Vase‐Kite Equilibrium of Resorcin[4]arene Cavitands Investigated Using Molecular Dynamics Simulations with Ball‐and‐Stick Local Elevation Umbrella Sampling

Abstract

A key feature of resorcin[4]arene cavitands is their ability to switch between a closed/contracted (Vase) and an open/expanded (Kite) conformation. The mechanism and dynamics of this interconversion remains, however, elusive. In the present study, the Vase‐Kite transitions of a quinoxaline‐based and of a dinitrobenzene‐based resorcin[4]arene are investigated using molecular dynamics (MD) simulations in three environments (vacuum, chloroform, and toluene) and at three temperatures (198.15, 248.15, and 298.15 K). The challenge of sampling the Vase‐Kite transition, which occurs experimentally on the millisecond time scale, is overcome by calculating relative free energies using ball‐and stick local elevation umbrella sampling (B&S‐LEUS) to enhance the statistics on the relevant states and to promote interconversion transitions. Associated unbiased MD simulations also evidence for the first time a complete Vase‐to‐Kite transition, as well as transitions between degenerate Kite1 and Kite2 forms and solvent‐exchange events. The calculated Vase‐to‐Kite free‐energy changes ΔG are in qualitative agreement with the experimental magnitudes and trends. The level of quantitative agreement is, however, limited by the force‐field accuracy and, in particular, by the approximate treatment of intramolecular interactions at the classical level. The results are in line with a less stable Vase state for the dinitrobenzene compared to the quinoxaline compound, and a negative entropy change ΔS for the Vase‐to‐Kite transition of the latter compound. Relative free energies calculated for intermediates also suggest that the Vase‐Kite transition does not follow a concerted mechanism, but an asynchronous one with sequential opening of the flaps. In particular, the conformation involving two adjacent flaps open in a parallel direction (cis‐p) represents a likely intermediate, which has not been observed experimentally to date.

Comprehensive Characterization of the Self‐Folding Cavitand Dynamics

“…These timescales are still not accessible for conventional MD simulations: low‐energy states relevant to these processes are separated by high‐energy barriers in the free‐energy landscape, which are rarely crossed over the course of a single unbiased MD simulation [12] . Recently, the exchange dynamics of related non‐hydrogen bonded cavitands with lower conformational interconversion barriers have been studied [13] …”

Stimuli‐Responsive Resorcin[4]arene Cavitands: Toward Visible‐Light‐Activated Molecular Grippers

“…We hypothesize at this stage, that electrostatic interactions between the semiquinone radical anion and the nearby quinoxaline walls as well as solvatione ffects facilitate the vase formation besides possible macrocycle strain effects. [43] The newly gained insights will pave the way to develop the next generation of light-activated molecular grippers and their implementation as sensors and nanodevices. Furthermore, the ability of cavitands 2-4,a nd 6 to be activated by multiple stimuli (host-guest interactions, solventc hanges, light,a nd chemicala nd electrochemical reactions), placed them as valuable switching units that can be used to develop stimuli-responsive materials or other applications where al arge molecular rearrangement and changes in the magnetic and photoluminescence properties are desired upon stimulation.…”

“…Our data suggest that the only noticeable requirement to trigger the conformational switching to the vase state is the formation of at least one semiquinone radical anion wall flap. We hypothesize at this stage, that electrostatic interactions between the semiquinone radical anion and the nearby quinoxaline walls as well as solvation effects facilitate the vase formation besides possible macrocycle strain effects …”

Mechanically‐Driven Vase–Kite Conformational Switch in Cavitand Cross‐Linked Polyurethanes

“…QxCav shows the ability to reversibly switch between two spatially well‐defined conformations: an expanded kite (C 2v symmetry) and a contracted vase (C 4v symmetry), according to the position of 1,4‐diazanaphtalene ‘flaps’, that can occupy either the equatorial or the axial positions, respectively (Figure ) . Interestingly, since all intermediate conformers are energetically disfavoured, only these two discrete forms exist . The energy barrier for a single flap interconversion has been estimated in 7.6 kcal mol −1 by DFT calculations .…”

“…[5] Interestingly, since all intermediate conformers are energetically disfavoured, only these two discrete forms exist. [6] The energy barrier for a single flap interconversion has been estimated in 7.6 kcal mol À 1 by DFT calculations. [7] The vase-kite interconversion has been extensively investigated in solution via different stimuli, such as pH, [8,9] temperature, [10] Zn 2 + coordination [11,12] and redox.…”