Methylation of Phenyl Rings in Ester-Stabilized Phosphorus Ylides Vastly Enhances Their Protonophoric Activity

We have recently discovered that ester-stabilized phosphorus ylides, resulting from deprotonation of a phosphonium salt such as [Ph3PCH2COOR], can transfer protons across artificial and biological membranes. To create more effective cationic protonophores, we synthesized similar phosphonium salts with one ((heptyloxycarbonylmethyl)(p-tolyl)bromide) or two ((butyloxycarbonylmethyl)(3,5-xylyl)osphonium bromide) methyl substituents in the phenyl groups. The methylation enormously augmented both protonophoric activity of the ylides on planar bilayer lipid membrane (BLM) and uncoupling of mammalian mitochondria, which correlated with strongly accelerated flip-flop of their cationic precursors across the BLM. An ester-stabilized triphenylphosphonium ylide precursor can carry protons across artificial and natural membranes. Methylation of aryl groups together with alkyl length shortening of this protonophore preserving its lipophilicity resulted in a 20-fold increase in the flip-flop rate constant of its cationic form. Accordingly, increased proton transport across lipid membranes and enhanced uncoupling of mitochondria were observed. image