Nitroso group transfer from substituted N-methyl-N-nitrosobenzenesulfonamides to amines. Intrinsic and apparent reactivity

Article abstract of DOI:10.1021/jo0006730

We have studied the nitroso group transfer from substituted N-methyl-N-nitrosobenzenesulfonamides to primary and secondary amines, observing that the rate of the reaction increases as a consequence of the presence of electron withdrawing groups on the aromatic ring of the nitrosating agents. The rate constants determined for the nitroso group transfer k_tr, give good Bronsted-type relationships between log k_tr (rate constant for nitroso group transfer) and pK_a/^R₂^NH₂⁺ and pK_a/^{leaving group}. The study of the nitrosation processes of secondary amines catalyzed by ONSCN and denitrosation catalyzed by SCN^-, in combination with the formation equilibrium of ONSCN, has enabled us to calculate the value of the equilibrium constant for the loss of the NO⁺ group from a protonated N-nitrosamine (pK_NO/^R₂^{N+ HNO}), which can be defined by analogy with pK_a/^R₂^NH₂⁺. The value of pK_NO/^X-NO for the loss of the NO⁺ group from an N-methyl-N-nitrosobenzenesulfonamide was obtained in a similar way. By using values of ΔpK_NO = pK_NO/^R₂^{N+ HNO} - pK_NO/^X-NO, we were able to calculate the equilibrium constant for the nitroso group transfer and characterize the transition state. On the basis of Bronsted-type correlations, we have obtained values of β_nucl/^norm and α_lg/^norm ? 0.55, showing a perfectly balanced transition state. In terms, of the Marcus theory, the calculation of the intrinsic barriers for the nitroso group transfer reaction shows that the presence of electron withdrawing groups on thearomatic ring of the N-methyl-N-nitrosobenzenesulfonamides does not cause these barriers to vary.

Full text of DOI:10.1021/jo0006730

J . Org. Chem. 2001, 66, 381-390
381
Nitr oso Gr ou p Tr a n sfer fr om Su bstitu ted
N-Meth yl-N-n itr osoben zen esu lfon a m id es to Am in es. In tr in sic a n d
Ap p a r en t Rea ctivity
Luis Garc´ıa-R´ıo,*,† J ose´ Ramo´n Leis,† J ose´ A. Moreira,† and Fa´tima Norberto‡
Departamento de Quı´mica Fı´sica, Facultad de Quı´mica, Universidad de Santiago,
15706 Santiago, Spain, and Departamento de Quı´mica e Bioqu´ımica, Faculdade de Cieˆncias,
Universidade de Lisboa, P-1749-016 Lisboa, Portugal
qflgr3cn@usc.es
Received May 2, 2000
We have studied the nitroso group transfer from substituted N-methyl-N-nitrosobenzenesulfona-
mides to primary and secondary amines, observing that the rate of the reaction increases as a
consequence of the presence of electron withdrawing groups on the aromatic ring of the nitrosating
agents. The rate constants determined for the nitroso group transfer, ktr, give good Bronsted-type
+
relationships between log ktr (rate constant for nitroso group transfer) and pKRa NH and pKaleaving
2
2
group. The study of the nitrosation processes of secondary amines catalyzed by ONSCN and
denitrosation catalyzed by SCN-, in combination with the formation equilibrium of ONSCN, has
enabled us to calculate the value of the equilibrium constant for the loss of the NO+ group from a
R2N+
NO
2
2
protonated N-nitrosamine (pK
HNO), which can be defined by analogy with pKRa NH +. The value
X-NO
of pK
for the loss of the NO+ group from an N-methyl-N-nitrosobenzenesulfonamide was
obtained in a similar way. By using values of ∆pKNO ) pK
calculate the equilibrium constant for the nitroso group transfer and characterize the transition
NO
R2N+HNO
NO
X-NO
NO
- pK
, we were able to
norm
nucl
norm
=
lg
state. On the basis of Bronsted-type correlations, we have obtained values of â
and R
0.55, showing a perfectly balanced transition state. In terms of the Marcus theory, the calculation
of the intrinsic barriers for the nitroso group transfer reaction shows that the presence of electron
withdrawing groups on the aromatic ring of the N-methyl-N-nitrosobenzenesulfonamides does not
cause these barriers to vary.
In tr od u ction
nitrosamine that can promote transnitrosation of a great
variety of nucleophiles is the N-methyl-N-nitroso-p-
toluenesulfonamide, MN-4-Me-BS. In the presence of
nucleophiles such as OH- or EtO- (Scheme 1) which
attack the SO2 group of MN-4-Me-BS, the latter decom-
poses to afford diazometane.5 However, unlike nitrosa-
mides and nitrosoureas, MN-4-Me-BS also undergoes
nucleophilic attack by amines at its NdO group to give
the corresponding nitrosamines,6 and meanwhile in acid
medium, as is common with other N-nitrosamines, deni-
trosation occurs.7 MN-4-Me-BS (diazald) is also known
to transfer its nitroso group, forming nitrosyl complexes.8
This paper will examine the nitroso group transfer
from substituted N-methyl-N-nitrosobenzenesulfona-
mides (Scheme 2) (MN-4-MeO-BS, MN-4-Me-BS, MN-4-
Cl-BS, MN-4-NO2-BS) to primary and secondary amines.
The use of different nitrosating agents will allow us to
study not just the effect of the nucleophile but also that
of the nitrosating agent on the rate of the process. The
Increasing attention is being paid to the chemistry of
nitrosamines owing to the toxicity1 and carcinogenic,2
mutagenic,3 and teratogenic4 properties of these com-
pounds. In this sense, transnitrosation from nitrosamines
to amines has important repercussions because noncar-
cinogenic nitrosamines or those with only a weak activity
have the potential to generate more powerfully carcino-
genic nitrosamines by transnitrosation in vivo, particu-
larly in the acid environment of the stomach, where
additional catalysis from naturally occurring nucleophiles
might also occur.
The N-N bond of a N-nitrosamine (R2N-NdO) can
undergo heterolytic or homolytic cleavage, producing
fragments capable of affecting nitrosation. The alterna-
tive possibility is that direct transfer of the NO group
can occur without the intermediacy of a free nitrosating
agent formed from the above fragments. This is the basis
of the so-called transnitrosation reactions of nitrosamines
where a direct transfer of the nitroso group occurs, by
attack of a nucleophile on the N-atom. The best studied
(5) (a) Pearce, M. Helv. Chim. Acta 1980, 63, 887. (b) Castro, A.;
Leis, J . R.; Pen˜a, M. E. J . Chem. Soc., Perkin Trans. 2 1989, 1861. (c)
Garc´ıa-Rio, L.; Leis, J . R.; Moreira, J . A.; Norberto, F. J . Phys. Org.
Chem. 1998, 11, 756.
* To whom correspondence should be addressed.
† Universidad de Santiago.
(6) Garc´ıa-R´ıo, L.; Iglesias, E.; Leis, J . R.; Pen˜a, M. E.; Rios, A. J .
Chem. Soc., Perkin Trans. 2 1993, 29.
(7) (a) Williams, D. L. H. J . Chem. Soc., Perkin Trans. 2 1976, 691.
(b) Garc´ıa-R´ıo, L.; Leis, J . R.; Moreira, J . A.; Norberto, F. J . Chem.
Soc., Perkin Trans. 2 1998, 11, 756.
(8) (a) Legzdins, P.; Reina, R.; Shaw, M. J . Organometallics 1993,
12, 1029. (b) Daff, P. J .; Legzdins, P.; Retting, S. J . J . Am. Chem. Soc.
1998, 120, 2688.
‡ Universidad de Lisboa.
(1) Barnes, J . M.; Magee, P. N. Br. J . Ind. Med. 1954, 11, 167.
(2) Chemical Carcinogens, 2nd ed.; Searle, C. E., Ed.; ACS Mono-
graph 182; American Chemical Society: Washington, DC, 1985.
(3) Zimmermann, F. K. Biochem. Pharmacol. 1971, 20, 985.
(4) Druckrey, H. Xenobiotica 1973, 3, 271.
10.1021/jo0006730 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/04/2001

382 J . Org. Chem., Vol. 66, No. 2, 2001
Garc´ıa-R´ıo et al.
(5 M) was slowly added. The mixture was stirred for 1 h. The
organic phase was separated and washed with water, and the
N-methyl-N-nitrososulfonamides were finally recrystallized
from dichloromethane/petroleum ether with a final yield of
80%. This method has the advantage of preventing the
hydrolysis of the nitrosoderivatives by sequestering the latter
in the organic phase as soon as they are formed. The secondary
and primary amines (Aldrich), pyrrolidine, piperidine, N-
methylpiperazine, piperazine, morpholine, glycine ethyl ester,
glycyl glycine, methoxyethylamine, glycine, and propylamine,
were of the highest available purity and in some cases were
distilled under argon and used shortly afterward.
Sch em e 1
All kinetic experiments were performed with a great excess
of the nucleophile over N-methyl-N-nitrososulfonamide. The
pH was controlled using buffer solutions of the nucleophile
itself, which were made up of amine and perchloric acid.
Because of their poor solubility in water, the N-methyl-N-
nitrososulfonamides were dissolved in a small amount of
organic solvent (dioxane) prior to the preparation of aqueous
solutions. The final concentration of organic solvent in the
medium was usually 3.3% (v/v). The reaction kinetics were
generally studied by following the change in absorbance
(generally in the range 250-270 nm for MN-4-MeO-BS, MN-
4-Me-BS, and MN-4-Cl-BS and in the range 290-340 nm for
MN-4-NO2-BS) using an spectrophotometer fitted with ther-
mostated cell holders (all experiments were carried out at 25
°C). The absorbance-time data always fitted the first-order
integrated equation, and kobs, the corresponding pseudofirst-
order rate constant, could be reproduced to within 3%.
The identity of the reaction products was confirmed from
the characteristics of the UV spectra of the reactions on
completion and in some cases by HPLC with 1:1 acetoni-
trile-water as the eluant, where retention times and peak
areas were compared with those of pure N-nitrosamines. In
every case we found quantitative N-nitrosamine formation
compatible with the spectral changes observed in kinetic
experiments.
Sch em e 2
results obtained show that for amines with similar steric
hindrance their reactivity against the substrate carriers
of the nitroso group varies linearly with their basicity.
The study of the nitrosation processes of secondary
amines by ONSCN and their corresponding denitrosation
catalyzed by SCN- enables us, in combination with the
protonation pKa of the nitrosamines, to define a scale for
the loss of the nitroso group with regard to a protonated
R2N+
NO
nitrosamine, pK
HNO. This scale is similar to the
+
.
basicity scale for proton-transfer reactions, pKaR NH
2
2
The reactivities of the different amines against the
different nitrosating agents correlate perfectly with the
calculated values of ∆pKNO, a behavior pattern similar
to that observed in proton-transfer reactions. The Marcus
theory9 of outer sphere electron-transfer reactions leading
to the relationship between kinetic and thermodynamic
barriers to chemical reaction has explained the empirical
findings concerning a certain number of reaction pro-
cesses including proton transfer,10 hydride transfer,11 or
methyl transfer12,13 reactions. This wide range of applica-
tions indicates that the Marcus theory could also be
invoked to explain nitroso group transfer reactions.
Resu lts
1. Nitr oso Gr ou p Tr a n sfer fr om Su bstitu ted N-
Meth yl-N-n itr osoben zen esu lfon am ides. Reactions be-
tween N-methyl-N-nitrosobenzenesulfonamides and sec-
ondary amines produce N-nitrosamines in quantitative
yield. Plotting kobs against the pH for constant total amine
concentration produced sigmoid curves that could be put
in linear form by plotting 1/kobs against [H+]. This
behavior is in keeping with the assumption that reaction
takes place directly with the basic form of the amine,
without the involvement of general acid or base cataly-
sis.6 When kobs was plotted against amine concentration,
good straight lines were produced, showing that the
reaction was of first order with respect to the amine (see
Figure 1). The kinetic law found for the present reactions
is given by eq 1
Exp er im en ta l Section
N-methylbenzenesulfonamides were synthesized by reaction
of the corresponding benzenesulfonyl chlorides with an excess
of methylamine in water. The products were extracted with
dichloromethane and washed with a solution of sodium hy-
drogen carbonate and water. N-methyl-p-toluenesulfonamide
and its nitroso derivative, MN-4-Me-BS, were supplied by
Ega-chemie and Merck, respectively. N-methyl-N-nitrososul-
fonamides were prepared using a biphasic water/dichloro-
methane mixture. The aqueous phase containing sodium ni-
trite and the organic phase containing the parent sulfonamide
were mixed together, and then concentrated perchloric acid
kobs ) kOH[OH-] + ktr[R2NH]
(1)
where kOH and ktr (values of ktr can be found in Table 1)
are the rate constants for hydrolysis5b,c and aminolysis
of the substrate. For all the reactions, the value of kOH
was negligible compared to the aminolysis term in eq 1.
The slopes of Bronsted-type plots (statistically corrected)
(9) (a) Marcus, R. A. J . Chem. Phys. 1956, 24, 966. (b) Marcus, R.
A. J . Chem. Phys. 1957, 26, 867.
(10) (a) Marcus, R. A. J . Phys. Chem. 1968, 72, 891. (b) Cohen, A.
O.; Marcus, R. A. J . Phys. Chem. 1968, 72, 4249. (c) Kresge, A. J . Acc.
Chem. Res. 1975, 8, 354.
(11) (a) Kreevoy, M. M.; Lee, I.-S. H. J . Am. Chem. Soc. 1984, 106,
2550. (b) Lee, I.-S. H.; Ostovic, D.; Kreevoy, M. M. J . Am. Chem. Soc.
1988, 110, 3989. (c) Lee, I.-S. H.; J eoung, E. H. J . Org. Chem. 1998,
63, 7275.
(12) Albery, W. J .; Kreevoy, M. M. Adv. Phys. Org. Chem. 1978, 16,
87.
obtained with the log ktr vs pKRa NH + values are collected
2
2
in Table 1 (ânuc values). The slope of Bronsted-type plots
group
obtained with the log ktr vs pKaleaving
values are also
group
reported in Table 1 (R1g values), where pKaleaving
refers to the substrate.
(13) (a) Lewis, E. S.; McLaughlin, M. L.; Douglas, T. A. J . Am. Chem.
Soc. 1985, 107, 6668. (b) Lewis, E. S. J . Phys. Chem. 1986, 90, 3796.
(c) Galezowski, W.; Ibrahim, P. N.; Lewis, E. S. J . Am. Chem. Soc.
1993, 115, 8660.
Primary amines react with N-methyl-N-nitrososulfon-
amides considerably more slowly than secondary amines

Nitroso Group Transfer
J . Org. Chem., Vol. 66, No. 2, 2001 383
equation can be simplified16
kobs ) (kNOKNO
+
+
nit
k
KONSCN[SCN-])KRa NH +[R2NH]tot (4)
ONSCN
nit
2
2
The intercept at the origin in the plots of kobs vs [SCN-]
(see Figure 3) corresponds with the nitrosation of the
corresponding amines by NO+. On the basis of the slopes
of the plots of kobs vs [SCN-], the rate constant for
nitrosation of secondary amines by ONSCN can be
calculated using the value given in the bibliography16 of
KONSCN ) 30 M-2. The values of knOiNt SCN obtained for the
ONSCN
nit
nitrosation of piperazine (k
) 1.13 × 107 M-1s-1),
ONSCN
morpholine (k
ylbenzylamine (k
) 1.35 × 107 M-1s-1), and N-meth-
F igu r e 1. Plot of kobs vs [amine] for nitroso group transfer
from MN-4-MeO-BS to several secondary amines at 25 °C: (O)
morpholine; (b) N-methylpiperazine; and (0) piperazine (first
nit
ONSCN
) 1.40 × 107 M-1s-1) agree with
nit
the value found by Williams and Meyer16 for the nitro-
sation of morpholine by ONSCN.
+
R2NH2
pKa). [MN-4-MeO-BS] ) 1 × 10-5M, pH ) pKa
.
The rate constants determined experimentally,
of similar basicity. By applying eq 1 (see Figure 2) we
can obtain kOH and ktr (see ktr data in Table 2). The slopes
of Bronsted-type plots (statistically corrected) obtained
ONSCN
k
, verify the Bronsted relationship (eq 5) on the
nit
ONSCN
basis of which the values of k
will be interpolated
nit
or extrapolated for each amine studied in the transni-
trosation process.
with the log ktr vs pKRa NH + values are collated in Table 2
3
(ânuc values). The slope of Bronsted-type plots obtained
group
with the log ktr vs pKaleaving
values are also collated
ONSCN
nit
log k
) 6.919 + 2.43 ×
2
in Table 2 (R1g values). It can be observed that the
primary amines react approximately 40 times more
slowly than the secondary amines of a similar basicity.
Since in sterically insensitive reactions small secondary
aliphatic amines are typically substantially more reactive
than primary amines of equal basicity,14 the above ratio
of ktr values which favors the secondary amines indicates
a small steric hindrance in the transition state.
2. Nitr osa tion of Am in es by ONSCN. For the
purpose of evaluating the equilibrium constant for the
nitrosation process of amines, it is necessary to find out
their nitrosation and denitrosation rates. In the bibliog-
raphy, a systematic study of the denitrosation of N-
nitrosamines catalyzed by SCN- can be found.15 If the
rate constants of the nitrosation of amines catalyzed by
ONSCN can be ascertained then the equilibrium constant
for the process can be evaluated.
+
2
10-2pKRa NH
(R ) 0.992) (5)
3. Den itr osa tion of N-Nitr osa m in es by SCN-.
Singer15a studied the denitrosation of different N-nitro-
samines in the presence of a constant concentration of
SCN-, [SCN-] ) 0.05 M. The denitrosation mechanism
of nitrosamines takes place through the initial protona-
tion of the N-nitrosamine and subsequent nucleophile
attack on the protonated N-nitrosamine (slow stage) (see
Scheme 4).
Under the experimental conditions the following rate
equation can be deduced:
KT
R2N+HNO
kobs
)
[H+](kH2O + kSCN[SCN])
(6)
des
des
K
a
SCN
k
des
R2+NHNdO + SCN-
{
} R2NH + ONSCN (2)
+HNO
where 1/KRa N
corresponds with the protonation con-
2
ONSCN
k
nit
stant of the N-nitrosamine. N-nitrosamines appear to
be 1010 less basic than the corresponding amines.17
Until recently, there has also been considerable doubt
about the site of protonation of N-nitrosamines, remi-
niscent of the controversy surrounding the protonation
of amides. The best available evidence, however, now
suggests that the most stable conjugate acid for N-
nitrosamines is that which results from O-protonation18
The nitrosation of N-methylbenzylamine, morpholine,
and piperazine has been studied in the presence of SCN-
in conditions where the concentration of NaNO2 was in
deficit. The influence of the SCN- concentration on the
rate of nitrosation of N-methylbenzylamine, morpholine,
and piperazine was studied at [HClO4] ) 0.30M, [R2NH]
) 0.10M, and [NaSCN] ranging from 3.3 × 10-3 to 4.00
× 10-2 M. The pseudo-first-order rate constants, kobs
,
were in all cases found to depend linearly on the
concentration of SCN- (see Figure 3). The following
expression for kobs in the amine nitrosation by ONSCN
can be derived from Scheme 3.
(14) (a) Hall, H. K., J r. J . Org. Chem. 1964, 29, 3539. (b) J encks,
W. P. Catalysis in Chemistry and Enzymology; McGraw-Hill: New
York, 1969; Chapter 2.
(15) (a) Singer, S. S. J . Org. Chem. 1978, 43, 4612. (b) Singer, S. S.;
Singer, G. M.; Cole, B. B. J . Org. Chem. 1980, 45, 4931. (c) Singer, S.
S.; Cole, B. B. J . Org. Chem. 1981, 46, 3461.
(16) Meyer, T. A.; Williams, D. L. H. J . Chem. Soc., Perkin Trans.
2 1981, 361.
(17) Challis, B. C.; Challis, J . A. The Chemistry of Amino, Nitroso
and Nitro Compounds and their Derivatives; Patai, S., Ed.; Wiley: New
York, 1983; Chapter 26.
(18) (a) Challis, B. C.; Challis, J . A. In Comprehensive Organic
Chemistry; Sutherland, I. O., Ed.; Pergamon: Oxford, 1979; Vol. 2;
Chapter 9.9. (b) Bagno, A.; Bujnicki, B.; Bertrand, S.; Comuzzi, C.;
Dorigo, F.; J anvier, P.; Scorrano, G. Chem.sEur. J . 1999, 5, 523.
kobs
)
+ + kONSCNKONSCN[SCN-])KRa NH +[R2NH]tot[H+]
NO
2
2
(knit
K
NO
nit
KHa NO + [H+](1 + KNO+[H+] + KONSCN[H+][SCN-])
2
(3)
Under the experimental conditions of this study this

384 J . Org. Chem., Vol. 66, No. 2, 2001
Ta ble 1. Com p ila tion of Ra te Con sta n ts for Nitr oso Gr ou p Tr a n sfer fr om Su bstitu ted
Garc´ıa-R´ıo et al.
N-Meth yl-N-n itr osoben zen esu lfon a m id es to Secon d a r y Am in es: P yr r olid in e (P YR), P ip er a zin e (P IP ),
+
2
N-Meth ylp ip er a zin e (Me-P IP ), Mor p h olin e (MOR), a n d P ip er a zin e Secon d p KRa NH (P IP -H+)
2
+
2
RSO2N(CH3)H
pKRa NH
.
pKa
.
2
a
b
amount of this species must be present in acidic media
though a tautomeric equilibrium constant, KT.
In the absence of any added nucleophiles it is believed
that in aqueous solution the solvent acts as the nucleo-
phile for the denitrosation reaction. This reaction is
necessarily slower than the nucleophile catalyzed reac-
tions. In the experimental conditions used by Singer it
H2O
des
SCN
des
is shown that k
, k
[SCN] 22 in such a way that on
the basis of the values of kobs the product KTkSCN can be
des
obtained. A Bronsted relationship between KTkSCN and
pKRa NH can be established.
des
+
2
2
+
2
) ) 9.357 - 1.29pKaR NH
(R ) 0.996)
(7)
SCN
des
2
log(KTk
F igu r e 2. Plot of kobs vs [amine] for nitroso group transfer
from MN-4-Cl-BS to several primary amines at 25 °C: (O)
glycine ethyl ester; (b) glycil glycine; and (0) methoxyeth-
On the basis of the Bronsted relationship, the values
+
ylamine. [MN-4-Cl-BS] ) 1 × 10-5M, pH ) pKaRNH3
.
of KTkSCN for the amines used in this study can be
des
ONSCN
nit
interpolated. The calculated values for k
and KT
where resonance stabilization of the positive charge is
feasible (1).
SCN
k
allow us to evaluate the equilibrium constant of
des
the nitrosation/denitrosation process by ONSCN. An
important question at this point is if KT depends or not
on the nature of the substituents bonded at the amino
nitrogen atom. We did not find studies in the bibliography
concerning this equilibrium constant for nitrosamines.
However, we think that the percentage of N-protonated
nitrosamine is independent of the pKa values for proto-
nation of the nitrosamines because no resonance effects,
due to the substituents, are involved in the stabilization
of the positive charge at the amine nitrogen atom of the
nitrosamines used in this work.
The alternative conjugate acids (2, 3) cannot undergo
Discu ssion
1. Evid en ce of a Con cer ted Mech a n ism . As we
have seen, the denitrosation process of an N-nitrosamine
takes place through its protonation. Next, a nucleophile
attack on the N-protonated form of the nitrosamine takes
place in the rate limiting step. By applying the principle
of microscopic reversibility, we can conclude that the slow
similar resonance stabilization, and they are expected to
be of higher energy. This is supported by INDO calcula-
tions19 as well as 1H NMR studies.20,21 However, since
the formation of an N-conjugate acid (2) is necessary to
explain N-N fission in denitrosation processes, a small
(19) Chow, Y. L. Acc. Chem. Res. 1973, 6, 354.
(20) Kuhn, S. J .; McIntyre, J . S. Can. J . Chem. 1966, 44, 105.
(21) Olah, G. A.; Donovan, D. J .; Keefer, L. K. J . Natl. Cancer Inst.
1975, 54, 465.
(22) (a) Williams, D. L. H. Nitrosation; Cambridge University
Press: New York, 1988. (b) Williams, D. L. H. Adv. Phys. Org. Chem.
1983, 19, 381.

Nitroso Group Transfer
J . Org. Chem., Vol. 66, No. 2, 2001 385
Ta ble 2. Com p ila tion of Ra te Con sta n ts for Nitr oso Gr ou p Tr a n sfer fr om Su bstitu ted
N-Meth yl-N-n itr osoben zen esu lfon a m id es to P r im a r y Am in es: Glycin e Eth yl Ester (gee), Glycyl Glycin e (ggl),
Meth oxyeth yla m in e (MeOEtNH2), Glycin e (glc), a n d P r op yla m in e (P r NH2)
+
RSO2N(CH3)H
pKRa NH
.
pKa
.
3
a
b
nucleophiles and also to nonbasic nucleophiles because
of the fairly strong acid concentrations required.22
We can propose the following mechanistic scheme
(Scheme 5) for the nitroso group transfer from N-methyl-
N-nitrososulfonamides to amines. The first step is the
rate limiting one. In this step, the nitroso group transfer
from N-methyl-N-nitrososulfonamide to the amine takes
place. Subsequently in fast stages the protonation of the
anion of the sulfonamide will take place (depending on
the experimental pH value) and the deprotonation of the
N-nitrosamine. These processes should not be included
in the rate-determining step, since the inverse nitroso
group transfer process from the N-nitrosamine to any
nucleophile must occur through the protonated form of
the N-nitrosamine. In addition, in a previous study6 we
investigated the kinetic solvent isotope effect on the
nitroso group transfer from MN-4-Me-BS to different
primary, secondary, and tertiary amines. We can assume
that nitroso group transfer from N-methyl-N-nitrososul-
fonamides involves a mechanism in which the leaving
group is not aided by any kind of proton transfer. This
assumption is supported by the isotope effects close to
unity for primary, secondary, and tertiary amines and
for the azide ion and rules out proton transfer from either
the amine or the solvent in the rate-controlling step.
There exist at least two possible mechanisms for the
nitroso group transfer. One is a mechanism of the
addition-elimination type and another involves a direct
(concerted) displacement of the NdO group as in the case
of the basic hydrolysis of alkyl nitrites.23 Williams24 and
J encks25 have applied a methodology considering that if
it can be predicted that a change in the rate-limiting step
for a putative stepwise mechanism (Scheme 6) will occur
with a given range of substituents, then the absence of a
break at the predicted point in a linear free energy
relationship is evidence of a single-step mechanism. Plots
F igu r e 3. Plot of kobs vs [NaSCN] for nitrosation of (O)
morpholine and (b) N-methylbencylamine at 25 °C and ionic
strength 0.50 M (NaClO4). [Amine] ) 0.10 M, [HClO4] )
0.30M.
Sch em e 3
of log ktr vs ∆pKa ) pKNucleophile - pKlag obey an excellent
a
Bronsted rate law (not shown). There were no cases of
stage involved in the nitroso group transfer from substi-
tuted N-methyl-N-nitrososulfonamides to amines must
be the reverse of the denitrosation of N-nitrosamines.
This behavior is evidenced by the fact that the direct ni-
trosation of nucleophiles by nitrosamines (denitrosation)
is clearly established15 but is limited to fairly powerful
breaks in the correlation at the point of ∆pKa ) 0.
(23) Oae, S.; Asai, N.; Fujimori, K. J . Chem. Soc., Perkin Trans. 2
1978, 571.
(24) (a) Williams, A. Acc. Chem. Res. 1989, 22, 387. (b) Williams, A.
Adv. Phys. Org. Chem. 1992, 27, 1.
(25) J encks, W. P. Bull. Soc. Chim. Fr. 1988, 218.

386 J . Org. Chem., Vol. 66, No. 2, 2001
Garc´ıa-R´ıo et al.
Sch em e 4
Sch em e 5
Sch em e 6
However, the leaving groups from the hypothetical
intermediate in the reverse direction (nucleophile) are
structurally not the same as those in the forward direc-
tion. So application of this methodology is inconclusive
in our study.
try of alkyl nitrites or N-methyl-N-nitrosobenzene-
sulfonamides and the chemistry of carboxylic esters:
carboxyl chemistry is dominated by the formation of
tetrahedral intermediates, whereas it is assumed that
nitroso compounds transfer the NdO group intact in
water.
Bronsted slopes reported in Tables 1 and 2 are dra-
matically large. A possible explanation is that the deni-
trosation reaction involves a two unit change in charge
at the sulfonamide nitrogen, from positive in the nitroso
compound (Ar-SO2-N(CH3)+dN-O-) to negative in the
product (Ar-SO2-N(CH3)-). With a change of charge of
two units in the reaction vs only one in the reference
reaction (the acid dissociation), these values become
reasonable. This change of charge of two units is only
compatible with a concerted mechanism for nitroso group
transfer, so the stepwise mechanism shown in Scheme 6
can be ruled out. The existence of a concerted mechanism
for the nitroso group transfer from N-methyl-N-ni-
trosobenzenesulfonamides to amines agrees with the
results obtained for the nitrosation of amines by alkyl
nitrites in an aqueous medium6 and for the basic hy-
drolysis of alkyl nitrites.23 The fact that nitrogen is more
electronegative than carbon and has a lone pair probably
explains the significant differences between the chemis-
2. Eva lu a tion of Equ ilibr iu m Con sta n ts. The at-
tack of primary and secondary amines on substituted
N-methyl-N-nitrosobenzenesulfonamides has a simple
Bronsted type dependence on the pKa of the correspond-
ing amine (ânuc values can be obtained from Tables 1
and 2). To carry out a rigorous interpretation of the
Bronsted exponents with the aim of characterizing the
structure of the transition state, it is necessary to
normalize ânuc and Rlg through the values of âeq. In
the nitroso group transfer reactions under investigation
here, the equilibrium is displaced toward the forma-
tion of the N-nitrosamine to such an extent that it is not
possible to determine it experimentally. However, the
equilibrium constant of the transfer process can be
evaluated indirectly through the equilibrium constants
for the nitrosation/denitrosation of the corresponding
N-nitrosamines and N-methyl-N-nitrosobenzenesulfon-
amides.

Nitroso Group Transfer
Sch em e 7
J . Org. Chem., Vol. 66, No. 2, 2001 387
nitrosamines should reflect extensive delocalization of the
amino nitrogen lone-pair electrons into the π-system of
the NdO group. Electron diffraction studies27 show that
N-N and N-O bond orders are ca. 1.5, implying a
structure intermediate between the following valence
structures 4.
Hypothetical liberation equilibrium of the nitroso group
on the basis of a protonated N-nitrosamine can be written
as
Independent evidence for considerable charge develop-
ment in the ground state comes from dipole moments for
aliphatic N-nitrosamines.28 As the basicity of the amine
increases, there will also be an increase in the stability
of the resonant form with a positive charge on the
nitrogen atom and consequently the stability of the
N-nitrosamine will increase.29
+
N HNO
R
2
R2+NHNdO {KNO
} R2NH + NO+
(8)
on the basis of which and by analogy with proton-transfer
equilibria, we can write pK
R2N+HNO
NO
R2N+HNO
.
NO
) -log K
The difficulty in estimating the value of the tautomer-
ization constant between nitrosamine O-protonated and
N-protonated, KT, means that on the basis of the Bron-
sted correlations, eq 5 and eq 7, we obtain a value for
R2N+HNO
NO
X-NO
The use of the values of pK
and pK
en-
NO
ables us to evaluate the equilibrium constant,30 KtrKT,
for the rate-limiting step of the nitroso group transfer
the equilibrium constant, Ke2xp ) KTkSCN/kONSCN, which
+HNO
X-NO
NO
2
nit
(Scheme 5) as log(KtrKT) ) pKR N
- K
) ∆pKNO
corresponds with the quotient Ke2xp )dKes TK2 (K2 ) kSCN
/
NO
(values in Table 3).
des
ONSCN
nit
k
). The combination of the following equilibria
As we can observe in Table 3, the equilibrium constant
corresponding with the nitroso group transfer process
depends on the value of the tautomerization constant KT.
This constant has not been determined experimentally
but its value is considered to be KT < 5%.17 If we assume
an arbitrary value of KT ) 0.01, then the values of the
equilibrium constant Ktr would be 2 logarithmic units
bigger than those shown in Table 3.31 Even with these
values of Ktr, we would observe that the nitroso group
transfer process would not be thermodynamically favor-
able and should lead to a mixture of equilibrium between
the N-nitrosamine and the N-nitrososulfonamide. How-
ever, in stages after the slow step, the deprotonation of
the protonated N-nitrosamine should occur, and this
process should take place at a rate controlled by diffusion
of the reagents, as is usual for proton transfers between
nitrogen and oxygen atoms. Once the N-nitrosamine is
R2N+HNO
NO
(Scheme 7) gives us an expression for K
:
K2KNO
+
R2N+HNO
K
)
(9)
NO
KONSCN
from which we obtain
Ke2xpKNO
KONSCN
+
R2N+HNO
KTK
)
(10)
NO
When the values given in the bibliography16,22 for KNO
+
,
KNO ) 3.5 × 10-7M-1 and KONSCN, KONSCN ) 30M-2 are
+
+HNO
used, the values of KTKR N
presented in Table 3 can
2
NO
be calculated.
By analogy we can define the equilibrium constant for
the loss of the nitroso group from an N-methyl-N-
formed, it will not revert to products reacting with
nitrosobenzenesulfonamide with formation of its anion,
R2NNO
NO
sulfonamide. A simple evaluation of the pK
corre-
X-NO
NO
K
.
sponding to the unprotonated N-nitrosamine shows that
the latter should be approximately 35 units greater than
R2N+HNO
NO
the corresponding (pK
- log KT).33
(26) Meyer, T. A.; Williams, D. L. H.; Bonnett, R.; Ooi, S. L. J . Chem.
Soc., Perkin Trans. 2 1982, 1383.
(27) Rademacher, P.; Stolevik, R. Acta Chem. Scand. 1969, 23, 660.
(28) (a) Cowley, E.; Partington, J . J . Chem. Soc. 1933, 1255. (b)
George, M.; Wright, G. J . Am. Chem. Soc. 1958, 80, 1200. (c) Hall, P.
G.; Horsfall, G. S. J . Chem. Soc., Perkin Trans. 2 1973, 1280.
This equilibrium constant can easily be calculated from
the values of the equilibrium constant for the nitrosation/
denitrosation of the sulfonamides,7b K3, and the acidity
constant of the N-methylbenzenesulfonamides,5c Ka
(Scheme 8).
(29) If KT is strongly dependent on the protonation pKa of the
2N+HNO
nitrosamines, then calculated values of pKNRO
- log KT (Table 3)
R2N+HNO
should yield pKNO
values that are independent of the basicity of
X-NO
NO
K
) K3Ka
(12)
the parent amine. These values should be incompatible with experi-
mental studies of nitroso group transfer in acid medium from an
N-nitrosamine to another amine.
X-NO
NO
Table 3 shows the calculated values of pK
for the
(30) Ktr is the equilibrium constant for the rate limiting step. The
problem is that as a consequence of the equilibrium constant of
tautomerization between the O-protonated and N-protonated nitro-
samine, only KtrKT is available from the analysis.
substituted N-methyl-N-nitrosobenzenesulfonamides.
The results show that the most basic amines (or
sulfonamides) produce the most stable N-nitrosocom-
pounds. The stability of the N-nitrosamines according to
the basicity of the corresponding amines had already
been made clear by studying the nitroso group transfer
in acid medium from an N-nitrosamine to another
amine.15a,b,26 The structure and stereochemistry of N-
(31) A reviewer suggested to use a KT value of KT ) 10-7 by analogy
with Fersht’s result for simple carboxamides (see ref 32). Using KT
)
SCN
10-7 yields
a
diffusion control value of
k
for N-nitroso-O,N-
des
+
2NH2
dimethylhydroxylamine (pKaR
) 4.72 in water from ref 15b) (see
eq 7) that is not in agreement with the experimental evidence,
suggesting that KT should be smaller that 10-7
(32) Fersht, A. R. J . Am. Chem. Soc. 1971, 93, 3504.
.

388 J . Org. Chem., Vol. 66, No. 2, 2001
Ta ble 3. Com p ila tion of Equ ilibr iu m Con sta n ts for Nitr oso Gr ou p Tr a n sfer fr om
Garc´ıa-R´ıo et al.
N-Meth yl-N-n itr osoben zen esu lfon a m id es to Secon d a r y Am in es
R2N+HNO
NO
a
For N-nitrosamines we obtain pK
- log KT.
norm
nucl
Sch em e 8
amount of charge lost by the amine (â
) is the same
norm
amount of charge received by the sulfonamide (R
).
lg
Usually, the size of the transition-state imbalance mea-
sured by RCH - âB is considered to correlate with the
degree of charge stabilization by resonance. Therefore,
the balanced nature of the transition state has significant
repercussions on the stabilization of the negative charge
of the anionic form of the sulfonamide.
4. Sta biliza tion of th e Nitr ogen Nega tive Ch a r ge
by th e r-Su lfon yl Gr ou p . The mechanism by which
carbanion stabilization by sulfur occurs has generated
great interest;36 in particular, R-sulfonyl carbanions have
long been a widely debated subject.37 The sulfonamides
are apparently similar to the amides, but the sulfonyl
group, unlike the carbonyl group, does not seem to have
a capacity for delocalizing the electron pair of the
nitrogen. Various studies carried out involving sulfon-
amides38,39,40 point out that the 6 structure has an
3. Ch a r a cter iza tion of th e Tr a n sition Sta te. The
values of the equilibrium constant for the rate-limiting
step in the nitroso group transfer, KTKtr, enable us to
represent the log ktr vs log(KtrKT) ) ∆pKNO for the
nitrosation of an amine by the different N-methyl-N-
nitrosobenzenesulfonamides. From these plots we can
norm
lg
obtain the values of R
, which can be considered a
measurement of the charge development on the nitrogen
atom of the nitrososulfonamide. An equivalent represen-
tation of log ktr vs log(KtrKT) ) ∆pKNO for the nitrosation
of the different amines for each N-nitrososulfonamide
norm
nucl
enables us to obtain â
. Table 3 shows the values of
norm
nucl
norm
. It can be seen that both values remain
lg
â
and R
virtually constant despite variation in both the amine and
the nature of the nitrosating agent.34
insignificant contribution in its stabilization. The absence
of any significant stabilization by resonance is probably
due to the fact that the d orbitals of the sulfur act like a
“plug” for the p-π electrons donated by the nitrogen. The
effect of the sulfonyl group must be fundamentally
inductive. In any case, we cannot discard any influence
of the resonant form 7, resulting from the delocalization
of the negative charge in the 3d orbitals of the sulfur (not
involved in the sulfur-oxygen bond39,41,42).
The transition state of the majority of chemical reac-
tions has the potential for being imbalanced. In fact,
whenever there is more than one process involved in a
reaction, there will be an imbalance if these processes
have developed nonsynchronously at the transition state.35
The results obtained for the nitroso group transfer from
N-methyl-N-nitrosobenzenesulfonamides to amines show
norm
nucl
norm
= 0. This result indicates that the
lg
that â
- R
transition state is closely balanced. It implies that the
(36) Bernasconi, C. F.; Kittredge, K. W. J . Org. Chem. 1998, 63,
1944.
(37) Terrier, F.; Kizilian, E.; Goumont, R.; Faucher, N.; Wakselman,
C. J . Am. Chem. Soc. 1998, 120, 9496 and references therein.
(38) Chardin, A.; Laurence, C.; Berthelot, M.; Morris, D. G. J . Chem.
Soc., Perkin Trans. 2 1996, 1047.
(39) Ruostseuo, P.; Karjalainen, J . Spectrochim. Acta 1981, 37A, 535.
(40) Mollendal, H.; Grundnes, J .; Klaboe, P. Spectrochim. Acta 1981,
24A, 1669.
(41) Laughlin, R. G. J . Am. Chem. Soc. 1967, 89, 4268.
(42) Hovius, K.; Zuidema, G.; Engberts, J . B. F. N. Recl. Trav. Chim.
1971, 90, 633.
R2N+HNO
(33) pKRN2ONNO values can be obtained as pKNR2ONNO ) pKNO
+ p
are
KaR
- pKRa HNO, where typical values of pKaR
and pKRa
2NH
2N+
2NH
+HNO
2
35 and 0, respectively. So, typical pKNRO
values should be ap-
2NNO
R2N+HNO
proximately 35 units larger than (pKNO
- log KT) (values in
Table 3).
(34) R
norm
1g
norm
nucl
and â
values in Table 3 are not compatible with KT
being very dependent on protonation pKa of the nitrosamines.
(35) (a) Bernasconi, C. F. Adv. Phys. Org. Chem. 1992, 27, 119. (b)
Bernasconi, C. F. Acc. Chem. Res. 1992, 25, 9. (c) Bernasconi, C. F.
Acc. Chem. Res. 1987, 20, 301.

Nitroso Group Transfer
J . Org. Chem., Vol. 66, No. 2, 2001 389
shows an Eigen type plot of the statistically corrected rate
constants for nitroso group transfer between secondary
amines and N-methyl-N-nitrososulfonamides, log(ktr/p),
against ∆pKNO ) log Ktr + log KT. The good linear
correlation is maintained with a slope of 0.54 ( 0.01.
Therefore, approximately 55% of the substituent effect
on the equilibrium constant (Ktr) for formation of the
N-nitrosamine is expressed in the rate constant for its
formation (ktr). The results shown in Figure 4 do not
show any type of deviation from the linearity. The
linearity of this empirical rate-equilibrium correlation,
which spanned a range of 10 pKNO units and included
both thermodynamically favorable and unfavorable reac-
tions, stands in sharp contrast with the reports of
changes in Bronsted exponents for a wide range of
proton-transfer reactions from carbon acids.44,45,46
There are a great many examples of rate-equilibrium
relationships where no curvature can be detected. Re-
cently Amyes and Richard have measured rates of proton
abstraction by hydroxide from ethyl acetate47 and ethyl
thiolacetate.48 In combination with previously measured
rates of proton abstraction from simple aldehydes and
ketones;49 these results lead to a linear Bronsted plot
extending over 14 log units in equilibrium and 5 log units
in rate. This extended linearity is not consistent with a
constant Marcus intrinsic barrier but could be interpreted
in terms of varying intrinsic barriers. Recently Page et
al.50 have extended a rate-equilibrium correlation for
proton transfer to a hydroxide ion from carbon acids
activated by a mono carbonyl group. The linearity of this
Bronsted relationship now spans 19 pKa units and covers
proton transfers in both thermodynamically favorable
and unfavorable directions.
F igu r e 4. Plot of log ktr vs ∆pKNO for nitroso group transfer
from substituted N-methyl-N-nitrosobencenesulfonamides to
secondary amines. See text for ∆pKNO evaluation.
Recently Bernasconi and Kittredge36 have researched
the stabilization of carbanions in R to sulfur atoms by
using an approach that combines kinetic and thermody-
namic data. It is based on the assumption that the kind
of factors that potentially stabilize the transition state
of the deprotonation of a carbon acid are the same as
those that potentially stabilize the carbanion, i.e., polar-
izability, d-p π-bonding, negative hyperconjugation, and
possibly others. It makes use of the fact that typically
the relative importance of these factors in stabilizing the
transition state is not the same as in stabilizing the
carbanion. As has been amply demonstrated,35 the tran-
sition state of the deprotonation of carbon acids activated
by π-acceptors is imbalanced, in the sense that sp3fsp2
rehybridization of the R-carbon and charge delocalization
into the π-acceptor group lag behind proton transfer. In
short, the reason for this lag is that the degree of charge
delocalization into the π-acceptor group (Y) is coupled
with the degree of C-Y bond formation which in turn
depends on the fraction of charge that has been trans-
ferred from the base to the carbon acid. Since neither
C-Y π-bond formation nor charge transfer are complete
at the transition state, the charge delocalized into the Y
group is just a fraction of a fraction and is therefore quite
small.35,43
The Marcus theory9,10 basically predicts nonlinear free
energy relationships because of its quadratic form.
2
∆G0
2
∆G0
∆Gq ) ∆Gq0 +
+
(13)
16∆Gq0
where ∆Gq is the free energy of activation for reaction of
a given ∆G0, the free energy change for the process, and
∆Gq0 is the “intrinsic barrier” corresponding to the free
energy of activation when ∆G0 is zero. In the case of
proton transfer, ∆G0 is given by the difference in pKa
between the proton donor and acceptor. The same
formalism can be applied for nitroso group transfer
reactions. In our case, ∆G0 is given by the difference in
pKNO between the nitroso group donor and acceptor. From
the previous equations, we can also obtain a value of R
for the transition state.
The stabilization by resonance of the negative charge
in R at the sulfonyl group would give rise to an imbal-
anced transition state during the nitroso group transfer
norm
nucl
process. The results given previously show that â
-
norm
R
= 0, suggesting that the charge development on
lg
the nitrogen atom in R at the sulfonyl group is similar to
that which exists on the aminic nitrogen. This result is
contrary to what would be expected if the transition state
was stabilized by a resonance effect, and it appears
clearly that stabilization of a negative charge by the
electron-withdrawing SO2 group must be the result of
polarization effects rather than of conjugative dπ-pπ
bonding or negative hyperconjugation.
∂∆Gq
∂∆G0
1
2
∆G0
R )
)
1 +
(14)
q
(
)
4∆G0
From this equation we can see that when the thermo-
dynamics of the system, ∆G0, are roughly in balance
5. Ra te-Equ ilibr iu m Rela tion sh ip s for Nitr oso
Gr ou p Tr a n sfer . Logarithmic plots of the statistically
corrected rate constants for proton transfer reactions
against the statistically corrected ionization constants of
the acids are the most usual type of representation,
enabling us to obtain information about these processes.
Figure 4, drawn up using the data from Tables 1 and 3,
(44) Murray, C. J .; J encks, W. P. J . Am. Chem. Soc. 1990, 112, 1880.
(45) Gunthrie, J . P. Can. J . Chem. 1979, 57, 1177.
(46) Argile, A.; Carey, A. R. E.; Fukata, G.; Harcourt, M.; More-
O’Ferrall, R. A.; Murphy, M. G. Isr. J . Chem. 1985, 26, 303.
(47) Amyes, T. L.; Richard, J . P. J . Am. Chem. Soc. 1996, 118, 3129.
(48) Amyes, T. L.; Richard, J . P. J . Am. Chem. Soc. 1992, 114, 10297.
(49) Keefe, J . R.; Kresge, A. J . Kinetics and mechanism of enolization
and ketonization. In The Chemistry of Enols; Rappoport, Z., Ed.;
Wiley: Chichester, 1990; pp 399-480.
(50) Heathcote, D. M.; Atherton, J . H.; De Boos, G. A.; Page, M. I.
J . Chem. Soc., Perkin Trans. 2 1998, 541.
(43) Kresge, A. J . Can. J . Chem. 1974, 52, 1897.

390 J . Org. Chem., Vol. 66, No. 2, 2001
Garc´ıa-R´ıo et al.
Ta ble 4. Va lu es of log k0 - slop e log KT for Nitr oso
Gr ou p Tr a n sfer fr om
N-Meth yl-N-n itr osoben zen esu lfon a m id es to Secon d a r y
Am in es
as may be witnessed by the recent important applications
of this concept for a variety of chemical reactions.
Intrinsic barriers are used mainly as means of under-
standing reactivity trends in nonidentity reactions. In the
framework of the valence bond configuration mixing
model (VBCM),53 the intrinsic barrier in SN2 reactions
is determined by the vertical electron-transfer energy and
by the “extra delocalization” properties of the charge
transfer states. The constancy of the values of log k0 -
slope log KT when the substituents vary on the aromatic
ring is consistent with a balanced transition state and
suggests that the electron density on the nitrogen atom
of the sulfonamide remains practically constant.
substrate
log k0 - slope log KT
σ
MN-4-MeO-BS
MN-4-Me-BS
MN-4-Cl-BS
-0.47 ( 0.07
-0.46 ( 0.1
-0.50 ( 0.02
-0.44 ( 0.07
-0.27
-0.17
0.23
MN-4-NO2-BS
0.78
compared to the kinetic barrier ∆Gq0, then the transition
1
state is symmetrical, with R approximately equal to /2.
On the other hand, if the thermodynamics are favorable
1
to the reaction, ∆G0 < 0, then R will be less than /2 and
the transition state will be reactant like. Conversely, if
Con clu sion s
the reaction is thermodynamically uphill, then R is
1
greater than /2 and the transition state is product like.
On the basis of this study the following results are
particularly worthy of note: (1.) The results obtained
have shown that the nitroso group transfer from N-
methyl-N-nitrosobenzenesulfonamides to amines takes
place directly via a concerted mechanism. The calculation
of the equilibrium constants for these processes has
enabled us to quantify the charge development on the
nucleophile and leaving group in the transition state of
the reaction. The results obtained show that the transi-
tion state is perfectly synchronic, which by applying the
methodology recently developed by Bernasconi and Kit-
tredge36 enables us to show that the sulfonyl group does
not participate in the establishment by resonance of the
negative charge situated on the nitrogen atom in position
R. (2.) The establishment of a rate-equilibrium relation-
ship for nitroso group transfer has enabled us to carry
out a quantitive explanation of the reactivity observed
in a similar way to the proton-transfer reactions. The
absence of curvature in the rate-equilibrium correlation
has been interpreted in terms of the Marcus theory of
electron transfer applied to nitroso group transfer reac-
tions. (3.) The study of the nitroso group transfer from
substituted N-methyl-N-nitroso-benzenesulfonamides to
amines shows that the rate of the process is accelerated
by the presence of substituents which withdraw charge.
This result is chiefly due to the greater thermodynamic
conductive force of the reaction. Hence, the intrinsic
reactivities of the nitrososulfonamides remain practically
constant.
When a linear free energy relationship gives a constant
Bronsted exponent, i.e., it is not curved over a range of
free energies for the reaction, then the simplest inter-
pretation is that the transition state structure is “con-
stant”. Within the context of the Marcus theory, linearity
can be attributed to either a large intrinsic barrier or to
a variable intrinsic barrier which changes with ∆G0.51
For an elementary reaction, the intrinsic barrier is
generally defined as ∆Gq0 ) ∆G1q ) ∆G-q 1 when ∆G0 ) 0
and the intrinsic rate constant as k0 ) k1 ) k-1 when K1
) k1/k-1 ) 1. The concept of the “intrinsic barrier” was
introduced by Marcus9,10 and is currently considered to
be a parameter with more physical meaning than the
“current” reaction barrier because it is a purely kinetic
parameter of a reaction and is independent of its ther-
modynamic driving force. In other words, it is, at least
in principle, a parameter that describes the reactivity of
a group of series of reactions independently of the
thermodynamics of a particular member of the series.
Table 4 shows the intrinsic rate constants (log k0) for
the nitroso group transfer from N-methyl-N-nitrosoben-
zenesulfonamides to secondary amines. The sum52 log k0
- slope log KT is obtained because of the tautomerization
constant between the O-protonated and the N-protonated
nitrosamine. The values of log k0 - slope log KT were
interpolated or extrapolated from the plots of log ktr vs
∆pKNO for ∆pKNO ) 0. As we can see, the values of the
intrinsic rate constants for the nitroso group transfer
from substituted N-methyl-N-nitrosobenzenesulfona-
mides to secondary amines do not vary with the substit-
uents of the aromatic ring of the sulfonamide, and a mean
value of log k0 - slope log KT ) -0.48 ( 0.04 can be
assumed.
Ack n ow led gm en t. Financial support from the Di-
reccio´n General de Ensen˜anza Superior of Spain (Project
PB96-0954) and Xunta de Galicia (PGIDT00PXI20907PR)
is gratefully acknowledged. J . A. Moreira thanks Fun-
dac¸a˜o para a Cie´ncia e Tecnologia of Portugal (PRAXIS
XXI/BD/5219/95).
The concept of intrinsic barriers has become a corner-
stone in the epistemology of physical organic chemistry,
J O0006730
(51) Bunting, J . W.; Kanter, J . P. J . Am. Chem. Soc. 1993, 115,
11705.
(52) Slope refers to the line in Figure 4, with a numerical value of
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