CHAPTER I

INTRODUCTION

Since the classic work of Berthelot and St. Gilles

(1) on the formation and hydrolysis of ethyl acetate, the

study of the kinetics and mechanism of ester hydrolysis has

produced a very substantial literature. It ~s well known

that Guldberg and Waage drew largely on this work when

generalising the principle of mass action in relation to

kinetics (2).

Three phases can be distinguished in the sUbsequent

development of the subject. The first concerns the study of

the kinetics of ester hydrolysis without particular reference

to mechanism. The emphasis was on the establishment of rate

laws rather than on the elucidation of the steps through

which the transformation of the reactants to products occured.

Thus Holmberg found that in the alkaline hydrolysis of

O-acetyl malic acid, the asymmetric group did fully retain

its stereochemical configuration and so he concluded that

it did not separate during the course of reaction (3).

Reicher examined in a quantitative way, the constitutional

effects on the second-order rate of alkaline hydrolysis of

aliphatic esters of carboxylic acids having branched and

unbranched alkyl groups (4). He found that alkyl group

retarded the reaction. Olson (5), Skrabal (6) and

Kindler (7) extended the work of Reicher and established

the accelerating influence of such groups as Cl, co2Me

2

etc. and the retarding influence of a negative ionic charge.

The second phase in the development is the appli­

cation of the electronic theory of organic chemistry to the

problem. Side by side with this development, the acqui­

sition of knowledge regarding the kinetic behaviour of

esters during hydrolysis continued to be made, but,

increasingly attempts were made to interpret the kinetic

data on the basis of the electronic theory and thus to get

some idea of the mechanistic aspect. The elucidation of

mechanism was considerably aided by the availability of

powerful new techniques such as the radio isotopy, spectro­

photometry etc. The definitive paper on the application of

electronic theory to ester hydrolysis is generally regarded

as the one by Day and Ingold which appeared in 1941 (8).

Later, and more exhaustive review has been published by

Bender (9). Parallel to this development, there has taken

place many important investigations on the more detailed

aspects of the subject. Mention may be made of the

elaboration of Hammett's h0 functi�n by Bunnett (10) and

by Yates and McClelland (11) as applied to the study of

ester hydrolysis.

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The third phase of the development of the subject

relates to an extension of allied fields. Thus the role

of neighbouring group acting as a catalyst has been the

subject of much investigation, the idea being that such

studies would contribute to a knowledge of the mechanism

of the cataly,:tic action of enzymes. Another fruitful

field has been provided by the study of the mechanism of

phosphate reactions. Mention must also be made of attempts,

notably by Bender, Bruice, Bunton, Jencks and others to

study the catalytic action of enzymes from a physical

organic stand point.

Kinetic salt effects had been observed in a number

of reactions of carboxylic acid derivatives. For example,

the alkaline and acid hydrolysis of ethyl acetate exhibited

a slight negative salt effect (12). The salt effect on

alkaline hydrolysis was found to confirm to the predictions

of the ion-dipolar molecular rate theory (13). More

striking salt effects in ester hydrolysis had been observed

in reactions involving charged esters. In the alkaline

hydrolysis of half esters of dicarboxylic acids with alkali

metal salts there was a negative specific salt effect whose

magnitude depends on the distance of the charge from the

4

reaction centre ( 14). In reactions of esters containing a

quaternary ammonium group, specific salt effect was found

�o be negative for acid hydrolysis and positive for

alkaline hydrolysis and again increases as the distance

increased between the positively charged quaternary

nitrogen atom and the reaction centre. These salt effects

were consistent with the postulated transition state for

the reaction (15).

The work relating to the effect of added electrolytes

on the kinetics of nucleophilic aliphatic substitution

reaction can be said to have begun in the late ninteen

thirties. By that time Hughes and Ingold had adumbrated

their theory that reactions belonging to this category had

two possible mechanism available to them namely the SN1 and

SN2 mechanism (16). The rate determining step of the SN

1

mechanism was assumed to be the formation of a carbonium

ion. Since the formation of the carbonium ion must involve

the postulation of a transition state more polar than the

initial state, it \\0.S suggested that the addition of electro­

lytes should increase the rate of the reaction between

uncharged reactants. Using the Debye Ruckel model, a theory

of salt effects was set up and illustrated with reference

to the solvolysis of alkyl halides in aqueous organic

solvents (17). The conclusion was that the increase in the

rate of a reaction was due essentially to an ionic atmosphere

5

effect so that the effect depended only on the charge type

of the electrolyte and not on its identity. In the

situation when the electrolyte had an anion in common with

the alkyl halide, an additional effect, called the mass

law effect could also operate; but this would be in addition

to its ionic strength effect (17,18) and would be important

with relatively stable carbonium ions and in solvents of

low nucleophilicity (19). In 1942 Lucas and Hammett showed

that in the SN1 hydrolysis of t-butyl nitrate in aqueous

dioxan addition of sodium hydroxide, instead of increasing

the rate, actually caused a small decrease. They suggested

that this might be due to a drying action by the electrolyte

(20). While conceding that this suggestion was quite

plausible, Hughes, Ingold and Benfey reexamined this question

in detail and found that the anomalies of this type are

general for electrolyte having anions in common with the

solvent (18). Similar results were obtained later by

Grunwald (21) and by Bunton (22). However Salomaa studied

the solvolysis of 2,3-dichlorodioxan in presence of different

concentrations of sodium hydroxide. In all cases the

mechanism was SN1. He found that hydroxide ion did not have

any effect on the rate even in least aqueous solvents. At

very high OH- concentrations, there did appear to be a

decrease, the significance of which is not clear (23).

Taft's finding that even simple electrolyte h9ve

6

specific salt effect on the initial and transition state in

the hydrolysis of t-butyl chloride in water must mean that

the nature of substrate must also be reckoned with in account-

ing for such effects (24). No doubt the effect of the

electrolytes on the 'structuredness' of water is also

important but this action will not be dependent on the

nature of the sUbstrate.* In aqueous organic solvent system,

further complications can arise of which mention may be

made of two, (i) The electrolyte may salt out the substrate

into the organic co-solvent thus reducing the activity

coefficient of the initial state. A simple example of this

is pointed by Ramaswamy Iyer (25); addition of sodium

chloride caused an increase in rate for t-butyl chloride,

a reduced increase in rate in the case of t-amyl chloride

and decrease in rate for diethyl methyl carbinyl chloride

and of triethyl carbinyl chloride, the decrease increasing

as the series is ascended; the solvent used was aqueous

acetone. (ii) The second effect is specific to the

* This statement needs clarification. The effect of anychange in the environment caused by the addition of anelectrolyte will not be the same for all substrates. Con­sider, for example, two transition states one which cangenerate a carbonium ion and the other, a carbanion. Thesolvation characteristics of these two will be differentand any change in the character of the solvent might affectthem differently. But i~ such a stand is taken then theuse~ distinction that is possible by considering the effectof ~he electrolyte on the water separately from thespecific salt effect dependent on the identity of thesubstrate (and on the mechanism of solvolysis) will belost.

7

substrate and depends upon a situation where an involvement

between the transition state and the anion from the electro­

lyte centre lead to an energetically more favourable path­

way than the one involving salvation in the usual sense.

The same workers have shown, in the system noted above,

that addition of lithium perchlorate caused marked rate

increases with all four substrate, their magnitude being

closely similar (26). It is clear, therefore, that it may

be more advantageous to obtain data in solvent water, on the

variation of the activities of both the initial and transi­

tion state with the addition of electrolytes. This is not

to imply that any conclusion arrived at thereby could

automatically be extrapolated to aqueous organic solvent

system. All that is meant is that the study of using a

single solvent may offer less difficulty in interpretation.

Objections has been taken to the method of

separately evaluating the activity coefficients of the

tnitial and transition states for understanding the role

of the solvent on the ground that it will not lead to an

understanding of the mechanisms of these processes (27).

The criticism, as it stands, is certainly valid, but it

cannot be deni.ed that if we know the effect of the solvent

on the initial and transition state s�parately, it would

be helpful in the elucidation of the mechanism. Further

more, as Blandamer has emphasised some results such as

8

the heat capacity of activation do appear to point to the

importance of the initial state properties (28). One

other simple example may be of relevance. The enthalpy

of activation for the solvolysis of t-butyl chloride in

water is 2.2 k.cal/mole more than in 80% aqueous acetone.

Taft has shown that this is due to the stabilization of

the ground state in water and using the two point charge

model he calculates that 0.2 electron is transferred from

carbon to chlorine (29). The enthalpy of activation for

the solvolysis of 1-phenylneopentyl chloride in water is

7.2 k.cal/mole less than in 80% aqueous acetone. This

has been ascribed to the destabilization of the initial

state due to minimal solute-water interaction (30)..

There is one other aspect which deserves mention.

The literature on every aspect of organic reaction mechanism

is very extensive and expanding at an everincreasing rate.

Use of sophisticated mathematical models and of high speed

computors)kinetic isotope effects, labelling experiments,

spectrophotometric techniques of bewildering variety and

complexity, to mention examples only, has been lavishly

made in this exercise. The consequences are largely two

(i) Different approaches have often led to opposite con­

clusions (ii) The sheer volume of published work has led

to massive intellectual indigestion. Lest this should be

thought too sweeping a generalisation, the author would

like to cite in support of her stand the present states of

the mechanism of nucleophilic aliphatic substitution

reactions. It is not intended to review the subject but

rather to note how some of the leading workers differ in

their approaches to and the interpretation of the field.

Schleyer's stand can be summarised thus (i) The

molecularity of the reaction is not dependent on the extent

to which the bond to the leaving group is broken but depends

on whether or not_nucleophilic attack occurs be:f!re the trnn­

sition state in the rate determining ste£ (31)(italics in text).

(ii) Ingold's SN1 category is designated "classical SN1" and

is thought to be defunct; in other words, there is no

reaction in which the formation of the free carbonium

ion(carbocation in Sch�leyer's terminology) is rate­

determining (iii) Many reactions which were formerly

thought to proceed by the SN1 mechanism are really SN2

reaction since nucleophilic solvent participation occurs

before the transition state is formed. It follows from

this that the number of reactions proceeding by the SN1

mechanism, particularly in the commonly used solvent

systems is much sm aller than was assumed to be earlier

(iv) The SN2 mechanism might involve nucleophilic attack

on the covalent substrate giving rise to the product directly

(in which case it is called the classical SN2 mechanism) or

might involve the intermediary of ion pairs ,lwhen it is

designated SN2 (intermediate) mechanism7. Aside from

the relatively unimportant distinction* between the

classical SN2 mechanism and the SN2 (intermediate)

mechanism the distinction between the Hughes - Ingold

theory and that of Schleyer can be conveniently high

lighted as follows. Regarding the transition from the

SN1 to SN2 mechanism (the so called border line region)

Ingold has stated that the tranS3ition must be gradual

since in such a situation there can be varying degrees

1 ()

of nucleophilic assistance from the solvent. Schleyer's

position can be understood if we extend this "region" to

the whole category of nucleophilic aliphatic substitution

reactions. At one extreme we have a small number of

reactions which could be called SN1 in Schleyer's termino­

logy. And as we move over we will have the bulk of such

reactions, all of which belong to the SN2 category which

wi:ll occur with varying degree of nucleophilic assistance

from the solvent, to which should be added the rider that

free carbonium ions are not formed in any reactions.

* The word relative is used adversely and is meant to meanthat at the present stage of development, the difficultyin distinguishing between these two mechanism is formidablein most cases Lsee for example Bordwell ref (3217. But atime may come when advances in the field make it possiblefor such distinctions to be made with confidence. Whenthis happens this qualification will become redundant.

11

Sneen's thesis is that all nucleophilic substi~on

proceed through the intermediary of ion-pairs and is quite

similar to Winstein's theory except in certain minor matter

. of detail (33). Winstein would allow the formation of a

kinetically free carbonium ion in a much larger number of

cases than would Sneen. Indeed according to Sneen the

only case of such a kind is the solvolysis of triphenyl­

methyl chloride in polar environment. Again Winstein would

allow the operation of the II classical SN2 mechanism" but

Sneen is of the view that nucleophilic attack occurs as a

discrete, rate determining step on a contact ion pair.

The views of Hammett, the doyen among physical

organic chemists can be summarised thus. He unequvocally

agrees with the stand of Ingold that in suitable cases the

free carbonium ion mechanism is implicated. flIn solvents

which are favourable to the existence of free ions rather

than of ion pairs or larger aggregates the solvolytic

reactions of tertiary alkyl and benzhydryl derivatives are

satisfactorily interpreted in terms of the free carbonium ;on

mechanism". This is not to suggest that the agreement with

Ingold is total. In the case of secondary system, Hammett

has reservations. In such cases the implications of ion

pairs as intermediate is quite likely.

It must be emphasised that the object in presenting

12

this short review is not to minimise the importance of the

work of these investigators and others. Rather it is to

show how difficult it is to attempt a discuwsion of the

mechanism of these reactions in view of widely differing

views entertained by the leading workers. It may be as

well to attempt a discussion as to how these conflicts

have arisen. It appears to the present author that two

reasons can broadly be argued. Firstly many of the con­

clusions are arrived at using newly developed techniques on

the significance of which there cannot be room for legiti­

mate dissent. Consider for example, Shiner's scheme for

the interpretation of the rate and products of solvolytic

reactions which is based on the Winstein scheme (35). One

of the lines of evidence Shiner has used in support of his

scheme is theoC -deuterium kinetic isotope effects. Shiner

is of the view that anoC -deuterium isotope effect close

to unity (range 0.97 - 1 .06) indicates a classical SN2

reaction. Humski et al. have also come to a similar con­

clusion and remarked 11no SN2 reactions are known which

show isotope effects larger than about 1 .04" (36). Schleyer

however, is of the view that larger kinetic isotope effects

are consistent with the SN2 mechanism; if this basis is

accepted it will follow as Bentley and Schleyer remark •In

retrospect, it is remarkable that a variety of secondary

substrates , giving isotope effects greater than 1 .15 - 1 .16

were all shifted from the classical heterolysis mechanism

(k_1 rate determining) to Shiner's mechanism (~2 rate deter­

minin~. This left only one firmly established example,

pinacoyl solvolysis, of the classical heterolysis mechanism

and it would appear to be a good example of the tail wagging

the dog~U (37). The second facgor arises because the main

concern in the recent work has been to delineate the finer

features of the mechanism and this again contributes to the

prevailing diversity of views in two ways; firstly, the

magnitude of the contribution to the rate of the various

additional factors may be small and, it is well known, the

significance of such quantities can be doubtful; secondly the

basis on which discussion is attempted qan also be different.

This latter point can be illustrated by an example. Ingold

assumed that formic acid is a highly polar, highly non-nucleo­

philic.solvent (38). Yet, according to Schleyer formic acid

possess considerable nucleophilic properties (39).

SIDllVJARY OF PRESENT "\'lORK

The considerations outlined above have been kept in

mind by the author. in the choice of the problem and the dis­

cussions of the results. The problem relates to the

solvolysis in water, of 1-phenylethyl hydrogen succinate

and six para-substituted derivatives (CH30, CH

3, C2H

5, F,

14

Cl and Br). Rate data and activation parameters have been

evaluated. The results show that the values of the acti-

vat ion parameters of all compound other than the p-Cl and

p-Br derivatives fall into one class while those for the

last two compounds form another set. The Okomoto-Brown

plot is a linear one; again for all excepting these two

derivatives. The suggestion is made that the first five

compounds show the behaviour which is characteristic of

the BAL1 mechanism (SN1 according to Bender) while the

other two follow what is generally observed as the BAC 2

mechanism. The values of the activation parameters are

consistent with this interpretation.

Of the seven esters prepared only two esters are

solid p-Cl and p-Br derivatives. The rate of hydrolysis

of p-Br derivative is very slow, so only one ester

1-E-chlorophenyl ethyl hydrogen succinate is employed for

use in the evaluation of the activity coefficient of the

initial and transition state as a function of the identity

and concentration of various electrolytes(NaCl, KCl, NaN03

,

NaBr, LiCI04 , Li2S04 and N~04). One significant feature

of the result is that the electrolytes have practically no

effect on the activity coefficient of the initial state

except for high concentration of the electrolyte. It is

assumed that the substrate-water interaction is such that

a change in structuredness of water does not change the

activity coefficient of the substrate. The structure

breaking effect of the electrolyte on the transition

state is in the increasing order.

15