Gated Molecular Recognition and Dynamic Discrimination of Guests

Abstract

Some highly efficient enzymes, e.g., acetylcholinesterase, use gating as a tool for controlling the rate by which substrates access their active site to direct product formation. Mastering gated molecular encapsulation could therefore be important for manipulating reactivity in artificial environments, albeit quantitative relationships that describe these processes are unknown. In this work, we examined the interdependence between the thermodynamics (DeltaG(o)) and the kinetics (DeltaG(in)(double dagger) and DeltaG(out)(double dagger)) of encapsulation as mediated by gated molecular basket 1. For a series of isosteric guests (2-6, 106-107 A(3)) entering/exiting 1, we found a linear correlation between the host-guest affinities (DeltaG(o)) and the free energies of the activation (DeltaG(in)(double dagger) and DeltaG(out)(double dagger)), which was fit to the following equation: DeltaG(double dagger) = rhoDeltaG(o) + delta. Markedly, the kinetics for the entrapment of smaller guest 7 (93 A(3)) and bigger guest 8 (121 A(3)) did not follow the free energy trends observed for 2-6. Thus, it appears that the kinetics of the gated encapsulation mediated by 1 is a function of the encapsulation's favorability (DeltaG(o)) and the guest's profile. When the size/shape of guests is kept constant, a linear dependence between the encapsulation potential (DeltaG(o)) and the rate of guests' entering/departing basket (DeltaG(in/out)(double dagger)) holds. However, when the potential (DeltaG(o)) is fixed, the basket discriminates guests on the basis of their size/shape via dynamic modulation of the binding site's access.

On the mechanism of action of gated molecular baskets: The synchronicity of the revolving motion of gates and in/out trafficking of guests

“…In the case of self-assembled hosts, however, the slippage, gating and possible partial or full disassembly of the capsule constitute mechanistic alternatives for the exchange of guests [4]. In the last decade, we [9–14] and others [7–8 15–18] have studied gated molecular encapsulation in artificial and natural systems [19]. …”

On the Nature of the Transition State Characterizing Gated Molecular Encapsulations

“…This, in turn, corroborates the absence of interchange mechanism ( Figure 2C) [19], whereby free guests substitute the one of the same kind trapped in the host. Alternatively, a molecule of solvent 5 could approach [1][2] to via its sizeable side aperture "push" the encapsulated guest out and thereby give complex [1][2][3][4][5] ( Figure 2D); note that, in this situation [28], the gates ought to "open" so that the substitution takes place. In line with this mechanistic hypothesis, varying the size of solvent molecules should have an effect on the rate by which guest 2 departs the basket: more sizeable compounds should create a greater van der Waals strain, while entering or exiting the host (vide infra), to affect the in/out exchange!…”

“…In essence, the basket undergoes a rapid thermal racemization (∆G ‡ rac < 11 kcal/mol) to, occasionally, permit the entrance/departure of guest molecules [27]. For a series of isosteric guests we found a linear dependence between the host-guest affinities (∆G°) and the free energies of activation (∆G ‡ in and ∆G ‡ out ), which was fit to the following equation: ∆G ‡ in/out = ρ in/out ∆G° + δ [28] On the basis of rather small ρ in values (0.08-0.25), we hypothesized that an early transition state characterizes gated encapsulations [27,28]; this was additionally supported with a relatively poor stereo-selectivity of [29]. To investigate the nature of the transition state of gated molecular encapsulations in greater details, we hereby used dynamic 1 H-NMR spectroscopy to measure rate coefficients (k out ) by which 1,1,1-tribromoethane 2 (V = 107 Å 3 ) departs from the interior of basket 1 in four aromatic solvents 3-6 ( Figure 1).…”

Highly diastereoselective synthesis of a novel functionalized benzocyclotrimer

“…After 30 min, an aqueous 10% NH 3 solution (20 ml) was added and the mixture was stirred until the brown solid disappeared. The mixture was extracted with diethyl ether (3 × 20 ml) and the combined ethereal extracts were dried over MgSO 4 . Volatile materials were removed in vacuo, and the residue was purified by column chromatography on neutral aluminum oxide with EtOAc/n-hexane (3:7) as eluant.…”

“…[2][3][4][5][6][7][8][9][10][11][12][13][14][15] Amongst these, benzocyclotrimers bearing aromatic rings are characterized by large stiff cavities. The cavities are particularly deep and suitable for supramolecular applications in case of the more symmetrical syn-diastereomer, which is generally obtained in lower yields.…”