide is treated with NH3, an alkylammonium halide formed.

 The free amine can be released by neutralization of the salt with NaOH

 It is difficult to control the alkylation and stop at a 1° amine so that it will

yield the 2°, 3° amine and even tetraalkylammonium halide

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Gabriel Synthesis
 An imide is a compound with two acyl groups bonded to a nitrogen.
 The Gabriel synthesis, converts alkyl halides into primary amines
via the hydrolysis of an imide.

 it is a general method for producing 1° amines to the exclusion of

higher alkylation product.
 In the first step, a base removes a proton from the nitrogen of
phthalimide.
 The resulting nucleophile reacts with an alkyl halide. Because this
is an SN2 reaction, it works best with primary alkyl halides
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Mechanism

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 Vi) Epoxide ring opening
 Epoxides open up readily in both acidic and basic media b/c of the strain
associated with the three-membered ring

 Grignard reagents react primarily at the less-substituted ring carbon of

substituted oxirane.

 If the epoxide is derived from a cyclic olefin, the rxn with a

nucleophile yields a trans-di substituted ring

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vii) The Malonic Ester Synthesis:
 Synthesis of Carboxylic Acids
 alkylation of an -carbon and decarboxylation of a -dicarboxylic acid
can be used to prepare carboxylic acids of any desired chain length.
 The procedure is called the malonic ester synthesis because the starting
material for the synthesis is the diethyl ester of malonic acid.

 The methylene (-CH2-) group is flanked by two carbonyl group as a

result the protons are acidic 24
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 Because alkylation is an SN2 rxn, it works best for methyl halides and
primary halides

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 Carboxylic acids with two substituents bonded to the -carbon can
be prepared by carrying out two successive -carbon alkylations.

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 viii) The Acetoacetic Ester Synthesis:
 Synthesis of Methyl Ketones
 The only difference between the acetoacetic ester synthesis and the
malonic ester synthesis is the use of acetoacetic ester rather than
malonic ester as the starting material.
 The difference in starting material causes the product of the
acetoacetic ester synthesis to be a methyl ketone rather than a
carboxylic acid.

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 Decarboxylation of -keto carboxylic acid

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 4.2 Elimination Reactions
 In an elimination Reaction, a small fragment is ejected from a
molecule, and unsaturation (multiple bonding) is introduced.

 There are three convinient categories of eliminations (E2, E1cb, and E1).

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 B-Y and carbon-carbon bond formation, as well as Y-carbon and X-
carbon bond cleavage, all occur simultaneously
 No discrete intermidate
 it is called E2 elimination. “E” stands for elimination and “2” stands
for bimolecular the two reactants invoved in the transition state

 The rate law tells us that both tert-butyl bromide and hydroxide ion
are involved in the rate-determining step of the reaction.
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 E1cb Mechanism
 E1cb = first-order elimination from a carbanion

Carbanion intermediate
 The Y-C bond cleaves hetrolytically.
 The carbanion intermediate subsequently decompose to olefin.
 E1cb is the least common of the three mechanisms
 it occurs mainly in cpds which stabilize the carbanion by resonance or
inductive effects:

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 E1 mechanism
 involves initial loss of X- with no cleavage of the Y-C bond
 “E” stands for elimination and “1” stands for unimolecular

 Carbocation formation is the rate-determining step

 the rate of rxn is independent of the concentration of the base (B-)
 examples: 1) dehydration of alcohol in strongly acidic solutions

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2) The reaction of tert-butyl bromide with water to form 1-
methylpropene

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THE ZAITSEV’S RULE
 an elimination occurs to give the most stable, more highly
substituted alkene
 For some dehydrohalogenation reactions, a single elimination
product is possible:

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 Dehydrohalogenation of many alkyl halides yields more than one product:

 When a small base such as ethoxide ion or hydroxide ion is used, the
major product of the reaction will be the more stable alkene.

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E2 reactions, do not always follow Zaitsev‟s rule. For example:
A bulky base such as potassium tert-butoxide in tert-butyl alcohol
favors the formation of the less substituted alkene

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 E1 versus E2
 The mechanistic course of a given elimination depends on a number
of factors:
 the rate law: E1 = unimolecular, does not include the base term
 E2 = bimolecular, include the base
E1 favored by:-
 absence of a strong base (such as -OH or -NH2)
 substrate that can form a stable carbocation
 presence of a good leaving group (such as water, iodide, or acetate)
 use of a polar solvent (such as water, methanol, or acetic acid) that
favore the formation of carbocation
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 SUBSTITUTION VERSUS ELIMINATION
 all nucleophiles are potential bases and all bases are potential
nucleophiles.
 Nucleophilic substitution rxns and elimination rxns often compete
with each other.
SN2 VERSUS E2
 eliminations occur best by an E2 path when carried out with a high
concentration of a strong base and high temperature.
 substitution reactions by an SN2 path often compete with the
elimination reaction.

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i) structure of substrate
Primary halides and ethoxide: substitution is favored.

Secondary halides: elimination is favored

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 Tertiary halides: no SN2 rxn, elimination reaction is highly favored
 Elimination reactions can be favored by:-
 1) Increasing rxn temperature: elimination is favored when the
reaction is carried out at higher temperature.

SN1(9%) E2(99%)

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 Eliminations have higher free energies of activation than
substitutions because eliminations have a greater change in bonding
(more bonds are broken and formed).
2) Use a strong sterically hindered base such as the tert-butoxide ion:
inhibit its reactivity by substitution, so elimination rxns take place..

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3) The relative basicity and polarizability of base/nucleophile
 Use of a strong, slightly polarizable base such as amide ion (-NH2)
or alkoxide ion (especially a hindered one) tends to increase the
likelihood elimination (E2)
 Use of a weakly basic ion such as a Cl-, CH3COO- or a weakly basic
and highly polarizable one such as Br-, I-, or RS- increases the
likelihood of substitution (SN2)

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TERTIARY HALIDES: SN1 VERSUS E1
E1 reactions are favored:
 with substrates that can form stable carbocations.
 by the use of poor nucleophiles (weak bases).
 by the use of polar solvents.
 It is usually difficult to influence the relative position between SN1 and
E1 products.
 SN1 reaction is favored over E1 rxn in most unimolecular rxns,
especially at lower temperatures.

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Exercise
For each of the following reactions, (1) indicate whether elimination will
occur via an E2 or an E1 reaction, and (2) give the major elimination
product of each reaction, ignoring stereoisomers:

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Application of Elimination Reactions
1) dehydration of alcohols
 Heating most alcohols with a strong acid causes them to lose a
molecule of water and form an alkene:

 The reaction is an elimination and is favored at higher temperatures.

 The most commonly used acids in the laboratory are Brønsted acids
proton donors such as sulfuric acid and phosphoric acid.
 The experimental conditions –– temperature and acid concentration ––
that are required to bring about dehydration are closely related to the
structure of the individual alcohol. 143
4645
i) Primary alcohols are the most difficult to dehydrate:

ii) ii) Secondary alcohols usually dehydrate under milder conditions:

iii) Tertiary alcohols are usually dehydrated under extremely mild

conditions:

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 Relative ease of order of dehydration of alcohols:

mechanism of alcohol dehydration

 The mechanism is an E1 reaction in which the substrate is a
protonated alcohol (or an alkyloxonium ion).

slow

 This step is slow and rate determining 47

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 The order of stability of carbocations is 3° > 2° > 1° > methyl:

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2) dehydrohalogenation of alkyl halides
 The removal of the elements of a hydrogen halide (HX) from an alkyl
halide
 - elemination
 a concerted reaction
 A primary or secondary alkyl halide is used if possible in order to bring
about an E2 reaction.

 Reactivity of R-X : R-F < R-Cl < R-Br < R-I

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3) alkenes by debromination of vicinal dibromides
 Vicinal (or vic) and
 geminal (or gem) dihalides:

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 4) Hofmann Elimination
 An amine is exhaustively methylated to the quaternary ammonium salt.
 The halide salt is converted to the hydroxide salt by treatment with silver
oxide.
 The quaternary ammonium hydroxide is then thermally decomposed via a
concerted E2 mechanism to give the alkene.

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 If the quaternary ammonium ion has more than one -carbon, the
major alkene product is the one obtained by removing a proton
from the -carbon bonded to the greater number of hydrogens.

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 5) Cope Elimination
 It is thermal decomposition of an amine oxide.
Step 1: Oxidation of a 3° amine gives an amine oxide.

Step 2: If the amine oxide has at least one -hydrogen, it undergoes thermal
decomposition to give an alkene

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6) Acetate pyrolysis
 A chemical transformation produced by applying heat to a single
compound is called a pyrolysis rxn, results olefins
 acetate formation is an esterification rxn

 heating the acetate to high temperatures results in the elimination

of acetic acid

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 4.3 Addition Reactions
 It can be electrophilic, nucleophilic or radical in character, depending on
the type of species that initiate the process.
 addition to simple carbon – carbon double bonds is normally either
electrophilic or radical induced. Example: addition of HBr

 By contrast, the addition reactions exhibited by the carbon- oxygen double

bond, in simple aldehydes and ketones, are usually nucleophilic in
character.
eg. Cyanohydrins
formation
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Electrophilic Addition Reactions
 It is the most common type of addition reactions
 The relatively loosely held  electrons of the carbon–carbon double
bond are attacked by an electrophile.

Examples:
 Hydration of alkenes

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 Hydrohalogenation of alkenes

 Hydroboration of alkenes

 Halogenation of alkenes

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 Mechanism

 Intermediate (1) is in equilibrium with intermediates (2) and (3).

 The relative importance of (2) and (3) depends on structural factors
(such as the nature of X, and the substituents on the olefin). 58
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Reactivity
 Substituents have effect on the reactivity of alkenes
 since the addition reaction begins when a positive reactant attacks the 
electrons of the double bond, anything that increases the density of
electrons on the double bond will enhance its reactivity toward this attack.
 Electron-donating substituents on the double bond, for example, will have
this effect, while electron-withdrowing substituents will have the opposite
effect.
 e.g. Increase the alkyl groups (electron releasing) on a double bond
increase its reactivity toward bromination.

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 Markovnikov’s rule:
 When a hydrogen halide adds to an unsymmetrical alkene, the
addition occurs in such a manner that the halogen attaches itself to
the double-bonded carbon atom of the alkene bearing the lesser
number of hydrogen atoms.

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 the presence of a peroxide causes anti-Markovnikov addition of HBr
 it changes the mechanism of the reaction in a way that causes Br.
 to be the electrophile (antiMarkovnikov‟s)

Mechanism of Radical addition

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Michael Addition is a conjugate additions of enolate anion to α, β –
unsaturated carbonyl compounds

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 Application of Addition Reactions
1) Addition of halogen
Alkenes react rapidly with chlorine and bromine in non-nucleophilic
solvents to form vicinal dihalides.

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 A test for the presence of carbon-carbon multiple bonds:

 Alkanes do not react appreciably with bromine or chlorine at room

temperature and in the absence of light.

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mechanism of halogen addition: Addition of Bromine to an Alkene

Step 1

Step 2

A bromide ion attacks at the back side of one carbon => anti addition
of halogen to alkene

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 Anti addition of bromine to cyclopentene:

 Attack of the bromide ion at the other carbon of the bromonium ion
results in the formation of the other enantiomer.

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2) Addition of Hydrogen Halides If the electrophilic reagent that adds
to an alkene is a hydrogen halide (HF, HCl, HBr, or HI), the product of
the reaction will be an alkyl halide:
Examples:

 they are symmetrical alkenes

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 Based on markovnikov’s rule: the addition of HX to an
unsymmetrical alkenes is regioselective

The addition of HBr to propene: the main product is 2-bromopropane.

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 3) Addition of hypohalous acids (HOX)
 The oxygen of HOX bears a potential negative charge (HO-X)
because oxygen is more electronegative than halogens except for
fluorine.
 Markovnikov‟s addition of HOX results in the bonding of the
oxygen to the more substituted carbon

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 4) HYDRATION ALKENES
 The acid-catalyzed addition of water to the double bond of an alkene
is a method for the preparation of low molecular weight alcohols
that has its greatest utility in large-scale industrial processes.
 The acids most commonly used to catalyze the hydration of alkenes
are dilute solutions of sulfuric acid and phosphoric acid.

 The addition of water to a double bond is usually regioselective and

follows Markovnikov‟s rule
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 The acid-catalyzed hydration of alkenes follows Markovnikov‟s
rule.
 the reaction does not yield 1° alcohols except in the special case of
the hydration of ethene.

 The mechanism for the hydration of an alkene is the reverse of the

mechanism for the dehydration of an alcohol.
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 5) Hydroboration-Oxidation
 The reaction leads to syn and anti-Markovnikov addition of water to
alkenes

 Hydroboration: Synthesis of Alkylboranes

 The elements of hydrogen and boron are added across the double
bond

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 6) The Diels – Alder cycloadditions
 it is [4 + 2] cycloaddition reaction
 Overall, two new  bonds are formed at the expense of two  bonds
 it is exceedingly useful for synthesizing six – membered rings.

 The product of a Diels – Alder reaction is often called an adduct.

 The conjugated diene is a 4-electron system
Examples of dienes:

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 The dienophile (“diene lover”) is a 2-electron system
Examples of dienophiles

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Factors Favoring the Diels-Alder Reaction
 The simplest possible example of a Diels-Alder reaction goes at
very low yield and requires high temperatures.
 To proceed in good yield and at low temperature the dienophile
should have electron-withdrawing groups
 It also helps if the diene has electron-releasing groups
 Dienes with electron-donating groups and dienophiles with
electron-withdrawing group can also react well together

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Stereochemistry of the Diels – Alder reactions
The following factors are among the reasons why Diels – Alder
reactions are so extraordinarily useful in synthesis:-
1) The Diels-Alder reaction is stereospecific i.e. the reaction is a syn
addition, and the configuration of the dienophile is retained in the product.
Examples:-

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2) dienes, necessity, reacts in the s-cis conformation rather than the s-
trans.

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3) The Diels – Alder reaction occurs primarily in an endo rather than
an exo fashion. For cyclic adducts there are two possible
configurations.
• If substituent is oriented cis to the longest or more unsaturated
bridge, it is said to be endo.
•When it is directed to trans to the bridge it is exo.

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 When bicyclic addus are formed; the chief product is normally the
endo isomer “ Alder’s Endo Rule”.
 steric hindrance at the bonding site may inhibit or prevent the Diels
– Alder reactions
 when EWGs on the Dienophile and EDGs on the diene facilitate
Diels-Alder reactions

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7) Oxidation of Alkenes: Epoxidation and Hydroxylation An alkene
can be oxidized to an epoxide by a peroxyacid. The overall reaction
amounts to the transfer of an oxygen atom from the peroxyacid to the
alkene.

an O¬O bond is weak and easily broken

Epoxidation results in a cyclic ether with an oxygen atom

Stereochemistry of addition is syn
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MCPBA in CH2Cl2 are the usual conditions
•Addition of acid results in a trans-1,2-diol

Treatment of the epoxide with aqueous acid give a trans diol

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8) Oxidations of Alkenes: Syn 1,2-Dihydroxylation
 Either OsO4 or KMnO4 will give 1,2 diols (glycols)

Mechanism for Syn Hydroxylation of Alkenes

 Cyclic intermediates result from reaction of the oxidized metals
 The initial syn addition of the oxygens is preserved when the
oxygen-metal bonds are cleaved and the products are syn diols
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Oxidative Cleavage of Alkenes
 Reaction of an alkene with hot KMnO4 results in cleavage of the
double bond and formation of highly oxidized carbons
 Unsubstituted carbons become CO2, monosubstituted carbons
become carboxylates and disubstituted carbons become ketones

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 9) Ozonolysis of Alkenes
 Cleavage of alkenes with ozone and workup with zinc in acetic
acid leads to less highly oxidized carbons than products from
cleavage with hot KMnO4.

 Unsubstituted carbons are oxidized to formaldehyde,

monosubstituted carbons are oxidized to higher aldehydes and
disubstituted carbons are oxidized to ketones

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 Mechanism of Ozonolysis
 Ozone adds across the double bond to form the initial ozonide
which rearranges to a highly unstable ozonide
 The ozonides react with zinc and acetic acid to effect the cleavage

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WORKUP PROCEDURES FOR OZONOLYSIS
Two types of workup (decomposition of the ozonide) are possible.

Aldehydes survive intact and are not oxidized with reductive

conditions.
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EXAMPLES

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Reading Assignment
 Peracid oxidation
 Glycol formation

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 4.4. Rearrangement Reactions

What is Rearrangement Reactions?

 The term of “rearrangements” is used to describe organic reactions
which involve the migration of an H atom or of a larger molecular
fragment.
 A group moves from one atom to another in the same molecule.
 The most common migration are from an atom to an adjacent one
(called 1, 2-shifts).
 Usually results a product with a different carbon skeleton from the
reactant

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4.4.1. Rearrangement to an electron-deficient carbon
(A) Wagner-Meerwein rearrangements
• Wagner-Meerwein Rearrangements are [1,2]- rearrangements of H
atoms or alkyl groups in carbocation that do not contain any
heteroatoms attached to C-1 or C-2.

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(B) Pinacol-pinacolone Rearrangements
• Mechanism of the pinacol rearrangement of a symmetrical glycol

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 Which hydroxyl group is lost as water? Or which carbocation
forms first?
 What is the inherent shifting tendency (migratory aptitude) of
different substituent groups? or Which group migrates?
 What is the influence of steric hindrance and other strain factors on
the rearrangement?
 Are epoxides formed as intermediates in the pinacol
rearrangement?
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Which carbocation ion forms first?
Regioselectivity of the pinacol rearrangement of an unsymmetrical
glycol

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 Which group migrates?

Phenyl group
move first

Group moved as the following order:

tertiary alkyl＞aryl＞H＞secondary alkyl ＞primary alkyl＞methyl
Explain the following experimental facts：

When R=CH3,（B）and（C）are formed；

When R=Ph, only（C）is formed.
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4.4.2 Rearrangement to electron-deficient oxygen
Baeyer – Villiger Oxidative rearrangements
•It is acid catalyzed reaction of ketones with hydroperoxide
derivatives such as

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 Mechanism

 order of migration is 3° alkyl > aryl>2° alkyl >1° alkyl > methyl.
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4.4.3 Rearrangement to electron–deficient Nitrogen
(A) The Beckmann Rearrangement
 When an oxime is treated with strong concentrated acid, such as
H2SO4 or H3PO4, it is converted into an amide
 Useful for the preparation of amides from ketones
 Catalyzed by protic or Lewis acid

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Mechanism

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 The group which is a trans (or anti) relationship to the hydroxyl
group is the one that migrates
 The rxn of ketone and hydroxylamine forms an oxime whose –OH
group is in a predominantly trans relationship to the larger of the
two groups on the ketone

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(B) The Hofmann Rearrangement
 All of the rearrangements we have discussed so far are carried out
in acidic media and involve cationic intermediates
 the Hofmann rearrangement, however, occurs in basic solutions
and involves a neutral electron-deficient species known as a nitrene
 It occurs when a primary amide,RCONH2, is treated with Br2 and
base

 the resulting amines have one less carbon than the starting amides

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 Mechanism

 The Hofmann rearrangement provides a good way to prepare amine

from acids of one additional carbon atom, since the latter may be
readily converted into amides:
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