Per-Ola Norrby

Copper‐Catalyzed Cross‐Couplings with Part‐per‐Million Catalyst Loadings

Due to the importance of functionalized arenes as scaffolds in applied organic materials and biologically relevant molecules, metal-catalyzed cross-couplings have gained significant attention in recent years. 2] Among them Ullmann type C X bond formations are particularly attractive because they often allow the use of low-cost starting materials in combination with readily available copper salts. Whereas the initial protocols required high temperatures and over-stoichiometric quantities of metal, recent approaches involving wellchosen and optimized metal–ligand combinations allow for milder reaction conditions and catalytic turnover. Despite these significant advances it has to be noted that commonly in these catalytic Ullmann type reactions both TONs (turnover numbers) as well as TOFs (turnover frequencies) remain rather limited resulting in the requirement of metal salt amounts in the range of 5 to 10 mol%. Lowering the catalyst loading leads to extended reaction times and decreased product yields. Here, we report on Ullmann type reactions with “homeopathic amounts” of copper salts. During investigations of iron-catalyzed cross-coupling reactions 8] it was noted that for some substrate combinations the catalyst activity depended on the metal salt source and its purity. Those observations suggested a closer look into the effects of metal traces under the applied reaction conditions. Taking into account the results by Taillefer and others on Fe/Cu co-catalyses, copper became the prime metal of choice. To our surprise we found that even with catalyst loadings in the 0.01 mol% range of copper(II) salts N-, O-, and S-arylations were possible to provide the corresponding products in yields > 90%. As a representative example, the coupling between pyrazole (1) and phenyliodide (2, 1.5 equiv) to provide N-arylated product 3 [Eq. (1)] was studied in detail. Further reaction components were N,N’dimethylethylenediamine (DMEDA) as (potential) ligand (20 mol %), K3PO4·H2O as base (2 equiv) [12] and toluene as solvent. The reaction mixture was kept under inert atmosphere at 135 8C in a sealed microwave tube for 24 h.

Conformational energy penalties of protein-bound ligands

The conformational energies required for ligands to adopt their bioactive conformations were calculated for 33 ligand–protein complexes including 28 different ligands. In order to monitor the force field dependence of the results, two force fields, MM3 and AMBER, were employed for the calculations. Conformational analyses were performed in vacuo and in aqueous solution by using the generalized Born/solvent accessible surface (GB/SA) solvation model. The protein-bound conformations were relaxed by using flat-bottomed Cartesian constraints. For about 70% of the ligand–protein complexes studied, the conformational energies of the bioactive conformations were calculated to be ≤3 kcal/mol. It is demonstrated that the aqueous conformational ensemble for the unbound ligand must be used as a reference state in this type of calculations. The calculations for the ligand–protein complexes with conformational energy penalties of the ligand calculated to be larger than 3 kcal/mol suffer from uncertainties in the interpretation of the experimental data or limitations of the computational methods. For example, in the case of long-chain flexible ligands (e.g. fatty acids), it is demonstrated that several conformations may be found which are very similar to the conformation determined by X-ray crystallography and which display significantly lower conformational energy penalties for binding than obtained by using the experimental conformation. For strongly polar molecules, e.g. amino acids, the results indicate that further developments of the force fields and of the dielectric continuum solvation model are required for reliable calculations on the conformational properties of this type of compounds.

The Mechanism for the Rhodium-Catalyzed Decarbonylation of Aldehydes: A Combined Experimental and Theoretical Study

The mechanism for the rhodium-catalyzed decarbonylation of aldehydes was investigated by experimental techniques (Hammett studies and kinetic isotope effects) and extended by a computational study (DFT calculations). For both benzaldehyde and phenyl acetaldehyde derivatives, linear Hammett plots were obtained with positive slopes of +0.79 and +0.43, respectively, which indicate a buildup of negative charge in the selectivity-determining step. The kinetic isotope effects were similar for these substrates (1.73 and 1.77 for benzaldehyde and phenyl acetaldehyde, respectively), indicating that similar mechanisms are operating. A DFT (B3LYP) study of the catalytic cycle indicated a rapid oxidative addition into the C(O)-H bond followed by a rate-limiting extrusion of CO and reductive elimination. The theoretical kinetic isotope effects based on this mechanism were in excellent agreement with the experimental values for both substrates, but only when migratory extrusion of CO was selected as the rate-determining step.

Mechanistic Investigation of Iron‐Catalyzed Coupling Reactions

The mechanism of the iron‐catalyzed cross‐coupling of aryl electrophiles with alkyl Grignard reagents is studied by a combination of GC monitoring, Hammett competition experiments, and DFT calculations. The reaction follows a pathway where an FeI complex, formed in situ, reacts in a rate‐limiting oxidative addition with the aryl electrophile. A rapid thermoneutral transmetalation from a Grignard reagent occurs either before or after the oxidative addition, with little to differentiate between the two pathways. A reductive elimination of the resulting alkyl aryl FeIII complex closes the catalytic cycle. Iron in lower oxidation states can act as a competent precatalyst by oxidation into the FeI–FeIII cycle. FeII complexes can give FeI catalysts through reductive elimination of a bimetallic complex. Added ligands, dilution, and powerful aryl electrophiles all serve to increase the stability of the active catalyst, presumably by counteracting oligomerization of low‐valent iron.

A Comparison of Conformational Energies Calculated by Several Molecular Mechanics Methods

Several commonly used molecular mechanics force fields have been tested for accuracy in conformational energy calculations. Differences in performance between the force fields are discussed for different classes of structures. MMFF93 and force fields based on the MM2 or MM3 functional form are found to perform significantly better than other force fields in the test, with average conformational energy errors around 0.5 kcal/mol. CFF91 also reaches this accuracy for the subset in which fully determined parameters are used, but it doubles the overall error due to use of estimated parameters. Harmonic force fields generally have average errors exceeding 1 kcal/mol. Factors influencing accuracy are identified and discussed.

Pyranoside phosphite-oxazoline ligands for the highly versatile and enantioselective ir-catalyzed hydrogenation of minimally functionalized olefins. A combined theoretical and experimental study.

A modular set of phosphite-oxazoline (P,N) ligands has been applied to the title reaction. Excellent ligands have been identified for a range of substrates, including previously challenging terminally disubstituted olefins, where we now have reached enantioselectivities of 99% for a range of substrates. The selectivity is best for minimally functionalized substrates with at least a moderate size difference between geminal groups. A DFT study has allowed identification of the preferred pathway. Computational prediction of enantioselectivities gave very good accuracy.

Mechanism, Reactivity, and Selectivity in Palladium-Catalyzed Redox-Relay Heck Arylations of Alkenyl Alcohols

The enantioselective Pd-catalyzed redox-relay Heck arylation of acyclic alkenyl alcohols allows access to various useful chiral building blocks from simple olefinic substrates. Mechanistically, after the initial migratory insertion, a succession of β-hydride elimination and migratory insertion steps yields a saturated carbonyl product instead of the more general Heck product, an unsaturated alcohol. Here, we investigate the reaction mechanism, including the relay function, yielding the final carbonyl group transformation. M06 calculations predict a ΔΔG⧧ of 1 kcal/mol for the site selectivity and 2.5 kcal/mol for the enantioselectivity, in quantitative agreement with experimental results. The site selectivity is controlled by a remote electronic effect, where the developing polarization of the alkene in the migratory insertion transition state is stabilized by the C–O dipole of the alcohol moiety. The enantioselectivity is controlled by steric repulsion between the oxazoline substituent and the alcohol-bearing alkene substituent. The relay efficiency is due to an unusually smooth potential energy surface without high barriers, where the hydroxyalkyl-palladium species acts as a thermodynamic sink, driving the reaction toward the carbonyl product. Computational predictions of the relative reactivity and selectivity of the double bond isomers are validated experimentally.

Deriving force field parameters for coordination complexes

Abstract The process of deriving molecular mechanics force fields for coordination complexes is outlined. Force field basics are introduced with an emphasis on special requirements for metal complexes. The review is then focused on how to set up the initial model, define the target, refine the parameters, and validate the final force field. Alternatives to force field derivation are discussed briefly.

α‐Arylation by Rearrangement: On the Reaction of Enolates with Diaryliodonium Salts

Surprising equilibration: A new mechanism for the title reaction is supported by DFT calculations and experimental observations. The CI and OI intermediates are isoenergetic and equilibrate quickly ...

Combined Experimental and Theoretical Study of the Mechanism and Enantioselectivity of Palladium- Catalyzed Intermolecular Heck Coupling

The asymmetric Heck reaction using P,N-ligands has been studied by a combination of theoretical and experimental methods. The reaction follows Halpern-style selectivity; that is, the major isomer is produced from the least favored form of the pre-insertion intermediate. The initially formed Ph-Pd(P,N) species prefers a geometry with the phenyl trans to N. However, the alternative form, with Ph trans to P, is much less stable but much more reactive. In the preferred transition state, the phenyl moiety is trans to P, but significant electron density has been transferred to the alkene carbon trans to N. The steric interactions in this transition state fully account for the enantioselectivity observed with the ligands studied. The calculations also predict relative reactivity and nonlinear mixing effects for the investigated ligands; these predictions are fully validated by experimental testing. Finally, the low conversion observed with some catalysts was found to be caused by inactivation due to weak binding of the ligand to Pd(0). Adding monodentate PPh3 alleviated the precipitation problem without deteriorating the enantioselectivity and led to one of the most effective catalytic systems to date.