Synthesis of N-alkoxybenzimidoyl azides and their reactions in electrophilic media

Article abstract of DOI:10.1002/poc.1608

A new general route to N-alkoxybenzimidoyl azides [ArC(N₃)=NOR] from a reaction of N-alkoxybenzimidoyl bromide [ArC(Br)=NOR] with sodium azide in DMSO is described. These reactions result in the Z-geometric configuration. These compounds show a moderate degree of thermal stability as assessed by differential scanning calorimetry, and lack reactivity in traditional 1,3-dipolar cycloaddition 'click' reactions. Upon exposure to electrophilic compounds (trifluoroacetic acid or acetyl chloride), these azide compounds can react by two pathways: a Schmidt-type rearrangement to form an N-alkoxyurea or an isomerization - cyclization reaction pathway to form an N-alkoxytetrazole. The route of the reaction has no dependence on solvent polarity and appears to depend upon the electrophile (H⁺ vs. CH₃CO⁺): reaction of the azide with trifluoroacetic acid results predominantly in the urea; reaction with acetyl chloride results solely in the tetrazole. Calculations indicate that the urea product is thermodynamically favored over the tetrazole product. They also indicate that both reaction conditions result in an equilibration between the starting azide and the tetrazole with the tetrazole being the major component in this equilibrium mixture. The fact that the azide also undergoes a Schmidt-type rearrangement to form an N-alkoxyurea when treated with trifluoroacetic acid appears to indicate that the barrier for aromatic ring migration is lower in the protonated azide produced on reaction with trifluoroacetic acid than in the acetylated azide produced on reaction with acetyl chloride. Copyright

Full text of DOI:10.1002/poc.1608

Research Article
Received: 7 May 2009,
Accepted: 4 July 2009,
Published online in Wiley InterScience: 15 September 2009
(www.interscience.wiley.com) DOI 10.1002/poc.1608
Synthesis of N-alkoxybenzimidoyl azides and
their reactions in electrophilic media
a
a
a
*
Debra D. Dolliver , Thomas Sommerfeld , Megan L. Lanier , Jordan
A. Dinsera, Richard P. Ruckera, Rebecca J. Webera and Artie S. McKimb
A new general route to N-alkoxybenzimidoyl azides [ArC(N3)¼NOR] from a reaction of N-alkoxybenzimidoyl bromide
[ArC(Br)¼NOR] with sodium azide in DMSO is described. These reactions result in the Z-geometric configuration. These
compounds show a moderate degree of thermal stability as assessed by differential scanning calorimetry, and lack
reactivity in traditional 1,3-dipolar cycloaddition ‘click’ reactions. Upon exposure to electrophilic compounds
(trifluoroacetic acid or acetyl chloride), these azide compounds can react by two pathways: a Schmidt-type
rearrangement to form an N-alkoxyurea or an isomerization–cyclization reaction pathway to form an N-alkoxyte-
trazole. The route of the reaction has no dependence on solvent polarity and appears to depend upon the electrophile
(HR vs. CH3COR): reaction of the azide with trifluoroacetic acid results predominantly in the urea; reaction with acetyl
chloride results solely in the tetrazole. Calculations indicate that the urea product is thermodynamically favored over
the tetrazole product. They also indicate that both reaction conditions result in an equilibration between the starting
azide and the tetrazole with the tetrazole being the major component in this equilibrium mixture. The fact that the
azide also undergoes a Schmidt-type rearrangement to form an N-alkoxyurea when treated with trifluoroacetic acid
appears to indicate that the barrier for aromatic ring migration is lower in the protonated azide produced on reaction
with trifluoroacetic acid than in the acetylated azide produced on reaction with acetyl chloride. Copyright ß 2009
John Wiley & Sons, Ltd.
Supplementary information may be found in the online version of this paper.
Keywords: azide rearrangement; azidoxime ether; imine azide; oxime azide; tetrazole
There are a few reactivity studies focusing on other azidoxime
derivatives in acidic/electrophilic media, but the results appear to
INTRODUCTION
Organoazides have been historically considered as useful
synthetic intermediates in the formation of primary amines
and heterocycles.[1] With the advent of ‘click’ chemistry,
organoazides have found their way into an increasing number
of synthetic schemes because of the efficiency of their copper-
catalyzed 1,3-dipolar cycloaddition reactions.[2–4] However,
organoazides are also considered dangerous as they may
violently and explosively liberate nitrogen. Despite these
inherent risks, azides have become important intermediates in
be inconsistent. For instance, Hegarty et al. found that hydrazonyl
azide (1Zj) rearranged in acidic media (trifluoroacetic acid or
2.2 M sulfuric acid/acetic acid) to form a semicarbazide (2j)
(Scheme 1).[8] This reaction was thought to proceed through a
Schmidt-type rearrangement, where the azide nitrogen is
protonated and the R group on carbon migrates to the electron
deficient nitrogen. Plenkiewicz et al. found that phenyl azidoxime
(1Zb) cyclized to form a tetrazole (3b) upon treatment with an
acyl chloride in an inert solvent (Scheme 1). This reaction was
thought to proceed throþugh a reversible interaction between the
the synthesis of some pharmaceuticals such as TamifluTM [5]
In
.
—
this paper, we report a general synthesis of a sub-class of
organoazides, N-alkoxybenzimidoyl azides, and discuss the
unusual chemistry of these compounds.
electrophile [CH C O] and the imine nitrogen, followed by
—
3
isomerization to the E-isomer, and then spontaneous cyclization.
In contrast to the work done by Hegarty, Plenkiewicz reported
that this same cyclization occurred with trifluoroacetic acid in
‘moist’ benzene, but he made no mention of the aforementioned
rearrangement reaction.[9,10]
There are a few papers examining azidoxime derivatives,[6–10]
but some of these azidoximes are unstable and quickly
decompose to their corresponding nitriles at room tempera-
ture.[7] Surprisingly, there are only two references of an azidoxime
ether, 1Zd, in the literature (Scheme 1).[6,10] These papers report
the synthesis of 1Zd by methylating N-hydroximidoyl azide (1Zb).
Neither paper offers much supporting characterization data, nor
do they explore its reactivity, other than commenting that it
appears to be ‘surprisingly stable.’[6] This atypical azide behavior
caused some controversy about whether this azidoxime ether
existed in the open chain or in the tetrazole form. This was
resolved when Eloy found this compound to have a strong
absorption in the IR region typical for azides.[6]
*
Correspondence to: D. D. Dolliver, Department of Chemistry and Physics,
Southeastern Louisiana University, Hammond, LA 70402, USA.
E-mail: ddolliver@selu.edu
a
b
D. D. Dolliver, T. Sommerfeld, M. L. Lanier, J. A. Dinser, R. P. Rucker, R. J. Weber
Department of Chemistry and Physics, Southeastern Louisiana University,
Hammond, Louisiana 70402, USA
A. S. McKim
Gaylord Chemical Company, Slidell, Louisiana 70459-1209, USA
J. Phys. Org. Chem. 2010, 23 227–237
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D. D. DOLLIVER ET AL.
Scheme 1. Azidoxime derivatives and reported reactions in electrophilic media
In this paper, we not only report a new general route to N-
alkoxybenzimidoyl azides (azidoxime ethers 1Zd–1Zi), but we
also discuss the reactions of these compounds in acidic/
electrophilic media and compare these data to prior experimen-
tal work.
product formation. This finding indicates that the azide
substitution reaction may be occurring via a different mechanism
than the AN þ DN mechanism ascribed to methoxide substitution
of (Z)-N-alkoxybenzimidoyl fluoride.[11]
These compounds proved to be stable enough to be isolated
by chromatographic means and to be stored in a laboratory
without further storage requirements for several days without
significant decomposition. Only one geometric isomer was
isolated and/or detected in the reaction mixture, regardless of
the substituent on the ring or the alkyl group attached to oxygen.
X-ray crystallographic study confirmed 1Zh to be in the Z-
configuration.[12] It is, therefore, assumed that the other reactions
also result in the Z-isomer of the product. This preference for the
Z isomer had been previously noted in 1Zb and had been
explained as resulting from intramolecular hydrogen bonding
EXPERIMENTAL RESULTS
Synthesis of (Z)-N-alkoxybenzimidoyl azides (1Zd–1Zi) was
readily accomplished by reacting the corresponding (Z)-N-
alkoxybenzimidoyl bromide (4Zd–4Zi) with sodium azide in
dimethyl sulfoxide (Scheme 2) with fair to excellent yields.
Interestingly, attempts to prepare 1Zd–1Zi by reaction of (Z)-N-
alkoxybenzimidoyl fluoride [ArC(F)¼N-OR] resulted in little
Scheme 2. Synthesis of (Z)-N-alkoxybenzimidoyl azides
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N-ALKOXYBENZIMIDOYL AZIDES IN ELECTROPHILIC MEDIA
makes these azidoxime compounds atypical, but further
investigation into causal factors for this behavior is beyond
the scope of the work outlined in this paper (Scheme 4).
Instead, this paper focuses on the reaction of these azidoximes
in acidic/electrophilic media, specifically looking at the factors
that influence a Schmidt-type rearrangement reaction to form a
urea (Scheme 6) versus the factors that cause a cyclization
mechanism (Scheme 7) to form a tetrazole. The proposed
mechanisms for these processes appear to depend on the
electrophile interacting with compound 1Z at two different
locations: the azide nitrogen to form 5 or the imine nitrogen to
form 6 (Scheme 5).
Scheme 3. Attempt to synthesize the E-azide
As previously noted, Hegarty described the rearrangement of
hydrazonyl azide 1Zj to the semicarbazide 2j when placed in
trifluoroacetic acid.[8] He proposed a mechanism analogous to a
Schmidt-type rearrangement, where the protonated species
(5jHR) undergoes a migration of the R group to the electron-
deficient nitrogen to form a protonated carbodiimide (7jHR),
which subsequently reacts with water to form urea (2j)
(Scheme 6). Hegarty also found that this reaction occurred on
treatment with 2.2 M sulfuric acid/acetic acid.
Alternatively, Plenkiewicz found that treatment of azidoxime
1Zb with an acid chloride in cyclohexane or benzene resulted in
the formation of a tetrazole.[9,10] This reaction was later
substantiated by Hegarty, who proposed a reversible acety-
lation–isomerization–cyclization pathway as indicated in
Scheme 7.[18,19] In this pathway, the intermediate 6 has a less
double bond character between the carbon and nitrogen due to
resonance and can thereby rotate so that the Y substituent is
‘trans’ to the azide functionality (8). Once in this configuration,
the electrophile can dissociate, and the molecule can cyclize to
form the tetrazole 3. Interestingly, Plenkiewicz also found that
trifluoroacetic acid reacted with 1Zb to form the tetrazole but
made no mention of urea formation.[10]
Reactions of 1Zd were run under similar conditions, using
either trifluoroacetic acid or acetyl chloride as the electrophile,
and these reactions yielded primarily the urea 2d in the former
and the tetrazole 3d in the latter. Both of these reactions gave
good isolated product yields, which are reported in the
Experimental section of this paper.
As these reactions differ in both the nature of the electrophile
and the nature of the solvent, it was thought to be wise to
thoroughly investigate the effect, if any, of the solvent on the
reaction pathway. The previous rearrangement reactions had
been run in either trifluoroacetic acid or acetic acid, and the
cyclization reactions had been run in cyclohexane or benzene. To
determine the effect of solvent (polar vs. nonpolar), a series of
reactions utilizing either trifluoroacetic acid or acetyl chloride as
between the oxime hydrogen and an azide nitrogen,[13] but this
would not account for the Z-isomer preference in compounds
1Zd–1Zi.
Attempts at making the E-isomer of the azide were not
successful when starting from 4E (Scheme 3). When 4E was
reacted with sodium azide in DMSO, the Z-isomer of the azide
was produced (1Z) along with other decomposition products but
1E was not detected. Additionally, the E-isomer of the azide could
not be produced by irradiating 1Z, using the same technique
used to produce 4E from 4Z,[14] as this technique simply led to
rapid decomposition of the starting material and complex
product formation. This is most likely due to loss of molecular
nitrogen as is seen when irradiating azidobenzene, which forms a
reactive nitrene in solution.[15]
As these types of compounds are stable to chromatographic
separation and storage, differential scanning calorimetry (DSC)
was performed on 1Ze to fully assess thermal stability. The
sample was heated (5.0 K minꢀ1) in an aluminum pan under a N2-
atmosphere with an empty pan acting as a reference. A thermal
energy of 275 kJ molꢀ1 for 1Ze was measured while heating with
thermal decomposition beginning at 132.5 8C and a maximum
energy at 149.8 8C (refer to supplementary information). This
indicates that these compounds are less prone to explosive
decomposition than azidobenzene.[16]
As many studies are currently underway with ‘click’ cycloaddi-
tion reactions, where organoazides react either under copper-
catalyzed conditions with alkynes to form triazoles[17] or with
electron-poor nitriles to form tetrazoles,[3,4] the reactivity of 1Zd
was investigated under both of the aforementioned reaction
conditions. Subjecting 1Zd to an acylcyanide,[3] p-toluenesulfonyl
cyanide,[4] or an alkyne with copper catalysis[17] by published
procedures, resulted in essentially no reaction of the azide. This
reticence to participate in 1,3-dipolar cycloaddition reactions
Scheme 4. Lack of reactivity of 1Zd to 1,3-dipolar cycloaddition reactions
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D. D. DOLLIVER ET AL.
Scheme 5. Possible interactions of the electrophile with1Za–d, j
Scheme 6. Proposed mechanism for rearrangement
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N-ALKOXYBENZIMIDOYL AZIDES IN ELECTROPHILIC MEDIA
Scheme 7. Proposed mechanism for isomerization/cyclization
the acid/electrophile were carried out in a variety of solvents with
varying dipole moments: cyclohexane (0.00 D), chloroform
(1.04 D), dichloromethane (1.60 D), water (1.85 D), and sulfolane
(4.35 D). The reactions were also run in pure trifluoroacetic acid.
When 1Zd was placed in pure trifluoroacetic acid, the urea
product 2d was dominant, but tetrazole 3d was also formed. The
urea/tetrazole ratio at reaction completion was 96:4. The results of
this work in different solvents are shown in Table 1. All of these
reactions were stopped when close to completion (when at least
88% of the starting azide (1Zd) had been consumed as shown in
Table 1), and thus were taken at different reaction times
depending upon the solvent. These results indicate that solvent
polarity may affect the rate of the reaction but has little or no
effect on the product distribution. In other words, when
trifluoroacetic acid is the electrophile, the urea product 2d is
always strongly favored. Some tetrazole 3d (5.0–7.7%) is also
formed in this reaction with a urea (2d)/tetrazole (3d) ratio of
16:1 in dichloromethane and 10:1 in chloroform. Interestingly, the
reactions of 1Zd with trifluoroacetic acid which were run in water
or sulfolane were very slow and showed no product formation at
greater than 48h reaction time. While tracking these reactions for a
week, low yields of urea were noted. One possible explanation for
this observation is that the equilibrium concentrations of 5 and
6 are very low in solvents which can also be protonated, and this
results in slow reaction rates. The reaction could not be run in a
very nonpolar solvent like cyclohexane for purposes of comparison
due to the poor solubility of trifluoroacetic acid in this solvent.
When acetyl chloride is the electrophile, 1Zd can be
quantitatively transformed into the tetrazole (3d in Table 1) if
the reaction is allowed to reach completion. There is no evidence
for any rearrangement to form a urea in this reaction. These
findings indicate that the electrophile is the critical component in
determining the choice of reaction pathway.
To verify our results, we also ran the reaction of 1Zd with
trifluoroacetic acid and with acetyl chloride in deuterated
chloroform to monitor reaction progress by NMR. Our results
were similar to the product distributions found when monitoring
the reactions in CHCl3 by HPLC (Table 1). Reaction of 1Zd with
trifluoroacetic acid in CDCl3 gave product ratios 96:4 for urea 2d/
tetrazole 3d as monitored by NMR. The NMR results of the
reaction of 1Zd with acetyl chloride showed only tetrazole 3d in
solution at the completion of the reaction.
In the reaction of 1Zd with trifluoroacetic acid in deuterated
chloroform, there were signals for the OCH3 protons on each of
the following molecules: 4.31 ppm for the tetrazole (3d), 4.02
ppm for the unreacted azide (1Zd), and 3.82 ppm for the urea
(2d). Interestingly, if the reaction is run in CDCl3, which has been
˚
dried over 4 A molecular sieves, there will also be a fourth signal
on the shoulder of the azide peak at approximately 4.06 ppm,
which is not completely resolved from the azide peak. This could
be the carbodiimide species (7d, protonated or not), which is
intermediate in the production of urea but which is hydrolytically
unstable in HPLC mobile phase (ACN/H20) and thereby not seen
by our HPLC analysis.
Another interesting finding that supports the involvement of a
carbodiimide species in the trifluoroacetic acid rearrangement
reactions, run in chloroform, is that another substance is
identified by HPLC if aliquots are directly injected into the HPLC
without first quenching in ACN/H2O solution. When doing this,
the peak for urea 2d is broad and ill defined, and another broad
peak is seen with a retention time intermediate between the
more polar urea and the less polar azide. If water is added to
the reaction aliquot and mixed for approximately 20 min, the
unidentified peak disappears and the urea peak 2d sharpens
substantially. This is thought to indicate that carbodiimide
present in the dry reaction conditions is hydrolyzed to the urea
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D. D. DOLLIVER ET AL.
on migration through the HPLC column. If quenched in water
prior to injection on the HPLC, all the remaining carbodiimide is
converted into urea.
COMPUTATIONAL RESULTS
To substantiate our experimental conclusions, we explored the
energetics of these mechanisms by computational means. Prior
computational work indicated that the tetrazole is favored over
the open-chain azide.[20] No prior computational study was found
in the literature for the pathway leading to the rearrangement
product.
This section reports computed structures and relative energies
of azide 1, tetrazole 3, carbodiimide 7, and urea 2, as well as
structures and energies for the transition states associated with
the ring closing reaction leading from 1E to 3 and the
isomerization reaction leading from 1Z to 1E. Moreover, the
difference in Gibbs free energy between 1Z and 3 is computed,
and for 1Z, the energetics associated with protonation and
acetylation at the azide N to form 5a-dHR or 5a-dAcR and imine
N to form 6a-dHR versus 6a-dAcR are compared.
The initial step of the computational study is finding the
minimal energy structures of 1Za, 3a, 7a, and 2a. For this task,
four theoretical methods, HF, MP2, BLYP, and B3LYP, were used in
*
combination with the 6-31G basis set (acronyms are explained in
the Computational methods section). As expected for closed-
shell organic molecules without appreciable strain, the computed
equilibrium geometries obtained with these four methods are
similar, and, in particular, the MP2 and B3LYP structures are very
close. To compare the relative energies of these molecules, their
energies were recomputed at the B3LYP geometries using the 6-
**
311G basis set, and as an additional method, CCSD(T) was
employed. The results are shown in Fig. 1. The CCSD(T) method is
presumably the most reliable method employed, and MP2 and
B3LYP yield relative energies close to the CCSD(T) result
(differences of less than 5 kcal molꢀ1), whereas HF and BLYP
do not (differences in excess of 10 kcal molꢀ1). As B3LYP is
computationally less expensive than MP2, it was selected to study
the larger methyl and phenyl substituted molecules.
In addition to method comparison, Fig. 1 also provides a first
glimpse of the potential energy surface for the reactions of azide
1Z. Formation of carbodiimide 7 and urea 2 is predicted to be
strongly exothermic, whereas the product of ring closure,
tetrazole 3, is predicted to be essentially isoenergetic with azide
1Z: our presumably most accurate value for the energy of the ring
closing reaction of 1Za to 3a is the CCSD(T) result of
ꢀ3.1 kcal molꢀ1
,
MP2 yields ꢀ2.2 kcal molꢀ1
,
and B3LYP
þ0.33 kcal molꢀ1
.
Having established relative energies of 1Za, 3a, 7a, and 2a,
the influence of phenyl substitution at the carbon atom of 1Za
to produce 1Zb and methyl substitution at the oxime oxygen to
produce 1Zc or 1Zd were investigated. Figure 2 shows B3LYP
results for the relative energies of 1Z, 3, 7, and 2 with different R
groups. While methyl substitution has only a small effect on the
relative energies, phenyl substitution stabilizes 3 and destabilizes
2 and 7 with respect to 1Z. On an absolute scale, the effects are in
the order of a few kcal molꢀ1, which translate into a 10% effect for
the formation of the carbodiimide 7 or the urea 2. In contrast, the
reaction energy for tetrazole formation is small, and substitution
has a major impact on the relative energy of 1Z and 3. Both,
methyl substitution at the O atom and phenyl substitution at the
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N-ALKOXYBENZIMIDOYL AZIDES IN ELECTROPHILIC MEDIA
Table 2. Energy and Gibbs free energy difference between
azide 1Z and tetrazole 3. The results have been obtained using
the G3MP2 method
DEr (kcal/mol)
DGr (kcal/mol)
1Za ! 3a
1Zb ! 3b
1Zd ! 3d
ꢀ2.6
ꢀ4.1
ꢀ5.7
ꢀ1.4
ꢀ2.9
ꢀ4.2
Gibbs free energies, and based on the computed DG values for
the tetrazole formation reaction, we predict equilibrium
concentration ratios of 1:12 for 1Za/3a, 1:130 for 1Zb/3b, and
1:1200 for 1Zd/3d.
Figure 1. Relative energies of 1Za and its reaction products computed
with different theoretical methods. These four species contain different
numbers of atoms; to compare their energies, the energy of H2O was
added to 3a and 1Za, the energy of H2O and N2 was added to 7a, and the
To gain further insight into the mechanism of the reactions
connecting 1Z and 3, transition states connecting 1Z with 1E
(barrier for rotation between 6 and 8), and 1E with 3 were
investigated (Scheme 7). The formation of 1E from 1Z is assumed
to involve protonation of the imine N atom to form 6, which
effectively lowers the carbon–nitrogen bond order, followed by
subsequent rotation, and finally deprotonation.[21] The Z isomer
was found to be more stable than the E isomer: DE ¼ ꢀ0.82 kcal/
mol for 1Ea-1Za, DE ¼ ꢀ2.9 kcal/mol for 1Ed-1Zd. The structure
of the transition state connecting protonated 6HR and 8HR is
shown in Fig. 3 together with the barrier heights for the
associated isomerization reactions of 6aHR and 6bHR. For the
**
energy of N2 was added to 2a. The 6-311G basis set and the B3LYP/6-
*
31G optimized geometries have been used for all computations.
C atom, stabilize 3 with respect to 1Z (Fig. 2), and, for instance
going from 1Za/3a to 1Zd/3d more than doubles the reaction
energy.
Clearly, the energy difference between 1Z and 3 is crucial for
*
this study. However, while B3LYP with a 6-31G basis is, in view of
unsubstituted azide 6aHR, the barrier height is 28.9 kcal molꢀ1
.
the small reaction energy, insufficient, CCSD(T) calculations for
the phenyl substituted compounds are prohibitively expensive
(at least for us). Therefore, the G3MP2 method was used to
compare 1Z and 3, and the results are collected in Table 2. The
G3MP2 method is expected to predict this type of isomerization
energy very accurately, and indeed, for the reaction 1Za ! 3a,
the G3MP2 value of ꢀ2.6 kcal molꢀ1 is close to the CCSD(T) result
of ꢀ3.1 kcal molꢀ1. Moreover, the G3MP2 method also yields
Phenyl substitution lowers the barrier height dramatically to
18.5 kcal molꢀ1 for 6bHR. In contrast, phenyl substitution has
virtually no effect on the barrier for ring closure of 1E yielding 3,
which is about 20 kcal molꢀ1 for both, 1Ea and 1Eb (Fig. 4).
Figure 3. Transition state for the isomerization of protonated 6aHR to
protonated 8aHR (dashed) and protonated 6bHR to 8bHR (solid). The
energy profiles have been obtained by fixing the ONCN torsion angle and
Figure 2. Relative energies of reaction products of 1Za, 1Zb, 1Zc, and
1Zd. The results have been obtained using the B3LYP method and the 6-
*
31G basis set. These four species contain different numbers of atoms; to
*
optimizing all other coordinates using B3LYP/6-31G calculations. In
compare their energies, the energy of H2O was added to 3 and 1Z, the
energy of H2O and N2 was added to 7, and the energy of N2 was added to
2. The color scheme used is: blue: a; red: b; purple: c; green: d.
addition, the transition states have been localized, and for the
6aHR ! 8aHR reaction the structure of the transition state is shown.
The Newman-like projection is looking down the C—N bond of the azide.
J. Phys. Org. Chem. 2010, 23 227–237
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D. D. DOLLIVER ET AL.
SUMMARY OF EXPERIMENTAL RESULTS
Reaction of the azide 1Zd with acetyl chloride results in only
tetrazole 3d, regardless of solvent polarity, as detected by HPLC
and NMR. The product is thought to form via reversible
acetylation of the imine nitrogen of 1Zd to form 6dAcR, which
lessens the double bond character of the carbon–nitrogen bond
and allows for Z/E isomerization. Once the E isomer is formed, it
spontaneously cyclizes to form 3d which is the favored species in
the equilibrium mixture and thus the predominant species
detected experimentally. It is felt that acetylation of the azide
nitrogen to form 5dAcR also occurs in the equilibrium mix, but
the barrier to rearrangement is prohibitively high in this
acetylated species.
Reaction of 1Zd with trifluoroacetic acid results primarily in the
urea 2d with minor amounts of the tetrazole 3d. These reaction
conditions also result in an equilibration between 1Zd, 5dHR,
6dHR, 8dHR, 1Ed, and 3d; however, the urea 2d is the
predominant species detected as the reaction draws to
completion. This indicates that the barrier for migration of the
phenyl ring in 5dHR to form the thermodynamically preferred
7dHR is relatively low and may occur at room temperature.
Subsequent reaction of 7dHR with water results in the urea 2d.
This same phenyl migration is not seen in going from 5dAcR to
7dAcR, and it is presumed that the barrier for migration in this
acetylated species is higher than that for the protonated species
due to steric factors.
Figure 4. Transition state for ring closure of 1Ea to yield 3a (dashed)
and 1Eb to yield 3b (solid). The energies have been obtained from B3LYP/
*
6-31G calculations, and for the 1Ea ! 3a reaction the structure of the
transition state is shown.
Figure 4 also shows the structure of the transition state linking
1Ea and 3a.
Regarding the acid catalyzed isomerization of 1Z and 1E,
the competition between protonation and acetylation of the
azide and imine N atoms of 1Za and 1Zb to form 5 versus 6
was investigated. Results obtained with the G3MP2 method
are collected in Table 3. For both, protonation and acetylation,
the imine N is, by far, the preferred position with DDG values
in the order of 16–17 kcal molꢀ1. Phenyl substitution some-
what increases this preference for protonation, and somewhat
decreases the preference for acetylation, yet the overall effect
of substitution is small.
Finally, let us briefly comment on computational results from
the search for a transition state connecting 1Z and 7. We
examined two possible intermediates, a nitrene and a protonated
nitrene resulting from N2 elimination from 1Z and 5, respectively.
Preliminary calculations show that the wave functions of these
hypothetical intermediates have substantial multi-configuration
character, suggesting that multi reference methods, such as the
complete-active-space self-consistent field or multi reference
configuration interaction methods, would be required to study
transition states and intermediates of this reaction.
SUMMARY OF COMPUTATIONAL RESULTS
Regarding theoretical approaches, our results suggest that B3LYP
*
with a 6-31G basis set is an acceptable method for predicting
structures and energy differences. Two noteworthy exceptions
are the isomerization energy of 1Z and 3, which requires more
reliable methods due to its small value, and the structure of
intermediates associated with N2 elimination from 1Z, which
requires the use of multi-configuration methods. Regarding the
energetics of the two reactions of 1Za, the computational results
show that urea formation is highly exothermic, whereas ring
formation is exothermic by only a few kcal/mol. Substitution at
the C and O atoms (as in 1Zb, 1Zc, and 1Zd) has only a small
influence on its reaction energies. However, there are again two
exceptions. First, owing to the intrinsically small isomerization
energy of 1Z to 3, small differences matter, and ring formation is
far more strongly preferred for the substituted compounds. The
second exception is the barrier between the protonated 6a-dHR
and 8a-dHR, which is significantly lowered by phenyl substi-
tution. Thus, the phenyl-substituted azides will establish equi-
librium with their associated tetrazole isomers far more rapidly.
Since both barriers, 1Z to 1E and 1E to 3, can readily be
overcome at room temperature, we predict that in solution, the
rate of establishing equilibrium between 1Z and 3 is effectively
controlled by the pH, with a low pH permitting fast equilibration.
In other words, the results for the transition states suggest that in
acidic solution, equilibrium between 1Z and 3 will be established
rapidly, and the computed DGr values suggest that 3 will be, by
far, the most dominating species.
Table 3. Difference in Gibbs free energy (DDG) for the
addition of an electrophile (Hþ or Acþ) at the azide and imine
N atoms of 1Z to form 5HR versus 6HR and 5AcR versus 6AcR.
Addition at the imine N is preferred, independent of phenyl
substitution and the attacking electrophile. The results have
been obtained using the G3MP2 method, the unit is
kcal molꢀ1
—
—
—
H, Y OH
—
—
Ph, Y OH
— —
—
R
R
a
b
The formation of urea, 2, if the barrier can be overcome, is
strongly exothermic and exergonic (no large S contribution here)
and irreversible. So, if the barrier for N2 elimination can be
overcome, urea will be the only product. Experimental results
Hþ DDG(5Hþ–6Hþ)
Acþ DDG(5Acþ–6Acþ)
17.3
15.9
19.8
14.3
www.interscience.wiley.com/journal/poc
Copyright ß 2009 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2010, 23 227–237

N-ALKOXYBENZIMIDOYL AZIDES IN ELECTROPHILIC MEDIA
suggest that Hþ is a catalyst for this reaction, whereas the Lewis
acid Acþ is not. A possible explanation for the lack of urea
formation in the reaction of 1Zd with acetyl chloride could be
that it involves a higher barrier to migration of the phenyl group
to the electron-deficient nitrogen due to steric effects of the
associated acetyl group in intermediate 5dAcR. This would make
this route noncompetitive with the isomerization–cyclization
pathway at room temperature, and thereby all the product
formation would result from the cyclization route in the reaction
with acetyl chloride.
B3LYP.[22–24] The underlying basis sets are Pople’s 6-31G and
*
6-311G split-valence sets.[25,26] All the considered systems
**
have closed-shell electronic ground states, and core electrons
were included in the correlation treatment. Moreover, the
composite G3MP2[27] method was used. The following computer
codes were used: GAMESS-UK[28] for HF, MP2, and density
functional calculations, MAB version of ACES II[29] for MP2 and
CCSD(T) calculations, and Gaussian03[30] for G3MP2.
EXPERIMENTAL METHODS
1H-NMR spectra were acquired at 300.13 MHz, and the 13C-NMR
spectra at 75.47 MHz using a Bruker AC 300 spectrometer in (2H)
chloroform. New compounds showed the required number of
carbons in the 13C-NMR spectrum. Low-resolution mass spectra
were obtained on a Hewlett-Packard 5890 series II GC/5971 series
mass selective detector. FT-IR spectra were acquired on a Perkin
Elmer 16 PC FT-IR. HPLC was used to monitor reaction progress
when synthesizing the azides, using an Econosphere C18 column,
CONCLUSIONS
A new general synthesis on (Z)-N-alkoxybenzimidoyl azides
(1Zd–1Zi) has been described above. These compounds exhibit a
higher degree of thermal stability than many organoazides and
are not amenable to 1,3-dipolar cycloaddition reactions by
standard ‘click’ reaction conditions. Reactions in electrophilic
media have shown these compounds to undergo two different
reaction routes: a rearrangement to form an N-alkoxyurea after
reaction with water and an isomerization–cyclization pathway to
form a tetrazole. Reaction in trifluoroacetic acid solution results
primarily in the formation of the urea 2 from the rearrangement
pathway with only minor amounts of tetrazole 3 product from
the isomerization–cyclization pathway. Reaction in acetyl
chloride solution results only in the tetrazole product 3 formed
via the isomerization–cyclization pathway. The choice of the
reaction pathway depends upon the electrophile and is not
greatly influenced by solvent polarity.
5 mm, 150 ꢂ 4.6 mm, MP 90:10 MeOH/H2O at 1.0 ml minꢀ1
;
detection at 254 nm. The HPLC method used to monitor
cyclization versus rearrangement utilized a Sunfire C18 column,
5 mm, 250 mmꢂ 4.6 mm, 70:30 ACN/H2O at 1.0 ml minꢀ1, with
detection at 254 nm. Elemental analyses were performed at
Midwest Microlabs, LLC, in Indianapolis, IN.
Procedure to monitor the effect of solvent on cyclization
versus rearrangement
Molar absorptivity correction curves at 254 nm were determined
by HPLC analysis of solutions containing known quantities of
pure azide, urea, and tetrazole versus a known quantity of the
internal standard (ethylbenzene). These correction factors were
performed for the following ratios: urea 2d: ethylbenzene ratios
of 1:2, 1:3, 1:4, 1:5, 1:20, 1:30, 1:40; azide 1Zd/ethylbenzene ratios
of 1:1, 1:2, 1:3, 1:4, 1:6, 1:20, 1:30, 1:40; and tetrazole 3d/ethyl
benzene ratios 1:3, 1:5, 1:7, 1:9, 1:20, 1:30, 1:40. There was linear
response along these concentrations with the following correc-
tion factor line equations: [ethylbenzene]/[1Zd] ¼ 0.027X þ 0.002,
R2 ¼ 0.999; [ethylbenzene]/[2d] ¼ 0.077X þ 0.009, R2 ¼ 0.999;
[ethylbenzene]/[3d] ¼ 0.024X ꢀ 0.007, R2 ¼ 0.997.
Calculations show that the urea product 2 is more thermo-
dynamically stable than the tetrazole product 3. Both protonation
and acetylation of the azide appear to be more favorable at the
imine nitrogen as in 6 as opposed to the azide nitrogen as in 5.
Calculations show that the equilibration in electrophilic media of
1Z, 6, 8, 1E, and 3 can be rapidly established at room
temperature, and that the tetrazole 3 will be the dominant
species in this equilibrium mixture. Calculations, however, also
show that there should also be some electrophile addition at the
azide nitrogen to form 5 in the equilibrium mixture as well. In the
reaction of 1Zd, for instance, there is likely to be both 5dHR and
6dHR formed in reaction with trifluoroacetic acid. Likewise, both
5dAcR and 6dAcR are probably formed in the reaction of 1Zd
with acetyl chloride. If the barrier for migration is relatively small,
the substituent on the imine carbon may migrate to the electron-
deficient nitrogen to form a species like 7dHR, which is highly
favored thermodynamically. The step is essentially irreversible at
room temperature, so it is inconsequential that there may only be
a small concentration of species 5 in the equilibrium mixture.
Upon hydrolysis of 7dHR, the urea 2d is formed. It is believed that
this migrational barrier must be relatively large, going from
5dAcR to 7dAcR, and thus no product is detected for this
reaction route in the reaction of 1Zd with acetyl chloride.
The reagents were measured in a small screw-top vial
containing a stir bar in the following order: azide (0.06 mmol),
solvent (0.6 ml), and electrophilic or acidic reagent (0.4 mmol).
After the addition of the final reagent, the flask was immediately
sealed and stirred at room temperature.
At a time when greater than 88% of the starting material had
been consumed (as determined by prior trials), the reaction was
quenched with 25 ml of 70:30 ACN/H2O solution containing a
known concentration of ethylbenzene so that the ending
concentration of all species was approximately 30:1 ethylben-
zene: (azide þ urea þ tetrazole). Correction factor calibration
curves were used to calculate the moles of azide 1Zd, urea
2d, and tetrazole 3d in the reaction mixture based on the known
amount of ethylbenzene in the reaction mixture.
COMPUTATIONAL METHODS
General procedure for the preparation of
(Z)-N-alkoxybenzimidoyl azides (1Zd–1Zi)
The computational methods employed in this study are the
Hartree–Fock (HF) method, second-order many-body pertur-
bation theory (MP2), the coupled cluster method with single and
double substitutions and non-iterative triple substitutions
(CCSD(T)), and two density functional approaches BLYP and
A solution of approximately 0.1 M (Z)-N-alkoxybenzimidoyl
bromide (4Zd–4Zi) and 0.5 M sodium azide in dimethyl sulfoxide
was placed in a screw-top sealed reaction vial and stirred.
J. Phys. Org. Chem. 2010, 23 227–237
Copyright ß 2009 John Wiley & Sons, Ltd.
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D. D. DOLLIVER ET AL.
Reaction temperature and duration varied depending on the
substituent on the aromatic ring. All reactions were monitored
with HPLC to assess the disappearance of the starting bromide
compound. With complete disappearance of the bromide
compound (4Zd–4Zi), the reaction mixture was poured onto
ice (50 g) and extracted with dichloromethane (3 ꢂ 20 ml). The
combined organic extracts were washed with water (3 ꢂ 10 ml),
dried over anhydrous magnesium sulfate, and evaporated under
reduced pressure to give a crude azide product. This was either
purified by silica gel chromatography or radial chromatography.
13C-NMR (CDCl3): d 55.34, 62.60, 113.72, 122.82, 127.79, 142.82,
161.18.
IR data (neat, cmꢀ1): 2935, 2147, 2096, 1609, 1593, 1513, 1326,
1256, 1173, 1059.
Anal. Calcd. for C9H10N4O2: C, 52.42; H, 4.89; N, 27.17, Found: C,
52.67; H, 5.10; N, 27.02.
MP 37.0–38.0 8C (uncorrected) Thomas–Hoover apparatus.
Preparation of 4-chloro-O-methylbenzohydroximoyl azide
(1Zg)
This compound was prepared by the above procedure, using 4-
chloro-O-methylbenzohydroximoyl bromide (4Zg) (166.8 mg,
0.67 mmol) and sodium azide (241.3 mg, 3.7 mmol) in DMSO
(5.3 g). This reaction mixture was heated to 70 8C with stirring for
48 h and worked up as indicated above. The product was purified
by radial chromatography (silica plate), using hexane as the
eluant to yield a white solid (0.0984 g, 61.4%). The sample was
further purified for elemental analysis by recrystallization, using
methanol.
Preparation of O-methylbenzohydroximoyl azide (1Zd)
This compound was prepared by the above procedure using O-
methyl benzohydroximoyl bromide (4Zd) (800 mg, 3.728 mmol)
and sodium azide (1.21 g, 18.7 mmol) in DMSO (32 g). This
reaction mixture was stirred by heating for 72 h and worked up as
indicated above. The product was purified by silica gel
chromatography (Merck grade 10181, 40A, 50 g), using 10%
dichloromethane/hexane as eluant. The product was obtained as
a clear, slightly yellow liquid (0.462 g, 2.47 mmol, 70.3%).
1H-NMR (300 MHz, CDCl3): d 4.02 (s, 3H, OCH3), 7.34–7.42 (m, 3H,
ArH), 7.73–7.76 (m, 2H, ArH).
13C-NMR (CDCl3): d 62.75, 126.22, 128.31, 130.18, 130.37,
142.89.
IR (neat, cmꢀ1): 2201, 2147, 2096, 1594, 1564, 1327, 1058.
Anal. Calcd. for C8H8N4O: C, 54.54; H, 4.58; N, 31.80, Found: C,
54.38; H, 4.69; N, 31.58.
1H-NMR (300 MHz, CDCl3): 4.00 (s, 3H, OCH3); 7.32 (d, J 7.8 Hz,
2H, ArH); 7.67 (d, J 7.8 Hz, 2H, ArH).
13C-NMR (CDCl3): 62.77, 127.33, 128.42, 128.90, 136.15, 141.77.
IR data (Nujol, cmꢀ1): 2189, 2143, 2097, 1590, 1323, 1057.
Anal. Calcd. for C8H7ClN4O: C, 45.62; H, 3.35; N, 26.60; Cl, 16.83;
Found: C, 45.97; H, 3.67; N, 26.29; Cl, 16.91.
MP 57.7–58.8 8C, uncorrected, MEL-TEMP capillary.
Preparation of 4-nitro-O-methylbenzohydroximoyl azide
(1Zh)
Preparation of 4-methyl-O-methylbenzohydroximoyl azide
(1Ze)
This compound was prepared by a method described in a
previous paper.[12]
This compound was prepared by the above procedure, using 4-
methyl-O-methylbenzohydroximoyl bromide (4Ze) (788.1 mg,
3.45 mmol) and sodium azide (1.12 g, 17.3 mmol) in DMSO
(31 g). This reaction mixture was stirred with heating at 70 8C for
72 h and worked up as indicated above. The product was purified
by silica gel chromatography, using 10% DCM/hexane as eluant.
The product was obtained as a clear, slightly yellow liquid
(0.490 g, 2.58 mmol, 75%).
1H-NMR (300 MHz, CDCl3): d 2.38 (s, 3H, CH3); 4.00 (s, 3H, OCH3);
7.18 (d, J 8.2 Hz, 2H, ArH); 7.63 (d, J 8.2 Hz, 2H, ArH).
13C-NMR (CDCl3): d 21.36, 62.62, 126.15, 127.53, 129.01, 140.38,
142.99.
IR data (neat, cmꢀ1): 2201, 2147, 2096, 1612, 1592, 1463, 1322,
1058.
Preparation of 4-chloro-O-isopropylbenzohydroximoyl azide
(1Zi)
This compound was prepared by the above procedure, using 4-
chloro-O-isopropylbenzohydroximoyl bromide (4Zi) (167 mg,
0.67 mmol) and sodium azide (0.241 g, 3.7 mmol) in DMSO
(5.3 g). This reaction mixture was heated to 70 8C with stirring for
48 h and worked up as indicated above to obtain 146 mg crude
product. The product was purified by radial chromatography
using hexane as eluant. The product was obtained as a white
crystalline substance (0.0984 g, 0.41 mmol, 61%).
1H-NMR (300 MHz, CDCl3): d 1.35 (d, J 6.1 Hz, 6H, CH3); 4.43 (m, J
6.1 Hz, 1H, CH); 7.32 (d, J 8.4 Hz, 2H, ArH); 7.70 (d, J 8.4 Hz, 2H, ArH).
13C-NMR (CDCl3): d 21.18, 76.38, 127.10, 128.23, 129.18, 135.73,
141.00.
IR data (neat, cmꢀ1): 2210, 2158, 2105, 1596, 1591, 1492, 1325,
988.
Anal. Calcd. for C9H10N4O: C, 56.83; H, 5.30; N, 29.46; Found: C,
56.96; H, 5.46; N, 29.12.
Preparation of 4-methoxy-O-methylbenzohydroximoyl
azide (1Zf)
Anal. Calcd. for C10H11ClN4O: C, 50.32; H, 4.65; N, 23.47; Cl,
14.85, Found: C, 50.59; H, 4.62; N, 23.16; Cl, 14.89.
This compound was prepared by the above procedure, using 4-
methoxy-O-methylbenzohydroximoyl bromide (4Zf) (400 mg,
1.64 mmol) and sodium azide (0.50 g, 7.7 mmol) in DMSO
(15 g). This reaction mixture was heated to 70 8C with stirring
for 72 h and worked up as indicated above. The product was
purified by radial chromatography (silica gel plate), using 10%
dichloromethane /hexane as eluant. The product was obtained as
a clear, slightly yellow liquid (0.142 g, 0.69 mmol, 42%).
Preparation of 1-methoxy-3-phenylurea (2d)
This compound has been made previously by reacting O-
methylhydroxylamine with phenyl isocyanate,[31] and we report
here an alternate route of preparation of this compound and
complete spectroscopic data. This experimental procedure was
used to independently synthesize this compound for full
characterization and for use in establishing HPLC correction
factors.
1H-NMR (300 MHz, CDCl3): d 3.83 (s, 3H, CH3); 3.98 (s, 3H, CH3);
6.88 (d, J 7.9 Hz, 2H, ArH); 7.67 (d, J 7.9 Hz, 2H, ArH).
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Copyright ß 2009 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2010, 23 227–237

N-ALKOXYBENZIMIDOYL AZIDES IN ELECTROPHILIC MEDIA
A solution of O-methylbenzohydroximoyl azide (1Zd) (494 mg,
2.80 mmol) in trifluoroacetic acid (10 g) was placed in a screw-top
sealed reaction flask. The reaction was allowed to stir at room
temperature for 30 min. The reaction mixture was taken up in
60 ml of dichloromethane, washed with water (3 ꢂ 50 ml), and
dried over anhydrous magnesium sulfate. The dichloromethane
was removed by rotary evaporation. The crude product was
recrystallized, using hexane and ethyl acetate to yield white
crystals (242 mg, 1.46 mmol, 52%).
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[11] J. E. Johnson, D. D. Dolliver, L. Yu, D. C. Canseco, M. A. McAllister, J. E.
Rowe, J. Org. Chem. 2004, 69, 2741.
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Chagnard, J. E. Johnson, D. C. Canseco, F. R. Fronczek, C. D. Bryan, J. R.
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[13] I. V. Tselinskii, S. F. Mel’nikova, T. V. Romanova, Russ. J. Org. Chem.
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Int. Ed. 2002, 41, 2596.
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Rowe, J. Org. Chem. 2004, 69, 2741.
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[27] G3MP2: L. A. Curtiss, P. C. Redfern, K. Raghavachari, V. Rassolov, J. A.
Pople, J. Chem. Phys. 1999, 110, 4703.
[28] GAMESS-UK: Program package GAMESS-UK, M. F. Guest, I. J. Bush, H.
J. J. van Dam, P. Sherwood, J. M. H. Thomas, J. H. van Lenthe, R. W. A.
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version see www.cfs.dl.ac.uk/gamess-uk
[29] ACES II: Program package ACES II, J.F. Stanton, J. Gauss, J.D. Watts, P.G.
Szalay, R.J. Bartlett, with contributions from A.A. Auer, D.E. Bernholdt,
O. Christiansen, M.E. Harding, M. Heckert, O. Heun, C. Huber, D.
1H-NMR (300 MHz, CDCl3): d 3.79 (s, 3H, OCH3), 7.10–7.50 (m, 5H,
ArH), 7.60 (br s, 1H, NH), 7.85 (br s, 1H, NH).
13C-NMR (CDCl3): d 64.64, 119.62, 123.93, 129.02, 137.10,
156.89.
IR (Nujol mull, cmꢀ1): 3306, 3213, 1652, 1594, 1532, 1465, 1449,
1377, 1237, 1098.
Preparation of 1-methoxy-5-phenyl-1H-tetrazole (3d)
A solution of O-methylbenzohydroximoyl azide (1Zd) (378 mg,
2.15 mmol) and acetyl chloride (110 mg, 13.9 mmol) in chloroform
(23 ml) was placed in a round bottom flask and sealed with a glass
stopper. The reaction was allowed to stir at room temperature for
24 h. The reaction mixture was then washed with saturated
sodium bicarbonate solution (3 ꢂ 10 ml), dried over anhydrous
magnesium sulfate, and the solvent was removed by rotatory
evaporation. The crude product was purified by microdistillation,
using a cold finger apparatus. The purified product was a clear
liquid (273 mg, 1.55 mmol, 72.2%).
1H-NMR (300 MHz, CDCl3): d 4.31 (s, 3H, OCH3), 7.53–7.60 (m, 3H,
ArH), 8.09–8.13 (m, 2H, ArH).
13C-NMR (CDCl3): d 67.80, 121.91,127.64, 129.20, 131.85, 145.95.
IR (neat, cmꢀ1): 3065, 2950, 1608, 1540, 1473, 1462, 1278, 1245,
1103, 955.
Anal. Calcd. for C8H8N4O: C, 54.54; H, 4.58; N, 31.80 Found: C,
54.65; H, 4.70; N, 31.54.
´
Jonsson, J. Juselius, W.J. Lauderdale, T. Metzroth, C. Michauk, D.P.
O’Neill, D.R. Price, K. Ruud, F. Schiffmann, M.E. Varner, J. Vazquez and
´
Acknowledgements
¨
the integral packages MOLECULE (J. Almlof and P.R. Taylor), PROPS
(P.R. Taylor), and ABACUS (T. Helgaker, H.J. Aa. Jensen, P. Jørgensen,
and J. Olsen). For the current version see www.aces2.de.
The authors acknowledge the financial support for this research
from the American Chemical Society Petroleum Research Fund
Grants (PRF #44412-GB1and PRF#47344-GB6) and Louisiana
Board of Regents Grants [LEQSF(2006-09)-RD-A-25 and
LEQSF(2007-12)-ENH-PKSFI-PES-06].
[30] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman, J. A. Montgomery, ,Jr T. Vreven, K. N. Kudin, J. C. Burant,
J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi,
G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O.
Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V.
Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O.
Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K.
Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski,
S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D.
Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G.
Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P.
Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C.
Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian03: Program
package Gaussian 03, Gaussian, Inc., Wallingford CT, (2004).
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J. Phys. Org. Chem. 2010, 23 227–237
Copyright ß 2009 John Wiley & Sons, Ltd.
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