Conformational polymorphism of a simple tripodal podand bearing nitro functionality

Article abstract of DOI:10.1021/cg901153q

Tris[4-(nitrophenyloxy)ethyl]amine (L), a simple tripodal podand, may be reproducibly crystallized in either of three polymorphic forms. An understanding of the structural features associated with polymorphism in L has been made in terms of morphology, single-crystal structure, powder X-ray diffraction, and differential scanning calorimetric measurements. Polymorphs I, II, and III crystallize in three different crystal systems-triclinic (P1), monoclinic (P2₁/n), and orthorhombic (Pna2(1)), respectively-and single-crystal X-ray analysis revealed conformational differences in the arrangement of the flexible arms when crystallized from solutions under different growth conditions. The conformational difference results principally from the bridge-head amino torsion τ_amino (C-N1_amino-C-C) relative to the p-nitrophenol fragment. The different polymorphs display a range of different 3D hydrogen bonding arrangements, constructed from an intermolecular C-H-...O hydrogen bonding array. The supramolecular self-assembly features in the three forms are guided by the control methylene C-H-...N_amino dimeric interaction in form I, the π...π interaction in form II, and a weak C-H...π interaction in form III that differentiate the overall packing in the three forms

Full text of DOI:10.1021/cg901153q

DOI: 10.1021/cg901153q
Conformational Polymorphism of a Simple Tripodal Podand Bearing
Nitro Functionality
2
010, Vol. 10
754–760
Sandeep Kumar Dey and Gopal Das*
Department of Chemistry, Indian Institute of Technology Guwahati, Assam-781039, India
Received September 21, 2009; Revised Manuscript Received November 12, 2009
ABSTRACT: Tris[4-(nitrophenyloxy)ethyl]amine (L), a simple tripodal podand, may be reproducibly crystallized in either of
three polymorphic forms. An understanding of the structural features associated with polymorphism in L has been made in
terms of morphology, single-crystal structure, powder X-ray diffraction, and differential scanning calorimetric measurements.
Polymorphs I, II, and III crystallize in three different crystal systems;triclinic (P1), monoclinic (P2 /n), and orthorhombic
1
(Pna2(1)), respectively;and single-crystal X-ray analysis revealed conformational differences in the arrangement of the flexible
arms when crystallized from solutions under different growth conditions. The conformational difference results principally from
the bridge-head amino torsion τamino (C-N1amino-C-C) relative to the p-nitrophenol fragment. The different polymorphs
display a range of different 3D hydrogen bonding arrangements, constructed from an intermolecular C-H O hydrogen
bonding array. The supramolecular self-assembly features in the three forms are guided by the control methylene
3
3 3
C-H Namino dimeric interaction in form I, the π π interaction in form II, and a weak C-H
3 3 3
π interaction in form
3
3
3
3
3
3
III that differentiate the overall packing in the three forms.
7
1
. Introduction
molecular assemblies. Polymorphism perhaps tends to be
prominent in molecules that contain multiplehydrogen-bond-
ing moieties, thereby forming multiple supramolecular syn-
Polymorphism, as defined in McCrone’s words, is “the
ability of a given element or compound to crystallize as more
8
9
thons, and/or conformational flexibility, as exemplified in a
10
number of active pharmaceutical ingredients (APIs). Iso-
1
than one distinct crystal species”. Some crystals are confor-
mational polymorphs because of conformational variations
tropic van der Waals interactions also play an important role
in generating different molecular assemblies. Conformational
polymorphism has attracted considerable attention due to the
fact that it provides ideal systems for the study of structure-
2
of molecules in the solid state. Because of the dissimilarity in
solid-state structures, polymorphs of the substance can vary
significantly in their physicochemical properties. Polymorph-
ism has emerged as a solid-state property of outstanding
fundamental and practical importance; the impact is evident
by an outburst of publications, patents, conferences, and
11
property relationships, the effect of crystal forces on
12
molecular conformation, molecular-level control of crystal-
13
14
15
lization, and the prediction and design of crystal struc-
tures.
3
special issues of journals on this enigmatic phenomenon.
One of the main objectives in the study of polymorphism is to
understand the effect of various parameters of a crystalliza-
tion experiment in controlling the nucleation to obtain a
Ideally, one would like to obtain a particular polymorph
with one set of experimental crystallization conditions and
another polymorph with another set. However, this may not
always be possible and polymorphs may be obtained con-
comitantly whatever be the experimental conditions em-
ployed. In such cases, rapid identification and separation of
the polymorphs is necessary. The polymorph formation of a
given substance lies in a compromise between inter- and
intramolecular interactions which can be affected by crystal-
lization conditions. The structures and properties of tripodal
4
desired polymorph. The effect of solvent of crystallization,
an important parameter influencing nucleation, continues to
5
be the subject of investigations. However, the control of
crystal and network structures in a predictable manner still
remains an elusive task because of the delicate balance and
competition between directional noncovalent interactions,
such as hydrogen bonds, and nondirectional noncovalent
interactions, such as van der Waals (dispersive) packing
forces. Since the physicochemical properties of a compound
can differ critically from one form to another, inducing and
controlling a specific polymorph is of utmost importance,
particularly in the context of syntheses of drugs and pharma-
1
6
ligands have been well studied. However, these compounds
have not received any attention in the context of polymorph-
ism regardless of their intrinsic conformational flexibility.
17
18
During our systematic investigation of tripodal receptors,
6
wehave obtained three conformational polymorphs (I, II, and
III) of a podand L (Scheme 1) from different crystallization
conditions. Differences in molecular conformation of the
polymorphs are very likely a result of torsion angle differ-
ences. Here, we report the solvent mediated reproducible
crystallization of L into three different polymorphic forms,
a discussion of their crystal structures, and the results of
thermal studies along with their powder XRD and FT-IR
patterns.
ceuticals. The design and synthesis of new materials with
desired chemical and physical properties have been of recent
interest, and this involves the generation and study of struc-
tural motifs in crystals, which are essentially guided by precise
topological control through the manipulation of weak inter-
molecular interactions. There are a rich variety of intermole-
cular interactions that serve as tools in engineering such
*
E-mail: gdas@iitg.ernet.in.
r
pubs.acs.org/crystal
Published on Web 12/11/2009
2009 American Chemical Society

Article
Crystal Growth & Design, Vol. 10, No. 2, 2010 755
2
. Experimental Section
with increasing ω (width of 0.3ꢀ per frame) at a scan speed of 3 s/
frame. The SMART software was used for data acquisition. Data
integration and reduction were undertaken with SAINT and
2
.1. General. All reagents and solvents were obtained from
commercial sources and used as received. Propanol was dried using
anhydrous calcium chloride and distilled freshly following a stan-
dard procedure. The IR spectra were recorded on a Perkin-Elmer-
20
XPREP software. Multiscan empirical absorption corrections
were applied to the data using the program SADABS. Structures
were solved by direct methods using SHELXS-97 and refined with
21
Spectrum One FT-IR spectrometer with KBr disks in the range
4
2
22
full-matrix least-squares on F using SHELXL-97. All non-
hydrogen atoms were refined anisotropically. Hydrogen atoms
attached to all carbon atoms were geometrically fixed while the
hydrogen atoms of the tertiary amino nitrogen of the salts were
located from the difference Fourier map, and the positional and
temperature factors are refined isotropically. Structural illustra-
000-400 cm- . Powder X-ray diffraction data were recorded using
1
a Seifert powder X-ray diffractometer (XRD 3003TT) with a Cu KR
˚
source (λ = 1.54 A) on a glass surface of an air-dried sample. The
thermal analyses of the polymorphs were performed by using an
SDTA 851 e TGA thermal analyzer (Mettler Toledo) with a heating
rate of 2 ꢀC per min in a N atmosphere. Optical micrograph images
were taken in a Zeiss-Axio Cam-MRc microscope fitted with a
2
23
tions have been drawn with ORTEP-3 for Windows.
digital camera of air-dried samples on glass microslides.
2.2. Synthesis of L. Podand L has been prepared by modification
of a known literature procedure. To a solution of 4-nitrophenol
3
. Results and Discussions
19
3
.1. Crystal Structure Studies. The crystallographic data
(
(
5 g, 36 mmol) in dry n-propanol (30 mL) was added crushed NaOH
1.77 g, 43 mmol), and the solution was stirred at room temperature
and details of data collection for polymorphs I, II, and III are
given in Table 1. Solvent-induced conformational poly-
morphism of tripodal podand L arises from (i) the intrinsic
conformational flexibility of the molecule, (ii) the correlation
between the hydrogen bond donor ability of the alkyl groups
and the hydrogen bond acceptor ability of the oxygen atoms
of nitro groups, and (iii) the nature of crystallization sol-
vents. Crystal structure analyses reveal the presence of
interesting supramolecular features in all three polymorphs.
There are no intramolecular noncovalent interactions be-
tween the tripodal arms in polymorphs I and III whereas
polymorph II displays an intramolecular edge-to-face inter-
action between the phenyl rings of the two proximal arms.
The presence of various types of intermolecular noncovalent
interactions between the tripodal units results in markedly
different crystal packing in the three forms. The nitro
oxygen atoms act as acceptor and are involved in multiple
for 1 h. To the resulting suspension, tris(2-chloroethyl)amine hydro-
chloride (2.88 g, 12 mmol) was added at once, and the mixture was
stirred for another 1 h at room temperature. For completion of the
reaction, the mixture was refluxed for 8 h followed by removal of
the solvents under reduced pressure and addition of 20 mL of
cold water. The expected product was extracted from this mixture,
with 3 Â 30 mL of CHCl
3
. The organic layer was washed with
SO , and solvents were re-
water and dried over anhydrous Na
2
4
moved under reduced pressure. The crude product was purified by
column chromatography with 75% ethyl acetate (in petroleum
ether) as the eluent. The desired compound was a pale yellow solid.
Yield 65%.
2.3. X-ray Crystallography. In each case, a crystal of suitable size
was selected from the mother liquor and immersed in silicone oil,
and then it was mounted on the tip of a glass fiber and cemented
using epoxy resin. The intensity data were collected using a Bruker
SMART APEX-II CCD diffractometer, equipped with a fine focus
˚
1
.75 kW sealed tube Mo KR radiation (λ = 0.71073 A) at 298(3) K,
C-H
forms. Conformational polymorphism in podand L is also
O intermolecular hydrogen bonding in all three
3
3 3 3
Scheme 1. Molecular Structure of Tripodal Podand L
reflected from their different crystal morphologies.
3
.1.1. Polymorph I. This form crystallizes in the triclinic
space group P1 with Z = 2. An ORTEP plot of polymorph I
is shown in Figure 1a along with the atom numbering
scheme. The torsion τether involving N1amino-C-C-Oether
is in the folded conformation for the two arms composed of
the ethereal oxygens O1 and O4 and is in the extended
conformation for the third arm composed of the ethereal
Table 1. Crystallographic Data for Polymorphs I, II, and III
II
I
III
formula
fw
C
512.47
24
H
24
N
4
O
9
C
24
H
24
512.47
N
O
4 9
24 24 4 9
C H N O
512.47
crystal system
space group
triclinic
P1
9.252(2)
11.950(3)
12.445(3)
73.244(14
78.589(14)
70.475(14)
1233.9(5)
2
298(2)
0.107
1.379
monoclinic
P21/n
10.5408(6)
19.9111(12)
11.8327(8)
90.00
105.594(3)
90.00
2392.0(3)
4
298(2)
orthorhombic
Pna2(1)
23.1068(15)
23.107
4.6074(4)
90.00
90.00
˚
a (A)
˚
b (A)
˚
c (A)
R (deg)
β (deg)
γ (deg)
90.00
˚
V (A)
Z
T (K)
2460.0(3)
4
298(2)
0.108
1.386
-1
μ (cm
)
0.109
1.429
-3
d
cal (g cm
)
3
cryst dimens (mm )
no. of reflns collected
no. of unique reflns
no. of params
0.39 Â 0.31 Â 0.19
0.35 Â 0.29 Â 0.21
0.30 Â 0.22 Â 0.17
5904
2884
334
5786
3323
334
5963
4803
335
R1; wR2 (I > 2σ(I))
R(int)
GOF (F2)
0.0459; 0.1318
0.0326
1.016
0.0427; 0.1178
0.0615
0.954
0.0522; 0.1348
0.1149
0.921

7
56 Crystal Growth & Design, Vol. 10, No. 2, 2010
Dey and Das
oxygen O7 (Table 2). The two tripodal molecules of the unit
cell are oriented in the opposite direction with a strong
stacking and intermolecular C-H
O hydrogen bonding
3
3 3 3
interactions between the alkyl hydrogens with one or both
the oxygens from two nitro groups involving nitrogen N3
and N4. In addition, there are intermolecular nitro-nitro
electrostatic interactions involving all three nitro groups
dimeric association via the C-H N hydrogen bond invol-
3
3 3
ving the apical nitrogen N1 of either unit with the methylene
hydrogen H10B of the adjacent unit, forming a six membered
˚
˚
˚
hydrogen bonded ring (N1 C10 = 3.704 A, —C10-
(N3 O5 = 3.018 A and N4 O2 = 2.873 A) and a weak
3 3 3
3
3 3
3 3 3
H10B N1 = 175.40ꢀ), as depicted in Figure 1b. The
intermolecular edge-to-face interaction between H15 and the
phenyl ring involving carbon atoms C3-C8 (C1g)
3
3 3
dimers are further well organized via intermolecular
C-H O hydrogen bonding interactions between the alkyl
hydrogens with one or both of the oxygen atoms from each
nitro group generating a 3D sheetlike arrangement of tripo-
dal dimers when viewed along the crystallographic a axis
˚
(C15 C1g = 4.198 A, —C15-H15
C1g = 164.57ꢀ).
The phenyl ring (C1g) attached to oxygen O1 of a tripodal
3
3 3
3 3 3
3 3 3 3
unit is in π π interaction with the phenyl ring (C3g)
3
3 3
bonded to oxygen O7 of another tripodal moiety, creating
a one-dimensional chain along the c axis (Figure 2b). The
(Figure 1c). The nitro oxygens (O3, O5, O6, O8, and O9) act
as acceptors in C-H O intermolecular hydrogen bonding
distance between the centroids of the π π stacked phenyl
3
3 3
3 3 3
˚
with C O distances and C-H O angles ranging from
rings (C1g and C3g) is 3.734 A. The π π interaction
3
3 3 3 3 3
3 3 3
˚
3
.135 to 3.557 A and from 119.51 to 167.72ꢀ, respectively
Table 3). The nitro oxygen atoms O3, O5, O6, and O8 are
between two tripodal units is facilitated due to such an
orientation of the tripodal receptor arms that two arms
(
hydrogen bonded to alkyl hydrogens H24, H17A, H4, and
H8, respectively, whereas O9 forms bifurcated acceptor
hydrogen bonds to aromatic protons H15 and H23 of a
dimer (Table 3). Overall noncovalent interactions in the
solid-state result in the formation of three different types
of hydrogen bonded ring structures named as A, B, and C.
The repeated formation of an AB diad ring and a CBC type
triad is shown in Figure 1d.
Table 2. Molecular Conformation: Relevant Torsion Angles
I
II
III
(a) Torsion Involving N1aminoCCOether (τether
)
N1-C1-C2-O1
N1-C9-C10-O4
N1-C17-C18-O7
-75.86(2)
79.04(2)
-168.72(1)
65.82(2)
75.36(1)
70.33(1)
-69.96(2)
65.77(3)
-169.08(2)
3.1.2. Polymorph II. This form crystallizes in the mono-
clinic space group P2 /n with Z = 4. An ORTEP plot of
polymorph II is shown in Figure 2a along with the atom
(
b) Torsion Involving CCOether
C
phenyl (τphenyl
)
1
C1-C2-O1-C3
C9-C10-O4-C11
C17-C18-O7-C19
179.61(1)
-179.20(1)
-173.33(1)
-177.34(1)
-174.42(1)
-168.25(1)
-170.38(2)
178.89(2)
177.56(2)
numbering scheme. The torsion angles τether (N1amino
-
C-C-Oether) are all in the folded conformation for the three
tripodal arms, which is significantly different from the case
for the other two forms (Table 2). There is an intramolecular
(c) Torsion Involving CN1aminoCC (τamino
)
C1-N1-C9-C10
C1-N1-C17-C18
C9-N1-C1-C2
C9-N1-C17-C18
C17-N1-C1-C2
C17-N1-C9-C10
-56.66(2)
159.22(1)
-57.88(2)
-71.7(2)
69.58(2)
-142.52(1)
87.99(1)
-71.56(2)
-131.00(1)
68.78(2)
64.88(3)
79.45(2)
97.81(2)
-145.26(2)
-126.58(2)
-70.13(3)
edge-to-face (C-H
π) interaction between H20 and
3
3 3 3
the phenyl ring involving carbon atoms C11-C16
˚
(
C2g) (C20
51.71ꢀ). The tripodal units are self-assembled via π
C2g = 4.018 A, —C20-H20
3 3 3 3
C2g =
π
3
3 3 3
1
175.70(1)
77.45(2)
3
3 3
Figure 1. (a) ORTEP plot (50% probability ellipsoids) of polymorph I; (b) C-H
N dimeric interaction between two tripodal molecules in
3 3 3 O
3
3 3 3
the unit cell; (c) crystal packing diagram of polymorph I viewed along the crystallographic a axis; (d) repeating formation of C-H
hydrogen bonded rings AB diad and CBC triad.
3

Article
Crystal Growth & Design, Vol. 10, No. 2, 2010 757
involving oxygen atoms O1 and O7 of an unit are placed
almost opposite and parallel to each other and probably due
resulting in a one-dimensional stacking of tripodal moieties
along the c-axis. Each of these tripodal units are further
to the presence of intermolecular C-H
between nitro oxygen O8 and methylene hydrogen H9A. The
O interaction
involved in C-H π interaction between the aromatic
3
3 3 3
3 3 3
hydrogen H8 and the phenyl ring from a similar arm of
adjacent tripodal units, generating a brick-wall kind of
arrangement along the crystallographic c-axis (Figure 3b).
However, it is not possible to conclude definitively if a C-C
bond of the phenyl ring or the ring as a whole (centroid) is
π
π stacked one-dimensional chain is further cross-linked
3
3 3
via C-H
O interaction between the nitro oxygen O6 and
3
3 3 3
O9 with the aromatic hydrogens H8 and H16, respectively,
creating a three-dimensional hydrogen bonded network
(
Supporting Information).
.1.3. Polymorph III. This form crystallizes in the orthor-
more significant with respect to C-H π hydrogen bond-
3 3
3
3
ing. Details of these interactions are as follows: for
˚
hombic space group Pna2(1) with Z = 4 and Rint = 0.1149.
Although the unit cell is almost exactly metrically tetragonal,
the molecule could not be solved as such in the tetragonal
space group, probably because of the high Rint value of
C8-H8 C1g, C8 C1g = 4.056 A and —C8-H8
3 3 3 3 3 3
3 3 3
C1g = 151.63ꢀ, and for C18-H18B C3g, C18 C3g =
3 3 3 3 3
3
˚
˚
4.058 A and —C18-H18B C3g = 151.44 A. The nitro
3
3 3
oxygens O3 and O5 are engaged in bifurcated acceptor
hydrogen bonding to alkyl hydrogen H10A, H16 and
H2A, H2B, respectively, whereas O8 is in interaction with
the aromatic hydrogen H5, presenting a three-dimensional
0
.4201. An ORTEP plot of polymorph III is shown in
Figure 3a along with the atom numbering scheme. The
conformation involving the torsional angle τether (N1amino
-
C-C-Oether) is distinctly different from form II but similar
to form I with respect to the torsional angle involving the arm
composed of the ethereal oxygen O7. However, the differ-
ence could be observed for the other two arms composed of
the ethereal oxygens O1 and O4 that are in the folded
conformation, showing a change of 5.89ꢀ and 13.22ꢀ, respec-
tively (Table 2). Structural analysis revealed that the tripodal
moieties are stabilized by a considerably weak C-H
interaction and intermolecular C-H O hydrogen bond-
ing interactions between the alkyl hydrogen from all three
arms with one of the oxygens from each nitro group, unlike
in forms II and III. It is interesting to note that the alkyl
arrangement of C-H O hydrogen bonds with C
O
3 3 3
3 3 3 3
distances and C-H O angles ranging from 3.221 to 3.399
3
3 3
˚
A and from 120.66 to 147.29ꢀ, respectively (Table 3). The
crystal packing viewed along the ab plane shows that the
tripodal units are alternately and antiparallelly arranged,
with the apical nitrogen of each unit slightly tilted up and
down in sequence along the a axis (Supporting Information).
3.2. Rationalization of Structural Features. Polymorphs I,
II, and III crystallize in three different crystal systems:
π
3
3 3
3
3 3
triclinic (P1), monoclinic (P2 /n), and orthorhombic
1
(Pna2(1)), respectively. Polymorph I has two identical mo-
lecules in the unit cell, whereas polymorphs II and III have
four molecules each. Crystal structure analyses of the poly-
morphs reveal the absence of any noncovalent interactions
between the receptor arms, which might probably be respon-
sible for the flat and extended orientations of the arms in
polymorphs I and III, whereas there is an intramolecular
edge-to-face interaction between the phenyl rings of the
two proximal arms in form II. The molecules in different
forms differ significantly in the torsional angle τamino
hydrogen H18B is involved in intermolecular C-H π
interaction with the electron deficient nitrophenyl ring be-
longing to the identical arm of neighboring tripodal units,
3
3 3
Table 3. Relevant C-H
O Hydrogen Bond Interaction Data for
Polymorphs I, II, and III
3
3 3 3
˚
A) (A) d(D
˚
D-H
3 3 3 A
d(H
A) (A) —(DHA) (deg)
3
3 3 3 3
3 3 3 3
Polymorph-I
3.557
(C-N1amino-C-C), and notable changes are also observed
C24-H24
C17-H17A O5 2.566
C4-H4
C8-H8
C15-H15
C23-H23
3 3 O3
2.674
158.63
167.72
131.03
134.86
143.80
119.51
3
in torsion τether (N1amino-C-C-Oether) of form II compared
to relatively small differences in forms I and III. Almost
negligible changes are observed in torsion τphenyl
3.520
3.283
3.156
3.424
3.135
3
3 3
O6
O8
2.596
2.431
2.629
2.570
3
3
3 3 3
3 3 3
O9
O9
3
3
3 3 3
3 3 3
(C-C-Oether-Cphenyl) of the three polymorphs. Four of
the six torsional angles τamino are in the folded conformation,
and two are in the extended conformation in all three
polymorphs, but significant differences could be well ob-
served if we examine their torsional angle values. Upon
examining the torsion angles in the polymorphic structures
Polymorph-II
C8-H8
3 3 3 O6
2.443
2.587
2.684
3.349
3.506
3.549
164.28
158.35
155.24
3
C9-H9A O8
3
3 3 3
C16-H16
3 3 3 O9
3
(Table 2), it appears that the polymorphism is indeed a result
Polymorph-III
3.285
3.373
of the conformational flexibility of the single molecule.
Significant differences are also observed in most covalent
bond lengths and angles between the polymorphs, notably
the amino C-Namino-C angle is considerably greater in
form II than in other polymorphs for all the three arms
C5-H5
O8
2.515
2.515
2.672
140.27
147.29
120.66
136.50
121.87
3
3 3 3
C2-H2A O5
3
3 3
C2-H2B
O5
3.275
3.399
3.221
3
3 3 3
C10-H10A
O3 2.629
2.631
3
3 3 3
O3
C16-H16
3
3 3 3
Figure 2. (a) ORTEP plot (50% probability ellipsoids) of polymorph II and (b) π π stacking interaction in polymorph II along the c axis.
3 3
3

7
58 Crystal Growth & Design, Vol. 10, No. 2, 2010
Dey and Das
and small but notable changes are also reflected from the
bond angle involving Namino-C-C of the three forms
tripodal units or possibly with solvent molecules, thus
further affecting the habit of the crystals (Figure 4). The
relationship between the crystal structure and morphology
and external crystallization conditions is complex. Com-
pound L was crystallized at room temperature from a library
of solvents and binary solvent mixtures by slow evaporation
of homogeneous and saturated solutions until single crystals
were harvested with solvent remaining or almost evaporated.
All crystallization experiments were conducted in an unmo-
dified atmosphere. In the representative crystallization of
polymorph I, 100 mg of compound was dissolved in 6 mL of
acetonitrile or 0.5 mL of DMSO in a test tube at room
temperature. The test tube was sealed with aluminum foil
with a number of holes poked with a needle and allowed to
stand undisturbed for several days, leading to the formation
of thin yellow blocks of polymorph I, confirmed by examin-
ing the PXRD pattern of the crystallization batch and also
comparison with the simulated pattern based on the single
crystal structure determination. Slow evaporation of a satu-
rated solution of L in a 3:1 binary solvent mixture of ethanol
and acetic acid yielded high quality rhomboid shaped crys-
tals of polymorph II within 2-3 weeks. Polymorph III was
obtained from a saturated solution of 3:1 DMSO and acetic
acid solvent mixture that has reproducibly afforded thin light
yellow needles. It is worth mentioning that crystallization
from ethanol yielded both blocky and rhomboid shape
crystals of form I and II, respectively, with proportionally
greater quantities of form II, which could be well separated
with the help of a needle due to their different morphologies.
The concomitant formation of polymorphs I and II from
ethanol leads us to carry out the crystallization in a highly
protic medium of an ethanol-acetic acid solvent mixture
which yielded exclusively form II. Since form I has been
obtained exclusively from aprotic solvents (acetonitrile/
DMSO), concomitant crystallization of forms I and II from
ethanol gave us an indication of whether crystallization in a
(Supporting Information). The nitro group from one of the
arms of each polymorph is appreciably twisted out of
the phenyl plane by 8.88ꢀ(3), 14.04ꢀ(2), and 12.54ꢀ(6), invol-
ving nitrogen N3 in polymorphs I and II and N4 in poly-
morph III, respectively, but it is approximately coplanar
with the phenyl ring for the other two arms in the three
polymorphs. Polymorph II exhibits an intermolecular
nitro-nitro interaction which is not observed in the cases
of polymorphs I and III. The crystal packing is significantly
different in different polymorphs because of the different
combination of noncovalent interactions in each polymorph.
In polymorph I, all three nitro groups are involved in making
six C-H O hydrogen bonds through five oxygen atoms,
3
3 3
whereas, in polymorph II, two nitro groups involving the
nitrogen N3 and N4 are occupied in three hydrogen bonds
via three oxygen atoms. In contrast to polymorphs I and II,
five C-H O hydrogen bonding interactions are exhibited
3
3 3
by polymorph III involving one of the oxygen atoms from
each nitro group. Polymorphs I and III are involved in one
and two bifurcated C-H O hydrogen bonds, respectively,
3
3 3
while polymorph II exhibited no bifurcated hydrogen bond.
Most importantly, the supramolecular features in the three
forms are guided by the control of the methylene
C-H Namino dimeric interaction in form I, π π inter-
3
3 3 3 3 3
actions in form II, and weak C-H π interaction in form
3
3 3
III that differentiate the overall packing in the three poly-
morphs (Supporting Information).
3
.3. Crystal Growth and Habit. The morphology of the
crystal is another important manifestation of the quality of
the final products besides the crystal structure (Figure 4)
Regular-shaped crystals are generally more favorable over
anomalistic ones with respect to the practical usability.
Different crystallization parameters such as the type of the
solvent, the average levels of supersaturation, and so on are
important to obtain a desired crystal habit. The polarity of
the solvent is one of the most important properties that may
affect the habit of the growing crystal. Different solvents will
have different types of noncovalent interactions in the crystal
lattice with the podand molecule, which will change the
macroscopically crystal habit. Compound L is a polar
molecule with a tertiary nitrogen atom and three active nitro
groups, the presence of which facilitate the formation of
several intermolecular noncovalent interactions among the
Figure 4. Optical micrograph images highlighting the different
morphologies of three polymorphs of L.
Figure 3. (a) ORTEP plot (50% probability ellipsoids) of polymorph III and (b) C-H π stacking interaction in polymorph III along
3 3
3
the c axis.

Article
Crystal Growth & Design, Vol. 10, No. 2, 2010 759
highly protic medium might help us in generating only a
single polymorph of L. To investigate the influence of polar
solvent and temperature in controlling polymorphic struc-
2
4
ture, we have crystallized L by refluxing an ethanolic
solution for 3-4 h, allowed it to cool at room temperature,
and transferred it into a test tube for slow evaporation of the
solvent, which exclusively yielded polymorph III. In spite of
our repeated efforts, we were unable to obtain single crystals
of L suitable for single crystal analysis from low boiling
solvents such as DCM, chloroform, ethyl acetate, THF, and
methanol, and we always ended up having powders which
were found to contain a mixture of forms I and II
(Supporting Information) when analyzed by PXRD. The
crystallization experiments in different solvents showed that
the polymorphic formation of L is essentially guided by the
nature of the solvent.
3
.4. Phase Behaviors of Polymorphs. Polymorphs I and II
are quite stable at room temperature, but form III has been
observed to undergo a solid to solid phase transition to form
I at room temperature on storage over a period of about one
month or so, which was confirmed by PXRD and DSC
analyses. This simple observation argues strongly for the
metastable nature of polymorph III. More quantitative
evidence for the stability of polymorphs I and II and the
metastability of form III was obtained by differential scan-
ning calorimetry (DSC). DSC was conducted to investigate
the thermal properties of the three polymorphs, shown in
Figure 5. Measurements were carried out on all the forms in
three cycles: (1) heating from room temperature (25 ꢀC) to
Figure 5. DSC thermographs of polymorphs I, II, and III.
1
50 ꢀC; (2) cooling from 150 to 25 ꢀC; and (3) reheating
from 25 to 150 ꢀC. In all cycles, heating and cooling rates of
ꢀC/min were used. Each sample was prepared in two ways:
2
crushed and uncrushed crystals between the two aluminum
pans. No significant differences were observed in DSC
traces. Form I shows only one endothermic peak at 109 ꢀC
corresponding to melting of the polymorph with an onset
temperature of 104 ꢀC, and no phase transition is detected.
Form II displays a melting endotherm at 106.5 ꢀC with the
onset temperature near 98 ꢀC; the DSC trace is otherwise
featureless. Different from I and II, form III shows two
endothermic peaks. The first peak at 105 ꢀC with an onset
temperature of 100 ꢀC appears to be the solid-to-solid phase
transition to the more stable polymorph I while the second
endotherm with an onset of 106.0 ꢀC and a peak at 108 ꢀC
coincides with the melting of form I (confirmed by PXRD).
As all of the DSC samples were cooled to ambient tempera-
ture after heating, no thermal event was observed during the
cooling, indicating super cooled liquids were likely formed.
The melting endotherms of form I and II differ considerably
by 2.5 ꢀC and also show differences in the breadth of the
melting ranges. Form II has a comparatively broader range
of melting (∼15 ꢀC) than form I (∼10 ꢀC), also suggesting
the fact that form II has a slightly lower melting point than
form I (Figure 5). Thus, on completion of the DSC analysis,
it can be concluded that transformation of polymorph III to
the more stable polymorph I is kinetically very facile, as
transformation can also be observed at room temperature
and the transition is most likely to be monotropic. Further-
more, the enthalpies of transformation of the three forms
calculated from the DSC data are found to be -398, -474,
and -120 kJ mol- for polymorphs I, II, and III, respectively.
The PXRD is an important tool to determine the crystal-
line nature of the bulk sample. Figure 6 shows the PXRD
patterns of each polymorphic form collected at room
Figure 6. Experimental powder X-ray diffraction patterns of the
three polymorphs.
temperature, which confirm clearly that they represent dif-
ferent crystalline phases. The comparison with the simulated
patterns (Supporting Information) of all forms that are
based on the single crystal structures determined at 298 K
suggests that each crystallization batch was most likely of
one single polymorph, not a mixture of multiple poly-
morphs. The differences in the position and intensity of the
diffraction peaks indicate different possible crystal struc-
tures of L with preferable geometrical orientation. These
differences in bulk crystalline properties are in agreement
with the difference in their crystal structures. FT-IR spectra of
each polymorph collected at room temperature also indicate
different crystalline phases (Supporting Information). Though
significant differences were not observed in the mid-IR region
between the different polymorphic forms, notable changes
could be observed in the far IR and fingerprint regions arising
from the structural differences (e.g., the different hydrogen-
bonding arrangements).
1
4
. Conclusion
In summary, we describe the conformational polymor-
phism of a nitro functionalized tripodal podand for the first

7
60 Crystal Growth & Design, Vol. 10, No. 2, 2010
Dey and Das
time. Compound L exhibits conformational polymorphism
which results from the intrinsic conformational flexibility of
the molecule around the tertiary amino group and yields an
unprecedented set of three polymorphic forms by means of
traditional solvent induced crystallization. Remarkable dif-
ferences in the torsional angle values of τamino and τether in all
three polymorphs could possibly be the primary aspect for
different orientations of the tripodal arms around the apical
nitrogen. The crystals of different polymorphs exhibit differ-
(e) Sarma, J. A. R. P.; Desiraju, G. R. In Crystal Engineering:
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6) (a) Bernstein, J. Polymorphism in Molecular Crystals; Oxford Uni-
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arrangements together with other noncovalent interactions.
Considering the current intense interest in the phenomenon of
polymorphism, together with its importance to the field of
crystal chemistry, it is remarkable that all three of the poly-
morphs described here can apparently only be obtained as
single crystals from the desired solvent used, and these pre-
parations are reproducible. Thus, it may be concluded from
the above studies that the prenucleation aggregates assemble
in different supramolecular configurations depending on the
use of solvent combinations. However, it is not easy to
formulate a mechanism for polymorph induction based on
solvent polarity due to the complexity of the molecule.
Although a wide range of experimental conditions for produ-
cing polymorphs of L have been considered in the present
work, it wouldnot be surprisingif furtherpolymorphsof L are
found in the future. Indeed, our attempts to search for
polymorphs have been confined only to conventional crystal-
lization procedures from solution. A wide range of other
strategies provide the potential to generate further poly-
morphic forms, some of which are currently being explored
in our ongoing research. A systematic survey of solvent-
mediated polymorph generation in systems of this type, which
involves crystal structure studies of several substituted tripo-
dal molecules in terms of careful modeling studies and charge
density analyses, is currently being pursued to get further
insightsinto the natureof their packingmodes. Therefore, due
to the interesting structural and phase properties, the crystal
system may provide an excellent case for understanding
crystal growth and crystal packing.
2
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1
Acknowledgment. G.D. acknowledges DST (SR/S1/IC-
1/2008) and CSIR (01-2235/08/EMR-II), New Delhi, India,
J. Am. Chem. Soc. 1997, 119, 1767–1772. (c) Bonafede, S.; Ward, M.
J. Am. Chem. Soc. 1995, 117, 7853–7861. (d) Bernstein, J.; Davey, R.
J.; Henck, J.-O. Angew. Chem., Int. Ed. 1999, 38, 3441–3461.
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Elsevier: New York 1989.
0
for financial support; DST-FIST for its single crystal X-ray
diffraction facility; and Centre for Nanotechnology for pow-
der X-ray diffraction and CIF, IIT Guwahati.
(
(
(
16) (a) Mar tꢀı nez-Manez, R.; Sancenon, F. Chem. Rev. 2003, 103, 4419.
Supporting Information Available: Crystal structures of the three
polymorphs in the form of crystallographic information files (CIF),
bond parameters, angle parameters, and crystal packing diagrams.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(
b) Wu, B.; Liang, J.; Yang, J.; Jia, C.; Yang, X.; Zhang, H.; Tangb, N.;
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