Fluoroform is weakly acidic with a pK = 25–28 and quite inert. Attempted deprotonation results in defluorination to generate  and difluorocarbene (). Some organocopper and organocadmium compounds have been developed as trifluoromethylation reagents.
Fluoroform is a precursor of the Ruppert-Prakash reagent Trifluoromethyltrimethylsilane|, which is a source of the nucleophilic  anion.