Multivariate Characterization and Modelling of the Chemical Reactivity of Epoxides. Part II: Extension to Di‐ and Trisubstitution

The chemical reactivity toward 4-nitrobenzylpyridine (4-NBP) of a series of twelve mono-, di- and trisubstituted epoxides has been modelled by means of multivariate quantitative structure-property relationships (QSPRs). The models were established using theoretical descriptor variables and partial least squares (PLS) analysis. It was found that a multivariate set of eleven descriptor variables was sufficient to adequately model the chemical reactivity. Furthermore, there existed a non-linear relationship between the theoretical descriptors and the chemical reactivity. Two-component PLS models were generally required, using the second component to compensate for non-linearity in the first. The nature of the non-linearity suggests that different physico-chemical factors are regulating the chemical reactivity among two observed subgroups of epoxides. The reactivity of one group of five epoxides with one non-substituted ring carbon is regulated by the electronegative properties of the substituent on the other ring carbon, whereas the reactivity of seven di- and trisubstituted epoxides depends on a combination of the substitution pattern around the epoxide ring and the size of these substituents. Two additional points of general relevance for QSPR modelling are also addressed, namely predictor variable selection and appropriate transformation of the dependent variable.

[1]  Fredrik Lindgren,et al.  QSARs based on statistical design and their use for identifying chemicals for further biological testing , 1990 .

[2]  S. Wold,et al.  Nonlinear PLS modeling , 1989 .

[3]  Johann Gasteiger,et al.  The Anesthetic Activity and Toxicity of Halogenated Ethyl Methyl Ethers, a Multivariate QSAR Modelled by PLS , 1985 .

[4]  Timo Lotta,et al.  PLS modelling of structure—activity relationships of catechol O-methyltransferase inhibitors , 1992, J. Comput. Aided Mol. Des..

[5]  J. Hermens,et al.  Electrophiles and acute toxicity to fish. , 1990, Environmental health perspectives.

[6]  G. Cruciani,et al.  Generating Optimal Linear PLS Estimations (GOLPE): An Advanced Chemometric Tool for Handling 3D‐QSAR Problems , 1993 .

[7]  Johann Gasteiger,et al.  Multivariate structure‐activity relationships between data from a battery of biological tests and an ensemble of structure descriptors: The PLS method , 1984 .

[8]  J. Hermens,et al.  Classifying environmental pollutants , 1992 .

[9]  A. Höskuldsson.  PLS regression methods , 1988 .

[10]  G. Cruciani,et al.  Predictive ability of regression models. Part II: Selection of the best predictive PLS model , 1992 .

[11]  Joop L. M. Hermens,et al.  Quantitative correlation studies between the acute lethal toxicity of 15 organic halides to the guppy (Poecillah Reticulata) and chemical reactivity towards 4‐nitrobenzylpyridine , 1985 .

[12]  S. Wold.  Cross-Validatory Estimation of the Number of Components in Factor and Principal Components Models , 1978 .

[13]  W. von der Hude,et al.  Structure-activity relationships of epoxides: induction of sister-chromatid exchanges in V79 cells by enantiomeric epoxides. , 1992, Mutation research.

[14]  Svante Wold,et al.  A Strategy for Ranking Environmentally Occurring Chemicals. Part IV: Development of Chemical Model Systems for Characterization of Halogenated Aliphatic Hydrocarbons , 1991 .

[15]  Gerrit Schüürmann,et al.  QSAR analysis of the acute fish toxicity of organic phosphorothionates using theoretically derived molecular descriptors , 1990 .

[16]  R. Manne.  Analysis of two partial-least-squares algorithms for multivariate calibration , 1987 .

[17]  Eamonn F. Healy,et al.  Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model , 1985 .

[18]  L. Eriksson,et al.  Multivariate characterization and modeling of the chemical reactivity of epoxides , 1994 .

[19]  Svante Wold,et al.  A strategy for ranking environmentally occurring chemicals. Part III: Multivariate quantitative structure‐activity relationships for halogenated aliphatics , 1990 .

[20]  S. Wold.  Validation of QSAR's , 1991 .

[21]  Gerrit Schüürmann.  Quantitative Structure-Property Relationships for the Polarizability, Solvatochromic Parameters and Lipophilicity , 1990 .

[22]  M. Sjoestroem,et al.  Multivariate characterization and modeling of polychlorinated dibenzo-p-dioxins and dibenzofurans , 1992 .

[23]  J. Hermens,et al.  A quantitative structure-activity relationship for the acute toxicity of some epoxy compounds to the guppy , 1988 .