Effects of Internal Hydrogen Bonds between Amide Groups: Protonation of Alicyclic Diamides

Abstract

The proton affinity ( PA) of cyclopentane carboxamide 1, cyclohexane carboxamide 2 and their secondary and tertiary amide derivatives S1, S2, T1 and T2, was determined by the thermokinetic method and the kinetic method [ PA(1) = 888 ± 5 kJ mol−1; PA(2) = 892 ± 5 kJ mol−1; PA(S1) = 920 ± 6 kJ mol−1; PA(S2) = 920 ± 6 kJ mol−1; PA(T1) = 938 ± 6 kJ mol−1; PA(T2) = 938 ± 6 kJ mol−1]. Special entropy effects are not observed. Additionally, the effects of protonation have been studied using an advanced kinetic method for all isomers 3–7 of cyclopentane dicarboxamides and cyclohexane dicarboxamides (with the exception of cis-cyclopentane-1,2-dicarboxamide) and their bis-tertiary derivatives T3–T7 by estimating the PA and the apparent entropy of protonation Δ(Δ Sapp). Finally, the study was extended to bicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxamide 8 and its bis-tertiary derivative T8, to all stereoisomers of bicyclo[2.2.1]heptane-2,3-dicarboxamide 9, their secondary and tertiary amide derivatives S9 and T9, and to endo–endo–bicyclo[2.2.1]heptane-2,5-dicarboxamide 10 and the corresponding secondary and tertiary derivatives S10 and T10. Compared with 1 and 2, all alicyclic diamides exhibit a significant increase of the PA (ΔPA) and special entropy effects on protonation. For alicyclic diamides, which can not accommodate a conformation appropriate for building a proton bridge, the values of Δ PA and Δ(Δ Sapp) are small to moderate. This is explained by ion / dipole interactions between the protonated and neutral amide group which stabilize the protonated species but hinder the free rotation of the amide groups. If any of the conformations of the alicyclic diamide allows formation of a proton bridge, Δ PA and Δ(Δ Sapp) increase considerably. A spectacular case is cis-cyclohexane-1,4-dicarboxamide 7c which is the most basic monocyclic diamide, although generation of the proton bridge requires the unfavorable boat conformation with both amide substituents at a flagpole position. A pre-orientation of the two amide groups in such a 1,4-position in 10 results in a particularly large PA of < 1000 kJ mol−1. The observation of comparable values for Δ(Δ Sapp) for linear and monocyclic diamides indicates that a major part of the entropy effects originates from freezing the free rotation of the amide groups by formation of the proton bridge. This is corroborated by observing corresponding effects during the protonation of dicarboxamides containing the rigid bicyclo[2.2.1]heptane carbon skeleton, where the only internal movements of the molecules corresponds to rotation of the amide substituents.