Electronic and steric effects in thermal denitrosation of N-nitrosoamides

Article abstract of DOI:10.1021/jo001144z

N-Alkyl-N-nitrosoamides undergo competitive reactions whose rates are dependent upon the interplay of a number of factors. There already exists a significant body of work delineating the effects of pH on the partitioning of the nitrosoamides along their deaminative (-N₂) and denitrosative (- NO⁺ ) pathways. In this paper, the issue of pH dependence is discussed with particular attention to nitrosoamide decompositions in nonaqueous media. The role of the acidity of the medium in the partitioning of the nitrosoamide between deamination and denitrosation and in the choice of deaminative pathways is revisited. In nonaqueous media under near-neutral conditions, the partitioning's pH dependence is evidently accompanied by a sensitivity to structural features in the nitrosoamide. Thus, diminution of steric crowding around the N-nitroso moiety as well as the presence of strongly electron-withdrawing acyl units (i.e., those derived from strong acids, e.g., tosyl and trifyl) increase the relative yield of amides by encouraging the denitrosative pathway. A mechanism for thermal denitrosation of nitrosoamides under near-neutral conditions is proposed in which rapid protonation at the acyl O rather than slow protonation at the amidic N is the first step in the reaction profile. A rate-limiting, bimolecular reaction between the O-conjugate acid and adventitious nucleophiles at the nitrosyl group then occurs followed by rapid tautomerization to amide.

Full text of DOI:10.1021/jo001144z

J . Org. Chem. 2001, 66, 5679-5686
5679
Electr on ic a n d Ster ic Effects in Th er m a l Den itr osa tion of
N-Nitr osoa m id es
†
†
†
Ron W. Darbeau,* Edson V. Perez, J ennifer I. Sobieski, William A. Rose, Maria C. Yates,
†
Benjamin J . Boese, and Nyla R. Darbeau
Department of Chemistry, McNeese State University, Lake Charles, Louisiana 70609
rdarbeau@mail.mcneese.edu
Received J uly 27, 2000
N-Alkyl-N-nitrosoamides undergo competitive reactions whose rates are dependent upon the
interplay of a number of factors. There already exists a significant body of work delineating the
2
effects of pH on the partitioning of the nitrosoamides along their deaminative (-N ) and
+
denitrosative (-“NO ”) pathways. In this paper, the issue of pH dependence is discussed with
particular attention to nitrosoamide decompositions in nonaqueous media. The role of the acidity
of the medium in the partitioning of the nitrosoamide between deamination and denitrosation and
in the choice of deaminative pathways is revisited. In nonaqueous media under near-neutral
conditions, the partitioning’s pH dependence is evidently accompanied by a sensitivity to structural
features in the nitrosoamide. Thus, diminution of steric crowding around the N-nitroso moiety as
well as the presence of strongly electron-withdrawing acyl units (i.e., those derived from strong
acids, e.g., tosyl and trifyl) increase the relative yield of amides by encouraging the denitrosative
pathway. A mechanism for thermal denitrosation of nitrosoamides under near-neutral conditions
is proposed in which rapid protonation at the acyl O rather than slow protonation at the amidic N
is the first step in the reaction profile. A rate-limiting, bimolecular reaction between the O-conjugate
acid and adventitious nucleophiles at the nitrosyl group then occurs followed by rapid tautomer-
ization to amide.
In tr od u ction
O’s (both reactions producing the same hydrogen-bonded
O-conjugate acid, 2a ; Scheme 1, path a), and slowly at
the amidic N.3 Deamination then proceeds via species
2a formed in a rapid preequilibrium step (Scheme 1, path
a) and is believed to be the major pathway at low
acidity.3 In contrast, the rate-limiting N-protonation
derives the N-conjugate acid, 2b, that rapidly decays into
a nitrous acid equivalent and the corresponding amide
The issue of the competing modes of decompositions
of N-nitrosoamides (1) has been debated for decades.
,4
1
-5
1
2
Impressive and convincing work by White, Moss, Chal-
3
4
5
lis, Williams, and many others has led to the current
,4
beliefs that nitrosoamides decompose principally along
+
deaminative (-N
2
) and denitrosative (-“NO ”) pathways
that depend on pH3 and temperature.
,4
1,2
(
Scheme 1, path b). This pathway predominates at higher
In aqueous acidic systems, protonation of the nitroso-
amides is believed to occur rapidly at the acyl or nitrosyl
3
,4
acidity.
The relative rates of the N- vs O-protonations are
readily interpreted in terms of resonance interactions
among the lone pair of electrons on the amidic N and
the acyl and nitrosyl groups attached to the latter. Such
mesomerism then would enhance the basicities of the acyl
and nitrosyl O’s but diminish that of the amidic N. The
same argument is invoked to account for the pH profiles
of these aqueous reactions. Thus, the electronically
activated nitrosyl and acyl O’s are protonated more easily
(i.e., at lower acidities) than the amidic N, which because
its electron pair is dispersed among the nitrosyl and acyl
groups is poorly basic and becomes protonated only at
lower pH values.
*
To whom correspondence should be addressed.
Undergraduate research students at McNeese State University.
†
(1) (a) White, E. H.; De Pinto, J . T.; Polito, A. J .; Bauer, I.; Roswell,
D. F. J . Am. Chem. Soc. 1988, 110, 3708. (b) White, E. H.; Field, K.
W.; Hendrickson, W. H.; Dzadzic, P.; Roswell, D. F.; Paik, S.; Mullen,
P. W. J . Am. Chem. Soc. 1992, 114, 8023. (c) White, E. H.; McGirk, R.
H.; Aufdermarsh, C. A.; Tiwari, H. P.; Todd, M. J . J . Am. Chem. Soc.
973, 95, 8107. (d) White, E. H.; Dolak, L. A. J . Am. Chem. Soc. 1966,
8, 3790.
1
8
(
2) (a) Moss, R. A. J . Org. Chem. 1966, 31, 1082. (b) Moss, R. A.
Chem. Eng. News 1971, 49 (48), 28. (c) Moss, R. A. Acc. Chem. Res.
974, 7, 421. (d) Moss, R. A. Acc. Chem. Res. 1980, 13, 58. (e) Moss, R.
1
A. Acc. Chem. Res. 1989, 22, 15. (f) Moss, R. A.; Grover, E. R. J . Org.
Chem. 1976, 41, 1128. (g) Moss, R. A.; J oyce, M. A. J . Am. Chem. Soc.
978, 100, 4475. (h) Moss, R. A.; Landon, M. J . J . Am. Chem. Soc.
970, 92, 5755. (i) Moss, R. A.; Lane, S. M. J . Am. Chem. Soc. 1967,
9, 3655.
1
1
8
Under basic conditions, nitrosoamides may decompose
(3) (a) Berry, C. N.; Challis, B. C. J . Chem. Soc., Perkin Trans. 2
1
974, 1638. (b) Challis, B. C.; J ones, S. P. J . Chem. Soc., Perkin Trans.
1975, 153.
(
via attack at the acyl group to form trans-diazotic acids
and eventually diazoalkanes (Scheme 1, path c). Basic
2
6a
4) (a) Williams, D. L. H. J . Chem. Soc., Perkin Trans. 2 1975, 655.
b) Williams, D. L. H. J . Chem. Soc., Perkin Trans. 2 1976, 1838.
5) (a) Kirmse, W. J .; Moench, D. Chem. Ber. 1991, 124, 4 (1), 237.
b) Brosch, D.; Kirmse, W. J . J . Org. Chem. 1991, 56 (3), 907. (c)
attack on nitrosoamides at the nitrosyl group to form the
amide and nitrite appears feasible, but no reference to
(
(
(
6b
this reaction has been found (Scheme 1, path d).
Huisgen, R.; Ruchardt, C. J ustus Liebigs Ann. Chem. 1956, 601, 1. (d)
Wiberg, K. B.; Osterle, C. G. J . Org. Chem. 1999, 64, 7756. (e) Wiberg,
K. B.; Osterle, C. G. J . Org. Chem. 1999, 64, 7763. (f) Wiberg, K. B.;
Shobe, D. S. J . Org. Chem. 1999, 64, 7768. (g) Laughlin, R. G. J . Am.
Chem. Soc. 1967, 89, 4268. (h) Huisgen, R.; Ruchardt, C. J ustus Liebigs
Ann. Chem. 1956, 601, 1.
Thermal decay of N-nitrosoamides has been exten-
1,2,7
sively studied
and is believed to involve rate-limiting
rearrangement possibly via a charge-separated, oxadi-
azetyl entity7 to the trans-diazotate ester followed by
a
1
0.1021/jo001144z CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/28/2001

5
680 J . Org. Chem., Vol. 66, No. 17, 2001
Sch em e 1. p H-Dep en d en t Decom p osition Mod es of N-Alk yl-N-n itr osoa m id es
Darbeau et al.
Sch em e 2. Mech a n ism of Th er m a l Dea m in a tion of N-Alk yl-N-Nitr osoa m id es7a
fragmentation to a tight ion-pair containing a diazonium
ion and its nascent counterion (Scheme 2). Eventually,
dediazoniation of the diazonium ion (if R is capable of
forming an inductively or resonance-stabilized carbenium
alkyl cation is inaccessible (e.g., methyl, unstabilized
primary, etc).5b
Acid -Ca ta lyzed ver su s Th er m a l Dea m in a tion . The
requirements for acid-catalyzed deamination in aqueous
systems involve rapid protonation of either the acyl or
nitrosyl O followed by nucleophilic attack by water at the
activated carbonyl C (or sulfonyl S). Subsequent frag-
5
b
ion) generates the nitrogenous entity-separated ion pair
NESIP; Scheme 2),1,2,5a where the nitrogenous entity )
. The alkyl diazonium ion may effect alkylations if the
(
N
2

Thermal Denitrosation of N-Nitrosoamides
J . Org. Chem., Vol. 66, No. 17, 2001 5681
Ta ble 1. Effects of Ba sea a n d Acyl Gr ou p on
Den itr osa tion of N-Ben zyl-N-n itr osoa m id es a t 80 °C
mentation into the carboxylic (or sulfonic) acid and the
diazotic acid occurs. The latter after protonation then
dediazoniates via a uni- or bimolecular path depending
upon the nature of the alkyl group. The formation of the
acid moiety in
nitrosoamide
relative yield
of amide
equiv of basea
b
c
“
hydrogen-bridged” O-conjugate acid is an inherent step
acetic
0
2
0
2
0
8.2
1.5
4.2
0.7
0.5
in acid-catalyzed deamination and would require copla-
narity of the acyl group, the amidic N, the nitrosyl group,
and the H involved in hydrogen bridging (Scheme 1, path
a). Thus, the stereoelectronic requirement for these
deaminations would “lock” the nitrosyl and acyl groups
in the same plane through hydrogen bonding.
propanoic
dimethylacetic
trimethylacetic
p-toluenesulfonic
trifluoromethanesulfonic
0
2
0
2
0
2
0.0
0.0
24.8
4.8
40.0
15.0
In contrast, the stereoelectronic requirement for the
thermal rearrangement is met only after a ∼90° rotation
about the N-N bond (from the planarity necessary for
acidic deamination) bringing the nitrosyl group perpen-
dicular to the carbonyl group (Scheme 2). This spatial
arrangement is possible at relatively low acidity and
elevated temperatures so hydrogen bonding does not keep
the molecule in the planar geometry. Further, since
thermal deaminations are encouraged by steric crowding
a
For carboxamides, base ) Py; for sulfonamides, base ) 2,6-
b
c
di-tert-butyl-4-methylpyridine (DBMP). Equivalents. Yields mea-
sured by 1H NMR spectroscopy; standard deviation ∼0.6.
Resu lts a n d Discu ssion
Th er m a l Den itr osa tion of N-Nitr osoa m id es u n -
d er Nea r -Neu tr a l Con d ition s. A series of N-benzyl-
N-nitrosocarboxamides and N-benzyl-N-nitrososulfona-
mides were thermally decomposed in chloroform-d at 80
1
d,5h
of the N-nitroso amide moiety
formation of the trans-diazotate ester),7 the studies done
in aqueous acid on N-n-butyl-N-nitrosoacetamide at 25
(which is relieved on
a
1
3
°C. The product distribution was determined by H NMR
°
C, for example, are strongly favored to undergo the
spectroscopy. The N-benzyl-N-nitrosoamides were em-
ployed in the present study because their formation of
NESIPs containing benzyl carbocations through ther-
molysis has been well documented and is well under-
stood.1 The thermolyses were performed under near-
neutral conditions in chloroform (vide infra) so as to
minimize competition from the acid-catalyzed pathways
that require aqueous acid to provide both a proton source
for N-protonation and water as the denitrosating nucleo-
phile. A common, elevated temperature was used for all
decompositions to allow ready comparison of the data and
to compensate for the large half-lives of the N-nitroso-
acidic deamination. This would be so since the thermal
process is inhibited by the low temperature and the lack
of steric bulk in both the methyl and n-butyl groups
around the OdN-N-CdO unit, as well as the high
acidity that encourages the “hydrogen bridging” of the
nitrosyl and acyl units.
a,7
Acid -Ca ta lyzed Den itr osa tion . Acid-catalyzed deni-
trosation requires the slow protonation of the amidic N
followed by rapid attack by nucleophilic water on the
inductively activated nitrosyl N (Scheme 1, path b).3
Clearly, this pathway is favored by strongly acidic
aqueous conditions that could force protonation of the
weakly basic amidic N and that could supply a large
concentration of the only modestly nucleophilic water
molecules.
,4
tosylamide and the nitrosocarboxamides with simpler
acyl portions.1
d,5a,7f
Further, the “H-bridging” (that would
encourage the acidic deamination) would be readily
disrupted at this temperature.
Runs were performed in the presence and absence of
pyridines as proton sponges. For the nitrosocarboxam-
ides, pyridine was employed as the base because it was
inert to the reagents and products. But for the nitroso-
sulfonamides, 2,6-di-tert-butyl-4-methylpyridine (DBMP)
was used because pyridine was found to react with the
sulfonate esters to form N-benzylpyridinium ions. This
secondary reaction was eliminated through use of the
sterically hindered DBMP.
To date, the only documented factors affecting the
partitioning of the nitrosoamides along the deaminative/
denitrosative pathways have been external (pH and
temperature).1 Further, the issue of thermal denitro-
sation has never been addressed. This work examines
thermal denitrosations and the effects of intramolecular
factors on this phenomenon. In particular, the classical
roles of steric and electronic factors are examined.
-5
The data (Table 1) show several noteworthy trends
concerning the yield of amides, i.e., the extent of denit-
rosation. (1) It decreased in the presence of base, (2) it
(
6) (a) Streitwieser, A.; Schaeffer, W. D. J . Am. Chem. Soc. 1957,
7
9, 2893. (b) No literature references to this reaction have been found.
Some of the sources examined include refs 6c-f. (c) Smith, P. A. S.
The Chemistry of Open-Chain Nitrogen Compounds; W. A. Benjamin,
Inc.: New York, 1965; Vols. 1 and 2. (d) Overberger, C. G.; Anselme,
J . P.; Lombardino, J . G. Organic Compounds with Nitrogen-Nitrogen
Bonds; The Ronald Press Co.: New York, 1966. (e) Zollinger, H. Diazo
Chemistry I & II; VCH Publishers: New York, 1994. (f) Patai, S., Ed.
The Chemistry of Functional Groups: The Chemistry of diazonium and
diazo groups; J ohn Wiley and Sons: New York, 1978; Parts 1 and 2.
8
a
decreased with increasing steric bulk at the acyl position
[indeed no denitrosation occurs in the pivaloyl () tri-
methylacetyl) series], and (3) it increased with the rising
strength of the acid from which the acyl moiety is derived
(carboxylate to tosylate, to triflate).8
a
Th e Effect of th e Acid ity of th e Med iu m on
Th er m a l Den it r osa t ion s. In thermolyses of nitroso-
triflamides, denitrosation accounts for 40% of the prod-
ucts in the absence of base but for only 15% in the
presence of DBMP (Table 1). For nitrosotosylamides,
however, denitrosation accounts for 25% of the products
in the absence of base, but only ∼5% in the presence of
DBMP (Table 1). Similar diminutions in amide yields in
(
7) (a) Darbeau, R. W.; Pease, R. S.; Gibble, R. E. J . Org. Chem.
2
001, in press. (b) White, E. H.; Darbeau, R. W.; Chen, D.; Chen, S.;
Chen, Y. J . Org. Chem. 1996, 61, 7986. (c) Darbeau, R. W.; White, E.
H. J . Org. Chem. 1997, 62, 8091. (d) Darbeau, R. W.; White, E. H.;
Song, F.; Darbeau, N. R.; Chou, J . C. J . Org. Chem. 1999, 64 (16), 5966.
(
e) Darbeau, R. W.; Delaney, M. S.; Ramelow, U.; J ames, K. R. Org.
Lett. 1999, 1 (5), 796. (f) Darbeau, R. W.; White, E. H.; Nunez, N.;
Coit, B.; Daigle, M. J . Org. Chem. 2000, 65, 1115. (g) Darbeau, R. W.
White, E. H. J . Org. Chem. 2000, 65, 1121. (h) Song, F.; Darbeau, R.
W.; White, E. H. J . Org. Chem. 2000, 65, 1825.

5
682 J . Org. Chem., Vol. 66, No. 17, 2001
Darbeau et al.
the presence of base are observed in the N-nitrosocar-
boxamide series (Table 1).
protonation) for thermal denitrosation involves a step in
which electron density is actively shunted (by resonance)
into the acyl unit. If this is true, then initial protonation
of the nitrosoamide probably occurs at the acyl O rather
than the nitrosyl O, thus enhancing the flow of electron
density into the acyl group.8
This result indicates that like the denitrosations in
aqueous acid, the thermal nonaqueous reaction under
near-neutral conditions is acid-catalyzed. The formation
of the N-conjugate acid, 2b, in the low acidity of the
current media especially when pyridines are employed,
however, does not appear reasonable. Hence, a difference
between the denitrosative mechanisms in aqueous acid
and the present nonaqueous, near-neutral system would
appear to exist. Evidently, the reaction is still acid-
catalyzed, but (1) denitrosation is occurring at low acidity
and hence (2) the site of protonation leading to denitro-
sation is not the weakly basic amidic N. To the extent
c
Th e Effect of Ad d ed Nu cleop h iles on Den itr osa -
tion . N-Benzyl-N-nitrosotosylamide was allowed to de-
compose in DMSO-d at ambient and elevated temper-
6
atures; in some cases, selected nucleophiles were added.
Despite its higher thermal stability7 the N-nitroso-
tosylamide was chosen because of its ability to generate
relatively large yields of amide via denitrosation (Table
a,d
1
). DMSO was chosen because of its high polarity, which
that this is true, the conjugate acid along the reaction
7
a
path is not the N-conjugate as in the aqueous systems,3,4
tends to accelerate nitrosoamide decomposition and
encourage dissolution of the salts; it is also inert to the
added nucleophiles. The nucleophiles employed were
Br , CN , and I (n ) 5.7, 6.8, and 7.4, respectively),
which were utilized as their Et
and further, the protonation obviously involving a mod-
estly basic site would be fast. The only reasonable sites
for protonations are the nitrosyl O or the acyl O (vide
7
a
-
-
-
10
+
4
N
salts. The N-nitroso-
infra). Unlike in the aqueous system, two distinct species
will arise from O- vs N-protonation (vide supra).3,4
tosylamide (at δ 4.97, which undergoes no detectable
deamination after 48 h at 50 °C in DMSO) was incubated
separately in DMSO with 1 molar equiv of the tetraethyl-
ammonium salts at 20 °C in the dark. No reaction was
Electr on ic Effects in Th er m al Den itr osation . From
the sensitivity of the yield of amide to the variation in
the acyl unit from carboxyl to tosyl to triflyl, it appears
that the extent of denitrosation depends, at least in part,
on the acid-derived moiety in the starting nitrosoamide.
Two properties of the acyl moiety may be relevant to this
observation: (1) the basicity of the acyl O’s and (2) the
electron-withdrawing ability of acyl group. With respect
to the relative basicities of the acyl O’s, although the
carbonyl-O of the carboxamides is presumably more basic
than the sulfonyl-O’s of the sulfonamide, the O-protona-
tions are unlikely to be the step that distinguishes the
behavior of the carboxamides from the sulfonamides. This
interpretation is likely to be true since, with few
exceptions,9 proton transfer to oxygen bases is very fast
-
-
-
observed in the X ) Br case; for X ) CN and I ,
however, benzyl alcohol (δ 4.50) and N-benzyltosylamide
(δ 3.93) (48%:52% and 40%:60%, respectively) were
observed.
Since no deamination is occurring at this temperature,
the reaction products must arise from an independent
pathway that is sensitive to the nucleophilicity of the
added species (vide supra). We propose that the active
nucleophiles attack the N-nitrosotosylamide as in paths
“a” and “b” in Scheme 3. Path “a” ostensibly offers less
steric hindrance than does path “b”, which would explain
why the bulky iodide has a greater preference for it than
does the smaller cyanide ion. Interestingly, neither water
a,b
9
c
and essentially proceeds on encounter. In terms of
electron-withdrawing effects, however, when the sulfona-
mide is protonated it ostensibly acts as a better electron-
sink than the conjugate acid of the carboxamide (due to
classical charge dispersal via resonance, induction, and
sheer size).
(n ) 0) nor bromide (n ) 5.8) appear sufficiently nucleo-
philic to attack the N-nitrosotosylamide under these
conditions. The similarity of the % amide and % alcohol
as well as the similarities in relative yields with the
different active nucleophiles suggest that nucleophilic
attacks on the nitrosyl and sulfonyl groups have similar
rate constants. Interestingly, neither benzyl bromide,
benzyl cyanide, nor benzyl iodide was detected (absence
of signals at δ 4.53, 4.05, and 4.75, respectively), indicat-
ing that the potential pathway “c” (Scheme 3) is not
competitive here.
Since the extent of denitrosation under these condi-
tions depends on the electron-withdrawing ability of the
acyl moiety, it would appear that the rate-determining
step or one preceding it (but after the initial rapid
(
8) (a) The aqueous acidities of the acetic acid derivatives fall slightly
with increasing steric bulk. Thus, for the series MeCO H, EtCO H,
values are 4.8, 4.9, 4.9, and 5.0,
2
2
i
t
2 2 a
PrCO H, and BuCO H, the pK
8b
When solutions of the N-nitrosotosylamide in DMSO
respectively. Thus, the acidity and steric features are not truly
independent variables but may be treated roughly as such because of
-
-
were incubated at 20 °C in the presence of Br , I , and
the following: (i) the ∆pK
a
of 0.2 would appear to be less important
-
7d
CN , significant nitrosoamide hydrolyses to benzyl
alcohol occurs in the polar, deliquescent DMSO. The
observed benzyl alcohol probably also derives somewhat
from path “b” (Scheme 3) to a small extent, but largely
from hydrolysis of the labile nitrosoamides under these
conditions. Superimposed upon alcohol formation is deni-
trosation leading to amide formation.
t
than the significant increase in bulk from Me to Bu, (ii) despite the
i
increase in bulk from Et to Pr, no change in pK
yield of amide rises dramatically in the series carboxylate (pK
to tosylate (pK
a
occurs, and (iii) the
a
∼ 4.9)
a
∼ -6.5) to triflate (pK ∼ -10) indicating that the
a
suggested dependence of % denitrosation on the acidity of the acyl
moiety is valid. (b) Stability Constants and Stability Constants Supple-
ment; The Chemical Society, London, 1964 (Special Publication 17) and
1
971 (Special Publication 25); No. 1. (c) The possibility exists of an
equilibrium involving proton transfer between the acyl O and the
amidic nitrogen especially at elevated temperatures (which disrupts
H-bonding) in a fairly nonpolar solvent (which may enhance proton
acidity). However, the fact that denitrosation is significant at 20 °C in
DMSO in the presence of CN- and I- would suggest that such an
equilibrium would not be important. (d) When the nitrosotosylamide
Interestingly, at higher salt and nitrosoamide concen-
trations, the rate of nitrosoamide disappearance fell
linearly with decreasing concentrations of the N-ni-
trosoamide and of the active salt (Table 2), suggesting a
first order dependence on both [nitrosoamide] and [salt]
is heated in CDCl
occurs.
3 2 5
dried by distillation from P O no denitrosation
(
9) (a) Bade, M. L. J . Am. Chem. Soc. 1971, 93, 949. (b) Hibbert, F.
J . Chem. Soc., Chem. Commun. 1973, 463. (c) Eigen, M. Angew. Chem.
964, 3, 1.
1
(10) Swain, C. G.; Scott, C. B. J . Am. Chem. Soc. 1953, 75, 141.

Thermal Denitrosation of N-Nitrosoamides
J . Org. Chem., Vol. 66, No. 17, 2001 5683
Sch em e 3. P a th w a ys for Rea ction of Nu cleop h iles w ith N-n itr osoa m id es
Ta ble 2. Kin etic Da ta a ,b for Rea ction of
N-Ben zyl-N-n itr osotosyla m id e w ith Cya n id e in DMSO
a t 20 °C
at lower [nitrosoamide] and [salt] concentrations (Table
2
). Ostensibly, in this concentration-insensitive phase,
denitrosation does not compete with nitrosoamide hydroly-
approximated
relative rate
7d
ses.
The insensitivity of the system to [salt] in
c
-
[
NTS ]o (M) [CN ]o (M) ∆(% NTS)/∆t (min-1
)
this phase of the plot further supports the belief that
path “b”, Scheme 3 is poorly competitive in these reac-
tions.
e
0
0
0
0
0
0
.0625
.125
.25
.125
.25
0.125
0.125
0.125
0.25
0.25
0.5
3.9
4.0
4.0
4.3
8.2
1
1
1
1
2
4
e
e
e
e
.25
16.3
a
Method of initial rates used; decomposition after only 1 min
b
(
∼5% reaction) was considered. Runs were performed in at least
c
d
triplicate. NTS ) N-Benzyl-N-nitrosotoluenesulfonamide. Round-
e
ed to nearest whole number. Standard deviation ∼1.0.
(
vide supra; eq 1).11 It is to be noted, however, that the
reaction rate levels off and becomes essentially constant
(11) The formation of amide but no ester (i.e., denitrosation without
deamination) is due, in part, to a smaller activation energy for the
former process. Additionally, since deamination is first order in the
nitrosoamide5
h,7a
and zero order in the nucleophile, its rate is unaf-
fected by the concentration of the nucleophile. Conversely, denitrosa-
tion is first order in both the nitrosoamide and nucleophile and thus
a high concentration of the latter further enhances the denitrosative
pathway over the deaminative one. Nitrosoamide hydrolyses however,
which are also zero order in the nucleophile do successfully compete
with denitrosation and at low [salt] when denitrosation essentially
ceases only nitrosoamide hydrolysis occurs.

5
684 J . Org. Chem., Vol. 66, No. 17, 2001
Darbeau et al.
a
a
Ta ble 3. Dep en d en ce of Yield of Am id e on th e
Ta ble 4. Tim e-Dep en d en t Ra tio of % Am id e /% Ester
b
c
b,c
Nu cleop h ilicity of Ad d ed An ion s for Decom p osition of
(Alcoh ol) for Decom p osition of
N-Ben zyl-N-n itr osotosyla m id e in DMSO a t 80 °C
N-Ben zyl-N-n itr osoa m id es in th e P r esen ce of Iod id e in
DMSO a t 80 °C
anionc
I-
nucleophilicityb
relative % amidea
a
b,c d
[
% amide /% ester (alcohol) ]
7.4
6.8
5.7
87.2
42.0
35.6
-
CN
time (min)
N-nitrosotosylamide
N-nitrosoacetamide
-
Br
5
10
45
0.089
0.089
0.091
a
b
Yield relative to total amt of ester + amide. Data from ref
+
-
1
0. c Anions employed as Et4N X .
11.8
3.5
2.9
3.1
3.1
2.7
2.5
8
0
1
1
2
20
80
40
310
370
0.089
0.088
0.088
0.089
Additionally, the extent of denitrosation (and hence the
rate of amide formation), as evidenced by the yield of
amide, rose systematically with the nucleophilicity of the
ion (Table 3). These results suggest that both the ni-
trosoamide and the added salt () nucleophile) are
involved prior to, or at the rate-determining step (RDS)
leading to denitrosation.
Ster ic Effects in Th er m a l Den itr osa tion . With
respect to steric effects in the reaction, as the size of the
acyl group rises from methyl to ethyl, to isopropyl, to tert-
butyl, the yield of amide falls from 8.2 to 4.2, to 0.5, to 0,
respectfully, in the absence of base (Table 1). Evidently,
denitrosation is discouraged by steric hindrance at the
acyl group. Ostensibly, steric inhibition of resonance
between the N-nitroso moiety and the amido carbonyl
group mitigates against the efficient transmission of
electron-density between them. It is interesting that
a
The amide arises from denitrosation. b The esters () benzyl
acetate for the N-nitrosoacetamide and benzyl tosylate for N-
nitrosotosylamide) are products of the deaminative pathway.
c
Benzyl tosylate hydrolyses to benzyl alcohol under these condi-
tions; benzyl acetate is stable. d Runs performed in at least
duplicate; maximum standard deviation ∼0.2.
although steric crowding at the N-nitroso moiety encour-
ages thermal deamination,1
thermal denitrosation.
d,5h
it inhibits the competitive
A P r op osed Mech a n ism for Th er m a l Den itr osa -
tion . The dependence of thermal denitrosation upon the
electron withdrawing ability and size of the acyl moiety,
the improbability of N-protonation under nonaqueous,
8
c
near-neutral conditions, and the sensitivity of amide
formation to the identity and concentration of added
nucleophiles suggest that the mechanism of thermal
denitrosation occurs as follows. The first step is a rapid
protonation of the nitrosoamide at the acyl O; the
resultant O-conjugate acid then suffers attack at the
F igu r e 1. Overlay plot % N-nitrosoamide vs time (min) for
decomposition of N-benzyl-N-nitrosotosylamide in DMSO and
Et N CN at 20 °C.
4
nitrosyl N by an appropriate nucleophile (e.g., adventi-
tious moisture).8
d,12a,b
This latter reaction is encouraged
+
-
by electron donation into the acyl moiety. Such π-interac-
tion is apparently required to generate the tautomer of
the resultant amide (eq 1).
P r ot ogen esis u n d er Nea r -Neu t r a l Con d it ion s.
The proposed mechanism for thermal denitrosation re-
quires a fast, initial protonation of the acyl oxygen of the
nitrosoamide (eq 1). The question arises, however, as to
the source of the protons under these near-neutral
conditions.
though plots of % nitrosoamide vs time yield very good
2
binomial curves (R ) 0.963-0.997), the data are slightly
2
better fit (R ) 0.990-0.997, respectively) to trinomial
curves (although the highest order contribution is small,
-
3
∼10 ; Figure 1). In these N-nitrosotosylamide cases
though, the related plots of ln(%nitrosoamide) vs time
give straight lines (e.g., Figure 2; R2 ) 0.992). These
observations suggest that although the N-nitrosotosyla-
mide thermolyses approach simple-order ones, perhaps
some autocatalytic process is involved in the N-nitroso-
tosylamide case to the extent that as the reaction
progresses, agents are produced that accelerate the
N-nitrosoamide decomposition. We believe that these
Interestingly, in the N-nitrosotosylamide decomposi-
tions [but not the N-nitrosoacetamide ones (vide infra)]
in the presence of added iodide at 80 °C, the ratio of [%
amide/% ester (alcohol)1 (vide infra)] is not constant over
the course of the reaction (Table 4). Additionally, al-
2c
“
agents” are acidic.
(
12) (a) An alternative second step after rapid O-protonation is
Acids could conceivably be produced during nitroso-
amide thermolyses from reversible deprotonation of the
diazonium ion by its nascent counterion to yield the
+
spontaneous denitrosation of the O-conjugate acid to form NO and
the tautomer of the amide. Although, this option is indeed a possibility,
the formation of NO+ in a solvent of only modest polarity such as CDCl
3
1
2b
13a
(
in the present study) and in nonpolar solvents such as benzene and
diazoalkane/acid pair. This reaction sequence is com-
12b
hexane appears unlikely. (b) Darbeau, R. W. Ph.D. Thesis, The J ohns
Hopkins University, Baltimore, MD, 1996. (c) In the thermolyses of
the N-nitrosocarboxamides trace benzyl alcohol is formed from hy-
drolysis of the starting material. The ester is stable under these
conditions and does not undergo appreciable hydrolysis. Benzyl
tosylate, however, derived from N-nitrosotosylamide thermolyses, is
labile under these conditions and decomposes into benzyl alcohol.
petitive when the alkyl group of the diazonium ion (e.g.,
Me)1 is incapable of forming a stable carbocation, thus
3a
5d
allowing the diazonium ion to persist for bimolecular
7
d
collision with the counterion.1
3a,b
However, for mono- and
diaryldiazomethanes when the putative cation (e.g.,

Thermal Denitrosation of N-Nitrosoamides
J . Org. Chem., Vol. 66, No. 17, 2001 5685
F igu r e 3. Plot of ln(% N-nitrosoamide) vs time (min) for
decomposition of N-4-methoxybenzyl-N-nitrosopivalamide in
cyclohexane-d12 at 18 °C.
F igu r e 2. Plot of ln(% N-nitrosoamide) vs time (min) for
decomposition of N-benzyl-N-nitrosotosylamide in DMSO and
Et N CN at 20 °C.
4
+
-
tions occurring in nonaqueous, near-neutral conditions.
It would appear that the reaction occurs by initial, rapid
formation of an O-conjugate acid from protonation of the
acyl O, followed by a rate-limiting bimolecular nucleo-
philic attack at the nitrosyl group to form an intermedi-
ate that tautomerizes to the amide (eq 1). Evidently,
whereas thermal denitrosations of N-nitrosocarboxam-
ides follows third-order kinetics as described, such reac-
tions of N-nitrosotosylamides (and presumably any N-
nitrosoamide that generates an ester that easily hydrolyzes
into a strong acid) are prone to autocatalysis.
benzyl and diphenylmethyl) is stable, the rate constant
for dediazoniation is much faster than that for proton
transfer and the diazonium-diazoalkane equilibrium is
not competitive.1
3c,d
A likely initial source of protons is trace moisture
present in the modestly hygroscopic chloroform or the
deliquescent DMSO. Further, since chloroform undergoes
slow hydrolysis in the presence of moisture to produce
HCl, then the substrates in chloroform-based solution
would be exposed to trace acids. It should be borne in
mind that pyridinium ions are also mild acids so that
even in the presence of pyridines as proton sponges, a
proton source is readily available for protonation of the
nitrosoamides.
Additionally, however, in the N-nitrosotosylamide case,
facile hydrolysis of benzyl tosylate is clearly operational
at elevated temperatures as evidenced by the absence of
this ester as a reaction product and the appearance of
large yields of benzyl alcohol. Consequently, as the
reaction progresses, p-toluenesulfonic acid is generated
which in turn effects more efficient protonation of the
N-nitrosotosylamide than did the water molecules that
formed them. Thus, although the number of acids in the
system may be roughly the same, the acidity of the
medium rises and so the reaction accelerates as it
progresses.
In addition to the well-documented external effects
3,4
such as pH and temperature, the thermal denitrosation
reaction is subject to intramolecular effects as well. Thus
steric crowding at the acyl moiety diminishes the extent
of denitrosation whereas strongly electron-withdrawing
acyl groups encourage amide formation.
Exp er im en ta l Section
Ma t er ia ls a n d Met h od s. All commercial reagents were
reagent grade and were used without further purification.
Spectra were recorded on 300 MHz FT- NMR, FT-IR and UV-
vis spectrometers.
Sta bility of N-Ben zyl-N-n itr osoa m id es: Ha n d lin g a n d
Stor a ge. N-Benzyl-N-nitrosocarboxamides are thermolabile
2
oils and were stored under N in sealed tubes immersed in
liquid nitrogen. The nitrososulfonamides, which are solid and
more stable, were stored in desiccators at -50 °C. They are
labile in the presence of acids, bases, and moisture; being
photolabile they were handled in the dark. Ca u tion ! Nitrosoa-
mides should be handled with extreme care because of their
Evidently, the corresponding hydrolysis of the carboxy-
late esters is not competitive here since benzyl acetate
is stable under these conditions7
d,12c
and because no
enhanced yields of benzyl alcohol are observed. Addition-
ally, the % amide/% ester ratio is essentially constant
over the course of the reaction (Table 4) and a plot of
1
4a
possible mutagenicity
and carcinogenicity (local and sys-
temic).1 Efficient fume hoods and appropriate personal
protection (chemical-resistant gloves, safety glasses, lab coat,
etc.) are recommended when handling these compounds.
N-Alk ylca r boxa m id es, N-Alk ylsu lfon a m id es, a n d N-
Nitr osoa m id es. The toluenesulfonamide was prepared using
4b
ln(%nitrosoamide) vs time yields a straight line (Figure
2
3
; R ) 0.998).
1
5a
the method of Holmes and Ingold and nitrosated using the
Su m m a r y
While the considerable body of data concerning the
acid-catalyzed denitrosations of N-nitrosoamides in the
presence of aqueous acids appears valid, there is evi-
dently a mechanistic divergence for thermal denitrosa-
approach of Overberger and Anselme.1 All other amides were
5b
1
5c
prepared using the method of Heyns and von Bebenburg.
The preparations and physical properties of these compounds
(14) (a) Lee, K.; Gold, B.; Mirvish, S. Mutat. Res. 1977, 48, 131. (b)
Preussman, R.; Stewart, B. W. In Chemical Carcinogenesis, Searle,
C., Ed.; ACS Monograph No. 182; American Chemical Society: Wash-
ington, DC, 1984; p 643.
(13) (a) Hovinen, J .; Finneman, J . I.; Satapathy, S. N.; Ho. J .;
Fishbein, J . C. J . Am. Chem. Soc. 1992, 114, 10321. (b) Gautier, A. E.
Ph.D. Thesis, ETH Zurich, 1980. (c) Roberts, J . D.; Watanabe, W. J .
Am. Chem. Soc. 1950, 72, 4869. (d) More O’Ferrall, R. A.; Kwok, W.
K.; Miller, S. I. J . Am. Chem. Soc. 1964, 86, 5553.
(15) (a) Holmes, E. L.; Ingold, C. K. J . Chem. Soc. 1925, 127, 1800.
(b) Overberger, C. G.; Anselme, J . J . Org. Chem. 1963, 28, 592. (c)
Heyns, K.; v. Bebenburg, W. Chem. Ber. 1953, 86, 278. (d) White, E.
H. J . Org. Chem. 1954, 77, 6008.

5
686 J . Org. Chem., Vol. 66, No. 17, 2001
Darbeau et al.
and of their N-nitroso derivatives (prepared by the method of
at ambient temperature and then heated rapidly to the
1
5c
1
White ) have been previously reported in refs 1a (the trifla-
mide series), 7f (the pivaloyl series), and 7d (all other com-
pounds).
appropriate temperature after which a t
0
H NMR spectrum
1
was recorded. As before, H NMR spectra were then recorded
at intervals. From the data, rates were calculated in the usual
fashion.
Decom p osition of N-Nitr osoa m id es. In a typical run,
∼
10 mg of N-nitrosoamide and 2 equiv of pyridine (or 2,6-di-
tert-butyl-4-methylpyridine for the sulfonamides), as required,
were dissolved in 500 µL of the appropriate solvent (DMSO-
P r oof of th e Absen ce of Ben zyl Cya n id e, Ben zyl
Br om id e, a n d Ben zyl Iod id e fr om Decom p osition s in th e
P r esen ce of Et N X (X ) Br , CN, I). The absence of these
4
d
6 3
or CDCl ) in an NMR tube. The NMR tube was then
compounds was shown by comparisons of their chemical shifts
with those from decomposition mixtures and by spiking such
mixtures with the authentic compounds when new peaks were
observed. The chemical shifts of the benzylic methylene
protons of benzyl bromide, iodide, and cyanide in DMSO are
δ 4.53, 4.75, and 4.00, respectively.
attached to a special holder on a vacuum line. Prior to
evacuation at oil pump vacuum, the solution was frozen in
liquid N and then degassed and finally evacuated again and
2
flame-sealed while still under vacuum. The sealed tube was
then incubated at 80 °C until decomposition was complete (as
1
verified by the absence of starting material by H NMR).
Kin etic An a lyses of N-Nitr osoa m id e Den itr osa tion s.
In most typical runs, ∼10 mg of nitrosoamide and the required
Ack n ow led gm en t is made to the Calcasieu Parish
Industrial and Development Board Endowed Professor-
ship administered by the McNeese State University
Foundation, the Shearman Research Initiative admin-
istered by the Office of Research Services, MSU, and to
the Chemistry Department, MSU, for partial support
of this research. The contributions of Ms. J oan E. Vallee
are also acknowledged.
1
5
molar equiv of tetraethylammonium salt were dissolved in
00 µL of DMSO at room temperature in an NMR tube. In
the Method of Initial Rates, 500 µL of a stock solution
+
-
4
containing the requisite amount of Et N CN in DMSO was
added to an equal volume of a stock solution of the N-
nitrosotosylamide in DMSO in an NMR tube. The tube was
1
then rapidly shaken. For the runs at 20 °C, a t
0
H NMR
1
spectrum was taken and H NMR spectra were recorded at
intervals during the decomposition. For runs at elevated
temperatures, the sample tube was loaded into the NMR probe
J O001144Z