A study of electronic effects on the kinetics of thermal deamination of N-nitrosoamides

Article abstract of DOI:10.1021/jo001741l

N-4-R-Benzyl-N-nitrosopivalamides (1a-d; R = MeO, Me, H, NO₂) were allowed to decompose at 18 °C in C₆D₁₂, CDCl₃, CD₃CN, and d₆-DMSO, and the rates of decomposition were followed by ¹H NMR spectroscopy. The half-lives of the nitrosoamides were found to vary in a systematic way with the nature of the R group on the aromatic nucleus. Electron-releasing groups were found to decrease the stability of the starting nitrosoamide, whereas electron-withdrawing ones increased the nitrosoamides' thermal stability. A Hammett-type plot of log(rate constants of deamination) vs σ_p was linear (R² = 0.986) with a ρ-type value of -0.90 indicating development of significant positive charge at the benzylic position in the transition state of the rate-determining step. The thermal stability of the nitrosoamides was also found to be systematically affected by the polarity of the solvent: as the solvent polarity increased, so did the lability of the nitrosoamides. This observation of intra- and intermolecular electronic perturbations of the kinetics of nitrosoamide decomposition appears to be novel. A closer look at the rate-determining step of nitrosoamide thermolysis is made, and a mechanistic framework is proposed that accounts for both steric and electronic modulation of nitrosoamide stability as well as the greater thermal stabilities of the related N-nitrocarboxamides and N-nitrosotosylamides.

Full text of DOI:10.1021/jo001741l

J . Org. Chem. 2001, 66, 5027-5032
5027
A Stu d y of Electr on ic Effects on th e Kin etics of Th er m a l
Dea m in a tion of N-Nitr osoa m id es
Ron W. Darbeau,* Rebecca S. Pease, and Rebekah E. Gibble
Department of Chemistry, McNeese State University, Lake Charles, Louisiana 70609
rdarbeau@mail.mcneese.edu
Received December 14, 2000
N-4-R-Benzyl-N-nitrosopivalamides (1a -d ; R ) MeO, Me, H, NO2) were allowed to decompose at
1
18 °C in C6D12, CDCl3, CD3CN, and d6-DMSO, and the rates of decomposition were followed by H
NMR spectroscopy. The half-lives of the nitrosoamides were found to vary in a systematic way
with the nature of the R group on the aromatic nucleus. Electron-releasing groups were found to
decrease the stability of the starting nitrosoamide, whereas electron-withdrawing ones increased
the nitrosoamides’ thermal stability. A Hammett-type plot of log(rate constants of deamination) vs
σp was linear (R2 ) 0.986) with a F-type value of -0.90 indicating development of significant positive
charge at the benzylic position in the transition state of the rate-determining step. The thermal
stability of the nitrosoamides was also found to be systematically affected by the polarity of the
solvent: as the solvent polarity increased, so did the lability of the nitrosoamides. This observation
of intra- and intermolecular electronic perturbations of the kinetics of nitrosoamide decomposition
appears to be novel. A closer look at the rate-determining step of nitrosoamide thermolysis is made,
and a mechanistic framework is proposed that accounts for both steric and electronic modulation
of nitrosoamide stability as well as the greater thermal stabilities of the related N-nitrocarboxamides
and N-nitrosotosylamides.
In tr od u ction
N-Nitrosoamides are labile compounds of significant
interest in medicine,1a,b biochemistry,1c industry,1d and
organic chemistry.1e-i For example, they have been
implicated in mutagenesis1a and carcinogenesis1b but
have also been successfully employed in enzyme inhibi-
tion and active site mapping,1c as novel initiators of
addition polymerization,1d in unique synthetic methods,1e,f,g
and as probes for the elucidation of reaction mechan-
isms.1h-j
N-4-R-Benzyl-N-nitrosopivalamides (1a -d ), thermo-
lyze unimolecularly2 to generate very short-lived nitro-
genous entity-separated ion-pairs1k (NESIPs;1k 3) con-
taining reactive 4-R-benzyl cations and pivalate ion (eq
1).1d-i,2,3 Since the benzyl cation is incapable of rear-
rangements, fragmentations, and proton loss, SN1-type
reaction with the counterion (to yield ester) and any
sufficiently nucleophilic solvent (to yield solvent-derived
products ) SDPs) is its only fate. When the solvent is
nonnucleophilic to the carbocation under consideration,
e.g., the 4-R-benzyl cations with CDCl3,3a then the only
product of significance (usually >99%) is the ester.3a,4a
Almost half a century ago, the kinetics of N-alkyl-N-
nitrosoamide thermolyses were found to depend on steric
factors.2 Thus, as the alkyl and acyl portions of the
nitrosoamide become bulkier, the nitrosoamides become
less stable (e.g., the half-life of N-benzyl-N-nitrosoaceta-
mide at 25 °C in benzene is ∼1 month, but that of the
* To whom correspondence should be addressed.
(1) (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.; White,
E. H. J . Org. Chem. 2000, 65, 1121. (j) M.S. Thesis by Rebekah E.
Gibble, 2001, McNeese State University, Lake Charles, LA. (k) Pre-
viously referred to as nitrogenous molecule-separated ion-pairs
and inert molecule-separated ion-pairs (NSIPs and IMSIPs, respec-
tively).1d,f,g-i
(2) (a) Huisgen, R.; Ruchardt, C. J ustus Liebigs Ann. Chem. 1956,
601, 1. (b) White, E. H.; Dolak, L. A. J . Am. Chem. Soc. 1966, 88, 3790.
(3) (a) Darbeau, R. W.; White, E. H.; Song, F.; Darbeau, N. R.; Chou,
J . C. J . Org. Chem. 1999, 64, 4 (16), 5966. (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.
1973, 95, 5, 8107. (d) Song, F.; Darbeau, R. W.; White, E. H. J . Org.
Chem. 2000, 65, 1825.
(4) (a) A minor reaction accompanying thermolysis is denitrosation.
For nitrosopivalamides this pathway is not competitive.4f (b) Ph.D.
Thesis by Ron W. Darbeau, 1996, The J ohns Hopkins University,
Baltimore, Maryland. (c) Darbeau, R. W.; Gibble, R. E.; Pease, R. S. J .
Chem. Soc., Perkin Trans. 2, in press. (d) Darbeau, R. W.; Gibble, R.
E.; Pease, R. S. J . Chem. Soc., Perkin Trans. 2, in press. (e) Darbeau,
R. W.; Song, F.; Gallo, A., manuscript in preparation. (f) Darbeau, R.
W.; Perez, E. V.; Rose, W. A.; Sobieski, J . I.; Yates, M. C.; Boese, B. J .;
Darbeau, N. R. J . Org. Chem., accepted. (g) A semilog plot of k vs σp
was also linear (R2 ) 0.999).
10.1021/jo001741l CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/21/2001

5028 J . Org. Chem., Vol. 66, No. 15, 2001
Darbeau et al.
Sch em e 1. Rea ction P a th w a ys for Dea m in a tively
Gen er a ted 4-R-Ben zyl Ca tion s in Ben zon itr iles4c,d
trosoamides is believed to be the first step that results
in the formation of the trans-diazotate ester (2; eq 1).1c-i,2,3
Very little has been published concerning the details of
this transformation, however.5a It is conceivable that it
proceeds via a four-membered, oxadiazetyl-type entity (4,
eq 2)5a,b in which the benzyl carbon is adjacent to a
hypervalent, positively charged nitrogen atom5b similar
to that in the nitrilium ion from the deaminations in
benzonitriles.1j,4c,d It would appear therefore that if 4-R-
groups could affect the kinetics of the nitrilium ion then
they may effect a similar mediation of the stability of the
postulated TS of the purported RDS of nitrosoamide
thermolysis.
corresponding pivalamide () trimethylacetamide) under
the same conditions is ∼2 h).4b The explanation of this
observation ostensibly lay in the relief of steric strain
between the alkyl and acyl groups as the nitrosoamide
moiety rearranges into the labile trans-diazotate ester
(2) during the rate-determining first step of nitrosoamide
thermolysis (eq 1).3a,b
We have recently studied the formation of mixed
diacylamines from the deamination of N-4-R-benzyl-N-
nitrosopivalamides in 4-R-benzonitriles (Scheme 1).1j,4c,d
Those investigations indicated that the nature of the
R-group on the aromatic nucleus derived from the ni-
trosoamide significantly and systematically affected the
interception of the nitrilium ion by the available nucleo-
philes.1j,4c,d Electron-releasing groups (ERGs) decreased
the nitrilium ion’s reactivity, whereas electron-withdraw-
ing groups (EWGs) appeared to enhance the susceptibil-
ity of the onium ion to nucleophilic attack.1j,4c,d
These results are interesting in the context that para-
substituents are able to modulate the electrophilicity of
the carbon atom seven positions away and separated by
an sp3-hybridized site so 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 attachments to
the aromatic ring and to a positively charged sp-hybrid-
ized nitrilium N may facilitate transmission of the
electronic “information” between the para-substituent
and the nitrilium C.4e
The present study was aimed at testing the validity of
this hypothesis. It involved spectroscopic determinations
of the rates of decompositions of a series of N-4-R-benzyl-
N-nitrosopivalamides in various solvents at constant
temperature. Nitrosopivalamides 1a -d were used as the
source of the 4-R-benzyl cations in this study because of
their convenient rates of decomposition,1g,4c,d the absence
of side reactions,3,4a,f and because variation of the R-group
allowed systematic examination of any operating in-
tramolecular electronic effects.
The rate-determining step (RDS) of the thermal rear-
rangement of nitrosoamides e.g., N-4-R-benzyl-N-ni-
(5) (a) Huisgen (Huisgen et. al. Liebigs Ann. 562, 137 and Huisgen
et. al. Liebigs Ann. 574, 157) investigated the thermolyses of N-nitroso-
N-4-R-acetanilides in which 4-R-aryl (not benzyl) groups were present.
He believed that in these thermolyses, fragmentation of the diazotate
ester resulted in acyl rather than aryl cations. Since Huisgen’s work,
extensive studies (e.g., Ruchardt, C.; Tan, C. C.; Freudenberg, B.
Tetrahedron Lett. 1968, 37, 4019., Hassmann, V.; Ruchardt, C.; Tan,
C. C. Tetrahedron Lett. 1971, 42, 3885, and Ruchardt, C.; Tan, C. C.
Angew. Chem., Int. Ed. 1970 9 (7), 522) have demonstrated that aryl
diazoacetates also ionize into diazonium cations and acetate ions. In
the aryl case, however, the products generated from this ion-pair are
formed by homolytic pathways. Compared to the current study, these
reactions showed remarkably little sensitivity (∼15%) to the nature
of the R group and to the polarity of the solvent. Huisgen suggested
the presence of a resonance-stabilized oxadiazetyl species as the TS
in the nitrosoamide f diazotate ester isomerization. This postulation
was apparently not based solely upon the modulation of the reaction
kinetics by solvents or substituents since such modulation was small.
(b) The resonance forms 4a and 4b are likely to be of similar energy
so the structure of true 4, intermediate or activated complex, is
probably one with charge delocalization and partial deposition of
positive charge on both the oxadiazetyl O and the N more proximal to
the benzylic carbon. (c) The entity 6 is likely to be unstable because of
ring strain and charge separation as is 4 but also because two of the
three resonance forms shown possess tremendous electronic instability
because of the proximity of the positive charges. Thus 6 is both
sterically and electronically activated.
Resu lts a n d Discu ssion
Decom p osition of N-4-R-Ben zyl-N-Nitr osop iva la -
m id es (1a -d ) in CDCl3. Compounds 1a -d were allowed
to decompose in chloroform-d (ꢀ ) 4.80, π* ) 0.58),6 at
1
18 °C and the decompositions were followed by H NMR
spectroscopy (Table 1).7 Decompositions of 1a were also
performed in cyclohexane (ꢀ ) 2.0, π* ) -0.04),6 aceto-
nitrile (ꢀ ) 35.9, π* ) 0.75),6 and DMSO (ꢀ ) 46.5, π* )
1.00),6 to probe the effects, if any, of external electronic
(substrate-solvent) interactions (Table 2).7
(6) (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.6b,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.
(7) See “Supplemental Information” for more support data and plots.

Kinetics of Thermal Deamination of N-Nitrosoamide
J . Org. Chem., Vol. 66, No. 15, 2001 5029
Ta ble 1. Kin etic Da ta fr om th e Decom p osition of
N-4-R-Ben zyl-N-n itr osop iva la m id es in Ch lor ofor m -d a a t
18 °C7
R
rate constant (× 10-3 s-1
)
half-life (min)
σp
MeO
Me
8.56
7.39
6.43
1.05
81
94
108
660
-0.27
-0.14
0.00
H
NO2
0.78
a
[Nitrosoamide] ∼ 0.045 M.
Ta ble 2. Kin etic Da ta fr om th e Decom p osition of
N-4-Meth oxyben zyl-N-n itr osop iva la m id e in Va r iou s
Solven tsa a t 18 °C7
solventb
ꢀc
π*d rate constant (× 10-3 s-1
)
half-life (min)
cyclohexane 2.00 -0.04
2.54
8.56
273
81
34
20
chloroform
4.80
0.58
0.75
1.00
acetonitrile 35.9
20.6
34.6
F igu r e 2. Hammett-type plot of log k vs σp for decomposition
of N-4-R-benzyl-N-nitrosopivalamides (1a -d ) in chloroform-d
at 18 °C.
DMSO
46.5
a
b
[Nitrosoamide] ∼ 0.045 M. Deuterated solvents used. c Val-
d
ues from ref 6c. Values from refs 6b,c.
F igu r e 1. Plot of ln(% 1a ) vs time for decomposition of N-4-
MeO-benzyl-N-nitrosopivalamide (1a ) in chloroform-d at 18 °C.
F igu r e 3. Plot of ln(% 1a ) vs time for decomposition of N-4-
MeO-benzyl-N-nitrosopivalamide (1a ) in cyclohexane-d12 at 18
°C.
For the decompositions in CDCl3, the product distribu-
tion as a function of time was determined by H NMR
1
spectroscopy, looking specifically at the benzylic meth-
ylene protons of the product esters (∼ δ 5.2) and the
starting nitrosoamides (∼ δ 4.9) (Table 1). Plots (e.g.,
Figure 1)7 of the data (Table 1)7 using ln(% nitrosoamide)
vs time (min) yielded straight lines (R2 values 0.997-
1.000)7 as would be expected of first-order kinetics.2 From
the rate constants for each decomposition, the half-lives
were calculated and were found to vary systematically
from 81 min for R ) MeO, to 94 min for R ) Me, to 108
min for R ) H, and 660 min for R ) NO2 (Table 1). These
data suggest that an intramolecular electronic component
is present in nitrosoamide thermolyses to the extent that
ERGs accelerate nitrosoamide thermolyses whereas EWGs
stabilize the nitrosoamides.
Decom p osit ion of N-4-Met h oxyb en zyl-N-Nit r o-
sop iva la m id e (1a ) in Solven ts of Va r yin g P ola r ity.
The importance of the internal electronic perturbation
of the stability of 4 to the kinetics of nitrosoamide
thermolyses would suggest that similar modulation by
external factors might occur. Since there is significant
charge separation involved in going from 1 to 4, then
increasing the polarity of the medium would ostensibly
preferentially stabilize 4 (regardless of whether it is an
intermediate or an activated complex) leading to an
enhancement in the rate of thermolysis.
To investigate this effect, the most labile of the
nitrosoamides (1a ) was allowed to decompose at 18 °C
in solvents of varying polarity (cyclohexane, chloroform,
acetonitrile, and DMSO; Table 2; e.g., Figure 3).7 The
data (Table 2) show that as the solvent polarity rises,
the rate of decomposition also rises. Indeed, plots (Figure
4) of log k vs log ꢀ and vs π*6 for decompositions of 1a
are linear (R2 ) 0.939 and 0.971, respectively) confirming
the correlation between solvent polarity and the rate of
nitrosoamide decomposition.
A Hammet-type plot (Figure 2) of the log k (k ) rate
constants) for the thermolyses vs the σp values yields a
straight line (R2 ) 0.986)4g with a “F” value of -0.90. The
linearity of the plot confirms the existence of a correlation
between electronic effects in the alkyl portion of the
nitrosoamide and the latter’s thermal stability. Further,
the negative sign of “F” supports the notion of developing
positive charge at the benzyl carbon in the transition
state which would be the case during formation of the
strained heterocylic moiety 4.5a,b Ostensibly then, ERGs
stabilize the developing +ve charge at the benzyl carbon
in the TS thus facilitating the thermolysis; the converse
is true of EWGs.
The observation of significant inter- and intramolecular
electronic modulation of nitrosoamide stability to ther-
molysis appears to be novel5a and complements the
previously observed steric modulation of the reaction.2
Th e Na tu r e a n d Age of Sp ecies “4” a n d a Mech a -
n istic F r a m ew or k for Ra tion a liza tion of Ster ic a n d

5030 J . Org. Chem., Vol. 66, No. 15, 2001
Darbeau et al.
This would be so because although the relative stereo-
chemistry of R and R′ are very similar in both structures,
the distance between the benzyl Hs and the pivaloyl Hs
is only1.98 Å for the heterocyclic species 4. Ostensibly,
then the system should actually suffer an increase in
steric strain (due to ring strain and van der Waals strain)
on going from 1 f 4. To the extent that this is true, how
then does an increase in the steric bulk of R and R′
manifest an acceleration of thermolysis?
The answer appears to lay in the following argument.
The nitrosoamide is acyclic and possesses a significant
degree of flexibility. The presence of bulky groups around
the nitrosoamido moiety, will introduce steric strain
where little had existed. Such groups would be expected
to cause a significant increase in the energy of the
thermal ground state of the nitrosoamide. However,
species 4 is inherently energetic by virtue of its strained
oxadiaxetyl ring, endocyclic double bond, and charge
separation. Thus, although the introduction of bulky
groups at R and R′ will raise the energy of 4, the effect
is not as dramatic as in the nitrosoamide precursor.
Hence bulking up the R groups raises the nitrosoamide
energy more than it does that of 4 (or the activated
complex leading to it, if 4 is really an intermediate). The
effect then is one of preferential destabilization of the
ground-state rather than the TS of the RDS resulting in
a decrease of the activation energy of the RDS and the
observed steric acceleration.
F igu r e 4. Overlay plot of log k for thermolyses of N-4-MeO-
benzyl-N-nitrosopivalamide (1a ) in various solvents vs solvent
polarity terms (log ꢀ and π*6).
E lect r on ic E ffect s in Nit r osoa m id e Th er m olyses.
The enhancement of nitrosoamide thermolyses by ERGs
in the alkyl portion of the nitrosoamide and by polar
solvents supports the presence of a charge-separated
entity such as 4 along the reaction profile of the RDS.
Whether species 4 represents the activated complex (AC)
between the starting nitrosoamide and the diazotate
ester (2) of the RDS, or whether it is a true (but high
energy) intermediate between those two extreme minima
is an interesting question.
It is likely that the position (energy maximum or
minimum) of 4 along the reaction profile between 1 and
2 that flank it will vary in degree depending upon the
nature of R and the polarity of the solvent. Hence it is
more likely to be atop the lone energy barrier between 1
and 2 when R ) NO2, but may slip into an energy well
preceding the diazotate ester when R ) MeO. Similarly,
in nonpolar media that are unable to stabilize 4, the
entity is likely to crest the reaction profile but will occur
later along it in polar solvents. If 4 is the activated
complex of the lone step converting 1 f 2, then its
stabilization (by ERGs in polar media) would hasten
nitrosoamide thermolyses as observed. If instead 4 is a
high energy intermediate between 1 and 2, then from the
Hammond-Leffler postulate, stabilization of the acti-
vated complex preceding it (by ERGs in polar media)
would have the same effect. Thus regardless of the nature
of 4 (intermediate of activated complex) its stabilization
produces the rate enhancements observed.
Th e Rela tive Sta bilities of N-Nitr oso- a n d N-
Nitr oa m id es. N-Nitroamides, 5, like their N-nitroso
counterparts also undergo unimolecular thermolysis to
generate a NESIP.3a,8a In this case, however, the nitro-
genous molecule temporarily interspaced between the
ion-pair is N2O rather than N2 as formed in the N-nitroso
case (eqs 1, 3).3a,8a N-Nitroamide decomposition differs
While the presence of 4 in the RDS accounts for the
observed electronic effects,5a an interesting question
arises, however. How does the steric acceleration of
nitrosoamide thermolyses arise? Previously, relief of
steric strain around the N-nitrosoamido moiety (OdN-
N-CdO) was thought to be responsible for the observed
rate enhancement.2 This interpretation is consistent with
the marked difference in spatial separation of the acyl
and alkyl R groups in the nitrosoamide and in the
diazotate (eq 2). For example, computer molecular model-
ing gives the shortest distance between the closest
benzylic H-methyl H pair (of the pivalyl group) as being
3.54 Å for the nitrosoamide and 3.90 Å in the diazotate
ester.
If, however, the charge-separated, strained entity 4
does feature in the RDS (as is required to account for
the observed electronic effects), then no relief of steric
strain occurs when it is formed from the nitrosoamide.
from nitrosoamide decomposition in two other principal
ways: (1) the partitioning of the carbocation slightly

Kinetics of Thermal Deamination of N-Nitrosoamide
J . Org. Chem., Vol. 66, No. 15, 2001 5031
favors the solvent,3a,4b and (2) the N-nitroamides are less
labile.3a,4b,8a The former difference may arise because of
better shielding of the carbocation from its nascent
counterion by the more massive and heavier N2O (vs N2)8b
which allows the cation more opportunity to scavenge
molecules in the solvent cage leading to enhanced yields
of SDP.3a
A reasonable interpretation of the greater thermal
stability of the N-nitroamides follows. It is likely that
N-nitroamides, rearrange in a fashion similar to their
nitroso analogues and that this rearrangement proceeds
via a corresponding four-membered species, 6 (eq 3) that
is analogous to species 4 (eq 2). In this case, however, 6
is a significantly unstable entity due to contributions
from the resonance forms 6a and 6c in which positive
charges reside on adjacent atoms connected via short
NdX (X ) N, O) bonds. Interestingly, while resonance
form 6b is analogous to species 4a ,b, there is no corre-
sponding destabilizing resonance form of 4 that is
analogous to 6a ,c.5c
Fundamentally, therefore, the energy gap between 5
and 6 is larger than that between 1 and 4 and, regardless
of whether 4 and 6 are intermediates or transition states,
the result would be that the 5 f 6 conversion would be
less facile than the corresponding 1 f 4 reaction.
Consequently, N-nitroamides are more thermally stable
than N-nitrosoamides as observed.3a,8a
Th e Rela tive Sta bilities of N-Nitr osoca r boxa m -
id es a n d N-n itr osotosyla m id es. N-Nitrosotosylamides
(7) are much less labile than their nitrosocarboxamide
analogues.4b Assuming that the nitrosotosylamide to
diazotate ester conversion traverses a pathway analogous
to those above, then the thermostability of 7 would stem
from preferential stabilization of 7 or destabilization of
the corresponding TS/AC species, 8 (eq 4).
is a distorted square planar and the S is at the center of
a severely distorted trigonal bipyramid (eq 4).
Su m m a r y
Novel evidence for the existence of an electronic
modulation of the stability on N-alkyl-N-nitrosoamides
have been presented. Electron-releasing groups and polar
solvents accelerate N-nitrosoamide thermolysis whereas
electron-withdrawing groups and nonpolar media en-
hance the thermal stability of the nitrosoamides. The
identification of this electronic effect in N-nitrosoamide
thermolysis complements the steric effects in the reaction
observed almost a half century ago. Further, it allows
workers in deamination chemistry to rationally and more
efficiently exploit the decomposition of nitrosoamides as
a route to carbocations.
A comprehensive mechanistic framework has been
proposed that accounts for both the observed steric and
electronic effects as well as the relative stabilities of
N-nitroso-, N-nitrocarboxamides, and N-nitrosotosyla-
mides. In this mechanism, a high energy, strained, four-
membered, charge-separated heterocyclic entity lies be-
tween the N-nitrosoamide and the diazotate ester in the
RDS. This oxadiazetyl moiety may be an intermediate
or an activated complex and indeed, its age, duration,
and character may depend on the direction and extent
of electron drift to or from the diazetyl nucleus and the
ability of the medium to stabilize the charge separation.
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 ! Nitroso-
amides should be handled with extreme care because of their
possible mutagenicity1a and carcinogenicity (local and system-
ic).1b Efficient fume hoods and appropriate personal 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 from the method
of Heyns and von Bebenburg.9a N-4-Meth oxyben zylp iva la -
m id e mp 88-90 °C;9b IR (Nujol) 3331, 1636, 1538, 1518, 1461
cm-1; 1H NMR (CDCl3) δ1.25 (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;9b IR (Nujol) 3334, 1636, 1536,
1518, 1461 cm-1; 1H 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). N-
Ben zylp iva la m id e mp 81-82 °C (lit.9a mp 81-82 °C); IR
(KBr) 3309, 1689, 1510, 1390, 1375 cm-1 1H NMR (CDCl3)
;
Species 8 (comparable to 4 and 6, vide supra) would
be expected to be highly energetic partly because of
inherent ring strain but also because the rehybridization
of the sulfur during the 7 f 8 conversion requires its
change from a tetrahedral geometry to a severely dis-
torted trigonal bipyramid. Indeed, 8 is likely to be very
unstable (relative to 7) because the thiaoxadiazetyl ring
δ1.27 (s, 9H), 4.44 (d, 2H, J ) 7 Hz), 5.90 (bs, 1H), 7.26-7.32
(m, 5H). N-4-Nitr oben zylp iva la m id e mp 119-121 °C;9b IR
(Nujol) 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).
N-4-R-Ben zyl-N-n itr osop iva la m id es (1a -d ) were pre-
pared from the method of described in refs 1b,c. N-4-Meth -
oxyben zyl-N-n itr osop iva la m id e (1a ). IR (Neat) 1712, 1613,
1513, 1304, 1249, 1217 cm-1; 1H NMR (CDCl3) δ 1.45 (s, 9H),
3.75 (s, 3H), 4.90 (s, 2H), 6.78-7.18 (dd, 4H). N-4-Meth yl-
b en zyl-N-n it r osop iva la m id e (1b ). IR (Neat) 1714, 1505,
(8) (a) Garcia, J .; Gonzalez, J .; Segura, R.; Urpi. F.; Vilarrasa, J . J .
Org. Chem. 1984, 49, 3322. (b) The molecular diameters (σ) of N2 and
N2O are 3.681 Å and 3.879 Å, respectively. (Bird, R. B.; Stewart, W.
E.; Lightfoot, E. N. Transport Phenomena; Wiley: Chichester, 1960; p
744). The molecular volumes (VM) were calculated using VM
)
(4/3)πr3: VM(N2) ) 26.115 Å3; VM(N2O) ) 30.560 Å3. Thus, N2O is ∼17%
(9) (a) Heyns, K.; v. Bebenburg, W. Chem. Ber. 1953, 86, 278. (b)
No references to these compounds have been found.
larger than N2.

5032 J . Org. Chem., Vol. 66, No. 15, 2001
Darbeau et al.
1482, 1398, 1333, 1217 cm-1; 1H NMR (CDCl3) δ 1.42 (s, 9H),
2.28 (s, 2H), 4.90 (s, 2H), 7.12-7.12 (m, 4H). N-Ben zyl-N-
n itr osop iva la m id e (1c). IR (Neat) 1711, 1605, 1526, 1348,
1216 cm-1; 1H NMR (CDCl3) δ 1.45 (s, 9H), 5.01 (s, 2H), 7.05-
7.40 (m, 5H). UV (CH2Cl2) λmax 275 nm (ꢀ ) 500), 400 nm (ꢀ )
63) 394 nm (sh), 422 nm (ꢀ ) 66). N-4-Nitr oben zyl-N-
n itr osop iva la m id e (1d ). 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).
Decom p osition of N-Nitr osoa m id es (1a -d ). In a typical
run, ∼10 mg of the appropriate N-nitrosoamide, 1, was added
to 750 µL of the selected solvent in an NMR tube. The sample
was then loaded into the NMR probe at 18 °C and a time ) 0
1H NMR spectrum was taken. 1H NMR spectra were recorded
at intervals,7 and the integrals of the 4-R-benzyl pivalates and
undecomposed N-nitrosoamide were measured (Table 1).7 In
cyclohexane-d12, CDCl3, and d6-DMSO the ester and N-
nitrosoamide were the only benzyl compounds observed. In
CD3CN low yields of SDP1g were observed and were incorpo-
rated in the calculation of % nitrosoamide. Most runs remained
at 18.0 °C throughout; the maximal observed variation in probe
temperature during runs was 0.2 °C.
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 authors also wish to acknowledge
the contributions of Dr. Ernest F. Silversmith (Morgan
State University, Dept of Chemistry), Mrs. Nyla R.
Darbeau, and Ms. J oan E. Vallee.
Su p p or tin g In for m a tion Ava ila ble: Sample kinetic data
and plots for decompositions of 1a -d in chloroform and for
decomposition of 1a in various solvents. This information is
available free of charge via the Internet at http://pubs.acs.org.
J O001741L