This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Review Cite This: Cryst. Growth Des. 2019, 19, 1426−1453 pubs.acs.org/crystal A Practical Guide to the Design of Molecular Crystals Published as part of a Crystal Growth and Design virtual special issue Honoring Prof. William Jones and His Contributions to Organic Solid-State Chemistry Meriná K. Corpinot and Dejan-Kresimiř Bucař* Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, United Kingdom ABSTRACT: This Tutorial Review, aimed at both the novice and the seasoned solid-state chemist, provides a succinct overview of key findings that have, over the last half century, advanced our ability to make molecular crystals with targeted structures and desired properties. The article critically evaluates the efficiency and reliability of the well-established guidelines used by experimentalists in crystal engineering and highlights statistical and computational tools that are both advantageous to crystal design and accessible to experimental solid-state chemists. The systematic development of our subject will be difficult if the market requires an average investment exceeding 2.6 not impossible until we understand the intermolecular forces billion USD over more than a decade.9 The intensive responsible for the stability of the crystalline lattice of investment demanded by research and development (R&D) organic compounds; a theory of the organic solid state is a activities, and the need to rapidly respond to societal needs in requirement for the eventual control of molecular packing an efficient and environmentally friendly manner, drive current arrangement. Once such a theory exists we shall, in the efforts to minimize the cost, time, and risk associated with such present context of synthetic and mechanistic photochemistry, R&D projects. With this in mind, computational methods have ‘ ’ be able to engineer crystal structures having intermolecular been introduced into R&D to guide the fine-tuning of specialty contact geometry appropriate for chemical reaction, much chemicals.10 as, in other contexts, we shall construct organic conductors, The last three decades have also witnessed remarkable catalysts, etc. In short, any rational development of the advances in computational solid-state chemistry, advances physics and chemistry of the solid state must be based upon underpinned by continuously increasing computational pro- a theory of molecular packing; since the molecules studied cessing power and expanded funding for accessible super- are complex, the theory will most likely be empirical for computers. These advances have enabled the use of materials some time yet. Rules are now becoming available in what I modeling and crystal structure prediction of inorganic Downloaded via UNIV COLLEGE LONDON on February 21, 2019 at 14:10:40 (UTC). regard as phase three, the phase of crystal engineering. materials such as metal oxides11 and zeolites.12 Substantial 1 See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. G. M. J. Schmidt progress has also been made when it comes to the modeling of organic solids: for instance, recent reports describe the use of 1. INTRODUCTION crystal structure prediction and property calculations to accurately describe a range of feasible crystal structures and For centuries, molecular solids have been used as key the accompanying electronic13,14 or host−guest15,16 properties components in medicines,2 fertilizers,3 pesticides,4 inks and of a molecular compound in the solid state. This was paints.5 Their potential to perform as highly functional accomplished within a time frame that is appreciably shorter electronic and optical materials has recently also inspired the 6 than that needed to synthesize, characterize and test the solid- development of crystalline molecular semiconductors and 16 optoelectronics.7 The transformation of specialty chemicals state properties of the very same molecule. Given such into fit-for-purpose crystalline solids is a lengthy and expensive achievements, as well as the predictive accuracy and speed of process, one which, unfortunately, often fails to generate a the computational methods which are beginning to shape our marketable product due to a multitude of unfulfilled perform- pursuit of functional materials, it is reasonable to expect that ance and safety requirements (many of which are associated such predictive methods will soon become a cornerstone of with the solid-state properties of the target compound). The materials science. risky nature of such endeavors is best appreciated by considering the drug attrition rates in the pharmaceutical Received: June 26, 2018 industry,8 where the placement of an FDA-approved drug onto Published: December 6, 2018 © 2018 American Chemical Society 1426 DOI: 10.1021/acs.cgd.8b00972 Cryst. Growth Des. 2019, 19, 1426−1453 Crystal Growth & Design Review − This is particularly true of crystal engineering,1,17 23 a field concepts, theories, and ideas discussed herein and feel that deals with the design, synthesis, and use of molecular and encouraged to further develop the same. Although the field metal−organic crystals.24 This branch of solid-state chemistry has advanced significantly in the last two decades, the initial is primarily concerned with the synthesis of targeted solid-state goal of crystal engineersnamely, the development of a full structures that have desired properties, through an under- understanding of the intermolecular interactions that control standing and control of intermolecular interactions in the the structure and function of molecular crystals18is still crystal.19 Surprisingly, crystal engineering endeavors (at least unfulfilled. Considering that the focus in crystal engineering those pursued in academic circles) rarely involve the has progressively shifted from structure to function,41,42 it is manipulation of particle properties such as morphology, vital to reiterate Schmidt’s message from the epigraph to this particle size, and particle-size distribution, although such review: “the systematic development of our subject will be approaches meaningfully alter physicochemical solid-state difficult if not impossible until we understand the intermo- − properties of organic molecules.25 28 The crystal engineer’s lecular forces responsible for the stability of the crystalline aspiration to design materials with absolute meticulousness is lattice of organic compounds”.1 Such systematic advancement challenged by the fact that trivial changes to the molecular of crystal engineering can only be achieved through the structures (e.g., a H/F atom exchange) regularly result in continuous refinement of extant models, the construction of significantly and unpredictably altered crystal packing,29,30 entirely new models as necessary, and, crucially, rigorous while more profound changes (e.g., addition of hydrogen- testing of these models via well-crafted experiments. We bonding groups) might even affect the dimensionality and therefore hope that this review will prompt the practicing solid- topology of supramolecular solid-state structures.31,32 It is state chemist to rethink current crystal engineering practices therefore important that crystal engineers and solid-state and to consider the implementation of emerging predictive chemists develop design guidelines that are as practical and methods43 into their research programs to develop and test reliable as the synthetic blueprints that organic synthetic new theories. With this Tutorial Review, we also intend to chemists developed throughout the last century.33 complement other recent works along similar lines,44,45 by The crystal engineer and experimental organic solid-state providing a more holistic view of the topic at hand (rather than chemist generally resort to “predictive” guidelines that are focusing on particular aspects, such as the synthon approach) mainly derived from crystallographic studies, extensive surveys and by emphasizing promising statistical and computational of databases (such as the Cambridge Structural Database;34,35 tools for the design of molecular crystals that are easily 24 CSD), and other empirical data. While such guidelines are accessible to experimental solid-state chemists. useful when making alterations of the supramolecular patterns The reader should keep in mind that the scope of this review in a molecular crystal, their use does not permit the is limited to the design of crystals exclusively comprised of preparation of solids with targeted crystal structures, molecular entities (i.e., metal−organic crystals are excluded) particularly when molecules with a diverse range of functional and that the design principles and guidelines featured here are groups are involved. Nevertheless, such controlled changes to those that the authors regard as most relevant, established, and crystal structures based on these guidelines have been used to reliable. The nonspecialist is also referred to articles by 46 47 modulate (and often improve) the properties of a wide range Aitipamula et al. and Lusi for definitions of various types of of specialty chemicals that are central to modern living (e.g., multicomponent molecular crystals that will be discussed drug molecules,36 nutraceuticals,37 semiconductors,38 energetic herein. compounds39). There are thus numerous real-world examples that demonstrate the utility of crystal engineering