Generation and Stability of the gem-Diol Forms in Imidazole Derivatives Containing Carbonyl Groups. Solid-State NMR and Single-Crystal X-ray Diffraction Studies

Article abstract of DOI:10.1021/acs.jpca.7b12390

The stability of gem-diol forms in imidazolecarboxaldehyde isomers was studied by solid-state nuclear magnetic resonance (ss-NMR) combined with single-crystal X-ray diffraction studies. These methodologies also allowed determining the factors governing the occurrence of such rare functionalization in carbonyl moieties. Results indicated that the position of the carbonyl group is the main factor that governs the generation of geminal diols, having a clear and direct effect on hydration, since, under the same experimental conditions, only 36% of 5-imidazolecarboxaldehydes and 5% of 4-imidazolecarboxaldehydes were hydrated, as compared to 2-imidazolecarboxaldehydes, with which a 100% hydration was achieved. Not only did trifluoroacetic acid favor the addition of water to the carbonyl group but also it allowed obtaining single crystals. Single crystals of the gem-diol and the hemiacetal forms 2-imidazolecarboxaldehyde and N-methyl-2-imidazolecarboxaldehyde, respectively, were isolated and studied through ¹H ss-NMR. Mass spectrometry and solution-state NMR experiments were also performed to study the hydration process.

Full text of DOI:10.1021/acs.jpca.7b12390

Article
pubs.acs.org/JPCA
Cite This: J. Phys. Chem. A XXXX, XXX, XXX−XXX
Generation and Stability of the gem-Diol Forms in Imidazole
Derivatives Containing Carbonyl Groups. Solid-State NMR and
Single-Crystal X‑ray Diffraction Studies
Ayelen Florencia Crespi,† Agustín Jesus Byrne,† Daniel Vega,‡ Ana Karina Chattah,§
́
́
Gustavo Alberto Monti,§ and Juan Manuel Lazaro-Martínez*,†,∥
́
†Facultad de Farmacia y Bioquímica, Departamento de Química Organ
́
ica, Universidad de Buenos Aires, Junín 956 (C1113AAD),
Nacional de Energía Atomica, Av. Gral. Paz 1499 (1650) San Martín,
doba, Medina Allende s/n (X5000HUA), Cordoba, Argentina
CABA, Argentina
‡Departamento de Física de la Materia Condensada, Comision
Buenos Aires, Argentina
́
́
§FaMAF & IFEG-CONICET, Universidad Nacional de Cor
́
́
∥IQUIFIB-CONICET, Junín 956 (C1113AAD), CABA, Argentina
S
* Supporting Information
ABSTRACT: The stability of gem-diol forms in imidazolecarboxalde-
hyde isomers was studied by solid-state nuclear magnetic resonance (ss-
NMR) combined with single-crystal X-ray diffraction studies. These
methodologies also allowed determining the factors governing the
occurrence of such rare functionalization in carbonyl moieties. Results
indicated that the position of the carbonyl group is the main factor that
governs the generation of geminal diols, having a clear and direct effect
on hydration, since, under the same experimental conditions, only 36% of
5-imidazolecarboxaldehydes and 5% of 4-imidazolecarboxaldehydes were
hydrated, as compared to 2-imidazolecarboxaldehydes, with which a
100% hydration was achieved. Not only did trifluoroacetic acid favor the
addition of water to the carbonyl group but also it allowed obtaining
single crystals. Single crystals of the gem-diol and the hemiacetal forms 2-
imidazolecarboxaldehyde and N-methyl-2-imidazolecarboxaldehyde, re-
1
spectively, were isolated and studied through H ss-NMR. Mass spectrometry and solution-state NMR experiments were also
performed to study the hydration process.
of 2-imidazolecarboxaldehyde cannot be obtained with water
but by the addition of 95:5 (v/v) H2O/trifluoroacetic acid
(TFA; Scheme 1).19
1. INTRODUCTION
Understanding the chemistry of gem-diols is crucial for the
development of synthetic methods to obtain new organic
ligands, which are often used for the design of single-molecule
magnets and metal complexes.1−8 A high number of metal
complexes bearing gem-diols has been reported,4−16 in which
the presence of these moieties is generally demonstrated by
single-crystal X-ray diffraction.17−20 As a rule, the stability of
this functional group is not studied in the free ligand before the
preparation of the metal complex.
Among the wide variety of heterocyclic aldehydes used as
chelating ligands, the imidazolecarboxaldehyde isomers21−27
and pyridinecarboxaldehyde compounds7−10,13,14,28,29 are rele-
vant due to their potential capacity to remove toxic metals from
the body.21 In this context, we previously reported the isolation
of the neutral gem-diol form of the 2-imidazolecarboxaldehyde
in the solid state.20 This compound, together with the hydrated
form of 4-pyridinecarboxaldehyde11 and related compounds
(Scheme 1),19 was the first gem-diol form to be reported for
aromatic heterocyclic molecules. Particularly, the gem-diol form
As for biochemistry aspects, solution-state NMR and X-ray
crystallography experiments have been used to confirm the
formation of gem-diol and hemiacetal structures, for example, as
intermediate structures in the binding of α-chymotrypsin with a
macrocyclic peptidomimetic aldehyde.17 Particularly, X-ray
studies have been conducted to elucidate the structure of a
gem-diol intermediate in the catalysis exerted by the HIV-1
protease.30,31 Furthermore, solid-state NMR (ss-NMR) is a
useful methodology to elucidate the chemical composition of
mixtures in which both gem-diol and carbonyl forms are
present.19 In the latter cases, on the one hand, high-
performance liquid chromatography techniques may be used;
however, dissolution of the sample in acid/water mixtures and
proper optimization of the chromatographic system are
Received: December 16, 2017
Published: December 20, 2017
© XXXX American Chemical Society
A
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a
Scheme 1. Previous NMR Hydration Studies
a
Performed in pyridinecarboxaldehyde and 2-imidazolecarboxaldehyde compounds.
required. On the other hand, solution-state NMR studies can
be easily performed and analyzed in a broad variety of solvents
(D2O, D2O/NaOD, CD3OD, deuterated dimethyl sulfoxide
(DMSO-d6), D2O/TFA, among others).
To have an insight into the chemistry of gem-diol
compounds, the aim of this work was to study the gem-diol
generation in imidazolecarboxaldehydes through the combina-
tion of ss-NMR and single-crystal X-ray diffraction techniques.
Complementary analyses were performed by solution-state
NMR, high-resolution mass spectrometry (HRMS), and 1H ss-
NMR.
small-phase incremental alternation with 64 steps (SPINAL64)
sequence was used for heteronuclear decoupling during
acquisition with a proton field H1H satisfying ω1Η/2π =
γΗΗ1Η = 62 kHz.33 The spinning rate for all the samples was 10
kHz. Different contact times were used (1.0−2.0 ms) to obtain
a compromise between the signal-to-noise ratio in each scan
and the total time of the experiments, with number of scans
1
between 2000 and 4000. The two-dimensional (2D) H−13C
HETCOR experiment in the solid state was recorded following
the sequence presented by van Rossum et al.34 The contact
time for the CP was 150 μs to avoid relayed homonuclear spin-
diffusion-type processes. The magic angle pulse length was 2.55
1
μs. To obtain the H spectra, 64 points were collected with a
2. EXPERIMENTAL SECTION
dwell time of 35.5 μs. The acquisition time was 1.14 ms, and
2.1. Synthesis. TFA (99%), 4-pyridinecarboxaldehyde (P1,
97%), 4-methylthiazole-2-carboxaldehyde (T1, 97%), 2-thio-
phenecarboxaldehyde (T2, 98%), 1-methyl-2-imidazolecarbox-
aldehyde (A2, 98%), 4-methyl-5-imidazolecarboxaldehyde (A3,
99%), 4-imidazolecarboxaldehyde (A4, 98%), deuterium oxide
(D2O, 99.9 atom %D), DMSO-d6, (99.96 atom %D), and
methanol-d4 (CD3OD, >99.8 atom %D) were purchased from
commercial sources and were used without further purification.
The 2-imidazolecarboxaldehyde (A1)20 and ethyl 3-(5-formyl-
2,4-dimethyl-1H-pyrrol-3-yl)propanoate (P2) compounds were
synthesized according to previous reports.32
The general quantitative synthesis of the corresponding
neutral gem-diol solid forms for 2-imidazolecarboxaldehyde A1
(H1) and 4-pyridinecarboxaldehyde P1 (P1H) were performed
as described elsewhere.19,20 Solid imidazolium-trifluoroacetate
derivatives containing both gem-diol and hemiacetal (Hn.TFA
and HAn.TFA), carbonyl, and carboxylic acid moieties (An.TFA
and CAn.TFA) were prepared by incubation of 50 mmol of An
in 3 mL of 95:5 (v/v) TFA/H2O for 24 h at room temperature.
Solutions were then lyophilized and stored in a desiccator until
NMR measurements were performed.
1
the spinning rate was 10 kHz. The H MAS experiments were
performed in a Bruker Ascend-600 spectrometer equipped with
a 2.5 mm MAS probe with an operating frequency for protons
1
of 600.09 MHz. H chemical shifts were indirectly referenced
relative to neat tetramethylsilane using powdered glycine as an
external reference.
The solution-state NMR experiments were performed at
room temperature in a Bruker Avance-II 300 or Bruker Ascend-
600 spectrometer. To determine the hydration of the carbonyl
group, ∼30 mg of each compound was dissolved in D2O or
95:5 (v/v) D2O/TFA.
2.3. Single-Crystal X-ray Studies. Single-crystals were
grown and isolated by slow evaporation of the solvent at room
temperature from each solution, in which the solid compound
was dissolved as indicated in Section 2.1 without the
lyophilization step. Single-crystal X-ray diffraction data were
collected at room temperature, using a Gemini A diffrac-
tometer, Oxford Diffraction, Eos CCD detector with graphite-
monochromated Mo Kα (λ = 0.710 73 Å) radiation. Data-
collection strategy and data reduction followed standard
procedures implemented in the CrystAlisPro software. Differ-
ent reflections were collected for each sample, and they are
specified in the Supporting Information section. The structures
were solved using SHELXS-97 program35 and refined using the
full-matrix LS procedure with SHELXL-2014/7.36 Anisotropic
displacement parameters were employed for non-hydrogen
atoms. All hydrogen atoms were located at the expected
positions, and they were refined using a riding model.
2.4. HRMS Studies. The HRMS results were recorded in a
Bruker micrOTOF-Q II spectrometer equipped with an
electrospray ionization (ESI). The solid samples were dissolved
in 50:50 (v/v) water/methanol or 20:60:20 (v/v) water/
2.2. NMR Experiments. High-resolution 13C solid-state
spectra for the different compounds were recorded using the
ramp 1H−13C cross-polarization and magic angle spinning (CP-
MAS) sequence with proton decoupling during acquisition.
The 13C CP-MAS experiments were performed at room
temperature in a Bruker Avance-II 300 spectrometer equipped
with a 4 mm MAS probe. The operating frequency for protons
and carbons was 300.13 and 75.46 MHz, respectively. Glycine
was used as an external reference for the 13C spectra and to set
the Hartmann−Hahn matching condition in the cross-polar-
ization experiments in 13C spectra. The recycling time was 4 s.
The contact time during CP was 1500 μs for 13C spectra. The
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Figure 1. 13C CP-MAS spectra corresponding to the gem-diol form of the 2-imidazolecarboxaldehyde A1 (H1); the remaining solids obtained after
the evaporation of the solvents in a A1 (B) or A2 (C) 95:5 (v/v) TFA/H2O solutions and the gem-diol form of N-methyl-2-imidazolecarboxaldehyde
obtained from the sample in spectrum C dissolved in water and lyophilized (D). For the hemiacetal structures in spectra B and C, the assignment is
indicated with an apostrophe.
methanol/DMSO prior to the ESI HRMS determination in
positive mode.
prompted us to obtain TFA-salt crystals. X-ray studies of single
crystals obtained for A1 in 95:5 (v/v) TFA/H2O allowed
elucidating the chemical structure of H1.TFA, in which the gem-
diol moiety is present (Figure 2 and Supporting Information).
However, the analysis of the solid remaining after the complete
evaporation of the solvent revealed the presence of the hydrate
form (δ13C = 73.2 ppm, -CH(OH)2) together with a
hemiacetal form (HA1) (δ13C = 92.4 ppm, -CH(OH)-O−;
3. RESULTS AND DISCUSSION
3.1. Hydration Studies in 2-Imidazolecarboxalde-
hydes by 13C CP-MAS Solid-State NMR. The gem-diol
form of 2-imidazolecarboxaldehyde A1 (H1) was first studied by
ss-NMR (Figure 1). The 13C CP-MAS spectrum of the neutral
gem-diol form of A1 (H1) presented a signal at δ13C = 69.6 ppm
(-CH(OH)2), while the signal corresponding to the carbonyl
group at δ13C = 180.4 ppm (-CHO)20 in A1 was not observed,
which indicates that only the gem-diol derivative was present
(Figure 1A).
1
Figure 1B and Scheme S1). On the one hand, the H NMR
spectrum, obtained in DMSO-d6, of the crystalline sample
studied in Figure 1B showed that the hemiacetal (HA1, δ1H =
6.51 ppm, -CH(OH)-O−), carbonyl (A1, δ1H = 9.66 ppm,
-CHO) and gem-diol (H1, δ1H = 6.06 ppm, -CH(OH)2) forms
were present in 42%, 42%, and 16%, respectively (Figure S1
and Scheme S1). On the other hand, the same sample dissolved
in D2O only led to the gem-diol form with a proton chemical
shift of 6.12 ppm (Figure S2). These results indicated that 13C
CP-MAS NMR is the best technique for identifying gem-diols
by observing the range of 70−100 ppm.
1
The fact that the H NMR spectrum corresponding to A1
dissolved in 95:5 (v/v) D2O/TFA indicated that 100% of the
chemical entities corresponded to the gem-diol form (Table 1)
Table 1. Amount of gem-Diol and Aldehyde Forms for the
Indicated Carbonyl Compounds As Determined by 1H NMR
As for N-methyl-2-imidazolecarboxaldehyde (A2), prelimi-
1
1H NMR
nary H solution-state NMR studies have shown that, in the
absence of TFA, the hydration of the carbonyl group could not
be achieved (Figure S4). In contrast, the hydration was
quantitative in the presence of TFA (Table 1 and Figure S5). In
consequence, single crystals for A2 were obtained when 95:5
(v/v) TFA/H2O was employed, which indicated the presence
of the hemiacetal form (HA2.2TFA; Figure 2). Not only did
the 13C CP-MAS spectrum of the solid remaining after the
evaporation of solvents show the hemiacetal HA2.2TFA form
but also it demonstrated the presence of the gem-diol form of
A2 (H2.TFA; Figure 1C). Particularly, the hydrate and the
hemiacetal forms of A2 presented the same 13C chemical shift
signals (∼83 ppm, Figure 1C). Conversely, a difference of 20
ppm was observed between the gem-diol (H1, 73.1 ppm) and
the hemiacetal (HA1, ∼93 ppm) forms of A1 (Figure 1B).
The solid whose spectrum is depicted in Figure 1C was
dissolved in D2O and analyzed by 1H NMR, to show that only
the gem-diol form H2 was present (Figure S6). However, when
95:5 (v/v)
D2O
D2O/TFA
gem-
gem-
diol
compound
diol
aldehyde
aldehyde
2-imidazolecarboxaldehyde (A1)
100
100
100
100
N-CH3-2-imidazolecarboxaldehyde
(A2)
4-CH3-5-imidazolecarboxaldehyde
100
5
95
64
(A3)
4-imidazolecarboxaldehyde (A4)
2-CHO-4-CH3-thiazole (T1)
2-CHO-thiophene (T2)
4-pyridinecarboxaldehyde (P1)19
100
a
36
a
100
a
a
100
100
50
a
50
a
100
2-CHO-3,5-(CH3)2-4-PEt-pyrrole
b
(P2)
a
b
Insoluble in water. Ethyl 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-
yl)propanoate.
C
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Figure 2. Crystal structures for H1.TFA, A3.TFA, A4.TFA, and HA2.2TFA. The displacement ellipsoids for the non-H atoms in the figure were
drawn at the 50% probability level.
Figure 3. 1H MAS NMR spectra corresponding to a solid gem-diol form of 4-pyridinecarboxaldehyde at a MAS rate of 15 (A) and 30 (B) kHz and
the reduction to the initial MAS rates of 15 (C) and 5 (D) kHz.
the same solid was dissolved in DMSO-d6, the 1H NMR
spectrum displayed both the carbonyl (A2, δ1H = 9.71 ppm,
-CHO) and gem-diol (H2, δ1H = 6.14 ppm, -CH(OH)2) signals
(Figure S7 and Scheme S1). Unfortunately, all the single-crystal
samples obtained corresponded to the hemiacetal structure
HA2 and not to the gem-diol form (H2). The signals obtained in
the 13C CP-MAS spectrum of the solid obtained after the
lyophilization of the aqueous solution containing the
trifluoroacetates H2.TFA/HA2.2TFA corresponded to the
gem-diol form (H2, δ13C = 84.9 ppm, -CH(OH)2). This
assignment allowed the unequivocal identification of the carbon
resonance signals in the spectrum of Figure 1C, where H2 and
HA2 (δ13C = 83.2 ppm, -CH(OH)-O−) were present.
Regarding the solid sample containing both H1.TFA and
HA1.2TFA (Figure 1B), the nonequivalence of the hemiacetal
carbons at ∼94 ppm may be associated with either an
D
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1
Figure 4. H MAS NMR (30 kHz) spectra corresponding to gem-diol form of the 2-imidazolecarboxaldehyde (A), crystals obtained from a 2-
imidazolecarboxaldehyde 95:5 (v/v) TFA/H2O solution (B) or a N-methyl-2-imidazolecarboxaldehyde 95:5 (v/v) TFA/H2O solution (C), and the
gem-diol form of N-methyl-2-imidazolecarboxaldehyde (D). The chemical composition was obtained from the 13C CP-MAS spectra (Figure 1) and
1
the H MAS NMR spectra of this figure.
Figure 5. HRMS spectrum for the solid studied by ss-NMR in spectra B (Figure 1) dissolved in 50:50 (v/v) methanol/water.
asymmetry present in the molecule or with the presence of
more than one molecule per unit cell, since the treatment with
water only affects the relative content of each molecule in terms
of the gem-diol and hemiacetal forms (C2, Figure 1B and
Scheme S1).
and weakly associated water (WAW, δ1H = 1.0 ppm).37,38
However, when the MAS rate was increased to 30 kHz to
enhance the resolution of the proton line (Figure 3B), and
according to the line integration, 65% of the gem-diol form
reverted to the parent aldehyde. Under these experimental
conditions, the hemiacetal structure was also present in 5%, as
indicated by “HA” in Figure 3B. This fact is indicative that, at a
MAS rate of 30 kHz, the sample melted inside the rotor (mp
70−72 °C) with the consequent loss of water, which was
inferred by the proton aldehyde signal at δ1H = 9.7 ppm, giving
rise to a spectrum that is similar to that obtained when a
3.2. Hydration Studies in Imidazole-2-carboxalde-
hydes and 4-Pyridinecarboxaldehyde by 1H-MAS ss-
NMR. To explore the hydration process in molecules bearing
1
carbonyl groups, H ss-NMR spectra at different MAS rates
were obtained. Results for the hydrated form of 4-
pyridinecarboxaldehyde P1 are shown in Figure 3. Proton
resonance signals were tentatively assigned according to
previous hydration NMR results for the gem-diol forms of 4-
pyridinecarboxaldehyde and 3-chloro-4-pyridinecarboxaldehyde
in DMSO-d6 and D2O.19 At a MAS rate of 15 kHz, the
spectrum displayed broad signals that would correspond to the
gem-diol form of P1 (P1H; Figure 3A), since the 13C CP-MAS
(at 10 kHz MAS) only revealed the presence of the gem-diol
1
solution-state H NMR is performed. When the MAS rate was
reduced to 15−5 kHz, the broadening of the NMR lines was
observed again due to the solidification of the gem-diol inside
the rotor (Figure 3C,D). In addition, the water domains (SAW
and WAW) were recovered together with the proton of the
hydroxyl groups. It is noteworthy that the solid sample inside
the rotor did not recover its initial composition after the MAS
rate reduction (Figure 3D).
form.19 Interestingly, the H MAS NMR spectrum displayed
1
different water environments, which might be related to the
The same experiments were performed for the solid samples
containing H1, H1.TFA/HA1.2TFA, H2.TFA, and H2.TFA/
presence of strongly associated water (SAW, δ1H = 5.3 ppm)
E
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Figure 6. 13C CP-MAS spectra corresponding to 4-methyl-5-imidazolecarboxaldehyde A3 (A), A3.TFA (B), 4-imidazolecarboxaldehyde A4 (C), the
crystals obtained from a A4 95:5 (v/v) TFA/H2O solution (D), and the powder sample obtained from the sample in spectrum D dissolved in water
and then lyophilized (E).
1
HA2.2TFA, although the resolution at 30 kHz MAS in the H
NMR spectra was not enough to allow the elucidation of the
chemical composition of the solids (Figure 4). This
phenomenon is due to the superimposition of the signal
corresponding to the proton bound to the gem-diol carbon
(-CH(OH)2) and the aromatic protons at δ1H = 7−6 ppm
(Figure 4). Furthermore, the presence of SAW environments
observed for samples corresponding to spectra B and C (Figure
4) overlap with the resonance signal associated with the
hydroxyl groups of the gem-diol and hemiacetal moieties in H1
and H1.TFA/HA1.2TFA, respectively. Then, the aldehyde form
of compound A2 (25%) is observed at a proton chemical shift
of 9.7 ppm with 75% of a mixture of gem-diol and hemiacetal
structures. However, no evidence for the presence of the
aldehyde form was found in the 13C CP-MAS spectrum, in
which only the profiles corresponding to the gem-diol (H2) and
hemiacetal (HA2) forms were present. In addition, the 1H MAS
NMR spectrum of the sample containing only the gem-diol
form (H2), as determined by 13C CP-MAS experiments, shows
that the aldehyde (A2) structures were also present in the same
solid due to the interconversion of the gem-diol into the
carbonyl form at the high MAS rate (Figure 4D).
3.3. HRMS Experiments. To complement the study,
HRMS experiments were done for the solids studied in spectra
B and C of Figure 1 dissolved in 50:50 (v/v) methanol/water,
and the results are shown in Figure 5. For the crystals obtained
from 95:5 (v/v) TFA/H2O and 2-imidazolecarboxaldehyde
(A1), the oxonium was the main ion (m/z = 111.056 82), which
was generated after the loss of water from the corresponding
parent hemiacetal (m/z = 129.066 62 (M+H) or 165.063 45
(M+Na)). Such hemiacetal resulted from the addition of
methanol to the carbonyl group in 2-imidazolecarboxaldehyde
(m/z = 97.040 37 (M+H)). Regarding the gem-diol ion, a
relative abundance of only 0.7% was observed in methanol/
water, and no higher m/z ions were present in the sample
(Figure 5). Once again, the results obtained in HRMS
experiments performed with the crystals obtained from 95:5
(v/v) TFA/H2O and N-methyl-2-imidazolecarboxaldehyde
dissolved in 50:50 (v/v) methanol/water were in line with
the ss-NMR and X-ray analyses performed with 2-imidazole-
carboxaldehyde and presented above, in which the presence of
ions corresponding to the hemiacetal structure (HA2.2TFA)
could not be demonstrated (Figures 1, 2, and S31). However,
when the sample was dissolved in 20:60:20 (v/v) water/
methanol/DMSO, it was possible to increase the relative
content of the ions related to the gem-diol forms for 2-
imidazolecarboxaldehyde (H1, m/z = 115.04996, 19.5%) and
N-methyl-2-imidazolecarboxaldehyde (H2, m/z = 129.0673,
23%) (Figures S30 and S32).
To demonstrate that methanol altered the chemical
composition of the solid sample, the neutral gem-diol form
H1 (100%, according to 13C CP-MAS results) was dissolved in
deuterated methanol (CD3OD). After this procedure, the
contents of gem-diol and aldehyde were found to be 37% and
63%, respectively (Figure S3). When the solid sample studied
containing both H1.TFA and HA1.2TFA molecules (Figure
1B) was dissolved in DMSO-d6, the gem-diol (H1), aldehyde
(A1), and hemiacetal (HA1) forms were 16%, 42%, and 42%
(Figure S1), respectively, thus predicting that the gem-diol form
would be significantly reduced prior to the HRMS study. In
fact, the results obtained by HRMS performed in 20:60:20 (v/
v) water/methanol/DMSO for H1 showed a relative abundance
of only 19.5% for the gem-diol form (Figure S30).
3.4. Hydration Studies in 4- and 5-Imidazolecarbox-
aldehydes. To study the possibility of producing gem-diol
moieties in other positions of the imidazole ring, the hydration
of the carbonyl group in 4- and 5-imidazolecarboxaldehyde
compounds was analyzed. The crystals obtained from 95:5 (v/
v) TFA/H2O with A3 and A4 showed that the structures
corresponded to the carbonyl forms in both cases (Figure 2). In
addition, the analysis of the remaining solid obtained from
compound A4 indicated the presence of both the carbonyl and
the carboxylic acid derivatives, as assessed by NMR (Figure 6
and Supporting Information). Although the solution-state
NMR results for A3−4 showed that the gem-diol structure was
present in 5% and 40% in 95:5 (v/v) D2O/TFA (Table 1 and
Figures S8−S11), the gem-diol forms detected by solution-state
NMR experiments could not be isolated in the solid state
(Figure 6). For instance, when the sample containing 4-
formylimidazolium (A4.TFA) and 4-carboxy-imidazolium
(CA4.TFA) trifluoroacetates was dissolved in D2O, the gem-
diol content was 38% (Figure S12). This value is close to the
F
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one obtained when A4 was treated with 95:5 (v/v) D2O/TFA,
together with 38% and 24% for the carboxyl and carbonyl
derivatives, respectively (Table 1 and Figure S11). Moreover,
when the same solid containing both A4.TFA and CA4.TFA
was dissolved in DMSO-d6, the gem-diol form was not observed
(Figure S13).
A3−4 derivatives showed a lower degree of hydration of the
aldehyde group than A1 and A2. However, because of the high
reactivity of the aldehyde carbon toward water addition induced
by TFA, both gem-diol and hemicetal forms could be isolated
(H1, HA1, H2, and HA2). The single crystals of A3−4 showed
only the presence of aldehyde groups, in contrast to the gem-
diol and hemiacetal forms of A1 and A2, respectively (Figure 2).
These differences are due to the specific electronic density of
the imidazole ring positions; that is, one of the nitrogen atoms
is mesomeric electron-donating (N1), and the other one is
electron-withdrawing (N3).39 Taking into account these results,
it can be postulated that the lower reactivity of the aldehyde
group in A3 toward the addition of water would explain why in
copper, cadmium, zinc, and cobalt complexes the formyl group
remains unhydrated.21,40 The same results have been obtained
for a complex of zinc(II) and A4.23 An iron(III) complex was
also reported with a new 4-imidazolecarboxaldehyde ligand in
which the formyl group was not altered.41 In contrast, the
aldehyde group is hydrated to the gem-diol form in ruthenium-
(III) complexes with 2-imidazolecarboxaldehyde (A1) mole-
cules in the solution state.22
To demonstrate that the second position of the imidazole
ring is particularly effective for the generation of gem-diol
derivatives when the carbonyl group is present in this position,
other aromatic compounds were analyzed (Table 1 and
Supporting Information). For 2-thiophenecarboxaldehyde
(T2) and ethyl 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-
propanoate (P2), no evidence of hydration of the aldehyde
group was observed even when 95:5 (v/v) D2O/TFA was
employed (Table 1 and Figure S18). In contrast, 4-
methylthiazole-2-carboxaldehyde (T1) was completely hydrated
in TFA, demonstrating that the electronic density is a crucial
factor for the polarization of the carbonyl group and the
addition of water in acidic medium (Table 1 and Figure S16).39
Although 4-methylthiazole-2-carboxaldehyde (T1) was com-
pletely hydrated, as assessed by solution-state NMR experi-
ments, the gem-diol form was not solid; therefore, crystallo-
graphic and ss-NMR analyses could not be performed. Ethyl 3-
(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)propanoate dehyde (P2)
was selected, because the absence of free positions in the
aromatic ring prevents its decomposition by TFA. The X-ray
and ss-NMR results for this compound are shown in the
Supporting Information (Figures S27−S29).
Furthermore, the solid studied in spectrum D in Figure 6
shows that neutral A4 molecules (-CHO, δ13C = 181.9 ppm)
are still present in the crystalline samples and cannot be
inferred from the solution-state NMR experiments. However,
when the sample containing both A4 and A4.TFA was treated
with water, the sample became homogeneous, and only the
protonated A4 molecules were observed (Figure 6E).
As for the position of the carbonyl group in the imidazole
ring, our results showed a higher oxidative susceptibility when
the aldehyde was at position 4 of the imidazole ring than in the
case of 4-methyl-5-imidazolecarboxaldehyde. Thus, during the
incubation with TFA, 4-imidazolecarboxaldehyde was oxidized
to render the corresponding 4-carboxylic-imidazole acid due to
the progression to the gem-diol form after the addition of water,
which was higher than in the case of 4-methyl-5-imidazole-
carboxaldehyde.
Likewise, a 2D solid-state 1H−13C HETCOR was performed
to facilitate the analysis of the proton dimension and to clearly
discriminate the corresponding hydrogen atoms of the carboxyl
group of the CA4 in the mixture of compounds obtained in the
incubation of A4 in TFA (Figure 7). The splitting observed in
4. CONCLUSIONS
1
Figure 7. 2D H−13C HETCOR spectrum for the crystals obtained
This study assesses the generation and stability of the gem-diol
forms in imidazole derivatives containing carbonyl groups. The
hydration studies performed by solution- and solid-state NMR
indicated that the position of the carbonyl group was essential
to stabilize the gem-diol form or even to increase the reactivity
to obtain hemiacetal forms in 2-formylimidazole compounds.
The gem-diol or hemiacetal forms of A1−2 were obtained and
studied by ss-NMR and crystallographic techniques. In
addition, the corresponding carbonyl forms were observed in
A3−4 derivatives under the same conditions under which A1−2
were completely hydrated. These results indicate that positions
4 and 5 of the imidazole ring did not effectively sense the
electron-withdrawing character of the entire system upon
protonation, as observed for 2-thiophenecarboxaldehyde (T2)
and ethyl 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)propanoate
(P2).
from the TFA solution with 4-imidazolecarboxaldehyde A4.
the carbon dimension for the carbonyl carbon at δ ≈ 180 ppm
with its bound aldehyde hydrogen indicates the existence of a
group of A4 molecules constituted by protonated and neutral
species. Furthermore, two different kinds of protons can be
easily assigned in the indirect dimension. These protons are
associated with a long-range interaction with the carbon of the
carboxylic acid present in TFA and 4-carboxy-imidazole
molecules. The distance of such interaction, estimated through
NMR analysis, was obtained from crystallography experiments
performed with A4.TFA and was found to be 2.547 Å
(F3CCO2···H-N-Im; Figure 7).
Finally, the hydration studies conducted on 2-, 4-, or 5-
imidazolecarboxaldehydes indicated that the position of the
carbonyl group was key to obtain the gem-diol function by
treatment with TFA both in solution and in solid state. The
Unlike pyridinecarboxaldehydes, the formyl groups in
imidazolecarboxaldehydes do not incorporate water under
G
DOI: 10.1021/acs.jpca.7b12390
J. Phys. Chem. A XXXX, XXX, XXX−XXX

The Journal of Physical Chemistry A
Article
Situ Reactions of Picolinaldehyde and Acetylpyridine: Experimental
neutral conditions. Instead, the gem-diol forms can be generated
with the addition of TFA, which favors the nucleophilic
addition of water. This phenomenon is possible due to the
increase of the electron-withdrawing character of the imidazole
ring upon protonation. Remarkably, our results indicated that,
although TFA increased the gem-diol content, the position of
the formyl group determines the possibility of obtaining the
gem-diol solid structure, being the second position of the
imidazole ring the only one that particularly senses the
electron-withdrawing character. These differences are due to
the specific electronic density of the imidazole ring positions,
since the formyl group in 4-methyl-2-thiazolecarboxaldehyde
(T1) was completely hydrated, whereas such group was not
hydrated in 2-thiophenecarboxaldehyde (T2) and 3,5-dimethyl-
4-carboxyethylpyrrole-2-carboxaldehyde (P2) when the same
experimental conditions were employed.
and Theoretical Study. Chem. - Eur. J. 2013, 19, 17567−17577.
(3) Llano-Tome,
Fidalgo-Marijuan, A.; Fernan
́
F.; Bazan
́
, B.; Karmele Urtiaga, M.; Barandika, G.;
dez De Luis, R.; Arriortua, M. I. Water-
́
Induced Phase Transformation of a CuII-Coordination Framework
with Pyridine-2,5- Dicarboxylate and Di-2-Pyridyl Ketone: Synchro-
tron Radiation Analysis. CrystEngComm 2015, 17, 6346−6354.
(4) Tasiopoulos, A. J.; Perlepes, S. P. Diol-Type Ligands as Central
“players” in the Chemistry of High-Spin Molecules and Single-
Molecule Magnets. Dalt. Trans. 2008, 41, 5537−5555.
(5) Stamatatos, T. C.; Nastopoulos, V.; Tasiopoulos, A. J.; Moushi, E.
E.; Wernsdorfer, W.; Christou, G.; Perlepes, S. P. High Nuclearity
Single-Molecule Magnets: A Mixed-Valence Mn Cluster Containing
the Di-2-Pyridylketone Diolate Dianion High Nuclearity Single-
Molecule Magnets: A Mixed-Valence Mn26 Cluster Containing the
Di-2-Pyridylketone Diolate Dianion. Inorg. Chem. 2008, 47, 10081−
10089.
(6) Savva, M.; Skordi, K.; Fournet, A. D.; Thuijs, A. E.; Christou, G.;
Perlepes, S. P.; Papatriantafyllopoulou, C.; Tasiopoulos, A. J.
Heterometallic MnIII4Ln2 (Ln = Dy, Gd, Tb) Cross-Shaped Clusters
and Their Homometallic MnIII4MnII2 Analogues. Inorg. Chem. 2017,
56, 5657−5668.
(7) Wang, H.-S.; Yang, F.-J.; Long, Q.-Q.; Huang, Z.-Y.; Chen, W.;
Pan, Z.-Q. Syntheses, Crystal Structures, and Magnetic Properties of a
Family of Heterometallic Octanuclear [Cu6Ln2] (Ln = Dy(III),
Tb(III), Ho(III), Er(III), and Gd(III)) Complexes. New J. Chem.
2017, 41, 5884−5892.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jpca.7b12390.
■
S
Crystallographic information for each compound: crystal
data and structure refinement results, crystal structure
with numbering and packing schemes, tables of fractional
coordinates and equivalent isotropic displacement
parameters of the non-H atoms, bond lengths and
angles, atomic anisotropic displacement parameters,
hydrogen atom positions and torsion angles. Solution-
state NMR spectra for all the compounds studied in the
present work (PDF)
(8) Giannopoulos, D. P.; Cunha-Silva, L.; Ballesteros-Garrido, R.;
Ballesteros, R.; Abarca, B.; Escuer, A.; Stamatatos, T. C. New
Structural Motifs in Mn Cluster Chemistry from the Ketone/gem-Diol
and Bis(gem-Diol) Forms of 2,6-Di-(2-Pyridylcarbonyl)pyridine:
{MnII4MnIII2} and {MnII4MnIII6} Complexes. RSC Adv. 2016, 6,
105969−105979.
́
(9) Bravo-García, L.; Barandika, G.; Bazan, B.; Urtiaga, M. K.;
X-ray crystallographic data (CIF)
Arriortua, M. I. Thermal Stability of Ionic Nets with CuII Ions
Coordinated to Di-2-Pyridyl Ketone: Reversible Crystal-to-Crystal
Phase Transformation. Polyhedron 2015, 92, 117−123.
Structural data of H1.TFA, HA2.2TFA, A3.TFA, A4.TFA, and
P2 compounds were deposited as CIF files at the Cambridge
Crystallographic Database (CCDC Nos. 1471036, 1471037,
1471039, 1471041, and 1471044) and can be downloaded
freely from http://ccdc.cam.ac.uk.
(10) Efthymiou, C. G.; Raptopoulou, C. P.; Psycharis, V.;
Tasiopoulos, A. J.; Escuer, A.; Perlepes, S. P.; Papatriantafyllopoulou,
C. Copper(II)/di-2-Pyridyl Ketone Chemistry: A Triangular Cluster
Displaying Antisymmetric Exchange versus an 1D Coordination
Polymer. Polyhedron 2013, 64, 30−37.
AUTHOR INFORMATION
Corresponding Author
*Phone/Fax: +54-11-5287-4323. E-mail: lazarojm@ffyb.uba.ar
and jmlazaromartinez@gmail.com.
■
́
(11) Gonzalez Mantero, D.; Altaf, M.; Neels, A.; Stoeckli-Evans, H.
Pyridin-4-Ylmethanediol: The Hydrated Form of Isonicotinaldehyde.
Acta Crystallogr., Sect. E: Struct. Rep. Online 2006, 62, o5204−o5206.
(12) Melaiye, A.; Sun, Z.; Hindi, K.; Milsted, A.; Ely, D.; Reneker, D.
H.; Tessier, C. A.; Youngs, W. J. Silver(I)−Imidazole Cyclophane
Gem-Diol Complexes Encapsulated by Electrospun Tecophilic
Nanofibers: Formation of Nanosilver Particles and Antimicrobial
Activity. J. Am. Chem. Soc. 2005, 127, 2285−2291.
ORCID
Gustavo Alberto Monti: 0000-0001-6531-798X
Juan Manuel Lazaro-Martínez: 0000-0002-7189-6874
́
Notes
(13) Wang, W.; Spingler, B.; Alberto, R. Reactivity of 2-Pyridine-
Aldehyde and 2-Acetyl-Pyridine Coordinated to [Re(CO)3]+ with
Alcohols and Amines: Metal Mediated Schiff Base Formation and
Dimerization. Inorg. Chim. Acta 2003, 355, 386−393.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(14) Yang, G.; Tong, M. L.; Chen, X. M.; Ng, S. W. Bis(di-2-
Pyridylmethanediol-N, O,N’)- copper(II) Diperchlorate. Acta Crys-
tallogr., Sect. C: Cryst. Struct. Commun. 1998, 54, 732−734.
This work was performed with the financial support from
ANPCYT (PICT 2012-0151, PICT 2014-1295, and PICT
2016-1723), Univ. de Buenos Aires (UBACyT 2017-2019/
22BA), CONICET (PIP 2014-2016/130), and SeCyT Univ.
(15) Bock, H.; Van, T. T. H.; Schodel, H.; Dienelt, R. Structural
̈
Changes of Di(2-Pyridyl) Ketone on Single and Twofold Protonation.
Eur. J. Org. Chem. 1998, 1998, 585−592.
́
Nacional de Cordoba. A.F.C. and A.J.B. are grateful for their
doctoral and undergraduate fellowships granted by Univ. de
Buenos Aires, respectively.
(16) Wang, S. L.; Richardson, J. W.; Briggs, S. J.; Jacobson, R. A.;
Jensen, W. P. Stabilization of a Hydrated Ketone by Metal
Complexation. The Crystal and Molecular Structures of Bis-2,2’,
N,N’-Bipyridyl Ketone-Hydrate Nickel(II) Sulfate, Copper(II) Chlor-
ide and Copper(II) Nitrate. Inorg. Chim. Acta 1986, 111, 67−72.
(17) Zhang, X.; Bruning, J. B.; George, J. H.; Abell, A. D. A
Mechanistic Study on the Inhibition of α-Chymotrypsin by a
Macrocyclic Peptidomimetic Aldehyde. Org. Biomol. Chem. 2016, 14,
6970−6978.
REFERENCES
■
(1) Woodruff, D. N.; Winpenny, R. E. P.; Layfield, R. A. Lanthanide
Single-Molecule Magnets. Chem. Rev. 2013, 113, 5110−5148.
́
(2) Liu, J.-L.; Lin, W.-Q.; Chen, Y.-C.; Gomez-Coca, S.; Aravena, D.;
Ruiz, E.; Leng, J.-D.; Tong, M.-L. Cu(II)-Gd(III) Cryogenic Magnetic
Refrigerants and Cu8Dy9 Single-Molecule Magnet Generated by in
H
DOI: 10.1021/acs.jpca.7b12390
J. Phys. Chem. A XXXX, XXX, XXX−XXX

The Journal of Physical Chemistry A
Article
(18) Oslaj, M.; Cluzeau, J.; Orkic, D.; Kopitar, G.; Mrak, P.; Casar, Z.
A Highly Productive, Whole-Cell DERA Chemoenzymatic Process for
Production of Key Lactonized Side-Chain Intermediates in Statin
Synthesis. PLoS One 2013, 8, e62250.
(35) Sheldrick, G. M. Phase Annealing in SHELX-90: Direct
Methods for Larger Structures. Acta Crystallogr., Sect. A: Found.
Crystallogr. 1990, 46, 467−473.
(36) Sheldrick, G. M. A Short History of SHELX. Acta Crystallogr.,
Sect. A: Found. Crystallogr. 2008, 64, 112−122.
(19) Crespi, A. F.; Vega, D.; Chattah, A. K.; Monti, G. A.; Buldain, G.
(37) Turov, V. V.; Gun’ko, V. M.; Zarko, V. I.; Leboda, R.; Jablonski,
M.; Gorzelak, M.; Jagiello-Wojtowicz, E. Weakly and Strongly
Associated Nonfreezable Water Bound in Bones. Colloids Surf., B
2006, 48, 167−175.
́
Y.; Lazaro-Martínez, J. M. Gem-Diol and Hemiacetal Forms in
Formylpyridine and Vitamin-B6-Related Compounds: Solid-State
NMR and Single-Crystal X-Ray Diffraction Studies. J. Phys. Chem. A
2016, 120, 7778−7785.
(38) Gun’ko, V. M.; Savina, I. N.; Mikhalovsky, S. V. Cryogels:
Morphological, Structural and Adsorption Characterisation. Adv.
Colloid Interface Sci. 2013, 187−188, 1−46.
́
(20) Lazaro Martínez, J. M.; Romasanta, P. N.; Chattah, A. K.;
Buldain, G. Y. NMR Characterization of Hydrate and Aldehyde Forms
of Imidazole-2-Carboxaldehyde and Derivatives. J. Org. Chem. 2010,
75, 3208−3213.
(39) Berezin, M. Y.; Kao, J.; Achilefu, S. PH-Dependent Optical
Properties of Synthetic Fluorescent Imidazoles. Chem. - Eur. J. 2009,
15 (14), 3560−3566.
(21) Barszcz, B. Coordination Properties of Didentate N, O
Heterocyclic Alcohols and Aldehydes towards Cu(II), Co(II), Zn(II)
and Cd(II) Ions in the Solid State and Aqueous Solution. Coord.
Chem. Rev. 2005, 249, 2259−2276.
(22) Elliott, M. G.; Shepherd, R. E. Pentaammineruthenium(II/III)
Imidazole and Imidazolate Complexes of 2-Carboxylatoimidazole and
2-Imidazolecarboxaldehyde. Inorg. Chem. 1987, 26, 2067−2073.
(23) Won, M. S.; Lee, Y. H.; Rukmini, E.; Harrowfield, J. M.; Kim, Y.
Aldehyde Coordination in Template Reactions: Crystal Structure of a
Possible Reaction Intermediate. Inorg. Chem. Commun. 2013, 38, 156−
159.
́
(40) Barszcz, B.; Hodorowicz, S. A.; Stadnicka, K.; Jabłonska-
Wawrzycka, A. A Comparison of the Coordination Geometries of
Some 4-Methylimidazole-5-Carbaldehyde Complexes with Zn(II),
Cd(II) and Co(II) Ions in the Solid State and Aqueous Solution.
Polyhedron 2005, 24, 627−637.
(41) Li, J.; Molenda, M. A.; Biros, S. M.; Staples, R. J.; Chavez, F. A.
Assembly of a Mononuclear Ferrous Site Using a Bulky Aldehyde-
Imidazole Ligand. Inorganica Chim. Inorg. Chim. Acta 2017, 464, 152−
156.
(24) Seredyuk, M.; Gaspar, A. B.; Kusz, J.; Gutlich, P. Mononuclear
̈
Complexes of Iron(II) Based on Symmetrical Tripodand Ligands:
Novel Parent Systems for the Development of New Spin Crossover
Metallomesogens. Z. Anorg. Allg. Chem. 2011, 637, 965−976.
(25) Liao, Y. Te; Dutta, S.; Chien, C. H.; Hu, C. C.; Shieh, F. K.; Lin,
C. H.; Wu, K. C. W. Synthesis of Mixed-Ligand Zeolitic Imidazolate
Framework (ZIF-8−90) for CO2 Adsorption. J. Inorg. Organomet.
Polym. Mater. 2015, 25, 251−258.
(26) Brewer, C.; Brewer, G.; Butcher, R. J.; Carpenter, E. E.; Cuenca,
L.; Noll, B. C.; Scheidt, W. R.; Viragh, C.; Zavalij, P. Y.; Zielaski, D.
Synthesis and Characterization of manganese(II) and iron(III) d5
Tripodal Imidazole Complexes. Effect of Oxidation State, Protonation
State and Ligand Conformation on Coordination Number and Spin
State. Dalton Trans. 2006, 8, 1009−1019.
(27) Qin, L.-F.; Pang, C.-Y.; Han, W.-K.; Zhang, F.-L.; Tian, L.; Gu,
Z.-G.; Ren, X.; Li, Z. Optical Recognition of Alkyl Nitrile by a
Homochiral iron(II) Spin Crossover Host. CrystEngComm 2015, 17,
7956−7963.
(28) Cruz-Enriquez, A.; Baez-Castro, A.; Hopfl, H.; Parra-Hake, M.;
Campos-Gaxiola, J. J. Tetrakis(u-Acetato-k2O: O’)-bis[(3-Pyridine-
carboxaldehyde-kN’)]-dicopper(II)(CuCu). Acta Crystallogr., Sect.
E: Struct. Rep. Online 2012, 68, m1339−m1340.
(29) Efthymiou, C. G.; Papatriantafyllopoulou, C.; Aromi, G.; Teat,
S. J.; Christou, G.; Perlepes, S. P. A NiII Cubane with a Ligand
Derived from a Unique Metal Ion-Promoted, Crossed-Aldol Reaction
of Acetone with Di-2-Pyridyl Ketone. Polyhedron 2011, 30, 3022−
3025.
́
́
(30) Krzeminska, A.; Moliner, V.; Swiderek, K. Dynamic and
Electrostatic Effects on the Reaction Catalyzed by HIV-1 Protease. J.
Am. Chem. Soc. 2016, 138, 16283−16298.
(31) Das, A.; Mahale, S.; Prashar, V.; Bihani, S.; Ferrer, J. L.; Hosur,
M. V. X-Ray Snapshot of HIV-1 Protease in Action: Observation of
Tetrahedral Intermediate and Short Ionic Hydrogen Bond SIHB with
Catalytic Aspartate. J. Am. Chem. Soc. 2010, 132, 6366−6373.
(32) Davies, J. L. A Synthesis of 2,6-Diacetyldeuterioporphyrin II
Dimethyl Ester. J. Chem. Soc. C 1968, 1392−1396.
(33) Fung, B. M.; Khitrin, A. K.; Ermolaev, K. An Improved
Broadband Decoupling Sequence for Liquid Crystals and Solids. J.
Magn. Reson. 2000, 142, 97−101.
(34) van Rossum, B.-J.; Forster, H.; de Groot, H. J. M. High-Field
̈
and High-Speed CP-MAS 13C NMR Heteronuclear Dipolar-
Correlation Spectroscopy of Solids with Frequency-Switched Lee−
Goldburg Homonuclear Decoupling. J. Magn. Reson. 1997, 124, 516−
519.
I
DOI: 10.1021/acs.jpca.7b12390
J. Phys. Chem. A XXXX, XXX, XXX−XXX