Nitrosation of N-Methyl-4-tolylsulfonylguanidine

Article abstract of DOI:10.1039/a607544d

Kinetic studies for the nitrosation of N-methyl-4-tolylsulfonylguanidine identify a mechanism involving rapid nitrosation of the N-methyl nitrogen atom followed by slow, general-base-catalysed proton transfer.

Full text of DOI:10.1039/a607544d

View Article Online / Journal Homepage / Table of Contents for this issue
88 J. CHEM. RESEARCH (S), 1997
J. Chem. Research (S),
1997, 88–89†
Nitrosation of N-Methyl-4-tolylsulfonylguanidine†
J. Ramon Leis,*a Fa´tima Norberto,b,c Jose´ A. Moreirac and Jim Ileyd
aDepartmento de Qu´ımica-Fisica, Faculdad de Qu´ımica, Universidade de Santiago de
Compostela, 15706 Santiago de Compostela, Spain
bDepartmento de Qu´ımica, Faculdade de Cieˆncias, Universidade de Lisboa, 1700 Lisboa,
Portugal
cCECF, Faculdade de Farma´cia, Universidade de Lisboa, 1699 Lisboa, Portugal
dPOCRG, Department of Chemistry, The Open University, Milton Keynes, MK7 6AA, UK
Kinetic studies for the nitrosation of N-methyl-4-tolylsulfonylguanidine identify a mechanism involving rapid nitrosation of
the N-methyl nitrogen atom followed by slow, general-base-catalysed proton transfer.
The nitrosation of amines, amides, amidines and guanidines
has received much attention, due in large part to the poten-
tial carcinogenic properties of the N-nitroso products
formed. Nitrosation of amines in acidic medium occurs with
rate limiting attack of the nitrosating agent on the substrate,
while that of amides involves fast O-nitrosation followed by
slow proton transfer from the substrate and a fast internal
rearrangement to produce the N-nitrosamide.1–3 Clonidine, a
guanidine with antihypertensive properties, is nitrosated by
nitrous acid via slow deprotonation of the N-nitrosated sub-
strate.4 However, guanidines like clonidine provide a bridge
between amines and amides, because, in contrast to their
behaviour in acidic media, under neutral conditions nitrosa-
tion by alkyl nitrites takes place via the neutral substrate.4
To examine the effect of electron withdrawing groups on
the nitrosation of the guanidine moiety, we studied the nitro-
sation of N-methyltoluene-4-sulfonylguanidine (1) in acidic
medium and herein report our results.
Fig. 1 Dependence of initial rates of nitrosation of TSG upon (a)
[Hǹ], (b) [NOꢀ2 ] and (c) [TSG]
Experimental
and [NOꢀ2 ], the plot for dependence upon [Hǹ] is distinctly
N-Methyl-4-tolylsulfonylguanidine (1) (TSG) was synthesised
from N-methylguanidine hydrochloride using toluene-4-sulfonyl
chloride in acetone–aqueous sodium hydrochloride. TSG has mp
ing protonation of TSG in which nitrosation occurs via the
194–196 °C; dH (CDCl3) 2.38 (3 H, s), 2.76 (3 H, s), 7.22 (2 H, d, J
8.6 Hz), 7.75 (2 H, d, J 8.6 Hz); m/z 227, 155, 91, 72. N-Methyl-
N-nitroso-4-tolylsulfonylguanidine (2) (NTSG) was synthesised by
the method of White.5 NTSG has mp 168–170 °C; dH 2.43 (3 H, s),
3.18 (3 H, s), 7.32 (2 H, d, J 8.1 Hz), 7.87 (2 H, d, J 8.1 Hz); m/z 256
(Mǹ), 226 (MǹꢀNO); lmax 257 (log e 4.08).
curved. The plot can be rationalised by a mechanism involv-
unprotonated form of TSG; i.e.
TSGǹHǹ
x
TSGHǹ
(Ka = [TSG][Hǹ]/[TSGHǹ])
nitrosation
TSG
NTSG
For solubility reasons, kinetic studies were carried out at 25 °C in
water–dimethylsulfoxide (9:1 v/v) solutions at a constant ionic
strength of 0.5 mol dmꢀ3. Kinetic analyses were performed using
the initial rate method following the formation of NTSG, thus
obviating problems associated with decomposition of nitrous
acid.
Under the conditions of the reaction for the variation of
[Hǹ], the total concentration of TSG, [TSG]T, is given by
[TSG]T = [TSG]ǹ[TSGHǹ]
Thus, [TSG] = [TSG]T/(1ǹ[Hǹ]/Ka); as [Hǹ] increases
the amount of unprotonated TSG, the form which undergoes
nitrosation, decreases. The data in Fig. 1(a) can be fitted to
the rate equation
Results and Discussion
Nitrosation of TSG appears to occur at the N-methyl nitro-
1
gen atom, as evidenced by the large shift in the H NMR of
vi = k3[TSG]T[NOꢀ2 ][Hǹ]/(1ǹ[Hǹ]/Ka)
the N-methyl signal of NTSG as compared to that in TSG.
The effect of [Hǹ] on the initial rate of nitrosation of TSG
(holding [TSG] and [NOꢀ2 ] constant) is shown in Fig. 1(a).
Similar plots for the effects of [NOꢀ2 ] (holding [Hǹ] and
[TSG] constant) and [TSG] (holding [Hǹ] and [NO2ꢀ] con-
stant) are shown in Figs. 1(b),(c). While the reaction is shown
to have a simple, linear, first-order dependence upon [TSG]
from which a value of 0.39 mol dmꢀ3 for the acid dissocation
constant, Ka, for TSG can be obtained. This corresponds to a
pKa of 0.4. The third-order rate constant, k3, so obtained is
contained in Table 1, together with those from the slopes of
Figs. 1(b),(c) corrected for the concentration of unproto-
nated TSG, [TSG], at the acidity studied. The constant value
of k3 from the three different investigations reveals that the
nitrosation of TSG has a first-order dependence upon [TSG],
[NOꢀ2 ] and [Hǹ].
*To receive any correspondence.
†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).
Data for the influence of Clꢀ and Brꢀ, ions that catalyse
the nitrosation of amines but not of amides, upon the initial

View Article Online
J. CHEM. RESEARCH (S), 1997 89
Table 1 Dependence of observed rate constants for the nitrosation of TSG upon the concentrations
of reacting species
102k؅3/dm6a
102k3/dm6
Varying species
[Hǹ]
[TSG]T
[NOꢀ2 ]
105k؅/sꢀ1a
molꢀ2 sꢀ1
molꢀ2 sꢀ1
Hǹ
s
0.1
0.422
0.1
0.005
s
s
0.01
0.01
0.01
s
s
s
6.9
TSG
5.90
1.28
0.572
5.90
3.03
5.72
7.41
3.11b
7.19
NOꢀ2
0.001
ak؅ is the pseudo-first-order rate constant obtained from the slope of vi vs. the concentration of the
varying species. k؅3 is the third-order rate constant obtained by dividing k؅ by the concentrations of
the invariant species, uncorrected for the protonation of TSG. bIn D2O.
Table 2 Effect of added Clꢀ and Brꢀ ions on the initial rate of
buffers are consistent with this expectation. Similar correla-
tions are observed with dichloro- (DCA) and monochloro-
(MCA) acetic acid buffers, and the catalytic rate constants,
kcat, for the catalysis by the basic form of the buffer, [Bꢀ], is
obtained from plots of vi vs. [Bꢀ] using kcat = slope/
[NOꢀ2 ][Hǹ][TSG]corrected. A Brønsted plot for the three
buffers (Fig. 2) gives a value for b of 0.68. This is similar to
that for clonidine,4 and implies a slow proton transfer in the
rate determining step.
nitrosation of TSG
102[Clꢀ]/mol dmꢀ3
102[Brꢀ]/mol dmꢀ3
108vi/mol dmꢀ3 sꢀ1
—
—
5.44
5.24
5.53
5.48
5.26
—
2.0
4.0
—
—
3.3
20.0
—
The most likely mechanism for the nitrosation of TSG is
shown in Scheme 1. We cannot be sure of the exact structure
of the prototropic tautomer that reacts with NOǹ, but that
shown in Scheme 1 is the simplest that is consistent with the
experimental data. Fast, pre-equilibrium nitrosation of TSG
at the most nucleophilic, methyl-bearing nitrogen atom is
followed by slow protonation transfer to the medium.
According to Scheme 1, the rate of nitrosation can be
expressed as
Table 3 Effect of TCA buffers on the initial rate of nitrosation of
TSGa
10[TCA]/mol dmꢀ3
108vi/mol dmꢀ3 sꢀ1
0.429
0.858
1.287
1.717
2.575
4.56
4.90
5.11
5.28
6.13
v= k1K1K2[TSG][NOꢀ2 ][Hǹ][H2O]
ǹkcat[TSG][NOꢀ2 ][Hǹ][Bꢀ]
a[TSG]T = 0.001 mol dmꢀ3, [NO2ꢀ] = 0.01 mol dmꢀ3, pH 1.0.
For the reaction in the absence of general bases (other
than solvent water) the observed deuterium isotope effect,
kH3 /kD3 is 2.38. However, k3 = k1K1K2[H2O], so k3H/kD3 =
kH1 K1HKH2 [H2O]/k1DK1DK2D[D2O]. The value of [H2O]/[D2O] =
1.00, and KH1 /KD1 = 0.39,6 so assuming that there is a negligible
isotope effect upon K2, i.e. KH2 /K2D = 1, because it does not
involve a proton transfer, then the isotope effect upon the
step involving proton transfer, kH1 /k1D, is 2.38/0.39 = 6.1. This
is consistent with the proposed step being a slow proton
transfer from an acidic species to water.
Thus, the sulfonylguanidine moiety behaves like amides
and ureas towards nitrosation. It also has similar behaviour to
that of the cyclic guanidine, clonidine. However, clonidine is
a much more basic guanidine than TSG, cf. pK1s of 8.7 and
0.4 respectively; whereas it is the protonated form of cloni-
dine that is nitrosated, it is the unprotonated form of TSG
that is nitrosated.
Scheme 1 Mechanism of the nitrosation of TSG
J. A. M. acknowledges the Junta Nacional de Investigaç˜ao
Cient´ıfica e Technologica-Portugal for a ‘Programa Ciˆencia’
grant.
Received, 5th November 1996; Accepted, 6th November 1996
Paper E/6/07544D
References
1 G. Hallett and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2,
1980, 1371.
2 A. Castro, E. Iglesias, J. R. Leis, M. E. Pen˜a and J. Vazquez Tato,
J. Chem. Soc., Perkin Trans. 2, 1986, 1725.
3 J. R. Leis, M. E. Pen˜a, M. J. Blanco and L. Garcia-Rio, J. Chem.
Res. (S), 1992, 338.
Fig. 2 Brønsted plot for general base catalysis of nitrosation of
TSG
4 F. Norberto, J. A. Moreira, E. Rosa, J. Iley, J. R. Leis and M. E.
Pen˜a, J. Chem. Soc., Perkin Trans. 2, 1993, 1561.
5 E. H. White, J. Am. Chem. Soc., 1955, 77, 6008.
6 A. Castro, M. Mosquera, M. F. Rodriguez Prieto, J. A. Santaballa
and J. Vazquez Tato, J. Chem. Soc., Perkin Trans. 2, 1988, 1963.
rates of reaction (Table 2) reveal that these ions have no
catalytic effect. Thus, towards nitrosation, TSG behaves like
an amide, and its nitrosation should be subject to buffer
catalysis. The data in Table 3 for trichloroacetic acid (TCA)