Is Hyperconjugation Responsible For The Gauche Effect In 1-Fluoropropane And Other 2-Substituted-1-Fluoroethanes?

The energies and geometries of a series of 2-substituted-1-fluoroethanes were computed at the MP2/6-311++G**(6D)//MP2/6-31+G* level of theory for both the maxima and minima of the rotation about the C-C bond. The results did not support the predictions of a hyperconjugative model, that both 1,2-difluoroethane and 1-chloro-2-fluoroethane would strongly prefer a gauche conformation, and that 1-fluoro-2-silylethane would strongly prefer an anti conformation. The existence of competing electrostatic interactions between the fluorine and the substituents at C-2 was indicated by the detailed geometries of the gauche conformers and by the calculated sensitivity of the gauche-anti energy differences to the presence of a polar solvent. However, Fourier analyses of the torsional potential energies were wholly consistent with hyperconjugative electron donation into the C-F sigma* orbital contributing to the conformational preferences of these 1-fluoroethanes. Fourier analyses also showed that hyperconjugation contributes to the small variations in C-C and C-F bond lengths and in fluorine atomic charges that were computed. The torsional potential energies, variations in geometry and atomic charge, and sensitivity to solvent were all in accord with the expected ranking of hyperconjugative electron donating ability of bonds to carbon, C-Si \u3e C-H \u3e C-C \u3e C-Cl \u3e C-F

A Complex Stereochemical Relay Approach To The Antimalarial Alkaloid Ocimicide A1. Evidence For A Structural Revision

Ocimicide A1 (1) and the semisynthetic derivative ocimicide A2 (2) are highly potent antimalarial agents efficacious against chloroquine-sensitive and -resistant Plasmodium falciparum strains with IC50 values in the nanomolar and picomolar range, respectively. Members of this family have demonstrated radical cure in rhesus monkeys, without detectable toxicity, but their structure–function relationships and mechanism of action are unknown. Herein we describe a twelve-step synthesis of an advanced N-acylated pentacyclic precursor to the proposed structure of 1 (11% overall yield). Instability and poor P. falciparum growth inhibition of the corresponding free donor–acceptor cyclopropylamine, and large discrepancies between reported and both experimental and DFT-calculated 13C chemical shifts and coupling constants, suggest that substantial revision of the proposed structures may be necessary

Synthesis And Characterization Of (pyNO−)2GaCl: A Redox-Active Gallium Complex

We report the synthesis of a gallium complex incorporating redox-active pyridyl nitroxide ligands. The (pyNO−)2GaCl complex was prepared in 85% yield via a salt metathesis route and was characterized by 1H and 13C NMR spectroscopies, X-ray diffraction, and theory. UV–Vis absorption spectroscopy and electrochemistry were used to access the optical and electrochemical properties of the complex, respectively. Our discussion focuses primarily on a comparison of the gallium complex to the corresponding aluminum derivative and shows that although the complexes are very similar, small differences in the electronic structure of the complexes can be correlated to the identity of the metal

Ring Expansion Of Alkylidenecarbenes Derived From Lactams, Lactones, And Thiolactones Into Strained Heterocyclic Alkynes: A Theoretical Study

Strained cycloalkynes are of considerable interest to theoreticians and experimentalists, and possess much synthetic value as well. Herein, a series of cyclic alkylidenecarbenes—formally obtained by replacing the carbonyl oxygen of four-, five-, and six-membered lactams, lactones, and thiolactones with a divalent carbon—were modeled at the CCSD(T)/cc-pVTZ//B3LYP/6-311+G** and CCSD(T)/cc-pVTZ//CCSD/6-311+G** levels of theory. The singlet carbenes were found to be more stable than the triplets. The strained heterocyclic alkynes formed by ring expansion of these singlet carbenes were also modeled. Interestingly, the C≡C bonds in the five-membered heterocycles, obtained from the rearrangement of β-lactam- and β-lactone-derived alkylidenecarbenes, displayed lengths intermediate between formal double and triple bonds. Furthermore, 2-(1-azacyclobutylidene)carbene was found to be nearly isoenergetic with its ring-expanded isomer, and 1-oxacyclopent-2-yne was notably higher in energy than its precursor carbene. In all other cases, the cycloalkynes were lower in energy than the corresponding carbenes. The transition states for ring-expansion were always lower for the 1,2-carbon shifts than for 1,2-nitrogen or oxygen shifts, but higher than for the 1,2-sulfur shifts. These predictions should be verifiable using carbenes bearing appropriate isotopic labels. Computed vibrational spectra for the carbenes, and their ring-expanded isomers, are presented and could be of value to matrix isolation experiments

Spontaneous Transfer Of Chirality In An Atropisomerically Enriched Two-Axis System

One of the most well-recognized stereogenic elements in a chiral molecule is an sp(3)-hybridized carbon atom that is connected to four different substituents. Axes of chirality can also exist about bonds with hindered barriers of rotation; molecules containing such axes are known as atropisomers(1). Understanding the dynamics of these systems can be useful, for example, in the design of single-atropisomer drugs(2) or molecular switches and motors(3). For molecules that exhibit a single axis of chirality, rotation about that axis leads to racemization as the system reaches equilibrium. Here we report a two-axis system for which an enantioselective reaction produces four stereoisomers (two enantiomeric pairs): following a catalytic asymmetric transformation, we observe a kinetically controlled product distribution that is perturbed from the system\u27s equilibrium position. As the system undergoes isomerization, one of the diastereomeric pairs drifts spontaneously to a higher enantiomeric ratio. In a compensatory manner, the enantiomeric ratio of the other diastereomeric pair decreases. These observations are made for a class of unsymmetrical amides that exhibits two asymmetric axes-one axis is defined through a benzamide substructure, and the other axis is associated with differentially N,N-disubstituted amides. The stereodynamics of these substrates provides an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibrium

A Procedure For Computing Hydrocarbon Strain Energies Using Computational Group Equivalents, With Application To 66 Molecules

A method is presented for the direct computation of hydrocarbon strain energies using computational group equivalents. Parameters are provided at several high levels of electronic structure theory: W1BD, G-4, CBS-APNO, CBS-QB3, and M062X/6-31+G(2df,p). As an illustration of the procedure, strain energies are computed for 66 hydrocarbons, most of them highly strained

Rotamer-Restricted Fluorogenicity Of The Bis-Arsenical ReAsH

Fluorogenic dyes such as FlAsH and ReAsH are used widely to localize, monitor, and characterize proteins and their assemblies in live cells. These bis-arsenical dyes can become fluorescent when bound to a protein containing four proximal Cys thiols—a tetracysteine (Cys4) motif. Yet the mechanism by which bis-arsenicals become fluorescent upon binding a Cys4 motif is unknown, and this nescience limits more widespread application of this tool. Here we probe the origins of ReAsH fluorogenicity using both computation and experiment. Our results support a model in which ReAsH fluorescence depends on the relative orientation of the aryl chromophore and the appended arsenic chelate: the fluorescence is rotamer-restricted. Our results do not support a model in which fluorogenicity arises from the relief of ring strain. The calculations identify those As–aryl rotamers that support fluorescence and those that do not and correlate well with prior experiments. The rotamer-restricted model we propose is supported further by biophysical studies: the excited-state fluorescence lifetime of a complex between ReAsH and a protein bearing a high-affinity Cys4 motif is longer than that of ReAsH-EDT2, and the fluorescence intensity of ReAsH-EDT2 increases in solvents of increasing viscosity. By providing a higher resolution view of the structural basis for fluorogenicity, these results provide a clear strategy for the design of more selective bis-arsenicals and better-optimized protein targets, with a concomitant improvement in the ability to characterize previously invisible protein conformational changes and assemblies in live cells

Amide neighbouring-group effects in peptides: phenylalanine as relay amino acid in long-distance electron transfer

In nature, proteins serve as media for long‐distance electron transfer (ET) to carry out redox reactions in distant compartments. This ET occurs either by a single‐step superexchange or through a multi‐step charge hopping process, which uses side chains of amino acids as stepping stones. In this study we demonstrate that Phe can act as a relay amino acid for long‐distance electron hole transfer through peptides. The considerably increased susceptibility of the aromatic ring to oxidation is caused by the lone pairs of neighbouring amide carbonyl groups, which stabilise the Phe radical cation. This neighbouring‐amide‐group effect helps improve understanding of the mechanism of extracellular electron transfer through conductive protein filaments (pili) of anaerobic bacteria during mineral respiration

OGA Inhibition By GlcNAc-Selenazoline

The title compound, which differs from the powerful O-GlcNAcase (OGA) inhibitor GlcNAc-thiazoline only at the chalcogen atom (Se for S), is a much weaker inhibitor in a direct OGA assay. In human cells, however, the selenazoline shows comparable ability to induce hyper-O-GlcNAc-ylation, and the two show similar reduction of insulin-stimulated translocation of glucose transporter 4 in differentiated 3T3 adipocytes. (C) 2010 Elsevier Ltd. All rights reserved

N-Methylimidazole Promotes The Reaction Of Homophthalic Anhydride With Imines

The addition of N-methylimidazole (NMI) to the reaction of homophthalic anhydride with imines such as pyridine-3-carboxaldehyde-N-trifluoroethylimine (9) reduces the amount of elimination byproduct and improves the yield of the formal cycloadduct, tetrahydroisoquinolonic carboxylate 10. Carboxanilides of such compounds are of interest as potential antimalarial agents. A mechanism that rationalizes the role of NMI is proposed, and a gram-scale procedure for the synthesis and resolution of 10 is also described