Search

Stoichiometric ternary and quaternary, and nonstoichiometric quinary molecular solids were engineered based on structural inequivalence and combinatorial approaches from 2-nitroresorcinol. A total of 32 binary, ternary, quaternary and quinary solids were characterized. The great difficulty in obtaining such solids is that crystallization must occur in a single step from precursors in solution, with multistep sequences, as are typical in solution syntheses, not being possible in most situations., A synthetic strategy for the formation of stoichiometric quaternary and non­stoichiometric quinary solids is outlined. A series of 2-nitro­resorcinol-based quaternary cocrystals were developed from binary precursors in two conceptual stages. In the first stage, ternary solids are synthesized based on the structural inequivalence at two recognition sites in the binary. In the second stage, the ternary is homologated into a stoichiometric quaternary based on the same concept. Any cocrystal without an inequivalence becomes a synthetic dead end. The combinatorial approach involves lower cocrystal systems with different structural environments and preferred synthon selection from a synthon library in solution. Such are the stepping stones for the isolation of higher cocrystals. In addition, a quaternary cocrystal of 4,6-di­chloro­resorcinol is described wherein an unusual synthon is observed with two resorcinol molecules in a closed loop with two different ditopic bases. The concept of the virtual synthon in binaries with respect to isolated ternaries is validated for the 4,6-di­chloro­resorcinol system. It is possible that only some binary systems are amenable to homologation into higher cocrystals. The reasons for this could have to do with the existence of preferred synthon modules, in other words, the critical components of the putative higher assembly that cannot be altered. Addition of the third and fourth component might be more flexible, and the choices of these com­ponents, possible from a larger pool of chemically related molecules.

This recommendation proposes a definition for the term “chalcogen bond”; it is recommended the term is used to designate the specific subset of inter- and intramolecular interactions formed by chalcogen atoms wherein the Group 16 element is the electrophilic site.

The acid···amide dimer heterosynthon in cocrystals of aromatic acids and primary amides is identified by marker peaks in the IR spectra that are characteristic of individual N-H···O and O-H···O interactions and also of the extended synthon. The O-H···O hydrogen bond is crucial to heterodimer formation in contrast to the N-H···O bond. A combinatorial study, tuning the chemical nature of acid and amide functionalities, leads to 22 cocrystals out of 36 crystallization attempts. Four quadrants I-IV are 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 its 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 the eight cocrystals obtained. The strong-weak and weak-strong combinations in quadrants II and III are expectedly ambivalent. This exercise highlights the effect of molecular features on supramolecular behavior. Quadrant I crystals, with their propensity for the planar acid···amide heterodimer are suitable for the engineering of crystals that can be sheared. This quadrant favors the formation of elastic crystals too. The overall result is that 57% (4 in 7) of all crystals in this quadrant are deformable, compared with 14% (1 in 7) in the three other quadrants. This work is a complete crystal engineering exercise from synthon identification to a particular desired crystal packing to property selection. One can virtually anticipate the mechanical property of a putative acid···amide cocrystal from a knowledge of just the molecular structures of the constituent acid and amide molecules.

Solid solutions (SS) of benzoic acid (BA) and 4-fluorobenzoic acid (4FBA) are monitored with respect to increasing fluorine content. All 10 SS studied take a crystal structure that is different from the crystal structures of either BA or 4FBA and retain structural uniformity over a wide range of composition. Adoption of a crystal structure different from either of the parent structure types is a unique observation in the context of SS. It implies the influence of directional interactions in the formation of the SS; this idea is strengthened by the observations made in this study. All the structural and interaction parameters monitored follow trends with respect to fluorine content. There is indication of the effect of C–H···F hydrogen bonds in the structures.

A strategy has been developed to achieve six-component molecular solids. The first part of the protocol involves the design and development of a family of stoichiometric quaternary cocrystals. It relies on the idea that when a molecule is in two distinct crystallographic environments in a lower-order cocrystal it becomes susceptible to substitution by a new molecule at the site where it is more weakly bound, if it is enthalpically advantageous to do so. Accordingly, a binary cocrystal acts as a stepping stone to a ternary, and so on. However, the subject system ran into a synthetic dead end at the level of quaternary cocrystals, in that no further crystallographic inequivalences could be found. This necessitated the development of the second part of the protocol, which exploits the shape-size similarities of 2-chloro-, 2-bromo-, and 2-methylresorcinols (CRES, BRES, and MRES respectively) and circumvents this synthetic dead end to achieve several five-and six-component solids, wherein the fifth and sixth c...

What is 'structure' in the context of a molecular solid?

A strategy is outlined for the design of hand-twisted helical crystals. The starting point in the exercise is the one-dimensional (1D) plastic crystal, 1,4-dibromobenzene, which is then changed to a 1D elastic crystal, exemplified by 4-bromophenyl 4'-chlorobenzoate, by introduction of a molecular synthon -O-CO- in lieu of the supramolecular synthon Br···Br in the precursor. The 1D elastic crystals are next modified to two-dimensional (2D) elastic crystals, of the type 4-bromophenyl 4'-nitrobenzoate where the halogen bonding and C-H···O hydrogen bonding are well-matched. Finally, varying the interaction strengths in these 2D elastic crystals gives plastic crystals with two pairs of bendable faces but without slip planes. Typical examples are 4-chlorophenyl and 4-bromophenyl 4'-nitrobenzoate. This type of 2D plasticity represents a new type of bendable crystals in which plastic behavior is seen with a fair degree of isotropic character in the crystal packing. The presence of two sets of bendable faces, generally orthogonal to each other, allows for the possibility of hand-twisting of the crystals to give grossly helical morphologies. Accordingly, we propose the name hand-twisted helical crystals for these substances.

A hand twistable hydrogen bonded two-dimensional plastic crystal, 4-pyridinyl 4-nitrobenzoate hydrate, is obtained from a brittle precursor using a retrosynthetic design strategy based on molecular/supramolecular equivalence.

This retrospect describes research in our group in the University of Hyderabad and in the Indian Institute of Science, Bangalore over a period of 25 years on a topic in structural chemistry that has been both intriguing and invigorating. The theme of hydrogen bond-based amine-hydroxy recognition in organic crystals is cast against an overall background of developments in crystal engineering from the early 1990s up to the present time. This article is divided into two parts: the first is a somewhat autobiographical and sometimes informal account of how and why various things were done over the years, while the second takes the form of a current result-oriented study.

Multicomponent solid forms of the BCS class IV drug furosemide (FSM) were obtained upon liquid assisted grinding with coformers anthranilamide (ANT), 4-toluamide (TOL), 2-picolinamide (PCM), piperazine (PPZ), 2,3,5,6-tetramethylpyrazine (TMPZ), pyrazine (PYZ), 2-picolinic acid (PIC), isoniazid (INZ), and theophylline (THP), and identified with powder X-ray diffraction. Solid forms FSM–TMPZ (2:1), FSM–ANT (1:1), FSM–PPZ (1:1), and FSM–TOL ethanol solvate (1:1:1) were further characterized with single crystal X-ray diffraction and differential scanning calorimetry; a sesquihydrate structure for FSM–PCM (1:1:1.5) was additionally confirmed with thermogravimetric analysis. The thermodynamically stable form I of FSM contains O–H···O acid···acid and N–H···O sulfonamide dimer synthons and chains. These synthons are modified in the cocrystals/salts sometimes leading to changes in physicochemical properties. The FSM–PPZ (1:1) salt converted to a thermodynamically more stable form FSM–PPZ (2:1) within 1 h. The appa...

A combinatorial synthetic approach is described for the isolation of quaternary cocrystals. The strategy outlines chemical and geometrical modulations in the long-range synthon Aufbau modules (LSAMs) to systematically increase the number of components., A synthetic strategy is outlined whereby a binary cocrystal may be developed in turn into a ternary and finally into a quaternary cocrystal. The strategy hinges on the concept of the long-range synthon Aufbau module (LSAM) which is a large supramolecular synthon containing more than one type of intermolecular interaction. Modulation of these interactions may be possible with the use of additional molecular components so that higher level cocrystals are produced. We report six quaternary cocrystals here. All are obtained as nearly exclusive crystallization products when four appropriate solid compounds are taken together in solution for crystallization.

Intermolecular interactions and crystal packing of three polymorphs of the title compound are described in the context of their different mechanical properties. Molecular features of compounds that may be prone to such property differentiated polymorphism are discussed.

A new monoclinic polymorph, form II, of 3,4-dimethoxycinnamic acid has been isolated and shows a different photochemical and photomechanical property from the previously reported triclinic form I. The solid-state 2 + 2 photodimerization of these polymorphs is rationalized on the basis of minimum and maximum molecular movement during the reaction – the so-called Kaupp and Schmidt models for these reactions., A new monoclinic polymorph, form II (P21/c, Z = 4), has been isolated for 3,4-dimethoxycinnamic acid (DMCA). Its solid-state 2 + 2 photoreaction to the corresponding α-truxillic acid is different from that of the first polymorph, the triclinic form I (, Z = 4) that was reported in 1984. The crystal structures of the two forms are rather different. The two polymorphs also exhibit different photomechanical properties. Form I exhibits photosalient behavior but this effect is absent in form II. These properties can be explained on the basis of the crystal packing in the two forms. The nanoindentation technique is used to shed further insights into these structure−property relationships. A faster photoreaction in form I and a higher yield in form II are rationalized on the basis of the mechanical properties of the individual crystal forms. It is suggested that both Schmidt-type and Kaupp-type topochemistry are applicable for the solid-state trans-cinnamic acid photodimerization reaction. Form I of DMCA is more plastic and seems to react under Kaupp-type conditions with maximum molecular movements. Form II is more brittle, and its interlocked structure seems to favor Schmidt-type topochemistry with minimum molecular movement.

An elastic organic crystal, 2,6-dichlorobenzylidine-4-fluoro-3-nitroaniline (DFNA), which also shows thermosalient behavior, is studied. The presence of these two distinct properties in the same crystal is unusual and unprecedented because they follow respectively from isotropy and anisotropy in the crystal packing. Therefore, while both properties lead from the crystal structure, the mechanisms for bending and thermosalience are quite independent of one another. Crystals of the low-temperature (a) form of the title compound are bent easily without any signs of fracture with the application of deforming stress, and this bending is within the elastic limit. The crystal structure of the a-form was determined (P2(1)/c, Z = 4, a = 3.927(7) angstrom, b = 21.98(4) angstrom, c = 15.32(3) angstrom). There is an irreversible phase transition at 138 degrees C of this form to the high-temperature beta-form followed by melting at 140 degrees C. Variable-temperature X-ray powder diffraction was used to investigate the structural changes across the phase transition and, along with an FTIR study, establishes the structure of the beta-form. A possible rationale for strain build-up is given. Thermosalient behavior arises from anisotropic changes in the three unit cell parameters across the phase transition, notably an increase in the b axis parameter from 21.98 to 22.30 angstrom. A rationale is provided for the existence of both elasticity and thermosalience in the same crystal. FTIR studies across the phase transition reveal important mechanistic insights: (i) increased pi...pi repulsions along 100] lead to expansion along the a axis; (ii) change in alignment of C-Cl and NO2 groups result from density changes; and (iii) competition between short-range repulsive (pi...pi) interactions and long-range attractive dipolar interactions (C-Cl and NO2) could lie at the origin of the existence of two distinctive properties.

The variation of hardness as a function of the number of carbon atoms in α,ω-alkanedicarboxylic acids, C(N)H(2N-2)O4 (4≤N≤9), was examined by recourse to nanoindentation on the major faces of single crystals. Hardness exhibits odd-even alternation, with the odd acids being softer and the even ones harder; the differences decrease with increasing chain length. These variations are similar to those seen for other mechanical, physical, and thermal properties of these diacids. The softness of odd acids is rationalized due to strained molecular conformations in them, which facilitate easier plastic deformation. Relationships between structural features, such as interplanar spacing, interlayer separation distance, molecular chain length, and signatures of the nanoindentation responses, namely, discrete displacement bursts, were also examined. Shear sliding of molecular layers past each other during indentation is key to the mechanism for plastic deformation in these organic crystals.

The nanoindentation response of the (001) face of sodium saccharin dihydrate is examined. The structure can be demarcated into regular and irregular regions or domains. The regular domains have solid-like and the irregular ones have liquid-like characteristics. Therefore, these domains impart a microstructure to the crystal. The indent face (001) is prominently developed in this crystal and unambiguously presents the regular and irregular regions to nanoindention. Average values of elastic modulus and hardness show a distinct bimodal mechanical response. Such a response has been observed in the case of intergrown polymorphs of aspirin and felodipine. We examine two possible reasons as to why the responses could be for bimodal in this crystal. The first possibility could be that the two domains correspond to regions of the original dihydrate and a lower hydrate that is obtained by the loss of some water. The second possibility could be that these responses correspond to regular and irregular regions in the structure. Nanoindentation is a very useful technique in the characterization of molecular solids, as a complementary technique to X-ray crystallography, because it samples different length scales.

The notion of structure is central to the subject of chemistry. This review traces the development of the idea of crystal structure since the time when a crystal structure could be determined from a three-dimensional diffraction pattern and assesses the feasibility of computationally predicting an unknown crystal structure of a given molecule. Crystal structure prediction is of considerable fundamental and applied importance, and its successful execution is by no means a solved problem. The ease of crystal structure determination today has resulted in the availability of large numbers of crystal structures of higher-energy polymorphs and pseudopolymorphs. These structural libraries lead to the concept of a crystal structure landscape. A crystal structure of a compound may accordingly be taken as a data point in such a landscape.

In the context of processing of molecular solids, especially pharmaceuticals, hardness is an important property that often determines the manufacturing steps employed. Through nanoindentation studies on a series of omeprazole polymorphs, in which the proportions of the 5- and 6-methoxy tautomers vary systematically, we demonstrate that solid-solution strengthening can be effectively employed to engineer the hardness of organic solids. High hardness can be attained by increasing lattice resistance to shear sliding of molecular layers during plastic deformation.

The intermolecular interactions and structural features in crystals of seven halogenated N-benzylideneanilines (Schiff bases), all of which exhibit remarkable flexibility, were examined to identify the common packing features that are the raison d'être for the observed elasticity. The following two features, in part related, were identified as essential to obtain elastic organic crystals: 1) A multitude of weak and dispersive interactions, including halogen bonds, which may act as structural buffers for deformation through easy rupture and reformation during bending; and 2) corrugated packing patterns that would get interlocked and, in the process, prevent long-range sliding of molecular planes.

Weak hydrogen bonds of the type C–H⋯X (X: N, O, S and halogens) have evoked considerable interest over the years, especially in the context of crystal engineering. However, association patterns of weak hydrogen bonds are generally difficult to characterize, and yet the identification of such patterns is of interest, especially in high throughput work or where single crystal X-ray analysis is difficult or impossible. To obtain structural information on such assemblies, we describe here a five step IR spectroscopic method that identifies supramolecular synthons in weak hydrogen bonded dimer assemblies, bifurcated systems, and π-electron mediated synthons. The synthons studied here contain C–H groups as hydrogen bond donors. The method involves: (i) identifying simple compounds/cocrystals/salts that contain the hydrogen bonded dimer synthon of interest or linear hydrogen bonded assemblies between the same functionalities; (ii) scanning infrared (IR) spectra of the compounds; (iii) identifying characteristic spectral differences between dimer and linear; (iv) assigning identified bands as marker bands for identification of the supramolecular synthon, and finally (v) identifying synthons in compounds whose crystal structures are not known. The method has been effectively implemented for assemblies involving dimer/linear weak hydrogen bonds in nitrobenzenes (C–H⋯O–NO), nitro-dimethylamino compounds (NMe2⋯O2N), chalcones (C–H⋯OC), benzonitriles (C–H⋯NC) and fluorobenzoic acids (C–H⋯F–C). Two other special cases of C–H⋯π and N–H⋯π synthons were studied in which the band shape of the C–H stretch in hydrocarbons and the N–H deformation in aminobenzenes was examined.

The crystal structure landscape of the 2:1 benzoic acid:dipyridylethylene cocrystal (BA:DPE-I) is explored experimentally with fluoro-substituted benzoic acids and extended with studies employing the Cambridge Structural Database (CSD). The interpretation of the cocrystal landscape is facilitated by considering the kinetically favored and robust acid–pyridine heterosynthon as a modular unit. Information based on high-throughput crystallography shows that polymorphs and pseudopolymorphs may belong to the same landscape but arise from different crystallization pathways because of complex and different kinetic features, and secondary synthon preferences. Using the CSD as a guide, the coformer was changed from 1,2-bis(4-pyridyl)ethylene (DPE-I) to 1,2-bis(4-pyridyl)ethane (DPE-II) and this provides an extended interpretation of the BA:DPE-I cocrystal landscape, also highlighting the complexity of the kinetic–thermodynamic dichotomy during the molecule-to-crystal progression.

A large number of crystal forms, polymorphs and pseudopolymorphs, have been isolated in the phloroglucinol-dipyridylethylene (PGL:DPE) and phloroglucinol-phenazine (PGL:PHE) systems. An understanding of the intermolecular interactions and synthon preferences in these binary systems enables one to design a ternary molecular solid that consists of PGL, PHE, and DPE, and also others where DPE is replaced by other heterocycles. Clean isolation of these ternary cocrystals demonstrates synthon amplification during crystallization. These results point to the lesser likelihood of polymorphism in multicomponent crystals compared to single-component crystals. The appearance of several crystal forms during crystallization of a multicomponent system can be viewed as combinatorial crystal synthesis with synthon selection from a solution library. The resulting polymorphs and pseudopolymorphs that are obtained constitute a crystal structure landscape.

Intergrowth polymorphism refers to the existence of distinct structural domains within a single crystal of a compound. The phenomenon is exhibited by form II of the active pharmaceutical ingredient felodipine, and the associated microstructure is a significant feature of the compound's structural identity. Employing the technique of nanoindentation on form II reveals a bimodal mechanical response on specific single-crystal faces, demonstrating distinct properties for two polymorphic forms within the same crystal.