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Abstract 2641 presented at 2025 ASBMB meeting 

Abstract The chemiluminescent light‐emission pathway of phenoxy‐1,2‐dioxetane luminophores attracts growing interest within the scientific community. Dioxetane probes undergoing rapid flash‐type chemiexcitation exhibit higher detection sensitivity than those with a slow glow‐type chemiexcitation rate. We discovered that dioxetanes fused to non‐strained six‐member rings, with hetero atoms or inductive electron‐withdrawing groups, present both accelerated chemiexcitation rates and elevated chemical stability compared to dioxetanes fused to four‐member strained rings. DFT computational simulations supported the chemiexcitation acceleration observed by spiro‐fused six‐member rings with inductive electron‐withdrawing groups of dioxetanes. Specifically, a spiro‐dioxetane with a six‐member sulfone ring exhibited a chemiexcitation rate 293‐fold faster than that of spiro‐adamantyl‐dioxetane. A turn‐ON dioxetane probe for the detection of the enzyme β‐galactosidase, containing the six‐member sulfone unit, exhibited a S/N value of 108 in LB cell growth medium. This probe demonstrated a substantial increase in detection sensitivity towardsE. colibacterial cells expressing β‐galactosidase, with an LOD value that is 44‐fold more sensitive than that obtained by the adamantyl counterpart. The accelerated chemiexcitation and the elevated chemical stability presented by dioxetane containing a spiro‐fused six‐member ring with a sulfone inductive electron‐withdrawing group, make it an ideal candidate for designing efficient turn‐on chemiluminescent probes with exceptionally high detection sensitivity. 

Abstract Radical substitution is a useful method to functionalize heterocycles, as in the venerable Minisci reaction. Empirically observed regiochemistries indicate that the CF₂H radical has a nucleophilic character similar to alkyl radicals, but the CF₃radical is electrophilic. While the difference between •CH₃and •CF₃is well understood, the reason that one and two Fs make little difference but the third has a large effect is puzzling. DFT calculations with M06-2X both reproduce experimental selectivities and also lead to an explanation of this difference. Theoretical methods reveal how the F inductive withdrawal and conjugative donation alter radical properties, but only CF₃becomes decidedly electrophilic toward heterocycles. Here, we show a simple model to explain the radical orbital energy trends and resulting nucleophilicity or electrophilicity of fluorinated radicals.