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) CH(2) 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 Fe(2)[(μ-SCH(2))(2)NH](CO)(4)(PMe(3))(2) (1) react with a mixture of HBF(4) and CH(2)O to give three isomers of [Fe(2)[(μ-SCH(2))(2)NCH(2)](CO)(4)(PMe(3))(2)](+) ([2](+)). X-ray crystallography verified the NCH(2)Fe 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–CH(2) bond, allowing interchange of all three diastereoisomers. Using (13)CH(2)O, the methylenation begins with formation of [Fe(2)[(μ-SCH(2))(2)N(13)CH(2)OH](CO)(4)(PMe(3))(2)](+). Protonation converts this hydroxymethyl derivative to [2](+), concomitant with (13)C-labelling of all three methylene groups. The Fe–CH(2)N bond in [2](+) is electrophilic: PPh(3), hydroxide, and hydride give, respectively, the phosphonium [Fe(2)[(μ-SCH(2))(2)NCH(2)PPh(3)](CO)(4)(PMe(3))(2)](+), 1, and the methylamine Fe(2)[(μ-SCH(2))(2)NCH(3)](CO)(4)(PMe(3))(2). The reaction of [Fe(2)[(μ-SCH(2))(2)NH](CN)(2)(CO)(4)](2−) with CH(2)O/HBF(4) gave [Fe(2)[(μ-SCH(2))(2)NCH(2)CN](CN)(CO)(5)](−) ([4](−)), the result of reductive elimination from [Fe(2)[(μ-SCH(2))(2)NCH(2)](CN)(2)(CO)(4)](−). The phosphine derivative [Fe(2)[(μ-SCH(2))(2)NCH(2)CN](CN)(CO)(4)(PPh(3))](−) ([5](−)) was characterized crystallographically.