ꢀ
Lazaro Martınez et al.
JOCArticle
SCHEME 1. Chemical Structures of 2-Substituted Imidazole Derivatives
solid-state 17O NMR, which is a useful tool to prove the
tautomeric form of the R-keto functional group commonly
found in intermediates of enzymatic reactions.6 In addition,
the hydrate, keto, and enol forms of oxalacetic acid have
been studied by 13C NMR in the solution state.7
In particular, the imidazole-2-carboxaldehyde (4) is an
important reagent in the synthesis of active compounds. In
this field, imidazole derivatives bearing chiral carbinamine
structures with relevance in medicinal chemistry,8 thiosemi-
carbazone complexes for the search of new therapeutic agents,9
substituted quinoline derivatives with anti-breast cancer
activity,10 and some semicarbazones with antimicrobial acti-
vity have been synthesized from 4.11
was synthesized following the report of Godefroi et al.
(Scheme 1, 1-4).15 Scheme 1 also shows the 2-substituted
imidazole derivatives studied in the present work.
In the synthetic route reported by Godefroi et al., 3 is
treated in hydrochloric acid for 22 h and is then isolated and
precipitated with NaHCO3 solution (pH=8.0) in order to
obtain 4 (Scheme 1).15 However, instead of this, according
to our results, the compound obtained was the aldehyde-
hydrate form (4aq) in the solid state and the aldehyde form
(4) in the solution state (Figure 1). Interestingly, in com-
pound 4, the signal corresponding to the carbon of the carbo-
nyl group at 181.3 ppm, present in the 13C NMR spectrum in
DMSO-d6 or D2O/NaOH (Figure 1), was absent in the 13
C
On the other hand, tautomerism in five-membered hetero-
cyclic compounds has been studied in a variety of ways
because of its importance in the reactivity of compounds in
chemical processes and its effect on biological systems.12-14
In particular, Hollstein et al. have studied how the tempera-
ture, solvents, concentration, and size of the substituent on
2-substituted imidazoles and benzimidazoles can have effects
on tautomerism.12 In imidazole molecules, the hydrogen
atom may be bound either to the N1 (1H form) or to the N3
atom (3H form) of the aromatic ring as a consequence of the
prototropic tautomerism at nitrogen atoms.
The aim of the present work was to study the existence and
stability of the aldehyde-hydrate form of 4, by using spectro-
scopic techniques in the liquid and solid states. We also
carried out studies in 2-substituted imidazole derivatives in
order to study the influence of hybridization on the carbon
adjacent to the imidazole ring in the tautomeric process.
CP-MAS spectrum (Figure 1c). In addition, a new resonance
peak at 69.6 ppm appeared in the solid-state spectrum assign-
ment to the carbon of the gem-diol.
Next we decided to study which medium favors the
existence of the aldehyde (4) or the hydrate (4aq) from the
mixture reaction after the hydrolysis of 3. With this aim, we
changed the pH of the resulting solution after the hydrolysis
of 3 to either 9.5 or 6.5 (Scheme 2). Afterward, we were
successful in extracting 4 from the mixture at both pHs using
an apparatus for continuous extraction with methylene chlo-
ride, indicating that 4 was soluble around the pH at which
4aq precipitated. The FTIR results for the solids obtained
from aqueous solutions at pH = 6.5 and 9.5 with CH2Cl2
demonstrate that both compounds presented the carbonyl
stretching at 1685 cm-1 and the same FTIR spectra, in
contrast with the solid at pH=8.0. The FTIR spectrum of
the solid 4aq showed the stretching of the C-O bond at 1084
cm-1 and the deformation in the plane of the C-O-H at
1287 cm-1 among other bands. In addition, the FTIR-ATR
spectrum of the corresponding solution of the solid 4aq
dissolved in methanol showed that this compound evolved
completely to the aldehyde form, in agreement with the
results obtained from the 13C NMR in D2O or DMSO-d6
(Figure 1 and Supporting Information).
2. Results and Discussion
2.1. NMR and FTIR Studies of Imidazole-2-carboxalde-
hyde (4) and Its Hydrate Form (4aq). In the present work 4
(6) Zhu, J.; Geris, A. J.; Wu, G. Phys. Chem. Chem. Phys. 2009, 11, 6972–
6980.
(7) Buldain, G.; De los Santos, C.; Frydman, B. Magn. Reson. Chem.
1985, 23, 478–481.
(8) Perl, N. R.; Leighton, J. L. Org. Lett. 2007, 9, 3699–3701.
To confirm the structure of 4aq after the synthetic process,
we performed a 1H-13C HETCOR NMR experiment in the
solid state (Figure 2). The 2D spectrum reveals clear and
resolved correlations between carbons and their bound
(A, B, and C correlations) or neighboring protons (D and
E correlations). Additionally, the presence of a resonance
signal at 10.3 ppm in the 1H spectrum can be assigned to a
R-OH proton. This kind of proton, as well as protons from
~
€
ꢀ
(9) Casas, J. S.; Castineiras, A.; Rodrıguez Arguelles, M. C.; Sanchez, A.;
ꢀ
ꢀ
ꢀ
ꢀ
Sordo, J.; Vazquez Lopez, A.; Vazquez Lopez, E. M. Dalton Trans. 2000, 14,
2267–2272.
(10) Shi, A.; Nguyen, T. A.; Battina, S. K.; Rana, S.; Takemoto, D. J.;
Chiang, P. K.; Huaa, D. H. Bioorg. Med. Chem. Lett. 2008, 18, 3364–3368.
€
ꢀ
(11) Rodrıguez Arguelles, M. C.; Mosquera Vazquez, S.; Sanmartın
Matalobos, J.; Garcıa Deibe, A. M.; Pelizzi, C.; Zani, F. Polyhedron 2010,
29, 864–870.
(12) Papadopoulos, E. P.; Hollstein, U. Org. Magn. Reson. 1982, 19, 188–191.
(13) Minkin, V. I.; Garnovskii, A. D.; Elguero, J.; Katritzky, A. R.;
Denisko, O. V. Adv. Heterocycl. Chem. 2000, 76, 157–323.
(14) Dolzhenko, A. V.; Pastorin, G.; Dolzhenko, A. V.; Chui, W. K.
Tetrahedron Lett. 2009, 50, 2124–2128.
(15) Bastiaansen, L. A. M.; Van Lier, P. M.; Godefroi, E. F. Organic
Synthesis; Wiley: New York, 1990; Collect. Vol. VII, pp 287-290.
J. Org. Chem. Vol. 75, No. 10, 2010 3209