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formation. The reaction was advantageously employed to ach-
ieve sequence specic and nonracemized synthesis of a tetra-
peptide and pentapeptide in appreciable yields. Being the rst
report of constructing sequence-specic peptides from non-
catalyzed reactions, this method may prove to be an economical
method for peptide synthesis.
Acknowledgements
Financial assistance by DST and CSIR, New Delhi, is gratefully
acknowledged. AS and SK thank DST, New Delhi, and CSIR, New
Delhi, for fellowship.
Scheme 3 Plausible steps for peptide bond formation under non-
catalyzed, aqueous phase reaction conditions.
H2N–CHR–COOH form (also agreeing with the isoelectric
point). Theoretical calculations show an energy barrier of 5.6
kcal molꢁ1 between the zwitterionic and non-ionic forms of
glycine,18 and a possibility of water-mediated proton transfer
Notes and references
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3 S. W. Fox and K. Harada, Science, 1958, 128, 1214.
4 E. Imai, H. Honda, K. Hatori, A. Brack and K. Matsuno,
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5 R. Finking and M. A. Maraheil, Annu. Rev. Microbiol., 2004,
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6 R. B. Merrield, J. Am. Chem. Soc., 1963, 85, 2149.
7 A. El-Faham and F. Albericio, Chem. Rev., 2011, 111, 6557.
8 V. R. Pattabiraman and J. W. Bode, Nature, 2011, 480, 471.
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from NH3 to COOꢁ within an amino acid. The transitory
+
association of a water molecule was observed with N-Cbz-
Gly(OH) and L-(H)Val(OMe) complex (m/z 357.1682, calcd m/z
357.1656) (Fig. S20A and B†). Therefore, it seems that heating
an aqueous solution of two amino acids may promote the
proton transfer and conversion of ionic amino acids to their
non-ionic forms (6, Scheme 3) before their condensation takes
place. Moreover, no peptide bonds were formed at pH 2–4.5 and
8.0–10.0. The amino acids were found to be in the carboxylate
form under basic conditions (Fig. S21 and chart S1†); therefore,
there is no chance of coupling of the carboxylate group of one
amino acid with the NH2 group of the second amino acid. The
role of water in these reactions was critical as the reaction did 10 (a) N. Kaur, X. Lu, M. C. Gerhengorn and R. Jain, J. Med.
not proceed by heating at 120 ꢀC in the absence of water.
Moreover, no peptide bond was formed when the amino acid
Chem., 2005, 48, 6162; (b) J. Rivier, W. Vale, M. Monahan,
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solution in toluene/xylene was heated to 120 ꢀC. In the non- 11 (a) T. R. Pearce, K. Shroff and E. Kokkoli, Adv. Mater., 2012,
ionic form, two amino acids may have interacted through their
COOH and NH2 groups.19 The lack of formation of adducts
between N,N-dimethyl glycine and N-Cbz-glycine (no mass peak
24, 3803; (b) L. T. Eliassen, G. Berge, B. Sveinbjornsson,
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amino acids were detected in all the reactions (Fig. S20C–E†). Nat. Rev. Drug Discovery, 2012, 11, 37.
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detected during the reaction of N-Cbz-val and gly(OMe)$HCl, 16 H. Lundberg, F. Tinnis, N. Selander and H. Adolfsson, Chem.
which was performed in D2O. Most probably, a concerted loss of Soc. Rev., 2014, 43, 2714.
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reports on condensation reactions ‘in water’.20 Hence, H-bonds
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S. V. Chankeshwara, Green Chem., 2007, 9, 1335; (b)
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37374 | RSC Adv., 2014, 4, 37371–37374
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