Abstract
The central role of Coulombic interactions in enzyme catalysis has inspired multiple approaches to sculpting electrostatic potential fields (EPFs) for controlling chemical reactivity, including ion gradients in water microdroplets, the tips of STMs, and precisely engineered crystals. These are powerful tools because EPFs can affect all reactions, even those whose mechanisms do not involve formal charges. For some time now, supramolecular chemists have become increasingly proficient in using encapsulation to control stoichiometric and catalytic reactions. However, the field has not taken advantage of the broad range of nanocontainers available to systematically explore how EPFs can affect reactions within their inner-spaces. With that idea in mind, previously, we reported on how positively and negatively charged supramolecular capsules can modulate the acidity and reactivity of thiol guests bound within their inner, yoctoliter spaces (Cai, X.; Kataria, R.; Gibb, B. C. J. Am. Chem. Soc. 2020, 142, 8291–8298; Wang, K.; Cai, X.; Yao, W.; Tang, D.; Kataria, R.; Ashbaugh, H. S.; Byers, L. D.; Gibb, B. C. J. Am. Chem. Soc.2019, 141, 6740–6747). Building on this, we report here on the cyclization of 14-bromotetradecan-1-amine inside these yoctoliter containers. We examine the rate and activation thermodynamics of cyclization (Eyring analysis), both in the absence and presence of exogenous salts whose complementary ion can bind to the outside of the capsule and hence attenuate its EPF. We find the cyclization rates and activation thermodynamics in the two capsules to be similar, but that for either capsule attenuation of the EPF slows the reaction down considerably. We conclude the capsules behave in a manner akin to covalently attached electron donating/withdrawing groups in a substrate, with each capsule enforcing their own deviations from the idealized SN2 mechanism by moving electron density and charge in the activated complex and TS, and that the idealized SN2 mechanism inside the theoretical neutral host is relatively difficult because of the lack of solvation of the TS.
Highlights
Inspired by the strength and long range of Coulombic interactions and their central role in the properties of enzymes,[1−6] multiple approaches for controlling chemical reactions by sculpting electrostatic potential fields (EPFs) have been considered.[7]
As a step toward understanding how the EPFs of hosts can affect the reactions of internalized guests, we recently reported on two, oppositely charged, yoctoliter containers built from positand 1 and octa-acid 2 (Figure 1).[38−40] Through the hydrophobic effect, these cavitands dimerize around guests to form container complexes possessing identically shaped, low dielectric inner-spaces that differ in one key point; namely, the yoctoliter inner-spaces of 12 and 22 are, respectively, enveloped in a positive and negative EPF generated by the watersolubilizing charged groups of each cavitand
We have observed that rates of macrocyclization of α,ω-thio-alkane halides inside 12 are almost 4 orders of magnitude faster than inside 22.42 These findings showed that the stabilization of the transition states (TS) for cyclization was greater than that of thiolate stabilization, suggesting a rather complex mechanism by which these capsules affect chemical reactivity
Summary
Inspired by the strength and long range of Coulombic interactions and their central role in the properties of enzymes,[1−6] multiple approaches for controlling chemical reactions by sculpting electrostatic potential fields (EPFs) have been considered.[7]. We have shown that bound thiol guests are more acidic inside 12, by up to 2.5 pKa units (it transpires that guest motif has a much larger effect on pKa).[41] We have observed that rates of macrocyclization of α,ω-thio-alkane halides inside 12 are almost 4 orders of magnitude faster than inside 22.42 These findings showed that the stabilization of the transition states (TS) for cyclization was greater than that of thiolate stabilization, suggesting a rather complex mechanism by which these capsules affect chemical reactivity.
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