N-Substituted Derivatives of the Azadithiolate Cofactor from the [FeFe] Hydrogenases: Stability and Complexation

Angamuthu, Raja; Chen, Chi-Shian; Cochrane, Tyler R.; Gray, Danielle L.; Schilter, David; Ulloa, Olbelina A.; Rauchfuss, Thomas B.

doi:10.1021/acs.inorgchem.5b00290

Cited by 19 publications

(24 citation statements)

References 48 publications

(95 reference statements)

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“…The conversion of Complex B into [2Fe] H entails many steps: loss of CO, formation of a [2Fe-2SR] center, and, most remarkable of all, the generation of the adt cofactor. It is well known that adtH 2 and adt 2− are unstable (40), which implies that the cofactor is produced on an Fe 2 template. The 2Fe-2S clusters are well known to mediate the biosynthesis of other organosulfur cofactors (biotin and lipoic acid) (19,41).…”

Section: Effortsmentioning

confidence: 99%

The binuclear cluster of [FeFe] hydrogenase is formed with sulfur donated by cysteine of an [Fe(Cys)(CO) ₂ (CN)] organometallic precursor

Rao

Pattenaude

Alwan

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The enzyme [FeFe]-hydrogenase (HydA1) contains a unique 6-iron cofactor, the H-cluster, that has unusual ligands to an Fe–Fe binuclear subcluster: CN−, CO, and an azadithiolate (adt) ligand that provides 2 S bridges between the 2 Fe atoms. In cells, the H-cluster is assembled by a collection of 3 maturases: HydE and HydF, whose roles aren’t fully understood, and HydG, which has been shown to construct a [Fe(Cys)(CO)2(CN)] organometallic precursor to the binuclear cluster. Here, we report the in vitro assembly of the H-cluster in the absence of HydG, which is functionally replaced by adding a synthetic [Fe(Cys)(CO)2(CN)] carrier in the maturation reaction. The synthetic carrier and the HydG-generated analog exhibit similar infrared spectra. The carrier allows HydG-free maturation to HydA1, whose activity matches that of the native enzyme. Maturation with 13CN-containing carrier affords 13CN-labeled enzyme as verified by electron paramagnetic resonance (EPR)/electron nuclear double-resonance spectra. This synthetic surrogate approach complements existing biochemical strategies and greatly facilitates the understanding of pathways involved in the assembly of the H-cluster. As an immediate demonstration, we clarify that Cys is not the source of the carbon and nitrogen atoms in the adt ligand using pulse EPR to target the magnetic couplings introduced via a 13C3,15N-Cys–labeled synthetic carrier. Parallel mass-spectrometry experiments show that the Cys backbone is converted to pyruvate, consistent with a cysteine role in donating S in forming the adt bridge. This mechanistic scenario is confirmed via maturation with a seleno-Cys carrier to form HydA1–Se, where the incorporation of Se was characterized by extended X-ray absorption fine structure spectroscopy.

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Section: Effortsmentioning

confidence: 99%

The binuclear cluster of [FeFe] hydrogenase is formed with sulfur donated by cysteine of an [Fe(Cys)(CO) ₂ (CN)] organometallic precursor

Rao

Pattenaude

Alwan

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…390 The instability of the normal azadithiols is related to the basicity of the amine. Azadithiols with nonbasic amines are stable.…”

Section: Synthesis Of Diiron(i) Dithiolato Carbonyls From Iron(i) mentioning

confidence: 99%

Synthesis of Diiron(I) Dithiolato Carbonyl Complexes

2016

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Virtually all organosulfur compounds react with Fe(0) carbonyls to give the title complexes. These reactions are reviewed in light of major advances over the past few decades, spurred by interest in Fe2(μ-SR)2(CO)x centers at the active sites of the [FeFe]-hydrogenase enzymes. The most useful synthetic route to Fe2(μ-SR)2(CO)6 involves the reaction of thiols with Fe2(CO)9 and Fe3(CO)12. Such reactions can proceed via mono-, di-, and triiron intermediates. The reactivity of Fe(0) carbonyls toward thiols is highly chemoselective, and the resulting dithiolato complexes are fairly rugged. Thus, many complexes tolerate further synthetic elaboration directed at the organic substituents. A second major route involves alkylation of Fe2(μ-S2)(CO)6, Fe2(μ-SH)2(CO)6, and Li2Fe2(μ-S)2(CO)6. This approach is especially useful for azadithiolates Fe2[(μ-SCH2)2NR](CO)6. Elaborate complexes arise via addition of the FeSH group to electrophilic alkenes, alkynes, and carbonyls. Although the first example of Fe2(μ-SR)2(CO)6 was prepared from ferrous reagents, ferrous compounds are infrequently used, although the Fe(II)(SR)2 + Fe(0) condensation reaction is promising. Almost invariably low-yielding, the reaction of Fe3(CO)12, S8, and a variety of unsaturated substrates results in C–H activation, affording otherwise inaccessible derivatives. Thiones and related C═S-containing reagents are highly reactive toward Fe(0), often giving complexes derived from substituted methanedithiolates and C–H activation.

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“…7 Synthesis of azadithiolato complexes Fe 2 (adt R )(CO) 6 , however, require specialized methods (Scheme 4). Free azadithiols (RN-(CH 2 SH) 2 ) and azadithiolates ([RN(CH 2 S) 2 ] 2− ) are unstable, 31 so these azadithiolates must be constructed on the diiron framework.…”

Section: Diiron Azadithiolates Fe2(adtr)(co)6–xlxmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Diiron Azadithiolates as Models for the [FeFe]-Hydrogenase Active Site and Paradigm for the Role of the Second Coordination Sphere

2015

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CONSPECTUS The [FeFe] hydrogenases (H2ases) catalyze the redox reaction that interconverts protons and H2. This area of biocatalysis has attracted attention because the metal-based chemistry is unusual, and the reactions have practical implications. The active site consists of a [4Fe–4S] cluster bridged to a [Fe2(μ-dithiolate)(CN)2(CO)3]z center (z = 1− and 2−). The dithiolate cofactor is [HN(CH2S)2]2−, called the azadithiolate ([adtH]2−). Although many derivatives of Fe2(SR)2(CO)6–xLx are electrocatalysts for the hydrogen evolution reaction (HER), most operate by slow nonbiomimetic pathways. Biomimetic hydrogenogenesis is thought to involve intermediates, wherein the hydride substrate is adjacent to the amine of the adtH, being bonded to only one Fe center. Formation of terminal hydride complexes is favored when the diiron carbonyl models contain azadithiolate. Although unstable in the free state, the adt cofactor is stable once it is affixed to the Fe2 center. It can be prepared by alkylation of Fe2(SH)2(CO)6 with formaldehyde in the presence of ammonia (to give adtH derivatives) or amines (to give adtR derivatives). Weak acids protonate Fe2(adtR)(CO)2(PR3)4 to give terminal hydrido (term-H) complexes. In contrast, protonation of the related 1,3-propanedithiolate (pdt2−) complexes Fe2(pdt)(CO)2(PR3)4 requires strong acids. The amine in the azadithiolate is a kinetically fast base, relaying protons to and from the iron, which is a kinetically slow base. The crystal structure of the doubly protonated model [(term-H)Fe2(HadtH)(CO)2(dppv)2]2+ confirms the presence of both ammonium and terminal hydrido centers, which interact through a dihydrogen bond (dppv = cis-C2H2(PPh2)2). DFT calculations indicate that this H---H interaction is sensitive to the counterions and is strengthened upon reduction of the diiron center. For the monoprotonated models, the hydride [(term-H)Fe2(adtH)(CO)2(dppv)2]+ exists in equilibrium with the ammonium tautomer [Fe2(HadtH)(CO)2(dppv)2]+. Both [(term-H)Fe2(HadtH)(CO)2(dppv)2]2+ and [(term-H)Fe2(adtH)(CO)2(dppv)2]+ are highly active electrocatalysts for HER. Catalysis is initiated by reduction of the diferrous center, which induces coupling of the protic ammonium center and the hydride ligand. In contrast, the propanedithiolate [(term-H)Fe2(pdt)(CO)2(dppv)2]+ is a poor electrocatalyst for HER. Oxidation of H2 has been demonstrated, starting with models for the oxidized state (“Hox”), for example, [Fe2(adtH)-(CO)3(dppv)(PMe3)]+. Featuring a distorted Fe(II)Fe(I) center, this Hox model reacts slowly with high pressures of H2 to give [(μ-H)Fe2(adtH)(CO)3(dppv)(PMe3)]+. Highlighting the role of the proton relay, the propanedithiolate [Fe2(pdt)-(CO)3(dppv)(PMe3)]+ is unreactive toward H2. The Hox-model + H2 reaction is accelerated in the presence of ferrocenium salts, which simulate the role of the attached [4Fe–4S] cluster. The redox-complemented complex [Fe2(adtBn)(CO)3(dppv)-(FcP*)]n+ catalyzes both proton reduction and hydrogen oxidation (FcP* = (C5Me5)Fe(C5Me4CH2PEt2)).

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N-Substituted Derivatives of the Azadithiolate Cofactor from the [FeFe] Hydrogenases: Stability and Complexation

Cited by 19 publications

References 48 publications

The binuclear cluster of [FeFe] hydrogenase is formed with sulfur donated by cysteine of an [Fe(Cys)(CO) ₂ (CN)] organometallic precursor

The binuclear cluster of [FeFe] hydrogenase is formed with sulfur donated by cysteine of an [Fe(Cys)(CO) ₂ (CN)] organometallic precursor

Synthesis of Diiron(I) Dithiolato Carbonyl Complexes

Diiron Azadithiolates as Models for the [FeFe]-Hydrogenase Active Site and Paradigm for the Role of the Second Coordination Sphere

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N-Substituted Derivatives of the Azadithiolate Cofactor from the [FeFe] Hydrogenases: Stability and Complexation

Cited by 19 publications

References 48 publications

The binuclear cluster of [FeFe] hydrogenase is formed with sulfur donated by cysteine of an [Fe(Cys)(CO) 2 (CN)] organometallic precursor

The binuclear cluster of [FeFe] hydrogenase is formed with sulfur donated by cysteine of an [Fe(Cys)(CO) 2 (CN)] organometallic precursor

Synthesis of Diiron(I) Dithiolato Carbonyl Complexes

Diiron Azadithiolates as Models for the [FeFe]-Hydrogenase Active Site and Paradigm for the Role of the Second Coordination Sphere

Contact Info

Product

Resources

About

The binuclear cluster of [FeFe] hydrogenase is formed with sulfur donated by cysteine of an [Fe(Cys)(CO) ₂ (CN)] organometallic precursor

The binuclear cluster of [FeFe] hydrogenase is formed with sulfur donated by cysteine of an [Fe(Cys)(CO) ₂ (CN)] organometallic precursor