Nitroso group transfer from N-nitrososulfonamides to thiolate ions. Intrinsic reactivity

Article abstract of DOI:10.1016/j.tet.2006.06.060

The nitroso group transfer from N-nitrososulfonamides to thiolate ions was studied. Based on the results, the reaction rate is strongly dependent on the nature of the leaving group (α_lg ≈ - 1.30), but virtually independent of the basicity of th

Full text of DOI:10.1016/j.tet.2006.06.060

Tetrahedron 62 (2006) 8822–8829
Nitroso group transfer from N-nitrososulfonamides to thiolate
ions. Intrinsic reactivity
a,y
b,
C. Adam, L. Garcıa-Rıo, J. R. Leis and J. A. Moreira
b
c
*
´
´
a
ꢀ
Departamento de Quımica, Area de Quımica Organica, F.I.Q., UNL, Santiago del Estero 2829, 3000 Sante Fe, Argentina
´
Departamento de Quımica Fısica, Facultad de Quımica, Universidad de Santiago, 15782 Santiago, Spain
´
ꢀ
b
´
CIQC, Departamento de Quımica e Bioquımica, Faculdade de Ciencias e Tecnologıa, Universidade do Algarve,
´
´
c
´
´
Campus de Gambelas, 8005-139 Faro, Portugal
^
´
Received 17 April 2006; revised 2 June 2006; accepted 15 June 2006
Available online 24 July 2006
Abstract—The nitroso group transfer from N-nitrososulfonamides to thiolate ions was studied. Based on the results, the reaction rate is
strongly dependent on the nature of the leaving group algz ꢀ1:30 , but virtually independent of the basicity of the thiol ðbnucz0:10Þ.
À
Á
This dependence is ascribed to the presence of a nucleophile desolvation equilibrium ðbdÞ that is followed by the attack of the thiolate ion
À
Á
on the nitroso group b0nuc via a concerted mechanism. The equilibrium constants for the loss of a nitroso group from a nitrosothiol and
an N-nitrososulfonamide were used to obtain the equilibrium constants for the different reactions involved. By using rate–equilibrium
0norm
correlations, the parameters anlgorm, bd, and b
Ó 2006 Elsevier Ltd. All rights reserved.
were obtained.
nuc
1. Introduction
acceptor. One well-known example is the nitroso group
transfer from N-methyl-N-nitroso-p-toluenesulfonamide to
cysteine.11
The physiological properties of NO,1,2 particularly those of
vasodilation3 and of the inhibition of platelet aggregation,4
can explain the enormous interest aroused by the chemistry
of S-nitrosothiols (RSNO) in the last few years. They have
also been identified as bodily fluids, notably as S-nitrosoglu-
tathione5 and S-nitrosoalbumins.6 Indeed, the current belief7
is that NO is transported around the body as RSNO (mostly
as the nitrosoalbumins), from which NO can be released
under certain conditions.
Recently, our group12 calculated the equilibrium constants
for the loss of an NO+ group from a protonated N-nitros-
R2NH NO
+
amine ðpK
Þ and an N-methyl-N-nitrosobenzenesul-
NO
+
NO
Þ. The relation DpKNO ¼ pKNRONH
ꢀ
XꢀNO
allows one to calculate the equilibrium constant
2
fonamide ðpK
NO
XꢀNO
pK
NO
for the transfer of a nitroso group from an N-nitrososulfon-
amide to an amine. In fact, this allowed us to derive a single
rate–equilibrium correlation spanning a range of 10 pKNO
units and including both thermodynamically favorable and
unfavorable reactions. In the light of the Marcus theory,
the calculated intrinsic barriers for nitroso group transfer
reactions reveal that the presence of electron-withdrawing
groups on the aromatic ring of N-methyl-N-nitrosobenzene-
sulfonamide does not alter such barriers.
S-Nitrosothiols are very readily generated in solution by
conventional nitrosation of thiols, and examples have been
known for about a 100 years.8 Nitrosation of thiols has been
examined mechanistically and follows the pattern of amine
nitrosation, in which both acid- and halide ion-catalysis
occur.9 In contrast with the corresponding nitrosation of
alcohols by sodium nitrite in mildly acidic solution, the equi-
librium position corresponding to thiol nitrosation lies
well over the right, with equilibrium constant10 of 105–
106 Mꢀ1. S-Nitrosothiols can also be obtained in a neutral
or alkaline medium via transnitrosation, the nitroso group
being transferred from an NO group donor to a suitable
The purpose of this work was to expand a previous treatment
of the nitroso group transfer from an N–N]O donor to an
acceptor sulfur atom. To this end, we studied the nitroso
group transfer from N-nitrososulfonamides to thiols
(Scheme 1). The N-nitrososulfonamides used borne substi-
tuents of variable electron-releasing ability on their aromatic
rings. The thiols used [viz. methyl thioglycolate (MTG),
methylmercaptopropionate (MMP), mercaptoethanol (ME),
and ethanothiol (EtSH)] were chosen on the grounds of their
basicity.
Keywords: Kinetics; Mechanism; Nitrosation; Thiol; Sulfonamide.
* Corresponding author. Tel.: +34 981 563100; fax: +34 981 595012;
e-mail: qflgr3cn@usc.es
y
Researcher from CONICET.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.060

C. Adam et al. / Tetrahedron 62 (2006) 8822–8829
8823
high (105–106 Mꢀ1) and difficult to quantify owing the insta-
bility of the products. In this work, we used an alternative
approach based on the nitrosation of 1,3-dimethyl urea in
an acid medium containing variable concentrations of the
thiol (see Scheme 2).
O
S
O
O
S
O
Me
k2
Me
-
+
RS-N=O
-
+
RS
X
N
X
N
O
N
4-MeO
4-Me
4-Cl
4-NO2
KNO
NO+
+
H2O
HNO2
+
H+
Scheme 1.
O
C
O
C
kDMU
H+
2. Results
+
NO+
+
MeHN
NMe
MeHN
NHMe
+
N
O
Previous studies revealed that the formation of nitrosothiols
by nitroso group transfer occurs via the basic form of the
thiol.11 Figure 1 illustrates the good linear relationship
between the observed rate constant and the thiolate concen-
tration (reaction showed in Scheme 1) in the nitrosation of
mercaptoethanol:
RSH
k-1
k1
RS-N=O
Scheme 2.
+
H+
Â
Ã
kobs ¼ k2 RSꢀ
ð1Þ
Kinetic experiments were performed at a constant sodium
nitrite concentration (1.00ꢁ10ꢀ4 M), [DMU]¼5.00ꢁ
10ꢀ3 M, [HClO4]¼0.50 M and an ionic strength (NaClO4)
of 1.00 M. As can be seen in Figure 2, the observed rate
constant increased with increasing thiol concentration. The
linear increase in kobs was the result of two simultaneous,
competitive processes, namely, the nitrosation of DMU13
and that of the thiol.14 Based on the nitrosation mechanisms
for DMU and thiols in an acid medium, the observed rate
constant can be expressed as
The slopes of the plots of Figure 1 were used to calculate the
bimolecular rate constants shown in Table 1. From such rate
constants and the pKa values for the corresponding thiols and
sulfonamides, we calculated parameters bnuc and alg, which
are also shown in Table 1. As can be seen, the bimolecular
rate constants increased very slightly with increase in nucle-
ophile basicity ðbnuc < 0:1Þ; on the other hand, the nature of
the leaving group was much more influential than the corre-
ꢀ
ꢀ
ꢀ
ꢀ
À
Á
sponding deprotonation equilibria alg > 1 . Accurately
interpreting these values in quantitative terms requires their
normalization with respect to the corresponding equilibrium
process.
Â
Ã
Â
Ã
Â
Ã
+
+
+
kobs ¼ kDMUKNO
H
½DMUꢂ+k1KNO½RSHꢂ H +k
H
ꢀ1
ð2Þ
where kDMU is the bimolecular rate constant for the nitrosa-
As noted earlier, the equilibrium constants for the formation
of nitrosothiols from the parent thiols and NO+ were very
tion of dimethyl urea, and k1 and k are the formation and
ꢀ1
0,6
0,4
0,2
0
60
40
20
0
20
15
10
5
0
0,02
0,04
0,06
0
0
0.2
0.
4
0.6
[RSH] / M
[RS-] / M
Figure 2. Influence of the mercaptoethanol concentration on kobs and on the
variation of the absorbance at 250 nm during the nitrosation of DMU.
[DMU]¼5.00ꢁ10ꢀ3 M; [HClO4]¼0.50 M; [NaNO2]¼1.00ꢁ10ꢀ4 M; ionic
strength¼1.00 M (NaClO4). T¼25.0 ꢃC.
Figure 1. Influence of the thiolate concentration on kobs for the nitrosation of
mercaptoethanol (reaction showed in Scheme 1) by (B) 4-MeO, (C) 4-Me,
(,) 4-Cl, and (-) 4-NO2. T¼25.0 ꢃC.
Table 1. Bimolecular rate constants, k2 (Mꢀ1 sꢀ1), for the nitroso group transfer from N-nitrosobenzene-sulfonamides to thiolate ions
pKalg
pKanuc
7.81
9.45
9.72
10.6
bnuc
MTG
MMP
MercEt
EtSH
11.7
11.6
11.1
10.7
4-MeO
4-Me
4-Cl
4-NO2
alg
9.76ꢄ0.05
12.6ꢄ0.7
34.6ꢄ0.3
194ꢄ2
11.7ꢄ0.1
15.8ꢄ0.2
46.3ꢄ0.5
227ꢄ8
13.5ꢄ0.2
17.6ꢄ0.6
57.9ꢄ0.3
351ꢄ9
14.6ꢄ0.5
19.2ꢄ0.5
64.1ꢄ0.7
375ꢄ8
0.06ꢄ0.01
0.07ꢄ0.01
0.10ꢄ0.02
0.10ꢄ0.03
ꢀ1.2ꢄ0.1
ꢀ1.2ꢄ0.1
ꢀ1.3ꢄ0.1
ꢀ1.4ꢄ0.1

8824
C. Adam et al. / Tetrahedron 62 (2006) 8822–8829
decomposition rate constants, respectively, of the nitroso-
thiol and KNO is the equilibrium constant for the formation
of NO+ from HNO2 and H+. Eq. 2 allowed us to calculate
the nitrosation rate constant for the thiol, k1. Because the for-
mation equilibrium constants for nitrosothiols are usually
3. Discussion
The bimolecular rate constants k2 for the nitroso group trans-
fer from N-nitrosobenzene-sulfonamides to thiolate ions
(Table 1) were much greater than those obtained with sec-
ondary amines as the nucleophiles. In fact, the rate constant
for the nitroso group transfer from N-methyl-N-nitroso-p-
toluenesulfonamide to mercaptoethanol ðpKa ¼ 9:72Þ is
roughly 300 times greater than that for another nucleophile
such as piperazine ðpKa ¼ 9:82Þ.12 This higher strength of
the sulfur nucleophiles is well documented in the literature
as evidenced by the different values in Ritchie’s N+ scale.16
very large, k must be very small relative to k1 and kDMU
;
ꢀ1
this precludes the kinetic determination of k
.
ꢀ1
As can be seen from Figure 2, the addition of RSH decreased
the absorbance change at 250 nm due to the nitrosation of
DMU. Such a decrease was a result of the formation of the
nitrosothiol, which absorbs at 330 nm. Therefore, the absor-
bance change can be related to the amounts of nitrosodi-
methyl urea (MNU-NO) and nitrosothiol (RSNO) formed.
The variation in absorbance in the absence of added thiol,
ðDAÞ0, and in its presence, DA, can be related with the nitro-
sation equilibrium constant of the thiol through the follow-
ing equation:
3.1. Reaction mechanism
The mechanism by which a nitroso group is transferred from
an N-nitrosobenzenesulfonamide to a thiol involves the nu-
cleophilic attack of the thiolate ion to the nitroso group
and the release of the anion from the sulfonamide, which
constitutes the rate-determining step of the process. Subse-
quently, the sulfonamide ion is protonated to an extent pro-
portional to the acidity of the medium (see Scheme 3).
ðDAÞ0ꢀDA
ðDAÞ0
KNOK1½RSHꢂ
¼
ð3Þ
1+KNOK1½RSHꢂ
where KNO is the equilibrium constant for the formation of
NO+ from HNO2 and H+, and was taken15 to be
3.5ꢁ10ꢀ7 Mꢀ1; and K1 is the equilibrium constant for the
RS-
+
H+
RSH
O
S
O
O
S
O
Me
Me
formation of the nitrosothiol, K1 ¼ k1=k
.
K2
ꢀ1
RS-
N-
N
+
RS-N=O
OH-
+
N
X
O
X
N
Figure 3 illustrates the good fitting of the absorbance
changes of Figure 2, and those obtained using different di-
methyl urea concentrations to Eq. 3. The fit allows the prod-
uct K1KNO to be established, K1KNO ¼ ð270 ꢄ 17Þ Mꢀ1. By
using the value of KNO, we can get the nitrosation equilib-
rium constant for mercaptoethanol, K1 ¼ 7:71 ꢁ 108. From
similar plots to that of Figure 3 we have obtained the forma-
tion equilibrium constants for the nitrosothiols used in this
work (see Table 2).
O
S
O
O
S
O
Me
H
Me
1/Ka
N-
+
+
H2O
X
X
Scheme 3.
There are at least two possible mechanisms for the nitroso
group transfer. One is of the addition–elimination type and
the other involves the direct (concerted) displacement of the
N]O group as in the alkaline hydrolysis of alkyl nitrites.17
Because the Bronsted slopes, alg, of Table 1 are smaller
than ꢀ1, the formation of the transition state is more strongly
influenced by the development of negative charge than
the acidity equilibrium of the sulfonamide. N-nitroso
compounds stabilize by resonance between two different
structures:18 R–N–N]O4R–N+]N–Oꢀ. A possible ex-
planation is that the transnitrosation reaction involves a two
unit change in charge at the sulfonamide nitrogen, from pos-
itive in the nitroso compound (Ar–SO2–N(CH3)+]N–Oꢀ)
to negative in the product (Ar–SO2–N(CH3)ꢀ) (Scheme 4).
This change or charge of more than one unit, algz ꢀ1:3,
in the reaction versus only one in the reference reaction,
pKalg (the acid dissociation of the sulfonamide), is only com-
patible with a concerted mechanism for nitroso group trans-
fer, ruling out the stepwise mechanism shown in Scheme 4.
1
0.8
0.6
0.4
0.2
0
0
0.02
0.04
0.06
[RSH] / M
Figure 3. Plot of ðDAÞ0ꢀDA=ðDAÞ0 versus the thiol concentration, Eq. 3,
for the nitrosation of DMU in the presence of variable concentrations
of mercaptoethanol. [HClO4]¼0.50 M; [NaNO2]¼1.00ꢁ10ꢀ4 M; ionic
strength¼1.00 M (NaClO4). T¼25.0 ꢃC. (B) [DMU]¼5.00ꢁ10ꢀ3 M;
(C) [DMU]¼3.00ꢁ10ꢀ3 M; (,) [DMU]¼2.00ꢁ10ꢀ3 M.
concerted
O
S
O
CH3
N
O-
N
O
N
O
S
O
CH3
k3
H3C
O
k4
+
RS-
Table 2. Formation equilibrium constants for the studied nitrosothiols at an
ionic strength of 1.00 M (NaClO4) at 25.0 ꢃC
N-
+
RS-N=O
N
S
SR
k-3
O
O
S
O
CH3
N+
N O-
Thiol
MTG
MMP
MercEt
EtSH
stepwise
pKa
K1
7.81
9.45
9.72
10.6
1.8ꢁ108
6.1ꢁ108
7.7ꢁ108
9.0ꢁ108
Scheme 4.

C. Adam et al. / Tetrahedron 62 (2006) 8822–8829
8825
The variation of the nucleophilic reactivity with the basicity
of the nucleophile shows behavior clearly different from that
of the nitrogen or carbon nucleophiles. The nitroso group
transfer rate constant increases slightly by 55% by increas-
ing the basicity of the nucleophile approximately 615 times.
The same increase in basicity brings a rise of more than
104% in the rate constants of amine19 or carbanion nitrosa-
tion20 by N-methyl-N-nitroso-p-toluenesulfonamide. Such
a difference of behavior is made clear when establishing a
Bronsted correlation giving values of bnucz0:8 for the nitro-
sation of primary and secondary amines by N-methyl-N-
nitroso-p-toluenesulfonamide,12 whereas thevaluesobtained
for the nitrosation of the sulfur nucleophiles studied is close
to bnucz0:08.
account this approach, we can assume that bnuc is given by
Eq. 4:
d log k2 d log Kdk20 d log Kd d log k20
bnuc
¼
¼
¼
+
d pKaRSH
d pKaRSH
d pKaRSH d pKaRSH
¼ bd+b0nuc
ð4Þ
In view of the fact that the higher the basicity of RSꢀ, the
more difficult the desolvation is, bd < 0 can be expected.
Thus, if bnuc is low, bnuc may be dominated by bd and be
close to zero or even negative. The values reported in the
literature where bnuc values are quite low for thiolate ion
addition to a variety of electrophiles are very common.25
This change in the sensitivity of the reaction to the basic
strength of the nucleophile is unusual although not without
precedent and it has traditionally been regarded as a conse-
quence of the effect of desolvation on the reaction rate or on
reactivity–structure correlations. In fact, there are many
cases where the rate of certain nucleophilic attacks has
been found to decrease as the basicity of the nucleophile is
increased, leading to negative Bronsted exponents. This be-
havior has been observed for some phosphoryl transfer reac-
tions to amines,21 and for reactions of highly reactive
carbocations with amines22 and for reactions of thiolate
ions with Fischer carbene complexes.23 In the same way,
values of the Bronsted exponent close to zero have been
found for reactions of diphenylketene with amines.24 Studies
carried out by Jencks21 indicate that these anomalous
Bronsted exponents result form a requirement for partial
desolvation of the nucleophile prior to reaction. The desolva-
tion is usually considered to be a pre-equilibrium that occurs
in a separate step, in such a way that a two-step model like
that illustrated in Scheme 5 can be adopted for a nucleophilic
attack.
3.2. Determination of equilibrium constants
Accurately interpreting Bronsted exponents with a view to
characterizing the structure of the transition state entails nor-
malizing bnuc and alg through beq. In the nitroso group
transfer reactions studied here, the equilibrium is displaced
to the formation of the nitrosothiol to such an extent that it
precludes its experimental determination. Moreover, nitro-
sothiols are unstable compounds and decompose under
a wide variety of conditions. The equilibrium constant
for a process involving the loss of an NO+ group from a nitro-
sothiol can be calculated from the equilibrium constant for
the formation of the nitrosothiol from its parent thiol and
NO+, K1, and the acidity constant for the thiol, KaRSH (see
Scheme 6).
1/K1
RSNO
+
H+
RSH + NO+
KaRSH
RS-
NO+
+
H+
RSH
RSH
RSNO
RS-
+
K
KaRSH / K1
NO
=
Scheme 6.
Kd
RS- Sol
RS-
k´2
+
Sol
RSH
NO
Table 3 lists the K
values obtained for various thiols in
RSH
the form of pK , as well as the previously reported values
Me
+
NO
RS-
for the corresponding nitrososulfonamides.12 Based on the
results, the most basic sulfonamides or thiols produce the
most stable N-nitroso compounds, which is consistent with
the above-described behavior of N-nitrosamines. The depen-
dence of the stability of N-nitrosamines on the basicity of
the parent amines was previously demonstrated in the
nitroso group transfer from an N-nitrosamine to another
amine in an acid medium.26,27 The structure and stereo-
chemistry of N-nitrosamines should reflect delocalization
Products
N
N O
R´
Scheme 5.
As Scheme 5 shows, the experimental value of the rate con-
stant for the process of nucleophilic attack corresponds
to the product Kdk20 , where Kd is the equilibrium constant
for the partial desolvation of the nucleophile. Taking into
Table 3. Equilibrium constants for the loss of an NO+ group from a nitrosothiol or N-nitrososulfonamide and for the nitroso group transfer from a nitroso-
sulfonamide to a thiol, K2
norm
pKNO
16.1
18.23
18.61
19.55
EtSH
b
nuc
MTG
MMP
MercEt
acceptor
NO
donor
NO
log K2 ¼ DpKNO ¼ pK
ꢀ pK
20.12
19.83
18.83
17.55
4-MeO
4-Me
4-Cl
ꢀ4.02
ꢀ1.89
ꢀ1.51
ꢀ0.57
ꢀ0.28
0.72
2.00
0.55ꢄ0.03
0.05ꢄ0.01
0.05ꢄ0.01
0.08ꢄ0.02
0.08ꢄ0.03
ꢀ3.73
ꢀ1.6
ꢀ1.22
ꢀ0.22
1.06
ꢀ2.73
ꢀ0.6
4-NO2
norm
ꢀ1.45
0.68
0.50ꢄ0.01
a
0.51ꢄ0.03
0.54ꢄ0.02
lg

8826
C. Adam et al. / Tetrahedron 62 (2006) 8822–8829
of the lone-pair electrons of the amino nitrogen into the
p-system of the N]O group. Electron diffraction studies28
have shown that N–N and N–O bond orders are ca. 1.5,
which is consistent with a structure in between the valence
structures of Scheme 7.
independent of the particular substituent of the N-nitrososul-
fonamide, consistent with the previous results for the nitroso
group transfer from N-nitrososulfonamides to amines.12
The bnnourcm values obtained for the nitroso group transfer from
N-nitrososulfonamides to amines are also close to 0.50,
which is consistent with a symmetric transition state for
R
R
R
R
+
the reaction. The small values obtained in this work
ðb
N
N
N
N
O-
norm
nuc
O
¼ 0:05Þ suggest the presence of a thiolate desolvation
equilibrium encompassed by the rate constant. Based on
Scheme 5, b
slope for the desolvation of the thiolate ion and b
for the nitroso group transfer.
Scheme 7.
¼ bd + b0nnuocrm, where bd is the Bronsted
norm
nuc
0norm
that
nuc
Independent evidence for considerable charge development
in the ground state comes from dipole moments for aliphatic
N-nitrosamines.29 As the basicity of the amine increases,
there will also be an increase in the stability of the resonance
form with a positive charge on the nitrogen atom and conse-
quently the stability of the N-nitrosamine will increase.
Previous studies on the nitroso group transfer from N-nitro-
sosulfonamides12 revealed that stabilization by the SO2
group of the negative charge that develops on the nitrogen
atom of the sulfonamide during the reaction must be the re-
sult of polarization effects rather than of conjugative dp–pp
bonding or negative hyperconjugation. This is consistent
with the results for the mechanism by which carbanions
with a sulfur atom31 or sulfonyl group32 in a are stabilized.32
The absence of resonance effects from the stabilization of
negative charge in a to sulfur atoms is supported by the
fact that anlgorm + bnnuocrm ¼ 1. One can therefore assume that
The equilibrium constant for the rate-determining step of
the nitroso group transfer reaction, K2, can be calculated
from pKNO for the N-nitrososulfonamide (the nitroso group
donor) and the nitrosothiol (the acceptor), using the relation
log K2 ¼ DpKNO ¼ pKacceptor ꢀ pKdonor. Table 3 lists the
NO
NO
log K2 values thus obtained. As can be seen, based on
the equilibrium constant for the nitroso group transfer, the
process will be thermodynamically unfavorable and lead
to a mixed equilibrium between the N-nitrososulfonamide
and the nitrosothiol in most cases. However, the sulfonamide
will be protonated in a diffusion-controlled step at a later
stage of the process. As a result, the backward reaction of
the nitroso group transfer from a nitrosothiol to the neutral
form of the sulfonamide will simply not occur. Also, nitroso-
thiols decompose rapidly,30 so the nitroso group transfer will
be quantitative.
the Bronsted exponent for the nitroso group transfer from
0norm
N-nitrososulfonamides to thiolate ions (Scheme 5), b
,
nuc
should be 0.50. Accordingly, bd should be ꢀ0.45, which is
consistent with the expectations ðbd < 0Þ as the difficulty
of desolvating the thiolate ion should increase with increas-
ing basicity of RSꢀ.
3.4. Intrinsic rate constants
The Marcus theory33 for outer sphere electron transfer reac-
tions relates kinetic and thermodynamic barriers in a chemi-
cal reaction. This theory has allowed the experimental
results for a large number of processes including proton,34
hydride ion,35 and methyl group36,37 transfers to be ex-
plained. Such a wide scope suggests that the Marcus theory
should also be applicable to nitroso group transfers.
3.3. Characterization of the transition state
The equilibrium constant for the rate-determining step in the
nitroso group transfer, K2, allows one to derive rate–equilib-
rium relationships. In fact, the resulting plots can be used to
calculate anlgorm and bnnuocrm (see Fig. 4), which are measures of
charge development on the nitrogen atom of the N-nitroso-
The Marcus theory33 predicts non-linearity in free energy
relations by introducing a quadratic term:
sulfonamide and the sulfur atom of the thiolate ion, respec-
norm
tively. The a
and bnnuocrm values thus obtained are listed in
lg
2
Table 3. As can be seen, the anlgorm values are close to 0.50 and
DG0
DG0
DGs ¼ DGs0 +
+
ð5Þ
2
16DGs0
3
2.5
2
where DGs is the free energy of activation for the reaction
concerned, DG0 the free energy change for the process and
DGs0 the intrinsic barrier corresponding to the free energy
of activation at DG0 ¼ 0. The associated rate constant and
intrinsic rate constant are k and k0, respectively. In proton
transfer reactions, DG0 is determined by the pKa difference
between the proton donor and acceptor. An identical formal-
ism can be used with nitroso group transfers. In our case,
DG0 will be determined by the pKNO difference between
the nitroso group donor (i.e., the N-nitrososulfonamide)
and acceptor (thiolate ion).
1.5
1
0.5
-4
-2
0
2
pKNO
We used the results of Figure 4 to calculate the intrinsic rate
constant, k0, for the nitroso group transfer from N-nitroso-
sulfonamides to thiols as the rate constants at DpKNO ¼ 0.
Figure 4. Plot of log k2 versus DpKNO for the nitroso group transfer from
N-nitrososulfonamides to (B) MTG, (C) MMP, (,) MercEt, and (-)
norm
lg
EtSH. The slopes of the lines provide an a
value of 0.50.

C. Adam et al. / Tetrahedron 62 (2006) 8822–8829
8827
The intrinsic constants thus obtained increased with decreas-
ing basicity of the thiol; thus, log k0 was 3.0 for MTG
ðpKa ¼ 7:81Þ, 2.0 for MMP ðpKa ¼ 9:45Þ, 2.0 for MercEt
ðpKa ¼ 9:72Þ, and 1.75 for EtSH ðpKa ¼ 10:6Þ. These
results are consistent with the need to desolvate thiolate
ions, the desolvation increasing in difficulty with increase
in the basicity of the thiol. In order to suppress the effect
of desolvation on log k0, we used a bd value of ꢀ0.45 to
establish the following equation
Albery and Kreevoy36 examined methyl transfer reactions in
the light of the Marcus theory and determined the intrinsic
barriers DGs0 for various identity reactions where the nucleo-
phile and leaving group were the same. In this way, they
obtained the DGs0 values 147, 213, 133, 111, 99, and
97 kJ molꢀ1 (corresponding to the log k0 values ꢀ12.98,
ꢀ24.45, ꢀ10.53, ꢀ6.67, ꢀ4.57, and ꢀ4.22) for H2O,
CNꢀ, Fꢀ, Clꢀ, Brꢀ, and Iꢀ, respectively. These results for
methyl group transfers show that the intrinsic rate constant
is very strongly dependent on the nature of the nucleophile,
in fact, it varies by a factor of 106 from Fꢀ to Iꢀ.
log k2 +0:45pKaRSH ¼ intercept+b0nucpKaRSH
ð6Þ
Figure
5
illustrates the good correlation between
The above-described high thermodynamic affinity was re-
cently shown not to fully account for the high nucleophilicity
of thiolate ions.25f In fact, an important contribution comes
from an enhanced intrinsic rate constant. This was demon-
strated for the reaction of thiolate ions with a-nitrostilbene
in 1:1 Me2SO/water, for which log k0 ¼ 3:43, is much
greater than for the reaction of piperidine/morpholine with
the same substrate ðlog k0 ¼ 1:43Þ.44 An attractive explana-
tion for the enhanced k0 value is that the soft acid–soft base
interaction, which is responsible for the high thermody-
namic stability of the thiolate ion adduct develops ahead
of C–S bond formation. This is interesting because it con-
trasts with most other product-stabilizing factors develop-
ment of which typically lags behind bond formation at the
transition state, thereby lowering k0.45 One common feature
of product-stabilizing factors such as resonance, solvation or
intramolecular hydrogen bonding is that they are ‘created’
by the reaction (i.e., they would not exist in the absence of
bond formation). At best, these factors could conceivably
develop synchronously with bond formation, but not
possibly ahead of it. By contrast, soft–soft interactions are
rooted in the polarizability of the interacting molecules
and may not require a substantially developed bond to
make themselves felt.
log k2 + 0:45pKaRSH and DpKNO for the nitroso group transfer
from N-nitrososulfonamides to various thiolate ions. The fig-
ure is similar to the traditional log plots of proton transfer
rate constants versus acid ionization constants. As can be
seen, the rate constant for the nitroso group transfer and
the equilibrium constants are linearly related. This is consis-
tent with the previous results for the nitroso group transfer
from N-nitrososulfonamides to secondary amines.12 The lin-
earity of the rate–equilibrium constant empirical correlation
apparent from Figure 5 includes both thermodynamically
favorable and unfavorable reactions. It should be noted
that this linear relationship contradicts reported Bronsted
exponent changes for a wide range of proton transfers
from carbon acids.38 However, a number of absolutely linear
rate–equilibrium plots for proton abstraction by OHꢀ ions
exist39,40 that span 19 pKa units and include favorable and
unfavorable proton transfer processes.
The results of Figure 5 can be used to calculate the intrinsic
rate constants for the nitroso group transfer from N-nitroso-
sulfonamides to secondary amines ðlog k0 ¼ ꢀ0:5Þ and
thiols ðlog k0 ¼ 6:3Þ. The large difference between the reac-
tivity of amines and thiolate ions is a result of the latter being
highly effective nucleophiles and superior to oxyanions or
amines of comparable pKa in many nucleophilic addition re-
actions.41 One of the reasons for such a high reactivity is
their high carbon basicity (i.e., their high equilibrium con-
stants for nucleophilic addition).42 Within the framework
of hard–soft acid–base interactions,43 this can be understood
as the soft (polarizable) electrophile having stronger affinity
for the soft sulfur bases than for the hard nitrogen or oxygen
bases.
4. Conclusions
On the basis of this study, the following results are particu-
larly worthy of note.
(1) The nitroso group transfer from N-nitrososulfonamides
to thiolate ions takes place directly via concerted mech-
anism. The rate of the reaction is strongly dependent on
the nature of the leaving group, but virtually independent
of the basicity of the thiolate ion. This is a result of the
presence of a prior equilibrium for the desolvation of
thiolate ions.
8
6
4
(2) The calculated equilibrium constants for the nitroso
group transfers allowed charge development on the
nucleophile and leaving group in the transition state to
be quantified. Because the sulfonyl group is not involved
in the establishment by resonance of the negative charge
on the nitrogen atom in a, the nucleophilic sensitivity of
the reaction can be resolved into a desolvation term and
a bond formation term.
2
0
-2
-4
-6
-8
-6
-4
-2
0
2
4
pKNO
(3) The establishment of a rate–equilibrium relation for the
nitroso group transfer allowed us to derive a quantitative
explanation for the observed reactivity similarly to pro-
ton transfer reactions. The absolute linearity of the rate–
equilibrium correlation was interpreted in the light of the
Figure 5. Plot of (B) log k2+0:45pKaRSH versus DpKNO for nitroso group
transfer from N-nitrososulfonamides to thiolate ions and (C) log k2 versus
DpKNO for nitroso group transfer from N-nitrososulfonamides to secondary
amines.

8828
C. Adam et al. / Tetrahedron 62 (2006) 8822–8829
Marcus theory of electron transfer as applied to the
Acknowledgements
nitroso group transfer process. The accelerating effect
of substituents withdrawing charge from the aromatic
ring of the N-nitrososulfonamide is mainly due to the
greater thermodynamic driving force of the reaction.
Hence, the intrinsic reactivities of nitrososulfonamides
remain virtually constant.
ꢀ
This work was funded by Spain’s Ministerio de Educacion y
Ciencia (Project CTQ2005-04779), Xunta de Galicia
(PGIDT03-PXIC20905PN and PGIDIT04MT209003PR),
~
and Fundac¸ao para a Ciencia e Tecnologia (Portugal
POCI/QUI/57077/2004).
^
Supplementary data
5. Experimental
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.06.060.
N-methylbenzenesulfonamides were synthesized by react-
ing the corresponding benzenesulfonyl chlorides with excess
methylamine in water. The resulting products were extracted
with dichloromethane and washed with a solution of sodium
hydrogen carbonate and water. N-methyl-p-toluenesulfon-
amide and its nitroso derivative were supplied by Ega-Chemie
and Merck, respectively. N-Methyl-N-nitrososulfonamides
were prepared from a biphasic water/dichloromethane
mixture. The aqueous phase, containing sodium nitrite,
and the organic phase, containing the parent sulfonamide,
were mixed together and slowly supplied with concentrated
(5 M) perchloric acid. Following stirring for 1 h, the organic
phase was separated and washed with water, N-methyl-N-
nitrososulfonamides being finally recrystallized in a 80%
yield from a dichloromethane/petroleum ether mixture.
This method has the advantage that it avoids the hydrolysis
of the nitroso derivatives by sequestering them in the organic
phase as they form. All other reagents were obtained in the
highest available purity from Aldrich and used as received.
References and notes
1. (a) Feldman, P. L.; Griffith, O. W.; Stuehr, D. J. Chem. Eng.
News 1993, 26–38; (b) Stamler, J. S.; Singel, D. J.; Loscalzo,
J. Science 1992, 258, 1898–1902; (c) Butler, A. R.; Williams,
D. L. H. Chem. Soc. Rev. 1993, 22, 233–241; (d) Williams,
D. L. H. Org. Biomol. Chem. 2003, 1, 441–449.
2. Richter-Addo, G. B.; Legzdins, P.; Burstyn, J. Chem. Rev. 2002,
102, 857–859.
3. Bauer, J. A.; Fung, H. L. J. Pharmacol. Exp. Ther. 1991, 256,
249–254.
4. Radomski, M. W.; Palmer, R. M. J.; Moncada, S. Br. J.
Pharmacol. 1987, 92, 181–187.
5. Gaston, B.; Reilly, J.; Drazen, J. M.; Fackler, J.; Ramdev, P.;
Arnelle, D.; Mullins, M. E.; Sugarbaker, D. J.; Chee, C.;
Singel, D. J.; Loscalzo, J.; Stamler, J. S. Proc. Natl. Acad.
Sci. U.S.A. 1993, 90, 10957–10961.
The pKa values of thiols in water at 25.0 ꢃC, ionic
strength ¼ 1.00 M (NaClO4) were determined potentio-
metrically. The obtained values are compatible with those
existing in the bibliography.46 The pKa values of the sulfon-
amides were known from the previous studies.46c
6. Stamler, J. S.; Jaraki, O.; Osborne, J.; Simon, D. I.; Keaney, J.;
Vita, J.; Singel, D.; Valeri, C. R.; Loscalzo, J. Proc. Natl. Acad.
Sci. U.S.A. 1992, 89, 7674–7677.
7. Myers, P. R.; Minor, R. L.; Guerra, R.; Bates, J. N.; Harrison,
D. G. Nature 1990, 345, 161–163.
8. Tasker, H. S.; Jones, H. O. J. Chem. Soc. 1910, 1910–1918.
´
´
All kinetic experiments were performed with a large excess
of nucleophile relative to N-methyl-N-nitrososulfonamide,
the concentration of the latter ranged from (1–2)ꢁ10ꢀ4 M.
The pH was controlled by using the nucleophile itself as
buffering agent in solutions with NaOH. Because of their
low solubility in water, the N-methyl-N-nitrososulfonamides
were dissolved in a small amount of organic solvent (di-
oxane) prior to preparing the aqueous solutions. The final
concentration of organic solvent in the reaction medium
was smaller than 3.3% (v/v) in all instances. The reaction
kinetics was studied by monitoring the formation of the
nitrosothiol via the absorbance at 330 nm, which was mea-
sured with an Applied Photophysics stopped-flow spectro-
photometer. The reaction was found to be first order up to
about 90% conversion. Each kinetic run was repeated at least
five times in order to obtain an average value for the pseudo
first-order rate constant, kobs. The standard error for kobs
was always less than 3%. All experiments were performed
at 25.0 ꢃC.
9. Iglesias, E.; Garcıa Rıo, L.; Leis, J. R.; Pen˜a, M. E.; Williams,
D. L. H. J. Chem. Soc., Perkin Trans. 2 1992, 1673–1679.
10. Beloso, P. H.; Williams, D. L. H. Chem. Commun. 1997, 89–90.
´
11. Adam, C.; Garcıa-Rıo, L.; Leis, J. R. Org. Biomol. Chem. 2004,
´
2, 1181–1185.
´
´
12. Garcıa-Rıo, L.; Leis, J. R.; Moreira, J. A.; Norberto, F. J. Org.
Chem. 2001, 66, 381–390.
13. Castro, A.; Iglesias, E.; Leis, J. R.; Pen˜a, M. E.; Vazquez Tato,
J. J. Chem. Soc., Perkin Trans. 2 1986, 1725–1729.
14. Aldred, S. E.; Williams, D. L. H.; Garley, M. J. Chem. Soc.,
Perkin Trans. 2 1982, 777–782.
15. (a) Bayliss, N. S.; Dingle, R.; Watts, D. W.; Wilkie, R. C. Aust.
J. Chem. 1963, 16, 933–942; (b) Ridd, J. H. Adv. Phys. Org.
Chem. 1978, 15, 1–49.
16. Ritchie, C. D. Can. J. Chem. 1986, 64, 2239–2250.
17. Oae, S.; Asai, N.; Fujimori, K. J. Chem. Soc., Perkin Trans. 2
1978, 571–577.
18. (a) Williams, D. L. H. Nitrosation; Elsevier: Amsterdam, 2004;
(b) Kuhn, S. J.; McIntyre, J. S. Can. J. Chem. 1966, 44, 105–
109; (c) Olah, G. A.; Donovan, D. J.; Keefer, L. K. J. Natl.
Cancer Inst. 1975, 54, 465–472; (d) Chow, Y. L. Acc. Chem.
Res. 1973, 6, 354–360.
19. Garcıa-Rıo, L.; Iglesias, E.; Leis, J. R.; Pen˜a, M. E.; Rios, A.
J. Chem. Soc., Perkin Trans. 2 1993, 29–37.
20. Leis, J. R.; Pen˜a, M. E.; Rios, A. J. Chem. Soc., Perkin Trans. 2
1993, 1233–1240.
ꢀ
The equilibrium constant of nitrosothiol formation was de-
termined from the nitrosation of 1,3-dimethyl urea (DMU)
in the presence of variable concentrations of a thiol. Exper-
iments were conducted with [NaNO2] much smaller than
those of DMU and RSH. The reaction was monitored at
250 nm, where nitrosothiols absorb negligibly.
´
´

C. Adam et al. / Tetrahedron 62 (2006) 8822–8829
8829
21. Jencks, W. P.; Haber, M. T.; Herschlag, D.; Nazaretian, K. L.
J. Am. Chem. Soc. 1986, 108, 479–483.
33. (a) Marcus, R. A. J. Chem. Phys. 1956, 24, 966–978; (b)
Marcus, R. A. J. Chem. Phys. 1957, 26, 867–871.
22. (a) Richard, J. P. J. Chem. Soc., Chem. Commun. 1987, 1768–
1769; (b) McClelland, R. A.; Kanagasabapathy, V. M.; Banait,
N. S.; Steenken, S. J. Am. Chem. Soc. 1992, 114, 1816–
1823.
34. (a) Marcus, R. A. J. Phys. Chem. 1968, 72, 891–899; (b)
Cohen, A. O.; Marcus, R. A. J. Phys. Chem. 1968, 72,
4249–4256; (c) Kresge, A. J. Acc. Chem. Res. 1975, 8,
354–360.
23. Bernasconi, C. F.; Kittredge, K. W.; Flores, F. X. J. Am. Chem.
Soc. 1999, 121, 6630–6639.
24. Andraos, J.; Kresge, A. J. Am. Chem. Soc. 1992, 114, 5643–
5646.
35. (a) Kreevoy, M. M.; Lee, I.-S. H. J. Am. Chem. Soc. 1984, 106,
2550–2553; (b) Lee, I.-S. H.; Ostovic, D.; Kreevoy, M. M.
J. Am. Chem. Soc. 1988, 110, 3989–3993; (c) Lee, I.-S. H.;
Jeoung, E. H. J. Org. Chem. 1998, 63, 7275–7279.
25. (a) Bernasconi, C. F.; Fassberg, J.; Killion, R. B., Jr.;
Rappoport, Z. J. Am. Chem. Soc. 1989, 111, 6862–6864; (b)
Bernasconi, C. F.; Fassberg, J.; Killion, R. B., Jr.; Rappoport,
Z. J. Am. Chem. Soc. 1990, 112, 3169–3177; (c) Bernasconi,
C. F.; Ketner, R. J.; Chen, X.; Rappoport, Z. J. Am. Chem.
Soc. 1998, 120, 7461–7468; (d) Bernasconi, C. F.; Ketner,
R. J.; Chen, X.; Rappoport, Z. Can. J. Chem. 1999, 77, 584–
594; (e) Hupe, D. J.; Jencks, W. P. J. Am. Chem. Soc. 1977,
99, 451–464; (f) Bernasconi, C. F.; Killion, R. B., Jr. J. Am.
Chem. Soc. 1988, 110, 7506–7512; (g) Gilbert, H. F.; Jencks,
W. P. J. Am. Chem. Soc. 1977, 99, 7931–7947; (h) Ritchie,
C. D.; Gandler, J. R. J. Am. Chem. Soc. 1979, 101, 7318–
7323; (i) Bernasconi, C. F.; Schuck, D. F. J. Org. Chem.
1992, 57, 2365–2373; (j) Bernasconi, C. F.; Ketner, R. J.
J. Org. Chem. 1998, 63, 6266–6272; (k) Buncel, E.; Cannes,
C.; Chatrousse, A. P.; Terrier, F. J. Am. Chem. Soc. 2002,
36. Albery, W. J.; Kreevoy, M. M. Adv. Phys. Org. Chem. 1978, 16,
87–157.
37. (a) Lewis, E. S.; McLaughlin, M. L.; Douglas, T. A. J. Am.
Chem. Soc. 1985, 107, 6668–6673; (b) Lewis, E. S. J. Phys.
Chem. 1986, 90, 3756–3759; (c) Galezowski, W.; Ibrahim,
P. N.; Lewis, E. S. J. Am. Chem. Soc. 1993, 115, 8660–8668.
38. (a) Murray, C. J.; Jencks, W. P. J. Am. Chem. Soc. 1990, 112,
1880–1889; (b) Guthrie, J. P. Can. J. Chem. 1979, 57, 1177–
1185; (c) Argile, A.; Carey, A. R. E.; Fukata, G.; Harcourt,
´
M.; More OFerrall, R. A.; Murphy, M. G. Isr. J. Chem. 1985,
26, 303–312.
39. (a) Amyes, T. L.; Richard, J. P. J. Am. Chem. Soc. 1996, 118,
3129–3141; (b) Amyes, T. L.; Richard, J. P. J. Am. Chem.
Soc. 1992, 114, 10297–10302.
40. Heathcote, D. M.; Atherton, J. H.; De Boos, G. A.; Page, M. I.
J. Chem. Soc., Perkin Trans. 2 1998, 541–546.
ꢀ
124, 8766–8767; (l) Terrier, F.; Guevel, E.; Chatrousse, A. P.;
41. (a) Friedman, M.; Cavins, J. F.; Wall, J. S. J. Am. Chem. Soc.
1965, 87, 3672–3682; (b) Rosenberg, M.; Balaz, S.; Sturdik,
E.; Kucher, A. Collect. Czech. Chem. Commun. 1987, 52,
425–430; (c) Rappoport, Z.; Topol, A. J. Org. Chem. 1989,
54, 5967–5977; (d) Bernasconi, C. F.; Paschalis, P. J. Am.
Chem. Soc. 1989, 111, 5893–5902.
42. (a) Hine, J.; Weimar, R. D. J. Am. Chem. Soc. 1965, 87, 3387–
3396; (b) Sander, E. G.; Jencks, W. P. J. Am. Chem. Soc. 1968,
90, 6154–6162; (c) Bone, R.; Cullis, P.; Wolfenden, R. J. Am.
Chem. Soc. 1983, 105, 1339–1343.
43. Pearson, R. G.; Songstad, J. J. Am. Chem. Soc. 1967, 89, 1827–
1836.
44. Bernasconi, C. F.; Renforw, R. A. J. Org. Chem. 1987, 52,
3035–3041.
45. Bernasconi, C. F. Adv. Phys. Org. Chem. 1992, 27, 119–238.
46. (a) Irving, R. J.; Nelander, L.; Wadsoe, I. Acta Chem. Scand.
1964, 18, 769–787; (b) Silva, C. O.; Silva, E. C.;
Nascimento, M. A. C. J. Phys. Chem. A 2000, 104, 2402–
Moutiers, G.; Buncel, E. Chem. Commun. 2003, 600–601.
26. (a) Singer, S. S. J. Org. Chem. 1978, 43, 4612–4616; (b) Singer,
S. S.; Singer, G. M.; Cole, B. B. J. Org. Chem. 1980, 45, 4931–
4935.
27. Meyer, T. A.; Williams, D. L. H.; Bonnett, R.; Ooi, S. L.
J. Chem. Soc., Perkin Trans. 2 1982, 1383–1387.
28. Rademacher, P.; Stoelevik, R. Acta Chem. Scand. 1969, 23,
660–671.
29. (a) Cowley, E. G.; Partington, J. R. J. Chem. Soc. 1933, 1255–
1257; (b) George, M.; Wright, G. J. Am. Chem. Soc. 1958, 80,
1200–1204; (c) Hall, P. G.; Horsfall, G. S. J. Chem. Soc., Perkin
Trans. 2 1973, 1280–1284.
30. Adam, C.; Garcıa-Rıo, L.; Leis, J. R.; Ribeiro, L. J. Org. Chem.
2005, 70, 6353–6361.
´
´
31. Bernasconi, C. F.; Kittredge, K. W. J. Org. Chem. 1998, 63,
1944–1953.
32. Terrier, F.; Kizilian, E.; Goumont, R.; Faucher, N.; Wakselman,
C. J. Am. Chem. Soc. 1998, 120, 9496–9503 and references
therein.
´
2409; (c) Garcıa-Rıo, L.; Leis, J. R.; Moreira, J. A.;
Norberto, F. J. Phys. Org. Chem. 1998, 11, 756–760.
´