Reactions of carbonyl compounds in basic solutions. Part 33. 1 Effect of 2-trichloro-and tribromoacetyl substituents on the alkaline hydrolysis of methyl benzoate, as well as the hydrolysis of the corresponding benzoate anions and ionisation/ring-chain tautomerism of the corresponding acids

Article abstract of DOI:10.1039/a807438k

Rate coefficients have been measured for the alkaline hydrolysis of methyl 2-trichloro-and tribromoacetylbenzoate, as well as the alkaline hydrolysis of the corresponding 2-trichloro-and tribromobenzoate anions, in 30% (v/v) dioxane-water at several temperatures. The relative rates of hydrolysis and activation parameters demonstrate relatively rapid hydrolysis via neighbouring group participation by the acyl-carbonyl group in the ester hydrolysis and slower hydrolysis via intramolecular fission of the adducts in the benzoate anion hydrolysis. The pK_a values of the corresponding benzoic acids have been measured in water and their ring-chain tautomeric equilibrium constants determined.

Full text of DOI:10.1039/a807438k

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Reactions of carbonyl compounds in basic solutions. Part 33.1
Effect of 2-trichloro- and tribromoacetyl substituents on the
alkaline hydrolysis of methyl benzoate, as well as the hydrolysis
of the corresponding benzoate anions and ionisation/ring–chain
tautomerism of the corresponding acids
Keith Bowden* and Sivani Raja
Department of Biological and Chemical Sciences, Central Campus, University of Essex,
Wivenhoe Park, Colchester, Essex, UK CO4 3SQ. E-mail: keithb@essex.ac.uk
Received (in Cambridge) 23rd September 1998, Accepted 27th October 1998
Rate coefficients have been measured for the alkaline hydrolysis of methyl 2-trichloro- and tribromoacetylbenzoate,
as well as the alkaline hydrolysis of the corresponding 2-trichloro- and tribromobenzoate anions, in 30% (v/v)
dioxane–water at several temperatures. The relative rates of hydrolysis and activation parameters demonstrate
relatively rapid hydrolysis via neighbouring group participation by the acyl-carbonyl group in the ester hydrolysis and
slower hydrolysis via intramolecular fission of the adducts in the benzoate anion hydrolysis. The pKa values of the
corresponding benzoic acids have been measured in water and their ring–chain tautomeric equilibrium constants
determined.
Reviews2 of neighbouring group participation by proximate
carbonyl groups in the alkaline hydrolysis of esters have been
made recently. In these, criteria have been established for this
type of intramolecular catalysis and further model systems have
been studied.3 Based on these investigations,2,3 a series of
studies of the synthesis and hydrolysis of reactive esters of
aspirin and related anti-inflammatory drugs4 and of metro-
nidazole5 as prodrugs have been made.
2-Trihaloacetylbenzoate esters can hydrolyse, in principle, in
two ways. The first is by hydrolysis of the ester.3 The second is
with the alkaline hydrolysis of the corresponding benzoate
by hydrolysis of the trihaloacetyl group itself. The latter can
anions and the ionisation of the corresponding benzoic acids.
also occur for the product of ester hydrolysis, the 2-trihalo-
acetylbenzoic acid.6
The latter measurements have been used to determine the
equilibrium constants for the ring–chain tautomerism of the
Ring–chain tautomerism has been shown to occur in a num-
ber of 2-acetylbenzoic acids,7,8 as shown in eqn. (1). The equi-
corresponding acids. The hydrolysis studies will serve as
model systems for the hydrolysis of further reactive esters of
metronidazole10 as prodrugs.
(1)
Results and discussion
Both the methyl esters 1a,b suffer relatively rapid alkaline
hydrolysis to the corresponding anions of the carboxylic acids.
The latter react more slowly to the final products of hydrolysis.
Thus, the hydrolysis of the 2-trihaloacetylbenzoate anions
results in cleavage resulting in the formation of the trihaloform
and the anion of phthalic acid.11 This is shown in reaction (4)
below.
librium constant, Ke for the tautomeric equilibrium (1) is given
by eqn. (2). A number of methods, e.g. IR, UV and H NMR
1
Ke = aring/achain
(2)
spectroscopy, can be used to make quantitative studies of these
equilibria. However, if one of the tautomeric forms is pre-
dominant, it is difficult to use any of these methods. If the
predominant form is relatively much less acidic than the other,
it is possible to use measurement of pKa values to estimate Ke.
The alkaline hydrolysis of the esters
The alkaline hydrolysis of the methyl esters is of first-order
both in ester and hydroxide anion. Rate coefficients for the
alkaline hydrolysis of the methyl 2-trihaloacetylbenzoates are
shown in Table 1. The activation parameters are shown in
Table 2.
The rates of hydrolysis of both esters are relatively rapid. The
rate ratios of the esters to that of methyl benzoate (k2 at 30 ЊC
in 30% (v/v) dioxane–water equals 0.0328 dm3 molϪ1 sϪ1)12 can
be calculated to give the values shown in Table 3. The expected
rate ratios for “normal” hydrolysis are also shown and are
those estimated from the known polar and steric effects of
T
Thus, the true pKa value, pKa , is related to the observed value
by the relation (3).9 If the pKa is known and a reliable estimate
of the pKaT can be made, Ke can be calculated.
pKaT = pKa Ϫ log (Ke ϩ 1)
(3)
We describe here the preparation and alkaline hydrolysis of
methyl 2-trichloro- and tribromoacetylbenzoates, 1a,b, together
J. Chem. Soc., Perkin Trans. 2, 1999, 39–42
39

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Table 1 Rate coefficients (k2) for the alkaline hydrolysis of methyl
2-trihaloacetylbenzoates and the corresponding benzoate anions in
30% (v/v) dioxane–watera
k2/dm3 molϪ1 sϪ1
2-Substituent
T/ЊC 30.0
40.0
50.0
60.0
λ/nmb
Methyl benzoate
COCBr3
COCCl3
13.45
49.9
22.5
61.6
33.65
54.45
280
(37.3)c (83.4)d 277
Benzoate anion
COCBr3
COCCl3
0.118
0.468
0.216
0.866
0.396
1.39
0.658
2.375
280
277
a Rate coefficients were reproducible to 3%. b Wavelength used to
monitor alkaline hydrolysis. c At 25.0 ЊC. d At 45.0 ЊC.
Table 2 Activation parameters for the alkaline hydrolysis of methyl
2-trihaloacetylbenzoates and the corresponding benzoate anions in
30% (v/v) dioxane–water at 30 ЊCa
2-Substituent
∆H‡/kcal molϪ1 b
∆S‡/cal molϪ1 KϪ1 b
Scheme 1
Methyl benzoate
COCBr3
COCCl3
8.6
6.3 ( 1.0)
Ϫ25
Ϫ30 ( 3)
Benzoate anion
COCBr3
COCCl3
11.0
10.1
Ϫ27
Ϫ27
a Values of ∆H‡ and ∆S‡ are considered accurate to within 300 cal
molϪ1 and 1 cal molϪ1 Ϫ1, respectively, except where shown in
parentheses. b 1 cal = 4.184 J.
K
factor of ca. four observed in 30% aqueous dioxane at 30 ЊC.
The faster rate of the trichloro substrate, compared to that of
the tribromo substrate, arises mainly from the decreased steric
bulk of the trichloromethyl group which favours formation of
the adduct.
For the alkaline hydrolysis of the more reactive methyl esters
employing neighbouring group participation by carbonyl
groups, the enthalpies of activation are exceptionally small and
are associated with rather large negative entropies of activ-
ation.2a,3 As shown in Table 2, this is true for both the esters 1a,b
studied here.
The reaction pathway is shown in Scheme 1. The rate
determining step for the esters 1a and 1b could be either the
formation of the initial adduct, kЈ1, or the intramolecular
nucleophilic attack, kЈ2. The former appears to be the case for
very reactive systems such as the 2-formyl and acetylbenzoate
systems,2a,3 and for the two esters 1a and 1b studied here, based
on the evidence from the entropy of activation.
Table 3 Relative rate ratios of the alkaline hydrolysis of the methyl
esters at 30 ЊC
k/ko
Expected for
“normal” hydrolysis
Ester
Observed
Enhanced, re
1a
1b
[1c
410
1520
7270
1.0
2.0
5.0
410
760
1500]a
a Lit.3b values in water.
ortho-substituents on the alkaline hydrolysis of methyl and
ethyl benzoates13 together with the para-σ values of related acyl
groups.14 In both cases, rate enhancements, re, shown in Table 3,
are very large, indicating the occurrence of intramolecular cata-
lysis.2 A mechanistic pathway for the alkaline hydrolysis of the
methyl 2-acylbenzoates is shown in Scheme 1. The correlation
of the rates of the alkaline hydrolysis of esters 4 in 70%
(v/v) dioxane–water at 20 ЊC using σ* and Es for R15 is shown in
The alkaline hydrolysis of the benzoate anions
The alkaline hydrolysis of the 2-trihaloacetylbenzoate anions is
of first-order both in benzoate and hydroxide anions. Rate
coefficients for the alkaline hydrolysis of the benzoate anions
are shown in Table 1. The activation parameters are shown in
Table 2.
14
eqn. (5) below. The σ* and Es values for CBr3 and CCl3 are
2.43, Ϫ2.43 and 2.65, Ϫ2.06, respectively.
log (k/ko) = 1.30 σ* ϩ 1.08 Es
(5)
The rates of hydrolysis are considerably slower than those of
the corresponding esters. Again the trichloro substrate reacts
faster than the tribromo substrate. The activation parameters
This predicts a faster rate for 1b than 1a by a factor of ca. five
in 70% aqueous dioxane at 20 ЊC and compares well with the
40
J. Chem. Soc., Perkin Trans. 2, 1999, 39–42

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Table 4 Ionisation of the 2-substituted benzoic acids in water at
25 ЊCa
Table 5 Physical properties of previously unreported methyl 2-trihalo-
acetylbenzoates
2-Substituent
pKa
Estimated pKT
Ke
Elemental analysis
Found (%) (Required)
a
COCBr3
COCCl3
5.10
4.99
3.1
3.1
100 ( 25)
78 ( 20)
Compound
Mp/ЊC
Appearancea
C
H
Other
a The observed pKa values were reproducible to 0.02 unit and the
1a (C10H7Br3O3) 113–115 Colourless
28.9
1.8
58.0 (Br)
estimated pKTa values are considered to be 0.1 unit.
needles
(29.0) (1.7) (57.8) (Br)
42.6 2.6 37.5 (Cl)
(42.7) (2.5) (37.8) (Cl)
1b (C10H7Cl3O3) 81–83
Colourless
needles
indicate a bimolecular pathway. The relative ease of formation
of the adduct for the less bulky trichloro substrate decreases
∆H‡ and increases the rate of reaction, cf. ref. 6(b). The reac-
tion pathway is shown in Scheme 2, which is similar to that
a Recrystallisation solvent benzene–hexane.
previously unreported methyl esters are shown in Table 5,
together with their appearance and elemental analysis.
Measurements
Rate coefficients for the alkaline hydrolysis were determined
spectrophotometrically by use of a Perkin-Elmer Lambda 16
UV–VIS spectrophotometer. The reactions were followed at the
wavelengths shown in Table 1. The procedure was that
described previously.20 The substrate concentrations were ca.
1 × 10Ϫ4 mol dmϪ3 and the base concentrations were ca.
2 × 10Ϫ4 to 2 × 10Ϫ2 mol dmϪ3. The primary products of the
alkaline hydrolysis of the esters were found to be the anions of
the corresponding acids in quantitative yield. The secondary
products of the latter reaction and the alkaline hydrolysis of the
corresponding benzoate anions were found to be the anions of
phthalic acid and the trihaloform. The phthalic acid products
were isolated in quantitative yield. The presence of the trihalo-
forms was confirmed by glc analysis. The kinetics of the latter
reactions were found to be identical if studied using methyl
ester or acid as substrate. Both reactions were found to be
first-order in both base and substrate. For the ester
hydrolysis, the second-order rate coefficients were checked by
the method devised by Corbett,21 which can be applied if the
excess used is only two-fold. Good isosbestic points were
observed for all substrates in both reactions by judicious
variation in the base concentrations, i.e. the relative rate of
ester to benzoate anion hydrolysis is >70. The products were
both further confirmed spectrophotometrically by com-
parison of the spectrum of the acid in base with that of the
reaction product.
Scheme 2
proposed for related substrates.6 The rate determining step
would appear to be the decomposition of the initial adduct, kЉ2,
to form the carbanion. The latter is relatively rapidly proton-
ated to give the haloform.
The ring–chain tautomerism of the acids
The IR spectra of the acids in tetrachloromethane or chloro-
form clearly indicate that the acids are predominantly cyclic,
i.e. in tetrachloromethane the acids corresponding to 1a and 1b
have lactone carbonyl stretching frequencies observed at 1818
and 1802 cmϪ1, respectively, alone, cf. ref. 8,16. The 1H and 13
C
NMR spectra confirm the cyclic nature of the compounds, but
do not allow quantitative measurements of the equilibrium to
be made.
In Table 4 are shown the pKa values of the acids, together
with estimates of pKa values of the chain tautomers. The latter
are based on the pKa value of 2-benzoylbenzoic acid in water
(3.535),17 together with the polar substituent effects of Ph, CBr3
The apparent pKa values of the acids in water at 25 ( 0.1) ЊC
were measured as described previously.19 The pKa of benzoic
acid in water was found to be 4.20 and the aqueous solution
contained 2% dioxane to ensure solubility of the 2-substituted
benzoic acids. Under the conditions of the measurements, the
decomposition of the anion of the 2-trihaloacetylbenzoic acid
was very slow and does not affect the determinations.
and CCl3 and their transmission.18 The Ke values for 2-tri-
14
bromo- and trichloroacetylbenzoic acids in water are shown
in Table 4 as 100 and 78, respectively. These are significantly
greater than those for 2-acetyl- and benzoylbenzoic acids which
are ca. 4 and 0.07, respectively.8 The relatively large steric bulk
and powerful electron-withdrawing effect of the CBr3 and CCl3
groups favour the formation of the ring tautomer.7,8
Acknowledgements
We thank Amy Bringes for carrying out some preliminary
studies.
Experimental
Materials
The decomposition of tribromo- or trichloroacetic acid in
dimethyl sulfoxide in the presence of phthalic anhydride gave
2-tribromo- or trichloroacetylbenzoic acid, respectively.16 The
methyl esters were prepared from the corresponding acid and
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J. Chem. Soc., Perkin Trans. 2, 1999, 39–42