Basicities and Nucleophilicities of Pyrrolidines and Imidazolidinones Used as Organocatalysts

Abstract

The Brønsted basicities pK aH (i.e., pK a of the conjugate acids) of 32 pyrrolidines and imidazolidinones, commonly used in organocatalytic reactions, have been determined photometrically in acetonitrile solution using CH acids as indicators. Most investigated pyrrolidines have basicities in the range 16 < pK aH < 20, while imidazolidinones are significantly less basic (10 < pK aH < 12). 2-(Trifluoromethyl)­pyrrolidine (A14, pK aH 12.6) and the 2-imidazoliummethyl-substituted pyrrolidine A21 (pK aH 11.1) are outside the typical range for pyrrolidines with basicities comparable to those of imidazolidinones. Kinetics of the reactions of these 32 organocatalysts with benzhydrylium ions (Ar2CH+) and structurally related quinone methides, common reference electrophiles for quantifying nucleophilic reactivities, have been measured photometrically. Most reactions followed second-order kinetics, first order in amine and first order in electrophile. More complex kinetics were observed for the reactions of imidazolidinones and several pyrrolidines carrying bulky 2-substituents, due to reversibility of the initial attack of the amines at the electrophiles followed by rate-determining deprotonation of the intermediate ammonium ions. In the presence of 2,4,6-collidine or 2,6-di-tert-butyl-4-methyl-pyridine, the deprotonation of the initial adducts became faster, which allowed the rate of the attack of the amines at the electrophiles to be determined. The resulting second-order rate constants k 2 followed the correlation log k 2(20 °C) = s N(N + E), where electrophiles are characterized by one parameter (E) and nucleophiles are characterized by the two solvent-dependent parameters N and s N. In this way, the organocatalysts A1–A32 were integrated in our comprehensive nucleophilicity scale, which compares n-, π-, and σ-nucleophiles. The nucleophilic reactivities of the title compounds correlate only poorly with their Brønsted basicities.

Holistic Prediction of the pKa in Diverse Solvents Based on a Machine‐Learning Approach

“…The p K aH of aminocatalyst is frequently employed as a rough estimation of its nucleophilicity. Recently, Mayr and co‐workers have experimentally determined the p K aH of a series of commonly used secondary aminocatalysts, including those privileged ones . The acidity of these protonated molecules ranges from 10.54 to 24.02.…”

Holistic Prediction of the pKa in Diverse Solvents Based on a Machine‐Learning Approach

“…Thenucleophilicity of aminocatalysts is akey parameter that defines their catalysis in enamine or iminium-based transformations.The pK aH of aminocatalyst is frequently employed as ar ough estimation of its nucleophilicity.R ecently,M ayr and co-workers have experimentally determined the pK aH of as eries of commonly used secondary aminocatalysts,i ncluding those privileged ones. [28] Thea cidity of these protonated molecules ranges from 10.54 to 24.02. These data were used as out-of-sample test for our model.…”

Electrophilicities of 4‐Nitrobenzochalcogenadiazoles

“…The slopes close to 1 indicate the applicability of Eq (1). [30][31][32][33][34] On this basis, the values of the electrophilicity parameters E of Table 3. Characteristic 13 C NMR in DMSO-d6 of the 4-nitrobenzochalcogenadiazoles 1 and σ-adducts 4 c and 4 f [a] Values reported by Miranda and al.…”