Aluminum Montmorillonite/Polyaniline Hybrid Composite-Based Organogels for the Expurgation of Carcinogenic Chlorophenols and Congo Red Dye from Defiled Water Sources.

Chlorophenol and Congo Red dye being highly toxic are well known for their carcinogenic activity. This work focuses on preparing an organogel for the removal of both chlorophenol and Congo Red. PAni molecules were grafted in situ between the layers of montmorillonite (MMT) to form a PAni/MMT composite, which was further modified to form a gel structure. The composite was thoroughly characterized by high-resolution X-ray diffraction (HR-XRD), Fourier transform infrared (FT-IR) analysis, Brunauer-Emmett-Teller (BET) analysis, and thermogravimetric analysis (TGA). The gel was further analyzed by scanning electron microscopy (SEM) and by studying the rheological properties. The resulting gel exhibited an impressive solvent uptake, with a maximum of 2084% (20 times) for chlorophenol, while the dye adsorption capacity was 349.72 mg/g with 99.44% removal efficiency. The adsorption proceeded with the pseudo-second-order model followed by the Langmuir monolayer adsorption model and Weber's intraparticle diffusion model. The sorbent was found to be selective among cationic dyes while retaining 83% of dye even in the fifth cycle. The hybrid sorbent shows great promise for sustainable purposes, and the results of this study are certainly encouraging.

PCy3-assisted Ag(I)-catalyzed click reaction for regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles at room temperature.

An approach towards Cu-free click chemistry has been developed in this work. Silver-catalyzed PCy3-ligand-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles at room temperature has been developed. Regioselectivity of the reaction was confirmed from the results of single-crystal X-ray diffraction (SC-XRD) of one of the products. SC-XRD of ex situ-generated Ag-PCy3 complex helped us propose a plausible mechanism for the reaction. This reaction was indicated to exhibit a catalytic activity level similar to that for the in situ-generated complex. The methodology was found to work well with benzyl azides, phenyl azides, terminal alkynes and internal alkynes in aqueous medium. The one-pot three-component reaction leading to 1,2,3-triazole synthesis also proceeded well.

Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs.

The subject of crystal engineering started in the 1970s with the study of topochemical reactions in the solid state. A broad chemical definition of crystal engineering was published in 1989, and the supramolecular synthon concept was proposed in 1995 followed by heterosynthons and their potential applications for the design of pharmaceutical cocrystals in 2004. This review traces the development of supramolecular synthons as robust and recurring hydrogen bond patterns for the design and construction of supramolecular architectures, notably, pharmaceutical cocrystals beginning in the early 2000s to the present time. The ability of a cocrystal between an active pharmaceutical ingredient (API) and a pharmaceutically acceptable coformer to systematically tune the physicochemical properties of a drug (i.e., solubility, permeability, hydration, color, compaction, tableting, bioavailability) without changing its molecular structure is the hallmark of the pharmaceutical cocrystals platform, as a bridge between drug discovery and pharmaceutical development. With the design of cocrystals via heterosynthons and prototype case studies to improve drug solubility in place (2000-2015), the period between 2015 to the present time has witnessed the launch of several salt-cocrystal drugs with improved efficacy and high bioavailability. This review on the design, synthesis, and applications of pharmaceutical cocrystals to afford improved drug products and drug substances will interest researchers in crystal engineering, supramolecular chemistry, medicinal chemistry, process development, and pharmaceutical and materials sciences. The scale-up of drug cocrystals and salts using continuous manufacturing technologies provides high-value pharmaceuticals with economic and environmental benefits.

Utilization of Aryl(TMP)iodonium Salts for Copper-Catalyzed N-Arylation of Isatoic Anhydrides: An Avenue to Fenamic Acid Derivatives and N,N'-Diarylindazol-3-ones.

Herein, we report a general method for copper-catalyzed N-arylation of isatoic anhydrides with unsymmetrical iodonium salts at room temperature. The developed catalytic protocol is mild and operationally simple, and aryl(TMP)iodonium trifluoroacetate is employed as the arylating partner. The methodology offers the broad applicability of both structurally and electronically diverse aryl groups from aryl(TMP)iodonium salts to access N-arylated isatoic anhydrides in moderate to excellent yields (53-92%). Moreover, the substituted isatoic anhydrides are equally compatible with the protocol too. To demonstrate the synthetic utilities of the N-arylation process, we also report an alternative approach for biologically relevant fenamic acid derivatives and N,N'-diarylindazol-3-ones in a one-pot step economical system. In addition, the scale-up synthesis of flufenamic acid is also illustrated.

Redox-Neutral Three-Component Coupling of Phenacyl Azides, Aldehydes, and 1,3-Dicarbonyls to Access ß-Enaminodiones.

Heating an equimolar mixture of phenacyl azides, aldehydes, and cyclic 1,3-dicarbonyls to 100 °C without any solvent, catalyst, or additive led to efficient three-component redox-neutral coupling to yield ß-enaminodiones in high yields (75-86%). The scope of the synthetic method that gives dinitrogen and water as the only byproducts was successfully demonstrated by synthesizing 34 structurally diverse ß-enaminodiones by taking differentially substituted phenacyl azides, aldehydes and 4-hydroxycoumarins, and 4-hydroxy-1-methylquinolin-2(1H)-one and dimedone.

Molecular-iodine catalyzed selective construction of cyclopenta[b]indoles from indoles and acetone: a green gateway to indole-fused cycles.

Molecular-iodine catalyzed access to an important class of bio-relevant indole derivatives, cyclopenta[b]indoles, has been achieved via a cascade addition/intramolecular cyclization reaction of indoles and acetone. Explorations of diverse substitution patterns revealed an essential substrate-control in the reaction. The high-density electronic core of indole is pivotal in favouring the formation of indolyl-cyclopenta[b]indole derivatives; in contrast, the electron deficiency of the core hindered the cyclization process, directing the formation of bis(indolyl)propanes. Investigations on the mechanistic pathway revealed that bis(indolyl)alkanes were the intermediates for the addition-cyclization process. This simple experimental method provides sustainable synthetic access to cyclopentannulated indoles.

Room temperature ligand-free Cu2O-H2O2 catalyzed tandem oxidative synthesis of quinazoline-4(3H)-one and quinazoline derivatives.

An efficient and simple copper catalytic system has been developed for the synthesis of medicinally important 2-substituted quinazoline-4(3H)-ones from 2-aminobenzonitrile and benzyl alcohol derivatives and additionally 2-substituted quinazolines from 2-aminobenzylamine and benzaldehyde derivatives. Mild oxidant H2O2 was utilized, providing excellent product yields. The molecular structure of one of the compounds was substantiated through SC-XRD. The versatility of the protocol was demonstrated through gram-scale syntheses.

N,N'-Dimethylurea as an efficient ligand for the synthesis of pharma-relevant motifs through Chan-Lam cross-coupling strategy.

N,N'-Dimethylurea (DMU) is introduced as a ligand to aid the Chan-Lam N-arylation of primary amides, amines, and 3-aminophenols with arylboronic acids and its ester derivative as the arylating associate. The developed methodology is catalyzed by Cu and its in situ complexation with DMU brings about efficient synthesis of N-arylated anilines, 3-aminophenols, and primary amides in moderate to good yields (50-90%). The [Cu2(OAc)4(DMU)2] complex is synthesized and characterized by single crystal structure elucidation. The catalyst is cheap, free from prior synthesis of a metal complex, provides chemoselectivity towards the N-arylation of 3-aminophenols, and is suitable for mono-arylation of primary amides. The synthetic utility of the methodology is tested in the post-modification of two active pharmaceutical ingredients (APIs). The developed catalytic system extends the scope of N,N'-dimethylurea as an auxiliary in inexpensive and versatile Cu catalysis.

Metal-Free Regioselective N2-Arylation of 1H-Tetrazoles with Diaryliodonium Salts.

We describe a simple, metal-free regioselective N2-arylation strategy for 5-substituted-1H-tetrazoles with diaryliodonium salts to access 2-aryl-5-substituted-tetrazoles. Diaryliodonium salts with a wide range of both electron-rich and previously challenged electron-deficient aryl groups are applicable in this method. Diversely functionalized tetrazoles are tolerable also. We have devised a one-pot system to synthesize 2,5-diaryl-tetrazoles directly from nitriles. The synthetic utility of this method is furthered extended to late-stage arylation of two biologically active molecules.

Oriented Crystallization on Organic Monolayers to Control Concomitant Polymorphism.

Nucleation events and crystal growth can be guided by molecular recognition at interfaces through intermolecular interactions. The short-acting antimicrobial sulfa drug sulfathiazole is known for its concomitant crystallization, which has five known polymorphs, due to conformational flexibility and hydrogen-bond synthon variation. In its development stage of a drug the issue of concomitant crystallization needs to be addressed with respect to patent litigation, including legal actions to protect patents against infringement. A functional self-assembled monolayer (SAM) of organic thiol on a gold surface has been employed as an efficient approach to control concomitant nucleation of such flexible drugs. The crystallization on a SAM surface is mostly kinetically driven and often leads to the nucleation of novel metastable forms. Spectroscopic, thermal analysis and X-ray diffraction studies reveal that a previously unknown, sixth form of the drug nucleates on the designed SAM surface.

Regioselectivity of the trifluoroethanol-promoted intramolecular N-Boc-epoxide cyclization towards 1,3-oxazolidin-2-ones and 1,3-oxazinan-2-ones.

The intramolecular N-Boc-epoxide cyclization leading to the formation of 1,3-oxazolidin-2-one and 1,3-oxazinan-2-one derivatives has scarcely been reported in the literature. More specifically, the intramolecular cyclization of N-Boc aniline-tethered 2,3-disubstitued epoxides has never been disclosed. Herein, we demonstrate that this reaction could proceed in a diastereoselective fashion in refluxing trifluoroethanol, in the absence of any external promoter or catalyst. Substrates bearing an alkyl group at the C-3 position furnished 1,3-oxazolidin-2-ones in a completely regioselective fashion via 5-exo epoxide ring-opening cyclization, thereby paving the way to synthesize alkyl side chain-bearing analogs of the antidepressant drug toloxatone. On the other hand, replacing the alkyl group with an aryl group resulted in easily separable mixtures of 1,3-oxazolidin-2-ones and 1,3-oxazinan-2-ones, the former being obtained as the major products. Remarkably, a tetralin-bearing substrate underwent fully regioselective 6-endo ring closure to form the corresponding 1,3-oxazinan-2-one. Our present study on the intramolecular ring opening-cyclization of epoxides with a tethered N-Boc group is the most comprehensive to date and features broad substrate scope, mild transition metal-free conditions, excellent functional group tolerance, and scalability.

Switching of regioselectivity in base-mediated diastereoselective annulation of 2,3-epoxy tosylates and their N-tosylaziridine analogs with 2-mercaptobenzimidazole.

A base-mediated dinucleophilic cyclization of readily accessible 2,3-epoxy tosylates with 2-mercaptobenzimidazole has been developed for the one-pot diastereoselective synthesis of benzimidazole-based tricyclic compounds equipped with two stereogenic centres. With trans-substrates bearing an aryl or alkyl substituent at the C3 position, the reaction involves an initial S-C1 bond-forming intermolecular alkylation followed by an N-C3 bond-forming, endo-selective intramolecular epoxide ring-opening cyclization reaction. A spectacular regioselectivity switching (tandem S-C3 and N-C1 bond formation reactions) was observed with related trans-N-tosylaziridine substrates. Wide substrate scope, complete diastereoselectivity, high to complete regioselectivity and mild transition metal-free conditions render this protocol particularly efficient and practical.

Ruthenium(II)-Catalyzed Dearomatized C-H Activation and Annulation Reaction of Vinylnaphthols with Alkynes: Access to Spiro-Pentacyclic Naphthalenones.

The ruthenium(II)-catalyzed annulation of vinylnaphthols and alkynes is described. The reaction proceeds through C-H activation, dearomatization, and alkyne insertion. This reaction affords spiro-pentacyclic naphthalenones that have biological significance in good yields.

Phenolate-induced intramolecular ring-opening cyclization of N-tosylaziridines: access to functionalized benzoxacycles.

Phenolate-induced, diastereo- and regioselective intramolecular exo-tet ring-opening cyclization of N-tosylaziridines has been achieved for the first time. The N-tosylaziridine substrates bearing a tethered (ortho-(tert-butyldimethylsiloxy))aryl substituent, prepared directly from the corresponding olefins under Sharpless aziridination conditions, furnished functionalized 2,3-dihydrobenzofuran, chroman, and 1-benzoxepane derivatives in excellent yields when treated with tetrabutylammonium fluoride (TBAF) at room temperature. Our ability to synthesize benzoxacycle-based N-tosyl-protected amino alcohols, that are otherwise difficult to obtain by traditional synthetic routes, has opened the door to diversify the chemistry of ß-amino alcohols. We also succesfully performed the Baeyer-Villiger oxidation of a salicylaldehyde ether bearing a tethered N-tosylaziridine moiety with m-CPBA followed by tandem saponification and 6-exo-tet aziridine ring-opening cyclization, furnishing the corresponding trans-3,4-disubstituted-1,4-benzodioxane derivative. Overall, the study has unveiled a new entry to the synthesis of benzoxacycles and has also broadened the impact of aziridines as synthetic building blocks.

Ruthenium(II)-Catalyzed Synthesis of Spirobenzofuranones by a Decarbonylative Annulation Reaction.

The first decarbonylative insertion of an alkyne through C-H/C-C activation of six-membered compounds is reported. The Ru-catalyzed reaction of 3-hydroxy-2-phenyl-chromones with alkynes works most efficiently in the presence of the ligand PPh3 to provide spiro-indenebenzofuranones. Unlike previously reported metal-catalyzed decarbonylative annulation reactions, in the present decarbonylative annulation reaction, the annulation occurs before extrusion of carbon monoxide.

cis-Diastereoselective synthesis of chroman-fused tetralins as B-ring-modified analogues of brazilin.

We have synthesized a series of cis-6a,7,8,12b-tetrahydro-6H-naphtho[2,1-c]chromen-6a-ols as B-ring-modified analogues of (±)-brazilin. A completely regio- and cis-diastereoselective intramolecular Friedel-Crafts epoxy-arene cyclization of 1-tetralone-derived glycidyl ethers catalyzed by Brønsted acids was used as the key step. Our worries concerning the formation of cis-trans product mixtures and their probable conversion to naphthopyran derivatives via dehydration of the tertiary hydroxy group were laid to rest. Additionally, the angular hydroxy group of one of the synthesized products has been reductively removed by a diastereoselective method which should be useful in future for preparing libraries of chroman-fused tetralins with trans-stereochemistry at the ring junction.

On the connection between nonmonotonic taste behavior and molecular conformation in solution: The case of rebaudioside-A.

The diterpene steviol glycoside, rebaudioside A, is a natural high potency non-caloric sweetener extracted from the leaves of Stevia rebaudiana. This compound shows a parabolic change in sweet taste intensity with temperature which contrasts with the general finding for other synthetic or natural sweeteners whose sweet taste increases with temperature. The nonmonotonic taste behavior was determined by sensory analysis using large taste panels. The conformational landscape of rebaudioside A was established at a range of temperatures by means of nuclear magnetic resonance and molecular dynamics simulation. The relationship between various conformations and the observed sweetness of rebaudioside A is described.

Oxido- and mixed-ligand peroxido complexes of niobium(V) as potent phosphatase inhibitors and efficient catalysts for eco-friendly styrene epoxidation.

The present study describes the facile synthesis and comprehensive characterization of new oxido and peroxidoniobium(V) complexes with biogenic ligands, maltol (malt) and deferiprone (def) in their co-ordination sphere, viz., [NbO(malt)3]2·9H2O (1), Na2[Nb(O2)3(malt)]·H2O (2) and Na2[Nb(O2)3(def)]·2H2O (3). The complexes were characterized using various analytical and spectroscopic techniques (FTIR, Raman, NMR, UV-visible, TGA, ICP-OES and elemental analysis). The charge neutral complex 1 was further characterized by single crystal XRD analysis, and the proposed structures of the peroxidoniobium (pNb) complexes 2 and 3 were validated by density functional theory (DFT) studies. A comparative investigation on the in vitro effect of the title compounds and a set of previously reported polymer-anchored peroxidoniobium complexes, [Nb(O2)3(sulfonate)2]3--PSS [PSS = poly(sodium 4-styrene sulfonate)] (5), [Nb2(O2)6(carboxylate)2]4--PA [PA = poly(sodium acrylate)] (6) and [Nb(O2)3(carboxylate)]2--PMA [PMA = poly(sodium methacrylate)] (7), on the activity of the model enzyme wheat thylakoid acid phosphatase has revealed that each of the compounds is an effective inhibitor of the enzyme (IC50 values varying within the range 1-64 µM). The results of the detailed enzyme kinetic study demonstrated that the compounds induce their inhibitory effect via distinct pathways. The oxidoniobium complex 1 as well as polymer-anchored pNb complexes acted as classical non-competitive inhibitors of ACP, whereas the monomeric pNb complexes emerged as mixed inhibitors of the enzyme (Kii > Ki). Notably, the complexes serve as excellent recyclable catalysts for selective styrene epoxidation with H2O2, affording 99% styrene conversion, ≥98% epoxide selectivity and a high turnover number of 1740 under eco-friendly solventless conditions.

Pd(II)-Catalyzed alkyne annulation through allylic isomerization: synthesis of spiro-cyclopentadiene pyrazolones.

The Pd(ii)-catalyzed activation of Csp2-H bond and double alkyne annulation which proceeds via allylic isomerization is reported for the first time. This reaction of antipyrines with alkynes provides an efficient synthetic route for the biologically important spiro-cyclopentadiene pyrazolones. In the presence of Lawesson's reagent, this Pd(ii)-catalyzed annulation reaction affords another spiro-cyclopentadiene pyrazolone which displays very good fluorescence properties.

Evidence of protonation induced intra-molecular metal-to-metal charge transfer in a highly symmetric cyanido bridged {Fe2Ni2} molecular square.

The possibility to induce intra-molecular metal-to-metal charge transfer in a cyanido bridged tetranuclear square shaped {Fe2Ni2} complex by employing protonation as an external stimulant is explored. Two cyanido bridged square shaped tetranuclear complexes, [{Ni(TPA)(µ2-NC)2Ni(CN)2}2]·4H2O (2) and [{Ni(TPA)(µ2-NC)2Fe(bbp)(CN)}2]·10H2O (3) [TPA = tris(3,5-dimethylpyrazol-1-ylmethyl)amine and H2bbp = bis(2-benzimidazolyl)pyridine], are synthesized and characterized. Low temperature magnetic measurements reveal that complex 3 has dominant ferromagnetic interactions between low-spin FeIII (S = 1/2) and high-spin NiII (S = 1) ions. UV-visible spectrophotometric measurements and electrochemical studies establish that reversible intra-molecular metal-to-metal electron transfer can be triggered in 3 upon the addition of either an acid or a base.