Ligand Design

Professor Todd Marder (Durham University, UK) chaired the first session of the meeting. Professor Hans de Vries (DSM Pharmaceutical Products, The Netherlands) gave the Keynote lecture, which provided an overview of cross-coupling reactions and issues of ‘ligand design’ versus ‘ligand-free’ catalysis. His 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. Professor de Vries then went on to present several mechanisms for the modified Ullmann reaction, highlighting the importance of copper(III) species, but also issues surrounding the complex catalytic reaction systems.

A careful study of manganese-catalysed C–H oxidation with hydrogen peroxide showed that specially designed multidentate ligands were oxidised to pyridine-2-carboxylic acid prior to catalytic substrate oxidation, which explains the observed catalytic activity (Scheme I). This work by Wesley R. Browne (University of Groningen, The Netherlands) showed that some caution should be exerted in ligand design, metal catalysis and reaction mechanism analysis, especially where the ligand can change chemical form under the catalytic reaction conditions used.

Selective Catalysis

The second session was chaired by Warren B. Cross (University of Leicester, UK) who introduced a Keynote lecture from Professor Aiwen Lei (Wuhan University, China). Professor Lei discussed selective oxidative cross-coupling using palladium(II) catalysis (with a suitable oxidant) between two different nucleophiles (for example Process A, Scheme II) and went on to elaborate on issues surrounding the rates of reductive elimination processes. Crucially, fast reductive elimination and transmetallation rates were found to determine the selectivity of the heterocoupling reaction.

George Fortman (University of St Andrews, UK) discussed work on the synthesis of gold–acetylides formed by alkyne C–H activation. The serendipitous discovery of a palladium-catalysed regioselective C–H functionalisation of 2-pyrones was then reported by Professor Fairlamb. Two catalysts were used in this work, namely trans-Pd(Br)N-Succ(PPh₃)₂ and Pd₂(dba-4-OMe)₃ (N-Succ = succinimide; dba-4-OMe = 1,5-bis-(4′-methoxyphenyl)penta-1E, 4E-dien-3-one).

The third session of the meeting was chaired by Professor Fairlamb, and began with a Keynote lecture by Professor Jennifer Love (The University of British Columbia, Canada). Love presented a brief overview of carbon–fluorine activation processes including cross-coupling reactions of polyfluoroarenes. She focused on the development of nickel and platinum catalyst systems for arylboronic acid cross-coupling with fluoroarenes containing ortho-directing groups. This presentation was followed by Professor Philippe Dauban (Centre National de la Recherche Scientifique (CNRS), France), who presented studies of catalytic aminations involving nitrene insertion into C–H bonds (Scheme III). The selective C–H functionalisation of secondary methylene carbon centres in the presence of other secondary sites was a particular highlight.

During the discussion session of these lectures, several of the pharmaceutical chemists present at the meeting debated the role of fluoroaryl groups in pharmaceutical compounds. Several viable synthetic methods for incorporating fluoro substituents into arenes were highlighted.

Mechanistic Aspects

The fourth session of DD12 was chaired by Professor Susan Gibson (Imperial College London, UK), and began with an invited lecture by John M. Brown (Oxford University, UK). Brown introduced anilide activation of adjacent C–H bonds in the palladium-catalysed Fujiwara-Moritani reaction using catalytic Pd(OAc)₂ in the presence of tosic acid and p-benzoquinone. Kinetic aspects such as induction periods and palladacycle formation were presented as well as synthetic aspects. During the discussion session a number of mechanistic aspects of these processes were raised, which led to David (Dai) Davies (University of Leicester, UK) defining the ambiphilic metal ligand activation (AMLA) process in which the number of atoms thought to be involved in the transition state is specified, as illustrated in Scheme IV for AMLA-4 (4 electrons) and AMLA-6 (6 electrons) intermediates which are of general relevance to C–H activation. The concerted metalation-deprotonation (CMD) is identical to AMLA-6.

Esteban P. Urriolabeitia (University of Zaragoza, Spain) reported stoichiometric and catalytic regioselective C–H functionalisations including a palladium-catalysed oxidative etherification of iminophosphoranes. Finally, a combined theoretical and experimental study on the use of ruthenium vinylidene complexes as catalysts for carbon–oxygen bond formation was presented by Jason M. Lynam (University of York, UK). The role of carboxylate ‘acetate’ ligands was discussed, and a variant of the AMLA/CMD mechanism proposed, namely the ligand-assisted-proton shuttle (LAPS) (Scheme V).

The fifth session was chaired by Anthony Haynes (The University of Sheffield, UK). Professor Zhang-Jie Shi (Peking University, China) gave an interesting presentation, particularly the unusual results of a ‘metal-free’ coupling of an aryl halide with an arene using potassium tert-butoxide and 1,10-phenanthroline (4).

Dai Davies went on to present alkyne insertion reactions of cyclometallated pyrazole and imine complexes of iridium, rhodium and ruthenium, with emphasis on establishing substrate/catalyst/product correlations through detailed structural and spectroscopic studies. The last speaker of the session, Xavi Ribas (Universitat de Girona, Spain), discussed reductive elimination from a ‘model’ aryl–Cu(III)–halide species which was triggered by a strong acid, and its relevance to the mechanism of Ullmann-type couplings (Scheme VI).

C–H Activation

The sixth session was chaired by Professor Peter Scott (The University of Warwick, UK), and the first invited lecture was from Professor Robin Bedford (University of Bristol, UK). Bedford presented an introduction to the field of ‘C–H activation’, and went on to discuss mild and selective ‘solvent-free’ aromatic C–H functionalisation/halogenation reactions catalysed by Pd(OAc)₂. The second lecture was given by Professor Fairlamb on surface-catalysed Suzuki-Miyaura cross-coupling over palladium nanoparticles stabilised by polyvinylpyrrolidinone (PVP). This work, in collaboration with Professor Adam Lee, gave details about the reaction mechanism, including results from kinetic studies, X-ray photoelectron spectroscopy (XPS) and X-ray absorption spectroscopy (XAS), of a heterogeneous surface-catalysed Suzuki cross-coupling (Figure 1). Extended X-ray absorption fine structure (EXAFS) measurements proved particularly informative in showing that palladium nanoparticles do not change size in a typical Suzuki-Miyaura cross-coupling. Finally, Professor Yoshiaki Nakao (Kyoto University, Japan) presented a nickel-catalysed alkenylation of aromatic C–H bonds in indoles and pentafluorobenzene.

The seventh session was chaired by Jason M. Lynam and the Keynote lecture was given by Professor William D. Jones (University of Rochester, USA). Professor Jones discussed various kinetic and thermodynamic aspects of C–H bond activation by transition metals. A key focus of the lecture was placed on the ortho-fluorine effect by drawing on both rhodium–carbon and carbon–hydrogen bond energy correlations in a series of fluorinated aromatic hydrocarbons (Figure 2). Professor Robin Perutz (University of York, UK) delivered a presentation on studies in collaboration with Professor Odile Eisenstein (Université Montpellier II, France), discussing the effect of ortho-fluorine substituents on Pd/C catalysed C–C bond formation, particularly C–H functionalisation and the CMD/AMLA-6 mechanism. Together, the Jones and Perutz presentations showed that one should consider both C–H acidity and metal–carbon (aryl) bond strengths when explaining the regioselective C–H functionalisation accelerated by ortho-fluorine substituents.

Theoretical Aspects

The final session was chaired by Professor Odile Eisenstein, and began with an invited lecture by Professor Stuart Macgregor (Heriot-Watt University, UK). Macgregor delivered an introduction to theoretical approaches, following previous comments on the strengths, weaknesses and pitfalls of certain aspects of density functional theory (DFT) calculations. More detailed computational studies were presented on catalytic alkene hydroarylation with [CpIr((κ²-OAc)(PH₃)]⁺, with particular emphasis on the AMLA-6 mechanism. This once again highlighted the key role played by the ‘flexible’ acetate ligand. Eric Clot (Université Montpellier II, France) went on to present a DFT study of the mechanism of Pd(PR₃)-catalysed benzocyclobutene formation via C(sp³)–H activation. In the final presentation, Professor Mike George (The University of Nottingham, UK) presented a combined experimental (fast time-resolved infrared spectroscopy (TRIR)) 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 versus cyclic alkanes by half-sandwich rhodium complexes. Interestingly, C–H activation in cyclic alkanes depends primarily on the strength of alkane–metal binding. Note that this paper appeared in a later issue of Dalton Transactions (5).

Poster Prizes

Following the conference dinner in the famous Durham Castle, Professors Love and Perutz awarded four poster prizes. The poster content of the awardees (Figure 3) highlighted the breadth of subjects covered and the high standard of all of the posters presented at the meeting. The winning posters were:

Concluding Remarks

From the oral presentations, numerous posters and lively discussions at the DD12 meeting, there was overwhelming evidence that a better understanding of the mechanisms of metal-catalysed C–X and C–H functionalisation processes is emerging. Quite strikingly, studies in inorganic and organometallic coordination chemistry, theoretical and kinetic studies, new synthetic methodologies and applications are driving this understanding. The platinum group metals play an important role in many of the catalytic processes under discussion.

As a first joint discussion conference between the RSC Dalton and Organic Divisions, it was a great success, and showed quite clearly that both the organic and inorganic communities need to work together to deliver powerful, clean and efficient methods for the preparation of functionalised organic building blocks and fine chemicals.