Reductive cleavage mechanism of methylcobalamin: elementary steps of Co-C bond breaking

Density functional theory has been applied to the investigation of the reductive cleavage mechanism of methylcobalamin (MeCbl). In the reductive cleavage of MeCbl, the Co-C bond is cleaved homolytically, and formation of the anion radical ([MeCbl]*-) reduces the dissociation energy by approximately 50%. Such dissociation energy lowering in [MeCbl]*- arises from the involvement of two electronic states: the initial state, which is formed upon electron addition, has dominant pi*corrin character, but when the Co-C bond is stretched the unpaired electron moves to the sigma*Co-C state, and the final cleavage involves the three-electron (sigma)2(sigma*)1 bond. The pi*corrin-sigma*Co-C states crossing does not take place at the equilibrium geometry of [MeCbl]*- but only when the Co-C bond is stretched to 2.3 A. In contrast to the neutral cofactor, the most energetically efficient cleavage of the Co-C bond is from the base-off form. The analysis of thermodynamic and kinetic data provides a rationale as to why Co-C cleavage in reduced form requires prior departure of the axial base. Finally, the possible connection of present work to B12 enzymatic catalysis and the involvement of anion-radical-like [MeCbl]*- species in relevant methyl transfer reactions is discussed.     

X-ray structures and homolysis of some alkylcobalt(III) phthalocyanine complexes

The first crystallographic data for sigma-bonded alkylcobalt(III) phthalocyanine complexes are reported. A single-crystal X-ray structure of CH(3)CH(2)Co(III)Pc (Pc = dianion of phthalocyanine) reveals that the solid consists of centrosymmetric face-to-face dimers in which the CH(3)CH(2)Co(III)Pc units retain their square pyramidal geometry. The structure appears to be the first one reported for a five-coordinate RCo(III)(chelate) complex with an electron-deficient equatorial system. The Co-C bond in CH(3)CH(2)Co(III)Pc (2.031(5) A) is the longest found in five-coordinate RCo(III)(chel) complexes (R = simple primary alkyl group). Another X-ray study demonstrates that CH(3)Co(III)Pc(py) has a distorted octahedral geometry with axial bonds of very similar length to those in methylcobalamin. The axial bonds are shorter than those in its octaethylporphyrin analogue, in accordance with a weaker trans axial influence in six-coordinate complexes containing an electron-deficient phthalocyanine equatorial ligand. A different trend has been observed for five-coordinate RCo(III)(chel) complexes: electron-rich equatorial systems seem to make the Co-C axial bond shorter. Kinetic data for the homolysis of RCo(III)Pc complexes (R = Me, Et) in dimethylacetamide are also reported. Homolysis of ethyl derivatives is faster. The Co-C bond dissociation energies (BDEs) for the pyridine adducts of the methyl and the ethyl derivative are 30 +/- 1 and 29 +/- 1 kcal/mol, respectively. The BDE for CH(3)CoPc(py) is considerably lower than that for MeCbl despite the very similar lengths of the axial bonds in the two complexes. The results of this work do not support any correlation between the Co-C bond length and the bond strength as defined by BDE.     

Co-C bond dissociation energy and reaction volume change of 2',5'-dideoxyadenosylcobalamin studied by laser-induced time-resolved photoacoustic calorimetry

Time resolved photoacoustic calorimetry (PAC) was applied to a study of the photolysis of a coenzyme B(12) analog 2',5'-dideoxyadenosylcobalamin, which lacks an -OH group at the 2' position of ribofuranose ring. In aqueous solution, we report for the first time the quantum yield Phi(d) (0.25+/-0.02), Co-C bond dissociation energy (BDE; 31.8+/-2.5 kcal mol(-1)) and reaction volume change deltaV(R) (6.5+/-0.5 ml mol(-1)) due to conformation changes of the corrin ring and its side chains accompanying the cleavage of the Co-C bond. These values for the analog are very similar to those for the natural cofactor. Based our results and previous studies, a possible explanation for the similarity in their structure and properties versus the large difference in their enzymatic activity is discussed.     

Theoretical investigations into the intermediacy of chlorinated vinylcobalamins in the reductive dehalogenation of chlorinated ethylenes

The reductive dehalogenation of perchloroethylene and trichloroethylene by vitamin B(12) produces approximately 95% (Z)-dichloroethylene (DCE) and small amounts of (E)-DCE and 1,1-DCE, which are further reduced to ethylene and ethane. Chloroacetylene and acetylene have been detected as intermediates, but not dichloroacetylene. Organocobalamins (RCbls) have been proposed to be intermediates in this process. Density functional theory based approaches were employed to investigate the properties of chlorinated vinylcobalamins and chlorinated vinyl radicals. They reveal that all vinyl radicals studied have reduction potentials more positive (E degrees >or= -0.49) than that of the Co(II)/Co(I) couple of B(12) (E degrees = -0.61 V), indicating that any (chlorinated) vinyl radicals formed in the reductive dehalogenation process should be reduced to the corresponding anions by cob(I)alamin in competition with their combination with Co(II) to yield the corresponding vinylcobalamins. The computed Co-C homolytic bond dissociation enthalpies (BDEs) of the latter complexes range from 33.4 to 45.8 kcal/mol. The substituent effects on the BDEs are affected by the stabilities of the vinyl radicals as well as steric interactions between (Z)-chloro substituents and the corrin ring. The calculated E degrees values of the cobalamin models were within approximately 200 mV of one another since electron attachment is to a corrin ring pi-orbital, whose energy is relatively unaffected by chloride substitution of the vinyl ligand, and all were >500 mV more negative than that of the Co(II)/Co(I) couple of B(12). Reduction of the base-off forms of vinyl- and chlorovinylcobalamin models also involves the corrin pi* orbital, but reduction of the base-off dichlorovinyl- and trichlorovinylcobalamin models occurs with electron attachment to the sigma(Co)(-)(C*) orbital, yielding calculated E degrees values more positive than that of the calculated Co(II)/Co(I) couple of B(12). Thus, cob(I)alamin is expected to reduce these base-off vinyl-Cbls. Heterolytic cleavage of the Co-C bonds is much more favorable than homolysis (>21 kcal/mol) and is significantly more exergonic when coupled to chloride elimination.     

Orbital interactions and their effects on 13C NMR chemical shifts for 4,6-disubstituted-2,2-dimethyl-1,3-dioxanes. A theoretical study

A theoretical study is employed to describe the orbital interactions involved in the conformers' stability, the energies for the stereoelectronic interactions, and the corresponding effects of these interactions on the molecular structure (bond lengths) for cis- and trans-4,6-disubstituted-2,2-dimethyl-1,3-dioxanes. For cis-4,6-disubstituted-2,2-dimethyl-1,3-dioxanes, two LPO --> sigma*C(2)-Me(8) interactions are extremely important and the energies involved in these interactions are in the range 6.81-7.58 kcal mol(-1) for the LP(O)(1) --> sigma*C(2)-Me(8) and 7.58-7.71 kcal mol(-1) for the LP(O)(3) --> sigma*C(2)-Me(8) interaction. These two LP(O) --> sigma*C(2)-Me(8) interactions cause an upfield shift, indicating an increased shielding (increased electron density) of the ketal carbon C(2) as well as the axial Me(8) group in the chair conformation. These LP(O) --> sigma*C(2)-Me(8) hyperconjugative anomeric type interactions can explain the 13C NMR chemical shifts at 19 ppm for the axial methyl group "Me(8)" and 98.5 ppm for the ketal carbon "C(2)". The observed results for the trans derivatives showed that for compounds 2a-c (R = -CN, -C[triple bond]CH, and -CHO, respectively) the chair conformation is predominant, whereas for 2d,f-h [-CH3, -Ph, -C6H4(p-NO2), -C6H4(p-OCH3), respectively] the twist-boat is the most stable compound and for 2e [-C(CH3)3] is the only form.     

Photolysis of methylcobalamin: identification of the relevant excited states involved in Co-C bond scission

The relevant excited states involved in the photolysis of methylcobalamin (MeCbl) have been examined by means of time-dependent density functional theory (TD-DFT). The low-lying singlet and triplet excited states have been calculated along the Co-C bond at the TD-DFT/BP86/6-31g(d) level of theory in order to investigate the dissociation process of MeCbl. These calculations have shown that the photodissociation is mediated by the repulsive 3(sigmaCo-C --> sigma*Co-C) triplet state. The key metastable photoproduct involved in Co-C bond photolysis was identified as an S1 state having predominantly dCo --> pi*corrin metal-ligand charge transfer (MLCT) character.     

Bond dissociation energies for radical dimers derived from highly stabilized carbon-centered radicals

[reaction: see text] The temperature dependence of the dissociation of dimers formed from highly stabilized carbon-centered radicals has been examined. Analysis of the data yields the bond dissociation energy (BDE) for the central head-to-head C-C bond in these compounds. For example, for the dimer derived from 3-phenyl-2-coumaranone, BDE is 23.6 kcal/mol and the C-C bond length 1.596 A, a rather long value for a sigma bond.     

How the Co-C bond is cleaved in coenzyme B12 enzymes: a theoretical study

The homolytic cleavage of the organometallic Co-C bond in vitamin B12-dependent enzymes is accelerated by a factor of approximately 10(12) in the protein compared to that of the isolated cofactor in aqueous solution. To understand this much debated effect, we have studied the Co-C bond cleavage in the enzyme glutamate mutase with combined quantum and molecular mechanics methods. We show that the calculated bond dissociation energy (BDE) of the Co-C bond in adenosyl cobalamin is reduced by 135 kJ/mol in the enzyme. This catalytic effect can be divided into four terms. First, the adenosine radical is kept within 4.2 angstroms of the Co ion in the enzyme, which decreases the BDE by 20 kJ/mol. Second, the surrounding enzyme stabilizes the dissociated state by 42 kJ/mol using electrostatic and van der Waals interactions. Third, the protein itself is stabilized by 11 kJ/mol in the dissociated state. Finally, the coenzyme is geometrically distorted by the protein, and this distortion is 61 kJ/mol larger in the Co(III) state. This deformation of the coenzyme is caused mainly by steric interactions, and it is especially the ribose moiety and the Co-C5'-C4' angle that are distorted. Without the polar ribose group, the catalytic effect is much smaller, e.g. only 42 kJ/mol for methyl cobalamin. The deformation of the coenzyme is caused mainly by the substrate, a side chain of the coenzyme itself, and a few residues around the adenosine part of the coenzyme.     

Methyl transfer reactivity of five-coordinate CH3CoIIIPc

CH3CoIIIPc (Pc = dianion of phthalocyanine) has been characterized by equilibrium studies of its trans axial ligation and cyclic voltammetry as a relatively "electron poor" model of methylcobalamin, which in noncoordinating solvents persists as a five-coordinate complex. Axial base (N-donors, PBu3, SCN-, weakly binding O-donors) inhibition of methyl transfer from CH3CoIIIPc shows that the reaction proceeds via the reactive five-coordinate species, even in coordinating solvents. The virtual inactivity of six-coordinate CH3CoIIIPc(L) complexes provides a reference point for important biological processes.     

The role of substituents on functionalized 1,10-phenanthroline in controlling the emission properties of cationic iridium(III) complexes of interest for electroluminescent devices

The photophysical and electrochemical properties of the novel complexes [Ir(ppy)(2)(5-X-1,10-phen)][PF(6)] (ppy = 2-phenylpyridine, phen = phenanthroline, X = NMe(2), NO(2)), [Ir(pq)(2)(5-X-1,10-phen)][PF(6)] (pq = 2-phenylquinoline, X = H, Me, NMe(2), NO(2)), [Ir(ppy)2(4-Me,7-Me-1,10-phen)][PF(6)], [Ir(ppy)2(5-Me,6-Me-1,10-phen)][PF(6)], [Ir(ppy)(2)(2-Me,9-Me-1,10-phen)][PF(6)], and [Ir(pq)2(4-Ph,7-Ph-1,10-phen)][PF(6)] have been investigated and compared with those of the known reference complexes [Ir(ppy)(2)(4-Me or 5-H or 5-Me-1,10-phen)][PF(6)] and [Ir(ppy)(2)(4-Ph,7-Ph-1,10-phen)][PF(6)], showing how the nature and number of the phenanthroline substituents tune the color of the emission, its quantum yield, and the emission lifetime. It turns out that the quantum yield is strongly dependent on the nonradiative decay. The geometry, ground state, electronic structure, and excited electronic states of the investigated complexes have been calculated on the basis of density functional theory (DFT) and time-dependent DFT approaches, thus substantiating the electrochemical measurements and providing insight into the electronic origin of the absorption spectra and of the lowest excited states involved in the light emission process. These results provide useful guidelines for further tailoring of the photophysical properties of ionic Ir(III) complexes.     

Hydrogen-mediated metal-carbon to metal-boron bond conversion in metal-carboranyl complexes

A hydrogen-mediated Ru-C to Ru-B bond conversion was observed experimentally and supported by the theoretical calculations. Treatment of [eta(5):sigma(C)-Me(2)C(C(5)H(4))(C(2)B(10)H(10))]Ru(COD) (1) bearing a Ru-C(cage) sigma bond with PR(3) in the presence of H(2) gave Ru-B(cage) bonded complexes [eta(5):sigma(B)-Me(2)C(C(5)H(4))(C(2)B(10)H(10))]RuH(2)(PR(3)) (R = Cy (2), Ph (3)) (sigma(C): Ru-C(cage) sigma bond; sigma(B): Ru-B(cage) sigma bond). Complex 3 was converted to [eta(5):sigma(B)-Me(2)C(C(5)H(4))(C(2)B(10)H(10))]Ru(L(2)) in the presence of L(2) (L(2) = dppe (4), PPh(3)/P(OEt)(3) (5), PPh(3)/pyridine (6)) via liberation of H(2) upon heating. These complexes were fully characterized by various spectroscopic techniques, elemental analyses, and single-crystal X-ray diffraction studies. DFT calculations show that this conversion process is both kinetically and thermodynamically favorable and requires involvement of a hydride ligand.     

Characterization of Co-C bonding in dichlorovinylcobaloxime complexes

This study combines theory and experiment in an examination of Co-C bonding and reductive Co-C cleavage in cobalt dichlorovinyl complexes. It is motivated by the role of dichlorovinyl complexes as intermediates in the dechlorination of trichloroethylene by cobalamin and cobalamin model complexes. A series of seven cis-1,2-dichlorovinyl(L)cobaloxime complexes were prepared (L = m- and p-substituted pyridines; cobaloxime = bis(dimethylglyoximato)cobalt). The complexes were characterized using 1H NMR, 13C NMR, cyclic voltammetry, and X-ray crystallography. Examination of the metrical parameters of the Co-C=C unit across the series shows very little change in the C=C bond length and a slight increase in the Co-C bond length with increasing electron-donating ability of the pyridine ligand. These structural changes along with electronic structure calculations indicate that Co-C pi-bonding is not important in these complexes. The stronger Co-C bonds of vinylcobaloximes compared to those of alkylcobaloximes are best explained by the higher s character at C. Changes in the reduction potential across the series indicate that the pyridine-bound form is the primary electrochemically active species. Theoretical examination of the Co-C cleavage following reduction supports the direct formation of the cis-1,2-dichlorovinyl anion and not the cis-1,2-dichlorovinyl radical.     

Which DFT functional performs well in the calculation of methylcobalamin? Comparison of the B3LYP and BP86 functionals and evaluation of the impact of empirical dispersion correction

Controversy remains regarding the suitable density functionals for the calculation of vitamin B(12) systems that contain cobalt. To identify the optimum functionals, geometry optimization calculations were performed on a full-size model of methylcobalamin (MeCbl) using the B3LYP, B3LYP-D, BP86, and BP86-D methods in conjunction with the 6-31G* basis set. Single-point energy evaluations were also performed with the 6-311+G(2d,p) basis set. Consistent with previous studies, the BP86-optimized geometry showed fairly good agreement with the experimental geometry. Various factors that may influence the homolytic bond dissociation energy (BDE) of the Co-C bond of MeCbl were systematically evaluated with these methods. Our analysis demonstrated that dispersion was the largest correction term that influenced the magnitude of BDE. Previous studies have shown that B3LYP significantly underestimates BDE, whereas BP86 gives BDE values that are fairly close to the experimental values (36-37 kcal/mol). The same trend in the relative magnitudes of the BDEs was observed in the present calculations. However, BP86 underestimated the BDE for a full model of MeCbl. When the amount of Hartree-Fock exchange in the B3LYP functional was reduced to 15% and the dispersion correction was made (i.e., B3LYP*-D), the calculated BDE was in good accord with experimental values. B3P86-D also performed well. A detailed analysis was undertaken to determine which atoms in cobalamin have large dispersion interactions with a methyl fragment of MeCbl.     

Water effect on the o-h dissociation enthalpy of para-substituted phenols: a DFT study

The effect of water on the O-H bond dissociation enthalpy (BDE) of para-substituted phenols has been investigated by means of DFT calculations. It is shown that the experimental BDE values are fairly well-reproduced by simple B3LYP/6-31G* calculations carried out on the phenol/phenoxyl-water complexes taking into account only hydrogen-bonding (HB) interactions of water molecules with molecular sites (HB model). On the contrary, the BDE values computed with the polarizable continuum model (PCM/B3LYP/6-31G*)8 are overestimated by about 3-4 kcal/mol. Discrepancy between theory and experiment increases using the PCM method in addition to the HB model. Calculations show that, in general, the HB interaction with water molecules decreases the BDE of phenols bearing electron-releasing groups while increasing the BDE of phenols bearing electron-withdrawing substituents. This opposite effect is explained by considering the resonance structures with charge separation both in phenols and in phenoxyl radicals. With electron donors, the phenoxyl radical is preferentially stabilized by the HB acceptor interaction with two water molecules, while with electron acceptors the phenol is preferentially stabilized by the HB donor interaction with one water molecule.     

Computational study of the halogen atom-benzene complexes

The structures of halogen atom-benzene complexes were investigated by modern DFT and ab initio computational methods. The spectroscopic properties of the complexes are also predicted and are in good agreement with experiment where such data have been reported. The fluorine atom-benzene complex is predicted to be a sigma complex due to the strength of a C-F bond. The chlorine atom-benzene complex is predicted to have an eta(1) pi complex structure, which is only slightly more favorable (1.1 kcal/mol with the BH&HLYP/6-311++G method including the ZPE correction) than a sigma complex but is significantly more stable (4.4 kcal/mol with the BH&HLYP/6-311++G method including the ZPE correction) than the eta(6) pi complex. The bromine and iodine benzene complexes are also predicted to prefer an eta(1) pi complex structure.     

Computational insights into the mechanism of radical generation in B12-dependent methylmalonyl-CoA mutase

ONIOM calculations have provided novel insights into the mechanism of homolytic Co-C5' bond cleavage in the 5'-deoxyadenosylcobalamin cofactor catalyzed by methylmalonyl-CoA mutase. We have shown that it is a stepwise process in which conformational changes in the 5'-deoxyadenosine moiety precede the actual homolysis step. In the transition state structure for homolysis, the Co-C5' bond elongates by approximately 0.5 Angstroms from the value found in the substrate-bound reactant complex. The overall barrier to homolysis is approximately 10 kcal/mol, and the radical products are approximately 2.5 kcal/mol less stable than the initial ternary complex of enzyme, substrate, and cofactor. The movement of the deoxyadenosine moiety during the homolysis step positions the resulting 5'-deoxyadenosyl radical for the subsequent hydrogen atom transfer from the substrate, methylmalonyl-CoA.     

Cleavage of carbon-carbon bonds of diphenylacetylene and its derivatives via photolysis of Pt complexes: tuning the C-C bond formation energy toward selective C-C bond activation

Carbon-carbon bond activation of diphenylacetylene and several substituted derivatives has been achieved via photolysis and studied. Pt0-acetylene complexes with eta2-coordination of the alkyne, along with the corresponding PtII C-C activated photolysis products, have been synthesized and characterized, including X-ray crystal structural analysis. While the C-C cleavage reaction occurs readily under photochemical conditions, thermal activation of the C-C bonds or formation of PtII complexes was not observed. However, the reverse reaction, C-C reductive coupling (PtII --> Pt0), did occur under thermal conditions, allowing the determination of the energy barriers for C-C bond formation from the different PtII complexes. For the reaction (dtbpe)Pt(-Ph)(-CCPh) (2) --> (dtbpe)Pt(eta2-PhCCPh) (1), DeltaG was 32.03(3) kcal/mol. In comparison, the energy barrier for the C-C bond formation in an electron-deficient system, that is, (dtbpe)Pt(C6F5)(CCC6F5) (6) --> (dtbpe)Pt(eta2-bis(pentafluorophenyl)acetylene) (5), was found to be 47.30 kcal/mol. The energy barrier for C-C bond formation was able to be tuned by electronically modifying the substrate with electron-withdrawing or electron-donating groups. Upon cleavage of the C-C bond in (dtbpe)Pt(eta2-(p-fluorophenyl-p-tolylacetylene) (9), both (dtbpe)Pt(p-fluorophenyl)(p-tolylacetylide) (10) and (dtbpe)Pt(p-tolyl)(p-fluorophenylacetylide) (11) were obtained. Kinetic studies of the reverse reaction confirmed that 10 was more stable toward the reductive coupling [the term "reductive coupling" is defined as the formation of (dtbpe)Pt(eta2-acetylene) complex from the PtII complex] than 11 by 1.22 kcal/mol, under the assumption that the transition-state energies are the same for the two pathways. The product ratio for 10 and 11 was 55:45, showing that the electron-deficient C-C bond is only slightly preferentially cleaved.     

Solvolysis of para-substituted cumyl chlorides. Brown and Okamoto's electrophilic substituent constants revisited using continuum solvent models

Brown and Okamoto (J. Am. Chem. Soc. 1958, 80, 4979) derived their electrophilic substitutent constants, sigma(p)+, from the relative rates of solvolysis of ring-substituted cumyl chlorides in an acetone/water solvent mixture. Application of the Hammett equation to the rates for the meta-substituted cumyl chlorides, where there could be no resonance interaction with the developing carbocation, gave a slope, rho(+) = -4.54 ( identical with 6.2 kcal/mol free energy). Rates for the para-substituted chlorides were then used to obtain sigma(p)+ values. We have calculated gas-phase C-Cl heterolytic bond dissociation enthalpy differences, Delta BDE(het) (= BDE(het)(4-YC(6)H(4)CMe(2)Cl) - BDE(het)(C(6)H(5)CMe(2)Cl)), for 16 of the 4-Y substituents employed by Brown and Okamoto. The plot of Delta BDE(het) vs sigma(p)+ gave rho(+) (SD) = 16.3 (2.3) kcal/mol, i.e., a rho(+) value roughly 2.5 times greater than experiment. Inclusion of solvation (water) energies, calculated using three continuum solvent models, reduced rho(+) and SD. The computationally least expensive model used, SM5.42R (Li et al. Theor. Chem. Acc. 1999, 103, 9) gave the best agreement with experiment. This model yielded rho(+) (SD) = 7.7 (0.9) kcal/mol, i.e., a rho(+) value that is only 24% larger than experiment.     

Equilibrium acidities and homolytic bond dissociation energies of acidic C-H bonds in alpha-arylacetophenones and related compounds

The equilibrium acidities (pK(AH)s) and the oxidation potentials of the congugate anions [E(ox)(A(-))s] were determined in dimethyl sulfoxide (DMSO) for eight ketones of the structure GCOCH(3) and 20 of the structure RCOCH(2)G, (where R = alkyl, phenyl and G = alkyl, aryl). The homolytic bond dissociation energies (BDEs) for the acidic C-H bonds of the ketones were estimated using the equation BDE(AH) = 1.37pK(AH) + 23.1E(ox)(A(-)) + 73.3. While the equilibrium acidities of GCOCH(3) were found to be dependent on the remote substituent G, the BDE values for the C-H bonds remained essentially invariant (93.5 +/- 0.5 kcal/mol). A linear correlation between pK(AH) values and [E(ox)(A(-))s] was found for the ketones. For RCOCH(2)G ketones, both pK(AH) and BDE values for the adjacent C-H bonds are sensitive to the nature of the substituent G. However, the steric bulk of the aryl group tends to exert a leveling effect on BDEs. The BDE of alpha-9-anthracenylacetophenone is higher than that of alpha-2-anthracenylacetophenone by 3 kcal/mol, reflecting significant steric inhibition of resonance in the 9-substituted system. A range of 80.7-84.4 kcal/mol is observed for RCOCH(2)G ketones. The results are discussed in terms of solvation, steric, and resonance effects. Ab initio density functional theory (DFT) calculations are employed to illustrate the effect of steric interactions on radical and anion geometries. The DFT results parallel the trends in the experimental BDEs of alpha-arylacetophenones.