Facile Substituent Exchange at H‐Phosphonate Diesters Limiting an Effective Synthesis of D‐Phosphonate Diesters

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 D2O, MeOD and ND2Bn has shown competitive behavior with hydrolysis, alcoholysis and aminolysis reactions, respectively. This facile substituent exchange for the addition of D2O and MeOD can be attributed to the similar energy required to eliminate ROH or H2O (ROD or HOD, R=iPr, Et, Me) from a pentavalent P(V) intermediate which is generated from axial delivery of an OD or OR group from D2O and MeOD, respectively. The trend in reaction rate for the exchange processes follows the order of R=Me>Et>iPr in (RO)(2)P(O)H and also depends on the nucleophilicity of the incoming group. Attempted synthesis of D-phosphonate diesters directly from PCl3 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.