The Entrapment of Chiral Guests with Gated Baskets: Can a Kinetic Discrimination of Enantiomers Be Governed through Gating?

Abstract

The capacity of gated hosts for controlling a kinetic discrimination between stereoisomers is yet to be understood. To conduct corresponding studies, however, one needs to develop chiral, but modular and gated hosts. Accordingly, we used computational (RI-BP86/TZVP//RI-BP86/SV(P)) and experimental (NMR/CD/UV/Vis spectroscopy) methods to examine the transfer of chirality in gated baskets. We found that placing stereocenters of the same kind at the rim (R(1) =CH3, so-called bottom) and/or top amide positions (R(2) =sec-butyl) would direct the helical arrangement of the gates into a P or M propeller-like orientation. With the assistance of (1)H NMR spectroscopy, we quantified the intrinsic (thermodynamic) and constrictive (kinetic) binding affinities of (R)- and (S)-1,2-dibromopropane 5 toward baskets (S3b/P)-2, (S3t/M)-3, and (S3bt/P)-4. Interestingly, each basket has a low ( ≤1.3 kcal mol(-1)), but comparable (de<10%) affinity for entrapping enantiomeric (R/S)-5. In terms of the kinetics, basket (S3b/P)-2, with a set of S stereocenters at the bottom and P arrangement of the gates, would capture (R)-5 at a faster rate (kin(R)/kin(S) =2.0±0.2). Basket (S3t/M)-3, with a set of S centers at the top and M arrangement of the gates, however, trapped (S)-5 at a faster rate (kin(R)/kin(S) =0.30±0.05). In light of these findings, basket (S3bt/P)-4, with a set of S stereocenters installed at both top and bottom sites along with a P disposition of the gates, was found to have a lower ability to differentiate between enantiomeric (R/S)-5 (kin(R)/kin(S) =0.8). Evidently, the two sets of stereocenters in this "hybrid" host acted concurrently, each with the opposite effect on the entrapment kinetics. Gated baskets are hereby established to be a prototype for quantifying the kinetic discrimination of enantiomers through gating and elucidating the electronic/steric effects on the process.

On the Transfer of Chirality, Thermodynamic Stability, and Folding Characteristics of Stereoisomeric Gated Baskets

“…Interestingly, lowering the temperature of the CD 2 Cl 2 solution of ( P / M )‐ 2 did not lead to the expected de‐coalescence of its 1 H NMR signals: The AB quartet experienced increased line‐broadening and the resonances corresponding to the aromatic protons shifted to a variable degree (Figure 4, A). The absence of a prominent change in the AB quartet (193–298.0 K) with temperature is in line with the exclusive formation of either ( P )‐ 2 (+)/( M )‐ 2 (–) or ( P )‐ 2 (–)/( M )‐ 2 (+),19a that is, the existence of both stereoisomeric pairs should give rise to two AB quartets in the slow 1 H NMR exchange regime, which does not correspond to our experimental observation (Figure 4, A). With one stereoisomeric pair dominating the mixture, however, one would expect to observe a single AB quartet in both the slow and fast 1 H NMR exchange regime, slightly changing as the interconversion rate varies.…”

“…Its thermal stability is also very good with a low degree of unfolding at higher temperatures (104 °C). The stage is now set for investigating the relationship between the folding/dynamic characteristics of novel stereoisomeric baskets and the encapsulation of useful chiral molecules4b,19a in both polar and nonpolar media with a view to their use in sensor design35 and catalysis 5c…”

Homochiral D4-symmetric metal–organic cages from stereogenic Ru(II) metalloligands for effective enantioseparation of atropisomeric molecules

“…These NMR observations imply more dynamic host–guest interactions for S -BINOL⊂ Λ -MOC-16 inclusion compared with R -BINOL⊂ Λ -MOC-16 inclusion at the room temperature. Broadening of H resonance is indicative of slow and restricted molecular rotation and tumbling 54 55 as well as of a comparable guest exchange rate with the NMR timescale. For the S -BINOL⊂ Λ -MOC-16 system, faster guest exchange dynamics may present, showing averaged influence on host protons either inside or outside.…”

On the Nature of the Transition State Characterizing Gated Molecular Encapsulations

“…A fundamental understanding of encapsulation processes mediated by dynamic hosts is important for controlling the outcome of chemical reactions [38], resolution of enantiomers by gating [29], and completing a precise delivery of molecules [39,40]. The results of our study contribute to such efforts.…”

“…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).…”