Not Your Usual Bioisostere: Solid State Study of 3D Interactions in Cubanes

Abstract

Previous studies by Desiraju and co‐workers have implicated the acidic hydrogen atoms of cubane as a support network for hydrogen bonding groups. Herein we report a detailed structural analysis of all currently available 1,4‐disubstituted cubane structures with an emphasis on how the cubane scaffold interacts in its solid‐state environment. In this regard, the interactions between the cubane hydrogen atoms and acids, ester, halogens, ethynyl, nitrogenous groups, and other cubane scaffolds were cataloged. The goal of this study was to investigate the potential of cubane as a substitute for phenyl. This could be achieved by analyzing all contacts that are directed by the cubane hydrogen atoms in the X‐ray crystal structures. As a result, we have established several new cubane interaction profiles, such as the catemer formation seen in esters, the preferences of halogen–hydrogen contacts over direct halogen bonding, and the stabilizing effects caused by the cubane hydrogen atoms interacting with ethynyl groups. These interaction profiles can then be used as a guide for designing cubane bioisosteres of known materials and drugs containing phenyl moieties.

Evolution of abiotic cubane chemistries in a nucleic acid aptamer allows selective recognition of a malaria biomarker

“…The extraordinary platonic solid cubanes have intrigued chemists for decades (35)(36)(37) and are now important functional groups in a wide range of pharmaceuticals and agrochemicals (36,38). Cubanes are benzene bioisosteres with unique properties: 1) unlike benzene, cubane is biologically stable and inherently nontoxic; 2) enhanced water solubility compared to benzene due to the disruption of π stacking; and 3) formation of unusual C-H•••O hydrogen bonds caused by the strong s-character in the C-H bonds itself induced by the p-character of the C-C bonds (39,40). Synthetic and medicinal chemistry approaches for cubane function discovery can be challenging, so we considered the possibility of developing a Darwinian approach to the evolution of macromolecules functionalized by cubane bioisosteres.…”

“…A Unique Hydrogen Bond within the Cubane-Protein Complex Structure. Unlike phenyl or other simple arene moieties, cubane can also engage in the formation of stabilizing C−H cubane •••O bonds due to the rather high acidity of the cubyl H atoms (40). Such nonclassical hydrogen bonds also seem to occur between a dU C unit of the aptamer and a carbonyl unit of amino acids of PvLDH.…”

An Insight into Non‐Covalent Interactions on the Bicyclo[1.1.1]pentane Scaffold

“…The few examples known offer a window to a fascinating structural chemistry including each of these rigid linker motifs. Previous studies by Desiraju and our research group demonstrated different modes of interaction for a variety of cubane derivatives [10e,f] . Alongside the exploration and modernization of the synthetic chemistry of scaffold hydrocarbon molecules in our laboratory [11] investigations of the supramolecular interactions of BCP derivatives offer insight into the expected intermolecular interactions engaged and promoted by this subunit.…”

Supramolecular architectures sustained by delocalised C–I⋯π(arene) interactions in molecular crystals and the propensity of their formation

“…The common feature of all supramolecular zig-zag chains is their propagation by crystallographic glide symmetry, see ESI Table 4. A representative chain in the crystal of 93 157 is shown in Fig. 10(a).…”