Comparison of zwitterionic N-alkylaminomethanesulfonic acids to related compounds in the Good buffer series

Abstract

Several N-alkyl and N,N-dialkylaminomethanesulfonic acids were synthesized (as zwitterions and/or sodium salts) to be tested for utility as biological buffers at lower pH levels than existing Good buffer compounds (aminoalkanesulfonates with a minimum of two carbons between amine and sulfonic acid groups as originally described by Norman Good, and in common use as biological buffers). Our hypothesis was that a shorter carbon chain (one carbon) between the amino and sulfonic acid groups should lower the ammonium ion pKa values. The alkylaminomethanesulfonate compounds were synthesized in aqueous solution by reaction of primary or secondary amines with formaldehyde/sodium hydrogensulfite addition compound. The pKa values of the ammonium ions of this series of compounds (compared to existing Good buffers) was found to correlate well with the length of the carbon chain between the amino and sulfonate moeties, with a significant decrease in amine basicity in the aminomethanesulfonate compounds (pKa decrease of 2 units or more compared to existing Good buffers). An exception was found for the 2-hydroxypiperazine series which shows only a small pKa decrease, probably due to the site of protonation in this compound (as confirmed by X-ray crystal structure). X-ray crystallographic structures of two members of the series are reported. Several of these compounds have pKa values that would indicate potential utility for buffering at pH levels below the normal physiological range (pKa values in the range of 3 to 6 without aqueous solubility problems) – a range that is problematic for currently available Good buffers. Unfortunately, the alkylaminomethanesulfonates were found to degrade (with loss of their buffering ability) at pH levels below the pKa value and were unstable at elevated temperature (as when autoclaving) – thus limiting their utility.