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 evaluation. 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 engineering community.
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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 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 retrosynthetic approaches provided crystal engineers with a new strategy for the targeted synthesis of assemblies. Being trained as © XXXX American Chemical Society
Photograph courtesy of Sunil Varughese. Copyright 2012.
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.
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INTRODUCTION
In his 1989 book, Desiraju defined the term “Crystal Engineering”.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
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molecular recognition units. This concept, though simple, has far-reaching implications particularly in crystal design and crystal 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 envisioned 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 multicomponent crystals has been known for over 150 years, indeed from the early days of the inception of organic synthesis, noncovalent 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 methods10chemical variations, solid solutions, or multicomponent systemsto 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 polymorphism. Such rare, unconventional, or unforeseen incidents open up new avenues to the observation of the course of crystallization, to provide inputs toward synthon evolution throughout the crystallization processes and further to reveal the fine balance
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.
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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 interactions in terms of their attractive nature, directionality, electrostatic 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 comprehensive 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 approachgenerally applied in covalent synthesisthat 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 B
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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.
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 structures1D vs 2D and 3D; isostructural vs polymorphic; stacked vs interlocked; single component vs multicomponentto qualitatively assess the intricate connection 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 nanoindentation, 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
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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.
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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.
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FUTURE OUTLOOK Being a relatively young field, crystal engineering has undergone drastic changes in its outlook and acceptability across the spectrum 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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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected] (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.
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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. C
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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. 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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