Tuning of a Hydrogen-Bonded Organic Framework by Liquid-Assisted Mechanosynthesis between Trans-Aconitic Acid and Isonicotinamide.

Cocrystallization of trans-aconitic acid (TACA) and isonicotinamide (INA) using liquid assisted mechanochemical grinding results in a unique supramolecular hydrogen-bonded organic framework (HOF) system encapsulating various organic solvents (liquid guest) with the formation of channel inclusion compounds. Dimension and shape of the framework is dependent on the solvent used during liquid assisted grinding (LAG). Although crystal structure of the cocrystal (TACA) ⋅ (INA) ⋅ (HO)@(INA) has been determined by Single Crystal X-ray diffraction (SCXRD), crystal structures of 3 cocrystal HOFs were determined by microcrystal electron diffraction (MicroED) and synchrotron X-ray diffraction due to lack of suitable single crystal.

L-Proline catalyzed multi-component synthesis of -pyridyl-tetrahydroisoquinolines and their α-C(sp)-H oxygenation.

Herein, we report an effective multi-component synthesis that starts with readily available starting materials and accesses poly-substituted pyridine derivatives by using L-proline as a benign catalyst. This process uses cyclic amines, aldehydes, and malononitrile in a condensation reaction to produce a variety of pyridine derivatives under mild conditions. Furthermore, depending on the catalysts used, the selective synthesis of an amide and/or an aldehyde functionality is achieved through α-C(sp)-H oxygenation of the tertiary amine moiety in the resultant pyridine derivatives.

In Situ Ni(II) Complexation Induced Deprotonation of Bis-Thiourea-Based Tweezers in DMSO-Water Medium: An Approach toward Recognition of Fluoride Ions in Water with Organic Probe Molecules.

Recognition of fluoride in water through the fluoride-induced Brönsted acid-base deprotonation reaction of an organic probe molecule is still a challenging task owing to the lower basicity of fluoride ions and the instability of the conjugate base of the probe molecules in aqueous medium. Herein, we report a complementary strategy in which the conjugate base of the studied bis-thiourea molecule in dimethyl sulfoxide (DMSO) medium is simultaneously stabilized through chelation of the Ni(II) ion, which eventually facilitates the recognition of the fluoride ion in water samples. The recognition methodology is validated colorimetrically and electrochemically, and finally, the applicability of the approach is explored with water samples collected from fluoride-affected areas.

Revisiting Dimorphs of 4-n-octyloxybenzoic Acid: Contrasting Mechanical Property and Surface Wettability.

4-n-octyloxy benzoic acid is known to exhibit liquid crystalline properties, and under normal pressure and temperature conditions, it exists as at least two crystalline polymorphs. We revisited the system and discovered that single crystals of one of the polymorphs display plastic deformation, whereas the other is brittle. n-octyl chains are arranged in an end-to-end fashion, forming slip planes in the plastically deformable polymorph, whereas they are interdigitated in the crystal structure of the brittle polymorph.

Non-stoichiometric carbamazepine cocrystal hydrates of 3,4-/3,5-dihydroxybenzoic acids: coformer-water exchange.

The cocrystallisation of carbamazepine (CBZ) with 3,4-/3,5-dihydroxybenzoic acids (34/35DHBA) with different stoichiometries formed molecular alloys, exchanging a water molecule, in their isostructural CBZ dihydrate form. Furthermore, we show a correlation between the mechanical properties of the CBZ-DHBA cocrystals with the amount of coformer present.

Polymorphs with Remarkably Distinct Physical and/or Chemical Properties.

Polymorphism in crystals is known since 1822 and the credit goes to Mitscherlich who realized the existence of different crystal structures of the same compound while working with some arsenate and phosphate salts. Later on, this phenomenon was observed also in organic crystals. With the advent of different technologies, especially the easy availability of single crystal XRD instruments, polymorphism in crystals has become a common phenomenon.

Mechanochemical Synthesis of Polymorphic Urea ⋅ Adipic Acid Cocrystal as a Sustained-Release Nitrogen Source.

A 2 : 1 urea ⋅ adipic acid cocrystal was obtained in two polymorphic forms (Form I reported earlier, and Form II synthesized in this study) using mechanochemistry as well as solution crystallization. Lower solubility and leaching study showed the newly synthesized urea ⋅ adipic acid 2 : 1 cocrystal to be an efficient sustained-release nitrogen fertilizer compared to commercially available urea.

Colorimetric detection of fluoride ions in aqueous medium using thiourea derivatives: a transition metal ion assisted approach.

This work explores the position of the hydroxyl moiety and its participation in intramolecular H-bonding towards dictating the fluoride selective colorimetric response in functionalized thiourea derivatives. The study reveals the pivotal aspect of the hydroxyl moiety in C2 towards attaining selectivity for fluoride over acetate and dihydrogenphosphate ion. Furthermore, a methodology employing stabilization of deprotonated thiourea through metal ion (Ni and Cu) coordination is proposed for the colorimetric sensing of fluoride in water medium.

Stimuli-responsive aggregation-induced fluorescence in a series of biphenyl-based Knoevenagel products: effects of substituent active methylene groups on π-π interactions.

A series of three biphenyl-based Knoevenagel products (denoted 1a, 1b, 1c) with active methylene groups has been synthesized. Compounds 1a and 1b show strong solid-state fluorescence, whereas 1c displays low emission. Effects of substituent groups in condensed phase packing of the molecules have been investigated and correlated with their photophysical properties.

L-Proline-catalyzed regioselective C1 arylation of tetrahydroisoquinolines through a multicomponent reaction under solvent-free conditions.

Here we disclose the C1 arylation of tetrahydroisoquinolines (THIQ) through regioselective C(sp3)-H functionalization using a multicomponent reaction. The reaction was performed by reacting THIQ, aldehydes and aminopyrazoles or indoles under neat conditions with l-proline as a catalyst. The regioselectivity of the products was confirmed by X-ray analysis and spectroscopic data.

Effect of solvent polarity in mechanochemistry: preparation of a conglomerate vs. racemate.

Cocrystallization of racemic dl-tartaric acid (dl-ta) and achiral isoniazid (ISN) was investigated using mechanochemistry. Neat grinding (NG) and liquid-assisted grinding (LAG) in the presence of non-polar liquids result in the formation of a conglomerate (ISN·d-ta/ISN·l-ta); whereas LAG with polar liquids yields racemic salt ISN·dl-ta. The effect of solvent polarity and dipole moment in mechanochemistry is discussed.

Efficient Access to Imidazo[1,2- a]pyridines/pyrazines/pyrimidines via Catalyst-Free Annulation Reaction under Microwave Irradiation in Green Solvent.

An expeditious catalyst-free heteroannulation reaction for imidazo[1,2- a]pyridines/pyrimidines/pyrazines was developed in green solvent under microwave irradiation. Using HO-IPA as the reaction medium, various substituted 2-aminopyridines/pyrazines/pyrimidines underwent annulation reaction with α-bromoketones under microwave irradiation to provide the corresponding imidazo[1,2- a]pyridines/pyrimidines/pyrazines in excellent yields. The synthetic methodology appears to be very simple and superior to the already reported procedures with the high abundance of commercial reagents and great ability in expanding the molecular diversity.

First-line antituberculosis drug, pyrazinamide, its pharmaceutically relevant cocrystals and a salt.

A few pyrazinamide (Pyz) cocrystals involving hydroxybenzoic/cinnamic acid derivatives [2,4-dihydroxybenzoic acid (24DHBA); 2,6-dihydroxybenzoic acid (26DHBA); 3,5-dihydroxybenzoic acid (35DHBA) and nutraceutical molecule ferulic acid (FRA)] and the first example of a molecular salt with p-toluenesulfonic acid (pTSA) have been prepared and characterized using various solid-state techniques. A high-temperature cocrystal polymorph of Pyz·FRA has been characterized from the endothermic peaks observed using differential scanning calorimetry. The presence of substituent groups carrying hydrogen bond donors or acceptors and their influence on supramolecular synthon formation has been investigated using a Cambridge Structural Database search.

An investigation of the causes of cocrystal dissociation at high humidity.

The dissociation at high humidity of cocrystals formed between caffeine and theophylline with a series of dicarboxylic acids is investigated and found to be driven by the partial dissolution of the acid, rather than by the formation of caffeine/theophylline hydrate. It is shown that partial dissociation occurs under all humidity conditions, and that cocrystals of compounds which do not form hydrates also dissociate by this mechanism. The observations made in this study indicate that cocrystal instability at high humidity will be a widespread issue, especially for cocrystals where the two coformers have widely differing aqueous solubilities, as is likely for systems where cocrystallisation is being used as means of improving the aqueous solubility, or dissolution rate, of a compound.

Use of in situ atomic force microscopy to follow phase changes at crystal surfaces in real time.

AFM of cocrystals: Atomic force microscopy can be used to observe phase changes at crystal surfaces where the transformation is accompanied by a change in the spacing between layers of molecules. The conversion of a metastable polymorph of the caffeine-glutaric acid cocrystal into the thermodynamically stable form was analyzed continuously in situ using intermittent-contact-mode atomic force microscopy.

Pharmaceutical cocrystals and poorly soluble drugs.

In recent years cocrystal formation has emerged as a viable strategy towards improving the solubility and bioavailability of poorly soluble drugs. In this review the success of numerous pharmaceutical cocrystals for the improvement of the solubility and dissolution rates of poorly soluble drugs is demonstrated using various examples taken from the literature. The role of crystal engineering principles in the selection of appropriate coformers and the nature of the supramolecular synthons present within the crystals are described.

Polymorphic form IV of olanzapine.

2-Methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine, C(17)H(20)N(4)S, commonly known as olanzapine, is a psychotropic agent that belongs to the thienobenzodiazepine class of drugs. A new polymorph form IV was obtained upon attempted cocrystallization with nicotinamide in a 1:1 ratio from an ethyl acetate solution. Two butterfly-like molecules form centrosymmetric dimers stabilized by weak C-H···π interactions between the 4-methylpiperazin-1-yl fragment and the benzene/thiophene aromatic system.