Summary
We had concluded in previous work that ring opening of a 2-alkyl-5(4H)-oxazolone by water or ammonia leads to transient high-energy imidol intermediates which instantly tautomerize to the native amides. Using the MOPAC molecular orbital program, detailed geometric and energetic characteristics of the tautomerism of a peptide bond have been determined on the AM1 level. The results demonstrate that tautomerism of a peptide bond comprises a three-stage process involving three successive transition states and a bimolecular mechanism: (i) E→Z peptide bond isomerization followed by dimerization, (ii) concerted double-hydrogen exchange leading to an α-hydroxyimine (imidic acid) followed by splitting of the dimer, and (iii) Z→E N-methylimine inversion. While pathway (iii→ii→i) is predicted as a feasible route terminating in the formation of a peptide bond, the inverse route (iii←ii←i) is excluded as a possible initial step in the generation of a 5(4H)-oxazolone intermediate.
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Ciarkowski, J., Chen, F.M.F. and Benoiton, N.L., J. Comput.-Aided Mol. Design, 5(1991) 585.
Dewar, M.J.S., Zoebisch, E.G., Healy, E.F. and Stewart, J.J.P., J. Am. Chem. Soc., 107(1985) 3902.
Benoiton, N.L. and Chen, F.M.F., Can. J. Chem., 59(1981) 384.
Chen, F.M.F. and Benoiton, N.L., Can. J. Chem., 65(1987) 619.
Chen, F.M.F. and Benoiton, N.L., J. Chem. Soc. Chem. Commun., (1981) 336.
Katritzky, A.R. and Lagowski, J.M., Adv. Heterocyclic Chem., (1963) 1 and 2.
Albert, A., Heterocyclic Chemistry, Athlone Press, London, 1968.
Elguero, J., Marzin, C., Katritzky, A.R. and Linda, P., Adv. Heterocyclic Chem., (1975) Suppl. No. 1.
Beak, P., Acc. Chem. Res., 10 (1977) 186.
Kwiatkowski, J.S., Zielinski, T.J. and Rein, R., Adv. Quantum Chem., 18(1986) 85.
Szczesniak, M., Szczepaniak, K., Kwiatkowski, J.S., KuBulat, K. and Person, W.B., J. Am. Chem. Soc., 110(1988) 8319, and refs. therein.
Baeyer, A. and Oekonomides, S., Ber. Dtsch. Chem. Ges., 15(1882) 2093.
Schlegel, H.B., Gund, P. and Fluder, E.M., J. Am. Chem. Soc., 104(1982) 5347, and refs. therein.
Stewart, J.J.P., MOPAC: A General Molecular Orbital Package, modified by Eger, M., to suit IBM/370-compatible scalar computers utilizing VS/FORTRAN version 4.1.4. or higher compilers, 1988, QCPE 459.
Bingham, R.C., Dewar, M.J.S. and Lo, D.H., J. Am. Chem. Soc., 97(1975) 1285.
Dewar, M.J.S. and Thiel, W., J. Am. Chem. Soc., 99(1977) 899.
Roberts, J.D. and Caserio, M.C., Basic Principles of Organic Chemistry, W.A. Benjamin, New York, NY, 1965, pp. 675–676.
Roberts, J.D. and Caserio, M.C., Basic Principles of Organic Chemistry, W.A. Benjamin, New York, NY, 1965, pp. 509–510.
Harmony, M.D., Laurie, V.W., Kuczkowski, R.L., Schwendeman, R.H., Ramsay, D.A., Lovas, F.J., Lafferty, W.J. and Maki, A.G., J. Phys. Chem. Ref. Data, 8(1979) 619.
Lumbroso, H. and Pappalardo, G.C., J. Mol. Struct., 43(1978) 97.
Gross, E. and Meienhofer, J., In Gross, E. and Meienhofer, J., (Eds.) The Peptides, Vol. 1 (Analysis, Synthesis, Biology), Academic Press, New York, NY, 1979, pp. 1–64.
Pimentel, G.C. and McClellan, A.L., The Hydrogen Bond, W.H. Freeman & Co., San Francisco, CA, 1960.
Dewar, M.J.S., Healy, E.F. and Stewart, J.J.P., J. Chem. Soc. Farad. Trans. II, 80(1984) 227.
JonesIII, F.M. and Arnett, E.M., Prog. Phys. Org. Chem., 11(1974) 263.
Srivastava, R. and Smith, B.D., J. Phys. Chem. Ref. Data, 16(1987) 219.
Jackman, L.M., In Jackman, L.M. and Cotton, F.A. (Eds.) Dynamic Nuclear Magnetic Resonance, Academic Press, New York, NY, 1975, Chap. 7.
Zimmerman, S.S., In Udenfriend, S., Meienhofer, J. and Hruby, V. (Eds.) The Peptides, Vol. 7 (Analysis, Synthesis, Biology), Academic Press, New York, NY, 1985, pp. 165–212.
Chen, F.M.F. and Benoiton, N.L., Can. J. Chem., 65(1987) 619.
Chen, F.M.F., Slebioda, M. and Benoiton, N.L., Int. J. Pept. Protein Res., 31(1988) 339.
Janoschek, R., Theoret. Chim. Acta, 32(1974) 49.
Dreyfus, M., Maigret, B. and Pullman, A., Theoret. Chim. Acta, 17(1970) 109.
Ladell, J. and Post, B., Acta Crystallogr., 7(195) 559.
Itoh, K. and Shimanouchi, T.J., J. Mol. Spectrosc., 42(1972) 86.
Luck, W.A.P., Naturwissenschaften, 52(1965) 25, 49.
Seki, S., Suzuki, K. and Koide, T., J. Chem. Soc. Japan, Pure Chem. Sec., 77(1956) 346.
Badger, R.M. and Rubalcava, M., Proc. Natl. Acad. Sci. USA, 40(1954) 12.
Schuster, P., Zundel, G. and Sandorfy, C., The Hydrogen Bond, Vols. 1–3, North-Holland, Amsterdam, 1976.
Cook, M.J., Katritzky, A.R., Taagepera, M., Singh, T.D. and Taft, R.W., J. Am. Chem. Soc., 98(1976) 6048.
Scanlan, M.J., Hillier, I.H. and MacDowell, A.A., J. Am. Chem. Soc., 105(1983) 3568.
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Ciarkowski, J., Chen, F.M.F. & Benoiton, N.L. Reaction mechanisms in peptide synthesis. Part 2. Tautomerism of the peptide bond. J Computer-Aided Mol Des 5, 599–616 (1991). https://doi.org/10.1007/BF00135317
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DOI: https://doi.org/10.1007/BF00135317