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. The limit of detection value for the fluoride ion in water medium was found to be 0.2 and 0.3 ppm with UV-visible spectroscopy and differential pulse voltammetry measurements, respectively. The methodology is also demonstrated on a paper strip for the detection of the fluoride ion with the naked eye and a smartphone-based RGB sensor. The scheme has been shown to be effective in enhancing the aqueous fluoride recognition ability of the organic probe molecules with acidic hydrogen prone to deprotonation by the fluoride ion.

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. Due to the difference in the arrangement of the -COOH group and alkyl chains, the major faces of the crystals of both polymorphs possess significant differences in the wettability towards moisture.

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. Almost 37 % of compounds (single component) are polymorphic to date. As the energies of the different polymorphic forms are very close to each other, small changes in crystallization conditions might lead to different polymorphic structures. As a result, sometimes it is difficult to control polymorphism. For this reason, it is considered to be a nuisance to crystal engineering. It has been realized that the property of a material depends not only on the molecular structure but also on its crystal structure. Therefore, it is not only of interest to academia but also has widespread applications in the materials science as well as pharmaceutical industries. In this review, we have discussed polymorphism which causes significant changes in materials properties in different fields of solid-state science, such as electrical, magnetic, SHG, thermal expansion, mechanical, luminescence, color, and pharmaceutical. Therefore, this review will interest researchers from supramolecular chemistry, materials science as well as medicinal chemistry.

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 (Ni2+ and Cu2+) coordination is proposed for the colorimetric sensing of fluoride in water medium. The mechanism of interaction is thoroughly studied by UV-Vis, 1H NMR, ESR spectroscopy, electrochemical techniques and further validated by DFT calculations. This study reveals the formation of an in situ Ni2+ complex that shows greater stability in aqueous medium. The methodology is applied in the detection of fluoride in groundwater samples.

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. The formation of an azomethine ylide intermediate is crucial for obtaining the regioselectivity.

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.

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. Interestingly, compound 1a exhibits mechanofluorochromism with emission color changes from yellow to green (wavelength shift of 40 nm) after mechanical grinding. Furthermore, fluorescence of 1a and 1b is turned off under alkaline conditions, making them potential candidates for aggregation-enhanced emission-based pH sensors.

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 H2O-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. The present synthetic sequence is visualized as an environmentally benign process which allows the introduction of three points of structural diversity to expand chemical space with excellent purity and yields. The anti-inflammatory and antimicrobial activities of the derivatives were evaluated. Screening results uncovered three derivatives with strong inhibition of albumin denaturation and two derivatives were active on Proteus and Klebsiella bacteria. These positive bioassay results implied that the library of potential anti-inflammatory agents could be rapidly prepared in an ecofriendly manner, and provided new insights into drug discovery for medicinal chemists.

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. Equilibrium solubility of all the binary complexes of Pyz follows the order of their coformer solubility, i.e. Pyz+·pTSA- > Pyz·35DHBA > Pyz > Pyz·26DHBA > Pyz·24DHBA > Pyz·FRA. A twofold enhancement in solubility of Pyz+·pTSA- molecular salt compared with the parent drug suggests a potential drug formulation for the treatment of tuberculosis.

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. Evidence for improved animal pharmacokinetic data is given for several systems. A summary is provided of our current understanding of the relationship between cocrystal structure and solution phase interactions on solubility as well as those factors that influence overall cocrystal thermodynamic stability.

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. Form IV consists of a herringbone arrangement of dimers, whereas the previously reported form II has parallel dimers. Both crystal structures are sustained by an N-H···N hydrogen bond.