Publisher Summary This chapter focuses on the principle of non-perfect synchronization (PNS), a prime example of a physical organic concept that deals with chemical reactivity in a qualitative or semiquantitative way. The basic idea of the PNS is to relate certain features of transitionstate structure, deduced from substituent or solvent effects on rates and equilibria, to chemical reactivity. PNS describes the relationship between intrinsic rate constants and transition-state imbalances. The transition state of the majority of chemical reactions has the potential for being imbalanced. Among the PNS factors, the only ones that appear to develop ahead of bond formation are the soft acid–soft base interaction between a nucleophile and electrophile in thiolate ion additions to olefins, and steric effects. In view of the universality of the PNS, it would expect that it also operates in enzyme catalyzed reactions. No systematic studies have been performed in the area of enzyme reactions that would specifically address the contribution to the rate by the avoidance of PNS effects.

The Principle of Non-perfect Synchronization

Electrophilic reactivity of coordinated cyclic π-hydrocarbons

A number of approaches for the synthesis of the 1H-indol-2-yl-1H-quinolin-2-one ring system found in the potent and selective KDR kinase inhibitor 1 are described. The preparation and reaction of trimethylsilylnitrobenzene 26 with 2-methoxy-3-quinolinecarboxaldehyde 28 afforded alcohol 30, which was the key intermediate for the preparation of the target compounds. Conversion of alcohol 30 to either nitroketone 36 or nitrostyrene 45 set the stage for reductive cyclization and the formation of indole 25. The quinolin-2-one functionality was unmasked in the last step to provide compound 1 in 56−60% overall yield from readily available starting materials.

Synthesis of 5-substituted-1H-indol-2-yl-1H-quinolin-2-ones: a novel class of KDR kinase inhibitors.

Synthesis, Characterization, and Reaction Chemistry of PtCl2[P(m-C6H4SO3Na)3]2, an Alkyne Hydration Catalyst

We report on a structural (multinuclear NMR), thermodynamic (pKa), and kinetic (Marcus intrinsic reactivity) study of the ionization of benzylic carbon acids activated by an exocyclic (α) SO2CF3 group and SO2CF3 or S(O)(NSO2CF3)CF3 in the para position of the phenyl ring. The latter exerts an enormous acidifying effect of ca. 8 pK units as compared with 4-H benzyltriflone in Me2SO solution, (corresponding to remarkably high Hammett σ values σp ≈ 1.35, σp- ≈ 2.30). In considering the origin of this effect, important information was derived in comparing medium effects on pKa's for NO2, SO2CF3, and S(O)(NSO2CF3)CF3 activated carbon acids. Highly contrasting behavior was thus induced by H2O → Me2SO transfer, with a large decrease in acidity of α-nitro activated carbon acids but a large increase in acidity of α-SO2CF3 analogues, leading to remarkable inversions in C−H acidity. These results support the view that in the case of the triflones the carbanion negative charge resides for the most part at the exocycl...

Superacidifiers: assessing the activation and the mode of charge transmission of the extraordinary electron-withdrawing SO2CF3 and S(O)(=NSO2CF3)CF3 substituents in carbanion stabilization.

Relative acidifying effects of tricarbonylchromium(0) and p-nitro groups upon di- and triphenylmethanes

Rates of reversible proton abstraction from 2,2′,4,4′-tetranitrodiphenylmethane and 2,4,4′-trinitrodiphenylmethane by a variety of bases in 50% water–50% dimethyl sulphoxide have been measured at 25 °C. Bronsted αCH and βB values have been determined and show a charge imbalance in the transition states for these reactions, in accord with findings for similar carbon acids involving extensive charge delocalization on ionization. Intrinsic rate constants (in the Marcus sense), ko′ have been obtained for these systems, and are shown to vary considerably with choice of catalyst type. As expected, high intrinsic energy barriers for these ionizations are predicted, arising from the extensive molecular and solvent reorganization required to produce planar, delocalized carbanions, Data for the former compound have also been obtained in water, which allow a direct estimation of its pKaH2O value to be made; pKaH2O= 13.16.

Transition state imbalance in the ionization of nitroaromatic hydrocarbons:2,2',4,4'-tetranitrodiphenylmethane and 2,4,4'-trinitrodiphenylmethane in aqueous dimethyl sulphoxide solutions

The rates of proton abstraction and carbanion protonation have been measured for the title compounds in methanolic dimethyl sulphoxide and, where possible, in aqueous dimethyl sulphoxide solutions. These data allow estimates of their pKa values in water to be made, and provide a revised value for the pKa of 4-nitrotoluene in dimethyl sulphoxide solution.

The relative acidities of 4-nitro-, 2,4-dinitro-, and 2,4,6-trinitro-toluene

Rate constfnts for hydrogen or deuterium abstraction from bis-(2,4-dinitrophenyl)methane by methoxide ion have been determined in methanol, methanol–dimethyl sulphoxide, and deuteriated methanol solutions, together with the temperature variation of proton abstraction and carbanion protonation for the hydrogen-containing substrate in methanol. Isotope and solvent effects confirm the rate-limiting proton transfer.

Proton abstraction from bis-(2,4-dinitrophenyl)methane by methoxide ion

The solvent dependence of proton abstraction from various nitrophenylmethanes has been examined for aqueous dimethyl sulphoxide and methanolic dimethyl sulphoxide solutions. Even though the compounds studied vary considerably in thermodynamic acidity (pKa), their proton-abstraction rates all show the same solvent dependence. It is suggested that the transition states for these reactions all occur at similar positions on the reaction pathway, and that transition state imbalances exist for these proton transfers.

Jacques Lelievre

Papers

Relative acidifying effects of tricarbonylchromium(0) and p-nitro groups upon di- and triphenylmethanes

Transition state imbalance in the ionization of nitroaromatic hydrocarbons:2,2',4,4'-tetranitrodiphenylmethane and 2,4,4'-trinitrodiphenylmethane in aqueous dimethyl sulphoxide solutions

The relative acidities of 4-nitro-, 2,4-dinitro-, and 2,4,6-trinitro-toluene

Proton abstraction from bis-(2,4-dinitrophenyl)methane by methoxide ion

Solvent dependence of the ionization of nitrophenylmethanes