Synthesis, mechanism of formation, and molecular orbital calculations of arylamidoximes

Article abstract of DOI:10.1007/s00706-009-0186-7

A simple and easy synthesis of ten arylamidoximes from arylnitriles and hydroxylamine is described. The formation of the arylamides has been observed to a much lesser extent in the present work. A new mechanism for the formation of arylamidoximes, as well

Full text of DOI:10.1007/s00706-009-0186-7

Monatsh Chem (2009) 140:1319–1324
DOI 10.1007/s00706-009-0186-7
ORIGINAL PAPER
Synthesis, mechanism of formation, and molecular orbital
calculations of arylamidoximes
Rajendra M. Srivastava Æ Maria C. Pereira Æ
Wagner W. M. Faustino Æ Kaline Coutinho Æ
´
˜
Janaına V. dos Anjos Æ Sebastiao J. de Melo
Received: 16 February 2009 / Accepted: 2 September 2009 / Published online: 10 October 2009
ꢀ Springer-Verlag 2009
Abstract A simple and easy synthesis of ten arylami-
doximes from arylnitriles and hydroxylamine is described.
The formation of the arylamides has been observed to a
much lesser extent in the present work. A new mechanism
for the formation of arylamidoximes, as well as arylamides,
from arylnitriles and hydroxylamine is suggested. Quantum
mechanical calculations have been carried out to support
this mechanism. The enthalpy of formation in conjunction
with atomic charges of the reactants and intermediates
helped to understand more about the generation of the
products.
their chemical usefulness, this class of compounds pos-
sesses pronounced biological activities. Two reviews
treating this subject provide the details of such activities [1,
2]. In fact, amidoximes are mainly used as NO generators
in vivo, having neuromodulatory and neurotransmittory
actions [8]. Another interesting feature concerning ami-
doximes is that they can be used as prodrugs for amidines,
once endogenous cellular reductases reduce amidoximes to
amidines [9–11]. Amidoximes are less basic than amidines
and are not protonated under physiological conditions,
enhancing intestinal absorption by diffusion [12]. In
addition, two antithrombotic drugs, sibrafibran and ximel-
agatran, were developed using this principle of latentiation
[13].
Keywords Arylamidoximes ꢀ Amides ꢀ Quantum
chemical calculations ꢀ Density functional calculations ꢀ
Reaction mechanisms
For a long time, our group has been involved in synthe-
sizing 1,2,4-oxadiazole derivatives from arylamidoximes
[6, 14]. Their synthesis always produced varying quantities
of arylamides as well. However, the quantity of amide
increases when there is an electron-withdrawing group at the
phenyl ring. We therefore decided to investigate the reaction
of arylnitriles and hydroxylamine with a view to clarify the
mechanism of formation of the principal product as well as
to reduce the formation of the undesired amide. Although
all amidoximes described in this paper are known, we
have developed a simpler procedure for synthesizing
arylamidoximes, using hydroxylamine hydrochloride and
arylnitriles at room temperature in the presence of sodium
bicarbonate. Therefore, we describe herein the synthesis of
ten benzamidoximes 6a-6j (Scheme 1) under relatively
mild conditions that we have standardized in our laboratory.
A more appropriate mechanism of formation of arylami-
doximes and arylamides is suggested. In order to support
this mechanism, quantum mechanical calculations were
performed, which indeed gave some insight about the
reaction mechanism.
Introduction
Amidoximes are an interesting class of compounds. They
can serve as starting materials for the synthesis of valuable
heterocyclic and other useful compounds [1–7]. Besides
R. M. Srivastava (&) ꢀ M. C. Pereira ꢀ
W. W. M. Faustino ꢀ J. V. dos Anjos
´
Departamento de Quımica Fundamental,
Universidade Federal de Pernambuco, Recife, PE, Brazil
e-mail: rms@ufpe.br; rms_indu@yahoo.com
K. Coutinho
Departamento de Fısica Geral, Universidade de Sa˜o Paulo,
Sa
´
˜o Paulo, SP, Brazil
S. J. de Melo
´
Departamento de Antibioticos,
Universidade Federal de Pernambuco,
Recife, PE, Brazil
123

1320
R. M. Srivastava et al.
Scheme 1
Results and discussion
Once the oxygen atom of hydroxylamine attacks the carbon
atom of the nitrile, the carbon atom of the intermediate 3
becomes still a harder acid, and now the nitrogen atom of
the –O–NH2 moiety can attach to this carbon, forming an
oxaziridine ring 4 as an unstable intermediate. Once a
three-membered ring is formed, its opening in a normal
way should occur through O1–C3 bond cleavage, which
will have thermodynamic control. At higher temperature,
ring opening may take place either through O1–C3 or N2–
C3 bond cleavage, thus providing more amide. Scheme 4
provides a complete picture of the mechanism of formation
of the products.
Stephenson et al. [15] found that treatment of 4-cyano-
pyridine or nitriles of the type X-C6H4CN (X = o-NO2,
p-CN, p-Cl, or p-CF3) with excess of hydroxylamine in
methanol yielded amidoximes (III), but contaminated with
varying amounts (17–55%) of the corresponding amides
(VI) as shown in Scheme 2. The above authors also pro-
posed the mechanism of amide (VI) formation as given in
Scheme 3.
Our suggestion concerning the mechanism is the fol-
lowing: The hard and soft acid base principle (the HSAB
principle) [16–18] can be applied in the reaction between
arylnitriles and hydroxylamine. Hydroxylamine is an
ambident nucleophile, so either the oxygen or nitrogen
atom of this molecule may attack the carbon atom of the
nitrile, which behaves as a moderately hard acid. Since a
strong base would prefer to bind a strong acid, we con-
vincingly feel that the oxygen atom attacks the carbon
atom of the nitrile group preferentially and this reaction is
kinetically controlled. There are examples where O-acy-
lhydroxylamine derivatives have been isolated as major
initial products from the reaction of hydroxylamine with a
number of acylating agents at neutral pH [19]. Ambident
nucleophilic behavior of hydroxylamine has been demon-
strated earlier [20]. Alkyloxylation of a, b-unsaturated
esters and nitriles at b-carbon has also been reported [21].
Also, it is important to comment on the mechanism of
formation of the amides. Stephenson and colleagues [15]
considered the attack of the nitrogen atom of hydroxyl-
amine on the nitrogen atom of (IV) with the formation of
(VI) and (VII) (see Scheme 3). Compound (VII) further
reacts with a molecule of hydroxylamine to afford a mol-
ecule of nitrogen, two molecules of water and a molecule
of ammonia. We feel that the initial attack of the hydroxyl-
amine nitrogen at the nitrogen atom of (IV) in a SN2
manner is very difficult because both nitrogen atoms
involved in the reaction are electron deficient. Therefore,
this kind of reaction is less favorable. Alternatively, the
imine part of the nitrogen atom, which has higher electron
density, picks up a proton from the –OH of NH2OH and
leaves the oxygen atom of hydroxylamine negatively
Scheme 2
123

Synthesis, mechanism of formation, and molecular orbital calculations of arylamidoximes
1321
one molecule of each reactant, arylnitrile, and hydroxyl-
amine. Only one stable geometry was found, which is
shown in Fig. 1a. In this cluster, the binding energy of the
molecules is 21.4 kJ mol-1, and they form a hydrogen
bond between the hydroxyl group of hydroxylamine and
the nitrile nitrogen. It can also be seen that the hydroxyl-
amine oxygen atom (QO = -0.563) plays a stronger role
as a base than the nitrogen atom (QN = -0.331). This
supports our idea that the oxygen atom attacks the nitrile
carbon.
Scheme 3
In addition to these findings, it can also be noticed that:
charged, which would easily attack the NH2 group of 7 to
provide 8 (Scheme 4).
•
The atomic charges obtained from quantum mechanical
calculations show that the oxygen atom of hydroxyl-
amine has a higher charge compared with the nitrogen
atom (see Fig. 1a). This clearly indicates that the
electronic charges, as well as electron density, are higher
either at the neutral or negatively charged (H2NO-)
oxygen atom of hydroxylamine.
In Fig. 1 the optimized geometries and the atomic
charges for the most important atoms involved in the
reaction mechanism are shown. We performed geometry
optimization calculations to analyze which of the hydrox-
ylamine atoms (nitrogen or oxygen) would first attack the
nitrile carbon. This way, we analyzed a cluster containing
Scheme 4
EtOH/H2O
Cl
NaHCO3
H2O CO2
Ar
NaCl
H2CO3
H3N
OH
H2N
OH
+
+
+
r.t.
H2CO3
+
C
N
+
HO
NH2
5
1
2
NH2
Ar
NH
Ar
NH2
Ar
C
C
O
H2N
OH
C
O
O
NH2
NH
+
- NH2OH
O
NH2
NH2
3
8
7
4
Ar
NH
OH
Ar
NH2
C
C
Ar
NH2
+ NH2OH
C
+
H2N
O
NH2
HN
N
OH
O
5
10
6
9
H
N
HO
NH2
10
HN
NH
+ H2O
12
11
H2N
OH
H2O
+
N2
+
NH3
123

1322
R. M. Srivastava et al.
Fig. 1 Optimized geometries
for reagents 1 and 2 (a),
intermediates 3 (b), 4 (c), and 5
(d), and for product 6 (e). The
atomic charges are shown in the
structures, and they reproduce
the electrostatic potential
obtained in quantum
calculations
•
•
Since there is a lot of water in the reaction medium, the
following equilibrium is also expected:
is of high energy, this attraction justifies the formation of a
three-membered ring. Thus, the C–O bond cleavage should be
favored, and intermediate5 (see Fig. 1d) can be formed. Next,
the tautomerization process may occur easily, and product 6
(see Fig. 1e) is generated.
H2N ꢁ OH þ H2O ꢀ H2N ꢁ Oꢁ þ H3Oþ
Two molecules of hydroxylamine should give the
equilibrium given below:
The enthalpy of formation calculations for 3, 4, 5, and 6
were performed in order to analyze their energies (Fig. 2).
These energies were calculated as a function of the
hydrogen-bonded cluster formed by the reagents (1 and 2).
These calculations indicate that 6 is more stable than 3 by
38.1 kJ mol-1. Our calculations also disclose that tautomer
5 is 47.7 kJ mol-1 less stable than 6.
þ
H2N ꢁ OH þ H2N ꢁ OH ꢀ H3 N ꢁOH þ ꢁO ꢁ NH2
•
Protonation of the oxygen atom from the second
molecule of hydroxylamine should also take place to
provide the following:
Also, our efforts to calculate the transition state between
8 and 7 did not work out, but the mechanism of amide
formation, as depicted in Scheme 4, seems reasonable.
Once this happens, the negatively charged oxygen atom of
hydroxylamine 8 should attack the nitrogen atom of 7, giving
arylamide 9 and an unstable O-aminohydroxylamine 10.
This latter product must rearrange to 11, which dispropor-
tionates to diimide 12 and water. It is this diimide that is the
source of hydrogen and should cause the hydrogenolysis of
hydroxylamine to give H2O, N2, and NH3.
þ
H2N ꢁ OH þ H2N ꢁ OH ꢀ ꢁO ꢁ NH2 þ H2 O ꢁNH2
Once the hydroxylamine oxygen atom attacks the nitrile
carbon, the intermediate 3 is formed (see Fig. 1b), and it is
23.4 kJ mol-1 more stable than the reagents cluster (see
Fig. 1a). Analyzing the calculated atomic charges at the imine
carbon atom (QC = 0.721) and the hydroxylamine nitrogen
atom in intermediate 3 (QN = -0.654), we can see that there
is a strong and attractive electrostatic interaction between
the amine nitrogen atom and imine carbon atom. This favors
the formation of the oxaziridine ring 4. The optimized
geometry for intermediate 4 is shown in Fig. 1c. In this three-
memberedring,thecalculatedatomicchargesshowastronger
bonding between the carbon (QC = 0.662) and the nitrogen
(QN = -0.510), rather than between the carbon and the
oxygen (QO = -0.241) atoms. Although the oxaziridine ring
In conclusion, we achieved an easy synthesis of ten
arylamidoximes under relatively mild conditions. The
formation of unwanted arylamides under these conditions
is very little. Geometry optimizations and charge densities
obtained by quantum mechanical calculations employing
the B3LYP/6-311 ? G(d) method helped us to propose
new mechanisms for the formation of arylamidoximes and
arylamides. These calculations also furnished the enthalpy
123

Synthesis, mechanism of formation, and molecular orbital calculations of arylamidoximes
1323
Computational methods
Ab initio quantum mechanical calculations were performed
to determine geometries, energy and atomic charges for
reagents 1 and 2, intermediates 3, 4, and 5, and product 6.
The atomic charges were obtained from an electrostatic fit
using the CHELPG procedure [25, 26]. All calculations
were performed using the Gaussian 03 program [26, 27]
and the density-functional method, with the hybrid func-
tional B3LYP [28] and the 6-311 ? G(d) basis set. The
solvent effects were included in the calculations using the
continuum approach with a polarizable continuum model
(PCM) [29–31], where all geometries were re-optimized.
Atomic charges and enthalpy of formation of the inter-
mediates were also calculated.
Fig. 2 Enthalpy of formation of compounds 3, 4, 5, and 6 as a
function of hydrogen-bonded cluster generated by the reagents 1
and 2. The solvent effect was considered as a continuum model
(parenthesis)
Acknowledgments We gratefully acknowledge the financial assis-
tance of the Brazilian National Research Council (CNPq) to R.M.S,
J.V. d. A., and K.C.
of formation of compounds 3, 4, 5, and 6, which gave more
information about the mechanism of formation of the
products.
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