The emergent properties that arise from self-assembly and molecular recognition phenomena are a direct consequence of non-covalent interactions. Gas-phase measurements and computational methods point to the dominance of dispersion forces in molecular association, but solvent effects complicate the unambiguous quantification of these forces in solution. Here, we have used synthetic molecular balances to measure interactions between apolar alkyl chains in 31 organic, fluorous and aqueous solvent environments. The experimental interaction energies are an order of magnitude smaller than estimates of dispersion forces between alkyl chains that have been derived from vaporization enthalpies and dispersion-corrected calculations. Instead, it was found that cohesive solvent-solvent interactions are the major driving force behind apolar association in solution. The results suggest that theoretical models that implicate important roles for dispersion forces in molecular recognition events should be interpreted with caution in solvent-accessible systems.

The hydrophobic effect plays a central role in determining the structure, activity, and properties of biomolecules and materials. In contrast, the general manifestation of this phenomenon in other solvents—the solvophobic effect—although widely invoked, is currently poorly defined because of the lack of a universally accepted descriptor. Here we have used synthetic molecular balances to measure solvent effects on aromatic, aliphatic, and fluorous nonpolar interactions. Our solvent screening data combined with independent experimental measurements of supramolecular association, single-molecule folding, and bulk phase transfer energies were all found to correlate well with the cohesive energy density (ced) of the solvent. Meanwhile, other measures of solvent cohesion, such as surface tension and internal pressure, gave inferior correlations. Thus, we establish ced as a readily accessible, quantitative descriptor of solvophobic association in a range of chemical contexts.

Fluorocarbons often have distinct miscibility properties compared to their nonfluorinated analogues. These differences may be attributed to van der Waals dispersion forces or solvophobic effects, but their contributions are notoriously difficult to separate in molecular recognition processes. Here, molecular torsion balances were used to compare cohesive alkyl and perfluoroalkyl interactions in a range of solvents. A simple linear regression enabled the energetic partitioning of solvophobic and van der Waals forces in the self-association of apolar chains. The contributions of dispersion interactions in apolar cohesion were found to be strongly attenuated in solution compared to the gas phase, but still play a major role in fluorous and organic solvents. In contrast, solvophobic effects were found to be dominant in driving the association of apolar chains in aqueous solution. The results are expected to assist the computational modelling of van der Waals forces in solution.

Recent advances in bioorthogonal catalysis are increasing the capacity of researchers to manipulate the fate of molecules in complex biological systems. A bioorthogonal uncaging strategy is presented, which is triggered by heterogeneous gold catalysis and facilitates the activation of a structurally diverse range of therapeutics in cancer cell culture. Furthermore, this solid‐supported catalytic system enabled locally controlled release of a fluorescent dye into the brain of a zebrafish for the first time, offering a novel way to modulate the activity of bioorthogonal reagents in the most fragile and complex organs.

The synthetic biology toolbox lacks extendable and conformationally controllable yet easy-to-synthesize building blocks that are long enough to span membranes. To meet this need, an iterative synthesis of α-aminoisobutyric acid (Aib) oligomers was used to create a library of homologous rigid-rod 310-helical foldamers, which have incrementally increasing lengths and functionalizable N- and C-termini. This library was used to probe the inter-relationship of foldamer length, self-association strength, and ionophoric ability, which is poorly understood. Although foldamer self-association in nonpolar chloroform increased with length, with a ∼14-fold increase in dimerization constant from Aib6 to Aib11, ionophoric activity in bilayers showed a stronger length dependence, with the observed rate constant for Aib11 ∼70-fold greater than that of Aib6. The strongest ionophoric activity was observed for foldamers with >10 Aib residues, which have end-to-end distances greater than the hydrophobic width of the bilayers used (∼2.8 nm); X-ray crystallography showed that Aib11 is 2.93 nm long. These studies suggest that being long enough to span the membrane is more important for good ionophoric activity than strong self-association in the bilayer. Planar bilayer conductance measurements showed that Aib11 and Aib13, but not Aib7, could form pores. This pore-forming behavior is strong evidence that Aibm (m ≥ 10) building blocks can span bilayers.

Chains of hydrogen bonds such as those found in water and proteins are often presumed to be more stable than the sum of the individual H bonds. However, the energetics of cooperativity are complicated by solvent effects and the dynamics of intermolecular interactions, meaning that information on cooperativity typically is derived from theory or indirect structural data. Herein, we present direct measurements of energetic cooperativity in an experimental system in which the geometry and the number of H bonds in a chain were systematically controlled. Strikingly, we found that adding a second H‐bond donor to form a chain can almost double the strength of the terminal H bond, while further extensions have little effect. The experimental observations add weight to computations which have suggested that strong, but short‐range cooperative effects may occur in H‐bond chains.

A simple solvent model enables dissection of solvent effects to reveal the pseudo-gas-phase behaviour of molecular balances. Post-print of a peer-reviewed article published by the Royal Society of Chemistry.

SN‐38, the active metabolite of irinotecan, is released upon liver hydrolysis to mediate potent antitumor activity. Systemic exposure to SN‐38, however, also leads to serious side effects. To reduce systemic toxicity by controlling where and when SN‐38 is generated, a new prodrug was specifically designed to be metabolically stable and undergo rapid palladium‐mediated activation. Blocking the phenolic OH of SN‐38 with a 2,6‐bis(propargyloxy)benzyl group led to significant reduction of cytotoxic activity (up to 44‐fold). Anticancer properties were swiftly restored in the presence of heterogeneous palladium (Pd) catalysts to kill colorectal cancer and glioma cells, proving the efficacy of this novel masking strategy for aromatic hydroxyls. Combination with a Pd‐activated 5FU prodrug augmented the antiproliferative potency of the treatment, while displaying no activity in the absence of the Pd source, which illustrates the benefit of achieving controlled release of multiple approved therapeutics—sequentially or simultaneously—by the same bioorthogonal catalyst to increase anticancer activity.