Salvatore Profeta

A distance geometry study of ring systems : Application to cyclooctane, 18-crown-6, cyclododecane and androstanedione

Abstract We present the application of distance geometry methods to the generation of structures of a sampling of organic molecules: cyclooctane, cyclododecane, 18-crown-6, and androstane-3,17-dione. The method provides a simple, convenient method to generate either a random sample of molecular conformations, or to generate specified conformations. Using this approach, we found a new, relatively low-energy conformation of 18-crown-6. We also demonstrated that the lowest energy structure of cyclododecane was not exactly of D 4 symmetry, which had been previously assumed in molecular mechanics optimization.

Guest-Accelerated Molecular Rotor

A molecular rotor was designed in which the rate of rotation is accelerated by guest complexation. The binding of an acetate guest to the urea groups lowers the barrier of the adjacent C(aryl)-N(imide) bond by 2 to 4 kcal/mol. This behavior is in contrast to most molecular rotors in which guest complexation slows rotation.

Mean geometry of the thiopeptide unit and conformational features of dithiopeptides and polythiopeptides

The mean geometry of the thiopeptide [Ca-N-C(=S)-Ca] unit has been derived from an analysis of X-ray crystal structure data, as well as MM2 and Gaussian 80/82 calculations. The conformational flexibilities of dithiopeptides with glycl- and alanyl-side chains have been investigated by molecular mechanics. Minimum energy conformations were examined using interactive computer graphics molecular modeling techniques. Alanyl-dithiopeptide substitution within an oligopeptide results in considerable restriction of conformational freedom whereas the effect is minimal for glycyl-dithiopeptide substitution. Polyglycyl-thiopeptide adopts a left-handed three or fourfold or right-handed threefold helical structure with favorable interchain C = S...H-N hydrogen bond interactions. A poly-L-alanyl-thiopeptide prefers a left-handed threefold poly-L-proline-like helical structure.

Discovery of imidazole glycerol phosphate dehydratase inhibitors through 3-D database searching

Imidazole glycerol phosphate dehydratase (IGPD) has become an attractive target for herbicide discovery since it is present in plants and not in mammals. Currently no knowledge is available on the 3-D structure of the IGPD active site. Therefore, we used a pharmacophore model based on known inhibitors and 3-D database searches to identify new active compounds. In vitro testing of compounds from the database searches led to the identification of a class of pyrrole aldehydes as novel inhibitors of IGPD.

Rotational potential energy functions in ethylchlorosilane,(chloromethyl)methylsilane, and (chloromethyl) chlorosilane: MM2, MNDO, and ab initio calculations

Abstract The rotational potential energy functions of ethylchlorosilane (ECS), (chloromethyl) methylsilane (CMMS),and (chloromethyl) chlorosilane (CMOS) have been examined by ab initio (GAUSSIAN-82), semi-empirical (MNDO), and molecular mechanics (MM2) techniques, and have been compared with those of carbon analogs, i.e. 1 -chloropropane (CP) and 1,2-dichloroethane (DCE). While ab initio (3-21G(∗)) calculations give excellent agreement with available experimental data in geometries and relative conformational energies, the MNDO technique shows a definite shortcoming, namely, that relative energies are unacceptably insensitive to conformational changes involving rotation around the central C-C and C-Si bonds, even though the geometries are reproduced reasonably. On the basis of these calculations, we have developed additional MM2 torsional parameters and have applied these in a conformational study of the title compounds. Interpretation of our calculations suggests that: (1) silicon compounds barely show steric congestion, which means that the bonded and non-bonded energy terms are less important factors when compared with corresponding carbon analogs. (2) ECS and CMMS show the “gauche effect”, which is due to attractive interaction between methyl and chlorine. (3) In CMCS, as two chlorine atoms approach, the repulsive interaction between the two vicinalchlorine atoms rises, apparently as a result of the near parallel alignment between two large vicinal C-Cl and Si-Cl bond dipoles.

Development of a molecular mechanics (MM2) force field for α-chlorosilanes

Abstract Molecular mechanics (MM2) parameters for silanes which have a Si-C-Cl fragment have been developed based on available experimental data and ab initio molecular orbital (MO) calculations. Molecular properties, mainly rotational barriers and geometries, of α-chlorosilanes have been studied using our new MM2 parameter set. Changes in the Si-C bond lengths and several bond angles of α-chlorosilanes due to the additional attachment of polar atom(s) have been investigated utilizing ab initio calculations. An electronegativity correction to both bond lengths and angles helps MM2 to reproduce results from ab initio calculations. The new force field has been applied to the conformational analysis of l-(chloromethyl)-1,2-dimethylsilacyclopentane, a model used in our studies of rearrangements of α-halosilanes.

Differential reactivity of thiophene-2-carboxylic and thiophene-3-carboxylic acids: Results from DFT and Hartree-Fock theory.

In the course of investigating the propensity of aromatic acids to react with selected nucleophiles, we came across an interesting difference in yields for two structurally similar thiophene carboxylic acids. Given that these yields were consistent across more than 40 repetitions for each structure, we felt that the difference was real, and worth exploration. To extract the potential steric and electronic origins of such differences, we employed both DFT B3LYP/6-31G* and HF/6-311+G** levels of theory to evaluate structures and energetics. Two somewhat different pictures emerge of the origin of the differences between the carboxylic acids and their individual conformations. In particular, Hartree-Fock calculations with the larger 6-311+G** basis set, which includes multiple diffuse functions, show a profound difference in the delocalization of the LUMO, relative to the DFT method which, expectedly, provides a more localized picture of the contributions to the LUMO. For each of the conformers, the molecular electrostatic potential and the ionization potential (ESP and IP, respectively), together with charge distributions, dipole moments and orbital energies have been explored. A potential explanation for the somewhat more reactive character of the thiophene-2-carboxylic acid appears to arise from the presence of a conformer which has an internal hydrogen bond to the thiophene sulfur, which, in turn, polarizes the acid function significantly relative to other conformers, and optimizes the angle of attack of the nucleophile.

The structure of the cyclooctadecane ring system. 1,10-Cyclooctadecanedione

Abstract The crystal structure of the title compound was determined by X-ray crystallography and solved by direct methods; the molecule has C 2h symmetry. The carbon atoms are arranged in a diamondoid lattice, but not of the rectangular type that might have been expected. The dipole moment for the conformation found in the crystal is zero, while the observed dipole moment of the compound in solution is 2.78 D. Molecular mechanics calculations were carried out on several of the large number of possible conformation. Of those studied, the conformation found in the crystal had the lowest energy.

Relative Energies and Structural Features of Small Amines and Their Ammonium Analogs: Results From 6-31G* Optimizations and an Mm2 Ammonium Force Field

An MM2 force field that reproduces the structural fea tures and relative energies of quaternary aliphatic amines as derived from ab initio calculations at the 6-31G* level has been completed. The purpose of the study is to provide Medicinal Chemists with a method of evaluating the structures and conformational ener gies of ammonium species typically found in pharma ceuticals. Full Cartesian coordinate geometry optimiza tions at the 6-31G* level are followed by single-point Møller-Plesset Perturbation calculations through the MP3 level, which were performed on CRAY X-MP/4, CRAY Y-MP/464, and VAX 8800 machines using Gaus sian 80(UCSF). Methyl-, ethyl-, propyl-, and ethylmethyl- amines, N-Methylpiperidine, 2-Methylpiperidine, and corresponding ammonium systems are used to evalu ate changes in structure, barrier heights, and relative energies resulting from quaternization.