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Phosphine-modified thioester derivatives are shown to serve as efficient precursors to phosphine-stabilized ferrous acyl thiolato carbonyls.  Diverse thioester phosphines containing a variety of aryl and alkylthio substituents can be prepared from thiols and 2-diphenylphosphinobenzoic acid via carbodiimide coupling.  The phosphine thioesters afforded iron(II) acyl thiolato derivatives from sources of Fe(0) and the simplest thioester Ph2PC6H4-2-C(O)SPh gave the cleanest products.  The reaction generates both Fe(SPh)[Ph2PC6H4C(O)](CO)3 (1) and the diferrous diacyl Fe2(SPh)2(CO)3[Ph2PC6H4C(O)]2, which gives carbonylates to give the monomer.  For the extremely bulky arylthioester Ph2PC6H4C(O)SC6H4-2,6-(2,4,6-trimethylphenyl)2, oxidative addition is arrested at the stage of the Fe(0) adduct of the phosphine.  Complex 1 reacts with cyanide to give Et4N[Fe(Ph2PC6H4C(O)(SPh)(CN)(CO)2] (Et4N[2]).  The 13C and 31P NMR spectra indicate that the substitution is stereospecific and cis to P.  The IR spectrum of [2]- in CH2Cl2 solution very closely matches that for HmdCN.  XANES and EXAFS measurements confirm the close similarity.  Complex 1 also stereospecifically forms a derivative with TsCH2NC, but it is more labile than the cyanide derivative.  Tricarbonyl 1 was found to reversibly protonate to give thermally labile derivative, IR measurements of which indicate that the acyl and thiolate ligands are not protonated in Hmd.

The PhS derivative 1 was examined in detail and shown to adopt a structure very similar to the one modeled for the active site of the CO-inhibited form of Hmd.  The major difference is the presence of the phosphine ligand in place of the pyridyl group of the GP cofactor, but the phosphorus center offers the distinct advantage of enabling 31P NMR analysis of reaction mixtures.  The pathway for the oxidative addition of the thioester to Fe(0) is illuminated by the finding that bulky phosphine thioesters form adducts of the type Fe(Ph2PC6H4COSR)(CO)4.  The oxidative addition of the thioester can then be envisioned to proceed via coordination of the thioether-like sulfur center.  Thus, the oxidative addition would be preceded by formation of Fe(2-Ph2PC6H4COSR)(CO)3, thereby setting the stereochemistry.  Whereas the phosphine facilitates oxidative addition of the thioester, the low affinity of Fe(0) for pyridines prevented incorporation of the more biomimetic N-heterocyclic ligand on the Fe(CO)3 center.

Hmd stereoselectively binds 13CO.  In contrast, the extracted Fe-GP cofactor, which is a dicarbonyl competent for reconstitution, does not bind CO, probably reflecting the fact that all six coordination sites are occupied in this form.  In this regard, model 1 more closely resembles the isolated Fe-GP cofactor than the holoenzyme. This can be due to geometrical reasons.  In fact, the iron binding site of Hmd wild type has been reported to possess a highly distorted geometry, which is shaped by the protein environment.  Addition of CN- and TsCH2CN to 1 resulted in models for the respective inhibited forms of Hmd.  As indicated by comparisons of the XANES and IR spectra for Hmd and HmdCN (M. marburgensis), [Fe(Ph2PC6H4C(O)(SPh)(CN)(CO)2]- replicates the major details of the electronic structure of the active site.  This closeness of match represents compelling evidence for the presence of a ferrous center in Hmd.  31P NMR data show that both CN- and TsCH2CN effect stereoselective replacement of CO.  The IR spectroscopy of the models containing CN- and 13CN- closely match the spectra for the respective HmdCN and Hmd13CN states.  In the case of the less basic ligand TsCH2CN, the adduct remains labile, as evidenced by isomerization and further reaction above -5 ºC.  

The results also highlight the anomalous effect of cyanide on the IR spectrum of Hmd.  In HmdCN, two CO bands are shifted to higher energies by 9 and 12 cm-1.  In this conversion, CN- is assumed to displace a labile ligand such as water.  Nonetheless, it is extremely ? that CO bands shift to higher energy upon installing a cyanide ligand.  For example the average of the two CO bands is 50 cm-1 lower in [Fe(Ph2PC6H4C(O)(SPh)(CN)(CO)2]- compared with Fe(Ph2PC6H4C(O)(SPh)(CO)3.  One possible explanation for this anomaly is that CN- affects the second coordination sphere of the ferrous center in Hmd, such as the protonation state of the pyridone.

The tricarbonyl monomer was also susceptible to reversible protonation, but only with strong acids.  The CO bands for the protonated tricarbonyl occur at 20-30 cm-1 above those seen for HmdCO.  Furthermore the protonated derivative is unstable at temperatures above –30 ºC.  Collectively, these findings suggest that in HmdCO the thiol and acyl ligands are not protonated.