Hydrolysis of aryl N-methyl-N-arylsulfonylcarbamates

Article abstract of DOI:10.1039/b009146o

Tertiary sulfonylcarbamates 1 were prepared by reaction of a sulfonamide anion with aryl chloroformates. These previously unreported compounds hydrolyse in aqueous media to the parent sulfonamide and phenol. The pH-rate profile shows both spontaneous and base-catalysed processes. The reaction is also catalysed by buffers. Kinetic data for the hydrolysis of these compounds by HO^- are best interpreted in terms of a mechanism involving rate-limiting formation of a tetrahedral intermediate from nucleophilic attack of hydroxide ion at the carbamate carbonyl carbon atom. For the 4-nitrophenylsulfonyl compound 1h decomposition of the tetrahedral intermediate appears to be rate-limiting with the sulfonamide anion, rather than the phenoxide, functioning as the leaving group. The buffer-catalysed process is consistent with general base-catalysed attack of water at the carbamate carbonyl carbon atom.

Full text of DOI:10.1039/b009146o

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Hydrolysis of aryl N-methyl-N-arylsulfonylcarbamates
M. Eduarda M. Araújo,a Margarida Campelo,a,b Jim Iley*c and Fátima Norberto*a,b
a Departamento de Química e Bioquímica, CECUL, Faculdade de Ciências,
Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
b CECF, Faculdade de Farmácia, Universidade de Lisboa, Avenida das Forças Armadas,
1649-109 Lisboa, Portugal
2
c Chemistry Department, The Open University, Milton Keynes, UK MK7 6AA
Received (in Cambridge, UK) 13th November 2000, Accepted 27th February 2001
First published as an Advance Article on the web 15th March 2001
Tertiary sulfonylcarbamates 1 were prepared by reaction of a sulfonamide anion with aryl chloroformates. These
previously unreported compounds hydrolyse in aqueous media to the parent sulfonamide and phenol. The pH–rate
profile shows both spontaneous and base-catalysed processes. The reaction is also catalysed by buffers. Kinetic data
for the hydrolysis of these compounds by HOϪ are best interpreted in terms of a mechanism involving rate-limiting
formation of a tetrahedral intermediate from nucleophilic attack of hydroxide ion at the carbamate carbonyl carbon
atom. For the 4-nitrophenylsulfonyl compound 1h decomposition of the tetrahedral intermediate appears to be
rate-limiting with the sulfonamide anion, rather than the phenoxide, functioning as the leaving group. The buffer-
catalysed process is consistent with general base-catalysed attack of water at the carbamate carbonyl carbon atom.
Carbamates have a range of interesting pesticidal and anti-
fungal activities,1 and their chemistry in aqueous media has
been well studied.2 Thus, secondary carbamates hydrolyse via
an E1cb mechanism whereas the tertiary analogues follow an
addition–elimination pathway. Difunctional carbamates, which
incorporate an additional functional group at the carbamate
nitrogen atom, e.g. 1, are much less well studied, so we have
initiated a programme to investigate and exploit such com-
pounds. Recently, secondary sulfonylcarbamates have been
reported to act as angiotensin II receptor antagonists,3
the acidic sulfonylcarbamate moiety acting as an isostere
for the tetrazole group in the antihypertensive agent losartan.4
Surprisingly, there are few studies reported on the chemical
reactivity of difunctional carbamates. Secondary phenyl-
sulfonylcarbamates have been shown to hydrolyse via an
E1cb mechanism to form a sulfonyl isocyanate,5 whereas phenyl
N-methyl-N-thiobenzoylcarbamate hydrolyses via a general
base-catalysed pathway.6 Presently, we have been investigating
the previously unreported tertiary N-arylsulfonylcarbamates 1
and to aid our studies we have examined the hydrolysis of these
compounds in aqueous alkaline media. Herein we present our
results.
spectrometer; chemical shifts are reported in ppm relative to
TMS as internal standard and coupling constants, J, are
given in Hz. Mass spectra were recorded using a VG Mass
Lab 20-250.
Synthesis of substrates
Compounds 1 were obtained by one of two methods: A or B.
Method A. The appropriate sulfonamide (20 mmol) was dis-
solved in anhydrous DMF (10 cm3) and sodium hydride
(20 mmol) was added under N2 with stirring. After 30 min,
the corresponding aryl chloroformate (20 mmol) in dry DMF
(10 cm3) was added slowly. The reaction was allowed to proceed
for 30 min, then poured into water (100 cm3) and the solid
filtered and purified by column chromatography (diethyl ether–
petroleum ether 1 : 1).
Method B. The appropriate sulfonamide (20 mmol) was dis-
solved in anhydrous THF (20 cm3). The mixture was stirred and
maintained under N2 at room temperature while butyllithium
(10 mmol) was added. After 30 min, the corresponding aryl
chloroformate (20 mmol) in dry DMF (10 cm3) was added
slowly. After 1 h the solvent was removed and the residue
redissolved in dichloromethane and purified as described in
method A.
4-Chlorophenyl N-methyl-N-(4-tolylsulfonyl)carbamate 1a.
Method A, 20%; method B, 30%. Mp 70–72 ЊC; νmax/cmϪ1 1743
(C᎐O), 1360, 1160 (SO ); δ (CDCl3) 2.46 (3H, s, ArMe), 3.51
᎐
2
H
(3H, s, NMe), 6.9 (2H, d, J = 9, CO2Ar), 7.3 (2H, d, J = 9,
CO2Ar ), 7.33 (2H, d, J = 9, ArSO2), 7.86 (2H, d, J = 9, ArSO2);
m/z (EI) 339. Found: C, 52.8; H, 4.2; N,4.1%. C15H14ClNSO4
requires: C, 53.0; H, 4.15; N, 4.1%.
Experimental
Melting points were determined using a Kofler camera Bock
Monoscop M and are uncorrected. Elemental analyses were
performed by Medac Ltd., Brunel Science Park, Englefield
Green, Egham, Surrey, UK. IR spectra were obtained using
a Nicolet Impact 400 Spectrophotometer. H NMR spectra
were recorded in CDCl3 solutions using a JEOL JNM-LA 300
Phenyl N-methyl-N-(4-tolylsulfonyl)carbamate 1b. Method B,
14%. Mp 82–83 ЊC; νmax/cmϪ1 1756 (C᎐O), 1367, 1184 (SO );
δH (CDCl3) 2.45 (3H, s, ArMe), 3.51 (3H, s, NMe), 6.96 (2H,
d, J = 9.2, SO2Ar), 7.32 (5H, m, CO2Ar), 7.89 (2H, d, J = 9.2,
SO2Ar); m/z (EI) 306 (M+). Found: C, 59.0; H, 5.0; N, 4.5%.
C15H15NSO4 requires: C, 59.0; H, 4.95; N, 4.6%.
᎐
2
1
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J. Chem. Soc., Perkin Trans. 2, 2001, 494–497
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b009146o

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Table 1 Pseudo-first-order rate constants, kobs, for the hydrolysis of 1a
in NaOH and NaOD solutions
4-Tolyl N-methyl-N-(4-tolylsulfonyl)carbamate 1c. Method B,
63%. Mp 90–91 ЊC; νmax/cmϪ1 1762 (C᎐O), 1367, 1150 (SO );
᎐
2
δH (CDCl3) 2.31 (3H, s, ArMe), 2.45 (3H, s, SO2ArMe), 3.51
(3H, s, NMe), 6.83 (2H, d, J = 9.2, SO2Ar), 7.11 (2H, d, J = 6.6,
CO2Ar), 7.32 (2H, d, J = 6.6, CO2Ar), 7.89 (2H, d, J = 9.2,
SO2Ar); m/z (EI) 319 (M+). Found: C, 60.2; H, 5.4; N, 4.4%.
C16H17NSO4 requires: C, 60.0; H, 5.4; N, 4.4%.
[NaOH]/10Ϫ2 M
kobs/10Ϫ4 sϪ1
[NaOD]/10Ϫ2 M
kobs/10Ϫ4 sϪ1
0.2
0.5
1.0
2.0
4.3
10
5.94
16.1
33.1
63.0
128
1.0
2.4
3.0
4.0
45
82
100
140
4-Methoxyphenyl N-methyl-N-(4-tolylsulfonyl)carbamate 1d.
Method A, 10%. Mp 89 ЊC; νmax/cmϪ1 1749 (C᎐O), 1367, 1150
319
᎐
(SO2); δH (CDCl3) 2.45 (3H, s, SO2ArMe), 3.51 (3H, s, NMe),
3.77 (3H, s, OMe), 6.84 (4H, m, CO2Ar), 7.31 (2H, d, J = 9,
SO2Ar), 7.88 (2H, d, J = 9, SO2Ar); m/z (FAB+) 336 (MH+);
(FABϪ) 334 (MϪ). Found: C, 57.3; H, 5.1; N, 4.2%. C16H17NSO5
requires: C, 57.4; H, 5.0; N, 4.2%.
4-Chlorophenyl N-methyl-N-(4-methoxyphenylsulfonyl)carb-
amate 1e. Method A, 10%. Mp 64 ЊC; νmax/cmϪ1 1756 (C᎐O),
᎐
1367, 1167 (SO2); δH (CDCl3) 3.51 (3H, s, NMe), 3.88 (3H, s,
OMe), 6.99 (2H, d, J = 9, SO2Ar), 7.11 (2H, d, J = 9, CO2Ar),
7.31 (2H, d, J = 9, CO2Ar), 7.9 (2H, d, J = 9, SO2Ar); m/z (EI)
355 (M+); (FAB+) 356 (MH+). Found: C, 50.6; H, 4.0; N, 3.9%.
C15H14ClNSO5 requires: C, 50.9; H, 3.9; N, 3.5%.
4-Chlorophenyl
N-methyl-N-(4-chlorophenylsulfonyl)carb-
amate 1f. Method A, 12%. Mp 95–97 ЊC; νmax/cmϪ1 1785(C᎐O),
᎐
Fig. 1 pH–rate profile for 1a.
1367, 1170 (SO2); δH (CDCl3) 3.51 (3H, s, NMe), 6.93 (2H, d,
J = 9, CO2Ar), 7.31 (2H, d, J = 9, CO2Ar), 7.51 (2H, d, J = 9,
SO2Ar), 7.93 (2H, d, J = 9, SO2Ar); m/z (EI) 359 (M+). Found:
C, 46.7; H, 3.1; N, 3.9%. C14H11Cl2NSO4 requires: C, 46.7;
H, 3.2; N, 3.9%.
employed UV spectroscopy, also monitoring decomposition of
substrate. Thus, an aliquot (30 mm3) of an acetonitrile solution
of the substrate (5 mM) was injected into a thermostatted
cuvette containing the buffer solution (substrate concentration
ca. 0.05 mM). The change in the UV spectrum was monitored
at an appropriate wavelength with respect to time and pseudo-
first-order rate constants, kobs, were obtained from plots of
ln (At Ϫ A∞) versus time.
4-Chlorophenyl N-methyl-N-(phenylsulfonyl)carbamate 1g.
Method B, 57%. Mp 77–79 ЊC; νmax/cmϪ1 1769 (C᎐O), 1368,
᎐
1163 (SO2); δH (CDCl3) 3.53 (3H, s, NMe), 6.89 (2H, d, J = 9,
CO2Ar), 7.31 (2H, d, J = 9, CO2Ar), 7.69 (5H, m, SO2Ar);
m/z (EI) 325 (M+); (FAB+) 326/328 (MH+). Found: C, 51.6; H,
3.7; N, 4.3%. C14H12ClNSO4 requires: C, 51.9; H, 3.8; N, 4.3%.
Product analysis
In all experiments the final HPLC chromatograms and/or
UV spectra were identical to those of a mixture of the corre-
sponding sulfonamide and phenol. Compound 1a was studied
on a larger scale (20 mg) and hydrolysed both in sodium
hydroxide and in piperidine buffer. In both cases, phenol and
the corresponding sulfonamide were isolated quantitatively.
4-Chlorophenyl N-methyl-N-(4-nitrophenylsulfonyl)carbamate
1h. Method B, 30%. Mp 118–121 ЊC; νmax/cmϪ1 1756 (C᎐O),
᎐
1367, 1184 (SO2); δH (CDCl3) 3.57 (3H, s, NMe), 6.96 (2H, d,
J = 9.2, CO2Ar), 7.32 (2H, d, J = 9.2, CO2Ar), 8.20 (2H, d,
J = 9.2, SO2Ar), 8.32 (2H, d, J = 9.2, NO2Ar); m/z (EI) 372/350
(M+). Found: C, 45.7; H, 3.1; N, 7.6%. C14H12ClN2SO6 requires:
C, 45.3; H, 3.0; N, 7.6%.
Results and discussion
4-Phenyl N-methyl-N-(4-nitrophenylsulfonyl)carbamate 1i.
The sulfonylcarbamates 1 hydrolyse to the corresponding
sulfonamide and phenol, implying that hydrolysis proceeds by
attack at the carbamate carbonyl, rather than at the sulfonyl,
group. In buffer solutions, we found no evidence for the forma-
tion of an intermediate that could be formed upon nucleophilic
attack of the buffer species at the carbamate. Pseudo-first-order
rate constants, kobs, for the hydrolysis of 1a were determined in
NaOH solutions (Table 1) and in aqueous buffers (imidazole,
phosphate, borate, hydrogen carbonate, n-butylamine, piper-
idine). These data gave rise to the pH–rate profile in Fig. 1,
which reveals spontaneous and hydroxide ion-catalysed path-
ways. As described below, in the HOϪ-catalysed region the
reactions are also buffer-catalysed. Thus, kobs is governed by
eqn. (1), in which kw is the pseudo-first-order rate constant for
Method A, 67%. Mp 143–145 ЊC; νmax/cmϪ1 1758 (C᎐O), 1334,
᎐
1182 (SO2); δH (CDCl3) 3.57 (3H, s, NMe), 6.99 (2H, d, J = 8.6,
CO2Ph), 7.26 (1H, m, CO2Ph), 7.36 (2H, d, J = 8.6, CO2Ph),
8.20 (2H, d, J = 8.8, SO2Ar), 8.38 (2H, d, J = 8.8, NO2Ar);
m/z (HRMS) 336.0417 (calc. 336.0416). Found: C, 50.1; H, 4.0;
N, 8.4; S, 9.2%. C14H12N2SO6 requires: C, 50.0; H, 3.6; N, 8.3;
9.5%.
4-Methoxyphenyl
amate 1j. Method A, 65%. Mp 119–120 ЊC; νmax/cmϪ1 1746
(C᎐O), 1377, 1179 (SO ); δ (CDCl3) 3.77 (3H, s, NMe), 6.84
N-methyl-N-(4-nitrophenylsulfonyl)carb-
᎐
2
H
(2H, d, J = 9.2, CO2Ar), 6.89 (2H, d, J = 9.2, CO2Ar), 8.20 (2H,
d, J = 8.8, SO2Ar), 8.37 (2H, d, J = 8.8, NO2Ar); m/z (HRMS)
366.0504 (calc. 366.0521). Found: C, 49.3; H, 4.3; N, 7.6; S,
8.8%. C15H14N2SO7 requires: C, 49.2; H, 3.85; N, 7.65; S, 8.75%.
kobs = kw + kHO[OH] + kB[B]
(1)
Kinetic studies
pH-independent hydrolysis and kHO and kB are, respectively,
the second-order rate constants for catalysis of hydrolysis by
HOϪ and by the buffer.
All studies in buffer solutions up to pH 10 were monitored
following the decomposition of substrate using an HPLC sys-
tem comprising a Merck RP8 column and an eluant of 50%
CH3CN in 0.01 M pH 7 KH2PO4. Studies at higher pH
Values of kHO for compounds 1a–j were determined from
plots of kobs versus [HOϪ] (Table 2). Hydrolysis of compound 1a
J. Chem. Soc., Perkin Trans. 2, 2001, 494–497
495

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Ϫ
Table 2 Second-order rate constants, kOH , for the hydroxide ion-
intermediate in the reaction of trimethylamine with phenyl
acetates,10 and ρ ӷ 2.0 for reaction of trimethylamine with 2,4-
dinitrophenyl quinolinecarboxylates where C–O bond breaking
of the leaving phenol is of critical importance in the transition
state.11 Nevertheless, correlation with σϪ is surprising. More
commonly, hydrolysis of aryl carbamates is characterised by
correlation of the aryl substituents with σ.2,9,12 Only when there
is substantial C–O bond cleavage, and therefore significant
increase in negative charge at the carbamate O atom, for
example in E1cb mechanisms,12,13 is there correlation with σϪ.
One explanation for this might be that the presence of the
strongly electron-withdrawing arylsulfonyl group on the nitro-
gen atom may increase the extent of electron delocalisation
from the carbamate oxygen atom in the ground state of the
substrate. On formation of the tetrahedral intermediate such
delocalisation is removed, which would result in greater change
in the electron density residing on the phenol oxygen for the N-
arylsulfonyl compounds as compared with simpler carbamates.
Whatever the reason, a similar observation has been made for
N-acylcarbamates.14
Clearly, it is not possible to say from the current data whether
the sulfonamide anion or the aryloxide anion acts as the leaving
group (Scheme 1, steps c or d). Both paths give rise to the
same products. Based on pKa values one might predict the aryl-
oxide to be the better leaving group; the pKas of the 4-MeO-,
4-Me-, 4-H- and 4-Cl-phenols are 10.2, 10.19, 9.95 and 9.38,
respectively,15 whereas those of the N-methyl 4-MeO-, 4-Me-,
4-H-, 4-Cl- and 4-NO2-benzenesulfonamides are 11.83,16
11.63,16 11.43,17 11.0816 and 10.31,16 respectively. However,
in the reaction of aryl carbonates with pyridine nucleophiles
the tetrahedral intermediate decomposes with the nitrogen-
containing leaving group being some 104 times a better leaving
group than an aryloxide of the same pKa 18 (see also below).
The substituent effect in the arenesulfonamide moiety
(compounds 1a, e–h) is illustrated in Fig. 2. Compounds 1a, e–g
show reasonable linear correlation to yield a ρ value of 0.8, the
correlation being with σ. This is unsurprising, as the nitrogen
catalysed hydrolysis of 1a–j at 25 ЊC
kOH /MϪ1 sϪ1
Ϫ
1a
1b
1c
1d
1e
1f
0.318, 0.329,a 0.197,b 0.312,c 0.498,d, 0.574,e 0.952f
0.178
0.102
0.135
0.208
0.574
0.422
0.640
0.483
0.873
1g
1h
1i
1j
a In D2O. b 17 ЊC. c 21 ЊC. d 31 ЊC. e 35 ЊC. f 40 ЊC.
was also studied in sodium deuteroxide solutions (Tables 1
and 2) enabling a solvent deuterium isotope effect of 0.97 for
the hydroxide ion-catalysed reaction to be determined. This is
consistent with hydroxide ion acting as a nucleophile rather
than a general base. Further, the temperature effect on kHO for
1a gives rise to values for ∆H‡ of 45 kJ molϪ1 and ∆S‡ of Ϫ104
J KϪ1 molϪ1. These values are characteristic of a mechanism
involving nucleophilic attack by HOϪ at the carbonyl carbon
(Scheme 1).7,8
Substituents in the aryl carbamate ring (compounds 1a–d)
give rise to a Hammett correlation for kHO that is somewhat
better using a σϪ value (ρ = 1.2, r2 = 0.98), rather than a σ value
(ρ = 0.83, r2 = 0.88), for the MeO substituent. The magnitude
of ρ is also consistent with rate-limiting nucleophilic attack of
the hydroxide ion at the carbamate carbonyl carbon atom
(Scheme 1, step a).8,9 Alternative processes, e.g. rate-limiting
breakdown of a tetrahedral intermediate with expulsion of an
aryloxide ion (Scheme 1, step d), or direct displacement of the
aryloxide ion, are generally characterised by much higher ρ
values. For example, ρ = 2.5 for rate-limiting breakdown of the
Scheme 1 Pathways for the hydroxide ion and general base-catalysed hydrolysis of aryl sulfonylcarbamates.
496
J. Chem. Soc., Perkin Trans. 2, 2001, 494–497

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tetramethylpiperidine reveals that kB for the piperidine reaction
is only a modest 6-fold greater than that for its sterically
hindered analogue . This points to a general base-catalysed
process (Scheme 1, path b); for general base-catalysed reactions
steric hindrance around the basic centre only slightly affects
reactivity, whereas for nucleophilic reactions the steric effect
is usually larger.19 For instance, 2-methylpyridine is over 103
times less reactive than pyridine in its nucleophilic reaction
with 2,4-dinitrophenyl acetate20 and acetic anhydride,21 and,
for the nucleophile-catalysed hydrolysis of N-nitro-N-methyl-
acetamide, piperidine was found to be ca. 300 times more
reactive than 2,2,6,6-tetramethylpiperidine.22 A further pointer
to a general base-catalysed process is the solvent deuterium
isotope effect of 1.4 on the piperidine-catalysed reaction
(Table 3). This is consistent with the involvement of O–H bond
breaking in the rate-limiting step. Further, the values of kB for
piperidine, n-butylamine and 2,2,2-trifluoroethanol can be used
to define a Brønsted line of slope 0.6 (r2 = 0.93), an observation
typical of general base catalysis.19
Fig. 2 Hammett plot for the hydrolysis of 1 showing the effect of the
substituent in the arylsulfonyl ring.
Table 3 Second-order rate constants, kB, for the buffer-catalysed
hydrolysis of 1a at 25 ЊC
Catalytic species
pKaЈ
kB/MϪ1 sϪ1
Thus, whereas secondary sulfonylcarbamates, i.e. those con-
taining the –SO2NH– functionality, react via an E1cb elimin-
ation pathway involving ionisation of the sulfonamide group,
the tertiary analogues, for which the E1cb pathway is blocked,
undergo hydrolysis either by nucleophilic attack of HOϪ or
by general base-catalysed attack of water at the carbamate
carbonyl. Not surprisingly, the E1cb pathway is the more
favoured, the secondary substrates being ca. 105–106 times more
reactive than the tertiary analogues reported here.
2,2,2-Trifluoroethanol
Piperidine
2,2,6,6-Tetramethylpiperidine
n-Butylamine
12.27
11.36
11.23
10.80
0.60
0.258, 0.180a
0.040
0.065
a In D2O.
lone pair does not directly interact with the substituent in
the arylsulfonyl ring. However, the sign of ρ indicates that the
electron density in the arylsulfonyl moiety increases as the
transition state is approached, in contrast with secondary N-
arylsulfonylcarbamates, which hydrolyse by an E1cb mechanism
giving rise to a ρ value for the arylsulfonyl moiety that is nega-
tive (Ϫ0.66).5 Again, our data are consistent with a transition
from the substrate, in which the nitrogen lone pair is delocalised
into a planar carbamate group, to a tetrahedral intermediate, in
which delocalisation of the nitrogen lone pair into an adjacent
carbonyl is not possible but in which stabilisation is afforded by
the arylsulfonyl group. The mechanism shown in Scheme 1 is
consistent with these data. However, the 4-nitrophenylsulfonyl
compound 1h appears much less reactive than expected. We
interpret this as indicating a change in rate-limiting step with
decomposition of the tetrahedral intermediate being rate-
limiting for compound 1h (Scheme 1, steps c or d). Moreover,
we suspect that for the 4-nitrophenylsulfonyl compounds 1h–j
it is the sulfonamide, rather than the phenoxide, anion that
functions as the leaving group during decomposition of the
intermediate (Scheme 1, path c). Thus, kHO values for these
compounds reveal little substituent effect in the aryl carbamate
ring (indeed, 1j bearing a 4-MeO substituent is slightly more
reactive than 1h bearing 4-Cl). If the phenoxide anion were
functioning as the leaving group, as discussed above, one
would expect a significant substituent effect with the electron-
withdrawing substituents enhancing reactivity. However, for a
sulfonamide anion leaving group one would anticipate either
a negligible substituent effect in the aryl carbamate group
(as the negatively charged oxygen atom in the intermediate
should provide the major electron ‘push’ for the departing
leaving group) or one that slightly favours electron-releasing
substituents as found here.
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Buffer catalysis was examined for 1a using piperidine, 2,2,6,6-
tetramethylpiperidine, butylamine and 2,2,2-trifluoroethanol.
Second-order rate coefficients, kB, for buffer catalysis were
determined from the slopes of plots of kobs versus the concen-
tration of the basic form of the buffer, and these are contained
in Table 3. Comparison of the data for piperidine and 2,2,6,6-
J. Chem. Soc., Perkin Trans. 2, 2001, 494–497
497