Reactions of Carbonyl Compounds in Basic Solutions. Part 30.1 the Effect of 2-Formyl, 2,6-Diformyl and 2-Trifluoroacetyl Substituents on the Alkaline and Neutral Hydrolysis of Methyl Benzoate and Phenyl Acetate

Article abstract of DOI:10.1039/a703218h

Rate coefficients are measured for the alkaline hydrolysis of methyl 2-formyl-, 2,6-diformyl- and 2-trifluoroacetyl-benzoates and for the alkaline and neutral hydrolysis of 2-formyl-, 2,6-diformyl-4-methyl- and 2-trifluoroacetyl-phenyl acetates in water at several temperatures: the relative rates of hydrolysis and activation parameters demonstrate neighbouring group participation by the acyl-carbonyl groups in the ester hydrolysis.

Full text of DOI:10.1039/a703218h

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404 J. CHEM. RESEARCH (S), 1997
J. Chem. Research (S),
1997, 404–405†
Reactions of Carbonyl Compounds in Basic Solutions.
Part 30.1 The Effect of 2-Formyl, 2,6-Diformyl and
2-Trifluoroacetyl Substituents on the Alkaline and Neutral
Hydrolysis of Methyl Benzoate and Phenyl Acetate†
Keith Bowden,* Jamshid Izadi and Sarah L. Powell
Department of Biological and Chemical Sciences, Central Campus, University of Essex,
Wivenhoe Park, Colchester, Essex CO4 3SQ, UK
Rate coefficients are measured for the alkaline hydrolysis of methyl 2-formyl-, 2,6-diformyl- and 2-trifluoroacetyl-benzoates
and for the alkaline and neutral hydrolysis of 2-formyl-, 2,6-diformyl-4-methyl- and 2-trifluoroacetyl-phenyl acetates in
water at several temperatures: the relative rates of hydrolysis and activation parameters demonstrate neighbouring group
participation by the acyl-carbonyl groups in the ester hydrolysis.
Prodrugs have been designed as reversible derivatives of
drugs to eliminate undesirable properties of the drug.2 While
the linkage employed in forming prodrugs has been various,
the formation of esters has been common.3 Esters can be
hydrolysed either by enzymes or non-enzymatically to liber-
ate the parent drug. There are clear advantages in using
esters whose hydrolysis is facile and can be tuned by com-
paratively simple structured changes.
Neighbouring group participation by suitably situated car-
esters 1a and 2a were used as reference compounds.4,7 The alkaline
hydrolysis of the methyl benzoates is of first-order both in ester and
in hydroxide anion. However, the hydrolysis of the phenyl acetates is
of first-order in ester and both zero- and first-order in hydroxide
anion. The products of the hydrolysis of all the esters were the
corresponding phenol or methanol and the corresponding benzoate
or acetate anion. The rate coefficients for the hydrolysis of the esters
in water are shown in Table 1 and the activation parameters in
bonyl groups in the alkaline hydrolysis of esters has been
recently reviewed.4 Criteria have been established for the
detection and delineation of this behaviour. For powerful
facilitation, the acyl group substituent should be electron-
withdrawing and have modest steric ‘bulk’.4,5 Thus, the alka-
line hydrolysis of methyl 2-formylbenzoate has been studied
at 25.0 °C in water6 and at several temperatures in 70% (v/v)
1,4-dioxane–water7 and the alkaline and neutral hydrolysis of
2-formylphenyl acetate at 25.0 °C in water.8
Table 2.
Table 2 Activation parameters for the alkaline hydrolysis of substituted
We describe here the hydrolysis, under alkaline conditions,
of model esters. The esters are methyl benzoates and phenyl
acetates ortho-substituted with acyl groups designed to
achieve high reactivity, i.e. 2-formyl, 2,6-diformyl and 2-tri-
fluoroacetyl substituents.
methyl benzoates and phenyl acetates at 20.0 °C in watera,b
Methyl benzoates
Subst.
DH‡/kcal mol–1b
DS‡/cal mol–1 k–1b
2-CHO
2,6-(CHO)2
2-C(CF3)O
2.7
ꢀ35
1.2
ꢀ33
2.4 (1.4)c
ꢀ37 (ꢀ31)c
Results
The prepared model compounds were methyl 2-formyl-, 2,6-difor-
myl- and 2-trifluoroacetyl-benzoate, 1a–c, and 2-formyl-, 2,6-difor-
myl-4-methyl- and 2-trifluoroacetyl-phenyl acetates, 2a–c. The
Phenyl acetates
Subst.
2-CHO
2,6-(CHO)2, 4-Me
2-C(CF3)O
6.3 (8.5)d
ꢀ14 (ꢀ40)d
ꢀ20 (ꢀ48)d
ꢀ17 (ꢀ36)d
Table 1 Rate coefficients (k2) for the alkaline hydrolysis of substituted
3.1 (6.5)d
methyl benzoates and phenyl acetates in water (at constant ionic strength
ꢀ0.1 (10.9)d
a,b
of 0.1 mol dm–3
)
10–2 k2/dm3 mol–1 s–1
aValues of DH‡ and DS‡ are considered to be accurate to <300 cal mol–1
and <2 cal mol–1 K–1, respectively. b1.8 (v/v) 1,4-dioxane–water. cUsing
Methyl benzoates at 30.0 °C
Subst.
at 60.0 °C
l/nmc
k3/dm6 mol–2 s–1 dNeutral or water-catalysed reaction.
.
Discussion
2-CHO
2,6-(CHO)2
2-C(CF3)O
19.1
31.1
302
308
232
Relative Rates.sThe rate ratios for the hydrolysis of the
esters to that of either methyl benzoate (k2 at
30.0 °C = 1.28Å10ꢀ1 dm3 molꢀ1 sꢀ1)9 or phenyl acetate [k2
(alkaline) and k1 (neutral) at 27.0 °C = 180 dm3 molꢀ1 sꢀ1 and
9.0Å10ꢀ8 sꢀ1, respectively]9 can be calculated to give the
values shown in Table 3. Estimates of the rate ratios for
unassisted hydrolysis using the known polar and steric effects
of 2-substituents on the alkaline hydrolysis of methyl ben-
zoates and phenyl acetates,10,11 as well as the Hammett equa-
tion12 and the neutral hydrolysis of phenyl acetates,13 have
been made and are shown in Table 3. In all cases, the rate
enhancements, re, shown in Table 3, are both significant, i.e.
P10, and very large. They all strongly indicate the occur-
rence of intramolecular catalysis.4 Mechanistic pathways for
the alkaline hydrolysis of the methyl 2-acylbenzoates and
2-acylphenyl acetates have been shown as Scheme 1 for the
exocyclic and Scheme 2 for the endocyclic intramolecular
catalysis in our review.4b A novel pathway for the neutral
475
617
9.30 (1010)d
14.6 (1350)d
10–5 k2/dm3 mol–1 s–1
Phenyl acetates
Subst.
at 27.0 °C
at 37.0 °C
at 47.0 °C
2-CHO
2,6-(CHO)2, 4-Me
2-C(CF3)O
1.30 (64.0)e
11.8 (42.8)e
1.87 (102)e
14.8 (64.1)e
2.68 (165)e
17.4 (89.7)e
320
354
10 600 (7.96)e 11 000 (14.3)e 11 200 (26.5)e 268
aRate coefficients are the mean of at least two determinations and were
reproducible to within <3%. b1.8% (v/v) 1,4-dioxane–water.
cWavelengths used to monitor hydrolysis. d10–2 k3/dm6 mol–2 s–1
e104 k1/s–1 (neutral or water-catalysed reaction).
.
*To receive any correspondence (e-mail: keithb@essex.ac.uk).
†This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

View Article Online
J. CHEM. RESEARCH (S), 1997 405
K1
Table 3 Relative rate ratios of the alkaline hydrolysis of the esters in
water at 30 °C for 1a–c and 27 °C for 2a–c
OH
C
O
O
O
O
k1
R′
O
R
R′
HO
R
C
C
C
+
H2O
k-1
k/k0
Expected for
‘normal’ hydrolysis
Ester
Observed
Enhanced re
k-2
k2 K2
1a
1b
1c
2a
2b
2c
14 900
371 000
7270
5.0
25
5.0
3000
15 000
1500
OH
C
O
O
K3
k-3
R′
R′
C
OH
C
OH
O
722 (7.1Å104)a
6560 (4.8Å104)a
5.89Å106 (8.8Å103)a
5.0 (5.0)a
25 (25)a
8.0 (8.0)a
140 (1.4Å104)a
260 (1.9Å103)a
7.4Å105 (1.1Å103)a
HO
R
O
C
R
k3
fast (–H+)
aNeutral hydrolysis.
O
R
CO–
C
HO
+
R′
2
hydrolysis of the 2-acylphenyl acetates is shown in Scheme
1.
Scheme 1
The increased rates of the alkaline reaction hydrolysis of
the two 2,6-diformyl esters 1b and 2b, relative to those of the
2-formyl esters 1a and 2a, are those expected on the basis of
the statistical factor, i.e. Å2, and of the activating effect of a
‘meta’-formyl group on the formyl group undergoing nucleo-
philic attack. A combination of an electron-withdrawing
effect, i.e. s1 = 0.40,14 and a significant steric ‘bulk’ effect, i.e.
Es = ꢀ2.40,12 for the trifluoromethyl substituent would
account for the relative rate of the alkaline hydrolysis of 1c,
cf. ref. 5. The remarkably rapid rate of reaction for 2c was
unexpected.
Activation Parameters.sFor the alkaline hydrolysis of the
more reactive methyl esters employing neighbouring group
participation, the enthalpies of activation are exceptionally
small and are associated with rather large negative entropies
of activation.4 As shown in Table 2, this is true for the methyl
esters 1a–c studied here. The same reaction for the phenyl
acetates studied here displays very small enthalpies of activa-
tion, but the entropies of activation are normal for a
bimolecular reaction. The neutral or water-catalysed reac-
tions of the phenyl esters 2a–c also have relatively small
enthalpies of activation, with very large negative entropies of
activation. The latter are very comparable to those found for
the neutral hydrolysis of a number of reactive esters.15 This
would appear to be the first observation of intramolecular
catalysis by carbonyl groups of neutral or water-catalysis of
ester hydrolysis.
extrapolated to zero buffer concentrations. Hydroxide anion con-
centrations of 1Å10ꢀ3 to 1Å10ꢀ2 mol dmꢀ3 were used where
required. The hydrolysis of the methyl esters 1a and 1b is of first-
order in both substrate and hydroxide anion. For the methyl ester
1c, the reaction is both first- and second-order in hydroxide anion.
The hydrolysis of the acetate esters is of first order in substrate and
of both zero and first order in hydroxide anion.
Received, 9th May 1997; Accepted, 8th July 1997
Paper E/7/03218H
References
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Experimental
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Materials.s2,6-Diformylbenzoic acid was obtained by bromina-
tion of 2,6-dimethylbenzoic acid and subsequent hydrolysis.16 Oxi-
dation of 4-methyl-2,6-bis(hydroxymethyl)phenol in stages gave
2,6-diformylphenol.17 2-Trifluoroacetylbenzoic acid was prepared
by the lithiation of 1,2-dibromobenzene and reaction with methyl
trifluoroacetate and carbon dioxide.18 The Fries rearrangement of
phenyl trifluoroacetate gave 2-trifluoroacetylphenol.19 The methyl
esters of the acids were prepared from the corresponding acid and
diazomethane.7 The phenyl acetates were prepared by treatment of
the corresponding phenol in acetic anhydride with concentrated
sulfuric acid or pyridine.20 The purity of the acids, phenols and
esters was monitored by 1H and 13C NMR and IR spectroscopy, as
well as mass spectrometry. The mp values of the acids, phenols and
esters, after repeated recrystallization and drying under reduced
pressure (P2O5), was in agreement with literature6,16–19 values, as
was the boiling point of 2-trifluoroacetylphenyl acetate.21 The fol-
lowing previously unreported esters gave satisfactory elemental
analysis. Methyl 2,6-formylbenzoate had mp 65–66 °C and was
recrystallised from benzene–hexane. 2,6-Diformyl-4-methylphenyl
acetate had mp 110–111 °C and was recrystallised from benzene–
hexane. Methyl 2-trifluoroacetylbenzoate had mp 67– 68 °C and
was recrystallised from hexane.
11 T. Nishioka, T. Fujita, K. Kitamura and M. Nakajima, J. Org.
Chem., 1975, 40, 2520.
12 C. D. Johnson, The Hammett Equation, Cambridge University
Press, Cambridge, 1973.
13 V. Gold, D. G. Oakenfull and T. Riley, J. Chem. Soc. B, 1968,
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ford and C. F. H. Tipper, Elsevier, Amsterdam, 1972, vol. 10, ch.
2.
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Hopkins and E. F. Bachmann, Can. J. Chem., 1979, 57, 3320.
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Measurements.sRate coefficients for the alkaline and neutral or
water-catalysed hydrolysis were determined spectrophotometri-
cally. The reactions were followed at the wavelengths shown in
Table 1. The procedure used was that described previously.22 The
products of the reactions were found to be either the anions of the
corresponding carboxylic acids or the phenols in quantitative yield
and were further confirmed spectrophotometrically. Rates were