Building upon Supramolecular Synthons: Some Aspects of Crystal

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Building upon Supramolecular Synthons: Some Aspects of Crystal Engineering Arijit Mukherjee* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India Division of Molecular Imaging and Photonics, Department of Chemistry, KU Leuven, Celestijnenlaan 200 F, B-3001 Leuven, Belgium ABSTRACT: It has been 20 years since the concept of supramolecular synthon was introduced with the purpose of rational supramolecular synthesis. While this concept has been greatly successful in employing a retrosynthetic approach in crystal engineering, the past few years have seen a continuous evolution of supramolecular synthons from being a synthetic subunit to a basic unit for understanding the dynamics of crystallization. This review attempts to give a glimpse of such developments.

rystal engineering is defined as “the understanding of intermolecular interactions in the context of crystal packing and in the utilization of such understanding in the design of new solids with desired physical and chemical properties”.1 If crystals are supramolecular equivalents of molecules, crystal engineering is a supramolecular equivalent of organic synthesis. In this sense, the aim in crystal engineering is to correlate molecular structures with crystal structures. However, finding an empirical model to establish such correlation was difficult. Despite some remarkable efforts made in early 1970s2 (mainly by changing molecular substitution and observing the effect in resulting crystal structures), a general model was absent. Crystallization, which is often considered as a supramolecular reaction, follows the Curtin−Hammet principle which states that the population of the final products is largely dictated by the energy barrier of formation rather than relative enthalpic differences (Figure 5).3 Hence, it is more likely to observe kinetic (metastable) products instead of the thermodynamic one in any crystallization. Therefore, any model based completely on close packing (geometrical model), as proposed by Kitaigorodskii,4 would fail to propose a realistic structure in most cases. Adopting a model completely based on the interaction hierarchy (i.e., chemical model) is also not viable as close packing forces usually play a deciding role in the final stages of crystallization. In reality, many structures are dictated by both chemical as well as geometrical models in a complex convoluted way. This could be a reason why crystal structures are most often considered as emergent properties (lacking a direct correlation with the functional groups present in the respective molecular structures).5 To be more precise, understanding this dichotomy between geometrical and chemical models in the formation of crystal structures constitutes the central problem of crystal engineering.

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To this end, and to predict crystal structures from molecular structures, a model was required that took into account the components of both the geometrical and the chemical models. In this context, and drawing an analogy with the synthon from molecular chemistry, the concept of the supramolecular synthon was introduced. “Supramolecular synthons are structural units within supermolecules which can be formed and/or assembled by known or conceivable synthetic operations involving intermolecular interactions.”6 In a direct sense, the concept of supramolecular synthons exemplifies a retrosynthetic approach to supramolecular chemistry where one can break the crystal structures into supramolecular synthons, and based on their relative abundance in the database, new design strategies can be formulated. In this manner, synthons are also probabilistic in nature. Supramolecular synthons are representative of spatial arrangements of intermolecular interactions, and in this regard, they take both chemical and geometrical factors into account. More tellingly, this approach, as opposed to all other approaches in the past, considers a convergent way of analyzing crystal structures. Therefore, when one starts with a crystal structure and deconstructs it to the smallest nonreducible unit, i.e., synthon, both geometrical and chemical factors get deconstructed, and it is here where synthons score over individual molecules (or functional groups) in terms of consistency and robustness. Therefore, it must be noted that the similarity between a synthon and the entire crystal structure decides the utility of the whole concept. An astute example that shows how this concept can be used in crystal synthesis is demonstrated by taking a few crystal Received: February 17, 2015 Published: May 12, 2015 3076

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Figure 1. Some of the synthons that are discussed in this review: Top (from left to right): carboxylic acid dimer, acid−pyridine, phenol−pyridine, phenol−carboxylic acid; bottom: phenol−aniline tetramer, nitro−iodo, chloro−chloro type I, and chloro−chloro type II synthons.

Figure 2. A schematic showing synthon identification, retrosynthetic analysis, and subsequent application in crystal design by taking two very popular synthons in crystal engineering: hydrogen bonded carboxyl dimer (homosynthon) and halogen bonded iodo···nitro synthon (heterosynthon).

participates in the formation of a cocrystal is called as a coformer). To identify the synthons that are responsible for such organization between different molecular species, the terms homosynthon and heterosynthon were introduced. Heterosynthons that signify recognition between different functionalities play a crucial role in cocrystal synthesis.7 Synthesis of cocrystals is usually a difficult task as crystallization is often considered as a purification technique producing crystals of single molecules. Therefore, it is only possible to successfully synthesize a cocrystal when the formation of heterosynthons is energetically favorable compared to that of homosynthons. Many design strategies were formulated during this period to overcome this challenge.8 A successful design strategy is usually based upon robust heterosynthons and their mutual insulation. This insulation among the synthons was successfully employed in the design of ternary cocrystals based on the relative pKa values of the individual coformers.9 However, the legal and industrial importance of cocrystals was realized in practice through the synthesis of pharmaceutical cocrystals.7,10 Pharmaceutical cocrystals are usually designed by taking suitable coformers (GRAS molecules) with active pharmaceutical ingredients (API). All this helped crystal

structures having I···NO2 and carboxyl dimer synthons as shown in Figure 2. Naturally enough, as the concept of supramolecular synthon was introduced with the objective of reducing the complexity and enhancing the predictability of supramolecular synthesis, research in the first decade after introduction of this concept was focused mainly on two points: (a) identification of synthons and (b) formulation of design strategies by using the robust synthons. Although the ultimate goal of crystal engineering is to design desired new materials in a logical manner, identification of robust synthons and understanding their hierarchy were prerequisites for that exercise. After identification, synthons are used in designing supramolecular networks based on their robustness and transferability. However, synthon transferability often suffers from the presence of multiple functional groups, and insulation among synthons is required to transfer synthons from one structure to another. A major development in this period is reflected in the synthesis of cocrystals based on robust synthons. Cocrystals represent a class of molecular solids that consist of more than one molecule in the lattice (each of the molecules that 3077

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Figure 3. (a) The three forms in the cocrystal system of 4-hydroxybenzoic acid/4,4′-bipyridine show different combinations of the four possible synthons. (b) The Form I of the synthon polymorphs of 4-hydroxybenzoic acid/4,4′-bipyridine system shows the mutual insertion of the native structures of the coformers into each other.

progressively shifted from synthesis to much deeper issues concerning the mystery of crystallization itself. It was realized over the years that synthons can also be considered as the basic structural units that carry over kinetic information from the molecular to the supramolecular level, and thus the detection of synthons and their mutual dynamics may shed light on the crystallization mechanism. The occurrence of higher Z′ structures points toward this direction, and these structures were correctly referred as “fossil relics” or “crystallization snapshots”.18 Having tried to place crystal engineering research based on the concept of supramolecular synthon after the first decade of its introduction into a personal perspective, I would now like to present some of the fascinating current research in the second phase. As the great volume of exciting research has been done in this area in the past few years, it may be difficult, if not impossible, to cover all of the developments in the given length of this review. Therefore, this review will concentrate only on some of the key concepts (by taking only a few representative examples) that are built upon the concept of supramolecular synthons.

engineering of molecular solids to be more relevant in the pharmaceutical industry by integrating legal issues with scientific aspects. It has been shown in several studies that many pharmaceutical cocrystals have better physiochemical properties (e.g., solubility, bioavailability) compared to the native APIs. Research in this field is still very active, and significant variations have been shown in the design of cocrystals in recent times.11 Apart from synthesis, the concept of supramolecular synthons also proved helpful when integrated with the crystal structure prediction (CSP) protocol.12 CSP is a computational exercise that generates multiple crystal structures within a reasonable energy and density range for a given molecule. However, the calculation and ranking in almost every CSP protocol hint only about the relative enthalpies of the systems. The kinetic factors that affect the crystallization outcome in a profound way are very difficult to interpret only from CSP results. As synthons are implicitly contained with such kinetic information, they can be integrated with the CSP protocol to find the most probable structure of the respective compound in a more reliable way. Once the utility of the synthon concept was realized, especially in the form of strong synthons, considerable efforts were made to the discovery and understanding of weaker synthons, especially halogen bonded synthons. Noncovalent interactions with halogens were identified many years ago by Hassel,13 but proper understanding of its supramolecular role and subsequent exploitation as a synthon in crystal engineering were achieved only in the late 1990s.14 Apart from halogen bonding synthons, many excellent studies were carried out to understand the role of other weaker synthons. Notable among them are C−H···O and C−H···F.15 These synthons, however weak, were applied in several design strategies.16 Therefore, this period that immediately succeeded the introduction of the concept and spanned almost a decade saw the development of the concept mainly on the synthetic front. Pharmaceutical cocrystals highlighted the possibility of utilizing the concept in a practical perspective, and a few efforts were made to design functional materials.17 With most of the robust synthons being identified and subsequently applied to the design of new crystalline materials, the role of supramolecular synthons in crystal engineering

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SYNTHON POLYMORPHISM IN COCRYSTALS: TOWARD THE CONCEPT OF A LANDSCAPE Although the frequency of polymorphism in cocrystals is comparable with that of single components,19 it usually arises from packing or conformational differences rather than from difference in synthons. Synthon polymorphism in cocrystals,20 where the origin of polymorphism lies in the difference in synthons, is very rare and is observed only when there is a competition among the functional groups and/or when the dichotomy between geometrical and chemical factors dictates the crystallization. One such case of synthon polymorphism was observed in the 1:2 cocrystal of 4,4′-bipyridine and 4hydroxybenzoic acid.20b First of all, the choice of coformers in this particular system restricts the possible synthon choices to four as shown in Figure 3a. The two synthon polymorphs which are also concomitant in certain solvents (such as MeOH and isopropanol) sustain through different synthon combinations. Form I, which is the thermodynamic form, is formed by the combination of acid−acid dimer and phenol−pyridine 3078

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Figure 4. Crystallization profile of 6-amino-2-phenylsulphonylimino-1,2-dihydropyridine: This compound crystallizes in three forms. Two of them show the presence of catemer synthon (however, only the form I is shown here to represent catemers), while the other form sustains through a dimer synthon. However, chemical perturbation (such as o-Cl vs p-Cl substitution) can be used as a tool to obtain structures with a particular synthon preference.

Figure 5. (a) Pathways of crystallization. There can be many kinetic pathways of a given crystallization. Structural landscape can be used to exploit these kinetic possibilities. (b) The genotype-phenotype approach can be useful both in the understanding of kinetic pathways and designing new structures.

synthon, whereas form II, a kinetic form, sustains by the combination of acid−pyridine and phenol−acid synthon. A more detailed structural analysis of the thermodynamic form reveals that the packing of this form can be described as mutual insertion of the native crystal structures of the coformers (whereas in the kinetic form, this feature is only partial) as shown in Figure 3b. This mutual relationship is indicative of the importance of close-packing, and observing such a dominance of close packing in a strongly hydrogen bonded system like this highlights its importance in the later stages of crystallization. Moreover, this example ensures that dichotomy between geometrical and chemical factors is prevalent in almost every crystallization event. It may also be possible that the basis of chemical model sometimes originates from the geometrical model. Along with these two synthon polymorphs, a pseudo polymorph (Form III) was also obtained by crystallization in DMSO that adopts a different combination of synthons, namely, acid−pyridine and phenol−pyridine synthons in its crystal structure. Taken all these forms together, it can be assumed that all the four synthons (that are possible with the choice of coformers) may be present in the solution, and it may

need only slight perturbations such as variation in solvent or other experimental conditions to realize a particular synthon combination in the observed crystal structure. This invokes the idea of a landscape. The idea of the structural landscape reflects a holistic approach that sheds more importance on the idea of a structure than the structure for a particular molecule. Therefore, not only higher Z′ structures, but every structure, within the scope of the idea of a landscape, may be considered as a crystallization snapshot. It is only possible to get a glimpse of crystallization pathways while all the structures are analyzed from such holistic viewpoint.21 This idea of looking at a crystal structure as a part of a pool of crystal forms leads to the concept of structural landscape.

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STRUCTURAL LANDSCAPE: THE DICHOTOMY ILLUSTRATED Crystals are often considered as just static three-dimensional objects. As shown already in the previous example of synthon polymorphism, it is, however, conceptually useful to consider them as parts of a profile (similar to the concept of an energy landscape).22 With the advent of high throughput crystallography, it is possible now to extend such an idea of crystal energy 3079

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Figure 6. (a) Top: Two hydrogen bonded modules (shown in blue and red) that are connected by Cl···Cl halogen bonds (green) form an LSAM (purple) in the structure of 3,4,5-trichlorophenol. Blindness is observed between the two modules (the propagation of two modules is shown by the arrows in respective colors. (b) The interpretation of the crystal structure of 3,4,5-trichlorophenol in terms of an LSAM.

the five forms indicating evolution of the landscape from the probabilistic nature of synthons. The difference at the secondary level of these structures is a clear indication of the role of close packing of primary synthons only in the final stages of crystallization. If the whole landscape, particularly for this example, can be visualized as an energy versus density map, the primary synthons (such as tetramers vs catemers) may be correlated with vertical profiling of the landscape with significant energy differences, while the secondary synthons can be matched with a horizontal profile where the differences arise mainly from the density of close packing rather than relative energies (Figure 5). Apart from using cocrystallization experiments as perturbations to explore a landscape, the landscape of cocrystals can also be accessed.27 Such landscapes may contain some of the features of the individual landscapes. Moreover, as cocrystals are usually formed based on predictable heterosynthons between two different molecules, landscapes of cocrystals are likely to be more informative about secondary synthons. Recently, such an exercise has been performed by adopting a combinatorial approach. In this approach, six 4-substituted benzoic acids were cocrystallized with six 4-substituted pyridines forming a matrix.28 This matrix, while analyzed as a whole, is representative of the global features and provides justification for the pKa rule. On the other hand, each row and each column of this matrix reflect several local features such as topological similarity, the propensity of hydration, and synthon competition among others. For example, while one analyzes the row of 4cyanopyridine cocrystals in detail, the tetrameric primary synthon module can be taken as the genotype, while 4substituents to the benzoic acid and pyridine rings that are mainly responsible to determine higher order synthons play second fiddle and can be called phenotypes (Figure 5b). Once the genotype is fixed, the secondary association can be controlled by changing the phenotypes. These genotype−phenotype associations of synthons can be particularly useful when multiple functional groups are present in the system and determining the final outcome is difficult.

landscape in the domain of experimental crystal structures by minor chemical perturbations. These experimentally accessible structural profiles, which in brief map (or can provide insights about) different stages of crystallization, are called structural landscapes.23 A twodimensional projection of such landscapes is shown in Figure 5. As supramolecular synthons are kinetic subunits, they can be used as tools to analyze such landscapes to understand different evolutionary pathways and to find a mutual relationship between various forms or by transferring the features from one landscape to another.24 The importance of the structural landscape in relation with the synthons can easily be realized if one considers polymorphic systems. Polymorphism, which is often considered as the “nemesis” of crystal design, can be understood better with the concept of the landscape because this concept lends a way to study structures with small chemical perturbations. This aspect of a landscape can be illustrated by the crystallization profile of 6-amino-2-phenylsulphonylimino-1,2-dihydropyridine (Figure 4). It was shown with the aid of chemical substitution that the synthons, catemer, and dimer synthons belong to the same landscape.25 Cocrystallization (apart from its synthetic value) can be helpful to explore the structural landscape of a particular compound. Such an exercise was performed with orcinol, 5methyl-1,3-dihydroxybenzene, that can exist in three different conformations: syn-syn, anti-anti, and syn-anti.23a The three conformations are very close in energy, and the higher Z′-form (Z′ = 8) which shows the presence of all three conformers in one crystal structure confirms the same. Orcinol, while cocrystallized with aromatic N-bases, showed diverse synthon possibilities. This is indicative of multiple kinetic pathways for crystallization. However, cocrystals with bi-N-acceptors showed specific conformation preference (syn-syn) indicating less variability in crystallization mechanism. Notable among them is the cocrystal of orcinol and 4,4′-bipyridine. Although two forms with very distinct synthon choices were identified for this crystal at first, a later study showed the presence of three more additional forms.26 The system sustains through a robust and modular phenolic OH···Npyridine primary synthon in four among 3080

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Figure 7. (a) An LSAM is formed by combining an amine-phenol tetrameric hydrogen bonded synthon with the antiparallel π···π stacking synthon between two trichlorophenol rings. (b) Halogen bond is used as structural glue to bind the LSAMs. (c) A pictorial depiction of the dissociation of the octamer LSAMs into the tetramers as demonstrated by NMR spectroscopy.

Therefore, with modular primary synthons, the phenotype organization may result in topological similarity between two completely different classes of compounds. This genotype− phenotype organization suggests that synthon concept can be utilized to its fullest in the understanding of crystal structures when it is highly modular in nature. Modularity in itself ensures two important aspects of crystal structure analysis: (1) it restricts the chance of deformability and (2) helps to understand the extent of insulation and hence enhances the chance of tuning the phenotypes and other related secondary features.

complementary modularity is observed in the packing of synthon II. The interactions present in this synthon and their extension into the infinite ladder are similar to what observed in the 3,5-dichlorophenol native structure. The uniqueness of this structure lies not only in the modularity of synthons but also in the complementarities of their organization. In line with the conclusions from an older study30 on the dichlorophenols, this observation may be explained on the basis of the possibility of formation of two different types of strong hydrogen bonded synthons that belong to two completely different structural classes (synthon I belongs to the β-class, whereas synthon II relates more to non-β structural family). Therefore, from the viewpoint of the synthon concept, the crystal structure of 3,4,5-trichlorophenol is nothing but an amalgam of the crystal structures of 4chlorophenol and 3,5-dichlorophenol. This type of direct manifestation of synthon modularity to a structural level is extremely rare and is called as structural modularity. At least two points should be noted from this study, which can be of further interest: (1) As synthon is often considered as a crystallization precursor, it may be assumed that both the synthons are present in solution. In the later stages of crystallization, they may come together with the help of a Cl···Cl halogen bond. (2) This structure can be better described by considering the assembly of I···II as a basic unit rather than the individual synthons (Figure 6b). In this manner, slightly bigger synthons may sometimes carry more information in comparison with the smaller ones. These bigger synthons, which are primarily composites of smaller synthons and rich in information content, are called as long-range synthon Aufbau modules (LSAM). As stated earlier, the success of the synthon concept depends on the similarity between the final structure and the smallest synthons, and therefore the LSAM concept is more useful when the final structure is close to the assembly of the primary synthons rather than the individual primary synthons themselves. As every structure can be interpreted as a network, it may be possible to define a LSAM in every structure, but it may only be possible to employ LSAM concept

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MODULARITY AT ITS EXTREME: STRUCTURAL MODULARITY Modularity is an important component in any design, and synthons are inherently modular in nature. However, the modularity of synthons while expressed at a structural level highly depends on the synthon hierarchy. In the end, as every structure represents an optimization of geometrical and chemical factors, the modularity of individual synthons is often compromised. It is therefore rare for a structure to retain all the individual synthon modularity intact. However, one such case where modular synthons define a structure is observed in the structure of 3,4,5-trichlorophenol.29 The crystal structure of 3,4,5-trichlorophenol is dominated by two primary hydrogen bonded synthons (Figure 6) that are connected to each other by a Cl···Cl short contact. One of the two primary synthons is a discrete tetramer (I), whereas the other one is a tetrameric ladder (II) formed with O−H···O and O···Cl interactions. Discrete tetramers (synthon I) are connected with each other with the aid of Cl···Cl halogen bonds of length of 3.205 Å. More intriguingly, synthon I is reminiscent of the primary synthon observed in the crystal structure of (the β form of) 4chlorophenol. In other words, the assembly of synthon I is almost independent of the role of Cl-atoms in the 3- and 5positions with the 4-chloro substituent playing a similar role as it does in the crystal structure of 4-chlorophenol. Similarly, a 3081

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Figure 8. Crystal structure of 3,4-dichlorophenol is sustained through both type I (light green) and type II (green) halogen···halogen contacts. Insulation among hydrogen bonded and halogen bonded synthons in mutually perpendicular directions result in their plastic bending property.

Moreover, the formation of LSAMs in solution may most often lead to the formation of thermodynamic products that are more robust with less chance of polymorphism. In a recent study, with the aid of solution NMR studies, it has been shown that LSAMs can be detected in solution. It is also recognized that the association of smaller synthons takes place in a sequential manner. From the viewpoint of a landscape, the transferability of structural features within the same landscape or with a related but different landscape is much easier in terms of LSAMs as deformability is less in these bigger modules. It must be mentioned here that LSAMs can also be useful in sorting the structures in synthon-based crystal structure prediction. It has already been shown that the larger synthons can be used as a sorting criterion in reducing the number of probable structures in a CSP protocol.33 This advantage of LSAMs is yet to be explored.

successfully in crystal design, while the synthon components of an LSAM operate in an insulated manner (e.g., in orthogonal directions).

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LSAMS IN CRYSTAL ENGINEERING A deficiency of the synthon concept lies in the fact that most design strategies are based on primary synthons that are mostly zero or one-dimensional in nature. Therefore, complete crystal structures cannot be designed, only basic patterns. This problem can be attributed to the feeble nature of the weaker interactions. It must also be noted that while the individual contribution of these weaker interactions in deciding the final packing is relatively small, the combined effect of these weaker synthons is important. One way to tackle this problem is to consider a combination of synthons following a hierarchy that more or less gives the primary module for the crystallization. The main advantage of LSAMs over smaller supramolecular synthons lies in the fact that they help one to understand a crystal structure in a completely modular way, and as bigger modules are less prone to deformability, the finer details of crystal structures can be controlled in a more precise manner. In this context, in a very recent study, 3,4,5-trichlorophenol was chosen as one of the coformers in crystallization with other halogenated anilines. The aminophenol structural family is known to be versatile in its supramolecular features, and it was shown in the past that among the three types of synthons that are observed (infinite chain, hexamer, and tetramers) in this structural class, tetramers are rare and arise mainly in the presence of dominant steric factors.31 The LSAM-based cocrystal design strategy is focused mainly on these tetramer synthons, and a combination of this synthon with π···π stacking between two trichlorophenol rings results in an LSAM as shown in Figure 7a.32 It has been shown that at least two cell dimensions can be predicted a priori for the designed cocrystal structures. The LSAM found in the cocrystals of 3,4,5trichlorophenol was also found to be robust as it was transferrable to the cocrystals of 2,3,4-trichlorophenol, again with the predictable cell dimensions. Apart from this synthetic point of view, LSAMs are also important from the viewpoint of crystallization mechanism. In this context, LSAM, being a higher order aggregate, appears at the later stages in crystallization and therefore contains more geometric and chemical information than the smaller synthons.

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HALOGEN BONDED SYNTHONS The proliferation of strongly hydrogen bonded synthons in structural design has very often been cited as a deficiency of the concept of supramolecular synthons. However, research in halogen bonded synthons, which stays at the forefront of the crystal engineering research today, stands as an exception. It also serves as an alternative to the hydrogen bonds at least from the perspective of synthesis. The interactions between halogen atoms, X···X (X = Cl, Br, and I), although identified a long time ago, have been appreciated as design elements only much later. However, once recognized,34 these interactions continue to be of significant interest to a crystal engineer, mainly because of their directionality and ability to cover the structural middle ground between strong and weak hydrogen bonds, and also because of the bigger sizes of halogens compared to hydrogen atoms. In recent times, several design strategies have been formulated especially by combining the halogen bonds with the hydrogen bonds in different ways and also by exploiting the graded strength of the halogen bonds that makes them an excellent tool for structural insulation.35 Apart from synthesis and their relevance from the viewpoint of structure and dynamics (which is where the concept of supramolecular synthon is evolving toward) halogen bonded synthons also serve as exceptional tools as they represent the 3082

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solid state. In this context, the employment of infrared techniques by Davey and co-workers in detecting the synthons in solution may stand as a pioneering effort. With the help of FTIR studies in the concentrated solutions of tetrolic acid, this study showed that a direct relationship exists between selfassociation in solution and the synthon patterns in the corresponding crystalline solids.42 Following the same line and integrating Raman with IR, ter Horst and co-workers later showed that the polymorphism in isonicotinamide can be linked with the variation of solvents and hydrogen bonding in solution kinetically drives the nucleation toward a specific form with particular synthons.43 These results are indicative of the significance of synthons even in the early stages of crystallization. In conjunction with IR, other techniques (such as NMR) are also used successfully to depict the synthon patterns in solution.32 In a very recent study, the presence of LSAMs in solution is shown with the aid of NMR experiments. The NMR studies which were performed in solution with varying dilution showed that the LSAMs dissociate in a manner that is consistent with the synthon hierarchy. Apart from the identification of synthons in solution that deal more with mechanistic features of crystallization and nucleation, different techniques are also employed in the solid state to get the synthon patterns especially in the bulk powder or in cases where getting a single crystal structure seems formidable. Two-dimensional heteronuclear magic-angle spinning (MAS) NMR was used to identify COOH···Narom and C−Harom···OC synthons in the indomethacin−nicotinamide cocrystal.44 A four-step method has been introduced very recently to identify multiple synthons in a powder mixture with the help of nonoverlapping IR spectral features.45 A drawback in the synthon concept is that it is qualitative in nature. Although the qualitative nature of this concept makes it convenient for practical use, it needs parallel developments for the quantitative analysis of synthons. A quantitative understanding of the hierarchy of synthons can help the crystal engineers to explore the concept of synthons in more detail. In this line, Dunitz and Gavezzoti have recently studied the cohesive energies and thermal stabilities of molecular systems pertaining to some popular synthons.46 This study provides insights into the absolute and relative strength of the synthons. In this manner, on one hand, it relates the energetics of a crystal structure to the concept of synthons, and on the other, it paves a way for a better understanding of synthon hierarchy. Shishkin and co-workers, with the help of energy vectors and constructing basic structural motif (BSM), have highlighted this issue in more detail.47 As supramolecular synthons capture the geometric and chemical features of a particular group of interactions, it is likely that the BSMs may be considered as being constructed by supramolecular synthons. Studying a set of crystal structures, Shishkin and co-workers concluded that while primary synthons are important in terms of primary recognition, secondary synthons may actually determine the organization. Understanding the energetics of supramolecular synthons may help one to understand that each type of synthon plays a crucial role at different levels of aggregation, and hence, energetically, the organization through supramolecular synthons occurs in a stepwise manner. Parallel to these developments, synthon-based fragments approach (SBFA) is adopted where the modularity of synthons is used for transferring charge density derived multipolar

dichotomy between chemical and geometrical models in a very distinct way. The two types of contacts, as recognized by Sakurai et al.36 and subsequently named type I and type II halogen···halogen contacts by Desiraju and Parthasarathy,37 actually represent this dichotomy. Type I contacts are formed by “head on” approach of two halogens making it more geometrical, whereas type II contacts, having a “side on approach” geometry that permits the interaction between an electropositive region on one halogen to the electronegative region on the other, qualify as true halogen bonds and are more chemical in nature.35,38 However, one problem that restricts proper distinction between these contacts is related to the fact that halogen··· halogen interactions are often dominated by stronger interactions. One can tackle this problem by choosing systems that have halogen bonds placed in the orthogonal directions to the stronger interactions. This gives the required insulation to distinguish between different interactions. In this context, the structure of 3,4-dichlorophenol is an ideal case for such a study. The structure of 3,4-dichlorophenol is one of the rare ones where the hydrogen bonding operates in a perfectly orthogonal direction to the halogen contacts, and both the type I and type II contacts are observed in this structure (Figure 8). In a recent study, it has been shown that alternative substitutions of −Cl by −Br in the structure of 3,4dichlorophenol produce completely different structures.39 This example shows that the halogen bonding preference for Br is different from Cl. Cl prefers to form type I contacts while Br prefers type II. The structural difference between 3,4dichlorophenol and 4-bromo-3-chlorophenol also gets manifested in their mechanical properties. While 3,4-dichlorophenol shows plastic bending, elastic bending is observed for 4-bromo3-chlorophenol. Such a difference in mechanical response arises from the greater strength of Br···Br halogen bonded synthons compared to that of Cl···Cl. In exploration of the orthogonality to its extreme, an LSAMbased strategy was also adopted where halogen bonding is used to control one cell dimension when the other two are controlled by stronger interactions such as hydrogen bonding and π···π stacking. It was observed that the cell length along which the halogen bonded synthons operate varies within a small range resulting in the synthons that are predictable (Br··· O, I···O, and I···O) (Figure 6b). This example also illustrates that in this manner, in line with the genotype−phenotype approach, if an LSAM itself can be considered as a genotype of the studied structural class, halogen bonds can serve as prospective phenotypes. Parallel to these directions, a significant amount of research has been dedicated to computational developments to understand halogen bonding interactions. New techniques have been employed to provide useful insights into the nature of halogen bonds.40 Other weaker interactions (such as chalcogen bonds or pnicogen bonds) are also being studied.41

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IDENTIFICATION AND RANKING OF SUPRAMOLECULAR SYNTHONS The developments which are already described above deal with the changing role of supramolecular synthons from being a synthetic tool to the basic kinetic unit to understand the crystallization. This evolution of the concept would not have been possible without complementary and significant developments in the search for new experimental techniques that can detect supramolecular synthons both in solution and in the 3083

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Crystal Growth & Design parameters.48 This approach which combines synthon concept with both experimental and theoretical charge density studies awaits further developments in the near future.

ACKNOWLEDGMENTS

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REFERENCES

I thank Dr. Rahul Banerjee for his valuable comments in the preparation of this manuscript.

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CONCLUSIONS Research on supramolecular synthons in the last 20 years has helped the concept to evolve continuously. It may seem to be a mere coincidence, but the titles of the two reviews that appeared with a gap of 41 years, the first by J. M. Robertson49 and the second by G. R. Desiraju,50 carry the signature of this evolution. The title of Robertson’s review in 1972 was “Molecules and Crystals”, whereas part of the title of Desiraju’s in 2013 review says “Molecule to Crystal”, and, at least from my perspective, the transition from and to to in these titles (with the other two words Molecule and Crystal intact, which signify chemistry and crystallography respectively) reflects the phase of intellectual developments in the subject, and the lion’s share of this transition can be credited to the developments in the concept of the supramolecular synthon. From the time of Robertson, when elucidation of a crystal structure was itself a formidable task, the emphasis of the subject has shifted to the building up process keeping supramolecular synthons in focus. By today, a synthon is of mechanistic significance in the whole structural landscape rather than being a mere structural descriptor. In other words, the focus on supramolecular synthons is slowly shifting from synthesis to dynamics. This transition from a reductionist to a fairly holistic viewpoint has managed to create many new possibilities concerning fundamental issues related to crystallization. The advent of high throughput crystallography and employment of other techniques in crystal engineering will enable us to address issues such as synthon evolution in solution or mutual dynamics between various forms more quantitatively.51 This approach which was originally coined to design crystal structures in a predictable manner may also be used as an ideal tool to understand the emergence of complexity. Each topic discussed in this review may only give a glimpse of the new areas that await further exploitation in the near future. To name a few, a combinatorial approach based on a virtual synthon library has recently been used to formulate new design strategies for ternary cocrystals.52 The four-step IR method leads the way of distinguishing small variations in weaker synthons.53 Apart from typical crystal engineering ventures, it would also be interesting to see how the concept can be exploited in the fields that still stay in the outliers of mainstream crystal engineering research. For example, how can the synthon concept be exploited in designing new gel materials?54 How can this concept be utilized in understanding the organization of molecules on the surface?55 The detection of synthons in solution and understanding their mutual dynamics may also be helpful to employ supramolecular synthons in dynamic systems. Therefore, after 20 years of the introduction, the concept of supramolecular synthons offers more versatility than ever before. It would be intriguing to see how the horizon of the supramolecular synthon expands in the coming decade and further.

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Review

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. 3084

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