Revisitation of the PCl5-chlorination reaction of α-amino acids: Spectroscopic and DFT insights, and synthesis of the L-proline-derived 2,5-diketopiperazine

The traditional chlorination reaction of alpha-aminoacids with PCl5 was elucidated by means of spectroscopic and DFT studies. Thus [NH2(CH2)(3)CHC(O)Cl]Cl, 1, and [RCH(NH3)C(O)Cl][Cl] (R = H, 3; R = CH3, 4; R = CH2-Ph, 5; R = CH2CHMe2, 6) were obtained in high yields from equimolar amounts of PCl5 and L-proline, glycine, L-alanine, L-phenylalanine and L-leucine, respectively. Compounds 3-6 resulted to be stable at room temperature under nitrogen atmosphere, whereas 1 rapidly degraded under the same conditions, both in the solid state and in solution. The 1: 2 molar reaction of PCl5 with L-proline selectively afforded the salt 2, showing better inertness than the homologous 1. The slow degradation reaction of 2 may represent a strategy for the clean synthesis of the L-proline-derived 2,5-diketopiperazine, which was recovered in ca. 60% yield from a dichloromethane solution stirred at room temperature for several days and purged with nitrogen gas in order to remove the released HCl. Compounds 1-6 were characterized by elemental analysis and IR spectroscopy, and by NMR spectroscopy in the cases of soluble 1 and 2. Furthermore, the structures of 1-6 were computationally optimized by means of DFT functionals. According to the spectroscopic and DFT outcomes, 1-6 exist in solution as tight ion pairs featured by NH center dot center dot center dot Cl cation-anion interactions, leading to possible HCl formation and consequent condensation reactions. The less stability observed for 1-2 respect to 3-6 should be associated with the relatively high Delta G value of the condensation step. (C) 2014 Published by Elsevier B.V.