Reaction of essentially free benzyl cations with acetonitrile; synthesis of ethanimidic carboxylic anhydrides and unsymmetrical diacylamines

Article abstract of DOI:10.1021/jo991600n

Benzyl cations were generated via the thermal decomposition of N-benzyl- N-nitrosopivalamide in acetonitrile and acetonitrile-water mixtures at 25 °C. The first-formed (primary) benzylating agent, the benzyl cation, was scavenged competitively by pivalate (trimethyl acetate) ion to yield benzyl pivalate, by acetonitrile to yield the corresponding N-benzylnitrilium ion, and by water (when present) to yield benzyl alcohol. The nitrilium ion underwent a cascade of reactions to yield an array of products whose identities and relative yields as a function of time were used to elucidate the mechanistic paths involved. Thus, the N-benzylnitrilium ion reacted with pivalate ion to yield the Z-isomer of N-benzylethanimidic pivalic anhydride, followed by its conversion into the E-isomer. This article appears to be the first to document compounds of this type. The E-isomer is labile under the reaction conditions, rearranging into N-acetyl-N-pivalylbenzylamine. In the presence of water as a diluent, a significant fraction of the nitrosoamide was hydrolyzed to benzyl alcohol; hydrolysis of the nitrilium ion yielded N- benzyl acetamide. The yield of hydrosylates was directly proportional to the mole fraction of water in the medium.

Full text of DOI:10.1021/jo991600n

J . Org. Chem. 2000, 65, 1115-1120
1115
Rea ction of Essen tia lly F r ee Ben zyl Ca tion s w ith Aceton itr ile;
Syn th esis of Eth a n im id ic Ca r boxylic An h yd r id es a n d
Un sym m etr ica l Dia cyla m in es
Ron W. Darbeau,* Emil H. White,† Nicholas Nunez, Brian Coit, and Mark Daigle
Departments of Chemistry, McNeese State University, Lake Charles, Louisiana 70609 and
The J ohns Hopkins University, Baltimore, Maryland 21218
Received October 14, 1999
Benzyl cations were generated via the thermal decomposition of N-benzyl-N-nitrosopivalamide in
acetonitrile and acetonitrile-water mixtures at 25 °C. The first-formed (primary) benzylating agent,
the benzyl cation, was scavenged competitively by pivalate (trimethyl acetate) ion to yield benzyl
pivalate, by acetonitrile to yield the corresponding N-benzylnitrilium ion, and by water (when
present) to yield benzyl alcohol. The nitrilium ion underwent a cascade of reactions to yield an
array of products whose identities and relative yields as a function of time were used to elucidate
the mechanistic paths involved. Thus, the N-benzylnitrilium ion reacted with pivalate ion to yield
the Z-isomer of N-benzylethanimidic pivalic anhydride, followed by its conversion into the E-isomer.
This article appears to be the first to document compounds of this type. The E-isomer is labile
under the reaction conditions, rearranging into N-acetyl-N-pivalylbenzylamine. In the presence of
water as a diluent, a significant fraction of the nitrosoamide was hydrolyzed to benzyl alcohol;
hydrolysis of the nitrilium ion yielded N-benzyl acetamide. The yield of hydrosylates was directly
proportional to the mole fraction of water in the medium.
In tr od u ction
molecule shields the carbenium ion from the counterion
initially, allowing for surprisingly efficient trapping of
the carbenium ions by molecules in the solvent cage.1,3a-c
No catalysts or other reagents are required for carboca-
tion formation; consequently the reaction is a “clean” one,
and only a limited number of low-yielding competing
reactions occur.1a,3c
N-Alkyl-N-nitrosoamides, e.g., N-benzyl-N-nitrosopiv-
alamide (1), decompose to produce very short-lived
nitrogen-separated ion pairs (NSIPs) (2) (eq 1).1 The
The counterion and the solvent compete for the car-
benium ion in irreversible reactions, and the high speed
of the counterion-carbocation reaction to yield ester,
limited by the rate of diffusion of N2 into the medium,
results in the carbenium ion having only a limited time
to react with the medium before being scavenged by the
counterion;1a,c thus, reaction conditions can usually be
arranged to lead to kinetically determined products.1a,c,3a
In these reactions, the yields of solvent-derived products
(SDPs) increase with the reactivity of the cation, with
the nucleophilicity of the solvent, and in an inverse
manner with the nucleophilicity of the counterion.1a,3d
In earlier work, it was shown that the decomposition
of N-benzyl-N-nitrosotrifluoromethanesulfonamide in CH3-
CN produces N-benzylacetonitrilium trifluoromethane-
sulfonate in quantitative yield. Ostensibly, the nitrilium
salt arose principally via the N2-separated benzyl cation/
triflate ion ion pair; some (secondary) benzylation by the
labile benzyl triflate was also involved.1b The present
study was aimed, principally, at the trapping of benzyl
cations by acetonitrile in the presence of a more nucleo-
philic carboxylate ion (npivalate ≈ 2.7; ntriflate < 0)4 and the
investigation of the cascade of subsequent reactions and
rearrangements.
unimolecular process2 generates an ion pair containing
a carbenium ion, which is essentially unsolvated and
probably represents as free and reactive a carbenium ion
as can be formed in the liquid phase.1,3a-c The nitrogen
* Address correspondence to this author at McNeese State Univer-
sity.
† This paper is dedicated to the memory of Professor Emil H. White,
1926-1999.
(1) (a) Darbeau, R. W.; White, E. H.; Song, F.; Darbeau, N. R.; Chou,
J . C. J . Org. Chem. 1999, 64, 5966. (b) White, E. H.; De Pinto, J . T.;
Polito, A. J .; Bauer, I.; Roswell, D. F. J . Am. Chem. Soc. 1988, 110,
3708. (c) 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. (d) White, E. H.; McGirk, R. H.; Aufdermarsh, C. A.; Tiwari, H.
P.; Todd, M. J . J . Am. Chem. Soc. 1973, 95, 8107.
(3) (a) White, E. H.; Darbeau, R. W.; Chen, Y.; Chen, D.; Chen, S.
J . Org. Chem. 1996, 61, 7986. (b) Darbeau, R. W.; White, E. H. J . Org.
Chem. 1997, 62, 8091. (c) Darbeau, R. W. Ph.D. Thesis, The J ohns
Hopkins University, Baltimore, Maryland. (d) The yield of SDP also
rises but to a lesser extent with decreasing temperature and when
the nitrogenous molecule is N2O rather than N2.1a,3c
(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.
10.1021/jo991600n CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/27/2000

1116 J . Org. Chem., Vol. 65, No. 4, 2000
Darbeau et al.
Ta ble 1. Tim e-Dep en d en t P r od u ct Distr ibu tion fr om th e Decom p osition of N-Ben zyl-N-n itr osop iva la m id e (1)a in CD3CN
a t 25 °C
relative amounts (%)b
ethanimidic anhydrides
reaction time
(min)
nitrosoamide
benzyl pivalate
diacyl benzylamine
benzyl alcohol
1
3
5a ; Z
5b; E
6
9
5
15
40
74
71
42
18
0
23
22
43
58
72
1.8
2.0
7.0
2.0
0
0.6
3.0
4.0
6.0
0
0.0
1.0
3.0
13
0.6
1.0
1.0
3.0
5.0
70
24 hc
23
a
b
Concentration ≈ 0.045 M. Average of triplicate runs; standard deviation ≈ 0.5. c Product distribution was unchanged after a further
2 days at 25 °C.
Ch a r t 1. Rea ction P a th w a y for th e
Decom p osition of N-Ben zyl-N-n itr osop iva la m id e in
CD3CN
The product distribution as a function of time (Table
1) was followed by H NMR spectroscopy. With time, a
1
steadily increasing amount of benzyl pivalate (3) was
observed along with a small amount of benzyl alcohol
(vide infra) (Table 1); in addition, signals were observed
at δ 5.21, 4.38, and 4.82. The sum of the integrals for
the latter three signalssnormalized for the extent of the
reactionswas essentially constant. These integrals varied
in a manner suggesting that the δ 4.38 signal arose from
the compound responsible for the δ 5.21 signal, and that
the former compound was converted, in turn, to the
compound responsible for the δ 4.82 signal. After 24 h,
the decomposition of the nitrosoamide was complete and
both intermediates (at δ 5.21 and 4.38) had been fully
converted into the δ 4.82 compound, which was stable
under the reaction conditions (Table 1).
On the basis of the probable mechanism of the decom-
position (eq 1 and Chart 1) it seemed reasonable that the
δ 4.82 compound was N-acetyl-N-pivalylbenzylamine (6).
The structure of the diacylamine (6) was confirmed, in
part, through NMR comparison with samples of 6 pre-
pared from the reaction of N-benzyl pivalamide and
acetyl chloride. Chromatography on silica gel afforded a
colorless oil whose physical data and elemental analysis
were consistent with the diacylamine structure assigned
(6). Further, the addition of 20 equiv of NH3 to diacyl-
amine (6) led to the diminution and eventual disappear-
ance of the signal assigned to 6 and the simultaneous
appearance of signals due to N-benzylacetamide (NBA,
11) and N-benzylpivalamide (NBP, 12) (eq 2 and Table
2).
Resu lts a n d Discu ssion
N-Benzyl-N-nitrosopivalamide (1) was used as the
source of the benzyl cation because of its convenient rate
of decomposition at 25 °C (t1/2 is ∼30 min in CD3CN)
arising from steric acceleration of the rearrangement step
(eq 1) by the tert-butyl group.2 The rapid decomposition
of nitrosoamide (1) at 25 °C under neutral conditions
permits spectroscopic observation of thermolabile, tran-
sient intermediates.
(4) The nucleophilicity, n, of a reagent is defined within the linear
free energy relationship, log(k/ko) ) sn”, where k is the rate constant
for the SN2 reaction of a substrate (chosen by Swain and Scott to be
MeI) with a particular nucleophile at 25 °C.; ko is the corresponding
rate constant with a standard nucleophile (chosen by Swain and Scott
to be water). The term s is a parameter that gauges the sensitivity of
the substrate toward variation in the nucleophiles. Swain, C. G.; Scott,
C. B. J . Am. Chem. Soc. 1953, 75, 141.
Imidic anhydrides 5a ,b are reasonable products to
expect from the decomposition of nitrosoamide 1 in
acetonitrile because the benzyl cation is known to react
with CH3CN to form the nitrilium ion 4, which is stable
in the presence of weakly nucleophilic counterions.1b

Reaction of Benzyl Cations with Acetonitrile
J . Org. Chem., Vol. 65, No. 4, 2000 1117
Ta ble 2. Tim e-Dep en d en t P r od u ct Distr ibu tion in th e
Rea ction of Am m on ia w ith Dia cyla m in e (6)a -d
lone pair of electrons on the nucleophile and the develop-
ing negative charge in the sp2-hybrid of the distal vinylic
carbon is probably responsible for this observation. The
5a f 5b rearrangement probably occurs via inversion
through nitrogen.7
The rearrangement of the imidic anhydride 5b to the
diacylamine (6) requires overlap of the unshared elec-
trons of nitrogen with the π* orbital at the carbonyl
carbon (eq 3) (a similar orientation of the nitrosyl oxygen
benzyl
diacyl
benzyl N-benzyl
N-benzyl
time pivalate benzylamine alcohol acetamide pivalamide
(h)
(3)
(6)
23
8.0
0.0
(9)
(11)
(12)
0
2
72
74
73
5
5
5
0
9
15
0
4
7
24e
a
b
Average of duplicate runs; standard deviation ≈ 0.5%. Acet-
amide and pivalamide must have been present but were not
observed (see text). c Twenty equivalents of ammonia were used.
d
Obtained after total decomposition (24 h) of nitrosoamide (1) in
dry acetonitrile; the diacylbenzylamine (6) was the only reactive
compound present. e Product distribution was unchanged after a
further 3 days at 25 °C.
Ch a r t 2. Sites of Nu cleop h ilic Atta ck on On iu m
Ion s5
Additionally, the pivalate ion is the major nucleophile
in the present system that leads to observable product.
Consequently, nitrilium ion/pivalate ion reaction would
be expected. In general, reactions between nucleophiles
and onium ions appear to be dominated by reaction of
the nucleophile at the carbon of the carbon-heteroatom
multiple bond (path b, Chart 2).5 Nucleophilic displace-
ments (path a, Chart 2) and deprotonations (path c, Chart
2) appear to be minor reactions.5
Support for the structures of the imidic anhydrides
5a ,b was obtained as follows: (1) The amounts of the
imidic anhydrides rose and then fell with time, while that
due to the diacylamine (6) rose steadily (Table 1). (2)
When the integrals of the benzyl signals for all the benzyl
compounds present from time ) 0 to time ) 24 h were
prorated to 2 hydrogens, the percentage of the sum of
the integrals (benzyl) for 5a , 5b, and 6 was constant (24.7
( 1.4%), which indicates the conversion of 5a ,b into the
diacylamine (6).
The reaction of pivalate ion (as in path b, Chart 2) with
the nitrilium ion (4) can lead to two geometric isomers.
The product distribution as a function of time (Table 1)
shows that the Z-isomer is formed initially and subse-
quently converts to the E-form. The stereochemistry of
this addition is analogous to that observed in the reac-
tions of good nucleophiles, e.g., methoxide and mercap-
tides, with acetylenes,6a which give the trans product.6
In the present case, the Z-isomer is formed more rapidly
than the E-isomer despite the greater steric strain in the
former. Minimization of electronic repulsion between the
and the carbonyl carbon is required for rearrangement
of N-nitrosoamides).1-3 These requirements are met in
the E- but not in the Z-configuration.
The present manuscript appears to be the first to
document the formation, stability, interconversion, and
rearrangement of imidic carboxylic anhydrides.8
Un sym m etr ica l Dia cyla m in es. Symmetrical diacyl-
amines are readily prepared from the corresponding
amine and acid chlorides or anhydrides;9a they can also
be prepared from amides if the entering acyl group is the
same as that already present in the amide.9b Unsym-
metrical diacylamines, however, are prepared with dif-
ficulty and in low yield by the conventional approaches
because acylation/deacylation equilibria favor the forma-
tion of the symmetrical diacylamine possessing the acyl
group of the acylating species.9 For example, refluxing
of NBP with acetyl chloride (∼51 °C) or acetic anhydride
(∼140 °C) led to diacetylbenzylamine, even in pyridine
as solvent;3c with gentle heating (30-50 °C), no reaction
occurred.3c NBA does not react with pivalyl chloride at
25 °C (72 h) or under reflux (107 °C) in the presence or
absence of base (Na2CO3 and/or pyridine).3c Steric hin-
drance involving the bulky pivalyl group is probably
operating in these cases.
(7) The Chemistry of Doubly-Bonded Functional Groups; Patai, S.,
Ed.; J ohn Wiley and Sons: London, 1977.
(8) (a) We have been unable to find any literature references to this
class of compounds. Some of the sources examined follow. (b) Smith,
P. A. S. The Chemistry of Open-Chain Nitrogen Compounds; W. A.
Benjamin, Inc.: New York, 1965; Vols. 1 and 2. (c) Overberger, C. G.;
Anselme, J . P.; Lombardino, J . G. Organic Compounds with Nitrogen-
Nitrogen Bonds; The Ronald Press Company: New York, 1966. (d)
Reference 7.
(9) (a) Meyer, H. J .; Nolde, C.; Thomsen, I.; Lawesson, S. O. Bull.
Soc. Chim. Belg. 1978, 87, 621. (b) Mariella, R. P.; Brown, K. H. J .
Org. Chem. 1971, 36, 735.
(5) Perst, H. Oxonium Ions in Organic Chemistry; Verlag Chemie
Academic Press: New York,1971; pp 58-59.
(6) (a) Truce, W. E. Nucleophilic Reactions of Thiols and Acetylenes
and Chloroethylenes. In Organic Sulfur Compounds; Kharasch, N.,
Ed.; Pergamon Press Ltd.: London, 1961; Vol. 1, (b) Miller, S. I. J .
Am. Chem. Soc. 1956, 78, 6091. (c) Truce, W. E.; Simms, J . A. J . Am.
Chem. Soc. 1956, 78, 2756. (d) The trans isomer is equivalent to the
Z-isomer in the present study.

1118 J . Org. Chem., Vol. 65, No. 4, 2000
Darbeau et al.
Ch a r t 3. Rea ction P a th w a ys for Decom p osition of
Nitr osoa m id e (1) in Aceton itr ile-Wa ter Mixtu r es
Decomposition of nitrosoamide (1) in dry acetonitrile
at 25 °C followed by chromatographic fractionation of the
product mixture affords the unsymmetrical diacylamine
(6) (Rf ) 0.7 in 50% ether/CH2Cl2) in ∼23% yield.
Oth er P oten tia l Rea ction P a th w a ys. Several other
pathways and products from the decomposition of 1 in
acetonitrile appear feasible in principle but were not
observed. Perhaps the most compelling of these pathways
are the deprotonation of the nitrilium ion (4) to form the
azacumulene (or ketenimine) (7) and the intramolecular
Friedel-Crafts reaction of the onium ion (4) to yield the
isoindole (8). Molecular models of the nitrilium ion show
C
that the π-systems of the aromatic nucleus and the nitrile
moiety are poorly aligned for effective overlap. The
removal of a proton from the carbon atom â to the
heteroatom of an onium ion is rarely observed (Chart 2).5
The observed formation of benzyl alcohol (Table 1) from
traces of moisture in the “dry” acetonitrile runs must be
due to reaction of adventitious water with a benzylating
species. In principle, the latter may be the first-formed
benzyl cation, the nitrilium ion (4), or the starting
N-nitrosoamide (1). The first option is unlikely because
of the short lifetime1c,d of the cation and the unfavorable
distribution of nucleophiles in the medium (CD3CN/H2O
> 104).1a,3b The second option is also unlikely because
alcohol formation would result from an SN2 displacement
reaction (with CH3CN as the departing group). Displace-
ment reactions, however, would be expected to be slower
than nucleophilic attack on the carbon that is multiply
bonded to the charged heteroatom,5 which would produce
NBA, 11. However, no NBA is observed (Table 1), so the
alcohol probably does not arise from a water/nitrilium
ion reaction.
Benzyl alcohol, 9, probably originates from hydrolysis
of the starting nitrosoamide (1). Reaction of water at the
pivalyl group would lead to pivalic acid and benzyldiazoic
acid (10) (C6H5CH2NdN-OH), which then would yield
benzyl alcohol by subsequent reactions. Low yields (<1%)
of benzyl alcohol have been observed during the ther-
molyses of other N-benzyl-N-nitrosoamides in benzene-
toluene3c and chloroform,3c and the same mechanism
involving trace moisture is probably involved in the
present case.
The larger yield of NBA over NBP is somewhat
surprising. This result indicates that NH3 apparently
attacks the more sterically hindered pivalyl group in
preference to the acetyl group. A reasonable interpreta-
tion of this observation follows. Molecular models show
that nonbonded interactions operating in the diacyl-
amine, 6, force the tert-butyl group out of the plane of
the acetamide moiety (eq 2). Thus there is little overlap
of the n-electrons of the nitrogen and the π* orbital of
carbonyl group of the pivalyl moiety. Resonance interac-
tion involving the n-electrons of the nitrogen would thus
occur within the acetyl function but not within the pivalyl
group, rendering the latter more reactive than the fomer.
Additionally, the bulky pivalyl group is oriented such that
the tert-butyl moiety physically obstructs one face of the
acetyl group from nucleophiles (eq 2) and blocks solvation
of the developing negative charge if a nucleophile reacts
with the opposite face. This steric feature also provides
an explanation for difficulties in the synthesis by the acid
chloride.
Decom p osition of N-Ben zyl-N-n itr osop iva la m id e
(1) in Aceton itr ile-Wa ter Mixtu r es. In dry acetoni-
trile, the only nucleophiles that compete for the cation
are acetonitrile and the pivalate ion. When the mole
fraction of water is increased, it can effectively enter into
bimolecular reactions and compete against other nucleo-
philes.
Rea ction of Am m on ia w ith N-Acetyl-N-p iva lyl-
ben zyla m in e (6). A 20-fold excess of ammonia was
added to the diacylamine. More NBA (11) than NBP (12)
was formed (Table 2). The formation of these amides from
the reaction of NH3 with the diacylamine, 6, (Table 2) is
consistent with the structure of 6. Acetamide and piv-
alamide must also have formed from the treatment of
the product mixture with ammonia (eq 2). However, the
former possesses a trideuteriomethyl group and is thus
N-Benzyl-N-nitrosopivalamide (1) was decomposed in
CD3CN-D2O mixtures in the presence of 2 equiv of
pyridine at 25 °C. The half-life of the nitrosoamide (1) in
CD3CN-D2O was ∼30 min at 25 °C, essentially un-
changed from the value in dry acetonitrile, (t1/2 in CD3-
CN was also ∼30 min at 25 °C).
Benzyl pivalate (3), the imidic anhydrides (5a ,b), the
diacylamine (6), benzyl alcohol (9), and pivalic acid were
observed. In addition, in this case, NBA was formed.
Competition by water for the nitrilium ion, 4, is now
1
not visible in the H NMR spectrum, while the tert-butyl
signal of the latter is unresolved from that of the
nitrosoamide (1) or the ester (3).

Reaction of Benzyl Cations with Acetonitrile
J . Org. Chem., Vol. 65, No. 4, 2000 1119
Ta ble 3. Tim e-Dep en d en t P r od u ct Distr ibu tion a fr om Decom p osition of N-Ben zyl-N-n itr osop iva la m id e (1)b in
CD3CN-Wa ter a t 25 °C
yields (%)
imidic anhydrides
nitrosoamide
benzyl pivalate
diacyl benzylamine
benzyl alcohol
NBA
timec
24 h
1
3
5a ; Z
5b; E
6
9
11
d
XD O ) 0.0079
2
0.0
72
0.0
0.0
23.0
5.0
0.0
d
XD O ) 0.25
2
10
20
40
70
77
60
40
19
0.0
18
25
34
43
52
1.1
3.4
6.0
3.0
0.0
0.4
1.0
1.2
0.0
0.0
0.2
1.2
3.6
8.0
13.0
3.0
8.0
13.0
23.0
28.0
0.3
1.4
2.2
4.0
7.0
24 h
d
XD O ) 0.5
2
24 h
0.0
49
0.0
0.0
2.0
36.0
15.0
a
b
d
Averaged from triplicate runs; standard deviation ≈ 0.5%. Concentration ≈ 0.045 M. c Time in min unless otherwise stated. Mole
fraction.
observed in the formation of NBA10 (Chart 3, Table 3).
The yield of the imidic anhydrides (5) is lower that in
the anhydrous runs (Table 1) because of diversion of the
nitrilium ion by water to NBA and because the anhy-
drides are probably hydrolyzed by water (Chart 3).
Finally, the yield of benzyl alcohol increases with water
concentration (Table 3), most likely because of the
increase in the hydrolysis of the nitrosoamide. Direct
competition by water for the benzyl cation is probably
also responsible, though to a smaller extent.
added to the solid material (under N2), and the suspension
was cooled to -78 °C. A solution of N2O4,(l) (0.2 cm3, 3.1 mmol)
in CH2Cl2 (1.0 cm3) at -78 °C was then added at -78 °C to
the stirred suspension, which was then allowed to warm to
-25 °C over 10 min. After a further 15 min at -25 °C, the
suspension was evaporated in vacuo for ∼15 min until a lemon
yellow color was observed. Ether at -20 °C was then added,
and the suspension was washed in turn with saturated
solutions of NaCl, Na2CO3, and NaCl at -5 °C. The organic
phase was dried over Na2SO4 at -30 °C and then evaporated
in vacuo (at -30 °C) to yield 0.11 g (0.5 mmol, 100%) of a lemon
yellow oil. The synthesis and isolation were performed in the
1
dark: IR (neat) 1720, 1605, 1502, 1390, 1375 cm-1; H NMR
Exp er im en ta l Section
(CD3CN) 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 nm (sh),
422 nm (ꢀ ) 66).
Ma ter ia ls a n d Meth od s. Benzylamine, pivalyl chloride,
acetyl chloride, pyridine, acetonitrile-d3 (99.5% atom D),
deuterium oxide (99.8% atom D), sodium acetate, phosphorus
pentoxide, and benzyl benzoate were obtained from the Aldrich
Chemical Co. Ammonia and dinitrogen tetroxide were pur-
chased from The Matheson Gas Company. Commercial re-
agents were used without further purification. Spectra were
recorded on 300 MHz FT-NMR, FT-IR and UV-vis spectrom-
eters. TLC analyses were performed on UV-fluorescent silica
gel plates.
Sta bility of N-Ben zyl-N-n itr osop iva la m id e. Ha n d lin g
a n d Stor a ge. N-Benzyl-N-nitrosopivalamide is thermolabile
and was prepared as needed. It is labile in the presence of
acids, bases, and moisture; being photolabile it was handled
in the dark. Ca u tion ! Nitrosoamides should be handled with
extreme care because of their possible mutagenicity11a and
carcinogenicity (local and systemic).11b Efficient fume hoods
and appropriate personal protection (chemical-resistant gloves,
safety glasses, lab coat, etc.) are recommended when handling
these compounds.
N-Acetyl-N-p iva lylben zyla m in e (6). A solution of N-
benzyl pivalamide (95.5 mg, 0.5 mmol) in acetyl chloride (1
cm3, 14 mmol) was cooled to -20 °C and was then treated with
pyridine (40 mL, 0.5 mmol) with stirring; a white precipitate
of pyridine hydrochloride formed. The solution was then
refluxed for 12 h. The acetyl chloride was removed in vacuo,
and the residue was fractionated by preparative TLC using
50% ether/CH2Cl2. The band at Rf ) 0.7 was eluted with ether;
removal of the ether in vacuo yielded a pale yellow oil (5.5
mg, 0.025 mmol, 5%): 1H NMR (CDCl3) δ 1.26 (s, 9H), 2.24 (s,
3H), 4.89 (s, 2H), 7.21-7.32 (m, 5H).
The major product of the above reaction was diacetylben-
zylamine [1H NMR (CDCl3) δ 2.23 (s, 6H), 4.97 (s, 2H), 7.21-
7.32 (m, 5H)]. With gentle heating (30-50 °C), no reaction
occurred. NBA did not react with pivalyl chloride at 25 °C or
under reflux regardless of the presence of base (Na2CO3 and/
or pyridine).
Decom p osition of Nitr osoa m id e (1). In a typical run, ∼5
mg of 1 was dissolved in 500 µL of solvent (CD3CN or CD3-
CN-D2O) in an NMR tube. The solution was frozen with liquid
N2, and the tube was degassed at oil pump vacuum, evacuated,
and flame-sealed. The sealed tube was then incubated at 25
°C, and the reaction was followed by NMR. The half-life was
∼30 min. The products observed were benzyl pivalate, 3, (δ
5.07); E-ethanimidic anhydride, 5b , (δ 4.38); Z-ethanimidic
anhydride, 5a , (δ 5.21); N-acetyl-N-pivalylbenzylamine, 6, (δ
4.82); and benzyl alcohol, 9, (δ 4.56). Only the benzyl signals
are reported (in CD3CN); acetyl signals are fully deuterated
and thus not visible in the 1H NMR spectrum. The methyl
signals of the pivalyl groups of the compounds in this study
are indistinguishable from each other.
Isola tion of N-a cetyl-N-p iva loylben zyla m in e (6) fr om
Decom p osition of Nitr osoa m id e (1) in CH3CN. In a typical
run, nitrosoamide (1) (50 mg, 22.7 mmol) was dissolved in 1
cm3 CH3CN (dried over Na2SO4), and the solution was set aside
in the dark at 25 °C for 24 h. The solution was concentrated
in vacuo and was then fractionated by preparative TLC using
ether/CH2Cl2. Ethereal elution of the band at Rf ) 0.7 followed
N-Ben zylp iva la m id e was prepared from the method of
Heyns and von Bebenburg:12a mp 81-82 °C (lit.12b 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); UV (ET2O) λmax ) 284 nm (ꢀ ) 209).
N-Ben zyl-N-n itr osop iva la m id e (1). A mixture of N-
benzylpivalamide (95.5 mg, 0.5 mmol), NaOAc (250 mg, 3.0
mmol), and Na2SO4 (0.5 g) was dried at oil pump vacuum.
Methylene chloride (3.0 cm3) freshly distilled from P2O5 was
(10) (a) A semilog plot of % NBA (y) vs mole fraction of water (x)
yields a straight line: log y ) 26.5x - 0.20; R2 ) 1.00. (b) A product
mixture from a run that had been allowed to stand at 25 °C until all
of the nitrosoamide had decomposed and all of the imidic anhydrides
(5a ,b) had rearranged to the diacylamine (6).
(11) (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.
(12) (a) Heyns, K.; V. Bebenburg, W. Chem. Ber. 1953, 86, 278. (b)
Beilstein Vol. 12, 3rd Suppl. p 2346.

1120 J . Org. Chem., Vol. 65, No. 4, 2000
Darbeau et al.
by removal of the solvent in vacuo yielded a pale yellow oil
(42 mg,. 182 mmol). Anal. Calcd for C14H19N02: C, 72.11; H,
8.15; N, 6.01; O, 13.73. Found: C, 72.28; H, 8.05; N, 6.09; O,
13.58. 1H NMR (CDCl3) δ 1.26 (s, 9H), 2.24 (s, 3H), 4.89 (s,
2H), 7.21-7.32 (m, 5H). Due caution must be exercised during
the separation because benzyl pivalate elutes with an Rf of
∼0.8 under the same conditions.
through a serum stopper whose underside was copiously lined
with Teflon tape. The tube was shaken for ∼30 s and NMR
spectra were taken after 2 and 24 h; the relative yields of
benzyl pivalate (3), N-acetyl-N-pivalylbenzylamine (6), benzyl
alcohol, NBP, and NBA were measured (Table 2).
Ack n ow led gem en t is made to the donors of the
Petroleum Research Fund, administered by the Ameri-
can Chemical Society, for support of this research. The
authors also acknowledge the contributions of Christian
Ryder, Amy Schmidt, and Kimberly J ohnson.
Tr ea tm en t of a Decom p osed Sa m p le of Nitr osoa m id e
(1) in CD3CN w ith Am m on ia . A product mixture from a
decomposition run was analyzed by 1H NMR to ensure the
absence of anhydrides, 5, (at δ 5.02 and 4.36) and nitrosoam-
ide, 1, (at δ 4.93) and the presence of the diacylamine, 6, (at
δ 4.80). Ammonia (20 equiv) was injected into the NMR tube
J O991600N