The Darbeau-White-Gibble reaction: An N-nitrosoamide-mediated Ritter-type reaction. Part I. A study of electronic, steric, and orbital effects in the nucleophile1a

Article abstract of DOI:10.1039/b102014p

Benzyl cations were generated via thermal decomposition of N-benzyl-N-nitrosopivalamide in molten 4-R-substituted benzonitriles (R = NH₂, Me₂N, MeO, Me, H, F, and CF₃). In each case, the benzyl cation was intercepted competitively by pivalate ion to yield benzyl pivalate and by the benzonitriles to yield the corresponding N-4-R-benzonitrilium ion. The latter onium ions reacted with pivalate ion to form benzimidic anhydrides which rearranged to yield N-4-R-benzoyl-N-pivaloylbenzylamines (i.e. unsymmetrical diacylamines). The yield of diacylamines (maximum ～10.6% for R = H) is smaller than from the corresponding reactions in acetonitrile and varied systematically with the nature and location of the R group on the aromatic nucleus. Both electron-releasing and electron-withdrawing groups at the para position effected a diminution of the yield of diacylamine; indeed for R = NH₂, no diacylamine was formed. ortho Substitution of the aromatic nucleus resulted in significantly diminished yields of diacylamine, as did nucleophilic attack on the nitrilium ion by pivalate rather than acetate. Thus, both electronic and steric effects in nucleophilic attack on the nitrilium carbon were observed. The ratios of counterion-derived product to solvent-derived product for both the first-formed benzyl cation and the less reactive benzonitrilium ion are similar. This observation is interpreted in terms of the intermediacy of nitrogenous entity-separated ion-pairs in these deaminations.

Full text of DOI:10.1039/b102014p

View Article Online / Journal Homepage / Table of Contents for this issue
The Darbeau–White–Gibble reaction: an N-nitrosoamide-mediated
Ritter-type reaction. Part I. A study of electronic, steric, and
1a
orbital effects in the nucleophile
a
a
a
a
a
2
Ron W. Darbeau,* Rebekah E. Gibble, Rebecca S. Pease, Davin E. Bridges, Luis M. Siso
b
and Derrill J. Heurtin
a
Department of Chemistry, McNeese State University, Lake Charles, LA 70609, USA.
E-mail: rdarbeau@mail.mcneese.edu
Alfred M. Barbe High School, Lake Charles, LA 70605, USA
b
Received (in Cambridge, UK) 19th February 2001, Accepted 3rd May 2001
First published as an Advance Article on the web 6th June 2001
Benzyl cations were generated via thermal decomposition of N-benzyl-N-nitrosopivalamide in molten
-R-substituted benzonitriles (R = NH , Me N, MeO, Me, H, F, and CF ). In each case, the benzyl cation
4
2
2
3
was intercepted competitively by pivalate ion to yield benzyl pivalate and by the benzonitriles to yield the
corresponding N-4-R-benzonitrilium ion. The latter onium ions reacted with pivalate ion to form benzimidic
anhydrides which rearranged to yield N-4-R-benzoyl-N-pivaloylbenzylamines (i.e. unsymmetrical diacylamines).
The yield of diacylamines (maximum ∼10.6% for R = H) is smaller than from the corresponding reactions in
acetonitrile and varied systematically with the nature and location of the R group on the aromatic nucleus.
Both electron-releasing and electron-withdrawing groups at the para position effected a diminution of the yield
of diacylamine; indeed for R = NH , no diacylamine was formed. ortho Substitution of the aromatic nucleus
2
resulted in significantly diminished yields of diacylamine, as did nucleophilic attack on the nitrilium ion by
pivalate rather than acetate. Thus, both electronic and steric effects in nucleophilic attack on the nitrilium
carbon were observed. The ratios of counterion-derived product to solvent-derived product for both the first-
formed benzyl cation and the less reactive benzonitrilium ion are similar. This observation is interpreted in
terms of the intermediacy of nitrogenous entity-separated ion-pairs in these deaminations.
SN1-type reaction with the counterion and the solvent is its only
Introduction
fate. Cation–solvent reactions must occur before diffusion of
the nitrogenous molecule from between the ions in the solvent
cage as the latter process leads to internal collapse of the ion-
N-Benzyl-N-nitrosopivalamide (1, NBNNP) undergoes uni-
2
molecular thermolysis to produce very short-lived nitrogenous
entity-separated ion-pairs (NESIPs; 2) containing the benzyl
pair to give the corresponding ester. Thus, the N molecule is
2
cation and pivalate ion initially separated by a nitrogen mole-
implicated in the partitioning of the carbocation between its
1
b,3
cule [eqn. (1)]. The carbenium ion of the NESIP is exceed-
nascent counterion and the medium; the longer the N molecule
2
remains in the pocket between the ions, the greater opportunity
that is afforded the carbenium ion to interact with the medium.
Essentially then, the counterion and the solvent compete for
the carbenium ion and the high speed of the carbenium–
counterion reaction to yield an ester, limited by the rate of
(
1)
diffusion of N into the medium, results in the carbenium ion
2
having only a limited time to react with the medium before
3a,c,f
undergoing ion-pair collapse with the counterion.
The yield
of solvent-derived products (SDPs) increases with the reactivity
of the cation, with the mole fraction and nucleophilicity of the
active solvent, and in an inverse manner with the nucleophil-
3a
icity of the counterion. The yield of SDP also generally rises,
3a,g
but to a lesser extent, with decreasing temperature and when
3a
the nitrogenous molecule is N O rather than N .
2
2
The reactions of the carbenium ion with nucleophiles may be
irreversible if the products, e.g. carboxylate esters or alkylated
3
a
aromatics, are stable under the reaction conditions. However,
ionization of products from both solvent–carbenium ion
ingly reactive due, in part, to the low activation energy required
for the loss of the nitrogen molecule from the alkanediazonium
precursor, thus allowing the cation to be formed with minimal
4a
(e.g. onium ions from phenylcarbenium ion–acetone reactions)
and ion-pair collapse (e.g. labile benzyl esters, such as those
1,3
1b,3b
solvent participation. Additionally, the temporary screening
of the cation from its counterion by the sheer physical presence
of the nitrogenous molecule results in the maximal positive
formed when the counterion is triflate
) have been observed.
In a previous study, the utility of the deamination of N-
nitrosoamides in nitriles as an alternative method of prepar-
ation of unsymmetrical diacylamines (DAAs) in modest yields
1b,3
charge at the electron-deficient center. When the cation, e.g.
phenylcarbenium ion, is stable and devoid of β-hydrogens,
1b
was reported. In that study, 1 was allowed to decompose in
1
084
J. Chem. Soc., Perkin Trans. 2, 2001, 1084–1090
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b102014p

View Article Online
acetonitrile to form the corresponding ester as well as the
N-benzylacetonitrilium ion. The onium ion was scavenged
by pivalate to form the labile (Z)-ethanimidic anhydride,
which isomerized by inversion through nitrogen into the
anticipated that the nucleophilicity of benzonitrile would be
larger than that of acetonitrile and might thus result in larger
yields of SDP.
N-Nitrosoamide 1 was again used as the source of the benzyl
cation in this study because of its convenient rate of decom-
position (t1/2 ∼30 min in PhCN at 25 ЊC) arising from steric
acceleration of the rearrangement step [eqn. (1)] by the tert-
(
E)-diastereomer; rearrangement of the latter yielded N-acetyl-
1b
N-pivaloylbenzylamine (Scheme 1) in 23% yield.
2
butyl group. Further, a more direct comparison of the present
results in benzonitrile versus those obtained previously in
1b
acetonitrile could be made.
Results and discussion
Decomposition of N-benzyl-N-nitrosopivalamide (1) in 4-R-
substituted benzonitriles
Compound 1 was allowed to decompose in the molten 4-R-
benzonitriles; for R = NH2 and Me N the decomposition
2
temperature was 90 ЊC and for R = MeO, Me, H, F, CF , the
3
reactions were run at 60 ЊC. Our preference would have been
to carry out all of these decompositions at 25 ЊC because the
companion study in acetonitrile was performed at that tem-
1b
perature. † Additionally, we had previously observed that
nitrosoamide decomposition in equimolar benzene–toluene
mixtures at elevated temperatures resulted in diminished yields
3a,g
of SDP. † Heating to 60 ЊC was necessary in the cases of
R = MeO, Me, H, F, and CF because it was the lowest common
3
temperature at which those 4-R-benzonitriles were liquidठ(at
7
60 Torr). Similarly 90 ЊC was the lowest temperature at which
the p-amino- and p-dimethylaminobenzonitriles were molten.
4b
A previous study has shown that only (molten) solvents and
the counterion in the solvent cage can effectively compete for
the caged deaminatively generated carbenium ion, and as
such the benzonitriles would all have to be in the liquid phase
(
i.e. solvent) to enter efficiently into bimolecular reaction
with the carbenium ion. The product distribution was stable to
prolonged exposure to 60 ЊC, § but prolonged heating at 90 ЊC
resulted in DAA decomposition. However, no appreciable
decomposition occurs after heating of the product mixture at
Scheme 1 Reaction pathways for nitrogen-separated ion-pairs in
benzonitriles.
9
0 ЊC for ∼1 h, so data reported here were taken in this safe
window after decomposition.
The product distribution as a function of the 4-R substituent
This (Darbeau–White–Gibble) reaction may be considered
as a variation of the Ritter reaction [eqn. (2)]. This version,
1
(
Table 1) was determined by H NMR spectroscopy, looking
specifically at the methylenic protons of the benzyl signals of
the products. The mixed DAAs were identified based partially
upon the established chemistry of the nitrile group in the
(
2)
1b
presence of the deaminatively generated benzyl cations. Also
their chemical shifts (δ 4.77–4.83) were in the same region
as that of the (benzylic methylene) signal of N-acetyl-N-
1b
pivaloylbenzylamine (δ 4.82, prepared in a previous study ).
The benzyl-4-R-benzamides (δ 4.64–4.65) were identified in a
however, differs from the traditional Ritter reaction in three
ways; (1) the source of the carbocation is deamination rather
than alcohol protolysis; (2) the principal scavenger of the
nitrilium ion is the nascent counterion of the deaminative
carbenium ion rather than water, and (3) the major product
is a DAA rather than an amide. Since traditional methods of
unsymmetrical DAA preparations are low yielding, require
forcing conditions, and are otherwise flawed, the nitroso-
amide-mediated Ritter-type reaction may represent a synthetic-
ally viable alternative route to this class of compounds.
In an effort to systematically examine this cascade of reac-
tions, and to further delineate the mechanism of this reaction as
well as the limitations of the methodology, the decomposition
of 1 in substituted benzonitriles was investigated. The benzo-
nitriles were chosen because appropriate substitution of the
aromatic nucleus allowed methodical investigation of any
electronic and/or steric effects operational in the reaction.
Additionally, because the aromatic nucleus has a ϩR effect on
groups involving a benzylic atom multiply bonded to one more
electronegative than it (e.g., carbonyl, iminyl, sulfonyl, etc.), we
similar fashion (δbenzyl
= 4.65). The other products,
benzamide
benzyl pivalate (δ 5.10) and benzyl alcohol (δ 4.56) were ident-
ified from their chemical shifts and by spiking with authentic
material.
The data (Table 1) show that as the 4-R-group is varied from
CF , to MeO, to NH , the yield of mixed diacylamines rises
3
2
1b
from ∼8 to ∼11.0% and then falls again to 0%. There are three
†
The yields of DAA from decomposition of N-nitrosoamide, 1, in
1b 3g
acetonitrile at 25 and 90 ЊC are indistinguishable at ∼23%.
‡
The melting points of the 4-R-benzonitriles used in the present study
are: R = NH2 (mp = 83–85 ЊC); Me N (mp = 73–75 ЊC); MeO (mp =
2
57–59 ЊC); R = Me (mp = 26–28 ЊC); R = H (mp = Ϫ12 to Ϫ14 ЊC);
R = CF (mp = 39–41 ЊC); R = F (mp = 35–37 ЊC). Source: Aldrich
3
Handbook of Fine Chemicals and Laboratory Equipment 2000–2001.
The product mixture (including benzyl pivalate) is stable under the
§
current conditions as illustrated by the fact that a sample solution after
total decomposition of 1 in benzonitrile at 60 ЊC was kept at 60 ЊC for
2
more days; no significant change in the product distribution was
observed (vide supra).
J. Chem. Soc., Perkin Trans. 2, 2001, 1084–1090
1085

View Article Online
a
b
Table 1 Product distribution from the decomposition of N-benzyl-N-nitrosoamides in 4-R-C H CN and o-toluonitrile at 60 ЊC
6
4
Relative yield(%)
Solvent-derived products
R
Ester
DAA
Benzylbenzamides
Benzyl alcohol
%SDP
% Benzamide of SDP
NBNNP Decomposition
c
c
c
c
c
c
c
c
p-NH2
100.0
90.1
86.1
86.4
85.9
84.5
88.9
89.7
0.0
8.7
11.0
10.7
0.1
10.6
9.8
8.1
0.0
1.2
2.8
2.9
14.0
4.9
1.3
2.2
0.0
0.0
0.1
0.0
0.0
0.0
0.0
0.0
0.0
10.1
13.8
13.6
14.1
15.1
11.1
10.3
0.0
12.9
20.3
21.3
99.3
32.5
11.7
21.4
p-Me N
2
p-MeO
p-Me
o-Me
H
p-F
p-CF3
NBNNA Decomposition
d
H
85.0
13.0
1.9
0.1
14.9
12.8
a
b
c
Average of at least triplicate runs. Max std deviations: ester ∼0.3; DAA ∼0.2; amide ∼0.3; alcohol ∼0.2. Concentration ∼0.045 M. Ester = benzyl
d
pivalate. Ester = benzyl acetate.
Fig. 1 A simple view of the orientation of the p-orbitals in the
benzonitriles.
interesting aspects of this result: (1) the yields of DAAs are
significantly smaller in the benzonitriles [even with powerful
electron-withdrawing and electron-releasing groups (EWGs
and ERGs, respectively) at the para position of the aromatic
Fig. 2 Pathways for nucleophilic attack on the benzonitrilium ion.
nucleus] than in the acetonitrile case where 23% mixed DAA
was observed; † (2) the yield of mixed diacylamines is maximal
for R = MeO (and approximates those for R = Me and H); and
1b
attack on the nitrilium carbon is obliged to occur perpendicular
to the aromatic π-cloud and coplanar with the skeleton of the
aromatic nucleus (Fig. 2). Indeed, molecular models indicate
that the ortho protons are almost in the direct path of the
incoming nucleophile (Fig. 2) thus mitigating against nucleo-
philic attack on the nitrilium ion and diminishing the yields of
SDP.
(
3) in general, relative to R = H, both ERGs and EWGs effect
a relative decrease in % DAA (Table 1). Thus, for the
very strongly electron-releasing NH group, no DAA is formed
2
at all.
With respect to the first observation, the nitrilic N of the
benzonitriles would be expected to be more nucleophilic than
that of acetonitrile because of π-donation to it by the aromatic
nucleus (although some hyperconjugation would be expected
with acetonitrile). To the extent that this is true, the benzo-
nitriles would intercept more of the phenylcarbenium ions
than would acetonitrile. However, the phenyl group evidently
effects a deactivation of the N-benzylbenzonitrilium ion with
respect to nucleophilic attack. This deactivation, which is
believed to possess both an electronic and a steric component
A free energy correlation analysis of the data
ϩ
The Yukawa–Tsuno equation is log(k /k ) = ρ[σ ϩ r(σR
Ϫ
R
H
R
σR)] where k, ρ and σ have their usual meanings and r is a
measure of the through-conjugation occurring in the system.
When r = 1, as in the reference solvolysis of 2-aryl-2-chloro-
propanes, the relationship simplifies to the Hammett-type
ϩ
relationship: log(k /k ) = ρσ . In the present case, since a
R
H
R
(
vide infra), ostensibly leads to lower yields of SDP including
cationic site is also generated in resonance with the aromatic
nucleus, an r value of unity is assumed. Further if the Curtin–
Hammett relationship applies, then the yields of the DAAs are
assumed to be related to their rates of formations, hence the
term ‘log[(%DAA) /(%DAA) ]’ replaces ‘log(k /k )’. A plot
the mixed DAAs.
The electronic deactivation by the phenyl group probably
arises from π-electron donation towards the positive nitrilium
N (where the electron demand is higher than in the uncharged
nitrile). This ϩR resonance effect minimizes the electrophilicity
of the nitrilium carbon and makes it less prone to nucleophilic
attack. Consequently a smaller yield of nitrilium ion-derived
product (i.e. SDP) is formed, as observed.
R
H
R
H
(Fig. 3) of our data using log[(%DAA) /(%DAA) ] vs. the
R
H
5a
appropriate σ term (Table 2) for the series Me N to CF
yields a smooth binomial curve (R = 0.954). In this plot, σ
p
2
3
ϩ
2
p
values are used for R = Me N, MeO, and Me where through-
2
With regard to the phenyl ring’s steric deactivation of the
nitrilium ion, the following argument is made. A simple view of
the orientation of the p-orbitals in the benzonitriles (Fig. 1)
reveals that in order for stabilizing conjugation to exist between
the phenyl ring and the nitrile group, one of the p-orbitals on
the nitrilium carbon (and by extension, a p-orbital on the
nitrilium N) must be coplanar with the p-orbitals on the
aromatic nucleus. Since the p-orbital on the nitrilium C that is
coplanar with those on the aromatic nucleus is involved in
bonding, it is essentially unavailable (or at least less available)
than is the one orthogonal to it. Consequently, nucleophilic
conjugation would be expected to feature between the R-group
and the nitrilium unit. However, σ values are employed for
p
R = F and CF since their effect on the reaction center is likely
3
to be limited to induction in which case the more traditional
Hammett equation: log(k /k ) = ρσ , applies. For R = H,
R
H
p
ϩ
σp = σp = 0, by definition.
Presumably, the resonance interaction between the aromatic
nucleus and the α-nitrile group would be mediated by the
electronic nature of the 4-R group. Thus, strong ERGs would
enhance the electron density and hence the nucleophilicity of
the nitrilic N. Consequently, the nucleophilicity of the nitriles
1
086
J. Chem. Soc., Perkin Trans. 2, 2001, 1084–1090

View Article Online
ϩ
Fig. 3 Yukawa–Tsuno-type plot for the decomposition of N-benzyl-N-nitrosopivalamide in 4-R-benzonitriles. σp and σ used for σ as appropriate.
p
Table 2 Free energy data from the decomposition of N-benzyl-N-
nitrosoamide in 4-R-benzonitriles at 60 and 90 ЊC
reactions evidently have similar activation energies, maxim-
ization of %DAA would require a group that does not abate
either event, i.e. one that is neither electron-withdrawing nor
releasing: H (as observed).
However, although the above argument is generally true, i.e.
diminished yields of DAA are observed for EWGs and the
(
%DAA)R/
log[(%DAA)R/
(%DAA)H]
R
%DAA
(%DAA)H
σ
a
NH2
0.0
8.8
11.0
10.7
10.6
9.8
0.0
Ϫ1.3 a
ERGs Me N and NH relative to H; no relative diminution is
Me N
0.80
1.01
1.00
1.00
0.92
0.76
Ϫ0.080
0.003
0.002
0.000
Ϫ0.035
Ϫ0.120
Ϫ1.7
2
2
2
a
MeO
Me
H
F
CF3
Ϫ0.78 a
Ϫ0.31
0.000b
0.15
observed for the ERGs MeO and Me. The source of this
inconsistency is unclear and is currently under further study.
Decomposition of N-benzyl-N-nitrosopivalamide in o-toluonitrile
b
8.1
0.53
a
ϩ
b
To probe the veracity of the steric argument (vide supra), 1 was
allowed to decompose in o-toluonitrile at 60 ЊC. The data
σp used. σp used.
(
0
Table 1) show that the yield of mixed diacylamine was only
.1%. This significant diminution in the DAA yield supports the
would rise in the order CF to Me N¶ with the former being least
3
2
belief that the nucleophile is obliged to attack in the plane of
the aromatic nucleus and is therefore prone to steric hindrance
by groups, e.g., methyl, at the ortho-position. It is interesting
that even though only one of the two electronically viable
approaches to the nitrilium C is completely impeded, almost no
attack from the other side occurs as evidenced by the low yield
of DAA. Since only one of two faces is electronically
deactivated (vide supra) then, from a purely statistical view-
point, a 50% decrease in yield would have been expected. The
virtual absence of DAA under these circumstances suggests
that the methyl group may exert more than just steric hindrance
of the approach of the nucleophile during its attack on the
nitrilium ion. An electronic and/or enhanced (or “supersteric”)
adept at capturing the benzyl cation and the latter being the
most proficient at it. In short, both the rates of formation (and
the yields) of the benzonitrilium ion would be greatest when
R = Me N¶ and least when R = CF .
2
3
Diametrically opposed to the ERGs’ electronic enhancement
of the rates of formation and (hence) yields of the nitrilium
ions, however, is their electronic deactivation of the nitrilium
ions to nucleophilic attack. This would be so since the greater
the flow of electron density to the nitrilium carbon, the more
resistant it would be to nucleophilic attack and thus the smaller
would be the yield of mixed diacylamine.
A similar argument can be constructed for the opposing
effects of EWGs on the yields of DAAs. Hence, EWGs would
diminish the nucleophilicity of the nitrile and reduce its ability
to capture the benzyl cation. This effect would ostensibly lead
to diminution of the %DAA. However, EWGs would sub-
sequently increase the electrophilicity of the nitrilium ion and
lead to an enhancement of the yield of DAA.
4c
effect may be involved. This issue is under further
4c
investigation.
Decomposition of N-benzyl-N-nitrosoacetamide in benzonitrile
As a further test of the steric argument, and to illustrate the
sensitivity of the reaction to steric effects in the nucleophile,
N-benzyl-N-nitrosoacetamide (NBNNA) was decomposed in
benzonitrile at 60 ЊC. The nitrosoacetamide was chosen because
the nucleophilic counterion it generates is acetate, which,
From the non-linearity of the Yukawa–Tsuno-type plot (Fig.
3
), it would appear then that both of these opposing factors are
significant, and are governed by similar activation energies.
Thus, the non-linearity supports the reasonable assertion that
the rate-determining step for DAA formation occurs after the
comparatively fast ion–molecule (i.e. benzyl cation–benzo-
nitrile)interactionsandion-pair(i.e.benzonitriliumion–pivalate
ion) combination so that both of these steps will affect the
yields of DAA.
although roughly as nucleophilic as pivalate [n
≈ npivalate =
acetate
5b
4
.3(in MeOH) ], is significantly smaller than the pivalate group
(
formed when 1 is decomposed). The data (Table 1) show that
the yield of unsymmetrical DAA is 13% (vs. 10.6% when the
counterion is pivalate). This 23% increase in the yield of mixed
diacylamine is ostensibly due to diminished steric interactions
between the acetate ion and the nitrilium carbon. Evidently, the
carboxylate oxygens in their approach to the available lobe of
the p-orbital of the nitrilium C must come sufficiently close to
the ortho hydrogen for significant steric interaction between it
Since the maximal yield of DAA arises roughly for R = H
Table 1) it would suggest that both EWGs and ERGs reduce
(
the yield of DAA. The former do so by reducing the ability of
the starting nitrile to capture the cation and the latter by com-
promising nucleophilic attack on the nitrilium ion. Since both
t
and the alkyl groups (Me and Bu).
ϩ
¶
Although the σp for Me N is larger than that for NH the question of
2
2
6
The virtual absence of benzyl alcohol
steric inhibition of resonance arises. Thus, the Me N group may be less
2
adept than NH at pushing electron density to the nitrile/nitrilium sys-
2
Table 1 shows that the yield of the alcohol is essentially zero for
all decompositions suggesting that the formation of alcohol
is unaffected by the identity or position of the aromatic sub-
tem via the aromatic nucleus because interactions between the methyl
groups and the o-protons ostensibly twist the lone pair of electrons on
6
N out of plane with the aromatic ring.
J. Chem. Soc., Perkin Trans. 2, 2001, 1084–1090
1087

View Article Online
a
stituent or by the nature of the carboxylate. This observation
suggests that the pathway leading to the formation of benzyl
alcohol is essentially independent of that leading to SDPs
and ester. Since the latter are produced from a common
intermediate—the benzyl cation—it would appear that alcohol
formation in this case does not involve capture of water by the
benzyl cation since this reaction would be expected to be sensi-
tive to the electrophilicity of the cation.
Table 3 Product distributions from ion-pair collapse and solvent
interaction for benzyl cations and benzonitrilium ions from the decom-
position of N-benzyl-N-nitrosoamides in 4-R-C H CN at 60 ЊC
6
4
Relative yield(%)
Ion-pair collapse
Cation
Solvent-derived product
b
b
Benzyl
Nitrilium
87 c
13 c
In previous studies, the formation of benzyl alcohol was
attributed to hydrolyses of the labile N-nitrosoamides rather
than water-interception of transient intermediates along the
∼80
∼20
a
b
Averaged data from Table 1; o-toluonitrile data were excluded. Std
c
dev. ∼1.1. Std.dev. ∼1.2.
1b,4a
reaction pathway (e.g. benzyl cations, etc.).
The low mole
fraction of water in the medium minimizes the likelihood of
significant benzyl cation–water reaction.
1b,3a,4a
ions possess no significantly greater liberty to “choose” their
nucleophiles than the phenylcarbenium ions that spawned them
because the latter yield ∼87% product from reaction with the
counterion while the former yield ∼80% product from the same
species (Table 1). (2) This result suggests that the highly reactive
benzyl cations are more selective than their derivative benzo-
nitrilium ions despite the fact that the latter would be more
stable by at least the energy of the C–N σ-bond and significant
ion–dipole stabilization by the now proximal solvent molecules.
It may be that the nascent counterion of the carbenium ion
has a positional advantage over the medium for scavenging the
carbenium ion. However, once the carbenium ion reacts with
solvent, the resulting nitrilium ion evidently remains in the
original cage and still has an opportunity to interact with
adventitious moisture.
The yield of benzyl pivalate
To the extent that the nucleophilicities of the benzonitriles
rise through the series R = CF to R = Me N, ¶ the number of
3
2
first-formed phenylcarbenium ions that are intercepted by the
nitrile should also rise in that order. Since formation of ester
and benzonitrilium ion are competitive events, if the benzo-
nitrilium ions were formed irreversibly, then the yield of ester
would be expected to fall markedly in the series R = CF3
to R = Me N. ¶ The fact that this is not observed (Table 1)
2
suggests that the formation of the nitrilium ion is a reversible
process.
The first-generation phenylcarbenium ion formed by deamin-
ation of 1 must be reversibly intercepting the nitrile to form the
nitrilium ion. The latter is scavenged by the counterion and by
water but also dissociates to re-form a benzyl cation–solvent
ion-pair. The carbenium ion in this latter ion–solvent pair
would be more complexed than is the first-generation species
because of greater exposure to both solvent and counterion
as the nitrogen departure progresses. Consequently, this
generation of benzyl cation would be expected to be less
It would appear though that the counterion is still favored
over water by this second-generation electrophile probably
because (1) it is still close to the newly formed nitrilium ion and
is coulombically drawn to the latter after the rapid departure
of N from between the initial ion-pair and (2) by the time
2
the nitrilium ion forms, N diffusion would have progressed
2
appreciably to begin exposing the new nitrilium ion to the
counterion for ion-pair collapse to the imidic anhydride.
4a
reactive than the first-formed species.
The yields of N-benzylbenzamides
Stereoelectronic effects in partitioning of deaminatively
generated nitrilium ions
The N-benzylbenzamides are believed to arise from scavenging
of the N-benzylnitrilium ions by adventitious moisture present
in the hygroscopic nitriles (Scheme 1).|| The benzamides, which
are also considered to be SDPs because they are derived from
the nitrilium intermediates, vary significantly in yield with both
the identity and position of the substituent on the aromatic
nucleus (Table 1). Interestingly, when a methyl group is present
at the o-position, the relative yield of the benzylbenzamide
Two issues, however, remain to be addressed: (1) why is there
such a similarity between the relative yields (Table 3) from ion-
pair collapse vs. reaction with solvent for both the highly
reactive benzyl cation (for which the solvent is ArCN ϩ trace
H
2
O) and the less reactive benzonitrilium ion (for which the
solvent is functionally trace H O)? Additionally, (2) why are the
2
yields of DAA significantly smaller in the benzonitrile series
than with acetonitrile, even though electronic effects appear to
favor the former?
(
with respect to SDPs) is >99%. This result is consistent with
the presence of much larger steric hindrance to nucleophilic
attack at the nitrilium C in the o-toluonitrilium species.
Consequently, small nucleophiles like water are more adept at
intercepting the ion than their bulkier competitor—pivalate.
Interestingly, however, if only the SDPs are considered, then,
with the exception of the case when the substituent is o-Me, the
relative yield of the benzamides from the substituted benzo-
nitriles is roughly the same [e.g. 21.3% (R = p-Me), 21.4%
It cannot be reasonably argued that a similarity exists
between the reactivities of the deaminatively generated benzyl
cation and its product from ion–molecule reaction—the
benzonitrilium ion (vide supra). If the reactivities are so dis-
parate why does DAA not form essentially exclusively from
the more selective nitrilium ion, in the solvent cage with the
counterion? How do trace water molecules have the chance to
interact with the nitrilium ion prior to ion-collapse?
(
R = CF ), 20.3% (R = p-MeO); Table 1]. This observation
3
suggests that roughly 20% of the N-benzylnitrilium ions
without o-substitution) are intercepted by moisture leading to
amide formation||** (Scheme 1). Evidently, (1) the nitrilium
Consider Scheme 2 in which the orientations of the benzyl
cations formed from dediazoniation of the benzenediazonium
ion are shown. The cations are drawn to show their spectrum
of positions relative to the pivalate ion. Of the positions of
the rapidly rotating benzyl cations, the only one that can lead
directly to the ester is 3a in which a lobe of the p-orbital is
oriented directly at pivalate. Structures 3b and 3c after rotation
to 3a (about the z- and y-axes, respectively) may also lead to the
ester. However, all of these species can lead to nitrilium ion
(
|
| N-Benzylacetamide is formed in similar fashion from nucleophilic
attack by water on the acetonitrilium ion when NBNNP is decomposed
1
b
in acetonitrile–water mixtures.
* There is the possibility of an S reaction between the pivalate and the
*
N
benzyl carbon of species 3aЈ to form an ester. This route to ester forma-
tion evidently does not significantly enhance the yield of ester probably
(
even 3a as long as the N molecule shields it from pivalate) and
2
because the reaction is S 1 and the tight ion-pair formed is in equi-
N
on nitrilium ion formation, from 3a, two hurdles to DAA
formation arise. (1) The reaction site for DAA formation is now
significantly removed from the necessary nucleophile pivalate:
librium with 3aЈ. The existence of the steady-state population of 3aЈ
and the ion-pair then will not appreciably affect the product distribu-
tion, as is observed.
1
088
J. Chem. Soc., Perkin Trans. 2, 2001, 1084–1090

View Article Online
Scheme 2 Orientations of benzyl cations and their nitrilium ions relative to pivalate ions in the solvent cage.
and back lobes of 3c] there is only one option for ion-collapse
right lobe of 3a). Further, the only species capable of forming
ester can be diverted into SDP.
(
The low mobility of the benzonitrilium ion and the inherent
difficulty in orienting groups for reaction to DAA would also
explain the relatively low yield of DAA in the benzonitrile
series. Even for benzonitrile, i.e. when 4-R = H, however, the
onium ion is 73% more massive than that in the acetonitrile
case. As a result, the acetonitrilium ions are ostensibly more
agile than are the benzonitrilium ions and are thus capable of
meeting the stereoelectronic requirement for DAA formation
much faster than the benzonitrile cases. This greater mobility
would lead to the observed larger yields of DAA from ion-pair
collapse.
Fig. 4 Pathways of approach of pivalate to the nitrilium C. Pathways
a” and “c” are very facile; pathways “b” are at a dihedral angle of
60 Њ from the H atoms roughly in their approach.
“
∼
Since resonance interactions are absent between the CH and
3
CN groups in acetonitrile (except for some hyperconjugation),
the pivalate ion would ostensibly be free to attack either one of
four lobes of the p-orbitals on the nitrilium C (vs. only two in
the benzonitrilium ion; Figs. 1, 4). Further, because the methyl
hydrogens in the acetonitrilium ion do not impose the same
steric restrictions on the bonding approach of pivalate ion,
ion-collapse is more favored in tight acetonitrilium–pivalate
ion-pairs than in the corresponding benzonitrilium ion case.
Consequently, the yield of DAA is larger from deaminations in
acetonitrile than in benzonitrile, as observed.
not only is it several bonds away, it is now on the opposite face
of the organic cation†† (2) The nitrilium ion is at least 124%
heavier that the antecedent benzyl cation‡‡ and thus translates
and rotates much more slowly.
The stereoelectronic requirement for DAA formation would
involve translation/rotation of the ions relative to each other
such that the pivalate ion effectively travels to the other face of
the nitrilium ion to attack the electron-deficient, sp-hybridized
carbon. This process must extend beyond the lifetime of the
NESIP (i.e. N diffusion is likely to be complete before nitrilium
2
ion–pivalate ion collapse) because NESIPs do not even survive
Summary
long enough to allow complete scrambling of stereochemistry
3c
from chiral nitrosoamides through cation rotation, or scram-
The formation of mixed diacylamines from deamination of
nitrosoamides in nitriles (the Darbeau–White–Gibble reaction)
appears to be a general phenomenon extendable beyond the
3c
bling of carboxylate oxygens. Thus even after N diffusion, the
2
nitrilium ion–pivalate reaction to DAA is delayed by steric
difficulties.
The nitrilium ion, therefore, having only two “predators”
1b
simple aliphatic cases. The yield of diacylamines is sensitive to
electronic and steric effects as well as to orbital considerations
in the nitrile. In general, electron-releasing groups enhance the
nucleophilicity of the nitrile N, facilitating capture of the
benzyl cation; however, they exert a yield decreasing effect
by diminishing the electrophilicity of the sp-hybridized C of
the nitrilium adduct. Conversely, EWGs diminish the yield of
the nitrilium intermediate by reducing the nucleophilicity of the
N, but subsequently make the nitrilium ion more electrophilic.
The interplay of these opposing effects results in curvature of
the Yukawa–Tsuno plot (Fig. 3). The plot has a maximum
at approximately R = H since this group does not abate the
kinetics of either the nitrile–benzyl cation, or the nitrilium–
carboxylate reactions. The ortho-methyl group dramatically
diminishes the yield of DAA in a fashion that cannot be
reasonably accounted for only by steric hindrance to the
approach of the nucleophile.
(
pivalate and H O) is afforded significant opportunity to react
2
with water even though the latter is only modestly nucleophilic
and present in trace amounts. Thus the yield of amide (SDP
with respect to the nitrilium ion) is larger than what would have
been predicted based upon the electrophilicity of the onium
ion, the low nucleophilicity and mole fraction of water in the
medium. It is important to appreciate that although there are
five options for benzyl cation interactions with solvent [left lobe
(
of the p-orbital) of 3a, top and bottom lobes of 3b and front
†
† The mass of the benzyl cation is 91 whereas the mass of the N-
benzylbenzonitrilium ion is 204; a 124% enhancement in mass even
with 4-R = H.
‡
‡ The relative yield of amide varies from ∼12% (R = F) to ∼33% (R = H)
(
Table 1); the mean, mode and median values are all ∼20%.
J. Chem. Soc., Perkin Trans. 2, 2001, 1084–1090
1089

View Article Online
Interestingly, the yields of products from solvent interception
relative to those from ion-collapse are similar from both the
highly reactive first-formed benzyl cation and the significantly
less reactive benzonitrilium ion. This observation suggests that
the deaminatively generated carbenium ions on reaction with
solvent molecules form onium ions that reside inside the
original solvent cage. Because the reaction site on the nitrilium
ion is now distal and is on the other face relative to the counter-
ion, there is a significant pause in effecting reaction between
the carboxylate ion and the nitrilium C. During this delay the
nitrilium ions are appreciably scavenged by even trace species of
low nucleophilicity such as water. The duration of the interlude
prior to ion-pair collapse is mediated by the mass of the
nitrilium ion and of the counterion: the larger these species, the
longer is the delay and the larger is the yield of solvent-derived
product. These observations are consistent with the model of
nitrogenous entity-separated ion-pairs in deamination.
Proof of thermal stability of product mixture
At 60 ؇C. The product mixture from a decomposition of 1 in
benzonitrile (R = H) at 60 ЊC was analyzed and the distribution
was found to be ester 84.6, DAA 10.4, benzamide 5.0, benzyl
alcohol 0.0%. The mixture was heated at 60 ЊC for 48 h and
then reanalyzed: ester 84.3, DAA 10.1, benzamide 5.0, benzyl
alcohol 0.6%. This result indicates that the product distribution
is statistically unchanged on prolonged heating and that the
product mixture is stable at 60 ЊC. Trace benzyl alcohol present
after heating ostensibly arises from hydrolysis of the ester and
diacylamine.
At 90 ؇C. The product mixture from a 40 min (∼12 half-lives)
decomposition of
1 in 4-dimethylaminobenzonitrile was
1
analyzed by H NMR spectroscopy and its composition was
found to be ester 90.1, DAA 8.7, benzyl alcohol 1.2%. The
sample was heated at 90 ЊC and its composition was determined
at 20 min intervals. No significant change was observed until
t = 100 min: ester 89.0, DAA = 8.4, benzyl alcohol = 1.5%. The
extra benzyl alcohol ostensibly arises from hydrolysis (vide
supra).
Experimental
Materials and methods
All commercial reagents were reagent grade and were used
1
without further purification. Chemical shifts in the H NMR
Acknowledgements
spectra are reported in ppm downfield from internal tetra-
ϩ
methylsilane. Spectra were recorded on JEOL Eclipse
Acknowledgement is made to the Calcasieu Parish Industrial
and Development Board Endowed Professorship administered
by the McNeese State University Foundation, the Shearman
Research Initiative administered 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 Ms Joan E. Vallee and Mrs
Nyla R. Darbeau.
3
00 MHz FT-NMR, Perkin Elmer 1600 Series FT-IR, and
Beckman Model 25 UV–Vis Spectrometers.
Stability of N-benzyl-N-nitrosopivalamide; handling and storage
N-Benzyl-N-nitrosopivalamide is thermolabile and was stored
under N in capped tubes immersed in liquid nitrogen. It is
2
labile in the presence of acids, bases, and moisture; being
photolabile it was handled in the dark. Caution! Nitroso-
amides should be handled with extreme care because of
References
7a
their possible mutagenicity and carcinogenicity (local and
7b
1 (a) Paper 2 on the generation of unsymmetrical diacylamines from
N-nitrosoamide deaminations in nitriles; (b) previous paper: R. W.
Darbeau, E. H. White, N. Nunez, B. Coit and M. Daigle, J. Org.
Chem., 2000, 65, 1115.
systemic). Efficient fume hoods and appropriate personal pro-
tection (chemical-resistant gloves, safety glasses, lab coat, etc.)
are recommended when handling these compounds.
2
(a) R. Huisgen and C. Ruchardt, Justus Liebigs Ann. Chem., 1956,
601, 1; (b) E. H. White and L. A. Dolak, J. Am. Chem. Soc., 1966, 88,
3790.
N-Benzylpivalamide. N-Benzylpivalamide was prepared by
8a
the method of Heyns and von Bebenburg; mp (ether–hexane)
8b
1
3 (a) R. W. Darbeau, E. H. White, F. Song, N. R. Darbeau and
J. C. Chou, J. Org. Chem., 1999, 64, 5966; (b) E. H. White, J. T.
De Pinto, A. J. Polito, I. Bauer and D. F. Roswell, J. Am. Chem.
Soc., 1988, 110, 3708; (c) E. H. White, K. W. Field, W. H.
Hendrickson, P. Dzadzic, D. F. Roswell, S. Paik and P. W. Mullen,
J. Am. Chem. Soc., 1992, 114, 8023; (d ) E. H. White, R. H. McGirk,
C. A. Aufdermarsh, H. P. Tiwari and M. J. Todd, J. Am. Chem. Soc.,
1973, 95, 8107; (e) E. H. White, R. W. Darbeau, Y. Chen, D. Chen and
S. Chen, J. Org. Chem., 1996, 61, 7986; ( f ) R. W. Darbeau and E. H.
White, J. Org. Chem., 1997, 62, 8091; (g) R. W. Darbeau, R. S. Pease,
R. S. Nolan and B. Smith, in A closer look at internal collapse of
nitrogenous molecule separated ion-pairs, in preparation.
81–82 ЊC (lit. mp 81–82 ЊC); IR (KBr) ν /cmϪ 3309 (NH),
max
t 1 t
1
4
689 (C᎐O), 1375 ( Bu); H NMR (CDCl ) δ 1.27 (9H, s, Bu),
᎐
3
.44 (2H, d, J = 7 Hz, CH ), 5.90 (1H, br s, NH), 7.26–7.32 (5H,
2
3
Ϫ1
Ϫ1
m, Ph); UV λmax (Et O)/nm 284 (ε/dm mol cm 209).
2
N-Benzyl-N-nitrosopivalamide (1). Compound 1 was pre-
Ϫ1
pared by the method described in ref. 1b. IR (Neat) νmax/cm
1
t
1
720 (C᎐O), 1605 (N᎐O), 1375 ( Bu); H NMR (CD CN) δ 1.45
᎐ ᎐
3
t
(
(
9H, s, Bu), 4.97 (2H, s, CH ), 7.05–7.40 (5H, m, Ph); UV λ
2 max
3 Ϫ1 Ϫ1
CH Cl )/nm 275, 400, and 394sh (ε/dm mol cm 500, 63,
2 2
4
(a) F. Song, R. W. Darbeau and E. H. White, J. Org. Chem., 2000, 65,
825; (b) R. W. Darbeau, D. J. Heurtin, L. M. Siso, R. S. Pease, R. E.
Gibble, D. E. Bridges and N. R. Darbeau, J. Org. Chem., 2001, 66,
681; (c) R. W. Darbeau, R. S. Pease, E. V. Perez and R. E. Gibble,
in preparation.
6
6).
1
Decomposition of nitrosoamide (1)
2
In a typical run, ∼75 µl of 1 were added to 750 mg of the
appropriate nitrile in an Opticlear vial. The sample was then
placed in an oven at 60 ЊC for 1 h (∼12 half-lives). The sample
was taken out of the oven and 200 µl were removed and added
to 400 µl of CDCl3 in an NMR tube and NMR spectra
were recorded. The products observed were benzyl pivalate
ϩ
5
(a) Values of σp and σp taken from N. Isaacs, Physical Organic
nd
Chemistry, 2 edn., John Wiley & Sons, Inc., 1995, pp. 152–153; (b)
C. G. Swain and C. B. Scott, J. Am. Chem. Soc., 1953, 75, 141.
6 G. W. Wheland, The Theory of Resonance, Wiley, New York, 1944,
p. 195.
7
(a) K. Lee, B. Gold and S. Mirvish, Mutat. Res., 1977, 48, 131; (b) R.
Preussman and B. Stewart, W. Chemical Carcinogenesis, ed. C. Searle,
ACS Monograph No. 182, American Chemical Society, Washington,
DC, 1984, p. 643.
(a) K. Heyns and W. v. Bebenburg, Chem. Ber., 1953, 86, 278; (b)
Beilstein Vol. 12, 3rd Suppl. p. 2346.
(
δ 5.10), N-aryl-N-pivaloylbenzylamine (∼δ 4.82), benzyl-4-R-
benzamides (δ 4.65), and benzyl alcohol (δ 4.56). The methyl
signals of the pivaloyl groups of the compounds in this study
are indistinguishable from each other.
8
1
090
J. Chem. Soc., Perkin Trans. 2, 2001, 1084–1090