Electronic effects in the N-nitrosation of N-benzylpivalamides

Article abstract of DOI:10.1021/jo011002k

A series of N-4-R-benzylpivalamides (R = MeO, Me, H, CF₃, and NO₂) was nitrosated using a standardized solution of N₂O₄ in CDCl₃ at -40°C. The reactions, which produced the corresponding N-4-R-benzyl-

Full text of DOI:10.1021/jo011002k

2942
J . Org. Chem. 2002, 67, 2942-2947
Electr on ic Effects in th e N-Nitr osa tion of N-Ben zylp iva la m id es
Ron W. Darbeau,* Rebecca S. Pease,† and Edson V. Perez
Department of Chemistry, McNeese State University, Lake Charles, Louisiana, 70609
rdarbeau@mail.mcneese.edu
Received October 15, 2001
A series of N-4-R-benzylpivalamides (R ) MeO, Me, H, CF3, and NO2) was nitrosated using a
standardized solution of N2O4 in CDCl3 at -40 °C. The reactions, which produced the corresponding
N-4-R-benzyl-N-nitrosopivalamides, were followed by 1H NMR spectroscopy. The rate of nitrosation
was found to vary in a systematic way with the nature of the 4-R-group on the aromatic ring.
Thus, electron-releasing groups increased the rate of the reaction, whereas electron-withdrawing
ones decelerated N-nitrosation. In a similar fashion, the nitrosations were accelerated in polar
solvents but were slower in solvents of low polarity. The sensitivities of N-nitrosation to these
intra- and intermolecular electronic effects are compared to those from a previous study examining
the dependence of the kinetics of nitrosoamide thermolyses on the same factors.
In tr od u ction
using nitric oxide synthases (NOS)3a,c and are believed
to mediate effects including generation of NO in the
brain,3d neurotransmission,3e and long-term potentiation,3e
as well as the regulation of smooth muscle and vascular
tone3f and immunological responses to microorganisms
and tumors.3g
N-Nitrosations are very useful reactions in vitro,
allowing access to a variety of N-nitroso compounds of
synthetic2e-g and mechanistic value.2h-j,4 Among these
compounds are the N-nitrosoamides. Many details con-
cerning N-nitrosation of amides have been elucidated.1
For example, the amide f N-nitrosoamide conversion is
known to be generally most efficient when NOX or N2O4
is used in nonaqueous media.1 Additionally, steric crowd-
ing at either the N-alkyl or acyl groups evidently decrease
the efficiency of the reaction to the extent, for example,
that N-nitrosation of N-tert-butylpivalamide does not
occur.5a There is a surprising dearth of information
available, however, concerning the effects of intra- and
N-Alkylamides (e.g., N-benzylpivalamides, 1; eq 1)
undergo a rich and varied chemistry that has been well-
studied and documented.1 Despite their sluggishness
toward reactions at the amidic N, as compared to their
more nucleophilic amine counterparts, amides do undergo
a number of interesting substitutions at nitrogen.1
Nitrosating agents such as alkyl nitrites, nitrous acid,
nitrosonium salts, nitrosyl halides (NOX), and dinitrogen
tetroxide (N2O4), for example, successfully convert pri-
mary and secondary amides into their corresponding
N-nitrosoamides (2; eq 1).
(2) (a) Lee, K.; Gold, B.; Mirvish, S. Mutat. Res. 1977, 48, 131. (b)
Preussman, R.; Stewart, B. W. Chemical Carcinogenesis; Searle, C.,
Ed.; ACS Monograph No. 182; American Chemical Society: Washing-
ton, DC, 1984; p 643. (c) White, E. H.; J elinski, L. W.; Politzer, I. R.;
Branchini, B. R.; Roswell, D. R. J . Am. Chem. Soc. 1981, 103, 4231.
(d) Darbeau, R. W.; Delaney, M. S.; Ramelow, U.; J ames, K. R. Org.
Lett. 1999, 1 (5), 796. (e) White, E. H.; De Pinto, J . T.; Polito, A. J .;
Bauer, I.; Roswell, D. F. J . Am. Chem. Soc. 1988, 110, 3708. (f)
Darbeau, R. W.; White, E. H. J . Org. Chem. 1997, 62, 8091. (g)
Darbeau, R. W.; White, E. H.; Nunez, N.; Coit, B.; Daigle, M. J . Org.
Chem. 2000, 65, 1115. (h) White, E. H.; Darbeau, R. W.; Chen, Y.; Chen,
D.; Chen, S. J . Org. Chem. 1996, 61, 7986. (i) Darbeau, R. W.; Gibble,
R. E.; Pease, R. S. Siso, L. M.; Heurtin, D. J . J . Chem. Soc., Perkin
Trans. 2 2001, 1084. (j) Darbeau, R. W.; Gibble, R. E.; Pease, R. S.
submitted to J . Chem. Soc., Perkin Trans. 2. (k) Gibble, R. E. M.S.
Thesis, McNeese State University, Lake Charles, LA, 2001.
(3) (a) Huang, H.; Hah, J . M.; Silverman, R. B. J . Am. Chem. Soc.
2001, 123, 2674. (b) Koshland, D. E., J r. Science 1992, 258, 186. (c)
Steuhr, D. J . Annu. Rev. Pharmacol. Toxicol. 1997, 22, 477. (d)
Schmidt, H. H. H. W.; Murad. F. Biochem. Biophys. Res. Commun.
1991, 181, 1372. (e) Schmidt, H. H. H. W.; Walter, U. Cell 1994, 78,
919. (f) Fo¨rstermann, U.; Pollock, J . S.; Schmidt, H. H. H. W.; heller,
M.; Murad. F. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 1788. (g)
MacMicking, J .; Xie, Q. W.; Nathan, C. Annu. Rev. Immunol. 1997,
15, 323.
The N-nitrosoamides themselves are labile compounds
of significant interest in physical organic chemistry as
probes for the elucidation of reaction mechanisms, espe-
cially those believed to involve carbocations as inter-
mediates.2a-c They have also been employed as novel
initiators of addition polymerization2d and in unique
synthetic methods.2e-g N-Nitroso compounds, in general,
possess intriguing properties with impact in medicine2h,i
and biochemistry;2j for example, they have been impli-
cated in mutagenesis2h and carcinogenesis2i but have also
been successfully employed in enzyme inhibition and
active site mapping.2j
In vivo nitrosation/denitrosation phenomena are fairly
recently discovered,3 but wide ranging reactions that
occur via the intermediacy of nitric oxide (NO),3a Science’s
1992 “molecule of the year”.3b These reactions proceed
* To whom correspondence should be addressed.
† Currently a Research Associate/Visiting Lecturer in the Chemistry
Department at McNeese State University.
(1) Smith, P. A. S. In Open-chain nitrogen compounds. 2, 1st ed.;
W. W. Benjamin, Inc.: New York. 1965; pp 137-202.
(4) Darbeau, R. W.; Perez, E. V. Sobieski, J . I.; Rose, W. A.; Yates,
M. C.; Boese, B. J .; Darbeau, N. R. J . Org. Chem. 2001, 66, 5679.
(5) (a) Darbeau, R. W.; Pease, R. S.; Guillory, M.; Perez, E. V.;
Delaney, M. S. In preparation. (b) Pease, R. S.; Guillory, M.; Davis,
G.; Perez, E. V.; Darbeau, R. W. In preparation.
10.1021/jo011002k CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/03/2002

N-Nitrosation of N-Benzylpivalamides
J . Org. Chem., Vol. 67, No. 9, 2002 2943
Sch em e 1. P oten tia l P a th w a ys for N-Nitr osa tion
of N-Alk yla m id es
F igu r e 1. Examples of ammonium ions containing N+ â to
the 4-R-benzyl system.
delocalized over the N-C-O system and is therefore of
limited availability to an electrophile. Additionally, the
N-protonated nitrosoamide (3) is a high-energy species
because the positive charge on the N is adjacent to both
a carbonyl C and a nitrosyl N with significant positive
dipoles (3a T 3b T 3c; Scheme 1).
The more likely scenario for N-nitrosation is shown in
Scheme 1, path b and involves attack by the carbonyl O
on the nitrosating agent to generate the O-nitroso species
(4a ). Rapid deprotonation and rotation about the C-O
bond derives the conformer 4b in which the nitroso group
but not the lone pair of electrons on the amidic N meets
the stereoelectronic requirement for intramolecular O f
N nitroso transfer. Inversion through N derives 4c, in
which both the n-pair and the NdO group are properly
oriented for the isomerization to the N-nitrosoamide (2)
(Scheme 1, path b). Presumably, on the basis of the
relative steric bulk of the acyl and alkyl groups flanking
the amide unit, O-nitrosation may conceivably yield 4b
directly.5a
It has been recently demonstrated1i-k,6a that 4-R sub-
stituents on aromatic rings can modulate the chemistry
of hypervalent positively charged nitrogen atoms sepa-
rated from the aromatic ring by the sp3-hybridized
benzylic methylene group (Figure 1).1i-k,6a These observa-
tions are interesting in the context that para-substituents
are able to modulate the chemistry at a site seven
positions away in such a fashion that simple conjugation
is not possible. It may be argued though that the
polarizability of the aromatic nucleus and the paucity of
electron density at the benzylic carbon due to its attach-
ments to the aromatic ring and to a positively charged,
sp-hybridized nitrilium N may facilitate transmission of
the electronic “information” between the para-substituent
and the nitrilium C.1i-k,6a
To the extent that an entity like 4a (which also
possesses the generic structure in Figure 1) is present
along the reaction pathway, then the variation in the 4-R
substituent on the starting amide should result in
systematic modulation of the rates of N-nitrosation.
Similarly, the reaction would also be expected to be
susceptible to solvent effects, since the entity 4a is
charged whereas the starting amide is neutral. An
interesting question also arises as to whether the N-
nitrosation is more or less sensitive to substituent/solvent
effects than the corresponding deamination reaction,
which progresses via a charge-separated entity 5 akin
to 4a (Figure 1). This information would be useful in the
preparation, storage, and use of N-nitrosoamides, since
workers would be able to determine the ideal conditions
under which to effect nitrosoamide formation based upon
the structure of the amide.
intermolecular electronic factors on the kinetics of N-
nitrosation.
Darbeau et al recently presented evidence for the
existence of an electronic modulation of the thermal
stability of N-alkyl-N-nitrosoamides.6a Electron-releasing
groups (ERGs) and polar solvents were found to acceler-
ate N-nitrosoamide thermolysis, whereas electron-with-
drawing groups (EWGs) and nonpolar media enhance the
thermal stability of the nitrosoamides.6a The identifica-
tion of this electronic effect in N-nitrosoamide thermoly-
sis complements the steric effects observed almost a half
century ago.6b,c Further, it allows workers in deamination
chemistry to rationally and more efficiently exploit the
decomposition of nitrosoamides as a route to carbocations.
We decided to launch a companion investigation of the
role (if any) of electronic effects on the rate of N-
nitrosation of amides. This study would complement the
related one on N-nitrosoamide thermolysis (vide supra)6a
and would also be of practical use to chemists interested
in amide/nitrosoamide chemistry, especially with regard
to efficient nitrosoamide preparation and storage.
The N-nitrosation of amides may arguably occur via
two pathways (Scheme 1). In pathway “a”, there is a
direct attack by the lone pair of electrons of the amidic
N on the nitrosating agent. Rapid deprotonation of the
resultant ammonium ion (3) then derives the N-nitrosoa-
mide. This mechanism is somewhat suspect, because the
nonbonded pair of electrons on the amidic N is strongly
(6) (a) Darbeau, R. W.; Pease, R. S.; Gibble, R. E. J . Org. Chem.
2001, 66, 5027. (b) Huisgen, R.; Ruchardt, C. J ustus Liebigs Ann.
Chem. 1956, 601, 1. (c) White, E. H.; Dolak, L. A. J . Am. Chem. Soc.
1966, 88, 3790.
The present study was aimed at investigating the
effects of substituents and solvent polarity upon N-
nitrosation of amides. It involved H NMR spectroscopic
1

2944 J . Org. Chem., Vol. 67, No. 9, 2002
Darbeau et al.
Ta ble 1. Kin etic Da ta fr om th e N-Nitr osa tion of
N-4-R-Ben zylp iva la m id es in Ch lor ofor m -d a a t -40 °C
rate constant
half-life
(min)
R
(×10-2 s-1
)
σp
MeO
Me
H
3.33
2.04
21
34
-0.27
-0.14
0.00
1.23
57
CF3
NO2
0.344
0.179
202
388
0.53
0.78
a
[Nitrosoamide] ∼ 0.045 M.
Ta ble 2. Kin etic Da ta fr om th e N-Nitr osa tion of
N-Ben zylp iva la m id e in Va r iou s Solven tsa a t -40 °C
rate constant
half-life
(min)
solventb
ꢀc
π* d
(×10-2 s-1
)
CD3CN
CD2Cl2
CDCl3
35.9
8.93
4.80
2.38
0.75
0.82
0.58
0.54
0.03
1.61
1.23
0.815
1684
43
57
F igu r e 2. Plot of ln(% N-benzylpivalamide) vs time for the
N-nitrosation reaction in CDCl3 at -40 °C.
toluene-d8
85
a
b
[Benzylpivalamide] ∼ 0.045 M. Deuterated solvents used.
c Values from ref 7c. Values from refs 7b,c.
d
determinations of the rates of nitrosations of a series of
N-4-R-benzylpivalamides in various solvents at constant
temperature. N-4-R-Benzylpivalamides (1a -e; R ) MeO,
Me, H, CF3, NO2) were used because variation of the
R-group allowed systematic examination of any operating
intramolecular electronic effects. Dinitrogen tetroxide
was used as the nitrosating agent.
Resu lts a n d Discu ssion
N-Nitr osa tion of N-4-R-Ben zylp iva la m id es (1a -
e) in CDCl3. Standard solutions of N-4-R-benzylpivala-
mides (1a -e) in chloroform-d (ꢀ ) 4.80, π* ) 0.58)7 at
-40 °C in NMR tubes were treated with freshly prepared
standard solutions of N2O4 in CDCl3 also at -40 °C. The
F igu r e 3. Hammett-type plot of log kR/kH vs the appropriate
σp for the N-nitrosations of N-4-R-benzylpivalamides in CDCl3
at -40 °C.
1
reactions were followed by H NMR spectroscopy exam-
ining the product distribution as a function of time by
looking specifically at the 1H NMR signals of the benzylic
methylene protons of the product nitrosoamides (singlets,
∼δ 4.9) and the starting amide (doublets, ∼δ 4.4) (Table
1). Nitrosations of N-benzylpivalamide (1c) were also
performed in toluene (ꢀ ) 2.38, π* ) 0.54),7 methylene
chloride (ꢀ ) 8.93, π* ) 0.82),7 and acetonitrile (ꢀ ) 35.9,
π* ) 0.75),7 to probe the effects, if any, of external
electronic (substrate-solvent) interactions (Table 2).
For the nitrosations in CDCl3, plots (e.g. Figure 2)8 of
the data (Table 1)8 using ln(% amide) vs time (min)
yielded straight lines (R2 values 0.998-1.000), confirming
that the nitrosations are first-order in the amide. From
the rate constants for each decomposition, the half-lives
were calculated and were found to vary systematically
from 21 min for R ) MeO to 34 min for R ) Me, to 57
min for R ) H, to 202 min for R ) CF3, and to 388 min
for R ) NO2 (Table 1). These data suggest that an
intramolecular electronic component is present in the
N-nitrosation of amides to the extent that ERGs acceler-
ate nitrosoamide formation, whereas EWGs stabilize the
amides to nitrosation.
A Hammett-type plot (Figure 3) of the log(kR/kH) (k )
rate constants) for the thermolyses vs the appropriate
σp values yields a straight line (R2 ) 0.994) with a “F”
value of -1.17. The linearity of the plot confirms the
existence of a correlation between electronic effects in the
alkyl portion of the nitrosoamide and the rate of N-
nitrosation. Further, the negative sign of “F” supports the
notion of developing positive charge at the benzyl carbon
in the transition state (TS), which would be the case
during formation of species 4a . Evidently then, ERGs
stabilize the developing positive charge at the benzyl
carbon in the TS, thus facilitating the nitrosation; the
converse is true of EWGs.
Nitr osa tion of N-Ben zyl-N-Nitr osop iva la m id e (1c)
in Solven ts of Va r yin g P ola r ity. The existence of the
internal electronic perturbation of the rate of nitrosation
would suggest that similar modulation by external factors
might occur. Since there is development of positive charge
involved in going from 1 to 4a , then increasing the
polarity of the medium would be expected to preferen-
tially stabilize 4a (vs 1), leading to an enhancement in
the rate of N-nitrosation.
To investigate this effect, the pivalamide that under-
goes nitrosation at the most convenient rate (1c) was
treated with a 5-fold excess of N2O4 at -40 °C in solvents
of varying polarity (toluene, chloroform, methylene chlo-
ride, and acetonitrile; Table 2; e.g., Figure 4).8 The data
(Table 2) show that as the solvent polarity rises, the rate
of nitrosation also rises. Indeed, a plot (Figure 4) of log
(7) (a) The π*azo value is a general dipolarity/polarizability index
that gauges the ability of a solvent to stabilize an ionic or polar species
by means of its dielectric effect. Values of π* are based upon the
solvochromatic parameters of azomerocyanine dyes.5b,c (b) Kamlet, M.
J .; Aboud, J .-L. M.; Abraham, M. H.; Taft, R. W. J . Org. Chem. 1983,
48, 2877. (c) Buncel, E.; Rajagopal, S. Acc. Chem. Res. 1990, 23, 226
and references therein.
(8) Only representative data and plots are given.

N-Nitrosation of N-Benzylpivalamides
J . Org. Chem., Vol. 67, No. 9, 2002 2945
nonnucleophilic to the nitrosoamide, as in the thermolysis
reaction, the solvent must be nonnucleophilic to both the
amide and N2O4. Also, the reaction temperature limited
the solvent choice to those with melting points below -40
°C, which eliminated DMSO and cyclohexane, as well as
a number of other potential media.
Initially, acetonitrile, methylene chloride, chloroform,
and toluene were chosen, since they appeared to conform
to all the solvent requirements and provided a reasonably
wide range of polarities (ꢀtol ) 2.38, ꢀCD CN ) 35.9).
3
However, amide nitrosation in acetonitrile proceeded at
an exceedingly low rate (even lower than in toluene),
which is inconsistent with the rest of the data (Table 2).
One possible explanation for this observation could be
interaction between the lone pair of electrons on aceto-
nitrile and N2O4 (eq 2). Since the nucleophilicity of the
F igu r e 4. Plot of log k vs log ꢀ for the N-nitrosations of
N-benzylpivalamide in various solvents at - 40 °C.
k vs log ꢀ for nitrosations of 1c is linear (R2 ) 0.994),
confirming the correlation between solvent polarity and
the rate of nitrosoamide decomposition.
The observation of inter- and intramolecular electronic
modulation of the kinetics of N-nitrosation of amides
appears to be novel.
R a t e Con st a n t s fr om N-Nit r osa t ion of N-Alk yl
Am id es. The rate constant (k) for the first-order ther-
molysis of nitrosoamides, for example, can be readily
determined from plots of ln[nitrosoamide] vs time.6a In
such cases, the slope of the line ) k.6a On the other hand,
the rate of the N-nitrosation reaction, a second-order
reaction, depends on the concentrations of both the amide
and dinitrogen tetroxide in the solution. Consequently,
the slope of a ln[amide] vs time plot (Figure 2) does not
represent the true k value but instead gives k′ ()ktrue
-
[N2O4]). The value of ktrue can then be calculated if the
[amide] and [N2O4] are known. In this case, the concen-
tration of amide is followed by H NMR, and the initial
amide is low as a result of delocalization of the lone pair
of electrons on the nitrogen (eq 2) and the acetonitrile
()solvent) is abundant, the latter is apparently able to
successfully compete with the amide for reaction with
N2O4 at low temperatures (eq 2). Nitrosation appeared
to occur as the solution quickly changed from blue (due
to the presence of N2O4 at low temperature) to yellow
(due to formation of the yellow N-nitrosoamide) as it
warmed to room temperature. The implication, therefore,
is that the acetonitrile generates an intermediate (e.g.,
6; eq 2) on reaction with N2O4. This species then transfers
NO+ to the amide at elevated temperature. A reasonable
structure of the intermediate and a mechanism for its
formation and decay are shown in eq 2.
A study is currently underway to investigate the
details of this proposed intermolecular N f O nitroso
transfer reaction, including the activation energy and
threshold temperature for trans-nitrosation and other
potential reaction pathways of the hypothesized N-
nitrosonitrilium ion 6.5b
Com m en ts on th e Use of N2O4 a s th e Nitr osa tin g
Agen t. The analyses presented thus far have centered
on the properties of the substrate and the solvent.
However, interesting effects could potentially arise due
to the use of N2O4 as the nitrosating agent. For example,
some authors believe that the active concentration of the
NO-carrier forms of N2O4 is influenced by the solvent
polarity.9a Thus, the predominant N2O4/2NO2 equilib-
rium converts one species with formal charges on two
atoms into two equivalent molecules each with formal
charges on two atoms. The reaction as written then would
1
concentration of N2O4 is known. Since the N2O4 is in
significant excess, it can be reasonably assumed that its
concentration is constant and that the reaction follows
pseudo-first-order kinetics (e.g., Figure 2). This assump-
tion of essential constancy of [N2O4] appears to be valid
in practice, since plots of ln[amide] vs time yield straight
lines (e.g., Figure 2).
A Note on th e Ch oice of Solven ts for Low -Tem -
p er a tu r e N-Nitr osa tion of Am id es. In the previous
study examining the roles of electronic effects on the
thermolyses of N-nitrosoamides,6a the choice of solvents
was limited to those that would be nonnucleophilic to the
nitrosoamide. This condition would be necessary because
any process (apart from unimolecular thermolysis) that
scavenges the nitrosoamide would accelerate its rate of
disappearance and skew the kinetics. Additionally, it was
preferable for the solvent to undergo little or no reaction
with the deaminatively generated benzyl cation, since the
1H NMR signals of the benzylic methylene groups may
appear in the region δ 4.9-5.2, where the nitrosoamide
and ester respectively appear. The use of a solvent that
is nonnucleophilic or poorly nucleophilic to the cation
therefore provides a spectrum clear of unwanted signals
in the diagnostic region. The solvents used (DMSO,
acetonitrile, chloroform, and cyclohexane)6a provided a
wide range of polarities while conforming to these previ-
ously mentioned constraints.
The present investigation of the N-nitrosation reaction
presented more limitations, however. In addition to being

2946 J . Org. Chem., Vol. 67, No. 9, 2002
Darbeau et al.
be encouraged in polar solvents that could better stabilize
NO2 over N2O4. Consequently, as the solvent’s polarity
changes, [N2O4] also changes and the rate of nitrosation
would vary as well. However, this factor is believed to
be very minor, if at all active, in the present study for
the following reasons:
(1) As solvent polarity rises, the concentration of the
principal NO-carrier form falls and a rate deceleration
should be observed. This is not the case. Indeed, the
reaction rate rises as the polarity of the inert solvent
rises.
former reaction was performed at -40 °C and the latter
at room temperature. The N-nitrosations would be far
too rapid to be monitored by H NMR at room tempera-
ture, even in nonpolar solvents. Conversely, the deami-
nations would be prohibitively slow at -40 °C. Conse-
quently, since the values of k are temperature-dependent
and a common reaction temperature is somewhat elusive,
determinations of kR(nitrosation)/kR(deamination) are impractical.
1
Comparisons of series rate constants between both
reactions, however, are feasible and interesting. Thus the
ratio of kMeO/kNO for N-nitrosation of amides is 18.6
2
(2) A plot of log k vs log ꢀ is linear (R2 ) 0.994; Figure
4). If the [N2O4]-decreasing effect of rising solvent polarity
was significant, then because it is diametrically opposed
to the polar solvent’s role in preferentially stabilizing the
transition state for nitrosation (vide supra), nonlinearity
would have been expected in Figure 4.
(Table 1), whereas that for thermal deamination of the
corresponding N-nitrosoamides is 8.2.6a The implication
then is that the formation of nitrosoamides (via N-
nitrosation of amides) is somewhat more sensitive to
electron effects than is their thermolytic deamination.
This result presumably arises because the characters of
the transition states of both reactions are similar in terms
of the presence of the hypervalent positive N-atom â to
the aromatic nucleus (Figure 1), resulting in somewhat
similar electronic perturbations from the various 4-R
groups. However, since the entity 4a is actually charged,
whereas 5 is zwitterionic (vide supra), a greater field
effect may be operational in the nitrosation reaction than
in deamination, resulting in a slightly greater sensitivity,
as observed. The origin of the somewhat greater value
of F for nitrosation (-1.17) than that for deamination
(-0.88)6a presumably also lies in the field effect argu-
ment.
(3) The [N2O4] was kept deliberately high, thus even
with equilibria decreasing the [N2O4], because of the large
initial [N2O4], there would be a permanent kinetic excess
of nitrosating agent. This is particularly so because no
nitrations are effected under these conditions by the NO2-
carrier forms present in the system (vide infra).
(4) Finally, since the NO2 is not consumed in this
reaction (no nitrosations occur; vide infra), any N2O4 that
reacts should be rapidly replaced by the reversion of the
inactive NO2 in equilibrium with it. Hence the actual
amount of N2O4 should be essentially in constant excess.
A second phenomenon important to this discussion is
the ONONO2/NO+ + NO3-equilibrium that would in-
crease the nitrosating activity of the system in polar
solvents. However, ONONO2, from which the nitro-
sonium ion is generated, is likely to be less abundant in
polar solvents than is N2O4, since the latter possesses a
larger degree of charge separation. In any event, the
linearity of the log k vs log ꢀ plot (Figure 4) in the face of
the plethora of counterpoised equilibria suggests that
these equilibria probably do not affect the concentration
of active nitrosating agents to a significant degree.
Alternatively, the N-nitrosation of amides may be so
facile as to be insensitive to the slight (or modest) changes
in the concentrations and activities of the various nitro-
sating agents encountered in the present system. In all
likelihood, the correct answer may derive contributions
from both postulates.
From a more practical standpoint, we did not purify
the N2O4 used for these experiments, despite the fact that
commercial N2O4 contains some NO and N2O3, which are
nitrosating agents.9b However, even if some fraction of
the nitrosations were effected by agents other than the
prevalent N2O4, it should be true universally in all the
systems examined and evidently leads to a constant
effect, since all of our plots involving log k are linear. In
any event, this study focused on the roles of electronic
factors (intramolecular and substrate-solvent) on the
rates of amide nitrosation; hence, identification of all
potential nitrosating agents is not crucial to the study.
A Com p a r ison of th e Electr on ic Sen sitivities of
N-Nitr osoa m id e F or m a tion a n d Deca y. No attempts
to compare the rate constants for nitrosation and deami-
nation for a given R group have been made, because the
Su m m a r y
Novel evidence for the existence of an electronic
modulation of the kinetics of N-nitrosation of N-alkyla-
mides has been presented. Electron-releasing groups and
polar solvents accelerate N-nitrosoamide formation,
whereas electron-withdrawing groups and nonpolar me-
dia enhance the resistance of the amide to nitrososation.
The identification of this electronic effect in N-alkylamide
nitrosation allows workers in deamination chemistry to
rationally and more efficiently exploit the preparation
and decomposition of nitrosoamides as a route to car-
bocations. It would also appear that the factor determin-
ing the relative rates of nitrosoamide formation and
decay is the reaction temperature. Thus, in the present
case -40 °C allows successful and rapid nitrosation
without appreciable nitrosoamide deamination. The rapid
rate of N-nitrosation apparently exerts a kind of nitro-
sative leveling effect and renders the reaction insensitive
to subtle changes in the concentrations and activities of
the various nitrosating agents in dissolved N2O4.
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-4-R-Ben zyl-N-n itr osop iva la m id es; Ha n -
d lin g a n d Stor a ge. The N-4-R-benzyl-N-nitrosopivalamides
are thermolabile and unstable in the presence of acids, bases,
and moisture; being photolabile, they were handled in the
dark. The dry, neutral oils were stored in desiccators under
N2 in capped tubes immersed in liquid nitrogen. Ca u tion !
Nitrosoamides should be handled with extreme care because
of their possible mutagenicity2a and carcinogenicity (local and
systemic).2b Efficient fume hoods and appropriate personal
(9) (a) Churney, K. L. Dissertation Abstr. Int. 1962, 46. (b) Cotton,
F. A.; Wilkinson, G. In Advanced Inorganic Chemistry: A Comprehen-
sive Text, 6th ed.; J ohn Wiley and Sons: New York, 1999; pp 328-
330.

N-Nitrosation of N-Benzylpivalamides
J . Org. Chem., Vol. 67, No. 9, 2002 2947
protection (chemical-resistant gloves, safety glasses, lab coat,
etc.) are recommended when handling these compounds.
N-4-R-Ben zylp iva la m id es were prepared by the method
of Heyns and von Bebenburg.10a
Integrals of the N-4-R-benzyl-N-nitrosopivalamides and the
unreacted N-4-R-benzylpivalamides were measured.
P r oof of th e P r esen ce of N-Nitr osoa m id e a n d th e
Absen ce of N-Nitr oa m id es. FT-IR, 1H NMR, and UV-vis
spectra were recorded on samples obtained from nitrosations.
From the nitrosation of N-benzylpivalamide, for example, the
data are as follows: IR (neat) 1720, 1605, 1502, 1390, 1375
cm-1; 1H NMR (CDCl3) δ 1.45 (s, 9H), 4.97 (s, 2H), 7.05-7.40
(m, 5H); UV (CH2Cl2) λmax 275 nm (ꢀ ) 500), 400 nm (ꢀ ) 63),
394 (sh), 432 nm (ꢀ ) 66). No signals indicative of other species,
e.g. of N-nitroamides [e.g., N-benzyl-N-nitroacetamide: IR
N-4-Meth oxyben zylp iva la m id e: mp 88-90 °C;10b IR (Nu-
jol) 3331, 1636, 1538, 1518, 1461 cm-1; 1H NMR (CDCl3) δ 1.25
(s, 9H), 3.78 (s, 3H), 4.35 (d, 2H, J ) 7 Hz), 5.84 (bs, 1H), 6.82-
7.20 (dd, 4H).
N-4-Meth ylben zylp iva la m id e: mp 94-96 °C;10b IR (Nujol)
1
3334, 1636, 1536, 1518, 1461 cm-1; H NMR (CDCl3) δ 1.25
(s, 9H), 2.38 (s, 3H), 4.44 (d, 2H, J ) 7 Hz), 5.87 (bs, 1H), 7.20
(s, 4H).
(neat) 1580, 1375 cm-1
observed.
;
1H NMR (CDCl3) δ 5.27]11 were
N-Ben zylp iva la m id e: mp 81-82 °C (lit.10a mp 81-82 °C);
IR (KBr) 3309, 1689, 1510, 1390, 1375 cm-1; 1H NMR (CDCl3)
δ 1.27 (s, 9H), 4.44 (d, 2H, J ) 7 Hz), 5.90 (bs, 1H), 7.26-7.32
(m, 5H).
Nitr osa tion of N-Ben zylp iva la m id e in Solven ts of
Va r yin g P ola r ity. Individual samples were prepared by
adding 8.6 mg of N-benzylpivalamide and 46.3 mg of DBMP
into each of three NMR tubes. For each run, 800 µL of solvent
(toluene-d8, acetonitrile-d3, or methylene chloride-d2) was
added to a sample that was loaded into the NMR probe and
cooled to -40 °C, and a pre-nitrosation spectrum was taken.
The sample was ejected and 140 µL of the cold N2O4 solution
(prepared in CDCl3 as described above) was injected by syringe
into the NMR tube, and the tube was shaken and quickly
loaded into the probe. A time ) 0 1H NMR spectrum was taken
immediately, followed by a minimum of four additional spectra
at appropriate time intervals, while a temperature of -40 °C
was maintained. Integrals of the N-4-R-benzyl-N-nitrosopiv-
alamides and the unreacted N-4-R-Benzylpivalamides were
measured.
N-4-Tr iflu or om et h ylb en zylp iva la m id e: mp 111-113
1
°C;10b IR (Nujol) 3359, 1641, 1518, 1458, 1377 cm-1; H NMR
(CDCl3) δ 1.25 (s, 9H), 4.54 (d, 2H, J ) 7 Hz), 6.08 (bs, 1H),
6.39-8.22 (dd, 4H).
N-4-Nitr oben zylp iva la m id e: mp 119-121 °C;10b IR (Nu-
jol) 3359, 1641, 1518, 1462, 1377 cm-1; 1H NMR (CDCl3) δ 1.25
(s, 9H), 4.54 (d, 2H, J ) 7 Hz), 6.08 (bs, 1H), 6.39-8.22 (dd,
4H).
Nitr osa tion of N-4-R-Ben zylp iva la m id es. A stock solu-
tion of ∼1.6 M N2O4 solution was prepared by bubbling N2O4-
(g) by syringe through a Teflon cap (vented with a needle and
blanketed with nitrogen gas) into 4.5 mL of CDCl3 at -20 °C
until the volume increased to 5.0 mL. The resulting solution
was kept at -20 °C using a dry ice-acetone bath. Individual
samples were prepared by adding 4.52 × 10-5 mol of each N-4-
R-benzylpivalamide (R ) MeO, Me, H, CF3, and NO2) and 800
µL of 0.2825 M 2,6-di-tert-butyl-4-methylpyridine (DBMP)
solution into separate NMR tubes and capping with Teflon
tape and a serum stopper. For each run, the N-4-R-benzylpiv-
alamide sample was loaded into the NMR probe and cooled to
-40 °C and a prenitrosation 1H NMR spectrum was taken.
The sample was ejected and 140 µL of the cold N2O4 solution
was injected by syringe into the NMR tube; the mixture was
then rapidly shaken and quickly loaded back into the probe.
A time ) 0 1H NMR spectrum was taken immediately, followed
by a minimum of four additional spectra at appropriate time
intervals, while a temperature of -40 °C was maintained.
Acknowledgment 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 authors also wish to acknowledge
the contributions of Mrs. Nyla R. Darbeau and Ms. J oan
E. Vallee.
J O011002K
(11) (a) Darbeau, R. W. Ph.D. Thesis, the J ohns Hopkins University,
Baltimore, MD, 1996. (b) Darbeau, R. W.; White, E. H.; Song, F.;
Darbeau, N. R.; Chou, J . C. J . Org. Chem. 1999, 64 (16), 5966.
(10) (a) Heyns, K.; v. Bebenburg, W. Chem. Ber. 1953, 86, 278. (b)
Beilstein, 3rd; Vol. 12, Suppl. p 2346.