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Issue 12, 2002
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Ring size configuration effect and the transannular intrinsic rates in bislactam macrocycles

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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 transcis (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 ciscis 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] = kobs.f/kobs.r = Kak2[H2O]/[H+]/k−2Kw/[H+] = Kak2[H2O]/k−2Kw; where Ka is the acidity equilibrium constant of the cyclol form, Kw = 10−14 M2 and k2 and k−2 are the second order rate constants for the specific exchange catalysis. Therefore, both, the macrocycle formation (kobs.f) and the cyclol formation (kobs.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.

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

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Publication details

The article was received on 23 Jul 2002, accepted on 25 Sep 2002 and first published on 01 Nov 2002


Article type: Paper
DOI: 10.1039/B207233E
Citation: J. Chem. Soc., Perkin Trans. 2, 2002, 2078-2082
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    Ring size configuration effect and the transannular intrinsic rates in bislactam macrocycles

    T. Guedez, A. Núñez, E. Tineo and O. Núñez, J. Chem. Soc., Perkin Trans. 2, 2002, 2078
    DOI: 10.1039/B207233E

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