Roger Gallo

The Quantitative Analysis of Steric Effects in Heteroaromatics

Publisher Summary This chapter describes the quantitative analysis of steric effects in heteroaromatics. This chapter illustrates that, important progress in the quantitative analysis of steric effects in heteroaromatics has been made recently by linear free energy relationships (LFER), geometrical, and theoretical methods. Heterocycles have been used to propose and exemplify new concepts and new parameters in physical organic chemistry. This chapter is concerned with the importance of steric effects in rationalizing the reactivity and dynamic stereochemistry of heteroaromatics and with recent attempts to bridge the gap between them. There has been a decisive evolution in the treatment of steric effects in heteroaromatic chemistry. A better knowledge of static and dynamic stereochemistry has helped greatly in understanding not only intramolecular but also intermolecular steric effects associated with rates and equilibria. Quantum and molecular mechanics calculations will certainly be used in the future to a greater extent. Heteroaromatics have features in common with aromatic hydrocarbons. However, the variety of geometrical situations, the number of heteroatoms and their associated reactivity, and the ease of monitoring stereochemistry often associated with the presence of heteroatoms all have made, and continues to make, heterocycles exceptional probes for better understanding of reactivity, structures, and the relations between them.

Gear effect—10: Conformational aspects of the positive or negative buttressing effects of methyl groups: polymethylpyridines

Abstract The effect of the shape of a methyl group on reactivity, which cannot be accounted for by considering a methyl group as a spherical substituent with the appropriate van der Waals radius, was considered in kinetics of alkylalion of substituted pyridines and barriers to rotation and ground state conformations of an isopropyl group attached to a planar framework. The perturbation of a methyl group by an o-methyl group is accounted for by a unique conformational explanation which involves the polyhedral shape of the methyl group.

Applications of Phase Transfer Catalysis in Heterocyclic Chemistry

Publisher Summary Phase transfer catalysis (PTC) methodology has already gained wide application in the chemistry of heterocyclic compounds. Most of such reactions were or can be carried out under traditional conditions, but PTC usually increases the yields and purity of the products, and provides a much simpler procedure for the reactions and for the isolations of the products. The main advantages connected with the application of PTC in heterocyclic chemistry are the same as for the general application of this methodology. PTC more generally, applications of twophase systems, is one of the most important recent methodological developments in organic synthesis. PTC reactions can be carried out without organic solvents or, if necessary, using solvents in small quantities sufficient to dissolve the reactants. Besides the application of this technique for synthesis and transformations of a variety of heterocyclic systems on a laboratory scale, PTC is used for manufacturing heterocyclic compounds for pharmaceutical, plant protection, or other applications. It is important because it simplifies procedures, eliminates expensive, inconvenient, and dangerous reactants and solvents, and also allows one to perform many reactions that otherwise proceed unsatisfactory or do not proceed at all.

Molecular mechanics modelling of siderophores

Abstract Molecular mechanics (MM) (empirical force field) calculations of iron chelates (siderophores) with potential pharmacological and agrochemical applications are reported. Excellent agreement was found between the calculated (MM) and observed (X-ray) geometries of a siderophore having three catechol side arms (ferric bicapped TRENCAM). The complexing ability of the bidentate subunits catechol, hydroxamate and oxalic acid as determined with MM and physico-chemical methods, is reported and discussed. The geometries of Fetris(hydroxamate) and of desferrioxamine E are compared. Heptacoordinated aqua-EDTA-iron complexes have a capped trigonal prism geometrical arrangement similar to the one observed in the crystal structure. The parameters for iron (Fe(III)) and Fe-O or Fe-N (to complement the MM2 parameters) are given.

Use of steric effects in determining the position of the transition state for the SN2 reaction between methyl iodide and Δ4-thiazoline-2-thiones

The quantitative nucleophilic reactivity of some 3-alkyl-Δ4-thiazoline-2-thiones (1) towards methyl iodide is described. Bulky alkyl groups increase the rate of S-alkylation and this unexpected behaviour is explained by strain release in the transition state. It is shown that the rate acceleration is closely related to the conformational state of the 3-alkyl group. Using steric effects to examine the transition state, we have shown that it is, in regard to the heterocyclic ring, 65% along the reaction co-ordinate from the initial state.

Determination of a new scale of ortho-steric parameters S0 from N-methylation of pyridines

The kinetics of quaternisation by methyl iodide of 33 substituted pyridines was measured in acetonitrile at 30 °C; the reactions were followed by n.m.r. with a competitive technique. The relative rate constants were similar to those observed in other polar aprotic solvents. Steric effects exist for all the ortho-substituents and can be estimated from the deviation from the Bronsted plot. A scale of ortho-steric parameters (S0) is proposed. There is no significant dependance of S0 on the Dougard–Decroocq solvent parameters and a complete lack of correlation between S0 and the electronic effects of substituents. The relative S0 values agree with other experimental estimations of the steric size of substituents. The S0 parameters are discussed in terms of substituent structure in connection with the Taft–Kutter–Hansch E8 and Charton υ parameters. The general applicability of a unique scale of steric parameters is discussed.

QUANTITATIVE STUDY OF THE NUCLEOPHILICITY OF THE THIOCARBONYL GROUP IN HETEROCYCLIC COMPOUNDS

Abstract When the kinetic constants of reactions between alkyl iodides and a number of hetero-cyclic thiocarbonyl derivatives are measured in solvent acetone, the reactivity extends over three orders of magnitude. The increasing nucleophiliticy is found in the series: Bulkiness of the alkyl group in the alkylating agent has little influence when compared to the pyridine case. A correlation is found between the nucleophilic polarization energy calculated with HMO approximation and the measured constants.

Kinetics of N-methylation reactions and X-ray data of quaternary thiazolium salts. The N ‘lone’ pair orientation in the thiazole ring

Kinetic measurements show that in 2- and 4-substituted thiazoles bulkyl 4-alkyl substituents have a stronger deactivating effect upon N-methylation than 2-alkyl isomers. This experimental result, corrected for electronic effects (pKa) and conformational preference, suggests that the ‘true’ steric hindrance of an alkyl substituent towards an electrophilic centre approaching nitrogen is greater for the 4-position (ΔΔΔG‡= 570 cal mol–1). The geometries of thiazole [microwaves (12)] and thiazolium salt (X-rays) allow an interpretation of this difference of apparent bulkiness in terms of ‘easier in plane bond distortion at C(2) in thiazole’ and ‘unsymmetrical orientation of the lone pair’. Its axis, rather than lying along the [graphic omitted] bisectrix (15) seems to be ‘nearer’ to the C(4) carbon.

Design and molecular mechanics calculations of new iron chelates

Empirical force field calculations are described with new ligands APn, having two carboxylic acids and two pyrocatechol functions and forming octahedral chelates with ferric ion. The design of the ligands is described with reference to other siderophores. New parameters for treating FeIII are derived from spectroscopic data and are used to complement Allinger MM2 parameters. The calculated strain energies in the series APn show optimum stability of the chelate with a length of the polymethylene spacer corresponding to n= 4. Distortions in the octahedron are consistent with similar variations in X-ray structure. The threo configuration of one of the four geometrical isomers is preferred for the AP4 iron chelates.

Angular versus linear transition state in nucleophilic reactions of thioketones

The steric effect of o-methyl groups is much more pronounced for N-alkylation with Mel, Etl, and PriI or aza-aromatic compounds than for S-alkylation of heterocyclic thiones. This is explained by comparison of van der Waals interactions in the transition states of chosen homomorphic systems; an angular transition state is shown to conform with the measured kinetic constants.