The Reaction of Phosphate Esters with Nucleophiles

A. J. Kirby and A.G. Varvoglis, The Reactivity of Phosphate Esters Reactions of Mono Esters with Nucleophiles. Nucleophilicity Independent of Basicity in a Bimolecular Substitution Reaction, J. Chem. Soc. B, 1968, 135. 

The mechanism of phosphate ester hydrolysis by hydroxide is shown in Figure 1 for a phosphodiester substrate. A SN2 mechanism with a trigonal-bipyramidal transition state is generally accepted for the uncatalyzed cleavage of phosphodiesters and phosphotriesters by nucleophilic attack at phosphorus. In uncatalyzed phosphate monoester hydrolysis, a SN1 mechanism with formation of a (POj) intermediate competes with the SN2 mechanism. For alkyl phosphates, nucleophilic attack at the carbon atom is also relevant. In contrast, all enzymatic cleavage reactions of mono-, di-, and triesters seem to follow an SN2... 

Stereochemical analysis of the products using [ieO, 170, lsO] phosphate ester methods show that the PGM reaction proceeds with overall retention of configuration at phosphorus,200 which indicates that an even number of phosphoryl transfers are involved. The catalytic reactions of both a- and /i-PGM proceed via a phosphoenzyme intermediate, formed by the reaction of an active-site nucleophile with Gl,6-diP. The a-PGM utilizes an active-site Ser nucleophile, while /i-PGM uses an active-site Asp. The phosphorylated PGM binds either G1P or G6P and transfers the phosphoryl group to the C(6)OH or C(l)OH, respectively (Scheme 3). 

The Role of Nucleophile Solvation. The value of = 0 for the reaction of substituted pyridines with 2,4-dinitrophenyl phosphate (76) is puzzling. If the value of is a measure of the amount of the bond formation to the nucleophile in the transition state, this value might be taken to mean that there is no bond formation to the nucleophile in the transition state. This is obviously not the case, because there is a large increase in the rate of disappearance of the phosphate ester with increasing concentration of the nucleophile the reactions follow simple second-order kinetics. 

Structure of the substrate and the reaction conditions determine the transition state for reaction with a particular nucleophile 104, 105). The extreme cases are generally described as the dissociative and associative substitution mechanisms. The fully dissociative mechanism entails the formation of monomeric metaphosphate monoanion as a discrete intermediate and was first formulated by F. H. Westheimer, who pioneered the physical organic chemistry of the hydrolysis of phosphate esters 106, 107). This mechanism is depicted in Eq. (40) and is possible only for phosphomonoesters with good leaving groups, examples of which are shown. 

Synthetic Methods.—The preparation of phosphate esters by 5n2 attack of phosphate ester anions on carbon is receiving more attention following the realization that the poor nucleophilicity commonly associated with such anions is due to solvation and ion-pairing effects. Thus tetra-methylammonium di-t-butyl phosphate reacts with primary and secondary alkyl iodides in aprotic solvents to give the corresponding triesters (1) from which the t-butyl groups are readily removed by trifluoracetic acid. The proposal of a similar S 2 mechanism in the reaction of triphenylphosphine and ethyl azodicarboxylate with a phosphate diester in the presence of an... 

The reaction of alkoxide ions with alkynyliodonium salts is unproductive, leading to only decomposition products rather than the desired alkoxyacetylenes. Similarly, reaction of R3SiO does not lead to any siloxyalkynes. In contrast the softer sulfonate, carboxylate, and phosphate nucleophiles all readily react with alkynyliodonium salts leading to the corresponding alkynyl sulfonate, carboxylate and phosphate esters [4]. 

The reaction of a large number of other nucleophiles with iminium salts will at least be mentioned in this section. Among the nucleophiles which react with iminium salts are cyanide 48,115-119), mercaptide 48), alkoxide 48), amine 120), azide 44), phosphine 44), and phosphate ester 44). One can say with little reservation that almost all nucleophiles will react... 

Elimination usually involves loss of a proton together with a nucleophilic group such as -OH, -NH3+, phosphate, or pyrophosphate. However, as in Eq. 13-18, step c, electrophilic groups such as -COO-can replace the proton. Another example is the conversion of mevalonic acid-5-pyrophosphate to isopentenyl pyrophosphate (Eq. 13-19) This is a key reaction in the biosynthesis of isoprenoid compounds such as cholesterol and vitamin A (Chapter 22). The phosphate ester formed in step a is a probable intermediate and the reaction probably involves a carbo-cationic intermediate generated by the loss of phosphate prior to the decarboxylation. 

The phosphorus-based nerve gases and insecticides act by deactivating acetylcholinesterase. Note that all of these compounds have a good leaving group on the phosphorus. They react readily with the nucleophilic hydroxy group of the enzyme to form a phosphate triester in a reaction that is very similar, both in its mechanism and its product, to the reaction of an acyl chloride with an alcohol to form an ester ... 

In the case of phosphates, the triesters are most susceptible to nucleophilic attack and hence the base-catalyzed reaction generally predominates in the pH-rate profile of these esters. Phosphate diesters, with the exception of small ring cyclic ones, are relatively unreactive in neutral... 

A mild and efficient deprotection of phosphate triesters involves nucleophilic attack by weakly basic nucleophiles such as iodide, thiolate and amines at the O-C bond with synchronous expulsion of a phosphate diester as the leaving group [Scheme 7.6]. The reaction is especially useful for the deprotection of methyl, benzyl and allyl phosphates as in Scheme 7.8 shown below. An analogous reaction occurs with carboxylic esters but the conditions required are more stringent because the carboxylate anion is a poorer leaving group (see section 6.3.1),... 

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