Selective Recognition of Quaternary Ammonium Ions by Structurally Flexible Cages^†

Abstract

Macrocycles | Molecular recognition | Host-guest systems | Supramolecular chemistry | ThermodynamicsThe binding behaviors of three structurally similar and flexible cages to a series of quaternary ammonium ions have been systematically studied. The cage with phenyl sidewalls is new; moreover, its structure and conformational states have been characterized by NMR, 2D NMR, and X-ray crystallography. The results reveal that the three cages show quite high binding affinities and selectivities to different guests. Enthalpy-entropy compensation was invoked to explain the different binding performance. Moreover, a six-component, high-fidelity self-sorting system was successfully constructed by using these cages and three guests. This suggests that conformationally flexible hosts may also achieve high binding affinities and selectivities, which is in contrast to the traditional point of view -only preorganized and rigid hosts are able to do so. This research advocates that conformational flexibility should also be seriously considered in host design.

Dealing with Induced Fit, Conformational Selection, and Secondary Poses in Molecular Dynamics Simulations for Reliable Free Energy Predictions

“…Compound 1 adapts its conformation to the binding guest via an induced fit mechanism . In Figure , we show the two main conformations of macrocycle 1 .…”

“…Compounds 1 and 2 were simulated in vacuo . This was done to sample the full attainable conformational space without mediation of intercalated apolar solvent molecules (such as CHCl 3 or C 2 H 2 Cl 2 ) experimentally favoring the symmetric forms . For both 1 and 2 , simulations were hence conducted on a single macrocyclic molecule at constant temperature using a Nosé thermostat .…”

“…In Figure 1, we show the structures of macrocycles 1 and 2 and of the ligand ODR of the first bromodomain of human BRD4. The structures of 1 and 2 were obtained from Cambridge Crystallographic Data Centre, CCDC 2051483 27 and CCDC 1950443. 28 Phenyl [5]-cage 1 is characterized by two rapidly exchanging structures due to the flipping of the three phenyl sidewalls.…”

“…28 Phenyl [5]-cage 1 is characterized by two rapidly exchanging structures due to the flipping of the three phenyl sidewalls. 27 The two conformations can be distinguished in NMR experiments when 1 selectively binds to quarternary ammonium ions via an induced fit mechanism. Compound 2 (amide naphthotube) has five different conformations due to the flipping of the nonequivalent naphthyl moieties around the amide and aminomethyl junctions.…”

“…One of the two rapidly exchanging conformations is in general selected when 1 binds specifically to quaternary ammonium cations. 27 4.1.1. HREM Simulations.…”