The mechanism for inhibition of [FeFe]-hydrogenases by formaldehyde is examined with model complexes. Key findings: (i) CH2 donated by formaldehyde covalently link Fe and the amine cofactor, blocking the active site and (ii) the resulting Fe-alkyl is a versatile electrophilic alkylating agent. Solutions of Fe2[(μ-SCH2)2NH](CO)4(PMe3)2 (1) react with a mixture of HBF4 and CH2O to give three isomers of [Fe2[(μ-SCH2)2NCH2](CO)4(PMe3)2]+ (+). X-ray crystallography verified the NCH2Fe linkage to an octahedral Fe(ii) site. Although + is stereochemically rigid on the NMR timescale, spin-saturation transfer experiments implicate reversible dissociation of the Fe-CH2 bond, allowing interchange of all three diastereoisomers. Using 13CH2O, the methylenation begins with formation of [Fe2[(μ-SCH2)2N13CH2OH](CO)4(PMe3)2]+. Protonation converts this hydroxymethyl derivative to +, concomitant with 13C-labelling of all three methylene groups. The Fe-CH2N bond in + is electrophilic: PPh3, hydroxide, and hydride give, respectively, the phosphonium [Fe2[(μ-SCH2)2NCH2PPh3](CO)4(PMe3)2]+, 1, and the methylamine Fe2[(μ-SCH2)2NCH3](CO)4(PMe3)2. The reaction of [Fe2[(μ-SCH2)2NH](CN)2(CO)4]2- with CH2O/HBF4 gave [Fe2[(μ-SCH2)2NCH2CN](CN)(CO)5]- (-), the result of reductive elimination from [Fe2[(μ-SCH2)2NCH2](CN)2(CO)4]-. The phosphine derivative [Fe2[(μ-SCH2)2NCH2CN](CN)(CO)4(PPh3)]- (-) was characterized crystallographically.
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