Nucleophilic substitution at phosphorus

On the other hand, evidence against an intermediate hypervalent tetracoordinated phosphorus anion in nucleophilic substitutions at phosphorus in tertiary phosphines was put forward by Kyba the fact that the substitution reaction 3 occurs with complete inversion of configuration at phosphorus was interpreted to mean that it proceeds without even one pseudorotation of 9, which makes the passage through such an intermediate unlikely ( ). 

This chapter covers the main synthetically useful phosphonylation reactions, the corresponding processes of phosphinylation and tertiary phosphine oxide formation along with some related reactions. In all these reactions the phosphorus reactant (a phosphite, phosphonite, phosphinite, or derivative or tautomer thereof) is the nucleophilic component, herein these reactants are referred to collectively as phosphorus(III) reactants/acids, as appropriate in general these reagents are best used freshly distilled. Syntheses of phosphonates, phosphinates and tertiary phosphine oxides by nucleophilic substitution at phosphorus is not covered (for reviews of this area see Refs 6 and 16). 

Phillion, D.P., and Cleary. D.G., Disodium salt of 2-[(dihydroxyphosphinyl)difluoromethyl] propenoic acid. An isopolar and isosteric analogue of phosphoenolpyruvate, J. Org. Chem., 57, 2763, 1992. Eymery, F.. lorga, B.. and Savignac, P, Synthesis of phosphonates by nucleophilic substitution at phosphorus. The SNP(V) reaction. Tetrahedron, 55, 13109, 1999. 

Krol, E.S., and Thatcher, G.R.J., Hydrolysis of phosphonoformate triesters. Rate acceleration of a millionfold in nucleophilic substitution at phosphorus, J. Chem. Soc., Perkin Trans. 2, 793, 1993. 

Eymery, E, lorga, B., and Savignac, R, Synthesis of phosphonates by nucleophilic substitution at phosphorus. The SNP(V) reaction. Tetrahedron, 55, 13109, 1999. 

The synthesis of phosphonates by nucleophilic substitution at phosphorus by carbon nucleophiles and methods of synthesis of natural products containing a... 

Westheimer s guidelines for associative nucleophilic substitution at phosphorus 122... 

WESTHEIMER S GUIDELINES FOR ASSOCIATIVE NUCLEOPHILIC SUBSTITUTION AT PHOSPHORUS... 

In this section, we shall attempt to cover the literature to December 1987 as it relates to the guidelines for associative nucleophilic substitution at phosphorus. The queries that have been raised about these guidelines will be examined and conclusions about their future modification and predictive value will be drawn. Special consideration will be made of the effect of ring size reactivity. In Section 4 the influence of the guidelines on biological Sn2(P) mechanisms will be discussed, particularly in relation to the biologically important five- and six-membered cyclic phosphates 2, 3 -cNMP 3, 5 -cNMP and cIPj. ... 

The extensive review of Hall and Inch (1980b) on the stereochemistry of nucleophilic substitution at phosphorus indicates that a lack of stereospecificity is the rule rather than the exception in the presence of a six-membered ring. They have bravely attempted to define trends in specific six-membered systems, but are forced to conclude that ... the incorporation of phosphorus into a six-membered ring, in itself, provides no overriding influence on reaction. ... 

Associative nucleophilic substitution at phosphorus contained in a six-membered ring is not a rapid process relative to the analogous reaction of acyclic compounds. Whereas associative reactions of five-mem bered sp>ecies are dominated by the influence of special strain effects, the same is not true for six-membered species. One must therefore bear in mind that other competitive processes may become significant in the reaction of six-membered ring phosphorus compounds with nucleophiles. For example, it has been suggested that the cAMP derivative [92] is hydrolysed by a dissociative Sf l mechanism (Scheme 32) (Bottka and Tomasz, 1985). 

Although direct information has come from studies on phosphate esters, studies on other tetrahedral and pentacoordinate phosphorus species have been required to elucidate principles such as pseudorotation, apicophilicity and the trigonal bipyramidal transition state. Application of the guidelines for associative nucleophilic substitution at phosphorus, discussed in the previous section of this review, has led to a good understanding of many biological mechanisms involving substitution at phosphorus. 

The central role of cyclic nucleotides in regulating a wide range of important biological functions requires examination of the mechanisms of their enzymic synthesis and breakdown. Above all, their biological importance demands a response to the question What design feature of cyclic nucleotides makes these molecules ideal as intracellular messengers In the light of the subject of this review, we must add the rider Is there a role for nucleophilic substitution at phosphorus in protein kinase activation ... 

In the foregoing examples of nucleophilic substitution at phosphorus(v), an associative mechanism appears to operate. In contrast, both solvent effects and product stereochemistry in solvolysis of methyl A -cyclohexyl-phosphoramidothioic chloride can be interpreted much more readily in terms of a dissociative mechanism of reaction via the three-co-ordinated transition state (16). Stereochemical studies of reactions of cyclic phos-phorus(v) esters also suggest a dissociative mechanism. ... 

Inch and co-workerspioneered, in the 1970s, the preparation of many phosphorinane oxides and sulfides derived from carbohydrates, confirming their utility in the study of stereochemical aspects in nucleophilic substitutions at phosphorus. Some of the compounds they prepared are shown in Figure 3.9. 

Similar nucleophilic substitution at phosphorus with the loss of alkoxide instead of halide vide supra) also occurs readily. Thus, under a nitrogen atmosphere (to avoid oxidation at phosphorus) when four or more equivalents of phenylmagnesium bromide are treated with trimethyl phosphite (Equation 10.75), triphenylphosphine is cleanly obtained. However, if three or fewer equivalents of the same Grignard reagent are used, then dimethyl phenylphosphonite, methyl diphenylphosphinite, and triphenylphosphine are all found (Equation 10.76) with the exact ratio being. 

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