Anhydrous Monoalkylguanidines in Aprotic and Nonpolar Solvents: Models for Deprotonated Arginine Side Chains in Membrane Environments

In this study, the synthesis of crystalline dodecylguanidine free base and its spectroscopic characterization in nonpolar environments are described. IR as well as 1 H and 15 N NMR spectra of the free base dissolved in aprotic solvents are substantially different from the previously reported spectra of arginine, or other monoalkylguanidinium compounds, at high hydroxide concentrations. The current results provide improved modeling for the spectroscopic signals that would be expected from a deprotonated arginine in a nonpolar environment. On the basis of our spectra of the authentic dodecylguanidine free base, addition of large amounts of aqueous hydroxide to arginine or other monoalklyguanidinium salts does not deprotonate them. Instead, hydroxide addition leads to the formation of a guanidinium hydroxide complex, with a dissociation constant near ∼500 mM that accounts for the established arginine p K value of ∼13.7. We also report a method for synthesizing a compound containing both phenol and free-base guanidine groups, linked by a dodecyl chain that should be generalizable to other hydrocarbon linkers. Such alkyl-guanidine and phenolyl-alkyl-guanidine compounds can serve as small-molecule models for the conserved arginine-tyrosine groupings that have been observed in crystallographic structures of both microbial rhodopsins and G-protein-coupled receptors.