Hydrolysis of Carboxylic Esters PDF

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Prof Chandan Saha...

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1

Hydrolysis of Carboxylic Esters A carboxylic ester is hydrolysed to a carboxylic acid and an alcohol or phenol when heated with aqueous acid or aqueous alkali. In acidic solution, the reaction is reversible (why?). O R

O

+

+

C O

H

H2O

R

+

C

R1

O

OH

R1

H

The position of the equilibrium depends on the relative concentration of water and the alcohol. In aqueous solution, hydrolysis occurs. In alcoholic solution, the equilibrium is shifted in favor of ester. Under alkaline condition, of course, ester hydrolysis is essentially irreversible (why?). The carboxylic acid is obtained as its salt, from which it can be liberated by the addition of mineral acid. O R

+

C O

O

+

H

HO

R

C

R1

+

R1

OH

O O +

H

R

C OH

Alkaline hydrolysis of ester is called saponification because it is used in the production of soaps from fats. For example: H2 C

O

HC

O

H2 C

O

O C C17H35 O C C17H35 O C C17H35

a g ly c e r id e , a ty p ic a l fa t, g ly c e ry l tris te a ra te

+3

N aO H

H2 C

OH

HC

OH

H2 C

OH

O

+3

H35C17 C -

g ly c e r o l

+

O Na

a soap

Despite its association with fatty-acid chemistry, the term saponificioatn is used generally to refer the hydrolysis in alkali of any ester of carboxylic acid. Let us consider the mechanistic details of the hydrolysis of carboxylic esters. The mechanistic designations AAC2 and BAC2 are given to the acid-catalysed and base-induced mechanisms, respectively. The A denotes acid catalysis, while B denotes base induction.

2

The AC designation indicates acyl-oxygen cleavage. The digit 2 has its usual significance, indicating the bimolecular nature of the rate-determining step. AAC2 mechanism +

O R

OH

+

+ H ,fa s t

C

R

+

O

C

- H ,fa s t

R1

R O

R

+ H2O , s l o w

C

R1

O

O R1

C

fa s t

H

OH , f a s t

+ R1

OH , s l o w

R

OH

C

R

+

+

OH

O

+

- H ,fa s t

C

OH

OH

R1

OH2

OH

- R1

O

C +

R1 +

+

R

- H2O, f a s t

+

HO

fa s t

OH

OH

+ H ,fa s t

R

C OH

Acid catalysis speeds up the hydrolysis by protonation on carbonyl oxygen and thus rendering carbonyl carbon more susceptible to nucleophilic attack by water molecule and again acid catalysis also has the effect of promoting the loss of the leaving group, the alcohol molecule. Since the acid catalysed hydrolysis of ester is reversible, according to the principle of microscopic reversibility, the mechanism for hydrolysis taken in opposite direction is the mechanism for esterification of a carboxylic acid under acid catalysed condition. BAC2 mechanism O

O R

+

C O

s lo w

OH

R

C

fa s t

R1

OH O

O R

+

C O

fa s t s lo w

O R1

O

R1

fa s t, ir re v e r s ib le

R

+

C

HO

R1

O

H

Alkali promotes the hydrolysis of ester by providing the strongly the strongly nucleophilic reagent –OH. This reaction is essentially irreversible, as the last step of this reaction is an acid-base reaction in which a strong acid and a strong base reacts to yield a weak base and a weak acid. Let us look at the various aspects of the two mechanisms we have written, and see what evidence there is for each of them. AAC2 mechanism: a) The rate law for acid catalysed hydrolysis has shown to be second order, first order in both ester and hydrogen ion concentration, i.e., Rate = k [ester] [H3O+]

3

b) Also, evidence for acyl-oxygen heterolysis has been obtained in several ways, e.g., Ingold et al.(1939) showed that acid catalysed hydrolysis of methyl hydrogen succinate in water enriched with 18O gave methanol with no extra 18O. 18

O

O

CH3

H2 C CH2

+

+

H2 C

H

18

H2O

C

CH2

C

CH2 H2 C

O

18

OH

+ H3C

H2 C

COOH

OH

COOH

CH2

Thus, acyl-oxygen heterolysis must have occurred during the acid catalysed hydrolysis of ester. Furthermore, Roberts et al. (1938) esterified benzoic acid with methanol enriched with 18O under acid catalysed condition and obtained water not enriched with 18O. O

+ H3C

C

18

O

+

H

OH

+

C 18

OH

O

H2O

CH3

Thus, acyl-oxygen heterolysis must have occurred during acid catalysed esterification. c) N.m.r. spectra support preferential protonation of the carbonyl oxygen of the ester during hydrolysis and of the acid during esterification. d) It should be noted that the rate determining step for esterification is the addition of alcohol, whereas that for hydrolysis is the addition of water. In both cases, the rate determining step involves change of hybridisation of the carbon atom of the carbonyl group from sp2 to sp3, and consequently steric retardation can be expected to increase as R increases in size, e.g. (esterification with methanol): O

A c id s

H3C

C

H3C

CH2

OH

R e la tiv e r a te s

1 .0

CH3

O H3C

C OH

0 .5 1

C CH3

C2H5

O H5C2

C OH

0 .0 3 7

O C

C C2H5

OH

0 .0 0 0 1 6

Another example of this type is as follows (esterification with ethanol): CH3 H3CH2C

A c id s

H3C

COOH

H CH

H3CH2C

CH3 COOH

COOH H3C H

R e la tiv e ra te s

1 .0 0

0 .0 0 0 4

to s lo w to m e a s u r e

e) The formation of a tetrahedral intermediate (an associative process) in the rate limiting step is borne out by the activation parameters observed for acid catalysed hydrolysis of simple ethanoate ester:

4

ΔH ≠ = 75 kJ mol -1; ΔS ≠ = -105 J K -1 mol -1 . Problem I: 1. Account for the gradual loss 18O content in the unreacted ester during acid catalysed hydrolysis of RCH2CO18-OCH3. BAC2 mechanism: a) It has long been known that the alkaline hydrolysis of esters is a second order reaction, i.e., Rate = k [ester] [-OH] b) Evidence for acyl-oxygen heterolysis has been obtained in several ways, e.g., Polanyi et al. (1934) showed that the alkaline hydrolysis of n-pentyl acetate in water enriched with 18 O gave n-pentyl alcohol containing no 18O. 18

O 18

H3C

+

C O

OH

H3C

C 18

C5H11

18

O

+

O

H3C

C5H11

O

+ HO

C 18

OH

C5H11

-

O

Therefore acyl-oxygen heterolysis must have occurred. c) Another method uses optical activity as a diagnostic test for demonstrating acyl-oxygen heterolysis. If the alcohol group is optically active, and if B AC2 mechanism operates, then the ion R1O – will be liberated and will retain its optical activity since R 1— O bond is never broken. Various examples of retention are known when the reaction is bimolecular. For example, when sec-butyl alcohol of specific rotation +13.8 0 was actually converted into the benzoate and the benzoate was hydrolysed in alkali, there was obtained sec-butyl alcohol of specific rotation +13.8 0. O Ph

+

C Cl

O

Me H

O

p y r id in e

C H Et

(+ ) 2 -b u ta n o l

Ph

O

C

Me O

OH

Ph

+ HO

C O

C H Et

Me C H Et

(+ ) 2 -b u ta n o l

This complete retention of configuration strongly indicates that bond cleavage occurs between oxygen and the acyl group. d) Finally, according to the mechanism, attack by hydroxide ion on carbonyl carbon does not displace alkoxide ion in one step,

5 O

O R

+ HO

C O

HO

C

R1

O

O





HO

O R1

C

+

O

R1

O

C

R1

R

R

R

+ HO

tr a n s itio n s ta te

but rather two steps with the formation of a tetrahedral intermediate. This alternative mechanism was considered more or less equally likely until 1950 when elegant work on isotopic exchange was reported by Myron Bender. Bender carried out the alkaline hydrolysis of carbonyl-labeled ethyl benzoate, 18

O

C O

C2H5

in ordinary water, and focused his attention, not on the product, but on the reactant. He interrupted the reaction after various periods of time, and isolated the unconsumed ester and analysed it for 18O content. He found that in alkaline solution the ester was undergoing not only hydrolysis but also exchange of its 18O for ordinary oxygen from the solvent. This oxygen exchange is not consitent with one-step mechanism. Oxygen exchange is consistent with a two-step mechanism in the following way: 18

Ph

18

O

+ HO

C O

Ph

18

O O

C

Et

Et

+

C

Ph

O

Et

OH

OH

L a b e le d e s te r S ta r tin g m a te r ia l

O

18

H2O Ph

O

C

18

HO Ph

C

O O

+ HO

Et 18

OH Ph

Ph

C

+ O

U n la b e le d e s te r E xc h a n g e p ro d u c t

O 18

18

HO

Et 18

HO

Ph

O

C

H2O

O

Et

C O

OH O

Et

Ph

+O

C O

Et

6

e) The rate-limiting step is almost certainly attack of -OH on the original ester. This is borne out by the activation parameters for the base-induced hydrolysis of MeCOOEt: ΔH ≠ = 112 kJ mol -1; ΔS ≠ = -109 J K -1 mol -1. f) Here the rate-limiting step involves the change in hybridisation from sp2 to sp3, and consequently steric retardation can be expected to increase as R increases in size. These anticipated results have been observed in practice, e.g., O

E s te r s

Me

C

Et O

R e la tiv e r a te s

O

O i-Pr

C

Et

O

O

Et

Et

0 .1 0

0 .4 7

1 .0 0

C

Problem II: 1. Explain the following observations: For the saponification of 4-t-butylcyclohexyl p-nitrobenzoates k trans / k cis =2.5 whereas for the saponification ethyl 4-t-butylcyclohexanecarboxylates k trans / k cis =20. In the base-induced hydrolysis of ester, electron-withdrawing substituents in either the acyl or the alkoxy group facilitate the reaction. Since the tetrahedral intermediate formed in the rate-limiting step is negatively charged, it and the transition state leading to it are stabilised by electron withdrawal. Thus we have the following observations: Cl

O

E s te r s

Me

C Me

O

1

Me

O C

O Et

O

Me

16000 O

O

O C

C

Cl

761

O

O CH

CH2 C O

R e la tiv e r a te s

Cl

O

Et

C

Et

E s te rs Me

R e la tiv e r a te s

0 .6 6

NO2

1 .0 0

6 3 .5

7 O

O

O C

Et

O

O Et

C

O C

Et

E s te r s OMe

R e la tiv e r a te s

k

m -M e O

> k H> k

OMe p -M e O

The electron withdrawing polar effect of one ester group on the other in diethyl oxalate (EtOOC-COOEt) is great enough to cause this ester to be hydrolysed even by water, towards which ethyl acetate is inert. If the carbonyl group is conjugated with an electronreleasing group, reactivity decreased by ground state stabilisation. The partitioning of the tetrahedral intermediate between reversion to starting material by loss of hydroxide ion and formation of product by expulsion of the alkoxide ion is strongly affected by substituents in the alkoxy group. Electron-withdrawing groups shift the partitioning in favor of loss of the alkoxide ion and favor the hydrolysis. For this reason, exchange of carbonyl oxygen with solvent does not occur in basic hydrolyses when the alkoxy group is good leaving group. This has been demonstrated, for example, for esters of phenols. Because phenols are much stronger acids than alcohols, their conjugate bases are better leaving groups than simple alkoxide ions. Aryl esters are, therefore, hydrolysed faster than alkyl esters and without observable exchange of carbonyl oxygen with solvent. O

O R

O

+ HO

C O

s lo w

R

Ar

C

OAr

fa s t

R

O

+O

C

OH

OH

Ar HO

R

C

+ HO

Ar

O

These substituent effects can be summarised in a general way for B AC2 mechanism by noting the effect of substituents on each step of the mechanism: O

O R

+ HO

C O

R

C

R1

OH

O R

C OH

O R1

O O R1

R

C

+

O

OH

Problem III: 1. Complete the following stepwise saponification:

R1

fa v o r e d b y e le c tr o n w ith d r a w in g s u b s titu e n ts in b o th R a n d R 1 s tro n g ly fa v o r e d b y e le c tr o n - w ith d r a w in g s u b s titu e n ts in R 1

8 COOMe H2 C COOMe

HO

OH

1)KO H , M eO H 3 m in , r e flu x 2 ) H 3O +

?

1) 40% NaO H 1 m in , 9 5 0 2) H 3O +

?

1 ) N a O H , e th e ly n e g ly c o l re flu x 2 ) H 3O +

?

COOMe

2. Alkaline hydrolysis of ethyl acetate is found to be much more rapid in dimethyl sulfoxide-water than in ethanol-water. Explain. Lactones are cyclic esters and hence are much favored over hydroxy-acid in the acidic hydrolysis equilibrium as long as they are five- or six-member rings. All lactones may be hydrolysed in base to hydroxy-carboxylates as the carboxylate anion is highly stabilised through resonance, but on acidification the five- or six-member lactones are often spontaneously reformed. O

+

H , - H 2O O CH2

O HO

+ H 2O

C

CH2

+

H2 C

OH CH2

OH

H

O

H2 C

C O

CH2 OH

The more substituted the lactone ring the more readily it forms, the more difficult its hydrolysis. We have the following data regarding hydrolytic equilibrium of lactones:

9 E q u lib r iu m C o m p o s itio n H y d r o x y A c id , %

L a c to n e F o r m u la

O

95

2

98

91

9

79

21

O

O

O

75

H3C H3C

5

O

O

O

H3C

73

O

H3C H3C

27 O

O

H3C

L a c to n e , %

O

25

O

This ease of ring closure as a function of substituents on the ring atoms is known as “Thorpe-Ingold effect” or “gem dialkyl effect”. This can be explained considering the following points: a) The C-C-C bond angle in propane is 112.5 0, whereas that in neopentane is 109028/. Thus during the ring formation, the introduced angle strain is reduced for the rings bearing gemdialkyl groups than it would be in absence of such groups. Obviously this is true for three-, four- and five-member ring compounds. b) The gem-dialkyl groups in open chains substantially increase the number of gauche interactions, thus increasing enthalpy. When rings are formed, since some gauche interactions are now intraannular, and therefore attenuated. Thus the ring formation for the systems having gem dialkyl groups is associated with favorable change in enthalpy. c) At the same time, branching diminishes the mobility, and hence the entropy of chains, but has much less effect in this regard in rings, which are already more restricted in their motions. Thus entropy change in ring closure is made more favorable by alkyl substitution.

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The Thorpe-Ingold effect or the gem-dialkyl effect is found for halohydrin cyclisation as obvious from the following table: Compound

Relative Rate of Cyclisation

HOCH2CH2Cl HOCH2CHClCH3 CH3CHOHCH2Cl HOCH2CCl(CH3)2 (CH3)2COHCH2Cl (CH3)2COHCHClCH3 CH3CHOHCCl (CH3)2 (CH3)2COHCCl (CH3)2

1 5.5 21 248 252 1360 2040 11600

It is also seen in other contexts. For example, whereas C 6H5CH2SCH2CH2CH2OTs methanolyses without rearrangement and at a rate comparable to that of sulfur-free analogue, C6H5CH2SC(CH3)2CH2CH2OTs solvolyses at an accelerated rate and with complete rearrangement to C6H5CH2SCH2CH2C(CH3)2OCH3, indicating extensive sulfur participation via four member thietanonium salt i...