Mechanism of the acid-catalyzed hydrolysis of N-acylsulfamates

Article abstract of DOI:10.1016/j.tetlet.2007.08.107

The kinetics of hydrolysis of a series of N-acylsulfamate esters p-XC₆H₄OSO₂NHCOR as models for more complex, biologically important compounds has been examined. Structure-reactivity, solvent-reactivity, thermodynamic data, etc. support a bimolecular mechanism involving water in the transition state (TS).

Full text of DOI:10.1016/j.tetlet.2007.08.107

Tetrahedron Letters 48 (2007) 7574–7577
Mechanism of the acid-catalyzed hydrolysis of N-acylsulfamates
William J. Spillane* and Jean-Baptiste Malaubier
Chemistry Department, National University of Ireland, Galway, Ireland
Received 28 July 2007; revised 16 August 2007; accepted 30 August 2007
Available online 4 September 2007
Abstract—The kinetics of hydrolysis of a series of N-acylsulfamate esters p-XC6H4OSO2NHCOR as models for more complex,
biologically important compounds has been examined. Structure-reactivity, solvent-reactivity, thermodynamic data, etc. support
a bimolecular mechanism involving water in the transition state (TS).
Ó 2007 Elsevier Ltd. All rights reserved.
There has been an upsurge of interest in sulfamate
esters, R1OSO2NR2R3, and sulfamides, R1R2NSO2-
NR3R4, both cyclic and open chain, in the last decade
or so and this is mainly, though not entirely, because
of their many potential and proven uses in medicinal
and biological chemistry.1–3 So extensive is the interest
in the sulfamate group in particular that it has become
something of an ubiquitous group in chemistry.
(Fig. 1), which reached phase III of clinical trials, the
sulfamate esters 2a–e, which are competitive inhibitors
of the pantothenate synthetase-catalysed condensation
of D-pantoate and b-alanine to form pantothenate,6
several methionyl- and isoleucylsulfamates, which inhibit
methionyl-tRNA and isoleucyl-tRNA synthetases,7
a
b-aspartyl-AMP sulfamate,8 which inhibits human
asparagine synthetase and a sulfamate analogue of
luciferyl-AMP, which inhibits firefly luciferase.9
Recently, a phosmidosine analogue, in which the proline
and 8-oxoadenosine moieties are linked by an acylsulf-
amate bridge, has been prepared.10 Some years ago a
number of acyl derivatives of EMATE, the steroidal
sulfatase inhibitor, were prepared but were generally
found to be less potent than the parent compound.11
Certain biomolecules possessing closely related moieties,
such as the N-(oxycarbonyl)sulfamate esters, –OSO2-
NHCOO– and the N-(carbonyl)sulfamate esters,
–OSO2NHCO–, have also been shown to be very impor-
tant in biological chemistry and a very thorough mech-
anistic study of a series of the former type of esters was
made some years ago.4 The latter class, which are
broadly N-acylsulfamates, include the important lipid-
regulating and anti-atherosclerotic agent Avasimibe 1.5
Despite its obvious importance, the chemistry of the
acylsulfamate group has not been explored and in the
NH2
N
N
N
O
OSO2NHCOR
OSO2NHCO
N
HO
OH
1
2
a: R = t-BuCO-
b: R = MeO(CH2)2CHOH-
c: R = MeOCH2C(CH3)2CHOH-
d: R =
e: R =
t
t
-BuCHOH-
-BuCH(NH3+)-
Figure 1. Examples of biologically important N-acylsulfamates.
*
Corresponding author. Tel.: +353 91 492475; fax: +353 91 525700; e-mail: william.spillane@nuigalway.ie
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.107

W. J. Spillane, J.-B. Malaubier / Tetrahedron Letters 48 (2007) 7574–7577
7575
current work we have studied, particularly in acidic
media, the hydrolysis of a series of aryl-substituted
N-acylsulfamates, XC6H4OSO2NHCOR, (R = Pr) 3.
temperatures.16–18 At 70 °C, the temperature at which
most rate studies were carried out in this work, in 1 M
acid a half-life of 34.7 h was determined for the
hydrolysis of sulfamic acid.17 The half-lives of com-
pounds 3 to give sulfamic acid, phenol and n-butyric
acid (Scheme 1) vary from 0.65 to 1.6 h so hydrolysis
of the sulfamic acid is very slow and is not an issue in
the time scale of the kinetic runs.
We prepared a series of N-acyl- and N-sulfonylated sul-
famates of types R1OSO2N(ArCH2)COR2 and R1OSO2-
N(ArCH2)SO2R2, respectively, by benzoylation/
sulfonylation of the monoesters12 but since these
compounds lacked a hydrogen on the nitrogen, they
were rather unreactive. More recently, because of the
potential of sulfamate esters as sweeteners,13 we have
prepared several series of mainly new acylsulfamates
of the general type p-XC6H4OSO2NHCOR, including
the seven compounds where R = Pr and X is a: Cl, b:
Br, c: I, d: F, e: H, f: CH3, g: CF3 using general
methods.14,15
Partial Ho/pH-rate profiles for compounds 3 have been
determined (Fig. 2). These rate profiles show that acid-
catalysis ceases at approximately pH 0.5, at which point
the substrate should be substantially protonated.
Apparent pKas for the equilibrium in Scheme 2 for
3a–f can be obtained from the pH-rate profiles19 and
values between 0.5 (3a) and 0.8 (3f) were calculated. A
value could not be obtained for 3g since it did not show
the curvature that characterises the other plots.
Since several modes of cleavage could be envisaged for
the acid-catalysed hydrolysis of acylsulfamates 3, a
product study was carried out using the p-Cl compound
3a and this was found to hydrolyse according to the
pathway shown in Scheme 1 giving rise to products 5a,
6 and 7. Compound 8 does not form under the kinetic
conditions used, but would form under more forcing
conditions.
When the pKa values were plotted against Hammett d
values, a q value of À0.61 (r = 0.981) was obtained. This
q is much lower than that for the protonation of aryl-
sulfonamides, ArSO2NR2 (R = H, Me), which gave a
value of ꢀÀ2 for two limited series.20 This is due to
the extra oxygen atom between the aryl-substituents
and the protonation site in compounds 3 compared to
the arylsulfonamides. Since the effects are principally
inductive, the insertion of an extra atom or group can
cause a dramatic falling off in q, for example, the pro-
tonation of substituted anilines has a q of about À2.7,
while that of a series of ring-substituted benzylamines
is about À0.7.21
The rates of production of p-chlorophenol 5a (UV mea-
surements) and of n-butyric acid 7 (GC measurements)
were almost identical. Thus there is concomitant break-
age of the S–O and the C–N bonds in 3a. In aqueous
acid sulfamic acid 6 decomposes much more slowly,
but it eventually produces the quantity of sulfate 8
expected from a known amount of 3a. A number of
groups have studied the acid-catalysed hydrolysis of
sulfamic acid in various acids and over a range of
Structure-reactivity effects were examined by studying
the effect of varying the substituents (X) in compounds
3 in 1 M HCl at 70 °C on the rates of reaction. Hammett
(Fig. 3) and Bro¨nsted (Fig. 4) plots, respectively,
H
2O, H+
+
+
p
-ClC6H4OSO2NHCO-Pr
p
-ClC6H4OH
HOSO2NH2
PrCO2
H
70 ºC
3a
5a
6
7
H2O, H+
very slow
Ka
O
S
O
S
+
NH2
ArO
ArO
NH
O
O
(NH4)2SO4
O
O
3
4
8
Scheme 2.
Scheme 1. Hydrolysis pathway.
-3.4
Cl
F
Br
I
Me
H
-3.9
-4.4
-4.9
-5.4
-1
0
1
2
3
H0
pH
Figure 2. Partial H0/pH rate profiles of 3a to 3f.

7576
W. J. Spillane, J.-B. Malaubier / Tetrahedron Letters 48 (2007) 7574–7577
-3.3
-4.0
-4.1
-3.4
-3.5
-3.6
-3.7
-3.8
-3.9
-4
CF3
Br
-4.2
-4.3
-4.4
-4.5
-4.6
I
Cl
90%
water
10%
water
H
F
CH3
-1
0
1
2
3
4
-0.2
-0.1
0
0.1
0.2
(Ar-OH)
0.3
0.4
0.5
0.6
YOTS
σ
Figure 5. Grunwald–Winstein plot of the hydrolysis of 3a.
Figure 3. Hammett plot of the leaving group in the hydrolysis of 3a–g.
from stronger binding of water in its TS compared to the
other compounds.
illustrate these effects. A Hammett q of 0.81 (r = 0.986)
and a blg of À0.27 (r = 0.971) were obtained for seven
compounds.
The accumulated evidence from the above studies indi-
cates that at low pH 0–1 the mechanism involves attack
of a water molecule at the protonated substrate 4, which
will be substantially present at these pHs. The blg value
of À0.27 supports a small degree of cleavage of the
Solvent-reactivity effects were looked at by changing the
water–ethanol ratio of the medium from 10% to 90% in
0.1 M HCl at 65 °C, and the rates for the hydrolysis of
3a were plotted against Grunwald–Winstein YOTS
values22 giving the plot shown in Figure 5. This gives
a slope, m, of 0.09 (r = 0.973) which is very low and
points to the minimal effect of the ionizing power of
the solvent, suggesting instead that a water molecule
plays an important role as a nucleophile in the TS.
H
H
O
.
.
.
.
.
.
.
δ−
H2O, H+
70 ˚C
+
.......
ArOSO2NHCO-Pr
ArO
SO2NH2-CO-Pr
δ+
H2O, H+
The substantially negative entropies for the hydrolysis
measured at various temperatures are given in Table 1
for 3a–g compounds and they also suggest that the TS
includes a water molecule. The larger value for the
strongly electron-withdrawing CF3 compound may arise
ArOH + HOSO2NH2 + HO2C-Pr
Scheme 3. Proposed reaction mechanism.
-3.3
-3.4
CF3
-3.5
Br
Cl
-3.6
-3.7
-3.8
-3.9
-4
I
H
F
CH3
8
8.5
9
9.5
10
10.5
pKa (Ar-OH)
Figure 4. Bro¨nsted plot (blg) of the hydrolysis of 3a–g.
Table 1. Activation parameters for the acid-catalysed (1 M HCl) hydrolysis of p-X-phenyl-N-(n-propylcarbonyl)sulfamates (3a to 3g)a
p-X
DH kJ molÀ1
DS J molÀ1 KÀ1
p-X
DH kJ molÀ1
DS J molÀ1 KÀ1
CF3
Br
I
88.7
100.4
99.4
5
6
5
5
À53.5
À22.5
À26.3
À28.3
3
1
2
2
F
H
CH3
100.4
101.4
104.0
6
5
6
À14.5
À23.3
À20.0
1
2
1
Cl
98.6
a Eyring plots (correlation coefficients >0.99) using seven points at temperatures between 40 °C and 70 °C. The errors shown are standard deviations.

W. J. Spillane, J.-B. Malaubier / Tetrahedron Letters 48 (2007) 7574–7577
7577
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Acknowledgements
The authors acknowledge support from the NUI, Gal-
way Millennium, Alumni and Corrib Funds and the
Institute of Chemistry of Ireland. We thank Professor.
T. W. Bentley, University of Wales, Swansea, UK, for
helpful suggestions.
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