The structure and dynamic properties of 1H-pyrazole-4-carboxylic acids in the solid state

Article abstract of DOI:10.1524/zpch.2013.0377

The structure of three simple pyrazole-4-carboxylic acids unsubstituted in position 1 (NH derivatives) 1H-pyrazole-4-carboxylic acid (1), 3(5)-methyl-1H-pyrazole-4-carboxylic acid (2) and 3,5-dimethyl-1H-pyrazole-4- carboxylic acid (3) are discussed based

Full text of DOI:10.1524/zpch.2013.0377

Z. Phys. Chem. / DOI 10.1524/zpch.2013.0377
© by Oldenbourg Wissenschaftsverlag, München
The Structure and Dynamic Properties of
1H-Pyrazole-4-Carboxylic Acids in the Solid State
2
2
By Lourdes Infantes1 ∗, M. Angeles Garc´ıa , Concepcio´n Lo´pez ,
,
´
Rosa M. Claramunt1 2 ∗, and Jose´ Elguero3
,
,
1
Departamento de Cristalograf´ıa y Biolog´ıa Estructural, Instituto de Qu´ımica-F´ısica ‘Rocasolano’,
CSIC, Serrano, 119, E-28006 Madrid, Spain
Departamento de Qu´ımica Orga´nica y Bio-Orga´nica, Facultad de Ciencias, Universidad Nacional de
2
Educacio´n a Distancia (UNED), Senda del Rey 9, E-28040 Madrid, Spain
Instituto de Qu´ımica Me´dica, Centro de Qu´ımica Orga´nica ‘Manuel Lora-Tamayo’, CSIC, Juan de la
3
Cierva, 3, E-28006 Madrid, Spain
Dedicated to Prof. Dr. Hans-Heinrich Limbach on the occasion of his 70th birthday
(Received December 14, 2012; accepted in revised form March 21, 2013)
(Published online June 3, 2013)
Hydrogen Bonds / Multinuclear NMR / Solid-State Proton Transfer /
Tautomerism
The structure of three simple pyrazole-4-carboxylic acids unsubstituted in position 1 (NH
derivatives) 1H-pyrazole-4-carboxylic acid (1), 3(5)-methyl-1H-pyrazole-4-carboxylic acid (2) and
3,5-dimethyl-1H-pyrazole-4-carboxylic acid (3) are discussed based on crystallographic results (two
new structures) and solid-state NMR (CPMAS). Compounds 1 and 3 present polymorphism and
one of the polymorphs of each compound shows solid-state proton transfer (SSPT). Compound 2
presents tautomerism that has been studied by NMR, both in the solid-state and in solution at low
temperature.
1. Introduction
Considerable attention has been paid to the solid-state dynamic properties of pyra-
zoles [1–4]. These properties involve the solid-state proton transfer (SSPT) of protons
between the N atoms in cyclamers (dimers, trimers and tetramers) with rates that are
appropriate to be studied by NMR. A very different case of SSPT is observed when
studying 1H-pyrazole-4-carboxylic acid (1) [5,6] (Scheme 1).
Unlike simple pyrazoles, which form dimers, trimers, tetramers and catemers, com-
pound 1 shows an intriguing case of coupled proton and heavy atom motions. Single
crystal X-ray crystallography indicated that the molecule forms tapes linked by double
* Corresponding authors. E-mail: xlourdes@iqfr.csic.es; rclaramunt@ccia.uned.es

L. Infantes et al.
Scheme 1.
Fig. 1. Solid state tautomerism of 1 between two forms A and B as observed by solid state 15N CPMAS
NMR. As OH· · · N hydrogen bonds are slightly shorter than the O· · · HN hydrogen bonds, two adjacent
PCA molecules form a downward angle in A and an upward angle in B [6].
hydrogen bonds (HBs) between the pyrazole and carboxyl groups (Fig. 1), exhibiting
dynamic or static proton disorder. Monomers of 1H-pyrazole-4-carboxylic acid form
hydrogen bonds with adjacent molecules using the C=O (HB acceptor) and the OH
(HB donor) of the carboxylic group as well as the C=N (HB acceptor) and the NH (HB
donor) of the 1H-pyrazole ring.
A single 15N line was observed at room temperature by 15N CPMAS NMR at
−135.4 ppm (referred to external MeNO2) ppm indicating that the disorder is dynamic,
caused by a rapid degenerate proton tautomerism.
Using a combination of longitudinal 15N and 2H relaxometry, the rate constants of
the double HH, HD and DD transfers in solid dimeric units of 1 ribbons were deter-
mined. Within the margin of error, no kinetic isotope effects (KIE) were observed. This
is unusual as compared to pyrazole dimers and benzoic acid dimers, which exhibit large
kinetic HH/HD/DD isotope effects. The absence of KIE in PCA was associated with
small molecular reorientations preceding proton tunneling and during proton tunnel-
ing. Cu(II) complexes of 1 have been used to synthesize new MOF with interesting
magnetic properties [7].
The unique properties of 1 reported above prompted us to explore other 1H-
pyrazole-4-carboxylic acids [the 3(5)-carboxylic acids are more common [8–10] but
lack the necessary quasi-symmetric structure]. In the CSD [11], there are very few com-
pounds having a 1H-pyrazole-4-carboxylic acid structure with the N2 lone pair free,
actually only two: compound 1 (refcode TIDLIB and TIDLIB01, determined at 150 and
293 K) and WEHLAX, but this compound having a carboxylate anion at position 5,
forms a O–H···O HB [12].

The Structure and Dynamic Properties of 1H-Pyrazole-4-Carboxylic Acids in the Solid State
Therefore, we selected the two pyrazoles closer in structure to 1 studying its C-
monomethyl 2 and the C,C-dimethyl 3 derivatives. In this paper, we report their prop-
erties in solution and in the solid state and compare them with those of 1.
2. Methods
1H-pyrazole-4-carboxylic acid (1) and 3(5)-methyl-1H-pyrazole-4-carboxylic acid (2)
were purchased from Aldrich and used with no further purification. 3,5-Dimethyl-
1H-pyrazole-4-carboxylic acid (3) was prepared according to the literature [13,14] as
described below.
Ethyl diacetoacetate (1.72 g, 0.01 mol) was dissolved in 25 mL of 20% aqueous
acetic acid and the solution cooled down to 10 ◦C. Then 98% hydrazine (0.01 mol) was
added dropwise with magnetic stirring keeping the temperature around 15–20 ◦C. After
the addition was completed the reaction mixture was stirred at room temperature for
12 h. The solution was then concentrated under reduced pressure, co-evaporated with
heptane several times, and the final residue crystallized from heptane to afford the ethyl
ester of 3, which after standard saponification with 25 mL of 2N aqueous KOH, gave
rise to 3,5-dimethyl-1H-pyrazole-4-carboxylic acid (3). The two-step reaction over-
all yield in pure acid, crystallized from petroleum ether, was 48%. The sample thus
obtained melted with decomposition at 215.3 ◦C (Differential Scanning Calorimetry).
When the compound was recrystallized from a mixture of water-ethanol, dissolved
in the minimum amount of hot water and with addition of ethanol until dimness, it
melted with decomposition at 254.4 ◦C (Differential Scanning Calorimetry).
2.1 Crystallographic part
A summary of crystal data and refinement parameters is given in Table 1. Acicular and
dendritic crystals were obtained by slow evaporation of water for compound (2) and
a water/methanol mixture for compound (3) respectively. A fragment of both com-
pounds was carefully cut and chosen for X-ray crystallography. These fragments were
covered with perfluoropolyether oil and mounted in fiber loops. Diffraction data were
collected at 120 K on a Bruker-IμS microfocus source with Cu Kα radiation, equipped
with an Apex-II CCD area detector and an Oxford Cryosystems cooling device. The
structures were solved by direct methods using SHELXS-97 [15] and refined by full-
matrix least-squares procedures. Non-hydrogen atoms were refined with anisotropic
displacement parameters and the hydrogen atoms were introduced into the geometri-
cally calculated positions and refined riding on the corresponding parent atoms with
exception of the donor hydrogens, NH and OH, that were included in positions iden-
tified from the difference Fourier maps. NH hydrogens were refined free while OH
hydrogens were refined as riding.
CCDC 915011 (2) and CCDC 913741 (3) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
Graph Sets. Description of the intermolecular hydrogen bond motifs observed in
the title compounds has been done along the manuscript using the Etter-Bernstein graph

L. Infantes et al.
Table 1. Crystal data and structure refinement for 5-methyl-1H-pyrazole-4-carboxylic acid (2) and 3,5-
dimethyl-1H-pyrazole-4-carboxylic acid (3).
(2)
(3)
Empirical formula
Formula weight
C5H6N2O2
126.12
C6H8N2O2
140.14
Temperature
Wavelength
293(2) K
1.54178 Å
Crystal system, space gro◦up
Monoclinic, P21/c
a = 4.8504(2)
b = 6.2826(3)
c = 18.3052(9)
90, 92.383(3), 90
557.33(4)
4, 1.503
1.010
264
Orthorhombic, Pca21
a = 13.203(3)
b = 3.9520(7)
c = 12.172(3)
90, 90, 90
635.1(2)
4, 1.466
0.944
296
Unit cell dimensions (Å, )
Volume (Å3)
Z, calculated density (Mg/m3)
Absorption coefficient (mm−1
F(000)
)
Crystal size (mm)
0.32 × 0.08 × 0.04
4.84–65.80
−5 ≤ h ≤ 4
−7 ≤ k ≤ 7
−21 ≤ l ≤ 21
3938/952
0.39 × 0.10 × 0.07
6.71–64.34
−15 ≤ h ≤ 15
−4 ≤ k ≤ 3
−14 ≤ l ≤ 14
2657/972
θ range for data collection (◦)
Limiting indices
Reflections collected/unique
R(int)
0.0754
0.0785
Completeness (%)
Refinement method
98.6 (θ = 65.80)
98.4 (θ = 64.34)
Full-matrix least-squares on F2
Data/restraints/parameters
Goodness-of-fit on F2
R1/wR2 indices [I > 2σ(I)]
R1/wR2 indices (all data)
Largest diff. peak and hole (e·Å−3
952/0/89
1.145
0.0615/0.1647
0.0718/0.1722
0.264/−0.281
972/1/95
1.095
0.0474/0.0869
0.0629/0.0918
0.206/−0.192
)
set [16]. Following this methodology, in compounds 1, 2 and 3 infinite chains and dis-
crete rings designated as C and R respectively can be observed. These letters come
together with numbers that denote the number of donors and acceptors used in each
motif, separated by a coma, and the size of the motif (corresponding to the number of
atoms in the repeat unit) indicated in parentheses. For example, R4,2(8) means a ring
with 4 hydrogens donors, 2 atoms acceptors and a total of 8 atoms in the repeated unit.
2.2 Experimental NMR
NMR spectra in solution were recorded on a Bruker DRX 400 spectrometer (9.4 Tesla,
400.13 MHz for 1H, 100.62 MHz for 13C and 40.56 MHz for 15N) with a 5-mm inverse-
detection H-X probe equipped with a z-gradient coil. Chemical shifts (δ in ppm) are
1
given from internal solvent DMSO-d6 2.49 for H and 39.5 for 13C, HMPA-d18 2.51
1
1
for H and 35.8 for 13C, MeOD-d4 3.31 for H and 49.2 for 13C and THF-d8 3.58 for
1H and 67.4 for 13C. For 15N NMR, nitromethane (0.00) was used as external stan-
dard. Variable-temperature experiments were recorded with the same spectrometer and
a Bruker BVT3000 temperature unit was used to control the temperature of the cooling

The Structure and Dynamic Properties of 1H-Pyrazole-4-Carboxylic Acids in the Solid State
gas stream and an exchanger to achieve low temperatures. gs-HMQC (1H-13C), gs-
HMBC (1H-13C), gs-HMQC (1H-15N) and gs-HMBC (1H-15N), were carried out with
the standard pulse sequences [17] to assign the 1H, 13C and 15N signals.
Solid-state 13C (100.73 MHz) and 15N (40.60 MHz) CPMAS NMR spectra have
been obtained on a Bruker WB 400 spectrometer at 300 K using a 4 mm DVT probe-
head. Samples were carefully packed in a 4-mm diameter cylindrical zirconia rotor with
1
Kel-F end-caps. Operating conditions involved 3.2 >s 90˚ H pulses and decoupling
field strength of 78.1 kHz by TPPM sequence. 13C spectra were originally referenced
to a glycine sample and then the chemical shifts were recalculated to the Me4Si [for
the carbonyl atom δ (glycine) = 176.1 ppm] and 15N spectra to 15NH4Cl and then
converted to nitromethane scale using the relationship: δ15N(MeNO2) = δ15N(NH4Cl)
−338.1 ppm.
Typical acquisition parameters for 13C CPMAS were: spectral width, 40 kHz; re-
cycle delay, 15 s; acquisition time, 30 ms; contact time, 7 ms; and spin rate, 12 kHz.
In order to distinguish protonated and unprotonated carbon atoms, the NQS (Non-
Quaternary Suppression) experiment by conventional cross-polarization was recorded;
before the acquisition the decoupler is switched off for a very short time of 25 μs [18,
19]. Typical acquisition parameters for 15N CPMAS are: spectral width, 40 kHz; recy-
cle delay, 15 s; acquisition time, 30 ms; contact time, 7 ms; and spin rate, 6 kHz. The
rotational frequencies were ca. 12 kHz (for 13C) and 6 kHz (for 15N).
Variable temperature experiments were performed with a Bruker BVT-3000 tem-
perature unit to control the temperature of the cooling gas stream, and an exchanger to
achieve low temperatures. To avoid problems at low temperatures caused by air mois-
ture, anhydrous N2 was used as bearing, driving, and cooling gas. Cylindrical zirconia
rotors of 4-mm diameter with boron nitride caps were used.
3. Results and discussion
3.1 1H-pyrazole-4-carboxylic acid (1)
The data of compound 1 needed for the following discussion concern crystallography
(Figs. 1 and 2) and CPMAS NMR (Fig. 3) [5,6].
The crystal structure of compound 1 (Fig. 2) shows the disorder (static or dynamic)
of the protons involved in the HBs. Our previous 15N NMR studies [5,6] proved the
existence of two polymorphs of 1: i) an amorphous phase exhibiting proton order, ob-
served when compound 1 is precipitated rapidly, presenting two signals at −102 ppm
(N2) and −169 ppm (N1H). The amorphous phase was always accompanied by a crys-
talline one. The defects of this phase can be annealed using moderate heating. Thus,
the initial sample corresponded to a metastable phase. The subsequent studies were
then performed on the annealed sample to which we assigned the crystalline struc-
ture. ii) A crystalline phase (Fig. 2) showing proton disorder, which at RT presents an
average signal at −135.4 ppm, and below 250 K two signals at −105 and −166 ppm,
respectively. Therefore, the disorder is dynamic.
We have measured again the 15N chemical shifts and observed for the crystalline
phase a singlet at −136.2 ppm (N1 and N2). The corresponding 13C chemical shifts ap-
pear at 166.4 (CO2H), 137.0 (C3 and C5) and 113.2 ppm (C4) (Fig. 3). Lowering the

L. Infantes et al.
Fig. 2. Crystal structure of compound 1 along the b axis showing the ribbons and their 3D packing.
Fig. 3. 13C and 15N CPMAS NMR of the crystalline phase of compound 1.
temperature till 203 K does not show any broadening of the C3/C5 signal. If SSPT is
suppressed they are expected at about 134 (C5) and 140 ppm (C3) [20]; the difference
in frequencies between C3 and C5 is too small to succeed in observe them carrying out
DNMR (Dynamic NMR) experiments at temperatures accessible to our instruments.
3.2 1H-3(5)-methylpyrazole-4-carboxylic acid (2)
The crystal structure of 2 was determined here for the first time. Slender needle-like
crystals were obtained suitable for mono-crystal X-ray diffraction experiment. The
compound crystallizes from water in a sea-urchin-like morphology with small and brit-
tle spines. A fragment of a spine was used for crystal determination (Fig. 4). Note that
there is no proton disorder either in the NH or in the OH.

The Structure and Dynamic Properties of 1H-Pyrazole-4-Carboxylic Acids in the Solid State
Fig. 4. X-Ray molecular structure of 2. Ellipsoids are drawn at the 50% probability level.
Fig. 5. Crystal structure projection of compound 2b along the (−104) axis. The hydrogen bond network
can be observed in the layers and also the stacking (pyrazole ring· · · carboxylic acid dimer ring) among
adjacent layers.
The structure corresponds to the 5-methyl tautomer 2b. The HB network is repre-
sented in Fig. 5. A large central pseudo-ring is clearly apparent.
Solid-state NMR experiments show no dynamic disorder (no SSPT) in agreement
with the HB network (we have verified that the crystals used for X-ray diffraction were
identical to those used for NMR). The discussion of the CPMAS NMR spectra will be
based on the 2b tautomeric structure since this is the one present in the crystal (Fig. 5).
In13C signals at 169.6 (CO2H), 149.0 (quaternary C5), 143.3 (C3H), 110.6 (C4) and

L. Infantes et al.
Fig. 6. 13C and 15N CPMAS NMR of the 2b tautomeric form present in the crystal.
1
Table 2. H, 13C and 15N chemical shifts of compound 2 in solution. In bold, signals belonging to the 3-
methyl tautomer 2a.
DMSO-d6
300 K
CD3OD
300 K
HMPA-d18
300 K
HMPA-d18
268 K
THF-d8
300 K
THF-d8
203 K
1H NH
12.4
7.86
N.o.
7.91
13.8 (vb)
7.63
14.0 (1H)
7.80
11.0 (vb)
7.78
12.0 (b)
7.89
1H H3/H5
7.57
2.40
7.88
2.45
1H CH3
2.41
2.48
2.41 (vb)
2.43
2.43
2.44
12.0 (b)
146.7
1H CO2H
13C C3/C5
(C–CH3)
13C C4
12.4
145.0
N.o.
147.9
13.0 (vb)
13.0 (1H)
149.2
141.2
112.1
132.2
142.2
13.3
11.0 (vb)
146.6
∗
∗
∗
111.0
138.7
112.8
140.5
112.0
139.6
111.9
139.8
13C C5/C3
(C–CH)
13C CH3
11.3
11.8
11.9
12.2
∗
10.8
∗
∗
13C CO2H
15N N1H
164.8
N.o.
167.4
N.o.
164.9
−165.3
−165.3
N.o.
165.5
165.6
N.o.
−138.8∗∗
∗
15N N2
N.o.
N.o.
−118.7∗∗
N.o.
∗
1
N.o.: not observed; vb: very broad; b: broad; since the signals were very broad in H NMR, the 13C and
15N NMR spectra were not recorded; these signals do not belong to N1H or N2 but correspond to an
∗∗
average of 2a and 2b, one belonging to the N close to the methyl group (−138.8 ppm) and the other to
the N far from the methyl group (−118.7 ppm).
12.4 ppm (Me) are observed. In 15N CPMAS two narrow signals appear at −96.2 ppm
(N2) and −165.6 ppm (N1H) (Fig. 6). All attempts to find another polymorph or an-
other desmotrope [21] were unsuccessful: crystallization in water, crystallization in
methanol, and adding water to a saturated solution in methanol, all yield the same kind
of crystals.
As we are interested in tautomerism [22–24] and since only compound 2 presents
it, we carried out a series of experiments in solution (Table 2). Comparison with other

The Structure and Dynamic Properties of 1H-Pyrazole-4-Carboxylic Acids in the Solid State
Fig. 7. Estimated chemical shifts of tautomers 2a and 2b.
Fig. 8. 13C NMR spectrum in HMPA-d18 at 268 K.
pyrazoles was used to assign the different signals [20,25] (Fig. 7). Those correspond-
ing to 13C are rather accurate but those corresponding to 15N are less good owing to the
different nature of hydrogen bonds. The results in DMSO-d6 and in CD3OD, both at
300 K, correspond to intermediate rates of exchange and not be further discussed.
1
In HMPA-d18 there is 25% of 2a and 75% of 2b (by integration of the H NMR
signals of H3/H5 at 7.80 and 7.57 ppm). So, this corresponds to the classical case
where the tautomer present in the solid state (2b) is also the major tautomer in solu-
tion [22,23]. The 13C NMR spectrum in HMPA-d18 at low temperature (Fig. 8) shows
the signals of the most abundant tautomer (2b) as narrow lines and those of the less
abundant tautomer (2a) as broad lines; this different broadening is a simple conse-
quence of the tautomerization rates being faster for the less abundant tautomer [26,27].
In THF-d8 at 203 K, two signals are split and, although they are too close
for a proper integration, the proportions can be estimated to 65 10% of 2b and

L. Infantes et al.
Fig. 9. X-Ray molecular structure of 3. Ellipsoids are drawn at the 50% probability level.
35 10% of 2a. In THF-d8 at 300 K the average signals of the 15N atoms (−138.8 and
−118.7 ppm, Table 2); when the estimated values of Fig. 7 were interpolated this led to
60–65% of 2b and 35–40% of 2a.
In HMPA-d18 solution at 268 K, the experimental 13C values (Table 2) and the esti-
mated 13C values of Fig. 7 differ from +0.8, −1.2 and +1.6 ppm for tautomer 2a and
from −1.8, +1.6 and +0.2 ppm for tautomer 2b. If these differences are within the ex-
pected errors, the solid-state results (differences, +5.0, +3.7 and +1.8 ppm) are less
satisfying. These differences correspond to crystal field effects shifting all signals to
higher frequencies in particular the C5 quaternary carbon atom.
3.3 1H-3,5-dimethylpyrazole-4-carboxylic acid (3)
Although only very small and fine needles were obtained from a dendritic crystal
growth by slow evaporation of a water/methanol mixture, the structure of this com-
pound has been solved (Fig. 9). The secondary structure is depicted in Fig. 10, showing
layers through NH···O and OH···N interactions. As in the case of compound 2, proton
disorder is not observed.
In CPMAS NMR a reciprocal behavior was observed for 3 compared with 1. The
crystalline compound does not show any SSPT, which is consistent with the X-ray
structure showing a 3D-network incompatible with fast proton-transfer in the solid
state. Our previous experience with SSPT indicates that for this phenomenon to occur
three conditions are necessary: i) the initial and final states should be the same, ii) the
transfers occur in a circular way, and iii) a limited number of protons (from 2 to 4) in-
tervene: all these conditions are fulfilled in pyrazole 1 (crystal polymorph) considering
that the protons jump in each pair of molecules are independent from the other pairs.
However, when compound 3 was in an amorphous state, SSPT occurs. We have already
reported that 3 presents SSPT [28] but were not aware at that time that this compound
presents polymorphism and was only when the X-ray structure was determined that we
realize that the structure that shows SSPT cannot correspond to the crystal structure.

The Structure and Dynamic Properties of 1H-Pyrazole-4-Carboxylic Acids in the Solid State
Fig. 10. Crystal packing of compound 3 along the c axis showing the hydrogen bond network in the layers
and the CH· · · O interactions that link the layers.
The CPMAS spectra of pyrazole 3 before crystallization show 13C signals at 166.5
(CO2H), 147.0 (C3 and C5), 109.4 (C4) and 14.4 ppm (3-CH3 and 5-CH3) and one 15
N
signal at −143.3 ppm (N1H and N2) (Fig. 11). When the above reported sample was
crystallized in a mixture of methanol/water and the crystals studied again by CPMAS
NMR the change was dramatic: 13C 168.0 (CO2H), 151.7 (C3), 147.3 (C5) (average
149.5), 109.6 (C4), 13.4 (3Me) and 12.6 (5Me) (average 13.0 ppm). In 15N CPMAS
NMR, two signals appear at −176.7 (N1H) and −107.3 (N2) (average −142.0 ppm)
(Fig. 11). These values show that the average signals do not exactly coincide with those
of the amorphous sample, i.e. both samples structurally differ. A reasonable hypothesis
is that the structure of the amorphous sample should be similar to that of crystalline 1.
Heating the crystalline sample up to 373 K does not modify the 13C CPMAS NMR
spectrum. However, if this sample is put in an agate mortar, some drops of methylene
chloride are added and the paste ground until dryness, then the solid recovered is again
the crystalline polymorph (13C CPMAS). On the other hand, if this variety is dissolved
in methanol (saturated solution) and quickly precipitated by adding water, the solid re-
covered is the amorphous polymorph (13C CPMAS). Its SSPT rate is not low enough to
observe broad signals in 13C CPMAS NMR at 203 K.
3.4 Hydrogen bond networks
The analyzed molecules (1–3) contain two functional groups, carboxylic acid and NH-
pyrazole ring, with several possibilities of hydrogen bond motifs. The hydrogen bond
networks observed in the crystals of 1, 2 and 3 are different. While molecules in com-
pounds 1 and 3 interact through OH· · · N and NH· · · O hetero-contacts, molecules in
compound 2 are bonded by OH· · · O and NH· · · N homo-interactions.

L. Infantes et al.
Fig. 11. 13C and 15N CPMAS NMR of the amorphous and crystalline phases of compound 3.
Molecules in 1 (Fig. 2) form infinite tapes containing R1,1(7) [16] hydrogen bond
rings by hetero-contacts among the carboxylic acid and the nitrogen atoms in the pyra-
zole ring. The 3D structure is formed by the stacking of the tapes, (π · · · π interactions
among the pyrazole rings), and the interactions with the adjacent layers of stacked tapes
by CH· · · O contacts.
The structure of compound 2 (Fig. 5) contains layers (−104) of molecules held
through two types of hydrogen bonds: OH· · · O and NH· · · N. The former, OH· · · O,
gives centrosymmetric carboxylic acid dimers described by the graph set [R2,2(8)]. The
later, NH· · · N, forms infinite chains of molecules along the b axis with a graph set
C1,1(3) describing this motif. The 3D structure is formed by the stacking of the pyra-
zole rings in one layer with the carboxylic acid dimer rings in the adjacent ones, up and
down.
The crystal structure of 3 (Fig. 10) shows layers (001) of molecules interacting
through hydrogen bonds involving the carboxylic acid and the nitrogen atoms of the
pyrazole: OH· · · N [C1,1(6), chains along a axis] and NH· · · O [C1,1(6), chains along a
axis]. The layers pack to form the crystal by CH(methyl group)· · · O=C(pyrazole ring)
interactions along the c direction.
The three different modes used by 1, 2b and 3 to create an HB network are repre-
sented in Fig. 12. The crystal structure of compound 1 is formed by parallel chains of
type a while that of compound 2b corresponds to an intercrossed structure of type b;
finally, compound 3 crystals present a tri-dimensional network of type a. Taking into

The Structure and Dynamic Properties of 1H-Pyrazole-4-Carboxylic Acids in the Solid State
Fig. 12. Possible catemers formed by 1H-pyrazole-4-carboxylic acids.
account the rules we have described previously for the SSPT phenomenon to be ob-
served, only compound 1 fulfills them. In compound 2b the mobility of protons in the
carboxylic acid dimers is possible but not in the chain of N–H· · · N HBs (condition iii
not observed). The same happens for compound 3 but in this case for the O–H· · · N
HBs.
3.5 Hydrogen-bonding propensity
Compounds 1, 2 and 3 are 1H-pyrazole-4-carboxylic acid derivatives where the only
functional groups are the carboxylic acid and the pyrazole. Therefore, these molecules
contain two HB donors (NH and OH) and three HB acceptors (–N=, O=C and OH),
which could combine in six different possible strong hydrogen bonds. CSDS 2012 re-
lease contains a new knowledge-based method, called logit hydrogen-bonding propen-
sity (LHP) method, to quantify the likelihood of H-bond formation for a specified
compound [29]. One of the possible applications of this methodology is the prediction
and assessment of the H-bonds for a real compound.
Having a molecule that contains only one carboxylic acid and one NH-pyrazole
as functional groups, its HB propensities calculated using the logit model of the
CSDS tool is: NH· · · O=C (0.78), NH· · · N (0.64), OH· · · O=C (0.63), OH· · · N (0.45),
NH· · · OH−C (0.37) and OH· · · OH−C (0.22). This tool provides a scoring for all pos-
sible hydrogen bond interactions in the crystal structure. In the title compounds, the
most likely NH· · · O=C interaction (the pairing with the highest propensity value, 0.78)
is observed in compounds 1 and 3 whereas compound 2 forms in place the second

L. Infantes et al.
Fig. 13. Putative hydrogen bond combinations for molecules that contain one carboxylic acid and one NH-
pyrazole. The horizontal axis represents the mean propensity for the H-bonds in a structure. The vertical
axis represents the mean participation likelihoods for the atoms in the hydrogen bonds (the scale is relative
to a zero base-line).
Fig. 14. SSPT of 1H-pyrazole-4-carboxylic acids in the solid state.
likely interactions (NH· · · N and OH· · · O). Exploring how the combinations of hydro-
gen bonds fit together using participation likelihoods, Fig. 13 shows a chart with all
feasible H-bond combinations; that is, each data point refers to a putative structure, with
unique H-bonding. Points in the bottom right of the chart are those structures with H-
bond combinations that might be possible. Compounds 1 and 3 are represented by the
same point (a) in the plot and compound 2 appears very close to this position (b); both
of them are in the lower-right hand corner of the plot and therefore, it is likely H-bonds
are observed in these compounds.

The Structure and Dynamic Properties of 1H-Pyrazole-4-Carboxylic Acids in the Solid State
4. Conclusions
We have represented schematically the different dynamic behavior of the three pyra-
zoles in the solid state in Fig. 14.
In the light of the results, 2 presents the most probable HB combinations for
those compounds containing only carboxylic acid and NH-pyrazole ring; while 1 and
3 present the second most likely combinations. These two observed HB possibilities
are very close in the likelihoods chart (points a and b in Fig. 13) and they are well
differentiated from the other putative HB combinations. Therefore, a new 1H-pyrazole-
4-carboxylic acid derivative will present one of these two HB combinations but we are
not able a priori to distinguish between them. It will be interesting to check whether it
is related to the pseudo-symmetry of the compounds. Probably the amorphous form of
3 has a structure similar to that of 1 shown in Fig. 2. The ab initio prediction of crys-
tal structures is still a challenge despite the progress made in recent years [30,31] and
we hope that the results presented in this paper will contribute to the solution of this
problem.
Acknowledgement
This work has also been financed by the Ministerio de Econom´ıa y Competitividad
of Spain (CTQ2009-13129-C02-02 and CTQ2010-16122). L.I. thanks Comunidad de
Madrid (Spain) for support (BIPEDD-2: S2010-BMD-2457).
References
1. A. Baldy, J. Elguero, R. Faure, M. Pierrot, and E.-J. Vincent, J. Am. Chem. Soc. 107 (1985)
5290–5291.
2. J. A. S. Smith, B. Wehrle, F. Aguilar-Parrilla, H.-H. Limbach, M. C. Foces, F. H. Cano,
J. Elguero, A. Baldy, M. Pierrot, M. M. T. Khurshid, and J. B. Larcombe, J. Am. Chem. Soc.
111 (1989) 7304–7312.
3. F. Aguilar-Parrilla, G. Scherer, H.-H. Limbach, C. Foces-Foces, F. H. Cano, and J. Elguero,
J. Am. Chem. Soc. 114 (1992) 9657–9659.
4. O. Klein, F. Aguilar-Parrilla, J. M. Lo´pez, N. Jagerovic, J. Elguero, and H.-H. Limbach, J. Am.
Chem. Soc. 126 (2004) 11718–11732.
5. C. Foces-Foces, A. Echevarr´ıa, N. Jagerovic, I. Alkorta, J. Elguero, U. Langer, O. Klein,
M. Minguet-Bonveh´ı, and H.-H. Limbach, J. Am. Chem. Soc. 123 (2001) 7898–7906
6. V. Torres, J. M. Lo´pez, U. Langer, G. Buntkowsky, H.-M. Vieth, J. Elguero, and H.-H. Lim-
bach, Z. Phys. Chem. 226 (2012) 1125–1147.
7. S. Su, Y. Zhang, M. Zhu, X. Song, S. Wang, S. Zhao, S. Song, X. Yang, and H. Zhang, Chem.
Commun. 48 (2012) 11118–11120.
8. J. Elguero, in: Comprehensive Heterocyclic Chemistry: Pyrazoles and their Benzo Deriva-
tives, Vol. 5, Katritzky, A. R., Rees, C. W. (Eds.), Pergamon, Oxford (1984).
9. J. Elguero, in: Comprehensive Heterocyclic Chemistry II: Pyrazoles, Vol. 3, Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V. (Eds.), Pergamon, Oxford (1996).
10. M. S. Ermolenko, S. Guillou, and Y. L. Janin, Tetrahedron 69 (2013) 257-263.
11. Cambridge Structural Database, F. H. Allen, Acta Crystallogr. B 58 (2002) 380; F. H. Allen
and W. D. S. Motherwell, Acta Crystallogr. B 58 (2002) 407; CSD version 5.32, update Feb.
2011, http://www.ccdc.cam.ac.uk.
12. E. V. Tretyakov, S. E. Tolstikov, G. V. Romanenko, Yu. G. Shvedenkov, R. Z. Sagdeev, and
V. I. Ovcharenko, Russ. Chem. B. Int. Ed. 54 (2005) 2169–2181.

L. Infantes et al.
13. W. J. Begley, T. H. Chen, F. D. Coms, and D. Singleton, Jr. Eur. Pat. Appl. EP 0751426 A1
(1997), Eastman Kodak Company, Rochester, New York 14650-2201 (US).
14. H. M. Mokhtar, A. T. F. Tag El-Din, and M. A. Tag Deshesh, Pakistan J. Sci. Ind. R. 30 (1987)
1.
15. G. M. Sheldrick, Acta Crystallogr. A 64 (2008) 112–122.
16. M. C. Etter, Accounts Chem. Res. 23 (1990) 120–126.
17. S. Berger and S. Braun, 200 and More NMR Experiments, Wiley-VCH, Weinheim (2004).
18. P. D. Murphy, J. Magn. Reson. 52 (1983) 343, ibid. 62 (1985) 303.
19. L. B. Alemany, D. M. Grant, T. D. Alger, and R. J. Pugmire, J. Am. Chem. Soc. 105 (1982)
6697–6704.
20. M. Begtrup, G. Boyer, P. Cabildo, C. Cativiela, R. M. Claramunt, J. Elguero, J. I. Garcia,
C. Toiron, and P. Vedsø, Magn. Reson. Chem. 31 (1993) 107–168.
21. J. Elguero, Cryst. Growth Des. 11 (2011) 4731–4738.
22. J. Elguero, C. Marzin, A. R. Katritzky, and P. Linda, The Tautomerism of Heterocycles, Aca-
demic Press, New York (1976).
23. V. I. Minkin, A. D. Garnovskii, J. Elguero, A. R. Katritzky, and O. V. Denisko, Adv. Hetero-
cycl. Chem. 76 (2000) 157–323.
24. R. M. Claramunt, J. Elguero, and A. R. Katritzky, Adv. Heterocycl. Chem. 77 (2000) 1–50.
25. R. M. Claramunt, D. Sanz, C. Lo´pez, J. A. Jime´nez, M. L. Jimeno, J. Elguero, and A. Fruchier,
Magn. Reson. Chem. 35 (1997) 35–75.
26. L. Infantes, C. Foces-Foces, R. M. Claramunt, C. Lo´pez, N. Jagerovic, and J. Elguero, Hete-
rocycles 50 (1999) 227–242.
´
27. R. M. Claramunt, M. A. Garc´ıa, C. Lo´pez, S. Trofimenko, G. P. A. Yap, I. Alkorta, and
J. Elguero, Magn. Reson. Chem. 43 (2005) 89–91.
28. R. M. Claramunt, M. A. Garc´ıa, C. Lo´pez, and J. Elguero, ARKIVOC vii (2005) 91–101.
29. P. T. A. Galek, L. Fa´bia´n, W. D. S. Motherwell, F. H. Allen, and N. Feeder, Acta Crystallogr. B
63 (2007) 768-782.
30. W. D. M. Motherwell, H. L. Ammon, J. D. Dunitz, A. Dzyabchenko, P. Erk, A. Gavez-
zotti, D. W. M. Hofmann, F. J. J. Leusen, J. P. M. Lommerse, W. T. M. Mooji, S. L. Price,
H. A. Scheraga, B. Schweizer, M. U. Schmidt, B. P. van Eijck, P. Verwer, and D. E. Williams,
Acta Crystallogr. B 58 (2002) 647–661.
31. G. M. Day, T. C. Cooper, A. J. Cruz-Cabeza, K. E. Hejczyk, H. L. Ammon, S. X. M. Boer-
rigter, J. S. Tan, R. G. Della Valle, E. Venuti, J. Jose, S. R. Gadre, G. R. Desiraju, T. S. Thakur,
B. P. van Eijck, J. C. Facelli, V. E. Bazterra, M. B. Ferraro, D. W. M. Hofmann, M. A. Neu-
mann, F. J. J. Leusen, J. Kendrick, S. L. Price, A. J. Misquitta, P. G. Karamertzanis, G. W. A.
Welch, H. A. Scheraga, Y. A. Amautova, M. U. Schmidt, J. van de Streek, A. K. Wolf, and
B. Schweizer, Acta Crystallogr. B 65 (2009) 107–125.