Signs of formation and chemical evolution of zwitterions in the reaction of 1-methyl-imidazole with cyanophenylacetylene and benzaldehyde

Article abstract of DOI:10.1007/s10593-012-0926-1

Primary monitoring of the three-component reaction of 1-methylimidazole with cyanophenylacetylene and benzaldehyde by EPR, UV, NMR, and IR spectroscopy has been carried out. Experimental evidence has been obtained for the formation of zwitterions and carbenes of the imidazole series as intermediates of a new functionalization reaction of the imidazole ring leading to 2-benzoyl-3-(1- methyl-1H-imidazol-2-yl)-3-phenylpropanenitrile.

Full text of DOI:10.1007/s10593-012-0926-1

Chemistry of Heterocyclic Compounds, Vol. 47, No. 11, February, 2012 (Russian Original Vol. 47, No. 11, November, 2011)
SIGNS OF FORMATION AND CHEMICAL EVOLUTION
OF ZWITTERIONS IN THE REACTION OF 1-METHYL-
IMIDAZOLE WITH CYANOPHENYLACETYLENE AND
BENZALDEHYDE*
L. V. Andriyankova1, K. V. Belyaeva1, L. P. Nikitina1, A. G. Mal'kina1,
T. I. Vakul'skaya1, S. S. Khutsishvili1, L. M. Sinegovskaya1, and B. A. Trofimov1**
Primary monitoring of the three-component reaction of 1-methylimidazole with cyanophenylacetylene
and benzaldehyde by EPR, UV, NMR, and IR spectroscopy has been carried out. Experimental evidence
has been obtained for the formation of zwitterions and carbenes of the imidazole series as intermediates
of a new functionalization reaction of the imidazole ring leading to 2-benzoyl-3-(1-methyl-1H-imidazol-
2-yl)-3-phenylpropanenitrile.
Keywords: aldehydes, carbenes, cyanoacetylenes, 1-substituted imidazoles, zwitterions, monitoring
reaction, multicomponent reactions, nucleophilic addition.
Systematic investigations of zwitterions generation, formed in heterocycles (azoles and azines) as a
result of nucleophilic attack of the "pyridine" nitrogen atom on the triple bond of electron-deficient acetylenes
[1-11] has enabled the suggestion that subsequent transfer of protons to the carbanionic center in the zwitterions
leads to a nucleophilic carbene of a new type, capable of interacting with a suitable electrophile as the third
component.
R3 = Me, n-Pr, n-Bu
R2
N
O
N
R
R 3
R 1
N
O
R1
R2
+
R3
+
N
R
O
Ph
R1 = Ph, R2 = CN;
R3 = Ph, 4-CNC6H4, 3-Py
N
R = Me, Et, i-Bu, Bn, and etc.
R1 = H, Ph; R2 = CO2Me, CN
CN
N
R
R 3
_______
*Dedicated to Academician M. G. Voronkov on his 90th birthday.
**To whom correspondence should be addressed, e-mail: boris_trofimov@irioch.irk.ru.
1A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky St.,
Irkutsk 664033, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1675-1679, November, 2011.
Original article submitted April 25, 2011.
1390
0009-3122/12/4711-1390©2012 Springer Science+Business Media, Inc.

Recently for the first time we have carried out a three-component reaction between 1-substituted
imidazoles, cyanophenylacetylene or methyl propinoate and aldehydes of aliphatic [12], aromatic, and
heteroaromatic [13] series. These reactions led respectively to the vinyl esters and substituted propanenitrile,
opening a new direction for the functionalization of the imidazole ring.
In the present study, attempts have been made to detect (by methods of EPR, UV, NMR, and IR
spectroscopy) zwitterions and carbene intermediates in the reaction between 1-methylimidazole (1), cyano-
phenylacetylene (2) and benzaldehyde (3), leading to the formation of 2-benzoyl-3-(1-methyl-1H-imidazol-
2-yl)-3-phenylpropanenitrile (4) [13].
O
Ph
N
N
O
+
Ph
CN + Ph
CN
N
N
Ph
Me
Me
2
3
1
4
As in previous studies [1-13], we suggest that the reaction begins with the formation of zwitterions of
intermediates A, A', which are then converted into carbenes B as a result of a proton transfer from the second
position of the imidazole ring to the carbanionic center. Subsequent interception of carbene B by aldehyde and
rearrangement of adducts C and 5 lead to a new functional derivative of imidazole 4.
Ph
Ph
Ph
H
_
_
+
N
N
N
3
CN
CN
CN
+
:
+
2
1
N
N
N
Me
Me
Me
A
B
A'
H
Ph
NC
N
+
N
O
Ph
Ph
N
CN
O
_
O
CN
N
N
N
Ph
Ph
Ph
Me
Me
Me
C
5
4
According to data of EPR reaction monitoring, in 20 min after mixing the reactants a weak singlet
appeared with a g-factor of 2.0044 (ΔH = 9.3 G; N = 2.4·1015 spin/g), the intensity of which gradually (during
40 min) increased to reach a maximum. It remained constant for 1 h. In the subsequent 24 h a slow decrease was
observed in the intensity of the signal until its disappearance. These results may be interpreted as signs of the
formation of ion-radical pair D, transferring then into zwitterion A.
.
+
N
CN
_
.
A
+
1
2
+
N
Ph
Me
D
1391

Fig. 1. UV spectra of the reaction mixture: 1 – after 3 h; 2 – after 24 h; 3 – after 170 h.
Formation of a charge-transfer complex (ion-radical pair D) is in agreement with the reaction mixture
UV spectrum evolution in which a significant maximum at 520 nm becomes apparent after 3 h, the intensity of
which grows with time (during 24 h) with a hypsochromic shift to 509 nm (Fig. 1). This shift may
hypothetically be linked with the transition of the ion-radical pair D into zwitterion A. The band at 509 nm then
gradually loses its intensity with the simultaneous appearance of a band at 250 nm, belonging to the
functionalized imidazole 4. After 170 h only this band remains in the spectrum.
1
In the H NMR spectrum of the reaction mixture 2 h after mixing the reactants singlets appeared in the
region of 4.49 and 5.10 ppm most probably belonging to the olefinic protons of the carbene intermediate B and
the vinyl ether 5. The most high-field signal (4.49 ppm), which was absent in the spectra of vinyl ether 5 [13]
and the final reaction product 4 [13], seemingly belongs to the carbene intermediate B. The lower field signal
(5.10 ppm) belongs to the intermediate vinyl ether 5 [13]. Low-field doublets also appeared in the spectrum in
the region of 4.85 and 5.78 ppm, belonging to the 3-CH and 2-CH protons of the final adduct 4. After 24 h the
intermediates signals intensity was reduced and intensity of the final product signals was correspondingly
increased. Simultaneously in the 13C NMR spectrum of the reaction mixture a signal was observed at 223.4 ppm
belonging to carbene B (the characteristic signal of stable imidazoline carbenes [14]).
5.10 ppm
H
Ph
4.49 ppm
NC
N
O
Ph
H
H
Ph
N
N
3
5.78 ppm
CN
O
:
CN
N
N
N
H
223.4 ppm
Me
Ph
Me
4.85 ppm
Ph
Me
4
B
5
In the IR spectrum of the reaction mixture after mixing the reactants a broad absorption band appeared
in the 2500-2700 cm-1 region, which may belong to the quaternary ammonium cation in zwitterion A [15, 16].
The intensity of this band was gradually increased in the first hour. Then (during 24 h) absorption in this region
was reduced. Simultaneously evolution was observed in the absorption band of the nitrile group, the broad band
at 2260-2280 cm-1 belonging to the starting cyanophenylacetylene (2) disappeared, and the absorption band of
the intermediate vinyl ether 5 was displayed at 2216 cm-1. This band then was smoothly transferred into a band
with a maximum at 2240 cm-1, assigned to the final (imidazol-2-yl)propanenitrile 4.
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The first monitoring of the three-component reaction of 1-methylimidazole with cyanophenylacetylene
and benzaldehyde (by EPR, UV, NMR, and IR spectroscopy) has therefore made it possible to obtain
experimental evidence of the formation of intermediate zwitterions and carbenes, as adducts of nucleophilic
attack of 1-methylimidazole at the triple bond of cyanophenylacetylene. Proof has been obtained of the higher
electrophilicity of cyanophenylacetylene compared with aldehydes when competing for the lone electron pair of
the "pyridine" nitrogen atom of the imidazole ring. The investigations carried out complement the fundamental
chemistry of both imidazole and acetylene.
EXPERIMENTAL
The IR spectra of compounds were recorded on a Bruker Vertex 70 double-beam spectrometer (range
400-4000 cm-1) for samples in a film. The UV monitoring was carried out on a Lambda 35 UV/Vis spectrometer
1
in the spectrometer cuvette. The H and 13C NMR spectra were recorded on a Bruker DPX-400 instrument (at
400 and 100 MHz). The EPR monitoring was carried out in CW mode on a Bruker ELEXSYS E 580
spectrometer in the spectrometer ampoule in an atmosphere of argon.
The process was monitored mainly by the signals of the corresponding protons and absorption bands
belonging to the compounds formed in samples of the reaction mixture.
IR Monitoring. A mixture of cyanophenylacetylene (2) (64 mg, 0.5 mmol), benzaldehyde (3) (53 mg,
0.5 mmol), and 1-methylimidazole (1) (41 mg, 0.5 mmol) in MeCN (2 ml) was stirred for 72 h at 20-25oC.
Samples were taken directly after mixing the reactants, then after 0.5, 1, 2, 4, 7, 13, 21, 33, 48, and 72 h.
UV Monitoring. Cyanophenylacetylene (2) (25 mg, 0.2 mmol), benzaldehyde (3) (21 mg, 0.2 mmol),
and 1-methylimidazole (1) (16 mg, 0.2 mmol) were placed in a flask with MeCN (10 ml). Test samples (0.1 ml)
were taken and diluted with MeCN (10 ml). The obtained solution was placed in the spectrometer cuvette
(20-25oC, d = 0.1 cm, concn. = 2.10-4 M). Spectra were recorded 3, 6, 11, 19, 27, 37, 52, 74, 98, 122, 146, and
170 h after mixing the reactants.
EPR Monitoring. A mixture of cyanophenylacetylene (2) (25 mg, 0.2 mmol), benzaldehyde (3) (21 mg,
0.2 mmol), and 1-methylimidazole (1) (16 mg, 0.2 mmol) in MeCN (0.15 ml) (20-25oC) was placed in the
spectrometer ampoule in an atmosphere of argon. Spectra were recorded 20, 40 min, 2.5, 4.5, 7, 12, 20, and 26 h
after mixing the reactants.
1H NMR Monitoring. A mixture of cyanophenylacetylene (2) (64 mg, 0.5 mmol), benzaldehyde (3)
(53 mg, 0.5 mmol), and 1-methylimidazole (1) (41 mg, 0.5 mmol) was stirred for 24 h at 20-25oC. Test samples
were taken, dissolved in CDCl3 (0.5 ml), and the spectra recorded at 2, 4, 6, 10, 12, 15, 20, and 24 h after mixing
the reactants.
The work was carried out with the financial support of the Russian Foundation for Fundamental
Investigations (grant No. 11-03-00203a), the Grants Council of the President of the Russian Federation (NSh
3230.2010.3), the Presidium of the Russian Academy of Sciences (Program 25), and the Division of Chemistry
and Materials Sciences of the Russian Academy of Sciences (No. 5.1).
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