biostudies-literatureMusolino SFMitacsDefence Research and Development CanadaCanada Research Chairs12138-12148https://www.ebi.ac.uk/biostudies/studies/S-EPMC8457397biostudies-literatureUnknown12(36)Diazirine reagents allow for the ready generation of carbenes upon photochemical, thermal, or electrical stimulation. Because carbenes formed in this way can undergo rapid insertion into any nearby C-H, O-H or N-H bond, molecules that encode diazirine functions have emerged as privileged tools in applications ranging from biological target identification and proteomics through to polymer crosslinking and adhesion. Here we use a combination of experimental and computational methods to complete the first comprehensive survey of diazirine structure-function relationships, with a particular focus on thermal activation methods. We reveal a striking ability to vary the activation energy and activation temperature of aryl diazirines through the rational manipulation of electronic properties. SignChemical scienceStructure-function relationships in aryl diazirines reveal optimal design features to maximize C-H insertion.PMC8457397CFPMN1-026-UBCIT11982DiLabio GAMusolino SFPei ZWulff JEBi LfalseStructure-function relationships in aryl diazirines reveal optimal design features to maximize C-H insertion.Diazirine reagents allow for the ready generation of carbenes upon photochemical, thermal, or electrical stimulation. Because carbenes formed in this way can undergo rapid insertion into any nearby C-H, O-H or N-H bond, molecules that encode diazirine functions have emerged as privileged tools in applications ranging from biological target identification and proteomics through to polymer crosslinking and adhesion. Here we use a combination of experimental and computational methods to complete the first comprehensive survey of diazirine structure-function relationships, with a particular focus on thermal activation methods. We reveal a striking ability to vary the activation energy and activation temperature of aryl diazirines through the rational manipulation of electronic properties. Sign2021-01-01T00:00:00Z2021 Sep2025-04-22T11:29:41.534Z2024-11-12T08:23:40.601ZS-EPMC84573973466757910.1039/d1sc03631a