Tri- and Tetraurea Piperazine Cyclophanes: Synthesis and Complexation Studies of Preorganized and Folded Receptor Molecules

A series of symmetrical tri- and tetrameric N-ethyl- and N-phenylurea-functionalized cyclophanes have been prepared in nearly quantitative yields (86-99%) from the corresponding tri- and tetraamino-functionalized piperazine cyclophanes and ethyl or phenyl isocyanates. Their conformational and complexation properties have been studied by single-crystal Xray diffraction, variable-temperature NMR spectroscopy, and ESI-MS analysis. The rigid 27-membered trimeric cyclophane skeleton assisted by a seam of intramolecular hydrogen bonds results in a preorganized ditopic recognition site with an all-syn conformation of the urea moieties that, complemented by a lipophilic cavity of the cyclophane, binds molecular and ionic guests as well as ion pairs. The all-syn conformation persists in acidic conditions and the triprotonated triurea cyclophane binds an unprecedented anion pair, H2PO4-center dot center dot center dot HPO42-, in the solid state. The tetra-N-ethylurea cyclophane is less rigid and demonstrates an induced-fit recognition of diisopropyl ether in the solid state. The guest was encapsulated within the lipophilic interior of a quasicapsule, formed by intramolecular hydrogen-bond-driven folding of the 36-membered cyclophane skeleton. In the gas phase, the essential role of the urea moieties in the binding was demonstrated by the formation of monomeric 1:1 complexes with K+, TMA(+), and TMP+ as well as the ion-pair complexes [KI+K](+), [TMABr + TMA](+) and [TMPBr + TMP](+). In the positive-mode ESI-MS analysis, ion-pair binding was found to be more pronounced with the larger tetraurea cyclophanes. In the negative mode, owing to the large size of the binding site, a general binding preference towards larger anions, such as the iodide, over smaller anions, such as the fluoride, was observed.