Hydrogen-Bond Analysis: Statistical and Computational versus Experimental Position Refinement

The relative accuracy with which O–H···O hydrogen-bonding parameters can be determined using the recently published polynomial neutron-normalization method is compared to that achieved using density functional optimizations at the M062X/6-31+G­(d,p), ωB97X-D/aug-cc-pVDZ, and B3LYP/6-31+G­(d,p) levels of theory. Calculations were repeated at the Hartree–Fock level utilizing the 6-31+G­(d,p) basis set. Pairwise comparisons of the results obtained from these methods with the values measured in neutron diffraction experiments show that the computational and statistical methods are comparable under the conditions applied

Experiences of alien control in schizophrenia reflect a disorder in the central monitoring of action.

Twenty-three acute psychotic patients who were drug free at the time of testing performed a motor task designed to elicit many errors. Normal subjects and many of the psychotic patients were able to correct these errors in the absence of visual feedback. The ability to make such corrections depends on the subject knowing what response he has just made. Patients with experiences of alien control of their thoughts and actions who formed a subgroup of those classified as schizophrenic, were significantly less likely to make error corrections in the absence of visual feedback. This result is consistent with our previous suggestion (Frith, 1987) that these symptoms are a consequence of problems with the central monitoring of responses

Crystal Engineering Approach to Generate Crystalline Inclusion Compounds in Which 5‑Hydroxyisophthalic Acid Serves as a Host

A series of seven crystalline inclusion compounds (CICs) in which 5-hydroxyisophthalic acid (HPA) serves as a host has been isolated. HPA self-assembles to consistently form 2-D hydrogen bonded networks with distorted honeycomb (<b>hcb</b>) topology when crystallized in the presence of guest molecules that contain a carbonyl moiety. In each of the seven structures, the <b>hcb</b> networks formed by HPA contain a phenolic OH group that is exposed to the walls of channels formed by stacking of the <b>hcb</b> networks. These phenolic moieties interact with the carbonyl group of guest molecules via OH (phenol)···O (carbonyl) hydrogen bonding. The consistency of the crystal packing herein is in contrast to the promiscuity in previously reported HPA crystal structures and suggests that HPA can serve as a host for a wide range of guests

Two-Step Mechanochemical Synthesis of Carbene Complexes of Palladium(II) and Platinum(II)

A mechanochemical strategy for the synthesis of <i>N</i>-heterocyclic carbene complexes is described, in which 1,3-dibenzylimidazole complexes of palladium and platinum are produced in a two-step process by grinding together the reactants with a mortar and pestle. Crystallographic characterization reveals that unlike the solution syntheses, which produce a mixture of products, the solid-state reactions occur under topochemical conditions affording isomerically and polymorphically pure products

Investigation into the Solid and Solution Properties of Known and Novel Polymorphs of the Antimicrobial Molecule Clofazimine

Clofazimine is an anti-mycobacterial agent used as part of a multidrug treatment for leprosy. Recently clofazimine has shown promising activity against multidrug resistant tuberculosis. Clofazimine has been previously known to exist in two different crystal forms, or polymorphs, which are triclinic (F I) and monoclinic (F II) in crystal structure. The thermodynamic relationship between, and the solubility of, these different crystal structures of clofazimine has not previously been characterized. In this work, their solid and solution properties are studied, and as a result, two novel polymorphs of clofazimine (an orthorhombic crystal polymorph and a high temperature polymorph with a monoclinic structure) are reported. The properties of these new solid forms are compared and contrasted with those of the two previously reported polymorphs using thermal, spectroscopic, and microscopic techniques. Molecular modeling studies were also carried out to predict the relative thermodynamic relationship and the crystal morphology of the polymorphs. There was an excellent correlation observed between the aforementioned experimental and molecular modeling results, allowing for the unequivocal determination of the thermodynamic relationship between all four polymorphs of clofazimine

Colloidal Cu₂ZnSn(SSe)₄ (CZTSSe) Nanocrystals: Shape and Crystal Phase Control to Form Dots, Arrows, Ellipsoids, and Rods

Herein, we report shape control in the CZTSSe nanocrystal system by tuning the occurrence of polytypism between wurtzite and zinc-blende phases. We have isolated the key control factors in this system and show that the choice of solvents/surfactants and precursors and how they are introduced can allow shape control from dots to ellipsoids to arrows and rods. The shape evolution is dictated by independently controlling the respective growth rates of either the zinc-blende or wurtzite regions in the polytypic system. We further show the extension of this synthetic control to eliminate polytypism while retaining anisotropy allowing for single-phase wurtzite nanorods of CZTSSe

The heterogeneous crystallization of a novel solvate of clozapine base in the presence of excipients

A new methanol solvate of clozapine base (CPB) has been identified. It exhibits different molecular arrangements and bonding environments at low and room temperatures, while still maintaining the same PXRD pattern throughout. Slurry experiments confirmed this CPB–MeOH solvate to be the thermodynamically stable form in suspension relative to CPB. The CPB–MeOH solvate was further characterised using TGA, DSC and VT-PXRD, with VT-PXRD confirming its conversion to CPB upon desolvation via heating. As confirmed by PXRD, CPB–MeOH solvate was also crystallized heterogeneously from MeOH in the presence of dextran (DEX), chitosan (CHT) and microcrystalline cellulose (MCC), with a significant reduction in induction time observed in the presence of all three excipients: 28, 18 and 15-fold in the presence of DEX, CHT, and MCC respectively. The CPB–MeOH solvate crystals in the resultant composite solids were desolvated to CPB upon heating to 120 °C for 6 h, causing their plate-like habit to deform to one containing pores and ridges. The accompanying increase in crystal surface area led to a 3 to 5-fold increase in the extent of CPB's dissolution from these desolvated CPB–MeOH crystals after 5 minutes and also after 1 h relative to normal CPB crystals. Therefore, the potential may exist to enhance the dissolution rate of a poorly-soluble active pharmaceutical ingredient (API), thereby improving its bioavailability, by crystallizing it as a solvate in the presence of an excipient heterosurface and thereafter desolvating the API crystals in the composite solid at high temperature. By so doing, it may no longer be necessary to mill such API crystals during drug formulatio

Cortisone and cortisol break hydrogen-bonding rules to make a drug–prodrug solid solution

Multidrug products enable more effective therapies and simpler administration regimens, provided that a stable formulation is prepared, with the desired composition. In this view, solid solutions have the advantage of combining the stability of a single crystalline phase with the potential of stoichiometry variation of a mixture. Here a drug–prodrug solid solution of cortisone and cortisol (hydrocortisone) is described. Despite the structural differences of the two components, the new phase is obtained both from solution and by supercritical CO2 assisted spray drying. In particular, to enter the solid solution, hydrocortisone must violate Etter’s rules for hydrogen bonding. As a result, its dissolution rate is almost double

Effect of Extra-Framework Anion Substitution on the Properties of a Chiral Crystalline Sponge

Chiral metal–organic materials, CMOMs, are of interest as they can offer selective binding sites for chiral guests. Such binding sites can enable CMOMs to serve as chiral crystalline sponges (CCSs) to determine molecular structure and/or purify enantiomers. We recently reported on the chiral recognition properties of a homochiral cationic diamondoid, dia, network {[Ni(S-IDEC)(bipy)(H2O)][NO3]}n (S-IDEC = S-indoline-2-carboxylicate, bipy = 4,4′-bipyridine), CMOM-5[NO3]. The modularity of CMOM-5[NO3] means there are five feasible approaches to fine-tune structures and properties via substitution of one or more of the following components: metal cation (Ni2+); bridging ligand (S-IDEC); linker (bipy); extra-framework anion (NO3–); and terminal ligand (H2O). Herein, we report the effect of anion substitution on the CCS properties of CMOM-5[NO3] by preparing and characterizing {[Ni(S-IDEC)(bipy)(H2O)][BF4]}n, CMOM-5[BF4]. The chiral channels in CMOM-5[BF4] enabled it to function as a CCS for determination of the absolute crystal structures of both enantiomers of three chiral compounds: 1-phenyl-1-butanol (1P1B); methyl mandelate (MM); ethyl mandelate (EM). Chiral resolution experiments revealed CMOM-5[BF4] to be highly selective toward the S-isomers of MM and EM with enantiomeric excess, ee, values of 82.6 and 78.4%, respectively. The ee measured for S-EM surpasses the 64.3% exhibited by [DyNaL(H2O)4] 6H2O and far exceeds that of CMOM-5[NO3] (6.0%). Structural studies of the binding sites in CMOM-5[BF4] provide insight into their high enantioselectivity

Practical and Highly Selective Sulfur Ylide-Mediated Asymmetric Epoxidations and Aziridinations Using a Cheap and Readily Available Chiral Sulfide: Extensive Studies To Map Out Scope, Limitations, and Rationalization of Diastereo- and Enantioselectivities

The chiral sulfide, isothiocineole, has been synthesized in one step from elemental sulfur, γ-terpinene, and limonene in 61% yield. A mechanism involving radical intermediates for this reaction is proposed based on experimental evidence. The application of isothiocineole to the asymmetric epoxidation of aldehydes and the aziridination of imines is described. Excellent enantioselectivities and diastereoselectivities have been obtained over a wide range of aromatic, aliphatic, and α,β-unsaturated aldehydes using simple protocols. In aziridinations, excellent enantioselectivities and good diastereoselectivities were obtained for a wide range of imines. Mechanistic models have been put forward to rationalize the high selectivities observed, which should enable the sulfide to be used with confidence in synthesis. In epoxidations, the degree of reversibility in betaine formation dominates both the diastereoselectivity and the enantioselectivity. Appropriate tuning of reaction conditions based on understanding the reaction mechanism enables high selectivities to be obtained in most cases. In aziridinations, betaine formation is nonreversible with semistabilized ylides and diastereoselectivities are determined in the betaine forming step and are more variable as a result