STEREOCHEMISTRY AND CHEMICAL

REACTIONS
III: Neighbouring Group Participation in Nucleophilic Substitution Reactions
 Not all nucleophilic substitutions take place withracemization or
inversion of configuration
 Some take place with overallretention of configuration
 One factor that leads to retention of configuration is a phenomenon
known asneighbouring group participation
 Let us see how it operates by examining the stereochemistry of two
reactions in which2-bromopropanoic acid is converted tolactic acid
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
1. Reaction with concentrated NaOH
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
2. Reaction with dilute NaOH in the presence of Ag2
O
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
c
o
2. Reaction with dilute NaOH in the presence of Ag2
On
t
d
.
 The results of the two inversions is an overall retention of configuration -
caused byparticipation of the neighbouring carboxylate ion
Consider Another Example
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
Example 2contd .
 A racemate of enantiomer A and B is obtained
 In enantiomer A there isretention of configuration at both chiral centers
 In enantiomer B there isinversion of configuration at both chiral centers
 This is unusual for a substitution reaction (Why?)
 This stereochemical outcome can be explained by the phenomenon of
neighbouring group participation
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
Example 2contd .
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
Example 2contd .
 An intramolecular SN
2
t
a
ke
s
pl
a
ce
t
op
r
o
d
uc
e
th
e
b
r
om
o
n
i
um
i
on
 Attack of the bromonium ion by bromide anion can take place at either
chiral carbon atom
 Attack throughpath a givesretention while attack throughpath b gives
inversion
 Attack atboth C-atoms is equally likely ; Hence in the overall reaction
retention andinversion takes place at equal rate – leading toa racemic
mixture
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
An Important Characteristic of Neighbouring Groups
 If a neighbouring group is to form a bridged cation,it must have
electrons to form the extra bond ; These may be:
 unshared pairs on atoms like S, O, N, or Br;

  electrons of a double bond or aromatic ring; or

  bonds (in some cases)

STEREOCHEMISTRY AND CHEMICAL
REACTIONS
An Important Characteristic of Neighbouring Groupscontd .

L = Leaving Group
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
Study Problem
 When optically active tosylate A was heated with acetic acid, the reaction
yielded almost exclusively the optically active acetate B. On the other hand,
heating the optically active tosylate C in acetic acid gave the racemic acetate D
and E. Provide an explanation for these results.
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
Solution (For the Reaction of Tosylate A)
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
Anchimeric Assistance: Another Perspective of Neighbouring
Group Participation
 We have seen examples of “abnormal”stereochemical outcomes
caused byneighbouring group participation

 But somethingbesides stereochemistry can be involved here

 If a neighbouring group helps to push out the leaving group – that is,
givesanchimeric assistance anchi
( = near;meros = parts) – it will
accelerate the reaction, sometimes tremendously

 Thus, neighbouring group participation is most often revealed by a

special kind of stereochemistry or by an unusually fast rate of reaction
and often both
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
Examples of Anchimeric Assistance in Nucleophilic Substitution
Reactions
 Consider the remarkable difference in the rates of the following two
substitution reactions, which are superficially similar:
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
How Do We Account for the Remarkable Difference in the Rates
of these Reactions?
 The rate of the second reaction is unusually large because of a “special
mechanism” that facilitates the reaction, a mechanism not available to
hexyl chloride

 The special mechanism we are speaking about here is the anchimeric

assistance by the neighbouring SULPHIDE group
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
Anchimeric assistance by the neighbouring SULPHIDE
Group
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
Consider another example of Anchimeric Assistance:
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
How Do We Account for the Above Relative Rates of Solvolysis of
2-Substituted Cyclohexyl chloride?
 Thetrans sulphide evidently gives strong anchimeric assistance (But
Why not thecis sulphide?)
 In anchimeric assistance, ananti relationship between the neighbouring
group and the leaving group is required for back-side attack
 In cyclohexane derivatives, onlytrans -1,2-substituted can assume an
anti relationship
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
Acetolysis of an Acetoxy Tosylate: Anchimeric Assistance by the
Acetate Group
 We have defined acetolysis as a solvolysis reaction whereby the solvent
is acetic acid (i.e., cleavage by acetic acid)

 Let us consider a substrate that is not only a tosylate but also an

acetate (an acetoxy tosylate)
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
Acetolysis of an Acetoxy Tosylate: Anchimeric Assistance by the
Acetate Groupcontd.
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
Summary of Experimental Observations for the Above Reaction

Substrate Comments on
Rel. Rate of
Product the Course of
(Diastereomer) Reaction
Reaction

Cis -acetoxy tosylate Trans -diacetate 1 Usual

Trans -acetoxy Racemictrans -

tosylate diacetate 800 Unusual
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
The observations can be depicted as follows:
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
Explanation:
 The reaction of the trans diastereomer show both a special kind
of stereochemistry and an unusually fast reaction rate; both of
the manifestations of a neighbouring group effect
 The neighbouring group is the acetoxy group, containing oxygen
with unshared electrons
 Through back-side nucleophilic attack, the acetoxy group helps
to push out the tosylate anion and, in doing so, inverts the
configuration at the carbon under attack (there is formed an
acetoxonium ion)
 The symmetrical acetoxonium ion undergoes nucleophilic
attack by the solvent at either of the two carbons – again with
inversion of configuration – and yields the product
STEREOCHEMISTRY AND CHEMICAL
REACTIONS
The Results?
 In half the molecules, retention at both carbons; in the other half,
inversion at both carbons
STEREOCHEMISTRY AND CHEMICAL
REACTIONS