Andrew J. Holder

Addendum to SAM1 results previously published

Abstract Corrected data and additional molecules are presented for the new SAM1 semiempirical method recently published by M.J.S Dewar, J.Y. Yu, and C. Jie.

Chain melting temperature estimation for phosphatidyl cholines by quantum mechanically derived quantitative structure property relationships.

Geometries for 62 phosphatidylcholines (PC) were optimized using the AM1 semiempirical quantum mechanical method. Results obtained from these calculations were used to calculate 463 descriptors for each molecule. Quantitative Structure Property Relationships (QSPR) were developed from these descriptors to predict chain melting temperatures (Tm) for the 41 PCs in the training set. After screening each QSPR for statistical validity, the Tm values predicted by each statistically valid QSPR were compared to corresponding Tm values extracted from the literature. The most predictive, chemically meaningful QSPR provided Tmvalues which agreed with literature values to within experimental error. This QSPR was used to predict Tm values for the remaining 21 PCs to provide external validation for the model. These values also agreed with literature values to within experimental error. The descriptor developed by the final QSPR was the second order average information content, a topological information-theoretical descriptor.

Photoreactivity of expanding monomers and epoxy‐based matrix resin systems

The relative photoreactivity of five expanding monomers (EMs) in homopolymerization, and as comonomers in a candidate low shrinkage dental matrix resin, were evaluated. The EMs were 2,8-dimethyl-1,5,7,11-tetraoxaspiro[5.5]undecane (DM-TOSU); 3,9-diethyl-3,9-dipropionyloxymethyl-1,5,7,11-tetraoxaspiro[5.5]undecane (DEDPM-TOSU); 1,3-dioxane-2-one (DOO); 4-methyl-1,3-dioxane-2-one (M-DOO); and 5,5-diethyl-1,3-dioxane-2-thione (DE-DOT). The candidate low shrinkage resin system was an 80/20 mixture of UVR-6105 epoxide/polytetrahydrofuran (Mn ≈ 250). All reaction mixtures contained a diaryliodonium salt as a photoinitiator and camphorquinone as photosensitizer. Reactivities were evaluated using photodifferential scanning calorimetry. For homopolymerizations, the reactivity ranking (based on time to exotherm peak and total enthalpy) was DE-DOT ≫ DM-TOSU > DOO > M-DOO ≥ DEDPM-TOSU. In the comonomer system, the reactivity ranking was M-DOO > DEDPM- TOSU > DM-TOSU > DOO ≥ DE-DOT. This experimental work was substantiated and extended by molecular modeling studies employing the AM1 semiempirical method. Heats of formation of protonated EM structures, and heats of formation and potential energies of possible polymerization pathways were estimated. The relative reactivities of EM-based polymerization systems are related to chemical structure and the dominance of the most favored reaction mechanism.

Evaluation of quantitative structure property relationships necessary for enantioresolution with lambda- and sulfobutylether lambda-carrageenan in capillary electrophoresis.

Lambda-carrageenan, a linear, high molecular weight sulfated polysaccharide, was successfully employed in both its native and sulfobutyl derivatized form as a chiral selector in capillary electrophoresis for the separation of enantiomers of basic pharmaceutical compounds. In order to characterize the chiral selectivity properties of this chiral selector, various structurally related racemic compounds were analyzed for enantiomeric interactions using capillary electrophoresis. The results of these studies were then rationalized and analyzed utilizing a general quantitative structure-property relationship (QSPR) evaluation in order to predict critical analyte structural requirements for successful enantiomeric separation. Important structural components of the analytes were found to include the aromatic content, the type of substitution on the aromatic ring, presence of a primary or secondary protonated amine, and an overall positive charge to the molecule.

A quantum mechanical quantitative structure–activity relationship study of the flexural modulus of C, H, O, N-containing polymers

OBJECTIVE The result of this research was to develop a quantum mechanically based QSAR model for polymer flexural modulus from structural features of small oligomers of the polymers. The final model was to have both explanatory power and be a reasonably accurate screening tool for new materials. METHODS A quantitative structure-activity relationship (QSAR) was developed using the CODESSA program from quantum mechanical information provided by the AM1 semiempirical method, as implemented in AMPAC. RESULTS A four-descriptor correlation equation with R(2)=0.91, also satisfying our other statistical criteria. A tetramer was determined to be a sufficient simulator for the polymer chain. The descriptors in the model show that rigidity of the monomer, electrostatic interactions and branching are the most important contributors to the flexural modulus value for a particular system. SIGNIFICANCE The QSAR model we have developed here is conceptually satisfying for flexural, and provides an easily usable tool for rational biomaterials design.

An AM1 semiempirical molecular orbital investigation of the group 14 [1.1.1]propellanes and bicyclo[1.1.1]pentanes

Abstract AM1 semiempirical calculations were performed on the group 14 [1.1.1]propellanes and bicyclo[1.1.1]pentanes. For the carbon and tin propellanes, the results were in agreement with several previous theoretical and experimental studies, predicting substantial bonding interaction between the bridgehead atoms in the case of carbon and none in the case of tin. Calculations on the silicon propellane were in sharp disagreement with ab initio calculations using a variety of basis sets. Both geometry and singlet-triplet splitting were incorrectly reproduced. The silicon propellane calculations were repeated using the HF/6-31G* basis set, and the singlet-triplet order was in agreement with the previous work. The germanium results show very strong charge localization. We suggest a possible reason for this observation.

A quantum mechanical quantitative structure–property relationship study of the melting point of a variety of organosilicons

We have developed quantitative structure-property relationship (QSPR) models that correlate the melting points of chain and cyclic silanes and siloxanes with their molecular structures. A comprehensive correlation was derived for a variety of molecules, but the quality of the comprehensive model was modest at best. This provided the impetus for the development of two additional models focused on silanes and siloxanes, respectively. Statistical analyses confirm the robustness of the refined models, and the chemical interpretation of the descriptors was consistent with effects expected for melting.

A Quantum Mechanical Study of Methacrylate Free-Radical Polymerizations

Theoretical calculations at the semiempirical and ab initio levels of theory have been completed for a series of methacrylate compounds reported in the literature as measured by pulsed-laser initiated polymerization in conjunction with size-exclusion chromatography (PLP-SEC). Modeling includes calculation of the Gibbs free energies (ΔG(‡)) and activation energies (E(a)). These results were then compared to experimental results. Semiempirical ΔG(‡) using AM1-CI calculations successfully predicted relative activation energies (R(2) = 0.89). HF and DFT methods more accurately predicted absolute activation energies, but the relative values were less reliable. Accurate quantitative structure property relationship (QSAR) models for propagation rate coefficients, k(p), were developed using AM1-CI and DFT. The semiempirical model included two charge descriptors, partial negatively charged surface area (PNSA), and minimum net atomic charge for oxygen (R(2) = 0.959). The DFT information, which included two quantum chemical descriptors (1-electron reactivity index for carbon and point charge component of the molecular dipole) calculated from the ground state structure, had improved statistics (R(2) = 0.979). A second DFT model is reported for 10 hydrocarbon methacrylate structures based on the 1-electron reactivity index for carbon (R(2) = 0.979). Theoretical results were also analyzed to provide an explanation for the unexpectedly large experimental k(p) values observed in the case of larger methacrylate monomers.

Quantum mechanical quantitative structure–activity relationships to avoid mutagenicity

OBJECTIVE The purpose of this work is to develop a quantum mechanically based quantitative structure-activity relationship (QMQSAR or QSAR hereafter) adequate to predict and explain Ames TA100-derived mutagenicities for a number of organic molecules. METHODS A set of 35 structurally similar molecules with epoxide (oxirane) functionalities and systematic, reliable experimental data were selected to construct a QSAR model. The SAM1 quantum mechanical method was used to perform conformational analysis and properties calculations. This QM information was used to compute a variety of descriptors. From this a two-descriptor regression model was constructed. RESULTS The two descriptors are ESP-HACA-1/TMSA and HOMO-LUMO energy gap. Statistical results for the model: R(2)=0.857, R(adj)(2)=0.818,R(cv)(2)=0.848,s(2)=0.0618. The variance inflation factor and significance for both descriptors were 1.082 and <0.001, respectively. The descriptors are related to transport across a membrane and to reactivity. SIGNIFICANCE The model we have presented here facilitates design of non-mutagenic monomers that may be useful for dental restorative composites. The model also serves as a screening tool for rating the mutagenicity of new candidate materials.

Semiempirical and ab initio conformational analysis of 2-methylene-8,8-dimethyl-1,4,6,10-tetraoxaspiro[4.5] decane with application of GIAO-SCF methods to NMR spectrum interpretation

The GIAO-SCF method for calculating isotropic nuclear magnetic shielding values has been utilized to explain certain features in the 1H-NMR spectrum of 2-methylene-8,8-dimethyl-1,4,6,10-tetraoxaspiro[4.5] decane. Population distributions of the low-energy conformers based on their ab initio energies were used to produce weighting factors for the individual calculated shielding values to calculate the weighted average of the shielding values for a complete set of conformers. The differences in 1H chemical shifts between the hydrogens of the two methyl groups and between the axial and equatorial hydrogens in 2-methylene-8,8-dimethyl-1,4,6,10-tetraoxaspiro[4.5] decane were shown to be due to energy differences between the chair and boat orientations of the six-membered ring and contribution from a twist-boat conformation. Results suggest a hypothesis that intramolecular differences in chemical shift might be calculated to a greater degree of accuracy than chemical shifts calculated relative to a standard.