Chemists are well trained to recognize what controls relative reactivities within a series of compounds. Thus, it is well-known how the rate of ionization of R-X is affected by the stabilization of the carbocation R(+), the nature of the leaving group X(-), or the solvent ionizing power. On the other hand, when asked to estimate the half-life of the ionization of a certain substrate in a certain solvent, most chemists resign. This question, however, is crucial in daily laboratory practice. Can a certain substrate R-X be handled in alcoholic or aqueous solution without being solvolyzed? Can a biologically active tertiary amine or azole be released by ionization of a quaternary ammonium ion? In this Account, we describe a straightforward means of addressing such experimental concerns. A semiquantitative answer to these questions is given by the correlation equation log k(25 °C) = s(f)(N(f) + E(f)), in which carbocations R(+) are characterized by the electrofugality parameter E(f), and leaving groups X(-) in a certain solvent are characterized by the nucleofugality parameter N(f) and the nucleofuge-specific sensitivity parameter s(f). As s(f) is typically around 1 (0.8 < s(f) < 1.2), ionization half-lives of around 1 h at 25 °C can be expected when E(f) + N(f) = -4. This correlation equation is formally analogous to the linear free energy relationship that was used to derive the most comprehensive nucleophilicity and electrophilicity scales presently available (Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. Reference Scales for the Characterization of Cationic Electrophiles and Neutral Nucleophiles. J. Am. Chem. Soc. 2001, 123, 9500-9512). By subjecting 628 solvolysis rate constants k(25 °C) for different benzhydryl derivatives (aryl(2)CH-X) to a least-squares minimization on the basis of the correlation equation, we obtained and tabulate here (i) the electrofugality parameters E(f) for 39 benzhydrylium ions and (ii) the nucleofuge-specific parameters N(f) and s(f) for 101 combinations of common leaving groups and solvents. We show that the E(f) parameters of the reference electrofuges can be used to determine N(f) and s(f) for almost any combination of leaving group and solvent. The nucleofuge-specific parameters of the reference systems can analogously be used to derive the electrofugalities E(f) of other types of carbocations. While it has long been recognized that good nucleophiles are not necessarily poor nucleofuges, it is now reported that there is also no general inverse relationship between electrophilicity and electrofugality. Although more electrophilic methyl- and methoxy-substituted benzhydrylium ions are generally weaker electrofuges, the inverse relationship between electrophilicity and electrofugality breaks down in the series of amino-substituted benzhydrylium ions. Because neither differential solvation of the carbocations nor steric effects are explicitly considered by this treatment, predictions for substrates ...

A series of 21 benzhydrylium ions (diarylmethylium ions) are proposed as reference electrofuges for the development of a general nucleofugality scale, where nucleofugality refers to a combination of leaving group and solvent. A total of 167 solvolysis rate constants of benzhydrylium tosylates, bromides, chlorides, trifluoroacetates, 3,5‐dinitrobenzoates, and 4‐nitrobenzoates, two‐thirds of which have been determined during this work, were subjected to a least‐squares fit according to the correlation equation log k25 °C = sf(Nf + Ef), where sf and Nf are nucleofuge‐specific parameters and Ef is an electrofuge‐specific parameter. Although nucleofuges and electrofuges characterized in this way cover more than 12 orders of magnitude, a single set of the parameters, namely sf, Nf, and Ef, is sufficient to calculate the solvolysis rate constants at 25 °C with an accuracy of ±16 %. Because sf≈1 for all nucleofuges, that is, leaving group/solvent combinations, studied so far, qualitative discussions of nucleofugality can be based on Nf.

The correlation equation log k(25 degrees C) = sf(Nf + Ef), where sf and Nf are nucleofuge-specific parameters referring to leaving group/solvent combinations and Ef are electrofuge-specific parameters referring to the incipient carbocation R+, are used to predict ionization rate constants of alkyl derivatives R--X. We show how to employ the Ef parameters of reference electrofuges and the sf and Nf parameters of reference nucleofuges reported in the preceding article for determining further sf, Nf, and Ef parameters. Since sf is usually close to 1.0, one comes to the semiquantitative rule that at 25 degrees C, compounds R--X for which Nf + Ef>-2 will solvolyze with half-lives of less than a minute, while the solvolysis half-lives will exceed 1 month if Nf + Ef<-6.5.

A series of X,Y-substituted benzhydryl phenyl carbonates 1 and X,Y-substituted benzhydryl methyl carbonates 2 were subjected to solvolysis in different methanol/water, ethanol/water, and acetone/water mixtures at 25 degrees C. The LFER equation, log k = sf(Ef + Nf), was used to derive the nucleofuge-specific parameters (Nf and sf) for phenyl carbonate (1LG) and methyl carbonate (2LG) leaving groups in a given solvent in SN1 type reaction. Kinetic measurements showed that phenyl carbonates solvolyze one order of magnitude faster than methyl carbonates. Optimized geometries of 1LG and 2LG at B3LYP/6-311G(d,p), B3LYP/6-311++G(d,p), and MP2(full)/6-311++G(d,p) levels revealed that negative charge delocalization in carbonate anions to all three oxygen atoms occurs due to negative hyperconjugation. Phenyl carbonate (1LG) is a better leaving group (Nf = -0.84 +/- 0.07 in 80% v/v aq EtOH) than methyl carbonate 2LG (Nf = -1.84 +/- 0.07 in 80% v/v aq EtOH) because of more pronounced negative hyperconjugation, which is characterized with a more elongated RO-C bond and more increased RO-C-CO angle in 1LG than in 2LG. Calculated affinities of benzhydryl cation toward methyl and phenyl carbonate anions (DeltaDeltaEaff = 11.7 kcal/mol at the B3LYP/6-311++G(d,p) level and DeltaDeltaEaff = 2.7 kcal/mol at the PCM-B3LYP/6-311++G(d,p) level in methanol, respectively) showed that 1LG is more stabilized than 2LG, which is in accordance with greater solvolytic reactivity of 1 than 2.

Nucleofugalities of pentafluorobenzoate (PFB) and 2,4,6-trifluorobenzoate (TFB) leaving groups have been derived from the solvolysis rate constants of X,Y-substituted benzhydryl PFBs and TFBs measured in a series of aqueous solvents, by applying the LFER equation: log k = s(f)(E(f) + N(f)). The heterolysis rate constants of dianisylmethyl PFB and TFB, and those determined for 10 more dianisylmethyl benzoates in aqueous ethanol, constitute a set of reference benzoates whose experimental ΔG(‡) have been correlated with the ΔH(‡) (calculated by PCM quantum-chemical method) of the model epoxy ring formation. Because of the excellent correlation (r = 0.997), the method for calculating the nucleofugalities of substituted benzoate LGs have been established, ultimately providing a method for determination of the S(N)1 reactivity for any benzoate in a given solvent. Using the ΔG(‡) vs ΔH(‡) correlation, and taking s(f) based on similarity, the nucleofugality parameters for about 70 benzoates have been determined in 90%, 80%, and 70% aqueous ethanol. The calculated intrinsic barriers for substituted benzoate leaving groups show that substrates producing more stabilized LGs proceed over lower intrinsic barriers. Substituents on the phenyl ring affect the solvolysis rate of benzhydryl benzoates by both field and inductive effects.