Crystal Engineering in the Desiraju Research Group in BangalorePublished 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

Photograph courtesy of Sunil Varughese. Copyright 2012.

ABSTRACT: Over the years, crystal engineering has transformed into a matureand multidisciplinary subject. New understanding, challenges, and opportunitieshave emerged in the design of complex structures and structure−property eval-uation. Revolutionary pathways adopted by many leaders have shaped and directedthis subject. In this short essay to celebrate the 60th birthday of Prof. Gautam R.Desiraju, we, his current research group members, contemplate the developmentof 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 crystalengineering community.

■ BACKGROUND

When a thought flashed through some of our minds aboutwriting a short essay on the contributions made by the researchgroup of Prof. Gautam R. Desiraju that have enriched varioustopics in crystal engineering, it was rather perplexing: where doesone start and how does onemake it “short”. Since it is entirely theresponsibility of the current groupmembers (other than Desirajuhimself) to record events in the group that changed the outlookof 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; itwas 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 amendedhis research strategy in tandem with the available resources.It is worth noting that his early research work in Hyderabadwas done with flimsy infrastructure and a minimal access todiffractometers. He focused mainly on the systematic analysisof Cambridge Structural Database (CSD) in conjunction withexperimental results. It seems incredible sometimes that overtwo-thirds of his long stint of 30 years in Hyderabad wenton without a diffractometer facility in the university! Notably,many important ideas and far-reaching findings were developedthrough his vigilant “crystal-gazing”, collaborations with overseascrystallographers and with the help of the CSD, in the processestablishing it as an indispensable part of the toolkit of a crystalengineer.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 inHyderabad helped ascertain the nature of weak interactions,thereby ensuring the firm establishment of their existence andconsequent acceptance into the league of conventional hydrogenbonds. Development of the supramolecular synthon and retro-synthetic approaches provided crystal engineers with a newstrategy for the targeted synthesis of assemblies. Being trained as

an organic chemist, his viewpoints and perceptions on weakhydrogen bonds and supramolecular synthons were essentiallyqualitative in nature and substantiated through circumstantialevidence. However, his close association with organic andphysical chemists as well as spectroscopists helped him gain amultidimensional outlook on his concepts. These developments,in fact, were the need of the hour and catalyzed the growth of thesubject. By the time he made up his mind to move to Bangalore,the studies of weak interactions and supramolecular synthonswere fast approaching a point of saturation. Hence one can thinkthat he was, in fact, looking forward to a fresh start. With nomatch for the first phase of his research in Hyderabad, hedeliberately tuned his second innings in Bangalore to have adistinct identity. As mentioned earlier, the studies in Hyderabadwere essentially qualitative and devoted to establishing the thennew concepts of weak interactions and supramolecular synthons.In Bangalore, however, his research turns out to be morequantitative in nature and focuses on the consolidation andvalidation of the qualitative concepts and postulates. This essaywill discuss a few prominent concepts developed by the groupthat changed the outlook of the subject.

■ INTRODUCTION

In his 1989 book, Desiraju defined the term “Crystal Engineer-ing”.1 Indeed the scope of the subject in its entirety is inherent inthe definition: “Crystal engineering is the understanding ofintermolecular interactions in the context of crystal packing andthe utilization of such understanding in the design of new solids withdesired physical and chemical properties” and it deciphers the areasof focus and illustrates the route-map for the future developmentof the subject. This short essay concentrates on this definition inthe context of a few activities of the research group that revolve

Received: June 1, 2012Revised: August 29, 2012

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around its three distinct targets: (i) the study of intermolecularinteractions, (ii) the study of crystal packing and design strategies,and (iii) the study of various properties in the context of crystalpacking.

■ SOME THOUGHTS AND A FEW REFLECTIONSThe role of intermolecular interactions in the formation ofcrystal 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 ofcrystal packing than as attractive and predictable forces. This isbecause weak hydrogen bonds lie in the energy range of −2 to−4 kcal/mol and also because the weakest of them are barelydistinguishable from van der Waals interactions. Followingthe paper by Taylor and Kennard2 on C−H...O interactions, thescientific front witnessed a prolific growth in the literatureon weak nonbonded interactions. Topical understanding thatemanated 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 theintriguing interplay between strong and weak interactions instructure formation are conspicuous and laid the foundations forfuture studies. His quest beyond the stringent definitions ofhydrogen bond by being open to all scientific observations madehim lead a veritable expedition in search of weak intermolecularinteractions. Cryocrystallization, variable temperature X-raydiffraction, high-throughput crystallography, nanoindentation,and crystal structure prediction were employed to study variousinteresting and challenging systems. The studies promptedstructural chemists to accept these interactions into the league ofconventional hydrogen bonds and to appreciate the beauty andever-changing characters of these interactions. His book on weakhydrogen bonds, coauthored with Steiner, entails a compre-hensive compilation of the developments in the study of weakinteractions and is an insightful blend of his perception on thetopic and his far-reaching vision on the future outlook of weakinteractions and their utility as design elements in crystal synthesis.3

Being a protagonist in propagating the importance of weakinteractions in crystal engineering, Desiraju's astute inputs haveenriched the topic to a large extent. Over the years the story ofweak interactions have metamorphosed from a stage thatdebated on its very existence to a level where it vies with theconventional hydrogen bonds in structure formation. Thisobvious change in the perception of weak hydrogen bonds isreflected in the new definition of the hydrogen bond adopted in abroader perspective, by the IUPAC task group on hydrogenbonds, to embrace these interactions as members of the family ofconventional hydrogen bonds.4 Bold stands and exploratoryapproaches adopted by a few futurist structural chemists haveculminated in the present understanding and acceptability of thistopic. Desiraju is one among them.The second main pillar of crystal engineering is the logical

arrangement of molecular units into crystal structures using theglue of noncovalent interactions, i.e., design algorithm and logicalconstruction. This not always being straightforward, Desirajuproposed the possibility of a retrosynthetic approachgenerallyapplied in covalent synthesisthat can effectively simplify thecrystal structure to smaller units.5 He called it supramolecularsynthon: structural units within supermolecules which can be formedand/or assembled by known or conceivable synthetic operationsinvolving intermolecular interactions. This well thought outapproach follows a reductionist view of the problem whichemphasizes the use of distinct intermolecular regions as modular

molecular recognition units. This concept, though simple, hasfar-reaching implications particularly in crystal design and crys-tal structure prediction (CSP) of cocrystals, particularly whenapplied in qualitative segregation and reranking of computergenerated 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 themodular unit as long-range synthon Aufbau modules (LSAM).6

Such an approach rests on the realization of a crystal as a biggersupramolecular entity; the larger we go in size, higher thespecificity and consequently better the understanding. Further inproposing a supramolecular synthon based fragments approach(SBFA), he utilized the modularity of supramolecular synthonsto model the electron density distribution in molecular crystalsobtained from routine X-ray data.7 This is achieved by mappingthemultipole parameters derived from the high resolution chargedensity studies directly to molecular fragments possessing asimilar supramolecular environment.The aforementioned retrosynthetic approach and the concept

of supramolecular synthon are being widely applied to achievetargeted synthesis of molecular complexes of fine chemicals andpharmaceutical compounds. Although formation of multi-component crystals has been known for over 150 years, indeedfrom the early days of the inception of organic synthesis, non-covalent synthesis attained logical reasoning when Desirajustated, “the very manifestation of co-crystallisation in a particularsystem implies that it is possible to dissect and analyse a fewsignif icant molecular interactions f rom amongst the larger numberthat actually determine the stable crystal structure. In other words, itis usually easier to understand why two molecules may co-crystalliserather than why a single molecule adopts a particular crystalstructure in preference to another.”8 Moving aside from mundanecocrystal studies, the group utilized size and shape mimicry ofmolecules to make binary cocrystals as a starting point to attainternary assemblies and extended the knowledge of interactions todesign novel drug−drug cocrystals. That the simultaneousadministration of two or more drugs can prevent the emergenceof multiple drug-resistant variants of microorganisms highlightsthe importance of such novel approaches in developing newstrategies in drug development.Desiraju in his 1995 review5 proposed that, “...if a crystal is

assumed to be a supermolecule then crystallization is nothing but areaction involving many molecules”. In a typical crystallizationevent, many kinetic minima are possible prior to attaining themost stable thermodynamic phase. Thus, each crystal structurecan be considered as a data point in a landscape (the themeoriginally introduced byDavey)9 of structural information, whichincludes polymorphs, pseudopolymorphs, high Z′ structures,solvates, hydrates and cocrystals. While some groups adopted insilico screening of crystal forms, the Desiraju group adoptedthe strategy of high-throughput crystallography and diversemethods10chemical variations, solid solutions, or multi-component systemsto determine the structural landscapeof compounds. The latter strategy provides unprecedentedopportunities to explore the possibilities of rare phenomena suchas cocrystal polymorphism,11 tautomeric polymorphism,12 andeven the coexistence13 of tautomeric and conformational poly-morphism. Such rare, unconventional, or unforeseen incidentsopen up new avenues to the observation of the course of crys-tallization, to provide inputs toward synthon evolution throughoutthe crystallization processes and further to reveal the fine balance

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that exists between various entropic and enthalpic factors thatdetermine the crystal structure.The third but in no way least important pillar of crystal

engineering is the logical correlation between the innatemolecular interactions and micro/macro level properties ofmolecular crystals. Mechanical behavior of a molecular crystalis a property that has major implications for large-scaleprocessing and handling of materials in industry. The wholestory of the study of mechanical behavior of crystals in the groupwas initiated by a systematic survey of molecular crystals with4 and 8 Å structures1D vs 2D and 3D; isostructural vspolymorphic; stacked vs interlocked; single component vsmulticomponentto qualitatively assess the intricate connec-tion between intermolecular interactions (a nano/micro levelproperty) with the mechanical phenomenon, such as bending(a macro level property).14 The studies attained a quantitativeapproach when nanoindentation and scratch experiments wereused to correlate mechanical properties of molecular crystals interms of close-packing and interaction anisotropy (saccharin),15

long-range molecular/layer migration in layered compounds(charge-transfer complexes),16 polymorphism, phase stability anddomain coexistence (aspirin polymorphs)17 and desolvationprocesses (sodium saccharin dihydrate).18 The studies thusintroduced to structural chemists techniques such as nano-indentation, which had largely confined to the engineeringcommunity. At this point, it is heartening to quote one of thestatements made by Desiraju in his 2007 review: “Indeed, some ofthe dif f icult questions posed in this review will yield their secrets onlywith the application of sophisticated experimental methods, whichcan make measurements in very small distances and time scales.”19

■ FUTURE OUTLOOKBeing a relatively young field, crystal engineering has undergonedrastic changes in its outlook and acceptability across the spec-trum of research. Contributions and revolutionary pathwaysadopted by many giants shaped and directed this subject. Theemergence of this field can be attributed more to crystal-clearthinking and logical deductions than to messy theoreticalderivations. Because of its versatile outlook and the closeassociation of the crystal engineering community with differentscientific disciplines over the years, the subject has matured asa horizontal, rather than a vertical, discipline. This holistic viewfurther enhanced the wider acceptance of the subject in thescientific arena and enabled its inclusion into the academiccurricula of various institutions. The recent textbook on crystalengineering,20 authored by Desiraju, Vittal and Ramanan,highlights the importance of the topic, and the successfulcommencement of Gordon Research Conference on crystalengineering, the first of them chaired by Desiraju, furtherunderscores its recognition.The research group has made significant contributions to

various aspects of crystal engineering, which enriched this area ofresearch over these years. Terms such as weak interactions andsupramolecular synthons are more often than not intertwinedwith the name of Desiraju. If one analyzes the research outputof the group, the diversity in it is fabulous. This diversity in theresearch and the thought processes make this group unique.Rather than being monotonous reports of crystal structures, thestudies involve a deep understanding of the structure−functionrelationship and are highly updated with recent trends. This isachieved in the group by closely following the literature and bypromoting comprehensive inter-/intragroup discussions. A newera of design of complex structures and structure−property

evaluation is inevitably upon us. The group is also gearing up toface the new challenges and opportunities, under the electrifyingleadership and stimulating guidance of Prof. Gautam R. Desiraju.

■ PUBLICATIONSOver 350 publications that emanated from the group have playeda major role in fostering the field of crystal engineering. Availablereviews can sometimes hint at the pace with which a particularsubject is developing and it is true for crystal engineering as well.Being knowledge database, such reviews are good value additionsto the regular articles. If one sees the publication pattern ofDesiraju, it is interesting to note that the number of reviewsavailable with respect to his original research articles is quite high.Interestingly, only a few of them are comprehensive literaturesurveys; most of them are compilations of ideas and viewpointsand hence can provide the deepest of insights to researchersworking in this field. These reviews are in fact a feast that can bedevoured, enjoyed, and celebrated. His vision and outlookregarding the future of the subject are always reflected in hisreviews, and hence they will stand the test of time. His threebooks on crystal engineering, together with the three editedmultiauthored books, are some of the best referred works in thefield.

■ GROUP AND COLLABORATIONSThe group comprises students from across the nation, fromnorth to south and east to west, bringing together the essenceand culture of the entire nation. The association of overseaspostdoctoral students with the group, in regular intervals, makesit 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 expertisewithin the institute, the collaboration is restricted to in-house.

■ AUTHOR INFORMATIONCorresponding 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 DrugResearch Institute, Lucknow−226 001, India.NotesThe 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 StructuralChemistry 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.

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(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. GrowthDes. 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: AText Book; World Scientific: Singapore, 2011.

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