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NMR Characterization of Hydrate and Aldehyde Forms of

Imidazole-2-carboxaldehyde and Derivatives
azaro Martı́nez,† Pablo Nicol
as Romasanta,† Ana Karina Chattah,‡ and
Juan Manuel L

Graciela Yolanda Buldain*,†
†
Departamento de Quı´mica Org
anica, Facultad de Farmacia y Bioquı´mica, Universidad de Buenos Aires,
Junı´n 956 (C1113AAD), Ciudad Aut
onoma de Buenos Aires, Argentina, and ‡Facultad de Matem
atica,
ordoba, IFFAMAF-CONICET, (5000) C

Astronomı´a y Fı´sica, Universidad Nacional de C
ordoba, Argentina

[email protected]
Received December 11, 2009

The existence and stability of the aldehyde-hydrate form of imidazole-2-carboxaldehyde (4) were
studied using FTIR together with solution- and solid-state NMR experiments. The results allowed us
to conclude that the hydrate form was stable and precipitated at pH=8.0 and that the aldehyde form
was isolated at pH=6.5 and 9.5. Moreover, the presence of the aldehyde-hydrate form was studied
through NMR experiments in D2O at both alkaline and acidic pH. In addition, the tautomeric forms
of the 2-substituted imidazole compounds were also analyzed to investigate the influence of the
hybridization on the carbon adjacent to the imidazole ring, by 13C NMR in DMSO-d6, acetone-d6,
and CDCl3. The presence of the syn- and anti-isomers of oxime 8 obtained from 4 were characterized
by solid-state NMR and variable-temperature NMR experiments in acetone-d6.

1. Introduction readily revert to the parent aldehyde.1-3 In particular,

chloral hydrate is a stable crystalline substance because, in
The few stable crystalline hydrates known (such as the
order to revert to chloral, a water molecule must be left out,
hydrate forms of cyclopropanone and polychlorinated alde-
and this is difficult by the electron-withdrawing character of
hydes and ketones) are those that have a strongly electro-
the Cl3CR group.4 Specifically, in the solid state, the sodium
negative group associated with the carbonyl group since, in
pyruvate is in the ketone form, whereas the lithium pyruvate
general, the hydrates can seldom be isolated because they
takes the gem-diol form.5 These forms have been studied by

(1) Schulman, E. M.; Bonner, O. D.; Schulman, D. R.; Laskovics, F. M. (3) Krois, D; Lehner, H. Monatsh. Chem. 1982, 113, 1019–1024.
J. Am. Chem. Soc. 1976, 98, 3793–3799. (4) Luknitskii, F. L. Chem. Rev. 1975, 75, 259–289.
(2) Gambaryan, N. P.; Rokhlin, E. M.; Zeifman, Y. V.; Ching Yun, C.; (5) Hanai, K.; Kuwae, A.; Sugawa, Y.; Kunimoto, K. K.; Maeda, S.
Knunyants, I. L. Angew. Chem., Int. Ed. 1966, 5, 947–956. J. Mol. Struct. 2007, 837, 101–106.

3208 J. Org. Chem. 2010, 75, 3208–3213 Published on Web 04/21/2010 DOI: 10.1021/jo902588s
r 2010 American Chemical Society
L
azaro Martı́nez et al.
JOC Article
SCHEME 1. Chemical Structures of 2-Substituted Imidazole Derivatives

solid-state 17O NMR, which is a useful tool to prove the was synthesized following the report of Godefroi et al.
tautomeric form of the R-keto functional group commonly (Scheme 1, 1-4).15 Scheme 1 also shows the 2-substituted
found in intermediates of enzymatic reactions.6 In addition, imidazole derivatives studied in the present work.
the hydrate, keto, and enol forms of oxalacetic acid have In the synthetic route reported by Godefroi et al., 3 is
been studied by 13C NMR in the solution state.7 treated in hydrochloric acid for 22 h and is then isolated and
In particular, the imidazole-2-carboxaldehyde (4) is an precipitated with NaHCO3 solution (pH = 8.0) in order to
important reagent in the synthesis of active compounds. In obtain 4 (Scheme 1).15 However, instead of this, according
this field, imidazole derivatives bearing chiral carbinamine to our results, the compound obtained was the aldehyde-
structures with relevance in medicinal chemistry,8 thiosemi- hydrate form (4aq) in the solid state and the aldehyde form
carbazone complexes for the search of new therapeutic agents,9 (4) in the solution state (Figure 1). Interestingly, in com-
substituted quinoline derivatives with anti-breast cancer pound 4, the signal corresponding to the carbon of the carbo-
activity,10 and some semicarbazones with antimicrobial acti- nyl group at 181.3 ppm, present in the 13C NMR spectrum in
vity have been synthesized from 4.11 DMSO-d6 or D2O/NaOH (Figure 1), was absent in the 13C
On the other hand, tautomerism in five-membered hetero- CP-MAS spectrum (Figure 1c). In addition, a new resonance
cyclic compounds has been studied in a variety of ways peak at 69.6 ppm appeared in the solid-state spectrum assign-
because of its importance in the reactivity of compounds in ment to the carbon of the gem-diol.
chemical processes and its effect on biological systems.12-14 Next we decided to study which medium favors the
In particular, Hollstein et al. have studied how the tempera- existence of the aldehyde (4) or the hydrate (4aq) from the
ture, solvents, concentration, and size of the substituent on mixture reaction after the hydrolysis of 3. With this aim, we
2-substituted imidazoles and benzimidazoles can have effects changed the pH of the resulting solution after the hydrolysis
on tautomerism.12 In imidazole molecules, the hydrogen of 3 to either 9.5 or 6.5 (Scheme 2). Afterward, we were
atom may be bound either to the N1 (1H form) or to the N3 successful in extracting 4 from the mixture at both pHs using
atom (3H form) of the aromatic ring as a consequence of the an apparatus for continuous extraction with methylene chlo-
prototropic tautomerism at nitrogen atoms. ride, indicating that 4 was soluble around the pH at which
The aim of the present work was to study the existence and 4aq precipitated. The FTIR results for the solids obtained
stability of the aldehyde-hydrate form of 4, by using spectro- from aqueous solutions at pH = 6.5 and 9.5 with CH2Cl2
scopic techniques in the liquid and solid states. We also demonstrate that both compounds presented the carbonyl
carried out studies in 2-substituted imidazole derivatives in stretching at 1685 cm-1 and the same FTIR spectra, in
order to study the influence of hybridization on the carbon contrast with the solid at pH=8.0. The FTIR spectrum of
adjacent to the imidazole ring in the tautomeric process. 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
2. Results and Discussion
1287 cm-1 among other bands. In addition, the FTIR-ATR
2.1. NMR and FTIR Studies of Imidazole-2-carboxalde- spectrum of the corresponding solution of the solid 4aq
hyde (4) and Its Hydrate Form (4aq). In the present work 4 dissolved in methanol showed that this compound evolved
completely to the aldehyde form, in agreement with the
(6) Zhu, J.; Geris, A. J.; Wu, G. Phys. Chem. Chem. Phys. 2009, 11, 6972– results obtained from the 13C NMR in D2O or DMSO-d6
6980. (Figure 1 and Supporting Information).
(7) Buldain, G.; De los Santos, C.; Frydman, B. Magn. Reson. Chem.
1985, 23, 478–481. To confirm the structure of 4aq after the synthetic process,
(8) Perl, N. R.; Leighton, J. L. Org. Lett. 2007, 9, 3699–3701. we performed a 1H-13C HETCOR NMR experiment in the
(9) Casas, J. S.; Casti~
neiras, A.; Rodrı́guez Arg€uelles, M. C.; S

anchez, A.;
Sordo, J.; V
azquez L
opez, A.; V
azquez L
opez, E. M. Dalton Trans. 2000, 14, solid state (Figure 2). The 2D spectrum reveals clear and
2267–2272. resolved correlations between carbons and their bound
(10) Shi, A.; Nguyen, T. A.; Battina, S. K.; Rana, S.; Takemoto, D. J.; (A, B, and C correlations) or neighboring protons (D and
Chiang, P. K.; Huaa, D. H. Bioorg. Med. Chem. Lett. 2008, 18, 3364–3368.
(11) Rodrı́guez Arg€ uelles, M. C.; Mosquera V
azquez, S.; Sanmartı́n E correlations). Additionally, the presence of a resonance
Matalobos, J.; Garcı́a Deibe, A. M.; Pelizzi, C.; Zani, F. Polyhedron 2010, signal at 10.3 ppm in the 1H spectrum can be assigned to a
29, 864–870. R-OH proton. This kind of proton, as well as protons from
(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. (15) Bastiaansen, L. A. M.; Van Lier, P. M.; Godefroi, E. F. Organic
Tetrahedron Lett. 2009, 50, 2124–2128. Synthesis; Wiley: New York, 1990; Collect. Vol. VII, pp 287-290.

J. Org. Chem. Vol. 75, No. 10, 2010 3209

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13
FIGURE 1. C NMR spectra in DMSO-d6 (a) and D2O/NaOH (b) of 4 and 13C CP-MAS (c) and NQS spectra (d) of 4aq. The inset shows the
carbon numbering used throughout the text for the 13C spectra.

FIGURE 2. 1H-13C HETCOR spectra of compounds 4aq and 4 in the solid state. Proton and carbon projections together with their
assignments are indicated in each dimension.

SCHEME 2. Experimental Conditions That Favor the Aldehyde clear correlation with another proton at 4.7 ppm (H6),
or the Hydrate Form of 4 supporting our conclusion that 4 was obtained as the alde-
hyde-hydrate form 4aq. Remarkably, the HETCOR spec-
trum of 4 showed new correlations in comparison with the
2D spectrum of 4aq (Figure 2). In particular, C2 presented a
correlation with the R-NH proton at 17.4 ppm (E), besides
the interaction with the aldehydic hydrogen at 11.3 ppm (D).
Then, to study the existence of the hydrate 4aq in acidic
solution, we obtained 1H and 13C NMR spectra of 4 in 5.44 M
TFA/D2O (Figure 3). Interestingly, it was possible to demon-
strate that 4 evolved completely to 4aq taking into account the
presence of the proton at 6.15 ppm and the absence of the
aldehydic proton at 9.63 ppm. Moreover, the 13C NMR
spectrum presented a carbon resonance at 82.0 ppm and not
carboxylic acids, are not usually seen in solution experiments the carbon at around 180 ppm, which finally demonstrated
because of a high degree of exchange.16 Interestingly, this that the hydrate form can be obtained in acidic solution.
proton is correlated with C6, which in addition presents a Possibly the electron withdrawing of the imidazolium
cation, which was generated in acidic conditions, may explain
(16) Roma~ nuk, C. B.; Manzo, R. H.; Garro Linck, Y.; Chattah, A. K.; the stability of the gem-diol form in 4aq. However, the solu-
Monti, G. A.; Olivera, M. O. J. Pharm. Sci. 2009, 98, 3788–3801. bility of either 4 or 4aq was dependent on the pH of the
3210 J. Org. Chem. Vol. 75, No. 10, 2010
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FIGURE 3. C (a) and 1H NMR spectra (b) of 4 in 5.44 M of TFA/D2O. The asterisks in the 13C NMR spectrum are for the TFA carbon
resonances.

13 13
FIGURE 4. C NMR spectra of 5 in DMSO-d6 (a) and CP-MAS (b) and NQS spectra (c) and C NMR spectra of 11 in CDCl3 (d) and
CP-MAS (e) and CPPI spectra (f).

medium, taking into account the acid-base properties of the of the quaternary carbon (C2). In contrast, 4 in D2O/NaOH or
imidazole ring (Scheme 2). D2O/TFA presented one well-resolved signal for C4-5 as a
Finally, we can summarize that the addition of water to the consequence of the fast proton transfer enhanced by the medium
carbonyl group in 4 was analogous to hemiacetal formation (Figure 1 and 3). Also, 2, 3, and 9 in DMSO-d6 showed equi-
and that it was catalyzed in acidic medium, precipitating the valence for C4-5 as a result of the protonation of the imidazole
stable hydrate form at pH = 8.0. As a result, the carbonyl ring during their synthetic process (see Supporting Information).
form in solution can be extracted with Cl2CH2. In basic An important fact to take into account in 4, 5, 8, and 11 was
medium we did not observe the presence of 4aq in solution the hybridization at the C6. When the hybridization at the men-
according with the NMR experiments in D2O/NaOH tioned carbon was sp2, two signals were observed in the 13C spec-
(Figure 1). Scheme 2 states the experimental conditions in tra for C4-5 in DMSO-d6 or CDCl3 (Figures 1, 4, and 5). How-
order to summarize which medium favors the forms 4 or 4aq. ever, if the hybridization at C6 was sp3, only one resonance signal
2.2. NMR Studies in 2-Substituted Imidazoles. The NMR was present for C4-5, as in the case of compounds 6, 7, 10. and 12
experiments in all compounds were measured in the order of (Figure 5 and Supporting Information). Previous studies of tau-
0.15 M and at 298 K. In the synthesized derivatives (4, 5, 8, 11), tomerism in azoles have used aprotic polar deuterated solvents
the nonmagnetic equivalence of C4 and C5 arose from a low (HMPT (hexamethylphosphoramide), DMF, and DMSO) in
tautomeric equilibrium between 1H and 3H forms in solution, order to reduce the rate of tautomeric exchange.17,18 However,
in the NMR time scale, giving rise to the same number of signals our results showed that the DMSO-d6 solvent did not substan-
as in the solid-state 13C spectra (Figures 1, 4 and 5). Tautomeric tially affect the proton transfer between the molecular associa-
exchange is practically stopped in the solid state as a result of the
tions of imidazole molecules in comparison with 11 in CDCl3. In
loss of molecular symmetry. In the case of compounds 4, 5, and
relation to 12 in CDCl3, the 13C NMR spectrum was in
11, 13C CP-MAS spectra revealed well-resolved peaks for the
C4-5. In the 13C spectra of the same compounds in solution
(17) Chenon, M. T.; Coupry, C.; David, M.; Grant, D. M.; Pugmire, R. J.
(Figures 1, 4, and 5), the signals corresponding to the mentioned J. Org. Chem. 1977, 42, 659–661.
carbons arose as two broad peaks with intensity lower than that (18) Toppet, S.; Wouters, G.; Smets, G. Org. Magn. Reson. 1978, 11, 578–579.

J. Org. Chem. Vol. 75, No. 10, 2010 3211

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FIGURE 5. C NMR spectra of 6 (a), 10 (b), and 8 (c) in DMSO-d6. The asterisk in the assignment of 8 is for the syn- beside the anti-isomer.

agreement with 6 and 7, indicating that the change in the

hybridization at C6 to sp3 produced the rapid interconversion
between the tautomeric forms independent of the characteristics
of the solvents.
In addition, according with our 2D NMR studies in the
solution state, the conformation of the Schiff bases 5 and 11
was the E in both cases (see Supporting Information). How-
ever, the presence of the Z isomers in rapid equilibrium
cannot be excluded.
These results indicate that the formation of a hydrogen
bond between the R-NH proton of the imidazole ring and
the oxygen or nitrogen of the substituent at C6 may stabilize 13
FIGURE 6. C CP-MAS (a) and NQS spectra (b) of 8.
the E conformation. In addition to this, the geometry
optimization performed using DFT at the B3LYP/6-31þG-
(2d,p) level using the GAUSSIAN 03 program19 showed unequivocal assignment of the syn/anti signals, the 1H
that the distances between the R-NH hydrogen and the spectra in DMSO-d6 or acetone-d6 showed that the mixture
nitrogen or oxygen in the imine or aldehyde group, respec- of syn/anti was 60:40 in both solvents. Maybe in the liquid
tively, were right for a hydrogen bond formation in 4, 5, 8, state the syn-conformation was slightly preferred in relation
and 11 (the distances were between 2.586 and 2.801 Å). to the ability of the R-OH group to interact with the
Finally, these results were in full agreement with the calcu- solvent.
lations, which favored the E isomer over the Z isomer by Finally, we performed variable-temperature NMR
29.60 kJ mol-1 in compound 5 and by 22.46 kJ mol-1 in 11, studies on 8 (Figure 7). The two well-resolved signals from
respectively. the protons of the imidazole ring for both the syn- and anti-
Then, there is a lower availability of the R-NH proton for isomers and the coalescence of C4-5/4*5* into one signal at
the intermolecular transfer between the 1H and 3H forms, 298 K indicated that the proton tautomerism rate was
thus reducing the rate of the exchange and generating the increased in acetone-d6 in contrast with the results in
existence of two prevalent tautomeric structures in the time DMSO-d6 (Figure 5). It is interesting to see that the ratio
of the NMR experiment.12 between the syn- and anti-isomers was not affected by the
On the other hand, the 13C CP-MAS spectrum of oxime 8 temperature from 298 to 202.3 K, indicating that the
allowed us to resolve the C4-5 (Figure 6) in comparison with isomerization and the tautomeric process were apparently
the 13C NMR spectrum in DMSO-d6 (Figure 5). In particular not connected. However, the R-OH and R-NH protons
the syn- and anti-isomers were present in the same amounts were exchangeable according with our 2D EXSY experi-
in the solid state (see NQS data, Figure 6b). Moreover, ments showing that the tautomeric process may also in-
taking into account the 2D-NMR results of 8 for the volve the R-OH protons of the oxime group. Additionally,
the 13C spectrum at 202.3 K showed two broad signals for
(19) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, C4,5/4*,5* as in the 13C CP-MAS. Protons of the R-OH from
M. A.; Cheesman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; the oxime group for each isomer were assigned according
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Petersson, G. A.; Nakatsuji, H.; Hada, M.;
with the HMBC results at 202.3 K (see Supporting
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishoda, M.; Nakajima, T.; Information).
Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, In addition, although the line broadening for the R-NH
H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Otcherski, J.; Ayala, P. Y.; proton signals is commonly associated with the quadru-
Morokuma, K.; Voth, G. A.; Salvador, P.; Danneberg, J. J.; Zakrzewski, polar coupling,20 in our case the tautomeric process was
V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; also involved in that broadening and the resolution in the
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.;
Baboul, A.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, R-NH proton signals was enhanced with the decrease in
A.; Piskorz, P.; Kamaromi, I.; Martin, L. R.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanaykkara, A.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, G.; Pople, J. A. (20) Harris, R. K. In Nuclear Magnetic Resonance Spectroscopy; Logman
GAUSSIAN 03, Revison B.03; Gaussian, Inc.: Pittsburgh, PA, 2003. Scientific and Technical: London, 1994.

3212 J. Org. Chem. Vol. 75, No. 10, 2010

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FIGURE 7. Variable-temperature 1H NMR spectra of 8 in acetone-d6.

temperature to 202.3 K associated with the low proton 4. Experimental Section
tautomerism rate (Figure 7).
4.1. Solid-State NMR Experiments. All solid-state NMR
experiments were performed at room temperature in a 300 MHz
3. Conclusions spectrometer equipped with a 4-mm MAS probe. High-resolution
13
The existence and stability of the hydrate and aldehyde C solid-state spectra were recorded using the ramp {1H}f{13C}
CP-MAS. NQS spectra were recorded for compounds 4aq, 5, and
forms of the imidazole-2-carboxaldehyde (4aq and 4) were
8.20 Spectral editing with the pulse sequence for cross-polarization
extensively characterized. We can summarize that the with polarization inversion (CPPI) was used in compound 11.21
hydrate form 4aq precipitated from aqueous solution at HETCOR spectra in the solid state were recorded for compounds
pH = 8.0 from the solid-state NMR results and that at 4, 4aq, 5, and 11 following the sequence presented by van Rossum
pH = 6.5 and 9.5 only 4 can be extracted with Cl2CH2 in et al.22 The contact time for the CP was 200 μs to avoid relayed
agreement with our FTIR and solid-state NMR experi- homonuclear spin-diffusion-type processes. The magic angle pulse
ments. Considering the liquid-state NMR results, hydrate length was 2.55 μs. To obtain the 1H spectra, 64 points were
4aq was the main species at pH < 6 and the aldehyde 4 the collected with a dwell time of 35.5 μs. The acquisition time was
main one at pH > 9. Moreover, the hydrate form evolved to 1.14 ms. The spinning rate was 10 kHz for all of the samples and
the aldehyde form in methanolic or DMSO solution. experiments.
We concluded that the tautomeric process between the 1H Acknowledgment. We thank CONICET (PIP 2010-12/
and 3H forms was not significantly disturbed by the DMSO- 441), Universidad de Buenos Aires (UBACyT 08-11/B002),
d6 solvent in compounds 4, 5, and 8. In particular, the oxime MinCyT (C
ordoba), Secyt-UNC, ANPCyT-FONCyT for
8 in acetone-d6 showed an increase in the rate of the financial support. J.M.L.M. thanks CONICET for his doc-
tautomeric exchange compared to the rate in the DMSO-d6 toral fellowships. P.N.R. thanks Universidad de Buenos
solvent. The variable-temperature NMR experiments of 8 Aires for his research fellowship for undergraduate students.
indicated that the isomerization and the tautomeric process
were apparently not connected. Supporting Information Available: Synthesis and copies
Finally, we can conclude that the intermolecular associa- of 1D- and 2D-NMR spectra of noncommercially available
tion in the time of the NMR scale was affected by the prepared compounds, FTIR and FTIR-ATR experiments,
hybridization and the nature of the substitution at C6. variable-temperature 13C spectra of 8, and geometry optimiza-
Moreover, the formation of hydrogen bonding between the tion figures of 5 and 11. This material is available free of charge
R-NH proton and the oxygen or the nitrogen of the carbonyl via the Internet at http://pubs.acs.org.
or imine group in 4, 5 and 11 may be the main cause of the
(21) Wu, X.; Zilm, K. W. J. Magn. Reson. 1993, 102, 205–213.
low tautomeric interconversion in the time of the NMR (22) van Rossum, B. J.; F€
orster, H.; de Groot, H. J. M. J. Magn. Reson.
experiment. 1997, 124, 516–519.

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