Pyridazines in crystal engineering. A systematic evaluation of the role of isomerism and steric factors in determining crystal packing and nano/microcrystal morphologies

Article abstract of DOI:10.1021/cg9015383

The present study focuses on understanding hydrogen bond patterns in a series of variably substituted pyridyl-pyridazines as a function of positional isomerism and steric factors. A relatively uncommon multiple hydrogen bond acceptor nature of pyridazine

Full text of DOI:10.1021/cg9015383

DOI: 10.1021/cg9015383
Pyridazines in Crystal Engineering. A Systematic Evaluation of the Role
of Isomerism and Steric Factors in Determining Crystal Packing and
Nano/Microcrystal Morphologies
2010, Vol. 10
2571–2580
Sunil Varughese# and Sylvia M. Draper*
#
School of Chemistry, Trinity College Dublin, College Green, D2, Ireland. Current Address: Solid State
and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India.
Received December 8, 2009; Revised Manuscript Received April 15, 2010
ABSTRACT: The present study focuses on understanding hydrogen bond patterns in a series of variably substituted pyridyl-
pyridazines as a function of positional isomerism and steric factors. A relatively uncommon multiple hydrogen bond acceptor
nature of pyridazine has been observed in the di- and tripyridazine compounds. With increasing aromatic substitution and
thereby steric hindrance, a systematic transition has been observed from close-packed to porous solvated assemblies. Distinct
morphologies of the organic nano/microparticles, obtained by the precipitation method, indicate that the molecules interact
with the solvent system in different ways.
Introduction
bond patterns and packing modes.13 Thus, a systematic evalu-
ation of supramolecular synthons consisting of C-H
hydrogen bonds in a series of conformationally flexible and
N
3 3 3
Pyridazines are a class of compounds known for their utility
as efficient electron acceptors in conjugated D-A-D
systems,1 as building units in several bioorganic compounds,2
and as ligands in the preparation of novel coordination
complexes.3 In addition to the multiple N-atom sites for
sustaining coordination to metal centers, this class of com-
pounds can also interact with suitable coformers with acidic
functionalities to generate novel supramolecular assemblies
with exotic frameworks. However, unlike the N-atom donor
ligands pyridines, pyrimidines, and pyrazines, the nitrogen-
rich, electron-deficient pyridazines are not well studied from a
crystal engineering perspective. The pKa value of pyridazine is
2.1, making it a weaker base as compared to pyridine
functionalities4 which is a well-studied moiety in noncovalent
synthesis. This in turn makes pyridazine a weak lone-pair
sterically hindered pyridazines is interesting.
In the present work, nine variably substituted pyridyl-
pyridazines (Scheme 1) have been synthesized and analyzed
for hydrogen bond patterns and three-dimensional supramo-
lecular architecture. The effect of steric hindrance in the crystal
packing was studied systematically using molecules with in-
creasing substitution. It was assumed that the labyrinthine
topology, steric hindrance, and pliability of the recognition
patterns would bring about variations in the three-dimensional
architecture. The aromatic heterocyclics included in the pre-
sent studies make an interesting series, with conformational
flexibility brought about by the C-C single bonds.
The compounds have been synthesized by the inverse
electron demand Diels-Alder reaction between the respective
tetrazines and the corresponding alkynes, as represented in
Scheme 1, and characterized using 1D 1H and 13C, 2D 1H-1H
COSY, and 13C-1H COSY NMR techniques, thermogravi-
metry, and powder (PXRD) and single crystal X-ray diffrac-
tion (SXRD). Crystals suitable for X-ray diffraction studies
wereobtained by slow evaporation/vapordiffusion. Although
we succeeded in obtaining single crystals of the 2-pyridyl and
4-pyridyl derivatives, 3-pyridyl compounds (2b and 3b) failed
to form crystals suitable for the SXRD studies, even after
several attempts. The structural details, along with the basic
recognition patterns of all the assemblies, are enumerated
followed by a collective analysis to understand the variations
in and the similarity of the recognition patterns. It is interest-
ing to note that in all the cases assemblies are stabilized by
donor and a good candidate to investigate weak C-H
N
3 3 3
hydrogen bonds in crystals. However, this class of compounds
for crystal design has scarcely been explored, as evident from a
CSD search.5 Further, it was noted that multiple hydrogen
bond acceptor function is uncommon in pyridazines.6 Thus,
substituted pyridazines make an interesting series to study
weak interactions in organic molecules.
Despite a surge in the utility of relatively stronger inter-
molecular interactions such as O-H O, O-H N,
N-H O, etc. in network designing and noncovalent synth-
esis, the seminal works of Dunitz, Gavezzotti, Bishop, Boese,
Desiraju, Ohkita, and Nangia to name a few, have made a
substantial contribution to the knowledge of weak interac-
tions and their utility in crystal engineering.7-11 In contrast to
3 3 3
3 3 3
3 3 3
the well studied C-H O hydrogen bonds, the assemblies
3 3 3
weak noncovalent interactions such as C-H N,
stabilized by C-H N hydrogen bonds are less in number.12
3 3 3
3 3 3
C-H π, and π π. The morphology of the nano/micro-
3 3 3
3 3 3
In addition to weak interactions, steric factors, isomerism,
and conformational preferences of molecules can bring about
subtle variations in supramolecular synthons and crystal
packing. Organic molecules with flexible torsions can in fact
generate dissimilar conformations with different hydrogen
crystals, prepared by a precipitation method using a dimethyl-
formamide(DMF)/water system, were studied using scanning
electron microscopy (SEM).
Results and Discussion
Monopyridazine Compounds (1a -1c). The 2-pyridyl moi-
eties in phenyl-3,6-di(2-pyridyl)pyridazine, 1a, are in a trans,
*To whom correspondence should be addressed. Phone: þ353-1-8962026.
E-mail: smdraper@tcd.ie.
r
2010 American Chemical Society
Published on Web 05/04/2010
pubs.acs.org/crystal

2572 Crystal Growth & Design, Vol. 10, No. 6, 2010
Varughese and Draper
Scheme 1. The Synthetic Reagents (x and y axes) and Reaction Conditions (y axis) Used to Produce the Pyridazine Products 1a-1c,
2a-2c, and 3a-3c
and the two pyridyl rings deviate from the mean plane of the
pyridazine by 53.3°, 49.7°, and 1.6° respectively and the
pyridyl heteroatoms are arranged gauche, syn to the pyri-
dazine aza-atoms. In the three-dimensional arrangement,
molecules make a corrugated sheet structure (Figure 2a)
wherein individual sheets are made of molecules, stabilized
...
by bifurcated C34-H34 N21/C15-H15
3 3 3
N
(H N 2.62
3 3 3
21
˚
and 2.81 A) hydrogen bonds (Figure 2b(A)). Adjacent tapes
interact through single point C43-H43 N31 (H N,
3 3 3 3 3 3
˚
2.67 A) hydrogen bonds, as shown in Figure 2b(B).
The 4-pyridyl derivative, 1c, exhibits considerable varia-
tion in the torsion angle with respect to its isomers, 1a and 1b.
While the phenyl ring is more aligned with the mean plane of
the pyridazine ring (40.3°), both the 4-pyridyl moieties show
an increase in the torsion angle (27.2° and 43.3°) and make
an entirely different recognition pattern. Two molecules of
1c interact to form a centrosymmetric dimer, through
˚
21 (H N, 2.80 A) hydrogen bonds, utilizing
C46-H46
one of the pyridyl ring (Figure 3b(A)). Adjacent dimers make
N
3 3 3
3 3 3
Figure 1. The three-dimensional packing and interactions in 1a.
˚
N11 (H N 2.62 A) hydrogen bonds, forming a
C44-H44
ladder-like assembly in 2D arrangement.
3 3 3
3 3 3
trans-arrangement with respect to the pyridazine heteroa-
toms and play no role in the hydrogen bond formation.14
This can be attributed to the orientation of the pyridyl rings
toward an unfavorable sterically demanding environment
resulting from the phenyl moiety. The molecules of 1a make
zigzag tapes, and adjacent tapes are stabilized by weak
Thus, the three isomers of the monopyridazines (1a-1c)
yielded close-packed structures, although with distinct three-
dimensional architectures. To evaluate the influence of the
degree of substitution and steric hindrance in crystal packing,
1,4-di- and 1,3,5-tripyridazine compounds were considered.
While all the compounds were synthesized as per the reaction
conditions represented in Scheme 1, the 3-pyridyl derivatives
failed to yield crystals suitable for SXRD analysis.
C-H(pyridine) π interactions (Figure 1).
3 3 3
Phenyl-3,6-di(3-pyridyl)pyridazine, 1b, has different con-
formational preferences and orientation of the heteroatoms
which in turn results in a different architecture. The phenyl
Dipyridazine Compounds (2a-2c). 1,4-Phenyl-bis[3,6-di-
(2-pyridyl)pyridazine], 2a, crystallizes in R3 space group,

Article
Crystal Growth & Design, Vol. 10, No. 6, 2010 2573
Figure 2. Crystal structure of 1b. (a) The undulated sheet structure. (b) The intermolecular interactions existing in an individual sheet. (The
linear arrangement of molecules is represented as thin red lines.)
Figure 3. (a) The layered architecture in 1c. (b) The intermolecular interactions and the ladder assembly.
Table 1. Crystallographic Information of 1b, 1c, 2a, 2c, and 3c
1b
1c
2a
2c
3c
CCDC No.
formula
CCDC 727300
C20H14N4
CCDC 727301
C20H14N4
CCDC 727302
C34H22N8, 2(CH3OH)
CCDC 727303
C34H22N8, 2(CH3OH)
CCDC 727304
2(C48H30N12),
2(C2H6NCHO), H2O
1697.76
triclinic
P1
9.977(7)
13.808(1)
16.792(1)
92.350(3)
100.730(2)
110.860(1)
2109.3(15)
1
1.337
123(2)
0.71073
0.086
50.38
11449
0.0766
7196
3692
formula wt
crystal system
space group
310.35
monoclinic
P21/n
14.359(4)
7.104(2)
15.820(5)
90
105.420(6)
90
1555.6(8)
4
1.325
123(2)
0.71073
0.082
50.10
15249
0.0365
2743
1854
217
1.020
0.0428; 0.1041
310.35
orthorhombic
Pbca
7.466(7)
10.534(1)
38.576(4)
90
90
90
3034(3)
8
1.359
606.68
trigonal
R3
35.650(5)
35.650(5)
6.306(2)
90
90
120
6941(3)
9
1.306
606.68
monoclinic
P21/c
11.776(1)
17.635(1)
7.598(2)
90
106.240(1)
90
1514.9(4)
2
1.330
123(2)
0.71073
0.086
50.04
15874
0.0215
2663
2492
211
1.036
0.0362; 0.0978
˚
a (A)
˚
b (A)
˚
c (A)
R (o)
β (o)
γ (o)
3
˚
V (A )
Z
D(calc) g/cm3
T (K)
123(2)
0.71073
0.084
123(2)
0.71073
0.085
λMo
μ (mm-1
2θ (o)
total reflns
)
50.18
56.74
15932
0.0456
2693
2126
217
28713
0.0488
3840
3139
210
R(int)
unique reflns
reflns used
no. of parameters
GOF on F2
final R1; wR2
595
0.989
0.0887; 0.2144
1.042
0.0382; 0.0864
1.134
0.0705; 0.1896
with a half molecule and a methanol in the asymmetric unit
(Table 1). The central phenyl ring is 56.8° out of the mean
plane of the pyridazine ring, while the pyridyl rings are closer
to the plane of the central pyridazine ring (26.5° and 3.6°).
Although the 2-pyridyl rings make a trans,trans conforma-
tion with the heteroatoms of the pyridazine ring, unlike in 1a,
the heterocycle plays an important role in stabilizing the
of three H-shaped molecules of 2a generates a triangular
˚
unit, with a side length of 21.92 A, as represented in Figure
4b. The inward looking heteroatoms of the 2-pyridyl moi-
eties together with the pyridazine functionality stabilize the
triangular unit, through a two-tier hydrogen bond network.
˚
While the C35-H35 N31 (H N 2.87 A) hydrogen bonds
3 3 3
3 3 3
involving three internally oriented 2-pyridyl units make the
inner core, the peripheral area is bound by bifurcated
assembly through C-H N hydrogen bonds . Interlocking
3 3 3

2574 Crystal Growth & Design, Vol. 10, No. 6, 2010
Varughese and Draper
Figure 4. Crystal structure of 2a. (a) The porous assembly with hexagonal channels. (b) The triangular units and the schematic representation
of the helical assembly. (c) The methanol clusters (inset shows a different orientation of the methanol cluster).
˚
C26-H26 N12/C26-H26 N11 (H N 2.50 and 2.59 A)
can be inferred that in addition to the position of the hydrogen
bond forming functionalities, the conformational preferences of
the molecules also play an important role in determining the
three-dimensional architecture.
Compared to 2a, in the 4-pyridyl compound (2c) all the
aromatic rings tend to deviate away from the mean plane of
the pyridazine ring (phenyl (62.2°); 4-pyridyl (13.4° and
33.0°)). Of the four pyridyl rings, two are bound to methanol
molecules; the other two pyridyl units make hydrogen bonds
with adjacent units. Each molecule interacts with adja-
3 3 3
3 3 3
3 3 3
hydrogen bonds, formed by the pyridazine moiety. These
interactions extend along the c-axis to form a helical assem-
bly, as represented in Figure 4b. The edge-sharing arrange-
ment of the triangular helical entities generates hexagonal
2
˚
frameworks with channels (12.45 ꢀ 12.45 A ) down the
c-axis. The channels are occupied by clusters of methanol
molecules. Each cluster is made of six molecules exhibiting a
cyclohexane-type chair conformation and stabilized by
˚
O(methanol) hydrogen bonds (H O, 1.90 A)
(Figure 4c). A similar unusual and interesting methanol hex-
amer with a S6 symmetry was reported previously by Wieghardt
O-H(methanol)
3 3 3
3 3 3
cent units through cyclic C35-H35 N11/C36-H36 N12,
3 3 3
3 3 3
˚
(H N, 2.69 and 2.70 A) hydrogen bonds, forming a
3 3 3
et al.15 The guest methanol molecules make C-H(methanol)
layered assembly (Figure 5a). Further, these layers make
a herringbone type arrangement. The arrangement of the
molecules generates porous networks with channels down
the z-axis. These channels are occupied by linear chains of
3 3 3
π(pyridine) interactions with the framework.
An isostructural hydrate form of the compound was
obtained from a CH2Cl2-hexane solution with disordered
water molecules occupying the channel.14 Schroder and co-
€
methanol molecules, stabilized by C90-H90C O90 (H O,
3 3 3
3 3 3
˚
2.88 A) hydrogen bonds. The guest molecules are held to the
workers reported two solid-state forms of compound 2a - a
chloroform solvate and a solvent-free form.16 In the chloro-
form solvate, pyridazines are arranged as columns, stabilized
˚
host framework through O90-H90 N21 (H N, 2.02 A)
3 3 3
3 3 3
hydrogen bonds (Figure 5).
by weak π π interactions and separated from the adjacent
Tripyridazine Compounds (3a-3c). Compared to the
mono- and dipyridazine compounds the 1,3,5-tripyridazine
molecule, 3a, is sterically hindered and make a paddle-wheel
topology.14 The molecules self-assemble to form a double-
3 3 3
columns by CHCl3 molecules. In the case of the nonsolvated
pure form, the molecules form a close-packed structure
generated by the interlocking of the H-type molecules and
stabilized by several centrosymmetric and noncentrosymmetric
walled porous assembly, stabilized by C-H N hydrogen
3 3 3
C-H N hydrogen bonds (see Supporting Information).
bonds involving both pyridyl and pyridazine moieties (Table 2).
The void space is occupied by diethyl ether molecules, held
3 3 3
Thus, unlike the close-packed structure observed in the case
of compound 1a, the 1,4-derivative form both porous and
nonporous assemblies. As the 2-pyridyl moieties exhibited a
trans,trans conformation in all the aforementioned cases, the
observed disparity in the recognition pattern and supramolecu-
lar architecture may be brought about by the torsional flexibility
possible in the molecules (see Supporting Information). Thus, it
to the host framework through C-H(ether)
π(pyridine) inter-
3 3 3
actions, involving the ethyl group and the aromatic
rings. Thus, by employing an increasing number of aro-
matic rings, molecules with labyrinthine topology can be
obtained that make it difficult to form solvent-free crystal
structures.17

Article
Crystals of the 4-pyridyl isomer, 3c, were grown by vapor
diffusion of diethyl ether into a DMF solution and the
compound crystallizes in P1, with a tripyridazine, a di-
methylformamide and water in the asymmetric unit. In the
crystal, four pyridazine molecules interact to form cavities,
as shown in Figure 6b, and are stabilized by several weak
Crystal Growth & Design, Vol. 10, No. 6, 2010 2575
methyl group of the solvent makes C-H N hydrogen
3 3 3
bonds with the pyridazine molecules and holds adjacent
molecules together.
Both the 1,3,5-tripyridazine compounds, 3a and 3c,
yielded porous solvated assemblies. Although in the tripyr-
idazine compounds the positions of the pyridine functional-
ities are in two distinct environments, the basic recognition
C-H N and C-H π interactions. In a typical assem-
3 3 3 3 3 3
bly, the pyridazine units are involved in the formation of
cyclic C322-H322 312/C323-H323 N311 (H N, 2.77
and 2.84 A) dimers while the pyridine units form centrosym-
patterns (the cyclic C-H N) are common to both their
3 3 3
N
crystal structures. Also, the pyridazine moieties exhibit
similar recognition patterns in both assemblies.
3 3 3
3 3 3 3 3 3
˚
metric C-H(pyridine) N(pyridine) hydrogen bonds. Of the six
3 3 3
4-pyridyl units available per molecule, five are involved in the
cyclic C-H N hydrogen bonds with the adjacent units,
3 3 3
while the remaining one interacts with disordered water
˚
molecules forming O300-H(water) N321 (O N, 2.85 A)
3 3 3
3 3 3
hydrogen bonds. The guest DMF molecules make multiple
C-H O hydrogen bonds with pyridazine molecules. The
3 3 3
Figure 5. (a) The zigzag layer formed in 2c (The guest methanol
molecules are represented in the space-fill mode) and the inter-
molecular interactions existing in a layer. (b) The cavity formed in
2c. The linear chain of methanol molecules in the channel is shown
in the inset.
Figure 6. (a) The double-walled porous network formed in 3a and
the intermolecular interactions stabilizing the assembly. (b) The
network formed in 3c, viewed along the y-axis. The solvent DMF
molecules are represented in space-fill mode.
o a
˚
Table 2. Characteristic Data of Hydrogen Bonds [Bond Lengths in A, Angles in ]
1a
1b
2.61 3.52 160
2.62 3.53 161
2.67 3.35 129
2.81 3.74 168
2.89 3.48 121
1c
2.56 3.47 160
2.62 3.54 162
2.65 3.46 144
2.69 3.57 155
2.80 3.55 136
2a
2.50 3.24 135
2.59 3.38 142
2.59 3.45 150
2.87 3.77 159
2c
2.65 3.49 148
2.69 3.48 141
2.70 3.45 137
2.74 3.50 137
3a
3c
C-H...N
2.81 3.66 149
2.53 3.48 178
2.60 3.37 138
2.70 3.47 138
2.73 3.53 142
2.73 3.51 140
2.86 3.61 137
2.59 3.48 157
2.63 3.36 134
2.67 3.30 124
2.75 3.44 130
2.77 3.51 135
2.82 3.49 129
2.83 3.44 123
2.84 3.53 130
2.84 3.51 128
C-H...O
2.37 3.32 172
2.66 3.50 148
2.88 3.43 119
2.90 3.56 163
2.30 3.24 171
2.41 3.32 159
2.65 3.60 171
2.80 3.59 141
2.91 3.50 122
O-H...O
O-H...N
1.90 2.70 159
2.02 2.85 169
a The three columns correspond to H A, D A (A) distances and D-H A (o) angle.
˚
3 3 3
3 3 3
3 3 3

2576 Crystal Growth & Design, Vol. 10, No. 6, 2010
Varughese and Draper
Figure 7. The overlap diagram of (a) mono-, (b) di-, and (c) tripyridydazine compounds. (Color code: green (2-pyridyl), yellow (3-pyridyl), and
red (4-pyridyl)). (d) The histogram representation of torsion angles (along the y-axis) exhibited by pyridazines a1-3 and c1-3 with respect to
the phenyl ring.
Analysis of Torsion Angles. A comparative analysis of the
torsion angles (calculated as the angles between the mean
planes of the rings) of the 2-pyridyl and 4-pyridyl pyridazine
compounds was carried out. From the overlap diagrams
of the mono-, di-, and tripyridazine, it was observed that
further to the orientation of the heteroatoms, the molecules
exhibit diverse conformational preferences. This also might
have contributed to the variation in the supramolecular
architecture (Figure 7). In the case of monopyridazines
(1a-1c), diverse three-dimensional architecture are ob-
served, although all are close-packed structures. In the
dipyridazine compounds (2a and 2c), the isomers exhibit
considerable conformational variation and are clearly visible
in the crystal packing. For the tripyridazine compounds 3a
and 3c, although large torsional shifts exist, the global
packing arrangement is not very perturbed, with the forma-
tion of porous solvated assemblies, perhaps due to the
operation of the same principles governing the space filling
in accordance with crystallographic symmetry rules.
The variations in the torsion angles of the pyridazine
moiety with respect to the phenyl rings are compiled to form
a chart (Figure 7d). The mono- and dipyridazine compounds
1a and 2a showed similar torsion angles as against 1c and 2c,
where a substantial variation exists (∼22°). While all the
three pyridylpyridazine substituents of 3a exhibit diverse
torsion angles with respect to the central phenyl ring, only
marginal shifts exist in 3c. Thus, along with the position of
the hydrogen bond forming functionalities, torsional varia-
tion brought about by the steric strain, lattice constraints,
solvent incorporation, etc. also might have contributed to
the final supramolecular architecture.
Variation in the Hydrogen Bond Patterns. The multiple
hydrogen bond acceptor properties of pyridazines are rela-
tively uncommon.6 In the present study, pyridazine moiety
exhibits three different supramolecular synthons as a func-
tion of degree of substitution and availability of hydrogen
bond forming functionalities in its vicinity. While monopyr-
idazines (1a and 1c) exhibited regular single point C-H
interactions, the pyridazine moiety acts as a multiple hy-
N
3 3 3
drogen bond acceptor in di- and triderivatives, making
bifurcated and noncentrosymmetric C-H N hydrogen
3 3 3
bonds (Figure 8a). Thus, the availability of more hydrogen
bond donors, although weak, brought about by the inc-
rease in substitution has resulted in distinct recognition
patterns in contrast to that of molecules with minimal
substitution.
The H N distance of the C-H N hydrogen bonds
3 3 3
3 3 3
observed in the assemblies are plotted in a chart for an easy
comparison (Figure 8b). The number of hydrogen bonds in
1a is substantially lower than in its 3- and 4-pyridyl counter-
parts, 1b and 1c. But, in 3a and 3c, the C-H N hydrogen
3 3 3
bonds are similar in number and H N bond distance.
3 3 3
This indeed is brought about by the enhanced availability of
hydrogen bond forming functionalities with the increase
in substitution, making the orientation of the heteroatoms
relatively insignificant.
Thermal Analysis and PXRD Studies. The stability
and phase purity of the assemblies were analyzed using

Article
Crystal Growth & Design, Vol. 10, No. 6, 2010 2577
thermogravimetry (TG) and powder X-ray diffraction
(PRXD). While the TG plots of 1a-1c, 2a, and 2c do not
show any solvent loss, 18% mass loss up to 400 °C was
observed in the case of 3a and can be attributed to the initial
loss of diethyl ether followed by breakdown of the assembly.
The crystals of 2a and 2c lose their crystalline luster once
exposed to air. The prior and rapid loss of solvent probably
accounts for the absence of weight loss, corresponding to
solvent, in the thermogravimetric plots. A molecule of lattice
water and two DMF units (12%) were lost in the case of 3c
by 200 °C, with further decomposition occurring with an
onset temperature of 425 °C (see Supporting Information).
Although there exist the effect of morphology and crystallite
size on some of the features of patterns, the peak positions of
the experimental diffraction patterns of compounds, 1a-1c
are consistent with that of the simulated. The powder
patterns for 2c, 3a and 3c show considerable variation with
respect to the simulated pattern along with a decrease in the
crystalline nature. This may be due to the collapse of the
molecular framework initiated by the solvent loss. However
in 2a the framework is maintained even after the removal of
solvent molecules, as evidenced from the similar experimen-
tal and simulated diffraction patterns (see Supporting In-
formation).
Nano/Microcrystal Analysis. The morphology variations
of nanocrystals as a function of steric interactions, π-π
stacking, and hydrogen bonding motifs is known in the
literature, although the manipulation of nanoparticle mor-
phology by altering the molecular geometry of the com-
pound has been met with limited success.16 Thus, a rational
and simple approach to synthesize organic nanocrystalline
materials is highly desirable for understanding the various
factors that influence the morphology variations and stabi-
lity. In conjunction with the structural analysis, the organic
nano/microparticles were prepared by the precipitation
method (by rapid injection of the respective compounds in
DMF into water). It was noticed that all nine compounds
Figure 8. (a) The variation in the hydrogen bond patterns observed
in pyridazines as a function of substitution. (b) A plot of hydrogen
bond distances in seven pyridazine compounds.
Figure 9. The SEM images of the nano/microparticles of 1a, 1b, and 1c. The observed transistion from spherical metastable particles to
microcrystals in the case of 1b is represented by the arrow.

2578 Crystal Growth & Design, Vol. 10, No. 6, 2010
Varughese and Draper
Figure 10. The SEM images of the nano/microcrystals of 2a-2c and 3a-3c. The magnified image of the particles, in the case of 2c is given
in inset.
yielded particles with distinct morphology, although they
lack monodispersity. To evaluate the stability of the nano/
microparticles formed, SEM studies were carried out three
times over a period of one week, one month and two months,
after the initial sample preparation. Except for 1b, all the
nano/microparticles were observed to be stable. Also the
experiments were carried out in similar conditions to estab-
lish the reproducibility, and the results were found to be
consistent.
The isomer effect of the compounds was analyzed by
comparing the morphology of the nano/microparticles ob-
tained in the case of 1a, 1b, and 1c (Figure 9). While
compounds 1a and 1c formed crystals with distinct faces
and edges, the 3-pyridyl compound, 1b, formed spherical
particles. Compound 1a formed bundles of long needles with
an average dimension of 50 ꢀ 3 μm; 1b yielded zero-dimen-
sional spherical particles with an average dimension of 1 μm.
Clusters of microparticles with the appearance of rice grains
with dimensions in the range of 700 nm to 2 μm were
obtained for 1c. The three isomers exhibited different hydro-
gen bond forming abilities in the supramolecular assemblies
and this in turn is reflected in the nano/microparticle
morphologies. This change in morphology can therefore be
attributed to the different interactions at a supramolecular
level brought about by variation in the position of the
pyridine heteroatoms and the influence of their interactions
with the solvent system. However, we are unaware of the
possibility of the solvent trapped in these particles. A similar
report of distinct nanostructures from isomeric molecules
was presented by Yao et al. using bis(iminopyrrole)benzenes
as representative examples.18 In a recent paper, Lee and co-
workers proposed that the variation in the morphology can
also be brought about by the dipole moments, with zero-
dimensional spherical nanoparticles formed by the molecules

Article
Crystal Growth & Design, Vol. 10, No. 6, 2010 2579
with a lower dipole moment.19 In the case of 1b, the particles
exhibited a spherical morphology, and over a period of two
months they transformed to microcrystalline particles. A
similar observation was reported for a series of intramole-
cular charge transfer (ICT) compounds.19 It was reported
that over a period of time the metastable aggregates dis-
solved and transformed to grow into crystallites along the
direction of the directional interactions. Although we have
not carried out an in situ experiment to analyze this phase
transition, it is possible to postulate that recrystallization
might have been involved in this process, as the amount of
these spherical particles were found to vary over a different
time period and also in repeated experiments. Such transitions
were not observed in the case of other pyridazines, as all the
other compounds yielded crystalline particles.
The particles obtained in the case of dipyridyl pyridazine
compounds, 2a, 2b, and 2c, also exhibited interesting
morphologies (Figure 10). While 2a formed circular flakes,
the 4-pyridyl analogue, 2c, formed blunt rectangular particles.
In the case of 2b, twisted crystals were obtained. Although
infinite helical tapes are known in gels and were reported earlier,
their crystalline counterparts for small molecules are relatively
uncommon.20 The 1,3,5-tripyridazine compounds (3a, 3b, and
3c) formed thin platelets with distinct features. In the case of 3a,
thin flakes of several micrometers were observed. Compounds
3b and 3c formed platelets with a dimension of ∼2 μm. The
distinct morphologies of the nanoparticles of tripyridazine
compounds may be due to the decrease in the molecular
planarity brought about by the increase in substitution, thus
making the rearrangement and stacking between molecules
more difficult. Similar observations of steric effects hindering
the formation of one-dimensional nanostructures and the for-
mation of thin platelets and nanoparticles instead can be found
in the literature.21 The results show that the morphology of the
nanostructures of small molecular organic materials can be
readily tuned by varying the isomer or the steric hindrance.
Attempts were made to prepare nanocrystals of the compounds
from DMF/toluene to study the solvent effects, but the systems
failed to form any assembly, possibly because of the solubility of
the compounds in the binary solvent system.
bond acceptor nature of pyridazine is observed in the di- and
trisubstituted compounds. The powder X-ray analysis clearly
indicates that in most of the solvated assemblies the molecular
frameworks collapse with the loss of solvents. The nano/micro-
particles of the pyridazines exhibit distinct morphologies and
indicate that the resulting disparity can be brought about by the
difference in the intermolecular interactions existing between the
molecules and also with the solvent system. Thus, the present
study contributes toward an understanding of hydrogen bond
patterns and crystal packing in a series of pyridazines as a
function of isomerism and steric effects and its consequence on
the morphology of nano/microcrystals.
Experimental Details
The chemicals were purchased from Aldrich and used without
further purification. Reagent grade toluene was used for the reaction.
The 1,4-phenylene-diacetylene and 1,3,5-phenylene-triacetylene were
prepared by Sonogashira coupling following the literature methods.22
The tetrazines were prepared from the corresponding cyanopyridines
as per the procedures available in the literature.23
General Procedure for 1a, 1b, and 1c. Phenyl acetylene (0.102 g;
1 mmol) and 3,6-di(2-pyridyl)tetrazine (0.236 g; 1 mmol) were
refluxed in 5 mL of toluene in a pressure tube (15 mL) at 140 °C
for 48 h. By the end of the reaction, the purple color disappears to
form a pale yellow precipitate. The solvent was removed under a
vacuum and the compound was run through a column on silica
using ethylacetate-methanol (9:1) as eluent.
General Procedure for 2a, 2b, and 2c. 1,4-Phenylene-diacetylene
(0.126 g; 1 mmol) and 3,6-di(2-pyridyl)tetrazine (0.472 g; 2 mmol)
was refluxed in 7 mL of toluene in a pressure tube (15 mL) at 160 °C
for 48 h. By the end of the reaction, the purple color disappears and a
pale yellow precipitate is formed. The compound was purified using
column chromatography on silica using dichloromethane-acetone
(7:3) as the eluent.
General Procedure for 3a, 3b, and 3c. 1,3,5-Phenylene-triacetylene
(0.150 g; 1 mmol) and 3,6-di(2-pyridyl)tetrazine (0.708 g; 3 mmol)
was refluxed in 10 mL of toluene in a pressure tube (25 mL) at 180 °C
for 48 h. By the end of the reaction, the purple color disappears and a
pale yellow precipitate is formed. The compound was purified using
column chromatography on silica using ethylacetate-methanol
(9:1) as eluent. (In the case of the preparation of 3c, the acetylene/
tetrazine ratio should exceed 1:5.)
X-ray Analysis. Single crystals of 1a-3c were carefully chosen
after they were viewed through a microscope supported by a
rotatable polarizing stage. The crystals were glued to a thin glass
fiber using NVH immersion oil and mounted on a diffractometer
equipped with an APEX CCD area detector. All the data were
collected at 123 K. The intensity data were processed using Bruker’s
suite of data processing programs (SAINT), and absorption correc-
tions were applied using SADABS.24 The structure solution of all
the complexes was carried out by direct methods, and refinements
were performed by full-matrix least-squares on F2 using the
SHELXTL-PLUS suite of programs.24 All the non-hydrogen atoms
were refined anisotropically, and the hydrogen atoms were fixed on
the calculated positions using appropriate AFIX commands and
were refined isotropically. Intermolecular interactions were com-
puted using the PLATON program.25
Nanoparticle Preparation and Analysis. The nanoparticles were
prepared by the rapid injection of 50 μL of 10-3 M compound
in DMF (filtered through a nanoporous alumina membrane
(Whatman, Anodisc 13)) to 20 mL of Millipore water under
ultrasonication. The turbid solution was kept at isothermal condi-
tions (40 °C) for 48 h and was filtered through anodisc (20 nm). The
morphology of the nanoparticles was analyzed using a TESCAN
scanning electron microscope using a beam voltage of 5 kV.
Thermal Analysis. Thermogravimetric analyses were carried out
using a Perkin-Elmer Pyris 1 TG analyzer, and the experiments were
carried out in inert atmosphere with a heating rate of 10 °C/min.
Conclusion
A series of mono-, 1,4-di-, and 1,3,5-tripyridylpyridazines
have been synthesized and analyzed. The hydrogen bond
properties and crystal packing were found to depend on the
positional isomerism and steric effects. Although the extent of
influence of steric hindrance and isomerism in crystal packing
cannot be reached a posteriori, it is known in the literature
that efficiency of close packing decreases with an increase in
steric hindrance and uneven topology of the molecules. While
close-packed assemblies were observed in monopyridazines,
both porous and close-packed systems are formed in di-
pyridazine derivatives. The trisubstituted compounds with
labyrinthine topology consistently yielded porous solvated
assemblies. In all the cases, the steric strain of the molecules
were analyzed by calculating the angles between the best least-
squares planes of the rings and were found to be a function
of the extent of substitution. In all the cases, the assemblies
are stabilized by weak noncovalent interactions such as
C-H N, C-H π, and π π. In the present series of
3 3 3
3 3 3
3 3 3
compounds, due to the steric strain, the interactions extend
well beyond the sum of the van der Waals radii, thus making it
weaker in nature. The relatively uncommon multiple hydrogen
Acknowledgment. This material is based upon works sup-
ported by Science Foundation Ireland [05PICAI819]. S.V.

2580 Crystal Growth & Design, Vol. 10, No. 6, 2010
Varughese and Draper
thank Prof. T. N. Guru Row and Dr. S. Philip Anthony for
fruitful discussions.
Craig, D. C.; Scudder, M. L. Eur. J. Org. Chem. 2001, 863–873.
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Supporting Information Available: Additional crystallographic
and spectroscopic information, figures, tables, TG plots, PXRD
patterns, and SEM images. This information is available free of
charge via the Internet at http://pubs.acs.org/.
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