Synthesis of β-Pyridyl α-Amino Acids: Conformationally Sensitive Charge Transfer-Based Fluorophores.

Unnatural α-amino acids with charge transfer-based poly aromatic side chains have been designed as conformationally sensitive fluorophores. These were prepared using a hetero-Diels-Alder reaction and a Knoevenagel-Stobbe process to generate a biaryl pyridyl unit, followed by iron-catalyzed bromination and a Suzuki-Miyaura cross-coupling reaction to complete the triaryl system. A photophysical study led to the discovery of a -methoxy analogue which exhibited viscosity-sensitive fluorescence in which emission could be controlled between twisted and planar conformations.

A Second Glass Transition Observed in Single-Component Homogeneous Liquids Due to Intramolecular Vitrification.

On supercooling a liquid, the viscosity rises rapidly until at the glass transition it vitrifies into an amorphous solid accompanied by a steep drop in the heat capacity. Therefore, a pure homogeneous liquid is not expected to display more than one glass transition. Here we show that a family of single-component homogeneous molecular liquids, titanium tetraalkoxides, exhibit two calorimetric glass transitions of comparable magnitude, one of which is the conventional glass transition associated with dynamic arrest of the bulk liquid properties, while the other is associated with the freezing out of intramolecular degrees of freedom.

Computational infrared and Raman spectra by hybrid QM/MM techniques: a study on molecular and catalytic material systems.

Vibrational spectroscopy is one of the most well-established and important techniques for characterizing chemical systems. To aid the interpretation of experimental infrared and Raman spectra, we report on recent theoretical developments in the ChemShell computational chemistry environment for modelling vibrational signatures. The hybrid quantum mechanical and molecular mechanical approach is employed, using density functional theory for the electronic structure calculations and classical forcefields for the environment.

Multiscale QM/MM modelling of catalytic systems with ChemShell.

Hybrid quantum mechanical/molecular mechanical (QM/MM) methods are a powerful computational tool for the investigation of all forms of catalysis, as they allow for an accurate description of reactions occurring at catalytic sites in the context of a complicated electrostatic environment. The scriptable computational chemistry environment ChemShell is a leading software package for QM/MM calculations, providing a flexible, high performance framework for modelling both biomolecular and materials catalysis. We present an overview of recent applications of ChemShell to problems in catalysis and review new functionality introduced into the redeveloped Python-based version of ChemShell to support catalytic modelling.

Correction: Hydrogen-activation mechanism of [Fe] hydrogenase revealed by multi-scale modeling.

[This corrects the article DOI: 10.1039/C4SC01605J.].

Low-frequency vibrational modes in G-quadruplexes reveal the mechanical properties of nucleic acids.

Low-frequency vibrations play an essential role in biomolecular processes involving DNA such as gene expression, charge transfer, drug intercalation, and DNA-protein recognition. However, understanding the vibrational basis of these mechanisms relies on theoretical models due to the lack of experimental evidence. Here we present the low-frequency vibrational spectra of G-quadruplexes (structures formed by four strands of DNA) and B-DNA characterized using femtosecond optical Kerr-effect spectroscopy.

Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation.

There is considerable interest in developing drugs and probes targeted to mitochondria in order to understand and treat the many pathologies associated with mitochondrial dysfunction. The large membrane potential, negative inside, across the mitochondrial inner membrane enables delivery of molecules conjugated to lipophilic phosphonium cations to the organelle. Due to their combination of charge and hydrophobicity, quaternary triarylphosphonium cations rapidly cross biological membranes without the requirement for a carrier.

Polyamorphism Mirrors Polymorphism in the Liquid-Liquid Transition of a Molecular Liquid.

Liquid-liquid transitions between two amorphous phases in a single-component liquid have courted controversy. All known examples of liquid-liquid transitions in molecular liquids have been observed in the supercooled state, suggesting an intimate connection with vitrification and locally favored structures inhibiting crystallization. However, there is precious little information about the local molecular packing in supercooled liquids, meaning that the order parameter of the transition is still unknown.

Synthesis of Functionalized Indolines and Dihydrobenzofurans by Iron and Copper Catalyzed Aryl C-N and C-O Bond Formation.

A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N- or O-arylation step leading to indolines, dihydrobenzofurans, and six-membered analogues. The general applicability and functional group tolerance of this method were exemplified by the total synthesis of the neolignan natural product, (+)-obtusafuran.

Synthesis of fused tricyclic systems by thermal Cope rearrangement of furan-substituted vinyl cyclopropanes.

A novel method for the stereoselective construction of hexahydroazuleno[4,5-b]furans from simple precursors has been developed. The route involves the use of our recently developed Brønsted acid catalysed cyclisation reaction of acyclic ynenones to prepare fused 1-furanyl-2-alkenylcyclopropanes that undergo highly stereoselective thermal Cope rearrangement to produce fused tricyclic products. Substrates possessing an E-alkene undergo smooth Cope rearrangement at 40 °C, whereas the corresponding Z-isomers do not react at this temperature.

An investigation into the unusual linkage isomerization and nitrite reduction activity of a novel tris(2-pyridyl) copper complex.

The copper-containing nitrite reductases (CuNIRs) are a class of enzymes that mediate the reduction of nitrite to nitric oxide in biological systems. Metal-ligand complexes that reproduce the salient features of the active site of CuNIRs are therefore of fundamental interest, both for elucidating the possible mode of action of the enzymes and for developing biomimetic catalysts for nitrite reduction. Herein, we describe the synthesis and characterization of a new tris(2-pyridyl) copper complex ([Cu(NO)]) that binds two molecules of nitrite, and displays all three of the common binding modes for [Formula: see text], with one nitrite bound in an asymmetric quasi-bidentate κ-ONO manner and the other bound in a monodentate fashion with a linkage isomerism between the κ-ONO and κ-NO binding modes.

The electronic and solvatochromic properties of [Co(L)(bipyridine)] (L = o-catecholato, o-benzenedithiolato) species: a combined experimental and computational study.

Complexes of Co(iii) containing mixed chelating diimine and o-quinone ligand sets are of fundamental interest on account of their fascinating magnetic and electronic properties. Whilst complexes of this type containing one diimine and two o-quinone ligands have been studied extensively, those with the reverse stoichiometry (two diimines and one o-quinone) are much rarer. Herein, we describe a ready route to the synthesis of the complex [Co(o-catecholate) (2,2'-bipyridine)] (1), and also report the synthesis of [Co(o-catecholate)(5,5'-dimethyl-2,2'-bipyridine)] (2) and [Co(o-benezenedithiolate)(5,5'-dimethyl-2,2'-bipyridine)] (3) for the first time.

Electron density, disorder and polymorphism: high-resolution diffraction studies of the highly polymorphic neuralgic drug carbamazepine.

Analysis of neutron and high-resolution X-ray diffraction data on form (III) of carbamazepine at 100 K using the atoms in molecules (AIM) topological approach afforded excellent agreement between the experimental results and theoretical densities from the optimized gas-phase structure and from multipole modelling of static theoretical structure factors. The charge density analysis provides experimental confirmation of the partially localized π-bonding suggested by the conventional structural formula, but the evidence for any significant C-N π bonding is not strong. Hirshfeld atom refinement (HAR) gives H atom positional and anisotropic displacement parameters that agree very well with the neutron parameters.

Selective superoxide generation within mitochondria by the targeted redox cycler MitoParaquat.

Superoxide is the proximal reactive oxygen species (ROS) produced by the mitochondrial respiratory chain and plays a major role in pathological oxidative stress and redox signaling. While there are tools to detect or decrease mitochondrial superoxide, none can rapidly and specifically increase superoxide production within the mitochondrial matrix. This lack impedes progress, making it challenging to assess accurately the roles of mitochondrial superoxide in cells and in vivo.

Insights into enzymatic halogenation from computational studies.

The halogenases are a group of enzymes that have only come to the fore over the last 10 years thanks to the discovery and characterization of several novel representatives. They have revealed the fascinating variety of distinct chemical mechanisms that nature utilizes to activate halogens and introduce them into organic substrates. Computational studies using a range of approaches have already elucidated many details of the mechanisms of these enzymes, often in synergistic combination with experiment.

Terahertz underdamped vibrational motion governs protein-ligand binding in solution.

Low-frequency collective vibrational modes in proteins have been proposed as being responsible for efficiently directing biochemical reactions and biological energy transport. However, evidence of the existence of delocalized vibrational modes is scarce and proof of their involvement in biological function absent. Here we apply extremely sensitive femtosecond optical Kerr-effect spectroscopy to study the depolarized Raman spectra of lysozyme and its complex with the inhibitor triacetylchitotriose in solution.

Expanding the palette of phenanthridinium cations.

5,6-Disubstituted phenanthridinium cations have a range of redox, fluorescence and biological properties. Some properties rely on phenanthridiniums intercalating into DNA, but the use of these cations as exomarkers for the reactive oxygen species (ROS), superoxide, and as inhibitors of acetylcholine esterase (AChE) do not require intercalation. A versatile modular synthesis of 5,6-disubstituted phenanthridiniums that introduces diversity by Suzuki–Miyaura coupling, imine formation and microwave-assisted cyclisation is presented.

Experimental Electron Density and Neutron Diffraction Studies on the Polymorphs of Sulfathiazole.

High resolution X-ray diffraction data on forms I-IV of sulfathiazole and neutron diffraction data on forms II-IV have been collected at 100 K and analyzed using the Atoms in Molecules topological approach. The molecular thermal motion as judged by the anisotropic displacement parameters (adp's) is very similar in all four forms. The adp of the thiazole sulfur atom had the greatest amplitude perpendicular to the five-membered ring, and analysis of the temperature dependence of the adps indicates that this is due to genuine thermal motion rather than a concealed disorder.

Total syntheses of multiple cladiellin natural products by use of a completely general strategy.

The enantioselective total syntheses of 10 cladiellin natural products have been completed, starting from the known allylic alcohol (+)-14, which can be prepared in large quantities. The bridged tricyclic core of the cladiellins has been constructed via three ring-forming reactions: (i) an intramolecular reductive cyclization between an aldehyde and an unsaturated ester, mediated by samarium(II) iodide, to form a tetrahydropyranol; (ii) reaction of a metal carbenoid, generated from a diazo ketone, with an ether to produce an ylide-like intermediate that rearranges to produce E- or Z-oxabicyclo[6.2.

Switching the stereochemical outcome of 6-endo-trig cyclizations; synthesis of 2,6-cis-6-substituted 4-oxopipecolic acids.

A base-mediated 6-endo-trig cyclization of readily accessible enone-derived α-amino acids has been developed for the direct synthesis of novel 2,6-cis-6-substituted-4-oxo-L-pipecolic acids. A range of aliphatic and aryl side chains were tolerated by this mild procedure to give the target compounds in good overall yields. Molecular modeling of the 6-endo-trig cyclization allowed some insight as to how these compounds were formed, with the enolate intermediate generated via an equilibrium process, followed by irreversible tautomerization/neutralization providing the driving force for product formation.

Discovery of a multi-bond forming, four-step tandem process: construction of drug-like polycyclic scaffolds.

A one-pot tandem process involving an Overman rearrangement, ring closing enyne metathesis and a hydrogen bonding directed Diels-Alder reaction has been developed for the efficient diastereoselective synthesis of functionalised amino substituted tetralin and indene ring systems.