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Facile Substituent Exchange at H ‐Phosphonate Diesters Limiting an Effective Synthesis of D ‐Phosphonate Diesters
Author(s) -
Lee Keng Lung,
Feld Joey,
BenTal Yael,
Guo Zhaoyang,
Hume Paul,
Leitao Erin M.
Publication year - 2019
Publication title -
asian journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.846
H-Index - 44
eISSN - 2193-5815
pISSN - 2193-5807
DOI - 10.1002/ajoc.201900430
Subject(s) - phosphonate , chemistry , substituent , nucleophile , reactivity (psychology) , medicinal chemistry , hydrolysis , aminolysis , stereochemistry , organic chemistry , catalysis , medicine , alternative medicine , pathology
Research on using H ‐phosphonate diesters to introduce phosphorus functionality into molecules and polymers, some of which have medicinal applications, has recently attracted a lot of attention. Deuterium labelling to yield the corresponding D ‐phosphonate diesters, although desirable in order to help with the mechanistic elucidation of reactions containing H ‐phosphonate diesters, has been demonstrated to be a challenge. Deuterium exchange at H ‐phosphonate diesters using D 2 O, MeOD and ND 2 Bn has shown competitive behavior with hydrolysis, alcoholysis and aminolysis reactions, respectively. This facile substituent exchange for the addition of D 2 O and MeOD can be attributed to the similar energy required to eliminate ROH or H 2 O (ROD or HOD, R= i Pr, Et, Me) from a pentavalent P(V) intermediate which is generated from axial delivery of an OD or OR group from D 2 O and MeOD, respectively. The trend in reaction rate for the exchange processes follows the order of R=Me>Et> i Pr in (RO) 2 P(O)H and also depends on the nucleophilicity of the incoming group. Attempted synthesis of D ‐phosphonate diesters directly from PCl 3 and alcohols or via lithiation reactions further demonstrated just how sensitive the H/D‐scrambling process is. These results have implications for the general reactivity of H ‐phosphonate diesters towards water, alcohol, and amines and their potential to selectively undergo substitution at either P‐ OR or P‐ H . Moreover, insight into the mechanism(s) of selective deuterium exchange, for example to give D ‐phosphonate diesters via the direct exchange of D for H, was illuminated through this research.