Modulating supramolecular reactivity using covalent switches on a pyrazole platform

Article abstract of DOI:10.1021/cg301391s

Systematic co-crystallizations of halogen- methyl- and nitro-substituted pyrazoles with a library of 20 aromatic carboxylic acids have been carried out using melt and solution-based experiments. The solids resulting from all reactions were screened using infrared spectroscopy in order to determine if a reaction (co-crystal or salt) had taken place. The halogenated pyrazoles, including their dimethyl analogues, gave a supramolecular yield of 55-70%. Replacing a halogen atom (R-X, X = Cl, Br, I) with a nitro (R-NO₂) group drops the success rate significantly to 10% due to the reduced charge on the basic nitrogen atom of the pyrazole. Eleven crystal structures were obtained: six were co-crystals and five were salts (including one hydrate). In all six co-crystals, dimeric pyrazole...acid assemblies were constructed via a combination of O-H - -N(pyz) and N-H - -O hydrogen bonds corresponding to a 100% supramolecular yield. A variety of weaker halogen-bonds CN - -I, I - -I and X - -O^- connect dimers into infinite one-dimensional chains. In contrast, the salts displayed a variety of stoichiometries and a much wider range of noncovalent interactions, although a charge-assisted N⁺-H - -O^- hydrogen bond was present in all five structures. In general, the salts lack structural and stoichiometric predictability and stability as compared to the co-crystals. Furthermore, the overall electrostatic charge on the key binding sites on the pyrazole backbone can be modulated by using specific covalent switches, which in turn can increase (or decrease) the success rate for a reaction.

Full text of DOI:10.1021/cg301391s

Article
pubs.acs.org/crystal
Modulating Supramolecular Reactivity Using Covalent “Switches” on
a Pyrazole Platform
Published as part of the Crystal Growth & Design virtual special issue In Honor of Prof. G. R. Desiraju
Christer B. Aakeroy,* Evan P. Hurley, and John Desper
̈
Department of Chemistry, Kansas State University, 213 CBC Building, Manhattan, Kansas, 66502, United States
S
* Supporting Information
ABSTRACT: Systematic co-crystallizations of halogen- methyl- and nitro-
substituted pyrazoles with a library of 20 aromatic carboxylic acids have been
carried out using melt and solution-based experiments. The solids resulting from
all reactions were screened using infrared spectroscopy in order to determine if a
reaction (co-crystal or salt) had taken place. The halogenated pyrazoles, including
their dimethyl analogues, gave a supramolecular yield of 55−70%. Replacing a
halogen atom (R-X, X = Cl, Br, I) with a nitro (R-NO2) group drops the success
rate significantly to 10% due to the reduced charge on the basic nitrogen atom of
the pyrazole. Eleven crystal structures were obtained: six were co-crystals and five
were salts (including one hydrate). In all six co-crystals, dimeric pyrazole···acid
assemblies were constructed via a combination of O−H---N(pyz) and N−H---O
hydrogen bonds corresponding to a 100% supramolecular yield. A variety of
weaker halogen-bonds CN---I, I---I and X---O− connect dimers into infinite one-
dimensional chains. In contrast, the salts displayed a variety of stoichiometries and a much wider range of noncovalent
interactions, although a charge-assisted N+-H---O− hydrogen bond was present in all five structures. In general, the salts lack
structural and stoichiometric predictability and stability as compared to the co-crystals. Furthermore, the overall electrostatic
charge on the key binding sites on the pyrazole backbone can be modulated by using specific covalent switches, which in turn can
increase (or decrease) the success rate for a reaction.
n important goal of crystal engineering is to design
functional materials,1 which requires access to a library of
interaction. The ditopic binding site on the pyridine molecule
combines a very strong acceptor moiety N(py), and a very
weak donor, C−H. In order to determine how important the
balance between these two contacts is, as far as offering a
competitive and successful synthon goes, we decided to
systematically examine the ability of a variety of pyrazole
molecules containing halogen atoms, methyl, and nitro
substituents to form co-crystals with an approaching carboxylic
acid. The desired synthon is again expected to involve a ditopic
site on the base, but this time, the heterocyclic nitrogen is a
rather poor hydrogen-bond acceptor, whereas the adjacent N−
H donor is strong (relative to N and C−H, respectively, in
pyridine), Scheme 2.
A
synthons capable of facilitating the construction of heteromeric
solid-state architectures with predictable composition, metrics,
and topologies.2 In order to assemble a toolbox of reliable and
robust synthons3 that can realize the desired supramolecular
target, it is necessary to carry out systematic structural studies
of molecules equipped with structurally ‘active’ functional
groups and to determine their binding preferences in
competitive environments.
Hydrogen-bond based synthons are commonly used in
crystal engineering, as they are strong (in the context of
noncovalent interactions), directional, and potentially very
selective, and within this group, the carboxylic acid---pyridine
heterosynthon, Scheme 1, has been particularly prominent.4,5
The communication between molecules in this pair is
dictated by the primary O−H---N(py) hydrogen bond
complemented (sometimes) by a secondary C−H---O
Scheme 2. The Targeted Carboxylic Acid---Pyrazole
Heterosynthon
Scheme 1. The Carboxylic Acid---Pyridine Heterosynthon
Received: September 23, 2012
Revised: October 15, 2012
© XXXX American Chemical Society
A
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a
Potentially, carboxylic acid---pyrazole interactions, which
could parallel carboxylic acid---pyridine interactions (same
Scheme 3. The Nine Pyrazoles Used in This Study
graph set notation, R2 (7)),6 can offer a reliable and predictable
2
motif that may expand our current crystal engineering toolbox
for targeted supramolecular synthesis. However, since the angle
between the N−H bond and the lone pair on the adjacent
nitrogen atom is somewhat large to provide a perfect fit with a
carboxylic acid, the viability of this interaction has yet to be
established. In fact, a few pyrazole/carboxylic acid crystal
structures have been published previously,7,8 which indicate
that head-to-head acid···pyrazole dimers are less likely than a
trimer or catemer-type interaction. In addition to the
fundamental importance of intermolecular bonds, carboxylic
acid---azole interactions, such as those occurring with pyrazoles,
play an important role in active ingredients in many
agrichemicals9 and in membrane protein antagonists.10
Furthermore, halogenated pyrazoles are part of the backbone
of some important agrichemicals11 and have also shown
promising antitumor activity.12 Thus, the ability to form co-
crystals of pyrazole-containing compounds would provide
access to a larger number of solid forms which could optimize
physicochemical properties of a particular active ingredient.
One way of ‘dialing-in’ the strength of any heterosynthon,
including azole---acid combinations, is to use covalent ‘switches’
that modify the electrostatic nature of the functional groups
that participate in the intermolecular interaction under
consideration. Obviously, well-established covalent synthesis
allows us to decorate any molecular fragment with substituents
in suitable positions. For example, methyl and methoxy groups
can be added for the purpose of increasing the 'negative' charge
on a specific hydrogen-bond acceptor site, thus making it more
likely to accept an electrostatically driven hydrogen-bond
interaction; the addition of electron withdrawing groups will
have the opposite effect.
a
Pyrazole (halo and nitro analogues) on top. Dimethyl pyrazole (and
halo analogues) on bottom.
for single-crystal X-ray diffraction studies. In one case, suitable
crystals were directly obtained from the melt.
EXPERIMENTAL SECTION
■
All chemicals were purchased from Aldrich and used without any
further purification unless otherwise noted. Chloropyrazole and
bromopyrazole were synthesized according to a report by Zhao and
co-workers.16 Iodopyrazole was synthesized according to a procedure
by Elguero.17 The 4-halo-(3,5-dimethyl) pyrazoles were synthesized
according to Ehlert and co-workers.18 Melting points were determined
on a Fisher-Johns melting point apparatus and are uncorrected. Single
crystal X-ray data were collected on a Bruker Apex diffractometer.
AM1/PM3/DFT charge calculations were performed using Spartan
software. Infrared data were collected on a Thermo Scientific Nicolet
380 FT-IR using a ZnSe crystal. Melt experiments were performed by
weighing equimolar amounts (1:1 pyrazole/acid) in a test tube and
gently heating the two solids together using a Pamran Co. Inc.
(Waukesha, WS) HEJET model HJ700 heat gun until the two
components appeared melted together. NMR data were collected on a
Bruker 200 MHz instrument, unless otherwise noted.
In this study, we set out to establish if relatively minor
changes to the pyrazole backbone have a noticeable effect on
the ability of pyrazole derivatives to form co-crystals13 with a
series of carboxylic acids. As weak and medium strength
hydrogen bonds are primarily electrostatic in nature, we
postulated that the supramolecular yield of these reactions
will reflect changes in electrostatic potentials on the
participating species. Molecular electrostatic potential surface
(MEPS) calculations were thus performed (using both
semiempirical14 and DFT methods), in order to estimate the
relative charge differences on the hydrogen-bond donor/
acceptor sites in the participating pyrazole molecules.
SYNTHESIS
■
Co-crystals: Synthesis of 4-Bromo-1H-pyrazole:3,5-dini-
trobenzoic Acid (1:1). To a vial, 4.3 mg (0.029 mmol) of 4-
bromo-1H-pyrazole was added along with 1 mL of methanol.
To a separate vial, 6.1 mg (0.029 mmol) of 3,5-dinitrobenzoic
acid was added along with 1 mL of methanol. The two
solutions were combined in a vial, covered in parafilm (1
pinhole), and left for slow evaporation. Colorless prisms were
obtained after several days. mp 135−140 °C.
Synthesis of 4-Iodo-1H-pyrazole:3,5-dinitrobenzoic Acid
(1:1). To a vial, 12.6 mg (0.065 mmol) of 4-iodo-1H-pyrazole
was added along with 0.5 mL of methanol. To a separate vial,
13.8 mg (0.065 mmol) of 3,5-dinitrobenzoic acid was added
along with 0.5 mL of methanol. The two solutions were
combined in a vial, covered in parafilm (3 pinholes), and left for
slow evaporation. Colorless plates were obtained after several
days. mp 123−125 °C.
The experimental work utilized nine different pyrazoles,
Scheme 3, and 20 carboxylic acids, Table 1.
The compounds shown in Scheme 3 have been function-
alized in order to make slight alterations to the electrostatic
charge on the hydrogen-bond acceptor, N(pyz), and the main
hydrogen-bond donor, N−H.
In Scheme 4, our approach for mapping out the synthetic
landscape15 for reactions between pyrazoles and carboxylic
acids is summarized.
To minimize any potential problems with solubility differ-
ences between the two reactants in each case, the substances
were melted together, and the solid formed upon cooling was
characterized using IR spectroscopy. Any reaction that resulted
in reaction (co-crystal or salt formation), as determined via
infrared spectroscopy, was subsequently used for crystal growth
experiments from solution in order to obtain crystals suitable
Synthesis of 4-Iodo-1H-pyrazole:4-cyanobenzoic Acid
(1:1). To a vial, 15.2 mg (0.078 mmol) of 4-iodo-1H-pyrazole
was added along with 0.5 mL of methanol. To a separate vial,
11.5 mg (0.078 mmol) of 4-cyanobenzoic acid was added along
with 0.5 mL of methanol. The vial containing the acid was
heated until fully dissolved, then added to the solution
containing the pyrazole. The vial was covered in parafilm
(three pinholes) and left for slow evaporation. Colorless prisms
were obtained after several days. mp 189−190 °C.
Synthesis of 4-Chloro-3,5-dimethyl-1H-pyrazole:4-hy-
droxy-3-methoxybenzoic Acid (1:1). To a vial, 7.3 mg (0.056
B
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a
Table 1. Twenty Carboxylic Acids Used in This Study
a
Acids listed in order of increasing acidity. pKa values obtained from Scifinder scholar.
The two solutions were combined in a vial, covered in parafilm
(1 pinhole), and left for slow evaporation. Colorless prisms
were obtained after several days. mp 156−160 °C.
Scheme 4. Flow Chart for Supramolecular Synthesis of Co-
Crystals Employed in This Study
Synthesis of 4-Bromo-3,5-dimethyl-1H-pyrazole:3,5-dini-
trobenzoic Acid (1:1). To a vial, 5.7 mg (0.033 mmol) of 4-
bromo-3,5-dimethyl-1H-pyrazole was added along with 1 mL of
methanol. To a separate vial, 7.1 mg (0.033 mmol) of 3,5-
dinitrobenzoic acid was added along with 1 mL of methanol.
The two solutions were combined in a vial, covered in parafilm
(1 pinhole), and left for slow evaporation. Colorless plates were
obtained after several days. mp 155−158 °C.
Salts. Synthesis of 4-Chloro-3,5-dimethyl-1H-pyrazo-
lium:2,4-dinitrobenzoate:4-chloro-3,5-dimethyl-1H-pyrazole
(1:1:1). To a vial, 5.6 mg (0.043 mmol) of 4-chloro-3,5-
dimethyl-1H-pyrazole was added along with 200 μL of
methanol. To a separate vial, 9.2 mg (0.043 mmol) of 2,4-
dinitrobenzoic acid was added along with 200 μL of methanol.
The two solutions were combined in a vial, covered in parafilm
(1 pinhole), and left for slow evaporation. Colorless plates were
obtained after several days. mp 100−102 °C.
Synthesis of 4-Iodo-3,5-dimethyl-1H-pyrazolium:3,5-dini-
trobenzoate (1:1). To a vial, 5.4 mg (0.024 mmol) of 4-iodo-
3,5-dimethyl-1H-pyrazole was added along with 200 μL of
methanol. To a separate vial, 5.2 mg (0.024 mmol) of 3,5-
dinitrobenzoic acid was added along with 200 μL of methanol.
mmol) of 4-chloro-3,5-dimethyl-1H-pyrazole was added along
with 200 μL of methanol. To a separate vial, 9.6 mg (0.057
mmol) of 4-hydroxy-3-methoxybenzoic acid was added along
with 200 μL of methanol. The two solutions were combined in
a vial, covered in parafilm (1 pinhole), and left for slow
evaporation. Colorless spheres were obtained after several days.
mp 205−209 °C.
Synthesis of 4-Chloro-3,5-dimethyl-1H-pyrazole:3,5-dini-
trobenzoic Acid (1:1). To a vial, 5.3 mg (0.041 mmol) of 4-
chloro-3,5-dimethyl-1H-pyrazole was added along with 200 μL
of methanol. To a separate vial, 8.9 mg (0.042 mmol) of 3,5-
dinitrobenzoic acid was added along with 200 μL of methanol.
C
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The two solutions were combined in a vial, covered in parafilm
(1 pinhole), and left for slow evaporation. Colorless prisms
were obtained after several days. mp 138−142 °C.
Synthesis of 1H-Pyrazolium:2,6-dichlorobenzoate:2,6-di-
chlorobenzoic Acid (1:1:1). To a test tube, 13.1 mg (0.19
mmol) of 1H-pyrazole was added along with 39.3 mg (0.21
mmol) of 2,6-dichlorobenzoic acid. The solids were heated
using a heat gun until both components had melted. The melt
was allowed to cool to room temperature, yielding colorless
plates. mp 71−73 °C.
Synthesis of 1H-Pyrazolium:3,5-dinitrobenzoate:3,5-dini-
trobenzoic Acid (1:1:1). To a small beaker, 29.1 mg (0.43
mmol) of 1H-pyrazole was added and dissolved in 1 mL of
absolute ethanol (200 proof). To a separate beaker, 91.4 mg
(0.43 mmol) of 3,5-dinitrobenzoic acid was added and
dissolved in 1 mL of absolute ethanol (200 proof). The two
solutions were combined in a beaker, covered with parafilm (5
pinholes), and left for slow evaporation. Colorless plates were
obtained after several days. mp 146−148 °C.
Table 3. AM1, PM3, and DFT Calculations on All Nine
Pyrazoles
a
AM1
(H)
AM1
(N)
PM3
(H)
PM3
(N)
DFT
(H)
DFT
(N)
molecule
1.H
178
194
200
200
254
171
188
193
191
−251
−236
−230
−231
−260
−256
−238
−239
−237
156
167
169
161
280
141
150
152
150
−307
−289
−283
−282
−297
−308
−298
−293
−302
245
269
273
−186
−159
−160
1.Cl
1.Br
1.I
1.NO2
2.H
315
226
260
253
−162
−195
−172
−171
2.Cl
2.Br
2.I
a
Values are given in kJ/mol. DFT calculations performed at 6-31+G*
level of theory. DFT calculations could not be performed on
iodopyrazoles.
resulted in a reaction (salt or co-crystal). A total of 11 crystal
structures were subsequently obtained (ESI).
Crystal Structures (Co-Crystals). The crystal structure
determination of 1.Br:N shows that the outcome is a co-crystal
with the intended 1:1 stoichiometry with four unique molecules
in the asymmetric unit cell.
Synthesis of 3,5-Dimethyl-1H-pyrazolium:3,5-dinitroben-
zoate Hydrate (1:1). To a small beaker, 27.9 mg (0.29 mmol)
of 3,5-dimethyl-1H-pyrazole was added and dissolved in 1 mL
of absolute ethanol (200 proof). To a separate beaker, 62.3 mg
(0.29 mmol) of 3,5-dinitrobenzoic acid was added and
dissolved in 1 mL of absolute ethanol (200 proof). The two
solutions were combined in a test tube and left for slow
evaporation. Colorless prisms were obtained after several days.
mp 120−124 °C.
The acidic protons remain on the two unique carboxylic
acids as shown by the significantly different CO/C−O(H)
bond lengths, 1.219(4)/1.325(4) Å, and 1.219(4)/1.312(4) Å,
respectively. The driving force for the reaction is the
heteromeric O−H---N(pyz)/N−H---O synthon, which we
define as “head-to-head dimers”, Figure 1. These dimers are
organized into one-dimensional (1-D) chains via C−Br---
O(nitro) halogen bonds; r(C−Br---O) is 3.148 Å and the C−
Br---O angle is 154°.
The crystal structure of 4-iodopyrazole:4-cyanobenzoic acid,
1.I:H, displays a very similar primary supermolecule, a head-to-
head dimer constructed from a neutral O−H---N(pyz)/N−H---
O synthon, Figure 2. The dimers assemble into infinite 1-D
chains by CN---I halogen bonds, where the CN---I distance is
3.183 Å with a C−I---N angle of 179.38°.
The crystal structure of 1.I:N also contains 1-D chains where
dimer formation occurs via O−H---N(pyz) and N−H---O
interactions. The dimers are connected into 1-D chains through
C−H---O synthons. The chains are linked together in a stair-
step fashion through I---I (type I) halogen bonds, Figure 3. The
I---I distance is 3.698 Å and the C−I---I angle is 136.54°.
The crystal structure of 2.Cl:B contains head-to-head
heterodimers formed via O−H---N(pyz) and N−H---O
synthons, Figure 4. The N−H proton is bifurcated between
the CO oxygen from one acid and the O−H oxygen from a
second symmetry-related neutral acid. The synthons combine
to form an extended zigzag chain.
The structure of 2.Cl:N also contains neutral heterodimers
formed by O−H---N(pyz) and N−H---O synthons. The dimers
extend into 1-D chain via C−Cl---O synthons. The C−Cl---O
distance is 3.065 Å and the C−Cl---O angle is 169.98°, Figure
5.
Covalent Synthesis. Six pyrazole molecules were synthe-
sized using published procedures and characterized by 1H
NMR spectroscopy and melting-point, Table 2.
1
Table 2. H NMR Data, Yields, and Melting Points for Six
Pyrazoles
%
yield
molecule 1H NMR values [lit. value]
melting point [lit. value]
1.Cl
1.Br
1.I
7.58 (s, 2H, CH) [7.55, s,
73−74 °C [75−76 °C]13
49
2H, CH]16
7.61 (s, 2H, CH) [7.53, s,
2H, CH]16
89−91 °C [91−92 °C]19
104−105 °C [108 °C]14
30
47
62
38
52
7.65 (s, 2H, CH) [7.64, s,
2H, CH]17
2.Cl
2.Br
2.I
2.25 (s, 6H, CH3) [2.25, s, 106−108 °C [117−118
6H, CH3]18
°C]13
2.26 (s, 6H, CH3) [2.26, s, 116−119 °C [122 °C]16
6H, CH3]18
2.27 (s, 6H, CH3) [2.27, s, 135−136 °C [not
6H, CH3]18
reported]
Charge Calculations. AM1, PM3, and DFT calculations
were performed to establish the maxima and minima in the
MEPS at the relevant hydrogen-bond donor/acceptor sites,
Table 3.
Co-Crystal Screen. A co-crystal screen using IR spectros-
copy was carried out for a total of 180 (9 × 20) pyrazole-
carboxylic acid combinations, Table 4. A reaction, co-crystal or
salt, was deemed to take place when the resulting solid
displayed broad stretches in the 2500 cm−1 and 1900 cm−1
region, indicative of O−H---N(pyz) intermolecular hydrogen-
bond interactions that are only possible if the solid contains
both components.
Similarly, in the crystal structure of 2.Br:N, an infinite chain
is observed where O−H---N(pyz) and N−H---O synthons
drive cocrystal formation. The C−Br---O− distance is 3.022 Å
and the C−Br---O− angle is 174.25°, Figure 6.
Salts. The first example of a salt was revealed in the
structure determination of the 2.Cl:T. Furthermore, not only
has the proton been transferred from the acid to the base, but
Single-Crystal Data. On the basis of IR spectroscopy we
were able to determine that 101 of the 180 experiments
D
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Table 4. Summary of Prominent IR Stretches (cm−1) from the Melt Experiments between Nine Pyrazoles and 20 Carboxylic
a
Acids
acids
1.H
1.Cl
1.Br
1.I
1.NO2
2.H
2.Cl
2.Br
2.I
A
B
C
2499, 1897,
1666
2507, 1874,
1674
2488, 1855,
1679
2507, 1897,
1691
2496, 1879,
1667
2491, 1878,
1667
2491, 1881,
1671
2448, 1870,
1675
2452, 1838,
1671
D,E, F
G
2440, 1862,
1682
2535, 1865,
1693
2535, 1872,
1686
2382, 1870,
1679
H
I
2464, 1862,
1729
2396, 1865,
1693
2469, 1885,
1699
2503, 1897,
1699
2553, 1893,
1687
2541, 1889,
1675
2357, 1850,
1695
2382, 1883,
1695
2436, 1885,
1702
2425, 1862,
1698
2401, 1835,
1679
2491, 1893,
1721
2484, 1891,
1687
2632, 1889,
1720
2448, 1878,
1688
2429, 1889,
1695
J
2397, 1928,
1690
2499, 1867,
1675
2350, 1858,
1704
2429, 1850,
1708
2468, 1897,
1708
2456, 1862,
1716
K
L
2487, 1874,
1690
2429, 1854,
1690
2417, 1846,
1687
2433, 1893,
1683
2429, 1866,
1683
2533, 1912,
1679
2433, 1881,
1694
2495, 1878,
1683
2476, 1891,
1695
2397, 1881,
1712
2390, 1901,
1720
2417, 1893,
1716
M
N
O
P
Q
R
S
2517, 1936,
1679
2515, 1878,
1682
2495, 1881,
1682
2476, 1904,
1695
2499,1917,
1679
2511, 1921,
1679
2448, 1885,
1687
2436, 1866,
1702
2413, 1854,
1698
2405, 1823,
1691
2413, 1827,
1691
2492, 1851,
1683
2519, 1842,
1701
2413, 1889,
1704
2433, 1846,
1698
2492, 1932,
1704
2521, 1887,
1720
2448, 1874,
1702
2526, 1874,
1674
2522, 1885,
1678
2459, 1842,
1708
2554, 1897,
1699
2386, 1901,
1691
2357, 1912,
1720
2464, 1893,
1706
2491, 1893,
1702
2464, 1885,
1704
2546, 1862,
1698
2488, 1887,
1712
2483, 1909,
1712
2358, 1893,
1675
2452, 1909,
1712
2440, 1885,
1709
2483, 1893,
1709
2499, 1897,
1713
2415, 1897,
1704
2491, 1885,
1708
2476, 1901,
1716
2483, 1881,
1704
2468, 1889,
1708
2296, 1932,
1647
2421, 1909,
1702
2435, 1822,
1699
T
2429, 1866,
1713
2425, 1878,
1706
2366, 1881,
1708
2374, 1881,
1709
2522, 1893,
1717
2464, 1889,
1704
2456, 1878,
1699
2358, 1885,
1704
supramolecular
yield (%)
11/20 = 55% 13/20 = 65% 12/20 = 60% 12/20 = 60% 2/20 = 10% 14/20 = 70% 11/20 = 55% 14/20 = 70% 12/20 = 60%
a
Note: numbers represent wavenumbers (cm−1) observed.
Figure 1. Infinite 1-D chain in the crystal structure of 1.Br:N driven by
O−H---N(pyz) and N−H---O synthons. N−O---Br interactions
extend the dimers into a 1D chain.
Figure 3. An overview of the 2-D layer in the crystal structure of 1.I:N.
Figure 2. Infinite 1-D chain in the crystal structure of 1.I:H driven by
O−H---N(pyz) and N−H---O synthons. CN---I interactions extend
the dimers into 1D chains.
Figure 4. Infinite 1-D zigzag chain in the structure of 2.Cl:B..
an additional neutral pyrazole molecule is also included in the
lattice, Figure 7. The three building blocks are assembled into
discrete trimers, driven by N−H---O, N−H---N, and charge-
assisted N−H+---O− synthons.
The reaction between 2.I and N also results in an ionic
compound. A combination of charge-assisted N−H+---O−, N−
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Figure 5. 1-D chain of in the structure of 2.Cl:N.
Figure 6. 1-D chain in the crystal structure of 2.Br:N.
Figure 9. Discrete tetramers formed between in the crystal structure of
1.H:R.
Figure 10. A zigzag chain in the crystal structure of pyrazolium 3,5-
dinitrobenzoate 3,5,-dinitrobenzoic acid.
Figure 7. A hydrogen-bonded trimer in the crystal structure of 4-
chloro-3,5-dimethylpyrazolium 2,4-dintrobenzoate 4-Cl-3,5-dimethyl-
pyrazole.
H---O, and N−H---O− synthons produce tetramers, Figure 8,
which are connected into a ladder-like motif via C−I---O−
interactions, with a C−I---O− distance of 3.089 Å and a C−I---
O− angle of 177.59°.
forms an O−H---O synthon to complete the structure while a
C−H---O− interaction generates the 1-D chains.
The proton transfer from N to 2.H produces the only
solvated crystal structure in this series. The main feature is a
trimer involving all three components, Figure 11. The N−H
proton interacts directly with the oxygen from water to form a
N−H---O synthon. The O−H(water)---O(carbonyl) synthon
completes the trimer.
Table 5 displays the relevant hydrogen-bond distances for
the crystal structures obtained.
Figure 8. Tetramers (subsequently linked into ribbon) formed in the
solid product resulting from a combination of 2.I and N.
The reaction between 1.H and R also produces an ionic
compound where the main feature of the crystal structure is a
tetramer, Figure 9, held together by charge-assisted N−H+---O−
synthons.
Figure 10 depicts a zigzag chain formed by charge-assisted
N−H+---O− synthons in the crystal structure of the ionic
compound produced when 1.H was allowed to react with N.
The N−H proton is bifurcated between a CO oxygen from a
second neutral acid and the carboxylate oxygen directly
involved in the hetero dimer. The second neutral acid also
Figure 11. A hydrated ion-pair in the crystal structure of 3,5-
dimethylpyrazolium 3,5,-dinitrobenzoate hydrate.
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Table 5. Summary of Hydrogen-Bond Geometries
structure
D−H···A
d(D−H)
d(H···A)
d(D···A)
2.834(4)
∠(DHA)
1.Br:N
N111−H111···O221
N112−H112···O222
O211−H211···N121
O212−H212···N122
O(11)−H(11)···N(22)
N(21)−H(21)···O(12)
O(11)−H(11)···N(22)
N(21)−H(21)···O(12)
O(31)−H(31)···N(42)
N(41)−H(41)···O(32)
N(11)−H(11)···O(22)
O(21)−H(21)···N(12)
O(24)−H(24)···O(22)#1
N(11)−H(11)···O(22)
O(21)−H(21)···N(12)
N(11)−H(11)···O(22)
O(21)−H(21)···N(12)
N(11)−H(11)···O(38)
N(12)−H(12)···N(22)
N(21)−H(21)···O(37)
N11A H11A O21
0.87(5)
0.75(5)
0.88(5)
0.89(5)
0.96(2)
0.79(2)
0.87(2)
0.78(2)
0.83(2)
0.76(2)
0.89(3)
0.90(3)
0.84(4)
0.758(18)
0.814(18)
0.98(5)
1.28(5)
1.15(2)
0.92(2)
0.78(3)
0.88
2.11(5)
2.18(5)
1.80(5)
1.79(5)
1.70(2)
2.16(2)
1.75(2)
2.31(2)
1.84(2)
2.28(2)
2.18(3)
1.76(3)
2.01(4)
2.619(17)
1.810(19)
2.49(5)
1.30(5)
1.41(2)
1.91(3)
1.98(3)
1.85
140(4)
145(5)
175(5)
167(5)
171(2)
141(2)
177(2)
136(2)
176(2)
140(2)
136(3)
174(3)
131(3)
130.6(16)
161.6(18)
128(3)
173(4)
167(2)
166(2)
167(3)
168.4
2.828(4)
2.674(4)
2.657(4)
1.I:H
1.I:N
2.6521(17)
2.8225(17)
2.6225(17)
2.9250(17)
2.6671(18)
2.9050(18)
2.875(2)
2.Cl:B
2.654(2)
2.636(2)
2.Cl:N
2.Br:N
2.Cl:T
3.1647(13)
2.5946(13)
3.180(5)
2.578(4)
2.541(2)
2.811(2)
2.740(2)
2.I:N
N11B H11B O21
0.88
2.20
2.713(6) 3.005(9)
3.024(6) 2.772(7)
151.1
N12A H12A O23
0.880.88
2.191.91
158.6
N12B H12B O23
164.3
1.H:R
1.H:N
N11 H11 O21
0.87(4)
0.92(4)
0.83(5)
0.88
1.94(4)
1.78(4)
1.75(5)
2.30
2.797(4)
166(4)
158(4)
171(5)
119.7
N12 H12 O21
2.650(4)
O31 H31 O22
2.575(4)
N11A2−H11A2···O312
N12A2−H12A2···O322
N11B2−H11B2···O312
N12B2−H12B2···O222
O211−H211···O311
O212−H212···O312
N11 H11 O21
2.843(17)
3.059(17)
2.620(3)
0.88
2.22
160.6
0.89(4)
0.83(4)
0.86(4)
0.79(4)
0.995(17)
0.967(16)
0.890(19)
0.888(18)
1.73(4)
1.99(4)
1.67(4)
1.72(4)
1.595(17)
1.713(16)
1.851(19)
1.880(18)
178(4)
149(3)
172(3)
177(4)
167.2(15)
162.0(15)
174.9(17)
178.9(18)
2.741(3)
2.522(3)
2.517(3)
2.H:N
2.5747(14)
2.6490(14)
2.7390(13)
2.7681(13)
N12 H12 O1W
O1W H1A O22
O1W H1B O22
solid is obtained (one anion, one cation, one neutral acid) even
though CO band is again shifted by 12 cm−1.
DISCUSSION
■
Theoretical Calculations. According to the calculations,
Our results from the co-crystal screening indicate that adding
a halogen atom to the pyrazole backbone does not change the
overall efficiency of the supramolecular yield as compared to
the unsubstituted pyrazole and dimethylpyrazole. For the latter
two the success rate is 55−70%, compared with a 60%−70%
success rate for the halogenated pyrazoles. The similarities in
supramolecular yield can be ascribed to the fact that neither
methyl groups nor halogen atoms significantly alter the
electrostatic potential on the primary binding sites of the
pyrazole moiety. However, our calculations did indicate that
nitropyrazole is considerably less basic (and the N−H
hydrogen atom is substantially more acidic) than the
corresponding moieties in the other pyrazoles. We therefore
assumed that any hydrogen-bond interaction between nitro-
pyrazole and a carboxylic acid would be relatively weak and less
likely to drive a successful co-crystallization. In fact, the
supramolecular yield for nitropyrazoles dropped to 10%, which
is consistent with the hypothesis that the magnitude of the
electrostatic component of the hydrogen-bond is critical to
supramolecular effectiveness of such interactions.
the presence of two methyl groups or a halogen atom on the
pyrazole backbone has a relatively minor effect on the
electrostatic charges. The addition of the nitro group, however,
has a pronounced effect on the charges, notably on the acidic
N−H proton on the pyrazole molecule. Although the actual
numbers differ between different methodologies (AM1, PM3,
and DFT), the relative ranking of binding sites remain
unchanged. The question is, are these differences significant
enough to change the supramolecular yield?
Co-Crystal Screen. Although it is easy to distinguish
between reaction and no-reaction using IR spectroscopy, an
unambiguous determination of whether a salt or co-crystal has
formed is not always possible, especially since some reactions
produce solids that contain both ions and neutral molecules.
For example, the single-crystal data for 2.Cl:N show that the
composition in this solid is a 1:1 co-crystal and in the
corresponding IR spectrum the CO band of the acid has
shifted by 12 cm−1 compared with that of the free acid.
However, when the same pyrazole is combined with T, a 1:1:1
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Predicting salt or co-crystal formation from analysis of the
CO stretches (normalized against the neutral acid) turned
out to be difficult due the small changes in peak position (4−12
cm−1). However, the more acidic acids (based upon pKa values)
did show a higher propensity to form salts as found from single-
crystal diffraction data. Co-crystals were formed by acids with
pKa values in the 2.77−4.45 range, whereas salts were produced
by acids with pKa values in the 1.43−2.77 range.
Table 7. Bond Angles for Relevant Structures Containing
Halogen Bonding
compound
C−X---O− (X = Cl, Br) (deg)
1.Br:N
1.I:N
154
164
170
174
2.Cl:N
2.Br:N
Single Crystal Data. Analysis of the Cambridge Structural
Database (CSD) reveals the majority of structures containing
pyrazole are used as ligands in metal coordination complexes.20
In Table 6, the different motifs involving pyrazole molecules
are listed. A detailed analysis has been provided by Elguero and
co-workers.21
occasions a neutral acid was included, on one occasion a
neutral pyrazole molecule was included, and finally one
structure was hydrated. This behavior is fully consistent with
a previous report13 which suggests that co-crystals are more
likely to generate desirable stoichiometries whereas organic
salts are far more likely to appear with unexpected
stoichiometries.
As a result of the presence of neutral acids or bases, or a
solvent of crystallization, it is not possible to make many
general conclusions about how the competing intermolecular
interactions in this group of five compounds should be ranked
in terms of strength or proclivity.
Table 6. Summary of Crystal Structure Type Obtained for
a
Pyrazoles from Data in the CSD
dimers
trimers
tetramers
8 (CUMQOR, FITQEE, 2 (CUMQAD, CUMQEH,
3 (CUQHAX)
FITQEE01, OMEKAS,
TIDLIB, TIDLIB01)
CUQGOK, DASXEA, DASXEA10,
EBILUX, GOQXIT, HOQHUQ,
WIKZUL)
CONCLUSIONS
a
■
Ref codes shown in parentheses.
This study has established several points of general importance
to practical crystal engineering. First, the head-to-head
pyrazole---carboxylic acid synthon has shown itself to be a
valid and robust heterosynthon that can find considerable use
in the construction of co-crystals and extended architectures in
organic solids. Second, the connection between electrostatic
charge on a hydrogen-bond donor/acceptor site and the
supramolecular yield of subsequent co-crystallizations is
emphasized yet again. However, we have also refined this
conclusion by examining which substituents are capable of
effecting a noticeable change; the -NO2 moiety has a far greater
effect than -Me, -Cl, -Br, or -I. Third, practical crystal
engineering is likely to be more successful (in terms of
predicting stoichiometry and connectivity) if the solid form is a
neutral co-crystal as opposed to an organic salt. The structural
landscape15 of the latter is far more difficult to map out
primarily because chemical composition of the resulting solid is
highly unpredictable.
Most of the structures in Table 6 arise from 1H-pyrazole or
the 3,5-dimethyl-1H-pyrazole analogue: the majority of our
structures contain halogen-atom substituted pyrazoles.
Co-crystals: Six of the 11 crystal structures that were
obtained in this study were cocrystals, i.e., all components were
charge neutral. In each case, the desired head-to-head acid---
dimer was driving the co-crystal synthesis through a two point
2
O−H---N/CO---H−N synthon, [R2 (7)]. The dimers were
subsequently linked into chains through a variety of secondary
contacts depending on the nature of the substituents on the
pyrazole and/or acid backbone. We identified I---O2N, Br---
O2N, and Cl---O2N as well as I---N≡C and I---I (Type I)
interactions, and finally an O−H---OOHC hydrogen bond all
of which served to create chains of dimers. In the case of 1.I:H
the distance between nitrogen and iodine is 3.183 Å, which is
considerably shorter than the sum of their van der Waals radii
(3.53 Å)22 and in good agreement with similar CN---I cyano-
halogen interactions observed by Desiraju and Harlow.23 This
also indicates a favorable n → σ* donation from the nitrogen
lone-pair to the positive lobe on the iodine atom.24 It is
noteworthy that placing halogen-bond donors in the 4- position
on the pyrazole may allow for carboxylic acids, containing
suitable halogen-bond acceptors in the 4- position, to form
predictable supramolecular chains driven by the interplay
between hydrogen and halogen bonds.25 As expected, the only
halogen atom capable of forming Type I interactions in these
structures is the iodine atom due to its greater polarizability.
However, all three halogen atoms are capable of forming
weakly interacting halogen bonds with an O2N-acceptor site,
Table 7.
ASSOCIATED CONTENT
* Supporting Information
Tabulated crystallographic data. This information is available
free of charge via the Internet at http://pubs.acs.org/.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: aakeroy@ksu.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank NSF (CHE-0957607) and NSF GK-12 for financial
support.
■
Salts. In five of the 11 crystal structures that were obtained,
proton transfer was found to have taken place. In this series of
compounds, a charge assisted N−H+---−OOC hydrogen bond
was present in all five structures, again demonstrating the
importance of charge for structure directing hydrogen bonds. A
striking general difference between co-crystals and salts is the
fact that in the former group, all six compounds displayed the
expected 1:1 stoichiometry, whereas four of the five salts
offered an unexpected chemical stoichiometry. On two
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