Perspective

pubs.acs.org/crystal

Crystal Engineering in the Desiraju Research Group in Bangalore

Published as part of the Crystal Growth & Design virtual special issue In Honor of Prof. G. R. Desiraju
Shaunak Chakraborty, Ritesh Dubey, Sumy Joseph, Manish Kumar Mishra, Arijit Mukherjee,
Kafeel Ahmad Siddiqui, Srinu Tothadi, Tejender S. Thakur,*,# and Sunil Varughese*
Solid State and Structural Chemistry Unit, Indian Institute of Science Bangalore 560 012, India

ABSTRACT: Over the years, crystal engineering has transformed into a mature
and multidisciplinary subject. New understanding, challenges, and opportunities
have emerged in the design of complex structures and structure−property eval-
uation. Revolutionary pathways adopted by many leaders have shaped and directed
this subject. In this short essay to celebrate the 60th birthday of Prof. Gautam R.
Desiraju, we, his current research group members, contemplate the development
of some of the topics explored by our group in the context of the overall subject.
These topics, though not entirely new, are of significant interest to the crystal Photograph courtesy of Sunil Varughese. Copyright 2012.
engineering community.

■ BACKGROUND
When a thought flashed through some of our minds about
writing a short essay on the contributions made by the research
group of Prof. Gautam R. Desiraju that have enriched various
topics in crystal engineering, it was rather perplexing: where does
one start and how does one make it “short”. Since it is entirely the
responsibility of the current group members (other than Desiraju
himself) to record events in the group that changed the outlook
of the subject, the task becomes essentially formidable.
Research in India is generally determined by the system, rather
than the interest of the researcher, especially for a beginner; it
was no different for Desiraju. The bold swim against the stream,
and the wise with it, though they never lose their individuality.
Desiraju therefore adapted himself to the system and amended
his research strategy in tandem with the available resources.
It is worth noting that his early research work in Hyderabad
was done with flimsy infrastructure and a minimal access to
diffractometers. He focused mainly on the systematic analysis
of Cambridge Structural Database (CSD) in conjunction with
experimental results. It seems incredible sometimes that over
an organic chemist, his viewpoints and perceptions on weak
hydrogen bonds and supramolecular synthons were essentially
qualitative in nature and substantiated through circumstantial
evidence. However, his close association with organic and
physical chemists as well as spectroscopists helped him gain a
multidimensional outlook on his concepts. These developments,
in fact, were the need of the hour and catalyzed the growth of the
subject. By the time he made up his mind to move to Bangalore,
the studies of weak interactions and supramolecular synthons
were fast approaching a point of saturation. Hence one can think
that he was, in fact, looking forward to a fresh start. With no
match for the first phase of his research in Hyderabad, he
deliberately tuned his second innings in Bangalore to have a
distinct identity. As mentioned earlier, the studies in Hyderabad
were essentially qualitative and devoted to establishing the then
new concepts of weak interactions and supramolecular synthons.
In Bangalore, however, his research turns out to be more
quantitative in nature and focuses on the consolidation and
validation of the qualitative concepts and postulates. This essay
will discuss a few prominent concepts developed by the group
that changed the outlook of the subject.

two-thirds of his long stint of 30 years in Hyderabad went
on without a diffractometer facility in the university! Notably,
many important ideas and far-reaching findings were developed
through his vigilant “crystal-gazing”, collaborations with overseas
crystallographers and with the help of the CSD, in the process
establishing it as an indispensable part of the toolkit of a crystal
engineer.
His research debut at the crossroads of the history of crystal
engineering was the entry of the right person at the right time.
Those were the early days of crystal engineering. His research in
Hyderabad helped ascertain the nature of weak interactions,
thereby ensuring the firm establishment of their existence and
consequent acceptance into the league of conventional hydrogen
bonds. Development of the supramolecular synthon and retro-
synthetic approaches provided crystal engineers with a new
strategy for the targeted synthesis of assemblies. Being trained as
■
INTRODUCTION
In his 1989 book, Desiraju defined the term “Crystal Engineer-
ing”.1 Indeed the scope of the subject in its entirety is inherent in
the definition: “Crystal engineering is the understanding of
intermolecular interactions in the context of crystal packing and
the utilization of such understanding in the design of new solids with
desired physical and chemical properties” and it deciphers the areas
of focus and illustrates the route-map for the future development
of the subject. This short essay concentrates on this definition in
the context of a few activities of the research group that revolve
Received: June 1, 2012
Revised: August 29, 2012
Published: September 5, 2012

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Crystal Growth & Design
around its three distinct targets: (i) the study of intermolecular
interactions, (ii) the study of crystal packing and design strategies,
and (iii) the study of various properties in the context of crystal
packing.
■ SOME THOUGHTS AND A FEW REFLECTIONS
The role of intermolecular interactions in the formation of
crystal structures is well accepted although structural chemists,
until recently, considered weak interactions such as C−H···O,
C−H···N, and C−H···π rather as mere consequences of
crystal packing than as attractive and predictable forces. This is
because weak hydrogen bonds lie in the energy range of −2 to
−4 kcal/mol and also because the weakest of them are barely
distinguishable from van der Waals interactions. Following
the paper by Taylor and Kennard2 on C−H...O interactions, the
scientific front witnessed a prolific growth in the literature
on weak nonbonded interactions. Topical understanding that
emanated from the research group of Desiraju on weak inter-
actions in terms of their attractive nature, directionality, electro-
static characters, effect of donor group acidity as well as the
intriguing interplay between strong and weak interactions in
structure formation are conspicuous and laid the foundations for
future studies. His quest beyond the stringent definitions of
hydrogen bond by being open to all scientific observations made
him lead a veritable expedition in search of weak intermolecular
interactions. Cryocrystallization, variable temperature X-ray
diffraction, high-throughput crystallography, nanoindentation,
and crystal structure prediction were employed to study various
interesting and challenging systems. The studies prompted
structural chemists to accept these interactions into the league of
conventional hydrogen bonds and to appreciate the beauty and
ever-changing characters of these interactions. His book on weak
hydrogen bonds, coauthored with Steiner, entails a compre-
hensive compilation of the developments in the study of weak
interactions and is an insightful blend of his perception on the
topic and his far-reaching vision on the future outlook of weak
interactions and their utility as design elements in crystal synthesis.3
Being a protagonist in propagating the importance of weak
interactions in crystal engineering, Desiraju's astute inputs have
enriched the topic to a large extent. Over the years the story of
weak interactions have metamorphosed from a stage that
debated on its very existence to a level where it vies with the
conventional hydrogen bonds in structure formation. This
obvious change in the perception of weak hydrogen bonds is
reflected in the new definition of the hydrogen bond adopted in a
broader perspective, by the IUPAC task group on hydrogen
bonds, to embrace these interactions as members of the family of
conventional hydrogen bonds.4 Bold stands and exploratory
approaches adopted by a few futurist structural chemists have
culminated in the present understanding and acceptability of this
topic. Desiraju is one among them.
The second main pillar of crystal engineering is the logical
arrangement of molecular units into crystal structures using the
glue of noncovalent interactions, i.e., design algorithm and logical
construction. This not always being straightforward, Desiraju
proposed the possibility of a retrosynthetic approachgenerally
applied in covalent synthesisthat can effectively simplify the
crystal structure to smaller units.5 He called it supramolecular
synthon: structural units within supermolecules which can be formed
and/or assembled by known or conceivable synthetic operations
involving intermolecular interactions. This well thought out
approach follows a reductionist view of the problem which
emphasizes the use of distinct intermolecular regions as modular
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molecular recognition units. This concept, though simple, has
far-reaching implications particularly in crystal design and crys-
tal structure prediction (CSP) of cocrystals, particularly when
applied in qualitative segregation and reranking of computer
generated structures based on the order of synthon propensity.
In terms of a larger supramolecular space consisting of more
number of molecules and intermolecular interactions, he en-
visioned a higher order of molecular packing and defined the
modular unit as long-range synthon Aufbau modules (LSAM).6
Such an approach rests on the realization of a crystal as a bigger
supramolecular entity; the larger we go in size, higher the
specificity and consequently better the understanding. Further in
proposing a supramolecular synthon based fragments approach
(SBFA), he utilized the modularity of supramolecular synthons
to model the electron density distribution in molecular crystals
obtained from routine X-ray data.7 This is achieved by mapping
the multipole parameters derived from the high resolution charge
density studies directly to molecular fragments possessing a
similar supramolecular environment.
The aforementioned retrosynthetic approach and the concept
of supramolecular synthon are being widely applied to achieve
targeted synthesis of molecular complexes of fine chemicals and
pharmaceutical compounds. Although formation of multi-
component crystals has been known for over 150 years, indeed
from the early days of the inception of organic synthesis, non-
covalent synthesis attained logical reasoning when Desiraju
stated, “the very manifestation of co-crystallisation in a particular
system implies that it is possible to dissect and analyse a few
signif icant molecular interactions f rom amongst the larger number
that actually determine the stable crystal structure. In other words, it
is usually easier to understand why two molecules may co-crystallise
rather than why a single molecule adopts a particular crystal
structure in preference to another.”8 Moving aside from mundane
cocrystal studies, the group utilized size and shape mimicry of
molecules to make binary cocrystals as a starting point to attain
ternary assemblies and extended the knowledge of interactions to
design novel drug−drug cocrystals. That the simultaneous
administration of two or more drugs can prevent the emergence
of multiple drug-resistant variants of microorganisms highlights
the importance of such novel approaches in developing new
strategies in drug development.
Desiraju in his 1995 review5 proposed that, “...if a crystal is
assumed to be a supermolecule then crystallization is nothing but a
reaction involving many molecules”. In a typical crystallization
event, many kinetic minima are possible prior to attaining the
most stable thermodynamic phase. Thus, each crystal structure
can be considered as a data point in a landscape (the theme
originally introduced by Davey)9 of structural information, which
includes polymorphs, pseudopolymorphs, high Z′ structures,
solvates, hydrates and cocrystals. While some groups adopted in
silico screening of crystal forms, the Desiraju group adopted
the strategy of high-throughput crystallography and diverse
methods10chemical variations, solid solutions, or multi-
component systemsto determine the structural landscape
of compounds. The latter strategy provides unprecedented
opportunities to explore the possibilities of rare phenomena such
as cocrystal polymorphism,11 tautomeric polymorphism,12 and
even the coexistence13 of tautomeric and conformational poly-
morphism. Such rare, unconventional, or unforeseen incidents
open up new avenues to the observation of the course of crys-
tallization, to provide inputs toward synthon evolution throughout
the crystallization processes and further to reveal the fine balance
dx.doi.org/10.1021/cg300749a | Cryst. Growth Des. 2012, 12, 4688−4691
Crystal Growth & Design
that exists between various entropic and enthalpic factors that
determine the crystal structure.
The third but in no way least important pillar of crystal
engineering is the logical correlation between the innate
molecular interactions and micro/macro level properties of
molecular crystals. Mechanical behavior of a molecular crystal
is a property that has major implications for large-scale
processing and handling of materials in industry. The whole
story of the study of mechanical behavior of crystals in the group
was initiated by a systematic survey of molecular crystals with
4 and 8 Å structures1D vs 2D and 3D; isostructural vs
polymorphic; stacked vs interlocked; single component vs
multicomponentto qualitatively assess the intricate connec-
tion between intermolecular interactions (a nano/micro level
property) with the mechanical phenomenon, such as bending
(a macro level property).14 The studies attained a quantitative
approach when nanoindentation and scratch experiments were
used to correlate mechanical properties of molecular crystals in
terms of close-packing and interaction anisotropy (saccharin),15
long-range molecular/layer migration in layered compounds
(charge-transfer complexes),16 polymorphism, phase stability and
domain coexistence (aspirin polymorphs)17 and desolvation
processes (sodium saccharin dihydrate).18 The studies thus
introduced to structural chemists techniques such as nano-
indentation, which had largely confined to the engineering
community. At this point, it is heartening to quote one of the
statements made by Desiraju in his 2007 review: “Indeed, some of
the dif f icult questions posed in this review will yield their secrets only
with the application of sophisticated experimental methods, which
can make measurements in very small distances and time scales.”19
■
FUTURE OUTLOOK
Being a relatively young field, crystal engineering has undergone
drastic changes in its outlook and acceptability across the spec-
trum of research. Contributions and revolutionary pathways
adopted by many giants shaped and directed this subject. The
emergence of this field can be attributed more to crystal-clear
thinking and logical deductions than to messy theoretical
derivations. Because of its versatile outlook and the close
association of the crystal engineering community with different
scientific disciplines over the years, the subject has matured as
a horizontal, rather than a vertical, discipline. This holistic view
further enhanced the wider acceptance of the subject in the
scientific arena and enabled its inclusion into the academic
curricula of various institutions. The recent textbook on crystal
engineering,20 authored by Desiraju, Vittal and Ramanan,
highlights the importance of the topic, and the successful
commencement of Gordon Research Conference on crystal
engineering, the first of them chaired by Desiraju, further
underscores its recognition.
The research group has made significant contributions to
various aspects of crystal engineering, which enriched this area of
research over these years. Terms such as weak interactions and
supramolecular synthons are more often than not intertwined
with the name of Desiraju. If one analyzes the research output
of the group, the diversity in it is fabulous. This diversity in the
research and the thought processes make this group unique.
Rather than being monotonous reports of crystal structures, the
studies involve a deep understanding of the structure−function
relationship and are highly updated with recent trends. This is
achieved in the group by closely following the literature and by
promoting comprehensive inter-/intragroup discussions. A new
era of design of complex structures and structure−property
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Perspective
evaluation is inevitably upon us. The group is also gearing up to
face the new challenges and opportunities, under the electrifying
leadership and stimulating guidance of Prof. Gautam R. Desiraju.
■ PUBLICATIONS
Over 350 publications that emanated from the group have played
a major role in fostering the field of crystal engineering. Available
reviews can sometimes hint at the pace with which a particular
subject is developing and it is true for crystal engineering as well.
Being knowledge database, such reviews are good value additions
to the regular articles. If one sees the publication pattern of
Desiraju, it is interesting to note that the number of reviews
available with respect to his original research articles is quite high.
Interestingly, only a few of them are comprehensive literature
surveys; most of them are compilations of ideas and viewpoints
and hence can provide the deepest of insights to researchers
working in this field. These reviews are in fact a feast that can be
devoured, enjoyed, and celebrated. His vision and outlook
regarding the future of the subject are always reflected in his
reviews, and hence they will stand the test of time. His three
books on crystal engineering, together with the three edited
multiauthored books, are some of the best referred works in the
field.
■ GROUP AND COLLABORATIONS
The group comprises students from across the nation, from
north to south and east to west, bringing together the essence
and culture of the entire nation. The association of overseas
postdoctoral students with the group, in regular intervals, makes
it international.
One can notice that while in Hyderabad, the group was
involved in international collaborations, while here in Bangalore,
and with the accessibility of required infrastructure and expertise
within the institute, the collaboration is restricted to in-house.
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: tejenderthakur@gmail.com (T.S.T.); s.varughese@
yahoo.co.uk (S.V.).
Present Address
#
Molecular and Structural Biology Division CSIR-Central Drug
Research Institute, Lucknow−226 001, India.
Notes
The authors declare no competing financial interest.
■
REFERENCES
(1) Desiraju, G. R. Crystal Engineering. The Design of Organic Solids;
Elsevier: Amsterdam, 1989.
(2) Taylor, R.; Kennard, O. J. Am. Chem. Soc. 1982, 104, 5063−5070.
(3) Desiraju, G. R.; Steiner, T. The Weak Hydrogen Bond in Structural
Chemistry and Biology; Oxford University Press: Oxford, 1999.
(4) Desiraju, G. R. Angew. Chem., Int. Ed. 2011, 50, 52−59.
(5) Desiraju, G. R. Angew. Chem., Int. Ed. 1995, 34, 2311−2327.
(6) Ganguly, P.; Desiraju, G. R. CrystEngComm 2010, 12, 817−833.
(7) Hathwar, V. R.; Thakur, T. S.; Guru Row, T. N.; Desiraju, G. R.
Cryst. Growth Des. 2011, 11, 616−623.
(8) Sarma, J. A. R. P.; Desiraju, G. R. J. Chem. Soc., Perkin Trans. II 1985,
1905−1912.
(9) Blagden, N.; Davey, R. J. Cryst. Growth Des. 2003, 3, 873−885.
(10) Dubey, R.; Pavan, M. S.; Desiraju, G. R. Chem. Commun. 2012, 48,
9020−9022.
(11) Mukherjee, A.; Desiraju, G. R. Chem. Commun. 2011, 47, 4090−
4092.
(12) Bhatt, P. M.; Desiraju, G. R. Chem. Commun. 2007, 2057−2059.
dx.doi.org/10.1021/cg300749a | Cryst. Growth Des. 2012, 12, 4688−4691
Crystal Growth & Design Perspective

(13) Tothadi, S.; Bhogala, B. R.; Gorantla, A. R.; Thakur, T. S.; Jetti, R.
K. R.; Desiraju, G. R. Chem. Asian J. 2012, 7, 330−342.
(14) Reddy, C. M.; Padmanabhan, K. A.; Desiraju, G. R. Cryst. Growth
Des. 2006, 6, 2720−2731.
(15) Kiran, M. S. R. N.; Varughese, S.; Reddy, C. M.; Ramamurty, U.;
Desiraju, G. R. Cryst. Growth Des. 2010, 10, 4650−4655.
(16) Varughese, S.; Kiran, M. S. R. N.; Ramamurty, U.; Desiraju, G. R.
Chem. Asian J. 2012, 7, 10.1002/asia.201200224.
(17) Varughese, S.; Kiran, M. S. R. N.; Solanko, K. A.; Bond, A. D.;
Ramamurty, U.; Desiraju, G. R. Chem. Sci. 2011, 2, 2236−2242.
(18) Kiran, M. S. R. N.; Varughese, S.; Ramamurty, U.; Desiraju, G. R.
CrystEngComm 2012, 14, 2489−2493.
(19) Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 8342−8356.
(20) Desiraju, G. R.; Vittal, J. J.; Ramanan, A. Crystal Engineering: A
Text Book; World Scientific: Singapore, 2011.

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