RESUMO
The diiodobinorsnoutane, bi(5-iodopentacyclo[4.3.0.0(2,4).0(3,8).0(5,7)]non-4-yl) (5), exists in a sterically hindered gauche conformation rather than an anti or an averaged (freely rotating) C2v structure. Density functional theory (DFT) predictions place the gauche conformation 11 kcal/mol more stable than the anti conformation with a barrier of 17 kcal/mol connecting the minima. These are consistent with variable-temperature NMR (17.1 ± 0.8 kcal/mol) estimates and X-ray analysis. Predictions of the torsional profiles of the yet-unsynthesized bromo-, chloro-, and fluoro- analogues show a progressive lowering of the barriers.
RESUMO
The absolute stereochemistry of chiral drugs is usually established via X-ray crystallography. However, vibrational circular dichroism (VCD) spectroscopy coupled with quantum mechanics simulations offers a rapid alternative to crystallography and is readily applied to both crystalline and non-crystalline samples. VCD is an effective complement to X-ray analysis of drug candidates, and it can be used as a high-throughput means of assessing absolute stereochemistry at all phases of the discovery process (hundreds of assignments per year). The practical implementation (or fee-for-service outsourcing) of VCD and selected case studies are illustrated with an emphasis on providing utility and impact to pharmaceutical discovery programs.
Assuntos
Preparações Farmacêuticas/química , Aminoquinolinas/química , Dicroísmo Circular/instrumentação , Cristalografia por Raios X , N-Metilaspartato/química , Receptores Histamínicos H3/química , Receptores Histamínicos H3/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Infrared spectra recorded for 1,5-dimethyl-2,8:4,6-semibullvalenetetracarboxylic acid dianhydride (12) in the condensed and vapor phase clearly prove that in the vapor phase the dianhydride 12 is a homoaromatic ground state semibullvalene.
Assuntos
Anidridos/química , Hidrocarbonetos Aromáticos com Pontes/química , Espectrofotometria Infravermelho/métodos , Estrutura MolecularRESUMO
Integration of a Raman probe into a commercially available microwave synthesizer has demonstrated unprecedented utility in understanding chemical processes within the rapidly emerging field of microwave-assisted organic synthesis. The real-time spectral feedback afforded by this system has facilitated analysis of reaction mechanisms, reactive intermediates, and reaction kinetics via optical sampling through the sidewall of the sealed reaction vial within the microwave chamber. The feasibility, attributes, and limitations of the system are illustrated using amine coupling and Knoevenagel coupling example reactions. In addition to the reported analyses, this system provided the safety of remote sensing, adequate sensitivity, ease of alignment, and optimized "depth of field" for analysis of solutions with solids content.
Assuntos
Tecnologia de Fibra Óptica/instrumentação , Microquímica/métodos , Micro-Ondas , Sistemas On-Line , Compostos Orgânicos/química , Compostos Orgânicos/efeitos da radiação , Análise Espectral Raman/instrumentação , Análise Espectral Raman/métodos , Campos Eletromagnéticos , Desenho de Equipamento , Análise de Falha de Equipamento , Estudos de Viabilidade , Compostos Orgânicos/análise , Compostos Orgânicos/síntese química , TemperaturaRESUMO
Atropisomers exist when axial chirality is present as a result of conformationally restricted rotation around a single bond. The interconversion rate of the individual atropisomers is critical to the assessment of chiral stability of a drug throughout scale-up, development, production, and storage as well as in vivo pharmacokinetics. We describe the application of vibrational circular dichroism spectroscopy coupled with quantum mechanics simulations to assign the absolute axial chirality and measure the racemization half-life of a series of potential anxiolytic drugs that act as γ-aminobutyric acid modulators.