Current Bioactive Compounds 2009, 5, 321-352 321

1573-4072/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

Chemistry and Relevant Biomimetic Applications of Group 6 Metals Systems Supported by Scorpionates

Maura Pellei*, Grazia Papini, Giancarlo Gioia Lobbia and Carlo Santini

University of Camerino, Department of Chemical Sciences, via S. Agostino 1, I-62032 Camerino, Italy

Abstract: The structural and functional properties of group 6 metal complexes with scorpionate ligands, used as synthetic analogues for the binding sites of the molybdenum and tungsten enzymes, are the subject of the present review. The group 6 elements molybdenum and tungsten are the only second and third row transition metals essential to all forms of life on Earth. Molybdenum is found at the active sites of nitrogenase and all of the more than 50 known Mo-molybdopterin (Mo-MPT) enzymes that play vital roles in plant, animal, and human health, the carbon, sulfur, and nitrogen cycles, biofeedback systems, and the control of global climate; tungsten is also associated with MPTbased ligands in all its known biological manifestations. Chemical approaches to molybdenum enzyme sites have been directed toward mimicking a portion of the structural center in order to ascertain the role of that particular feature of the center on the chemical reactivity and the spectroscopic properties of the center. Here we attempt to analyze the overall progress on synthetic analogues of these enzyme centers and dissect the contributions of systems in which coordination spheres contain poly(pyrazolyl)borate ligands, focusing primarily on research that has appeared since the structures of the active sites of representative enzymes have become known.

Keywords: Tris(pyrazolyl)borates, molybdenum enzymes, biomimetic, model complexes.

1. INTRODUCTION

It is well established that a number of metal ions are essential to life [1, 2]. A major determinant of their func-tional relevance in living systems is that a substantial frac-tion of enzymes require metals for their catalytic activity. A wide variety of metal-dependent enzymes are found in Nature, which acts, in fundamental biological processes, including photosynthesis, respiration and nitrose fixation [3]. Over the years, a wealth of knowledge on enzymes has been accumulated, including data on three-dimensional structures, kinetic and biochemical properties, and reaction mechanisms [4].

As metalloprotein chemistry is governed by the environ-ment close to the metal center(s), a fertile field of investiga-tion is concerned with the preparation of low molecular weight complexes that mimic the structural or functional features of protein active sites. The synthetic analogue or model approach provides insights into bioinorganic systems through the synthesis and study of closely related ‘model’ compounds. It garners structural, electronic, spectroscopic, and chemical information crucial to a complete unders-tanding of enzyme behavior.

Trofimenko’s scorpionate ligands have been extensively used in biomimetic chemistry as spectator ligands, which modulate the electronic and steric properties of the metal ion and of the co-ligands or actor ligands, but are not directly involved in the metal-based reactivity. Poly(pyrazolyl) borates can in many ways mimic histidine nitrogen ligation, so, it is possible to synthesize simple models for active sites

*Address for correspondence to this author at the University of Camerino, Department of Chemical Sciences, via S. Agostino 1, I-62032 Camerino, Italy; Tel/Fax: +39 (0)737 402213; E-mail: maura.pellei@unicam.it

of bio-organic macromolecules such as enzymes. In recent years complexes of these ligands were successfully used to mimic the activity of enzymes containing various metals such as vanadium, manganese, iron, cobalt, nickel, copper, zinc, molybdenum and tungsten.

An important aim of the vanadium chemistry is to model vanadium histidine interactions thought to be present in the enzyme haloperoxidase [5]. The occurrence of vanadium in living systems and the relevant chemistry have been reviewed [6]. Recently, the vanadium complexes of general type [VO(O2)(Tp)(Hpz)] (Tp = hydrotris(pyrazol-1-yl)bo-rate, Hpz = pyrazole) and [VO(O2)(pzTp)(Hpz)] (pzTp = tetrakis(pyrazol-1-yl)borate) were synthesized, characterized and indicated as model for haloperoxidase (VHPO) enzymes [7, 8], that are able to catalyze the oxidation of halides to corresponding hypo-halous acids, which readily undergo halogenation of organic substrates or conversion of hydrogen peroxide to singlet oxygen and generation of halides. The pseudooctahedral V(IV) complexes with tris(pyrazolyl) borate ligands, [(Tp)V(O)Cl].dmf and [(Tp*)V(O)Cl].dmf (dmf = dimethylformamide, Tp* = hydrotris(3,5-dimethyl-pyrazol-1-yl)borate) were found to exhibit potent biological activity [9].

Mimicking the activity of manganese superoxide dismu-tase and of various binuclear manganese enzymes active in redox functions was approached with [(TpiPr2)Mn(OBz)] and related binuclear complexes [10-12] such as the [(TpiPr2)Mn2( -FOBz)3(HpziPr2)2] [13]. Dehydrative condensation of the dinuclear Mn(III)-bis( -oxo) complex [(TpiPr2Mn)( -O)]2

with H2O2 in the presence of 2-methylimidazole yielded the imidazole-containing peroxomanganese(III) complex [(TpiPr2)Mn( 2-O2)(HimMe)]. This complex may mimic the essential role of the ‘‘distal’’ histidine residue in the hemoglobin/myoglobin system [14].

322 Current Bioactive Compounds 2009, Vol. 5, No. 4 Pellei et al.

In the area of iron-containing enzymes, the behavior of the oxo-bridged di-iron enzyme hemerythrin was approxi-mated with complexes such as [{TpFe}2( -O)( -OOCR)] and [{TpFe}2( -OH)( -OOCR)] [15-17], while the complex [Fe(TpiPr2)(OBz)(CH3CN)] was regarded as a synthetic model for the dioxygen binding site of nonheme iron proteins [18]. The aliphatic -keto carboxylate, [FeII(O2CC(O)CH3)(TpPh2)], and the carboxylate complexes, [FeII(OBz)(TpPh2)]and [FeII(OAc)(TpPh2)(HpzPh2)], were synthesized and studied to clarify the key role that the -keto functionality plays in oxygen activation by -keto acid-dependent iron enzymes [19]. The complex [Fe(TpiPr2)(OOPtn)] has been described as a relevant model for potential intermediates in pterin-dependent hydroxylases [20]. Other related complexes were regarded as structural and functional models of catechol dehydrogenases [21] and as peroxo intermediate in the methane monooxygenase hydroxylase reaction cycle [22]. The complex [Fe(catecholate)(Tp*)(Hpz*)] has been prepared and its reactivity toward oxygen investigated as model for the catechol dioxygenases [23].

The cobalt complexes [Co(X)(Tpx) (X = N3, NCS; Tpx = Tp*, TpPh) have been used as catalysts in the bicarbonate dehydration reaction in the presence of inhibitors [24, 25].

Monomeric five-coordinate Ni-cysteine complexes of tris(3,5-disubstituted-pyrazolyl)borates (Tp* and TpPh,Me)and L-cysteine (diethyl ester and amino acid forms) were studied as being of relevance to the nickel component of the active site in several hydrogenase enzymes, which partici-pate in the bio-generation of hydrogen and methane, as well as in nitrogen fixation [26]. Hydrotris(3-phenyl-5-methyl-pyrazoyl)boratonickel(II) complexes with organoxanthate or dithiocarbamate coligands equilibrate between 2- and 3-chelation modes of the scorpionate ligand in solution, connecting N2S2 square-planar and N3S2 pyramidal ligand fields and a spin crossover. The complexes also exhibit quasi-reversible oxidations at low anodic potentials, thus modeling the structure, dynamics, and redox reactivity of the reduced nickel superoxide dismutase (NiSOD) active site [27].

Oxygen binding, activation, and reduction constitute processes carried out by copper enzymes, and the use of scorpionate-copper derivatives for modeling purposes has been reviewed [28]. Specific tris(pyrazolyl)borate copper complexes were used for modeling the active site in the phenylalanine hydroxylase [29], the copper–ethylene binding sites in plants [30], the copper center of galactose oxidase [31], in poplar plastocyanin [32], in mixed-valence tricopper(I,II,I) complexes with thiolate bridges as synthetic models of the putative {Cu2}

3+ sites in nitrous oxide reductase and cytochrome c oxidase [33], in oxyhaemo-cyanin and oxytyrosinase [34, 35], and in blue copper proteins [36]. For example, in the last application, the spectral properties of the copper complexes of Tp* and p-nitrobenzenethiolate or O-Et cysteinate are similar to those of the blue (type I) Cu proteins and allow certain definite conclusions to be drawn concerning the origin of the distinctive UV-visible, resonance Raman, and EPR spectral features (EPR = Electron paramagnetic resonance) of the proteins [36]. Similarly the tetrahedral copper(II)-thiolato complexes [Cu(TpiPr2)(StBu)] [37, 38], [Cu(TpiPr2)(SC6F5)]

and [Cu(TpiPr2)(SCPh3)] [39-42] bear close spectroscopic similarities to blue copper proteins. Spectroscopic and theoretical studies of mononuclear copper alkyl and hydroperoxo complexes have been reported and the Cu(II)-superoxo species are likely involved in the chemistry at several copper protein active sites, such as Cu/Zn superoxide dismutase, dopamine monooxygenase, peptidylglycine -hydroxylating monooxygenase [43]. In this contest the [Cu(O2)(TpiBu,iPr)] [44] and [Cu(O2)(TpAd,iPr)] [45] complexes have been investigated in order to elucidate the electronic structure of the diamagnetic mononuclear side-on CuII-superoxo complexes. The [{Cu(TpiPr2)}2(S2)], both in the side-on and end-on Cu2(S2) cores, have been prepared and compared with the peroxide analogous [46]. Theoretical chemistry investigations on a series of scorpionate copper complexes interacting with O2, have been performed by DFT methods and the effect of the substituents in 3- and 5-position of the tris(pyrazolyl)borate ligands, TpR,R', was analyzed [47-49]. These calculations reveal that the type of bridging oxygen, peroxo, or bisoxo is strongly influenced by the nature and position of the R substituents. The electronic effects of ligands at the 5-position are not significant, but peroxo complexes are favored by electron-withdrawing groups at the 3 position while bis-oxo ones are strongly sterically disfavored. Other model complexes relevant to enzymes have been described as the EPR-silent species [Cu(L)(TpPh)]+ (HL = 2-hydroxy-3-methylsulfanyl-5-methyl-benzaldeyde), showing spectroscopic similarity with the galactose oxidase [50], or [Cu(OAr)(TpiPr2)] (Ar = 4-F-C6H4;2,6-Me2C6H3) described as a model of intermediates of tyrosinase catalyzed oxidation of phenols [51], and [Cu (TpCOOEt,Me)(H2O)2]CIO4 as a structural model for many of the enzymes of the vicinal oxygen chelate superfamily [52].

In the past years both Tpx and Tmx have received consi-derable attention with respect to modeling zinc enzymes [53] and studies have been directed mainly to mimic carbonic anhydrase, liver alcohol dehydrogenase, 5-aminolevulinate dehydratase, and Ada DNA repair protein behavior [54]. A wide work in this field has been done in zinc complexes related to carbonic anhydrase, and the complexes [(Tpx)Zn(OH)] (including Tpx incorporating hydrogen bonding accepting ester substituents) have been synthesized, widely characterized and proved to be a good functional model for that enzyme [55-60].

In recent years many efforts have been focused to the design of hydrophilic copper(I) derivatives as in the case of the partial substitution of the ‘CuP4’ arylphosphine coordi-nation sphere with heterocyclic thiones [61], acetonitrile [62]and N-heterocycles, producing ‘mixed-ligand’ type comp-ounds [62]. Following a similar ‘mixed-ligand’ approach, several N2-scorpionate ligands have been attached to a coordination vacant lipophilic ‘CuP2’ moiety (P2 = bidentate dppe or two monodentate arylphosphines). The use of scorpionate co-ligands such as the dihydrobis(3-nitro-1,2,4-triazol-1-yl)borate [63], [H2B(tzNO2)2]

-, the bis(1,2,4-triazol-1-yl)acetate [64], [HC(CO2)(tz)2]

-, and the bis(3,5-dimethyl-pyrazol-1-yl)acetate [64], [HC(CO2)(pzMe2)2]

-, had the double aim at increasing the water solubility and the kinetic inertness of the resulting mixed-complex. Some less hydrophobic copper(I) compounds, {[H2B(tzNO2)2]Cu [(PR3)2]}, where R = m-tolyl or p-fluorophenyl, were proved to be easier to handle during the in vitro tests, and they

Group 6 Metals Systems Current Bioactive Compounds 2009, Vol. 5, No. 4 323

retained high cytotoxic activity against a panel of human tumor cell lines [63]. The substitution of arylphosphines with hydrophilic tris(hydroxymethyl)phosphine (thp) allowed the preparation of more hydrophilic species stable in aqueous media with improved cytotoxic properties [64]. In particular, mononuclear copper(I) complexes of the type {[L]Cu(thp)2}(L = [HC(CO2)(tz)2]

- or [HC(CO2)[(pzMe2)2]-) were found to

possess antiproliferative activity against different human tumor cell lines markedly higher than that shown by cisplatin [64]. Chemosensitivity tests performed on cisplatin sensitive and resistant human cancer cell lines (ovarian cancer 2008 vs. C13* and cervix cancer A431 vs. A431/Pt) established that (scorpionate)Cu(thp)2 type compounds were able to overcome cisplatin resistance, supporting the hypothesis of a different mechanism of action compared to that exhibited by the reference drug. Marzano et al. hypothesized that the cytotoxic activity of these copper(I) complexes might be correlated to their ability to trigger paraptosis, a non-apoptotic mechanism of cell death [63]. The 64Cu-labeled complexes of two scorpionate ligands, with the thp coligands, [HC(CO2)(pzMe2)2Cu(thp)2] and [HC(CO2)(tz)2Cu(thp)2], have been prepared to evaluate their usefulness as PET radiopharmaceuticals [65].

The complex [(TpMe,Ph)2Zn2(H3O2)]ClO4 [66] has been discussed for the relevance of its structure in terms of hydrolytic zinc enzymes, that use hydrogen-bond stabilized water nucleophiles to perform peptide bond cleavage. The protective pocket provided by the pyrazolylborate ligands TpCum,Me and TpPh,Me has made it possible to obtain stable and inert zinc complexes TpxZn-base of the anionic nucleobases (i.e. thymine, uracil, dihydrouracil, cytosine, adenine, guanine, diaminopurine, xanthine, hypoxanthine) in their deprotonated forms [67, 68] and to investigate the reactivity of aminoacids toward zinc [69, 70]. The complex [Zn(OH) TpCum,Me] has been reported to cleave activated amides and ester [71]. The tetrahedral zinc complex [(TpMe,Ph)ZnOH] was combined with acetohydroxamic acid, 3-mercapto-2-butanone, N-(methyl)mercaptoacetamide, -mercaptoetha-nol, 3-mercapto-2-propanol, and 3-mercapto-2-butanol to generate [(TpMe,Ph)Zn(ZBG)] (ZBG = zinc-binding group). These complexes were used as model to determine the mode of binding for three different types of thiol-derived matrix metalloproteinase (MMP) inhibitors [72].

A number of ligands suitable for modeling liver alcohol dehydrogenase (LADH) have been reported and their hydroxo zinc complexes also described [73-75]. For example the tris(2-thioimidazolyl)borate zinc complexes (Tm = tris(2-thioimidazolyl)borate) [Zn (TmMes)(ROH)]+, (R = Me, Et), exhibit a coordination environment that resembles aspects of that in LADH [76]. Studies on the functional modeling of alcohol dehydrogenase showed that TmZn complexes promote both the dehydrogenation of iso-PrOH and the hydrogenation of pentafluorobenzaldehyde [77]. The catalytic cycle of liver alcohol dehydrogenase was also modeled by [TptBu,MeZn]L species [78], while other comp-lexes mimicked the activity of alkaline phosphatase [79].The mononuclear zinc thiolate complexes [(TpPh,Me)Zn(SR)] were investigated and allowed to react with metallo- -lactamase CcrA from B. fragilis and proved to be modest to strong inactivators [80]. The activity of cobalamine inde-pendent methionine synthase was approached through com-plexes such as [(Tp*)Zn(SR)] and [(TpPh,Me)Zn(SR)] [81].

Several papers appeared in literature which report on the mechanism of action of LADH (liver alcohol dehyd-rogenase), showing examples of tris(pyrazolyl)hydroborato zinc complexes for the formation of alkoxides [82] and hydride transfer to the NAD+ models [83]. The tris(2-mercapto-1-phenylimidazolyl)hydroborato ligand, [TmPh], was used to prepare the complex [TmPh]ZnOH that represents a good structural model for the Zn enzyme 5-aminolevulinate dehydratase (ALAD) [84]. Tetrahedral Zn complexes of the NS2 donor ligand [phenyl(3-tert-butylpyra-zolyl)bis((tert-butylthio)methyl)borate] were designed to model the active sites in Escherichia coli methionine synthases; in particular the protonolysis of [Ph(pztBu)BttBu]Zn(CH3) by PhSH in toluene yielded [Ph(pztBu)BttBu]Zn(SPh), a synthetic analogue of the homocysteine ligated form of cobalamin-independent methionine synthase (Met E) [85]. Zinc enzyme modeling with zinc complexes containing polar tris(pyrazolyl)borate ligands with pyridyl and carbox-amido substituents, have been reported by Vahrenkamp and coworkers [86].

The structural and functional properties of group 6 metals complexes with scorpionate ligands, used as synthetic analogues for the binding sites of the molybdenum and tungsten enzymes, are the subject of the present review.

2. GROUP 6 METALS

The group 6 elements molybdenum and tungsten are the only second and third row transition metals essential to all forms of life on Earth. Molybdenum is found at the active sites of nitrogenase and all of the more than 50 known Mo-MPT enzymes (MPT = ‘molybdopterin’ or Metal-binding Pterin ene-1,2-dithiolate) that play vital roles in plant, animal, and human health, the carbon, sulfur, and nitrogen cycles, biofeedback systems, and the control of global climate [87, 88]. The Mo-MPT enzymes feature active sites composed of a single (mononuclear) Mo atom coordinated by one or two MPT-based ligands; tungsten is also associated with MPT-based ligands in all its known biological manifestations.

Chemical approaches to molybdenum enzyme sites have been directed toward mimicking a portion of the structural center in order to ascertain the role of that particular feature of the center on the chemical reactivity and the spectroscopic properties of the center. Here we attempt to analyze the overall progress on synthetic analogues of these enzyme centers and dissect the contributions of systems in which coordination spheres contain poly(pyrazolyl)borate ligands. This review will focus primarily on research that has appeared about pyrazolylborates group 6 metals chemistry since the structures of the active sites of representative enzymes have become known (since about 1995). Existing sources [89-97] provide background to earlier work in this area. The enzymology and other aspects of molybdenum biochemistry have been extensively considered elsewhere [87, 98-101] and are beyond the purview of this review.

2.1. Molybdenum: General Chemistry

High oxidation state metal-oxo chemistry is the key to catalysis of half-reaction (3) in molybdenum and tungsten enzymes:

324 Current Bioactive Compounds 2009, Vol. 5, No. 4 Pellei et al.

X + MVIO XO + MIV (1)

MIV + H2O MVIO + 2 H+ + 2 e- (2)

X + H2O XO + 2 H+ + 2 e- (3)

Eqn. (1) represents an oxygen atom transfer (OAT) reac-tion [90, 102]. Eqn. (2) is a coupled electron–proton transfer (CEPT) reaction in which the active site is regenerated [91]. The detailed molecular mechanism employed by an enzyme varies with the nature of its substrate X. Most pterin enzymes mediate formal oxygen atom exchange between substrate X and water (Eqn. 3) [90] and the reaction coupled to electron transfer between substrate X/XO, an Fe S center, heme, or flavin.

The OAT reaction is now well established for molyb-denum [90, 91, 102]. In particular, interconversion of cis-MoVIO2 and MoIVO complexes is promoted by a range of oxygen atom donors and acceptors via associative mechanisms. The ability of a dimethyl sulfoxide reductase enzyme to mediate reaction (1) in either direction has been interpreted in these terms [103]. An example of structurally well characterised catalytic system based upon the tris(pyra-zolyl)borate ligand is the complex [(Tp*)Mo(O2)(SPh)][104] (Fig. 1).

BHN N

N N

MoS

O

ONN

Fig. (1). [(Tp*)Mo(O2)(SPh)].

The dithiophosphate complexes [(Tp*)MoO(S2P(OEt)2]and [(Tp*)MoO2(S2P(OEt)2] are further examples of oxo-Mo(IV) and dioxo-Mo(VI) complexes that undergo facile oxygen atom transfer reactions and catalyze the oxidation of PPh3 by Me2SO (Fig. 2).

The catalytic system described here employs the sterically encumbering Tp* ligand to prevent Mo(V) dimer formation:

MoIVO + MoVIO2 [MoVO]2( -O) (4)

The forward and reverse reactions are first order with respect to both complex and substrate, consistent with bimolecular reactions involving mononuclear species.

The CEPT reaction depends upon bonding in M=O systems permitting dramatic modulation of the pKa of the O atom upon change of oxidation state of metal M. Formal reduction of a cis-MoVIO2 centre increases its basicity by population of * orbitals with significant oxo character [105, 106].

2.2. Structure and Function of MPT Ligands

All molybdenum enzymes, with the notable exception of the nitrogenases [87, 107, 108], involve a single metal atom bound to one or two molecules of a special ligand, originally named ‘‘molybdopterin’’ (MPT) [87, 109-111] (Fig. 3). However, as MPT also binds tungsten [112-116] this moiety is better named as the metal-binding pyranopterin ene-1,2-dithiolate, retaining the abbreviation MPT. MPT is com-prised of a pterin, with pyrimidine and pyrazine rings, the latter being linked to a pyran ring that carries both an ene-1,2-dithiolate (dithiolene) that coordinates the Mo (or W) as a bidentate ligand and a –CH2OPO3

2- group.

The Mo-MPT enzymes are widely distributed in microorganisms, plants and animals [87]. In prokaryotic

BHN N

N N

MoS

O

ONN

P O

S

OBH

N N

N N

Mo S

O

SNN

P

O

OPPh3 OPPh3

Me2S=OMe2S

Fig. (2). OAT reaction and oxidation of PPh3 by Me2SO.

HN

N NH

HN

O

O

H2N

S-

S-

OP

OR

O

O-

R absent or a nucleotide

HN

N NH

HN

O

O

H2N

S

S

OP

O-

O

O-

Mo

(a) (b)

Fig. (3). (a) Pyranopterindithiolate. (b) Minimal structure of the molybdenum cofactor and Pterin centre with pyran ring attached at positions 6 and 7. A 1,2-dithiolate unit capable of acting as a bidentate ligand to metal M occupies positions 1’ and 2’ of the pyran ring. The phosphate substituent is elaborated to a dinucleotide in enzymes from prokaryotic organisms.

Group 6 Metals Systems Current Bioactive Compounds 2009, Vol. 5, No. 4 325

enzymes, the phosphate group of MPT is usually linked to the phosphate group of a 5’-nucleotide of cytidine, gua-nosine, adenosine, or inosine; these are commonly referred to as ‘dinucleotides’, and are abbreviated, for example, as MGD (MPT-Guanosine Dinucleotide).

Three Mo-MPT enzymes have been found in mammals: (1) xanthine dehydrogenase has many, varied roles in purine catabolism, drug metabolism, and oxidative stress response, (2) aldehyde oxidase is important in drug metabolism and the synthesis of retinoic acid from retinal, and (3) sulfite oxidase plays a crucial role in the detoxification of sulfite produced in the degradation of cysteine and methionine. Genetic Mo-MPT deficiency in humans results in serious neurological disorders and infant death, while enzyme dysfunction manifests in a variety of afflictions.

Four MPT enzymes have been found in plants: (1) nitrate reductase catalyzes the conversion of nitrate to nitrite, a key step in the assimilation of nitrogen, (2) aldehyde oxidase catalyzes steps in the formation of phytohormones such as abscisic acid and indole-3-acetic acid, (3) xanthine dehy-drogenase is involved in ureide synthesis, purine catabolism, senescence, and oxidative stress response, and (4) sulfite oxidase is responsible for the detoxification of sulfite, produced during sulfur assimilation or from air pollution. Molybdenum deficiency in plants affects many species, causing poor vigor and chlorosis (yellowing) of the leaves, whereas Mo-MPT deficiency causes loss of function and death.

The majority of Mo-MPT enzymes (including all those in the DMSO reductase family, where DMSO = dimethyl sulfoxide) are found in microbes. They are responsible for metabolic functions and the adaptation of the organism to available nutrient levels and environmental conditions.

The Mo-MPT enzymes are classified into two broad functional types: oxotransferases and hydroxylases (Fig. 4).

The enzymes are generally referred to as oxotransferaseswhen the substrate is transformed by primary oxygen atom

transfer [89], and as hydroxylases when bound or unbound water or hydroxide is directly involved in the substrate transformation reaction.

The term oxotransferase [117] is not universally accepted, and the nomenclature of molybdenum and tungsten enzymes [88] and the associated pyranopterindithiolate (Fig.3) remains an active area of discussion [118]. Oxotrans-ferases catalyze oxygen atom transfer (OAT) to (for oxidases) or from (for reductases) the central atom of simple oxoanions, and S- and N-oxides, employing water as the source or destination of active oxygen ( O). The mediating role of molybdenum in oxygen transfer is obvious from equations (1) and (2) in Section 2.1, which combine to give the overall catalytic reaction in equation (3). The hydroxy-lases generally catalyze the insertion of an oxygen atom into C–H bonds of heterocyclic aromatic compounds and aldehydes, the oxygen atom again being derived from water (Eqn. 4).

From the combined structural information, Hille [87, 98, 119] has classified molybdenum enzymes into three families based upon their protein sequences and the structures of their oxidized active sites (Fig. 4); these being the xanthine oxidase (Mo hydroxylases), sulfite oxidase, and dimethyl sulfoxide reductase families, named after their archetypical member.

Some important examples of reactions catalyzed by Mo-MPT enzymes are:

1) Dimethyl sulfoxide reductase:

Me2SO + 2H+ + 2e- Me2S + H2O

2) Nitrate reductase (dissimilatory/assimilatory):

NO3- + 2H+ + 2e- NO2

- + H2O

3) Formate dehydrogenase:

HCOO- CO2 + H+ + 2e-

S

MoS

Y

S

S

X

S

MoS

OS-Cys

OH(H2O) S

Mo

S

S

OH(H2O)

O

Mo-MPT Enzymes

Oxotransferases Hydroxylases

DMSO reductase Family Sufite Oxidase Family Xanthine Oxidase Family

Fig. (4). Classification of Mo-MPT enzymes. X and Y represent ligands such as oxygen (oxo, hydroxo, water, serine, aspartic acid), sulfur(cysteine), and selenium atoms (selenocysteine).

326 Current Bioactive Compounds 2009, Vol. 5, No. 4 Pellei et al.

4) Arsenite oxidase:

H2AsO3- + H2O HAsO4

2- + 3H+ + 2e-

5) Polysulfide reductase:

Sn2- + H+ + 2e- Sn-1

2- + HS-

6) Trimethylamine N-oxide reductase:

Me3NO + 2H+ + 2e- Me3N + H2O

7) Sulfite oxidase:

SO32- + H2O SO4

2- + 2H+ + 2e-

8) Xanthine oxidoreductase (dehydrogenase):

xanthine + H2O uric acid + 2H+ + 2e-

9) Aldehyde oxidoreductase:

RCHO + H2O RCO2H + 2H+ + 2e-

10) Carbon monoxide oxidoreductase (dehydrogenase):

CO + H2O CO2 + 2H+ + 2e-

Oxotransferases isolated from prokaryotes belong to the DMSO reductase family. These enzymes include DMSO reductase, biotin S-oxide reductase, trimethylamine N-oxide reductase, dissimilatory nitrate reductase, formate dehydro-genase, selenate reductase, and arsenite oxidase; they feature distorted trigonal prismatic [MoVIO(X)L2] (X = serinate, cysteinate, selenocysteinate, and so on; L = MPT-based ligand) oxidized active sites. Some members of the DMSO reductase family, such as formate dehydrogenase and polysulfide reductase, catalyze reactions other than net OAT. Only two oxotransferases, sulfite oxidase and assimilatory nitrate reductase, have been identified in eukaryotes; they are members of the sulfite oxidase family and contain square-pyramidal cis-[MoVIO2L(cysteinate)] oxidized active sites. The hydroxylases are all members of the xanthine oxidase family. These unique enzymes contain square-pyramidal [MoVIOS(OH)L] oxidized active sites featuring a cataly-tically essential terminal sulfido ligand (or bridged Mo–S–Cu) moiety. Again, several members of this family catalyze unusual reactions, including the conversion of CO to CO2 by CO dehydrogenase, hydroxyl group transfer by pyrogallol transhydroxylase, and dehydroxylation by 4-hydroxy-benzolyl-CoA reductase.

In Figs. (5-10) are shown some schematic representations of active sites in the xanthine oxidase (Figs. 5 and 6), sulfite oxidase (Fig. 7), and DMSO reductase (Figs. 8-10) families in the oxidized (MoVI) and reduced (MoIV) states.

S

MoVIS

S

OH/H2O

OS

MoIVS

SH

O/N

O

(a) (b)

Fig. (5). Aldehyde oxidoreductase [120-122] (D. gigas, D. sulfuricans); xanthine oxidase/dehydrogenase [123-125] (bovine).

S

MoVIS

O

S

OHCuI S-Cys

Fig. (6). Carbon monoxide dehydrogenase [126] (O. carboxi-dovorans).

S

MoVIS

O

S-Cys

OS

MoVIS

O

S-Cys

OH/H2O

(a) (b)

Fig. (7). Sulfite oxidase [127-129] (chicken liver); nitrate reductase [130] (A. thaliana).

S

MoVIS

O

S

S

O-Ser

S

MoIVS S

S

O-Ser

(a) (b)

Fig. (8). DMSO reductase [131] (R. sphaeroides).

S

MoVIS

O

S

S

O-Cys

S

MoIVS S

S

O-Cys

(a) (b)

Fig. (9). Nitrate reductase [132] (D. desulfuricans).

S

MoVIS

O

S

S

Se-Cys

S

MoIVS S

S

Se-Cys

(a) (b)

Fig. (10). Formate dehydrogenase [133, 134] (E. coli).

The enzymes cycle through the molybdenum oxidation states Mo(IV), Mo(V) (paramagnetic), and Mo(VI). For the xanthine oxidase family of enzymes, the Mo(V) species are formed in the oxidative (from Mo(IV) to Mo(VI)) portion of the reaction cycle which regenerates the resting enzyme. The interrogation of paramagnetic states by electron magnetic resonance techniques such as electron paramagnetic reso-nance (EPR), electron nuclear double resonance (ENDOR), and electron spin echo envelope modulation (ESEEM) has provided a wealth of structural and mechanistic information

Group 6 Metals Systems Current Bioactive Compounds 2009, Vol. 5, No. 4 327

for: xanthine oxidases [135-139]; sulfite oxidases and sulfite dehydrogenase [140-145]; DMSO reductase [146-149]; nitrate reductases [150-154].

Prior to the availability of detailed knowledge of active site structures, extensive research was performed on molyb-denum-mediated oxo transfer [89-91], often with the explicit desire that it ultimately be relevant to enzyme action. One highly significant consequence of that research and conti-nuing investigations is that the atom-transfer chemistry of molybdenum is the best defined synthetically, structurally, and mechanistically of any element. More studies focused on the minimal primary oxo-transfer reaction (Eqn. 5):

MoIVO + EO MoVIO2 + E (5)

in which atom transfer proceeds by direct interaction of substrate and metal center. Systems that were intended to be biologically realistic were sterically constructed so as to repress or eliminate the usually irreversible -oxo “dimeri-zation” reactions (Eqn. 4).

The identify of active sites structures (Figs. 5-10) pose additional challenges for the synthetic bioinorganic chemist in that several of the features of these centers were not known for complexes of molybdenum prior to the determi-nation of the enzyme crystal structures. Specific synthetic problems are, for example: the formation of the uncommon {MoVIOS} group in the ligand environment site of aldehyde oxidoreductase and xanthine oxidase/dehydrogenase; the stabilization of the five-coordinate {MoVIO2} center of sulfite oxidase in the presence of a strongly reducing ligand environment of three thiolates; and the synthesis of monooxo and desoxo sites with appropriately simulated protein ligands.

Chemical approaches to molybdenum enzyme sites have been directed toward mimicking a portion of the structural center in order to ascertain the role of that particular feature on the chemical reactivity and the spectroscopic properties of the center. Here we attempt to analyze the overall progress on synthetic analogues of these enzyme centers and dissect the contributions of systems in which coordination spheres contain poly(pyrazolyl)borate ligands. The most extensively studied compounds contain the readily accessible hydrotris (3,5-dimethylpyrazolyl)borate ligand (Tp*). Infact, Tp* and related tripodal ligands enable stable mononuclear MoVI/V/IV

complexes to be isolated. These ligands contain no anionic sulfur donors, but their complexes have mimicked the overall reaction cycle of SO that involves incorporation of oxygen from water into the substrate via both two-electron and one-electron steps [155, 156]. These complexes also provide vehicles for investigating individually the effects of mono- and dithiolate ligands on the electronic structure of the molybdenum center.

2.3. Mo(VI) Complexes Supported by Scorpionate Ligands

Nitrido complexes are usually prepared by metathesis of MoNCl3 or nitridochloromolybdate species; improved syn-theses for (NEt4)2[MoNCl5] and (NEt4)2[MoNCl4] have been reported [157]. Diamagnetic [(Tp*)MoVINCl2] (Fig. 11) and paramagnetic NEt4[(Tp*)MoVNCl2] are obtained from the reactions of (NEt4)2[MoNCl5] with KTp* but only [(Tp*) MoN(N3)2] is isolated when Na[MoN(N3)4] is reacted with

NaTp*. The azide complex, [(Tp*)MoN(N3)2], exhibits a distorted octahedral geometry [157]. Reaction of MoCl4

(NCEt)2 with Me3SiN3 followed by addition of NaTp* produces mixed crystals of [(Tp*)MoN(N3)2] and [(Tp*) MoNCl(N3)] [158].

BHN N

N N

MoCl

Cl

NNN

Fig. (11). [(Tp*)MoVINCl2].

Tris(pyrazolyl)borate bis(imido)-complexes such as [(Tp*)Mo(NtBu)2Cl] (Fig. 12) and [(Tp*)Mo(NtBu)(NHtBu) Cl]BF4 are known and the structure of [(Tp*)Mo(NtBu)2Cl] has been determined [159].

BHN N

N N

MoN

N

ClNN tBu

tBu

Fig. (12). [(Tp*)Mo(NtBu)2Cl].

Tris(pyrazolyl)borate imido(oxo)-complexes, [(Tp)Mo (NAr)O(CH2CMe2Ph)] and [(Tp*)Mo(NR)OCl] (R = 4-(X)C6H4; X = Me, NH2, NMe2; Fc derivatives), have been prepared by hydrolysis [160] or reaction of primary amines with [(Tp*)MoOCl2] in the presence of NEt3 and air respectively [161].

Hydrazido and organohydrazido complexes are interme-diates in the reduction or utilization of dinitrogen in biolo-gical and chemical systems and are potential catalysts for alkene polymerization and metathesis reactions [162]. Spe-cies such as [(Tp)Mo(NNPh2)2Cl] and [(Tp*)Mo(NNPh2)2

Cl] (Fig. 13) have been prepared and structurally charac-terized [163].

BHN N

N N

MoN

N

ClNN NPh2

NPh2

Fig. (13). [(Tp*)Mo(NNPh2)2Cl].

Oxo complexes continue to dominate high-valent Mo chemistry. Trioxo–MoVI complexes are generated under stro-ngly oxidizing conditions in the presence of robust or chelating ligands. Complexes of this type are colorless and exhibit four-coordinate tetrahedral or six-coordinate distorted octahedral structures. For example, oxidative decarbony-lation of NEt4[(Tpx)Mo(CO)3] (Tpx = Tp, Tp*) by dimethyl-dioxirane, produces NEt4[(Tpx)MoO3]

.2H2O [164]. The anion of [(Tp)MoO3]

- (Fig. 14) exhibits a distorted octahe-

328 Current Bioactive Compounds 2009, Vol. 5, No. 4 Pellei et al.

dral geometry and a network of H bonds involving all three oxo ligands.

BHN N

N N

MoO

O

ONN

Fig. (14). [(Tp)MoO3]-.

Dioxo-MoVI complexes, having applications as oxidation catalysts, enzyme and metal oxide surface models, sensors, drugs, etc., have been reported since 1985. Tris(pyrazolyl) borate complexes containing carbon-donor coligands, [(Tp*) MoO2R] (R = Me, CH2SiMe3), are produced in the reactions

of [(Tp*)MoO2Cl] with RMgX [165] or AlMe3 followed by oxidation [166]. An X-ray structure of [(Tp*)MoO2(Me)] revealed a distorted octahedral geometry [166] (Fig. 15).

BHN N

N N

MoO

O

MeNN

Fig. (15). [(Tp*)MoO2(Me)].

Many dioxo-MoVI complexes containing tris(pyrazolyl) borate ligands have been prepared and characterized as part of a broad exploration of bio-relevant MoVI-MoIV chemistry (Fig. 16).

BH NN

N N

Mo

O

O

XNN

KTpx

+

MoO2X2

-KX

- [O]

+ [O]

BH NN

N N

Mo O

XNN

(1)

BHN N

N N

Mo

O

XNN

OB H

NN

NN

Mo

O

X N N

PR3

BH NN

N N

Mo

O

O

XNN

PR3

sol

BH NN

N N

Mo

O

sol

XNN

BH NN

N N

Mo

O

Y

XNN

[HaI]

[HaI]

BH NN

N N

Mo

O

Cl

ClNN

PPh3

KTpx

+

MoOCl3(thf)-KX

X-/Y-

BH NN

N N

MoS

Cl

ClNN

X-/X22-

BH NN

N N

MoS

X

XNN

BH NN

N N

MoO

O

XNN

HS-

BH NN

N N

Mo

S

O

XNN

(2)

(r1)

(r2)

(r3)

(r4)

(r5)(r6)

(r7)

(r8)

(r9)

(r10)

B2S3

(r11)(r12)

(3)

(4)

(5)

NEt3/H2O

TpxMoO2X

Fig. (16). (r1) Bu4SH, thf/CH3CN [104]. (r2) PPh3, DMSO; X = Cl, Br, NCS, OPh, SPh, SBn, SCHMe2 [156, 167]. (r3) Toluene [167]. (r4) Tpx = TpiPr, PR3, C6H6 or CH3CN; X = Cl, Br, OPh, SPh [168]. (r5) Coordinating solvents such as CH3CN [168]. (r6) Y = OMe, Cl; chlorinated solvents or MeOH [156]. (r7) Y = OMe, Cl; chlorinated solvents or MeOH [156]. (r8) Tpx = TpiPr, PPh3 in pyridine (py) or lutidine (lut) [169]. (r9) HX/Net3 or NaX (X-/Y- = Cl-, NCS-, N3

-, OR-, SR- or dianions), toluene, 70°C [170]. (r10) Tpx = Tp*, NEt3/H2O in dry toluene at reflux [169]. (r11) B2S3 in dry and deoxygenated CH2Cl2 [171]. (r12) Et3N in CH2Cl2; X = OPh, 2-(ethylthio)phenolate (etp), 2-(n-propyl)phenolate (pp); X2 = benzene-1,2-diolate (cat), 4-methylbenzene-1,2-dithiolate (tdt), benzene-1,2-dithiolate (bdt) [172].

Group 6 Metals Systems Current Bioactive Compounds 2009, Vol. 5, No. 4 329

Reaction of MoO2X2 (X = Cl, Br), MoO2X2L2 (X = F, Cl, Br; L = OPPh3, DMSO), or (NEt4)2[MoO2(NCS)4] with KTp*, KTpPr, or KTzMe2 yields [(Tpx)MoO2X] (X = F, Cl, Br, NCS) (Fig. 16, species (1)). Related complexes (X = OMe, OEt, OPh, SiPr, SPh, SBz, etc.) may be generated through methathesis with HX/NEt3 or alkali metal salts [104, 167]. Compounds of the type [(Tp*)MoVIO2X] exhibit oxo transfer to phosphines for X = Cl, Br, OPh, and several thiolates [155, 156]. For X = SPh, the resultant [(Tp*)MoIVO(SPh)(py)] complex has been isolated in the presence of pyridine and structurally characterized.

The oxo-thio complex, [(TpiPr)MoOS(OPh)] (Fig. 17,species (2)), is generated in the reaction of [(TpiPr)MoO (OPh)(OPEt3)] (Fig. 17, species (1)) with propylene sulfide [173]. The properties of the complex, especially the observation of strong 1s (Mo=S) S K pre-edge XAS features, are consistent with the presence of a monomer in

solution but only a redox dimer, [(TpiPr)MoO(OPh)]2( -S2)(Fig. 17, species (3)), has been isolated in the solid state [173]. Oxo-thio complexes undergo sulfur rather than oxygen atom transfer to tertiary phosphines and to cyanide. The MoIVO species can be reoxidized upon addition of Me2SO and it has been shown that these compounds catalyze the oxidation of tertiary phosphines to phosphine oxides by Me2SO [174]. Even more interesting than this reversible two-electron oxygen-atom-transfer chemistry is the cycle of reactions that is observed when phosphines are reacted with [(Tp*)MoO2(SPh)] in the presence of small amounts of water [155, 156]. These conditions result in the formation of [(Tp*)MoVO(OH)(SPh)], which can be detected by its EPR spectrum. Oxidation regenerates the starting MoVIO2

compound, which can then react with additional phosphines. When the reaction is carried out in labeled water, the label is incorporated into the phosphine. This analogue system remains the only one that catalyzes a two-electron oxidation

(1) (2)

(3)

(i)

BHN N

N N

Mo

ONN X

SB H

NN

NN

Mo

ON NX

S

BHN N

N N

Mo

ONN X

SBH

N N

N N

Mo

ONN X

O

PR3

S

Fig. (17). (i) Propylene sulfide in CH3CN [173].

S

MoVIS

O

S-Cys

O

SO32- S

MoIVS

O

S-Cys

O-SO32-

H2O/OH-

SO42-

S

MoIVS

O

S-Cys

OH

Cyt cIII

Cyt cII

S

MoVS

O

S-Cys

OHCyt cIII

Cyt cII + H+

Fig. (18). Proposed reaction cycle for sulfite oxidase.

330 Current Bioactive Compounds 2009, Vol. 5, No. 4 Pellei et al.

of the substrate by an oxygen-atom-transfer reaction with the subsequent regeneration of the oxidized molybdenum center by incorporation of water and successive one-electron transfers, passing through MoV. Thus, this minimal system incorporates the key components of the reaction proposed for sulfite oxidase (Fig. 18), in that the oxygen atom that is incorporated into substrate ultimately comes from water and reoxidation of the molybdenum center proceeds through two sequential one-electron steps.

The oxosulfido-Mo(VI) complexes, [(Tp*)MoOS (S2PR2)] (R = iPr, Ph), contain a -bonded sulfido ligand sta-bilized by a weak, intramolecular S---S interaction involving the monodentate dithiophosphinate ligand [175]. They are formed by sulfur atom transfer from propylene sulfide to [(Tp*)MoO(S2PR2)] and they are amenable to reduction to biologically relevant oxosulfido- and oxo(hydrosulfido)-Mo(V) species, and participate in clean biomimetic

reactions, e.g., cyanolysis and regeneration by sulfide [175]. Related hydro(5-iso-propylpyrazol-1-yl)bis (3-isopro-pylpyrazol-1-yl)borate complexes, [(TpiPr*)MoOS (S2PR2)], are also known [176]. In addition, some unperturbed oxosulfido-Mo(VI) complexes, [(TpiPr)MoOS(OAr)]n, (n = 1, 2; OAr = OPh or alkyl substituted phenolate or naphtholate derivative) have been prepared and isolated [177] as the -disulfido-Mo(V) dimers, [(TpiPr)MoO(OPh)]2 ( -S2) (Fig. 17,species (3)) [173] and [(TpiPr)MoO]2( -S2)( -O) and the “downstream” derivatives (thermodynamic products) [177] (Fig. 19).

The oxosulfido-Mo(VI) complexes are also amenable to electrochemical or chemical reductions providing access to authentic oxosulfido-Mo(V) complexes [173]. These, in turn, react with Cu(I) species to produce [(TpiPr)MoO(OAr)( -S)Cu(Me3tcn)] complexes (Me3tcn = 1,4,7-trimethyl-1,4,7-triazacyclononane), unprecedented models for the paramag-

BHN N

N N

Mo

ONN

O S

R

OP

Et

Et

Et

BHN N

N N

Mo

ONNO

R

S

BHN N

N N

Mo

ONN O

R

S

BHN N

N N

Mo

ONN

O

R

S

B HNN

NN

Mo

ON NO

R

S

BHN N

N N

Mo

ONN O

S

B HNN

NN

Mo

ON NS

H2O, -ArOH

+e-

BHN N

N N

Mo

ONN

O

R

S Cu L

[CuIL]+

MoO(m-S)Cu

Fig. (19). Synthesis and reactions of [(TpiPr)MoOS(OAr)] complexes; L = 1,4,7-trimethyl-1,4,7-triazacyclononane.

Group 6 Metals Systems Current Bioactive Compounds 2009, Vol. 5, No. 4 331

netic MoO( -S)Cu site (Fig. 19) of Carbon Monoxide Dehydrogenase (CODH) [178].

The [(Tp*)MoVIO2(SAr)] compounds undergo reversible electrochemistry in rigorously anhydrous solvents to give [(Tp*)MoVO2(SAr)]- complexes with distinctive EPR spectra [104]. Addition of water leads to protonation of one of the oxo groups to form [(Tp*)MoVO(OH)(SAr)], whose EPR spectra show a splitting, from the exchangeable proton, comparable to that observed for the Mo OH proton in the low-pH form of sulfite oxidase [179]. The monoanions can also be generated by reaction of the dioxo compound with Cp2Co [104]. When Tp* is replaced by the rela- ted tripodal ligand hydrotris(3,5-dimethyl-1,2,4-triazolyl-1-yl)borate (TzMe2), the resultant [Cp2Co][(TzMe2)MoVO2(SPh)] species was isolated and its X-ray structure determined [106, 180].

The covalency of the Mo SR interaction has been investigated by sulfur K-edge spectroscopy and DFT calcu-lations for [(Tp*)MoO2(SR)] compounds. It was suggested that the Mo SR torsional angle plays a role in selecting the equatorial oxo group for transfer [181]. However, Kirk and co-workers [182] have proposed that the primary role of the Mo SR torsional angle is to modulate the potential of the molybdenum site of SO and perhaps provide a super-exchange pathway for electron regeneration of the active site [183].

Complexes of the type [(Tpx)MoO2(S2PR2)] (R = alkyl, alkoxy) [174, 184], (Fig. 20, species (1)) can be accessed by metathesis but oxidation of the corresponding MoIV comp-lexes [(Tpx)MoO(S2PR2)] (Fig. 20, species (2)) provides more reliable syntheses. The X-ray structures of

BH NN

N N

Mo

O

S

S2PR2NN

BH NN

N N

MoO

S2PR2

OHNN

BH NN

N N

MoO

S2PR2

ONN

BH NN

N N

MoO

S2PR2

ONN

KTpx + MoIVO(S2PR2)2

BH NN

N N

Mo

S

S

ONN

PR

R

(2)

(1)

-e-, -H+

OH-

+e-

-e-

+e-

-e-

BH NN

N N

Mo

S

S

SNN

PR

R

B2S3

BH NN

N N

Mo

S

S

SNN

PR

R+e-

-e-

BH NN

N N

MoO

S

S2PR2NN

HS-

-e-

+e-

(3)

(4)

(5)

(ii)

(iii)

(iv)

(v)

(vi)

(vii)

(viii)

(ix)(x)

(xi)

(xii)

(xii)

(6)

BH NN

N N

MoS

S

ONN

PR

R

(i)

X'O

X'X

XO

S

CN-

PPh3 + H2OOPPh3

OH-

Fig. (20). (i) Tpx = Tp*; S2PR2 (R = Me, Et, iPr, Ph) in refluxing toluene [184]. (ii) B2S3 in CH2Cl2 [176]. (iii) [FeCp2]PF6 in dry thf/CH3CN [176]. (iv) X = PPh3; X’O = Me2SO, C5H5NO, NO3

- [174, 184]. (v) CN-, O2/H2O [175]. (vi) [184]. (vii) [175]. (viii) H2O [184]. (ix) [184]. (x) [184]. (xi) [184]. (xii) [176]. (xiii) C5H5NO in toluene at 55°C [184].

332 Current Bioactive Compounds 2009, Vol. 5, No. 4 Pellei et al.

[(Tp*)MoO2X] (X = S2P(OEt)2 [174], NCS [167], SPh [104]) and [(TpiPr)MoO2(OMe)] reveal distorted octahedral geometries defined by fac-Tpx and mutually cis-oxo and X ligands. Unlike most dioxo-MoVI complexes, Tpx complexes generally undergo reversible or pseudo-reversible, one-electron reductions producing stable EPR-active MoV species (Fig. 20, species (3)).

Redox potentials are influenced greatly by the nature of X and correlate with Hammett functions [104, 169]. These MoVI complexes are the cornerstones of synthetic enzyme models encompassing many biologically relevant oxidation states, oxo centers, reactions and informing electronic structure (Fig. 20) [156].

Oxo-molybdenum complexes containing hydrotris(pyra-zolyl)borate [155, 156] ligands feature in the more notable, functional OAT systems. A long-standing mechanistic des-cription of OAT from dioxo-MoVI centers to tertiary phosphines involves nucleophilic attack by the phosphine on an empty Mo=O * orbital. Experimental evidence for the proposed intermediate was provided through the in situdetection of species of the general formula [(Tp*)MoO (OPPh3)X], in which X = SPh, OPh, Br, and Cl [168]. Confirmation of the existence of OAT intermediates came through the isolation and structural characterization of [(TpiPr)MoO(OPR3)X] (X = Cl, substi-tuted phenolate, or alkyl thiolate) (Fig. 17, species (1)) [168, 185, 186] and [(Tp*)MoO(OPMe3)Cl] [187, 188]. This ligands system models for the reduction of DMSO by DMSO reductase and the oxidation of sulfite by sulfite oxidase, in which a catalytically labile oxygen atom is passed from the enzyme to the substrate with the concomitant transfer of two electrons [155, 156]. Recent calculations have predicted similar intermediates in other oxo-transfer model systems such as [(TpiPr)MoO(OPh)(OPR3)] (PR3 = PEt3 or PPh2Me) [189]. The nascent MoIVO species abstracts halogen from halogenated solvents to generate [(Tp*)MoVOX(halogen)] [167, 169]. This reaction is useful for synthesizing MoVOcomplexes with two different halide ligands. Compropor-tionation to give binuclear compounds with Mo2O3 cores has been observed in dry toluene [167]. The oxygen-atom transfer (OAT) and coupled electron-proton transfer chemistries of this and related systems have been reviewed by Young [190].

Oxo–thio complexes are useful to understand the unique oxo-thio MoVI active site in the Mo hydroxylases. In particular sulfur-atom transfer from propylene sulfide to green [(Tpx)MoO(S2PR2)] (R = alkyl, Ph) (Fig. 20, species

(2)) producing red [(Tpx)MoOS(S2PR2)] (Fig. 20, species (4)) [175], oxygen-atom transfer to [(Tpx)MoS(S2PR2)] (Fig.20, species (5)) [176], providing an alternative route to related complexes. Available spectroscopic and structural data for octahedral [(Tp*)MoOS(S2P

iPr2)], are consistent with the stabilization of the oxo–thio center by an S…Sinteraction [176]. Reduction or oxidation of the complexes [(Tpx)MoOS (S2PR2)] (Fig. 20, species (4)) produces MoV

species with concomitant S-S redox [191].

2.4. Mo(V) Complexes Supported by Scorpionate Ligands

Mononuclear Mo(V) complexes are relatively rare due to the propensity of Mo(V) to form di- or poly-nuclear species.

The dioxo-Mo(VI) complexes [(Tpx)MoO2X] (Tpx = Tp*, TpiPr or TzMe2; X = Cl, Br, NCS, OMe, OEt, OPh, SiPr, SPh, SCH2Ph) have been synthesized and characterized [104]. Cobaltocene reduction of [(Tpx)MoVIO2(SPh)]complexes (Tpx = Tp*, TpiPr or TzMe2 yielded extremely dioxygen-sensitive cobaltocenium salts of the cis-dioxo-Mo(V) radical anions cis-[(Tpx)MoVO2(SPh)]- [106], that can be isolated in some cases as CoCp2[(Tpx) MoO2(SPh)] (Fig.21). Freshly prepared solutions of CoCp2[(Tpx)MoVO2(SPh)] exhibited a broad EPR signal characteristic of a cis-[MoVO2]

+ complex. The signal was stable when Tpx = Tp* or TpiPr but when Tpx is the TzMe2 it was replaced by a proton-coupled signal characteristic of a cis-[MoVO(OH)]2+ center. The complex [(Tp*)MoVO(OH) (SPh)] was isolated as a coprecipitate with its conjugate base salt [CoCp2][(Tp*) MoVO2(SPh)] [106].

The complexes [(Tp*)MoVIO2X] (X = Cl, Br, NCS, OPh, SPh, SCH2Ph) are converted to air-stable complexes [(Tp*)MoVO(OSiMe3)X] by one-electron coupled electron-electrophile transfer (CEET) reactions involving cobaltocene and the electrophilic reagent Me3SiCl [192]. These complexes may also be obtained from [(Tp*)MoVO(OH)X] by reaction with Me3SiCl in the presence of base. The detailed redox properties of [(Tp*)MoVO(OR)X] (R = SiMe3, alkyl, aryl) differ from those of [(Tp*)MoVO(OH)X]. Centres [MoVO(OR)] are candidates for the stable “inhi-bited” forms of certain molybdenum enzymes formed under conditions which apparently disfavour the catalytically active [MoVO(OH)] centres [192].

The Tp* ligand also provides a vehicle for preparing a wide range of stable MoVO complexes. Indeed, the [(Tp*) MoO(X,Y)] complexes (X,Y = Cl, NCS, NC, OR, SR, and the dianions of ethylene glycol, mercaptoethanol, dimer-

BH NN

N N

MoO

O

SPhNN

BH NN

N N

MoO

O

SPhNN

BH NN

N N

MoO

O

SPhNN

CoCp2 CoCp2

+e-

-e-

Fig. (21). Electrochemical or chemical reduction of [(Tpx)MoO2(SPh)] (Tpx = Tp*, TpiPr or TzMe2).

Group 6 Metals Systems Current Bioactive Compounds 2009, Vol. 5, No. 4 333

captoethane, catechol, o-mercaptophenol, o-aminophenol, o-aminobenzenethiol, and toluenedithiol) provided the first extensive library of monomeric MoVO species, structurally characterized and investigated by EPR [170]. These compounds clearly showed a correlation of g and A(95Mo) parameters with the nature of X and indicated that SO should have at least two sulfur atoms in the inner coordination sphere. These compounds also provided evidence that ligand-based protons could give the large splittings for exchangeable protons that are observed in SO [170].

The spectroscopic results on the Mo(V) states of sulfite oxidase have also provided impetus for synthesizing and characterizing a series of [(Tp*)MoO(dithiolene)] com-pounds [170, 193-203] including [(Tp*)MoO(bdt)] [193, 195, 196], [(Tp*)MoO(tdt)] [170, 193], [(Tp*)MoO(bdtCl2)][202] and [(Tp*)MoO(qdt)] (qdt = quinoxaline-2,3-dithiolate) [194, 201]. The basic coordi-nation geometry of these complexes is depicted in Fig. (22).

BHN N

N N

M

O

S

SNN

Fig. (22). Basic stereochemistry of the [(Tp*)MoVO(dithiolene)] system showing the bidentate equatorial dithiolene ligands coordinated to the Mo center. The CS effective coordination geometry in this system places the mirror plane coincident with the M=O bond vector (directed along the z axis) and bisecting the MoN2 and MoS2 chelate angles defined by the N2S2 mean equatorial plane (x-y).

Recently, Holm and co-workers have synthesized and characterized a number of Mo mono-dithiolene complexes, including those possessing a third sulfur donor (thiolate) ligand, that mimic the [MoVIO2] and [MoVO] active-site structures of sulfite oxidase [204]. Kirk, Carrano, and co-workers have also synthesized and characterized new oxo-Mo monodithiolene models for sulfite reductase [205, 206]. Nonetheless, [(Tp*)MoO(dithiolene)] compounds [207] re-main important first-generation spectroscopic benchmarks for understanding the electronic structure of pyranopterin-containing molybdenum enzymes, especially xanthine oxidase and sulfite oxidase [193, 197, 208].

The EPR spectra of [(Tp*)MoVO(dithiolate)] complexes are essentially identical [196, 202], as would be expected, because the EPR parameters are primarily determined by the first coordination sphere of the MoVO center, which is the same for these compounds. For [(Tp*)MoVO(dithiolate)] complexes, the lowest energy ionization does show some dependence upon the nature of the arenedithiolate, with compounds possessing electron-withdrawing groups being somewhat more difficult to ionize [201, 202]. In 1,2-dichlo-roethane solution, cyclic voltammograms of [(Tp*)MoVO(dithiolate)] complexes show two reversible waves due to one-electron oxidation and reduction reactions to the corresponding MoVI and MoIV species [203]. The potentials

depend on the substituents on the arenedithiolate, and the oxidation potential correlates with the lowest energy gas-phase ionization energy [202]. The heterogeneous electron-transfer rates are essentially independent of the substituents [198, 203], in contrast to the [(Tp*)MoVO(4-OC6H4X)Cl] and [(Tp*)MoVO(4-OC6H4X)2] complexes (X = OEt, OMe, Et, Me, H, F, Cl, Br, I, and CN), in which both the potentials and the heterogeneous electron-transfer rates show a dependence on the para substituent (X) of the phenoxy group [209] (vide infra).

A structural feature of interest for dithiolate complexes is the fold angle of the dithiolate metallacycle along the S···S vector. Some years ago it was noted by Lauher and Hoffmann [210] that for Cp2M(dithiolate) compounds, this angle varies with the d-electron configuration of the metal. Compounds with a formal d0 configuration have large fold angles, whereas those with a d2 configuration show a fold angle closer to 0°. Large fold angles occur due to the stabilizing interaction of the filled symmetric sulfur porbital with the empty in-plane metal orbital, as shown schematically in Fig. (23).

Fig. (23). Bonding interaction of the symmetric combination of sulfur out-of-plane orbitals with the metal in-plane d orbitals upon folding of the dithiolate [211].

The [(Tp*)MoVO(dithiolate)] complexes have a 4d1

electron configuration, and the in-plane metal orbital is singly occupied. Dithiolate fold angles for these compounds range from 6.9 to 29.5° [202]. However, for [(Tp*)Mo(NO) (dithiolate)] compounds the fold angles are larger (41.4-44.4°) [211]. These large fold angles can be traced back to the electronic structure of the nitrosyl compounds. The presence of the [MoNO] fragment group results in the in-plane dxy orbital being empty, thereby favoring the folding interaction (Fig. 23). The availability of planar and folded geometries for dithiolate ligands provides a mechanism for the “electronic buffering” by these ligands [198].

The active sites of mononuclear molybdenum-containing enzymes contain a low-symmetry MoV-dithiolene inter-mediate whose structure can be probed using electron paramagnetic resonance (EPR). The relationship between experimental EPR spectra and the electronic and geometric structure of the active site can be difficult to establish, not least because of the low molecular symmetry. When density functional theory is used, it is possible to assess this relationship by systematically varying the geometric structure and comparing the theoretical EPR parameters with those obtained experimentally. Drew et al. [212] employed this approach to examine the relationship between the metal-dithiolate fold angle and the monoclinic spin Hamiltonian parameters (g, A, ) of the prototypical mononuclear molybdenyl model complex [(Tp*)MoO(bdt)] obtained by Joshi et al. [211]. By comparing the experimental EPR

334 Current Bioactive Compounds 2009, Vol. 5, No. 4 Pellei et al.

parameters with these results, they show that the metal-dithiolate fold angle of the complex in solution may be obtained from the non-coincidence angle that transforms the principal axes of g to those of A. This provides a useful method for probing the structure of the MoV intermediate of mononuclear molybdenum enzymes, where the electronic structure of the active site is modulated by the fold angle of the dithiolate ligand, the “metal-dithiolate folding effect”.

Oxosulfido-Mo(V) centers are implicated in the turnover of the enzymes under substrate limiting conditions [136]. Oxo-thio Mo(V) complexes, [(Tpx)MoOSX]- (X = Cl, Br, NCS, OMe, OEt, OPh, SiPr, SPh, SCH2Ph) and [(Tpx)MoOS (S2PR2)]

- (R = Me, Et, iPr, Ph) are the products of the reaction of [(Tpx)MoO2X] species (Fig. 16, species (1)) with HS- [184, 213]. The complex CoCp2[(TpiPr)MoOS(OPh)] has been isolated from the reaction of CoCp2 with monomeric [(TpiPr)MoOS(OPh)] [173].

Molybdenyl ([MoV=O]3+) complexes have been known for many decades, and their chemical, structural, spectro-scopic, and electronic properties are well documented [214]. Particular classes of complexes have been extensively studied by EPR spectroscopy; in particular: the halide and pseudohalide complexes containing six-coordinate octa-hedral [MoOX5]

2- and [MoOX4L]-, five-coordinate square pyramidal [MoOX4]

- [214, 215], the thiolates [MoO(SR)4]-

[182, 216-220] and the tris(pyrazolyl)borate complexes, [(Tpx)MoOXY] (X/Y = mono- and bidentate N-, O-, and S-donors) [104, 106, 192]. In particular, an extensive range of

complexes, [(Tp*)MoOXY] (Fig. 24) has been prepared and studied by Xiao and co-workers [104, 106, 192]. The starting materials are the [(Tp*)MoOCl2] complexes (Fig. 16, species (3)) prepared by reacting MoCl5 with thf and KTp* [170, 192, 221-226] and the [(Tp*)MoOI2] [227] complexes that are notable for their alternative syntheses. In situ-generated [(Tpx)MoO(XY)]+ species are accessible from MoVI/IV

species [176, 184, 196]. A related complex, [(Tp*)MoO(4-OC6H4OEt)2] NO3, has been isolated by Nemykin et al.[228] from the reaction of [(Tp*)MoO(4-OC6H4OEt)2] with (NH4)2Ce (NO3)6 (Fig. 25); it is a component of an OAT cycle featuring oxo-MoVI and desoxo-MoIV Tp* species.

Because Mo enzymes experience Mo(VI), Mo(V), and Mo(IV) states, it is important to investigate both the Mo(VI/V) and Mo(V/IV) couples. In this perspective, a series of [(Tp*)MoO(4-OC6H4X)2] complexes (X = OEt, OMe, Et, Me, H, F, Cl, Br, I, and CN) was investigated using electrochemistry and photoelectron spectroscopy to probe the effect of the remote substituent (X) on electron-transfer reactions at the oxomolybdenum core [209]. Cyclic voltammetry revealed that all of these neutral Mo(V) compounds undergo a quasireversible one-electron oxidation (MoVI/MoV) and a quasireversible one-electron reduction (MoV/MoIV) at potentials that linearly depend on the electronic influence (Hammett p parameter) of X. A nearly linear correlation exists for the first ionization energies in the gas phase and the Mo(VI/V) oxidation potentials in solution, indicating that solvent effects are negligible in these

O

O

XY =

S

S

O

O

S

S

O

O

S

S

O

O

S

S

O

O

O

S

O

S

O

S

S

S

O

HN

O

O N

NS

S

Cl

O

O

Cl

Cl

Cl O

O

S

S

S

HN

BH

N N

N N

MoV

X

Y

ONN

Fig. (24). [(Tp*)MoOXY] complexes; X = Y = Cl, I, N3, NCS, OMe, OEt, OPr, OPh, SMe, SEt, SPr, SiPr, SPh, O(4-ZC6H4) (Z = F, Cl, Br, I, CN, Me, Et, OH, OMe, OEt, OP(O)(OPh)2); X = O, Y = Br, NCS, OMe, OEt, OPr, SEt, SPr, SiPr, SPh; X = OSiMe3, Y = Cl, Br, NCS, OPh, SPh, SBn.

Group 6 Metals Systems Current Bioactive Compounds 2009, Vol. 5, No. 4 335

electrochemical measurements. These results for a series of oxo-Mo(V) complexes, with common donor atoms and stereochemistry, are consistent with the original proposal of Schultz and Olson [229] that the nature of the donor atom to the oxo-Mo(V) center primarily controls the rate of hete-rogeneous electron transfer in these systems. The reduction potentials of molybdenum enzymes that are presumed to have the same coordination environment can vary signi-ficantly. For example, the Mo(V/IV) couples of sulfite oxidase and plant nitrate reductase from eukaryotes, which both belong to the sulfite oxidase structural family, differ by

200 mV at pH 7 [87]. Thus, changes in the potentials of oxo-Mo centers of enzymes may have significant effects on the rates of electron transfer that are an integral part of their catalytic cycles.

A majority of the pyranopterin-containing molybdo-enzymes catalyze the formal transfer of an oxygen atom between substrate and solvent water [87] and these enzymes take part in the global nitrogen, sulfur, and arsenic cycles. A long-standing hypothesis states that the Mo active sites shuttle between dioxomolybdenum(VI) ([MoVIO2]

2+) and monooxomolybdenum(IV) ([MoIVO]2+) centers during the course of catalysis. Studies in several laboratories [90] have demonstrated that a variety of discrete oxomolybdenum complexes can carry out this chemistry when reacted with oxygen atom abstractors such as tertiary phosphines. Although, tertiary phosphines are not physiological subs-

trates, they are the most commonly used substrates for studying oxygen atom transfer (OAT) reactions in model inorganic systems. Interestingly, using 18O-labeling it has been convincingly demonstrated that the DMSO reductase (DMSOR) from Rhodobacter sphaeroides can catalyze the transfer of an oxygen atom from DMSO to a water-solu- ble tertiary phosphine [102]. The subsequent studies [131, 147, 230, 231] on the Rhodobacter sphaeroides enzyme were interpreted in terms of monooxomolybdenum(VI) ([MoVIO]4+) and desoxomolybdenum(IV) ([MoIV]4+) centers, respectively. The oxidized [MoVIO]4+ center regains the catalytic competency by coupled electron proton-transfer processes. The reactions reported in Fig. (25) demonstrated that a six-coordinate monooxo Mo(VI) center can carry out OAT chemistry in the absence of thiolate (or ene-dithiolate) donor ligands and the monooxo Mo(VI) center can be regenerated from a physiologically relevant water molecule. Thus, the chemistry described here parallels the previously proposed enzymatic reactions. These are important findings with respect to fully understanding the primary role of the pyranopterin ene-1,2-dithiolate in the oxidative and reductive half reactions of enzymes that cycle between monooxo Mo(VI) and desoxo Mo(IV) centers [228].

Spectroscopic studies, including IR, EPR [170, 192, 196, 221-225], single crystal EPR [232, 233], resonance Raman [193, 234], MCD (MCD = Magnetic Circular Dichroism) [193, 199, 201] photoelectron spectro-scopy [198] and L-

BHN N

N N

MoV

O

O

ONN

O

O

Et

Et

(NH4)2Ce(NO3)6

BHN N

N N

MoVI

O

O

ONN

O

O

Et

Et

NO3

-e-

PPh3

BHN N

N N

MoIV

O

O

O

NN

O

O

Et

Et

NO3

PPhPh Ph

-OPPh3

BHN N

N N

MoIV

O

O

NN

O

O

Et

Et

NO3

H2O -e-

Fig. (25). OAT cicle.

336 Current Bioactive Compounds 2009, Vol. 5, No. 4 Pellei et al.

edge XAS (XAS = X-ray Absorption Spectroscopy) [200] have contributed to a detailed understanding of the electronic structure of such complexes, particularly those with biolo-gically relevant dithiolene ligands.

More recently, McDonagh et al. reported the synthesis and spectroelectrochemical properties of 1- and 2-naph-tholate complexes and observed marked differences in the energy and intensity of the lowest-energy LMCT (LMCT = Ligand-to-Metal Charge Transfer) band of [(Tp*)MoOCl (OAr)] and [(Tp*)MoOCl(OAr)]+ [235]. The synthesis and characterization of [(TpiPr)MoOCl2] has also been reported [176]. Limited studies of [(Tpx)MoOCl2] have appeared as it is prone to dinucleation [(Tpx)MoOX]2( –O) [236] (Fig. 16,species (4)). The complex, [(L*)MoOCl2]Cl (L* = tris(3,5-dimethyl-1-pyrazolyl)methane), and related catecholate and ethanedithiolate derivatives have also been reported [237].

Thio–MoV centers are implicated in the turnover of industrial catalysts and enzymes but mononuclear thio-molybdenyl complexes are rare. The first complex of this type, [(Tp*)MoSCl2] (Fig. 16, species (5)), was prepared by sulfidation of [(Tp*)MoOCl2] (Fig. 16, species (3)) using B2S3 [171] and fully characterized [234, 238]. Derivatives such as [(Tp*)MoSX2] (X = OPh, 2-(ethylthio)phenolate

(etp), 2-(n-propyl)phenolate (pp); X2 = benzene-1,2-diolate (cat), 4-methylbenzene-1,2-dithiolate (tdt), benzene-1,2-dithiolate (bdt)) were described [172]. Related cationic complexes, e.g. [(Tpx)MoS(S2PR2)]

+ (Fig. 20, species (6)), have been prepared [176, 184].

2.5. Mo(IV) Complexes Supported by Scorpionate Ligands

The species [(Tp*)MoOL] (L = S2CNR2 (R = Me, Et) [239] (Fig. 26), L = S2PR2 (R = alkoxy, alkyl, Ph) [174, 184] (Fig. 20), L = pyridine-2-thiolate (pyS) [191]), are conve-niently produced by reacting MoOL2 with KTp* in refluxing toluene (Fig. 27). Attempts to prepare related complexes of TpiPr* (TpiPr* = HB(3-iPrpz)2(5-iPrpz)) were accompanied by a borotropic shift leading to [(TpiPr*)MoO(S2PR2)] (R = iPr, Ph) [176].

Reaction of [(Tp*)MoO(PyS)] with propylene sulfide forms the pyridine-2-dithio complex, [(Tp*)MoO(pyS2)], that can be reduced or oxidized to MoV species with con-comitant S-S redox [191] (Fig. 27).

The complexes [(Tp*)MoIVO(S2PR2)] (R = Me, Et, iPr, Ph) possess a bidentate S2PR2 ligand and abstract an oxygen

BH NN

N N

Mo

S

S

ONN

KTpx + MoOL2

C NR

R BH NN

N N

Mo

S

S

SNN

C NR

R(i) (ii)

Fig. (26). (i) Tpx = Tp*; L = S2CNR2 (R = Me, Et, nPr, nBu); toluene reflux [239]. (ii) B2S3 in dry and deoxygenated CH2Cl2 [239].

BHN N

N N

Mo

N

ONN

S

KTp* + MoOL2

SBH

N N

N N

Mo

N

ONN

SS

BHN N

N N

Mo

ONN

S

BHN N

N N

Mo

N

ONN

SS

N

S

+e-

-e-

Fig. (27). Reaction of [(Tp*)MoO(PyS)] with propylene sulfide.

Group 6 Metals Systems Current Bioactive Compounds 2009, Vol. 5, No. 4 337

atom from Me2SO or pyridine N-oxide to form [(Tp*) MoVIO2(

1-S2PR2)] in a bimolecular process [184].

The reverse reaction of [(Tp*)MoVIO2(1-S2PR2)] with

Ph3P in dry toluene produces [(Tp*)MoIVO(S2PR2)], but side reactions complicate kinetic analysis. Reduction of [(Tp*)MoVIO2(

1-S2PR2)] by HS- leads to [(Tp*)MoVO2

( 1-S2PR2)]-, which converts to [(Tp*)MoVOS( 1-S2PR2)]

-.Ferricinium oxidation of [(Tp*)MoIVO(S2PR2)] in moist solvents produces [(Tp*)MoVO(OH)(S2PR2)]. The MoVOcompounds were characterized by EPR spectroscopy. For the analogous tris(isopropylpyrazolyl)borate compound, reaction with boron sulfide produces [(TpiPr)MoIVS(S2PR2)], which undergoes oxo transfer to give [(TpiPr)MoVIOS( 1-S2PR2)]species [176].

Reaction of [(Tp*)MoO2X] with one equivalent of PR3 in donor solvents such as pyridine, lutidine, CH3CN and dmf produces [(Tp*)MoOX(sol)] via a transient OPR3 complex or unsaturated intermediate [156, 167]. The phosphine oxide complex, [(TpiPr)MoO(OPh)(OPEt3)], has been isolated and structurally characterized while unstable complexes of Tp* have been detected by mass spectrometry [168]. The X-ray structures of [(Tp*)MoO(S2CNEt2)] [239], [(Tp*)MoO {S2P(OEt)2}] [174], [(Tp*)MoOCl(py)] [167], [(Tp*)MoO (SPh)(py)] [156], [(TpiPr)MoO(S2P

iPr2)] [176], and [(TpiPr)MoO(OPh)(OPEt3)] [168] reveal distorted octahedral comp-lexes with short Mo=O bonds (generally < 1.68A Å) asso-ciated with a significant trans-influence (0.1-0.3 Å).

Many of the complexes above are important in enzyme model systems, the tris(pyrazolyl)borate ligands ensuring mononuclearity at MoVI, MoV, and MoIV levels during bio-logically relevant OAT and CEPT reactions (Figs. 16, 17 and20). This area was recently reviewed by Young [190].

Dinuclear complexes, [(Tp*)MoOCl]2( -L) (L = dipyri-dines), have also been structurally, spectroscopically, and electrochemically characterized by McCleverty and co-workers [240].

Species NEt4[(Tp*)MoO(S4)] was obtained as hydrolysis by-product in the reaction of NEt4[(Tp*)Mo(CO)3] and S8 in dmf/ether [241]. Hydrolysis also accounts for the unexpected products, [(Tp)MoO{C(4-C6H4Me)C(O)S}] and [(Tp)MoO (k3-4-S2CC6H4Me)], obtained in the reactions of [(Tp)Mo(4-CC6H4Me)(CO)L] (L = CO, PPh3) with CS2 [242] and S8 in refluxing thf [243], respectively.

The species [(Tp*)MoS(S2CNR2)] (R = Me, Et) [239] and [(TpiPr)MoS(S2PR2)] (R = iPr, Ph) (Fig. 20, species (5)) are produced in the reactions of oxo–MoIV analogs with B2S3

[176]. Reaction of NEt4[(Tpx)Mo(CO)3] (Tpx = Tp, Tp*) with an equivalent of S8 yields NEt4[(Tpx)MoS(S4)]. The complexes exhibit distorted octahedral geometries with terminal sulfido (Mo=S, 2.144 Å) and bidentate tetrasulfido (Mo–Sav, 2.247 Å and 2.294 Å, respectively) and facial Tpx

ligands [241].

Non-oxo complexes [(Tp*)MoX(S4)] (X = F, Cl, Br, NCS), have been produced by reaction of [(Tp*)MoO2X] with B2S3 and H2S mixtures. The very short Mo-S distances in [(Tp*)MoCl(S4)] (av. 2.192 Å) alternating S-S distances, planarity, and ring current of the tetrasulfido ligand are suggestive of strong Mo-S -bonding [244]. The blue/green [(Tp*)MoX(S4)] complexes (X = F, Cl, Br, NCS) react with

alkynes to yield mono(dithiolene) complexes such as structurally characterized [(Tp*)Mo{NCS)[S2C2(CO2Me)2}][245].

3. TUNGSTEN ENZYMES

The identification of tungsten as a bioelement is from a more recent date, and thus, it has come naturally to develop its biochemistry in comparison to that of molybdenum. Several aspects of W-biochemistry have been covered in recent reviews [246-248].

Tungsten enzymes are largely restricted to thermophilic organisms, which thrive in niche environments such as hot marine sediments and hydrothermal vents. In these extreme environments, the thermodynamic and kinetic attributes of tungsten appear to enhance the stability and performance of tungsten enzymes over molybdenum enzymes. The unusual biochemistry of the thermophiles is highlighted by their use of sulfur rather than dioxygen as terminal electron acceptor. However, it is in the assimilation of carbon from sources such as carbon dioxide, complex carbohydrates or proteins that the tungsten enzymes play key roles.

All known tungsten-containing enzymes have two pyranopterindithiolate ligands [249] and can be divided into two families: the aldehyde oxidoreductases that contain a non-modified tungsto-bispterin cofactor (Fig. 28), and the formate dehydrogenases which have a guanine monophos-phate attached to each pterin moiety (Fig. 29) [101].

HN

N

NH

HN O

PO3-

H2N

O S

S

NH

N

HN

NH

O-O3P

NH2

OS

S

W

Fig. (28). Tungsto-bispterin cofactor.

The best characterised enzyme is the aldehyde oxidoreductase of Pyrococcus furiosus [250], which catalyzes the reaction (Eqn. 6):

RCHO + H2O RCO2H + 2H+ + 2e– (6)

A formate dehydrogenase from Clostridium thermo-aceticum, which catalyzes the reaction (Eqn. 7):

HCO2– + H2O HCO3

– + 2H+ + 2e– (7)

is proposed to feature selenocysteine and 1,2-dithiolate ligands [251]. The tungsten formate dehydrogenases from two Methanobacterium strains are resistant to cyanide inactivation [87].

Despite remarkable insights provided by EXAFS (EXAFS = extended X-ray absorption fine structure) and X-ray crystallography, the detailed nature of the active sites in the tungsten enzymes remains uncertain. The presence of oxo, thio, mercapto, thiolato, selenolato and O- and N-donor ligands are all possible. The chemistry is expected to involve tungsten in oxidation states from W(IV) to W(VI). Chemical

338 Current Bioactive Compounds 2009, Vol. 5, No. 4 Pellei et al.

and EXAFS studies suggest that W=O, W=S, and/or W-SH groups may also be present [247, 250, 252]. Several com-pounds with these terminal functions have been prepared and investigated [253].

The WVIO2 group is relatively unreactive and nature may exploit sulfur ligands to enhance the oxidative capacity of tungsten centres. Several oxothio- and dithio-tungsten (VI) complexes of the hydrotris(3,5-dimethylpyrazolyl) borate ligand (Tp*) have been isolated using the high-valent WVIO2

and low-valent W0(CO)3 metal fragments as starting materials [254, 255]. These include the species [(Tp*) WVIOSX] and [(Tp*)WVIS2X] (X = OPh, SPh, SePh) [255]. tris(pyrazolyl)borate tungsten complexes combining electro-nically disparate -acid carbonyl and -base four electron-donor nitrile or chalcogenido ligands have been prepared and characterized [256]. The structures of the complexes are consistent with the mutual electronic requirements of the -acid and -base ligands involved in each case. The generation of a complete series of W(0), W(II), W(IV), and W(VI) complexes via oxidation/atom-transfer reactions demonstrates the viability of the selective synthesis of high-valent chalcogenido complexes via low-valent routes [256].

The reduction potentials of the WVIOS and WVIS2

complexes are 0.5–0.8 V more positive than those of the WVIO2 analogues and fall into the range observed for related MoVIO2 species. Terminal thio-ligation at WVI clearly facili-tates reduction. The oxothio- and dithio-tungsten(VI) com-

plexes are reducible at biologically accessible potentials whereas most of the dioxotungsten(VI) complexes are not easy reducible. In general, tungsten complexes are more difficult to reduce than their molybdenum counterparts at parity of ligation [257]. For example, the WVI/V and WV/IV

potentials of [(Tp*)WO(tdt)] are 382 and 272 mV more negative, respectively, than the potentials of the correspon-ding couples of [(Tp*)MoO(tdt)] [203].

The WVIOS and WVIS2 complexes interconvert with WIVO and WIVS species by sulfur atom transfer reactions (Fig. 30).

Interesting, cyanide ion inactivates xanthine oxidase/ dehydrogenase under oxidising conditions to produce a ‘desulfo’ MoVIO2 centre and SCN- [91]; in particular, the complex [(Tp*)MoVIOS(S2P

iPr2)] reacts with cyanide to produce SCN- quantitatively via a formal sulfur atom transfer, forming [(Tp*)MoIVO(S2P

iPr2)] under dry anaerobic conditions and [(Tp*)MoVIO2(S2P

iPr2)] in the presence of H2O and O2 [175] (Eqn. 8):

MoVIOS + CN- + H2O + O2 MoVIO2 + SCN- + H2O2 (8)

In contrast, several tungsten enzymes are not deactivated by cyanide [258].

A series of [(Tp*)WS2X] (X = OPh, SPh and SePh) complexes may be prepared from [(Tp*)WVIS2Cl] [254]. Solutions of [(Tp*)WVIS2X] react with alkynes to form (ene-1,2-dithiolate)tungsten(IV) complexes [255] (Fig. 31).

NH

N

NH

HNO NH2

OS

S

HN

N

HN

NH

OH2N

O S

S

W

OP

O

-O

O

OP

O

O-

O P

O

O-O

P

O

OO-

NH

N

N

O

NH2N

O

HOH

HH

HH

HN

N

N

O

H2N N

O

H OH

H H

H H

Fig. (29). Tungsto-bispterin cofactor with guanine monophosphate attached to each pterin moiety.

BHN N

N N

MS

S

ENN

P O

S

OBH

N N

N N

M S

E

SNN

P

O

OPPh3 S=PPh3

S8

E = O, S

Fig. (30). Sulfur atom transfer reactions.

Group 6 Metals Systems Current Bioactive Compounds 2009, Vol. 5, No. 4 339

These remarkably facile reactions are very rapid at room temperature, even with unactivated alkynes and including acetylene.

The complex [(Tp*)WIV(SePh){S2C2(Ph)(2-quinoxa-linyl)}] (Fig. 32) provides a structural and spectroscopic benchmark for the proposed site in the formate dehydro-genase. Interestingly, it decomposes rapidly in methanolic solution in air to give [(Tp*)WO2(OMe)], diphenyldiselenide and the 2-phenylthieno[2,3-b]-quinoxaline shown in Fig. (32) [255, 259].

This latter species is also formed in the oxidative decomposition of [Mo{S2C2(Ph)(2-quinoxalinyl)}3]

2-, in a reaction reminiscent of the formation of urothione (Fig. 33), the excretory by-product of molybdopterin in humans [260, 261], upon degradation of the molybdenum cofactor [262]; therefore, it is possible that degradation of pterin tungsten enzymes might produce urothione.

HN

N N

N

O

H2N S

S

OH

OH

Fig. (33). Urothione.

The recent crystallographic studies of various molyb-denum and tungsten enzymes emphasise the structural

diversity available to a cofactor ligand such as the pterin 1,2-dithiolate centre [120, 123, 128, 133, 263-269].

4. NITROGENASE AND RELATED SYNTHETIC MODELS HAVING PYRAZOLYLBORATE ANIONS

The most extensively studied nitrogenase enzyme con-tains iron and molybdenum metals, and is called molyb-denum nitrogenase [270-273]. In growth conditions where molybdenum concentration is low, a nitrogenase depending on iron and vanadium is expressed [274-277]. When both molybdenum and vanadium are unavailable, a third type of nitrogenase is expressed that contains iron as the only transition metal [274, 278, 279]. Mo-nitrogenase is the only one for which both detailed structural and mechanistic data are available [280-282]. The enzymatic complex comprises two proteins: the iron-protein (Fe-protein) and the molyb-denum iron-protein (MoFe-protein).

There are three catalytically necessary metal–sulfur clusters in iron–molybdenum nitrogenase: the Fe4S4 cluster in the Fe-protein, the FeMo-cofactor and the P-cluster.

The Fe-protein is the vehicle for a Fe4S4 cubane-type cluster, in which the tetrahedral coordination at each iron atom is completed by a cysteine residue (Fig. 34).

The Fe-protein is a homodimer, and the cluster lies at the interface between the two units, held by Cys97 and Cys132 from each subunit. The X-ray crystal structure of the Fe-protein shows that the iron–sulfur cluster is exposed to

BHN N

N N

W

ANN

S

S

O

O

O

O

BHN N

N N

W

A

NN

S

S

OO

O O

+

A = O, S or Se

Fig. (31). Synthesis of (ene-1,2-dithiolate)tungsten(IV) complexes.

BHN N

N N

W

SeNN

S

S

N N

MeOH

air, O2

BHN N

N N

W

ONN

Me

O

O SeSe

N N

SS

SS

N N

+ +

Fig. (32). Decomposition of [(Tp*)WIV(SePh){S2C2(Ph)(2-quinoxalinyl)}].

340 Current Bioactive Compounds 2009, Vol. 5, No. 4 Pellei et al.

solvent, a feature that presumably assists in acquisition of electrons from its natural electron donors (flavodoxin or ferredoxin) [283].

Fe SH

S

S

Fe

Fe

Fe

SSCys

SCys

SCys

SCys

Fig. (34). Structure of the Fe4S4 cluster of the Fe-protein.

The MoFe-protein is an 2 2 tetramer and contains two types of metal–sulfur centers: the so-called P-cluster of Fe8S7

stoichiometry that is located at the interface of each homologous subunit, and the FeMo-cofactor (MoFe7S9)found in each -subunit.

Fig. (35). Structures of the Iron-Molybdenum Cofactor (FeMo-co). [MoFe7( 2-S)3( 3-S)6( 6-N)] core. Identity of N atom is uncertain [282].

The iron–molybdenum cofactor (FeMo-co) of nitro-genase (Fig. 35) [269, 281, 282, 284, 285] is one of the most fascinating exhibits in bioinorganic chemistry, because it is here that the enzyme somehow catalytically cleaves the strong triple bond of N2 to give ammonia [286]. The FeMo-co has been observed in three redox states [281, 284, 287].

Two different structures are known for the P-cluster and are assigned to different cluster core oxidation states. In the reduced or PN (fully reduced) state, the Fe8S7 cluster can be described as two Fe4S4 cubes sharing one common hexacoordinate sulfur atom, the iron atoms being linked to the protein by cysteinate ligands, two of them bridging the

subcubes (Fig. 36). In the oxidized state POX state (P2+), oxidized by two electrons relative to PN, the central sulfur atom loses two bonds with two iron atoms in one of the subcubes, thus becoming more open. The tetrahedral coordi-nation of these two iron atoms is then completed by extra ligations from neighboring cysteine or serine residues [281, 282, 284].

Synthetic chemists have created iron–sulfur clusters that mimic the unusual distribution of iron atoms in PN [107, 288-294]. In particular monomeric clusters ([(Tp)2M2Fe6S9]

n-; M = Mo, n = 3; M = V, n = 4) are stabilized by the tris(pyra-zolyl)borate ligand, showing that the cluster topology found in PN can exist as a free entity in solution [291].

A route to such a cluster has been devised and is presented in Fig. (37) [291, 292]. It is based on the reactivity of an edge-bridged double cubane (EDBC), but one in which the molybdenum sites are trigonally symmetric in order to avoid isomeric product mixtures. The scheme begins with a self-assembly reaction (Fig. 37 reaction (i)), utilizing MoIV

complex [241], whose tetrasulfide ring is subject to reduc-tion to afford sulfide. The reaction yields [295] the first prepared trigonally symmetric MoFe3S4 single cubane (Fig.37, species (A)). By reductive substitution the cubane-like cluster with the [MoFe3S4]

3+ core oxidation state and chloro ligands at Fe (Fig. 37, species (A)) is converted to the phosphine substituted [MoFe3S4]

2+ cluster (Fig. 37, species (B)), which is reduced by borohydride to the edge-bridged double cubane (Fig. 37, species (C)) with the [Mo2Fe6S8]

2+

core. This is the first cluster isolated in the all-ferrous [MoFe3S4]

+ oxidation state. The species (C) upon subs-titution with chloride gives [(Tp)2Mo2Fe6S8Cl4]

4- and upon exposure to 3 equivalents of [Et4N][HS] rearranges into species (D), a topological analogue of the Fe8S7 P-cluster with the [Mo2Fe6S7]

5- core, isolated as the crystalline Et4N+

salt. Reaction (Fig. 37 reaction (iv)), proceeds with displacement of the phosphine ligands, substantial core rearrangement with incorporation of one additional sulfide atom, and binding of two terminal hydrosulfide ligands. One-half equivalent of dihydrogen is proposed but not established to account for the [Mo2Fe6S9]

+ core oxidation level, which is one electron more oxidized than 2[MFe3S4]

++S2-. In a related method, double cubane [(Tp)2Mo2Fe6S8Cl4]

4-

with 4 equiv of NaSH in acetonitrile gives (Fig. 37, species (D)).

Despite the heterogeneity of the metal content in the models, comparison with structures of the clusters of nitrogenase in the dithionite-reduced states [282] (Fig. 36

Fe S

S

S

Fe

Fe

Fe

S Fe

S

S

Fe

Fe

Fe

SSCys

SCys

SCys SCys

SCys Fe S

S

S

Fe

Fe

Fe

S Fe

S

S

Fe

Fe

Fe

SSCys

S

SCysSCys

SCys

SCys

SCys

N

OSer

(a) (b)

Fig. (36). Structure of the P-clusters of nitrogenase in: (a) the reduced state: [Fe8( 2-SCys)2( 3-S)6( 6-S)] core, (P-Cluster, PN state); (b) the oxidized state (POX).

Group 6 Metals Systems Current Bioactive Compounds 2009, Vol. 5, No. 4 341

(a)) demonstrates a close topological relationship between the PN cluster and species (D) reported in Fig. (37), which consists of two MoFe3( 3-S)3 cuboidal fragments linked by two 2-S atoms, simulating two 2-SCys bridges and one 6-S atom. The core bridging pattern is [Mo2Fe6( 2-S)2( 3-S)6( 6-S)]+. Each iron atom has distorted tetrahedral FeS4

coordination. Fragments of the precursor cluster (Fig. 37,species (C)), are evident as two [(Tp)MoFe3S3] portions of species (D) reported in Fig. (37). The molybdenum atoms retain distorted octahedral coordination, and mean Mo N, Mo S, and Mo Fe distances change less than 0.04 Å. With two MoFe3S4 cubanes present in species (C), a reasonable supposition is that the 6-S atom introduced in reaction (iv) of Fig. (37) originates in the external hydrosulfide reactant. However, using selenide as a surrogate for sulfide, reaction (Fig. 34 reaction (v)) was carried out [292]. Product cluster

(Fig. 37, species (E)) consists of two fragments [(Tp)2

Mo2Fe6S9]5-, doubly bridged by 2-X (X = S, Se) and related

by a two-fold axis. The bridge atoms occupy the positions of the hydrosulfide ligands in species (D) of Fig. (37).

The P-cluster structure could be stabilized in other molecules; in Fig. (38), with a procedure parallel to Fig. (37), the synthetic pathway for the vanadium-containing PN-cluster topological analogue is reported [291, 293, 296]. The initial step of phosphine substitution occurs without reduc-tion (Fig. 38, species (B)). Reduction of the cluster with cobaltocene yields double cubane (Fig. 38, species (C)), isostructural (R = Et) with the species (C) reported in Fig.(37) and one of only two clusters thus far isolated in the all-ferrous [VFe3S4]

+ oxidation state [296]. Reaction (iii) leads to cluster (D), obtained as the Et4N

+ salt.

Fe

SBH

N N

N N

N N S

MoFe

Fe

S

S

S

Fe

Mo

S

FeS

FeS

S

SH HS

B H

NN

NN

NN

BH

N N

N N

N N

MoS

S

S

S

S(i)

BH

N N

N N

N N S

MoFe

Fe

S

S

S

Fe

Cl

Cl

Cl

(ii)BH

N N

N N

N N S

MoFe

Fe

SH

S

S

Fe

PEt3

PEt3

PEt3

(iii)

BH

N N

N N

N NS

MoFe

Fe

S

S

S

Fe

Et3P

B H

NN

NN

NNS

MoFe

Fe

S

S

S

Fe

PEt3

PEt3

Et3P

(iv)

Fe

SBH

N N

N N

N N S

MoFe

Fe

S

S

S

Fe

Mo

S

FeS

FeSe

Se

Se Se

B H

NN

NN

NN

(v)

FeB H

NN

NN

NNS

MoFe

Fe

S

S

S

Fe

Mo

S

FeS

FeSe

Se

BH

N N

N N

N N

1- 1+

3-

5-

(A)(B)

(C)

(D)

(E)

Fig. (37). Synthetic pathway to the molybdenum-containing PN-cluster topological analogue of the PN cluster of nitrogenase. (i) 3FeCl2,3NaSEt, PPh3; (ii) PEt3, NaBPh4; (iii) (Bu4N)BH4; (iv) 3(Et4N)SH; (v) (Et4N)SeH.

342 Current Bioactive Compounds 2009, Vol. 5, No. 4 Pellei et al.

Clusters (D) reported in Figs. (37 and 38) are isostructural and nearly isoelectronic. The clusters have a crystallogra-phically imposed two-fold axis which contains atom 6-S and is perpendicular to the Fe4 plane in the center of the molecule.

The 6-S atom and its associated interactions constitute the most extraordinary part of the structures of the clusters (D) reported in Figs. (37 and 38). Sextuply-bridging sulfur atoms are not unprecedented in synthetic clusters, but they are rarely encountered. The Fe ( 6-S) Fe angles of 141.0° in species (D) of Fig. (37), and 140.8° in species (D) of Fig.(38) are identical and are the largest Fe S Fe bond angles in the structures [292, 293]. Clusters (D) reported in Fig. (37

and 38) have the same overall shape as the PN cluster. A best-fit superposition of the V2Fe6S9 core of species (D) in Fig. (38) with the core atoms of the PN cluster of nitrogenase (K. pneumoniae MoFe protein) [281] leads to an rms deviation of 0.33 Å in atom positions [107]. The corres-

ponding deviation for species (D) in Fig. (38) is 0.38 Å. One source of the deviation between synthetic clusters and the PN

cluster is the significantly larger Fe ( 6-S) Fe angle of 158° and its attendant effect on atom positions in the native cluster. The differences of a Mo2Fe6 or a V2Fe6 instead of an Fe8 metal content and two 2-S atoms instead of two 2-SCys

bridges notwithstanding. Therefore, clusters (D) reported in Figs. (37 and 38) are the initial examples of molecular topological analogues of the PN cluster of nitrogenase.

The syntheses reported in Fig. (37) and Fig. (38) show that the PN geometry can spontaneously assemble from a cubane synthon, hydrosulfide, and reducing agent. The Fe-protein is essential in the natural synthesis of working MoFe-protein, suggesting that a similar reductive cluster fusion could be relevant in the biosynthetic pathway.

High-nuclearity metal-sulfur clusters may function as precursors to other clusters related in structure to the P-

Fe

SBH

N N

N N

N N S

VFe

Fe

S

S

S

Fe

V

S

FeS

Fe

S

S

SH HS

B H

NN

NN

NN

BH

N N

N N

N N S

VFe

Fe

S

S

S

Fe

Cl

Cl

Cl

(i)BH

N N

N N

N N S

VFe

Fe

S

S

S

Fe

PR3

PR3

PR3

(ii)

BH

N N

N N

N NS

VFe

Fe

S

S

S

Fe

R3P

B H

NN

NN

NNS

VFe

Fe

S

S

S

Fe

PR3

PR3

R3P

(iii)

2- 1+

4-

(A)(B)

(C)

(D)

Fig. (38). Synthetic pathway to the vanadium-containing PN-Cluster Topological analogue of the PN cluster of nitrogenase; (i) PR3; (ii) Cp2Co; (iii) (Et4N)SH.

Group 6 Metals Systems Current Bioactive Compounds 2009, Vol. 5, No. 4 343

cluster (Fe8S9) and FeMo-cofactor cluster (MoFe7S9) of nitrogenase [297, 298]. In particular, the double cubane [(Tp)2Mo2Fe6S8(PEt3)4] system has been investigated as model for the reactivity of the nitrogenase PN cluster [291-293]; the complex sustains terminal ligand substitution with retention of the Mo2Fe6( 3-S)6( 4-S)2 core structure and rearrangement to the Mo2Fe6( 2-S)2( 3-S)6( 6-S) topology of the nitrogenase PN cluster [281, 284] upon reaction with certain nucleophiles. Distinct processes for the conversion of double cubanes to PN-type clusters are documented, affording the products [(Tp)2Mo2Fe6S9(SR)2]

3- [294], [(Tp)2

Mo2Fe6S9(SH)2]3- [299], [(Tp)2Mo2Fe6S8(OMe)3]

3- [294], [(Tp)2Mo2Fe6S7(OMe)4]

2- [294], [(Tp)2Mo2Fe6S9(OH)2]3-

[300], [(Tp)2Mo2Fe6S9(OMe)2(H2O)]3- [300], [{(Tp)2Mo2

Fe6S9( 2-O)}2]5- and [(Tp)2Mo2Fe6S8Q(QH)2]

3- (Q = S, Se) in which HQ- is a terminal ligand and Q2- is a 2-bridging atom in the core [300]. The reverse transformation of a PN-type cluster to an edge-bridged double cubane has been demonstrated by the reaction of [(Tp)2Mo2Fe6S8(OMe)3]

3-

with Me3SiX to afford [(Tp)2Mo2Fe6S8X4]2- (X = Cl, Br)

[294].

In biomimetic research, many fewer heterometal MFe3S4

cubane-type clusters have been synthesized with vanadium or tungsten than with molybdenum because of the well-established structural relationship of the latter to the molyb-denum coordination unit in the nitrogenase MoFe-protein [107, 301].

A structural relationship appears to exist between VFe3S4

clusters and the vanadium site in VFe-proteins [274, 275]. Far fewer vanadium than molybdenum single cubanes (SC) clusters, containing the [VFe3( 3-S)4] core of idealized trigonal symmetry, have been prepared since their inception in 1986-1987 [302-304], and the first and only examples of vanadium edge-bridged double cubanes (EBDC), with the core [V2Fe6S( 3-S)6( 4-S)2] of idealized centrosymmetry, were obtained in 2002 [291] (see Fig. 38). The two cluster types may be generalized as [(Tpx)VFe3S4X3]

z and [(Tpx)2

V2Fe6S8X4]z of variable oxidation level z with diverse Tpx

ligands (hydrotris(pyrazolyl)borate or tris(pyrazolyl) methanesulfonate) bound to the octahedral heterometal site and ligands X (X = phosphine, thiolate, or halide) at the tetrahedral iron sites. These matters are best pursued with clusters in which Tpx is constant, facilitating the isolation of clusters of either heterometal with the same charge z. Infact, the tris(pyrazolyl)borate ligand conforms to the trigonal symmetry of the SC core and in synthesis generally affords SCs with z = -2 and EBDCs with z = -3 or -4 in species carrying monoanionic ligands X [292, 293, 295, 296, 298, 305].

Recently, a series of single cubane and edge-bridged double cubane clusters containing the cores [VFe3( 3-S)4]

2+

and [V2Fe6( 3-S)6( 4-S)2]2+ have been prepared [306] by

ligand substitution of the phosphine clusters [(Tp)VFe3S4

(PEt3)3]+ and [(Tp)2V2Fe6S8(PEt3)4]. The single cubanes

[(Tp)VFe3S4L3]2- and double cubanes [(Tp)2V2Fe6S8X4]

4- (X = F, N3, CN, PhS) are shown by X-ray structures to have trigonal symmetry and centrosymmetry, respectively. Single cubanes form the three-member electron transfer series [(Tp)VFe3S4X3]

3-,2-,1-. The ligand dependence of redox poten-tials and electron distribution in cluster cores as sensed by 57Fe isomer shifts ( ) have been determined [306].

Examples of WFe3S4 clusters, nearly all in the form of tungsten-bridged double cubanes, were prepared nearly simultaneously with molybdenum containing clusters in the early development of M–Fe–S cluster chemistry [307-309]. Few others have been prepared since that time [310, 311]. The structures of tungsten–iron–sulfur clusters have been explored using reactions based on [(Tp*)WS3]

- as precursor, which reacts with FeCl2, NaSEt and S affording the cubane cluster [(Tp*)WFe3S4Cl3]

-, which with NaSEt is converted to [(Tp*)WFe3S4(SEt)3]

-. Treatment of [(Tp*)WFe3S4Cl3]- with

Et3P yields the edge-bridged double [(Tp*)2W2Fe6S8(PEt3)4]with the [W2Fe6( 3-S)6( 4-S)2] core. The cubane cluster [(Tp*)WFe3S4Cl3)]

- reacts also with an excess of Et3P, BH4-

and HS- leading a mixture of products, from which [(Tp*)2W2Fe5S9Na(SH)(MeCN)]3- was identified. This cluster, as closely related [(Tp)2Mo2Fe6S9(SH)2]

3-, exhibits a core topology [W2Fe5Na( 2-S)2( 3-S)6( 6-S)] very similar to the PN cluster of nitrogenase [312].

5. CONCLUDING REMARKS

Poly(pyrazolyl)borate ligands have given rise to a tremendous amount of chemistry with an amazing diversity. These ligands have been extensively used in biomimetic chemistry as spectator ligands, which modulate the electronic and steric properties of the metal ion and of the co-ligands, but are not directly involved in the metal-based reactivity. In recent years complexes of these ligands were successfully used to mimic the activity of enzymes containing molyb-denum or tungsten. Chemical approaches to molybdenum enzyme sites have been directed toward mimicking a portion of the structural core in order to ascertain the role of that particular feature of the center on the chemical reactivity and the spectroscopic properties. We have attempted to analyze the overall progress on synthetic analogues of these enzyme centers and examine the contributions of systems in which coordination spheres contain poly(pyrazolyl)borate ligands.

In recent years, the knowledge of these enzymes has increased dramatically, thanks to insights from advanced structural, spectroscopic, and molecular biological tech-niques. Model studies on metal complexes supported by poly(pyrazolyl)borate ligands have made vital contributions to our appreciation of the enzyme active sites and accurate active-site models are now emerging. This review has touched the surface of the chemical diversity exhibited by the molybdenum and tungsten enzymes. This diversity follows from variation of metal, ligand, pterin redox level and interaction with protein sidechains. Exploration of the structure and function of molybdenum enzymes, from molecular, cellular, environmental, and evolutionary pers-pectives, informs our knowledge of these important and interesting biomolecules. Investigations will move to a new sophistication via synergy between the enzyme structural work, active site modification by site-directed mutagenesis and continuing development of the fundamental chemistry.

ACKNOWLEDGEMENTS

This work was financially supported by Ministero dell’Istruzione dell’Università e della Ricerca (PRIN 20078EWK9B).

344 Current Bioactive Compounds 2009, Vol. 5, No. 4 Pellei et al.

ABBREVIATIONS

bdt = 1,2-Benzenedithiolate

cat = Benzene-1,2-diolate

CEET = Coupled electron-electrophile transfer

CEPT = Coupled electron-proton transfer

CODH = Carbon Monoxide Dehydrogenase

dmf = Dimethylformamide

DMSO = Dimethyl sulfoxide

DMSOR = DMSO reductase

EBDC = Edge-bridged double cubane

ENDOR = Electron nuclear double resonance

EPR = Electron paramagnetic resonance

ESEEM = Electron spin echo envelope modulation

etp = 2-(Ethylthio)phenolate

EXAFS = Extended X-ray absorption fine structure

FeMo-co = Iron–molybdenum cofactor

HPz = Pyrazole

LADH = Liver alcohol de-hydrogenase

LMCT = Ligand-to-Metal Charge Transfer

MCD = Magnetic Circular Dichroism

MGD = MPT-Guanosine Dinucleotide

MMP = Metalloproteinase

MPT = Molybdopterin

NISOD = Nickel superoxide dismutase

NMR = Nuclear magnetic resonance

OAT = Oxygen atom transfer

PN = The reduced state of the P-clusters of nitrogenase

POX = The oxidized state of the P-clusters of nitrogenase

pp = 2-(n-Propyl)phenolate

pzTp = Tetrakis(pyrazol-1-yl)borate

qdt = Quinoxaline-2,3-dithiolate

SC = Single cubane

tdt = 3,4-Toluenedithiolate

thf = Tetrahydrofurane

Tm = Hydrotris(methimazolyl)borate

Tp = Hydrotris(pyrazol-1-yl)borate

Tp* = Hydrotris(3,5-dimethylpyrazol-1-yl)borate

TpiPr = Hydrotris(3-isopropylpyrazol-1-yl)borate

TzMe2 = hydrotris(3,5-dimethyl-1,2,4-triazol-1-yl)borate

VHPO = Haloperoxidase

XAS = X-ray Absorption Spectroscopy

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Received: August 30, 2008 Revised: November 20, 2008 Accepted: November 22, 2008