Angew Chem Int Ed_Crystal Engg_A Holistic View_Desiraju_2007

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ReviewsSupramolecular Chemistry

G. R. Desiraju

DOI: 10.1002/anie.200700534

Crystal Engineering: A Holistic ViewGautam R. Desiraju*

Keywords: crystal engineering hydrogen bonds intermolecular interactions polymorphism supramolecular chemistry


Chemie 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2007, 46, 8342 8356



Crystal engineering, the design of molecular solids, is the synthesis offunctional solid-state structures from neutral or ionic building blocks, using intermolecular interactions in the design strategy. Hydrogen bonds, coordination bonds, and other less directed interactions define substructural patterns, referred to in the literature as supramolecular synthons and secondary building units. Crystal engineering has considerable overlap with supramolecular chemistry, X-ray crystallography, materials science, and solid-state chemistry and yet it is a distinct discipline in itself. The subject goes beyond the traditional divisions of organic, inorganic, and physical chemistry, and this makes for a very eclectic blend of ideas and techniques. The purpose of this Review is to highlight some current challenges in this rapidly evolving subject. Among the topics discussed are the nature of intermolecular interactions and their role in crystal design, the sometimes diverging perceptions of the geometrical and chemical models for a molecular crystal, the relationship of these models to polymorphism, knowledgebased computational prediction of crystal structures, and efforts at mapping the pathway of the crystallization reaction.

From the Contents1. Introduction 2. Crystal Design and Function 3. Intermolecular Interactions 4. Crystal Packing and Polymorphism. The Holistic Crystal 5. Crystal Structure Prediction (CSP) 6. Crystallization Mechanisms 7. Summary and Outlook 8343 8345 8347


8350 8351 8354

1. IntroductionCrystal engineering is the rational design of functional molecular solids.[1] This subject is of both fundamental and practical interest to solid-state and structural chemists, and also important to those who attempt to design other kinds of organized phases and assemblies. In a broader sense, the concepts of crystal engineering are applicable to any kind of intermolecular assembly, for example, protein-ligand recognition. Crystal engineering is therefore of very wide scope and accordingly, it has brought together investigators from a variety of disciplines. The field has its origins in organic chemistry, more specifically organic solid-state photochemistry,[2] and in physical chemistry, notably studies on the packing of molecular crystals,[3] exemplified respectively by the contributions of G. M. J. Schmidt (19501970) and A. I. Kitaigorodskii (19401980). It gained an identity of sorts by the 1980s, attracting crystallographers, solid-state chemists, theoreticians, and inorganic chemists to its ranks.[46] Today, the subject covers a community of at least 150 independent research groups, with two specialist journalsCrystal Growth and Design from the ACS and CrystEngComm from the RSCand even a dedicated webpage and a Wikipedia site maintained by the latter society. A working definition of crystal engineering, which I supplied in my 1989 book,[1] namely that it is the understanding of intermolecular interactions in the context of crystal packing and in the utilisation of such understanding in the design of new solids with desired physical and chemical properties, seems to have stood the test of time, and the subject today includes three distinct activities, which form a continuous sequence: 1) the study of intermolecular interactions; 2) the study of packing modes, in the context of these interactions and with the aim of defining a design strategy; and 3) the study of crystal properAngew. Chem. Int. Ed. 2007, 46, 8342 8356

ties and their fine-tuning with deliberate variations in the packing. In effect, these three stages represent the what, how, and why of crystal engineering. With so many researchers approaching the subject from various independent and attractive viewpoints, individual opinions on what crystal engineering is and what it can do are bound to differ.[726] Arguably, these differences have to do with style and taste. Fundamentally, however, there are two aspects of crystal engineering which are above debatethat it is a type of synthesis, and that a molecular crystal lends itself to the supramolecular paradigm. These ideas took root in the 1990s and need to be placed in the context of broader trends in the chemical sciences that occurred during that time.

1.1. Supramolecular Synthesis That a crystal can be viewed as a supramolecular entity follows from Lehns argument that a supermolecule is to the molecule as an intermolecular interaction is to the covalent bond,[27] and it was Dunitz who first expressed this notion explicitlythe crystal is a supermolecule par excellence, and knowledge and control of intermolecular interactions is as vital to crystal synthesis as is control of the covalent bond is to molecular synthesis.[28] The meaning and execution of synthesis in the supramolecular context were a parallel development in the mid-1990s, and three reviews are notable in this context. The first of these by Whitesides and co-workers appeared in early 1995 and explained the difference between

[*] Prof. Dr. G. R. Desiraju School of Chemistry, University of Hyderabad, Hyderabad 500 046 (India) Fax: (+ 91) 40-23010567 E-mail: [email protected] Homepage: ~ grd/

2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim


Reviewscovalent and supramolecular synthesis.[29] The former is enthalpically controlled and products are often kinetic, while in the latter, the energies involved are much smaller and therefore the products reflect a balance between enthalpy and entropy. Implicit in this discussion is that the products are formed in solution in both processes. This is not the case in crystallization, a largely kinetic process, and in the second of these reviews, which appeared in late 1995, I put forward the concept of supramolecular synthons, kinetically defined structural units that ideally express the core features or kernel of a crystal structure, and which encapsulate the essence of the crystal in terms of molecular recognition.[30] The synthon consists of molecular fragments and the supramolecular associations between them, and these associations need not be just hydrogen bonds and other directional interactions. An important, indeed critical, assumption is that the supramolecular synthon is a reasonable approximation to the entire crystal despite the simplification that is inherent in its definition.[31] The third of these reviews, which followed in 1997, is aptly titled Synthetic Supramolecular Chemistry and in it, the authors Fyfe and Stoddart discuss processes both in solution and involving crystallization.[32] While Whitesides and Stoddart generally considered zero-dimensional supramolecular objects as synthetic targets, my review focused exclusively on the crystal, which is a three-dimensional object. Attacking either of these types of target (zero-dimensional or higher-dimensional) has its own attractions and difficulties. Since the rest of this review will deal with crystals, it is not out of place to mention now the elegant strategies proposed for zero-dimensional supramolecular targets by Fujita,[33, 34] Stang,[35] Raymond,[36] Mirkin,[37] and Stoddart,[38] to name a few. In these cases, entropic considerations are of the greatest importance, and the supermolecule exists in solution before it gives a crystal, a necessary prerequisite perhaps for structural characterization, but crystallization is not implicated as a synthetic step.

G. R. Desiraju

1.2. Simplifying the Problem But what of the crystal? When one claims that a crystal is a supramolecular entity, one is admitting ipso facto that it is not possible to predict or directly anticipate the structure of aGautam R. Desiraju (born 1952, Madras, India; PhD, University of Illinois, 1976) has been associated, for over two decades, with the subject of crystal engineering and structural aspects of the hydrogen bond and other intermolecular interactions. He has authored two definitive books (Crystal Engineering: The Design of Organic Solids and The Weak Hydrogen Bond in Structural Chemistry and Biology) and is the recipient of several awards and recognitions including the Alexander von Humboldt Forschungspreis (2000) and the Third World Academy of Sciences Award in Chemistry (2000). He is a member of the editorial advisory boards of Chemistry An Asian Journal, Crystal Growth & Design, and CrystEngComm.

crystal from the structure of the constituent isolated molecule. The essence of supramolecular chemistry is that the structure and properties of the higher-level entities (supermolecules, crystals) cannot be predicted directly or immediately from those of the lower-level entities (molecules). Crystals represent a higher level of complexity than molecules, and crystal structure is accordingly an emergent property with crystallization being a supramolecular reaction.[39] The main aim of crystal engineering is to construct crystal structures from molecular structures. This is the synthetic step, and it is not straightforward because of the emergent nature of the crystal structure. To develop a synthetic strategy, a retrosynthetic step is invoked which effectively simplifies the crystal structure to a smaller unit called the synthon. Let us consider a molecule to consist of several functionalities or functional groups (F1, F2, Fn) and during crystallization, these functionalities come together through a process of molecular recognition uti