Designing ternary Co-crystals with stacking interactions and weak hydrogen bonds. 4,4′-bis-hydroxyazobenzene

Article abstract of DOI:10.1021/cg500263g

Three ternary co-crystals of the title compound are reported. The design strategy hinges on the identification of a robust synthon with O-H...N hydrogen bonds in a binary co-crystal. Construction of this module allows the tuning of π...π stacking interactions and weak hydrogen bonds to incorporate the third component into the crystal structure. Screening of various co-formers showed that a delicate balance of electrostatics is required for stacking to favor the formation of ternaries. A C-H...N hydrogen-bonded motif was also found to occur repetitively in the ternary co-crystals. The directional nature of weak hydrogen bonds allows them to be used effectively in this study.

Full text of DOI:10.1021/cg500263g

Article
pubs.acs.org/crystal
Designing Ternary Co-crystals with Stacking Interactions and Weak
Hydrogen Bonds. 4,4′-Bis-hydroxyazobenzene
Shaunak Chakraborty, Lalit Rajput, and Gautam R. Desiraju*
Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India
S
* Supporting Information
ABSTRACT: Three ternary co-crystals of the title compound are reported.
The design strategy hinges on the identification of a robust synthon with O−
H···N hydrogen bonds in a binary co-crystal. Construction of this module
allows the tuning of π···π stacking interactions and weak hydrogen bonds to
incorporate the third component into the crystal structure. Screening of
various co-formers showed that a delicate balance of electrostatics is required
for stacking to favor the formation of ternaries. A C−H···N hydrogen-bonded
motif was also found to occur repetitively in the ternary co-crystals. The
directional nature of weak hydrogen bonds allows them to be used effectively
in this study.
integrates both chemical and geometrical factors into the design
of ternaries.10 The utility of using halogen bonds in crystal
INTRODUCTION
■
With their undeniable relevance in the backdrop of
pharmaceutical sciences, the study of co-crystals has gained a
position of great importance in crystal engineering.1 The past
decade has seen an explosive growth in the design and synthesis
of multicomponent crystals, the formation of which are
enthalpically controlled.2 The advent of high-throughput co-
crystallization screening methods and the ever increasing size of
the Cambridge Structural Database,3 which, in turn, leads to the
surer identification of robust supramolecular synthons, have led
to numerous successful strategies for the design and synthesis
of binary co-crystals,4 with a concomitant increase in the
number of papers that deal with pharmaceutical co-crystals.5
Any co-crystal is difficult to design and isolate in the sense that
crystallization is inherently a purifying technique. A random
combination of compounds, if taken together for crystallization
in solution, will more often than not yield crystals of the
individual components. In this sense, designing a ternary co-
crystal is substantially more difficult than designing a binary.
However, it may be argued that binary co-crystals are the first
step toward the incorporation of three components in a single
crystal structure by systematic design. Because of the difficulty
in designing a ternary co-crystal, this activity poses a certain
charm and aesthetic appeal to a crystal engineer. Achieving this
goal entails a delicate balance of interactions that need to be
specific, and perhaps graded in strength. Although the
functional utility of these solids remains largely unknown,
finding this subtle balance provides an appealing enough
attraction to their design.
design was shown by the groups of Aakeroy, Nangia, Jones,
̈
Resnati, and Metrangolo.4c,d,11 The specific nature of halogen
bonds prevents any undesired synthon crossover,11c which can
be used very effectively to isolate ternary co-crystals. This was
demonstrated very recently by results from our group where
three ternary co-crystals were obtained by design, exploiting the
insulation of the acid-amide and the iodo-nitro synthons to gain
structural control.12
Phenolic compounds have always been interesting from the
crystal engineering perspective, because the moderately acidic
nature of the phenolic proton allows them to quite readily co-
crystallize with pyridine-like nitrogen bases. Varying the
molecular topology of the co-former can generate amazing
varieties in the crystal architecture and can give rise to
interesting crystal properties and intriguing applications, as has
been demonstrated by MacGillivray and others.13 The phenol−
pyridine (O−H···N) interaction is strong and robust enough
for it to be efficiently used in building a fixed module with two
of the three components of a ternary co-crystal, affording the
freedom to tune the incorporation of the third component as
required. Once this module is built, the third component could
be integrated into the structure via interactions that would not
compete with the O−H···N hydrogen bonds.
Here, we describe a strategy for the design of ternary co-
crystals with 4,4′-bis-hydroxyazobenzene (hereafter BHAB),
with a selection of pyridine-like nitrogen bases (Scheme 1),
which exploits the propensity of the two nitrogen atoms
Not many ternary co-crystals are reported in the literature.
The problem has been addressed independently by Aakeroy et
Received: February 21, 2014
Revised: March 18, 2014
Published: March 24, 2014
̈
al., and Nangia et al. using selections of hydrogen bond donors
and acceptors.6−9 Our group has employed a method that
© 2014 American Chemical Society
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Scheme 1. Schematic Diagrams of the Compounds Used. The Table Summarizes the Compound Codes
Figure 1. Basic hydrogen bonded structural modules in (a) B1 and (b) B2 and the extension of these modules to stacking in (c) B1 and (d) B2.
constituting the azo linkage as hydrogen bond acceptors and
uses them as anchor points in the design.
hereafter referred to as M. Individual modules are held together
by stacking between the ACR moieties, which results in a two-
dimensional sheet (Figure 1b).The structure extends in the
third dimension by the hydrogen atoms of ACR forming C−
H···N hydrogen bonds with the azo nitrogen atoms and C−H···
O hydrogen bonds with the hydroxyl groups of BHAB.
B2, obtained from co-crystallization of BHAB with PHE, has
a structure very similar to that of B1, with the same space group
and similar cell parameters. The interaction patterns are also
quite similar, barring the fact that the second pyridyl nitrogen
atom on PHE forms C−H···N hydrogen bonds with the
hydrogen atoms on the phenol rings of BHAB (Figure 1c,d).
Curiously, both heterocyclic N-atoms do not participate in
strong hydrogen bonding. Perhaps this is because the basicity of
PHE is suppressed with respect to ACR.
The similarities in the structures of B1 and B2 prompted the
thought that, since ACR and PHE have the same shape and
size, they could be effectively used in the synthesis of a ternary
co-crystal. If BHAB, ACR, and PHE were crystallized together,
it was expected that the stronger base (ACR) would form O−
H···N hydrogen bonds with BHAB and the third component
(PHE) would insert between two ACR molecules in the
module M shown in Figure 1a, aided by π overlap and/or C−
H···N hydrogen bonds. PHE could be expected to form C−
H···N hydrogen bonds more easily compared to ACR because
the hydrogen atoms on PHE are more acidic. This strategy
anticipates a hierarchy of interactions based on strength. Such a
RESULTS AND DISCUSSION
■
We describe four binary co-crystals of BHAB with acridine
(ACR), B1; phenazine (PHE), B2; isoquinoline (IQN), B3;
and quinoline (QN), B4; and three ternaries BHAB−ACR−
PHE, T1; BHAB−ACR−QNX, T2; and BHAB−ACR−QN,
T3 (Scheme 1). In keeping with the nature of the co-formers
used, the main stabilizing interaction in all the crystal structures
is the phenol−pyridine (O−H···N) hydrogen bond. Stacking
and weak hydrogen bonds (C−H···N) also play a big role in
the assembly.
All the nitrogen bases that have been used in this study have
the potential to form strong O−H···N hydrogen bonds as well
as π···π stacking interactions. The target was to build a robust
module with the stronger O−H···N hydrogen bonds in any
potential binaries and to tune the more pliable stacking
interactions to advance to the ternaries. The capability of these
compounds to form weak hydrogen bonds was another reason
for choosing them.
B1, obtained from co-crystallization of BHAB and ACR,
shows all the three types of interactions mentioned above. It
crystallizes in the space group P1, with a molecule of ACR and
̅
a half molecule of BHAB in the asymmetric unit. Two
molecules of ACR are hydrogen bonded to the two ends of
BHAB to form a module or large synthon (Figure 1a),
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Figure 2. Hydrogen bonding patterns in (a) B1 and (b) T1. BHAB carbons are shown in red and ACR in purple. The carbons of PHE have been
colored black.
Table 1. Co-formers Used in the Experiments
hierarchy has been alluded to in our earlier report where
hydrogen bonding and halogen bonding were used together to
obtain ternaries.
M is present and molecules of PHE have inserted themselves
between two of them, resulting in T1 having one cell axis
longer than B1 while the other two remain very close to it. The
azo linkage forms C−H···N hydrogen bonds in T1 as well. Two
PHE molecules form a closed C−H···N hydrogen-bonded
motif (Figure 2), which plays a crucial role in this crystal
structure as well as in T2 and T3. The fact that this C−H···N
hydrogen-bonded motif is needed for the three components of
This turned out to be valid when BHAB, ACR, and PHE
were co-crystallized to obtain a ternary BHAB−ACR−PHE
(T1). This crystallizes in the space group P1, with a half
̅
molecule of BHAB and one molecule each of ACR and PHE in
the asymmetric unit. As expected, the module (large synthon)
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Figure 3. Hydrogen bonding patterns in (a) T2 and (b) T3. Hydrogen bonds between ACR and (c) QNX in T2 and (d) QN in T3. C-face
projections of (e) T2 and (f) T3. Color codes: red and purple, module M; green, QNX; blue, QN. Notice that BHAB molecules lie on mirror planes.
the ternary co-crystal to come together may be disputed, since
the phenomenon appears on the surface to be another example
of shape-size mimicry where a crystallographically “free”
molecule is replaced by an isosteric one.10 The subsequent
experiments using various co-formers resembling ACR roughly
in shape and size and with the ability to stack (summarized in
Table 1) showed that the C−H···N hydrogen bonds are indeed
important. As Table 1 shows, ternaries were obtained in only
two instances, with QN and QNX, which strongly suggests that
this is not a case of simple shape-size mimicry. Details of the co-
crystallization experiments that were unsuccessful in producing
ternaries are given in the Supporting Information.
Ternary T2 crystallizes in the space group C2/m, with half
molecules each of BHAB, ACR, and QNX in the asymmetric
unit. The BHAB molecule is located on an inversion center,
and ACR and QNX on a mirror plane. The nitrogen atoms of
QNX show a 50:50 positional disorder. Module M is again
present here, with a QNX molecule sandwiched between two
ACR molecules. Interestingly, T2 has two cell axes the same as
T1, while the third has doubled possibly because of the C-
centering. The positional disorder of the basic nitrogen atoms
on QNX optimizes C−H···N hydrogen bonds with ACR in
module M (Figure 3a). The structure extends laterally via C−
H···N hydrogen bonds between ACR molecules and the
nitrogen atoms of the azo linkage of BHAB.
extends via C−H···N hydrogen bonds of ACR with the azo
linkage.
Table 1 is important for a proper understanding of the
principle behind the design of these three ternaries T1, T2, and
T3. ANTH and NAPH have almost the same size and shape as
ACR in addition to having a fair tendency for stacking. Given
this, their refusal to be incorporated between two electron-
deficient ACR molecules seems at first glance to be
counterintuitive. The reason could lie in electrostatics. When
either NAPH or ANTH undergoes donor−acceptor stacking
interactions with ACR, an event favorable in itself, electron
density is drawn away from the relatively electron-rich
carbocyclic rings into the electron-deficient heterocyclic rings
of ACR. This results in the C−H bonds of ACR becoming
poorer hydrogen bond donors, and this perhaps could hinder
building up of the M modules in the third dimension via weak
hydrogen bonding. The formation of a ternary is, therefore,
hindered kinetically. When the third component is a
heterocyclic system like QNX and QN, the stacking
interactions do not weaken the C−H···N hydrogen bonds
and the incorporation of the third component is allowed. QNX
and PHE, with two nitrogen atoms incorporated in the rings,
may even strengthen the weak hydrogen bonds by drawing the
electron cloud away from the ACR ring into themselves. A
similar argument can be used for PHE, and this explains why
no ternaries were obtained with the module in B2.
Ternary T3 also crystallizes in the space group C2/m, with
cell parameters very similar to those of T2. Here, too, QN
molecules have inserted themselves between two ACR
molecules of two modules and form C−H···N hydrogen
bonds after a fashion very similar to that seen in T2 (Figure 3).
The basic nitrogen atom on QN is also similarly disordered and
takes part in C−H···N hydrogen bond formation. T3 also
The case of IQN, which is also not incorporated into the
structure to form a ternary, is more interesting. Co-
crystallization of BHAB, ACR, and IQN results not even in
B1, but rather binary B3. The IQN molecule forms O−H···N
hydrogen bonds with BHAB on both sides to generate a closed
module that repeats in the crystal structure via C−H···π and
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Figure 4. (a) O−H···N hydrogen bonded module, (b) the C−H···N hydrogen bonds, and (c) C−H···O and C−H···π interactions in B3.
Figure 5. Direction-specific C−H···N hydrogen bonds those are crucial to the current strategy to work in (a) T1, (b) T2, and (c) T3. Color codes:
red and purple, module M; black, PHE; green, QNX; blue, QN.
C−H···O interactions. C−H···N interactions of the type seen in
B1 or B2 are absent here. The azo linkage does participate in
C−H···N hydrogen bonds, but the hydrogen bonds are
between two molecules of BHAB (Figure 4).
once again the role of weak hydrogen bonds in directing
structures and serves as another proof that a proper
understanding of them is necessary to effectively use them in
design.14
The fact that BHAB, ACR, and IQN do not form a ternary
shows that the system requires an auxiliary directional stabilizing
interaction beside the π···π interaction that is the principal
element of the design. The function of this is served by the C−
H···N interactions with the pyridyl nitrogen atoms but only if
the said nitrogen atoms are in the 1- and 4-positions of the ring.
The hydrogen bonds involving the azo linkage serve to support
the architecture (Figure 5).
The fact that a good π-overlap is essential for the formation
of this kind of ternary systems was proven when we tried to co-
crystallize BHAB, QN, and QNX. Instead of the three
components forming a ternary like T1, we obtained a binary
B4 (Figure S1 in the Supporting Information). The most
obvious reason for this seems to be the relatively poor overlap
between the smaller rings. The structure of B4 has been
described in the Supporting Information.
EXPERIMENTAL SECTION
■
General Information. ACR, PHE, QN, IQN, NAPH, ANTCN,
PHEN, and QNX were procured from Sigma Aldrich and were used
without further purification. 4-Nitrophenol for the synthesis of BHAB
was obtained from Spectrochem. All PXRD data were collected on a
Phillips X’Pert powder diffractometer equipped with an X’cellerator
detector within the 2θ scan range of 5−45°. All FTIR data were
collected with a Perkin-Elmer Frontier FTIR/FIR spectrometer within
a scan range of 4000−600 cm−1. The melting point data were collected
on an automated Buchi M-560 melting point apparatus, using glass
̈
capillaries.
Synthesis of BHAB. BHAB was prepared following a procedure
reported in the literature.15 5 g of 4-nitrophenol and 25 g of KOH
pellets were dissolved in 10 mL of water and heated at 120 °C for 1 h,
after which the temperature was raised to 200 °C. The reaction
mixture turned dark brown with vigorous effervescence. The reaction
mixture was allowed to cool to room temperature 30 min later, after
which it was dissolved in 50 mL of distilled water to obtain a dark red
solution. pH of the medium was brought down to 3 by adding conc.
HCl, and the product was extracted by washing the solution with
diethyl ether and evaporating the ether on a rotary evaporator setup.
The IR spectrum and the powder X-ray diffraction (PXRD) pattern of
the product after crystallization are given in the Supporting
Information. Yield: ∼80%.
CONCLUSIONS
■
Ternaries can be made and maybe will soon become more
common. We have shown that, after the “conventional”
hydrogen bonds and halogen bonds, weak interactions such
as π stacking and weak hydrogen bonds can also serve as a
handy tool in the preconceived synthesis of a target as complex
as a ternary co-crystal. The direction-specific nature of weak
hydrogen bonds is crucial to such a design. This emphasizes
Crystallization Experiments. BHAB−ACR Binary (B1). 0.25
mmol of BHAB and 0.5 mmol of ACR were ground together with a
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Table 2. Crystallographic Parameters of the Binary and Ternary Co-crystals
compound
formula
B1
B2
B3
B4
T1
T2
T3
C38H28N4O8
668.64
C36H26N6O2
574.63
C30H24N4O2
472.53
C30H24N4O2
472.53
monoclinic
P21/c
C62H44N8O2
933.05
C50H36N12O2
836.91
monoclinic
C2/m
C54H40N8O2
832.94
F.W. (g/mol)
crystal system
space group
T (K)
triclinic
triclinic
monoclinic
P21/c
triclinic
monoclinic
C2/m
P1
̅
P1
P1
̅
̅
150(2)
150(2)
7.113(7)
8.853(9)
13.291(13)
87.42(3)
82.830(17)
88.98(2)
829.5(14)
1
150(2)
5.9596(12)
26.981(5)
7.2509(15)
90
150(2)
12.294(15)
11.228(12)
8.951(11)
90
150(2)
150(2)
22.417(9)
12.883(5)
7.259(3)
90
150(2)
22.398(6)
12.941(4)
7.3577(18)
90
a (Å)
7.13770(10)
9.1419(11)
14.033(2)
82.56(4)
79.08(3)
69.21(3)
838.67 (16)
1
7.285(3)
12.925(6)
13.869(6)
113.069(9)
96.618(13)
104.486(7)
1129.5(8)
1
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
V (Å3)
91.048(12)
90
98.237(11)
90
95.275(18)
90
93.856(10)
90
1165.7(4)
2
1223(2)
2
2087.7(14)
2
2127.9(10)
2
Z
ρcalc (g/cm3)
θ range
F(000)
1.134
1.150
1.346
1.283
1.372
1.332
1.300
1.48, 27.50
348
1.55, 27.56
348
1.51, 27.51
506
1.67, 27.55
528
1.64, 27.49
506
1.82, 27.51
924
1.82, 27.47
924
μ (mm−1
)
0.071
0.074
0.086
0.082
0.085
0.086
0.082
R1 [I > 2σ(I)]
wR2
0.0784
0.0797
0.0588
0.0926
0.2309
1.150
0.0719
0.1020
0.2803
1.168
0.0878
0.2416
0.2415
0.1625
0.1770
0.2448
GOF
1.039
1.109
0.739
1.015
0.920
CCDC no.
985995
985996
985997
985998
985999
986000
986001
few drops of methanol and dissolved in a variety of solvents. Yellow
block-shaped crystals were obtained from THF after 3 days.
BHAB−PHE Binary (B2). 0.25 mmol of BHAB and 0.5 mmol of
PHE were ground together with a few drops of methanol and
dissolved in a variety of solvents. Yellow block-shaped single crystals
were obtained from THF after 3 days.
BHAB−IQN Binary (B3). 0.25 mmol of BHAB was dissolved in a
minimum amount of methanol, and 0.5 mL of IQN was added to it.
Yellow needle-like crystals were obtained after a period of 5 days.
BHAB−QN Binary (B4). 0.25 mmol of BHAB was dissolved in a
minimum amount of methanol, and 0.5 mL of QN was added to it.
Yellow platelike crystals were obtained after 7 days.
BHAB−ACR−PHE Ternary (T1). 0.25 mmol of BHAB and 0.5
mmol each of ACR and PHE were ground together with a few drops
of methanol and dissolved in a variety of solvents. Yellow needle-like
crystals were obtained from ethanol after 7 days.
BHAB−ACR−QNX Ternary (T2). 0.25 mmol of BHAB and 0.5
mmol of ACR were ground together with methanol and dissolved in a
small amount of THF. QNX (0.5 mL) was added to the solution.
Yellow needle-like crystals were obtained after 4 days.
ternary co-crystals. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: desiraju@sscu.iisc.ernet.in. Fax: +91 80 23602306.
Tel: +91 80 22933311.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.C. thanks the IISc for a JRF; L.R. thanks the DST for a Young
Scientist Fellowship. G.R.D. thanks the DST for the award of a
J.C. Bose Fellowship. We are thankful to Mr. Arijit Mukherjee
for helpful discussions.
REFERENCES
■
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platelike crystals were obtained after 4 days.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information contains structural description of
B4, hydrogen-bonding parameters, ORTEP diagrams, melting
points, PXRD, IR, characterization of BHAB, and the details of
the co-crystallization experiments that did not produce any
■
S
̌ ̌ ́
G. O.; Friscic, T.; Day, G. M.; Jones, W.; Lu, J.; Wei, M.; Evans, D. G.;
Duan, X. Angew. Chem., Int. Ed. 2011, 50, 12483−12486. (e) Thakur,
T. S.; Desiraju, G. R. Cryst. Growth Des. 2008, 8, 4031−4044.
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