Dalton Discussion 12: Catalytic C–H and C–X bond activation (DD12)

This themed issue of Dalton Transactions contains papers presented at the 12^th Dalton Discussion (DD12) conference held at Durham University (UK) from 13–15 September 2010. DD12 was the first Dalton Discussion to have been jointly organised by the Organic and Dalton divisions of the Royal Society of Chemistry (RSC). Applications of late metal catalysed cross-coupling reactions, involving the activation of C–X (X = halogen) or, more recently, C–H bonds, are commonplace in the synthesis of natural products, therapeutic agents, biological probes, and advanced materials. The aim of DD12 was to bring together organic and inorganic chemists from around the world to highlight and discuss important aspects (mechanism, methodology and application) of these state-of-the-art bond-forming transformations (highlighted by the award of the 2010 Nobel Prize in Chemistry to Profs Heck, Negishi and Suzuki). Several overlapping areas were addressed during the DD12 conference, namely:

• Ligand design for, and kinetic studies of, catalytic processes involving C–H and C–X activation;

• New vistas in C–X activation;

• Fundamental experimental aspects of C–X and C–H activation;

• Mechanistic and theoretical aspects of C–X and C–H activation.

The importance of these areas to modern chemistry was reflected by the 118 delegates from Europe, Asia, the Middle-East and North America, with interests spanning organic, organometallic and inorganic chemistries, including groups focused on theoretical and mechanistic aspects of these catalytic transformations (Fig. 1). It is important to note that one-quarter of the delegates were from major industrial organisations.

Fig. 1 LHS: Profs Aiwen Lei (Wuhan University), Todd Marder (Durham University), Ian Fairlamb (University of York), Zhang-jie Shi (Peking University), and Yoshiaki Nakao (Kyoto University). RHS: Poster prize winners, J. Panetier (Heriot-Watt University), T. Bob-Egbe (Imperial College London), A. I. Germeroth (University of Edinburgh), and A. G. Jarvis (University of York).

All of the papers in this themed issue of Dalton Transactions were submitted, refereed, and sent to the conference participants to read prior to the meeting, so that they would be especially well placed to participate in the active discussions which are the hallmark of the Dalton Discussion conference series. The meeting itself was comprised of eight sessions held over a period of three days, with no parallel sessions, such that all delegates were able to participate in each session. Individual sessions were initiated by either a keynote or an invited lecture, which typically provided a perspective on the topic as well as some specific new results. These were followed by up to three five minute contributed presentations. With the exception of session 6 (see below), questions were taken during the lively and lengthy discussions held after all of the lectures in a session had taken place.

DD12 was opened with welcoming remarks by Dr Philip Dyer and Prof. Graham Sandford of Durham University (UK). Prof. Ian J. S. Fairlamb of the University of York (UK) then gave a dedication in memory of Prof. Keith R. Fagnou of the University of Ottawa (Canada), who had made many important contributions to the areas addressed at this conference. The Royal Society of Chemistry, organising committee and participants of DD12 all expressed their deepest condolences to the family of Keith, who passed away on 11 November 2009. Earlier in 2009, Keith had been confirmed as a keynote speaker at DD12.

Prof. Todd Marder of Durham University (UK) chaired Session 1 of DD12, which began with a brief overview of cross-coupling reactions highlighting issues of “ligand design” vs. “ligand-free” catalysis by Prof. Hans de Vries of DSM Pharmaceutical Products (The Netherlands). This lecture nicely set the tone of the meeting and stimulated lots of discussion, for example, on the nature of the catalytically active species and the role of palladium nanoparticles. Prof. de Vries then presented several potential mechanisms for the modified-Ullmann reaction, highlighting Prof. Xavi Ribas' work in particular as good evidence for the involvement of Cu^III species. Dr Wesley R. Browne of the University of Groningen (The Netherlands) outlined manganese-catalysed C–H oxidation with H₂O₂, noting that his multidentate ligands oxidised to pyridine-2-carboxylic acid prior to catalytic oxidation of the substrate. Dr Browne provided some words of caution on ligand design and reaction mechanism analysis, as well as a philosophical view on the area. Both presentations nicely highlighted catalytic processes which can be carried out without the need for expensive ligands.

Session 2 of the meeting was chaired by Dr Warren B. Cross of the University of Leicester (UK). The session began with a keynote lecture from Prof. Aiwen Lei of Wuhan University (Peoples' Republic of China) who addressed selective oxidative cross-couping between two different nucleophiles. He discussed issues surrounding the rates of reductive elimination processes and noted that rapid reductive elimination and transmetallation rates determine the selectivity of the hetero-coupling reaction. Clearly, more work is required to understand fully the factors controlling transmetallation from various main group organometallic reagents to late transition metal centres. Dr George Fortman from the University of St Andrews (UK) then addressed the synthesis of gold-acetylides formed by alkyne C–H activation. A key role for gold-hydroxide species was highlighted. Prof. Ian J. S. Fairlamb then presented the discovery of a Pd-catalysed regioselective C–H functionalisation of 2-pyrones, which highlighted both synthetic application and mechanistic insight, including stoichiometric reactions that mirror, in part, the catalytic manifold. The Concerted-Metallation-Deprotonation (CMD) mechanism for C–H activation was discussed for the first time during this presentation which, along with the related Ambiphilic Metal Ligand Activation (AMLA) mechanism, was the subject of other presentations and more detailed discussion later in the meeting (session 4).

Session 3 of the meeting was chaired by Prof. Ian J. S. Fairlamb. The session began with a keynote lecture by Prof. Jennifer Love of the University of British Columbia (Canada) who presented an excellent overview of C–F activation processes including cross-coupling reactions of polyfluoroarenes. She highlighted the development of Ni and Pt catalyst systems for the cross-coupling of arylboronic acids with fluoroarenes containing ortho-directing groups. The second lecture was given by Prof. Philippe Dauban of CNRS Gif-sur-Yvette (France) who presented studies of catalytic aminations involving nitrene insertion into C–H bonds. A highlight of this presentation was the selective C–H functionalisation of secondary methylene carbon centres. During the discussion which followed the lectures, several of the pharmaceutical chemists present addressed the role of fluoroaryl groups in drugs. Various methods for incorporating fluoro substituents into arenes were mentioned.

Session 4 was chaired by Prof. Susan Gibson of Imperial College London (UK). The session began with an invited lecture from Dr John M. Brown of Oxford University (UK) focussing on anilide activation of adjacent C–H bonds in the Pd-catalysed Fujiwara–Moritani reaction. The lecture discussed both kinetic (lag periods and palladacycle formation) and synthetic aspects, linking with other studies in the area by Profs Lloyd-Jones and Booker-Milburn of the University of Bristol, and also Prof. de Vries at DSM Pharmaceutical Products. Following a number of key mechanistic aspects of these processes raised by Dr John Brown, Dr Dai Davies of the University of Leicester (UK) took to the blackboard to define AMLA-4 and identical CMD/AMLA-6 intermediates of relevance to C–H activation (Fig. 2).

Fig. 2 Dr Dai Davies (University of Leicester) highlighting AMLA and CMD mechanisms for C–H activation.

Subsequently, Prof. Esteban P. Urriolabeitia of the University of Zaragoza (Spain) presented details of both stoichiometric and catalytic regioselective C–H-functionalisations including a palladium-catalysed oxidative etherification of iminophosphoranes. Dr Jason M. Lynam of the University of York (UK) presented a combined theoretical and experimental study on the use of ruthenium vinylidene complexes as catalysts for C–O bond formation. The role of carboxylate ligands was discussed explicitly and a variant of the CMD mechanism proposed, namely Ligand-Assisted-Proton-Shuttle (LAPS).

Session 5 was chaired by Dr Anthony Haynes of the University of Sheffield (UK). The session was kicked-off with a lively keynote lecture by Prof. Zhang-jie Shi of Peking University (People's Republic of China). One of the most interesting and unusual results to be presented was a ‘metal-free’ coupling of an aryl halide with an arene using potassium tert-butoxide and 1,10-phenanthroline. This chemistry is similar to recent work published by Prof. Aiwen Lei. Both Profs Shi and Lei went to considerable lengths to demonstrate that trace metal was not responsible for the catalysis. This was followed by a presentation from Dr Dai Davies who discussed the alkyne insertion reactions of cyclometallated pyrazole and imine complexes of iridium, rhodium and ruthenium, with particular emphasis on establishing substrate/catalyst/product correlations through detailed structural and spectroscopic studies. Finally, Prof. Xavi Ribas of the University of Girona (Spain) discussed reductive elimination from a well-defined ‘model’ aryl-Cu^III-halide species which was triggered by acid and the potential relevance of Cu^III to Ullmann-type coupling reactions.

Session 6 was chaired by Prof. Peter Scott of the University of Warwick (UK). As an experiment, Prof. Scott ran the session with questions/answers/discussion following each lecture. The session began with an invited lecture from Prof. Robin B. Bedford of the University of Bristol (UK), who presented an interesting introduction to the field of ‘C–H activation’. Prof. Bedford went on to discuss the mild and selective “solvent-free” aromatic C–H functionalisation/halogenation reactions, related to previous work in solution reported by Prof. Zhang-jie Shi. Prof. Ian J. S. Fairlamb presented a paper detailing a surface-catalysed Suzuki–Miyaura cross-coupling over Pd nanoparticles stabilised by polyvinylpyrrolidinone (PVP), which was part of a collaborative project with Prof. Adam F. Lee of Cardiff University (UK). Details of the reaction mechanism (kinetics, XPS, EXAFS, etc.) of a heterogeneous Suzuki cross-coupling were presented that complemented the talk of Prof. Hans de Vries in session 1. Then, Prof. Yoshiaki Nakao of Kyoto University (Japan) presented studies of the nickel-catalysed alkenylation of aromatic C–H bonds such as those in indoles and pentafluorobenzene.

Session 7 was chaired by Dr Jason M. Lynam. A keynote lecture by Prof. William D. Jones of the University of Rochester (USA) addressed kinetic and thermodynamic aspects of C–H bond activation by transition metals, and the ortho-fluorine effect using both metal–carbon and carbon–hydrogen bond energy correlations of a series of fluorinated aromatic hydrocarbons. He exemplified a potential future strategy for the preparation of various cyano alkyls, the utility and importance of which was subsequently highlighted by Prof. Gibson during the ensuing discussion. This lecture led nicely to the following lecture presented by Prof. Robin N. Perutz of the University of York (UK). In work performed in collaboration with Prof. Odile Eisenstein of Université Montpellier 2 (France), Prof. Perutz discussed the effect of ortho-fluorine substituents on catalytic C–C bond formation, particularly C–H functionalisation and the CMD/AMLA-6 mechanism. Together, these talks highlighted the importance of the need to consider both C–H acidity and metal–carbon (aryl) bond strengths when explaining the regioselective C–H functionalisation accelerated by ortho-fluorine substituents.

Session 8 was chaired by Prof. Odile Eisenstein, and began with an invited lecture by Prof. Stuart Macgregor of Heriot-Watt University (UK) who gave a valuable introduction to theory following previous comments on the strengths, weaknesses and pitfalls of certain aspects of DFT calculations, highlighting its use in understanding reaction mechanisms. He discussed computational studies on catalytic alkene hydroarylation with [CpIr((κ²-OAc)(PH₃)]⁺, with particular emphasis on the role of an AMLA-6 mechanism, once again highlighting the key role played by the ‘flexible’ acetate ligand (and the role of anionic ligands in general in these types of processes). Prof. Eric Clot of Université Montpellier 2 (France) then presented a DFT study of the mechanism of Pd-catalysed benzocyclobutene formation via Csp³-H activation, which supported the experimental studies by Prof. Olivier Baudoin of the same institute. Finally, Prof. Mike George of the University of Nottingham (UK) presented a combined experimental (fast time-resolved IR) and theoretical investigation of the C–H activation of cyclic alkanes by cyclopentadienyl rhodium(I) carbonyl complexes. He highlighted the inherent mechanistic differences in C–H activation of linear vs. cyclic alkanes by half-sandwich Rh complexes, with the latter depending primarily on the strength of alkane-metal binding.†

One of the highlights of DD12 was the conference dinner held in the Great Hall (which dates from 1284) of the magnificent Durham Castle (Fig. 3). Following the dinner, Profs Love and Perutz awarded the four poster prizes to J. Panetier (Heriot-Watt University), A. I. Germeroth (University of Edinburgh), A. G. Jarvis (University of York) and T. Bob-Egbe (Imperial College London), and highlighted the breadth of subjects covered and the extremely high standard of all of the posters. Subsequently, Prof. Perutz asked the participants which discussion format they preferred: i) all lectures in a given session presented without questions, followed by an in-depth (broader) discussion; or ii) individual presentations each followed by shorter discussion (classical question and answer style). Interestingly, the DD12 participants overwhelmingly supported the former format, emphasising the importance of the discussion component of these conferences.

Fig. 3 Conference dinner in the Great Hall of Durham Castle.

From the oral presentations, numerous posters, and lively discussions at the DD12 conference, there is good evidence that a better understanding of the mechanisms of both C–X and C–H functionalisation processes is emerging. It is clear that inorganic and organometallic coordination chemistry, theoretical and kinetic studies, new synthetic methodologies and applications are playing a key role in this popular area of research. This first joint Organic Division/Dalton Division discussion conference clearly highlighted the key roles to be played by both the organic and inorganic communities, working in concert to deliver powerful, clean, and efficient methods for the preparation of functionalised organic building blocks, a clear measure of the meeting's success.

We are grateful for the generous sponsorship of the conference by BP and Pfizer, and the Dalton and Organic Divisions of the RSC, and for the poster prizes which were provided by Springer, Dalton Transactions, and Catalysis Science and Technology. The organising committee also thanks Rachel Thompson, Ruth Bircham, Dr Joanna Pugh, and Dr Ruth Doherty of the Royal Society of Chemistry, whose help made this conference possible.

 

Professor Todd B. Marder

(Durham University, UK) (Chair)

 

Dr Philip W. Dyer

(Durham University, UK)

 

Professor Ian J. S. Fairlamb

(University of York, UK)

 

Professor Sue Gibson

(Imperial College London, UK)

 

Professor Peter Scott

(University of Warwick, UK)

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Footnote

† This paper will appear in a future issue of Dalton Transactions (DOI: 10.1039/c0dt00661k).

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