Stability and nitrosation efficiency of substituted N-methyl-N-nitrosobenzenesulfonamides

Article abstract of DOI:10.1002/(SICI)1099-1395(1998100)11:10<756::AID-POC48>3.0.CO;2-D

A series of substituted N-methyl-N-nitrosobenzenesulfonamides [2,4,6-(CH₃)₃, 4-CH₃O, 4-CH₃ 4-Cl and 4-NO₂] were synthesized. All of them transfer their nitroso group to N-methylaniline in a quantitative manner, the more reactive being those substituted with electron-withdrawing groups, thus resembling some of the known alkyl nitrites. Studies of their acid denitrosation and base-catalysed hydrolysis demonstrated that the nitrosobenzenesulfonamides are fairly stable in aqueous media between pH 2 and 11. Their relative stability in aqueous media together with their ability to transfer the nitroso group to nucleophiles suggest their use as excellent alternatives to alkyl nitrites in both neutral and basic media.

Full text of DOI:10.1002/(SICI)1099-1395(1998100)11:10<756::AID-POC48>3.0.CO;2-D

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY, VOL. 11, 756–760 (1998)
Stability and nitrosation ef®ciency of substituted N-methyl-
N-nitrosobenzenesulfonamides
L. GarcõÂa-RõÂo,1 J. R. Leis,1* J. A. Moreira1 and F. Norberto2,3
1Departamento de QuõÂmica FÂõsica, Facultad de QuõÂmica, Universidad de Santiago, 15706 Santiago, Spain
2Departamento de QuõÂmica e BioquõÂmica, Faculdade de CieÃncias, Universidade de Lisboa, 1700 Lisbon, Portugal
3CECF, Faculdade de Farma cia, Universidade de Lisboa, Av. ForcËas Armadas, 1699 Lisbon, Portugal
Received 21 July 1997; revised 23 November 1997; accepted 22 December 1997
ABSTRACT: A series of substituted N-methyl-N-nitrosobenzenesulfonamides [2,4,6-(CH3)3, 4-CH3O, 4-CH3, 4-Cl
and 4-NO2] were synthesized. All of them transfer their nitroso group to N-methylaniline in a quantitative manner, the
more reactive being those substituted with electron-withdrawing groups, thus resembling some of the known alkyl
nitrites. Studies of their acid denitrosation and base-catalysed hydrolysis demonstrated that the nitrosobenzene-
sulfonamides are fairly stable in aqueous media between pH 2 and 11. Their relative stability in aqueous media
together with their ability to transfer the nitroso group to nucleophiles suggest their use as excellent alternatives to
alkyl nitrites in both neutral and basic media. 1998 John Wiley & Sons, Ltd.
KEYWORDS: N-methyl-N-nitrosobenzenesulfonamides; stability; nitrosation efficiency
INTRODUCTION
(pH < 4), the main nitrosating species for nucleophiles
such as amines, thiols and ketones are nitrosonium ion,
dinitrogen trioxide (N2O3) and nitrosyl halides.4,5
Exhaustive studies of the reactivities of these reagents
with a variety of nucleophiles (especially amines) have
The chemistry of nitroso compounds has attracted
considerable research effort owing to the proven toxic,
carcinogenic, mutagenic and teratogenic effects of these
substances1,2 on many animal species.3 Particularly since
the discovery that nitrosamines are powerful carcinogens
in all animal species which have been tested, the
nitrosation of secondary (and tertiary) amines has been
thoroughly studied, mainly from the viewpoint of the
possible in vivo formation of nitrosamines from naturally
occurring secondary amines and sources of nitrous acid in
foods and in water supplies. In this sense, nitrosation
from nitrosamines to amines has important repercussions,
since non-carcinogenic nitrosamines or those with only a
weak activity have the potential to generate more
powerfully carcinogenic nitrosamines by nitrosation in
vivo, particularly in the acidic environment in the
stomach, where additional catalysis from naturally
occurring nucleophiles might also arise.
shown that NO , NOCl, NOBr and N2O35 are extremely
‡
efficient in the nitrosation of moderately strong nucleo-
philes, the overall reaction rate often being totally or
partially diffusion controlled.
In basic or neutral medium, nitroprussiate and alkyl
nitrites are effective nitrosating agents, their sole
limitation being their relative instability. We have
recently demonstrated that N-methyl-N-nitroso-p-tolu-
enesulfonamide (MNTS) is an effective nitrosating agent
for strong nucleophiles such as amines,6 carbanions7 and
other sulfur and oxygen nucleophiles.8 In this paper, we
report a reactivity study on other substituted N-nitroso-
benzenesulfonamides, with a nitrosating behaviour very
similar to that of MNTS. Their power as nitrosating
agents is basically modulated by the substituent effect.
Nitroso compound formation is basically controlled by
the ability of nitrosating agents to donate the nitroso
group under various conditions. In acidic medium
EXPERIMENTAL
Sulfonamides substituted with electron-withdrawing
groups were prepared as exemplified for N-methyl-4-
nitrobenzenesulfonamide as follows. Methylamine solu-
tion in THF (Aldrich) (0.02 mol) was added to 4-
nitrobenzenesulfonylchloride (2.2 g, 0.01 mol) in THF
(5 ml). The crude product was purified by thin-layer
chromatography using silica gel as adsorbent and
*Correspondence to: J. R. Leis, Departamento de Qu´ımica F´ısica,
Facultad de Qu´ımica, Universidad de Santiago, 15706 Santiago, Spain.
Contract/grant sponsor: Direccio´n General de Ensen˜ansa Superior,
Spain; contract grant number: PB96-0954.
Contract/grant sponsor: Junta Nacional de Investigac¸a˜o Cientifı´ca e
Tecnolo´gica, Portugal; contract grant number: PRAXIS XXI/BD/
5219/95.
1998 John Wiley & Sons, Ltd.
CCC 0894–3230/98/100756–05 $17.50

STABILITY AND NITROSATION EFFICIENCY OF SUBSTITUTED NITROSOBENZENESULFONAMIDES
757
RESULTS AND DISCUSSION
pKa of N-methylbenzenesulfonamides
The pKa values of substituted N-methylbenzenesulfona-
mides were measured spectrophotometrically. Figure 1
shows the dependence of the absorbance spectra of N-
methyl-p-toluenesulfonamide on the acidity of the
medium between pH 7 and 12.02. The pKa values for
N-methylbenzenesulfonamides were obtained at wave-
lengths of 250, 245, 250, 250 and 300 nm for the 2,4,6-
(CH3)3, 4-CH3O, 4-CH3, 4-Cl and 4-NO2 derivatives,
respectively, and the equation
pKa†
Aa ‡ Ab10ꢀpH
A ˆ
ꢀ1†
pKa†
1 ‡ 10ꢀpH
Figure 1. Absorbance spectra of N-methyl-p-toluenesulfo-
namide at different pH values: (1) 7.00; (2) 11.02; (3) 11.62;
(4) 12.02. Inset: absorbance±pH dependence at 250 nm
where Aa and Ab are the absorbance of the acidic and
basic species of N-methyl benzenesulfonamides, respec-
tively.
Table 1 shows the pKa obtained values, which are
compatible with results reported in the literature.10
A
value of r(Ka) = 1.0 Æ 0.1 was obtained from the
Hammett correlation, showing the effect of electron-
withdrawing groups on the stabilization of the negative
charge. The pKa of 2,4,6-trimethyl-N-methylbenzenesul-
fonamide deviates from this correlation, probably owing
to a steric effect.11
dichloromethane as eluent (yield ca 30%). Sulfonamides
substituted with electron-donating groups were prepared
as exemplified for N-methyl 4-methoxybenzenesulfona-
mide as follows. Methylamine in aqueous solution
(Aldrich) was added to 4-methoxybenzenesulfonyl
chloride (2.1 g, 0.01 mol), and the precipitate was
recrystallized from light petroleum (yield ca 40%). N-
Methyl-N-nitrosobenzenesulfonamides were obtained by
nitrosation of the corresponding N-methylbenzenesulfo-
namide with N2O4 in organic media according the
method developed by White.9
All kinetic experiments were carried out at 25°C under
pseudo-first-order conditions, with the N-methyl-N-
nitrosobenzenesulfonamide always in deficiency. Be-
cause of the poor solubility in water of N-methyl-N-
nitrosobenzenesulfonamides, they were dissolved in a
small quantity of organic solvent (usually dioxane) prior
to preparation of aqueous solutions. The final concentra-
tion of organic solvent in the medium was usually 3.3%
(v/v), except for nitrosation to N-methylaniline (see
below). Reaction kinetics were studied by following the
change in absorbance (generally in the range 280–300 nm
for acid denitrosation and basic hydrolysis and 340 nm
for nitrosation to N-methylaniline) using a Uvikon 930 or
Milton Roy Spectronic 3000 array spectrophotometer.
Absorbance–time data always fitted the first-order
integrated equation, and k0, the corresponding first-order
pseudo-constant, was reproducible to within 3%.
Nitrosation to N-methylaniline
N-Methyl-N-nitrosobenzenesulfonamides
(X-MNBS)
can easily transfer their nitroso group to moderate
nucleophiles. Quantitative nitrosation (yield of N-
nitrosamine > 90%) of X-MNBS to N-methylaniline
was studied under pseudo-first-order conditions, with
deficiency of the nitrosating agent. The reaction medium
was chosen to be water–dioxane (1:1, v/v) because of the
low solubility of N-methylaniline in an aqueous medium.
Plotting k0
against total amine concentration yielded
good straight lines (Fig. 2), showing that the reaction was
of first order with respect to the amine and occurs by
nucleophilic attack of neutral amine at the nitroso group
of X-MNBS. Second-order rate constants for this reaction
are given in Table 2 together with the corresponding
constants for alkyl nitrites of similar reactivity.
Rate constants for nitrosation of N-methylaniline by
alkyl nitrites were estimated considering that MNTS
reacts similarly to 2-ethoxyethyl nitrite.6 Substituent
effects on alkyl nitrites were based on values previously
Table 1. pKa values of substituted N-methylbenzenesulfonamides
X
pKa
2,4,6-(CH3)3
12.66
4-CH3O
11.73
4-CH3
11.64
4-Cl
11.10
4-NO2
10.71
1998 John Wiley & Sons, Ltd.
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´ ´
L. GARCIA-RIO ET AL.
758
Figure 2. In¯uence of amine concentration on k0 for
nitrosation to N-methylaniline from substituted N-methyl-
N-nitrosobenzenesulfonamides. Substituent: (*) 4-NO2; (*)
4-Cl; (&) 4-CH3; (&) 4-CH3O; (~) 2,4,6-(CH3)3 at 25°C
obtained from their reactivity with other amines12 and
were extrapolated for N-methylaniline. X-MNBS are thus
found to behave very similarly to the more activated alkyl
nitrites.
Scheme 1
Reaction rates are sensitive to aromatic substituents
[the 4-NO2 derivative is 1000 times more reactive than
the 2,4,6-(CH3)3 derivative]. The rate increase observed
with electron-withdrawing substituents must be related to
the electrophilic character of the nitroso group and
stabilization of the partial negative charge generated in
the transition state of the reaction (Scheme 1).
For the deprotonation equilibrium of substituted N-
methylbenzenesulfonamides, the Hammett r value is
(Ka) = 1.0 Æ 0.1. A value of r(K1) = 1.47 for the equili-
brium (1) can be estimated using the values of the
equilibrium constants K2 and K3 (Scheme 2). The
equilibrium constant K2 was calculated using
k2 = 7.78 Â 1010 (Ref. 13) and k 2 = 0.188 was calculated
in turn using literature data for acidic denitrosation of the
N-methyl-N-nitrosoaniline14 and considering a pKa of
5.85 for the former compound. The values of K3 for the
different sulfonamides were obtained in our laboratory.15
For the nitrosation reaction, r(Ka) = 2.21 Æ 0.04, i.e. the
rate of nitrosation is more sensitive to substituent effects
than the equilibrium, implying that the transition state is
subject to greater stabilization by electron-withdrawing
substituents than the product ion.
These anomalous values have been observed in the
deprotonation of nitroalkanes.16 The ‘anomalies’ arise
because the substituent ‘sees’ more than one bond
change. In example given by Bordwell et al.,17 for
deprotonation of nitroalkanes, the carbon is more
negative in the transition state than in the product state
because the charge is not delocalized on the oxygen of the
nitro group at that stage. Anomalous effects should also
arise even if one of the major electronic changes were not
a bonding change but a solvation or hybribization
change.18 A condition could hold where solvation of an
atom does not keep in step with the bonding change. A blg
more negative than beq might occur owing to the weaker
solvation in the transition state than in the product state.
There is some evidence than this phenomenon occurs in
the alkaline hydrolysis of aryl esters of phenylmethane-
sulfonic acid.19 The oxygen is considered to be less
solvated in the transition state than in the product, thus
leading to a less dispersed charge, which will be more
susceptible to substituents than is the more solvated
ion.20
Table 2. Second-order rate constants for nitrosation of N-
methylaniline by N-methyl-N-nitrosobenzenesulfonamides in
dioxane±water (1:1, v/v) compared with the extrapolated
values of the corresponding nitrosation by activated alkyl
nitrites
1
1
X in X-MNBS k (M 1s
)
R in RONO
k (M 1/s
)
5
5
2,4,6-(Me)3
4-MeO
4-Me
1.67 Â 10
5.68 Â 10
1.05 Â 10
6.97 Â 10
1.27 Â 10
CH3CH2
EtOCH2CH2
BrCH2CH2
Cl2CHCH2
Cl3CCH2
1 Â 10
1 Â 10
Stability of substituted N-methyl-N-nitrosoben-
zenesulfonamides
5
4
4
2
4
4
3
2
6.5 Â 10
6.5 Â 10
7 Â 10
4-Cl
The stability in aqueous media is determined by their acid
hydrolysis (denitrosation) and also their basic hydrolysis
4-NO2
1998 John Wiley & Sons, Ltd.
JOURNAL OF PHYSICAL ORGANIC CHEMISTRY, VOL. 11, 756–760 (1998)

STABILITY AND NITROSATION EFFICIENCY OF SUBSTITUTED NITROSOBENZENESULFONAMIDES
759
Scheme 2
by the direct attack of HO on the sulfonyl group of
X-MNBS. Kinetic studies were carried out under pseudo-
first-order conditions with [X-MNBS] much lower
effects, yielding the observed insensitivity of X-MNBS to
acid denitrosation.
Basic hydrolysis of MNTS is often used to produce
diazomethane and this is the main reason why it has been
so much studied.22,23 This reaction occurs by direct
attack of HO on the sulfonyl group of X-MNBS and is
greatly accelerated by electron-withdrawing groups.
These groups increase the electrophilic character of
SO2 and thus facilitate the cleavage of the S—N bond.
‡
than [H ] or [OH ], keeping the ionic strength
(NaClO4) constant. Denitrosation and basic hydrolysis
show a linear dependence of the first-order pseudo-
‡
constant, k0, with H or HO concentration, so that both
processes are first order in both X-MNBS and catalyst
‡
(H or HO ). Second-order rate constants for denitrosa-
tion are not sensitive to the presence of substituents in the
aromatic ring of X-MNBS. This is consistent with a
concerted mechanism previously proposed for acid
denitrosation of MNTS.21 In the transition state, both
CONCLUSIONS
the breaking of the bond [N
N
=
ÁÁÁ
O] and protonation of
The main inconvenience for the use of alkyl nitrites
(RONO) as nitrosating agents arises from their instability
in aqueous medium due to their acidic24 and basic
hydrolysis.25 This is the reason why they are only used
between pH 8 and 11 and only with strong nucleophiles.
The stabilities of highly reactive alkyl nitrites (those with
electron-withdrawing substituents in the alkyl group) and
X-MNBS are compared in Fig. 3. The criterion used for
stability was a half-life of the nitrosating agent of
>60 min. As can be seen, X-MNBS are stable over a
much larger pH range than alkyl nitrites. In fact, they are
efficient even in the pH range 3–8 where no other
nitrosating species is reactive.
ÁÁÁ
‡
sulfonamide nitrogen [(O
=
N)—N H ] occur concur-
rently via a slightly imbalanced transition state. The
first step is facilitated by the presence of electron-
withdrawing substituents whereas, in contrast, the
second is facilitated by electron-donating groups. The
final result is therefore a balance between these two
X-MNBS are less stable than alkyl nitrites in basic
medium, but as the nucleophilic character increases with
increasing pKa of nucleophiles, it is expected that
competition between the reaction of X-MNBS with
OH or with any other nucleophile would favour the
nucleophiles susceptible to nitrosation, especially those
with high pKa.
The great advantage of using X-MNBS instead of alkyl
nitrites as nitrosating agents comes from their great
stability in acidic media, making possible efficient
nitrosation of moderate nucleophiles in the pH range 3–8.
Figure 3. pH stability range of alkyl nitrites and substituted
N-methyl-N-nitrosobenzenesulfonamides (de®ned by half-
lives > 60 min)
1998 John Wiley & Sons, Ltd.
JOURNAL OF PHYSICAL ORGANIC CHEMISTRY, VOL. 11, 756–760 (1998)

´
´
760
L. GARCIA-RIO ET AL.
7. J. R. Leis, M. E. Pen˜a and A. Rios. J. Chem. Soc., Perkin Trans. 2
1233 (1993).
Acknowledgements
8. J. R. Leis, M. E. Pen˜a and A. Rios. J. Chem. Soc., Perkin Trans. 2
587 (1995).
9. E. H. White. J. Am. Chem. Soc. 77, 6008 (1955).
10. G. Dauphin and A. Kergomard. Bull. Soc. Chim. Fr. 5, 486 (1961).
11. J. E. Leffler and E. Grunwald. Rates and Equilibria of Organic
Reactions. Wiley, New York (1963).
Financial support from the Direccio´n General de
Ensen˜ansa Superior, Spain (project PB96-0954), is
gratefully acknowledged. J. A. Moreira thanks the Junta
Nacional de Investigac¸a˜o Cientif´ıca e Tecnolo´gica of
Portugal (PRAXIS XXI/BD/5219/95).
12. L. Garcı´a-R´ıo, E. Iglesias, J. R. Leis, M. E. Pen
˜a and A. Rios. J.
Chem. Soc., Perkin Trans. 2 29 (1993).
13. E. Fabricio, E. Kalatzis and J. H. Ridd. J. Chem. Soc. 533 (1966).
14. I. D. Biggs and D. L. H. Williams. J. Chem. Soc., Perkin Trans. 2
107 (1975).
15. L. Garcia Rio, J. R. Leis, J. A. Moreira and F. Norberto. J. Chem.
Soc., Perkin Trans. 2. 1613 (1998).
REFERENCES
16. C. F. Bernasconi. Adv. Phys. Org. Chem. 27, 119 (1992).
17. F. G. Bordwell, W. J. Boyle, J. A. Hautala and Y. C. Yee. J. Am.
Chem. Soc. 91, 4002 (1969).
18. A. Williams. Adv. Phys. Org. Chem. 27, 1 (1992).
19. S. Thea, M. G. Harun and A. Williams. J. Chem. Soc., Chem.
Commun. 717 (1979).
20. W. P. Jencks, S. R. Brant, J. R. Gandler, G. Fendrick and C.
Nakamura. J. Am. Chem. Soc. 104, 7045 (1982).
21. D. L. H. Williams. J. Chem. Soc., Perkin Trans. 2 691 (1976).
22. Th. J. de Boer and H. J. Backer. Recl. Trav. Chim. Pays-Bas 73,
229 (1954); M. Pearce. Helv. Chim. Acta 63, 887 (1980).
23. T. H. Black. Aldrichim. Acta 16, 3 (1983).
24. L. Garc´ıa-R´ıo, E. Iglesias, J. R. Leis, M. E. Pen˜a and D. L. H.
Williams. J. Chem. Soc., Perkin Trans. 2 1673 (1992).
25. S. Oae, N. Asai and K. Fujimori. J. Chem. Soc., Perkin Trans 2 571
(1977).
1. R. Montesano and H. Bartsch. Mutat. Res. 32, 179 (1976); A. E.
Pegg. Adv. Cancer Res. 25, 195 (1977).
2. L. Tomatis and U. Mohr (Eds). Transplacental Carcinogenesis,
IARC Scientific Publications No. 4. IARC, Lyon (1973); D.
Yarosh. Mutat. Res. 145, 1 (1985).
3. P. N. Magee, R. Montesano and R. Preussmann. in Chemical
Carcinogenesis, edited by C. E. Searle, p. 141. American Chemical
Society, Washington, DC (1976).
4. D. L. H. Williams. Nitrosation. Cambridge University Press,
Cambridge (1988).
5. J. H. Ridd. Adv. Phys. Org. Chem. 1978, 16, 1; A. Castro, J. R. Leis
and M. E. Pen˜a. J. Chem. Res. (S) 216 (1986); J. Casado, A. Castro,
J. R. Leis, M. A. Lo´pez-Quintela and M. Mosquera. Monatsh.
Chem. 114, 639 (1983).
6. A. Castro, J. R. Leis and M. E. Pen˜a. J. Chem. Soc., Perkin Trans. 2
1861 (1989).
1998 John Wiley & Sons, Ltd.
JOURNAL OF PHYSICAL ORGANIC CHEMISTRY, VOL. 11, 756–760 (1998)