Chapter three:

Investigation of reaction mechanisms

1
 Introduction
 Organic reactions can be organized in two ways:
 What kind of reaction occurs, and
 how the reaction takes place.
 Initially, it is easier to consider what kinds of reaction occur.
 There are four important kinds of organic reactions these are: Addition,
Elimination, substitution and rearrangement reactions.

2
Substitution reaction, any of a class of chemical reaction in which an atom, ion, or
group of atoms or ions in a molecule is replaced by another atom, ion, or group.
 In a substitution reaction, the electronegative atom or group is replaced by another
atom or group.
 The atom or group that is substituted is called a leaving group.
 Substitution reaction is divided in to three general classes, depending on the type of
atom or group that acts as the substituent.

3
 Nucleophilic substitutions
 Alkyl halides (RX) are good substrates for substitution reactions.
 The nucleophile (Nu:_) displaces the leaving group (X:_) from the carbon
atom by using its electron pair or lone .
Nucleophile
 A nucleophile is any negative ion or any neutral molecule that has at least
one unshared electron pair.
 A nucleophile is a reagent that seeks positive center.
 The word nucleophile comes from nucleus, the positive part of an atom,
plus phile from Greek word philos meaning to love.

Leaving groups
 To be a good leaving group the substituent must be able to leave as a
relatively stable, weakly basic molecule or ion.
 In alkyl halides the leaving group is the halogen substituent –– it leaves as
a halide ion. 4
 Stepwise and concerted nucleophilic substitution reaction mechanisms

 The two main mechanisms for nucleophilic substitution of alkyl halides are
SN1 and SN2.
 In both SN1 and SN2 reactions, the mechanisms involve the loss of the
halide anion (X−) from RX.
 In fact, the preference between SN1 and SN2 mechanisms depends on
 the structure of the alkyl halide,
 the reactivity and structure of the nucleophile,
 the concentration of the nucleophile and the solvent in which
reaction is carried out.

5
 The SN2 (substitution, nucleophilic, bimolecular) Reaction
Kinetics
 The reaction is second order or bimolecular
 the rate depends on the concentration of both the nucleophile and the alkyl
halide.
Reaction rate = k[Nu][RX]
Reaction Mechanism
 In this mechanism, the attack of the nucleophile and the ejection of the
halide ion takes place simultaneously.
 Occur on one step mechanism “Concerted reaction”.
 Back side attack: Nu- must attack from the opposite direction from the
leaving group (x).
 The Back side attack of the Nu- causes Walden inversion of configuration.
(i.e. an R-enantiomer will be converted to an S-enantiomer).

6
 Cont..

 The nucleophile approaches the C_X bond at an angle of 180°.

7
Substrate
 Alkyl halides with bulky alkyl substituents react more slowly than those
with small alkyl substituents on the central carbon atom.
 Bulky substituents prevent the nucleophile from approaching the central
carbon atom.
 SN2 reactions can therefore only occur at relatively unhindered sites.
i.e for back side attack the carbon atom attached to (X) must not suffer from
steric hindrance.
 Reactivity of alkyl halides in SN2 mechanism.

8
 The SN1 (substitution, nucleophilic, unimolecular) reaction
Kinetics
 The reaction is first order or unimolecular
 the rate depends on the concentration of the alkyl halide only.
Reaction rate = k[RX]
Reaction Mechanism:
This is a stepwise mechanism (occur on two step mechanism).
Step 1: Slow step “Rate determining step”. (R.D.S).
 Formation of carboncation (cabcation).

Step 2: Fast step “Formation of product”.

9
 Cont..
 The reaction leads to the racemisation of a stereogenic centre in the starting
material (i.e. an R-enantiomer will be converted to a 50:50 mixture of R- and S-
enantiomers).
 This is because the nucleophile can equally attack either side of the planar
carbocation.

10
 Substrate:
 The more stable the carbocation intermediate, the faster the SN1 reaction (i.e. the
easier it is to break the C_X bond).
 Tertiary halides will therefore react faster than primary halides by this mechanism,
because a tertiary carbocation is more stable than a primary carbocation.
 Reactivity of alkyl halides in SN1 mechanism
Order of SN1 reactivity

Produces more stable product produces least stable product

R3CX > R2CHX > RCH2X > CH3X

terthiary alkyl halide > secondary alkyl halide > primery alkyl halide > methyl halide
(most reactive) ( least reactive)

11
Mechanism of SN1 reaction

12
 FACTORS AFFECTING THE RATES OF SN1 (stepwise) AND
SN2(concerted) REACTION MECANISMS
 The mechanism of a nucleophilic substitution reaction is influenced by the
 nature of the substrate,
 concentration and reactivity of the nucleophile,
 effect of the solvent and
 nature of the leaving group.
A. The effect of the structure of the substrate
SN2 Reactions:
 Simple alkyl halides show the following general order of reactivity in S N2 reactions:
Methyl > 1° > 2° >> 3° (unreactive due to steric effect)
SN1 Reactions:
 The primary factor that determines the reactivity of organic substrates in an S N1
reaction is the relative stability of the carbocation that is formed.
 Organic compounds that are capable of forming relatively stable carbocation can
undergo SN1 reaction at a reasonable rate.
Methyl <1° < 2° < 3° (due to the stability of carbocation intermediate)
13
 B. The effect of the concentration and strength of the nucleophile

 Neither the concentration nor the structure of the nucleophile affects the
rates of SN1 reactions since the nucleophile does not participate in the rate-
determining step.
 The rates of SN2 reactions depend on both the concentration and the
structure of the nucleophile.
 A negatively charged nucleophile is always a more reactive nucleophile
than its conjugate acid.
 Example: HO– is a better nucleophile than H2O; RO– is a better nucleophile
than ROH.
 Less sterically hindered groups make better nucleophiles as the can easily
more approach the electrophile.

Eg. CH3O- >CH3CH2O-> (CH3)2CHO- > (CH3)3CO-

14
15
16
17
18
19
 Chemical kinetics and thermodynamics of organic
reactions
• During a chemical reaction the reactants are converted into
products.
• The process can be described by its mechanism.
• Moreover, the energy changes taking place in each step can be
shown using a reaction coordinate diagram.
• It depicts the transition state threshold which requires certain amount
of activation energy. This is because the reactants are not reactive
under certain conditions.
• The reactants must be supplied with enough activation energy to
enable the reaction to proceed in the forward direction.
• The energy is supplied to the reactants by different energy sources
(spark, heat, etc.).
• The rate of reaction (k) and the kinetic energy required for activation
of reaction determines how fast any reaction reaches equilibrium. 20
• For a reaction: aA + bB = dD + eE
• Keq = [products] / [reactants] = [D]d[E]e/ [A]a[B]b
• The energy profile diagram for a reaction A + B = D + E is shown
below; here C is the intermediate formed:
• The successive intermediates are the molecules that are formed and
then react further in the course of the overall reaction.

21
• Any quantity that refers to the transition state is represented by the
doubledagger superscript (‡)
• ΔGo relates to equilibrium constant. The thermodynamic stability is
indicated by ΔGo.
• If ΔGo is negative the product is thermodynamically stable compared
to reactant and the reaction is said to be exergonic reaction.
• If ΔGo is positive the product is thermodynamically unstable
compared to reactant and the reaction is said to be endergonic
reaction.
• The kinetic stability of a component is indicated by ΔG‡.
• If ΔG‡ is large the compound (here in the above fig, the reactant) is
kinetically stable because it does not undergo that reaction rapidly.
• If ΔG‡ is small the compound (here in the above fig, the reactant) is
kinetically unstable i.e, it undergoes the reaction rapidly.

22
• For a reaction to take place spontaneously, the free energy of the
products must be lower than the free energy of the reactants; that is,
ΔG must be negative.

• The Gibbs free-energy (ΔG) change has an enthalpy component and

an entropy component, which are related by the following equation:

Where; ΔH = BDEbonds broken− BDEbonds formed

Example;

23
 Cont’d…

• The enthalpy term (ΔH) is the heat given off or the heat
consumed during the course of a reaction.

• In a molecule or compound the atoms are held together by bonds.

When new bonds are formed, heat is given off and when bonds are
broken, heat is consumed.

• Thus, ΔH is a measure of the bond-making and bond-breaking

processes that occur as reactants are converted into products.
• Entropy (ΔS) is defined as the degree of disorder of a system.

24
• Exothermic Reactions: If the bonds that are formed in a reaction are
stronger than the bonds that are broken, more energy will be released
as a result of bond formation than will be consumed in the bond-
breaking process and ΔH will be negative. Therefore, exothermic
reaction is a reaction with a negative ΔH.

• In exothermic reactions the products are more thermodynamically

stable than the reactants.

• The equilibrium constant for the reaction will be large (K>1)

for exothermic reactions. This has no effect on the rate of the
reaction.
• The rate depends on the activation energy (Ea).

25
ΔH

26
• Endothermic Reactions: If the bonds that are formed are weaker
than those that are broken, ΔH will be positive.

• Therefore, endothermic reaction is a reaction with a positive ΔH. In

endothermic reactions the reactants are more thermodynamically
stable than the products.

• The equilibrium constant for the reaction will be small (K<1) for
endothermic reactions because ΔH is positive.

• This has no effect on the rate of the reaction. The rate depends on the
activation energy (Ea).

27
 ΔH

There are certainly two factors which decides the outcome of a reaction,
these are:
1. Thermodynamic factor: the relative stability of the products
2. Kinetic factor: the rate of product formation

28
 Thermodynamics overview
• Thermodynamics is that branch of chemistry which describes the
properties of a system at equilibrium.

• The more stable a compound, the greater is its concentration at

equilibrium. Thus, if the products are more stable (have a lower free
energy) than the reactants, there will be a higher concentration of
products than reactants at equilibrium, and Keq will be greater than 1.

• On the other hand, if the reactants are more stable than the products,
there will be a higher concentration of reactants than products at
equilibrium.

29
Therefore, whether reactants or products are favored at equilibrium can
be indicated either by the equilibrium constant Keq or by the change in
free energy ΔGo.
Thermodynamics is only concerned with the final state of a
system and the mechanism of transformation does not matter at all.
The following comments help to clarify the meaning of this statement.

30
 Kinetic overview
• Kinetics is the study of the experimental measurement of macroscopic properties
of a reaction mixture and how the concentration of product and reactants changes
over time, ie, reaction rate.
• Kinetics describes the rates of reactions and how fast equilibrium is
reached, it gives no information about conditions once the reaction reaches
equillibrium.
• A kinetically controlled reaction involves lower temperatures and shorter
reaction times, which ensures that only the fastest reaction has the chance to
occur. The quantity related to kinetics is the rate constant (k).
• It is associated with the activation energy required for the reaction to move
forward, that is, the reactivity of the reactants.
• How fast the reaction occurs is independent of the type i.e whether a given
reaction is exergonic or endergonic. Kinetic stability has to do with the
pathway between reactants and products.
• Kinetic stability is largely dependent on the activation energy for the
reaction.

31
• The smaller the Ea the faster is the reaction.
Thus, anything that destabilizes the reactant or
stabilizes the transition state will make the reaction
go faster.

32
 Thermodynamics vs kinetics

Thermodynamics is all about “if”

• if a process or a reaction can occur or not
• if a systems is in stable equilibrium
• if sufficient driving force is present to enforce a favourable
transformation
Kinetics is all about “how”
• how fast or slow a process can occur, i.e., determining the rate
• how transition from nonequilibrium to equilibrium systems, or between
two equilibrium states occurs
• how to overcome the energy barrier to finish the transformation from
the starting (reactant) state to the final (product) state.

33
Relationship Between Equilibrium Constant and Free
Energy
• G° is related to the equilibrium constant Keq by the
following equation:

• The equilibrium constant, Keq, is a mathematical expression that relates

the amount of starting material and product at equilibrium.

34
• When Keq > 1, log Keq is positive, making G° negative, and energy is
released. Equilibrium favors the products.
• When Keq < 1, log Keq is negative, making G° positive, and energy is
absorbed. Equilibrium favors the reactants.

35
the energy of the transition state:

Activation energy may also be

defined as the minimum energy
required to start a chemical
reaction.

36
 quantitative correlation of rates and equilibria

• The most widely applied of these relationships

is the Hammett equation, which correlates
rates and equilibria for many reactions of
compounds containing substituted phenyl
groups.

37
 Linear Free Energy Relationships (LFER)

• Correlations between rates and equilibria of

reactions of compounds containing substituted
phenyl groups.
THE HAMMETT EQUATION
• The Hammett equation is an important
expression to explain linear free energy
relationships
• It was developed as a correlation of reactivities
(rates) and equilibria in reactions of meta- and
para-substituted benzene derivatives.
38
Hammett (1935) found that for a number of reactions
involving a series of m- and p-substituted benzene
derivatives, a plot of the log of the rate constant (k) or
equilibrium constant (K) for one reaction vs log k or log K
for another reaction gave a fairly straight line.

A plot of log k for reaction 1 vs. log K for reaction 2 gives a

good straight line if the points for the ortho substituents
are omitted.

39
40
Linear Free Energy Relationships (LFER)

41
The m- or p- substituent is far removed from the reaction
center, no steric effect upon it. By contrast, the o-substituent
has steric effect 42
43
44
45
Stated in words, the change in the standard free energy of activation
produced by a substituent X is proportional to the change in the
standard free energy produced by the same substituent in ionization of
benzoic acids in H2O at 25°C.
Because of this straight line r/s b/n the free energy terms for these two
d/t reactions series, straight line is obtained. Generally such relation is
referred to as linear free energy relationships

46
47
48
• σ is fixed by the substituent (substituent constant)
and measures the effect of a substituent on the K
a of benzoic acid (H2O, 25 °C).
• Since electron withdrawing substituents increase
the acidity of benzoic acids, substituents having a
net electron-withdrawing effect (compared to H)
have positive σ values, and
• those with a net electron donating effect
(compared to H) have negative σ values.

49
50
51
• The difference between σ meta and σ para of a given
substituent are due to the difference in importance
between inductive and resonance effects (i.e., σI and σR).
• Resonance effects are governed by the ability of a
particular substituent to effect electron distribution
through resonance structures.
• Resonance contributions can only occur for ortho and
para substituents, although ortho substituents are
excluded from the Hammett treatment because steric
effects play a complicating role.

52
• Meta substituents will have a negligible resonance
contribution (σR=0) and are almost entirely due to
inductive effects (σmeta=σI).
• Inductive effects arise as a result of
electronegativity differences and diminish with the
distance between the substituent and the reactive
centre.
• Thus, σI will generally be greater for meta than
para substitution, because of their closer
proximity.

53
σ R and σI are the reaction constants, which reflect the sensitivity
of the system towards resonance and inductive effects.
54
55
Rate NO2 & CH3
substituent wrt H

56
57
58
59
60
• Meaning of ρ: The value of ρ is a measure of
how sensitive the reaction is towards the
nature of nearby substituents.
• ρ is positive, if substituents stabilize/destabilize
a negative or partial negative charge. EWG
• ρ is negative, if substituents stabilize/destabilize
a positive or partial positive charge. EDG

61
62
On the 2nd rxn

And therefore ρ is negative

63
64
• Therefore, EDG have – ρ and EWG have + ρ.
• a -ve ρ value indicating that ERGs strongly facilitate the
reaction and
+ ρ value , indicates that EWGs facilitate the reaction and
that the reaction is more sensitive (ρ > 1) to substituent
effects than the ionization of benzoic acids.
• larger ρ shows that the reaction is very sensitive to
substituent effects and implies that there is a relatively
large redistribution of charge in going to the TS.

65
References

66