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Mayr, Herbert; Ofial, Armin R. (2016): Philicities, Fugalities, and Equilibrium Constants. In: Accounts of Chemical Research, Vol. 49, No. 5: pp. 952-965
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The mechanistic model of Organic Chemistry is based on relationships between rate and equilibrium constants. Thus, strong bases are generally considered to be good nucleophiles and poor nucleofuges. Exceptions to this rule have long been known, and the ability of iodide ions to catalyze nucleophilic substitutions, because they are good nucleophiles as well as good nucleofuges, is just a prominent example for exceptions from the general rule. In a reaction series, the Leffler-Hammond parameter alpha = delta Delta G(double dagger)/delta Delta G degrees describes the fraction of the change in the Gibbs energy of reaction, which is reflected in the change of the Gibbs energy of activation. It has long been considered as a measure for the position of the transition state;thus, an alpha value close to 0 was associated with an early transition state, while an alpha value close to 1 was considered to be indicative of a late transition state. Bordwell's observation in 1969 that substituent variation in phenylnitromethanes has a larger effect on the rates of deprotonation than on the corresponding equilibrium constants (nitroalkane anomaly) triggered the breakdown of this interpretation. In the past, most systematic investigations of the relationships between rates and equilibria of organic reactions have dealt with proton transfer reactions, because only for few other reaction series complementary kinetic and thermodynamic data have been available. In this Account we report on a more general investigation of the relationships between Lewis basicities, nucleophilicities, and nucleofugalities as well as between Lewis acidities, electrophilicities, and electrofugalities. Definitions of these terms are summarized, and it is suggested to replace the hybrid terms "kinetic basicity" and "kinetic acidity" by "protophilicity" and "protofugality", respectively;in this way, the terms. "acidity" and "basicity" are exclusively assigned to thermodynamic properties, while "philicity" and "fugality" refer to kinetics. Benzhydrylium ions (diarylcarbenium ions) with para- and meta-substituents are used as reference compounds for these investigations, because their Lewis acidities and electrophilicities can be varied by many orders of magnitude, while the steric surroundings of the reaction centers are kept constant. The rate constants for their reactions with nucleophiles correlate linearly over a wide range with the Lewis acidities of the benzhydrylium ions: from slow reactions with late transition states to very fast reactions with early, reactant-like transition states (including reactions which proceed without an enthalpic barrier, Delta H-double dagger = 0). Thus, unequivocal evidence is obtained that even within a series of closely related reactions, the Leffler Hammond alpha cannot be a measure for the position of the transition state. Differences in intrinsic barriers lead to deviations from the linear rate-equilibrium correlations and give rise to counterintuitive phenomena. Thus, 1,4-diazabicyclo[2.2.2]octane (DABCO) reacts with lower intrinsic barriers than 4-(dimethylamino)pyridine (DMAP) and, therefore, is a stronger nucleophile as well as a better nucleofuge than DMAP. Common synthetically used S(N)2 reactions are presented, in which weak nucleophiles replace stronger ones. Whereas solvolysis rates of alkoxy- and alkyl substituted benzhydryl derivatives correlate linearly with the Lewis acidities of the resulting carbenium ions, this is not the case for amino-substituted benzhydrylium ions, where differerices in intrinsic barriers play a major role. The common rule that a structural variation, which increases the electrophilicity of a carbocation at the same tithe reduces its electrofugality, does not hold any longer. The need to systematically analyze the role of intrinsic barriers is emphasized.