Unusual bond formation in aspartic protease inhibitors: a theoretical study

The origin of the formation of the weak bond N|C...O involved in an original class of aspartic protease inhibitors was investigated by means of the electron localization function (ELF) and explicitly correlated wave-function (MRCI) analysis. The distance between the electrophilic C and the nucleophilic N centers appears to be controlled directly by the polarity and proticity of the medium. In light of these investigations, an unusual dative N-C bonding picture was characterized. Formation of this bond is driven by the enhancement of the ionic contribution C(+)-O(-) induced mainly by the polarization effect of the near N lone pair, and to a lesser extent by a weak charge delocalization N-->CO. Although the main role of the solvating environment is to stabilize the ionic configuration, the protic solvent can enhance the C(+)-O(-) configuration through a slight but cumulative charge transfer towards water molecules in the short N-C distance regime. Our revisited bond scheme suggests the possible tuning of the N-CO interaction in the design of specific inhibitors.     

Homocoenzyme B12 and bishomocoenzyme B12: covalent structural mimics for homolyzed, enzyme-bound coenzyme B12

Efficient electrochemical syntheses of "homocoenzyme B(12)" (2, Co(beta)-(5'-deoxy-5'-adenosyl-methyl)-cob(III)alamin) and "bishomocoenzyme B(12)" (3, Co(beta)-[2-(5'-deoxy-5'-adenosyl)-ethyl]-cob(III)alamin) are reported here. These syntheses have provided crystalline samples of 2 and 3 in 94 and 77 % yield, respectively. In addition, in-depth investigations of the structures of 2 and 3 in solution were carried out and a high-resolution crystal structure of 2 was obtained. The two homologues of coenzyme B(12) (2 and 3) are suggested to function as covalent structural mimics of the hypothetical enzyme-bound "activated" (that is, "stretched" or even homolytically cleaved) states of the B(12) cofactor. From crude molecular models, the crucial distances from the corrin-bound cobalt center to the C5' atom of the (homo)adenosine moieties in 2 and 3 were estimated to be about 3.0 and 4.4 A, respectively. These values are roughly the same as those found in the two "activated" forms of coenzyme B(12) in the crystal structure of glutamate mutase. Indeed, in the crystal structure of 2, the cobalt center was observed to be at a distance of 2.99 A from the C5' atom of the homoadenosine moiety and the latter was found to be present in the unusual syn conformation. In solution, the organometallic moieties of 2 and 3 were shown to be rather flexible and to be considerably more dynamic than the equivalent group in coenzyme B(12). The homoadenosine moiety of 2 was indicated to occur in both the syn and the anti conformations.     

Electroreduction of a series of alkylcobalamins: mechanism of stepwise reductive cleavage of the Co-C bond

The electrochemical (EC) reduction mechanism of methylcobalamin (Me-Cbl) in a mixed DMF/MeOH solvent in 0.2 M tetrabutylammonium fluoroborate electrolyte was studied as a function of temperature and solvent ratio vs a nonaqueous Ag/AgCl/Cl(-) reference electrode. Double-potential-step chronoamperometry allowed the rate constant of the subsequent homogeneous reaction to be measured over the temperature range from 0 to -80 degrees C in 40:60 and 50:50 DMF:MeOH ratios. Activation enthalpies are 5.8 +/- 0.5 and 7.6 +/- 0.3 kcal/mol in the 40:60 and 50:50 mixtures of DMF/MeOH, respectively. Digital simulation and curve-fitting for an EC mechanism using a predetermined homogeneous rate constant of 5.5 x 10(3) s(-1) give E degrees' = -1.466 V, k degrees = 0.016 cm/s, and alpha = 0.77 at 20 degrees C for a quasi-reversible electrode process. Digital simulation of the results of Lexa and Savéant (J. Am. Chem. Soc. 1978, 100, 3220-3222) shows that the mechanism is a series of stepwise homogeneous equilibrium processes with an irreversible step following the initial electron transfer (ET) and allows estimation of the equilibrium and rate constants of these reactions. An electron coupling matrix element of H(kA) = (4.7 +/- 1.1) x 10(-4) eV ( approximately 46 J/mol) is calculated for the nonadiabatic ET step for reduction to the radical anion. A reversible bond dissociation enthalpy for homolytic cleavage of Me-Cbl is calculated as 31 +/- 2 kcal/mol. The voltammetry of the ethyl-, n-propyl-, n-butyl-, isobutyl-, and adenosyl-substituted cobalamin was studied, and estimated reversible redox potentials were correlated with Co-C bond distances as determined by DFT (B3LYP/ LANL2DZ) calculations.     

DFT study of Co-C bond cleavage in the neutral and one-electron-reduced alkyl-cobalt(III) phthalocyanines

Density functional theory (DFT) has been applied to the analysis of the structural and electronic properties of the alkyl-cobalt(III) phthalocyanine complexes, [CoIIIPc]-R (Pc = phthalocyanine, R = Me or Et), and their pyridine adducts. The BP86/6-31G(d) level of theory shows good reliability for the optimized axial bond lengths and bond dissociation energies (BDEs). The mechanism of the reductive cleavage was probed for the [CoIIIPc]-Me complex which is known as a highly effective methyl group donor. In the present analysis, which follows a recent study on the reductive Co-C bond cleavage in methylcobalamin (J. Phys. Chem. B 2007, 111, 7638-7645), it is demonstrated that addition of an electron and formation of the pi-anion radical [CoIII(Pc*)]-Me- significantly lowers the energetic barrier required for homolytic Co-C bond dissociation. Such BDE lowering in [CoIII(Pc*)]-Me- arises from the involvement of two electronic states: upon electron addition, a quasi-degenerate pi*Pc state is initially formed, but when the cobalt-carbon bond is stretched, the unpaired electron moves to a sigma*Co-C state and the final cleavage involves the three-electron (sigma)2(sigma*)1 bond. As in corrin complexes, the pi*Pc-sigma*Co-C states crossing does not take place at the equilibrium geometry of [CoIII(Pc*)]-Me- but only when the Co-C bond is stretched to approximately 2.3 A. The DFT computed Co-C BDE of 23.3 kcal/mol in the one-electron-reduced phthalocyanine species, [CoIII(Pc*)]-Me-, is lowered by approximately 37% compared to the neutral Py-[CoIIIPc]-Me complex where BDE = 36.8 kcal/mol. A similar comparison for the corrin-containing complexes shows that a DFT computed BDE of 20.4 kcal/mol for [CoIII(corrin*)]-Me leads to approximately 45% bond strength reduction, in comparison to 37.0 kcal/mol for Im-[CoIII(corrin)]-Me+. These results suggest some preference by the alkylcorrinoids for the reductive cleavage mechanism.     

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.     

Photoinduced bond homolysis of B12 coenzymes. An FT-EPR study

A Fourier Transform Electron Paramagnetic Resonance (FT-EPR) study was made of free radicals produced by photoinduced homolytic cleavage of the Co—C bond in methyl- and 5′-adenosylcobalamine (B₁₂ coenzymes) and R(4-t-butyl-pyridyl)cobaloximes, R = methyl or ethyl. Spectra of methyl and adenosyl free radicals generated by the cobalamines show Chemically Induced Dynamic Electron Polarization (CIDEP) produced in precursor radical pairs. The polarization pattern can be accounted for in terms of bond cleavage via a singlet excited state of the cobalamines. In the case of methylcobalamine the polarization pattern is wavelength dependent confirming earlier findings that bond cleavage occurs via two reaction channels. Spectra of the methyl and ethyl radicals given by the cobaloximes show a remarkably strong dependence on solvent and the identity of the axial ligand trans to the leaving alkyl group. This illustrates that the character of the excited state involved in the bond cleavage reaction is strongly dependent on axial ligation of the cobalt ion.     

New developments in the field of vitamin B12: enzymatic reactions dependent upon corrins and coenzyme B12.

Simple corrins such as vitamin B₁₂ and vitamin B₁₂ coenzyme catalyze a variety of unusual enzymatic reactions of which some are still without analogy in organic or organometallic chemistry. The mechanisms of these reactions are currently the subject of lively discussion. The present review focuses attention on new ideas about the mode of action of vitamin B₁₂ coenzymes in enzymatic reactions.     

Ligand substitution behavior of a simple model for coenzyme B12

The ligand substitution reactions of trans-[CoIII(en)2(Me)H2O]2+, a simple model for coenzyme B12, were studied for cyanide and imidazole as entering nucleophiles. It was found that these nucleophiles displace the coordinated water molecule trans to the methyl group and form the six-coordinate complex trans-[Co(en)2(Me)L]. The complex-formation constants for cyanide and imidazole were found to be (8.3 +/- 0.7) x 10(4) and 24.5 +/- 2.2 M-1 at 10 and 12 degrees C, respectively. The second-order rate constants for the substitution of water were found to be (3.3 +/- 0.1) x 10(3) and 198 +/- 13 M-1 s-1 at 25 degrees C for cyanide and imidazole, respectively. From temperature and pressure dependence studies, the activation parameters delta H++, delta S++, and delta V++ for the reaction of trans-[CoIII(en)2(Me)H2O]2+ with cyanide were found to be 50 +/- 4 kJ mol-1, 0 +/- 16 J K-1 mol-1, and +7.0 +/- 0.6 cm3 mol-1, respectively, compared to 53 +/- 2 kJ mol-1, -22 +/- 7 J K-1 mol-1, and +4.7 +/- 0.1 cm3 mol-1 for the reaction with imidazole. On the basis of reported activation volumes, these reactions follow a dissociative mechanism in which the entering nucleophile could be weakly bound in the transition state.     

Bond characterization on a Cr-Cr quintuple bond: a combined experimental and theoretical study

A combined experimental and theoretical charge density study on a quintuply bonded dichromium complex, Cr(2)(dipp)(2) (dipp = (Ar)NC(H)N(Ar) and Ar = 2,6-i-Pr(2)-C(6)H(3)), is performed. Two dipp ligands are bridged between two Cr ions; each Cr atom is coordinated to two N atoms of the ligands in a linear fashion. The Cr atom is in a low oxidation state, Cr(I), and in low coordination number condition, which stabilizes a metal-metal multiple bond, in this case, a quintuple bond. Indeed, it gives an ultrashort Cr-Cr bond distance of 1.7492(1) ? in the complex. The bond characterization of such a quintuple bond is undertaken both experimentally by high-resolution single-crystal X-ray diffraction and theoretically by density functional calculation (DFT). Electron densities are depicted via deformation density and Laplacian distributions. Bond characterizations of the complex are presented in terms of topological properties, Fermi hole function, source function (SF), and natural bonding orbital (NBO) analysis. The electron density at the Cr-Cr bond critical point (BCP) is 1.70 e/?(3), quite a high value for metal-metal bonding and mainly contributed from the metal ion itself. The quintuple bond is confirmed with one σ, two π, and two δ interactions by NBO analysis and Fermi hole function. The molecular orbitals (MOs) illustrate that five bonding orbitals are predominantly contributed from the 3d orbitals of the Cr(I) ion. The effective bond order from NBO analysis is 4.60. The detail comparison between experiment and theory will be given. Additionally, three closely related complexes are calculated for systematic comparison.     

Interactions of polar hydrogen bond donor solvents with ions: a theoretical study

Structural Chemistry - Intermolecular interactions between molecules of protic solvents (water, methanol, formic acid, formamide, methylamine and ammonia) and monatomic ions (Li+, Na+, K+,...     

Predicting adsorption behavior of Triacanthine anticancer drug with pure B12N12 nano-cage: A theoretical study

Predicting adsorption behavior of the Triacanthine (TRC) anticancer drug on the surface of B₁₂N₁₂ nano-cage was investigated using DFT and TD-DFT methods by B3LYP/6-311+G(d) level in the water solution. The adsorption energies of the TRC-B₁₂N₁₂ complexes (A-C) were shown that the adsorption process is exothermic. The UV/Vis absorption and IR spectra analysis were calculated to investigate the changes happening in adsorption of TRC over nano-cage. According to the results, the interaction of the TRC drug from the N9 atom on the B₁₂N₁₂ nano-cage (model A) has the most chemical stability rather than models B and C. Based on NBO analysis, the charge transfer process has happened between the TRC drug and B₁₂N₁₂ nano-cage. Recovery time, charge difference (ΔN), and ELF analysis were calculated. It was understood that the B₁₂N₁₂ nano-cage can be a good carrier for the delivery of TRC anticancer medicine.     

A theoretical study of carbon-carbon bond formation by a Michael-type addition

A theoretical study of the Michael-type addition of 1,3-dicarbonyl compounds to α,β-unsaturated carbonyl compounds has been performed in the gas phase by means of the AM1 semiempirical method and by density functional theory (DFT) calculations within the B3LYP and M06-2X hybrid functionals. A molecular model has been selected to mimic the role of a base, which is traditionally used as a catalyst in Michael reactions, an acetate moiety to modulate its basicity, and point charges to imitate the stabilization of the negative charge developed in the substrate during the reaction when taking place in enzymatic environments. Results of the study of six different reactions obtained at the three different levels of calculations show that the reaction takes place in three steps: in the first step the α proton of the acetylacetone is abstracted by the base, then the nucleophilic attack on the β-carbon of the α,β-unsaturated carbonyl compound takes place generating the negatively charged enolate intermediate, and finally the product is formed through a proton transfer back from the protonated base. According to the energy profiles, the rate limiting step corresponds to the abstraction of the proton or the carbon-carbon bond formation step, depending on substituents of the substrates and method of calculation. The effect of the substituents on the acidity of the α proton of the acetylacetone and the steric hindrance can be analyzed by comparing these two separated steps. Moreover, the result of adding a positive charge close to the center that develops a negative charge during the reaction confirms the catalytic role of the oxyanion hole proposed in enzyme catalysed Michael-type additions. Stabilization of the intermediate implies, in agreement with the Hammond postulate, a reduction of the barrier of the carbon-carbon bond formation step. Our results can be used to predict the features that a new designed biocatalyst must present to efficiently accelerate this fundamental reaction in organic synthesis.     

Periodic trends in bond dissociation energies. A theoretical study

Bond dissociation energies (BDEs) of all possible A-X single bonds involving the first- and second-row atoms, from Li to Cl, where the free valences are saturated by hydrogens, have been estimated through the use of the G3-theory and at the B3LYP/6-311+G(3df,2pd)//B3LYP/6-31G(2df,p) DFT level of theory. BDEs exhibit a periodical behavior. The A-X (A = Li, Be, B, Na, Mg, Al, and Si) BDEs show a steady increase along the first and the second row of the periodic table as a function of the atomic number Z(X). For A-X bonds involving electronegative atoms (A = C, N, O, F, P, S, and Cl) the bond energies achieve a maximum around Z(X) = 5. The same behavior is observed when BDEs are plotted against the electronegativity chi(X) of the atom X. Thus, for A-X bonds (A = Li, Be, B, Na, Mg, Al, Si), the BDEs for a fixed A increases, grosso modo, as the electronegativity differences between X and A increase, with some exceptions, which reflect the differences in the relaxation energies of the radicals produced upon the bond cleavage. A similar trend, albeit less pronounced, is found for single A-X bonds, where A = C, N, O, F, P, S, and Cl. However, there is an additional feature embodied in the enhancement of the strength of the A-boron bonds due to the ability of boron to act as a strong electron acceptor. The trends in bond lengths and charge densities at the bond critical points are in line with the aforementioned behavior.     

A theoretical study of the Si-O bond in disiloxane and related molecules

Summary A comparison of semi-empirical (MNDO) and ab initio (GAUSSIAN) calculations for disiloxane and related molecules is given. The STO-3G^* basis set well reproduced the observed geometries of disiloxane (*), DZP, TZVP) gave much poorer agreement with the observed geometries.Comparison of the STO-3G^* and the STO-3G basis sets demonstrates the necessity of including d-orbitals on the silicon. However, the semi-empirical MNDO program gave, despite the absence of d-orbitals, a better approximation to the molecular geometry than the complex ab initio basis sets.Force field parameters have been calculated for k_SiOSi, k_OSiO, 0.089 and 0.73 mdyneÅ/rad², and the SiOSiO torsion which has a V₁ potential of –0.68 kcal/mol. In addition, the HSiOH torsion is shown to have a three-fold potential of 0.78 kcal/mol. These are profoundly different from the analogous carbon-oxygen force constants, demonstrating that C-O parameters cannot be transferred to the corresponding Si-O systems.     

H-Ge bond activation by tungsten carbonyls: An experimental and theoretical study

The activation of the Ge-H bond and the formation of several hydride complexes, characterized by high-field resonances, have been detected during the ¹H NMR spectroscopy monitoring of the photochemical reaction of Et₃GeH and Et₂GeH₂ with W(CO)₆ and the norbornadiene complex [W(CO)₄(η⁴-nbd)]. The activation of the Ge-H bond of triethylgermane in the photochemical reactions of tungsten(0) complexes has been applied in the hydrogermylation of norbornadiene (nbd), which leads to the formation of endo-triethylgermylnorbornene as the major product. The complex [{W(μ-η²-H-GeEt₂)(CO)₄}₂] has been fully characterized by NMR spectroscopy and by a single-crystal X-ray diffraction study. Evidence for the hydride ligand of the W(μ-η²-H-GeEt₂) group has been provided by ¹H NMR spectroscopy (δ = −9.02, ¹J_H-W = 31 Hz) and by DFT calculations. A DFT study of the structural properties and ¹H NMR chemical shifts of several possible intermediate σ and hydride complexes formed during the photochemical reaction of W(CO)₆ and Et₂GeH₂ has been performed.     

Co-C bond activation in methylmalonyl-CoA mutase by stabilization of the post-homolysis product Co2+ cobalamin

Despite decades of research, the mechanism by which coenzyme B12 (adenosylcobalamin, AdoCbl)-dependent enzymes promote homolytic cleavage of the cofactor's Co-C bond to initiate catalysis has continued to elude researchers. In this work, we utilized magnetic circular dichroism spectroscopy to explore how the electronic structure of the reduced B12 cofactor (i.e., the post-homolysis product Co2+ Cbl) is modulated by the enzyme methylmalonyl-CoA mutase. Our data reveal a fairly uniform stabilization of the Co 3d orbitals relative to the corrin pi/pi*-based molecular orbitals when Co2+ Cbl is bound to the enzyme active site, particularly in the presence of substrate. Contrastingly, our previous studies (Brooks, A. J.; Vlasie, M.; Banerjee, R.; Brunold, T. C. J. Am. Chem. Soc. 2004, 126, 8167-8180.) showed that when AdoCbl is bound to the MMCM active site, no enzymatic perturbation of the Co3+ Cbl electronic structure occurs, even in the presence of substrate (analogues). Collectively, these observations provide direct evidence that enzymatic Co-C bond activation involves stabilization of the post-homolysis product, Co2+ Cbl, rather than destabilization of the Co3+ Cbl "ground" state.