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 Hphosphonate 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 = iPr, 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 > 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 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. at 101 MHz and are given in parts per million relative to CDCl 3 (δ = 77.0 ppm). Chemical shifts for 31 P NMR spectra are recorded at 161.97 MHz and given relative to external 85% phosphoric acid (δ = 0 ppm). Data are represented as follows: chemical shift, multiplicity (app = apparent, br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants in Hertz (Hz), and integration.
A series of ammonium monosubstituted H‐phosphonate salts were synthesized by combining H‐phosphonate diesters with amines in the absence of solvent at 80 °C. Variation of the ester substituent and amine produced a range of ionic liquids with low melting points. The products and by‐products were analyzed by spectroscopic and spectrometric techniques in order to get a better mechanistic picture of the dealkylation and formal dearylation observed. For dialkyl H‐phosphonate diesters, (RO)2P(O)H (R=alkyl), the reaction proceeds via direct dealkylation with the reactivity increasing in the order R=iPr<Et<Me corresponding to DFT calculated activation enthalpies of 22.6, 20.8, and 17.9 kcal mol−1. For the diphenyl H‐phosphonate diesters, (PhO)2P(O)H, the dearylation was found to proceed via phenol‐assisted formation of a 5‐coordinate intermediate, (PhO)3PH(OH), from which P(OPh)3 and water were eliminated. The presence of an equivalent of water then facilitated the formation of P(OH)2OPh and the amine, R'NH2, subsequently abstracted a proton from it to yield [(PhO)PH(O)O]‐[R'NH3]+.
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