Close‐Shell Reductive Elimination versus Open‐Shell Radical Coupling for Site‐Selective Ruthenium‐Catalyzed C−H Activations by Computation and Experiments

Abstract

Ruthenium‐catalyzed σ‐bond activation‐assisted meta‐C−H functionalization has emerged as a useful tool to forge distal C−C bonds. However, given the limited number of mechanistic studies, a clear understanding of the origin of the site‐selectivity and the complete reaction pattern is not available. Here, we present systematic computational studies on ruthenium‐catalyzed C−H functionalization with primary, secondary, tertiary alkyl bromides and aryl bromides. The C−H scission and the C−C formation were carefully examined. Monocyclometalated ruthenium(II) complexes were identified as the active species, which then underwent inner‐sphere single electron transfer (ISET) to activate the organic bromides. The site‐selectivity results from the competition between the close‐shell reductive elimination and the open‐shell radical coupling. Based on this mechanistic understanding, a multilinear regression model was built to predict the site‐selectivity, which was further validated by experiments.

Visible Light‐Induced Ru‐Catalyzed Directing‐Group‐Assisted C−H Activation of Arenes

“…A competition experiment suggests the electron‐poor arenes are favorable substrates to the arylation compared with electron‐rich arenes. This phenomenon is similar to that of oxidative addition mechanism in high‐temperature Ru ortho ‐arylation [15] . The free cymene is detected in both blue light irradiation and ambient light, and photo acceleration of decomplexation of η 6 ‐arenes is observed.…”

“…This phenomenon is similar to that of oxidative addition mechanism in high-temperature Ru orthoarylation. [15] The free cymene is detected in both blue light irradiation and ambient light, and photo acceleration of decomplexation of η 6 -arenes is observed. Although the photoluminescence quenching is not achieved between complex Fa and aryl halides, the authors could not rule out an additional role for visible light in subsequent steps in the catalytic cycle.…”

DLPNO-CCSD(T) and DFT study of the acetate-assisted C–H activation of benzaldimine at [RuCl2(p-cymene)]2: the relevance of ligand exchange processes at ruthenium(ii) complexes in polar protic media

“…In particular, PCM and SMD solvation models have been successfully employed to investigate many ruthenium( ii )-catalyzed C–H activation and functionalization processes in almost all kinds of solvents (as 2-MeTHF, dioxane, toluene, DCE, acetonitrile, MeOH, TFE, tert -butanol, HFIP, or AcOH). 12–33 Nevertheless, the suitability of implicit solvent models for the study of ionic reactions that are performed in protic solvents is still controversial, as strong, specific, solvent–solute H-bonding interactions are seemingly ignored. These kinds of directed interactions are not captured by the CPCM and SMD models and this deficiency could compromise the accuracy of our results.…”

“…17 DFT studies covering the reactions of phenylpyrazoles, 18 benzylamines, 19 phenylpyridines, 20 N -aryl-oxazolidinones, 21 naphthols, 22 aryl carboxylic acids, 23 arylphosphonates, 24 arylacetamides, 16 d ,25 benzamides, 26 pyridylindoles, 27 phenylketones, 28 hydroxy-chromones 29 or phenylimidazoles 30 promoted by [RuCl 2 ( p -cymene)] 2 and acetate anions (or preformed Ru(OAc) 2 ( p -cymene)) support initial substrate ( A ) binding to the ruthenium precursor ( B ) followed by dissociation of a ligand (from C ) and creation of a key intermediate with a vacant site at which the M–C bond can form (see Scheme 2). Most of these electrophilic intermediates are cationic in nature ( D + ) 31 but alternative routes involving neutral intermediates equipped with two acetate ligands bound to the ruthenium ( F L ) and showing η 6 – η 2 slippage 32 or substitution of the arene co-ligand by solvent or a second substrate molecule 33 have been also reported. From either cationic or neutral intermediates the C–H activation event (to E + or G L , respectively) is followed by final HOAc exchange to form a stable cycloruthenate complex ( H ) or enable a subsequent functionalization process.…”

Late-stage meta-C–H alkylation of pharmaceuticals to modulate biological properties and expedite molecular optimisation in a single step

“…2a). These substrates were chosen to represent different levels of Lewis basicity and electronic properties, factors expected to have an impact both on the success and the site-selectivity of the C-H alkylation 27 . The presence of a phosphine ligand turned out to be crucial for higher reactivity as well as improved regioselectivity into the desired metafunctionalised products 3 28,29 .…”