title: Side reactions in the H-phosphonate approach to oligonucleotide synthesis: a kinetic investigation on bisacylphosphite formation and 5'-O-acylation.
abstract: A kinetic study on the reactions of pivaloyl chloride with a nucleoside H-phosphonate (bisacylphosphite formation), or a protected nucleoside with a free 5'-OH (5'-O-pivaloylation) has been carried out in the presence of differently substituted pyridines. The bisacylphosphite formation is a result of acylation of the mixed carboxylic-phosphonic acid anhydride to give the corresponding bispivaloylphosphite derivative. The rate of this reaction is dependent on the concentration of pyridine derivative and pivaloyl chloride. The 5'-O-pivaloylation reaction is also dependent on the concentration of pyridine derivative and pivaloyl chloride. The rate of both reactions is dependent on the basicity of the pyridine derivative, displaying a higher rate with more basic pyridines. The dependence of log k vs. pKa of pyridine is linear but the slopes are quite different for the two reactions (0.84 for bisacylation and 0.21 for 5'-O-pivaloylation). For both reactions considerably lower rates in the presence of sterically hindered pyridines suggest the existence of nucleophilic catalysis on pivaloyl chloride in reactions with non-hindered pyridines.
authors.affiliation: Division of Organic and Bioorganic Chemistry, MBB, Scheele Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Susannah
authors.initials: S
authors.lastname: Sigurdsson
authors.forename: Roger
authors.initials: R
authors.lastname: Strömberg
mesh_terms: D000097:Acetonitriles / Q000737:chemistry; D000215:Acylation; D000812:Anhydrides / Q000737:chemistry; D002855:Chromatography, Thin Layer; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009841:Oligonucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D010421:Pentanoic Acids / Q000737:chemistry; D017905:Phosphites / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry
chemical_list: D000097:Acetonitriles; D000812:Anhydrides; D009841:Oligonucleotides; D010421:Pentanoic Acids; D017905:Phosphites; D011725:Pyridines; C059099:pivaloyl chloride; C032159:acetonitrile