Inhibition of [FeFe]-Hydrogenase by Formaldehyde: Proposed Mechanism and Reactivity of FeFe Alkyl Complexes

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[(m-SCH2)2NH](CO)4(PMe3)2 (1) react with a mixture of HBF4 and CH2O to give three isomers of [Fe2[(m-SCH2)2NCH2](CO)4(PMe3)2]+ ([2]+).  X-ray crystallography verified the NCH2Fe linkage to an octahedral Fe(II) site. Although [2]+ 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[(m-SCH2)2N13CH2OH](CO)4(PMe3)2]+.  Protonation converts this hydroxymethyl derivative to [2]+, concomitant with 13C-labelling of all three methylene groups.  The Fe-CH2N bond in [2]+ is electrophilic: PPh3, hydroxide, and hydride give, respectively, the phosphonium [Fe2[(m-SCH2)2NCH2PPh3](CO)4(PMe3)2]+, 1, and the methylamine Fe2[(m-SCH2)2NCH3](CO)4(PMe3)2.  The reaction of [Fe2[(m-SCH2)2NH](CN)2(CO)4]2− with CH2O/HBF4 gave [Fe2[(m-SCH2)2NCH2CN](CN)(CO)5]− ([4]−), the result of reductive elimination from [Fe2[(m-SCH2)2NCH2](CN)2(CO)4]−. The phosphine derivative [Fe2[(m-SCH2)2NCH2CN](CN)(CO)4(PPh3)]− ([5]−) was characterized crystallographically.