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

Abstract

N-(2-Aminoacetyl)-ε-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 = k_obs.f/k_obs.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, k_obs.f and k_obs.r can be measured by the diastereotopic interconversions of 1c and 1d respectively. Therefore, K = k_obs.f/k_obs.r = k₂[H₂O]K_a/k₋₂K_w, where k₂ is the rate of cleavage of the cyclol 1c (of acidity constant K_a) 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 k_obs.f = k_o1c and k_obs.r = k_o1d 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.