Michael L. Singleton

Synthetic Support of De Novo Design: Sterically Bulky [FeFe]‐Hydrogenase Models

A twisted mimic: Upon oxidation of [(μ-SCH2C(CH3)2CH2S-){FeI(CO)2PMe3}2], rearrangement yields the mixed-valent FeIFeII cation in a square-pyramid/inverted square-pyramid geometry with a semibridging CO ligand, closely mimicking the [FeFe] hydrogenase enzyme active site. According to de novo design principles, the steric effect of bridgehead bulk in the S–S bridging ligand stabilizes this structure in the absence of the protein matrix.

A Cyclodextrin Host/Guest Approach to a Hydrogenase Active Site Biomimetic Cavity

The hydrophobic cavity of the active site of [FeFe]-Hydrogenase is mimicked by two cyclodextrin molecules which surround a 2Fe2S synthetic analogue of the active site, outfitted with an aryl sulfonate to promote inclusion into beta-cyclodextrin. The X-ray crystal structure of the clathrate shows an increased torsion angle between the apical CO ligands indicating that the supramolecular cage destabilizes the eclipsed geometry typical of diiron model complexes. Inclusion in the model second coordination sphere also has important effects on the electrochemical properties of the model complex including an approximately 80 mV shift of the Fe(I)Fe(I)/Fe(I)Fe(0) reduction and a change in the potential at which electrocatalytic reduction of protons by the diiron complex occurs.

Structural and Spectroscopic Features of Mixed Valent FeIIFeI Complexes and Factors Related to the Rotated Configuration of Diiron Hydrogenase

The compounds of this study have yielded to complementary structural, spectroscopic (Mössbauer, EPR/ENDOR, IR), and computational probes that illustrate the fine control of electronic and steric features that are involved in the two structural forms of (μ-SRS)[Fe(CO)2PMe3]2(0,+) complexes. The installation of bridgehead bulk in the -SCH2CR2CH2S- dithiolate (R = Me, Et) model complexes produces 6-membered FeS2C3 cyclohexane-type rings that produce substantial distortions in Fe(I)Fe(I) precursors. Both the innocent (Fc(+)) and the noninnocent or incipient (NO(+)/CO exchange) oxidations result in complexes with inequivalent iron centers in contrast to the Fe(I)Fe(I) derivatives. In the Fe(II)Fe(I) complexes of S = 1/2, there is complete inversion of one square pyramid relative to the other with strong super hyperfine coupling to one PMe3 and weak SHFC to the other. Remarkably, diamagnetic complexes deriving from isoelectronic replacement of CO by NO(+), {(μ-SRS)[Fe(CO)2PMe3] [Fe(CO)(NO)PMe3](+)}, are also rotated and exist in only one isomeric form with the -SCH2CR2CH2S- dithiolates, in contrast to R = H ( Olsen , M. T. ; Bruschi , M. ; De Gioia , L. ; Rauchfuss , T. B. ; Wilson , S. R. J. Am. Chem. Soc. 2008 , 130 , 12021 -12030 ). The results and redox levels determined from the extensive spectroscopic analyses have been corroborated by gas-phase DFT calculations, with the primary spin density either localized on the rotated iron in the case of the S = 1/2 compound, or delocalized over the {Fe(NO)} unit in the S = 0 complex. In the latter case, the nitrosyl has effectively shifted electron density from the Fe(I)Fe(I) bond, repositioning it onto the spin coupled Fe-N-O unit such that steric repulsion is sufficient to induce the rotated structure in the Fe(II)-{Fe(I)((•)NO)}(8) derivatives.

Sulfonated Diiron Complexes as Water-Soluble Models of the [Fe–Fe]-Hydrogenase Enzyme Active Site

A series of diiron complexes developed as fundamental models of the two-iron subsite in the [FeFe]-hydrogenase enzyme active site show water-solubility by virtue of a sulfonate group incorporated into the -SCH(2)NRCH(2)S- dithiolate unit that bridges two Fe(I)(CO)(2)L moieties. The sulfanilic acid group imparts even greater water solubility in the presence of β-cyclodextrin, β-CyD, for which NMR studies suggest aryl-sulfonate inclusion into the cyclodextrin cavity as earlier demonstrated in the X-ray crystal structure of 1Na·2 β-CyD clathrate, where 1Na = Na(+)(μ-SCH(2)N(C(6)H(4)SO(3)(-))CH(2)S-)[Fe(CO)(3)](2), (Singleton et al., J. Am. Chem. Soc.2010, 132, 8870). Electrochemical analysis of the complexes for potential as electrocatalysts for proton reduction to H(2) finds the presence of β-CyD to diminish response, possibly reflecting inhibition of structural rearrangements required of the diiron unit for a facile catalytic cycle. Advantages of the aryl sulfonate approach include entry into a variety of water-soluble derivatives from the well-known (μ-SRS)[Fe(CO)(3)](2) parent biomimetic, that are stable in O(2)-free aqueous solutions.

Increasing the Size of an Aromatic Helical Foldamer Cavity by Strand Intercalation

The postsynthetic modulation of capsules based on helical aromatic oligoamide foldamers would be a powerful approach for controlling their receptor properties without altering the initial monomer sequences. With the goal of developing a method to increase the size of a cavity within a helix, a single-helical foldamer capsule was synthesized with a wide-diameter central segment that was designed to intercalate with a second shorter helical strand. Despite the formation of stable double-helical homodimers (K(dim)>10(7) M(-1)) by the shorter strand, when it was mixed with the single-helical capsule sequence, a cross-hybridized double helix was formed with K(a)>10(5) M(-1). This strategy makes it possible to direct the formation of double-helical heterodimers. On the basis of solution- and solid-state structural data, this intercalation resulted in an increase in the central-cavity size to give a new interior volume of approximately 150 Å(3).

Influence of Sulf-Oxygenation on CO/L Substitution and Fe(CO)3 Rotation in Thiolate-Bridged Diiron Complexes

Kinetic studies of CO/L substitution reactions of the well-known organometallic complex (mu-pdt)[Fe(CO)(3)](2) (pdt = 1,3-propanedithiolate), complex 1, and its sulfur-oxygenated derivative (mu-pst)[Fe(CO)(3)](2) (pst = 3-sulfenatopropane-1-thiolate), 1-O, have been carried out with the goal of understanding the influence of the sulfenato ligand on the activation barrier to ligand substitution in such diiron carbonyl complexes which consists of two components: intramolecular structural rearrangement (or fluxionality) and nucleophilic attack by the incoming ligand. The CO/PMe(3) substitution reactions of complex 1 follow associative mechanisms in both the first and the second substitutions; the second substitution is found to have a higher activation barrier for the overall reaction that yields 1-(PMe(3))(2). Despite the increased electrophilicity of the Fe(CO)(3) unit in 1-O versus 1, the former reacts more sluggishly with PMe(3), where practical kinetic measurements are at such high temperatures that CO dissociation parallels the associative path. Kinetic studies have established that in complex 1-O both the first and the second CO/CN(-) substitutions proceed via associative paths with higher E(act) barriers than the analogous reactions with complex 1. Theoretical calculations (density functional theory) have been used in conjunction with variable temperature (13)C NMR spectral studies to examine the energy barriers associated with rotation of the Fe(CO)(3) unit. The activation energy required for rotation is higher in the sulfenato than in the analogous thiolato complexes. Thus, the greater barrier to structural deformation in 1-O inhibits its ability to expand its coordination number as compared to the thiolate, 1, resulting in slower reaction rates of both PMe(3) and CN(-) substitution reactions.

Orientation and Stereodynamic Paths of Planar Monodentate Ligands in Square Planar Nickel N2S Complexes

The well-established presence of histidine donors in binding sites of Ni-containing biomolecules prompts the study of orientational preference and stereodynamic nature of flat monodentate ligands (L = imidazoles, pyridine and an N-heterocyclic carbene) bound to planar N(2)SNi moieties. Square planar [N(2)SNiL](n+) complexes are accessed through bridge-splitting reactions of dimeric, thiolate-S bridged [N(2)SNi](2) complexes. The solid state molecular structures of three mononuclear products, and three monothiolate bridged dinickel complexes, reveal that the plane of the added monodentate ligand orients largely orthogonal to the N(2)SNiL square plane. Variable temperature (1)H NMR characterization of dynamic processes and ground state isomer ratios of imidazole complexes in their stopped exchange limiting spectra, readily correlate with density functional theory (DFT)-guided interpretation of Ni-L rotational activation barriers. Full DFT characterization finds Ni-L bond lengthening as well as a tetrahedral twist distortion in the transition state, reaching a maximum in the NHC complex, and relating mainly to the steric hindrance derived both from the ligand and the binding pocket. In the case of the imidazole ligands a minor electronic contribution derives from intramolecular electrostatic interactions (imidazole C-2 C-H(delta+)- - S(delta-) interaction). Computational studies find this donor-acceptor interaction is magnified in O-analogues, predicting coplanar arrangements in the ground state of N(2)ON(imid)Ni complexes.

The modular assembly of clusters is the natural synthetic strategy for the active site of [FeFe] hydrogenase.

The recognition of the presence of iron–sulfur clusters and their electron shuttling roles in redox-active enzymes is one of the giant steps in a march of almost 80 years towards understanding the enzymes that control hydrogen metabolism in microorganisms of ancient origin: hydrogenases. The versatility of the Fe/S/SR combination in structural and physical properties has been well-established through synergistic studies evolving from the laboratories of chemists, biochemists, and biophysicists. 3] The remarkable coincidences of FeS cluster reactivities in vitro (using synthetic analogues) and in vivo (in FeS cluster-containing proteins) impress regarding the minor role of the protein in determining the existence of the FeS clusters, and have led to proposals that small chunks of iron sulfide minerals might have been the first catalysts on planet earth. Their eventual incorporation into proteins led to such sophisticated constructs as are found in the inorganic/organometallic natural products shown in Scheme 1. 5–8] Clearly, the presence and alignment of multiple FeS clusters observed in the protein crystal structures of [NiFe] and [FeFe] hydrogenases (H2ases) can only be interpreted as the electron-transfer routes that connect the active sites to the electron-donor or -acceptor unit docked into the exterior of the protein. In the [FeFe] H2ase active site (Scheme 1e), one typical 4Fe4S cluster is “hard-wired” or directly attached to an unusual 2Fe subsite through a cysteinyl bridge. In this way, the composition of the “H-cluster”, the hydrogenproducing cluster of [FeFe] H2ase, resembles that of sulfite reductase (Scheme 1g) or acetyl-CoA synthase (Scheme 1 f); the 4Fe4S cluster has been called upon to serve as a redoxvariable metallothiolate ligand via its cysteinyl sulfur that bridges to the 2Fe subsite. That the 2Fe portion of the Hcluster is a genuine organometallic species, replete with carbon monoxide, cyanide, and a previously biologically unknown dithiolate cofactor, coupled with the impressive rate of the [FeFe] H2ase catalysis of H2 production from mild potential electrons and water as proton source, has brought global attention of chemists in search of an optimal synthetic analogue of the active site, without protein, as prospective molecular electrocatalysts for hydrogen production. An engaging and difficult challenge has been biosynthesis issues: How does nature generate and manage CN and CO, known to poison metal sites if uncontrolled? How is the azadithiolate that connects the irons within the 2Fe subsite made? How is the H-cluster assembled? Does a 6Fe supercluster precede and extrude the 2Fe subsite, or is the assembly modular? Insights into the first two questions have been gained in recent discoveries of gene products utilizing radical SAM (S-adenosyl methionine) pathways that result in degradation of tyrosine into p-cresol and the diatomic ligands, CO and CN , the latter presumably though a glycyl radical. Guidance to answers to the latter two questions is the focus of this Highlight on a structural report from Mulder, Peters, Broderick et al. , and additional biosynthetic and spectroscopic results on the nature of the 2Fe2S subsite precursor. 14] As to the question “How is the H-cluster assembled?”, the trivial answer of “very carefully” is without a doubt correct. Mulder et al. have been able to obtain the [FeFe] H2ase (also known as HydA) protein as expressed in the absence of the HydE, HydF, and HydG proteins required for the synthesis of the 2Fe subsite and the maturation of the enzyme into active form. The immature protein, produced without the accessory proteins and known as HydA, was derived from the Chlamydomonas reinhardtii green alga and expressed in E. coli ; its X-ray crystal structure was determined and compared to those of the holoprotein crystallized from C. pasteurianum and Desulfovibrio desulfuricans. Whereas both latter structures show the full H-cluster in the form of cysteine-bridged subsites, that is, 4Fe4S(m-SCys)2Fe, only the 4Fe4S cluster is found in HydA. The structure of HydA shows the already-present 4Fe4S cluster resides in a cavity at the end of a channel (8–15 wide and 25 long; Figure 1). Overlays of the structures of the immature or apoprotein that lacks the 2Fe subsite with the complete or [*] R. D. Bethel, M. L. Singleton, Prof. M. Y. Darensbourg Department of Chemistry, Texas A&M University College Station, TX 77843 (USA) Fax: (+ 1)979-845-0158 E-mail: marcetta@chem.tamu.edu Homepage: http://www.chem.tamu.edu/rgroup/marcetta/

Synthesis of 1,8-diazaanthracenes as building blocks for internally functionalized aromatic oligoamide foldamers.

The synthesis of a variety of 9-functionalized 1,8-diazaanthracene diesters and amino acids is described. Derivatization at the 9-position relies on facile reactions performed on the 9-chloro and 9-bromomethyl precursors. This has allowed the incorporation of nucleophilic or sensitive functional groups that otherwise cannot be incorporated under standard methods for synthesizing these compounds. Additionally, the synthesis of the protected amino acids via a high-yielding monosaponification and subsequent Curtius rearrangement has been accomplished on a multigram scale. These units, together with the functionalized derivatives, should prove to be useful monomers in the synthesis of aromatic oligoamide foldamers.