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Structural Conversions of Synthetic and Protein-Bound Iron−Sulfur Clusters R. H. Holm* and Wayne Lo† Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States ABSTRACT: Synthetic iron−sulfur clusters of general formulation [FemSqLl]z with core atoms Fe and S and terminal ligands L constitute a family of molecular clusters with remarkably diverse geometrical and electronic structures. Several structure types are also found in proteins. The large majority of research on these clusters has involved elucidation of physical properties. Here, we direct attention to reactivity in the form of cluster conversions in which the FemSq cores of reactants are transformed to new structures, usually of different nuclearity, in overall reactions such as self-assembly and fragment condensation and dissociation. An extensive body of core conversions, many of which have not been recognized as such, are presented including those in biological systems. All structural core types are depicted, and all core conversions are diagrammatically summarized. Clusters containing the cubane-type Fe4S4 core play a central role in conversion chemistry. The core conversion concept tends to reinforce the description of iron−sulfur cores as modular units subject to various covalent bond interactions that lead to different structures.

CONTENTS 1. Introduction 2. Cluster Conversions 2.1. Intracluster Reactants 2.2. Extracluster Reactants 3. Synthetic Core Conversions: Nuclearities 2, 3, 4 3.1. [Fe2S2]2+,1+ (1) ↔ [Fe4S4]2+ (4) 3.2. [Fe2S2]2+,1+ (1) ↔ [Fe4S6]0 (5) 3.3. Linear [Fe3S4]1+ (2b) → [Fe4S4]2+ (4) 3.4. Cuboidal [Fe3S4]0 (3) ↔ [Fe4S4]2+ (4) 3.5. Linear [Fe3S4]1+ (2b) → [Fe6S9]2− (9a) 3.6. [Fe4S4]2+ (4) → Prismatic [Fe6S6]4+,3+ (6) 3.7. [Fe4S4]2+ (4) → Basket [Fe6S6]2+ (7) 3.8. [Fe4S4]2+ (4) → [Fe8S6]4+ (11) 3.9. [Fe4S4]4+ (4) → [Fe8S7]4+ (13) 3.10. [Fe4S4]1+ (4) → [Fe8S8]0/[Fe16S16]0 (12/14) 4. Synthetic Core Conversions: Higher Nuclearities 4.1. Prismatic [Fe6S6]4+,3+ (6) ↔ [Fe2S2]2+ (1)/ [Fe4S4]2+ (4) 4.2. Prismatic [Fe6S6]3+ (6) → Basket [Fe6S6]2+ (7) 4.3. Prismatic [Fe6S6]4+ (6) → [Fe8S6]5+ (11) 4.4. Basket [Fe6S6]2+ (7) → [Fe4S4]2+ (4) 4.5. [Fe6S9]2− (9a) → [Fe4S4]2+ (4) 4.6. [Fe7S6]3+ (10) → [Fe6S6]2+ (7) 4.7. [Fe7S6]2+ (10) → [Fe8S8]0 (12) 4.8. [Fe8S8]0 (12) ↔ [Fe4S4]1+,0 (4) 4.9. [Fe16S16]0 (14) ↔ [Fe4S4]1+,0 (4) 4.10. α-[Na2Fe18S30]8− (15a) → [Fe4S4]2+ (4) 5. Heterometal Atom Incorporation 5.1. Conversions of Cuboidal and Linear Precursors 5.2. Other Examples © 2016 American Chemical Society

6. Iron−Sulfur−Nitrosyl Clusters 7. Biological Core Conversion 7.1. [Fe4S4]3+,2+,1+ (4) ↔ Cuboidal [Fe3S4]1+,0 (3) 7.1.1. Redox and Metal Ion Transfer 7.1.2. Primary Structure 7.2. Cuboidal [Fe3S4]1+ (3) ↔ Linear [Fe3S4]1+ (2b) 7.3. [Fe4S4]2+,1+ (4) ↔ [Fe2S2]2+,1+ (1) 7.3.1. Nitrogenase Fe Protein 7.3.2. Radical SAM Enzymes 7.3.3. FNR, IscA, and IscU Proteins 7.4. Heterometal Ion Incorporation 8. Comparative Synthetic and Nitrogenase Core Conversions 8.1. Cluster Biosynthesis 8.1.1. P-Cluster Biosynthesis 8.1.2. M-Cluster Biosynthesis 8.2. High-Nuclearity Synthetic Conversions 8.2.1. PN-Cluster 8.2.2. FeMo-Cofactor 9. Core Chalcogenide Exchange and Incorporation 9.1. Protein Reconstitution 9.2. Sulfur/Selenium Exchange 9.3. Selenide as a Surrogate in Synthesis 9.4. Nitrogenase 10. Epilogue 10.1. Addendum 10.1.1. [Fe2S]4+ 10.1.2. [Fe2S2]0 ↔ [Fe4S4]0 Author Information Corresponding Author

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Received: May 5, 2016 Published: November 8, 2016 13685

DOI: 10.1021/acs.chemrev.6b00276 Chem. Rev. 2016, 116, 13685−13713

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Present Address Notes Biographies Acknowledgments Abbreviations References

and vertex-shared Fe2S2 rhombs in two bridging patterns and lacking terminal ligands. Given the often facile variability of terminal ligands L, the core itself is the fundamental compositional and structural component of a cluster. Nineteen distinct core types are encompassed by these limits. A listing of these cores, nearly all of which are implicated in processes that convert one into another, is provided in Table 1 together with numerical designations (1−15), idealized symmetries, bridging sulfur atom connectivities, and iron oxidation states. Schematic structures are presented in Figure 1 including cyclic [Fe3S3]3+, which, although only trinuclear, is the most recently prepared member of the set.10 Numbers refer to core shapes for which there is nearly always more than one oxidation level. For simplicity of description, individual iron atoms are denoted by integral oxidation states but are nearly always electronically delocalized, as represented by mean oxidation states (e.g., Fe2+Fe3+3 = 4Fe2.75+). Note that the collection includes many structure types with multiple oxidation levels represented by core charge n. In all cases, oxidation level changes are largely metal-centered. Cores containing heterometal atoms are included in later sections. As might be expected from the proliferation of soluble iron−sulfur cluster compounds in chemistry and biology, virtually every property, chemical synthesis and reactivity, geometric and electronic structure, oxidation−reduction, and biological function, has been scrutinized in considerable detail. Indeed, structural variability of cluster cores and of protein scaffolds in the vicinity of a cluster has led to circumstantial attributions of “plasticity” to the clusters and their immediate surroundings. There remains another aspect of reactivity, transformation of one cluster core into another, whose chemical and biological significance has not always been appreciated. This property has been mentioned and sometimes illustrated in previous brief accounts addressing mainly biological systems.3,11−16 It is, in fact, a unifying component of iron−sulfur cluster structural diversity and reactivity. We single out cluster conversion, whose delineation here provides a more current and extensive treatment of the subject. Because of our interest in reactivity, we exclude from consideration alkali metal sulfidoferrates ([Fe2S6]6− and

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1. INTRODUCTION The principal distinguishing feature of the family of metal clusters composed of iron atoms with sulfide bridges is its compositional and structural diversity, exceeded among molecular clusters only by the vast iron-oxo/hydroxo family. With reference to previous nomenclature,1 iron−sulfur clusters [FemSqLl]z with charge z contain core units [FemSq]n of nuclearity m, bridging atoms q with connectivities μ2−6-S, and charge n to which are normally appended l terminal ligands L. A significant fraction of such clusters can be classified according to the nature of L. When L is a π-acceptor such as CO, NO, or C5H5− and its derivatives,2 the clusters are of the strong-field type and are expected to be structurally more robust than those with L σ/π donor ligands such as RS−, RO−, or halide.1,3,4 Weak-field clusters contain sites with smaller splittings of the d-orbital manifold, leading often to paramagnetism and enhanced core and terminal ligand lability. Clusters are accessible by chemical synthesis,1,3−5 and certain weak-field species, notably those with [Fe2S2], [Fe3S4], and [Fe4S4] core units, are also the products of biosynthesis.6 In this Review, we are concerned with selected reactivity features of both synthetic and biological weak-field clusters. Multiformity in the iron−sulfur molecular cluster family is readily recognized by nuclearities ranging from m = 2 to 18 and bridging sulfur (sulfide) atoms in the range q = 1−30. Systems with other types of anionic sulfur bridges (e.g., HS−, RS−, S22−) are not included. The family is delimited at the low-nuclearity end by the nonlinear and rhomboidal cores [Fe2S]7 (see Addendum) and [Fe2S2],3 respectively, and at the highnuclearity end by cyclic [Na2Fe18S30]8−,8,9 built up of edgeTable 1. Iron−Sulfur Weak-Field Cluster Cores no.

shape

symmetrya

core

Fe oxidation states

1 2a 2b 3 4 5 6 7 8 9a 9b 9c 10 11 12 13 14 15a 15b

rhombic cyclic linear dirhombic cuboidal cubane linear trirhombic prismatic basket octahedral fused octarhombic fused tetrarhombic fused trirhombic monocapped prismatic rhombic dodecahedral edge-bridged DCb sulfur-bridged DCc edge-bridged TCd cyclic polyrhomb (α)f cyclic polyrhomb (β)f

C2h D3h D2d C3v Td D2h D3d C2v Oh C2v C2v Cie C3v Oh C2h D3d D4 Ci Ci

[Fe2(μ2-S)2]2+,1+,0 [Fe3(μ2-S)3]3+ [Fe3(μ2-S)4]1+ [Fe3(μ2-S)3(μ3-S)]1+,0,1− [Fe4(μ3-S)4]4+,3+,2+,1+,0 [Fe4(μ2-S)6]0 [Fe6(μ3-S)6]4+,3+ [Fe6(μ2-S)(μ3-S)4(μ4-S)]2+ [Fe6(μ3-S)8]3+,2+,1+,0 [Fe6(μ2-S)6(μ3-S)2(μ4-S)]2− [Fe4(μ2-S)4(μ4-S)]0 [Fe4(μ2-S)2(μ3-S)2]2+ [Fe7(μ3-S)3(μ4-S)3]3+,2+ [Fe8(μ4-S)6]5+,4+ [Fe8(μ3-S)6(μ4-S)2]2+,0 [Fe8(μ3-S)6(μ6-S)]5+,4+ [Fe16(μ3-S)8(μ4-S)8] [Fe18(μ4-S)2(μ3-S)8(μ2-S)20]10− [Fe18(μ3-S)12(μ2-S)18]10−

Fe3+2, Fe3+Fe2+, Fe2+2 Fe3+3 Fe3+3 Fe3+3, Fe2+Fe3+2, Fe2+2Fe3+ Fe3+4, Fe3+3Fe2+, Fe3+2Fe2+2, Fe3+Fe2+3, Fe2+4 Fe3+4 Fe3+4Fe2+2, Fe3+3Fe2+3 Fe3+2Fe2+4 Fe4+Fe3+5, ..., Fe3+4Fe2+2 Fe3+4Fe2+2 Fe3+2Fe2+2 Fe3+2Fe2+2 Fe3+Fe2+6, Fe2+7 Fe3+Fe2+7, Fe2+8 Fe3+2Fe2+6, Fe2+8 Fe3+3Fe2+5, Fe3+2Fe2+6 Fe2+16 Fe3+14Fe2+4 Fe3+14Fe2+4

a

Idealized. bEdge-bridged double cubane. cSulfide-bridged double cubane. dEdge-bridged tetracubane. eStair-like configuration. fStructural isomers, no terminal ligands. 13686


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Figure 1. Depictions of the core structures [FemSq]n (1−15a) of weak-field iron−sulfur clusters, some of which (1, 2b−4, 13) are found in proteins. Accessible oxidation states n are indicated. Not shown is β-[Na2Fe18S30]8−, a bond isomer of 15a with a very similar overall shape.

[Fe4S10]8−, among others),17,18 whose cluster anions follow similar structural principles but whose solubilities direct their chemistry to the solid state.

2.2. Extracluster Reactants

These involve transformations conducted in the presence of an initial cluster and added reactants, which, among other roles, may function as inner-sphere redox reagents or as core or terminal ligands in the product cluster. If a reactant is a mononuclear metal complex or a metal cluster containing atom(s) M, one or more of these atoms may be incorporated into the final product. Bridging or terminal ligands of the original cluster are sometimes reactants and are subject to elimination or substitution. These two reaction types are subsumed in the four principal methods of cluster synthesis summarized below and in more detail elsewhere.1,19 (i) Self-Assembly: Spontaneous assembly of clusters from simple mononuclear precursors proceeding in one overall process. (ii) Fragment Condensation: Combination of a preexisting dior polynuclear cluster with itself or with another mononuclear or polynuclear species to form a higher nuclearity cluster.

2. CLUSTER CONVERSIONS As employed here, the term cluster conversion refers to any process by which an iron−sulfur cluster core is converted to another core with or without retention of composition and nuclearity, in a single or multistep process. This broad definition and several subsidiary points are compatible with prior usage of the term by others, which has been in general undefined. There are two limiting types of conversion reactions based on reactants. 2.1. Intracluster Reactants

These reactants involve transformations of an initial cluster [FemSqLl]z to a product cluster [FeaSbLc]y whose core contents FeaSb derive entirely from the initial reactant. When m = a and q = b, the reactant and product contain isomeric core structures. Terminal ligands and oxidation levels may vary. 13687


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Table 2. Conversions of Synthetic Clusters of Nuclearities 2, 3, and 4 reaction

core conversion 2+,1 +

[Fe2S2] (1) (2) (3) (4)

2−

2[Fe2S2 (SR)4 ]

3−

2[Fe2S2 (SR)4 ] 2−

(1) ↔ [Fe4S4 ] (4)

↔ [Fe4 S4 (SR)4 ]2 − + 2RS− + RSSR 2−

↔ [Fe4S4 (SR)4 ] +

2−

2−

22−24 2−

↔ [Fe4S4 I4]

3[Fe2S2I4]

2−

+ 2[FeI4]

[Fe2S2]

(6)

+ 4RS

+ 2[Cp2 Fe] + 4Cl → 2[Fe2S2 Cl4]

[Fe4S4 Cl4]

2−

2[Fe2S2 (SR)4 ]

20, 21

−

−

2+,1 +

(5)

refs 2+

+ 2[Cp2 Fe]

25

+ 2S

26 0

(1) ↔ [Fe4S6] (5)

+ 2S ↔ [Fe4 S6(SR)4 ]4 − + 2RSSR 3−

[Fe2S2 (SC6H4‐2‐CO2 )2 ]

27 4−

→ [Fe4S6(SC6H4‐2‐CO2 )2 ] 1+

28

2+

Linear [Fe3S4 ] (2b) ↔ [Fe4S4 ] (4) 3−

(7)

[Fe3S4 (SEt)4 ]

+ FeCl 2 + NaSEt

23

↔ [Fe4 S4 (SEt)4 ]2 − + 1/2EtSSEt + NaCl + Cl−

Cuboidal [Fe3S4 ]0 (3) ↔ [Fe4S4 ]2 + (4) (8) (9)

[Fe3S4 (LS3)]3 − + FeCl 2 → [Fe4S4 (LS3)Cl]2 − + Cl− 2−

+ 2[Meida]

3−

+ [Fe(Meida)2 ]2 − + EtS−

[Fe4 S4 (LS3)(SEt)]

29

2−

→ [Fe3S4 (LS3)]

29

Linear [Fe3S4 ]1 + (2b) → [Fe6S9]2 − (9a) (10)

[Fe3S4 (SEt)4 ]3 − → [Fe6S9(SEt)2 ]4 −

23

2+

4+,3 +

[Fe4S4 ] (4) ↔ Prismatic [Fe6S6] (11)

2−

3[Fe4S4 Cl4]

2−

(12)

3[Fe4S4 X4]

−

3−

+ 12NaOAr ↔ 2[Fe6S6(OAr)6 ] +

2−

+ 2[Cp2 Fe] ↔ 2[Fe6S6X 6] −

(6)

+ 12NaCl

30

+ 2[Cp2 Fe]

31

−

(X = Cl , Br , I ) (13)

1.5[Fe4S4 I4]2 − + Fe + 2I 2 ↔ [Fe6S6I6]2 − + [FeI4]1 − 2+

26, 32

2+

[Fe4S4 ] (4) → Basket [Fe6S6] (7) 2−

+ PR3 → [Fe6S6(PR3)4 I 2]

(14)

[Fe4 S4 I4]

(15)

[Fe4 S4 (Stip)2 {SC(NMe2)2 }2 ] + PR3 → [Fe6S6 (PR3)4 (Stip)2 ]

(16) (17)

2−

[Fe4S4 I4]

2−

[Fe4S4 L4]

33 33

−

+ FeI 2 , I , R3P → [Fe6S6(PR3)4 I 2] + [Fe(PEt 3)2 L 2] → [Fe6S6(PEt 3)4 L 2] 2+

34 −

−

(L = Cl , PhS )

35−37

4+

[Fe4S4 ] (4) → [Fe8S6] (11) (18)

2−

[Fe4S4 I4]

+ [FeI 2(PR3)2 ] → [Fe8S6I8]4 − + PR3 4+

34, 38

4+

[Fe4S4 ] (4) → [Fe8S7] (13) (19)

2[Fe4 S4 {N(SiMe3)2 }4 ] + 2R3P → [Fe8S7 {N(SiMe3)2 }4 (SPR3)2 ]a + 2R3PS

39, 40

[Fe4S4 ]1 + (4) ↔ [Fe8S8]0 /[Fe16S16]0 (12/14) (20)

2[Fe4 S4 (PR3)4 ]1 + + 2(Ph 2CO)− → [Fe8S8(PR3)6 ] + 2Ph 2CO + 2R3P

41

(21)

4[Fe4S4 (PR3)4 ] → 2[Fe8S8(PR3)6 ] + 4R3P ↔ [Fe16S16(PR3)8 ] + 8PR3

41

1+

2+

[Fe4S4 ] (4) ↔ [Fe8S8] (12) (22) a

i

2[Fe4 S4 (PPr 3)3 (SSiPh3)] ↔ [Fe8S8(PPr i 3)4 (SSiPh3)2 ] + 2PPr i 3

41

Two bridging μ2-N(SiMe3)2 groups.

(iii) Core Rearrangement: Transformation of a preexisting cluster to a different core geometry with retention of nuclearity. (iv) Fragmentation: Transformation of a preexisting cluster to a lower nuclearity cluster that ideally is a discernible substructure of the parent cluster.

For a process to qualify as a core conversion in the present context, at least one of the initial reactants must be an iron−sulfur cluster. If the shape or nuclearity of the product is different from the reactant, the initial cluster core must be augmented, diminished, or otherwise altered at some stage of the synthesis. Reactions that result in terminal ligand substitution only with 13688


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Table 3. Conversions of Precursor Synthetic Clusters of Nuclearities 6, 7, 8, and 15 reaction

core conversion 4+,3 +

[Fe6S6] (23) (24) (25)

2−

refs

2+

2+

(6) ↔ [Fe2S2] (1)/[Fe4S4 ] (4)

−

+ 2I ↔ [Fe4S4 I4]2 − + [Fe2S2 I4]2 −

[Fe6S6I6]

3−

−

2−

−

+ L ↔ [Fe4 S4 L4]

[Fe6S6Cl 6]

3−

2[Fe6S6Cl 6]

26 −

−

−

−

(L = Cl , Br , I , PhO , PhS )

2−

↔ 3[Fe4S4 Cl4]

44 45

3+

2+

[Fe6S6] (6) → [Fe6S6] (7) (26)

3−

+ [Fe(PEt 3)2 Cl 2] → [Fe6S6(PEt 3)4 Cl 2]

[Fe6S6Cl 6]

4+

35

5+

[Fe6S6] (6) → [Fe8S6] (11) (27)

2−

+ 2Fe + I− + I 2 → [Fe8S6I8]3 −

[Fe6S6I6]

38

2+

2+

[Fe6S6] (7) → [Fe4S4 ] (4) (28)

[Fe6S6(PEt 3)4 Cl 2] + X − → [Fe4S4 X4]2 −

(X = Cl−, RS−)

2−

35

2+

[Fe6S9] (9a) → [Fe4S4 ] (4) (29)

t

4−

[Fe6S9(SBu )2 ]

+ PhSH → [Fe4S4 (SPh)4 ]2 − 3+

46 2+

[Fe7S6] (10) → [Fe6S6] (7) (30)

[Fe7S6(PEt3)4 Cl3] → [Fe6S6(PEt 3)4 Cl 2]

35, 37

2+

0

[Fe7S6] (10) → [Fe8S8] (12) (31)

[Fe7S6(PEt3)5 Cl 2] + Pr i 2NHCMe2 → [Fe8S8(Pr i 2NHCMe2)6 ] 1+,0

0

[Fe8S8] (12) ↔ [Fe4S4 ]

47

(4)

(32)

[Fe8S8(Pr i 2NHCMe2)6 ] + 2Pr i 2NHCMe2 ↔ 2[Fe4S4 (Pr i 2NHCMe2)4 ]

47

(33)

[Fe8S8(PPr i 3)6 ] + 8Pr i 2NHCMe2 → 2[Fe4 S4 (Pr i 2NHCMe2)4 ] + 6PPr i 3

47

(34)

[Fe8S8(PPr i 3)6 ] + 2PPr i 3 + 2[Cp2Fe]1 + → 2[Fe4S4 (PPr i 3)4 ]1 + + 2[Cp2Fe]

48

i

(35)

−

1+

[Fe8S8(PPr 3)6 ] + 2R3SiO + 2[Cp2 Fe]

48

→ 2[Fe4S4 (PPr i 3)3 (OSiR3)] + 2[Cp2Fe]

[Fe16S16]0 (14) ↔ [Fe4S4 ]1+,0 (4) (36) (37)

[Fe16S16(PPr i 3)8 ] + 16Pr i 2NHCMe2 ↔ 4[Fe4 S4 (Pr i 2NHCMe2)4 ] + 8PPr i 3 i

i

i

[Fe16S16(PPr 3)8 ] + 2X 2 + 4PPr 3 ↔ 4[Fe4 S4 (PPr 3)3 X] 8−

47 48

2+

α‐[Na 2Fe18S30] (15a) → [Fe4S4 ] (4) (38)

8−

α‐[Na 2Fe18S30]

+ [Fe(SR)4 ]2 − → [Fe4S4 (SR)4 ]2 − + Na +

8

and heterometallic cases in Figure 3. They may be compared to earlier, less inclusive, schemes in 1997 and 2004.3,12 Conversions are detected by familiar techniques including UV/visible, EPR, resonance Raman, VTMCD, and XAS spectroscopies, crystallography, and electrochemistry. Alone or in combination, these methodologies provide in nearly all cases an unambiguous definition of the conversion product. In the tables that follow, citations of both synthetic and protein-based cluster conversions are extensive but not exhaustive. However, all recognized conversion types are included. All reactions or reaction systems were performed anaerobically and nearly all at room temperature. Double-headed arrows refer to systems that are, or are likely to be, “reversible” in the sense that two cluster cores can be converted by a forward and reverse reaction but not necessarily in the same system. Single-headed arrows denote irreversible processes. The extent of deconstruction of initial or intermediate clusters in the course of the conversion reaction has not been experimentally established in any case. Cluster formations from reactive mononuclear precursors such as [Fe(SR)4]1−,2− or the cage (i.e., noncluster)

retention of the core are considered cluster variations rather than core conversions. Synthetic cluster conversion processes in homogeneous or heterogeneous systems are summarized in Tables 2 and 3 in order of increasing nuclearity of the initial cluster. They are termed reactions or reaction systems (1)−(38), with the former applicable to the minority cases where there is sufficient information to identify all reactants and to formulate stoichiometrically balanced equations. In other cases, only the reactants and cluster products are specified. Processes are qualified as conversions on the basis of the essentiality of an initial cluster reactant and demonstration of a cluster product (excluding trace amounts), without determination of yield and information on the disruption of reactant cluster(s), although this is often necessary to product formation. Because the principal interest is in the formation of homometallic clusters, mononuclear iron species are included as reactants in Tables 2 and 3. The few examples of heterometallic clusters formed from an iron−sulfur reactant and a heterometallic species are collected in Table 4. Schemes depicting homometallic core formation are presented in Figure 2 13689


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Figure 2. Schematic representation of core conversion reactions of iron−sulfur clusters. Note the central position of cubane 4 in the scheme. Red arrows denote some of the conversions not proceeding through an isolated cluster 4.

complexes [Fe4(SR)10]2−23,42,43 as the only iron reactants are numerous but are outside the purview of core conversion. While usually insufficient for incisive descriptions, information for reactions or systems nonetheless provides a starting point for future improved conversions and mechanistic studies. Depictions of initial and final clusters involved in conversions are confined to their cores (Figures 2−4). These define cluster shapes and sites of terminal ligand binding. In general, cores are built by edge- and/or vertex-sharing of Fe2S2 rhombs. When terminally ligated, nearly all clusters display distorted tetrahedral coordination units (coordination in 8 is more nearly square pyramidal). The information that follows does not extend to detailed structural descriptions of cluster cores, which may be found in the Cambridge Structural Database and for proteinbound clusters in the Protein Data Bank. In addition, we have provided a recent detailed structural analysis and an extensive metric database of the cubane-type cores 4.49 Reactions of initial clusters of nuclearities 2−4 and higher are contained in Tables 2 and 3, respectively. A schematic overview of cluster conversions is presented in Figure 2. In the following sections, the term “core” is used to denote the core itself or occasionally an entire cluster, as appropriate.

3. SYNTHETIC CORE CONVERSIONS: NUCLEARITIES 2, 3, 4 3.1. [Fe2S2]2+,1+ (1) ↔ [Fe4S4]2+ (4)

Reactions (1) and (2), reported nearly 40 years ago,20 are the first established iron−sulfur core conversions of any type. Reaction (1) is a redox process in which thiolate bound to oxidized [Fe2S2]2+ core 1 is the initial reductant. A cluster such as [Fe2S2(SPh)4]2−, whose core is stable in aprotic solvents and in partially aqueous media (e.g., 80% Me2SO/H2O), slowly converts to a [Fe4S4]2+ cluster product with cubane core 4. Solvent-assisted thiolate dissociation, reduction by thiolate, and coupling of reduced dinuclear species is a possible overall twoelectron pathway, but the detailed steps are unknown. Conversion is in effect a dimerization of two unknown fragments [Fe2S2(SR)2]1−. Reaction (2) is interpretable as a nonredox dimerization of a fragment such as [Fe 2 S 2(SR)3 ]2− or [Fe2S2(SR)2]1− with liberation of 4 equiv of thiolate. Note that the [Fe2S2]1+ oxidation state 1 with only thiolate ligation has not been generated or isolated. This state has thus far been stabilized only with one or two nonthiolate chelating ligands.50−53 Both reactions are likely driven by formation of the [Fe4S4]2+ oxidation state, the most stable redox level of the tetranuclear cores [Fe4S4]n (n = 0 to 4+) and a thermodynamic sink in iron−sulfur− thiolate reaction chemistry. Reactions (1) and (2) are nearly 13690


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Reaction (5) is the only example of a single rhomb to linear trirhombic core conversion in solution. 3.3. Linear [Fe3S4]1+ (2b) → [Fe4S4]2+ (4)

In the presence of a thiolate reductant, linear cluster [Fe3S4(SEt)4]3− is capable of binding FeII. Reaction (7) results in a one-electron reduction of the all-ferric core of 2b to the notably stable cubane core 4 in high yield. This is one of many examples of spontaneous formation of the [Fe4S4]2+ oxidation level as a stability sink, particularly under reducing conditions. Reaction (7) is the only example of a dirhombic to cubane conversion, summarized as [Fe3S4]1+ + Fe2+ + e− ↔ [Fe4S4]2+. 3.4. Cuboidal [Fe3S4]0 (3) ↔ [Fe4S4]2+ (4)

Reaction (8) differs fundamentally from reaction (7) but yields the same isoelectronic core 4. Initial core 3 is 1e− more reduced than 2b and is stabilized in a cuboidal configuration by the semirigid trithiolate ligand LS3.55,56 The reaction proceeds by the nonredox capture of Fe2+ in a voided site of 3 and terminal ligand binding. With a small excess of [FeCl4]2− or FeCl2, reaction (8) in acetonitrile is quantitative. Reaction (9) proceeds by removal of Fe2+ as [Fe(Meida)2]2− by chelation and affords cluster 3 in ca. 75% overall yield. Together, reactions (9) and (8) lead to formation of cubane-type 4 and cuboidal 3. These reactions are summarized as the nonredox process [Fe3S4]0 + Fe2+ ↔ [Fe4S4]2+. Reaction (9) is the original method for preparation and isolation of clusters containing the cuboidal core.29

Figure 3. Heterometal atom incorporation reactions of cores 2b and 3 leading to clusters 16, and of cores 1, 2b, 4, and 6 affording rhombic dodecahedral clusters 17. Metals incorporated in 17 are indicated; see also Table 4.

3.5. Linear [Fe3S4]1+ (2b) → [Fe6S9]2− (9a)

Reaction (10) at elevated temperature in acetonitrile results in the low-yield formation of a hexanuclear cluster with core 9a containing eight fused Fe 2 S 2 fragments in idealized C 2v symmetry. Linear core 2b has been disrupted in the formation of this high-nuclearity cluster, which includes 2b, 3, and 5 as recognizable substructures but with different bridge atom connectivities as compared to the cores themselves. Isolation of 9a is aided by the lesser solubility of its Et4N+ salt (32% yield). The cluster is more conveniently prepared by self-assembly reactions with as yet unresolved fragment condensation steps.46,57,58 The preparation of 15ab is another instance of the structural unpredictability of FeII,III and sulfide in combination, the only evident restrictions being tetrahedral FeS4 coordination units and the avoidance of high negative cluster charge.

quantitative in acetonitrile solutions. Reaction (3) in effect is the spontaneous reverse of reaction (1), in which a [Fe4S4]2+ cubane core is oxidized by two electrons in the presence of redox-inactive chloride as a terminal ligand stabilizing the binuclear product. Last, reaction (4) of iodide clusters, which corresponds to a fourelectron reduction of the initial iron content, has been proposed from spectrophotometric observations. As will be seen, the conversions [Fe4S4]2+ ↔ [Fe2S2]2+ are well-documented in biological systems (section 7.3). 3.2. [Fe2S2]2+,1+ (1) ↔ [Fe4S6]0 (5)

Oxidative coupling of two dinuclear complexes with sulfur in reaction (5) results in the generation of sulfide (4EtS− → 2EtSSEt + 2S2−), which is captured by FeIII with displacement of thiolate. The product, isolated in low yield, is the tetranuclear cluster [Fe4S6(SEt)4]4− whose all-ferric core 5 consists of three planar vertex-shared [Fe2(μ2-S)2] rhombs arranged in D2h symmetry. The location of the sulfide produced in the reaction is not known and is likely scrambled over several positions. Very recently, a second example of this structure was discovered upon attempted recrystallization of the reduced dimer in system (6) from acetonitrile/ether. A crystalline Et4N+ salt of a linear tetraferric cluster was identified by crystallography, demonstrating core 5 stabilized as the bis(2-mercaptobenzoate) chelate. Dimensions of the cores in the two complexes are nearly identical to each other and to earlier linear [Fe2S2(SR)4]2− and [Fe3S4(SR)4]3− clusters.3,4,54 Interestingly, these complexes are the three lowest homologues in the series in which [FeIII(μ2-S)2] units with two, three, and four iron atoms are arranged linearly in rhombs. The limit to this series to three soluble compounds is unknown but may be truncated at higher nuclearities by reductive elimination of thiolate and conversion to cyclic (or otherwise more condensed) structures like 15a (Figure 1).

3.6. [Fe4S4]2+ (4) → Prismatic [Fe6S6]4+,3+ (6)

The prismane core 6 was first obtained by self-assembly methods after the preparation of 1 and 4.31,44,45 Thereafter, core conversions such as reactions (11)−(13) were developed, allowing ready access to this fundamental core geometry. In all cases, the cubane-type core must be disrupted to form a species of higher nuclearity. Additionally, reaction (11) involves ligand substitution to yield [Fe6S6]3+, whereas reactions (12) and (13) require partial oxidation of the iron reactants to achieve the [Fe6S6]4+ oxidation level. These reactions are among the early examples of the cubane to prismane conversion. 3.7. [Fe4S4]2+ (4) → Basket [Fe6S6]2+ (7)

Core 7 is a geometrical isomer of prismane core 6 and was originally prepared by self-assembly35 and later by cubane conversion reactions (14)−(17). Like 6 and 10, it is an example of an iron−sulfur cluster containing a Fe3(μ2,3-S)3 face. Basket core formation requires a tertiary phosphine with a cone angle near that of PEt3 (132°) and anionic terminal ligands. Although cores 6 and 7 have been obtained from conversion reactions of a common cluster precursor (e.g., [Fe4S4Cl4]2−), they have never 13691


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Figure 4. Cluster conversion scheme for iron−sulfur−nitrosyl clusters 18−28 including schematic structures and reactions.49,87−95

Fe4S3 cuboidal fragment (the inverse of 3) as a probable intermediate. Reaction of the fragment with an intact core in a subsequent step forms a double cubane containing as its most prominent feature a shared μ6-S vertex. The overall reaction requires a four-electron reduction of 2 equiv of cluster reactant (2[Fe4S4]4+ + R3P + 4e− → [Fe8S7]4+ + R3PS). A possible pathway has been proposed.5,39 Two sulfur-bridged double cubane clusters of the type [Fe 8 S 7 {μ 2 -N(SiMe) 2 } 2 {N(SiMe3)2}2L2] (L = SPEt3, SC(NMe2)2) have been isolated. Consistent with the definition of iron−sulfur cores, the two silylamido bridges that span iron atoms in opposite halves connected by μ6-S are omitted in 13 but are doubtless necessary for stability. These clusters are of particular interest because 13 is the core structure of the PN cluster of nitrogenase (section 8.1).63,64 The biosynthetic cluster also contains two μ2-S·Cys bridges connecting the two halves of the cluster. These clusters bear a structural relation to the interstitial sulfide-bridged double cubanes [Fe8(μ3-S)6(μ6-S)(μ2-SR)2(μ2-SR′)(SR)2],65 which have a similar core topography and include one μ6-S atom and three thiolate bridges linking the two halves (39, Figure 9). These clusters were not obtained by cluster conversion.

been interconverted because of differences in oxidation state and the phosphine ligand requirements for stability of 7. This work provides the only examples of cubane to basket conversion. 3.8. [Fe4S4]2+ (4) → [Fe8S6]4+ (11)

Reaction (18) is an impressive core conversion in which a cubane cluster is converted to an [Fe8(μ4-S)6] cluster in a single operation utilizing a mononuclear ferrous reactant. This process requires reduction to the all-ferrous level. The product core 11 contains an FeII8 cube whose faces are capped by six sulfur atoms in an arrangement close to Oh symmetry. Discrete M8S6 clusters are not common; the structure is similar to rhombic dodecahedral [Co8S6(SPh)8]4−59 and [Fe8S6I8]3−58 and is the inverse of [Fe6S8(PEt3)6]2+,1+,0,60−62 which are examples of 8. The optimized preparation uses excess FeI2 and leads to isolation as the Et4N+ salt (∼40%). Under slightly different reaction conditions, the basket cluster [Fe6S6(PR3)4I2] has been obtained.34 3.9. [Fe4S4]4+ (4) → [Fe8S7]4+ (13)

Clusters containing core 13 can be prepared in toluene by selfassembly or by conversion reaction (19) in which the reactant cluster is the only example of the all-ferric core [Fe4S4]4+. Sulfide is likely removed from a cluster as S0 in an uncommon twoelectron reaction (R3P + S2− → R3PS + 2e−), which generates a 13692


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3.10. [Fe4S4]1+ (4) → [Fe8S8]0/[Fe16S16]0 (12/14)

4.4. Basket [Fe6S6]2+ (7) → [Fe4S4]2+ (4)

Treatment of the clusters [Fe4S4(PR3)4]1+ with a strong reductant such as sodium benzophenone ketyl radical anion in reaction (20) generates the all-ferrous [Fe4S4]0 core whose phosphine ligands are labile. Clusters interact with loss of phosphine in reaction (21) to form the readily isolable edgebridged double cubane 12. The equilibrium steps can be manipulated with solvent and phosphine concentration to allow isolation of 12 and the edge-bridged tetracubane 14, which are less soluble than the other clusters in system (21). Phosphines are displaceable in [Fe4S4]1+ clusters by ligands such as Ph3SiS−, leading to the isolation of the [Fe8S8]2+ core in reaction (22) with retention of the edge-bridged double cubane motif. Reactions (21) and (22) proceed in good yields in solvents such as acetonitrile/ether; they are almost certainly cluster conversion reactions of the intact core structures 12 and 14. The reaction system with R = PPri3 has been worked out in detail with isolated yields of 55−75%.41 It should be noted that these reactions are the only two routes to the fully reduced and isolable [Fe4S4]0 clusters.47,66

Reaction of halide or thiolate with a typical basket cluster displaces phosphine, which is essential to stability of core 7, and leads to a basket to cubane conversion. Results are limited, but reactions such as (28) afford ca. 20−50% yields. 4.5. [Fe6S9]2− (9a) → [Fe4S4]2+ (4)

The fused octarhombic cluster [Fe6S9(SBut)2]2− undergoes ligand substitution with 2 equiv of benzenethiol to form [Fe6S9(SPh)2]4−. With a large excess of thiol, UV/visible and 1 H NMR spectra are developed similar to those of authentic [Fe4S4(SPh)4]2−. Consequently, in reaction system (29), the relatively acidic thiol fractures core 9a, presumably by proton transfer, leading to the cubane core 4 as the dominant product. 4.6. [Fe7S6]3+ (10) → [Fe6S6]2+ (7)

The starting cluster [Fe7S6(PEt3)4Cl3], with a monocapped trigonal prismatic core 10 of C3v symmetry, was prepared by selfassembly with a tertiary phosphine as an essential reactant. Phosphine and chloride ligands are attached to separate Fe3(μ3S)3 rings.69 Reaction 30 (Table 3) requires oxidation of the initial cluster and proceeds in good yield in situ in chloroform. Again, a phosphine-containing system affords a basket cluster product.

4. SYNTHETIC CORE CONVERSIONS: HIGHER NUCLEARITIES

4.7. [Fe7S6]2+ (10) → [Fe8S8]0 (12)

4.1. Prismatic [Fe6S6]4+,3+ (6) ↔ [Fe2S2]2+ (1)/[Fe4S4]2+ (4)

Under preparative conditions similar to those for [Fe7S6(PEt3)4Cl3], the one-electron reduced core 10 was isolated as [Fe7S6(PEt3)5Cl2].47 This compound serves as a useful precursor to clusters containing the all-ferrous cores [Fe4S4]0 (4) and [Fe8S8]0 (12). With the N-heterocyclic carbene Pri2NHCMe2, reaction (31) results in the conversion of a monocapped prismatic cluster to an edge-bridged double cubane cluster (52%).

The prismane clusters 6 are precursors in a variety of conversion reactions, among them (23)−(25) (Table 3). Equilibrium (23) and core disruption (24) reactions may proceed through a [Fe2S2]1+ intermediate. The efficient and unique reaction (25), which requires no reactant other than the original [Fe6S6]3+ cluster, is reported to proceed in quantitative yield. Collective observations indicate that prismane clusters tend to verge on metastability, and their isolation can be cation-dependent. These clusters are reactive to ligand substitution with both core retention and deconstruction. Unlike other thiolate-ligated clusters, the prismane cluster [Fe6S6(SPh)6]3− is unstable and readily forms [Fe4S4(SPh)4]2− in solution, whereas phenoxidetype ligands stabilize [Fe6S6]3+.44 Note that cubanes are both precursors to reactions (11)−(13) and products of prismanes in cluster conversions. Further considerations of reactivity and related properties are available.44,67,68

4.8. [Fe8S8]0 (12) ↔ [Fe4S4]1+,0 (4)

Double cubanes 12 are readily cleaved by excess carbene in reactions (32) (63%) and (33) (nearly quantitative) or with a variety of other ligands in the presence of a suitable oxidant to afford the cubane clusters 4 in the all-ferrous or one-electron oxidized state (20−50%). Reactions (32)−(35) are further examples of double to single cubane conversions leading to 4 in two different oxidation states. 4.9. [Fe16S16]0 (14) ↔ [Fe4S4]1+,0 (4)

4.2. Prismatic [Fe6S6]3+ (6) → Basket [Fe6S6]2+ (7)

This conversion retains core content but involves an isomeric structural change from prismatic to the basket configuration. The prismane (6) to basket (7) core conversion can be made directly by reaction (26) in 70% yield. This reaction requires reduction of the initial core by one electron, presumably furnished by the FeII reactant. Together with self-assembly, this is one of the first routes to basket clusters. It joins reactions (14)−(17) as means of access to basket core 7 with appropriate phosphines. Anionic ligands in these clusters are readily varied by metathesis of the chloride cluster with sodium salts. While this reaction demonstrates the prismane to basket transformation, a method to interconvert the two structures with the same or nearly the same ligand set has not been devised.

Reaction (36) is the overall conversion of a tetracubane to a cubane cluster in the all-ferrous oxidation state. The reaction is quantitative with excess carbene, which has a stronger binding affinity than does phosphine toward the iron sites.47 Reactions (35) and (37) provide entry to a significant class of 3:1 sitedifferentiated cubane clusters that are oxidized by one electron. The [Fe4S4(PPri3)4]1+ cluster is prone to substitution with anions X− to afford [Fe4S4(PPri3)3X]. Reactions (36) and (37) resulting in single cubane products have been performed primarily with the tetracubane 14. Given the probable occurrence of an equilibrium analogous to (21), double cubanes are likely reactants as well. Reactions (32)−(37) emphasize the efficacy of double and tetracubanes in the preparation of reduced single cubanes.

4.3. Prismatic [Fe6S6]4+ (6) → [Fe8S6]5+ (11)

4.10. α-[Na2Fe18S30]8− (15a) → [Fe4S4]2+ (4)

Reaction (27) at 60 °C assembles an iodide cluster with an idealized octahedral core 11 as the Et4N+ salt (40%). It and reaction (18) result in core expansion, conceptually by capping opposite sides of the prismatic core 6 with iron atoms. At present, these are the only two methods for preparation of these uncommon [Fe8S6]5+,4+ clusters.

The cyclic cluster [Na2Fe18S30]8− exists in two isomeric forms (α, β) differing in Fe−S bond connectivities.8,9 The arrangement of the α-form is depicted as 15a. These species are assembled in systems that apparently form the green linear chain polymer {[FeS2]1−}n as an intermediate. Lacking terminal ligands, they differ from all other discrete iron−sulfur clusters because there is 13693


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Table 4. Metal Ion Incorporation Reactions of Clustersa reaction

core conversion 1+,0

0

Cuboidal [Fe3S4 ] (3) + M 3−

(41)

[Fe3S4 (LS3)]

I,0

z

refs 1+,0

→ [MFe3S4 ]

(16)

z

+ [M L′n ] ↔ [L′mMFe3S4 (LS3)] + (n − m)L′

76, 78, 79

M = Cu I, Ag I , TlI, CoII , Ni II, Mo0 , W 0 Linear [Fe3S4 ]1 + (2b) + M1+,0 → [MFe3S4 ]2+,1+,0 (16)

(42)

[Fe3S4 (SR)4 ]3 − + [Ni(PPh3)4 ] → [(Ph3P)NiFe3S4 (SR)3 ]2 − + 3Ph3P + RS−

74, 75

(43)

[Fe3S4 (SR)4 ]3 − + xs[Co{P(OMe)3 }3(SR)] → [(RS)CoFe3S4 (SR)3 ]2 −

75

(44)

[Fe3S4 (SEt)4 ]3 − + [M(CO)3 [(OC)3 MFe3S4 (SEt)3 ]3 − + 3MeCN (MeCN)3 ]→

80, 81

M = Mo0 , W 0

+ 1/2EtSSEt

[FenSn]2 + (1, 2b, 4) → [M 2Fe6S6]2 + (17) (45) (46)

[FenSnL4]2 − + [Mo(CO)3 (MeCN)3 ] → [{(OC)3 Mo}2Fe6S6L6]zb [Fe4S4 I4]2 − + 2NiI 2 + PMe2Ph → [(PhMe2P)2 Ni 2Fe6S6I6]2 − 4+,3 +

[Fe6S6] 3−,2 −

(47)

82, 83

n = 2, 4, or 6; L = Cl−, RO− , NOc

[Fe6S6L6]

4+,3 +

(6) → [M 2Fe6S6]

84

(17)

+ 2[M(CO)3 (MeCN)3 ] → [{(OC)3 M}2Fe6S6L6]3−,4 −

82, 83, 85

L = Cl−, RO− ; M = Mo0 , W 0

a

Excluding M = Fe. bCore conversion of [FenSnI4]2+ (n = 2,4) with NiII reactants affords pseudo-octahedral clusters with different Ni:Fe ratios:84,86 [Fe3Ni5S6I8]4−, [(PhMe2P)4Fe4Ni4S6I4]. cAmbiguous oxidation state.

the cubane-type core 16 (Figure 3). The neutral core possesses a metal ion affinity sufficient to bind thiophilic monocations such as CuI, AgI, and TlI and supports [M1+Fe3S4]2+,1+ redox couples (reaction 41). Divalent metals such as CoII and NiII do not always bind effectively to the neutral core. However, when supplied in the reduced (MI) state (e.g., [M(PPh3)3Cl]), the metal reduces the core to the even more nucleophilic [Fe3S4]1− level, affording the stable heterometal cores [MFe3S4]1+ in which the oxidized metal has been captured. The compounds [M(CO)3(MeCN)3] (M = Mo, W) react directly with [Fe3S4]0 in a nonredox process to form [(OC)3MFe3S4(LS3)]3− in which a zerovalent M(CO)3 group fills the voided site. The [Fe3S4]1− fragment occurs in both synthetic and protein-bound cubanes, but has not been isolated separately, presumably because of its pronounced nucleophilicity toward protons and metal ions (cf., section 7.4).

no distinction between the core and the cluster. Reaction systems in Me2SO containing the α-isomer with 36 equiv of either ptolylthiol or [Fe(SPh)4]2− form the cubanes [Fe4S4(SR)4]2−, detected by UV/visible and 1H NMR spectra. The outcome is similar to reaction (29), in which the initial cluster also has the ratio S:Fe > 1. These results provide another instance of [Fe4S4(SR)4]2− clusters being the dominant product in the presence of FeII,III, a sulfide source, and thiolate. The preceding core conversions are summarized diagrammatically in Figure 2. About 20 conversions are recognized, involving all nuclearities in Figure 1 except 2a, hexanuclear 8, and tetranuclear 9bc, for which no reactions have been reported. The most prolific reactant in core conversion is the cubane 4 in several different oxidation states, a property that extends to other reactivity features of synthetic weak-field iron−sulfur clusters.

[Fe3S4 ]1 − (S = 5/2) > [Fe3S4 ]0 (S = 2)

5. HETEROMETAL ATOM INCORPORATION These reactions introduce one or two metal atoms into a preexisting iron−sulfur core structure, resulting in minor dimensional changes of the host core or conversion to a different structure. Leading examples are summarized in Figure 3 and Table 4. While the families of clusters containing one or two heterometal MFe3S4 cubane units variant in M are extensive, many such clusters have been obtained by self-assembly rather than by incorporation reactions.1,19,70−72

> [Fe3S4 ]1 + (S = 1/2)

(39)

[Fe3S4 ]1 + + M2+,1 + + ne− → [MFe3S4 ]2+,1 +

(40)

A complementary approach is provided by reactions (42)− (44), which were discovered before reaction (41) (Table 4). These do not require the prior preparation of a cuboidal cluster but instead utilize the linear all-ferric cluster 2b. Reaction with prereduced cobalt or nickel complexes leads to core reduction and rearrangement of [Fe3S4]1+ to the cubane-type [CoIIFe3S4]2+ and [NiIIFe3S4]1+ clusters 16, respectively, in which the Fe3S4 oxidation levels differ by one electron. In reaction (44), molybdenum and tungsten remain in the M0 state, and core reduction is apparently achieved by oxidation of bound thiolate. Reactions of type (41) are examples of fragment condensation, here between a preformed ligand in the form of cuboidal core 3 and a suitably labile metal source. Reactions (42) and (43) are fragment condensations in the form of reductive rearrangements

5.1. Conversions of Cuboidal and Linear Precursors

The cuboidal cluster [Fe3S4(LS3)]3− supports the three-member electron transfer series (39) with the indicated spin states arising from magnetic exchange effects. The series is written in the order of decreasing ferrous core character (Table 1) and thus of increasing electrophilicity. Metal ion incorporation reactions are subsumed by general reaction 40 (n = 0, 1),73 which usually utilizes [Fe3S4]0 as the reactant cluster with an appropriate metal precursor. Metal atom M is bound in the voided site of 3 to form 13694


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levels are evident with rhombic 18 and 1, cuboidal 19 and 20 (inverted) and 3, cubanes 21ab and 4, prismanes 23 and 6, and rhombic dodecahedral 24 and 11, and 25−27 and 17. Black cluster 19 is implicated as a reactant or product in the majority of core conversions. It is formed from dinuclear 18, cubanes 21a and 28, and octanuclear 24, and may be converted to the various clusters 18, 21b, 22, and 24. It is also a source of octanuclear 24 and prismane 23, from which heterobimetallic 25−27 may be obtained. Lacking reactivity analogies, the methods for these and other conversions are largely empirical. Iron−sulfur nitrosyls, with their relatively short Fe−N bond lengths and Fe−Fe separations, low oxidation states, and approximately linear Fe−N−O bond angles signifying the Fe− (NO)+ binding approximation,96 are the only strong-field iron− sulfur clusters with extensive, facile core conversion chemistry. Given the accelerated interest in the actual or potential biological properties of Fe−S−NO clusters,91 it may be anticipated that reaction pathways of such clusters will benefit from further scrutiny.

of linear 2b to cuboidal 3 with accompanying capture of the oxidized metal. As noted earlier, “the process can be likened to inner-sphere electron transfer with a persistent intermediate.”74 These methods together are of considerable scope and should offer feasible routes to other [MFe3S4]z clusters not yet obtained in substance. Isolated clusters generally show electron transfer series encompassing two or more members,74−77 leading to the possibility of isolating oxidation states not afforded by direct synthesis. Last, a new generation of tripodal trithiolate ligands78 suitable for 3:1 site-differentiated cluster stabilization may afford more efficacious synthesis of cuboidal clusters as compared to the LS3 system, and expands the range of metal ion incorporation reactions. 5.2. Other Examples

Remaining examples are summarized by reactions (45)−(47). These afford clusters containing the doubly capped prismane core 17 (M = Ni, Mo, W) of idealized D3d symmetry in yields usually in the 40−80% range. The overall stereochemistry is closely related to the rhombic dodecahedral structures noted earlier for M8S6 clusters. However, the diheterometal M2Fe6S6 core is unique to this class of compounds, which have not been obtained by means other than heterometal atom incorporation. In several cases, this core has been derived from the much simpler cores 1 and 4, which must be disassembled in the process of reaction (45) (ca. 50%). The efficient and elegant reaction (47) is the most general. Acetonitrile is readily displaced from the labile tricarbonyl precursor by binding to the sulfur atoms of the chairlike Fe6S6 ring of 6 in a manner similar to reaction (41), yielding single M(CO)3 prismanes. Two oxidation states [M2Fe6S6]3+,2+ are accessible, for which spectroscopic and electrochemical evidence establishes the Fe6S6 fragment oxidation levels and with an implied M0 assignment. The [Fe6S6]3+ level forms [M2Fe6S6]3+; excess tricarbonyl acts as a reductant, leading to the [M2Fe6S6]2+ state. The reduced fragment [Fe6S6]2+ has been otherwise realized only in the structurally distinct basket configuration 7. Last, product cores 17 of all clusters retain the prismatic Fe6S6 geometry of precursor 6 with only minor metric changes.82,83 Because the clusters were prepared with mol ratios M:Fe6S6 ≥ 2:1, it has not been established if monoheterometal MFe6S6 can be formed by core conversion, or whether there is a cooperative effect favoring 2:1 over 1:1 Fe6S6 binding. It has been reported that 1H NMR spectra of solutions of [{(OC)3Mo}2Fe6S6(OAr)6]3− are consistent with a disproportionation equilibrium involving [Mo(CO)3(MeCN)3] and the monoheterometal cluster.82 Reactant ratios [Mo(CO)3(MeCN)3]:23 less than 1:1 afford the diheterometal product 25, suggesting disproportionation of the monoheterometal cluster that may initially form under such circumstances.

7. BIOLOGICAL CORE CONVERSION The cluster types [Fe2S2] (1), linear [Fe3S4] (2b), cuboidal [Fe3S4] (3), and cubane-type [Fe4S4] (4) sustain conversions in the protein-bound condition. As with synthetic clusters, conversions effect changes in core structure; reactions of terminal ligands with little effect on cores are excluded. Nearly all processes involve cubane clusters 4 whose identification and extensive characterization date from the early 1970s.3,97 In the following sections, illustrative examples of core conversions are described; biological implications where understood and physicochemical characterization of converted clusters may be found in the sources cited. 7.1. [Fe4S4]3+,2+,1+ (4) ↔ Cuboidal [Fe3S4]1+,0 (3)

Aerobically purified ferredoxins with [Fe4S4]2+ centers often display a relatively weak, nearly isotropic EPR signal at g ≈ 2.01, observed at cryogenic temperatures. This feature was ultimately traced to a cluster formulated in early reports as [3Fe−3S] or [3Fe−xS]. Recognition of this conversion had depended upon identification of the 3-Fe component as 3, initially from studies of D. gigas Fd II and aconitase.98,99 Subsequent analytical and physical data established the [Fe3S4]1+ state (S = 1/2) as an impurity, resulting from oxidative damage to an original [Fe4S4]2+ cluster. Both types of clusters are frequently identified and quantitated by EPR spectra. The [Fe4S4]2+ state (S = 0) can be reduced to [Fe4S4]1+ whose usual spin ground state of S = 1/2 is recognized by its rhombic g ≈1.94-type spectrum at cryogenic temperatures. Examples of (inter)conversion reactions of clusters 3 and 4 are collected in Table 5. In addition to spectroscopic methods, direct electrochemistry of proteins, usually examined at pyrolytic graphite electrodes, has proven of much value in detecting and interpreting cluster conversion. The method affords redox potentials and their pH dependencies, and the number of electrons transferred. For example, the 7-Fe protein D. africanus Fd III contains two cluster types with E0′ = −140 and −410 mV, corresponding to the reversible one-electron couples [Fe3S4(S· Cys)3]2−,3− and [Fe4S4(S·Cys)3L]z,z−1, respectively.126 The higher potential of the 3-Fe couple is the typical behavior. In the following sections, Asp/Asp·CO2− and Cys/Cys·S− are residues in a polypeptide chain (donor groups specified). Of the plurative factors influencing cluster conversion, two are particularly evident.

6. IRON−SULFUR−NITROSYL CLUSTERS Although this Review focuses on weak-field iron−sulfur clusters, we take brief note of nitrosyl clusters to recognize certain unique parallels in structure and cluster conversion reactions between these strong-field and the preceding weak-field cases. The former are included in Figure 4 as citations to structures and reactivity.49,87−95 The scope is limited to reactants and products that bind only NO at terminal iron sites (except for 20 and 28). As in many investigations of Fe−S−NO chemistry, the venerable cluster anions 18 and 19 of Roussin’s red and black salts, respectively, figure prominently. Structural resemblances in shape if not in precise metric detail and isoelectronic oxidation 13695


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Table 5. Representative [Fe4S4]2+ ↔ Cuboidal [Fe3S4]0,1+ Conversions and Interconversions

a

proteina

cluster(s)b

refs

A. vinelandii Fd I C. pasteurianum Fd D. africanus Fd III D. fructosovorans [NiFe] hydrogenase D. gigas Fd II P. furiosus Fd Sulfolobus Fd aconitase E. coli DMSO reductase E. coli fumarate reductase lipoyl synthase lysine 2,3-aminomutase pyruvate formate-lyase activating enzyme ribonucleotide reductase activase (anaerobic)

[Fe4S4] 2[Fe4S4] [Fe3S4] + [Fe4S4] [Fe3S4] [Fe3S4] [Fe4S4] [Fe4S4] [Fe3S4] [Fe4S4] [Fe3S4] [Fe4S4] [Fe4S4]

100, 101 102−105 106−108 109 110, 111 112, 113 114 115−117 118 119 120 121, 122

[Fe3S4]

123

[Fe4S4]

124, 125

Includes some proteins from site-directed mutagenesis. cluster.

b

sites, a key feature in promoting core conversion in iron−sulfur systems. [Fe4S4 (S ·Cys)3 L]2 − /1 − ↔ [Fe3S4 (S· Cys)3 ]3 − + Fe2 + + L1 − /0

(48)

7.1.2. Primary Structure. Protein structure at all levels can contribute to the (de)stabilization of a given cluster type within a macromolecular environment. This is especially evident with the primary structures of ferredoxins in which the sequence run CysX-X-Cys-X-X-Cys often appears as a binding motif of [Fe4S4] clusters. Several illustrative cases are found in Figure 6.

Initial

7.1.1. Redox and Metal Ion Transfer. The 3 ↔ 4 core transformation is readily summarized by the square reaction scheme in Figure 5, which provides an overall description of

Figure 5. Square scheme for reversible core conversion reaction 4 ↔ 3 (a) by component reactions (b−e). Ground spin states of the various species are indicated. Figure 6. Schematic binding patterns for clusters in native and mutant (Asp14Cys) P. furiosus Fd and D. africanus Fd III (n = 3, 4). A carboxylate group of Asp or H2O/OH− is a probable fourth ligand in the P. furiosus 4-Fe protein and in the reconstituted (8-Fe) form of the D. africanus protein. X = 14Cys is a ligand in the mutant proteins.

cluster conversions. The scheme contains two well-documented one-electron transfer pairs, [Fe4S4]3+,2+ and [Fe3S4]1+,0, with members of one pair connected to the other pair by FeII incorporation or loss. Ground spin states of component species are indicated. In the usual case, a protein containing one or two [Fe4S4]2+ clusters is exposed to chemical or electrochemical oxidation to afford [Fe3S4]1+. Oxidants in overall conversion reaction (a) include dioxygen or ferricyanide (stronger) for easier stoichiometric control. This reaction may proceed by initial oxidation (b) to form [Fe4S4]3+ followed by Fe2+ release (c) to produce [Fe 3 S 4 ] 1+ . The tripositive cluster core (isoelectronic with the oxidized cluster in high-potential proteins) is a plausible intermediate but is infrequently detected, due to irreversible multielectron oxidative damage and/or competing formation of [Fe3S4]1+. Reaction (b) has been reported in the electrochemical oxidation of active aconitase.116 Interconversion can be accomplished by reduction (d), usually with dithionite, and Fe2+ incorporation (e), thereby recovering the initial [Fe4S4]2+ cluster. The apparent minimal stoichiometry of core conversion (a) of protein-bound clusters (L = Asp·CO2−, Cys·S−, H2O/OH−) is given by reaction 48. This reaction conveys the effective reversibility of FeII,III binding in tetrahedral

Aerobically isolated native P. furiosus Fd (Mr 7500) contains one [Fe3S4]1+ cluster and five Cys residues, two of which form a disulfide link. The 11Cys-(X)5-17Cys sequence is nonstandard by containing Asp instead of Cys at position 14. The remaining three Cys residues bind the cluster.113 The anaerobically prepared protein contains an [Fe4S4]2+ cluster in which the non-Cys ligand is presumably the carboxylate group of 14Asp as in [Fe4S4(S·Cys)3(O2C·Asp)]2−, or perhaps H2O/OH−. Reduction to [Fe4S4]1+ leads to a physical mixture of S = 1/2 and 3/2 ground states. The reduced protein is readily oxidized by dioxygen to the S = 0 [Fe4S4]2+ state and with excess ferricyanide to [Fe3S4]1+.99 Treatment with a reductant and Fe2+ completes cluster interconversion by demonstrable reactions (a), (d), and (e) (Figure 5). When isolated aerobically, the Asp14Cys mutant protein contains an [Fe4S4]2+ cluster with full cysteinate ligation made possible by the run 11Cys-X-X-14Cys-X-X-17Cys in which three Cys residues are coordinated. The cluster is apparently aerobically stable, but is oxidized by excess ferricyanide to 13696


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[Fe3S4]1+. The structures of the [Fe4S4]2+ and [Fe3S4]1+proteins have been determined by crystallography;127 the 14Cys residue detached by oxidation faces away from the 3-Fe cluster and does not significantly interact with it. Other proteins with a single cluster sustain conversion reactions. Among them are the celebrated cases of bovine and porcine aconitase.99 These are much larger proteins (Mr 80 kDa) with one cluster and one Cys-X-X-Cys binding motif and manifest analogous behavior. The enzyme is aerobically isolated, containing one [Fe3S4]1+ cluster.128 The classical activation procedure, by addition of FeII and a reducing agent, is a cluster conversion reaction, affording [Fe 4 S 4 (S·Cys) 3 (OH/ OH2)]2−/1−,129 replete with a labile binding site that enables substrate binding and activation.99 In some proteins with more than one cluster, conversion of a single cluster has been achieved without affecting the other. Consider the native oxidized protein D. africanus Fd III with seven Cys residues (Figure 6), whose iron content as isolated is distributed over [Fe3S4]1+ and [Fe4S4]2+ sites.126,130 The latter is a conventional [Fe4S4(S·Cys)4]2− cluster with an S = 1/2 ground state upon reduction to [Fe4S4]1+. When the protein reacts with FeII under reducing conditions, the other cluster undergoes conversion to a necessarily site-differentiated cluster [Fe4S4(S· Cys)3L]2−. Given its position in the sequence, ligand L is likely 14 Asp·CO2−. In the reduced state, the reconstituted cluster occupies an S = 3/2 ground state. When the Asp14Cys mutant protein is reconstituted with FeII and sulfide, an 8-Fe protein is isolated that contains two [Fe4S4(S·Cys)4]2− clusters, both in the S = 2 state when reduced. The mutation demonstrates two points: (i) non-Cys ligation is a likely factor in stabilizing the infrequently encountered S = 3/2 versus S = 2 state; and (ii) Asp (and presumably other non-Cys ligands) promote core conversion by the loss of iron from a [Fe4S4] cluster upon oxidation. However, neither of these are general requirements for the indicated behavior, as may be verified by examination of other systems in Table 5. The scheme in Figure 5 provides a template for all 3 ↔ 4 conversions currently recognized.

Dithionite reduction of purple aconitase under unfolding conditions also rapidly generates minority quantities of [Fe2S2]1+ and [Fe4S4]1+ (both detected by EPR). Although perhaps likely, it is unknown if the immediate precursor to [Fe2S2]1+ species is the linear cluster. The reduced 4-Fe cluster might have been formed by the reductive dimerization 2[Fe2S2]1+ → [Fe4S4]2+ (reaction (2), Table 2). The reverse possibility is encountered with certain 2-Fe Fds that unfold at different rates (pH ≈ 10, GuHCl), liberating iron and sulfide, some or all of which are incorporated into linear clusters.137 Linear structure 2 possesses intrinsic stability as evidenced by isolation of the synthetic species [Fe3S4(SR)4]3− with four separate terminal ligands.23 Such species are devoid of structurestabilizing components that might simulate a protein scaffold. These clusters are stable in anaerobic solution. Although a partially unfolded protein may present binding sites less spatially correlated than in the native state (and likened in the limit to independent ligands), such sites do not appear to be necessary or sufficient for the occurrence of protein-bound clusters. Linear 3Fe clusters have been detected by themselves or in the presence of different Fe−S clusters in other proteins, including E. coli dihydroxyacid dehydratase,138 pyruvate formate-lyase activating enzyme,123 mitochondrial glutaredoxin,139 and human cytosolic iron regulatory protein (cytosolic aconitase).140 In the last of these, a linear 3-Fe array has been identified with certainty by EXAFS analysis. An equally salient point is the impressive resiliency of the aconitase cluster binding region. With allowance of different Cys binding patterns, this region accommodates the full range of biological cluster structures with nuclearities three and four (viz., 2−4) in multiple oxidation states. Beyond this, there may be new cluster types not yet fully defined, such as that from P. furiosus Fd with an apparent nonlinear structure and possible composition [Fe3S4(S·Cys)4].141 Last, note that all-ferric cores 2 and 3 with different bond connectivities and electronic ground states (Table 1) are geometrical isomers. Except for irreversible reaction (26) (Table 3), there is as yet no clear demonstration of cluster conversion between isomeric forms in synthetic systems. Reaction 49 of isoelectronic cores anticipates perhaps the simplest conversion, from cuboidal 3 to the more stable linear core 2b. It is analogous to the aconitase conversion but has not been explored.

7.2. Cuboidal [Fe3S4]1+ (3) ↔ Linear [Fe3S4]1+ (2b)

The first instance of a protein-bound linear cluster 2b was recognized in partially unfolded aconitase in 1984,131 two years after the first synthesis of a linear [Fe3S4(SR)4]3− cluster.132 If inactive aconitase is maintained at pH ≈ 10 or in 4−8 M urea, the color changes from brown to purple (λmax 420, 500, 580 nm). Property comparisons between the protein and synthetic clusters, which feature a linear array of tetrahedral [Fe3+S4]1− units, characteristic UV/visible absorption and MCD spectra, and an exchange-coupled S = 5/2 ground state,23,133,134 have been valuable in establishing the structure of the purple chromophore. The brown → purple color change signals occurrence of the core conversion 3 → 2, which for all-Cys coordination can be minimally described as [Fe3S4(S·Cys)3]2− + Cys·S− → [Fe3S4(S·Cys)4]3−. Active aconitase cannot be converted to the purple form in the absence of dioxygen, suggesting that [Fe3S4]1+ produced by oxidation of [Fe4S4]2+ is the reactive cluster.131 The purple form is stable for several days when partially denatured but decomposes under altered conditions. In an unfolding medium (GuHCl, pH ≈ 10), several 7-Fe Fds display absorption spectra similar to that of purple aconitase.135,136 It is unestablished whether the original cluster [Fe3S4]1+ alone or with [Fe4S4]2+ contributes to the formation of the linear cluster.

[Fe3S4 (SR)3 ]2 − + RS− → [Fe3S4 (SR)4 ]3 −

(49)

7.3. [Fe4S4]2+,1+ (4) ↔ [Fe2S2]2+,1+ (1)

Many transformations in this general category, the most common of core conversions, can be summarized as the often reversible core conversion reaction 50 requiring an electron acceptor or donor. The forward reaction is fragmentation (oxidative dissociation, symmetric fission), and the reverse reaction is fragment condensation (reductive coupling, reductive dimerization). Some examples are collected in Table 6. We note also that this reaction type has been detected in the gas phase as [Fe4S4X4]2− → [Fe2S2X2]1−,142,143 for which a theoretical description has been proposed.144 [Fe4S4 ]2 + ↔ 2[Fe2S2 ]2 + + 2e−

(50)

7.3.1. Nitrogenase Fe Protein. Among the first examples of the conversion of protein-bound iron−sulfur clusters is the transformation 1 → 4 in an iron protein of nitrogenase.145,146 These α2 proteins contain one [Fe4S4(S·Cys)4] cluster bound between two identical subunits.147 Anaerobic reaction of the 13697


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Table 6. Representative Protein [Fe4S4]2+ ↔ [Fe2S2]2+ Conversions and Interconversions

a

protein

refs

nitrogenase Fe proteina,c anaerobic ribonucleotide reductaseb biotin synthaseb lipoate synthaseb pyruvate formate-lyase activase iron−sulfur cluster assembly protein (NifIsca)a

145, 146, 148 124, 150 151−154, 161 154, 155 156, 160 157

2[Fe2S2]2+ + 2[Fe4S4]2+ in a homodimer.162 The 4-Fe clusters can undergo reversible oxidation and reduction. In a crystalline form of the enzyme, dethiobiotin is located between the 2-Fe cluster and coordinated SAM.159 Given this spatial arrangement and the degradation of [Fe2S2]2+ during turnover, the cluster is a likely source of sulfur in the biotin product. In some instances, the formation of [Fe2S2]2+clusters and the attendant conversion under reducing conditions appear to have arisen due to insufficient anaerobic conditions during purification and use. Usually, in SAM enzymes and elsewhere, protein-bound [Fe4S4]2+ can be oxidized by dioxygen and [Fe2S2]2+ reduced by dithionite. A recent comprehensive account of SAM enzymes is available.162 7.3.3. FNR, IscA, and IscU Proteins. These proteins participate in the core conversion reaction 50, which is sometimes reversible and involves mainly or fully cysteinateligated clusters. FNR proteins are transcriptional activators of genes necessary to the synthesis of protein components in the respiratory apparatus of various organisms.12,15,163 They function as environmental sensors of dioxygen in cells and are implicated in a change from aerobic to anaerobic respiration pathways with dioxygen or fumarate/nitrate, respectively, as the terminal electron acceptor. Isc proteins are major components of the iron−sulfur cluster (Isc) biosynthesis apparatus. While not all behavioral aspects are understood, two types of bacterial proteins, IscU164,165 and IscA,157,166 display certain functional similarities. The former is designated a scaffold protein because it serves as a host for cluster assembly and transfer to a cluster carrier protein IscA, which is sometimes described as an alternate scaffold. Anaerobic E. coli FNR is a dimeric protein that recognizes specific DNA sequences and binds one [Fe4S4(S·Cys)4]2− in the N-terminal domain of each subunit. Upon exposure to dioxygen, oxidative dissociation to [Fe2S2(S·Cys)4]2+ occurs with a concomitant protein conformational change, separation of subunits, and diminished DNA binding.167,168 The reaction pathway of these events for the E. coli enzyme has been intensively examined163,169,170 and can be described in different ways, depending on the reduced oxygen products. Cluster conversion reactions 52−54 provide an abbreviated summary. Initial reaction 52 results in one-electron oxidation of the iron content and formation of a cuboidal [Fe3S4]1+ transient intermediate. It might be expected, and was originally proposed, that the next step is formation of a 2-Fe cluster in a process such as [Fe3S4]1+ → [Fe2S2]2+ + Fe3+ + 2S2− with the release of sulfide (HS−) into solution. It has now been shown that the fate of sulfide is oxidation to S0 in a reaction such as (53) with dioxygen acting as a four-electron oxidant in this example. Cysteinate persulfide ligands are formed by the reaction of sulfur and cysteinate. (A related reaction forming a monocysteinate persulfide cluster with liberation of 1 equiv of sulfide is easily formulated.163) Further, it was found that the bis(cysteinate persulfide) cluster in the presence of FeII and DTT can be backconverted to the original cluster in multistep reaction 54, which proceeds by ligand reduction in the absence of added sulfide.

A. vinelandii. bE. coli. cC. pasteurianum.

[Fe4S4]2+ cluster with 2,2′-bipyridyl in the presence of MgATP results in a biphasic process in which [Fe2S2]2+ as a cysteinatebound complex is released in the first stage. This species was identified by its UV/visible and resonance Raman spectra and by the EPR spectrum when reduced to [Fe4S4]1+. The conversion has been confirmed.148 In the presence of excess 2,2′-bipyridyl, with its classic high affinity for low-spin FeII, the first stage might be rationalized as the nonredox reaction 51. The second (slow) stage is proposed to involve breakdown of the 2-Fe cluster by chelation. [Fe4S4 ]2 + + 3bipy + 2H+ → [Fe2S2 ]2 + + 2[Fe(bipy)3 ]2 + + 2HS−

(51)

7.3.2. Radical SAM Enzymes. Reaction 50 and a variant in which only one 2-Fe product was identified have been observed in certain members of the radical S-adenosylmethionine (SAM) enzyme superfamily.149 The catalytic sites are structurally wellcharacterized159−162 and consist of a Fe4S4 cubane-type core 4 bound to the protein through three cysteinyl residues in the motif Cys-(X)5-Cys-(X)2-Cys, forming a 3:1 site-differentiated cluster. The unique iron atom is bound in a five-membered chelate ring with carboxylate oxygen and amino nitrogen donor atoms from the methionine portion of SAM. Reactions proceed by reduction of the cluster to the [Fe4S4]1+ state, inner-sphere electron transfer to SAM, and S−C bond cleavage to form methionine and the 5′-deoxyadenosyl radical. This radical is then quenched by hydrogen atom abstraction in subsequent events. Prominent examples of the conversion include pyruvate formatelyase activase (PFL-AE), anaerobic ribonucleotide reductase activase (aRNR), biotin synthase, and lipoyl synthase. Cluster structures have been demonstrated spectroscopically and by crystallography for PFL-AE158 and biotin synthase.159 Some uncertainty has attended cluster formulations of these enzymes at earlier stages of investigation. An increasing number of [Fe4S4] cluster-containing proteins have been found to undergo reversible conversion to [Fe2S2]2+ forms in the presence of dioxygen, possibly a protection mechanism against the effects of O2.162 Current evidence for the glycyl radical enzymes PLF-AE156 and aRNR124,150 supports one cluster 4 in the catalytic site that does not, as earlier proposed, bridge two subunits. The sulfur insertion enzymes biotin synthase151−154 and lipoyl synthase154,155 catalyze the formation of biotin from dethiobiotin and octanoyl-acyl carrier protein to the 6,8-dithiol lipoyl-acyl carrier protein, respectively. These also utilize [Fe4S4]2+,1+ clusters. Biotin synthase has been isolated aerobically or anaerobically with two [Fe2S2]2+ clusters per homodimer. These are convertible to [Fe4S4]2+,1+ by chemical means, with higher yields in the presence of added iron and sulfide. The fully functional form of the enzyme is now understood to incorporate

[Fe4S4 (S ·Cys)4 ]2 − + O2 → [Fe3S4 (S· Cys)3 ]2 − + Fe2 + + CysS− + O2•−

(52)

[Fe3S4 (S· Cys)3 ]2 − + Cys· S− + O2 + 4H+ → [Fe2S2 (S ·Cys)2 (SS ·Cys)2 ]2 − + Fe3 + + 2H 2O (53) 13698


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Figure 7. Abbreviated proposals of schematic pathways for the biosynthesis of the PN-cluster (31) and M-cluster/FeMo-co (33) of nitrogenase via the K-cluster (29), P* cluster (30), and L-cluster (32). Gene products involved in various stages of cluster maturation are indicated. Orientation of components of cluster pairs 29 and 30 is arbitrary. The asterisk in 30 denotes a subcluster component whose properties depart from those of a conventional [Fe4S4] cluster. Terminal ligands are specified only for final clusters 31 and 33, where they have been identified by crystallography. The carbide-bridged structure is a notional intermediate that might be involved in bridging two [Fe4S4] clusters in the formation of 32. The pathways follow the schemes of Ribbe et al.183 and are intended to show cluster structural changes in proceeding from 4 to the mature products 31 and 33. For depictions of the proposed role of Nif proteins in cluster synthesis, see Ribbe, Hu et al.183−188

to a point where low levels of dioxygen are tolerable. Considerable credence is lent to the foregoing picture by certain crystallographic observations. FeII−SSR binding is observed in persulfide derivatives of cysteinate dioxygenase.172 Further, the bis(cysteinate persulfide) cluster [Fe2S 2(S·Cys) (SS·Cys)2(Arg)] in the radical SAM enzyme HydE from T. maritima FNR173 provides a graphic example of reversible core conversion, [Fe4S4]2+ ↔ [Fe3S4]1+ ↔ [Fe2S2]2+, that is obligatory to a biological process. Reaction 53 is noteworthy as an aspect of FNR-type chemistry that is currently unique. One protein-bound biological iron-sulfide-percysteinate species has been charac-

[Fe2S2 (S· Cys)2 (SS ·Cys)2 ]2 − + 2Fe2 + + 4e− → [Fe4S4 (S ·Cys)4 ]2 −

(54)

The synthetic analogue clusters [Fe2S2(SR)4]2−,3− and [Fe4S4(SR)4]2−,3− are air-sensitive, particularly in solution.171 Low levels of dioxygen can allow clean oxidation of the reduced forms. However, continued aerial exposure of either form leads to decomposition, presumably by initial oxidation of terminal thiolate ligands followed by separation of intractable iron sulfides. Protein tertiary structure can stabilize cysteinate ligation 13699


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terized. The X-ray structure of a mutant form of A. vinelandii Fd I in which 13Tyr was replaced by Cys was found to contain a Cys· SS residue uncoordinated to a nearby Fe3S4 site.174 This form is unstable under reducing conditions; its ability as a sulfide source is unknown. Core conversion offers a facile means of varying core nuclearities between two and four in a synthetic or biological system. In the latter, this can extend the scope well beyond FNRtype systems. For example, it pervades the complex problem of iron−sulfur cluster biosynthesis,175 allowing passage from [Fe2S2] to [Fe4S4] sites in a single overall reaction involving core atoms. In brief, these proteins can be obtained as homodimers in a 2[Fe2S2]2+ form presumably efficiently evolved for the coupling of two dimers. Exposure to a reductant such as dithionite or DTT leads to formation of a [Fe4S4]2+ cluster, usually assumed to be at the interface of two subunits. The process can be repeated by oxidative dissociation, often by aerial exposure. These conversions are part of a general hypothesis for in vitro cluster maturation.

question as to the formation of the heterometal cubane structure 16, the first crystallographic proof has only been recently obtained with the Asp14Cys variant of P. furiosus Fd containing [AgFe3S4]2+ (S = 1/2).182 The cluster was prepared by the reaction of AgNO3 with the [Fe3S4]0 form of the protein followed by ferricyanide oxidation to [AgFe3S4]2+. This cluster is one of three in which stable binding is observed between the least nucleophilic member of series 39 and M1+, an interaction thus far restricted to soft (thiophilic) ions. The core conversion reaction 55 and those in Figure 5 make clear the parallel reactivity behavior of hetero- and homometallic (all-iron) systems. However, such a relationship does not extend to biological function, inasmuch as none has been established for any [MFe3S4]z protein-bound site. [Fe3S4 ]1 + + M2+,1 + + ne− → [MFe3S4 ]2+,1 +

(55)

8. COMPARATIVE SYNTHETIC AND NITROGENASE CORE CONVERSIONS As a remaining case of biological core conversion, we examine the current status of the biosynthesis of the clusters in nitrogenase, the most complex of the discrete metallostructures yet discovered. This microbial enzyme catalyzes the reduction of dinitrogen to ammonia in a complex process whose stoichiometry is usually represented by the reaction N2 + 8H+ + 16MgATP + 8e− → 2NH3 + H2 + 16MgADP + 16Pi. Given the complexity of the reaction (eight electrons), rupture of one of the strongest known bonds (NN 226 kcal/mol), and the often indiscriminate reactivity of FeII,III, it is not surprising that multiple gene products (Nif) are required to construct the intricate catalytic apparatus.183 The enzyme is a tetrameric assembly (NifDK, α2β2) in which an αβ dimer contains a P-cluster (31, Fe8S7) at the subunit interface and an M-cluster catalytic site (33, MoFe7S9C; designated FeMo-co when removed from the protein) within the α-subunit. These clusters are illustrated in Figure 7, which provides an abbreviated outline of their biosynthetic pathways based on biochemical and spectroscopic data and the incisive considerations of Ribbe, Hu, and their co-workers.183−188 To achieve a molecular interpretation of this enzyme, at least two diabolically difficult and interdependent challenges must be met: (i) determination of the sequential steps whose sum is the overall enzymatic reaction; and (ii) elucidation of the biosynthetic pathways leading to the complicated metalloclusters that are obligatory to enzyme function. Mechanistic questions inherent to (i) are under investigation.189,190 Here, we note that electrons are supplied via complex formation of NifH (the Fe protein containing one [Fe4S4] cluster/γ2 dimer) and NifDK (MoFe protein) by the pathway [Fe4S4] → P → M. Our concern is with aspect (ii) inasmuch as the polynuclear structures of 31 and 33 require stepwise assembly with the attendant likelihood of cluster conversion reactions. For example, incubation of M-cluster-deficient NifEN with NifH, MgATP, [MoO4]2−, dithionite, and homocitrate results in formation of NifEN to which two M-clusters are bound. In another case, an in vitro synthesis of FeMo-co is claimed from the reaction of Fe2+, sulfide, TP, MgCl2, a reductant, SAM, and several proteins.191,192 Clusters of the complexity of FeMo-co presumably derive from initial products of self-assembly, very likely followed by cluster conversion to build up the final core structure.1 This is our premise for examining cluster conversions possibly relevant to the biosynthesis of the metalloclusters of nitrogenase.

7.4. Heterometal Ion Incorporation

Core conversion by metal ion incorporation in preformed protein clusters is currently a far more restricted reaction type than in synthetic systems. Of the various incorporation reactions previously outlined in the latter systems (section 5), only the conversion of cuboidal 3 to the heterometal cubane 16 (Figure 3) has been established with certainty in proteins.70,73 This possibility was recognized for heterometals in 1986 after it had been shown in 1982 that 3-Fe clusters of aconitase and D. gigas Fd II, of unknown structures at the time, could be converted to [Fe4S4] clusters. Treatment of the D. gigas protein with Co(NO3)2 produced a new paramagnetic species formulated as [CoFe3S4]2+, isoelectronic with [Fe4S4]1+.177 Structures of core 3 have been established by protein crystallography for those Fe3S4 proteins utilized most extensively as hosts in metal ion incorporation. These are D. gigas Fd II,178 P. furiosus Fd (wild type,127 Asp14Cys mutant113), and the 7-Fe protein D. africanus Fd III, whose structure is represented by the closely related A. vinelandii Fd.179,180 Other than minor distortions in [Fe3S4]1+ structures and in the D. gigas Fd II [Fe3S4]1+,0 redox pair, the clusters are essentially isometric. Relevant cuboidal oxidation states in metal binding comprise series 39. Another state, all-ferrous [Fe3S4]2−, has been electrochemically detected by reduction of [Fe3S4]1+,0 with uptake of 3H+, but so far has not been directly implicated in metal binding. The most important states in metal binding are [Fe3S4]0,1−. The [Fe3S4]0 ground state spin of S = 2 is developed by an antiferromagnetic interaction between the valencedelocalized pair [Fe2S2]1+ (S = 9/2) and Fe3+ (S = 5/2). For [Fe3S4]1−, the coupling interaction involves FeII (S = 2), leading to the cluster spin S = 5/2.70,73 This state has not been generated in solution, reduction of [Fe3S4]0 instead passing directly to protonated [Fe3S4]2−. Metal atom incorporation reactions are subsumed by general reaction 55 (n = 0,1).73 Protein and a reductant are incubated with excess metal salt in a protein buffer solution, and the product is purified by chromatography. Proteins with M = Cr, Mn, Fe, Co, Ni, Cu, Ag, Zn, Cd, and Tl have been obtained,70,73,107,176,181 the majority with P. furiosus Fd. These clusters have been electronically well characterized by EPR, VTMCD, and Mössbauer spectroscopies. In nearly all cases, the cluster ground state spin is correctly predicted by antiferromagnetic coupling of the [Fe3S4]1+,0,1− and M2+,1+ spins. While there has been little 13700


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most distinctive structural component is the sextuply bridging μ6S atom, not yet encountered in any other biological construct. 8.1.2. M-Cluster Biosynthesis. At an early step in M-cluster assembly, the NifB system contains one SAM cluster and one Kcluster consisting of two nearby [Fe4S4] clusters 29. The Kcluster undergoes conversion (fragment condensation) with retention of iron−sulfur content to the L-cluster 32 in NifB. This process requires addition of a sulfur atom and interaction with the SAM cluster. SAM is chelated in an N/O mode to an iron site and is the ultimate source of carbon in the product. A SAM methyl group is transferred to the reacting L-cluster. In a series of steps beginning with hydrogen atom abstraction from the transferred methyl group by the 5′-deoxyadenosyl radical and two deprotonations, a carbon atom is generated and assumes a final interstitial position as μ6-carbide in the L-cluster 32 with core composition Fe8S9C. Radiolabeling with [14CH3]SAM leads to accumulation of the label in the L-cluster, demonstrating that label transfer occurs in the K-cluster → L-cluster step. The system undergoes interprotein cluster transfer to tetrameric NifEN, resulting in a NifEN conformation that carries two [Fe4S4] clusters at αβ interfaces and two L-clusters near the protein surface. As shown by the X-ray structure of NifEN,200 these clusters are analogous to the P- and M-clusters, respectively, in the mature MoFe-protein (NifDK) of nitrogenase. Resolution of the X-ray data (at 2.6 Å), while not sufficient to identify the detailed L-cluster stereochemistry, does reveal the α2β2 protein structure, positions of the [Fe4S4] and Lclusters, and the absence of molybdenum and homocitrate from the L-cluster. EXAFS analysis indicates that the L-cluster skeletal structure resembles that of FeMo-co but with an iron atom in place of molybdenum.206 Carbon originates as the methyl group of Sadenosylmethionine. Its presence was affirmed209,210 nearly a decade after the discovery of a central atom X = C, N, or O by Xray methods (1.16 Å resolution).211 The proposed cluster model 32 is comprised of two Fe4S3C cubane-like portions sharing the common vertex atom μ6-C and bridged by three μ2-S atoms to form the overall cluster Fe8S9C of idealized C3 symmetry. More detailed descriptions and mechanistic speculations concerning carbon atom inclusion in the L-cluster and other steps in the biosynthesis are available.162,183,185,186,210 Biosynthesis of the M-cluster is completed by the treatment of NifEN with molybdate, homocitrate, and NifH, thereby converting the L-cluster to MoFe7S9C with homocitrate bound. Interprotein cluster transfer of M-clusters from NifEN to Δnif B NifDK produces NifDK, containing two PN-clusters and two M-clusters. This completes the biosynthesis of the fully active MoFe protein of nitrogenase. It might be noted that NifEN containing two [Fe4S4] clusters and two M-clusters can catalytically reduce the nitrogenase substrates acetylene and azide but cannot evolve dihydrogen or reduce dinitrogen.212 Acid treatment of this protein and extraction into NMF affords the Lcluster (sometimes termed the “precursor” cluster) in moderate yield and high purity. The Δnif B NifEN (a precursor-deficient NifEN protein) may be reconstituted with the precursor to NifEN, which is less active in acetylene and azide reduction than is as-isolated NifEN. Of course, the isolation in solution of the Lcluster from NifEN, just as the pioneering experiment of Shah and Brill213 over 30 years ago, supports the proposition that such cofactors are sufficiently stable to be isolable in the pure condition.

To proceed, we provide an abridged description of apparent reaction pathways drawn mainly from Ribbe et al.183 We emphasize that the means of protein scaffolding and transfer of intermediate clusters, themselves of uncertain structures, and the exact order of events in a given pathway are largely unknown. Any venture into cluster biosynthesis is enabled in large part by the indispensable crystallographic structure determinations of the Fe protein and the P-cluster and M-cluster of the MoFe protein first reported about 25 years ago193 and supplemented by additional structures thereafter.194−201 8.1. Cluster Biosynthesis

This event is initiated by the formation of small Fe−S clusters. In the environment of the scaffold protein NifU, the pyridoxalphosphate dependent cysteine desulfurase NifS catalytically removes S0 from cysteine with formation of alanine and percysteinate, the latter of which is subject to reduction (CysSSH + 2e− → Cys-S− + HS−), producing sulfide for cluster formation. Product [Fe2S2]2+ clusters202 are then convertible to [Fe4S4]2+164,203 by reductive dimerization (50). At this point, the scheme (Figure 7) divides with one branch leading to the PNcluster 31 and the other to the M-cluster 33. In the branch leading to the PN-cluster, two [Fe4S4] clusters are transferred to NifDK. Here, each cluster is inserted into the α and β subunits, resulting in a pair of [Fe4S4] clusters located in close vicinity at the αβ interface. In the branch leading to the M-cluster 33, two [Fe4S4] clusters are transferred to NifB where they are juxtaposed into the K-cluster 29, consisting of a pair of nearby [Fe4S4] clusters. Current evidence suggests that one K-cluster and one [Fe4S4] cluster (the “SAM” cluster, vide infra) are likely associated with one NifB protein. 8.1.1. P-Cluster Biosynthesis. P-clusters have been detected in three oxidation states, all-ferrous PN (the usual asisolated form), and one- and two-electron oxidized P+ and P2+, respectively.204 The following refers primarily to the PN form (31), which is attainable by an in vitro enzymatic synthesis using Δnif H NifDK, NifH, MgATP, and dithionite. While the most is known about this form, individual steps in the synthesis and their order have not been established. Interpretation of P-cluster assembly in the NifDK environment as a stepwise process is critically dependent upon several bis-dimer NifDK gene products.183 These are devoid of M-clusters and contain αβ dimers in an α2β2 arrangement with metal clusters at αβ interface sites. NifDK proteins do not have M-clusters because the deletion strains from which they were isolated lack NifB or NifH, the proteins essential for M-cluster formation. Clusters appear to be sequentially implicated in the following conformations of proteins that are generated upon strategic deletion of nif genes: Δnif H NifDK (two [Fe4S4] pairs), Δnif B Δnif Z NifDK (one P*and one P-cluster), and Δnif B NifDK (two P-clusters). The sequence terminates with formation of two mature PN clusters at the interfaces. Spectroscopic properties of intermediate P*cluster 30 are indicative of one conventional [Fe4S4] unit and one that is altered from the usual arrangement, perhaps by the inclusion of a nonsulfur core or terminal atom or by a covalent interaction between the two subclusters.205−208 Nonetheless, under maturation conditions, the P*-cluster converts to an essentially normal PN-cluster structure. The collective evidence affords a scenario in which the subclusters in a P*-cluster (2[Fe4S4]) coalesce by reductive coupling to a mature PN cluster ([Fe8S7]) with elimination of sulfur. The cluster is built of two highly distorted Fe4S3 fragments connected by two μ2-S·Cys bridges and one μ6-S atom in idealized Cs stereochemistry. The 13701


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8.2. High-Nuclearity Synthetic Conversions

implicate two appropriately juxtaposed, independently biosynthesized [Fe4S4] clusters with other reagents and protein structural features in the environment of the gene product. While subsequent cluster-forming reactions themselves are unknown, it is useful to summarize the most pertinent results available from synthetic systems. 8.2.1. PN-Cluster. The most significant result thus far is that the essential core structure [Fe8S7] = [Fe8(μ3-S)6(μ6-S)] (13, Figure 1) can be achieved by chemical synthesis. Some of the initial results yielding topologically credible PN-cluster structures were obtained with the readily preparable heterometal single cubanes [MFe3S4]2+ (16, M = V, Mo, W). Leading results obtained in the Harvard laboratory are summarized in Figure 9.229−231 The most efficient procedure involves two core conversions. The single cubane (SC) core 16 is dimerized with loss of labile tertiary phosphine to the centrosymetric edgebridged all-ferrous double cubane (EBDC) [M2Fe6S8]2+ = [M2Fe6(μ3-S)6(μ4-S)2]2+ (37) under reducing conditions. This step is followed by sulfide incorporation in the core in a polar medium such as acetonitrile to afford [M2 Fe 6S9 ]0,1+ = [M2Fe6(μ2-S)2(μ3-S)6(μ6-S)]0,1+ (38). Yields are ca. 70%. The product core carries one μ6-S atom and superimposes on the protein core structure calculated from crystallographic coordinates sufficiently to allow description as a structural analogue.19 It is not a chemical analogue because of the two M heteroatoms and two μ2-S rather two μ2-SR bridges. Nonetheless, these species demonstrate that iron−sulfur clusters with heterometals can stabilize the PN core. The two core conversions in the operative scheme SC → EBDC → PN-type are evident in Figure 9. The approach of the Nagoya laboratory5,39,65,232,233 has involved self-assembly in low dielectric media, thereby enhancing formation of uncharged products. The system [Fe{N(SiMe3)2}2]/S/SC(NMe2)2 and the sterically encumbered thiol TipSH produce [Fe8S7{N(SiMe3)2}4(SC(NMe2)2)2] in yields up to 80% yield in toluene. The Fe8(μ3-S)6(μ6-S) core 13 is also available from the reaction of [Fe3 (μ 2 -STip) 4 (N{SiMe3}2)2], thiourea, and a hindered thiol. This and similar reactions are not considered core conversions because the starting complex does not contain a sulfide core (section 1). Treatment with PhSH/Et3N causes core conversion of 13 to a lower nuclearity ([Fe4S4(SPh)4]2−, 43%). A particularly interesting example of core conversion is provided by the reaction of [Fe4S4{N(SiMe3)2}4] with a tertiary phosphine to produce another cluster 13 in which a phosphine sulfide replaces terminal tetramethylthiourea (section 3.9). The core conversion of [Fe4S4]4+ to [Fe8S7]4+ has been aptly described as reductive fusion (mean product oxidation state Fe2.25+) by Ohki et al.39 8.2.2. FeMo-Cofactor. While the [MoFe7CS9] core 33 can be assembled in systems containing simple reactants and the appropriate gene products (section 8.1.2), no strictly abiological protocol has been discovered for the synthesis of that core or others credibly resembling it. PN-cluster analogues come the closest. These do contain one sulfide and two thiolate or disilylamidate groups connecting two highly distorted cubanelike parts that are additionally bridged by one μ6-S atom. While these departures from 33 together with heterometal atoms in 38 provide obstacles, none is likely to be more vexing than the deliberate or serendipitous introduction of interstitial carbon (as carbide) in a core with a physiologically relevant oxidation state. In terms of just carbide coordination, no molecular entity comes closer than [Fe6C(CO)16]2−234 in which a carbon atom resides at the center of an Fe6 octahedron at 1.88−1.91 Å,235 but the formal

Adopting Figure 7 as an outline of probable events in the synthesis of PN- and M-clusters, we consider instances of cluster formation by conversion reactions of polynuclear species. We focus first on the K-cluster 29, which, although a transient precursor of L-cluster 32, can be accumulated on a NifEN-B fusion protein. Evidence was adduced from analytical and EPR data that a SAM cluster and the K-cluster occupy nearby proteinbound positions, and that the eight Fe atoms of the latter are incorporated in a SAM-dependent formation of the L-cluster by a merging of two [Fe4S4] modules.183,188 While the distance between and relative orientation of the subclusters of 29 are unknown, it is of interest that similar arrangements have been detected. In 8-Fe Fds, two [Fe4S4(S·Cys)4] clusters are present in the same molecule (Mr ≈ 6.2 kDa) but are not directly bound to each other as in Figure 8, which summarizes clusters without and with

Figure 8. Depictions of 2[Fe4S4] cluster arrangements: in a protein environment without covalent attachment (29) and supported by an idealized synthetic Cys-containing helical peptide (34). Discrete covalently bridged synthetic clusters (35, 36) are perhaps plausible; however, 35 (X = HS−) and 36 have not been prepared.

covalent connections. Structurally verified cases include, among others, P. aerogenes and C. acidiurici Fds, whose tertiary structures are very similar.214,215 The intercluster Fe···Fe, S···S, and cluster centroid distances of 8.7−8.8, 9.0−9.1, and 11.5−11.6 Å, respectively, obviate direct bond-making/breaking interactions. Polyferredoxins with proposed multiple ferredoxin domains of nonbonded clusters may be similar.216,217 Synthetic versions of this situation include bis(cluster) peptides in which helical polypeptide structure separates [Fe4S4] units at distances dependent upon Cys residue positions in the coils.218,219 The arrangement 34 of two helices and two clusters is merely illustrative. Other examples of distantly separated clusters include those in the electron transfer conduits of hydrogenases.220,221 In contradistinction to these cluster arrangements, several types of synthetic, covalently bridged double cubanes with one (3578,222−226) and two (12,41,227 Figure 2) points of attachment are recognized. A third type, 36, is of doubtful steric plausibility; it has not been prepared. However, clusters with persulfide bridges have been proposed as oxidation products of [Fe4S4(SH)4]2−.228 Inasmuch as 29 and P*-cluster 30 derive from 4 and are not covalently coupled, any cluster conversion would appear to 13702


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Figure 9. Core conversion reaction pathways to PN-type clusters: 16 → 37 → 38 showing core and full structures; 4 → 13 showing full structures. Cluster 39 is the closest topological approach to FeMo-co obtained by chemical synthesis.

0.37 Å. Taking these effects into account, visual atom superposition clearly upholds a core structural relationship. Further, it has been perceived by Ohki et al.65 that rupture of one Fe−(μ2-S)−Fe bridge by reaction with thiolate and reduction could result in [Fe8S7(μ2-SR)2(SR)4]1−, a potential entry to a PN analogue with the biologically relevant feature of two thiolate bridges. The challenge of a μ6-C interstitial component together with terminal Cys·S−Fe and Mo−N·His and MoO2(homocitrate) coordination must be met before the creation of an authentic synthetic analogue can be declared.

iron oxidation state is completely unrealistic for a protein site. The most recent Mo K-edge XAS and theoretical results236,237 and X-ray anomalous dispersion refinement238 for synthetic compounds and FeMo-co have led to a revised oxidation state assignment of Mo3+ with spin-coupled iron sites in the as-isolated state of the cofactor. Previously, the Mo4+ description has been widely favored. This situation projects three arrangements for which the experimental ground state spin S = 3/2 would apply: [Mo3+Fe2+6Fe3+C4−S2−9]4−, [Mo3+Fe2+3Fe3+4C4−S2−9]1−, and [Mo3+Fe2+Fe3+6C4−S2−9]1+. Of these, the anomalous dispersion results are most consistent with the monoanionic core and three iron atoms more reduced than the other four (mean oxidation state Fe2.57+). Before these developments, the Mo3+ state was favored over Mo4+ based on an empirical correlation between observed isomer shift and mean iron oxidation state.3 The latter leads to estimation of the molybdenum oxidation state by difference if the core charge n is known.239 In various cubanetype Mo−Fe−S clusters with six-coordinate heterometal sites resembling the immediate coordination unit MoS3NO2 in FeMoco, the Mo3+ designation appears preferable. While synthesis of the foregoing cores or those containing Mo4+ in the corresponding valence electron range remains a prime goal in FeMo-co synthesis, significant progress has been made in the construction of topologically similar clusters.5,65 A system containing preisolated [Fe2(μ2-S-Dmp)2(S-Tip)2] and sulfur in toluene affords octanuclear [Fe8S7(STip)(SDmp)4] (39, Figure 9) with the core [Fe8S7]5+ = [Fe8(μ3-S)6(μ6-S)]5+ and a slight quantity of isostructural [Fe8S7{N(SiMe3)2}(SDmp)2(STip)2] in which the disilylamide occupies a μ2position. The structures of 39 and FeMo-co (33) differ by three μ2-SR and a μ6-S bridge in the former and sulfide and carbide bridges in the latter, as well as a larger distortion of the six interior irons from a regular trigonal prismatic arrangement. The mean Fe−(μ6-S) bond length exceeds the mean Fe−(μ6-C) distance by

9. CORE CHALCOGENIDE EXCHANGE AND INCORPORATION 9.1. Protein Reconstitution

The classic experiments by Hong and Rabinowitz240,241 with C. pasteurianum Fd under alkaline conditions demonstrated in 1970 that iron−sulfur sites in the holoprotein undergo separate exchange with FeII and Na2S. The reactions were quickened by urea, suggesting that alteration in protein folding makes the sites more accessible. Inasmuch as the protein is now known to be of the 2[Fe4S4] type, these were the first observations of exchange, albeit nearly degenerate, of core atoms in biological or synthetic iron−sulfur clusters containing the cubane 4. Thereafter, Moulis and Meyer242 prepared a variation of clostridial Fd by reaction of the apoprotein with Fe3+ and a selenide source. Further, they observed exchange between sites in the native protein and free selenide, leading to “hybrid” proteins with mixed chalcogenide cores. The apoprotein of the iron protein of K. pneumoniae nitrogenase was reconstituted using selenocystine, FeII, and cysteine desulfurase and shown to contain an Fe4Se4 cluster.243 The subject has been reviewed.244 13703


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9.2. Sulfur/Selenium Exchange

The initial reactions in columns A and B and C of Figure 11 are based primarily on trigonal complex [(Tp*)WS3]1− (42).248 Column A recapitulates the sequence, affording the PN-cluster structural analogue 38 (Figure 9). A key issue in the reaction pathway consisting of two fragment condensations is the final position of sulfide from reactant hydrosulfide in the product. With selenide as a reactant, a disordered structure was found with 50% sulfur and selenium distributions over the two μ2-Q bridges.249 Sulfide was not detected at any other position. In column B, 42 incorporates Fe2+ and selenide to form the WFe3S3Se cubane 43, which upon reduction to the all-ferrous state is transformed to the EBDC 44 by formation of two Fe-(μ4Se) bridges. Reaction with hydrosulfide results in the PN-type cluster 45 and with hydroselenide, cluster 46. In column C under different conditions, 42, FeCl2, and hydrosulfide produce 47. Reaction with Na2Se leads to 48, a reduced form of 46. Note that the WS3 fragment of 42 remains intact in all reaction types, acting as a template for cluster construction. Consequently, bridge formation is confined to the far more labile iron sites. We regard selenide as a sulfide surrogate that enables sulfur atom tracking in cluster conversions that cannot be followed in another way.250 These results do not lead to mechanisms, but any proposed pathway should be consistent with them.

Core atom reactivity was pursued in reaction system (56) consisting of the synthetic clusters [Fe4Q4(SR)4]z (Q = S, Se) of the same charge (z = 2−, 3−) in acetonitrile in the absence of other reagents.245 The system with R = p-C6H4Me was particularly advantageous because of the resolution of isotropically shifted m-H and p-Me signals, allowing detection of all species. A complete mixture of five species generates eight signals of each type. Systems at or near equilibrium were obtained for 2− clusters at ca. 50 °C over several days; exchange among 3− clusters was much faster and proceeded to completion within hours at room temperature. Dinuclear clusters [Fe2Q2(S-pC6H4Me)4]2− also undergo exchange, but the systems are complicated by formation of tetranuclear species, likely under the stoichiometry of reaction (1) (Table 2). [Fe4S4 (SR)4 ]2 − /3 − + [Fe4Se4(SR)4 ]2 − /3 − ⇌

∑ [Fe4S4 − nSen(SR)4 ]2 − /3 −

(n = 1 − 3)

(56)

Given the cubane-type structure of core 4, in which each bridging atom is connected to an iron atom by three nominal bonds, S/Se exchange is not expected to be facile. However, at equal charge and coordination number, the radius difference r(Se2−−S2−) ≈ 0.10−0.15 Å leads to restricted dimensional differences in comparable structures. For instance, the core volume difference of the cubanes [Fe4Q4(SEt)4]2− (Q = S, Se) is slight, VSe−VS ≈ 1.0 Å 3.49 Essentially isomorphous structures are expected and should promote the otherwise different processes of protein reconstitution or atom exchange. The reconstitution of clostridial ferredoxin has been examined with limiting amounts of iron and sulfide. After purification, the protein was isolated with the same content as the native protein; that is, “no iron-poor or sulfide-poor ferredoxins containing less than 8 equiv of iron and sulfide could be recovered.”240 The reconstitution of ferredoxin has been colorfully described as “all-or-nothing” by Hong and Rabinowitz.240 In the absence of intermediates, we consider the overall process as self-assembly, which, however, must consist of a rapid sequence of fragment condensations to achieve the holoprotein.

9.4. Nitrogenase

Incubation of selenocyanate with A. vinelandii nitrogenase under fixing conditions leads to the remarkable result summarized in Figure 12A,B.251 The system was monitored by crystallographic methods at 1.60 Å resolution. Selenide is incorporated specifically at the site Se2B with the expulsion of sulfide, and the protein retains some dinitrogenase and acetylene reductase activity. The new core has the composition MoFe7CS8Se without appreciable change in structure from the native form. Over time, selenide migrates to sites 3A and 5A in the “belt” region of the structure. At high turnover numbers, all cluster selenide is lost, apparently by sulfide displacement. The source of sulfide and its delivery are currently unknown. In a seemingly closely related development, a carbonyl complex has been identified in which μ2-CO bridges the same two iron atoms involved in the selenide bridge of the starting cluster252 (Figure 12C). Some selenide density appears at the other two belt iron sites. The selenide reaction differs from protein reconstitution and from S/Se exchange in system (56) where (so far as is known) the two reactants are intact clusters. In synthetic systems, selenide can be placed in receptor clusters with external selenide and introduced into others in the course of cluster conversions (Figures 10 and 11). The involvement of the same iron atoms in both CO binding and S/Se exchange suggests that the properties of belt iron atoms may be critical to catalysis. The work of Spatzal et al.251 provides the first glimpse of the nitrogenase catalytic site and its possible rearrangements under turnover conditions.

9.3. Selenide as a Surrogate in Synthesis

The reactivity of selenide in various synthetic cluster manipulations is illustrated in Figure 10. Here, the trigonal

Figure 10. Chalcogenide incorporation reactions of [(tBu3tach)MS3] (40, M = Mo, W) to form the MS3Se cubane clusters [(tBu3tach)MS3Se(SR)3] (41).

10. EPILOGUE Last, the pathways [Fe2S2] (1) → [Fe3S4] (3) → [Fe4S4] (4) → [Fe8S8] (12), [Fe4S4] (4) → [Fe8S7] (13), and others in Figure 2, exemplify the reactivity and structural relationships within the family of weak-field iron−sulfur clusters. These amply justify the modular description applied to these compounds nearly 20 years ago12 and more recently in an analysis of the electronic features of the EBDC structure.253 The interdependent modular elements of the core include ionic sizes, roughly constant Fe− S bond distances, high-spin configurations, and (distorted) tetrahedral stereochemical preference at Fe2+,3+ sites. Abetted by

Mo6+ complexes [(tBu3tach)MS3] (40, M = Mo, W)246 readily support chalcogenide incorporation with Na2Q (Q = S, Se) to form the clusters 41 by fragment condensation.247 A variety of substituted clusters [MFe3S3Se]2+,3+ have been prepared in this way; core distortions are small and volumes increase by 1.5− 1.9%. In this and subsequent work, a strongly bound tridentate ligand acts as a protecting group for the M site. Selenide positions were determined by X-ray methods in all cases. 13704


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Figure 11. Scheme showing the use of Se in following the outcome of various cluster conversions starting with [(Tp*)WS3]1−. Products include those with EBDC (37, 44), PN-type (38, 45, 46), and cuboidal (Fe6S9-type; 47, 48) structures. Reproduced with permission from ref 250. Copyright 2012 American Chemical Society.

metal sites in combination can generate a truly Brobdingnagian collection of some 19 core structures (Table 1, Figure 1). With sulfide clusters of Co2+,3+, there are some indications of a similar but currently much more restricted cluster set, including Co4S4 (cubane-type) and Co8S8 (rhomb-bridged noncubane) structures.254 Much more needs to be done to place cluster synthesis and reactivity on a rational basis. Investigators interested in this endeavor need recognize that the [Fe8S7] (13, 31) and [(Fe/ Mo)Fe7CS9] (32, 33) clusters are unique to biology and specifically to nitrogenase. Together with carbon monoxide dehydrogenases255 and hydrogenases220,221 (inter alia), these represent the most exacting challenges of cluster design and synthesis in contemporary biomimetic inorganic chemistry. Such cluster syntheses would mark a singularly impressive event in the field, which is, after all, the inorganic version of natural product organic synthesis. Synthetic bioinorganic objectives usually lack regiospecificity of reactions at variant labile metal sites and recourse to the immense body of superlative methodology that defines organic synthesis. Core conversion has been demonstrated as an unequivocal reaction pathway for cluster synthesis, although the outcome is not always predictable. The most probable occurrence of core conversion is the formation of the EBDC structure (12, 37) from two cubanes, which requires the removal of a single ligand at each of two metal sites. The

Figure 12. (A) Side-on view of the structure of A. vinelandii M-cluster after incubation with SeCN− (1.60 Å) resolution. S2A, S5A, and Se2B are designated as belt atoms. (B) Structure in (A) viewed along the Fe− C−Mo axis. (C) Structure of the mono-CO adduct of (A) along the axis in (B) showing CO occupying the Se site. Adapted with permission from ref 251. Copyright 2015 eLife Sciences Publications; https:// creativecommons.org/licenses/by/4.0/legalcode.

the μ2−6 bridging proclivity of sulfur, the family of weak-field iron−sulfur clusters is enabled with the rhombic Fe2S2 core 1 as the fundamental unit. With the possible exception of iron oxo/hydroxo species, no other molecular cluster family exhibits comparable breadth and depth in structure and function, and thus in cluster conversions. It is evident that the variable bridging capability of sulfide and the structural and electronic features of four-coordinate high-spin 13705


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ACKNOWLEDGMENTS Research on iron−sulfur clusters in our laboratory has been supported by NIH Grant 28856. We acknowledge useful discussions with Professors S. C. Lee and M. Ribbe, and assistance with manuscript preparation by C. K. Ryder.

occurrence of intermediates of nuclearities 4−8 in the synthesis of the PN and FeMo-co clusters makes reasonable the proposition that core conversions will inevitably be demonstrated as steps in the biosynthesis and chemical synthesis of these clusters. 10.1. Addendum

ABBREVIATIONS aRNR anaerobic ribonucleotide reductase activase Asp·CO2 aspartate(1−) bipy 2,2′-bipyridyl C. acidiurici Clostridium acidiurici C. pasteurianum Clostridium pasteurianum co cofactor Cp2Fe ferrocene Cys·S cysteinate(1−) Cys·SS percysteinate(1−) D. africanus Desulfovibrio africanus D. gigas Desulfovibrio gigas Dmp 2,6-bis(mesityl)phenyl DMSO dimethyl sulfoxide DTT dithiothreitol EBDC edge-bridged double cubane E. coli Escherichia coli EXAFS extended X-ray absorption fine structure Fd ferredoxin FNR fumarate and nitrate reduction regulatory protein GuHCl guanidinium chloride Isc iron−sulfur cluster K. pneumoniae Klebsiella pneumoniae L terminal ligand (generalized) LS3 1,3,5-tris(4,6-dimethyl-3-mercaptothio)-2,4,6tris(p-tolylthio)-benzenate(3−) M metal (generalized) Meida N-methylimidodiacetate(2−) Nif, nif nitrogen-fixing NMF N-methylformamide P. furiosus Pyrococcus furiosus Pi inorganic phosphate PFL-AE pyruvate formate-lyase activase Pri2NHCMe2 1,3-diisopropyl-4,5-dimethylimidazol-2-xylidene pyX 3- and 4-substituted pyridine Q sulfide, selenide SAM S-adenosylmethionine SC single cubane Tip 2,4,6-tris(isopropyl)phenyl Tp tris(pyrazolyl)hydroborate(1−) Tp* tris(3,5-dimethylpyrazolyl)hydroborate(1−) T. maritima Thermotoga maritima Stip 2,4,6-triisopropylbenzenethiolate(1−) VTMCD variable-temperature magnetic circular dichroism X amino acid residue XAS X-ray absorption spectroscopy

Attention is directed to several reports noted as revision of this Review was completed. 10.1.1. [Fe2S]4+. One other example of this monosulfido bridged core, in the form of [Fe2S(OR)4(THF)2], has been prepared and characterized.256 10.1.2. [Fe 2 S 2 ] 0 ↔ [Fe 4 S 4 ] 0 . Reaction 57 between tetranuclear cluster 4 (Figure 9) and substituted pyridines in aromatic solvents results in ligand replacement and formation of binuclear clusters. Reaction 57 is noteworthy because it is the first core conversion Fe2S2 ↔ Fe4S4 in which both species are allferric, and because it is facilitated by reversible binding of a terminal ligand.257 2[Fe2S2 {N(SiMe3)2 }2 (pyX)2 ] ⇌ [Fe4S4 {N(SiMe3)2 }4 ] + 4pyX

(57)

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Present Address †

W.L.: 5812 NW 25th Avenue, Camas, Washington 98607, United States. Notes

The authors declare no competing financial interest. Biographies Richard H. Holm was born in Boston, MA. He spent his early years on Nantucket Island and in Falmouth, MA where he received his secondary school education. He is a graduate of the University of MassachusettsAmherst (B.S. degree) and Massachusetts Institute of Technology (Ph.D. in chemistry; advisor F. A. Cotton). He has served on the faculties of the University of Wisconsin, M.I.T., and Stanford University. Since 1980 he has been at Harvard University, where he has been Chair of the Department of Chemistry. As of 2006 he has been Higgins Research Professor and is now Higgins Emeritus Professor of Chemistry. His research interests are centered in inorganic and bioinorganic chemistry with emphasis on the synthesis and properties of molecules whose structures and reactivities are relevant to biological processes. With Professor Edward I. Solomon, he has been the guest coeditor of three thematic issues in Chemical Reviews: Bioinorganic Enzymology I (1996), Biomimetic Inorganic Chemistry (2004), and Bioinorganic Enzymology II (2014). Wayne Lo was born in Taipai, Taiwan. He graduated from National Chung-Hsing University (B.S. degree), University of MassachusettsBoston (M.Sc. degree), and Boston College (Ph.D. degree, advisor W. H. Armstrong). He has worked as a postdoctoral research associate with Professor R. H. Holm at Harvard University. His research interests are in inorganic and bioinorganic chemistry, with emphasis on systems with manganese and iron−sulfur clusters. He is presently employed in the chemical/semiconductor industry.

REFERENCES (1) Lee, S. C.; Lo, W.; Holm, R. H. Developments in the Biomimetic Chemistry of Cubane-Type and Higher-Nuclearity Iron-Sulfur Clusters. Chem. Rev. 2014, 114, 3579−3600. (2) Ogino, H.; Inomata, S.; Tobita, H. Abiological Iron-Sulfur Clusters. Chem. Rev. 1998, 98, 2093−2121. 13706


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