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Cage catalysis continues to create significant interest, yet catalyst function remains poorly understood. Herein, we report mechanistic insights into coordination-cage-catalyzed Michael addition using kinetic and computational methods. The study has been enabled by the detection of identifiable catalyst intermediates, which allow the evolution of different cage species to be monitored and modeled alongside reactants and products. The investigations show that the overall acceleration results from two distinct effects. First, the cage reaction shows a thousand-fold increase in the rate constant for the turnover-limiting C-C bond-forming step compared to a reference state. Computational modeling and experimental analysis of activation parameters indicate that this stems from a significant reduction in entropy, suggesting substrate coencapsulation. Second, the cage markedly acidifies the bound pronucleophile, shifting this equilibrium by up to 6 orders of magnitude. The combination of these two factors results in accelerations up to 10 9 relative to bulk-phase reference reactions. We also show that the catalyst can fundamentally alter the reaction mechanism, leading to intermediates and products that are not observable outside of the cage. Collectively, the results show that cage catalysis can proceed with very high activity and unique selectivity by harnessing a series of individually weak noncovalent interactions.

The kinetics of sulfur transfer from titanocene (poly)sulfides ( R Cp 2 TiS 5 , Cp 2 TiS 4 CMe 2 , Cp 2 Ti(SAr) 2 , Cp 2 TiCl(SAr)) to sulfenyl chlorides (S 2 Cl 2 , RSCl) have been investigated by a combination of stopped-flow UV-Vis/NMR reaction monitoring, titration assays, numerical kinetic modelling and KS-DFT calculations. The reactions are rapid, proceeding to completion over timescales of milliseconds to minutes, via a sequence of two S-S bond-forming steps ( k 1 , k 2 ). The archetypical polysulfides Cp 2 TiS 5 (1a) and Cp 2 TiS 4 C(Me 2 ) (2a) react with disulfur dichloride (S 2 Cl 2 ) through rate-limiting intermolecular S-S bond formation ( k 1 ) followed by a rapid intramolecular cyclization ( k 2 , with k 2 ≫ k 1 [RSCl]). The monofunctional sulfenyl chlorides (RSCl) studied herein react in two intermolecular S-S bond forming steps proceeding at similar rates ( k 1 ≈ k 2 ). Reactions of titanocene bisthiophenolates, Cp 2 Ti(SAr) 2 (5), with both mono- and di-functional sulfenyl chlorides result in rapid accumulation of the monothiophenolate, Cp 2 TiCl(SAr) (6) ( k 1 > k 2 ). Across the range of reactants studied, the rates are relatively insensitive to changes in temperature and in the electronics of the sulfenyl chloride, moderately sensitive to the electronics of the titanocene (poly)sulfide ( ρ (Ti-(SAr)) ≈ -2.0), and highly sensitive to the solvent polarity, with non-polar solvents (CS 2 , CCl 4 ) leading to the slowest rates. The combined sensitivities are the result of a concerted, polarized and late transition state for the rate-limiting S-S bond forming step, accompanied by a large entropic penalty. Each substitution step {[Ti]-SR' + Cl-SR → [Ti]-Cl + RS-SR'} proceeds via titanium-assisted Cl-S cleavage to generate a transient pentacoordinate complex, Cl-[Cp 2 TiX]-S(R')-SR, which then undergoes rapid Ti-S dissociation., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Coordination cage catalysis has commonly relied on the endogenous binding of substrates, exploiting the cavity microenvironment and spatial constraints to engender increased reactivity or interesting selectivity. Nonetheless, there are issues with this approach, such as the frequent occurrence of product inhibition or the limited applicability to a wide range of substrates and reactions. Here we describe a strategy in which the cage acts as an exogenous catalyst, wherein reactants, intermediates and products remain unbound throughout the course of the catalytic cycle. Instead, the cage is used to alter the properties of a cofactor guest, which then transfers reactivity to the bulk-phase. We have exemplified this approach using photocatalysis, showing that a photoactivated host-guest complex can mediate [4 + 2] cycloadditions and the aza-Henry reaction. Detailed in situ photolysis experiments show that the cage can both act as a photo-initiator and as an on-cycle catalyst where the quantum yield is less than unity., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Since its discovery in mid-20 th century, the sensitivity of Nuclear Magnetic Resonance (NMR) has increased steadily, in part due to the design of new, sophisticated NMR experiments. Here we report on a liquid-state NMR methodology that significantly increases the sensitivity of diffusion coefficient measurements of pure compounds, allowing to estimate their sizes using a much reduced amount of material. In this method, the diffusion coefficients are being measured by analysing narrow and intense singlets, which are invariant to magnetic field inhomogeneities. The singlets are obtained through signal acquisition embedded in short (<0.5 ms) spin-echo intervals separated by non-selective 180° or 90° pulses, suppressing the chemical shift evolution of resonances and their splitting due to J couplings. The achieved 10-100 sensitivity enhancement results in a 100-10000-fold time saving. Using high field cryoprobe NMR spectrometers, this makes it possible to measure a diffusion coefficient of a medium-size organic molecule in a matter of minutes with as little as a few hundred nanograms of material., (© 2023. The Author(s).)

A 'principles and practice' tutorial-style review of the application of solution-phase NMR in the analysis of the mechanisms of homogeneous organic and organometallic reactions and processes. This review of 345 references summarises why solution-phase NMR spectroscopy is uniquely effective in such studies, allowing non-destructive, quantitative analysis of a wide range of nuclei common to organic and organometallic reactions, providing exquisite structural detail, and using instrumentation that is routinely available in most chemistry research facilities. The review is in two parts. The first comprises an introduction to general techniques and equipment, and guidelines for their selection and application. Topics include practical aspects of the reaction itself, reaction monitoring techniques, NMR data acquisition and processing, analysis of temporal concentration data, NMR titrations, DOSY, and the use of isotopes. The second part comprises a series of 15 Case Studies, each selected to illustrate specific techniques and approaches discussed in the first part, including in situ NMR ( 1/2 H, 10/11 B, 13 C, 15 N, 19 F, 29 Si, 31 P), kinetic and equilibrium isotope effects, isotope entrainment, isotope shifts, isotopes at natural abundance, scalar coupling, kinetic analysis (VTNA, RPKA, simulation, steady-state), stopped-flow NMR, flow NMR, rapid injection NMR, pure shift NMR, dynamic nuclear polarisation, 1 H/ 19 F DOSY NMR, and in situ illumination NMR., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA.