Inclusion of Pentamidine in Carboxylated Pillar[5]arene: Late Sequential Crystallization and Diversity of Host–Guest Interactions

Abstract

Here we describe the inclusion of the minor-groove binding drug pentamidine in its extended conformation into the macrocyclic cavity of water-soluble carboxylated pillar[5]arene. The artificial host−guest system is manifested as an ensemble of three crystalline forms differing in the pillar[5]arene−pentamidine interaction mode, solvation type, and even stoichiometry. The strong hydrogen bonds of various types of amidinium−carboxylate (between pentamidine and pillar[5]arene) and carboxylic− carboxylate (between adjacent pillar[5]arenes) are realized in all complexes, rigidifying the assembly. However, it seems that more subtle effects, such as local solvation/desolvation, a certain degree of flexibility of both the host and guest, and variable protonation/ deprotonation state of the pillar[5]arene substituents, play significant roles in the peculiar crystallization behavior of the system. The snapshots of three crystal structures highlighting various binding geometries and intermolecular interaction modes between the same host and guest present exciting opportunities in terms of more holistic models of the host−guest systems, shifting from focusing our attention on "visible interactions" in one crystal structure to the appreciation of many subtle effects playing a combined role in the host−guest chemistry.

Carboxylated Pillar[6]arene Emulates Pillar[5]arene in the Host–Guest Crystal Complexes and Shows Conformational Flexibility in the Solution/Gas Phase

“…The 1:1 complex of CPA6 with dMV represents a classical inclusion associate, similar to that earlier reported for the CPA5 - PTM complex, in which the guest molecule is trapped in the host cavity by multiple and cooperative intra- (carboxylic-carboxylate) and intermolecular (carboxyl­(ate)-pyridinium cation) hydrogen bonds. A partial loss of symmetry of the complex is observed due to the greater flexibility of CPA6 compared to CPA5 : the plane of one of the aromatic rings is deflected with respect to the planes of the other rings, resulting in a conformational distortion and inclination of the entire complex.…”

“…In our further solid state structural studies CPA5 has shown its ability to complex viologen derivatives and to form coordination polymers with alkali-earth cations . Recently, we have demonstrated the rich host–guest chemistry of CPA5 -pentamidine crystal complexes highlighting the role of amidinium-carboxylate hydrogen bonding and cavity inclusion …”

“…19 Recently, we have demonstrated the rich host−guest chemistry of CPA5pentamidine crystal complexes highlighting the role of amidinium-carboxylate hydrogen bonding and cavity inclusion. 20 Despite the thriving interest in the aqueous complexation properties of larger pillar[n]arenes, 21,22 their solid state supramolecular chemistry has remained a mystery. Until now, there has been no reported crystallographic authentication of carboxylated pillar [6]arene (CPA6), which may be associated with difficult crystallogenesis 23 due to the conformational flexibility of the six-membered macrocycle and the degree of the deprotonation of the 12 ionizable carboxylic substituents.…”

Carboxylated Pillar[5]arene Meets Medicinal Biguanides: Host–Guest Complexes with Alexidine and Phenformin in the Crystal and Solution/Gas Phase

“…The main objective of this part of the study was the detailed structural characterization of the noncovalent complexes in the mother solutions from which the crystals grew, whereby identifying similarities and the differences between solid phase and solution/gas-phase chemistry . This unique insight into the precrystallization process using the IM-MS approach has been successfully applied previously to characterize several host–guest complexes with CPA5 and CPA6 , providing evidence of their distinct primary conformational ordering in mother solutions.…”