Mechanistic Insights into Nickamine-catalyzed Alkyl-Alkyl Cross-coupling Reactions

Within the last decades the transition metal-catalyzed cross-coupling of non-activated alkyl halides has significantly progressed. Within the context of alkyl-alkyl cross-coupling, first row transition metals spanning from iron, over cobalt, nickel, to copper have been successfully applied to catalyze this difficult reaction. The mechanistic understanding of these reactions is still in its infancy. Herein we outline our latest mechanistic studies that explain the efficiency of nickel, in particular nickamine-catalyzed alkyl-alkyl cross-coupling reactions

Bimetallic Oxidative Addition in Nickel-Catalyzed Alkyl-Aryl Kumada Coupling Reactions

The mechanism of alkylaryl Kumada coupling catalyzed by the nickel pincer complex Nickamine was studied. Experiments using radical-probe substrates and DFT calculations established a bimetallic oxidative addition mechanism. Kinetic measurements showed that transmetalation rather than oxidative addition was the turnover-determining step. The transmetalation involved a bimetallic pathway

Bimetallic Oxidative Addition Involving Radical Intermediates in Nickel-Catalyzed Alkyl-Alkyl Kumada Coupling Reactions

Many nickel-based catalysts have been reported for cross-coupling reactions of nonactivated alkyl halides. The mechanistic understanding of these reactions is still primitive. Here we report a mechanistic study of alkyl-alkyl Kumada coupling catalyzed by a preformed nickel(II) pincer complex ([(N2N)Ni-Cl]). The coupling proceeds through a radical process, involving two nickel centers for the oxidative addition of alkyl halide. The catalysis is second-order in Grignard reagent, first-order in catalyst, and zero-order in alkyl halide. A transient species, [(N2N)Ni-alkyl(2)] (alkyl(2)-MgCl), is identified as the key intermediate responsible for the activation of alkyl halide, the formation of which is the turnover-determining step of the catalysis

EurOP2E – the European Open Platform for Prescribing Education, a consensus study among clinical pharmacology and therapeutics teachers

Purpose Sharing and developing digital educational resources and open educational resources has been proposed as a way to harmonize and improve clinical pharmacology and therapeutics (CPT) education in European medical schools. Previous research, however, has shown that there are barriers to the adoption and implementation of open educational resources. The aim of this study was to determine perceived opportunities and barriers to the use and creation of open educational resources among European CPT teachers and possible solutions for these barriers. Methods CPT teachers of British and EU medical schools completed an online survey. Opportunities and challenges were identified by thematic analyses and subsequently discussed in an international consensus meeting. Results Data from 99 CPT teachers from 95 medical schools were analysed. Thirty teachers (30.3%) shared or collaboratively produced digital educational resources. All teachers foresaw opportunities in the more active use of open educational resources, including improving the quality of their teaching. The challenges reported were language barriers, local differences, lack of time, technological issues, difficulties with quality management, and copyright restrictions. Practical solutions for these challenges were discussed and include a peer review system, clear indexing, and use of copyright licenses that permit adaptation of resources. Conclusion Key challenges to making greater use of CPT open educational resources are a limited applicability of such resources due to language and local differences and quality concerns. These challenges may be resolved by relatively simple measures, such as allowing adaptation and translation of resources and a peer review system

Mechanistic Studies Related to Nickel-Catalyzed Alkyl-Alkyl Cross Coupling Reactions

Cross-coupling reactions of non-activated alkyl halides are potentially useful chemical transformations. At the same time, however, they are challenging due to a series of unproductive side reactions. Recently, significant progress has been made to overcome these difficulties. With judicious choice of metal, ligands, and reaction conditions, the normally problematic β- H elimination can be suppressed. As a consequence, a number of examples of the successful coupling of non-activated alkyl halides have been demonstrated. The mechanistic understanding of such reactions is, in most cases, still primitive. In the majority of cases, the active catalysts are generated in situ and remain unidentified and unknown. This dissertation is devoted to mechanistic studies of alkyl-alkyl cross-coupling catalyzed by a well-defined nickel pincer complex [(MeNN2)Ni-Cl] (1; Nickamine). This complex showed excellent activity for the cross-coupling of unactivated alkyl halides. Moreover, several nickel alkyl complexes bearing β-hydrogen atoms have been isolated. These features offered a unique platform to carry out mechanistic studies to gain a better understanding of nickel-catalyzed crosscoupling reactions. Chapter one provides examples of palladium-, iron-, cobalt-, and nickel-catalyzed alkyl-alkyl cross-coupling reactions. In each case mechanistic details are discussed. At the end of the chapter cross-coupling reactions using Nickamine are presented. In chapter two the propensity of isolated nickel alkyl complexes to undergo -hydride elimination is explored. Isomerization and olefin exchange experiments show that -hydride elimination is kinetically viable but thermodynamically unfavorable in [(MeNN2)Ni-alkyl] complexes. The intermediacy of an [(MeNN2)Ni-H] (6) species was corroborated by trapping experiments. The alkyl complex [(MeNN2)Ni-propyl] catalyzes olefin isomerization reactions. In chapter three the aforementioned nickel(II) hydride complex 2 was synthesized by reaction of [(MeNN2)Ni-OMe] (10) with Ph2SiH2, and was characterized by NMR and IR spectroscopy, as well as X-ray crystallography. Complex 6 was unstable in solution, and decomposed via two reaction pathways. The first pathway was through intramolecular N-H reductive elimination to III give MeNN2H and Ni particles. The second pathway was intermolecular, giving H2, Ni particles, and a five-coordinate Ni(II) complex [(MeNN2)2Ni] (12) as the products. Compound 6 reacted with ethylene and acetone, forming [(MeNN2)Ni-Et] (2) and [(MeNN2)Ni-OiPr] (13), respectively. Complex 6 also reacted with alkyl halides, yielding nickel(II) halide complexes and alkanes. The reduction of alkyl halides was rendered catalytic, using 1 as catalyst, NaOiPr or NaOMe as base, and Ph2SiH2 or Me(EtO)2SiH as the hydride source. The catalysis appeared to operate via a radical mechanism. In chapter four a detailed mechanistic study of alkyl-alkyl Kumada coupling catalyzed by the preformed nickel(II) pincer complex 1 is reported. The coupling proceeds through a radical process, involving two nickel centers for the oxidative addition of alkyl halide. The catalysis is 2nd order in Grignard reagent, 1st order in catalyst, and 0th order in alkyl halide. A transient species, [(MeNN2)Ni-Alkyl2](Alkyl2-MgCl), is identified as the key intermediate responsible for the activation of alkyl halide, the formation of which is the turnover-determining step of the catalysis. Finally, a catalytic cycle for Nickamine-catalyzed cross-coupling reactions was established. This dissertation elaborates the properties of nickel-alkyl and nickel-hydride complexes of the Nickamine system. It elucidates many mechanistic features of the alkyl-alkyl Kumada coupling reactions catalyzed by Nickamine, and establishes, for the first time, a bimetallic oxidative addition mechanism for nickel-catalyzed coupling reactions. The work significantly enhances the current understanding of cross-coupling reactions of alkyl halides

Why are (NN2)Ni pincer complexes active for alkyl-alkyl coupling: ß-H elimination is kinetically accessible but thermodynamically uphill

Isomerization and olefin exchange experiments show that β-H elimination is kinetically viable but thermodynamically unfavorable in [(MeNN2)Ni-alkyl] complexes. The intermediacy of Ni-hydride species was corroborated by a trapping experiment. The alkyl complex [(MeNN2)Ni-propyl] catalyzes olefin isomerization

Synthesis, Reactivity, and Catalytic Application of a Nickel Pincer Hydride Complex

The nickel­(II) hydride complex [(^MeN₂N)­Ni-H] (<b>2</b>) was synthesized by the reaction of [(^MeN₂N)­Ni-OMe] (<b>6</b>) with Ph₂SiH₂ and was characterized by NMR and IR spectroscopy as well as X-ray crystallography. <b>2</b> was unstable in solution, and it decomposed via two reaction pathways. The first pathway was intramolecular N–H reductive elimination to give ^MeN₂NH and nickel particles. The second pathway was intermolecular, with H₂, nickel particles, and a five-coordinate Ni­(II) complex [(^MeN₂N)₂Ni] (<b>8</b>) as the products. <b>2</b> reacted with acetone and ethylene, forming [(^MeN₂N)­Ni-O^<i>i</i>Pr] (<b>9</b>) and [(^MeN₂N)­Ni-Et] (<b>10</b>), respectively. <b>2</b> also reacted with alkyl halides, yielding nickel halide complexes and alkanes. The reduction of alkyl halides was rendered catalytically, using [(^MeN₂N)­Ni-Cl] (<b>1</b>) as catalyst, NaO^<i>i</i>Pr or NaOMe as base, and Ph₂SiH₂ or Me­(EtO)₂SiH as the hydride source. The catalysis appears to operate via a radical mechanism

Synthesis, Reactivity, and Catalytic Application of a Nickel Pincer Hydride Complex

The nickel­(II) hydride complex [(^MeN₂N)­Ni-H] (<b>2</b>) was synthesized by the reaction of [(^MeN₂N)­Ni-OMe] (<b>6</b>) with Ph₂SiH₂ and was characterized by NMR and IR spectroscopy as well as X-ray crystallography. <b>2</b> was unstable in solution, and it decomposed via two reaction pathways. The first pathway was intramolecular N–H reductive elimination to give ^MeN₂NH and nickel particles. The second pathway was intermolecular, with H₂, nickel particles, and a five-coordinate Ni­(II) complex [(^MeN₂N)₂Ni] (<b>8</b>) as the products. <b>2</b> reacted with acetone and ethylene, forming [(^MeN₂N)­Ni-O^<i>i</i>Pr] (<b>9</b>) and [(^MeN₂N)­Ni-Et] (<b>10</b>), respectively. <b>2</b> also reacted with alkyl halides, yielding nickel halide complexes and alkanes. The reduction of alkyl halides was rendered catalytically, using [(^MeN₂N)­Ni-Cl] (<b>1</b>) as catalyst, NaO^<i>i</i>Pr or NaOMe as base, and Ph₂SiH₂ or Me­(EtO)₂SiH as the hydride source. The catalysis appears to operate via a radical mechanism

Bimetallic Oxidative Addition in Nickel-Catalyzed Alkyl–Aryl Kumada Coupling Reactions

The mechanism of alkyl–aryl Kumada coupling catalyzed by the nickel pincer complex Nickamine was studied. Experiments using radical-probe substrates and DFT calculations established a bimetallic oxidative addition mechanism. Kinetic measurements showed that transmetalation rather than oxidative addition was the turnover-determining step. The transmetalation involved a bimetallic pathway