A R T I C L E S
Himo et al.
Scheme 3. Addition of an Azide Anion to a Nitrile through the
Intermediacy of an Imidoyl Azide
ꢀ ) 80. Some of the experiments were done in DMF, which
has a dielectric constant of ꢀ ) 37. As the solvation energy to
a first approximation is proportional to (1 - (3/2ꢀ)) for dipoles
and (1 - (1/ꢀ)) for charges for large ꢀ,19 the water and DMF
values give almost identical solvation energies. Since we are
mainly interested in reaction barriers (reactant - transition state)
and relative barriers, the differences are not significant.
(A, Scheme 3). This pathway is computed to be some 10 kcal/
mol lower in energy than the concerted [2 + 3] mechanism.
To the best of our knowledge, there are no reports concerning
the mechanistic details for the cases where nonprotic Lewis acids
are employed as catalysts for the addition of an azide ion to a
nitrile.
It has been recently shown that zinc salts are excellent
catalysts for this reaction;14 in fact, they function well even in
aqueous media, thereby enabling a more environmentally
friendly route to 1H-tetrazoles.15 When we follow this protocol,
simple heating (80-170 °C) of an aqueous reaction mixture of
nitrile, sodium azide, and catalytic zinc salt provides the 1H-
tetrazole in good yield following acidic workup. Seeking to
understand the mechanism of this catalysis, we have performed
model calculations using density functional methods to inves-
tigate the role of zinc. A comparison of measured reaction rates
of catalyzed with uncatalyzed tetrazole formation, for both intra-
and intermolecular cases, seems to corroborate the computational
findings.
The energies presented here include solvation effects with ꢀ
) 80, unless otherwise stated.
III. Experimental Details
To a solution of sodium azide (325 mg, 5 mmol) and zinc bromide
(1.12 g, 5 mmol) in water (7 mL) and 2-propanol (3 mL) was added
cyanopyrazine (21 mg, 0.2 mmol) and benzyl alcohol (21 mg). The
reaction was stirred at 23 °C, and aliquots were removed, added to a
biphasic solution of HCl (1 N, 1 mL) and ethyl acetate (5 mL), and
shaken. The organic layer was injected onto a GC, and the extent of
reaction was determined using benzyl alcohol as the internal standard.
The data showed zeroth order kinetics, with a calculated nitrile half-
life of 4.0 min. A second reaction was run as above except that no
zinc was added, and the reaction was heated in an oil bath set to 80
°C. Zeroth order kinetics were observed again, and the computed half-
life was 35 min.
A solution of 2-azidoethyl benzylcyanamide20 (0.05 mmol) in DMF
(5 mL) was heated in an oil bath set at 140 °C. Aliquots were removed
and added to ethyl acetate (5 mL), washed with water, dried, evaporated,
and analyzed by 1H NMR. Zeroth order kinetics were observed, and a
half-life of 24 h was calculated. In a similar experiment, zinc bromide
was added to the aforementioned mixture to bring its concentration to
0.05 M, and the resulting solution was heated in an oil bath set to 75
°C. The half-life was found to be 18 h. In a third experiment, aluminum
chloride was added to a solution of 2-azidoethyl benzylcyanamide (0.1
M) in 2-methyltetrahydrofuran (10 mL) to bring its concentration to
0.1 M, and the resulting solution was stirred at 23 °C. The half-life
was found to be 24 h.
II. Computational Details
All geometries and energies presented in the present study
are computed using the B3LYP16 density functional theory
method as implemented in the Gaussian98 program package.17
Geometry optimizations were performed using the triple-ú plus
polarization basis set 6-311G(d,p), followed by single-point
energy calculations using the larger basis set 6-311+G(2d,2p).
To evaluate the zero-point vibrational effects on energy,
Hessians were calculated at the B3LYP/lanl2dz level of theory.
Solvation energies were added as single-point calculations
using the conductor-like solvation model COSMO18 at the
B3LYP/6-311G(d,p) level. In this model, a cavity around the
system is surrounded by a polarizable dielectric continuum. The
dielectric constant was chosen as the standard value for water,
IV. Results and Discussion
The model calculations presented here will focus on the
simplest nitrile, namely acetonitrile (CH3CN). The conclusions
should, however, be of direct relevance to nitriles in general.
Before discussing the results, the modeling of the ZnII ligand
sphere deserves comment. The zinc was modeled by either
tetrahedral or octahedral coordination. These two models are
electronically very similar, since Zn2+ presents an essentially
degenerate coordination sphere. However, due to the different
steric effects in these two systems, the results can differ
somewhat, and the different possible mechanisms are considered
individually below.
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A. Azide Anion Bound to Zinc. Let us first consider the
situation where the azide anion (N3-) is bound to ZnII and the
acetonitrile undergoes the cycloaddition without coordinating
to zinc. The optimized transition state structures for this [2 +
3] cycloaddition reaction, modeled using tetrahedrally coordi-
nated zinc (three water ligands and the azide) or octahedrally
coordinated zinc (5 water ligands and the azide), are displayed
in Figure 1 (A and B, respectively). The energy barriers
(enthalpy including solvation) for these reactions are calculated
to 33.7 and 35.6 kcal/mol, respectively. Furthermore, making
the overall system charge-neutral by substituting one of the water
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J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
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9984 J. AM. CHEM. SOC. VOL. 125, NO. 33, 2003