Ring size configuration effect and the transannular intrinsic rates in bislactam macrocycles

Abstract

We have synthesized compounds: N-(2-aminoacetyl)-2-pyrrolidone (1) and N-(2-aminoacetyl)-2-piperidone (2). When these compounds are dissolved in aprotic or protic solvents a fast equilibrium ca. 1:1 between the cyclol form (tetrahedral intermediate) and the bislactam macrocycle is established. The same result has been reported previously for N-(2-aminoacetyl)-2-caprolactam (3). For compounds 2 and 3, dynamic ¹H-NMR (using the methylene signals α to the carbonyl and to the amino group) through spectrum simulation has been used to evaluate the exchange between the two mentioned forms at different pH. However, for compound 1 the exchange was evaluated using magnetization transfer technique. The more stable bislactam configuration of the macrocycle form in compounds 2 and 3, is the trans–cis (one lactam with the cyclic alkyl chains trans oriented and the other cis oriented). However, the same form for compound 1 has a more stable cis–cis bislactam configuration. This difference in configuration induces substantial changes in the appearance of the methylene ¹H-NMR signals that precludes the use of line-shape analysis to evaluate the rates. The rate law for the proposed mechanism of exchange between the cyclol form and the macrocycle is: K = [macrocycle]/[cyclol] = k_obs.f/k_obs.r = K_ak₂[H₂O]/[H⁺]/k₋₂K_w/[H⁺] = K_ak₂[H₂O]/k₋₂K_w; where K_a is the acidity equilibrium constant of the cyclol form, K_w = 10⁻¹⁴ M² and k₂ and k₋₂ are the second order rate constants for the specific exchange catalysis. Therefore, both, the macrocycle formation (k_obs.f) and the cyclol formation (k_obs.r) are specific base catalyzed; however the equilibrium constant is independent of pH. Since K is ca. 1, the ΔG^≠ associated with the measured rate constants represent the intrinsic barrier for this non-identical thermoneutral transformation where a cleavage of a tetrahedral intermediate is involved. The activation energies associated with the reverse rate constants then correspond to the intrinsic barrier for transannular cyclolization.