ICBMS UMR5246 – Université Lyon 1 – CNRS – CPE Dr Lionel Perrin Bâtiment Curien - 43, Bd du 11 Novembre 1918 ITEMM group leader 69622 VILLEURBANNE CEDEX lionel.perrin@univ-lyon1.fr FRANCE tel: (+33) (-0)4 72 44 81 68 http://www.icbms.fr

Sujet de thèse Exploration des mécanismes des réactions de transmétallation par modélisation moléculaire :

Apports et conséquences en chimie synthèse par voie organométallique et en catalyse de polymérisation

PhD project Computational mechanistic investigation of transmetalation reaction:

Insights and consequences in organometallic-based organic synthesis and polymerization catalysis

key words: computational chemistry, transmetalation, catalysis, organometallic reagents and complexes

Lionel PERRIN (DR CNRS, HDR, ITEMM team)

lionel.perrin@univ-lyon1.fr Transmetalation reactions are key transformation in most cross-coupling reactions,1 carbometalation reactions,2 and coordinative chain transfer polymerization3 (Figure 1).

In cross-coupling reaction, transmetalation commonly links oxidative addition with reductive elimination and thus enables catalysis among other criteria. In carbometalation reaction, transmetalation allows the in situ formation of the reactive catalytic species from common organometallic reagents. Finally, in coordinative chain transfer polymerization, transmetalation enables chain shuttling between the organometallic active site and organometallic dormant sites from which the fine control of the molecular weight distribution arises.

Figure 1. (A) Simplified catalytic cross-coupling cycle, (B) General reaction scheme in coordinative chain transfer polymerization

Currently, concerning transmetalation reactions, general reactivity trends are supported by the Hard & Soft Acid-Base theory, which tentatively justify the driving force of the reaction. So far, experimentally and theoretically, very little information is available at the molecular scale. Most of the studies focused on the Suzuki and Sonogashira couplings.4

1 Miyaura, N. Cross-Coupling Reactions, A Practical Guide Springer-Verlag, Berlin Heidelberg, 2002; Vol.219. 2 Copper mediated carbometalation reactions. Müller, D. S.; Marek. I. Chem Soc Rev. 2016, 45, 4552. 3 Coordinative chaîn transfer polymerization. Valente, A.; Mortreux, A.; Visseaux, M.; Zinck, P. Chem. Rev. 2013, 113, 3836. 4 Pre-transmetalation intermediates in the Suzuki-Miyaura reaction revealed : The missing link. Thomas, A.A.; Denmark, S.E. Science 2016, 352, 329. Anionic Pd(0) and Pd(II) Intermediates in Palladium-Catalyzed Heck and Cross-Coupling Reactions. Amatore, C.; Jutand, A.S. Acc.

The main reasons for the overall lack of information regarding the depiction and the understanding of the transmetalation reactions is: the short time of life of the species, their polymetallic nature, their heterogeneity of conformation, and their sensitivity to the chemical environment (solvent, co-solvent, salts, adjuvants). In this PhD project, we wish to address several aspects of transmetalation reaction by means of sate-of-the-art computational chemistry at the quantum level: - the speciation of organometallic reagents (organo-lithium, -magnesium, zincic) in solution - the mechanism of transmetalation between organometallic species - the relationship between the reactivity of polymetallic cluster depending on their shape and aggregation state - the influence of the chemical environment on the transmetalation and the subsequent reactivity of the species.

Scheme 1 illustrates a typical case of mechanistic interest, in which the transmetalation between Cu and Zn or Mg is the corner stone in the asymmetric carbometalation of prochiral olefin.5 Remarkably, the catalytic nature of the reaction depends on the reagent, but not its stereo outcome.

Scheme 1 Preparation of enantiomerically enriched and diastereoisomerically pure polysubstituted cyclopropanes by carbometalation reactions

The understanding of the match or mismatch within active catalyst / chain transfer agent couples in coordinative chain transfer polymerization will be another aspect addressed during the project.6 Currently, no rationale is available on this topic that only rely on an experimental trial and error strategy. This project will not only bring insights in the mechanism of transmetalation reaction but, new strategy of modeling complex polymetallic systems will emerge from the project via the combination of several state of the art sampling algorithms that are developed by partners (AFIR: S. Maeda, Hokkaido University; GSAM: P. Carbonnière, Université Pau; GERALDYN: C. Raynaud, Univ. Montpellier II). Aside, this project will find direct applications to ongoing experimental research project in which the ITEMM group is involved (I. Marek, Technion, Haïfa; C. Boisson, C2P2, CPE-Lyon, A. Amgoune, ICBMS, Université Lyon1). Ideal candidate for this PhD project must have either a strong background in theoretical physical / computational chemistry or in organic / organometallic chemistry with a strong will in understand and deciphering reaction mechanisms at the molecular scale.

Chem. Res. 2000, 33, 314. Distinguishing Between Pathways for Transmetalation in Suzuki-Miyaura Reactions. Carrow, B.P.; Hartwig, J.F. J. Am. Chem. Soc. 2011, 133, 2116. Transmetallation Versus β-HydrideElimination: The Role of 1,4-Benzoquinone in Chelation-Controlled Arylation Reactions with Arylboronic Acids. Sköld, C.; Kleimark, J.;Trejos,A.; Odell, L. R.; Nilsson Lill, S. O.; Norrby, P.-O.; Larhed, M. Chem. Eur. J. 2012, 18, 4714. Theoretical and computational studies of organometallic reactions : successful or not ? Sakaki, S.; Ohnishi,Y.-Y.; Sato, H. Chem. Rec. 2010, 10, 29. A Structural Investigation of Trivalent and Divalent Rare EarthThiocyanate Complexes Synthesised by Redox Transmetallation. Bakker, J.M.; Deacon, G.B.; Forsyth, C.M.; Junk, P.C.; Wiecko, M. Eur. J. Inorg. Chem. 2010, 2813. Density functional studies on diimine chelated palladium complex catalyzed Suzuki–Miyaura cross-coupling reaction: the impact of Lewis base employed in transmetallation process. Weng, C.-M. ; Hong, F.-E. Dalton Trans. 2011, 40, 6458. Experimental and Theoretical Study of Tunable 1,3-Lithium Shift of Propargylic/Allenylic Species, Transmetallation, and Pd-Catalyzed Cross-Coupling Reactions. Zhao, J. ; Liu,Y. ; He, Q. ; Li,Y. ; Ma, S. Chem. Eur. J. 2009, 15, 11361. A DFT study on Pd-catalyzed Suzuki cross-coupling polycondensation of aryl bromide monomers. Zhang, T.-X.; Li, Z. Comp. Theor. Chem. 2013, 1016, 28. Improved dimethylzinc-promoted vinylation of nitrones with vinylboronic esters. Praveenganesh, N.; De Candia, C.; Memboeuf, A.; Lendvay, G.; Gimbert, Y.; Chavant, P.Y. J. Organomet. Chem. 2010, 695, 2447. Kinetic Data for the Transmetalation/Reductive Elimination in Palladium-Catalyzed Suzuki-Miyaura Reactions : Unexpected Triple Role of Hydroxide Ions Used as Base. Amatore, C. ; Jutand,A. ; Le Duc, G. Chem. Eur. J. 2011, 17, 2492. DFT and ab initio study on mechanism of olefin hydroalumination by XAlBui2 in the presence of Cp2ZrCl2 catalyst. III. Efficiency of transmetallation in Cp2ZrRCl–XAlBui2 system. Pankratyev, E.Y.; Khursan, S.L.; Dzhemilev, U.M. J. Organomet. Chem. 2012, 718, 117. 5 Müller D.S.; Marek, I. Asymmetric Copper-Catalyzed Carbozincation of Cyclopropenes en Route to the Formation of Diastereo- and Enantiomerically Enriched Polysubstituted Cyclopropanes. J. Am. Chem. Soc., 2015, 137, 15414. Dian, L.; Müller, D.S.; Marek, I. Asymmetric Copper-Catalyzed Carbomagnesiation of Cyclopropenes. Angew. Chem. Int. Ed. 2017, 56, 6783–6787. 6 Polyethylene Chaîn Growth on Zinc Catalyzed by Olefin Polymerization Catalysts : A Comparative Investigation of Highly Active Catalyst Systems across the Transition Series. van Meurs, M.; Britovsek, G.J.P.; Gibson, V.C.; Cohen, S.A. J. Am. Chem. Soc. 2005, 127, 9913.