Epimeric Face-Selective Oxidations and Diastereodivergent Transannular Oxonium Ion Formation Fragmentations: Computational Modeling and Total Syntheses of 12-Epoxyobtusallene IV, 12-Epoxyobtusallene II, Obtusallene X, Marilzabicycloallene C, and Marilzabicycloallene D.

The total syntheses of 12-epoxyobtusallene IV, 12-epoxyobtusallene II, obtusallene X, marilzabicycloallene C, and marilzabicycloallene D as halogenated C15-acetogenin 12-membered bicyclic and tricyclic ether bromoallene-containing marine metabolites from Laurencia species are described. Two enantiomerically pure C4-epimeric dioxabicyclo[8.2.1]tridecenes were synthesized by E-selective ring-closing metathesis where their absolute stereochemistry was previously set via catalytic asymmetric homoallylic epoxidation and elaborated via regioselective epoxide-ring opening and diastereoselective bromoetherification. Epimeric face-selective oxidation of their Δ12,13 olefins followed by bromoallene installation allowed access to the oppositely configured 12,13-epoxides of 12-epoxyobtusallene II and 12-epoxyobtusallene IV. Subsequent exploration of their putative biomimetic oxonium ion formation-fragmentations reactions revealed diastereodivergent pathways giving marilzabicycloallene C and obtusallene X, respectively. The original configurations of the substrates evidently control oxonium ion formation and their subsequent preferred mode of fragmentation by nucleophilic attack at C9 or C12. Quantum modeling of this stereoselectivity at the ωB97X-D/Def2-TZVPPD/SCRF = methanol level revealed that in addition to direction resulting from hydrogen bonding, the dipole moment of the ion-pair transition state is an important factor. Marilzabicycloallene D as a pentahalogenated 12-membered bicyclic ether bromoallene was synthesized by a face-selective chloronium ion initiated oxonium ion formation-fragmentation process followed by subsequent bromoallene installation.

Experiment and computation: a combined approach to study the reactivity of palladium complexes in oxidation states 0 to IV.

As the accuracy of computational chemistry increases, and the advent of more powerful computers decreases the amount of time required to perform complex calculations, the use of this to investigate chemical systems becomes increasingly attractive. Particularly in combination with practical lab-based experimental and spectroscopic studies the application of in silico studies is a powerful tool for mechanistic investigations. In this review we demonstrate how a combined experimental and computational approach can yield mechanistic insight that could frequently not have been accessible to this high degree of certainty by utilising one of these two approaches alone. After an introduction describing the challenges of studying palladium-based chemistry, and how this combined approach can help to tackle these challenges (Section 1), we provide examples in which experiments have been used in tandem with computational chemistry. This discussion is categorised by palladium oxidation state for convenience: Pd(0) chemistry comprises discussion on oxidative addition in traditional Pd(0)/Pd(II) cross-coupling (Section 2); a section on odd oxidation state chemistry includes oxidation of Pd(0) to Pd(I) dimers, oxidative addition to Pd(I) dimers, oxidation of Pd(II) to Pd(III) dimers and subsequently reductive elimination from these Pd(III) dimers (Section 3); Pd(II) chemistry includes transmetallation, reductive elimination and the field of C-H activation relating to palladium catalysis (Section 4); and finally, a section on Pd(IV) chemistry focusses on reductive elimination from these complexes (Section 5).

Kinetic and computational studies on Pd(I) dimer-mediated halogen exchange of aryl iodides.

Building on our previous discovery and reactivity explorations of the Pd(I) dimer [(PtBu3)PdBr]2-mediated halogen exchange of aryl iodides [Chem. Sci. 2013, 4, 4434], this report presents kinetic studies of this process, giving first-order kinetic dependence in the Pd(I) dimer and aryl iodide. An activation free energy barrier of ΔG(‡) = 24.9 ± 3.3 kcal/mol was experimentally determined. Extensive computational studies on the likely reaction pathway were subsequently carried out. A variety of DFT methods were assessed, ranging from dispersion-free methods to those that better account for dispersion (M06L, ωB97XD, D3-DFT). While significant discrepancies in the quantitative prediction of activation barriers were observed, all computational methods consistently predicted the analogous qualitative reactivity that is in agreement with all spectroscopic and reactivity data collected. Overall, these data provide compelling additional support of the direct reactivity of Pd(I)-Pd(I) with aryl iodides.

Computational ligand design for the reductive elimination of ArCF3 from a small bite angle Pd(II) complex: remarkable effect of a perfluoroalkyl phosphine.

To date only three ligands are known to trigger the challenging reductive elimination of ArCF3 from Pd(II). We report the computational design of a bidentate trifluoromethylphosphine ligand that although exhibiting a generally ineffective small bite angle is predicted to give facile reductive elimination. Our experimental verification gave quantitative formation of ArCF3 at 80 °C within 2 h. This highlights the distinct effect of P-CF3 in organometallic reactivity and constitutes a proof-of-principle study of computational reactivity design.

Trifluoromethylation of ketones and aldehydes with Bu3SnCF3.

The (trifluoromethyl)stannane reagent, Bu3SnCF3, was found to react under CsF activation with ketones and aldehydes to the corresponding trifluoromethylated stannane ether intermediates at room temperature in high yield. Only a mildly acidic extraction (aqueous NH4Cl) is required to release the corresponding trifluoromethyl alcohol products. The protocol is compatible with acid-sensitive functional groups.

Utilization of a kinetic isotope effect to decrease decomposition of ceftriaxone in a mixture of D2O/H2O.

The discovery of cephalosporin and demonstration of its improved stability in aqueous solution, as well as enhanced in vitro activity against penicillin-resistant organisms, were major breakthroughs in the development of ß-lactam antibiotics. Although cephalosporins are more stable with respect to hydrolytic degradation than penicillins, they still experience a variety of chemical transformations. The present study offers an insight into the rates and mechanisms of ceftriaxone degradation at the therapeutic concentration in water, a mixture of water and deuterium oxide, and deuterium oxide itself at the neutral pH. Specific ceftriaxone degradation products were observed in aged samples (including a previously unreported dimer-type species), and by comparing the degradation rates in H2O and D2O, the observation of a kinetic isotope effect provided some valuable insight as to the nature of the initial ceftriaxone degradation. The effect of protium to deuterium isotope change on the degradation kinetics of ceftriaxone was evaluated using the method of initial rates based on HPLC analysis as well as by quantitative 1H NMR spectroscopy. Moreover, computational analysis was utilized to get a molecular insight into chemical processes governing the ceftriaxone degradation and to rationalize the stabilizing effect of replacing H2O with D2O.

A unifying stereochemical analysis for the formation of halogenated C15-acetogenin medium-ring ethers from Laurencia species via intramolecular bromonium ion assisted epoxide ring-opening and experimental corroboration with a model epoxide.

A unifying stereochemical analysis for the formation of the constitutional isomeric halogenated C(15)-acetogenin medium-ring ether natural products from Laurencia species is presented, where an intramolecular bromonium ion assisted epoxide ring-opening reaction of enantiomerically pure epoxides can account for ring-size, the position of the halogen substituents, and relative and absolute configurations of the known natural products. Experimentally, a model epoxide corroborates the feasibility of this process for concurrent formation of 7-, 8- and 9-ring ethers corresponding to the halogenated medium-ring ethers of known metabolites from Laurencia species.

Intramolecular bromonium ion assisted epoxide ring-opening: capture of the oxonium ion with an added external nucleophile.

9-Oxabicyclo[6.1.0]non-4-ene (1) undergoes intramolecular bromonium ion-assisted epoxide ring-opening using N-bromosuccinimide via a presumed oxonium ion that is subject to stereospecific, nonregioselective capture with added external nucleophiles producing novel bicyclo[4.2.1] and bicyclo[3.3.1] ethers. Carboxylic acids (as catalyzed by tetramethylguanidine), alcohols, water, and halides can all function as effective nucleophiles. Stereospecific direct opening of the bromonium ion with carboxylic acids was found to be a competing process where high dilution disfavors this pathway. Halogen-induced isotopic (13)C NMR shifts (Δδ CBr 1.3-1.9 ppb; Δδ CCl 8.6-8.7 ppb) were found to be most useful in unambiguously identifying halogen-bearing carbons, and correlation of these (13)C NMR shifts allowed ready assignment of diastereomeric structures. The structure of adducts 6b, 6c, 7b, 7c, 7d, and 8a-d were all elucidated by X-ray crystallography.