Aripiprazole?Montmorillonite: A New Organic–Inorganic Nanohybrid Material for Biomedical Applications

Poor aqueous solubility and the unpleasant taste of aripiprazole (APZ) have been recurring problems, owing to its low bioavailability and low patient tolerance, respectively. Herein, we prepared a nanohybrid system that was based on a bentonite clay material, montmorillonite (MMT), which could both mask the taste and enhance the solubility of APZ (i.e., APZ‐MMT). To further improve the efficacy of this taste masking and drug solubility, APZ‐MMT was also coated with a cationic polymer, polyvinylacetal diethylamino acetate (AEA). In vitro dissolution tests at neutral pH showed that the amount of drug that was released from the AEA‐coated APZ‐MMT was greatly suppressed (<1 %) for the first 3 min, thus suggesting that AEA‐coated APZ‐MMT has strong potential for the taste masking of APZ. Notably, in simulated gastric juice at pH 1.2, the total percentage of APZ that was released within the first 2 h increased up to 95 % for AEA‐coated APZ‐MMT. Furthermore, this in vitro release profile was also similar to that of Abilify®, a commercially available medication. In vivo experiments by using Sprague–Dawley rats were also performed to compare the pharmacokinetics of AEA‐coated APZ‐MMT and Abilify®. AEA‐coated APZ‐MMT exhibited about 20 % higher systemic exposure of APZ and its metabolite, dehydro‐APZ, compared with Abilify®. Therefore, a new MMT‐based nanovehicle, which is coated with a cationic polymer, can act as a promising delivery system for both taste masking and for enhancing the bioavailability of APZ.     

Can Cyclen Bind Alkali Metal Azides? A DFT Study as a Precursor to Synthesis

Can cyclen (1,4,7,10‐tetraazacyclododecane) bind alkali metal azides? This question is addressed by studying the geometric and electronic structures of the alkali metal azide‐cyclen [M(cyclen)N₃] complexes using density functional theory (DFT). The effects of adding a second cyclen ring to form the sandwich alkali metal azide‐cyclen [M(cyclen)₂N₃] complexes are also investigated. N₃^? is found to bind to a M⁺(cyclen) template to give both end‐on and side‐on structures. In the end‐on structures, the terminal nitrogen atom of the azide group (N1) bonds to the metal as well as to a hydrogen atom of the cyclen ring through a hydrogen bond in an end‐on configuration to the cyclen ring. In the side‐on structures, the N₃ unit is bonded (in a side‐on configuration to the cyclen ring) to the metal through the terminal nitrogen atom of the azide group (N1), and through the other terminal nitrogen atom (N3) of the azide group by a hydrogen bond to a hydrogen atom of the cyclen ring. For all the alkali metals, the N₃‐side‐on structure is lowest in energy. Addition of a second cyclen unit to [M(cyclen)N₃] to form the sandwich compounds [M(cyclen)₂N₃] causes the bond strength between the metal and the N₃ unit to decrease. It is hoped that this computational study will be a precursor to the synthesis and experimental study of these new macrocyclic compounds; structural parameters and infrared spectra were computed, which will assist future experimental work.     

Lanthanide‐to‐Lanthanide Energy‐Transfer Processes Operating in Discrete Polynuclear Complexes: Can Trivalent Europium Be Used as a Local Structural Probe?

This work, based on the synthesis and analysis of chemical compounds, describes a kinetic approach for identifying intramolecular intermetallic energy‐transfer processes operating in discrete polynuclear lanthanide complexes, with a special emphasis on europium‐containing entities. When all coordination sites are identical in a (supra)molecular complex, only heterometallic communications are experimentally accessible and a Tb→Eu energy transfer could be evidenced in [TbEu( L5 )(hfac)₆] (hfac=hexafluoroacetylacetonate), in which the intermetallic separation amounts to 12.6 Å. In the presence of different coordination sites, as found in the trinuclear complex [Eu₃( L2 )(hfac)₉], homometallic communication can be induced by selective laser excitation and monitored with the help of high‐resolution emission spectroscopy. The narrow and non‐degenerated character of the Eu(⁵D₀?⁷F₀) transition excludes significant spectral overlap between donor and acceptor europium cations. Intramolecular energy‐transfer processes in discrete polynuclear europium complexes are therefore limited to short distances, in agreement with the Fermi golden rule and with the kinetic data collected for [Eu₃( L2 )(hfac)₉] in the solid state and in solution. Consequently, trivalent europium can be considered as a valuable local structural probe in discrete polynuclear complexes displaying intermetallic separation in the sub‐nanometric domain, a useful property for probing lanthanido‐polymers.     

Transformation of Carbon Dioxide with Homogeneous Transition‐Metal Catalysts: A Molecular Solution to a Global Challenge?

A plethora of methods have been developed over the years so that carbon dioxide can be used as a reactant in organic synthesis. Given the abundance of this compound, its utilization in synthetic chemistry, particularly on an industrial scale, is still at a rather low level. In the last 35 years, considerable research has been performed to find catalytic routes to transform CO(2) into carboxylic acids, esters, lactones, and polymers in an economic way. This Review presents an overview of the available homogeneous catalytic routes that use carbon dioxide as a C(1) carbon source for the synthesis of industrial products as well as fine chemicals.     

Is DFT Accurate Enough to Calculate Regioselectivity? The Case of 1,3-Dipolar Cycloaddition of Azide to Alkynes and Alkenes

The importance of regioselectivity in 1,3-dipolar cycloadditions (DCs) makes it surprising that no benchmarking study on this problem has appeared. We investigated whether DFT calculations are an accurate tool to predict the regioselectivity of uncatalyzed thermal azide 1,3-DCs. We considered the reaction between HN₃ and 12 dipolarophiles, comprising ethynes HC≡C−R and ethenes H₂C=CH−R (R=F, OH, NH₂, Me, CN, CHO), which cover a broad range of electron demand and conjugation ability. We established benchmark data by the W3X protocol [complete-basis-set-extrapolated CCSD(T)-F12 energy with T-(T) and (Q) corrections and MP2-calculated core/valence and relativistic effects] and showed that core/valence effects and high-order excitations are important for accurate regioselectivity. Regioselectivities calculated using an extensive set of density functional approximations (DFAs) were compared with benchmark data. Range-separated and meta-GGA hybrids gave the best results. Good treatment of self-interaction and electron exchange are the key features for accurate regioselectivity. Dispersion correction slightly improves agreement with W3X results. The best DFAs provide the isomeric TS energy difference with an expected error ≈0.7 mh and errors ≈2 mh can occur. The isomer yield provided by the best DFA has an expected error of ±5 %, though errors up to 20 % are not rare. At present, an accuracy of 1–2 % is unfeasible but it seems that we are not far from achieving this goal.     

Structure and Bonding in First‐Row Transition‐Metal Dicarbides: Are They Related to the Stability of Met‐cars?

First-row transition-metal dicarbides MC(2) (M=Sc-Zn) have been investigated by using quantum-mechanical techniques. The competition between cyclic and linear isomers in these systems has been studied and the bonding scheme for these compounds is discussed through topological analysis of electron density. All of the systems have been found to prefer a C(2v)-symmetric arrangement, although for ZnC(2) the energy difference between this and the linear isomer is rather small. In most cases the C(2v)-symmetric structure corresponds to a T-shaped structure, with the exceptions of TiC(2), CoC(2), and NiC(2) which have been shown to be true rings. A detailed analysis of the variation of the energy of the system with geometry has been carried out. An analysis of the bonding, taking into account the main interactions between the valence orbitals of both fragments, the M atom and the C(2) molecule, has allowed the main features of these compounds to be interpreted. A clear correlation between the dissociation energies of the first-row transition-metal dicarbides and the bonding energies of the corresponding met-cars was observed.     

Can collision‐induced negative‐ion fragmentations of [M–H]– anions be used to identify phosphorylation sites in peptides?

A joint experimental and theoretical investigation of the fragmentation behaviour of energised [M-H](-) anions from selected phosphorylated peptides has confirmed some of the most complex rearrangement processes yet to be reported for peptide negative ions. In particular: pSer and pThr (like pTyr) may transfer phosphate groups to C-terminal carboxyl anions and to the carboxyl anion side chains of Asp and Glu, and characteristic nucleophilic/cleavage reactions accompany or follow these rearrangements. pTyr may transfer phosphate to the side chains of Ser and Thr. The reverse reaction, namely transfer of a phosphate group from pSer or pThr to Tyr, is energetically unfavourable in comparison. pSer can transfer phosphate to a non-phosphorylated Ser. The non-rearranged [M-H](-) species yields more abundant product anions than its rearranged counterpart. If a peptide containing any or all of Ser, Thr and Tyr is not completely phosphorylated, negative-ion cleavages can determine the number of phosphated residues, and normally the positions of Ser, Thr and Tyr, but not which specific residues are phosphorylated. This is in accord with comments made earlier by Lehmann and coworkers.     

HPLC of Metal Chelates: Separation of NiII and FeII as 2,2′-Bipyridine Complexes with Ion-Pair Chromatography

Abstract

The separation of 2,2′-bipyridine and its trischelate complexes of Ni^II and Fe^II was achieved on a μ-Bondapak-CN column using NCS as counter ion in the mobile phase (methanol-water mixtures). The retention volumes for the Ni chelate were found to vary exponentially with the concentration of KNCS in the mobile phase. The concentration of the metals in the effluents was checked by means of atomic absorption spectroscopy.     

ChemInform Abstract: How Many Networks Can Be Made from Four‐Coordinate Atoms?

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.     

DFT study of the mechanism of hydroamination of ethylene with ammonia catalyzed by diplatinum(II) complexes: Inner‐ or outer‐sphere?

A detailed analysis of the reaction profiles of the hydroamination reaction between ethylene and ammonia catalyzed by the diplatinum(II) [{Pt(NH₂)(μ‐H)(PPh₃)}₂] complex is presented herein using density functional theory computational techniques. The coordinatively unsaturated 14e T‐shaped [Pt(NH₂)(PPh₃)H] species resulted from the dissociation of the diplatinum [{Pt(NH₂)(μ‐H)(PPh₃)}₂] precatalyst are identified as the active catalytic species. All possible reaction pathways that constitute the entire catalytic cycle have exhaustively been investigated. Overall, the rate‐determining step of all catalytic cycles constructed was found to be the oxidative addition of ammonia that leads to the regeneration of the catalyst. According to the energy span model, the outer‐sphere mechanism for the hydroamination of ethylene with ammonia catalyzed by the diplatinum complexes is favored over the inner‐sphere one, whereas TOF values are in favor of the inner‐sphere mechanism. © 2012 Wiley Periodicals, Inc.     

Fluorescence of New o‐Carborane Compounds with Different Fluorophores: Can it be Tuned?

Two sets of o‐carborane derivatives incorporating fluorene and anthracene fragments as fluorophore groups have been successfully synthesized and characterized, and their photophysical properties studied. The first set, comprising fluorene‐containing carboranes 6 – 9 , was prepared by catalyzed hydrosilylation reactions of ethynylfluorene with appropriate carboranylsilanes. The compound 1‐[(9,9‐dioctyl‐fluorene‐2‐yl)ethynyl]carborane ( 11 ) was synthesized by the reaction of 9,9‐dioctyl‐2‐ethynylfluorene and decaborane (B₁₀H₁₄). Furthermore, reactions of the lithium salt of 11 with 1 equivalent of 4‐(chloromethyl)styrene or 9‐(chloromethyl)anthracene yielded compounds 12 and 13 . Members of the second set of derivatives, comprising anthracene‐containing carboranes, were synthesized by reactions of monolithium or dilithium salts of 1‐Me‐1,2‐C₂B₁₀H₁₁, 1‐Ph‐1,2‐C₂B₁₀H₁₁, and 1,2‐C₂B₁₀H₁₂ with 1 or 2 equivalents of 9‐(chloromethyl)anthracene, respectively, to produce compounds 14 – 16 . In addition, 2 equivalents of the monolithium salts of 1‐Me‐1,2‐C₂B₁₀H₁₁ (Me‐o‐carborane) and 1‐Ph‐1,2‐C₂B₁₀H₁₁ (Ph‐o‐carborane) were reacted with 9,10‐bis(chloromethyl)anthracene to produce compounds 17 and 18 , respectively. Fluorene derivatives 6 – 9 exhibit moderate fluorescence quantum yields (32–44 %), whereas 11 – 13 , in which the fluorophore is bonded to the C_cluster (C_c), show very low emission intensity (6 %) or complete fluorescence quenching. The anthracenyl derivatives containing the Me‐o‐carborane moiety exhibit notably high fluorescence emissions, with ?_F=82 and 94 %, whereas their Ph‐o‐carborane analogues are not fluorescent at all. For these compounds, we have observed a correlation between the C_c?C_c bond length and the fluorescence intensity in CH₂Cl₂ solution, comparable to that observed for previously reported styrene‐containing carboranes. Thus, our hypothesis is that for systems of this type the fluorescence may be tuned and even predicted by changing the substituent on the adjacent C_c.     

Can Coordination‐Driven Supramolecular Self‐Assembly Reactions Be Conducted from Fully Aliphatic Linkers?

The reaction between a preassembled Cu^I bimetallic molecular clip with a short intermetallic distance and a series of fully aliphatic cyano‐capped ditopic linkers with increasing lengths was investigated. It is shown that, depending on the length of the ditopic linkers, the rational design of unprecedented supramolecular compact metallacycles containing fully aliphatic walls is possible. The specific preorganized molecular arrangement of the molecular clip used favors stabilizing interlinker London dispersion interactions, which allow, as the length of the linkers increases, the selective formation of discrete compact metallacycles at the expense of 1D coordination polymers. The generalizability of this approach was demonstrated by the reaction of fully aliphatic cyano‐capped linkers with two other types of preassembled Cu^I bimetallic molecular clips that also had short intermetallic distances.