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

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(3) for N-(2-aminoacetyl)-2-caprolactam ( 3). For compounds 2 and 3, dynamic H-1-NMR (using the methylene signals alpha 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 H-1-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(a)k(2)[H2O]/[H+]/k(-2)K(w)/[H+] = K(a)k(2)[ H2O]/k(-2)K(w); where K-a is the acidity equilibrium constant of the cyclol form, K-w = 10(-14) M-2 and k(2) 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. DeltaG(not equal) 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.