Nucleophilic phosphorylation reaction

It s this ability to drive otherwise unfavorable phosphorylation reactions that makes ATP so useful. The resultant phosphates are much more reactive as leaving groups in nucleophilic substitutions and eliminations than the corresponding alcohols they re derived from and are therefore more likely to be chemically useful. 

Full details on the phosphorylation of water and alcohols by 4-nitrophenyl dihydrogen phosphate and the NfC H ) - and N(CH3) -salts of its mono- and dianion have been published 146>. Phosphoryl group transfer from the monoanion and dianion is thought to proceed via the monomeric POf ion. Addition of the sterically unhindered amine quinuclidine to an acetonitrile solution containing the phosphate monoanion and tert-butanol produces t-butyl phosphate at a faster rate than does the addition of the more hindered diisopropylethylamine. This nucleophilic catalysis of the phosphorylation reaction is also explained by the intermediacy of the POf ion. 

Figure 5.6 Nucleophilic displacement reactions involving glycosyl (A), acyl (B) or phosphoryl (C) group transfers.

Polyphosphates and phosphates have also been obtained under phase-transfer catalytic conditions by nucleophilic displacement reactions on haloalkanes, tosyl-oxyalkanes and sulphonium salts by polyphosphate or phosphate anions [e.g. 7, 11-15]. The procedure has been used with success for the phosphorylation of terpenes [11] and nucleosides [12, 13]. 

A corresponding reaction of acetate ion with AJP is also catalyzed by a bivalent metal ion. The reaction probably results in the formation of an acyl phosphate, which has not been identified as such but has been identified by trapping of the product with hydroxylamine. The best catalyst is beryllium ion, which catalyzes optimally at molar ratios of 1 to 1 or less. Acetate ion is presumably the reactive species, since the pH optimum of the reaction is 5. It is concluded from the pH effects in this study and in the transphosphorylation reaction that a complex of the metal ion and nucleophile must occur. Since acetate ion is a monodentate ligand, the mechanism postulated for the phosphorylation reaction above cannot be completely applicable to this case (36). 

The liberation of HC1 during the Yoshikawa phosphorylation can lead to undesired side reactions of unsaturated side chains of modified pyrimidines. Protocol 11 describes a modified procedure for the phosphorylation step, whereby a strong, non nucleophilic base (proton-sponge , l,8-bis(dimethylamino)naph-thalene) is added. We have found that addition of proton-sponge also increases the rate of phosphorylation and in circumstances even when it is not specifically required, its addition can also be beneficial for particularly slow phosphorylation reactions. 

Figure 1. Br0nsted-type plot of log k against the pK of oxygen nucleophiles for reactions with phosphorylated y-picoline monoanion. The solid line has a slope of = 0.13 and the dashed line has a slope of 0.25 UP).

Figure 4. Plot of -Big against the pK of the nucleophile for reactions of phosphorylated pyridine monoanions with oxygen nucleophiles (Sue = succinate, Cac = cacodylate, TFE = trifluoroethanol) (79).

Hence, the phosphorylation cycles represent a poised system for the reversible transfer of electrons from oxy anions [(HO)RO -> (HO)RO- + e ] to hydronium ions (H3O+ + e- —> H- + H2O), which is facilitated by (1) the coupling of the respective products to form H2O [(HO)RO- + H- —> H2O + R(O) -AGgp, 111 kcal mol ] and (2) the nucleophilic condensation reaction [ADP3- + R(O)]. Biological systems such as cytochrome-c oxidase and Photosystem 11 of green-plant photosynthesis produce net proton fluxes during turnover and thereby drive oxidative phosphorylation to store 5 kcal per mole of ATP produced from one mole of hydronium ions. 

Halopyrido[2,3-(/]pyrimidines suitable for nucleophilic exchange reactions are accessible by the conversion of the corresponding pyridone or pyrimidone functions with halogenating agents such as phosphoryl halides or phosphorus pentachloride (see Section 7.2.2.1.1.5.5.). 

A series of kinetic experiments reported by Herschlag and Jencks (7) addressed the influence of metal ions on phosphoryl transfer reactions for non-enzymic phosphoryl transfer between pyridine and carboxylate ions (and other nucleophiles). The reaction of actetate ion with phosphorylated -y-picoline monoanion and the reverse reaction of y-picoline with acetyl phosphate dianion are... 

The two major pathways for phosphorylation reactions in condensed phase are strikingly similar to those for the corresponding acylation reactions (19). One pathway is an addition-elimination process whereby a nucleophile adds to the phosphoryl group to give a pentacoordinate intermediate that collapses to product by elimination of a nucleophile (mechanism A, Scheme VI). The other pathway is a displacement process in which the phosphoryl group is transferred as tricoordinate metaphosphate to the attacking nucleophile (mechanism B, Scheme VI). Numerous studies have documented the intervention of metaphosphate in phosphorylation reactions in condensed phase, although metaphosphate has eluded direct detection (19-24). The purpose of the ICR study reported here was to see if gas-phase phosphorylation can be achieved and whether metaphosphate intermediates are involved. 

Initiation, similarly to propagation discussed in the next section, often proceeds by nucleophilic attack of the tricoordinated P-atomof the monomer U). For monomers with tetracoordinated P-atoms (ODPL, ODP) the reaction proceeds by attack of the nucleophilic phosphoryl O-atom 24). The mechanisms of these reactions were studied by NMR spectroscopy, and reaction products were directly observed for the system shown in Eq. (14-3) when R was CH3 ... 

Phosphoryl and sulfuryl transfer reactions are nucleophilic suhstitution reactions, and three limiting mechanisms can be envisioned. One is a dissociative S l-type mechanism, designated in the lUPAC nomenclature, in... 

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