Implications of Protonation and Substituent Effects for C−O and O−P Bond Cleavage in Phosphate Monoesters

Abstract

A recent study of phosphate monoesters that broke down exclusively through C-O bond cleavage and whose reactivity was unaffected by protonation of the nonbridging oxygens (Byczynski et al. J. Am. Chem. Soc. 2003, 125, 12541) raised several questions about the reactivity of phosphate monoesters, R-O-P(i). Potential catalytic strategies, particularly with regard to selectively promoting C-O or O-P bond cleavage, were investigated computationally through simple alkyl and aryl phosphate monoesters. Both C-O and O-P bonds lengthened upon protonating the bridging oxygen, R-O(H(+))-P(i), and heterolytic bond dissociation energies, DeltaH(C)(-)(O) and DeltaH(O)(-)(P), decreased. Which bond will break depends on the protonation state of the phosphoryl moiety, P(i), and the identity of the organosubstituent, R. Protonating the bridging oxygen when the nonbridging oxygens were already protonated favored C-O cleavage, while protonating the bridging oxygen of the dianion form, R-O-PO(3)(2)(-), favored O-P cleavage. Alkyl R groups capable of forming stable cations were more prone to C-O bond cleavage, with tBu > iPr > F(2)iPr > Me. The lack of effect on the C-O cleavage rate from protonating nonbridging oxygens could arise from two precisely offsetting effects: Protonating nonbridging oxygens lengthens the C-O bond, making it more reactive, but also decreases the bridging oxygen proton affinity, making it less likely to be protonated and, therefore, less reactive. The lack of effect could also arise without bridging oxygen protonation if the ratio of rate constants with different protonation states precisely matched the ratio of acidity constants, K(a). Calculations used hybrid density functional theory (B3PW91/6-31++G) methods with a conductor-like polarizable continuum model (CPCM) of solvation. Calculations on Me-phosphate using MP2/aug-cc-pVDZ and PBE0/aug-cc-pVDZ levels of theory, and variations on the solvation model, confirmed the reproducibility with different computational models.

Mechanochemistry of Phosphate Esters Confined between Sliding Iron Surfaces

“…This difference in reactivity can be rationalised through the inductive effect, since alkyl groups have more electron-donating character compared to hydrogen atoms. 50 There is also evidence in the literature suggesting that steric effects and hyperconjugation can also affect the susceptibility of phosphate esters to C−O bond cleavage; 51 however, the substituent effects observed below suggest that these are less important for the systems studied here. It is noteworthy that C−O cleavage is favoured in the current NEMD simulations over β−H elimination, which has previously been suggested to be the major route of C−O cleavage for both trialkylphosphates 23,24 and ZDDPs.…”

Kinetic Analysis of the Hydrolysis of Pentose‐1‐phosphates through Apparent Nucleoside Phosphorolysis Equilibrium Shifts**

“…Once generated, pentose‐1‐phosphates are valuable intermediates as they allow direct glycosylation of (nearly) any other nucleobase. Thus, irreversible hydrolysis of these sugar synthons represents a costly loss – both in vivo and in synthesis [8–11] . Previous work from Bunton and Humeres [12] had employed a colorimetric phosphate assay and work from our lab [13] had used TLC for a preliminary screening of pentose‐1‐phosphate stability.…”

Reactions of Carboxylic, Phosphoric and Sulfonic Acids and their Derivatives

“…93 N -(4-Methoxyphenyl)-3-(4-X-phenyl)-4-(methylsulfonoxymethyl)azetidinones (93; X = MeO, Cl, F) were attacked by secondary amines in DMF or MeCN at the sp 3 carbon, but by MeO − or NH 3 in MeOH by ring-opening attack at the sp 2 carbon (Scheme 25). The former attack led to 4-dialkylaminomethyl derivatives (94) The carboxyvinyltransferases catalyse the addition of hydroxy compounds, ROH, to phosphoenoylpyruvate (97) to form, via a tetrahedral intermediate, an enoylpyruvyl product and inorganic phosphate (Scheme 26). The enzyme-catalysed formation of phosphate was found to proceed exclusively via C-O cleavage and, surprisingly, neither protonation of the non-bridging oxygens nor interactions with cationic side-chains had measurable effects on the C-O bond cleavage.…”

“…Alkyl R groups capable of forming stable cations were more prone to C-O bond cleavage with Bu t > Pr i > Me. 97 β-Ketophosphonic acids (98) were found to undergo facile dephosphonylation under fairly mild conditions (Scheme 27). The rate of dephosphonylation was dependent on the electronic nature of the substituent at the carbon atom α to phosphorus, with electron-withdrawing groups accelerating the process.…”