Ming-Ju Huang

Neural network studies: Part 3. Prediction of partition coefficients

Abstract In a previous paper (N. Bodor, A. Harget and M.-J. Huang, J. Am. Chem. Soc., 113 (1991) 9480) we demonstrated the utility of a neural network approach in the estimation of the aqueous solubility of organic compounds. This approach has now been extended to the prediction of partition coefficients. A training set of AM1 calculated properties and experimental values for 302 compounds was used and, after training, the neural network was tested for its ability to predict the partition coefficients of 21 compounds not included in the training set. We also tested six more compounds with molecular properties out of the training set property range. A comparison was made with the results obtained from a previous study which had used a regression analysis approach (N. Bodor and M.-J. Huang, J. Pharm. Sci., 81 (1992) 272). The neural network results compared favorably with those given by the regression analysis approach, both for the training set and for the new compounds.

An AM1 molecular orbital study of α-d-glucopyranose and β-maltose: Evaluation and implications

Abstract Chemical reactivity and other characteristics of α- d -glucopyranose and β-maltose were evaluated within a semiempirical molecular orbital (AM1) framework. Theoretically generated structures compared well to those determined by X-ray crystallographic techniques. Calculations suggested that the secondary hydroxy functions (OH-2 and OH-3) of the mono- and di-saccharides were more acidic than the primary alcohol (OH-6), which is consistent with experimental findings. In addition, the enhanced reactivity of the OH-3 locus, which is observed upon OH-2 alkylation of the object sugars, was rationalized in terms of increased OH-3 acidity. The chemical behavior of the monomers examined may be insightful in explaining the reactivity of glucopyranose polymers.

Contributions of Molecular Orbitals Techniques to the Study of Dihydropyridines

The discovery that dihydropyridines constitute the operational subunits in important coenzymes such as NAD(P)H has directed major research efforts at understanding the redox chemistry of these heterocycles. Molecular orbital approaches have been extremely useful in this regard. This short review is designed to survey the application of semiempirical and ab initio techniques to the study of mechanisms of dihydropyridine oxidation, transition state structure and the mechanisms thought responsible for stereospecificity of enzymatic oxidoreductions which utilize NAD(P)H as a coenzyme

On the reactivity of CFnH3−nCH2X (n = 0, 1, 2, and 3, and X = H or Halogen atom)

Abstract Theoretical and experimental data are presented which concern the properties and reactivity of CFnH3−nCH2X (X = H, Cl, Br, and I; n = 0, 1, 2, and 3). Anomalous behavior is shown for CF3CH2X (X = Cl, Br, and I). This includes (i) tertiary amines do not react with CF3CH2X to form a quaternary salt; (ii) the 13C NMR chemical shift is more than 20 ppm upfield than expected; and (iii) AM1 semi-empirical molecular orbital calculations predict CC heterolytic bond cleavage is preferred to Cheterolytic bond cleavage. Regarding (iii) experimental data indicate a small preference for Cbond cleavage, but the difference may be within the error bars for some of the enthalpies.

Application of semiempirical molecular orbital techniques to the study of peroxidase-mediated oxidation of phenols, anilines, sulfides and thiobenzamides

Abstract Reaction rates for a variety of enzymatically mediated oxidations were obtained and related to semiempirical (AMI) ionization potentials and molecular orbital structures. Highly significant correlations were generated for both vertical and adiabatic ionization potentials and horseradish peroxidase-mediated oxidation of substituted phenols, anilines and thioanisoles. The highest occupied molecular orbital for all substrates were clearly π in nature and associated with significant contributions by component heteroatoms. The results suggest that the oxidations considered proceed via an initial electron abstraction giving rise to a substrate radical or radical cation. Finally, theoretical approaches were used in concert with experimental paradigms to define the mechanism of lactoperoxidase-catalyzed oxidation of thiobenzamides. The sultoxidative process was shown to proceed via a tightly coupled oxygen transfer from the enzyme to the substrate in which the initial step involved electron loss from the thiobenzamide. In addition, the thiobenzamide S-oxide oxygen was found to be exclusively derived from the hydrogen peroxide and not from other sources.

Dithionite reduction of pyridinium salts: an AM1 study

The dithionite reduction of some simple pyridinium salts was examined using the AM1 molecular orbital approximation. The reaction is highly selective, resulting in the almost exclusive formation of the 1,4-dihydropyridine derivatives. Electronic and steric effects do not seem to be responsible for this selectivity. A study of the relative thermodynamic stabilities, as reflected by the estimated heats of formation δHf, was performed for the 1,2,1,6, and 1,4 isomers of the intermediate sulfinate and sulfinic acid adducts, and for the reaction products. The relative stability of the products ( 1,4 ⪢ 1,6 ⪢ 1,2) is in agreement with the experimental findings, which indicate the preferential formation of the 1,4 isomers, suggesting thermodynamic control of the products. An equilibration of the products by a hydride transfer with the pyridinium salt can also explain the formation of the thermo-dynamically most stable 1,4-dihydropyridines.

Substituent effects on the stability of 1,4-dihydropyridines

Water addition across the 5,6-double bond of 1,4-dihydropyridines easily occurs in neutral or acidic media. The influence of substituents in positions N-1 and C-3 on this reaction has been theoretically investigated. The AM1 molecular orbital approximation was used for both simulated gas-phase and aqueous effects (COSMO modeling method). Since experimental evidence has shown that the rate-determining step of the reaction is a proton transfer from the general and to the C-5 position of the substrate, calculated proton affinities were used as reactivity indexes. The results indicated that electron-donating (+ I) substituents favor the water addition, while electron-withdrawing (− I) groups stabilize dihydropyridines toward this process. The important role of solvation factor versus gas-phase behavior, reflected in a modified order of the basicity and reactivity of the compounds in the examined series, was revealed.

On the mechanism of cephalosporin isomerization

Abstract A theoretical study of the Δ 3 ↔ Δ 2 isomerization of the cephalosporins is presented. Pairs of isomers, and various possible intermediates resulting during the Δ 3 double bond migration to the Δ 2 position are examined. Two model compounds, the 7-acetamido-desacetoxy cephalosporanic acid and 7-acetamido-3-chloro-3-cephem-4-carboxylic acids, having +1 and -1 substituents at C-3 as well as their methyl esters were considered for this study. The AM1 and PM3 molecular orbital techniques, which included solvent (water) effects were employed. The study explains the resistance of the cephalosporanic acids toward isomerization as a result of the impossibility to deprotonate at C-2, due to the easier deprotonation of the carboxylic functionality. The ratio of isomers in equilibrium mixtures of the esters is determined by their thermodynamic stabilities. Structural factors have an important role in this process.

Neural network studies 2. Use of a neural net to estimate oxidation energies for substituted dihydropyridines and related heterocycles

Abstract A perceptron-type neural net was applied to the prediction of oxidation energies for dihydropyridines and related heterocycles. A set of 71 energies corresponding to heats of formation differences for reduced and oxidized derivatives were used to train the net using a back propagation algorithm. A system using four hidden units produced good duplication of the input values (SD = 0.298) and was useful in predicting unknown values (SD = 1.80). Finally, the output matrix was helpful in determining substituent effects.

Ionic and radical intermediates of 3-substituted 5,6-dihydro-1,4,2-dioxazines: a theoretical (AM1) study

Abstract Stable carbocations ( A ), carbanions ( B ) and free radicals ( C ) are expected to result from 3-substituted-5, 6-dihydro-1,4,2-dioxazine 1 or their 3- (1-bromoalkyl) derivative 2 , due to the presence of a CN double bond, adjacent to the active methylene group. However, experimental data indicate that while A and C could be obtained, B was apparently too unstable to act as an intermediate in alkylations. A theoretical study of the structures and stabilities of A - C resulting from 1 and 2 (R = CH 3 ), in the framework of a semiempirical all-valence electron molecular orbital approximation (AMI) is described. The results obtained indicate that A and C can be stabilized by delocalization and accommodation of the positive charge and unpaired electron respectively, by conjugation, hyperconjugation and field effects. Although B has a non-uniform distribution of the charge due to a less planar shape, it should be stabilized by delocalization. Calculated energies of reaction ( E r ) for the formation of B , and deprotonation enthalpy (DPE) of 1 (R = CH 3 ) in comparison with the deprotonation of 3-methyl-4H-5,6-dihydrooxazine ( 6 ), a structurally related compound proven to lead to carbanions ( B ′ and B ″), could not explain the failure to perform carbanion-mediated alkylations.