A simple synthesis of 2,8-dithiacalix[4]arene 6 comprising two types of bridges (-CH2- and -S-) within a basic macrocyclic skeleton is reported. By optimizing the method we were able to replace 4 steps of the original stepwise procedure with one step in >50% yield, allowing multigram synthesis of the macrocycle. As documented by the H-1 NMR study, the presence of a mixed-bridge system enables direct observation of the so-called flip-flop rearrangement of the hydrogen bond array on the lower rim of the macrocycle. Moreover, the preliminary results showed quite unusual conformational outcomes for the alkylation reactions. The structure of the alkylated macrocycle was confirmed by single crystal X-ray analysis. (C) 2021 Elsevier Ltd. All rights reserved.

Within the mixed-bridge system the thiacalixarene fragment (Ar–S–Ar) is much more prone to spirocyclization than the calixarene one (Ar–CH2–Ar).

Contrary to theoretical predictions, direct alkylation of 2,14-dithiacalix[4]arene provides only four out of five basic conformers (atropisomers). To prepare the missing 1,2 (C)-alternate conformer, the indirect alkylation strategy was applied using 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane as a protective agent. As proved by the combination of NMR and X-ray crystallography, the position of the disiloxane bridge on the macrocycle is not fixed and can be changed under basic conditions, representing thus so far unknown rearrangement of the siloxane moiety. The subsequent dialkylation/deprotection and dialkylation enabled the synthesis of the last missing conformer. As demonstrated by several examples, the mixed-bridge macrocycle (with both CH2 and S bridging units) enables preparation of unusual conformers or substitution patterns, which are difficult to obtain, if at all, in classical calixarene chemistry. This feature makes 2,14-dithiacalix[4]arene a very promising candidate for the role of molecular scaffold or platform in various supramolecular applications.

The dialkylation of 2,14-dithiacalix[4]arene was studied employing various synthetic procedures known for the parent macrocycles (thiacalixarenes and/or classical calixarenes). The best results for distal dialkylation were achieved using the Mitsunobu reaction with the corresponding alcohols. Interestingly, due to the lower symmetry of the starting compound, the dialkylated derivatives represent inherently chiral systems. The introduction of chiral substituents thus leads to mixtures of diastereomers potentially useful for the separation of individual stereoisomers as demonstrated by chiral HPLC. The conformational behavior of the novel compounds was studied both in solution (NMR) and in the solid state (X-ray).

2,14-Dithiacalix[4]arene, prepared on a multigram scale, was alkylated using the reaction conditions well known from the chemistry of classical calixarenes or thiacalixarenes to study the specific conformational preferences and dynamic behavior of the corresponding tetraalkylated derivatives. As proved by the combination of the X-ray crystallography and dynamic NMR techniques, the presence of mixed bridges (-CH2- and -S- groups) within the basic skeleton brings about considerable changes in the mutual ratios of the individual conformers compared to the parent macrocycles. Interestingly, certain conformers, hardly accessible for common calixarenes/thiacalixarenes (e.g., 1,2-alternates) are easily prepared in very good yields in the case of 2,14-dithiacalix[4]arene, which makes this mixed-bridge system attractive as molecular scaffold for supramolecular applications.