Fluorophilicity of alkyl and polyfluoroalkyl nicotinic acid ester prodrugs

The fluorophilicity of a series of hydrocarbon and fluorocarbon-functionalized nicotinic acid esters (nicotinates) is measured from their partitioning behavior (log Kp) in the biphasic solvent system of perfluoro(methylcyclohexane) (PFMC) and toluene. The chain length of the hydrocarbon or fluorocarbon alkyl group of the ester ranges from one to twelve carbon atoms. Knowledge of the fluorophilicity of these solutes is relevant to the design of these prodrugs for fluorocarbon-based drug delivery. The experimental log Kp values range from −1.72 to −3.40 for the hydrocarbon nicotinates and −1.64 to 0.13 for the fluorinated nicotinates, where only the prodrug with the longest fluorinated chain (2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctyl nicotinic acid ester) partitions preferentially into the fluorinated phase (log Kp = 0.13). Predictions of the partition coefficients using solubility parameters calculated from group contribution techniques or molecular dynamics simulation are in reasonable agreement for the perhydrocarbon nicotinates and short chained perfluorinated nicotinates (≈0.3–39% deviation). Significant deviations from experimental partition coefficients (greater than 100%) are observed for the longest chain perfluoroalkyl nicotinates.

Graphical abstractThe fluorophilicity of hydrocarbon and fluorocarbon-functionalized nicotinates is measured and predicted from their partitioning in biphasic perfluoro(methylcyclohexane)/toluene solvents. Varying the hydrocarbon or fluorocarbon alkyl chain length of the ester (one–twelve carbon atoms) provides a systematic comparison of the effect of molecule structure on fluorophilicity.Figure optionsDownload full-size imageDownload as PowerPoint slide