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. 2024 Feb 1;15(13):4860-4870.
doi: 10.1039/d3sc04412b. eCollection 2024 Mar 27.

Kinetically controlled synthesis of rotaxane geometric isomers

Dillon R McCarthy  1 , Ke Xu  2 , Mica E Schenkelberg  1   2 , Nils A N Balegamire  1   2 , Huiming Liang  1 , Shea A Bellino  1 , Jianing Li  1   2 , Severin T Schneebeli  1   2
Affiliations

Kinetically controlled synthesis of rotaxane geometric isomers

Dillon R McCarthy et al. Chem Sci. .

Abstract

Geometric isomerism in mechanically interlocked systems-which arises when the axle of a mechanically interlocked molecule is oriented, and the macrocyclic component is facially dissymmetric-can provide enhanced functionality for directional transport and polymerization catalysis. We now introduce a kinetically controlled strategy to control geometric isomerism in [2]rotaxanes. Our synthesis provides the major geometric isomer with high selectivity, broadening synthetic access to such interlocked structures. Starting from a readily accessible [2]rotaxane with a symmetrical axle, one of the two stoppers is activated selectively for stopper exchange by the substituents on the ring component. High selectivities are achieved in these reactions, based on coupling the selective formation reactions leading to the major products with inversely selective depletion reactions for the minor products. Specifically, in our reaction system, the desired (major) product forms faster in the first step, while the undesired (minor) product subsequently reacts away faster in the second step. Quantitative 1H NMR data, fit to a detailed kinetic model, demonstrates that this effect (which is conceptually closely related to minor enantiomer recycling and related processes) can significantly improve the intrinsic selectivity of the reactions. Our results serve as proof of principle for how multiple selective reaction steps can work together to enhance the stereoselectivity of synthetic processes forming complex mechanically interlocked molecules.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. (a) Through-space controlled aminolysis in a rotaxane system. (b) This work applies the concept to the selective synthesis of rotaxane geometric isomers, while also introducing a strategy to enhance the selectivity in such reactions by coupling (see also Scheme 1) a formation reaction selective for the major geometric isomer with a depletion reaction with inverse selectivity.
Scheme 1
Scheme 1. A matrix of fast and slow aminolysis reactions (all fast ones are through-space controlled by the glyme-activating groups) leads to kinetic control of geometric isomerism with >40 : 1 selectivity for the major geometric isomer.
Fig. 2
Fig. 2. (a) Partial 1H–1H ROESY NMR (500 MHz, DCDl3) spectrum of the major geometric isomer (RDP[5]cat@MAfav) obtained from the aminolysis reaction of RDP[5]cat@diester with 3,5-dimethylbenzylamine. See the ESI for additional characterization data as well as the full 1H–1H ROESY NMR spectrum. The 1H–1H ROESY NMR spectrum shown in the figure clearly shows that the ethyl group on the pillar[5]arene ring is located proximal to the remaining active ester present in the axle of the favored geometric rotaxane isomer. The key NOE cross-peak between Het and Ho—which leads us to this conclusion—is highlighted in orange. (b) Non-covalent interaction plots calculated at the B3LYP-MM/LACVP* level of theory with the NCI method implemented in Jaguar (version 8.8) as detailed in the ESI. The NCI plots show the presence of attractive [C–H]⋯F interactions between the ethyl groups on the pillararene ring and one of the –CF3 functionalities of the 3,5-bis(trifluoromethyl)phenyl stopper. We hypothesize that these non-covalent interactions are primarily responsible for biasing the equilibrium distribution of the pillararene ring toward the side of the active-ester stopper, which results in the clear NOE cross-peak shown in panel (a).
Fig. 3
Fig. 3. (a) Complete kinetic pathway for through-space controlled stopper exchange with 3,5-dimethylbenzylamine as the nucleophile. 3,5-DMBA = 3,5-dimethylbenzylamine; Stopper = 3,5-bis(trifluoromethyl)phenol. Rate constants k1 and k1′ denote substitution at the activated ester (proximal to the catalytic the side-chain), while k2 and k2′ denote substitution at the ester distal to the catalyst. (b) Four representative 1H NMR spectra (500 MHz, CDCl3, 300 K) recorded at different time points over the course of the kinetics experiment. The three sets of amide protons (1 NH each for both RDP[5]cat@MAfav and RDP[5]cat@MAdisfav, 2 NH for RDP[5]cat@DA) are highlighted. A complete stack of the entire kinetics spectrum is shown in Fig. S1 in the ESI. (c) Concentrations of all three reaction products measured by quantitative 1H NMR spectroscopy with the TBB internal standard over the course of the reaction. The reaction was run at 30 °C as detailed in the ESI. Kinetics fits are shown as dashed lines. The kinetic fits were obtained using the Dynafit software package as detailed in the ESI. Derived rate constants with error bars (standard errors obtained from the Dynafit kinetic fits) are shown in the table on the right.
Fig. 4
Fig. 4. Comparison of aminolysis rate constants for RDP[5]cat@diester with different amine nucleophiles. All reactions were run at 30 °C as detailed in the ESI. See Fig. S1–S5 for the kinetic fits and stacks of the time-dependent 1H NMR spectra, which were used to determine all the rate constants. The kinetic fits were obtained using the Dynafit software package as detailed in the ESI. Numerical values for the derived rate constants with error bars (standard errors obtained from the Dynafit kinetic fits) are listed in Fig. 3c, S3b, and S5b.
Fig. 5
Fig. 5. Plots of the diastereoselectivity (d.r. = [RDP[5]cat@MAfav]/[RDP[5]cat@MAdisfav]) for the major geometric rotaxane isomers formed over time for the aminolysis reactions shown in Fig. 4. The concentrations of the products were obtained from the kinetic fits to the quantitative 1H NMR data shown in Fig. 3, S3b, and S5b.
Fig. 6
Fig. 6. DFT-calculated binding energies (B3LYP-MM/aug-cc-pVDZ//B3LYP-MM/LACVP* level of theory) between the different faces of the RDP[5]cat ring and the varying amide stoppers for both geometric isomers. The model systems used to calculate the binding energies are shown in insets at the top left of the figure. In the model systems for the disfavored rotaxane products (RDP[5]cat@MAdisfav-1-Model, RDP[5]cat@MAdisfav-2-Model, and RDP[5]cat@MAdisfav-3-Model), the tetraglyme chains do not directly interact with the varying amide stoppers. Therefore, for the models of the disfavored rotaxane products, the tetraglyme chains on the ring were replaced with ethyl substituents to simplify the conformational space and enable a more accurate search of the conformational space at the DFT level with these smaller model systems.
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