Kinetics and Mechanism of Nitrosation of N,N′-Dimethyl-N″ -cyanoguanidine

Article abstract of DOI:10.1039/a803199a

The nitrosation reaction of N,N′-Dimethyl-N″-cyanoguanidine is reversible and the mechanism is similar to that found for the nitrosation of amides and ureas.

Full text of DOI:10.1039/a803199a

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474 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 474±475$
Kinetics and Mechanism of Nitrosation of
N,N'-Dimethyl-N0-cyanoguanidine$
Pablo Herves,*a Richard G. Buttonb and D. Lyn H. Williamsc
aDepartamento de Quõmica Fõsica e Quõmica Organica, Universidade de Vigo, Spain
bZeneca Industries, Alderley Park, Cheshire, UK
cChemistry Department, University of Durham, Durham, UK
The nitrosation reaction of N,N'-Dimethyl-N0-cyanoguanidine is reversible and the mechanism is similar to that found
for the nitrosation of amides and ureas.
The nitrosation of amines, ureas, amides has received much
attention, owing in large part to the potential 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 free base form of the
substrate,1 while that of amides and ureas involves fast
O-nitrosation followed by slow proton transfer from
the substrate and a fast internal rearrangement to yield the
N-nitroso products.1±4 Guanidines can be considered nitro-
genated analogues of ureas. However, their peculiar struc-
ture makes them compounds of great basicity, and in this
sense, are more similar to amines than ureas. This situation
makes the kinetic study of the nitrosation of guanidines,
molecules that combine characteristics of both functional
groups, very interesting and provides a bridge between
amines and ureas.5
Results and Discussion
The pKa of CG was measured potentiometrically, and a
value of 7.9 was obtained, similar to literature values.6 This
means that at the working acidities, CG will exist mainly in
the protonated form.
The in¯uence of the concentration of the CG on k0,
the measured pseudo ®rst order constant, was studied at
‡
three di€erent constant H concentrations (0.1, 0.2 and
0.3 mol dm 3) and CG concentrations ranging from 0 to
2.0 Â10 2 mol dm 3. The plots (see Fig. 1) are all good
straight lines with signi®cant positive intercepts. The values
of both the slopes and intercepts increase with increasing
‡
[H ]. This behaviour is indicative of a ®rst order term with
respect to [CG] and, shows that the nitrosation of CG is an
equilibrium reaction [eqn. (1)]. The value of the equilibrium
constant can be obtained from the relation between the
slopes and the intercepts of each straight line. A value of
In the present work we report the results of a kinetic
3
‡
investigation in acid media (1.6 Â10 3±0.3 mol dm H ) of
1
K ˆ 150220 dm3 mol was obtained.
the nitrosation of N,N'-dimethyl-N0-cyanoguanidine (CG).
K
HNO2 ‡ CG „ NCG
ꢀ1†
Experimental
CG and N,N'-dimethyl-N-nitroso-N0-cyanoguanidine (NCG) were
obtained from Zeneca laboratories (UK). D2O was supplied by
CIEMAT (Spain). All other reagents were Merck products and
were used as received. Kinetics studies were carried out at 25 8C
and at a constant ionic strength of 0.5 mol dm 3. The analyses
of the kinetic data were performed using the integration method
following the formation of NCG spectrophotometrically at 280 nm.
Nitrosation of CG gives only one product as observed by HPLC.
This was shown to be identical to the sample of NCG, which was
prepared and authenticated independently.
Fig. 2 shows the in¯uence of acidity upon the reaction rate
at constant concentration of CG. The plot is a good straight
line that passes through the origin, indicative of a ®rst order
‡
dependence on the concentration of H . The data obtained
‡
in the studies of the in¯uence of [CG] and [H ] can be ®tted
to eqn. (2).
‡
‡
ko ˆ kn‰CGŠ‰H Š ‡ kd‰H Š
ꢀ2†
The value of the third order rate constant kn for the nitros-
ation of CG obtained from the di€erent experiments was
0.2420.01 dm6 mol 2 s 1, and the value of kd, the second
order rate constant for the denitrosation of NCG, obtained
was: (1.620.2) Â10 3 dm3 mol 1 s
1
.
Fig. 1 Influence of CG concentration on ko;
‡
‡
3
,
(w) [H ] ˆ 0.30 mol dm 3, (*) [H ] ˆ 0.204 mol dm
‡
3
(Q) [H ] ˆ 0.102 mol dm
*To receive any correspondence (e-mail: jherves@uvigo.es).
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
Fig. 2 Influence of acidity on the reaction rate;
3
3
[CG] ˆ 3.3Â10 mol dm

View Article Online
J. CHEM. RESEARCH (S), 1998 475
In order to explore the apparent di€erences between
amines and cyanoguanidine, we studied the in¯uence of
halide ions on the reaction rate. These ions catalyse the
nitrosation of amines (by way of nitrosyl halides generated
in situ) but not of amides and ureas. Table 1 shows the
e€ect of the addition of X to the reaction media on
the rate constant. As can be observed, there is no trace
of catalysis. Thus, towards nitrosation, CG behaves much
more like an amide or urea. Halide ions at these concen-
trations produce substantial catalytic e€ects in the nitros-
ation or diazotisation of amines.
Table 1 Influence of the concentration of X on the
3
3
pseudo first order constant, ko; [CG] ˆ 8.8Â10 mol dm
,
‡
3
[H ] ˆ 0.20 mol dm
102 [NaCl]/mol dm
102 [NaBr]/mol dm
104 ko/s
3
3
1
Ð
Ð
Ð
Ð
Ð
1.2
2.8
5.6
7.70
7.73
7.57
7.53
7.70
7.91
7.72
2.39
5.59
11.2
Ð
Ð
Ð
Scheme 1
(typically 0.3).7 Besides, taking into account the mechanism
outlined in Scheme 1, the observed value for the isotope
e€ect for the nitrosation reaction includes the in¯uence of
the isotopic substitution on the equilibrium constants K1
and K2 and on the rate constant for the slow step k3.
Replacement of water by deuteriated water increases the
value of K1 2.55 times.7 Assuming that there is a negligible
isotope e€ect upon K2 (since it does not involve a proton
transfer), then the value of the kinetic isotope e€ect on the
slow step, k3(H)/k3(D), can be estimated as 4.1. This is con-
sistent with the proposed step being a slow proton transfer
from an acidic species to the water.
It can be concluded that the basicity of the reactive form
is the main factor determining the mechanistic behaviour of
CG towards nitrosating agents. In acid media, it is the pro-
tonated form of CG, of very low basicity, which reacts. This
®ts in to the pattern of behaviour found for other nitrogen
nucleophiles of low basicity, such as ureas and amides,
which is quite di€erent to that found for the much more
basic amines. Interestingly the much less basic 2,4-dinitro-
aniline shows no halide ion catalysis,8 and so behaves more
like an amide or urea.
To study the mechanism of the process in more detail, the
possibility of the existence of general base catalysis, of
the type found in the nitrosation of amides and ureas, was
investigated. For this, a bu€er of monochloroacetic acid
(MCA) was employed. The results obtained (Table 2) are
indicative of signi®cant bu€er catalysis. This indicates
that the reaction is subject to a general base catalysis, and
implies a slow proton transfer in the rate determining step,
as occurs in the nitrosation of amides and ureas.
Table 2 Effect of MCA buffer on ko;
[CG] ˆ 8.8Â10 3 mol dm 3, pH ˆ 2.10
[MCA]/mol dm
3
1
105 ko/s
0.051
0.101
0.152
0.203
0.253
0.306
3.55
4.31
5.13
5.78
6.47
7.01
P. Herves acknowledges the Xunta de Galicia for ®nancial
support (XUGA30105A97).
The mechanism for the nitrosation of CG is shown in
Scheme 1. The ®rst step, the pre-equilibrium formation of
‡
‡
the nitrosating agent (NO or H2NO2 ) through protona-
tion of nitrous acid (K1), is followed by a fast equilibrium
reaction between the nitrosating agent with and the proto-
nated CG (K2), leading to the formation of an intermediate.
The ®nal step is a reversible rate limiting transfer of a pro-
ton from the intermediate to the reaction medium. This
mechanism leads to the rate eqn. (3) which coincides with
the experimental one [eqn. (2)]. This mechanism explains the
experimental rate equation, the absence of catalysis by X ,
and the existence of general base catalysis.
Received, 28th April 1998; Accepted, 11th May 1998
Paper E/8/03199A
References
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Perkin Trans. 2, 1991, 2091.
‡
‡
ko ˆ k3K2K1‰GCŠ‰H Š ‡ k ‰H Š
ꢀ3†
3
One other experimental indication that the slow step is a
proton transfer was obtained when the reaction was carried
out in D2O and the corresponding solvent isotope e€ect was
measured. The observed deuterium isotope e€ect for the
nitrosation reaction kn(H)/kn(D) is 1.6 and for the denitros-
ation reaction, kd(H)/kd(D) is 1.2. Once again, these results
con®rm that CG behaves like an amide or urea and not like
an amine, which should show inverse solvent isotope e€ects
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