ECE reaction pathways in the electrochemical reduction of dicyanocobalamin: Kinetics of ligand substitution in vitamin B12r cyanocob(II)alamin

The reduction of dicyanocob(III)alamin leads in a first stage to monocyanocob(II)alamin which can be partially converted into the base-off and base-on Co(II) complexes (B12r). The latter species are easier to reduce than the starting Co(III) complex leading to a single two-electron wave at low cyanide concentrations and/or low diffusion rates. Upon raising one of these two parameters two successive one-electron waves tend to be obtained corresponding to the Co(III)/Co(II) and Co(II)/Co(I) conversion respectively. The kinetics of the reduction process is investigated using potential-dependent potentiostatic chronoamperometry which allows a simpler analysis than cyclic voltammetry for systems involving a slow initial charge-transfer step. It is seen that the second electron, at the level of the first wave, comes from the electrode and not from the cyano-Co(II) complex in the solution. The reduction thus follows an ECE rather than a DISP-type mechanism in conditions where they can be distinguished by the usual electrochemical kinetic techniques. This contrasts with that which occurs in organic electrochemistry where the electron transfers are generally fast, while in the present case they are slow. The analysis of the reduction kinetics as a function of cyanide concentration gives some insight into the mechanism of the ligand substitution reaction at the Co(II). The kinetic data are discussed in terms of SN1-, SN2- and SNAr-like mechanisms.     

The profound influence of a single metal-carbon bond on the reactivity of bio-relevant cobalt(III) complexes

This Perspective reports the development of mechanistic insight over the past 6 years, on the substitution behaviour of cobalamins that contain a single Co-C bond. The effect of the alkyl group, located in the trans position, on the thermodynamic, kinetic and ground state trans effect, was studied in detail. The substitution reactions of different alkylcobalamins with CN- were investigated, the apparent mechanistic discrepancy reported for the co-enzyme B12 was resolved and a logical explanation could be offered. In addition, a complete picture of the effect of pressure on the UV-Vis spectra of different base-on and base-off cobalamins is presented, which clearly shows the role of the alkyl group in controlling the equilibrium between five- and six-coordinate species, and the possible participation of such species in the studied ligand substitution reactions. The kinetics of the base-on/base-off equilibration was studied for the first time using a pH-jump technique. All in all the novel mechanistic information adds to the understanding of the profound effect that a single metal-carbon bond can have on the reactivity of such Co(III) complexes.     

Methyl transfer from a hydrophobic vitamin B12 derivative to arsenic trioxide

The methylation reaction of arsenic trioxide conducted at 37 °C and pH 7.0 for 24 h using hydrophobic methylated vitamin B₁₂, (methyl) (aquo) heptamethylcobyrinate perchlorate, CH₃B₁₂ ester, as a methyl donor in the presence of reduced glutathione (GSH) yielded monomethylarsonous acid (MMA), dimethylarsinic acid (DMA), and trimethylarsine oxide (TMAO) as products with a methylation rate over 95%. In contrast, when methylcobalamin (CH₃B₁₂) was used as the methyl donor, only MMA and DMA were produced and the methylation rate dropped to around 20%. Reductive demethylation of a methyl-corrinoid coordination complex mediated by GSH is suggested as a mechanism of methyl transfer to arsenic trioxide. The differences observed for different corrinoid coordination complexes with respect to the reactivity of methyl transfer to arsenic is ascribable to differences inherent in the base-on (CH₃B₁₂) and base-off (CH₃B₁₂ ester) natures of the compounds.     

Assignment of 15N-NMR resonances of vitamin B12 analogues by 2D-[15N, 1H] long-range correlation: Fully [15N]-labelled Co-β-cyano-5-hydroxybenzimidazoylcobamide (factor III) and derivatives

The ¹⁵N-NMR spectra of vitamin B₁₂ analogues obtained in fully ¹⁵N-labelled form have been measured by direct and inverse (¹⁵N, ¹H) correlated spectroscopy. All resonances, except those of the NH₂ groups, have been assigned to individual N-atoms. The influences on δ (N) are analyzed and discussed which are caused by changing the α-face ligand from CN to H₂O or CH₃ and by switching the β-face ligand from the base-on to the base-off state. An implication of the correct resonance assignment on biosynthetic pathways is demonstrated.     

B12-retro-riboswitches: guanosyl-induced constitutional switching of B12 coenzymes

Complete B12 derivatives are natural "molecular switches" as a result of the coordinative switch ("base on" or "base off") of the natural nucleotide base. Certain predesigned B12-nucleotide conjugates were shown recently to behave as "retro riboswitches", in which the nucleotide environment modified the equilibrium between these two isomeric B12 structures. In contrast, the "reverse" situation has been discovered in natural B12 riboswitches, in which the binding of coenzyme B12 induces a conformational switch in the RNA species. The first (predesigned) B12-retro-riboswitches were DNA conjugates of methylcobalamin. We describe herein two representative B12-retro-riboswitches, in which an appended (RNA) nucleotide is used to destabilize the base-on form and induce the base-on to base-off switch. Through use of heterogeneous solid-phase synthetic methods, Co(beta)-cyanocobalamin-(3'-->2')-2'-methoxyguaninyl-3'-ate was prepared first as the crucial covalent RNA conjugate of vitamin B12. This cyanocorrinoid opened the door to two organometallic B12-nucleotide conjugates, which were made by electrosynthetic means: the cyanocorrinoid was cleanly methylated or adenosylated at the cobalt center to furnish covalent RNA conjugates of the organometallic B12 cofactors methylcobalamin and coenzyme B12, respectively. At room temperature, aqueous solutions of both of these organometallic RNA-B12 conjugates exhibited properties indicative of significant weakening of the axial (Co--N) bond (of their base-on forms) and of an enhanced formation of the base-off species. The base-on to base-off switch was studied by UV/Vis and NMR spectroscopic studies, which showed that the switch was very temperature-dependent and was accentuated with increasing temperatures. Thermodynamic data of the two organometallic RNA-B12 conjugates revealed an important contribution of entropic effects to the observed base-on to base-off switch. The two organometallic RNA-B12 conjugates thus acted as B12-retro-riboswitches and allowed the observation of a temperature-dependent reverse switch in the B12 cofactor moiety, induced by the appended nucleotide moiety. This behavior may be of interest in the "RNA-world" hypothesis, in which (simple) B12 derivatives are thought to act as possible catalytic enhancers ("cofactors") in RNA-based "B12 ribozymes".     

Cis-influence of hydroporphyrin macrocycles on axial ligation equilibria and alkyl exchange reactions of alkylcobalt(III) porphyrin complexes

Stability constants are reported for the coordination of pyridine and substituted pyridines to the alkylcobalt(III) complexes of octaethylporphyrin (OEP), t-octaethylchlorin (OEC), and ttt-octaethylisobacteriochlorin (OEiBC) in toluene solution. The stability constants correlate with the base strength of the nitrogenous ligand. A cis-influence of the macrocycle saturation level on the stability constants is observed. Stability constants for coordination of a given pyridine ligand to an alkylcobalt(III) complex are roughly 10 times smaller than the stability constants for the corresponding cobalt(II) complex. Analysis of a thermodynamic cycle demonstrates that this leads to decreased stability of the complex with respect to Co-C bond homolysis upon ligand coordination, a "base-on" effect. Alkyl exchange occurs between cobalt complexes of different tetrapyrroles. Equilibrium data establish that the exchange is nonstatistical and that the Co-C bond is stabilized by increasing the saturation of the tetrapyrrole macrocycle.     

Tailoring RuII Pyridine/Triazole Oxygenation Catalysts and Using Photoreactivity to Probe their Electronic Properties

Tuning of ligand properties is at the heart of influencing chemical reactivity and generating tailor‐made catalysts. Herein, three series of complexes [Ru(L)(Cl)(X)]PF₆ (X=DMSO, PPh₃, or CD₃CN) with tripodal ligands (L1–L5) containing pyridine and triazole arms are presented. Triazole‐for‐pyridine substitution and the substituent at the triazole systematically influence the redox behavior and photoreactivity of the complexes. The mechanism of the light‐driven ligand exchange of the DMSO complexes in CD₃CN could be elucidated, and two seven‐coordinate intermediates were identified. Finally, tuning of the ligand framework was applied to the catalytic oxygenation of alkanes, for which the DMSO complexes were the best catalysts and the yield improved with increasing number of triazole arms. These results thus show how click‐derived ligands can be tuned on demand for catalytic processes.     

Uranyl-Bound Tetra-Dentate Non-Innocent Ligands: Prediction of Structure and Redox Behaviour Using Density Functional Theory

Computational methods have been applied to understand the reduction potentials of [UO₂-salmnt-L] complexes (L=pyridine, DMSO, DMF and TPPO), and their redox behavior is compared with previous experiments in dichloromethane solution. Since the experimental results were inconclusive regarding the influence of the uranyl-bound tetra-dentate ‘salmnt’ ligand, here we will show that salmnt acts as a redox-active ligand and exhibits non-innocent behavior to interfere with the otherwise expected one-electron metal (U) reduction. We have employed two approaches to determine the uranyl (VI/V) reduction potentials, using a direct study of one-electron reduction processes and an estimation of the overall reduction using isodesmic reactions. Hybrid density functional theory (DFT) methods were combined with the Conductor-like Polarizable Continuum Model (CPCM) to account for solvation effects. The computationally predicted one-electron reduction potentials for the range of [UO₂-salmnt-L] complexes are in excellent agreement with shoulder peaks (∼1.4 eV) observed in the cyclic voltammetry experiments and clearly correlate with ligand reduction. Highly conjugated pi-bonds stabilize the ligand based delocalized orbital relative to the localized U f-orbitals, and as a consequence, the ligand traps the incoming electron. A second reduction step results in metal U(VI) to U(V) reduction, in good agreement with the experimentally assigned uranyl (VI/V) reduction potentials.     

Dioldehydratase Binds Coenzyme B12 in the “Base-On” Mode: ESR Investigations on Cob(II)alamin

Even in the enzyme-bound state the dimethylbenzimidazole ligand in the dioldehydratase from Salmonella typhimurium remains bound to the cobalt ion in contrast to some coenzyme B₁₂-dependent enzymes. Direct, ESR spectroscopic proof for this “base-on” binding mode was obtained by using a coenzyme in which one of the nitrogen atoms of the dimethylbenzimidazole ligand was ¹⁵N labeled (see schematic representation on the right).     

Metal exchange reactions in cadmium complexes with porphyrins of various structures

The reaction kinetics of the metal exchange Cd(II)-Cu(II) and Cd(II)-Zn(II) in the cadmium complexes (CdP) with porphyrin ligands (H₂P) differing by degree of stiffness (tetraphenylporphin, N-methyltetraphenylporphin, and tetraphenyltetrabenzoporphin) in the DMSO medium, was studied using spectrophotometric method. The rate of metal exchange reaction depends on the nature of the non-planatrity of H₂P in the structure of CdP complexes, as well as on the additional screening of the reaction center MN₄ by the extra-ligands and substituents. The reduction of the coordinating ability of the anion X⁻ in the structure of the solvate-salt of incoming metal M’X₂(Solv) _n−2 in a series: acetylacetonate > acetate > chloride > nitrate favors the metal exchange. In the most studied cases the reaction of CdP proceeds along a combined associative-dissociative mechanism. The order of the metal exchange reaction is found to be depending on temperature indicating a change in the contributions of associative and combined routes. The “pure” associative reaction mechanism in a medium of DMSO was for the first time found for the labile complex CdTPTBP with the saddle-type nonplanar ligand.     

Further study of the reaction of Fe2+ with CN-: synthesis and characterization of cis and trans [FeII,III(CN)4L2]n- complexes

The reaction of Fe2+ with CN-, which was first performed in 1704, has been used to synthesize a new series of basic [FeII,III(CN)4L2]n- complexes, where L is a monodentate ligand. trans-Na2[FeII(CN)4(DMSO)2] and cis-[NEt4]2[FeII(CN)4(pyridine)2] are synthesized by the direct reaction of FeCl2 with 4 equiv of CN- in DMSO or pyridine. Air oxidation of the latter compound gives cis-[NEt4][FeIII(CN)4(pyridine)2]. The non-cyanide ligands in these complexes undergo facile ligand exchange reactions with solvent. Reaction of cis-[NEt4]2[FeII(CN)4(pyridine)2] with CO at room temperature gives trans-[NEt4]2[FeII(CN)4(pyridine)(CO)].     

Antivitamin B12 Inhibition of the Human B12-Processing Enzyme CblC: Crystal Structure of an Inactive Ternary Complex with Glutathione as the Cosubstrate

B₁₂ antivitamins are important and robust tools for investigating the biological roles of vitamin B₁₂. Here, the potential antivitamin B₁₂ 2,4-difluorophenylethynylcobalamin (F2PhEtyCbl) was prepared, and its 3D structure was studied in solution and in the crystal. Chemically inert F2PhEtyCbl resisted thermolysis of its Co−C bond at 100 °C, was stable in bright daylight, and also remained intact upon prolonged storage in aqueous solution at room temperature. It binds to the human B₁₂-processing enzyme CblC with high affinity (K_D=130 nm ) in the presence of the cosubstrate glutathione (GSH). F2PhEtyCbl withstood tailoring by CblC, and it also stabilized the ternary complex with GSH. The crystal structure of this inactivated assembly provides first insight into the binding interactions between an antivitamin B₁₂ and CblC, as well as into the organization of GSH and a base-off cobalamin in the active site of this enzyme.     

Internal Spin Trapping of Thiyl Radical during the Complexation and Reduction of Cobalamin with Glutathione and Dithiothrietol

The activation of cobalamin requires the reduction of Cbl(III) to Cbl(II). The reduction by glutathione and dithiothreitol was followed using visible spectroscopy and electron paramagnetic resonance. In addition the oxidation of glutathione was monitored. Glutathione first reacts with oxidized Cbl(III). The binding of a second glutathione required for the reduction to Cbl(II) is presumably located in the dimethyl benzimidazole ribonucleotide ligand cavity. The reduction of Cbl(III) by dithiothreitol, which contains two thiols, is much faster even though no stable Cbl(III) complex is formed. The reduction, by both thiol reagents, results in the formation of thiyl radicals, some of which are released to form oxidized thiol products and some of which remain associated with the reduced cobalamin. In the reduced state the intrinsic lower affinity for the benzimidazole base, coupled with a trans effect from the initial GSH bound to the β-axial site and a possible lowering of the pH results in an equilibrium between base-on and base-off complexes. The dissociation of the base facilitates a closer approach of the thiyl radical to the Co(II) α-axial site resulting in a complex with ferromagnetic exchange coupling between the metal ion and the thiyl radical. This is a unique example of 'internal spin trapping' of a thiyl radical formed during reduction. The finding that the reduction involves a peripheral site and that thiyl radicals produced during the reduction remain associated with the reduced cobalamin provide important new insights into our understanding of the formation and function of cobalamin enzymes.     

Bottleable Neutral Analogues of [B2H5]− as Versatile and Strongly Binding η2 Donor Ligands

Herein we report the discovery that two bottleable, neutral, base‐stabilized diborane(5) compounds are able to bind strongly to a number of copper(I) complexes exclusively through their B?B bond. The resulting complexes represent the first known complexes containing unsupported, neutral σ_B?B diborane ligands. Single‐crystal X‐ray analyses of these complexes show that the X?Cu moiety (X=Cl, OTf, C₆F₅) lies opposite the bridging hydrogen atom of the diborane and is near perpendicular to the B?B bond, interacting almost equally with both boron atoms and causing a B?B bond elongation. DFT studies show that σ donation from and π backdonation to the pseudo‐π‐like B?B bond account for their formation. Astoundingly, these copper σ_B?B complexes are inert to ligand exchange with pyridine under either heating or photoirradiation.     

Diborabutatriene: An Electron‐Deficient Cumulene

The complexation of two equivalents of a cyclic (alkyl)(amino)carbene (CAAC) to tetrabromodiborane, followed by reduction with four equivalents of sodium naphthalide, led to the formation of the CAAC‐stabilized linear diboracumulene (CAAC)₂B₂. The capacity of the CAAC ligand to facilitate B₂→CAAC donation of π‐electron density resulted in important differences between this species and a previously reported complex featuring a B?B triple bond stabilized by cyclic di(amino)carbenes, including a longer B? B bond and shorter B? C bonds. Frontier orbital analysis indicated sharing of valence electrons across the entire linear C‐B‐B‐C unit in (CAAC)₂B₂, which is supported by natural population analysis and cyclic voltammetry.     

Complexation of nickel (II) ion with B3 vitamin in aqueous dimethyl sulfoxide

The stability change of nickel(II) ion complexes including one and two nicotinamide (B₃ vitamin) molecules in aqueous dimethyl sulfoxide (X_DMSO = 0–0.85 m.f.) was studied at 298.2±0.1 K and 0.25 ionic strength value (NaClO₄) using the potentiometric method. The first stage constant of complexation increased until organic solvent concentration was 0.5 m.f. and reduced at higher DMSO content. The difference between complex and central ions solvation is a dominating contribution into the Gibbs energy change of mononicotinamide complex formation reaction. When the second ligand molecule was bonded into the coordination compound, the nicotinamide contribution to Δ_trG_r rose and became prevailing at X_DMSO = 0.7–0.85. The ligand was found to replace a water molecule in the coordination sphere of the cation according to spectrophotometric study results.      

ESR studies on the intermolecular interactions of the mononitrosyl chelate complexes of iron

Using ESR the exchange of ligands was studied between mononitrosyl chelate complexes of iron and chelate complexes of nickel with the following ligands: dithiocarbamate (dtc), dithiophosphate (dtp), dithiocarbonate (xant), 8-quinolinethiolate, 8-hydroxyquinoline, acetylacetonate and o-hydroxy- benzylideneaniline. For some mixed-ligand complexes the exchange of the covalency of the metal—ligand bond was evaluated. The interaction of the mononitrosyl complexes with Lewis acids (I₂ and Br₂) and bases (pyridine, DMFA and DMSO) was studied in the cases of Fe(NO)(dtc)₂, Fe(NO)(dtp)₂ and Fe(NO)(xant)₂. In both of the latter cases the interactions with Lewis acids and bases led to the formation of paramagnetic dinitrosyl complexes, while with Fe(NO)(dtc)₂ hexacoordinated mononitrosyl complexes were formed. A reaction pathway is suggested and discussed for the formation of the dinitrosyl complexes and their composition.     

Synthesis of (η-arene)(η-cyclopentadienyl) iron (II) complexes with heteroatom and carbonyl substituents. Part I: Oxygen and carbonyl substituents

A series of reactions have been used to introduce oxygen substituents into (η-arene)(η-cyclopentadienyl) iron (II) complexes. Photochemical ligand exchange led to the formation of the first recorded trioxygenated complex as well as mono- and di-oxygenated species. Using microwave techniques, reaction times for S_NAr displacement reactions of halobenzene complexes by phenols were reduced from several hours to a few minutes. Phenols protected by either t-butylation or trimethylsilylation were found to give modest yields of the corresponding phenol complexes, using conventional thermal ligand exchange reactions. Without such protection, yields were extremely low. The above method led to the synthesis of the first example of a dihydroxybenzene complex. Some miscellaneous syntheses are also reported.The Nef reaction has been adapted to convert (η⁶-α-nitroalkylarene)(η⁵-Cp) iron (II) salts to corresponding aldehyde and ketone complexes. The α-nitroalkyl arene complexes were synthesised in good yields from (η⁶-halobenzene)(η⁵-Cp) iron (II) complexes using NaOtBu in DMSO. H/D exchange reactions with ²[H]₆-DMSO in the presence of K₂CO₃ showed partial D incorporation in the methyl group for the unreacted α-nitroethylbenzene complex and complete exchange for the carbanion generated by deprotonation. Conversion of the α-nitroalkylarene complexes to the corresponding aldehyde and ketone complexes was accomplished in moderate yields using three methods:

(A)

H₂O₂ and NaOtBu in DMSO followed by reaction with CF₃CO₂H.

(B)

SnCl₂/aq. HCl.

(C)

K₂CO₃ in DMF using microwave-mediated reactions.

In addition, two one-pot syntheses are reported using methods B and C.     

DNA Binding and Cleavage Activity of cis‐Cobalt Aromatic Oxime Complexes and Its Pyridine/imidazole Adducts

cis‐Cobalt complexes with salicycaldoxime(SAO), (Z)‐1‐(2‐hydroxyphenyl)ethanonoxime (HEO), (Z)‐1‐(2,5‐dihydroxyphenyl)ethanonoxime (DEO), (Z)‐1‐(2,5‐dihydroxyphenyl)(phenyl)methanonoxime (DPO) and their adducts with pyridine (Py) and imidazole (Im) were synthesized and characterized by elemental analysis, magnetic susceptibility, UV‐Vis and IR spectra. The electrochemical studies were carried by cyclic voltammeter, the peak potential separation and formal potential of complexes were independent of sweep rate or scan rate (ν) indicating a quasi reversible one‐electron redox process. Absorption studies and thermal denature studies revealed that each of these octahedral complexes is an avid binder of calf thymus DNA. The apparent binding constants for mixed ligand complexes are in order of ～10³‐10³ M^?1. Based on the data obtained in the DNA binding studies a partial intercalative mode of binding is suggested for these complexes. The nucleolytic cleavage activity of parent complexes and their pyridine adduct were carried out on double stranded pBR322 circular plasmid DNA by using a gel electrophoresis experiment in the presence and absence of oxidant (H₂O₂). All the metal complexes show enhanced cleavage activity in presence of oxidant. The hydrolytic cleavage of DNA of Co(DEO)₂ and Co(DPO)₂ is evidenced from the control experiments showing discernable cleavage inhibition in the presence of the hydroxyl radical inhibitor DMSO and EDTA.     

Theoretical Study on the Dissociation of Ligands in the Rhodium and Iridium Complexes Containing 1,1,1,5,5,5-Hexafluoroacetylacetonato

Functionalization of the inert C? H bonds of unsaturated molecules by transition metal complex is an important means to form new C? C bonds. The functionalization is usually initiated by the ligand dissociation of a complex. In this paper we employ both ab initio and density functional methods to explore the influence of central metals, conformation, solvent and protonation on the ligand dissociation of the (hfac‐O,O)₂M(L)(py) complexes [M=Rh(III) or Ir(III), hfac‐O,O=k²‐O,O‐1,1,1,5,5,5‐hexafluoroacetylacetonato, L=CH₃, CH₃CO₂, (CH₃CO)₂CH, CH₃O or OH, py=pyridine]. We demonstrate that ligand pyridine dissociates more easily than the "L" ligands under study in aprotic solvent and gas phase and the dissociation of pyridine is more facile in the trans‐conformation than in the cis‐isomer. These phenomena are rationalized based on electronic structure and molecular orbital interactions. We show that solvation only slightly stabilizes the complexes and does not change the ligand dissociation ordering. In particular, we show that pyridine is no longer the labile ligand in protic media. Instead, the oxygen‐containing ligands (apart from those like hfac that form a cyclic structure with the central metal) that coordinate to the central metal via oxygen atom become the labile ones. Finally our calculations indicate that hfac is a stable ligand, even in protic media.