Structural and Solvation Effects on Reactivity

The term nucleophilicity refers to the capacity of a Lewis base to participate in a nucleophilic substitution reaction and is contrasted with basicity, which is defined by the position of an equilibrium reaction with a proton donor, usually water. Nucleophilicity is used to describe trends in the rates of substitution reactions that are attributable to properties of the nucleophile. The relative nucleophilicity of a given species may be different toward various reactants and there is not an absolute scale of nucleophilicity. Nevertheless, we can gain some impression of the structural features 

Strong solvation lowers the energy of an anionic nucleophile relative to the TS, in which the charge is more diffuse, and results in an increased E. Viewed from another perspective, the solvation shell must be disrupted to attain the TS and this desolvahon contributes to the activation energy. 

Because the S y2 process is concerted, the strength of the parhally formed new bond is reflected in the TS. A stronger bond between the nucleophilic atom and carbon results in a more stable TS and a reduced activahon energy. 

A more electronegative atom binds its electrons more tightly than a less electronegative one. The process requires donation of electron density to an antibonding orbital of the reactant, and high electronegativity is unfavorable. 

Polarizability describes the ease of distortion of the electron density of the nucleophile. Again, because the S y2 process requires bond formahon by an electron pair from the nucleophile, the more easily distorted the attacking atom, the better its nucleophilicity. 

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An series of alternative, generally parameterized methods for introducing the effects of solvent into semi-empirical calculations are termed SMr, where the value of x represents the type and quality of parameterization27-76 81. These methods have potential value in studying solvation effects on the structure, electronic spectra, and reactivity of biologically... 

It is well known that interpretation of structural effects on reactivity in terms of enthalpy and entropy changes is often complicated, or even overwhelmed, by solvation phenomena. Cyclisation reactions are no exception. This is especially so for systems involving large polarity changes on going... 

Since gas-phase reactions are free from complications arising from solvation effects, a convenient starting point for a meaningful analysis of structural effects on reactivity would be the study of cyclisation reactions in the gas phase. Unfortunately, quantitative evidence of this sort is scanty. A section in Winnik s review (Winnik, 1981a) is devoted to cyclisation and the gas-phase conformation of hydrocarbon chains. From the numerous references therein one obtains a substantial body of evidence pointing to a general resemblance of cyclisation reactions in the gas phase with cyclisation reactions in solution. However, as Winnik has pointed out, gas-phase reactions have not been studied so far with the same kind of detail that is possible for reactions in solution. As a result, any attempt at understanding the relations between structure and reactivity in the area of cyclisation reactions must still rely heavily upon solution chemistry data. 

Alteration of positional selectivity will result from built-in solvation of the transition state by an adjacent carboxyl-related function.Aminations will be so affected by carboxyl, carboxylate ion, carboalkoxy and less so by carboxamido groups (cf. Section I,D,2,b, structure 12.) Other substitutions such as alkoxylations can be so affected by carboxamido and amidino groups (cf. Section I,D, 2,b, structure 14). The effect of the cyclic hydrogen-bonded form (63) of 2-carboxamidopyridine on the reactivity of a leaving group is not known. 

It should be emphasized that solvation of excited electronic states is fundamentally different from the solvation of closed-shell solutes in the electronic ground state. In the latter case, the solute is nonreactive, and solvation does not significantly perturb the electronic structure of the solute. Even in the case of deprotonation of the solute or zwitterion formation, the electronic structure remains closed shell. Electronically excited solutes, on the other hand, are open-shell systems and therefore highly perceptible to perturbation by the solvent environment. Empirical force field models of solute-solvent interactions, which are successfully employed to describe ground-state solvation, cannot reliably account for the effect of solvation on excited states. In the past, the proven concepts of ground-state solvation often have been transferred too uncritically to the description of solvation effects in the excited state. In addition, the spectroscopically detectable excited states are not necessarily the photochemically reactive states, either in the isolated chromophore or in solution. Solvation may bring additional dark and photoreactive states into play. This possibility has hardly been considered hitherto in the interpretation of the experimental data. 

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