Experimental intrinsic barriers to amide–amide interaction. Transannular cyclolization in a cyclic diamide

N-(2-Aminoacetyl)-e-caprolactam (1) was synthesized. When 1 is dissolved in aprotic solvents such as chloroform or dichloromethane and water (D2O), a ca. 1 ∶ 1 equilibrium is established between two isomeric forms: cyclol1c and macrocyclic diamide1d. The methylene protons –NHCH2CON– for both forms become diastereotopic. Therefore, the diastereotopic interconversion of 1c and 1d can be followed by dynamic 1H-NMR. In D2O, specific base catalysis is observed for both interconversions. Since the equilibrium K = kobs.f/kobs.r for the 1c = 1d transformation remains the same over the wide pD range studied (2 < pD < 11), a mechanism is proposed whereby the exchange occurs through the cyclol1c conjugate base. According to this mechanism, kobs.f and kobs.r can be measured by the diastereotopic interconversions of 1c and 1d respectively. Therefore, K = kobs.f/kobs.r = k2[H2O]Ka/k−2Kw, where k2 is the rate of cleavage of the cyclol 1c (of acidity constant Ka) conjugate base toward the macrocyclic diamide, and k−2 represents the reverse amino amide-to-carbonyl amide attack (transannular cyclolization). Values for k2 of 1.8 × 102 M−1 s−1 (ΔG‡ = 59.8 kJ mol−1 at 25 °C), and k−2 of 1 × 105 M−1 s−1 (ΔG‡ = 44.3 kJ mol−1 at 25 °C) were obtained. The uncatalyzed rates of kobs.f = ko1c and kobs.r = ko1d were also measured. These values are 2 s−1 (ΔG‡ = 71.1 kJ mol−1 at 25 °C) and 4 s−1 (ΔG‡ = 69.4 kJ mol−1 at 25 °C), respectively.