Mechanical Properties of Organic Solids - ACS Publications

Article Cite This: Acc. Chem. Res. XXXX, XXX, XXX−XXX

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From Molecules to Interactions to Crystal Engineering: Mechanical Properties of Organic Solids Subhankar Saha,†,‡ Manish Kumar Mishra,§ C. Malla Reddy,*,‡ and Gautam R. Desiraju*,† †

Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur Campus, Mohanpur 741 246, India § Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 9-127B Weaver-Densford Hall, 308 Harvard Street S.E., Minneapolis, Minnesota 55455, United States Acc. Chem. Res. Downloaded from pubs.acs.org by UNIV OF TEXAS AT EL PASO on 10/23/18. For personal use only.

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CONSPECTUS: Mechanical properties of organic molecular crystals have been noted and studied over the years but the complexity of the subject and its relationship with diverse fields such as mechanochemistry, phase transformations, polymorphism, and chemical, mechanical, and materials engineering have slowed understanding. Any such understanding also needs conceptual advancessophisticated instrumentation, computational modeling, and chemical insightlack of such synergy has surely hindered progress in this important field. This Account describes our efforts at focusing down into this interesting subject from the viewpoint of crystal engineering, which is the synthesis and design of functional molecular solids. Mechanical properties of soft molecular crystals imply molecular movement within the solid; the type of property depends on the likelihood of such movement in relation to the applied stress, including the ability of molecules to restore themselves to their original positions when the stress is removed. Therefore, one is interested in properties such as elasticity, plasticity, and brittleness, which are linked to structural anisotropy and the degree to which a structure veers toward isotropic character. However, these matters are still by no means settled and are system dependent. While elasticity and brittleness are probably displayed by all molecular solids, the window of plasticity is perhaps the one that is most amenable to crystal engineering strategies and methods. In all this, one needs to note that mechanical properties have a kinetic component: a crystal that is elastic under slow stress application may become plastic or brittle if the same stress is applied quickly. In this context, nanoindentation studies have shown themselves to be of invaluable importance in understanding structural anisotropy. Several problems in solid state chemistry, including classical ones, such as the melting point alternation in aliphatic straight chain dicarboxylic acids and hardness modulation in solid solutions, have been understood more clearly with this technique. The way may even be open to picoindentation studies and the observation of molecular level movements. As in all types of crystal engineering, an understanding of the intermolecular interactions can lead to property oriented crystal design, and we present examples where complex properties may be deliberately turned on or off in organic crystals: one essentially fine-tunes the degree of isotropy/anisotropy by modulating interactions such as hydrogen bonding, halogen bonding, π···π interactions, and C−H···π interactions. The field is now wide open as is attested by the activities of several research groups working in the area. It is set to take off into the domains of smart materials, soft crystals, and superelasticity and a full understanding of solid state reactivity.

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INTRODUCTION Mechanical properties of molecular crystals have long been known,1,2 but systematic studies might have been rendered difficult by the low melting points and softness of these substances. Co-grinding as a means of making multicomponent molecular crystals takes its inspiration from earlier works on industrial ball-milling of mixtures.3,4 Plasticity is important in tablet making of bulk drugs, but the methodology used has been empirical.5 There is a pressing need for sustainable solutions through molecular level understanding of crystal properties. Mechanical properties are surely linked to molecular movement under external stimulus. The simple topochemical argument for solid-state reactions is countered by the fact that all such reactions require some molecular movement.6 In fact, © XXXX American Chemical Society

many of them require gross molecular movements. Likewise, plasticity, elasticity, and brittleness must involve some molecular movement and migration. Other phenomena such as “curved” crystals, “jumping crystals”, and photosalience and thermosalience are of an older vintage, but again molecular movement is a must.7,8 This is a personal Account of the work conducted, over 15 years, on mechanical properties of molecular crystals in the research group of G.R.D., in the University of Hyderabad (with C.M.R.) and in the Indian Institute of Science, Bangalore (with M.K.M., S.S.). G.R.D.’s first encounter with this subject occurred back in 1989 when he noted that 4-chlorobenzoniReceived: August 24, 2018

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DOI: 10.1021/acs.accounts.8b00425 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

Figure 1. Categories of soft organic crystals.

reversible (elastic) deformations (Figure 1) in one or more directions. Other external stimuli like heat and light may lead to thermosalience and photosalience, respectively.7,8 The recently observed superelasticity (ferroelasticity) in organic crystals, as in shape memory alloys, is an example of reversible plastic deformation, accompanied by phase or gross domain transformation under applied load.14

trile exists as at least two polymorphs and that crystals of one of these exhibited a variety of curved habits.9 Informal inquiries with colleagues revealed that many of them had made similar observation but had not pursued the matter further, because the crystals were “not good”, a not atypical reaction in those days! C.M.R., as a Ph.D. student, made similar observations, namely, unusual curved faces in hexachlorobenzene much later in 2003.10 He noted that these crystals could be plastically deformed easily with a needle. He did not ignore his observation. Thus, we began our excursion into the area of soft crystals.11−13 Other groups got involved into what is now a very active field of research.14−16

Shearing Crystals

In 1,3,5-trichloro-2,4,6-triiodobenzene (1), planar layers mediated by directional I···I halogen bonds (Figure 2a)17 are close packed (Figure 2b). External shear parallel to the layers results in gross molecular movement (Figure 2c). The resulting I3 synthon is robust enough to generate isomorphous structures, e.g., with exchange of Cl by Me and Br. For shearing, the intralayer interactions need not be disrupted (Figure 2d). Nonspecificity of interlayer interactions can lead to boomerang-shaped twinned crystals (Figure 2e−g)! The presence of a layered crystal structure is, however, not a sufficient condition for shearing to occur.

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QUALITATIVE ANALYSIS OF MECHANICAL BEHAVIOR: UNDERSTANDING STRUCTURE−PROPERTY RELATIONS Elasticity, plasticity, and brittleness in solids depend on their intrinsic nature and the rate at which the load is applied.10−13 Most organic crystals are brittle with negligible regions of elastic and plastic response. In some cases, elastic and plastic regions occupy a broad enough range of applied stress to make visual observations possible. So, crystals can be divided into two categories, compliant and brittle. The former may be classified as showing irreversible (bending and shearing) and

Plastic Crystals

Plastically bent crystals seem to defy the traditional picture of rigid molecules in an invariant crystalline matrix, at best undergoing short-range movements. It is nontrivial to propose B


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(white regions between stacks) act as facile slip planes (Figure 3c). The expected change in interfacial angles is seen in Figure 3c (dotted lines). C.M.R. further continued the work on 2 toward experimental validation of our bending model.19 Very thick needles may also bend, showing that crystal habit does not determine the extent of plasticity.18 A brittle crystal may become compliant at higher temperatures, and meaningful comparisons between, e.g., isomorphous crystals, are best made at equivalent homologous temperatures (equal to T/Tm, where T = temperature of deformation and Tm = melting point in K).17 We turned to nanoindentation for more quantification. Measurement of hardness, H, a measure of the resistance to plastic deformation, on different crystal faces of another system 2-(methylthio)nicotinic acid revealed interaction anisotropy (Figure 3d).10 However, the nanoindenter was available only in a distant facility in Hyderabad and we had to wait for a few years until G.R.D. moved to Bangalore before it entered our research projects meaningfully. In contrast to metals, volume and thickness are conserved in the plastic bending of molecular crystals. In metals, ductility usually increases with crystal symmetry because the nature of the metallic bonds remains the same in all the structural forms of a particular metal, while the number of available slip systems (shear planes) increases with increasing symmetry.11−13 In molecular crystals, however, we believed from the outset that the mechanical response depends on a balance between the various intermolecular interactions in the crystal structure. For example, the higher-symmetry orthorhombic Form 1 of the antidepressant drug venlafaxine hydrochloride is less ductile than the lower-symmetry monoclinic Form 2 because C−H··· O interactions in Form 1 lead to more isotropy in the packing.10 Low-symmetry organic crystal structures are inherently anisotropic with complex structures. Symmetry considerations are too simplistic, and interaction dimensionality and slip plane topology need to be considered to describe mechanical properties.

Figure 2. (a) Intrasheet interactions in 1,3,5-trichloro-2,4,6triiodobenzene (1). (b) Side view. (c) Sheared crystal. (d) Shearing of planar layers on stress application. (e) Twinning caused by 60° rotation. (f, g) Multiply twinned crystal.

a molecular level mechanism with laboratory X-ray equipment because the diffracted spots in the deformed regions are highly diffuse. A structure−property relationship was proposed using the structures of undeformed plastic crystals in a set of 60 aromatic compounds.10,18 The bending in the archetype hexachlorobenzene (2) is anisotropic in that the crystals may be deformed only along [001] (Figure 3a).10 This anisotropy is

Elastic Crystals

Our first observation of an elastic organic crystal came in a study of the isomorphous 3,4-dichlorophenol (3) and 3chloro-4-bromophenol (4).20 Phenol 3 is plastic with onedimensional (1D) helical O−H···O columns and weak Cl···Cl interactions between adjacent columns. When the Cl···Cl interactions in 3 are partly replaced by the stronger Br···Br in 4, the plastic response becomes an elastic one (Figure 4). Perhaps the increase in interaction strength along the bendable directions in 4 does not permit easy slippage of molecules, namely, plasticity, and structural isotropy is enhanced to an extent that elasticity is possible. C.M.R., by now an independent faculty in Indian Institute of Science Education and Research (IISER), simultaneously reported (with his student Soumyajit Ghosh) the first elastically bendable molecular crystal, a caffeine cocrystal solvate.21 The arrival of the latter as a postdoctoral fellow in G.R.D.’s group led to a study of elastic polyhalogenated Schiff bases (say 5) (Figure 5a,b).22 In these isotropic crystals, molecules are π-stacked with moderate C−H···O/F and interlocked Cl···Cl/Cl···F interactions along the other two directions (Figure 5a). Interlocking prevents long-range molecular motion blocking irreversible plastic deformation. The intermolecular separations increase in the outer arc and decrease in the inner arc (Figure 5c). Isotropic interactions act as restoring forces from the bentsituation upon releasing the external load.

Figure 3. Hexachlorobenzene (2): (a) Plastic bending; (b) stacked columns along crystal length; (c) plastic deformation; (d) 2(methylthio)nicotinic acid. Hardness, H, vs depth, d, in nanoindentation on different crystal faces.

different from the isotropic deformation observed in certain high symmetry organic crystals and waxes. There are two main interaction types in the crystal structure of 2, dominant π···π and nonspecific Cl···Cl. The latter are oriented perpendicular to bending faces (Figure 3b). Anisotropic packing is a prerequisite for bending. The stronger π-stacks (blue disks) are the structural scaffolds, while weaker Cl···Cl contacts C


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Accounts of Chemical Research Thermo/Photosalient Crystals

Dynamic molecular crystals show mechanical motion under the influence of stimuli such as pressure, heat, and light.7,8 Thermosalient and photosalient crystals show gross motion upon heating/cooling and photoirradiation, respectively. We discovered thermosalience in the elastic crystal 5 (Figure 5d),23 to be triggered by significant anisotropic changes in the packing at the phase transition. Nanoindentation of the photosalient Form I of 3,4-dimethoxycinnamic acid (6) showed that this phenomenon occurs because of molecular movement that arises from the plasticity in the layered structure.24 The interlocked structure of Form II is expectedly brittle. We summarize in Figure 6 the characteristics of different types of qualitative mechanical behavior of crystals, before moving to their quantitative assessment by nanoindentation.

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QUANTITATIVE MEASUREMENT: NANOINDENTATION Nanoindentation is an outstanding method to monitor interaction anisotropy.11,12 Our interest in this experimental technique was initiated by Upadrasta Ramamurty, and together, in the Indian Institute of Science, we rapidly established it as a reliable tool in crystal engineering. This raising of our work from the qualitative to the quantitative domain made a big difference in the types of research problems we were able to handle. At the outset, we focused on understanding mechanical response in terms of crystal packing. An early example was provided by the anisotropic water loss in sodium saccharin dihydrate (see also below).11 Other examples followed quickly.

Figure 4. (a) Weak Cl···Cl interactions in 3,4-dichlorophenol (3) replaced by (c) stronger Br···Br interactions in 4-bromo-3chlorophenol (4); (b) plastic → (d) elastic change via increased structural isotropy.

Shear Instability and Bimodal Nanoindentation Response of the Pharmaceutical Solids

In the pharmaceutical context, differences in the internal structure of polymorphs can lead to variations in processing conditionsgrinding, formulation, and tablet making.5,11 Stress-induced phase transformations between polymorphs during grinding and tableting are generally undesirable. In the two energetically similar and structurally related aspirin polymorphs (I and II), nanoindentation demonstrated the likely shearing directions for the irreversible metastable Form II → thermodynamic stable Form I phase transformation (Figure 7a and b).25 These intergrowth polymorphs show microstructural heterogeneity. Intergrowth polymorphism can be identified through diffraction spots, but an in-depth characterization needs an independent technique with a much higher spatial resolution (nano- to submicrometer scale) such as nanoindentation. Nanoindentation with a needle tip of 100 nm revealed the coexistence of domains of Form I in crystals of pure Form II (Figure 7c and d). Regions corresponding to Forms I and II in the intergrowth crystal gave distinct hardness, H, and elastic modulus, E, values, and are consistent with the corresponding pure forms. E is a measure of the resistance to elastic deformation. In felodipine Form II, the microstructures in the crystal structure are seen clearly through the bimodal nanoindentation response.26 Clearly, nanoindentation is a useful local probe that complements diffraction methods. We next studied the regular and irregular domains in sodium saccharin dihydrate (Na(sac)·15/8H2O) (hereafter dihydrate), the commercial form of saccharin.27 The dihydrate consists of regular domains with a “solidlike” arrangement of saccharin

Figure 5. 2,6-Dichlorobenzylidene-4-fluoro-3-nitroaniline (5): (a) significant interactions; (b) elastic crystal; (c) mechanism for elasticity; (d) thermosalience caused by phase transformation from α → β polymorphs.

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Figure 6. Structure to property correlation for different mechanical responses of organic molecular crystals.

determine the crystal packing. The even acids effectively maintain the stable sawtooth conformation with minimum O··· O repulsions. However, the odd acids are more distorted from their equilibrium geometry and are forced to adopt a strained intramolecular geometry to reduce the unfavorable repulsions (Figure 8a). Thalladi et al. hypothesized that the strained

Figure 7. Aspirin polymorphs: (a) Form I; (b) Form II; (c) nanoindentation P−h curves; (d) domain coexistence in Form II crystals.

Figure 8. Dicarboxylic acid melting point alternation: (a) deviation of molecules from the mean plane in the crystal; (b) linear correlation between E and Tm; (c) schematic representation of packing to rationalize mechanical property alternation.

anions and irregular domains with a “liquidlike” arrangement of disordered saccharin anions, Na+ cations, and H2O molecules. The nanoindentation response on the (001) face shows a distinct bimodal mechanical response,27 reminiscent of aspirin and felodipine.

geometry in the odd acids results in their lower Tm values.28 To test this, we measured the mechanical properties of the acid series (n = 0−6) with nanoindentation and showed that E and H alternate in the same way as does Tm.29,30 The odd acids are softer and less elastic than the even ones, but the differences decrease with increasing chain length. The linear correlation between E and Tm confirms that both these properties depend on same structural factors (Figures 8b and c). In the odd acids, the molecules move during indentation (and relax their conformations) so as to decrease the repulsionsthis is manifested in low E and H values.

Melting Point Alternation in Dicarboxylic Acids

The alternation of melting points (Tm) in α,ω-alkanedicarboxylic acids, HO2C(CH2)nCO2H was observed by Baeyer in 1877. The even acids (n = 0,2,4) exhibit systematically higher Tm values than the odd acids (n = 1,3,5). The crystal structures of all these acids are formed with infinite one-dimensional O− H···O hydrogen-bonded chains with carboxylic acid dimers. Dispersive attractions between the n-alkyl chains and O···O repulsions between adjacent carboxyl groups compete to E


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Accounts of Chemical Research Solid Solution Hardening: Omeprazole

Five different isomorphous crystalline Forms I−V contain varying proportions of T1 and T2 from 0:100 to 15:85. Nanoindentation on the major face {001} of all five forms showed that the residual depth of penetration, hr, is in descending order from I to V (Figure 9b), softest to hardest.31 The hardening mechanism can be understood from Figure 9c. The layers in Form I slide without any resistance during indentation load resulting in low H. In Forms II−V, sliding is increasingly impeded because of the “interlayer” 5-methoxy groups in a Velcro fashion. Solid-solution hardening can thus be employed to control the H of organic solids by tuning shear resistance of slip. This is property engineering.

The H of a solid drug form has great significance in its formulation and manufacture. If a material is too soft, it is difficult to mill or grind and it will become pasty. If it is too hard, it may require substantially higher loads. Accordingly, a material with optimal H is always demanded. We turned our attention to methods of tuning H in a representative solid. Omeprazole is a blockbuster antiulcer drug. In solution and in its crystalline forms, both the 5-methoxy (T1) and 6-methoxy (T2) tautomers are found in different proportions (Figure 9a).

Other Structure−Property Correlations

Continuing with our previous theme of tuning H in molecular solids, we got interested in possible correlations between H and solubility in drugs since both properties seemed to depend on largely similar factors. When the intermolecular interactions are weak, e.g., interlayer, the structure is ruptured as easily by the solvent as it is by the nanoindenter needle; the measured H will be lower and solubility higher. Such correlations may only be established reliably in a series of polymorphs and is exactly the situation that prevails among the crystal forms of curcumin and sulfathiazole.32 Cocrystallization is a widely used approach to alter the solid-state physicochemical properties of drugs, including mechanical properties. We tuned the mechanical properties of voriconazole (VOR) and compared it to its cocrystal and salt forms.33 Nanoindentation results demonstrate that the salts are considerably stiffer and harder than VOR (and its cocrystals) because of the strong interlayer ionic interactions and hydrogen bonds, which offer resistance to the shearing of planes.

Figure 9. Omeprazole: (a) tautomers; (b) representative P−h curves of the five polymorphs; (c) crystal packing of I−V to show solid solution hardening.

Figure 10. (a) 4,4′-Bipyridine showing C−H···π interactions, responsible for brittleness. (b) Capping model to introduce more π···π, removing C− H···π. (c,d) Elastic cocrystals thus obtained. F


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Figure 11. σ-Hole and π-hole synthon mimicry: (a) stepwise strategy based on (b) only σ-hole synthons (halogen bonds); (d) both σ-hole and πhole synthons; and (e) only π-hole synthon. (c) Snapshots of elastic bending for (d).

Figure 12. (a−d) Structure and optical images of crystals involved in multistep supramolecular synthesis of halogen bonded 2D plastic crystals, used for (e) hand twisting.

plastically flexible crystals by introducing active slip planes using noninterfering interactions, namely, van der Waals, π···π stacking, and hydrogen bonding, showed that logic driven crystal engineering was feasible for mechanical properties.36 Any cocrystal is, in principle, structurally modular and is linked with supramolecular synthons.37 The hope is that structural modularity will lead to property modularity. In a 4,4′-bipyridine crystal, the molecules are twisted and this along with C−H···N hydrogen bonds drives the structure to an interlocked packing leading to brittleness (Figure 10). Elasticity is more likely if the interaction types are better balanced. The crucial move into the elastic domain would then seem to be facilitated by increasing the stacking; this was achieved by cocrystallizing with carboxylic acids, using the well-known acid···pyridine synthon. The acid derivatives are essentially capping agents which, if elaborated further with say halogen atoms X, allow for further expansion with X···X halogen bonds, which are good structural buffers for elastic behavior. This strategy proved to be unusually effective and several elastic crystals were obtained. A different strategy was employed to design three-dimensional (more isotropic) crystal structures without halogen bonds. Can we obtain more generality in crystal engineering by finding a synthon mimic for both the geometry and the chemical nature of a σ-hole-assisted halogen bond?38 In a typeII halogen bond, the negative equatorial region of a halogen is directed toward a positive σ-hole of another giving an angle of approximately 90° or orthogonal geometry (Figure 11a). Carbonyl···carbonyl contacts and nitro···nitro orthogonal interactions are typical examples of such π-hole-based synthons. Hence, we targeted the less studied carbonyl··· carbonyl contacts in crystalline aldehydes from a crystal engineering viewpoint.

The solid-state reactivity of picric acid with substituted hydrocarbons was rationalized long ago by Rastogi et al. on the basis of diffusion controlled surface migration.34 We induced such molecular migrations in two 1:1 charge transfer complexes of 1,2,4,5-tetracyanobenzene (TCNB) with pyrene (TCNB-pyrene) and phenanthrene (TCNB-phenanthrene) using nanoscratching experiments.35 TCNB−pyrene has a layered arrangement on the major faces of the crystals. However, 1:1 TCNB−phenanthrene has an offset arrangement and nanoscratch experiments yield significantly different results. The magnitude of such induced molecular migration depends on the orientation of the layer arrangement and the direction of the indenter tip movement.22 Instead of indenting, the three-point bending test was performed to estimate the elastic strain in order to quantify the elastic response. Accordingly, we estimated the maximum elastic strain for elastic organic crystals to be around 2%, which is very high compared to 0.5% for crystalline alloys, polymers and biomaterials.

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MECHANICAL PROPERTIES BY DESIGN: THIRD GENERATION CRYSTAL ENGINEERING By now, we had obtained a better idea about the types of crystal structures needed to demonstrate a particular mechanical property. With nanoindentation, we also had an estimate of the energies involved, and the degree of anisotropy or isotropy needed for, e.g., plastic or elastic responses. The underlying assumption was that there is a connection between structure and property, and given the mainline interest in crystal engineering in the G.R.D. group, it was of interest to assess the possibility of designing a crystal specifically so that it showed a particular mechanical response. A report by C.M.R.’s group in 2016 on design of mechanically reconfigurable, G


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Accounts of Chemical Research The first generation of crystal engineering deals with the understanding of structure−property relationship. The second phase involves designing a molecular structure for a targeted crystal structure. In the advanced third generation strategies, one may proceed directly from molecule to property design, for instance, to obtain elastic flexibility.38 The elastic cocrystal of 3,5-dichlorosalicylic acid and 3,5-dibromopyridine is shown in Figure 11 and contains orthogonal Br···Cl and Br···Br interactions. The halogens on the pyridine ring were replaced with formyl groups in order to achieve π-hole-based interactions along with the σ-hole interactions in the cocrystal of 4-pyridinecarboxaldehyde and 4-chlorosalicylic acid, which too was found to be elastic. Finally, the halogen atoms in the aromatic acid were replaced by the π-hole-forming functionality, nitro, so that all remaining σ-hole-based interactions might be replaced with π-hole-based interactions. Accordingly, we obtained the elastic cocrystal of 3,5-dinitrobenzoic acid with 4-pyridinecarboxaldehyde.38 Continuing on the theme of third generation crystal engineering, we strategized to alter macroscopic mechanical behavior and design hand-twisted helical crystals. We achieved this by varying interaction strength through selectively changing molecular and/or supramolecular synthons (Figure 12).39 Starting with the one-directionally (1D) plastic crystal, 1,4-dibromobenzene, we changed it to a 1D elastic crystal, 4bromophenyl-4′-chlorobenzoate by exchanging the supramolecular synthon Br···Br with a molecular synthon −O− CO− in the precursor. The 1D elastic crystals are then changed to two-directionally (2D) elastic crystals, of the type 4-iodophenyl 4′-nitrobenzoate by exploiting the similarity between halogen bonding and C−H···O hydrogen bonding. Finally, these 2D elastic crystals give plastic crystals, for example, 4-chlorophenyl and 4-bromophenyl 4′-nitrobenzoate. They possess two pairs of bendable faces (2D plasticity) but without slip planes. In this new type of bendable crystals, the plastic behavior is seen with a fair degree of isotropic character in the crystal packing. The two sets of orthogonal bendable faces make it possible to hand-twist the crystals to achieve helical morphologies. The other novel feature here is that we have two isomorphous structures, namely, the iodo compound in step 3 and the bromo compound in step 4, which have different properties (Figure 12). The fact that topology of structure need not correlate with property showed us how far we had come since our early experiments on, e.g., compounds 1 and 2, way back in the early 2000s! Synthon mimicry, of the molecule ≈ supramolecular type, was used to design a hand twistable hydrogen bonded twodimensional plastic crystal, 4-pyridinyl-4-nitrobenzoate hydrate, from a brittle precursor.40 The phenol analogue of the halogenated compound in Figure 13a is unsuited as a structural mimic for intramolecular conformational reasons: it is replaced with a pyridine which shows its characteristic hydrogen bond pattern with water, and this pattern has the same topology as the infinite halogen···halogen motif in the precursor. We returned to classical crystal engineering and the wellstudied acid···amide supramolecular synthon and connected this with mechanical responses of acid−amide cocrystals, in particular, plastic deformation. The acid···amide dimer heterosynthon in cocrystals of aromatic acids and primary amides is identified by IR marker peaks that are characteristic of individual N−H···O and O−H···O interactions and also of the extended synthon.41 A combinatorial study, tuning the chemical nature of acid and amide functionalities, led to 22

Figure 13. (a, b) Methodology of halogen bond/hydrogen bond equivalence; (c) application of retrosynthetic approach in obtaining (d) hydrogen bond based (e) hand twistable crystal.

cocrystals in 36 crystallization attempts (Figure 14). Four quadrants I−IV were defined based on acidity and basicity of the acid and amide components. The strong acid−strong base combination in quadrant I favors the planar acid···amide heterodimer in eight cocrystals. Quadrant IV with its weak acid−weak base combination is the least favored for the planar heterosynthon and synthon diversity is observed in its eight cocrystals. The strong−weak and weak−strong combinations in quadrants II and III are seen to be expectedly ambivalent. Quadrant I cocrystals, with their propensity for the planar acid···amide heterodimer, are suitable for shearing, very similar to systems we studied in the earliest days of our explorations. This quadrant also favors the formation of elastic crystals. To summarize, we are able to execute a complete crystal engineering study from IR synthon identification to a desired crystal packing to a particular property selection. Mechanical Properties and Polymorphism

Polymorphism in molecular crystals provides an opportunity to directly correlate structural changes to the observed mechanical properties. An early example (conducted by C.M.R. in his student days) concerned the trimorphs of 6-chloro-2,4dinitroaniline (hereafter, nitroaniline),42 while a recent example (studied by S.S.) deals with 4-bromophenyl-4bromobenzoate (hereafter, bromobenzoate).43 In the nitroaniline, Forms I and III are block-shaped while Form II exists as needles. Forms I and III are distinguished by their distinctive mechanical responses; Form I shears while Form III breaks in a brittle manner under applied load. In the bromobenzoate, elasticity is also observed (Figure 15). Form I contains πstacked columns. Among the two chemically different Br groups of the molecule, the Br with the stronger σ-hole is involved in type-II halogen bonds directed perpendicular to the major face (001). In this situation, electrostatic halogen bonds operate at long enough distances to act as suitable restoring forces for reversible elastic deformation. In Form II, H


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Figure 14. (a) From FIR spectroscopic detection to (c,d) property engineering, shearing (4-hydroxybenzamide+3-nitrobenzoic acid) and elastic (4-methylbenzamide+3-nitrobenzoic acid), via (b) a combinatorial study for acid···amide synthon.

Figure 15. Property differentiated polymorphism in (a−c) 6-chloro-2,4-dinitroaniline (or nitroaniline) and (d−f) 4-bromophenyl-4bromobenzoate (or bromobenzoate).

matter (gels, polymers, biomaterials), making them relevant for future applications in optoelectronics, actuators, and sensors for various practical and medical applications. The study of their mechanical properties is of fundamental importance and is both a science and an art. Compliant crystals are soft with an ability to absorb applied stress; they show plastic or elastic deformation while retaining their monolithic nature macroscopically. The latter may be soft or hard. Anisotropic 2D layered crystals with strong intralayer and weak interlayer interactions show plastic shearing across slip planes. Elastic crystals possess interlocked structures with buffering regions with soft interactionsvan der Waals, aromatic group

both the Br-groups are involved in type-II halogen bonds but interlocked C−H···π interactions lead to brittleness. Form III is structurally similar to Form I but Br with a lesser σ-hole forms weaker halogen bonds, which are no longer capable of buffering and weak enough to allow plasticity. Different crystal forms, with different mechanical properties, have somewhat similar crystal structures, and we begin to see a breakdown in strict structure−property correlations.

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CONCLUSIONS AND OUTLOOK Soft molecular crystals are fast emerging as new attractive targets in that they share properties of both crystals and soft I


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Accounts of Chemical Research mediated, and halogen bonding. These structural buffers absorb the stress and restore molecules back to their original positions upon withdrawal of the external force. Absence of these buffers can lead to brittle fracture. Nanoindentation can be utilized to study mechanical aspects of crystals from the nanoscale to microscale level and measure H and E. It may be used to probe different polymorphic domains in intergrown crystals at low limits of detection, due to its higher spatial resolution. The examples discussed here show that structural similarity need not always lead to property similarity. This structure−property correlation is also influenced by a balance among the interactions themselves. Interactions in slip planes, especially the softer ones, are the most sensitive to engineering macroscopic properties and thus offer a handle in tuning properties. Initial reports from our groups (G.R.D., C.M.R.) of organic single crystals with plastic or elastic flexibility have led to subsequent reports from others of very interesting soft functional organic crystals with fluorescence, semiconductivity, waveguide, mechanochromic luminescence properties, and reversible thermosalience.15,16,44 Molecular level studies of mechanical properties can throw light on the effect of interactions in solid-state dynamics, where the interplay of soft and hard interactions in crystal space is critical for design.45 It would therefore be possible to engineer defects and dislocations in molecular crystals using a crystal engineering approach; in other words, molecular movements themselves. This would have implications for designing bulk properties of organic solids, for instance, flowability, compactibility, and stability under mechanical milling.

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Gautam R. Desiraju has served on the editorial advisory board of Accounts of Chemical Research between 1998 and 2005 and as consulting editor between 2005 and 2009. He has published in Accounts in 1986, 1991, 1996, 2002, and 2014.

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ACKNOWLEDGMENTS We thank all coauthors in our cited publications. C.M.R. and G.R.D. thank the DST for Swarnajayanti and J. C. Bose fellowships, respectively.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Manish Kumar Mishra: 0000-0002-8193-3499 C. Malla Reddy: 0000-0002-1247-7880 Gautam R. Desiraju: 0000-0002-7708-9176 Notes

The authors declare no competing financial interest. Biographies Subhankar Saha obtained his B.Sc. and M.Sc. degrees from University of Kalyani. He got his Ph.D. in 2017 from the Indian Institute of Science, working with G. R. Desiraju on crystal engineering of plastic and elastic crystals. He is currently a postdoctoral researcher at Indian Institute of Science Education and Research, Kolkata with C. M. Reddy. Manish Kumar Mishra received his B.Sc. and M.Sc. degrees from Deendayal Upadhyay Gorakhpur University. He earned his Ph.D. in 2016 from the Indian Institute of Science, working with G. R. Desiraju and U. Ramamurty on nanoindentation. He is currently a postdoctoral associate at The University of Minnesota under the mentorship of C. C. Sun. C. Malla Reddy obtained his Ph.D. in 2006 from the University of Hyderabad under the joint supervision of G. R. Desiraju and K. A. Padmanabhan. After a postdoctoral fellowship in the Karlsruhe Institute of Technology, he started his independent research in IISER in 2008. His group works on crystal engineering and mechanical properties of crystals. J


Article

Accounts of Chemical Research (20) Mukherjee, A.; Desiraju, G. R. Halogen Bonds in Some Dihalogenated Phenols: Applications to Crystal Engineering. IUCrJ 2014, 1, 49−60. (21) Ghosh, S.; Reddy, C. M. Elastic and Bendable Caffeine Cocrystals: Implications for the Design of Flexible Organic Materials. Angew. Chem., Int. Ed. 2012, 51, 10319−10323. (22) Ghosh, S.; Mishra, M. K.; Kadambi, S. B.; Ramamurty, U.; Desiraju, G. R. Designing Elastic Organic Crystals: Highly Flexible Polyhalogenated N-Benzylideneanilines. Angew. Chem., Int. Ed. 2015, 54, 2674−2678. (23) Ghosh, S.; Mishra, M. K.; Ganguly, S.; Desiraju, G. R. Dual Stress and Thermally Driven Mechanical Properties of the Same Organic Crystal: 2,6-Dichlorobenzylidene-4- Fluoro-3-Nitroaniline. J. Am. Chem. Soc. 2015, 137, 9912−9921. (24) Mishra, M. K.; Mukherjee, A.; Ramamurty, U.; Desiraju, G. R. Crystal Chemistry and Photomechanical Behavior of 3,4-Dimethoxycinnamic Acid: Correlation Between Maximum Yield in the Solid State Topochemical Reaction and Cooperative Molecular Motion. IUCrJ 2015, 2, 653−660. (25) Varughese, S.; Kiran, M. S. R. N.; Solanko, K. A.; Bond, A. D.; Ramamurty, U.; Desiraju, G. R. Interaction Anisotropy and Shear Instability of Aspirin Polymorphs Established by Nanoindentation. Chem. Sci. 2011, 2, 2236−2242. (26) Mishra, M. K.; Desiraju, G. R.; Ramamurty, U.; Bond, A. D. Studying Microstructure in Molecular Crystals with Nanoindentation: Intergrowth Polymorphism in Felodipine. Angew. Chem., Int. Ed. 2014, 53, 13102−13105. (27) Mishra, M. K.; Ramamurty, U.; Desiraju, G. R. Bimodal Nanoindentation Response of the (001) Face in Crystalline Sodium Saccharin Dihydrate. Maced. J. Chem. Chem. Eng. 2015, 34, 51−55. (28) Thalladi, V. R.; Nüsse, M.; Boese, R. The Melting Point Alternation in α,ω-Alkanedicarboxylic Acids. J. Am. Chem. Soc. 2000, 122, 9227−9236. (29) Mishra, M. K.; Varughese, S.; Ramamurty, U.; Desiraju, G. R. Odd-Even Effect in the Elastic Modulii of α,ω-Alkanedicarboxylic Acids. J. Am. Chem. Soc. 2013, 135, 8121−8124. (30) Mishra, M. K.; Ramamurty, U.; Desiraju, G. R. Hardness Alternation in α,ω-Alkanedicarboxylic Acids. Chem. - Asian J. 2015, 10, 2176−2181. (31) Mishra, M. K.; Ramamurty, U.; Desiraju, G. R. Solid Solution Hardening of Molecular Crystals: Tautomeric Polymorphs of Omeprazole. J. Am. Chem. Soc. 2015, 137, 1794−1797. (32) Mishra, M. K.; Sanphui, P.; Ramamurty, U.; Desiraju, G. R. Solubility−Hardness Correlation in Molecular Crystals: Curcumin and Sulfathiazole Polymorphs. Cryst. Growth Des. 2014, 14, 3054− 3061. (33) Sanphui, P.; Mishra, M. K.; Ramamurty, U.; Desiraju, G. R. Tuning Mechanical Properties of Pharmaceutical Crystals with Multicomponent Crystals: Voriconazole as a Case Study. Mol. Pharmaceutics 2015, 12, 889−897. (34) Rastogi, R. P.; Singh, N. B. Solid-State Reactivity of Picric Acid and Substituted Hydrocarbons. J. Phys. Chem. 1968, 72, 4446−4449. (35) Varughese, S.; Kiran, M. S. R. N.; Ramamurty, U.; Desiraju, G. R. Nanoindentation as a Probe for Mechanically-Induced Molecular Migration in Layered Organic Donor-Acceptor Complexes. Chem. Asian J. 2012, 7, 2118−2125. (36) Krishna, G. R.; Devarapalli, R.; Lal, G.; Reddy, C. M. Mechanically Flexible Organic Crystals Achieved by Introducing Weak Interactions in Structure: Supramolecular Shape Synthons. J. Am. Chem. Soc. 2016, 138, 13561−13567. (37) Saha, S.; Desiraju, G. R. Using Structural Modularity in Cocrystals to Engineer Properties: Elasticity. Chem. Commun. 2016, 52, 7676−7679. (38) Saha, S.; Desiraju, G. R. σ−Hole and π−Hole Synthon Mimicry in Third-Generation Crystal Engineering: Design of Elastic Crystals. Chem. - Eur. J. 2017, 23, 4936−4943. (39) Saha, S.; Desiraju, G. R. Crystal Engineering of Hand-Twisted Helical Crystals. J. Am. Chem. Soc. 2017, 139, 1975−1983.

(40) Saha, S.; Desiraju, G. R. A Hand-Twisted Helical Crystal Based Solely on Hydrogen Bonding. Chem. Commun. 2017, 53, 6371−6374. (41) Saha, S.; Desiraju, G. R. Acid···Amide Supramolecular Synthon in Cocrystals: From Spectroscopic Detection to Property Engineering. J. Am. Chem. Soc. 2018, 140, 6361−6373. (42) Reddy, C. M.; Basavoju, S.; Desiraju, G. R. Sorting of Polymorphs Based on Mechanical Properties. Trimorphs of 6-Chloro2,4-Dinitroaniline. Chem. Commun. 2005, 2439−2441. (43) Saha, S.; Desiraju, G. R. Trimorphs of 4-Bromophenyl 4Bromobenzoate. Elastic, Brittle, Plastic. Chem. Commun. 2018, 54, 6348−6351. (44) Krishna, G. R.; Kiran, M. S. R. N.; Fraser, C. L.; Ramamurty, U.; Reddy, C. M. Crystal Engineering: the Telationship of Solid-State Plasticity to Mechanochromic Luminescence in Difluoroboron Avobenzone Polymorphs. Adv. Funct. Mater. 2013, 23, 1422−1430. (45) Rupasinghe, T. P.; Hutchins, K. M.; Bandaranayake, B. S.; Ghorai, S.; Karunatilake, C.; Bučar, D.-K.; Swenson, D. C.; Arnold, M. A.; MacGillivray, L. R.; Tivanski, A. V. Mechanical Properties of a Series of Macro- and Nanodimensional Organic Cocrystals Correlate with Atomic Polarizability. J. Am. Chem. Soc. 2015, 137, 12768− 12771.

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