Acid-base properties of cyclodextrins (CDs), persubstituted at C-6 by 3-mercaptopropionic
acid, sualphadex (Suα-CD), subetadex (Suβ-CD) and sugammadex (Suγ-CD, the antidote
of neuromuscular blocking steroids) were studied by 1H NMR-pH titrations. For each
CD, the severe overlap in protonation steps prevented the calculation of macroscopic
pKa values using the standard data fitting model. Considering the full symmetry of
polycarboxylate structures, we reduced the number of unknown NMR parameters in the
“Q-fitting” or the novel “equidistant macroscopic” evaluation approaches. These models
already provided pKa values, but some of them proved to be physically unrealistic,
deceptively suggesting cooperativity in carboxylate protonations. The latter problem
could be circumvented by adapting the microscopic site-binding (cluster expansion)
model by Borkovec, which applies pairwise interactivity parameters to quantify the
mutual basicity-decreasing effect of carboxylate protonations. Surprisingly, only
a single averaged interactivity parameter could be calculated reliably besides the
carboxylate ‘core’ microconstant for each CD derivative. The speciation of protonation
isomers hence could not be resolved, but the optimized microscopic basicity parameters
could be converted to the following sets of macroscopic pKa values: 3.84, 4.35, 4.81,
5.31, 5.78, 6.28 for Suα-CD; 3.82, 4.31, 4.73, 5.18, 5.64, 6.06, 6.54 for Suβ-CD and
3.83, 4.28, 4.65, 5.03, 5.43, 5.81, 6.18, 6.64 for Suγ-CD. The pH-dependent charge
of these compounds can now be accurately calculated, in support of designing new analytical
methods to exploit their charge-dependent molecular recognition such as in cyclodextrin-aided
chiral capillary electrophoresis.
