The construction of a synthetic analogue of the A-cluster of carbon monoxide dehydrogenase/acetylcoenzyme synthase, the site of acetylcoenzyme A formation, requires as a final step the formation of an unsupported [Fe4S4]-(mu(2)-SR)-Ni-parallel to bridge to a preformed cluster. Our previous results (Rao, P. V.; Bhaduri, S.; Jiang, J.; Holm, R. H. Inorg. Chem. 2004, 43, 5833) and the work of others have addressed synthesis of dinuclear complexes relevant to the A-cluster. This investigation concentrates on reactions pertinent to bridge formation by examining systems containing dinuclear and mononuclear Ni-parallel to complexes and the 3:1 site-differentiated clusters [Fe4S4(LS3)L'](2-) (L' = TfO- (14), SEt (15)). The system 14/[{Ni(Lo-S2N2)}M(SCH2CH2PPh2)](+) results in cleavage of the dinuclear complex and formation of [{Ni(Lo-S2N2)}-Fe-4(LS3)](-) (18), in which the Ni-parallel to complex binds at the unique cluster site with formation of a Ni(mu(2)-SR)(2)Fe bridge rhomb. Cluster 18 and the related species [{Ni(phma)}Fe4S4(LS3)](3-) (19) are obtainable by direct reaction of the corresponding cis-planar Ni-parallel to-S2N2 complexes with 14. The mononuclear complexes [M(pdmt)(SEt)](-) (M = Ni-parallel to, Pd-parallel to) with 14 in acetonitrile or Me2SO solution react by thiolate transfer to give 15 and [M-2(pdmt)(2)]. However, in dichloromethane the Ni-parallel to reaction product is interpreted as [{Ni(pdmt)(mu(2-)SEt)} Fe4S4(LS3)](2-) (20). Reaction of Et3NH+ and 15 affords the double cubane [{Fe4S4(LS3)}(2)(mu(2)-SEt)](3-) (21). Cluster 18 contains two mutually supportive Fe-(mu(2)-SR)-Ni-parallel to bridges, 19 exhibits one strong and one weaker bridge, 20 has one unsupported bridge (inferred from the H-1 NMR spectrum), and 21 has one unsupported Fe-(mu(2)-SR)-Fe bridge. Bridges in 18, 19, and 21 were established by X-ray structures. This work demonstrates that a bridge of the type found in the enzyme A-clusters is achievable by synthesis and implies that more stable, unsupported single thiolate bridges may require reinforcement by an additional covalent linkage between the Fe4S4 and nickel-containing components. (LS3 = 1,3,5-tris((4,6-dimethyl-3-mercaptophenyl)thio)-2,4,6-tris(p-tolylthio) benzene (3-); Lo-S2N2 = N,N'-diethyl-3,7-diazanonane-1,9-dithiolate(2-); pdmt = pyridine-2,6-methanedithiolate(2-); phma N,N'-1,2-phenylenebis(2-acetylthio)-acetamidate(4-); TfO = triflate.)