Nucleophilic displacements at phosphorus

Reactions.—Alkaline Hydrolysis. The first total resolution of a heterocyclic phosphonium salt containing an asymmetric phosphorus atom (128) has been reported, providing ready access to optically active phospholan derivatives of value for studies of the stereochemistry of nucleophilic displacement at phosphorus.124 Alkaline hydrolysis of (128) proceeds with retention of configuration at phosphorus to form the oxide (129). Stereochemical studies in the phospholan series have also been facilitated by the X-ray investigation125 of an isomer of l-iodomethyl-l-phenyl-3-methylphospholanium iodide, which is shown to have the structure (130). 

Apparently, the tendency of an Si—X bond to be stretched under the influence of a nucleophile controls its ability to be cleaved with inversion. Furthermore, it is noteworthy that similar effects are found in nucleophilic displacements at phosphorus (47). 

Intramolecular nucleophilic displacements at phosphorus in an acyclic system, which proceed via intermediate phosphoranes incorporated into a smallring system (Eq. (11)), may result in retention of configuration. Examples of such reactions include those of benzaldehyde ) and styrene oxide 5 )... 

From Azides and Phosphonis(ni) Compounds.—The azide synthesis of phos-phazenes has been used to obtain a novel trico-ordinate quinquevalent phosphorus compound, of the general type often postulated as an intermediate in nucleophilic displacements at phosphorus(v) ... 

Thus, the above observations can be taken as good evidence that the ease of stretching of the Si-X bond is a significant factor in directing the stereochemistry of substitution towards inversion of configuration. Similar effects are found in nucleophilic displacement at phosphorus (135). 

Reactions based on an initial nucleophilic displacement at phosphorus... 

The structural features of organophosphorus esters, which are very similar to those of the carboxylic acid esters, suggest that nucleophilic displacement at the central phosphorus atom will occur by an addition-elimination mechanism. Mechanistic studies, however, have demonstrated that hydrolysis occurs through direct nucleophilic displacement at phosphorus and does not involve formation of a pen-tavalent intermediate with H2O or OH (Hudson, 1965 Kirby and Warren, 1967). Accordingly, hydrolysis rates for phosphorus esters will be sensitive to electronic factors that alter the electrophilicity of the central phosphorus atom and steric interaetions that impede nucleophilic attack. 

Potential energy surfaces for nucleophilic displacements at phosphorus in dimethyl methyl-, chloromethyl-, dichloromethyl-, and trichloromethyl-phosphonates were computed by DFT methods. The results revealed that sequential introduction of chlorine substituents at the methyl group of a methylphosphonate diester increased the stability of TSs and intermediates leading to P-C bond cleavage. Indeed, the trichlorinated analogue (23) reacted with NaOMe exclusively via P-C bond dissociation to form dichlorocarbene, which was trapped by various alkenes to form the corresponding gem-dichlorocyclopropanes (24) (Scheme... 

Tricoordinate phosphorus >P-X compounds containing a suitable leaving group are indispensable in the synthesis of biophosphates and their structural analogues. In contrast to phosphoryl >P(0)-X and thiophosphoryl >P(S)-X, compounds they are spectacularly more reactive in nucleophilic displacements at the phosphorus centre. Westheimer has compared reactions of P compounds with nucleophiles to enzymatic reactions regarding their reactivity [1]. The essential feature of P compounds is their free electron pair with all the structural, stereochemical and mechanistic consequences that follow. P compounds have the structure of a trigonal pyra-... 

The rate of elimination seems in this case to be higher than that of isomerisation of 2 (reaction b) into the more stable hexaco-ordinate anion 3 (b). The latter does not undergo elimination to j4 under experimental conditions employed. These observations indicate that nucleophilic displacement at pentacoordinate phosphorus in 1 implies a trans-relationship of nucleophile to... 

One of the fascinating aspects of organophosphorus chemistry is the extent to which stereochemical and electronic factors control the rate and also the nature of the products of nucleophilic displacements at tetrahedral phosphorus. Our original goal in this work was to design a synthesis of diethylphosphonomethyl-alkenylphosphinates III. Unfortunately the condensation of I with aldehydes occurred primarily by path A (Scheme I) to give II... 

Adenylyl and guanylyl cyclases catalyze their respective cyclization reactions with inversion of configuration at P of ATP or GTP (55-59). There is no other evidence for the involvement of a nucleotidyl-enzyme in these reactions. Therefore, the mechanism apparently does not involve nucleophilic catalysis by the enzyme, but instead proceeds with intramolecular nucleophilic displacement of MgPPi from P of the substrate by the 3 -hydroxyl group. This forms cAMP or cGMP and MgPPj in an in-line reaction with a single displacement at phosphorus. 

Earlier, reference was made to the potential third mechanism associated with nucleophilic displacements at phosphoryl phosphorus, namely that which might involve the participation of a phosphaacylium cation. Mixed sulphonic-phosphonic or sulphonic-phosphinic anhydrides 645 (Z = O, R = Me or 4-methylphenyl) have been obtained from the free phosphorus(V) acid and the 1,2,4-triazole 646 in the presence of trifluoromethanesulphonic acid, or 645 (Z = O, R = CF3) from the imidazolides 647 and trifluoromethanesulphonic acid and / r/-butylphenylphosphinothioic acid with trifluoromethanesulphonic anhydride yield the mixed 0-anhydride 648 (R = CF3), some reactions of which are illustrated in Scheme 76 ". Of those reactions, the formation of the iodide 649, albeit in low yield when the reaction is carried out in MeOH, with stereochemical retention of configuration at phosphorus, contrasts with the inversion of configuration observed for the remainder, and which is normally encountered for Sn2(P) displacements. The reaction of648 with methoxybenzene to yield the phosphine sulphide 650 in a solvent of high ionizing power (1,1,1,3,3,3-hexafluoropropan-2-ol a lower yield was obtained in a... 

The major product in the reaction of the allyl anion with trimethylphosphite involves nucleophilic attack at phosphorus with subsequent elimination of methanol (equation 64) A similar series of addition/elimination reactions between several carbanions and trimethylphosphine have been observed in a flowing afterglow reactor (equation 65). In contrast, various carbanions react with trimethylphosphate via S 2 displacement at carbon (equation 66) ... 

For example, nucleophilic displacements at the tetracoordinate phosphorus center on models containing two potential departing groups, chlorine and fluorine, show that the former is replaced by hydroxide anion, alkoxy anions, and amines without breaking of the P—F bond (23). These properties are also expressed in a relatively high chemical stability of the tetracoordinate structures—PF(0)0 >P(0)F and even the tricoordinate >P—F, and are likely to be of importance in synthetic applications and biological interactions. 

Triazanaphthalene (449) is the most unstable of the pyrido-pyrimidines to ring-degradation at pH 2 or pH 7.7 The 4-oxo derivative was converted into the 4-thioxo compound via nucleophilic displacement of the acyloxy intermediate formed with phosphorus pentasulfide. The 4-carboxymethylthio-pyridopyrimidine underwent some substitution by hydroxide ion but primarily gave the ring-opening reaction, which is facilitated by resonance activation of the 2-position by the 6-aza moiety. 

The stereochemistries of the reactions between 0-aryl 0-methyl phosphonochloridothioates and nucleophiles have been studied in relation to the synthesis of 1,3,2-oxazaphospholidines. No displacement of chlorine takes place on treatment of O-methyl 0-4-nitrophenyl phosphonochloridothioate with 2-methoxyethanol, and in the presence of 1-phenylethylamine, it is only the latter which reacts. In addition, when the same phosphonochloridothioate is treated with sodium ethoxide, it is the 4-nitrophenoxy group, rather than chlorine, which is displaced. Both displacements were shown to occur with inversion of configuration at phosphorus. The use of such an acid chloride as a two-step 1cyclophosphorylating1 agent of 2-aminoalcohols to give 1,3,2-oxazaphospholidines (209), is illustrated. ... 

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