Aminolysis of phenyl N-phenylcarbamate via an isocyanate intermediate: Theory and experiment

Article abstract of DOI:10.1021/jo4002068

A comprehensive examination of the mechanism of the uncatalyzed and base-catalyzed aminolysis of phenyl N-phenylcarbamate by theoretical quantum mechanical methods at M06-2X/6-311+G(2d,2p) and B3LYP-D3/6-31G(d,p) levels, combined with an IR spectroscopic study of the reaction, was carried out. Three alternative reaction channels were theoretically characterized: concerted, stepwise via a tetrahedral intermediate, and stepwise involving an isocyanate intermediate. In contrast to dominating views, the theoretical results revealed that the reaction pathway through the isocyanate intermediate (E1cB) is energetically favored. These conclusions were supported by an IR spectroscopic investigation of the interactions of phenyl N-phenylcarbamate with several amines possessing varying basicities and nucleophilicities: n-butylamine, diethylamine, triethylamine, N-methylpyrrolidine, and trimethylamine. The reactivity of substituted phenyl N-phenylcarbamates in the aminolysis reaction was rationalized using theoretical and experimental reactivity indexes: electrostatic potential at nuclei (EPN), Hirshfeld and NBO atomic charges, and Hammett constants. The obtained quantitative relationships between these property descriptors and experimental kinetic constants reported in the literature emphasize the usefulness of theoretical parameters (EPN, atomic charges) in characterizing chemical reactivity.

Full text of DOI:10.1021/jo4002068

Article
pubs.acs.org/joc
Aminolysis of Phenyl N‑Phenylcarbamate via an Isocyanate
Intermediate: Theory and Experiment
Sonia Ilieva,* Didi Nalbantova, Boriana Hadjieva, and Boris Galabov*
Department of Chemistry and Pharmacy, University of Sofia, Sofia 1164, Bulgaria
S
* Supporting Information
ABSTRACT: A comprehensive examination of the mecha-
nism of the uncatalyzed and base-catalyzed aminolysis of
phenyl N-phenylcarbamate by theoretical quantum mechanical
methods at M06-2X/6-311+G(2d,2p) and B3LYP-D3/6-
31G(d,p) levels, combined with an IR spectroscopic study of
the reaction, was carried out. Three alternative reaction
channels were theoretically characterized: concerted, stepwise
via a tetrahedral intermediate, and stepwise involving an
isocyanate intermediate. In contrast to dominating views, the
theoretical results revealed that the reaction pathway through
the isocyanate intermediate (E1cB) is energetically favored.
These conclusions were supported by an IR spectroscopic
investigation of the interactions of phenyl N-phenylcarbamate with several amines possessing varying basicities and
nucleophilicities: n-butylamine, diethylamine, triethylamine, N-methylpyrrolidine, and trimethylamine. The reactivity of
substituted phenyl N-phenylcarbamates in the aminolysis reaction was rationalized using theoretical and experimental reactivity
indexes: electrostatic potential at nuclei (EPN), Hirshfeld and NBO atomic charges, and Hammett constants. The obtained
quantitative relationships between these property descriptors and experimental kinetic constants reported in the literature
emphasize the usefulness of theoretical parameters (EPN, atomic charges) in characterizing chemical reactivity.
the carbonyl carbon, while electron-donating aryl substituents
favor an elimination−addition mechanism (E1cB) via an
isocyanate intermediate. In an earlier work, Hegarthy and
Frost24d established for a series of aryl N-arylcarbamates that
the hydrolysis proceeds along the E1cB mechanism via
isocyanate. A shift to the BAC2 mechanism was found, however,
for carbamates containing poorer leaving (alkoxy) groups.
These authors also established that the reaction is base
catalyzed. Thus, the literature data reveal two alternative
pathways for the alkaline hydrolysis as a function of the nature
of aromatic substituents and the structure of the leaving group.
On the basis of kinetic studies, the currently accepted
mechanism for the aminolysis of aryl N-phenylcarbamates
assumes an analogous stepwise pathway, involving an initial
attack at the ester moiety by the amine nucleophile leading to
INTRODUCTION
■
Alternative interpretations of the mechanism of carbamate
aminolysis can be found in the literature.1−8 The carbamates
possess structural similarity with esters and carbonates.
Nucleophilic attack at the CO−O ester group has been
discussed as a key feature in the mechanisms of aminolysis of all
three classes of compounds.2−22 Depending on the structure of
the leaving group, a stepwise mechanism via a tetrahedral
intermediate or concerted pathway have been proposed for the
ester aminolysis.9−22 This reaction has been the focus of
numerous studies because it is the key process in the formation
of peptide bonds in living organisms.19,23 Carbamate derivatives
form a major class of acetylcholinesterase (AChE) and
butyrylcholinesterase (BChE) inhibitors.21,22 The inhibitory
interaction between carbamates and cholinesterases is em-
ployed as a basis for target-oriented drug design. The detailed
knowledge of the mechanisms of solvolytic reactions of
carbamates is of substantial interest because of their significance
in research on the mechanisms of AChE and BChE inhibition.
The alkaline hydrolysis of carbamates has been intensively
studied.24 The influence of substituents and leaving group
structure on the reaction mechanism has also been explor-
ed.24d,e Bergon and Calmon24e reported for the alkaline
hydrolysis of methyl carbanilates that a mechanistic shift
takes place depending on the nature of aromatic substituents.
Electron-withdrawing groups in the N-aryl ring favor an
addition−elimination route (BAC2) with nucleophilic attack at
the formation of a tetrahedral intermediate (Scheme 1).2−8
A
concerted mechanism is reported by Lee et al.4 for the
aminolysis of aryl N-phenylthiocarbamates. However, in an
early work Menger and Glass1 discussed two alternatives (E2
and E1cB) for the aminolysis of aryl N-phenylcarbamate, both
involving the formation of an isocyanate intermediate in the key
reaction stage. In 1986 Shawali et al.2 reinvestigated the kinetics
of aminolysis of mono- and disubstituted phenyl N-phenyl-
carbamates. The authors also conducted crossover synthetic
Received: January 30, 2013
© XXXX American Chemical Society
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Scheme 1. Possible Mechanisms for the Aminolysis of Phenyl N-phenylcarbamate: Concerted, Stepwise (BAC2), and E1cB
Mechanisms through Isocyanate
package.27 The geometry parameters of the reactant complexes,
experiments and IR spectroscopic analysis of reaction mixtures
intermediates, transition states, and products of the reaction studied
were fully optimized in the gas phase at the DFT level with B3LYP28
and M06-2X29 functionals in combination with 6-31G(d,p) and 6-
311+G(2d,2p)30 basis sets. The hybrid meta exchange-correlation
functional M06-2X has been systematically tested by comparing its
performance to other functionals for a variety of databases and is
recommended for applications involving main-group thermochemistry,
kinetics, and noncovalent interactions.29 The basis set employed in the
present research is of similar quality as some of the basis sets used in
assessing the performance of the M06-2X functional.29b The DFT-D3
dispersion corrections introduced by Grimme et al.31,32 were applied
to the energies of all B3LYP optimized structures. The attacking amine
nucleophile is modeled with an ammonia molecule. Each stationary
point along the reaction path was characterized as a minimum or as a
first-order saddle point with one imaginary frequency (for the
transition states) by frequency computations at the same level. The
zero-point vibrational energies (ZPE) and Gibbs free energies for all
structures were determined. All transition states were proved by
applying the intrinsic reaction coordinate (IRC)33 methodology.
Solvent effects were simulated with the self-consistent reaction field
(SCRF) method based on the integral equation formalism of the
polarized continuum model (IEFPCM).34 The standard dielectric
constant for the n-butylamine reaction medium, implemented in the
Gaussian program, was employed. The catalytic effect of a second
ammonia molecule was also considered. Thus, the aminolysis reaction
was modeled as uncatalyzed and base-catalyzed processes. Full
optimization of all structures in n-butylamine solution was performed.
The following reactivity indexes for the reaction center atoms were
computed at the M06-2X/6-311+G(2d,2p) level: electrostatic
potential at nuclei (EPN; VN, VH),35,36 natural bond orbital (NBO)
charges,37 and Hirshfeld atomic charges.38 The Hammett σ
constants39,40 were also applied in characterizing reactivity.
to examine the possibility for a E1cB mechanism (via
isocyanate) of the reaction. The experiments did not provide
evidence for the formation of an isocyanate intermediate. These
results led the authors to reject the possibility of a E1cB
mechanism. Their results were in agreement with earlier studies
of Furuya et al.25,26 The conclusions of a later kinetic study of
Lee et al.3 were also in accord with these views on the
mechanistic pathway for the aminolysis of aryl N-arylcarba-
mates. Parallel with the kinetic studies, Lee et al.3 analyzed the
2275−2240 cm−1 region in the infrared spectra of reaction
mixtures but did not find evidence for the formation of an
isocyanate intermediate.
In the present work we apply theoretical quantum
mechanical methods to model the aminolysis of phenyl N-
phenylcarbamate for molecules in isolation (gas phase) and in
the reactant amine medium. In contrast to the dominating
views, our theoretical results provide strong evidence that the
most favorable mechanism of the reaction is E1cB, involving
the intermediary formation of phenyl isocyanate. The energy
profile of the reaction along the isocyanate pathway is 7 kcal/
mol lower that the alternative routes through stepwise or
concerted mechanisms with nucleophile attack at the ester
moiety. Our theoretical conclusions were supported by
specially designed IR spectroscopic experiments on the
reactions of phenyl N-phenylcarbamate with amines with
similar basicity: n-butylamine, diethylamine, and triethylamine.
The experiments provided strong evidence for the formation of
phenyl isocyanate as an intermediate. Theoretical computations
and correlations with the experimental kinetic data of Shawali
et al.2 also revealed the nature of intramolecular charge
rearrangements determining the reactivity of aryl N-phenyl-
carbamates for the reaction examined.
The electrostatic potential at a nucleus Y can be expressed as
follows (in atomic units, boldface type denotes vector quantities):36
ZA
ρ(r)
|r − RY|
EXPERIMENTAL SECTION
VY ≡ V(RY) =
−
dr
∑
∫
■
|RA − RY|
(1)
A(≠Y)
Spectroscopy Experiments. The reactions between phenyl N-
phenylcarbamate and four amines (n-butylamine, diethylamine,
triethylamine, N-methylpyrrolidine) were followed by FTIR spectros-
copy. IR spectra of reaction mixtures of the reactant carbamate and
excess amines (1:6) in CCl4 were recorded for several hours at room
temperature and at 76 °C (boiling temperature of CCl4) in a 0.28 mm
NaCl cell. The interaction of phenyl N-phenylcarbamate in CCl4 with
trimethylamine (in a 1:1 solution in tetrahydrofuran and carbon
tetrachloride) was also followed by IR spectroscopy.
ZA is the nuclear charge of atom A with position vector RA, and ρ(r) is
the electron density at point r. Equation 1 contains a summation over
all atomic nuclei, treated as positive point charges, as well as
integration over the continuous distribution of the electronic charge.
Unlike atomic charges, which depend strongly on their definition and
additional approximations, the EPN values are rigorously defined
quantum mechanical quantities. Because of the 1/r dependence of the
electrostatic potential, a greater contribution to VY comes from the
local positive and negative charges around the respective atomic sites.
Computational Methods. Density functional theory computa-
tions were conducted by employing the Gaussian 09 program
B
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Figure 1. IEFPCM/M06-2X/6-311+G(2d,2p) optimized structures along the concerted aminolysis of phenyl N-phenylcarbamate.
from the concerted transition state CTS lead to the prereactive
complex CCTS between the reactants.
RESULTS AND DISCUSSION
■
As already pointed out, different reaction channels for the
aminolysis of aryl N-arylcarbamates are possible. In this work
we modeled theoretically the reaction pathways along the three
mechanisms discussed in the literature: concerted and
addition−elimination (BAC2) of the ester moiety as well as
elimination−addition (E1cB) mechanism through an isocya-
nate intermediate. These three possibilities are illustrated in
Scheme 1. Earlier computational results on the aminolysis of
esters17,18 showed that the concerted pathway involves an initial
nucleophilic attack along the C−O ester bond, while the
stepwise addition−elimination route begins with attack at the
carbonyl CO bond. In the initial stage of the elimination−
addition E1cB mechanism the nucleophile deprotonates the
reactant carbamate, resulting in the formation of a phenyl
isocyanate intermediate.
Stepwise Addition−Elimination (BAC2) Mechanism. The
stepwise addition−elimination pathway for the aminolysis of
phenyl N-phenylcarbamate involves two main stages. Again,
this potential reaction channel has been established to
dominate the aminolysis of certain esters.17 The principal
transition state structures along the addition−elimination
pathway of phenyl N-phenylcarbamate aminolysis are shown
in Figure 2. The first stage of the reaction is the addition of an
As already mentioned, theoretical computations (full
optimization and frequency calculations) of all critical
structures along the three reaction pathways (Scheme 1) have
been performed at two levels of theoryB3LYP-D3/6-
31G(d,p) and M06-2X/6-311+G(2d,2p)in both the gas
phase and simulated n-butylamine solution. The obtained
theoretical results are presented in detail in Tables S1−S4 of
the Supporting Information. The IEFPCM/M06-2X/6-311+G-
(2d,2p) results for the reaction profiles are further discussed.
The two theoretical methods employed provide similar energy
profiles of the studied processes.
Reaction Channels for the Aminolysis of Phenyl N-
Phenylcarbamate. Concerted Mechanism. This potential
reaction channel for the aminolysis of carbamates has been
studied in the case of ester aminolysis.17 As was mentioned, the
mechanistic pathway involves an attack of the nucleophile along
the ester C−O single bond, leading to the formation of a
transition state. The optimized structure of the concerted
transition state (CTS) in simulated n-butylamine medium is
shown in Figure 1.
The arrows in the transition state structures indicate the
normal coordinate of the imaginary frequency. The normal
mode vector of the imaginary frequency involves simultaneous
cleavage of the ester C−O bond and creation of the new urea
C−N bond. In CTS the distance between the carbonyl carbon
and the ester oxygen atoms is much longer (2.042 Å at
IEFPCM/M06-2X/6-311+G(2d,2p)) than the respective C−O
ester bond in the reactant phenyl N-phenylcarbamate (1.364
Å). The new C−N bond is close to formation with a length of
1.538 Å in CTS in comparison to 1.395 Å in the product N,N′-
diphenylurea. The IRC computations in the backward direction
Figure 2. IEFPCM/M06-2X/6-311+G(2d,2p) optimized structures
along the stepwise mechanism via a tetrahedral intermediate for the
aminolysis of phenyl N-phenylcarbamate.
N−H bond from the nucleophile to the carbonyl double bond
and formation of a tetrahedral intermediate (transition state
TS1, free energy barrier of 54.03 kcal/mol; Table 1). The main
vectors of the imaginary vibrational frequency for TS1 are
shown in Figure 2 and correspond to the C−N bond formation
and a proton transfer from the nucleophile NH3 to the carbonyl
oxygen, thus maintaining the neutrality of the forming
C
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Table 1. M06-2X/6-311+G(2d,2p) Computed Relative to
Reactant Energies in kcal/mol for the Transition State
Structures along the Uncatalyzed Concerted, Stepwise
(BAC2), and Isocyanate (E1cB) Mechanisms in the Gas
Phase and in Simulated n-Butylamine Medium
gas phase
in n-butylamine
structure
ΔE
ΔG
ΔE
ΔG
CTS
39.77
44.32
14.11
26.97
25.19
32.06
49.54
55.31
25.68
37.86
33.95
40.66
33.59
44.37
15.84
25.75
22.17
33.58
43.31
54.03
27.25
35.58
30.02
43.19
TS1
TSrot
TS2
IsoTS1
IsoTS2
tetrahedral intermediate. At the same time a change of the
hybridization of the carbonyl carbon from sp2 to sp3 takes place.
The CO bond is extended from 1.203 Å in the reactant to
1.329 Å in TS1. The new C−N bond has a length of 1.569 Å in
the TS1 transition state. IRC computations from TS1 in the
forward direction lead to the tetrahedral intermediate I1.
In the second stage the tetrahedral intermediate converts to
the products phenylurea and phenol via transition state TS2
(free energy barrier of 35.58 kcal/mol; Table 1). Breaking of
the C−O ester single bond and simultaneous restoration of the
CO bond takes place following a proton transfer between the
two oxygen atoms. The process of breaking/restoring occurs
after a proper space orientation of the O−H hydrogen atom
through a rotation that facilitates the proton-transfer process.
The rotation through TSrot (Figure 2) involves a free energy
barrier of 27.25 kcal/mol (Table 1).
E1cB Mechanism through Isocyanate. The third theoret-
ically modeled reaction channel for the aminolysis of phenyl N-
phenylcarbamate is the E1cB pathway, consisting of two
subsequent reactions with the intermediary formation of phenyl
isocyanate, suggested first by Menger and Glass.1 The
optimized structures of the stationary points along the
isocyanate pathway are shown in Figure 3. The first step of
the reaction is the formation of phenyl isocyanate and phenol.
The attacking NH3 nucleophile deprotonates the carbamate
nitrogen, while the C−O ester single bond breaks. A
simultaneous proton transfer from the carbamate nitrogen
toward the ester oxygen mediated by the nucleophile NH3
takes place to form the phenol molecule (Figure 3). These
processes are reflected in the main vectors of the imaginary
vibrational frequency of the first transition state IsoTS1 (free
energy barrier of 30.02 kcal/mol; Table 1), shown in Figure 3.
Thus, one of the final products of the aminolysisphenolis
formed during this first process of the E1cB pathway.
The second step of the process involves the addition of
ammonia to the nitrogen−carbon double bond of the phenyl
isocyanate leading to the product phenylurea through the
transition state IsoTS2. In this transition state the new C−N
urea bond is created. The main component of the transition
vector in IsoTS2 corresponds to a proton transfer between the
two nitrogen atoms (Figure 3).
The relative energies of the structures along the concerted,
addition−elimination stepwise, and isocyanate pathways com-
puted at M06-2X/6-311+G(2d,2p) are summarized in Table 1.
It can be seen that the evaluated free energy reaction barrier in
modeled n-butylamine medium for the isocyanate mechanism is
more favorable in comparison to the concerted and addition−
elimination stepwise pathways, respectively.
Figure 3. IEFPCM/M06-2X/6-311+G(2d,2p) optimized structures
along the two-stage mechanism for the aminolysis of phenyl N-
phenylcarbamate proceeding through formation of isocyanate in the
first step.
An intriguing problem emerges comparing computed
energies of the two transition states along the isocyanate path
(Table 1). The transition state IsoTS2 has higher energy with
regard to IsoTS1. It is known, however, that isocyanates are
highly reactive species. We followed experimentally the reaction
between phenyl isocyanate and excess n-butylamine (1:3) in
CCl4 at room temperature. The interaction is very fast, and the
isocyanate band (2260 cm−1) cannot be registered by IR
spectroscopy (Figure S1 in the Supporting Information). It is
expected, therefore, that the first step of the aminolysis
formation of the phenyl isocyanateshould be the rate-
determining stage. In order to resolve the discrepancy and take
into account that the experimental aminolysis is carried out in
the liquid phase with excess amine, we considered the general
base catalysis of the process. This catalytic process is modeled
by explicitly considering the participation of a second
nucleophile molecule in the three reaction channels.
General Base Catalysis. Under experimental conditions the
ester aminolysis reaction can take place as a catalyzed process
with a catalytic role of the nucleophile amine.10 The potential
energy surfaces for the general base-catalyzed aminolysis of
phenyl N-phenylcarbamate along the three pathways consid-
ered was searched by performing full optimization of the
stationary points at the M06-2X/6-311+G(2d,2p) level of
theory in the gas phase and in modeled n-butylamine solution
(IFPCM). The estimated energies of the process via the three
routes are given in Table 2 and visualized in Figure 4.
Transition state structures for the concerted, stepwise
addition−elimination, and isocyanate pathways of the catalyzed
aminolysis of phenyl N-phenylcarbamate are presented in
Figure 5.
The catalytic role of the second ammonia molecule mostly
affects the proton-transfer processes. The catalyst facilitates the
hydrogen transfer by forming proton transfer chains, thus
lowering the energy barriers. This deduction is supported by
the present computational results for the directions of the
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Table 2. M06-2X/6-311+G(2d,2p) Relative to Reactant
Energies in kcal/mol for the Transition State Structures
along the Catalyzed Concerted, Stepwise Addition−
Elimination, and Isocyanate Mechanisms in the Gas Phase
and in n-Butylamine
gas phase
in n-butylamine
structure
ΔE
ΔG
ΔE
ΔG
CTSCAT
22.32
21.01
11.82
15.07
9.88
43.01
42.31
32.20
32.87
28.73
21.44
19.75
12.97
16.49
5.99
41.57
40.77
33.20
33.85
23.01
19.04
TS1CAT
TS2CAT
IsoTS1CAT
IsoTS2CAT
IsoTS2CAT
a
*
−0.13
a
IsoTS2CAT* energies are relative to isolated PhNCO and 2NH3.
Figure 4. Energy diagram for the catalyzed aminolysis of phenyl N-
phenylcarbamate along the concerted, addition−elimination stepwise,
and isocyanate pathways from IEFPCM/M06-2X/6-311+G(2d,2p)
computations.
Figure 5. IEFPCM/M06-2X/6-311+G(2d,2p) optimized transition
states for the concerted, stepwise (BAC2), and isocyanate (E1cB)
pathways for the catalyzed aminolysis of phenyl N-phenylcarbamate.
transition vectors characterizing the CTSCAT, TS1CAT, TS2CAT
,
IsoTS1CAT, and IsoTS2CAT structures. The transition state
IsoTS2CAT can be realized with different hydrogen bonds
between phenyl isocyanate, ammonia and phenol. The lowest
energy transition state structure with a CO···H−OPh
hydrogen bond is presented in Figure 5 and is taken into
account when reading energy barriers. Under the reaction
conditions of excess NH3 nucleophile in the reaction medium,
the phenol product of the first reaction stage converts into
phenolate. Thus, the next process can be regarded as direct
addition of the nucleophile to the isocyanate via the transition
state IsoTS2CAT* (Figure 5). Again, this is a low-energy
transition state (Table 2; ΔE = −0.13 kcal/mol, ΔG = 19.04
kcal/mol, calculated relative to isolated PhNCO and two NH3
molecules) and the overall activation energy is determined by
the isocyanate formation stage.
nitrophenyl N-phenylcarbamate is at least 104 faster than the
aminolysis of p-nitrophenyl N-methyl-N-phenylcarbamate,
where isocyanate mechanism is unfeasible since N−H is
replaced by N−CH3. The energetics of the modeled reaction
pathways for the aminolysis of these two carbamates along the
BAC2 mechanism are compared in Table S5 (Supporting
Information). The IEFPCM/M06-2X/6-311+G(2d,2p) calcu-
lated free energy barrier for the catalyzed aminolysis of phenyl
N-methyl-N-phenylcarbamate through a stepwise BAC2 mech-
anism in n-butylamine is 42.06 kcal/mol. The respective energy
barrier for the aminolysis of phenyl N-phenylcarbamate is 40.77
kcal/mol (Table 2). The results reveal that the rate-controlling
barriers for these processes differ by only 1.3 kcal/mol. It is,
therefore, unlikely that the aminolysis of phenyl N-phenyl-
carbamate would proceed along a BAC2 mechanism, since the
reaction rates for the two processes considered would not differ
substantially, in contrast to the kinetic results of Menger and
Glass.1 The estimated barrier for the reaction proceeding along
the E1cB mechanism via isocyanate is distinctly lower at 33.85
kcal/mol (Table 2).
Considerable lowering of the second transition state energy
for the general base-catalyzed aminolysis along the isocyanate
pathway was obtained in comparison to the uncatalyzed process
(Table 2). Thus, the rate-determining stage of the catalyzed
process is the formation of phenyl isocyanatethe first step
through IsoTS1CAT. The obtained theoretical results (Table 2,
Figure 4) reveal that the free energy barrier of the isocyanate
pathway is distinctly lower (by 7−7.8 kcal/mol) than the
activation barriers of the two alternative reaction channels for
the aminolysis of phenyl N-phenylcarbamate. This conclusion is
strongly supported by the kinetic experiments of Menger and
Glass.1 These authors found that the aminolysis of p-
The second stage of the reaction along the E1cB mechanism
may follow two alternative routes, since nucleophilic attack is
possible along the CN and CO isocyanate bonds. These
two possibilities were theoretically explored for the base-
catalyzed processes in modeled n-butylamine medium. The
results are presented in Table S6 (Supporting Information).
The conversion of the phenyl isocyanate in phenylurea through
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Figure 6. IR spectra of the reaction mixture of phenyl N-phenylcarbamate and excess n-butylamine (A) and diethylamine (B) in carbon tetrachloride
solution taken for several hours at 76 °C (boiling temperature of CCl4).
Figure 7. (A) Formation of phenyl isocyanate from phenyl N-phenylcarbamate and triethylamine at 76 °C in CCl4. (B) Gradual disappearance of the
NCO band at room temperature.
the attack of the nucleophile along the CO isocyanate bond
takes place in two steps with formation of an intermediate: the
first step is the attack itself, followed by a rotation of the OH
group for obtaining the proper orientation for the next proton
transfer resulting in reaction products. The optimized transition
state structures are given in Figure S2 (Supporting
Information). The theoretical results (Table S6) showed that
the nucleophilic attack along the CN isocyanate bond is
energetically favored by 2.3 kcal/mol. This conclusion is also
supported by the comparative study of Muchall and
coauthors,41 who established that isocyanates hydrolyze
predominantly along the CN bond. These authors found
that the modeling of two explicit nucleophile molecules is
sufficient for a correct description of the process. Two explicit
ammonia molecules are taken into account in our study for the
base-catalyzed aminolysis.
IR spectra of reaction mixtures (Figure 6A) taken for several
hours at room temperature and at 76 °C (boiling temperature
of CCl4) did not reveal the formation of an isocyanate group
(in the 2280−2240 cm−1 region), in accord with the earlier
findings of Shawali et al.2 and Lee et al.3 Such a result is not
surprising, however, in view of the high reactivity of the
isocyanate in the reaction with n-butylamine. Therefore, the
detection of a stable intermediate for this process is unlikely, as
confirmed experimentally. Figure 6A shows the gradual
reduction of intensity of the carbamate CO stretching
band (at 1760 cm−1) and the rising intensity of the product
urea CO stretching at 1654 cm−1. The reaction of phenyl N-
phenylcarbamate with the more basic diethylamine (pKa =
11.02)42 proceeds in a similar way (Figure 6B). No isocyanate
band in the 2280−2240 cm−1 spectral region is found during
the process.
Experiments. As already discussed, Menger and Glass1
proposed an E1cB mechanism through isocyanate for the
aminolysis of p-nitrophenyl N-phenylcarbamate with diethyl-
amine in toluene. Shawali et al.,2 however, excluded the
presence of an isocyanate intermediate in the aminolysis of
phenyl N-phenylcarbamate on the basis of IR spectroscopic
experiments.
To analyze further the interaction between an amine and the
carbamate, we conducted analogous experiments employing
triethylamine as a nucleophile. Triethylamine (pKa = 10.75)42
has a basicity similar to that of n-butylamine and diethylamine.
At room temperature, no interaction between the two reactants
in CCl4 solution could be observed in the IR spectra of reaction
mixtures, recorded for several hours. When the experiment was
conducted at 76 °C, however, the formation of isocyanate was
clearly identified in the IR spectra (Figure 7A) with the
appearance of a band with the typical frequency for the phenyl
isocyanate NCO group at 2261 cm−1. A gradual increase
To verify our theoretical results and the above consid-
erations, we conducted an IR spectroscopic study on the
reaction of phenyl N-phenylcarbamate with n-butylamine (pKa
= 10.77)42 in carbon tetrachloride medium. The analysis of the
F
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Article
Figure 8. Formation of phenyl isocyanate from phenyl N-phenylcarbamate and N-methylpyrrolidine (A) and trimethylamine (B) at 76 °C in CCl4.
Scheme 2. Arylcarbamates Considered
of the isocyanate concentration over several hours was
observed. The accumulation of isocyanate is, evidently, a result
of the much slower reverse reaction of PhNCO with the
formed phenol to the initial phenyl N-phenylcarbamate. When
the reaction mixture was left at room temperature for several
hours, the intensity of the isocyanate band gradually decreased
until disappearing (Figure 7B). Evidently, an equilibrium
between phenyl N-phenylcarbamate and phenyl isocyanate is
the reason for these temperature-dependent shifts. The
important conclusion from these experiments is that an
amine with basicity similar to that of n-butylamine and
diethylamine is able to transform the carbamate into a stable
isocyanate as result of a hydrogen extraction process. It may,
therefore, be expected that n-butylamine and diethylamine
should also be able to extract hydrogen from the carbamate and
produce isocyanate in the principal reaction studied. The
elimination of hydrogen from the −NH−CO−O− grouping
may be considered as an example of an acid−base interaction
and, thus, be governed mostly by the basic properties of the
amine.
In general, however, the nucleophilicity of the amines may
also affect the mechanism of the aminolysis. As shown for the
hydrolysis reaction,24 a shift of mechanistic routes may take
place, depending on the leaving group and aryl substituents. It
may be argued that amines possessing higher nucleophilicity
will more readily attack the carbonyl group of the carbamate,
thus favoring the BAC2 route. The three amines considered so
far (n-butylamine, diethylamine, and triethylamine) possess
quite similar basicities, as discussed earlier. However, their
nucleophilic parameters (Mayr nucleophilcity values, N)43
differ in the following order: n-butylamine, 15.27; diethylamine,
15.10; triethylamine, 17.10.
amine with phenyl N-phenylcarbamate. N-Methylpyrrolidine
possesses distinctly higher nucleophilicity (N = 20.59)43 but
lower basicity (pKa = 10.32)42 in comparison to the other
amines considered so far. In spite of its much higher
nucleophilicity and lower basicity, N-methylpyrrolidine is also
able to abstract a proton from the carbamate group, resulting in
the formation of phenyl isocyanate. The NCO band
appears at 2259 cm−1 on heating the reaction mixture at 76 °C
(Figure 8A). We also conducted an analogous experiment with
trimethylamine (a solution of Me3N in tetrahydrofuran was
used). Trimethylamine possesses distinctly lower basicity (pKa
= 9.80)42 but high nucleophilicity (N = 23.05).43 Thus, it offers
good opportunities to test the influence of these properties on
the aminolysis. The experiment was conducted in an open flask
under reflux, containing phenyl N-phenylcarbamate dissolved in
a 1:1 mixture of carbon tetrachloride and a tetrahydrofuran
solution of Me3N. The concentration of trimethylamine varied
with time because of the low boiling temperature and
evaporation. Nevertheless, the formation of a NCO
band in the IR spectra (at 2260 cm−1) was clearly identified,
in spite of the complexity of the solvents and reactants (Figure
8B). It is seen that, despite its low basicity, trimethylamine is
also able to abstract hydrogen from the −NH−CO−O−
moiety and transform the carbamate into isocyanate under the
conditions studied. The nucleophilicity of the amine does not
appear to be of key importance for this hydrogen elimination
process.
The proposed mechanism for the aminolysis of phenyl N-
phenylcarbamate should not be automatically extrapolated to
other carbamate aminolysis processes, since as shown24 for the
alkaline hydrolysis of carbamates, the mechanistic features
depend strongly on the structures of all reactants.
To gain further insights into the effect of amine
nucleophilicity vs basicity, we followed by IR spectroscopy
the interaction between N-methylpyrrolidine and trimethyl-
Reactivity of Substituted Phenyl N-Phenylcarbamates
in the Aminolysis Reaction. The reactivities of substituted
phenyl N-phenylcarbamates in the aminolysis reaction were
G
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Article
a
Table 3. Rate Constants and Reactivity Indexes for the Series of Substituted Phenyl N-Phenylcarbamates (Scheme 2)
Hirshfeld charge (e)
NBO charge (e)
EPN (V)
b
c
c
R1
R2
log k3
qN
qH
qN
qH
ΔVO
ΔVH
σ−
H
H
H
H
H
H
H
H
H
H
−4.60
−4.78
−5.12
−5.34
−3.09
−3.67
−3.55
−1.76
−1.18
−0.08128
−0.08151
−0.08173
−0.08196
−0.07986
−0.08022
−0.08005
−0.07796
−0.07787
0.995
0.13445
0.13426
0.13401
0.13391
0.13552
0.13514
0.13532
0.13714
0.13679
0.984
−0.63998
−0.64016
−0.64042
−0.64082
−0.63823
−0.63849
−0.63822
−0.63591
−0.63542
0.995
0.41056
0.41044
0.41024
0.41017
0.41156
0.41118
0.41131
0.41294
0.41264
0.984
0
0
0
3-CH3
4-CH3
4-OCH3
3-Cl
−0.04607
−0.06375
−0.09066
0.22576
0.20628
0.23210
0.49867
0.57927
0.993
−0.03358
−0.04944
−0.06394
0.14304
0.13910
0.15466
0.33781
0.39280
0.992
−0.07
−0.17
−0.26
0.37
4-Cl
0.19
4-Br
0.25
3-NO2
4-NO2
r with log k3
0.71
1.27
0.976
Hirshfeld charge (e)
NBO charge (e)
EPN (V)
b
d
d
R1
R2
log k3
qN
qH
qN
qH
ΔVN
ΔVH
σ−
H
H
−4.60
−4.13
−3.28
−4.70
−0.08128
−0.08107
−0.07700
−0.08334
0.955
0.13445
0.13596
0.13876
0.13373
0.997
−0.63998
0.41056
0.41177
0
0
0
H
4-Cl
−0.64053
−0.64008
−0.63873
0.513
0.23575
0.62797
−0.05641
0.9997
0.19401
0.56172
−0.08938
0.998
0.19
1.27
−0.26
0.983
H
4-NO2
4-OCH3
0.41420
H
0.40983
r with log k3
0.996
Hirshfeld charge (e)
NBO charge (e)
EPN (V)
b
c
c
R1
R2
log k3
qN
qH
qN
qH
ΔVO
ΔVH
4-CH3
4-CH3
4-Cl
4-Cl
−4.56
−4.44
−3.96
−3.80
−3.33
−3.09
−2.73
−1.18
−1.16
−0.08155
−0.08032
−0.08082
−0.08022
−0.08023
−0.07875
−0.07891
−0.07853
−0.07847
0.13554
0.13658
0.13477
0.13462
0.13660
0.13763
0.13714
0.13668
0.13637
−0.64111
−0.64093
−0.63774
−0.63787
−0.63954
−0.63876
−0.63833
−0.63499
0.41145
0.41229
0.41078
0.41084
0.41236
0.41321
0.41293
0.41247
0.41218
0.04887
0.05643
0.13559
0.15836
0.32178
0.33057
0.33865
0.43952
0.53982
0.15806
0.17327
0.06519
0.09352
0.33604
0.36328
0.34562
0.26693
0.33542
3-Cl
4-CH3
3-CH3
4-Cl
4-Cl
4-Cl
4-Cl
3-Cl
3-Cl
4-Cl
3-NO2
4-NO2
4-CH3
4-CH3
−0.63457
a
b
c
The computations were performed at the M06-2X/6-311+G(2d,2p) level. From ref 2. ΔVO refers to the C−O ester oxygen; ΔVO = VO(R) −
VO(H); ΔVH = VH(R) − VH(H). VO(H) and VH(H) are the EPN values at the C−O oxygen and N−H hydrogen nuclei in the unsubstituted
d
derivative. ΔVN = VN(R) − VN(H); ΔVH = VH(R) − VH(H). VH(H) is the EPN value at the N−H hydrogen nucleus in the unsubstituted
derivative.
Figure 9. Plots of third-order experimental rate constants log k3 (taken from ref 2) for the aminolysis of substituted phenyl N-phenylcarbamates with
EPN values for the NH hydrogen atoms (ΔVH = VH(R) − VH(H)]: (A) series 1 and (B) series 2 from Scheme 2.
rationalized with the aid of electronic parameters. The three
series of compounds examined are presented in Scheme 2.
The kinetic constants for the process, reported by Shawali et
al.,2 were employed in analyzing the relationships between
structural variations and reactivity. We examined the effects of
structural changes on several theoretical quantities that
characterize the properties of particular atomic sites of the
functional group involved in the aminolysis process. Three
types of local reactivity descriptors were evaluated: NBO
atomic charges,37 Hirshfeld atomic charges,38 and electrostatic
potentials at the atoms35,36 of the N−H group (VN, VH) in the
reactant carbamates. As already discussed, the rate-controlling
H
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Article
stage of the reaction under general base catalysis along the
energetically favored E1cB pathway involves an attack of the
amine nucleophile at the N−H group, resulting in the
extraction of a hydrogen and formation of isocyanate.
concerted, stepwise addition−elimination via a tetrahedral
intermediate (BAC2), and a two-stage process involving
intermediary formation of phenyl isocyanate (E1cB). The
computational results reveal that the isocyanate route is the most
favorable pathway of the reaction. The free energy barrier of the
catalyzed E1cB process is 7.7 and 6.9 kcal/mol lower than the
activation barriers of the concerted and BAC2 mechanisms. The
theoretical results were confirmed by an IR spectroscopic study
on the reaction of phenyl N-phenylcarbamate with three amines
with similar basicity: n-butylamine, diethylamine, and triethyl-
amine. Two other tertiary amines, N-methylpyrrolidine and
trimethylamine, with distinctly different basicities and nucleo-
philicities in comparison to the other amines considered, were
also tested to assess the influence of amine properties on the
processes investigated. The formation of the NCO band
in the spectra is clearly manifested during the interaction of the
carbamate with triethylamine and N-methylpyrrolidine, thus
proving that isocyanate does indeed form under the attack of a
nucleophile. In spite of its low basicity, trimethylamine also
induces the formation of isocyanate under similar conditions.
The amine basicity rather than nucleophilicity is considered to
dominate the process of hydrogen abstraction and formation of
isocyanate. The Ph−NCO intermediate is not directly
observed during the reactions of phenyl N-phenylcarbamate
with n-butylamine and diethylamine. The ready explanation for
this finding is the high reactivity of the isocyanate in the
interaction with these amines. Thus, fast consumption of the
formed isocyanate does not allow its accumulation and
detection in the infrared spectra. The reactivity of substituted
phenyl N-phenylcarbamates is quantified by applying theoret-
ically derived reactivity indexes (atomic charges and electro-
static potentials at nuclei values) for the atoms of the reaction
center.
The calculated reactivity indexes for the first series of aryl N-
phenylcarbamates and the kinetic data employed2 are
summarized in Table 3. The final column in Table 3 contains
the σ− constants of the respective substituents. As discussed in
the preceding section, the theoretical computations as well as
the supporting experiments revealed that the general base-
catalyzed aminolysis via isocyanate is the favored pathway for
the reaction. Two main factors can be considered in regarding
the possibility for the isocyanate mechanism for the aminolysis
of arylcarbamates with a given amine as nucleophile: (1) the
stability of the leaving group and (2) the acidity of the NH
hydrogen atom in the reactant carbamate. We thus followed the
influence of polar groups in the aromatic ring on the EPN
values and NBO and Hirshfeld atomic charges of the N−H
reaction center in the initial carbamate reactants. As expected,
electron-withdrawing substituents increase the leaving group
ability and favor the interaction between the two reactants.
Inversely, electron-donating substituents, such as CH3 and
OCH3, hamper the interaction with the nucleophile. Since
hydrogen extraction was shown to be the rate-controlling stage
of the reaction, the best correlations are obtained with
theoretical parameters associated with the N−H hydrogen
(correlation coefficients are given in Table 3).
The plot between the experimental third-order rate constant
log k3 values and the electronic index EPN is illustrated in
Figure 9A. The results obtained demonstrate the accuracy of
the theoretical description of the local properties of reactants.
The second series of compounds (Scheme 2), presented in
the work of Shawali et al.,2 consists of diarylcarbamates
containing substituents in the aromatic ring next to the N−H
bond, thus influencing the acidity of the N−H hydrogen atom.
The electronic indexes considered reflect the influence of the
substituents. Therefore, a correlation between these indexes
and rate constants is expected as long as the first step of the
reaction is rate determining. This consideration is valid, since
the leaving groups are identical for all compounds in the series.
A good correlation is obtained between the rate constants and
electronic structure indexes, although the series contains only
four compounds. These data are presented in Table 3, Figure
8B, and Figure S3 (Supporting Information). The third series in
ref 2 includes diarylcarbamates with substituents in the phenyl
rings at both amide and ester moieties of the carbamates. For
these compounds the substituents play competitive roles in
both factors: the stability of the leaving group and the acidity of
the NH hydrogen atom. In this case, the intrinsic competition
between two different factors, influencing the reaction rate, is
not well reflected into a single electronic parameter. A
correlation with two electronic parameters is established for
all three series of molecules (eq 2).
ASSOCIATED CONTENT
■
S
* Supporting Information
Tables and figures giving comprehensive theoretical data,
additional experimental data, and Cartesian coordinates and
energies for all optimized structures along the reaction
pathways studied. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: silieva@chem.uni-sofia.bg; galabov@chem.uni-sofia.
bg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by FP7-REGPOT-2011-1 project
BeyondEverest and BG051PO001/3.3-05 project Science and
Business. We thank the reviewers for helpful suggestions.
log k3 = 1.37[EPN(O)] − 0.47[EPN(H)] + 0.02
REFERENCES
(2)
n = 21 r = 0.978
■
(1) Menger, F. M.; Glass, L. E. J. Org. Chem. 1974, 39, 2469−2470.
(2) Shawali, A. S.; Harhash, A.; Sidky, M. M.; Hassaneen, H. M.;
Elkaabi, S. S. J. Org. Chem. 1986, 51, 3498−3501.
(3) Koh, H. K.; Kim, O. S.; Lee, H. W.; Lee, I. J. Phys. Org. Chem.
1997, 10, 725−730.
(4) Oh, H. K.; Park, J.; Sung, D. D.; Lee, I. J. Org. Chem. 2004, 69,
3150−3153.
CONCLUDING REMARKS
■
Detailed theoretical modeling has been conducted for three
possible reaction channels for both uncatalyzed and general
base-catalyzed aminolysis of phenyl N-phenylcarbamate:
I
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The Journal of Organic Chemistry
Article
(5) Oh, H. K.; Jin, Y.; Sung, D. D.; Lee, I. Org. Biomol. Chem. 2005, 3,
1240−1244.
(29) (a) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215−
241. (b) Zhao, Y.; Truhlar, D. G. J. Chem. Theory Comput. 2008, 4,
1849−1868.
(30) (a) Curtiss, L. A.; McGrath, M. P.; Blaudeau, J. P.; Davis, N. E.;
Binning, R. C., Jr.; Radom, L. J. Chem. Phys. 1995, 103, 6104−6113.
(b) Clark, T.; Chandrasekar, G. W., J.; Schleyer, P. v. R. J. Comput.
Chem. 1983, 4, 294−301.
(31) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys.
2010, 132, 154104−154122.
(32) Goerigk, L.; Grimme, S. J. Chem. Theory Comput. 2010, 6, 107−
126.
(33) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154−
2161.
(34) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105,
2999−3093.
(35) Wilson, E. B. J. Chem. Phys. 1962, 36, 2232−2233.
(36) Politzer, P. In Chemical Applications of Atomic and Molecular
Electrostatic Potentials; Politzer, P., Truhlar, D. G., Eds.; Plenum Press:
New York, 1981; p 7.
(37) (a) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys.
1985, 83, 735−746. (b) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem.
Rev. 1988, 88, 899−926.
(38) (a) Hirshfeld, F. L. Theor. Chem. Acc. 1977, 44, 129−138.
(b) Ritchie, J. P. J. Am. Chem. Soc. 1985, 107, 1829−1837. (c) Ritchie,
J. P.; Bachrach, S. M. J. Comput. Chem. 1987, 8, 499−509.
(39) Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96−103.
(40) Hansch, C.; Leo, A.; Taft, W. Chem. Rev. 1991, 91, 165−195.
(41) Ivanova, E. V.; Muchall, H. D. J. Phys. Chem. 2007, 111, 10824−
10833.
(6) Castro, E. A.; Cubillos, M.; Iglesias, R.; Santos, J. G. Int. J. Chem.
Kinet. 2012, 44, 604−611.
(7) Sung, K.; Zhuang, B.-R.; Huang, P.-M.; Jhong, S. W. J. Org. Chem.
2008, 73, 4027−4033.
(8) Lee, H. W.; Oh, H. K. Bull. Korean Chem. Soc. 2010, 31, 475−
478.
(9) Bunnett, J. F.; Davis, G. T. J. Am. Chem. Soc. 1960, 82, 665−674.
(10) Jencks, W. P.; Carriuolo, J. J. Am. Chem. Soc. 1960, 82, 675−681.
(11) Bruice, T. C.; Mayahi, M. F. J. Am. Chem. Soc. 1960, 82, 3067−
3071.
(12) Williams, A. Acc. Chem. Res. 1989, 22, 387−392.
(13) Castro, E. A. Chem. Rev. 1999, 99, 3505−3524.
(14) Oh, H. K.; Ku, M. H.; Lee, H. W.; Lee, I. J. Org. Chem. 2002, 67,
8995−8998.
(15) Singleton, D. A.; Merrigan, S. R. J. Am. Chem. Soc. 2000, 122,
11035−11036.
(16) (a) Um, I. H.; Min, J. S.; Ahn, J. A.; Hahn, H. J. J. Org. Chem.
2000, 65, 5659−5663. (b) Um, I. H.; Kim, K. H.; Park, H. R.; Fujio,
M.; Tsuno, Y. J. Org. Chem. 2004, 69, 3937−3942.
(17) Ilieva, S.; Galabov, B.; Musaev, D.; Morokuma, K.; Schaefer, H.
F., III J. Org. Chem. 2003, 68, 1496−1502.
(18) Galabov, B.; Atanasov, Y.; Ilieva, S.; Schaefer, H. F., III J. Phys.
Chem. A 2005, 109, 11470−11474.
(19) Rangelov, M. A.; Vayssilov, G. N.; Yomtova, V. M.; Petkov, D.
D. J. Am. Chem. Soc. 2006, 128, 4964−4965.
(20) Bruice, T. C.; Benkovic, S. J. Bioorganic Mechanisms; W. A.
Benjamin: New York, 1966; Vol. 1.
(42) (a) Perrin, D. D., Dissociation Constants of Organic Bases in
Aqueous Solution; Butterworths: London, 1965 (Supplement, 1972).
(b) Serjeant, E. P.; Dempsey, B., Ionization Constants of Organic Acids
in Aqueous Solution; Pergamon: Oxford, U.K., 1979.
(43) (a) Kanzian, T.; Nigst, T. A.; Maier, A.; Pichl, S.; Mayr, H. Eur.
J. Org. Chem. 2009, 6379−6385. (b) Ammer, J.; Baidya, M.; Kobayashi,
S.; Mayr, H. J. Phys. Org. Chem. 2010, 23, 1029−1035. (c) Nigst, T. A.;
Antipova, A.; Mayr, H. J. Org. Chem. 2012, 77, 8142−8155.
(21) Jencks, W. P. Catalysis in Chemistry and Enzymology; McGraw-
Hill: New York, 1969.
(22) Page, M. I.; Williams, A. Organic and Bioorganic Mechanisms;
Longmans: Harlow, U.K., 1997.
(23) (a) Ban, N.; Nissen, P.; Hanssen, J.; Moore, P. B.; Steitz, T.
Science 2000, 289, 905−920. (b) Muth, G. W.; Ortoleva-Donnely, L.;
Strobel, S. A. Science 2000, 289, 947−950.
(24) (a) Dittert, L. W.; Higuchi, T. J. Pharm. Sci. 1963, 52, 852−857.
(b) Adams, P.; Baron, F. A. Chem. Rev. 1965, 65, 567−602.
(c) Williams, A. J. Chem. Soc., Perkin Trans. 2 1972, 808−812.
(d) Hegarty, A. F.; Frost, L. N. J. Chem. Soc., Perkin Trans. 2 1973,
1719−1728. (e) Bergon, M.; Calmon, J.- P. Tetrahedron Lett. 1981, 22,
937−940. (f) Wentworth, P., Jr.; Datta, A.; Smith, S.; Marshall, A.;
Partridge, L. J.; Blackburn, G. M. J. Am. Chem. Soc. 1997, 119, 2315−
2316.
(25) Furuya, Y.; Goto, S.; Itoho, K.; Urasaki, I.; Morita, A.
Tetrahedron 1968, 24, 2367−2375.
(26) Furuya, Y.; Itoho, S. K.; Shibata, O.; Ohkubo, K. Chem. Lett.
1972, 1, 971−974.
(27) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven, T.; Kudin,
K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone,
V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene,
M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 09 (Revision-
A.01); Gaussian, Inc., Wallingford, CT, 2009.
(28) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648−5652. (b) Becke,
A. D. J. Chem. Phys. 1996, 104, 1040−1046. (c) Lee, C. T.; Yang, W.
T.; Parr, R. G. Phys. Rev. B 1988, 37, 785−789.
J
dx.doi.org/10.1021/jo4002068 | J. Org. Chem. XXXX, XXX, XXX−XXX