136 Reaction Mechanism

CHAPTER

5
Reaction Mechanism
5.1. Nucleophilic substitution:
Types of Nucleophilic Substitution reactions:
(i) The SN2 Mechanism:
The reaction is preceded by a common single-step mechanism of second order reaction. The features of the
SN2 mechanism are inversion at the alpha-carbon, increases reactivity with increasing nucleophilicity of the
nucleophilic reagent.
alcohol
CH 3CH 2  Cl  KOH   CH 3CH 2OH  KCl

(ii) The SN1 Mechanism:

It not only shows first order kinetics, but the chiral 3º-alkyl bromide reactant undergoes substitution by the
modest nucleophile water with extensive racemization.
 
   (CH 3 ) 3 C – O H 2  Br  
(CH3 )3 C – Br  H 2 O  –H
   (CH 3 )3 C – OH  HBr

PES diagram for SN1 reaction

E2#
Energy 

R X–
E1 # R C+
Nu:
R

R E
R C X+ Nu: R +
R C Nu –
R R
X

Reaction Progress 

The first order kinetics of these reactions suggest a two-step mechanism in which the rate-determining step
consists of the ionization of the alkyl halide. In this mechanism, a carbocation is formed as a high-energy
intermediate, and this form bonds immediately to nearby nucleophiles.
Reaction Mechanism 137
Various features for SN1:
(i) The reactant having the tendency to form stable carbon cation, we expect the SN1 mechanism.
  (ii) Since nucleophiles only participate in the fast second step, recombination of the halide anion with the
carbocation intermediate simply reforms the starting compound.
(iii) The Hammond postulate suggests that the activation energy of the rate-determining first step will be inversely
proportional to the stability of the carbocation intermediate.
Carbocation Stability:
CH3 CH3
CH3 < CH3CH2 < H3C CH < H2C CH CH2 < C6H5CH2 H3C C CH3

(iv) The stereospecificity of these reactions may vary. The positively-charged carbon atom of a carbocation
has a trigonal (flat) configuration (it prefers to be sp2 hybridized), and can bond to a nucleophile equally
well from either face.

Problem: Predict which of the following reaction is occured by SN1, SN2 and neither SN1 nor SN2 mechanism.
H Br

(1) I + NaCN ethanol (2) s ethanol

? + NaN3 ?

H
CH3
S ethanol
(3) H C I acetone
?
(4) C + NaCN ?
3 + H3C CH3 s CH2 Br

CH3 C2H5
acetonitrile R acetone
(5) H3C C Cl + CH3OH ? (6) s + NaSCH3 ?
CH3 Br

acetone acetonitrile
(7) + NaI ? (8) + H2O ?
Cl Cl

Activation by electrophilic cations:

Heterolytic cleavage of the carbon-halogen bond of alkyl halides may be facilitated by the presence
of certain metal cations. In the extreme, carbocations may be generated as shown in the following
equation, where R is alkyl or hydrogen, and M = Al (n=3) or Fe (n=3) or Sn (n=4) or Zn (n=2).
 R 3C   MX n – X –
R 3 C – X  MX n (reactivity  Al  Fe  Sn  Zn) 
In aqueous or alcoholic solution it promotes ionization of the alkyl halide and the formation of SN1 products.
When silver nitrate is used with 1º or 2º-alkyl halides, rearrangement may occur before the product formation
stage. For example:
 CH3 3 CCH2 – Br  H 2O  AgNO3    CH 3  2 C  OH  CH 2 CH 3  AgBr  HNO3
 138 Reaction Mechanism
5.2. Elimination versus Substitution:
For many combinations of alkyl halides and nucleophiles, elimination reactions may compete with substitution,
–
R C C X
+ +
Electrophilic Nucleophilic
Sites Sites

In describing these, it is useful to designate the halogen-bearing carbon as alpha and the carbon atom adjacent
to it as beta, as noted in the first four equations shown below. Replacement or substitution of the halogen on the
α-carbon by a nucleophilic reagent is a commonly observed reaction, as shown in equations 1, 2, 5, 6 & 7
below. Also, since the electrophilic character introduced by the halogen extends to the β-carbons, and since
nucleophiles are also bases, the possibility of base induced H-X elimination must also be considered, as illustrated
by equation 3.
• Nucleophiles having basic characater give elimination reaction.
• Nucleophiles having non-basic character give substitution reaction.

alcohol
1. CH3CH2CH2CH2Br + CN CH3CH2CH2CH2CN + Br
  (fast)
CH3 CH3

 H alcohol H
2. 
+ CN + Br
 Br H
S
H CN
CH3 CH3
  alcohol
H3C C Br + CN H2C C + HCN + Br
3. 
 CH3 CH3

CH3
 alcohol
4. H3C C CH2 Br + CN No reaction

CH3

H3C CH3
alcohol
C Br + H3C S H3C S C + Br
5. C2H5 R (fast) S
C2H5
H H
H3C CH3
alcohol
C Br + H3C S H H3C S C + HBr
6. C2H5 R (slower) S
C2H5
H H
C3H7 C3H7 C3H7
acetonitrile R
C Br + H2O H O C + C O H + HBr
7. C2H5 R C2H5 R
C2H5
H CH3 H3C
R  alkyl group
Solvent
R – X  Nu :   Product X  Cl, Br or I
Nu : nucleophile
Reaction Mechanism 139
One conclusion, relating the structure of the R-group to possible products, should be immediately obvious. If
R- has no beta-hydrogens an elimination reaction is not possible, unless a structural rearrangement
occurs first. The first four halides shown below (a, b, c, d) do not give elimination reactions on treatment with
base, because they have no β-hydrogens. The two halides on the right (e, f) do not normally undergo such
reactions because the potential elimination products have highly strained double or triple bonds.

CH3
R
sp2 H sp2
H3C X H3C C CH2 X CH2 X C C CH2 X C X
sp2
(a) CH3 (b) R X
(c) (d) (e) (f)

no -hydrogents strained elimination product

Using the general reaction shown above as our reference, we can identify the following variables and observables.

Variables R change α-carbon from 1º to 2º to 3º if the α-carbon is a chiral center, set as (R) or (S)
X change from Cl to Br to I (F is relatively unreactive)
Nu: change from anion to neutral; change basicity; change polarizability
Solvent polar vs. non-polar; protic vs. non-protic
Observables Products substitution, elimination, no reaction.
Stereospecificity if the α-carbon is a chiral center what happens to its configuration?
Reaction Rate measure as a function of reactant concentration.

1. Nucleophilicity:
Nucleophilicity is thereby related to the relative rate of substitution reactions at the halogen-bearing carbon
atom of the reference alkyl halide.
Nucleophilicity: CH 3CO 2 –  Cl –  Br –  N 3 –  CH 3O –  CN –  SCN –  I –  CH 3S
Increasing Nucleophile Strength:
The cumulative results of studies of this kind has led to useful empirical rules pertaining to nucleophilicity:
(i) For a given element, negatively charged species are more nucleophilic (and basic) than equivalent neutral
species.
(ii) For a given period of the periodic table, nucleophilicity (and basicity) decreases on moving from left to
right.
(iii) For a given group of the periodic table, nucleophilicity increases from top to bottom (i.e. with increasing
size), although there is a solvent dependence due to hydrogen bonding. Basicity varies in the opposite
manner.
2. Solvent effects: Solvation of nucleophilic anions markedly influences their reactivity. Polar, aprotic solvents
such as DMSO (dimethyl sulfoxide), DMF (dimethylformamide) and acetonitrile do not solvate anions nearly
as well as methanol, but provide good solvation of the accompanying cations. Consequently, most of the
nucleophiles discussed here react more rapidly in solutions prepared from these solvents. These solvent effects
are more pronounced for small basic anions than for large weakly basic anions. Thus, for reaction in DMSO
solution we observe the following reactivity order :
Nucleophilicity:

I –  SCN –  Br   Cl   N 3  CH 3CO 2   CN  < CH 3O   CH 3S

3. The Alkyl Moiety:
• Crowded alkyl moiety gives elimination reaction.
• Less crowded alkyl moiety gives substitution reaction.
alcohol
1. CH3CH2CH2CH2Br + CN CH3CH2CH2CH2CN + Br
  (fast)
1º-bromide Rate = k1[R–Br][CN]
 140 Reaction Mechanism

CH3 CH3

 H alcohol H
2. + CN + Br

 Br H
R S
H CN
2º-bromide Rate = k2[R–Br][CN]

 CH3
CH3
 alcohol
H3C C Br + CN H2C C + HCN + Br
3. 
 CH3 CH3
Rate = k3[R–Br][CN]
H2
alcohol
4. (H3C)3C C Br + CN No reaction
 

H3C CH3
alcohol
C Br + H3C S H3C S C + Br
C2H5 R (fast) S
5. C2H5
H H
(R)-2-bromobutane Rate = k5[R–Br][CH3SN] (S)-2-(methylthio)butane

H3C CH3
alcohol
C Br + H3C S H H3C S C + HBr
C2H5 R (slower) S
6. C2H5
H H
Rate = k6[R–Br][CH3SN] (S)-2-(methylthio)butane

H3C C3H7 C3H7

acetonitrile R
C Br + H2O H O C + C O H + HBr
C2H5 S C2H5 C2H5 R
H CH3 H3C
7.
(S)-3-bromo-3-methylhexane
racemic 3-methyl--hexanol
Rate = k7[R–Br]
5.3. Elimination reaction:
Types of Elimination reaction:
(1) The E2 Reaction: We have not yet considered the factors that influence elimination reactions, such as example
3 in the group presented at the beginning of this section. Elimination of second order is called E2 reaction.
(CH3 ) 3 C – Br    CN  
   (CH 3 ) 2 C  CH 2    Br     HCN
For E2 reaction, there is no formation of intimate ion pair that is carbocation (if formed) is not stable.
H3C

SN 2 CH SCH3 + NaBr Rate = k[R–Br] [CH3S]

H3C H3C
CH Br
H3C H
E2 NaOCH3
C CH2 + CH3OH Rate = k[R–Br] [CH3O]
methanol
H3C + NaBr
Reaction Mechanism 141
If two or more structurally distinct groups of beta-hydrogens are present in a given reactant, then several
constitutionally isomeric alkenes may be formed by an E2 elimination. This situation is illustrated by the 2-
bromobutane and 2-bromo-2,3-dimethylbutane elimination examples given below.

H3C CH2 C CH2 20%

H
Br Butene
-hydrogens -hydrogens
KOH
H3C CH2 CH CH3 +
alcohol H3C C C CH3 80%
-carbon
H H
2-bromobutane Butene
(trans + cis)

(H3C)2HC C CH2 21%

CH3
-hydrogens Br -carbons 2, 3-dimethyl-1-butene
KOH
H3C CH C CH3 H3C CH3
-hydrogens alcohol 80%
CH3 CH3
H3C CH3

2, 3-dimethyl-2-butene
These results point to a strong regioselectivity favoring the more substituted double bond, an empirical statement
generally called the Zaitsev's Rule.

Bredt’s Rule: Double bond can never be formed to bridge head carbons in bicyclic system due to
impossibility of formation of planarity at bridge head carbon.

H H H H
C
–HCl
H H H C H C C
C
Cl H H
H H
C

AcO O
OH
O NH O

H
O
H
O
OH H
AcO
Taxol HO A brigehead double bond
OBz
in 1-bicyclo[3, 3, 1]octene
 142 Reaction Mechanism
2. Stereochemistry of the E2 Reaction:
E2 elimination reactions of certain isomeric cycloalkyl halides show unusual rates and regioselectivity that are
not explained by the principles thus far discussed. For example, trans-2-methyl-1-chlorocyclohexane reacts
with alcoholic KOH at a much slower rate than does its cis-isomer. Furthermore, the product from elimination
of the trans-isomer is 3-methylcyclohexene (not predicted by the Zaitsev rule), whereas the cis-isomer gives
the predicted 1-methylcyclohexene as the chief product.
Unlike open chain structures, cyclic compounds generally restrict the spatial orientation of ring substituents to
relatively few arrangements.
+ #
H B H
B
R C CH2 R C CH2 R C CH2 + BH + Br
H H
Br –
Br

 CH3 H CH3 CH3

H
CH3 H KOH

H
Cl alcohol
 Cl H H Cl (slow)
trans-isomer diaxial
1-chloro-2-methylcyclohexane (anti)

 CH3 Cl CH3
H CH3 CH3
H CH3 H KOH
 +
Cl
H alcohol
 Cl H H H H (fast)
cis-isomer diaxial minor
diaxial
(anti) product
(anti)
Br
CH3 H

H KOH
H3C  H3C
t-Bu H alcohol
H3C H (fast) H3C
H H
CH3 anti CH3 KOH
alochol
cis-isomer (very slow)
4-tert-butylcyclohexyl bromide
H
H t-Bu
CH3 H H
H H
Br
H3C H
t-Bu H
H H
H3C H Br
H anti
CH3
trans-isomer

Note: Both eleminating group must be antiperiplanar to each other.

3. The E1 Reaction:
Just as there were two mechanisms for nucleophilic substitution, there are two elimination mechanisms. The E1
mechanism is nearly identical to the SN1 mechanism, differing only in the course of reaction taken by the
carbocation intermediate. As shown by the following equations, a carbocation bearing beta-hydrogens may
function either as a Lewis acid (electrophile), as it does in the SN1 reaction, or a Brønsted acid, as in the E1
reaction.
Reaction Mechanism 143

Bronsted Acid CH2

CH3 H3C C + –OH2
H3C C H2O CH3
+
CH3 Base
or
Nucleophile CH3
Lewis Acid
H3C C OH2

CH3

 [(CH 3 )3 C  )]  Cl  H 2O 
(CH 3 )3 C – Cl  H 2O   (CH 3 )3 C – OH  (CH3 ) 2 C  CH 2
 HCl  H 2O

To summarize, when carbocation intermediates are formed one can expect them to react further by one or
more of the following modes:
1. The cation may bond to a nucleophile to give a substitution product.
2. The cation may transfer a beta-proton to a base, giving an alkene product.
3. The cation may rearrange to a more stable carbocation, and then react by mode E1 or E2.
Since the SN1 and E1 reactions proceed via the same carbocation intermediate.
The most important being the structure of the alkyl group and the nature of the nucleophilic reactant.
144
Note that halogens bonded to sp2 or sp hybridized carbon atoms do not normally undergo substitution
or elimination reactions with nucleophilic reagents.
Nucleophile Non-Basic Anionic Nucleophile
–
Alkyl Group ( Weak Bases: I , Br – , SCN – , N3–
– – –
,CH3CO2 , RS , CN etc. ) pKa's from -9
to 10 (left to right)
Primary Rapid S N 2 substitution. The rate may be
RCH 2 – reduced by substitution of β-carbons, as
in the case of neopentyl.
Secondary S N 2 substitution and / or E 2 elimination
R 2CH – (depending on the basicity of the
nucleophile). Bases weaker than acetate
(pKa = 4.8) give less elimination.
The rate of substitution may be reduced
by branching at the β c-arbons, and this
will increase elimination.
Tertiary E 2 elimination will dominate with most
R3 C – nucleophiles (even if they are weak
bases). No S N 2 substitution due to steric
hindrance. In high dielectric
ionizing solvents, such as water,
dimethyl sulfoxide & acetonitrile, S N 1
and E1 products may be expected.
Allyl Rapid S N 2 substitution for 1º and 2º -
H2C=CH–CH2 halides. For 3º -halides a very slow SN 2
substitution or, if the nucleophile is
moderately basic, E 2 elimination.
In high dielectric ionizing solvents,
such as water, dimethyl sulfoxide
and acetonitrile, SN1 and E1
products may be observed.
Benzyl Rapid S N 2 substitution for 1º and 2º -
C6 H5 CH2 – halides. For 3º -halides a very slow SN 2
substitution or, if the nucleophile is
moderately basic, E2 elimination. In high
dielectric ionizing solvents, such as
water, dimethyl sulfoxide & acetonitrile,
S N 1 and E1 products may be observed.
Basic Anionic Nucleophile
(Strong Bases: HO–, RO–)
pKa's > 15
Rapid SN 2 substitution.
E2 elimination may also
occur. e.g.
ClCH2 CH2Cl + KOH 
CH2=CHCl
E2 elimination will
dominate.
E2 elimination will
dominate. No SN2
substitution will occur.
In high dielectric ionizing
solvents SN1 and E 1
products may be formed.
Rapid SN 2 substitution
for 1º halides. E2
elimination will
compete with substitution
in 2º - halides, and
dominate in the case of
3º-halides. In high
dielectric ionizing
solvents SN1 and E1
products may be formed.
Rapid SN 2 substitution
for 1º halides (note there
are no β hydrogens). E2
elimination will compete
with substitution in 2º-
halides, and dominate in
the case of 3º-halides.
In high dielectric ionizing
solvents S N1 and E 1
products may be formed.
Reaction Mechanism
Neutral Nucleophile
( H2O, ROH, RSH, R3 N )
pKa's ranging from -2 to
11
SN 2 substitution.
(SH > NH 2 > OH )
SN 2 substitution.
(SH >NH2 > OH )
In high dielectric ionizing
solvents, such as water,
dimethyl sulfoxide &
acetonitrile, S N 1 and E 1
products may be formed
slowly.
E2 elimination with
nitrogen nucleophiles
(they are bases). No S N 2
substitution. In high
dielectric ionizing solvents
SN1 and E 1 products may
be formed.
Nitrogen and sulfur
nucleophiles will give
SN 2 substitution in the
case of 1º and 2º -halides.
3º-halides will probably
give E2 elimination with
nitrogen nucleophiles
(they are bases).
In high dielectric ionizing
solvents S N 1 and E 1
products may be formed.
Water hydrolysis will be
favorable for 2º & 3º-
halides.
Nitrogen and sulfur
nucleophiles will give
SN 2 substitution in the
case of 1º and 2º-halides.
3º-halides will probably
give E2 elimination with
nitrogen nucleophiles
(they are bases) . In high
dielectric ionizing solvents
S N1 and E1 products may
be formed . Water hydrolysis
will be favorable for 2º and
3º halides.
Reaction Mechanism 145

5.4. Neighbouring Group Participation:

The presence of nucleophilic groups in molecule undergoing nucleophilic substitution affects the kinetics and
stereochemistry of reaction. The involvement of nearby nucleophilic substitutents such as lone pair electrons of
group, in a substitution process is called neighbouring group participation.
The leaving group and participating group are in the trans-position.

O
1. Acetoxy CH3 C O group:

The rate of solvolysis of the cis and trans isomers of 2-acetoxy cyclohexyl p- toluene sulfonate differs by a
factor of about 670, trans isomers being more reactive one and the products obtained are also different.
OTs OTs
O O
OCCH3 OCCH3
K = 1.9 × 10–4S–1(100oC) K = 2.9 × 10–7S–1(100oC)

The diacetate obtained from the cis isomer is the trans-isomer (inverted stereochemistry) whereas retention of
configuration is observed for the trans isomer.
O O
OTs OCCH3 OTs OCCH3
CH3COO CH3COO
O O ; O O
CH3COOH
OCCH3 OCCH3 OCCH3 CH3COOH OCCH3

The results can be explained by the participation of the trans acetoxy group in the ionisation process. The
assistance provided by the acetoxy carbonyl group facilitates the ionisation of the tosylate group, accounting
for the rate enhancement. This kind of backside participation by adjacent acetoxy group is both sterically and
energetically favorable. The cation which is formed by participation is stabilised by two oxygen atoms and is for
more stable than a secondary carbocation. The acetoxonium ion is subsequently opened by nucleophilic attack
with inversion at one of the two equivalent carbons leading to the observed trans product. Whereas in case of
cis isomer, simple SN2 mechanism is involved.

2. The electron of C=C bond:

C=C bond are also envolved in neighbouring group participation reaction e.g. the anti tosylate isomer in
norbornyl systems are found to be more reactive toward acetolysis than that of saturated isomer by a factor of
about 1011. The product is also retention in configuration. This is due to being participation of -electron of
C=C bond to give ion which is more stabilised by delocalisation of the positive charge.

OTs TsO H TsO H OTs

H H

Norbornyl Norbornenyl Norbornenyl Norbornadienyl

Tosylate Tosylate (syn) Tosylate (anti) Tosylate

O
–
OTs OTs H OCCH3
H +
CH3COOH
+
 146 Reaction Mechanism
In contrast, syn isomers in which the double bond is not in the position to participate in the ionisation step
therefore it reacts 107 times slower than that of anti isomer. The reaction product is derived from a rearranged
carbocation ion that is stabilised by virtue of being allylic
TsO H
CH3COOH

O
CH3C
O
Stereochemistry can indicate neighbouring group participation:
reaction goes with
anti retention at this centre syn reaction goes with
diastereoisomer diastereoisomer inversion at this centre

OTs OAc OTs OAc

AcOH AcOH

OAc OAc OAc OAc

To explain this, we should first draw the six-membered rings in their real conformation. For the anti compound,
both substituents can be equatorial.
However, not much can happen in this conformation–but, if we allow the ring to flip, you can see
immediately that the acetate substituent is ideally placed to participate in the departure of the tosylate group.

O O
ring flip O O
AcO O O

OTs
O O
Both substitutents OTs Symmetrical
equatorial Both substituents
intermediate
axial

OAc
O O OAc
AcOH ring flip
AcO
OAc OAc OAc

3. Hydroxy group (–OH) and oxygen atom :

The hydroxy group acts as an intramolecular nucleophile i.e.; solvolysis of 4- chloro butanol in water gives a
product i.e; tetrahydrofuran. The reaction is much faster than solvolysis of 3-chloro prapanol under similar
condition
H2O
Cl CH2CH2CH2CH2–OH
+ HCl
O
In basic solution, the alkoxide ions formed by deprotonation are even more effective nucleophile. In ethanol
containing sodium ethoxide, 2-chloro-ethanol reacts about 5000 times faster than ethyl chloride. The product
is ethylene oxide confirming the involvement of oxygen atom as a nucleophile.
O
HOCH2CH2Cl OCH2CH2Cl H2C CH2 + Cl
Reaction Mechanism 147
Evidently, the extent of participation is a function of the stability of potential carbocation when an aryl group is
present at C–7 position, the resulting benzyl - typed stabilisation decreases the relative importance of participation
by double bond.
X O X

OC Ar OH
Dioxane
H2O

The factors which can affect C = C bond -electron cloud, may also affect on the relative rate.
Relative rate
TsO H
R1 = R2 = H 1.4 × 1012
R1
R1 = H R2 = CF3 15 × 106
R1 = R2 = CF3 1
R2

4. C-C bond or bonds as Neighbouring Group Participation:

Winstein and Trifan found that solvolysis in acetic acid of optically active exo - 2 - norbornyl brosylate gave a
racemic mixture of two exo - acelate.
Exo - isomer solvolysed about 350 time faster than that of endo isomer.

>
OBr H
H OBr
Exo-isomer Endo-isomer

This is due to that 1, 6 bond assist in departure of the leaving group (OBs-p-bromo benzene sulphonate) and
forming non-classical intermediate (carbocation) in Exo-isomer.

AcOH
AcO +
OBr – H+ OAc
H H H

AcOH
OBs OAc
H H

AcO
H
Whereas in case of endo isomer. The position is not favorable therefore it does not involve neighbouring group
participation but it reacts normally

CH3COOH O
H H + OC CH3
OBs O H
H3C C
O
 148 Reaction Mechanism
5. Aromatic -electron participation :

C C C C
X
Phenonium ion

The erythro isomer gives largely retention of configuration in the product. The result can be explained by/via the
bridged ion intermediate. Threo isomer where participation leads to an achiral intermediate which gives racemic
threo products.

CH3
C H CH3COOH CH3 H
C C C CH3
H C C H
+ H3 C C C CH
CH3 OTs H H
3
CH3 H CH3 O C CH3 H3CCO H
Erythro
O O Retention

H H H
C C CH3 CH3CO2H
H C C CH3 + H3C C C H
OTs C C H
CH3 H CH3 O C CH O CH3
H 3 H3C C
Threo CH3 CH3
O
O
Plane of symmetry Racemic mixture

6. Trans annular ether oxygen as Neighbouring Group Participation:

The relative rate for molecules show that three is a large acceleration in the case of replacement of 5-CH2
group by an ether oxygen.
O
X X X X
O
O

Relative rate : 1.0 0.014 0.14 4.85 × 104

The huge difference in rate that results from the alternative placement of oxygen in eight membered rings
reflects the relative stability of various oxonium ions that results from participation. B ion is much more favorable
than A and the rate retardation in first two case can be attributed to an unfavorable polar effect of the C-O
bond.

O O O

(A) (B) (C)

Acetolysis of both 4-methoxy - 1-pentyl brosylate and 5- methoxy-2- pentyl brosylate give the same mixture
of product is evidence of participation by ether oxygen in neighbouring group participation reaction