Formation and Trapping of the Thermodynamically Unfavoured Inverted-Hemicucurbit[6]uril

Abstract

Amplification of a thermodynamically unfavoured macrocyclic product through the directed shift of the equilibrium between dynamic covalent chemistry library members is difficult to achieve. We show for the first time that during condensation of formaldehyde and <i>cis</i>-<i>N,N'</i>-cyclohexa-1,2-diylurea formation of <i>inverted-cis</i>-cyclohexanohemicucurbit[6]uril (<i>i-cis</i>-cycHC[6]) can be induced at the expense of thermodynamically favoured <i>cis</i>-cyclohexanohemicucurbit[6]uril (<i>cis</i>-cycHC[6]). The formation of <i>i-cis-</i>cycHC[6] is enhanced in low concentration of the templating chloride anion and suppressed in excess of this template. We found that reaction selectivity is governed by the solution-based template-aided dynamic combinatorial chemistry and continuous removal of the formed cycHC[6] macrocycles from the equilibrating solution by precipitation. Notably, the <i>i-cis</i>-cycHC[6] was isolated with 33% yield. Different binding affinities of three diastereomeric <i>i-cis</i>-, <i>cis</i>-cycHC[6] and their chiral isomer (<i>R,R</i>)-cycHC[6] for trifluoroacetic acid demonstrate the influence of macrocycle geometry on complex formation.

Binding Between Cyclohexanohemicucurbit[n]urils and Polar Organic Guests

“…However, the determined K 1obs = 928 ± 17 M −1 and K 2obs = 501 ± 38 M −1 indicate refuted positive cooperativity ( K 2obs / K 1obs > 5/12 for 6:1 systems or K 2obs / K 1obs > 1/4 for 2:1 systems; for more details, see supporting information, page S9). In addition, both K obs are significantly different from the previously published K 1obs = 280 ± 10 M −1 , K 2obs = 630 ± 20 M −1 obtained for similar guest concentration ( Prigorchenko et al, 2019 ).…”

“…It was previously shown in methanol that changes of cycHC[8] chemical shifts ( δ ) in 1 H NMR are most pronounced for the protons H2 ax and H6 ax directing inside the cavity and indicating the position of the complexed anion ( Kaabel et al, 2017 ). Similarly, for a complex between cycHC[6] and externally bound trifluoroacetic acid in chloroform, the only slightly shifted signal is H1 ax directing outside the cavity ( Prigorchenko et al, 2019 ). Interestingly, the binding of porphyrins in dichloromethane has induced a noticeable upfield shift of all macrocycle signals (cycHC[6] or cycHC[8]) as a consequence of the proximity of the large porphyrin’s aromatic system ( Ustrnul et al, 2019 ).…”

“…In 2019, it was demonstrated that cycHC[ n ] exhibits binding to zinc(II) porphyrins in chlorinated solvents via coordination with carbonyl oxygen on their outer surface ( Ustrnul et al, 2019 ). At the same time, a study of inverted -cycHC[6] confirmed that strong organic acids are also bound from outside ( Figure 1 ) with stoichiometry assumed to be 2:1 (acid:cycHC[6]) ( Prigorchenko et al, 2019 ). These studies have shown the dependence of association constants on the geometry and size of the host.…”

Rapid Mechanochemical Synthesis of Amides with Uronium-Based Coupling Reagents, a Method for Hexa-amidation of Biotin[6]uril

“…Implementation of the two objectives mentioned above was required as a prerequisite for the third objective as our ultimate goal. Due to the interest of our group in the synthesis and supramolecular applications of macrocyclic host molecules, [38][39][40][41][42][43] we required a robust procedure for amide-functionalization of biotin [6]uril macrocycle (1), [44][45][46] to access the family of modified biotin [6]uril hosts. Despite the apparent ease of such a transformation, it also presented a substantial challenge: six-fold stepwise amidation of carboxylate groups in 1 is inevitably accompanied by accumulation of the "failed" underfunctionalized products if incomplete coupling occurs at each step.…”

“…Amide Coupling of Biotin [6]uril. As a part of our ongoing efforts towards the development of new chiral supramolecular receptors, [38][39][40][41][42][43] we needed an expedient synthetic procedure for derivatization of biotin [6]uril (1), 44 easily available in multigram quantities by HCl-catalyzed condensation of formaldehyde with D-biotin. The starting macrocyclic molecule, notable for its anion binding properties, common for the cucurbituril family, [73][74][75][76][77] satisfies 6 carboxylic functions, which could be conveniently coupled with various amines, thus providing facile access to a library of diversely functionalized chiral macrocyclic receptors.…”