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Ultrasound-assisted crystallization (sonocrystalliza- tion) was used to prepare a mixture of nano- and micrometer- sized crystals of the monoclinic form of paracetamol—a widely used analgesic known for its particularly problematic mechan- ical behavior under compression (i.e. poor tabletability). The nano- and micrometer-sized crystals yielded a powder which exhibits elastic moduli and bulk cohesions that are significantly higher than those observed in samples consisting of macro- meter-sized crystals, thus leading to enhanced tabletability without the use of excipients, particle coating, salt, or cocrystal formation. Experimental compaction and finite element anal- ysis were utilized to rationalize the significantly improved compaction behavior of the monoclinic form of paracetamol. The current demand for organic nanomaterials (1, 2) has triggered the development of fabrication methods for organic nanocrystals. (3-10) Recent pharmaceutical and biomedical research has shown that molecular nanocrystals are highly valuable in the context of drug delivery, biolabeling, and biosensing. (11, 12) Nanosizing of molecular crystals has also become a particularly popular approach in drug development with poorly soluble pharmaceutical agents (13) and is mainly used to enhance the solubility and bioavailability of the drug candidate. (14, 15) Surprisingly, other applications of molecular crystals, despite their unique physicochemical properties, have been relatively unexplored in biomedical (and other) sciences. We show herein through the use of sonocrystalliza- tion, (16, 17) that is, the use of ultrasound to facilitate crystal

The crystal and molecular structure of trans-1,2-bis(2-benzothiazolyl)ethene is reported. Crystal data for 1: monoclinic, space group C 2/c, a = 24.926(3) A, b = 4.843(1) A, c = 11.164(1) A, β = 105.274(5) °, V = 1300.0(3) A3, and D c = 1.50 g/cm3 for Z = 4 and R = 0.028. The molecule crystallizes in the form of a colorless plate and forms one-dimensional slipped π-stacks. The title compound crystallizes to form 1D slipped π-stacks in the solid state.

The mol­ecules of the title bis­(thio­morpholine) adduct of bis­(1,3-diphenyl­propane-1,3-dionato)cobalt(II), [Co(C15H12O2)2(C4H8NS)2], in the crystal structure are positioned on an inversion center at the inter­section of a twofold rotation axis and a perpendicular mirror plane. The two thio­morpholine ligands bond to the octahedral cobalt(II) ion in the axial coordination sites (trans configuration).

Photoreactive Ag(I) organosulfonate complexes involving (E)-methyl-3-(pyridin-3-yl)prop-2-enoate (3-PAMe) are reported. Argentophilic interactions stack 3-PAMe to undergo a head-to-head intermolecular [2+2] photodimerisation to generate (rctt)-dimethyl-3,4-bis(pyridine-3-yl)cyclobutane-1,2-dicarboxylate (3,3′-MeBPCD) in the solid state regioselectively and in quantitative yield. The organosulfonate participates in C–H…O interactions with the coordinated 3-pyridyl groups to effectively aid in crystal engineering of the reactivity.

Cocrystallisation of sildenafil with acetylsalicylic acid yields a 1 : 1 sildenafil–acetylsalicylic-acid cocrystal, as well as a 1 : 1 : 1 cocrystal salt involving a sildenafil cation, acetylsalicylate and salicylic acid. The 1 : 1 acetylsalicylic-acid-based cocrystal exhibits an enhanced intrinsic dissolution rate, as compared to sildenafil citrate (the active ingredient of Viagra®).

In the title complex, [Ni(C10H9O2)2(C10H17N)2], the Ni atom, which occupies a special position at an inversion centre, has an octa­hedral environment formed by four O atoms of two chelate benzoyl­acetonates [Ni—O 2.0409 (16) and 2.0187 (16) A, and O—Ni—O 90.36 (6)°] and two N atoms of the adamantylamine ligands [Ni—N = 2.176 (2) A]. The amine H atoms of the adamantylamine ligands do not participate in any hydrogen bonds, due to their steric shielding and the lack of accessible acceptors.

In the reaction of bis(1,3-di­phenyl-1,3-propane­dionato)­oxovanadium(IV) with pyridine, a 1:1 adduct is formed, viz bis(1,3-di­phenyl-1,3-propane­dionato-κ2O,O′)­oxo­(pyridine-κN)­vanadium(IV), [V(C15H10O2)2O(C5H5N)]. The V atom is surrounded by one pyridine ligand, two 1,3-di­phenyl-1,3-propandionate (dbm) ligands and one oxo group. The complex exhibits a distorted octahedral coordination, with the oxo group and pyridine ligand in a cis configuration. Pairs of mol­ecules of the adduct are connected by an intermolecular C41—H41⋯O1(−x, 2 − y, 1 − z) contact of 3.171 (3) A and thus form dimers in the solid state.

In the reaction of bis(1-phenyl­butane-1,3-dionato)­nickel(II) with di­methyl sulfoxide, the adduct bis­(di­methyl sulfoxide)­bis(1-phenyl­butane-1,3-dionato)­nickel(II), [Ni(C10H9O2)2(C2H6OS)2], is formed, in which two di­methyl sulfoxide (DMSO) mol­ecules are coordinated to the Ni atom through their O atoms in a trans arrangement. The compound crystallizes in space group P21/a with the Ni atom lying on a center of inversion. The coordination polyhedron around the Ni atom is a distorted octahedron. The chelate ring deviates slightly from planarity. The Ni—O bond distance to the DMSO O atom is slightly longer than that to the 1-phenyl­;butane-1,3-dionate ligand. In the crystal structure, two-dimensional frameworks are formed by C–H⋯O interactions.

A survey of the Cambridge Structural Database (CSD) revealed the existence of a new supramolecular homosynthon in oxovanadium coordination compounds (OCCs) that is based on non-covalent V=O...C interactions. V=O...C close contacts were found in 38.7% of structures containing vanadyl or pervanadyl groups. The V=O...C interaction is clearly distinguishable from a putative V=O...H–C hydrogen bond upon analysis of OCC crystal structures deposited in the CSD. In the majority of structures, the OCCs assemble to form dimers or polymers. The V=O...C interactions were also found to lead to self-assembly of two new oxovanadium β-diketonate complexes into dimers in the solid state.

In the adduct bis(1-phenyl-1,3-butanedionate)­bis(3-amino­pyridine)­nickel(II), [Ni(C10H9O2)2(C5H6N2)2], the NiII atom lies on a crystallographic center of symmetry. The coordination geometry around the NiII atom is distorted octahedral. Four O atoms of two 1-phenyl-1,3-butanedionate ligands form the equatorial plane, with Ni—O distances in the range 2.0160 (14)–2.0338 (14) A. The axial positions are occupied by N atoms of two 3-amino­pyridine ligands. The adduct mol­ecules translated by one unit along the a axis are linked by N—H⋯O hydrogen bonds, forming chains.

A discrete dinuclear Ag(I) complex undergoes a single-crystal-to-single-crystal transformation to generate a 1D coordination polymer with a polycyclobutane backbone.

Here, we highlight recent research involving atomic force microscopy investigations of molecular crystals, and focus particularly on the latest relevant advances in our knowledge of crystal-growth mechanisms and structure-property relationships in organic crystals. This brief survey features the importance of incorporating AFM into solid-state research as an essential tool for the informed design and construction of crystalline materials.

Multi-component organic nanocrystals that are comprised of two or more supramolecular building blocks can be used to extend the design and assembly scope of solid molecular materials. Herein, we report the use of ultrasonication to prepare halogen-bonded stilbene-based nano-cocrystals that exhibit different photoemission properties, including one- and two-phonon emission and fluorescence lifetimes, relative to those of macrodimensional crystals. The structural transformation from nano-cocrystals into nanocrystals upon heating results in a luminescence red-shift from greenish blue to yellow. The temperature-dependent ratiometric luminescence may allow such nano-cocrystals to be used as fluorescent sensors and thermosensitive materials.

Here, we highlight recent research involving atomic force microscopy investigations of molecular crystals, and focus particularly on the latest relevant advances in our knowledge of crystal-growth mechanisms and structure-property relationships in organic crystals. This brief survey features the importance of incorporating AFM into solid-state research as an essential tool for the informed design and construction of crystalline materials.

Nano- and micrometer-scale crystals of a self-assembled hexamer have been synthesized via sonochemistry. The application of ultrasonic irradiation afforded hollow rhombic-dodecahedral crystals of the C-methylcalix[4]resorcinarene hexamer. The formation of the hollow crystals is attributed to a reversed crystal growth mechanism heretofore described only in the synthesis of inorganic-based materials.

A ditopic hydrogen-bond-donor template in the form of resorcinol facilitates a [2+2] cross-photodimerisation of 4-Cl-stilbazole and 4-Me-stilbazole in a rare cocrystal solid solution. A photoreaction does not proceed with the olefins individually or as a solid solution composed solely of the two olefins.

Facile reactivity of hydrazides and aldehydes was explored as potential coupling partners for incorporation into M(CO)(3) (M = Re, (99m)Tc) based radiopharmaceuticals. Both 'click, then chelate' and 'prelabel, then click' synthetic routes produced identical products in high yields and lacked metal-hydrazide/-hydrazone interactions, highlighting the potential of this click strategy.

A resorcinol achieves a templated stereospecific and near-quantitative synthesis of a cofacial terpyridine in the solid state. The solid-state synthesis occurs in one-dimensional π-stacked columns with reactivities highly sensitive to peripheral groups attached to the template.

Metallogels form from Cu(II) ions and tetratopic ligand rctt-1,2-bis(3-pyridyl)-3,4-bis(4-pyridyl)cyclobutane. The tetrapyridyl cyclobutane has been synthesized in the organic solid state. The gel forms with a variety of counteranions and gels water. The hydrogel is thixotropic and is composed of nanoscale metal-organic particles (NMOPs), a high surface area of which likely accounts for the gelation of the polar aqueous medium. A shear stress profile of the thixotropic hydrogel gave a yield value of 8.33 Pa. A novel combination of atomic force microscopy (AFM) and scanning transmission X-ray microscopy (STXM) is used to assess the densities of individual NMOPs. A density of 1.37 g/cm(3) has been determined. A single-crystal X-ray diffraction study demonstrates the ability of the unsymmetrical cyclobutane 3,4'-tpcb to self-assemble with Cu(II) ions in [Cu(2)(hfac)(4)(3,4'-tpcb)](∞) (where hfac is hexafluoroacetylacetonate) to form a solvated 1D coordination polymer.

We report on a co-crystal of acetaminophen (APAP) and 2,4-pyridinedicarboxylic acid (PDA). The co-crystal was discovered by screening using the solution-mediated phase transformation (SMPT) technique. Despite the bulk solids of each component being white in color, the new co-crystal phase exhibited a red color. The new phase was analyzed using single-crystal X-ray diffraction and identified as (APAP).(PDA).(1). Structural analysis revealed PDA to exist in a hitherto unreported zwitterionic form in the co-crystal. A structural analysis of pure PDA revealed the presence of the zwitterion form in (PDA).(H(2)O) (2), as well. The components of 1 self-assemble as a three-dimensional (3D) hydrogen-bonded network with a pronounced 2D structure. The origin of the red color was investigated using density functional theory calculations, which demonstrate a decreasing pi-pi(*) separation involving the components of the solid.

Reaction of 4-vinylpyridine with AgClO(3) yields a crystalline solid that supports a stereospecific and quantitative [2+2] photodimerisation of two terminal olefins. Structural dynamics of the -CH[double bond, length as m-dash]CH(2) group, nature of the counterion, and extended packing influence the photoreactivity.

Two distinct "click" chemistry labeling approaches were investigated with dipyridylamine alkyne derivatives and M(CO)(3)(+) (M = Re, (99m)Tc). The triazole ring was found uncoordinated and was incorporated into the preparation of a crossover androgen receptor targeting inhibitor for prostate cancer.

Supermolecules with olefins organized by hydrogen-bond donor and acceptor templates and that react in the solid state rapidly form co-crystals via solvent-free and liquid-assisted grinding.

We describe how reactivity can be controlled in the solid state using molecules and self-assembled metal-organic complexes as templates. Being able to control reactivity in the solid state bears relevance to synthetic chemistry and materials science. The former offers a promise to synthesize molecules that may be impossible to realize from the liquid phase while also taking advantage of the benefits of conducting highly stereocontrolled reactions in a solvent-free environment (i.e., green chemistry). The latter provides an opportunity to modify bulk physical properties of solids (e.g., optical properties) through changes to molecular structure that result from a solid-state reaction. Reactions in the solid state have been difficult to control owing to frustrating effects of molecular close packing. The high degree of order provided by the solid state also means that the templates can be developed to determine how principles of supramolecular chemistry can be generally employed to form covalent bonds. The paradigm of synthetic chemistry employed by Nature is based on integrating noncovalent and covalent bonds. The templates assemble olefins via either hydrogen bond or coordination-driven self-assembly for intermolecular [2 + 2] photodimerizations. The olefins are assembled within discrete, or finite, self-assembled complexes, which effectively decouples chemical reactivity from effects of crystal packing. The control of the solid-state assembly process affords the supramolecular construction of targets in the form of cyclophanes and ladderanes. The targets form stereospecifically, in quantitative yield, and in gram amounts. Both [3]- and [5]-ladderanes have been synthesized. The ladderanes are comparable to natural ladderane lipids, which are a new and exciting class of natural products recently discovered in anaerobic marine bacteria. The organic templates function as either hydrogen bond donors or hydrogen bond acceptors. The donors and acceptors generate cyclobutanes lined with pyridyl and carboxylic acid groups, respectively. The metal-organic templates are based on Zn(II) and Ag(I) ions. The reactivity involving Zn(II) ions is shown to affect optical properties in the form of solid-state fluorescence. The solids based on both the organic and metal-organic templates undergo rare single-crystal-to-single-crystal reactions. We also demonstrate how the cyclobutanes obtained from this method can be applied as novel polytopic ligands of metallosupramolecular assemblies (e.g., self-assembled capsules) and materials (e.g., metal-organic frameworks). Sonochemistry is also used to generate nanostructured single crystals of the multicomponent solids or cocrystals based on the organic templates. Collectively, our observations suggest that the organic solid state can be integrated into more mainstream settings of synthetic organic chemistry and be developed to construct functional crystalline solids.

Tetratopic rctt-tetrakis(4-pyridyl)cyclobutane acts as an angular bifunctional ligand that yields a single-stranded helicate coordination polymer based on a Ln(III) ion.

In this microreview, we show how principles of coordination-driven self-assembly can be used to direct chemical reactivity in the organic solid state. We also show how products obtained from the templated solid-state reactions can be used as organic building units of metal–organic frameworks and coordination capsules. Self-assembled structures based on dinuclear ZnII and AgI complexes are used to direct stereocontrolled [2+2] photodimerizations of vinylpyridines in the solid state in up to quantitative yield. The products are used as bi- and polytopic ligands of self-assembled coordination capsules and metal–organic frameworks. We also describe emerging metal-based approaches to conduct mechanochemical reactions in organic solids. In addition to the field of supramolecular coordination chemistry, these observations impact the field of green chemistry.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

An achiral ligand, synthesized in the solid state via a coded hydrogen bond-directed organic synthesis, self-assembles with Cu(II) ions to form a chiral tetrahedral capsule that hosts an anion as a guest.

Co-crystal formation between caffeine and adipic acid has been explored over the years without success; utilizing the newly developed co-crystal screening method, we have finally discovered this “hidden” caffeine and adipic acid co-crystal.

In this microreview, we show how principles of coordination-driven self -assembly can be used to direct chemical reactivity in the organic solid state. We also show how products obtained from the templated solid-state reactions can be used as organic building units of metal-organic frameworks and coordination capsules. Self-assembled structures based on dinuclear Zn-II and Ag-I complexes are used to direct stereocontrolled [2+2] photodimerizations of vinylpyridines in the solid state in up to quantitative yield. The products are used as bi- and polytopic ligands of self-assembled coordination capsules and metal-organic frameworks. We also describe emerging metal-based approaches to conduct mechanochemical reactions in organic solids. In addition to the field of supramolecular coordination chemistry, these observations impact the field of green chemistry.

We show that a molecule constructed from an organic solid-state synthesis, namely, rctt-1,3-bis(2-pyridyl)-2,4-bis(4-pyridyl)cyclobutane (ht-2,4 ‘-tpcb) upon reaction with Cu(II) and Zn(II) ions gives one- (1D) and two-dimensional (2D) metal-organic frameworks (MOFs) of composition [Cu(hfac)(2)(2,4 ‘-tpcb-ht)](infinity) (where: hfac=hexafluoroacetylacetonate) (1) and [Zn(2,4 ‘-tpcb-ht)(2)(H2O)(2)](infinity)(2+), (2). Each MOF possesses uncoordinated, or free, 2-pyridyl groups that decorate the walls of each extended structure. (c) 2006 Elsevier B.V. All rights reserved.

Metal-organic polyhedra with surface-exposed organic groups have been designed. The polyhedra are based on concentric shells of alternating negative-positive-negative charges and have been used to design homochiral hosts.

Cocrystals are multicomponent solids with organic molecules assembled in combination to form a crystalline solid with properties different than the individual components. A cocrystal typically consists of a target molecule crystallized with a second molecule, or cocrystal former, employed to influence properties of the target (e.g., solubility). The conformer interacts with the target via intermolecular forces (e.g., hydrogen bonds) that hold the components together. The modularity of a cocrystal makes such solids attractive for applications where fine-tuning of properties is important (e.g., optical). In this presentation, we describe the use of sonochemistry to form cocrystals of nanoscale dimensions. In contrast to single-component solids, cocrystals present a fundamentally different challenge with respect to those reprecipitation methods used to form nanocrystals since the components of a cocrystal will tend to exhibit different solubilities. We show that sonochemistry affords nano-cocrystals with properties (e.g., reactivity) that contrast solids of macroscale dimensions. Related applications of sonochemistry to afford single-component nanocrystals will also be presented.

Cocrystals are modular multicomponent solids with exceptional utility in synthetic chemistry and materials science. A variety of methods exist for the preparation of cocrystals, yet, some promising cocrystal phases have proven to be intractable synthetic targets. We describe a strategy for the synthesis of the pharmaceutically relevant (caffeine)·(benzoic acid) cocrystal (1), which persistently failed to form using a broad range of established techniques. State-of-the-art crystal structure prediction methods were employed to assess the possible existence of a thermodynamically stable form of 1, hence to identify appropriate heteronuclear seeds for cocrystallization. Once introduced, the designed heteronuclear seeds facilitated the formation of 1 and, significantly they (or seeds of the product cocrystal) continued to act as long-lasting laboratory “contaminants”, which encouraged cocrystal formation even when present at such low levels as to evade detection. The seeding technique described thus enables the synthesis of cocrystals regarded as unobtainable under desired conditions, and potentially signifies a new direction in the field of materials research.

Mechanochemical cocrystallisation was utilised to prepare fluorescein cocrystals involving pyridyl-based cocrystal formers, which exhibit different crystal structures, thermal and optical properties than those obtained via solution-based crystallisation.

An approach to form organic thin films that employs multicomponent solids in the form of co-crystals has been developed. The components direct an intermolecular [2+2] photodimerization that we demonstrate exhibits a change in solubility that can be exploited as a negative photoresist for use in photolithography.

A series of cocrystals of acetaminophen and trans-1,2-bis(4-pyridyl)ethylene are reported wherein there is a lack of direct hydrogen-bonding between the components owing to interjected water molecules. A survey of the Cambridge Structural Database demonstrates that interjected water molecules involving cocrystals with similar components are rare. We term the lack of interaction as a ‘masked synthon’, which we aim to contribute to the development of synthon theory in organic solid-state chemistry.

Four new multi-component crystals of a carboxylic acid derivative of coumarin have been synthesised based on a hydrogen bond synthon approach.

The unsymmetrical tetratopic ligand rctt-1,2-bis(3-pyridyl)-3,4-bis(4-pyridyl)cyclobutane self-assembles with zinc(II) nitrate to form a 2D metal–organic framework with three distinct cavities.

Tetratopic rctt-tetrakis(4-pyridyl)cyclobutane acts as an angular bifunctional ligand that yields a single-stranded helicate coordination polymer based on a Ln(III) ion.