To examine inhibitor binding to an iron site resembling that of the metalloenzyme nitrile hydratase (NHase), a coordinatively unsaturated, five-coordinate FeIII thiolate complex was synthesized, and its reactivity examined. Ferricinium hexafluorophosphate induced oxidation of gem-dimethyl-protected [FeIIS2 Me2N3(Pr,Pr)] affords the chiral, five-coordinate complex [FeIIIS2 Me2N3(Pr,Pr)]+ (2) in reasonable yields. The magnetic properties and EPR of 2 are consistent with an S = 1/2 ground state. This unusual spin state, in conjunction with the low coordination number, of 2 result in unusually short Fe−S bonds (2.15(2) Å). Ligand constraints distort the S−Fe−N angles in 2 and create an open (132.3(1)°) reactive site. Azide binds to this site to afford a model for the azide-inhibited form of NHase [FeIIIS2 Me2N3(Pr,Pr)(N3)] (3). In MeOH azide binds reversibly, whereas in MeCN it binds irreversibly. This demonstrates that the secondary coordination sphere (i.e., the solvent, or possibly a protein binding pocket) can have a dramatic influence on the substrate binding properties of a metal complex. A variable-temperature equilibrium study in MeOH afforded thermodynamic parameters (ΔH = −5.2 ± 0.9 kcal/mol and ΔS = −12.4 ± 0.4 eu) for the binding of this inhibitor. The electronic spectrum of 3 displays an intense band at 708 (1600) nm similar to that (710 (∼1200) nm) of the pH = 7.3 form of NHase, and other six-coordinate cis-dithiolate ligated FeIII complexes synthesized by our group. EPR parameters for 3 (g = 2.23, 2.16, 1.99) are nearly identical to those of the azide-inhibited form of NHase (g = 2.23, 2.14, 1.99), suggesting that (1) the iron site of our model closely resembles that of the enzyme, and (2) azide binds directly to the metal ion in NHase. Reactivity is oxidation-state dependent, and the reduced analogue of 2, [FeIIS2N3(Pr,Pr)] (4), reversibly binds CO, but not azide, whereas oxidized 2 binds azide, but not CO.

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Nitrile hydratase is the first and only current example of a metalloenzyme containing a single non-heme Fe in a mixed N/Sligated coordination site.'-3 Its function is to hydrolyze nitriles to the corresponding amides in organisms which can live on R-CN as their sole C and N source. On the basis of EPR? MCD,5 resonance Raman, EXAFS,* and ENDOR' studies, the active site of nitrile hydratase is proposed to contain a six-coordinate, low-spin (S = ' / 2 ) Fe3+ ion ligated by two ciscysteinates, three N's, and a water: N The spectroscopic properties of nitrile hydratase are pHdependent, and two distinct forms (pH -7 and pH = 9) have been ~haracterized.~.' The high-pH form6 appears to be identical to the "substrate-bound'' form on the basis of its spectroscopic properties.4 Two impediments to the synthetic modeling of this enzyme have been the ease with which ferric ions oxidize thiolates to disulfides and the propensity of metal thiolates to o l i g~m e r i z e .~.~ The small number of reported monomeric Fe-(111) thiolate complexes attests to this.I0-l3 Mixed N-/SR--(1) Jin, H.; Tumer, I. M., Jr.; Nelson, M. J.; Gurbiel, R. J.; Doan, P. E.; Hoffman, B. M. J . Am. Chem. Soc. 1993, 115, 5290-1. (2) Nelson, M. J.; Jin, H.; Turner. I. M., Jr.; Grove, G.; Scarrow, R. C.; Brennan. B. A.: Que, L., Jr. J. Am. Chem. Soc. 1991, 113, 7072-3. (3) Nagasawa. T.; Ryuno, K.; Yamada, H. Biochem. Biophys. Res. Commun. 1986, 139, 1305-12. (4) Sugiura, Y.; Kuwahara, J.; Nagasawa, T.; Yamada, H. J. Am. Chem. (5) Johnson, M. K.: et al. Manuscript in preparation. (6) Jin. H.; Brennan, B. A,; Nelson, M. J.; et. al. Manuscript in preparation. (7) Honda, J.; Kandori, H.; Okada, T.; Nagamune, T.; Shichida. Y.; Sasabe, H.; Endo, I. ligated Fe(II1) systems are even rarer.I4-l6 Low-spin complexes of this type are extremely rare; most Fe(II1) compounds are S = 5 / 2 h i g h -~p i n '~. '~ or, at best, exist in a S = 5 / 2 -' / 2 spin equi1ibri~m.I~ Previously reported model compounds approximate the coordination geometry and metric parameters of the nitrile hydratase active site but do not reproduce the spin state and electronic spectral proper tie^.'^ Herein we report the synthesis, structure, and properties of a stable low-spin Fe(II1) thiolate complex which is remarkably similar to nitrile hydratase in terms of its electronic and geometric structure.Thiolate-ligated [Fe*11(AMIT)2]Cl (1) was synthesizedz0 via the Schiff-base condensation of ethylenediamine with a-mercaptoacetone at an Fe3+ template. This approach has provided access to a variety of mixed aminekhiolate S,Nyligated transition-metal complexes by our g r o~p .~' -*~ Although we have not yet obtained X-ray-quality crystals of l, (13) Sellmann, D.; Geck, M.; Knoch, F.; Ritter, G.; Dengler, J. J. Am. Chem. (14) Beissel, T.; Buerger, K. S.; Voigt, G.; Wieghardt, K.; Butzlaff, C.: (15) Marini, P. J.; Murray, K. S.; West, B. 0. J. Chem. Soc., Dalron Trans. (16) Fallon. G. D.; Gatehouse, B. M. J. Chem. Soc., Dalton Trans. 1975, (17) Greenwood, N. N.; Eamshaw, A. In Chemisrv of the Elemenrs; ...

A series of four structurally related cis-dithiolate-ligated Fe(III) complexes, [Fe III (DITpy) (3 and 4). The crystallographically determined mean Fe-S bond distances in 1-4 range from 2.196 to 2.232 Å and are characteristic of low-spin Fe(III)-thiolate complexes. The low-spin S = ½ ground state was confirmed by both EPR and magnetic susceptibility measurements. The electronic spectra of these complexes are characterized by broad absorption bands centered near ~700 nm that are consistent with ligand-to-metal chargetransfer (CT) bands. The complexes were further characterized by cyclic voltammetry measurements, and all possess highly negative Fe(III)/Fe(II) redox couples (~ −1 V vs SCE, saturated calomel electrode) indicating that alkyl thiolate donors are effective at stabilizing Fe(III) centers. Both the redox couple and the 700 nm band in the visible spectra show solvent-dependent shifts that are dependent upon the H-bonding ability of the solvent. The implications of these results with respect to the active site of the iron-containing nitrile hydratases are also discussed.

To examine how small structural changes influence the reactivity and magnetic properties of biologically relevant metal complexes, the reactivity and magnetic properties of two structurally related five-coordinate Fe(III) thiolate compounds are compared. (Et,Pr)-ligated [Fe(III)(S(2)(Me2)N(3)(Et,Pr))]PF(6) (3) is synthesized via the abstraction of a sulfur from alkyl persulfide ligated [Fe(III)(S(2)(Me2)N(3)(Et,Pr))-S(pers)]PF(6) (2) using PEt(3). (Et,Pr)-3 is structurally related to (Pr,Pr)-ligated [Fe(III)(S(2)(Me2)N(3)(Pr,Pr))]PF(6) (1), a nitrile hydratase model compound previously reported by our group, except it contains one fewer methylene unit in its ligand backbone. Removal of this methylene distorts the geometry, opens a S-Fe-N angle by approximately 10 degrees, alters the magnetic properties by stabilizing the S = 1/2 state relative to the S = 3/2 state, and increases reactivity. Reactivity differences between 3 and 1 were assessed by comparing the thermodynamics and kinetics of azide binding. Azide binds reversibly to both (Et,Pr)-3 and (Pr,Pr)-1 in MeOH solutions. The ambient temperature K(eq) describing the equilibrium between five-coordinate 1 or 3 and azide-bound 1-N(3) or 3-N(3) in MeOH is approximately 10 times larger for the (Et,Pr) system. In CH(2)Cl(2), azide binds approximately 3 times faster to 3 relative to 1, and in MeOH, azide dissociates 1 order of magnitude slower from 3-N(3) relative to 1-N(3). The increased on rates are most likely a consequence of the decreased structural rearrangement required to convert 3 to an approximately octahedral structure, or they reflect differences in the LUMO (vs SOMO) orbital population (i.e., spin-state differences). Dissociation rates from both 3-N(3) and 1-N(3) are much faster than one would expect for low-spin Fe(III). Most likely this is due to the labilizing effect of the thiolate sulfur that is trans to azide in these structures.

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A series of five-coordinate thiolate-ligated complexes [M II (tren)N 4 S Me2 ] + (M = Mn, Fe, Co, Ni, Cu, Zn; tren = tris(2-aminoethyl)amine) are reported, and their structural, electronic, and magnetic properties are compared. Isolation of dimeric [Ni II (SN 4 (tren)-RS dang )] 2 ("dang"= dangling, uncoordinated thiolate supported by H-bonds) using the less bulky [(tren)N 4 S] 1− ligand, pointed to the need for gem-dimethyls adjacent to the sulfur in order to sterically prevent dimerization. All of the gem-dimethyl derivatized complexes are monomeric, and with the exception of [Ni II (S Me2 N 4 (tren)] + , are isostructural and adopt a tetragonally distorted trigonal bipyramidal geometry favored by ligand constraints. The nickel complex uniquely adopts an approximately ideal square pyramidal geometry, and resembles the active site of Ni-superoxide dismutase (Ni-SOD). Even in coordinating solvents such as MeCN, only five-coordinate structures are observed. The M II -S thiolate bonds systematically decrease in length across the series (Mn-S > Fe-S > Co-S > Ni-S ~ Cu-S < Zn-S) with exceptions occurring upon the occupation of σ* orbitals. The copper complex, [Cu II (S Me2 N 4 (tren)] + , represents a rare example of a stable Cu II -thiolate, and models the perturbed "green" copper site of nitrite reductase. In contrast to the intensely colored, low-spin Fe (III)-thiolates, the M(II)-thiolates described herein are colorless to moderately colored, and highspin (in cases where more than one spin-state is possible), reflecting the poorer energy match between the metal d-and sulfur-orbitals upon reduction of the metal ion. As the d-orbitals drop in energy proceeding across the across the series M 2+ (M= Mn, Fe, Co, Ni, Cu), the sulfur-to-metal charge transfer transition moves into the visible region, and the redox potentials cathodically shift. The reduced M +1 oxidation state is only accessible with copper, and the more oxidized M +4 oxidation state is only accessible for manganese.