Computation has guided the design of conformationally-strained dioxolane-fused trans-cyclooctene (d-TCO) derivatives that display excellent reactivity in the tetrazine ligation. A water soluble derivative of 3,6-dipyridyl-s-tetrazine reacts with d-TCO with a second order rate k₂ 366 000 (±15 000) M⁻¹ s⁻¹ at 25 °C in pure water. Furthermore, d-TCO derivatives can be prepared easily, are accessed through diastereoselective synthesis, and are typically crystalline bench-stable solids that are stable in aqueous solution, blood serum, or in the presence of thiols in buffered solution. GFP with a genetically encoded tetrazine-containing amino acid was site-specifically labelled in vivo by a d-TCO derivative. The fastest bioorthogonal reaction reported to date [k₂ 3 300 000 (±40 000) M⁻¹ s⁻¹ in H₂O at 25 °C] is described herein with a cyclopropane-fused trans-cyclooctene. d-TCO derivatives display rates within an order of magnitude of these fastest trans-cyclooctene reagents, and also display enhanced stability and aqueous solubility.

Dirhodium(II) paddlewheel complexes have high utility in diazo-mediated cyclopropanation reactions and ethyl diazoacetate is one of the most commonly used diazo compounds in this reaction. In this study, we report our efforts to use tethered thioether ligands to tune the reactivity of Rh^II-carbene mediated cyclopropanation of olefins with ethyl diazoacetate. Microwave methods enabled the synthesis of a family of Rh^II complexes in which tethered thioether moieties were coordinated to axial sites of the complex. Different tether lengths and thioether substituents were screened to optimise cyclopropane yields and minimise side product formation. Furthermore, good yields were obtained when equimolar diazo and olefin were used. Structural and spectroscopic investigation revealed that tethered thioethers changed the electronic structure of the rhodium core, which was instrumental in the performance of the catalysts. Computational modelling of the catalysts provided further support that the tethered thioethers were responsible for increased yields.