Pierre Grenouillet

Design of a Genetic Algorithm for the Simulated Evolution of a Library of Asymmetric Transfer Hydrogenation Catalysts

A library of catalysts was designed for asymmetric-hydrogen transfer to acetophenone. At first, the whole library was submitted to evaluation using high-throughput experiments (HTE). The catalysts were listed in ascending order, with respect to their performance, and best catalysts were identified. In the second step, various simulated evolution experiments, based on a genetic algorithm, were applied to this library. A small part of the library, called the mother generation (G0), thus evolved from generation to generation. The goal was to use our collection of HTE data to adjust the parameters of the genetic algorithm, in order to obtain a maximum of the best catalysts within a minimal number of generations. It was namely found that simulated evolutions results depended on the selection of G0 and that a random G0 should be preferred. We also demonstrated that it was possible to get 5 to 6 of the ten best catalysts while investigating only 10 % of the library. Moreover, we developed a double algorithm making this result still achievable if the evolution started with one of the worst G0.

High-throughput screening of molecular catalysts using automated liquid handling, injection, and microdevices

A new concept for the high-throughput screening of multiphase reactions involving molecular catalysts is described. It combines pulse injections of catalysts and substrate and mixing in a microdevice. The novelty of the concept resides in dynamic sequential vs. batchwise operations. Some advantages over traditional batch parallel operations are lower inventory of sample (down to μg) coupled with accurate control of reaction time, larger range of operating conditions (pressure, temperature), simpler and fewer electromechanical moving parts and easy automation. Results on liquid-liquid (biphasic allylic alcohol isomerization), and gas-liquid (asymmetric hydrogenation) reactions indicates that the number of tests per day can easily reach 50 d - 1 with inventory of sample (Rh) per test as low as 5 μg.

High Throughput Screening and Evolution of a Library of Ligands in Asymmetric H-Transfer Reduction of Acetophenone

A library of 117 ligands was combined with three transition metals Ru, Rh and Ir and screened with three different operating conditions for the asymmetric H-transfer reduction of acetophenone into phenylethanol. The combinatorial approach was based on evolution of a first library containing 60 ligands. For the evolution, operators such as replication, regression, cross-over and mutation were used. The study was performed with a XYZ robot and fast chiral GC analysis. Over only 4 generations, the average targeted criterion, enantioselectivity, was increased from 20% to ca. 80% for the 4th generation. The best results provided enantiomeric excess up to 93%.

Catalytic cleavage of the SiSi bond of methylchlorodisilanes with nucleophiles: evidences for a stabilised silylene reaction intermediate

Abstract The methylchlorodisilanes MeCl 2 SiSiCl 2 Me, MeCl 2 SiSiClMe 2 and MeCl 2 SiSiMe 3 disproportionate in the presence of nucleophilic catalysts into the methylchlorosilanes MeSiCl 3 , Me 2 SiCl 2 , Me 3 SiCl and the polysilanes Si n Me n Cl n +2 , Si n Me n +1 Cl n +1 and Si n Me n +2 Cl n ( n =3–5). Qualitative kinetic studies of the disproportionation reveal that the catalytic activities of the nucleophiles are ranked according to: phosphine oxides (OPnBu 3 , OP(NMe 2 ) 3 )>chlorides (nBu 4 NCl, nBu 4 PCl)>phosphines (PnBu 3 , PiPr 3 , PMe 2 Ph, P(NMe 2 ) 3 , PCy 3 , PPh 3 )>phosphites (P(OPh) 3 ). For the PR 3 compounds, a correlation is observed between the π acceptor character the activity for the disproportionation, the lower π acceptor the nucleophile, the higher the rate. A two step mechanism is proposed which involves the formation of an intermediate followed by condensation with the substrate disilane to afford the polysilanes. Investigation of the reaction of the intermediate with hydrogen as a test reaction provides evidences for the condensation step to be rate limiting in the disproportionation. That result, combined with the fact that poor π acceptor nucleophiles (phosphine oxides, chlorides and trialkylphosphines) are more active disproportionation catalysts, supports the description of the intermediate as a stabilised silylene.

Application of a Micromixer for the High Troughput Screening of Fluid-Liquid Molecular Catalysis

High throughput synthesis methodologies, such as combinatorial techniques, are now applied to the discovery of molecular catalysts.1 Libraries of ligands which can be turned into catalysts by complexation to transition metals, are accessible. The effectiveness of this approach has been demonstrated for restricted libraries of compounds and in the case of single liquid phase catalysis.[2] However, numerous reactions of interest such as olefin oligomerisation, hydrogenation, carbonylation, hydroformylation, etc. are operated in gas-liquid or liquid-liquid systems. Inadequate control of phase and catalyst presentation, resulting from non-optimised agitation, may effectively have dramatic consequences in the estimation of selectivity and reactivity. For example, enantio- and regioselective catalysed reactions susceptible to mass transport effects, are known. Thus, a major challenge is to develop special reactors for rapid catalyst screening that would ensure good mass and heat transport, in a small volume. Application of such apparatus for intrinsic kinetic determination would also be of high interest. In this paper, a new concept to achieve High Throughput Screening (HTS) of polyphasic fluid reactions is proposed. As test reactions, a gas-liquid asymmetric hydrogenation and a liquid-liquid isomerisation have been chosen to validate our approach of HTS experiments. A preliminary work with the liquid-liquid system has been published recently.2

Co-dimerisation of 1,3-dienes and acrylic esters catalysed by cationic allylpalladium complexes: the role of phosphines

Basic phosphines, especially tributylphosphine, when added in 1 : 1 ratio to cationic allylpalladium complexes, allow the selective co-dimerisation of 1,3-dienes and acrylic esters to linear, unsaturated esters, presumably owing to the inducement of an η3–η1 shift of the allyl ligands by the phosphines.