An Unexpected Ireland-Claisen Rearrangement Cascade During the Synthesis of the Tricyclic Core of Curcusone C: Mechanistic Elucidation by Trial-and-Error and Automatic Artificial Force-Induced Reaction (AFIR) Computations.

In the course of a total synthesis effort directed toward the natural product curcusone C, the Stoltz group discovered an unexpected thermal rearrangement of a divinylcyclopropane to the product of a formal Cope/1,3-sigmatropic shift sequence. Since the involvement of a thermally forbidden 1,3-shift seemed unlikely, theoretical studies involving two approaches, the "trial-and-error" testing of various conceivable mechanisms (Houk group) and an "automatic" approach using the Maeda-Morokuma AFIR method (Morokuma group) were applied to explore the mechanism. Eventually, both approaches converged on a cascade mechanism shown to have some partial literature precedent: Cope rearrangement/1,5-sigmatropic silyl shift/Claisen rearrangement/retro-Claisen rearrangement/1,5-sigmatropic silyl shift, comprising a quintet of five sequential thermally allowed pericyclic rearrangements.

Computational elucidation of the reaction mechanism for synthesis of pyrrolidinedione derivatives via Nef-type rearrangement - cyclization reaction.

This paper reports a quantum chemical study of all stages of a one-pot synthesis of pyrrolidinedione derivatives from nitromethane and coumarin, which includes Michael addition, migration of an oxygen atom (Nef-type rearrangement), and cyclization to a pyrrolidine ring. The energy barrier of deprotonated nitromethane addition to coumarin is 21.7 kJ mol-1, while the barrier of proton transfer from the methylene to the nitro group in the nitromethyl group is notably higher, 197.8 kJ mol-1. The second stage of the reaction, migration of an oxygen atom within the nitromethyl group, occurs with lowest energy barrier, 142.4 kJ mol-1, when it is assisted by an additional water molecule. The last stage - cyclization, passes with a very low energy barrier of 11.9 kJ mol-1 but the tautomerization of the nitrosohydroxymethyl group to the hydroxy-N-hydroxyiminomethyl, necessary for the process, has an energy barrier of 178.4 kJ mol-1. Analogous calculations for the same process with the ethyl ester of 3-coumarin-carboxylic acid as substrate show that the relative energies of the intermediates and transition states are by at most 10-16 kJ mol-1 more stable than the corresponding structures with coumarin.

Assessment of the europium(III) binding sites on albumin using fluorescence spectroscopy.

Intrinsic fluorescence quenching of bovine serum albumin (BSA) and europium(III) luminescence in BSA complexes were investigated. The number of BSA binding sites (n) and equilibrium constant (Keq) values were determined from both measurements provided qualitatively different results. While the modified Stern-Volmer relation for BSA fluorescence quenching gave n = 1 at pH 4.5 and pH 6, two sets of binding sites were determined from Eu(3+) luminescence with n1 = 2, n2 = 4 at pH 6 and n1 = 1, n2 = 2 at pH 4.5. The model explaining the discrepancy between the results obtained by these fluorescent approaches was suggested, and the limitations in application of the "log-log" Stern-Volmer plots in analysis of binding processes were discussed.

Asymmetric phase-transfer catalysis with homo- and heterochiral quaternary ammonium salts: a theoretical study.

A thorough theoretical study of phase-transfer quaternary ammonium catalysts designed by the Maruoka group has been performed in an attempt to gain better understanding of the properties and catalytic behavior of the homo- and heterochiral forms of these systems. The conformationally flexible analogue is found to easily undergo interconversion from the homo- to the heterochiral form driven by the higher thermodynamic stability of the heterochiral isomer and resulting in alternation in catalytic behavior. Theoretical calculations of (1)H NMR spectra of the two isomers for different model systems are in good agreement with the experimental data, allowing us to conclude that the upfield shift of signals for the benzylic protons in the heterochiral form could be explained by an increase in the shielding effect of the aromatic parts of the system around these protons due to the conformational changes. By applying the automated transition state (TS) search procedure for the alkylation of glycine derivatives catalyzed by the homo-/heterochiral form of a conformationally rigid analogue, we were able to locate more than 40 configurations of the TS structures. In brief, the homochiral form was theoretically confirmed to catalyze the formation of the predominant R-product, while for the heterochiral form the catalytic activity is found to depend on two factors: (i) formation of a tight ion pair between the catalyst and the glycine derivative, which results in a decrease in the reaction rate, in agreement with the experimental data, and formation of only the R-product, and (ii) the possibility that the reaction occurs without the initial formation of the ion pair or after its dissociation, in which case the formation of an S-product is predominant. The combined effects of both factors would explain the lower reaction rate and the poor enantioselectivity observed experimentally for the heterochiral form.

Reverse hydrogen spillover on and hydrogenation of supported metal clusters: insights from computational model studies.

"Reverse" spillover of hydrogen from hydroxyl groups of the support onto supported transition metal clusters, forming multiply hydrogenated metal species, is an essential aspect of various catalytic systems which comprise small, highly active transition metal particles on a support with a high surface area. We review and analyze the results of our computational model studies related to reverse hydrogen spillover, interpreting available structural and spectral data for the supported species and examining the relationship between metal-support and metal-hydrogen interactions. On the examples of small clusters of late transition metals, adsorbed in zeolite cavities, we showed with computational model studies that reverse spillover of hydrogen is energetically favorable for late transition metals, except for Au. This preference is crucial for the chemical reactivity of such bifunctional catalytic systems because both functions, of metal species and of acidic sites, are strongly modified, in some cases even suppressed - due to partial oxidation of the metal cluster and the conversion of protons from acidic hydroxyl groups to hydride ligands of the metal moiety. Modeling multiple hydrogen adsorption on metal clusters allowed us to quantify how (i) the support affects the adsorption capacity of the clusters and (ii) structure and oxidation state of the metal moiety changes upon adsorption. In all models of neutral systems we found that the metal atoms are partially positively charged, compensated by a negative charge of the adsorbed hydrogen ligands and of the support. In a case study we demonstrated with calculated thermodynamic parameters how to predict the average hydrogen coverage of the transition metal cluster at a given temperature and hydrogen pressure.

Determination of the optimal position of adjacent proton-donor centers for the activation or inhibition of peptide bond formation--a computational model study.

The study reports a computational analysis of the influence of proton donor group adjacent to the reaction center during ester ammonolysis of an acylated diol as a model reaction for peptide bond formation. This analysis was performed using catalytic maps constructed after a detailed scanning of the available space around the reaction centers in different transition states, a water molecule acting as a typical proton donor. The calculations suggest that an adjacent proton donor center can reduce the activation barrier of the rate determining transition states by up to 7.2 kcal/mol, while no inhibition of the reaction can be achieved by such a group.

Support nanostructure boosts oxygen transfer to catalytically active platinum nanoparticles.

Interactions of metal particles with oxide supports can radically enhance the performance of supported catalysts. At the microscopic level, the details of such metal-oxide interactions usually remain obscure. This study identifies two types of oxidative metal-oxide interaction on well-defined models of technologically important Pt-ceria catalysts: (1) electron transfer from the Pt nanoparticle to the support, and (2) oxygen transfer from ceria to Pt. The electron transfer is favourable on ceria supports, irrespective of their morphology. Remarkably, the oxygen transfer is shown to require the presence of nanostructured ceria in close contact with Pt and, thus, is inherently a nanoscale effect. Our findings enable us to detail the formation mechanism of the catalytically indispensable Pt-O species on ceria and to elucidate the extraordinary structure-activity dependence of ceria-based catalysts in general.

Catalytic role of vicinal OH in ester aminolysis: proton shuttle versus hydrogen bond stabilization.

This computational study provoked by the process of peptide bond formation in the ribosome investigates the influence of the vicinal OH group in monoacylated diols on the elementary acts of ester aminolysis. Two alternative approaches for this influence on ester ammonolysis were considered: stabilization of the transition states by hydrogen bonds and participation of the vicinal hydroxyl in proton transfer (proton shuttle). The activation due to hydrogen bonds of the vicinal hydroxyl via tetragonal transition states was rather modest; the free energy of activation was reduced by only 5.2 kcal/mol compared to the noncatalyzed reaction. The catalytic activation via the proton shuttle mechanism with participation of the vicinal OH in the proton transfer via hexagonal transition states resulted in considerable reduction of the free energy of activation to 33.5 kcal/mol, i.e., 16.0 kcal/mol lower than in the referent process. Accounting for the influence of the environment on the reaction center by a continuum model (for ε from 5 to 80) resulted in further stabilization of the rate-determining transition state by 4-5 kcal/mol. The overall reduction of the reaction barrier by about 16 kcal/mol as compared to the noncatalyzed process corresponds to about 10(9)-fold acceleration of the reaction, in agreement with the experimental estimate for acceleration of this process in the ribosome.

Hierarchical approach to conformational search and selection of computational method in modeling the mechanism of ester ammonolysis.

We describe automated procedures for the first stages of a systematic computational investigation of reaction mechanisms. They include (i) selection of computational method and basis set based on statistical analysis of structural and energy data relating to experimental values, (ii) determination of all distinct conformations of transition states with large conformational freedom, and (iii) generation of unknown geometry of the transition states, based on pre-defined connectivity of the atoms involved in the reaction. For the conformational search we employed an efficient procedure for exploration of various possible conformations of the transition states and elimination of the equivalent structures in several steps using molecular-mechanical and quantum-mechanical methods. The procedure was applied to the determination of the structures of transition states and intermediates in the ammonolysis of monoformylated 1,2-ethanediol, which were subsequently used for identification of the lowest energy reaction paths. For the same reaction system we also used the approach for generation of the initial structures of transition states with unknown geometry. The reported procedures are implemented in the MolRan program suite.

Redox behavior of small metal clusters with respect to hydrogen. The effect of the cluster charge from density functional results.

Tetrahedral model iridium species [Ir(4)H(n)](q+) of different charge and hydrogen loading were described at the density functional level. The energy of dissociative adsorption of hydrogen was calculated to vary in the small interval from -63 kJ mol(-1) to -77 kJ mol(-1) (per H atom). Adsorption of hydrogen on Ir(4) and Ir(4)(+) induces an oxidation of the metal moiety, whereas the highly charged cluster Ir(4)(3+) is reduced upon hydrogen adsorption. The ligand shell acts as charge buffer as the metal moieties of the complexes [Ir(4)H(12)](q+) with maximum hydrogen loading carry very similar effective charges, irrespective of the total charge q. Similar effects were confirmed to occur on small clusters of other 4d and 5d transition metals.