Inframolecular acid–base properties of myo-inositol 1,2,6-trisphosphate analogues: influence of the hydroxyl groups, phosphate configuration and intracyclic atom substitution

The microscopic acid–base properties of analogues of d-myo-inositol 1,2,6-trisphosphate 1 are reported. These analogues differ by the hydroxyl configuration (l-chiro-inositol 1,2,3-trisphosphate 2) or the replacement of the inositol ring by a ring containing an atom of oxygen (1,5-anhydro-d-arabinitol 2,3,4-trisphosphate 3 and 1,5-anhydroxylitol 2,3,4-trisphosphate 4) or an atom of nitrogen (1,5-anhydro-1,5-imino-d-arabinitol 2,3,4-trisphosphate 5). In addition, the discussion includes the analogue of 1 where all three hydroxyls were removed (6). The studies, performed by potentiometric and 31P-NMR titrations in a 0.2 M KCl medium at 37 °C, allowed the resolution without approximation of the microprotonation scheme of the trifunctional molecules. The constants as well as the chemical shifts of the phosphorus nuclei that characterize each individual phosphate group are analyzed in terms of hydration and hydrogen bonding. Thus, for 2, the loss of a hydrogen bonding possibility between P-1 and OH-6 leads to an increase of the P-1 basicity with regard to 1. Also, by comparing 3 and 4 it appears that the lower basicity of P-2 for 4 with regard to 3 may be attributed to a more favourable interaction between P-1 and P-2 in 3 when the two possible chair forms are allowed. Moreover, for 5, the addition of the first equivalent of protons will protonate only about 75% of the amine, thus indicating that for polyfunctional molecules a given macroscopic protonation constant can hardly be attributed to a specific protonation site.