posted on 2024-02-01, 14:08authored byAlexander
J. Menke, Zachary P. Jacobus, Liam E. Claton, Onofrio Annunziata, Riccardo Capelli, Giovanni M. Pavan, Eric E. Simanek
For 24-atom triazine macrocycles,
protonation of the
heterocycle
leads to a rigid, folded structure presenting a network of hydrogen
bonds. These molecules derive from dynamic covalent chemistry wherein
triazine monomers bearing a protected hydrazine group and acetal tethered
by the amino acid dimerize quantitatively in an acidic solution. Here,
lysine is used, and the product is a tetracation. The primary amines
of the lysine side chains do not interfere with quantitative yields
of the desired bis(hydrazone) at concentrations of 5–125 mg/mL.
Mathematical modeling of data derived from titration experiments of
the macrocycle reveals that the pKa values
of the protonated triazines are 5.6 and 6.7. Changes in chemical shifts
of resonances in the 1H NMR spectra corroborate these values
and further support assignment of the protonation sites. The pKa values of the lysine side chains are consistent
with expectation. Upon deprotonation, the macrocycle enjoys greater
conformational freedom as evident from the broadening of resonances
in the 1H and 13C NMR spectra indicative of
dynamic motion on the NMR time scale and the appearance of additional
conformations at room temperature. While well-tempered metadynamics
suggests only a modest difference in accessible conformational footprints
of the protonated and deprotonated macrocycles, the shift in conformation(s)
supports the stabilizing role that the protons adopt in the hydrogen-bonded
network.