Conformational energies of reference organic molecules: benchmarking of common efficient computational methods against coupled cluster theory.

We selected 145 reference organic molecules that include model fragments used in computer-aided drug design. We calculated 158 conformational energies and barriers using force fields, with wide applicability in commercial and free softwares and extensive application on the calculation of conformational energies of organic molecules, e.g.

Well-defined palladium(0) complexes bearing N-heterocyclic carbene and phosphine moieties: efficient catalytic applications in the Mizoroki-Heck reaction and direct C-H functionalization.

Two series of well-defined palladium(0) complexes with phosphine-functionalized N-heterocyclic carbene ligands were prepared. These complexes featured six- and seven-membered chelate rings in the two series. Among the seven-membered chelate complexes, those featuring the PCy2 moiety exhibited observable fluxional behavior on the NMR time scale, corresponding to the interchange between two sets of conformations.

Molecular Mechanics (MM4) Studies on Unusually Long Carbon-Carbon Bond Distances in Hydrocarbons.

The carbon-carbon single bond is of central importance in organic chemistry. When the molecular mechanics MM4 force field was developed beginning in the early 1990s, C-C bond lengths were not known very reliably for many important molecules, and bond lengths greater than 1.6 Å were quite poorly known experimentally.

Catenanes: A molecular mechanics analysis of the (C13H26)2 Structure 13-13 D2.

Molecular mechanics (MM4) studies have been carried out on the catenane (C13H26)2, specifically 13-13D2. The structure obtained is in general agreement with second-order perturbation theory. More importantly, the MM4 structure allows a breakdown of the energy of the molecule into its component classical parts.

How Small Can a Catenane Be?

Catenanes are playing an increasingly important role in supramolecular chemistry. In attempting to identify the minimum number of carbon atoms in a viable catenane, the B3LYP, BP86, M06-2X, MM3, and MM4 methods were applied to study representative [2]catenane models, which consist of two mechanically interlocked saturated n-cycloalkanes ([CnH2n]2). The structures, energy variations, and electron density differences vary nearly monotonically from n = 18 to 11.

Formation of CC-type palladacycles with assistance from an apparently innocent NH(CO) functional group.

A novel cyclometalation pathway to form CC-type palladacycles is reported. Unlike common donor-assisted cyclometalation, the NH(CO) auxiliary group undergoes a deprotonation step to form a palladalactam intermediate. The coordinating nitrogen atom functions as an intramolecular base promoting selective C-H bond cleavage.

An improved theoretical approach to the empirical corrections of density functional theory.

An empirical correction to density functional theory (DFT) has been developed in this study. The approach, called correlation corrected atomization-dispersion (CCAZD), involves short- and long-range terms. Short-range correction consists of bond (1,2-) and angle (1,3-) interactions, which remedies the deficiency of DFT in describing the proto-branching stabilization effects.

Accurate prediction of the enthalpies of formation for xanthophylls.

This study investigates the applications of computational approaches in the prediction of enthalpies of formation (ΔH(f)) for C-, H-, and O-containing compounds. Molecular mechanics (MM4) molecular mechanics method, density functional theory (DFT) combined with the atomic equivalent (AE) and group equivalent (GE) schemes, and DFT-based correlation corrected atomization (CCAZ) were used. We emphasized on the application to xanthophylls, C-, H-, and O-containing carotenoids which consist of ∼ 100 atoms and extended π-delocaization systems.

A theoretical approach for accurate predictions of the enthalpies of formation of carotenes.

A computational approach has been designed for accurately determining enthalpies of formation (ΔH(f)) for the carotene species. This approach, named correlation corrected atomization (CCAZ), is based on the concept of bond and group additivity, and is applied along with density functional theory (DFT). Corrections to the deficiencies in DFT were divided into 1,2-, 1,3-, and 1,4- atomic interactions, which were determined by comparisons with the G3 data of the training set.

Selenoglycosides in silico: ab initio-derived reparameterization of MM4, conformational analysis using histo-blood group ABH antigens and lectin docking as indication for potential of bioactivity.

The identification of glycan epitopes such as the histo-blood group ABH determinants as docking sites for bacterial/viral infections and signals in growth regulation fuels the interest to develop non-hydrolysable mimetics for therapeutic applications. Inevitably, the required substitution of the linkage oxygen atom will alter the derivative's topology. Our study addresses the question of the impact of substitution of oxygen by selenium.

Conformational analysis of thioglycoside derivatives of histo-blood group ABH antigens using an ab initio-derived reparameterization of MM4: implications for design of non-hydrolysable mimetics.

Histo-blood group ABH antigens serve as recognition sites for infectious microorganisms and tissue lectins in intercellular communication, e.g. in tumor progression.

The important role of lone-pairs in force field (MM4) calculations on hydrogen bonding in alcohols.

An expanded treatment of hydrogen bonding has been developed for MM4 force field calculations, which is an extension from the traditional van der Waals-electrostatic model. It adds explicit hydrogen-bond angularity by the inclusion of lone-pair directionality. The vectors that account for this directionality are placed along the hydrogen acceptor and its chemically intuitive electron pairs.

Molecular mechanics (MM4) study of amines.

The MM4 force field has been extended to include aliphatic amines. About 20 amines have been examined to obtain a set of useful molecular mechanics parameters for this class. The vibrational spectra of seven amines (172 frequencies) calculated by MM4 have an overall rms error of 27 cm(-1), compared with corresponding MM4 value of 24 cm(-1) for alkanes.

Molecular mechanics (MM4) study of fluorinated hydrocarbons.

A molecular mechanics study of small saturated hydrocarbons (up to C-6) substituted by up to six fluorines has been carried out with the MM4 force field. A parameter set has been developed for use in the calculation of bond lengths, bond angles, torsion angles, conformational energies, barriers to rotation, dipole moments, moments of inertia, and vibrational frequencies for these compounds. The results are mostly in fair to good agreement with experiment and ab initio calculations.

The external-anomeric torsional effect.

The rotational barrier for a methyl group at the end of an anomeric system is sometimes lower than we might have anticipated. Thus, in the trans-trans conformation of dimethoxymethane, the barrier to methyl rotation is calculated (B3LYP/6-311++G(2d,2p)) to be 2.22 kcal/mol, just slightly smaller than the corresponding barrier to rotation of the methyl group in methyl propyl ether of 2.

Alcohols, ethers, carbohydrates, and related compounds. IV. Carbohydrates.

Ab initio calculations [B3LYP/6-311++G(2d,2p)] have been carried out on 84 conformations of 12 different sugars (hexoses), in both pyranose and furanose forms, with the idea of generating a data base for carbohydrate structural energies that may be used for developing the predictive value of molecular mechanics calculations for carbohydrates. The average value for the apparent gas phase anomeric effect for a series of 31 pairs of pyranose conformations was found to be 1.83 kcal/mol (vs.

Alcohols, ethers, carbohydrates, and related compounds. III. The 1,2-dimethoxyethane system.

Ethylene glycol, its dimethyl ether, and some related compounds have been studied using the MM4 molecular mechanics force field. The MM4 calculated structural and energetic results have been brought into satisfactory agreement with a considerable number of experimental data and MP2/6-311++G(2d,2p) ab initio calculations. The heats of formation of these compounds are also well calculated.

Alcohols, ethers, carbohydrates, and related compounds. II. The anomeric effect.

The anomeric effect has been studied for a variety of compounds using the MM4 force field, and also using MP2/6-311++G(2d,2p) ab initio calculations and experimental data for reference purposes. Geometries and energies, including conformational, rotational barriers, and heats of formation were examined. Overall, the agreement of MM4 with the experimental and ab initio data is good, and significantly better than the agreement obtained with the MM3 force field.

Alcohols, ethers, carbohydrates, and related compounds. I. The MM4 force field for simple compounds.

Simple alcohols and ethers have been studied with the MM4 force field. The structures of 13 molecules have been well fit using the MM4 force field. Moments of inertia have been fit with rms percentage errors as indicated: 18 moments for ethers, 0.

Molecular mechanics (MM3) calculations on lithium amide compounds.

The MM3 force field has been extended to deal with the lithium amide molecules that are widely used as efficient catalysts for stereoselective asymmetric synthesis. The MM3 force field parameters have been determined on the basis of the ab initio MP2/6-31G* and/or DFT (B3LYP/6-31G*, B3-PW91/6-31G*) geometry optimization calculations. To evaluate the electronic interactions specific to the lithium amides derived from the diamine molecules properly, the Lewis bonding potential term for the interaction between the lithium atom and the nonbonded adjacent electronegative atom such as nitrogen was introduced into the MM3 force field.