Molecular mechanics calculations on carbonyl compounds. III. Cycloketones

Molecular mechanics (MM4) calculations were carried out on cycloketones for ring sizes ranging from 4 to 11 carbon atoms. The MM4 relative energies for the various conformations of the cycloketones were compared to density functional theory (DFT) calculations (B3LYP/6‐31G*), which were also carried out in this work. For small ring sizes (n=4–6), calculated molecular geometries, dipole moments, moments of inertia, and vibrational spectra were compared to experimental data. The axial–equatorial energy differences in methyl‐substituted cyclohexanones were also calculated by MM4 and compared to ab initio, DFT, and experimental results. The results of the MM4 studies on cycloketones showed significant improvement from those of MM3 calculations performed in parallel with the MM4 calculations. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1451–1475, 2001     

Molecular mechanics calculations on carbonyl compounds. IV. Heats of formation

Molecular mechanics (MM4) calculations on the heats of formation of aldehydes and ketones were carried out for a total of 59 compounds (10 aldehydes and 49 ketones). Optimization of the heat of formation parameters was obtained by a least squares fit to the experimentally known heats of formation. With the optimized MM4 heat of formation parameters, the MM4 calculated heats of formation showed significant improvement over those of MM3. The standard and weighted root mean square deviations for the MM4 values were 0.35 and 0.31 kcal mol^?1, respectively, whereas for the MM3 values they were 0.42 and 0.39 kcal mol^?1, respectively. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1476–1483, 2001     

Theoretical studies of molecular conformation. II: Application of the SIBFA procedure to molecules containing carbonyl and carboxylate oxygens and amide nitrogens

The SIBFA procedure (Sum of Interactions Between Fragments computedAb initio, Ref [1]) is extended to the study of the conformational behavior of representative molecules containing amide nitrogens and carbonyl and carboxylate oxygens. The molecules studied are C- and N-ethylammonium formamide, C- and N-ethanol-formamide, ethylammonium formate and ethanolformate. The cases investigated include interactions of the types which occur between functional groups in proteins or ionophores. The accuracy of the procedure, assessed by comparing the results to those of correspondingab initio SCF computations, is very satisfactory. An application of the procedure to study the conformation of the glycyl and alanyl dipeptides as a function of the backbone torsional angles and is presented.     

Molecular mechanics calculations on carbonyl compounds. II. Open‐chain ketones

Open‐chain aliphatic ketones were studied with the molecular mechanics (MM4) force field. A total of seven compounds were examined. Structures were well fit, including moments of inertia. Rotational barriers, vibrational spectra, and dipole moments were also well fit. The overall root mean square errors for MM3 and MM4 were 0.27 and 0.18%, respectively, for the six moments of inertia (known experimentally for two compounds) and 31 and 20 cm^?1, respectively, for the vibrational frequencies (over 99 weighted modes). © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1426–1450, 2001     

The n→π* optical activity of chiral carbonyl compounds predicted to be optically inactive by the octant rule

The one-electron model of n* optical activity in chiral carbonyl compounds is carried to second-order in perturbation theory and the results are applied to systems which are predicted by the octant rule to yield zero n* optical activity. It is shown that second-order contributions to the n* rotatory strength lead to sector rules which are qualitatively different from those obtained from first-order contributions. Inclusion of three-way interactions involving the carbonyl chromophore and two different extrachromophoric perturbing groups (or atoms) lead to second-order contributions to the rotatory strength which can account for the n* optical activity in chiral carbonyl systems predicted to be optically inactive by the conventional quadrant and octant rules. These results are shown to be in agreement with the conclusions derived by Ruch and Schönhofer from a purely algebraic theory of molecular chirality.     

Synthetic applications of beta-fluoroalkylated alpha,beta-unsaturated carbonyl compounds

Beta-fluoroalkylated alpha,beta-unsaturated carbonyl compounds constitute efficient building blocks for the synthesis of complex fluorinated compounds. As the fluorinated moiety generally increases their reactivity, it also brings important modifications which can change the chemical behavior and selectivity. Their use has been already largely demonstrated. Nevertheless, the synthetic potential has not yet been fully explored and, consequently should play an important role in the design of new sophisticated fluorinated molecules. Nevertheless, it shall be important to develop new synthetic methods to enlarge their availability and their diversity.     

Standardless spectrochemical analysis and direct simulations of time-resolved vibronic spectra of polyatomic molecules, isomers and mixtures

The efficient method for calculation of dynamical time-resolved vibronic spectra of polyatomic molecules is proposed. It allows to perform direct real-time computer simulations of such spectra for models of complex compounds, isomers and multicomponent mixtures with quantum beats and non-radiative vibrational relaxation taken into account. The examples of calculated spectra show the ways of how to search and select optimal experimental conditions and retrieve the most informative data for solution of inverse spectral problems in different situations. The new method of standardless analysis based on time-resolved vibronic spectroscopy has been developed and its main ideas are presented here. This method is able to solve quantitative and qualitative spectrochemical problems for individual substances and multicomponent mixtures (even for species with similar optical properties) with the use of experimentally measured relative intensities of dynamical spectra only. The algorithms of how to perform analysis in various experimental conditions are proposed.     

An ant algorithm for the conformational analysis of flexible molecules

Originally, the ant system was developed for optimization in discrete search spaces such as the traveling salesman problem. We detail our adaptation of the algorithm to optimization in the continuous search space of conformational analysis. The parameters of the algorithm were tuned using a simple test molecule, undecane, and a drug molecule, imatinib. The algorithm is further tested on four more drug or drug-like molecules, on vitamin A and on alanine tetrapeptide.     

A molecular mechanics and semiempirical conformational analysis of the herbicide diuron inhibitor of photosystem II

The potential energy surface (PES) for the herbicide diuron (DCMU), a photosystem II inhibitor, has been extensively investigated using the quantum-mechanical semiempirical molecular orbital methods AM1 and PM3 and molecular mechanics method. A detailed conformational search has been carried out which revealed the occurrence of four genuine minimum energy structures. The relative stability of the conformers and rotational barriers to conformational interconversion were evaluated using distinct theoretical approaches. The results showed that thetrans form of the diuron molecule is more stable than thecis form in all methods, and so it may possibly be the biologically active isomer.     

Carbonylation of nitro and azo compounds in the presence of iron carbonyl catalysts

The reactions of nitro and azo compounds with carbon monoxide were studied in the presence of iron carbonyl catalysts. It was shown that these catalytic systems differ substantially from Pd- and Rh-containing catalysts. In the case of the iron catalysts, the products of coupling of molecules are formed as intermediates and azo compounds are the final reaction products. The reactions involving the palladium and rhodium catalysts proceed without the intermediate formation of the coupling products and lead to isocyanates or carbamates. When combined using PdCl₂ and Fe(CO)₅/Al₂O₃, the catalysts inhibit each other, especially in the presence of pyridine.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2460–2463, October, 1996.     

Catalytic olefination of carbonyl compounds. Effect of the structure of the carbonyl compound on the reaction

The mechanism of the novel reaction of catalytic olefination of carbonyl compounds was studied. The reaction involves the transformation of hydrazones of aromatic aldehydes and ketones into the corresponding dichloroalkenes and symmetrical azines by the treatment with carbon tetrachloride in the presence of CuCl as a catalyst. The stability of intermediate diazoalkanes is the main factor determining the direction of the reaction. In the case of sufficiently stable diazoalkanes, other products can be formed under the reaction conditions along with the products of catalytic olefination.     

Mg-promoted reductive coupling of aromatic carbonyl compounds with trimethylsilyl chloride and bis(chlorodimethylsilyl) compounds

Mg-promoted reductive coupling of aromatic carbonyl compounds (1) with chlorosilanes, such as trimethylsilyl chloride (TMSCl:2), 1,2-bis(chlorodimethylsilyl)ethane (3) and 1,5-dichlorohexamethyltrisiloxane (4), in N,N-dimethylformamide (DMF) at room temperature brought about selective and facile reductive formation of both of carbon-silicon and oxygen-silicon bonds to give the corresponding α-trimethylsilylalkyl trimethylsilyl ethers (5) and cyclic siloxanes (6), (7) in moderate to good yields, respectively. The present facile and selective coupling may be initiated through electron transfer from Mg metal to aromatic carbonyl compounds (1).     

House bulb light-induced photochemical acetalization of carbonyl compounds catalyzed by Eosin Y

We have systematically studied the reactions of acetalization and found that high reaction efficiency can be achieved using cheap and readily available organic Eosin Y as catalyst. The reaction proceeds smoothly under house bulbs and shows excellent functional group tolerance. The substrates of the reaction system are compatible with aromatic aldehydes, aliphatic aldehydes, aromatic ketones, and cyclic ketones with high yields.     

Palladium-bipyridine catalyzed conjugate addition of arylboronic acids to α,β-unsaturated carbonyl compounds in aqueous media

Palladium/bipyridine catalyzed conjugate addition of arylboronic acids to α,β-unsaturated carbonyl compounds in aqueous media was developed with high yields.     

3D superposition of chemical fragments for N‐membered rings: application to conformational analysis

In this paper a procedure is suggested for the 3D superposition of chemical fragments, which is specifically designed for rings molecules and can be combined with statistical multivariate procedures to extract useful conformational information. The procedure relies on the plane introduced by Cremer and Pople ‘A general definition of ring puckering coordinates. J. Am. Chem. Soc. 1975; 97 (6): 1354–1358’ to define the celebrated puckering coordinates, and provides a measure of distance between two geometrical conformations. Real datasets are analyzed to illustrate how it can be used as input to agglomerative clustering methods, multidimensional scaling analysis and allows to compute the centroid of a group of fragments. Copyright © 2010 John Wiley & Sons, Ltd.     

A CoMFA analysis with conformational propensity: An attempt to analyze the SAR of a set of molecules with different conformational flexibility using a 3D-QSAR method

CoMFA analysis, a widely used 3D-QSAR method, has limitations to handle a set of SAR data containing diverse conformational flexibility since it does not explicitly include the conformational entropic effects into the analysis. Here, we present an attempt to incorporate the conformational entropy effects of a molecule into a 3D-QSAR analysis. Our attempt is based on the assumption that the conformational entropic loss of a ligand upon making a ligand-receptor complex is small if the ligand in an unbound state has a conformational propensity to adopt an active conformation in a complex state. For a QSAR analysis, this assumption was interpreted as follows: a potent ligand should have a higher conformational propensity to adopt an `active-conformation'-like structure in an unbound state than an inactive one. The conformational propensity value was defined as the populational ratio, N<sub>active</sub>/N<sub>stable</sub>, of the number of energetically stable conformers, N<sub>stable</sub>, to the number of `active-conformation'-like structures, N_active. The latter number was calculated by counting the number of conformers that satisfied the structural parameters deduced from the active conformation. A set of SAR data of imidazoleglycerol phosphate dehydratase inhibitors containing 20 molecules with different conformational flexibility was used as a training set for developing a 3D structure-activity relationship by a CoMFA analysis with the conformational propensity value. This resulted in a cross-validated squared correlation coefficient of the CoMFA model with the conformational propensity value (R ² _cross = 0.640) higher than that of the standard CoMFA model (R ² _cross = 0.431). Then we evaluated the quality of the CoMFA models by predicting the inhibitory activity for a new molecule.