Kinetic and mechanistic studies of the hydrolysis of sulfamate esters: a non-elimination decomposition route

Article abstract of DOI:10.1016/j.tetlet.2007.11.208

The kinetics of hydrolysis at pH 2 and ionic strength (μ) = 1 of a series of sulfamate esters p-XC₆H₄OSO₂NH₂ have been examined using structure- and solvent-reactivity studies, thermodynamic data, a 'nucleophilicity test' and a kinetic solvent isotope effect to probe the mechanism of the hydrolysis. These esters can be regarded as models for the more complex medicinally and biologically important esters now under extensive study. The mechanism of hydrolysis involves the neutral ester undergoing nucleophilic attack by water in a bimolecular TS.

Full text of DOI:10.1016/j.tetlet.2007.11.208

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1049–1052
Kinetic and mechanistic studies of the hydrolysis of sulfamate esters:
a non-elimination decomposition route
*
William J. Spillane , Cheryl J. A. McCaw, Neil P. Maguire
Chemistry Department, National University of Ireland, Galway, Ireland
Received 23 October 2007; revised 19 November 2007; accepted 30 November 2007
Available online 5 December 2007
Abstract
The kinetics of hydrolysis at pH 2 and ionic strength (l) = 1 of a series of sulfamate esters p-XC H OSO NH have been examined
6
4
2
2
using structure- and solvent-reactivity studies, thermodynamic data, a ‘nucleophilicity test’ and a kinetic solvent isotope effect to probe
the mechanism of the hydrolysis. These esters can be regarded as models for the more complex medicinally and biologically important
esters now under extensive study. The mechanism of hydrolysis involves the neutral ester undergoing nucleophilic attack by water in a
bimolecular TS.
Ó 2007 Elsevier Ltd. All rights reserved.
In the late eighties only a small number of sulfamate
O
esters ROSO NH were known to display biological and
O
2
2
H N
S
O
2
1
potential medicinal properties, such as anticonvulsant,
anti-Parkinson, anti-bacterial and anti-viral activities.
O
2
3
4
5
Now almost twenty years on there has been a renaissance
in interest in this area driven mainly by the discovery of
new and more potent sulfamate esters that are or promise
to be highly efficacious in the treatment of a variety of con-
3
covering various aspects of the development of biologically
important sulfamate esters have appeared.
The aminolysis of various sulfamate esters in non-aque-
ous solvents has been the subject of study over some
years but apart from the seminal work of Williams and
10
6
ditions. For example, Topiramate, 1, which is in clinical
use, as an anti-epileptic drug and shows promise as an
7
anti-obesity drug, 667 Coumate 2, which has completed
11
phase 1 of clinical trials for treating hormone-dependent
12
Thea and their collaborators over twenty years ago there
8
breast cancer and Emate, 3, which has been found to be
has been a dearth of mechanistic studies in aqueous media
on sulfamate esters. These workers explored the mecha-
nisms mainly at intermediate and higher pHs and in a
recent paper it has been pointed out that ‘the major hydro-
9
an excellent inhibitor. Several recent authoritative reviews
O
S
NH2
13
O
O
O
lytic pathway at low pH has yet to be studied in detail’.
O
O
O
The indications are that in sharp contrast to the elimina-
tion mechanisms taking place at higher pHs and in non-
aqueous media bimolecular water attack at the neutral
sulfamate sulfur is occurring. In the present work we have
examined the mechanism taking place at lower pH partic-
ularly at pH ꢀ 2 and our findings and conclusions are
reported herein. A study of the decomposition mechanism
in this area of pH seems especially appropriate since those
O
S
H N
O
O
2
O
O
O
1
2
*
Corresponding author. Tel.: +353 91 492475; fax: +353 91 525700.
E-mail address: william.spillane@nuigalway.ie (W. J. Spillane).
0
040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.208

1050
W. J. Spillane et al. / Tetrahedron Letters 49 (2008) 1049–1052
6
8,14
sulfamate esters in use and in clinical trials
have been
3
2
1
orally administered so they would very quickly be sub-
jected to stomach environment where the pH is approxi-
mately 1–3.
0
-2 -1 -1 0
1
2
3
4
5
6
7
8
9
10 11 12 13 14
-
-
-
-
-
-
-
2
3
4
5
6
7
8
X
OSO NH
2 2
a: NO , b: Br, c: Cl, d: F, e: H, f: CH
2
3
H /pH
0
4
To probe the mechanism of the reaction of sulfamates at
0
Fig. 1. H /pH–Rate profiles for the hydrolysis of 4a in water (d) at 50 °C
and in 50% water–50% ACN (j) at 25 °C.
low pHs a series of esters of type 4 were prepared by stan-
1
3,15,16
dard methods.
Kinetics were followed by the appear-
ance of p-nitrophenol or other liberated phenols. Product
studies showed that sulfamate 4a was cleaved on hydrolysis
at pH 3 according to the pathway shown in Scheme 1. A
Thermodynamic data for the hydrolysis of compounds 4
under similar conditions are given in Table 1. The enthalpy
data display little variation as the substituent is varied but
the entropies change from being reasonably negative to
being slightly positive. Similar negative entropies have been
ꢂ4
spiked pH 3 solution containing 1 ꢁ 10 M of p-nitrophe-
nol and of sulfamic acid when compared (k
= 316 nm
max
for p-nitrophenol) with a rate solution after ten half-lives
at 50 °C gave an absorbance, which was within 91% of that
shown by the rate solution. The sulfamic acid produced in
interpreted as pointing towards a bimolecular S 2 mecha-
N
nism in related systems. Thus, for the hydrolysis of the
ꢂ1 ꢂ1
named compounds the following entropies (J mol
K )
ꢂ4
the reaction of 4a (conc. of 4.583 ꢁ 10 M) was deter-
have been measured: N,N-dimethylsulfamoyl chloride,
1
8
19
mined gravimetrically as barium sulfate and the amount
obtained corresponded to 98% of the expected sulfate.
Hydrolysis of sulfamic acid will not occur under the condi-
tions of the current rate study. In fact, at 50 °C and even at
ꢂ14.5, potassium p-nitrophenylsulfate, ꢂ18.5, sodium
2
0
thiosulfate, ꢂ16 and p-nitrophenyl N-methylsulfamate,
1
2b
ꢂ14.7.
The effect of solvent on reactivity was explored through
1
7
pH 1 the t1 of sulfamic acid is about 18 days. Thus these
/2
a series of Grunwald–Winstein plots using compound 4a in
results clearly confirm that the main flux of the reaction
proceeds as shown in Scheme 1.
a range of water/ACN from 100% to 25% H O and water/
2
acetone from 100% to 20% H O (v/v) mixtures in which the
2
H /pH–Rate profiles (Fig. 1) for the hydrolysis of 4a
0
pH was maintained at 2–2.7. Plots of logk versus YOTs val-
in water at 50 °C using 3M HCl over the pH range from
ues showed downward curvature with slopes (m ) ꢀ 0.1
s
0
to 10 and in 50% water–50% ACN at 25 °C from pH
2 to ꢀ13 were determined. The shapes of these were sim-
indicating that the ionizing power of the solvent plays a
minimal role. In a very recent work on the closely related
ꢀ
ilar to that previously determined from pH 2 to 12 for 4a in
acylsulfamates, ArOSO NHCOR a similar low value of
2
1
2a
water at 25 °C. The rate constants cannot be compared
directly because of differing temperature/medium. The
absence of acid catalysis in the pH range 0–5 is evident
and this is the region of most interest in the context of
the current work. Structure-reactivity, solvent-reactivity,
a test for nucleophilicity, thermodynamic data and deute-
rium kinetic solvent isotope effects (KSIE) were examined
in this pH region to discern the mechanism taking place.
A Hammett plot (Fig. 2) for the hydrolysis of com-
pounds 4 gave a q of 1.4 (r = 0.982) and a Bronsted plot
m for hydrolysis in water/ethanol was observed. This
s
was interpreted as indicating that a water molecule plays
an important role as a nucleophile in the TS, which in turn
2
1
was substantiated by other evidence.
To further examine the likely major role of solvent as a
nucleophile in the hydrolysis of 4a we have used a ‘nucleo-
2
2–24
philicity test’ pioneered by Bentley
in which two
(
Fig. 3) gave a b of ꢂ0.41 (r = 0.989). Rate measurements
0
lg
were carried out at pH 2 and at constant ionic strength
l = 1.0 M (with KCl). These q and b values indicate that
a moderate amount of negative charge builds up on the
phenolic oxygen in the TS of the reaction.
-
-
-
-
-
-
1
2
3
4
5
lg
6
-
pH 3
0.2
0
0.2
0.4
0.6
0.8
1
p-NO C H OSO NH
p-NO C H OH
+
HOSO NH
2 2
2
6
4
2
2
2
6
4
σ
H O, 50 ºC
2
4
a
Fig. 2. Hammett plot for the hydrolysis of compounds 4 in water at pH 2,
l = 1.0 M at 50 °C.
Scheme 1.

W. J. Spillane et al. / Tetrahedron Letters 49 (2008) 1049–1052
1051
0
1
2
3
4
5
6
-
-
-
-
-
-
H O
O
O
δ+
2
-
δ
XC H OSO NH
XC H4 O:
S
:OH2
6
4
2
2
6
NH2
7
7.5
8
8.5
9
9.5
10
10.5
XC H OH
+
HOSO NH
2 2
6
4
pKa
Scheme 2.
Fig. 3. Bronsted plot for the hydrolysis of compounds 4 in water at pH 2,
l = 1.0 M at 50 °C.
of bis(p-nitrophenyl) carbonate at pHs from 1 to 3 have
2
8
been reported. These values have all been interpreted in
favour of water involvement in the TS. However, values
of 0.96 in the hydrolysis (l = 1) of the bis-sulfamate,
Table 1
a,b
Activation parameters for hydrolysis of sulfamates 4a–4f
2
9
H NSO OCH –(CH ) –CH OSO NH
2
and of 1.26 for
±
±
±
±
2
2
2
2 5
2
2
p-X
DH
kJ mol
DS
(J mol
p-X DH
(kJ mol
DS
(J mol
19
ꢂ1
ꢂ1 ꢂ1
ꢂ1
ꢂ1 ꢂ1
K )
the neutral hydrolysis of potassium p-nitrophenylsulfate,
have been interpreted as evidence for unimolecular mecha-
nisms with very little bond formation in the TS.
(
)
K
)
)
c
NO
Br
Cl
a
2
95 ± 6
101 ± 6
104 ± 6
ꢂ22 ± 2
ꢂ19 ± 2
ꢂ8 ± 1
F
H
109 ± 6
109 ± 6
112 ± 6
1 ± 1
2 ± 0.7
7 ± 1
The reactive form of the ester at pH 2 will be the neutral
CH
3
molecule since the calculated pK for the ionization
a
pH 2 and ionic strength (l = 1.0 M).
Eyring plots (correlation coefficients >0.99) using four or five points at
b
þ
þ
p-NO C H OSO NH ꢀ H þ p-NO C H OSO NH
2
6
4
2
3
2
6
4
2
2
temperatures between 40 °C and 70 °C. The errors shown are standard
deviations.
c
A temperature range between 30 °C and 70 °C was used.
is ꢀꢂ9.36.
Finally, S–O cleavage in the TS is more likely than C–O
cleavage because (i) with p-nitrophenyl N-methylsulfamate
1
2b
S–O cleavage has been shown to take place
and (ii)
solvent mixtures with identical YOTs values but very differ-
ent N (nucleophilicity) values are used: if the reaction is
significantly slowed down in the solvent of lower
nucleophilicity, this suggests that the solvent is playing an
important role as a nucleophile. The ratio of the rates of
examination of a large number of papers dealing with
S–O versus C–O fission in aryl sulfonate and -sulfate esters
indicates that in most cases S–O breakage occurs. Interest-
ingly, for the aliphatic bis-sulfamate mentioned above
2
9
exclusive C–O fission is found.
hydrolysis of 4a at 50 °C in 45.8% ethanol/H O (v/v)
2
In conclusion, this work has shown that these sulfamate
esters hydrolyze to give a phenol and sulfamic acid as
exclusive reaction products (Scheme 1). The linear free
energy plots suggest that a moderate amount of negative
charge should be formed at the phenolic oxygen in the
TS so extensive bond-breaking of the S–OAr bond does
not occur at that stage. The entropies, the Grunwald–Win-
(
(
Y
= 1.83, N = ꢂ2.79) and 97% trifluoroethanol/H O
OTs
2
v/v) (Y
= 1.83, N = 0.28) is 48.2. The rate ratios
OTs
reported with different systems vary considerably but a
value of 48 is certainly significant and may be compared
with values of 78 for the solvolysis of 2,4,6-trimethyl-
2
2
benzenesulfonyl chloride, of 13.2 for the solvolysis of
2
3
benzoyl chloride, and of ꢀ300, which may be calculated
stein m values, the effect of reducing nucleophilicity and
s
for the solvolysis of N,N-dimethylsulfamoyl chloride in
1
8,25
the KSIE in general support the binding of a water mole-
cule in the TS. Thus, in summary, it is felt that a mecha-
nism of the type shown in Scheme 2 where a nucleophilic
water molecule attacks at sulfur leading to concomitant
S–OAr cleavage is well supported by the experimental
evidence in this Letter.
an array of aqueous binary mixtures.
Ratios even <1
2
4
have been noted with some aromatic systems such as
diphenylmethyl chloride and p-methoxybenzyl chloride.
A kinetic solvent isotope effect (KSIE) has been mea-
sured for the reaction of 4a using data (average of three
runs) in water and deuterium oxide with an ionic strength
4
(
6
k
l) = 1 (KCl), pH (pD) 2 (HCl/DCl) at 60 °C: 10 k
¼
H2O
4
:164 ꢃ 0:091 and 10 k
¼ 2:368 ꢃ 0:06 giving k
/
Acknowledgements
D2O
H2O
D O = 2.6. The interpretation of KSIEs is difficult but
2
broadly speaking values in the range of 1–3 support an
The authors acknowledge support from the NUI, Gal-
way Millennium, and Corrib Funds and the Institute of
Chemistry of Ireland. N.P.M. thanks Donegal County
Co. for a Grant. We thank Professors S. Thea, University
of Genoa, Italy, and T. W. Bentley, University of Wales,
Swansea, UK, for helpful discussions.
S 2 bimolecular reaction and values in the range of 1–1.4
N
2
6
may indicate an S 1 unimolecular mechanism. Bruice
N
reported a value of ꢀ2.8 for the pH-independent (2.5–
27
7
.6) hydrolysis of ethyl trifluorothioacetate at 30 °C
(
l = 1) and values from 2.88 to 2.20 for the hydrolysis

1052
W. J. Spillane et al. / Tetrahedron Letters 49 (2008) 1049–1052
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