Making benzamide cocrystals with benzoic acids: The influence of chemical structure

Article abstract of DOI:10.1021/cg101403j

An investigation into the creation of cocrystals of benzamide and substituted benzoic acids was undertaken and four new cocrystals were structurally characterized by single-crystal X-ray diffraction. The attempted cocrystallizations were only successful in those cases where electronwithdrawing functional groups were present as substituents on the benzoic acid. This experimental observation was supported by computational studies, which indicated that in these cases the intermolecular acid···amide interaction between the acid and benzamide was strengthened. A correlation between the interaction energy and the Hammett substitution constant in the applicable cases was displayed. The calculated energy of interaction between benzamide/salicylic acid dimers and benzamide/benzoic acid dimer are the same, yet only benzamide/salicylic acid forms a cocrystal. Lattice energy calculations on the salicylic acid/benzamide crystal structure and hypothetical benzoic acid/benzamide cocrystal structures indicate a difference of approximately 50 kJ mol in energy between these systems, suggesting that the other crystal packing forces are not sufficient to stabilize the benzoic acid/benzamide cocrystal.

Full text of DOI:10.1021/cg101403j

ARTICLE
pubs.acs.org/crystal
Making Benzamide Cocrystals with Benzoic Acids: The Influence
of Chemical Structure.
Published as part of a virtual special issue of selected papers presented at the 2010 Annual Conference of the
British Association for Crystal Growth (BACG), Manchester, UK, September 5ꢀ7, 2010.
Colin C. Seaton*,† and Andrew Parkin‡
†School of Chemical Engineering & Analytical Science, The Mill, University of Manchester, Oxford Road, Manchester,
United Kingdom, M13 9PL,
‡WestCHEM, Department of Chemistry, University of Glasgow, University Avenue, Glasgow, United Kingdom
ABSTRACT: An investigation into the creation of cocrystals of benzamide and substituted benzoic acids
was undertaken and four new cocrystals were structurally characterized by single-crystal X-ray
diffraction. The attempted cocrystallizations were only successful in those cases where electron-
withdrawing functional groups were present as substituents on the benzoic acid. This experimental
observation was supported by computational studies, which indicated that in these cases the
intermolecular acid amide interaction between the acid and benzamide was strengthened. A
3 3 3
correlation between the interaction energy and the Hammett substitution constant in the applicable
cases was displayed. The calculated energy of interaction between benzamide/salicylic acid dimers and benzamide/benzoic acid
dimer are the same, yet only benzamide/salicylic acid forms a cocrystal. Lattice energy calculations on the salicylic acid/benzamide
crystal structure and hypothetical benzoic acid/benzamide cocrystal structures indicate a difference of approximately 50 kJ molꢀ1 in
energy between these systems, suggesting that the other crystal packing forces are not sufficient to stabilize the benzoic acid/
benzamide cocrystal.
’ INTRODUCTION
for oxygen containing organic species (e.g., aldehydes, ketones,
esters, ethers, and carboxylic acids) the stability of molecular
complex with an organic acid increased as the strength of the
organic acid was increased.6 This was demonstrated by trichlor-
oacetic acid forming a range of complexes with almost all the
substances studied, while monochloroacetic acid and acetic acid
only formed a single complex.7 More recently, work by Aaker€oy
and co-workers has demonstrated the competition between
multiple binding sites within a molecule could be explained by
differences in the electrostatic potential of the sites, reflected in
the differing pKas of the functional groups.8 This highlights that
the strength of the intermolecular interactions between the
components is dependent on the whole molecular structure.
To develop a design strategy based on the effects of electron-
withdrawing and -donating groups upon the strength of the
supramolecular synthons, a quantitative understanding of these
processes is required. The formation of molecular complexes of
substituted benzoic acids with benzamide was selected as an
initial system for experimental and computational studies into
the effects of functional groups upon the formation of a selected
supramolecular synthon. The electron-donating and -withdraw-
ing nature of the functional groups on the benzoic acid were
varied, the change in binding energy between the components
calculated and compared with the success of cocrystallization.
The creation of multicomponent crystalline materials (such as
salts, molecular complexes or cocrystals) is an area of expanding
growth,1 driven by the study of pharmaceutical cocrystals.2 These
materials offer a possible route for the modification of the
physicochemical properties of an active pharmaceutical ingredi-
ent (API) without changing the pharmaceutical activity. How-
ever, the discovery of new complexes is currently often
serendipitous and so the designed creation of such materials
with required properties, still requires the development of a
deeper understanding of the processes that control their
formation.
The key design tool used to select suitable coformers for a
given substance is the concept of a supramolecular synthon.3
These are frequently occurring intermolecular interactions that
are expected to bind the two components together within in the
crystal, commonly identified through database searching. Often
the supramolecular synthons are considered in isolation from the
rest of the molecule; however interactions between the other
functional groups within the components also play a role in the
formation of the molecular complex. Recently, it was shown that
the formation of substituted benzoic acid cocrystals with an
acid acid ring dimer motif was promoted by the presence of
3 3 3
electron withdrawing functional group on one benzoic acid and
electron donating groups on the other component,4 using
Hammett substituent constants5 as a quantitative measure of
the electron withdrawing and donating nature of the functional
groups. Early studies into molecular complexes also noted that
Received: October 20, 2010
Revised:
March 3, 2011
Published: March 18, 2011
r
2011 American Chemical Society
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Table 1. pKa Values for Each Selected Coformer, Hammett Constant for the Substituted Benzoic Acids, and Whether or Not They
Form Benzamide Molecular Complexes
substance
pKa
Hammett constant (σ)
forms a Complex?
succinic acid
4.24
1.75
3.42
3.48
3.84
4.16
0.53
9.45
3.01
4.20
7.23
7.80
4.48
3.88
N/A
yes
yes
yes
yes
yes
yes
yes
yes
yes
no
pentafluorobenzoic acid
4-nitrobenzoic acid
3-nitrobenzoic acid
2-(hydroxymethyl)benzoic acid
4-(hydroxymethyl)benzoic acid
picric acid
0.34 (meta), 0.06 (para)
0.71
0.78
N/A
ꢀ0.27
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
resorcinol
salicylic acid
benzoic acid
4-nitrophenol
no
5, 5-diallylbarbituric acid
hexadecanedioic acid
cinnamic acid
no
no
no
There have been few previous studies into the formation of
benzamide molecular complexes with organic acids. A search of
the CSD only returns three complexes; succinic acid
(BZASUC),9 pentafluorobenzoic acid (1:1 ESATUN10 and 1:2
KEMCEL11), whereas the crystal structure of the complex with
4-nitrobenzoic acid has been reported.12 Additionally, the forma-
tion of molecular complexes between benzamide and 2-(hydroxy-
methyl)benzoic acid, 4-(hydroxymethyl)benzoic acid, 3-nitro-
benzoic acid, picric acid, resorcinol (1,3-dihydroxybenzene) and
salicylic acid has been identified by hot-stage microscopy but no
crystal structures have been determined (during the review of
this paper, a crystal structure of the salicylic acid/benzamide was
independently determined and published14).13 In contrast,
benzoic acid does not form a molecular complex, as indicated
by the presence of only a single eutectic point in the binary
phase diagram, which has been determined three times inde-
pendently.15ꢀ17 Four other systems; 5,5-diallylbarbituric acid,
4-nitrophenol, hexadecanedioic acid, and cinnamic acid have
also been shown by construction of binary phase diagrams not
to form molecular complexes with benzamide.13 The substi-
tuted benzoic acids that form molecular complexes with ben-
zamide all feature electron withdrawing substituents and are
stronger acids than benzoic acid (Table 1). In general the
stronger acids, as indicated by pKa values, form molecular
complexes, although there are anomalous results, e.g. resorcinol
is the weakest acid but forms a complex. This may be due to
unsuitability of pKa values to reflect binding preferences in the
solid state or a change in the intermolecular interactions
between resorcinol and the other coformers. The resorcinol
isomer, quinol (1,4-hydroxybenzene) is well-known host mo-
lecule forming numerous inclusion complexes,18 and although
fewer examples are known for resorcinol, it is possible that such
a structure is forming in this case, however a clarifying crystal
structure determination is still lacking for this system.
Figure 1. Schematic of acid amide ring dimer supramolecular
synthon.
3 3 3
determined, chemical species >1, a complete list of refcodes is
available as Supporting Information). However, because this is
the sole hydrogen bonding interaction between these species, it
may be possible to predict successful complex formation through
the calculation of the energy for this interaction between the
components. To test this hypothesis, we determined the inter-
action for selected substituted benzoic acids by ab initio calcula-
tions. The systems selected were the known complex forming
acids: pentafluorobenzoic acid (I), 4-nitrobenzoic acid (II),
3-nitrobenzoic acid (III) and salicylic acid (IV), the known
noncomplexing acids: benzoic acid (V), cinnamic acid (VI) and
acids with unknown complexing ability: 3,5-dinitrobenzoic acid
(VII), 2,4,6-trihydroxybenzoic acid (VIII), 4-aminobenzoic acid
(IX), 4-hydroxybenzoic acid (X), 4-hydroxy 3-nitrobenzoic acid
(XI), and 4-amino 3-nitrobenzoic acid (XII). 3,5-dinitrobenzoic
acid and 2,4,6-trihydroxybenzoic acid both contain electron-
withdrawing functional groups and are strong acids (pKa: 2.77,
1.62 respectively) thus they are predicted to form complexes with
benzamide. 4-aminobenzoic acid and 4-hydroxybenzoic acid
contain electron-donating functional groups and are weaker
acids (pKa: 4.90, 4.57, respectively) and are predicted not to
form complexes with benzamide. 4-Hydroxy 3-nitrobenzoic acid
and 4-amino 3-nitrobenzoic acid feature a combination of
electron-withdrawing and -donating groups and are intermediate
in acidity (pKa: 3.93, 4.19 respectively) but differ in Hammett
constant (σ = 0.34, 0.05 respectively). This pair of molecules will
test the competition between the additional functional groups.
To identify whether a given system forms a molecular complex
with benzamide, we undertook synthesis of the molecular
complexes by solution and solid-state routes. Where suitable
crystals were obtained, crystal structures were determined by
single crystal X-ray diffraction. Additionally, the phase diagrams
for 4-aminobenzoic acid, 4-hydroxybenzoic acid, 2,4,6-trihydrox-
ybenzoic acid, 4-hydroxy 3-nitrobenzoic acid and 4-amino
Since benzamide has a single amide group capable of partici-
pating in hydrogen bonding and the predicted supramole-
cular synthon for potential cocrystals with benzoic acid is the
acid amide ring dimer (Figure 1). Searching the CSD for the
3 3 3
occurrence of this interaction indicates that it is a relatively
uncommon supramolecular synthon (Conquest 1.11 on version
5.30 of the CSD,19 81 hits, only organics, 3D coordinates
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Crystal Growth & Design
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Table 2. Experimental Results for the Single-Crystal X-ray Diffraction
salicylic acid/
benzamide
3, 5-dinitrobenzoic acid/
benzamide
3-nitrobenzoic acid/
benzamide
4-hydroxy 3-nitrobenzoic 1, 3, 5-trihydroxybenzene
system
acid/benzamide
dihydrate
formula
fw
C7H6O2 C7H7NO2
259.25
C7H4N2O6 C7H7NO2
333.26
C7H5NO2 C7H7NO2
288.26
C7H4NO5 C7H7NO2
304.26
C6H6O3 2H2O
162.14
3
3
3
3
3
T (K)
100(2)
100(2)
100(2)
100(2)
100(2)
radiation (Å)
cryst syst, space group
a, b, c (Å)
Mo KR, 0.7107
monoclinic, P21/c
5.3419(5),
9.5609(8), 23.528(3)
90, 91.294(9), 90
1201.4(2)
Mo KR, 0.7107
monoclinic, P21/c
8.4617(18),
10.738(2), 16.049(3)
90, 99.334(7), 90
1438.9(5)
Mo KR, 0.7107
monoclinic, P21/c
16.2626(11),
6.8717(4), 11.9800(8)
90, 107.429(7), 90
1277.32(14)
Mo KR, 0.7107
monoclinic, P21/n
8.6105(7),
5.0229(3), 30.253(5)
90, 98.770(10), 90
1293.1(3)
Mo KR, 0.7107
orthorhombic, Pnma
6.5876(5),
13.5170(8), 8.0345(5)
90, 90, 90
R, β, γ (deg)
V (Å3)
715.43
4, 0.5, 1.505
Z, Z0,
4, 1, 1.433
4, 1, 1.538
4, 1, 1.499
4, 1, 1.563
density (g cmꢀ3
)
μ (mmꢀ1
)
0.106
0.126
0.116
0.125
0.133
cryst size (mm)
θmin/θmax
0.7 ꢁ 0.5 ꢁ 0.1
0.6 ꢁ 0.25 ꢁ 0.1
0.5 ꢁ 0.1 ꢁ 0.07
0.8 ꢁ 0.5 ꢁ 0.2
1.0 ꢁ 0.7 ꢁ 0.4
2.75/28.50
2.3/28.1
3.24/28.54
2.93/26.37
2.95/26.37
reflns collected/unique (Rint
data/restraints/params
GOF on F2
)
7148/2714 (0.0564)
2714/0/174
0.936
8755/3313 (0.033)
3313/0/261
0.9018
7464/2905 (0.0394)
2905/0/194
0.945
7151/2652 (0.0297)
2652/0/199
0.997
4322/761 (0.0343)
761/4/71
0.951
final R indices (I > 2σ(I)) R1/wR2
R indices (all data) R1/wR2
0.0668/0.1411
0.1166/0.1554
0.375/ꢀ0.281
0.0384/0.0931
0.0529/0.0980
0.37/ꢀ0.39
0.0423/0.1015
0.0684/0.1095
0.328/ꢀ0.291
0.0447/0.0955
0.0600/0.0998
0.281/ꢀ0.291
0.0463/0.1162
0.0598/0.1208
0.518/ꢀ0.247
largest diff. peak and hole (e Åꢀ3
)
3-nitrobenzoic acid with benzamide were investigated through
use of the Kofler contact method. In the Kolfer contact method,
the highest melting component is initially melted then solidified
onto a glass slide. The melted second component is then brought
in contact with the first component. This creates a zone of mixing
and upon cooling any existing cocrystal phase will form within
this region. The resulting mixture exhibits a concentration
gradient between each component and so by viewing the heated
sample through crossed polar filters, the eutectics between each
phase can be identified. If the system exhibits a single eutectic
then no cocrystal forms from the melt, while two or more
eutectics indicate the formation of a cocrystal phase. This system
has been successfully utilized to screen for nicotinamide cocrys-
tals with active pharmaceutical ingredients.20
slowly cooled. Clear lustrous plate crystals were obtained. 3, 5-dinitro-
benzoic acid (4.0689 g, 19 mmol) and benzamide (2.2836 g, 19 mmol)
were dissolved in methanol (25 mL). The solution was heated and
stirred to fully dissolve the solid material and left to cool to room
temperature. Upon slow evaporation of the solution colorless block
crystals were obtained. 2,4,6-trihydroxybenzoic acid monohydrate
(0.728 g, 4 mmol) and benzamide (0.6637 g, 5.5 mmol) were dissolved
in 95% ethanol (40 mL). Upon slow evaporation light brown block
crystals were obtained. 4-hydroxy 3-nitrobenzoic acid (0.8618 g, 5
mmol) and benzamide (0.5648 g, 5 mmol) were dissolved in methanol
(15 mL) with gentle heating. Upon cooling yellow plate crystals of the
complex were obtained.
Solvent-assisted grinding experiments were carried out for benzamide
with 4-aminobenzoic acid (0.2961 g (4aba), 0.3399 g (benzamide)),
4-hydroxybenzoic acid (0.2691 g (4hba), 0.3060 g (benzamide)),
4-amino 3-nitrobenzoic acid (0.3387 g (4a3nba), 0.2312 g (benzamide))
and 2,4,6-trihydroxybenzoic acid (0.3373 g (246thba), 0.2177 g
(benzamide)) with 5 drops (approximately 0.5 mL) of 95% ethanol
using a ball-mill for 30 min grinding at 30 Hz.
The binary phase diagram between salicylic acid and benzamide was
constructed from DSC profiles collected on a TA Q2000 DSC instru-
ment with RGS90 cooling unit. Temperature calibration was performed
using an indium metal standard. Mixtures in differing ratios of salicylic
acid and benzamide (approximately 5 mg) were weighed directly into
Tzero aluminum pans, which were then sealed. The samples were
subjected to a heat/cool/heat cycle from 30 to 160 °C with a heating
rate of 5°/min. The data from the final run were analyzed using TA
Instruments Universal Analysis 2000 software to obtain the solidius and
liquidius temperatures from the onset temperature of the eutectic peak
and the peak maxima of the higher melting peak.
The solid phases were identified through single crystal and powder
X-ray diffraction techniques. A single crystal data set for VII was
collected at 100 K on a Bruker APEX2 CCD diffractometer equipped
with an Oxford Cryosystems low temperature Cryostream device.22 The
data were collected and processed by the APEX2 software. The structure
was solved using Sir9223 and refined using full matrix least-squares on all
data using CRYSTALS.24 All non-hydrogen atoms were anisotropically
refined and the hydrogen atoms located in the difference map and freely
refined. The structures of III, IV, VIII, and XI were determined by single
crystal diffraction at 100 K on an Oxford X-caliber2 diffractometer with
Mo KR radiation with a graphite monochromator using an Oxford
’ EXPERIMENTAL METHODS
All chemicals were purchased from Sigma-Aldrich in the highest
purity available. While the majority of materials have purity greater than
95%, 2,4,6-trihydroxybenzoic acid monohydrate was only available in
90% purity with 1,3,5-trihydroxybenzene as the major impurity. The
materials were used as received. The known solubilities of benzamide in
methanol and water were used to select initial compositions, with the
assumption that the materials would have similar solubilities in these
solvents and so production of a congruently dissolving cocrystal will
occur at the molar ratio of the cocrystal. A 1:1 composition was selected
as the expected composition, although it is noted that variations in
cocrystal composition do occur and can be adjusted by solvent choice.21
Although this does not guarantee the location of all possible cocrystals,
this simple solvent screen combined with the hot-stage microscopy and
solid-state synthesis should indicate the thermodynamic stability of the
system. Metastable cocrystals may occur but location of these would
require a significantly more thorough screening process, utilizing
crystallization at differing temperatures, controlled cooling and wide
range of solvents.
3-Nitrobenzoic acid (1.044 g, 6 mmol) and benzamide (0.7811 g, 6
mmol) were dissolved in methanol (10 mL). Upon slow evaporation,
clear needle crystals of the complex were obtained. Salicylic acid (1.139
g, 8 mmol) and benzamide (1.127 g, 9 mmol) were dissolved in water
(40 mL). The solution was heated to dissolve the components and then
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Figure 2. Molecular structures of benzamide dimers with pentafluorobenzoic acid (I), 4-nitrobenzoic acid (II), 3-nitrobenzoic acid (two conformations
IIIa, IIIb), salicylic acid (IV), benzoic acid (V), cinnamic acid (VI), 3, 5-dinitrobenzoic acid (VII), 2, 4, 6-trihydroxybenzoic acid (VIII), 4-aminobenzoic
acid (IX), 4-hydroxybenzoic acid (X), 4-hydroxy 3-nitrobenzoic acid (two conformations XIa, XIb), and 4-amino 3-nitrobenzoic acid (two
conformations XIIa, XIIb).
Figure 3. Kolfer Contact Images for the systems (a) IX, (b) X, (c) XI, and (d) XII.
Cryosystems Cryostream 700 to maintain the temperature. The data
were collected and processed using CryAlisPro software.25 Structure
solution was carried out using Shelxs9726 and the structured refined
against F2 for all reflections by full matrix methods in Shelxl97.26 All non-
hydrogen atoms were refined anisotropically and the hydrogen atoms
were placed in geometric positions and refined as riding atoms except for
those bound to oxygen and nitrogen, which were freely refined. Single
crystal studies into the crystals obtained from 2,4,6-trihydroxybenzoic
acid and benzamide identified them as the dihydrate of 1,3,5-trihydrox-
ybenzene. The previously published structure27 was used as an initial
model for the structure refinement. The hydrogen atoms that are lacking
in the previous study were located from the Fourier difference map and
refined using AFIX 147 (hydroxybenzene hydrogens) and DFIX (water
hydrogens) constraints. The hydrogen atom temperature factors were
constrained by the values of the bonding atoms. Details of the final
refinements are given in Table 2.28
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Figure 4. PXRD of product from ethanol assisted grinding of benzamide with (a) 4-aminobenzoic acid, (b) 4-hydroxybenzoic acid, (c) 4-amino
3-nitrobenzoic acid, and (d) 2,4,6-trihydroxybenzoic acid. The experimental results are shown in black, a simulated pattern of benzamide in blue, and the
substituted benzoic acid in red.
Figure 5. (a) Formation of tetramer structure in III by a combination of strong hydrogen bonds. (b) Packing of dimers into a 2D sheet structure.
Carbon atoms are shown as green spheres, oxygen atoms as red, nitrogen atoms as blue, and hydrogen atoms as gray.
’ COMPUTATIONAL METHODS
chemie.unikarlsruhe.de/pub/jbasen.32 These are valence triple-ζ basis
sets with a polarization contribution and offer a suitable level of theory to
evaluate these weak interactions. After optimization and evaluation of
the dimer and individual monomers, the basis set superposition error
was evaluated by applying the counterpoise method.33 The final inter-
molecular energy was then calculated using eq 1, where Einter is the inter-
molecular energy, Eopt is the energy of the optimized structure, EAB is the
The intermolecular energy calculations were carried out using the
program orca29 with the initial molecular dimer constructed in Avoga-
dro. The initial model was optimized at the PBE/VDZ(P) level and then
the energies calculated at PBE/TVZP with the TVZ/J auxiliary basis set
using the Ahlrichs basis sets30 and polarization.31 The Ahlrichs auxiliary
basis sets were obtained from the TurboMole basis set library under ftp.
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Crystal Growth & Design
ARTICLE
energy of A and B in the geometry of the dimer and Ecounter is the
energy of A or B in the dimer with “ghost” atoms at the other mole-
cule sites.
In the cases of 3-nitrobenzoic acid, 4-hydroxy 3-nitrobenzoic acid,
and 4-amino 3-nitrobenzoic acid, two different conformations were
considered because they are systems that are not symmetric relative
to the carboxylic acid functional group (Figure 2).
Einter ¼ Eopt ꢀ EAopt þ EoBptðEAAB ꢀ EAcounter ¼ EBAB ꢀ EcBounter
Þ
ð1Þ
The lattice energy for the salicylic acid/benzamide cocrystal and
series of potential benzoic acid/benzamide cocrystals was evaluated
using the Dreiding force field34 and Gasteiger atomic point charges35
in the Material Studio program.36 Hypothetical benzoic acid/ben-
zamide cocrystals were constructed from the existing crystal struc-
tures by replacing the substituent groups with hydrogens, followed
by energy minimization of the cell parameters and atom positions.
The salicylic acid/benzamide cocrystal structure and the crystal
structures of the single component phases were also fully optimized
using the same method. The optimized energy includes contribu-
tions from both conformational and intermolecular interaction
terms and so the lattice energy of each system was calculated using
eq 2, where Elatt is the lattice energy, Ecrystal, the calculated energy of
crystal, Ni, the number of molecules of type i, Eiconf, the conforma-
tional energy of molecule of type i and n, the number of different
molecules.
AB
n
Ecrystal
Elattice
¼
ꢀ
Ei
ð2Þ
∑
n
conf
i¼0
Ni
∑
Figure 6. View along the a-axis of IV, showing the formation of
molecular ribbons between the salicylic acid:benzamide dimer, which
then pack together to form the 3D structure. The atom colors are the
same as in Figure 4.
i¼0
Figure 7. Formation of molecular ribbon in the crystal structure of VII,
with the interactions between the ribbons forming the 2D ladder. The
atom colors are the same as in Figure 4.
Figure 9. Formation of 2D sheet in the structure of trihydroxybenzene
dihydrate, by disordered orientations of water and OꢀH groups, viewed
down the a-axis.
Figure 8. (a) Formation of a 1D ribbon between the dimer units of XI, then packing into a sheet structure through OꢀH Onitro and CꢀH
π
3 3 3
3 3 3
interactions. (b) Packing of the sheets into the final 3D structure.
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Table 3. Geometric Parameters for the Acid Amide R2 (8) Dimer Motif in the Benzamide Cocrystals
2
3 3 3
syst
dC=Oacid (Å)
dCꢀOH (Å)
dC=Oamide (Å)
dCꢀNH2 (Å)
dO 3 3 3 N (Å)
dO 3 3 3 O (Å)
III
IV
1.212(2)
1.228(3)
1.228(2)
1.214(2)
1.319(2)
1.323(3)
1.329(2)
1.324(2)
1.239(2)
1.248(3)
1.261(2)
1.253(2)
1.331(2)
1.327(3)
1.346(2)
1.325(2)
3.042(1)
2.926(3)
2.933(2)
3.048(2)
2.525(1)
2.602(2)
2.589(2)
2.559(2)
VII
XI
Table 4. Energy of Hydrogen-Bonding Interaction for Each
Species with Benzamidea
IV also forms a 1:1 molecular complex. The ortho-hydroxy
group in salicylic acid forms an intramolecular OꢀH
O
3 3 3
hydrogen bond with the carboxylic acid group. The dimer is
substance
energy (kJ molꢀ1
)
formed through an acid amide interaction between the
3 3 3
OꢀH O and NꢀH O interactions, forming a second level
benzamide
ꢀ54.183
ꢀ61.452
ꢀ62.255
ꢀ62.380
ꢀ63.511
ꢀ63.556
3 3 3
3 3 3
R22(8) motif. These dimers then bind through a C(5) NꢀH
O
cinnamic acid
3 3 3
hydrogen bond between the benzamide amide groups to form a
4-aminobenzoic acid
4-hydroxybenzoic acid
benzoic acid
ribbon along the b-axis (Figure 6). These ribbons are stacked
along the a-axis through π π interactions, while CꢀH
π
3 3 3
3 3 3
interactions between the ribbons complete the 3D crystal
structure (Figure 6).
salicylic acid
4-amino 3-nitrobenzoic acid
pentafluorobenzoic acid
4-nitrobenzoic acid
ꢀ64.8267/ꢀ65.7539
ꢀ67.492
VII is a 1:1 molecular complex with the dimer bound together
through the expected acid amide interaction by an OꢀH
form a second level R22(8) motif. These dimers form a discrete
O
3 3 3
3 3 3
ꢀ67.897
and NꢀH
O hydrogen bonds that combine together to
3 3 3
4-hydroxy 3-nitrobenzoic acid
3-nitrobenzoic acid
ꢀ68.268/ꢀ67.159
ꢀ68.513/ꢀ68.589
ꢀ71.495
NꢀH Onitro hydrogen bond and in combination with the
3 3 3
acid...amide interaction a ribbon (second level C4 (20) motif) is
2, 4, 6-trihydroxybenzoic acid
4
formed along the b-axis around the 21 screw axis (Figure 7).
These stacks are interwoven with each other and held together by
3, 5-dinitrobenzoic acid
ꢀ72.501
a The values for 3-nitrobenzoic acid, 4-hydroxy 3-nitrobenzoic acid and
4-amino 3-nitrobenzoic acid are given for the two conformations of the
nitro group.
π
π interactions to form a 2D ladder structure (Figure 7).
The ladders are packed together to form the final 3D structure
3 3 3
through CarylꢀH Onitro hydrogen bonds.
3 3 3
XI forms a 1:1 molecular complex with the dimer again formed
through the OꢀH O/NꢀH O acid/amide R22(8) hydro-
’ RESULTS
3 3 3
3 3 3
gen bonds. Again, the nitro group is on the same side of dimer as
Hot-Stage Microscopy and Solvent-Assisted Grinding.
The application of the Kolfer contact method to IX, X, and
XII indicated that no cocrystal was stable by the presence of a
single eutectic (Figure 3a, b, d). This was supported by solution
crystallization and solvent-assisted grinding experiments that
produced mixtures of the starting materials (Figure 4aꢀc). For
XI, a clear single 1:1 cocrystal phase is observed in the experi-
ment (Figure 3c), which has a melting point intermediate to the
starting materials (169 °C versus 126 and 190 °C, respectively).
For VIII, the hot-stage experiment was unable to be performed
due to the thermal degradation of the trihydroxybenzoic acid
upon heating, whereas the PXRD of the solvent-assisted grinding
experiment appears to suggest that cocrystallization has not
occurred as the majority of peaks match the starting materials
(Figure 4d). However, there are weak peaks at higher angle that
may be due to a new phase and so the results of the study into
VIII are inconclusive.
the amide NH2 group forming motif XIb. These dimers form a
1D ribbon along the b-axis through a NꢀH Oamide C(4)
3 3 3
hydrogen bond (Figure 8a). These ribbons pack into a 2D sheet
lying in the bc-plane through an OꢀH Onitro hydrogen bond.
3 3 3
This hydrogen is bifurcated between this interaction and an
intramolecular interaction with the ortho nitro group
(Figure 8b). The combination of these two interactions form a
second level C(3) motif. The final 3D structure is generated
through the packing of the sheets by π π interactions.
3 3 3
The dihydrate of 1,3,5-trihydroxybenzene forms a layered
structure, through OH...O hydrogen bonds between hydroxy-
benzene and the water molecules (Figure 9). The hydroxyl
groups display an orientational proton disorder due to the
symmetry of crystal as the mirror plane of the unit cell lines
through the middle of the hydroxybenzene molecule. The
remaining OH group of the water links the sheets into the final
3D crystal structure through a OH O hydrogen bond to a
3 3 3
Crystal Structure Analysis. III forms a 1:1 complex where the
dimer is formed through an acid...amide interaction between the
OꢀH O and NꢀH O interactions, forming a second level
water molecule in the plane above.
Intermolecular Interactions. There is little variation in the
geometry of the acid amide interaction between the various
3 3 3
3 3 3
3 3 3
R22(8) motif. The nitro groups packs on the amide side of
complexes (Table 3). The systems that successfully form cocrys-
tals only introduce additional hydrogen bond acceptor sites as
the two hydroxyl containing systems (IV and XI) form intramo-
lecular hydrogen bonds. These additional binding sites, however,
generally do not compete as the other acceptor sites in amide and
benzamide forming motif IIIb. Pairs of dimers are held together
by a discrete NꢀH OdCacid interaction (Figure 5a). These
3 3 3
pairs of dimers pack into 1D ladders along the a-axis through
weaker CꢀH OdCamide and CꢀH Onitro interactions.
3 3 3
3 3 3
Further CꢀH Onitro interactions form 2D sheets from these
acid motifs. Although all form the same acid amide interac-
3 3 3
3 3 3
ladders (Figure 5b), which then pack through π π interac-
tions along the b-axis to form the final 3D structure.
tion to bind the two components together, the second hydrogen
3 3 3
of the benzamide is involved in a variety of NH O hydrogen
3 3 3
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Crystal Growth & Design
ARTICLE
Figure 10. (a) Plot of calculated hydrogen-bonding energy against the Hammett constants for each benzoic acid, (b) plot of calculated hydrogen-
bonding energies against the pKa values for each benzoic acid. In each case, a linear correlation line has been fitted by least-squares ((a) R2 = 0.982,
(b) R2 = 0.436).
Table 5. Calculated Crystal Energies, Lattice Energies, and Shifts in Unit-Cell Parameters of Known Salicyclic Acid/Benzamide
Cocrystal, Hypothetical Benzoic Acid/Benzamide Co-Crystal, and Individual Components
calcd cryst energy
lattice energy
shift in unit-cell
energy of cocrystal
system
salicylic acid/benzamide
(kJ molꢀ1
)
(kJ molꢀ1
)
params a, b, c, β (Å, deg)
formation (kJ molꢀ1 a
)
3
ꢀ226.13
ꢀ175.27
ꢀ126.06
ꢀ175.21
ꢀ156.04
ꢀ117.69
ꢀ110.43
ꢀ51.26
ꢀ159.57
ꢀ154.33
ꢀ147.84
ꢀ155.62
ꢀ153.84
ꢀ90.86
ꢀ0.5342, 0.4418, 0.0005, ꢀ2.607
ꢀ0.5234, 0.3965, ꢀ0.3781, ꢀ2.589
0.1779, ꢀ0.0261, 1.8771, 16.455
ꢀ2.1458, ꢀ0.0954, 4.8415, ꢀ19.319
1.0868, ꢀ0.0146, ꢀ0.8768, ꢀ0.967
ꢀ1.6663, 2.2751, 0.1605, 11.103
0.2615, ꢀ0.0669, ꢀ1.6526, 2.08
0.4508, ꢀ0.2717, ꢀ1.2162, ꢀ4.49
þ29.18
þ22.53
þ29.02
þ21.24
þ23.02
N/A
benzoic acid/benzamide (from SA/BZA)
benzoic acid/benzamide (from 3,5-DNBA/BZA)
benzoic acid/benzamide (from 4H3NBA/BZA)
benzoic acid/benzamide (from 3-NBA/BZA)
salicylic acid
benzamide
ꢀ97.89
N/A
benzoic acid
a Eformation = EABlatt ꢀ (EAlatt þ EBlatt).
ꢀ78.97
N/A
bonds. In III, the carbonyl group of the acid is utilized in an
intramolecular interaction with the OH group and so is unavail-
able to form intermolecular interactions with the amide group,
The ordering of the acid acid interactions, in general, agrees
3 3 3
with the experimental results, with the strongest interactions
belonging to those pairs that successfully form complexes except
for VIII where the experimental evidence for cocrystallization is
inconclusive. Plotting the predicted hydrogen bonding energy
against the value of the Hammett constant for the various
complexes displays a linear correlation between the two parameters
(Figure 10a). In contrast, plotting the energy against the pKa values
(Figure 10b) for the acids shows a weaker correlation. Thus the
Hammett constant appears to be a stronger predictor for complex
formation in this case than pKa. However, the lack of Hammett
constants for ortho positions highlights the limitations of this
approach. In addition, the prediction of the molecular conforma-
tion displayed by the meta-substituted systems is inconclusive.
Although the lowest energy conformation for III is the conforma-
tion observed in the crystal structure, this is not the case for XI,
where the higher energy conformation is observed. However, given
the important role played by all intermolecular interactions in
controlling the final crystal packing, this may not be unexpected.
The difference in binding energy for benzoic acid and salicylic
acid is insignificant (<0.05 kJ molꢀ1), yet one system forms a
cocrystal, whereas the other does not. This further indicates that
the interaction between the acid and amide groups alone does
not control the overall formation of the crystalline complex. To
investigate the role the other packing forces may be playing in the
selectivity of cocrystal formation, we evaluated the lattice energy
for the salicylic acid/benzamide and series of hypothetical
benzoic acid/benzamide cocrystals (Table 5). The calculated
energy of the salicylic acid/benzamide cocrystal is lower than all
thus the NH Oamide is the only remaining interaction available
3 3 3
to construct the crystal lattice. For the remaining systems, all
three feature the same 3-nitrobenozic acid fragment with differ-
ing substituents. In IV, a NH OdCacid hydrogen bond is
3 3 3
formed and the nitro group is only involved in weaker CH
O
3 3 3
bonding. In XI, an intramolecular interaction occurs between the
OH and nitro groups further reducing the effectiveness of the
nitro group as an acceptor. The additional electron donating
contribution of the OH group may also reduce the effectiveness
of the carbonyl oxygen of the acid group as a hydrogen donor as
the NH Oacid interaction observed in IV is replaced by an
3 3 3
NH Oamide interaction. In VII, the additional group is an
3 3 3
electron withdrawing nitro group, which appears to improve the
hydrogen-bond-accepting capabilities of the neighboring nitro as
the NH Oacid interaction in IV is replaced by a NH Onitro
3 3 3
3 3 3
interaction. Thus the interactions between the various functional
groups plays an important role in both controlling the formation
of the dimer between the component and the subsequent growth
of the crystal structure.
Binding Energies. The calculated energies from the ab initio
calculations are presented in Table 4. For comparison, the
hydrogen-bonding energy between two benzamide molecules
was also calculated, which shows that the interaction between
the acid and amide is a stronger interaction the amide amide
3 3 3
interaction. Previous studies into the calculation of dimer inter-
actionsbetweenacidandamidegroupsshowthesameconculsion.37
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dx.doi.org/10.1021/cg101403j |Cryst. Growth Des. 2011, 11, 1502–1511

Crystal Growth & Design
ARTICLE
Table 6. Intermolecular Interaction Energies (sum of 200
interactions) around Each Component in the Hypothetical
Benzoic Acid/Benzamide Cocrystals, Salicylic Acid/Benza-
mide, and the Single-Component Crystal Structures
experimentally from the heat of fusion of the cocrystal and
starting components and consideration of the binary phase
diagram.41 A number of multicomponent systems have shown
to be entropically stabilized and have a positive enthalpy of
formation.42 The binary phase diagram (Figure 11) for salicylic
acid/benzamide indicates that the cocrystal has a lower melting
point than either of the two starting materials. Such a phase
diagram for racemic compounds is taken as evidence for weak
binding between the enatiomers43 and so by comparison it would
be expected that the cocrystal to have a low energy of formation.
The enthalpy of formation determined from the phase diagram is
24.71 kJ molꢀ1 and so the cocrystal phase must be entropically
stabilized. This highlights a potential limitation of the application
of computational methods to cocrystal screening.
cluster energy (kJ molꢀ1
)
system
salicylic acid/benzamide
(benzamide, benzoic acid)
ꢀ103.32, ꢀ96.06
ꢀ101.98, ꢀ87.62
ꢀ78.33, ꢀ73.46
ꢀ92.34, ꢀ84.11
ꢀ92.08, ꢀ83.94
ꢀ99.81
benzoic acid/benzamide (from SA/BZA)
benzoic acid/benzamide (from 3,5-DNBA/BZA)
benzoic acid/benzamide (from 4H3NBA/BZA)
benzoic acid/benzamide (from 3-NBA/BZA)
salicylic acid
benzamide
ꢀ98.61
ꢀ84.32
benzoic acid
’ CONCLUSIONS
Although a cocrystal between benzamide and benzoic acid is
thermodynamically unfeasible, cocrystal phases can be created
through the addition of electron withdrawing groups to the
benzoic acid (positive Hammett constants). Ab initio DFT
calculations indicate that one contribution to the improved
stability is the increased strength of the intermolecular acid
3 3 3
amide interaction between the two components, which corre-
lates with the sign of the Hammett constant. However, this alone
is not enough to successfully predict the formation of a new
cocrystal, as shown by salicylic acid and 2,4,6-trihydroxybenzoic
acid. Although the salicylic acid/benzamide system has a similar
binding energy as the benzoic acid/benzamide system but does
successfully form a cocrystal, the 2,4,6-trihydroxybenzoic acid/
benzamide has one of the strongest binding energies but con-
clusive evidence of cocrystallization was not obtained. Compar-
ison of the lattice energies for salicylic acid/benzamide and
hypothetical benzoic acid/benzamide crystal structures gener-
ated from the other known cocrystals indicates that potential
benzoic acid/benzamide cocrystals are less stable by up to 10 kJ
molꢀ1 compared to the known cocrystals and so the other
packing forces play an important role in the successful formation
of cocrystal phase. However, calculation of the energy of
cocrystal formation for all cases indicates that the cocrystal is
unstable relative to the separate phases. Experimental determina-
tion of the binary phase diagram for the salicylic acid/benzamide
system reveals that the cocrystal has a lower melting point than
both single components and a positive enthalpy of formation
indicates that the cocrystal is entropically stabilized. Thus the
development of predictive tools for cocrystallization requires the
continuedexperimentalandcomputational investigationsinto both
successful and unsuccessful cocrystallization to gain insight into the
factors that influence and control the cocrystallization process.
Figure 11. Constructed binary phase diagram for salicylic acid and
benzamide. Experimental liquidius points are shown as open squares,
experimental solidius points as shown as filled circles, and calculated
ideal curves as black lines.
the potential benzoic acid/benzamide systems generated and so
the additional interactions within the structure may be favoring
the formation of the cocrystal in the salicylic acid case. To further
investigate the differences between the two structures, we
evaluated the bonding environment in Mercury (version 2.4)38
with the intermolecular interactions evaluated using the UNI
forcefield.39 The geometry of the benzamide molecule undergoes
little to no change between the five optimized structures with
only the torsion angle of the amide group relative to the benzene
ring changing in the range 150ꢀ170°. The energy of molecular
clusters around each component in each structure and the single
component phases was evaluated (Table 6), which shows that
the stronger intermolecular interactions are experienced by both
molecules in the salicylic acid/benzamide cocrystal compared to
the potential benzoic acid systems. However, the calculation of
the energy of the cocrystal formation for the systems indicates
that all are unfavored compared to individual components
(Table 5). This may be due to the simplistic model used for
the energy calculations, although previous computational studies
into the prediction of cocrystals formation,40 also failed to predict
the formation of the succinic acid/benzamide system compared
to the stable polymorph of benzamide. This failure was suggested
to be due to the sensitivity of the force fields used to the
pyramidalization of the benzamide amide group. However, the
enthalpy of formation of a cocrystal may be determined
’ ASSOCIATED CONTENT
S
Supporting Information. Crystallographic information
b
for each of the single crystal structure determinations (as .cif
and corresponding .fcf). Refcode list of structures displaying the
acid amide ring dimer (as .pdf). This material is available free
3 3 3
of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: Colin.Seaton@manchester.ac.uk. Tel: þ44 (0)161
3064362.
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Crystal Growth & Design
ARTICLE
’ ACKNOWLEDGMENT
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We thank Prof. Roger J. Davey and Dr Ghasala Sadiq for
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constants to cocrystallisation and Bradford University for access
to the DSC equipment to collect the binary phase diagram.
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