Periodic Reporting for period 1 - RATIO (Rationally-designed Turbo reagents for Innovative Organometallics)
Période du rapport: 2023-07-01 au 2025-06-30
Organic magnesium compounds, alias Grignard reagents, are inexpensive and mostly non-toxic polar reagents used to create new carbon-carbon bonds. Such features are ideal for the preparation of a wide variety of chemicals, like drug synthesis and soil-enriching fertilizers, making these molecules indispensable reagents in modern organic chemistry processes in academic laboratories and industries. Although commonly widespread, an even larger use of these reagents is hampered by their very low tolerance of protic solvents and their variable selectivity. Therefore, systematic improvements of these reagents are essential to empower chemists with low-cost and environmentally friendly new synthetic tools. A major discovery to enhance these reagents was made by adding lithium salts to the mixture, which improved both the reactivity and selectivity (turbo-Grignard). Moreover, the possibility to work in a non-miscible mixture of organic and green deep eutectic solvent (DES), asserted the opportunity for a more sustainable chemistry and prompted further studies that focus on the key role of these non-standard solvents.
An exhaustive study is required to face the evidence that numerous species coexist in solution, and that reactivity and abundance are not necessarily correlated. The project wants to understand the structure and reactivity of organomagnesium reagents and the effect of lithium salts in organic and organic/DES mixed solvents, tailoring a strategy based on all-atom reactive molecular dynamics. We want to study the structure of archetypal reagents in explicit solvent to elucidate the composition of such solutions, which is currently unknown. The results will be used to simulate carbon-carbon bond formation reactions, with the objective of obtaining the mechanism and energetics of such processes. Thus, it will be possible to apply rational design to the reactants to improve their reactivity and selectivity. Finally, a different area will be investigated, namely the reactivity of these molecules in mixed phases to unveil the beneficial effects of the added deep eutectic solvent.
An exhaustive study is required to face the evidence that numerous species coexist in solution, and that reactivity and abundance are not necessarily correlated. The project wants to understand the structure and reactivity of organomagnesium reagents and the effect of lithium salts in organic and organic/DES mixed solvents, tailoring a strategy based on all-atom reactive molecular dynamics. We want to study the structure of archetypal reagents in explicit solvent to elucidate the composition of such solutions, which is currently unknown. The results will be used to simulate carbon-carbon bond formation reactions, with the objective of obtaining the mechanism and energetics of such processes. Thus, it will be possible to apply rational design to the reactants to improve their reactivity and selectivity. Finally, a different area will be investigated, namely the reactivity of these molecules in mixed phases to unveil the beneficial effects of the added deep eutectic solvent.
The study relies on the simulation of reactive species in explicit solvent, hence the initial choice of DFT molecular dynamics. Moreover, the latest development in machine learning interatomic potentials (MLIPs) shows promising results in efficiently and effectively simulating all-atom systems in solution. Therefore, we chose to start with the development of an accurate MLIP for our selected organomagnesium reagents.
The training of an accurate MLIP needs a large amount of data. To obtain such data efficiently, we adopted an active learning procedure. It consisted of training a crude model on a small set of molecules and then leveraging the speed of the MLIP to obtain new data points. The relevant fraction of these new structures that was seen to be useful to augment our model was added to the training set. This procedure was repeated for several cycles until the model was able to describe the phase space of our solutions accurately. Comparison with literature results confirmed the validity of the obtained MLIP.
The resulting MLIP was used to simulate molecular dynamics trajectories of four reagents containing Mg of general formula RMgCl (R=Me, Et, iPr, tBu) to study their structure and reactivity in solution. We looked at three main aspects: association dynamics, solvation structure, and, finally, the energetics of a key process in the chemistry of these molecules, the Schlenk equilibrium. Results from this work shed light on the aspects that govern the four reagents in solution, highlighting the differences among them. In particular, the relationship of the reactivity with the bulk of the reagent nicely agrees with and explains experimental observations found in the literature.
On another front, the distribution, structure, and reactivity of one of the reagents, iPrMgCl, combined with a suitable substrate, acetophenone (AcPh), was studied in an organic/DES mixture with molecular dynamics simulations. The chosen deep eutectic solvent was a solution of choline chloride and glycerol, which was shown to improve the reactivity when used in combination with iPrMgCl in a tetrahydrofuran (THF) solution. We performed simulations of AcPh in bulk glycerol and DES, showing the key role of the added choline chloride salt. We also simulated the THF/DES mixture containing both iPrMgCl and AcPh; the analysis of the distribution of the species in the mixed phase shows that the organic substrate, initially located in the DES, slowly transfers to the organic solvent, whereas the Mg reagent tends to accumulate at the interface due to its amphipathic nature. The increased concentration of iPrMgCl at the interface, combined with the flow of AcPh from the DES to the organic solvent, creates the favourable conditions for the reaction to occur.
Finally, we modelled with a QM/MM approach the reaction of an iPrMgCl with AcPh in the mixed THF/DES phase. In this reaction, the formation of a new C-C bond results in the functionalization of AcPh, opening the road to many synthetic campaigns. Experimental results showed a net increase in reaction kinetics and a noticeable decrease in byproduct presence when conducted in mixed THF/DES phases. We focused on two main aspects that can affect the reactivity: the aggregation of iPrMgCl and the charge of the overall reacting complex. For each of the investigated systems, we also studied the energetics of the main competing reaction that causes unwanted byproducts. Analysis of the trajectories and of the energetics of the reaction showed how a synergistic combination of reagent aggregation, charge and localization at the DES interface helps to promote the main reaction pathway, suppressing any unwanted side products.
The training of an accurate MLIP needs a large amount of data. To obtain such data efficiently, we adopted an active learning procedure. It consisted of training a crude model on a small set of molecules and then leveraging the speed of the MLIP to obtain new data points. The relevant fraction of these new structures that was seen to be useful to augment our model was added to the training set. This procedure was repeated for several cycles until the model was able to describe the phase space of our solutions accurately. Comparison with literature results confirmed the validity of the obtained MLIP.
The resulting MLIP was used to simulate molecular dynamics trajectories of four reagents containing Mg of general formula RMgCl (R=Me, Et, iPr, tBu) to study their structure and reactivity in solution. We looked at three main aspects: association dynamics, solvation structure, and, finally, the energetics of a key process in the chemistry of these molecules, the Schlenk equilibrium. Results from this work shed light on the aspects that govern the four reagents in solution, highlighting the differences among them. In particular, the relationship of the reactivity with the bulk of the reagent nicely agrees with and explains experimental observations found in the literature.
On another front, the distribution, structure, and reactivity of one of the reagents, iPrMgCl, combined with a suitable substrate, acetophenone (AcPh), was studied in an organic/DES mixture with molecular dynamics simulations. The chosen deep eutectic solvent was a solution of choline chloride and glycerol, which was shown to improve the reactivity when used in combination with iPrMgCl in a tetrahydrofuran (THF) solution. We performed simulations of AcPh in bulk glycerol and DES, showing the key role of the added choline chloride salt. We also simulated the THF/DES mixture containing both iPrMgCl and AcPh; the analysis of the distribution of the species in the mixed phase shows that the organic substrate, initially located in the DES, slowly transfers to the organic solvent, whereas the Mg reagent tends to accumulate at the interface due to its amphipathic nature. The increased concentration of iPrMgCl at the interface, combined with the flow of AcPh from the DES to the organic solvent, creates the favourable conditions for the reaction to occur.
Finally, we modelled with a QM/MM approach the reaction of an iPrMgCl with AcPh in the mixed THF/DES phase. In this reaction, the formation of a new C-C bond results in the functionalization of AcPh, opening the road to many synthetic campaigns. Experimental results showed a net increase in reaction kinetics and a noticeable decrease in byproduct presence when conducted in mixed THF/DES phases. We focused on two main aspects that can affect the reactivity: the aggregation of iPrMgCl and the charge of the overall reacting complex. For each of the investigated systems, we also studied the energetics of the main competing reaction that causes unwanted byproducts. Analysis of the trajectories and of the energetics of the reaction showed how a synergistic combination of reagent aggregation, charge and localization at the DES interface helps to promote the main reaction pathway, suppressing any unwanted side products.
The project advanced the state of the art in two main areas: the composition of organic solutions of Grignard reagents and the effect of deep eutectic solvent on their reactivity.
We successfully developed the first MLIP for organomagnesium reagents that is freely available online and can be used by any researcher. Its application unveiled the delicate complexity of solutions of RMgCl in THF, showing how the nature of the R group determines the association state. Analysis of the Schlenk equilibrium showed how the thermodynamics and kinetics calculated from the simulations agree with the experimental results. These findings will pave the way for a more detailed understanding of the chemistry of Grignard reagents for their rational design.
We unveiled the role that the DES plays in enhancing the reactivity of organomagnesium reagents, up to now only speculated from indirect evidence. The project arrived at a detailed explanation of the different phenomena at play. The punctual knowledge that directly relates the microscopic behaviour to each macroscopic observation is a very important step forward toward advancing the understanding of using DES and polar organometallics together, and will certainly make a big impact amongst those who use DES as reaction media.
The next steps in furthering the results of the project will be to include analogous simulations considering turbo-Grignard reagents and how the presence of lithium salts modifies the structure and reactivity.
We successfully developed the first MLIP for organomagnesium reagents that is freely available online and can be used by any researcher. Its application unveiled the delicate complexity of solutions of RMgCl in THF, showing how the nature of the R group determines the association state. Analysis of the Schlenk equilibrium showed how the thermodynamics and kinetics calculated from the simulations agree with the experimental results. These findings will pave the way for a more detailed understanding of the chemistry of Grignard reagents for their rational design.
We unveiled the role that the DES plays in enhancing the reactivity of organomagnesium reagents, up to now only speculated from indirect evidence. The project arrived at a detailed explanation of the different phenomena at play. The punctual knowledge that directly relates the microscopic behaviour to each macroscopic observation is a very important step forward toward advancing the understanding of using DES and polar organometallics together, and will certainly make a big impact amongst those who use DES as reaction media.
The next steps in furthering the results of the project will be to include analogous simulations considering turbo-Grignard reagents and how the presence of lithium salts modifies the structure and reactivity.