ALBERT

Notizen: Ab initio MRD-CI calculations based on localized orbitals were carried out for cubane (neutral, carbocation, carboanion) both in our customary MODPOT basis set and in an all-electron 4-31G basis set. The calculated MRD-CI charge distributions on C1 (the skeletal atom from which the H- or H+ was removed) (ab initio MODPOT neutral 4.221, carbocation 3.796, carboanion 4.282; all-electron 4-31G neutral 6.171, carbocation 5.717, carboanion 6.078) indicate that the + or - charge does not remain localized on C1 but redistributes itself. This has significant implications for preparative reactions of energetically substituted cubanes. The MRD-CI population analyses differ somewhat from the SCF population analyses, especially in the calculated total overlap populations. To investigate this effect on electrostatic molecular potential contour (EMPC) maps generated from SCF or MRD-CI wave functions, we wrote additional routines to calculate EMPC maps from MRD-CI wave functions. The EMPC maps generated from SCF or MRD-CI wave functions are different if the molecule needs an MRD-CI multideterminant wave function to describe it adequately. The EMPC map is a one-electron property. One-electron properties are derived from the 1-matrix. The 1-matrix is different for SCF or MRD-CI wave functions. Thus, all the one-electron properties (EMPC maps, population analyses, bond deviation indices, etc.) are different when calculated from SCF or MRD-CI wave functions if MRD-CI wave functions are necessary to describe a system properly. We calculate these one-electron properties from the 1-matrix from the final natural orbitals. Our preliminary calculations for the dissociation pathway indicate it takes more energy to dissociate a bond in 1-nitrocubane than in octanitrocubane. Even in their ground electronic states at equilibrium geometry, both 1-nitrocubane and octanitrocubane require MRD-CI wave functions to describe them properly. The c2 of the single determinant SCF wave function is only 0.8401 for 1-nitrocubane and 0.8300 for octanitrocubane. There are contributions from skeletal excitations as there are for cubane itself as well as excitations involving the nitrogroup. As the bond in nitrocubane is dissociated to 8.00 bohrs, the c2 of the SCF contribution drops to only 0.4606 (1-nitrocubane) and 0.4445 (octanitrocubane). At this C1—N1 intermolecular distance, the largest excitations are in the C1—N1 bond: (C1—N1)2 → (C1—N1*)2, (C1—N1) → (C1—N1*). We also calculated the first electronically excited state for the dissociation pathway for selected points for both 1-nitrocubane and octanitrocubane.

Notizen: The hybrid method having features of ab-initio crystal orbital and ab-initio molecular cluster methods is proposed. In the approach presented the molecular crystal is treated as an infinite chain in a direction z, while two other directions are simulated by finite interactions of the molecular type. The new approach is especially useful for an investigation of anisotropic crystals. Test calculations for the carbon dioxide crystal are presented. The method was also employed for the investigation of a dissociation pathway of C—N bond in nitromethane in nitromethane crystal.

Notizen: The recently proposed ab initio method for calculation on many-electron molecular systems with the approximation of the inactive part of a molecule by a frozen molecular fragment was tested further in a case of the dissociation reaction of the C—F bond in n-fluoropropane. Results from the Hartree-Fock, multiple reference double-excitation configuration-interaction and second-order Møller-Plesset methods are presented. The reproduction of potential energy surfaces as well as the reproduction of electron density distribution are in excellent agreement with extended basis-set calculations. Different choices of fragments to be frozen have been examined.

Notizen: Ab initio LCAO-MO-SCF Gaussian basis function calculations have been performed for chlorpromazine and promazine. By prescreening for the size of the integrals before calculation, it was only necessary to calculate 12 million out of the possible 38.5 million integrals for chlorpromazine. By a novel procedure of processing the integral tapes for the SCF it was possible to cut down significantly on the amount of time for the SCF. The SCF calculations converged smoothly for both promazine and chlorpromazine. There is a sizeable energy gap between the energy of the highest occupied molecular orbitals in these molecules (which is of the order of -0.3 a.u.) and the lowest unoccupied molecular orbital (which is of the order of + 0.15 a.u.). The gross atomic populations of chlorpromazine and promazine resemble each other and differ only somewhat on the carbon atom to which the substituent is attached and the carbons and their hydrogens adjacent to it.

Notizen: Quantum chemical CNDO/2 calculations for the conformational preference of the side chain of thioridazine as a function of angle indicated the crystallographically determined structure gave the lowest energy. There is also a small region of conformational flexibility within the first 90° of rotation of the side chain. This is commensurate with the results which we had obtained previously for our similar calculations for promazine and its Cl and CF3 derivatives, perazine and its Cl and CF3 derivatives, and for the hypothetical hitherto unknown N-piperidinopromazine and its Cl and CF3 derivatives. The conformational profile of thioridazine resembles that of the perazines. The calculated gross atomic populations on the alkyl nitrogen in thioridazine was within the range we had previously found necessary for neuroleptic activity.

Notizen: Reference completely ab initio 6-3G and nonempirical 3G/MODPOT (ab initio effective core model potential) LCAO-MO-SCF calculations (using the same valence atomic orbital basis) were performed for a series of boron hydrides (B4H10, B5H9, B5H11, and B6H10) and a test 3G/MODPOT + VRDDO (variable retention of diatomic differential overlap for charge conserving integral prescreening) calculation were also performed for B5H9, B6H10, and B10H14. The agreement between the ab initio 6-3G and the corresponding 3G/MODPOT calculations was excellent for valence orbital energies, gross atomic populations, and dipole moments. The results also compared favorably to previous ab initio minimum STO basis results of Lipscomb and coworkers. The 3G/MODPOT + VRDDO calculations verified that for such spatially compact molecules (such as boron hydrides, which are fragments of polyhedra), the VRDDO procedure does not result in a noticeable savings in computer time for molecules of the size and shape of B5H9 and B6H10, in contrast to the savings previously realized for organic molecules of comparable atomic size. However, the agreement in calculational results between the 3G/MODPOT and the 3G/MODPOT+VRDDO results was still as extremely close as it had been for the organic molecules.3G/MODPOT calculations were also carried out for B8H12, B9H15, B10H14, B10H14-2, 1,2-C2B4H6, and 1,6-C2B4H6 and the results compared to the previous minimum STO basis results. For B10H14, the 3G/MODPOT+VRDDO method led to savings in computer time of 28% over the 3G/MODPOT method itself.The agreement of the 3G/MODPOT results with available experimental photoelectron spectral data for B5H9 and 1,6-C2B4H6 was as good as that of the previous ab initio minimum STO basis calculations.

Notizen: Ab initio MODPOT/VRDDO/MERGE calculations were carried out on carcinogenic 3-methylcholanthrene (3-MCA) and its metabolites. The results for 3-MCA were compared to our earlier similar calculations for carcinogenic benzo(a)pyrene (BP). Both compounds 3-MCA and BP are carcinogenic and are metabolically activated by similar mechanisms but in different positions. Both the calculated wave functions for 3-MCA and BP and the electrostatic molecular potential contour maps generated from these wave functions correctly reflect the similarity of mechanisms of metabolic activation and the differences in position. Our calculated results both for BP and for 3-MCA reflect accurately their experimentally observed behavior. Thus this combination of theoretical techniques can be used with confidence to describe the behavior of the polycyclic aromatic hydrocarbons (PAH's) and their metabolites. The ab initio MODPOT/VRDDO method incorporates two very desirable options into our fast ab initio Gaussian programs: MODPOT-ab initio effective core model potentials - and a charge-conserving integral prescreening approximation which we named VRDDO (variable retention of diatomic differential overlap). For orbital energies and population analysis the MODPOT/VRDDO results agree to essentially three decimal places with completely ab initio calculations using the same valence atomic basis set. For this series of very closely related congeners our recent MERGE technique which allows reuse of integrals from a common skeletal fragment was used. The ab initio MODPOT/VRDDO/MERGE calculations were carried out for 3-MCA, 3-MCA oxides, 3-MCA dihydrodiols, and 3-MCA dihydrodiolepoxides. The metabolites investigated were 3-MCA 9,10-oxide; 3-MCA 7,8-oxide; 3-MCA 9,10-dihydrodiol [trans(axial, axial); trans(equatorial, equatorial); cis(axial, equatorial); cis(equatorial, axial)]; and 3-MCA 9,10-dihydrodiol-7,8-epoxide [for both conformations A and B of the dihydrodiol and for all stereoisomers of the dihydrodiolepoxides relative to below and above the plane: ααα, and ααβ αβα αββ βαα βαβ ββα and βββ (most stable)]. Calculations were also carried out for opening of the C7—O—C8 epoxide ring both towards C7 and C8 for the most stable isomer Aβββ (above the ring). Opening the epoxide ring between C7 and O leads to a more stable intermediate than opening the epoxide ring between C8 and O. Again, however, as with opening the epoxide ring in BP 7,8-dihydrodiol-9,10-epoxide there is no buildup of positive charge on C7 in the 3-MCA metabolites as postulated by some cancer researchers, but rather the C7 becomes slightly more negative. Nor is there a buildup of negative charge on the O atom, but rather it becomes slightly more positive. As the epoxide ring is opened further than 90° for the O—C7—C8 or O—C8—C7 angles, there appears to be a possible mixing of configurations that is being investigated further.

Notizen: The electrostatic molecular potential contour maps were calculated for carcinogenic 3-methylcholanthrene (3-MCA) and a number of its metabolites {3-MCA 7,8-oxide and 3-MCA 9,10-oxide; 3-MCA 7,8-dihydrodiols[several stereoisomers: A trans(equatorial, equatorial) and A cis(equatorial, axial)]; 3-MCA 9,10-dihydrodiol-7,8-epoxide A βββ and 3-MCA 9,10-dihydrodiol-7,8-epoxide A αβα}. The maps were generated from our ab initio MODPOT/VRDDO/MERGE wave functions calculated for these species. The results of these maps for 3-MCA [similarly to our results for the maps we generated for benzo(a)pyrene (BP)] show that these electrostatic molecular potential contour maps can be used to indicate favored positions of attack for electrophilic species, such as “electrophilic” oxygen to form an epoxide as well as for positive ion attack. The 3-MCA maps indicate the favored site for attack and the pathways. The maps around 3-MCA 9,10-oxide and around 3-MCA 9,10-dihydrodiol-7,8-epoxide indicate the directional preferences for proton assisted epoxide ring opening. The maps around the 3-MCA dihydrodiols indicate that while for certain stereoisomers the “electrophilic” oxygen will prefer to attack from below, for other isomers it will prefer to attack from above. This gives great insight into the stereochemical preference for formation of different 3-MCA 9,10-dihydrodiol-7,8-epoxides.

Notizen: Theoretical and quantum chemical prediction of toxicity and toxicology is even more challenging than prediction of pharmacology, which is usually a one-stage event at a target site. For toxicity and toxicology, the concept of the “toxic triggering event” was developed which then leads to the cascade of subsequent physiological events. The strategy for computer-generated predictions in this area includes as the major components chemical automated substructure and “toxicophore” identification by powerful chemical substructure searching techniques developed in Europe, geometry optimizations (desirably by ab-initio intramolecular atom class-atom class pair-pair and three-body potentials), quantum chemical calculations (desirably ab-initio, incorporating optimal strategies for such computations on large molecules) on both the toxicant and its metabolites (the structures of which were generated by computer-assisted tracing of metabolic pathways), generation of the three-dimensional electrostatic molecular potential contour maps around the toxicants and their metabolites and matching of these by reverse image holography for new compounds whose toxicity has not yet been tested experimentally against those with a known toxic mechanism, matching of intermolecular interaction maps of untested compounds with known toxicants combined with matching observed physiologic signs and symptoms with “toxic triggering events” and specific pathologies, and using the concepts of systems analysis and control theory and catastrophe theory to track both the dynamic balance of endogenous biomolecules and interactions with these biomolecules. The necessary program modules are described, and the necessary data bases (both theoretical and physiological) are identified along with the form in which they may be used most expeditiously.

Notizen: In the propagation step of the cationic polymerization, oxetane reacts with the protonated oxetane formed in the initiation step, with concomitant ring opening of the protonated oxetane. To describe properly bond making or bond breaking, it is necessary to use MC-SCF or CI calculations. We have carried out ab initio MODPOT/VRDDO MRD-CI calculations (by the multireference double excitation-configuration interaction technique of Buenker and Peyerimhoff into which we have also meshed a number of desirable computational options for ab initio calculations on large molecules). The CI calculations were carried out on strictly orthogonalized localized occupied and virtual orbitals in the reaction region, with the remainder of the occupied molecular orbitals being folded into an effective CI Hamiltonian. The calculated potential energy surfaces indicate that a preferred pathway for this reaction resembles an SN2 reaction with the oxygen of the oxetane attacking linearly along the C4—O direction of the protonated oxetane and inversion of the hydrogens around the C4 atom.