Confined Lewis Acid/Base – Co-LAB

To achieve this goal, we first planned to design frustrated Lewis pairs (FLPs), based on the encapsulation of at least one of the two partners in a well defined cavity. The individual confinement of these different catalytic sites in molecular cages was intended to prevent their direct interactions. Thus, new systems had to emerge from the combination of multiple incompatible catalytic systems, working in synergy: either by activating together a single small molecule, or by acting as relay catalytic systems that will transform twice (or more) a same molecule by successive reactions.

New cages with a confined Lewis base could be synthesized. We were able to show that the encapsulation of this basic site (in the Lewis sense) avoided its reaction with a Lewis acid like titanium chloride. Thus, frustrated Lewis pairs could be obtained leading to original catalytic systems for the Morita Baylis Hilman reaction (Org. Chem. Front. 2022). Furthermore, very small sized cages were also obtained in order to frustrate the acid-base partners as much as possible. However, only the unfunctionalized cages could be isolated so far, as the synthesis led to non-expected cage structures with C1 symmetry (J. Org. Chem. 2021). Furthermore, we have also successfully confined a Lewis acid to a cage via its functionalization with a copper ion. This complex was found to be very efficient in catalyzing CUACC reactions even in the presence of nucleophilic sulfur derivative such as glutathione. The cage prevents the Lewis acid/base interaction between the Cu(II) ion and the sulfur atom of glutathione leading to a frustrated system, and allowing the catalytic activity of the copper complex even under biological conditions (Chem Comm. 2021).
On the theoretical side, our efforts so far have been focused on the development of an in principle exact and general approach (i.e., applicable not only to the ab initio Hamiltonians of quantum chemistry but also to the simpler model Hamiltonians that we wish to use in this project) of quantum entanglement based on the formalism of the density functional theory (DFT). The objective is to be able to fragment any electronic system and to put each fragment in the presence of a quantum «bath« (describing the environment) which is constructed in a self-consistent way by performing a DFT calculation on the whole system. The Schrödinger equation can then be solved simply for each cluster (a cluster being composed of a fragment and a bath), thus providing a local and detailed description of the electronic structure. The theory has so far been implemented for the Hubbard model in the ground state (invited paper, special issue of Computation 2022). We are currently working on its extension to excited states, based on our recent work in DFT for ensembles. We have recently published a journal article on this subject (Top Curr Chem 2022). A paper on a unified description of neutral and charged electronic excitations is also in preparation.

Our goal is now to introduce a boron atom as an acidic site in the Lewis sense in a cage, in order to obtain original Frustrated Lewis pairs. Moreover, we will also complex a phosphorus atom in the recently obtained «small« cage in order to study the influence of the size and symmetry of the cavity on the degree of frustration of this type of system. On the theoretical side, our objective for the next period is to build model Hamiltonians to describe the synthesized Lewis pairs. The latter will be solved by quantum nesting. In parallel we will continue to extend the theory to ab initio Hamiltonians.

1. “Frustrated Behavior of Lewis/Brønsted Pairs inside Molecular Cages” C. Li, A.-D. Manick, J.-P. Dutasta, X. Bugaut, B. Chatelet, A. Martinez Organic Chemistry Frontiers 2022, accepted, DOI:
10.1039/D2QO00011C.
2. “Hemicryptophane Cages with a C1-Symmetric Cyclotriveratrylene Unit.” C. Li, A.-D. Manick, M. Jean, M. Albalat, N. Vanthuyne, J.-P. Dutasta, X. Bugaut, B. Chatelet, A. Martinez* J. Org. Chem. 2021, 86, 15055–15062.
3. “A Tris(benzyltriazolemethyl)amine-based Cage as CuAAC Ligand tolerant to exogeneous bulky nucleophiles” G. Qiu, P. Nava, A. Martinez, C. Colomban Chem. Commun. 2021, 57, 2281-2284.
4. “Ensemble Density Functional Theory of Neutral and Charged Excitations.” F. Cernatic, B. Senjean, V. Robert, E. Fromager Topics in Current Chemistry 2022, 380
5. “Local Potential Functional Embedding Theory: A Self-Consistent Flavor of Density Functional Theory for Lattices without Density Functionals”- S. Sekaran, M. Saubanère, and E. Fromager, invited paper, special issue of Computation (2022), Preprint: arXiv:2202.08071

The development of catalysts for the activation of small molecules, such as H2, under mild and environmentally friendly conditions is one of the most important challenges for chemistry. In this context, the use of Frustrated Lewis Pairs (FLP) chemistry as catalyst appears particularly appealing to solve this issue. This project aims to confine FLP-type systems in molecular cages and apply them to small molecule activation and catalysis. These systems will also be tested on more complex substrates, in order to test their efficiency on other key reactions in the chemical industry such as Baylis Hillmann or Mannich reactions. The originality of our approach, when compared to other FLPs systems, lies in the encapsulation of the Lewis acid or base (or both) in molecular cages (hemicryptophanes), this will lead to nanoreactors with well-defined cavities just above the acid / base partners. This cavity will not only avoid direct Lewis acid-base interaction, but should also induce new reactivities by imposing unusual conformations and orientation on the encaged reagents. Thus more efficient catalytic systems are expected because of the desolvation and "stress" of the substrate inside the cavity. Moreover, hemicryptophanes are chiral hosts and able to selectively recognize substrates, opening the way for asymmetric catalysis. Thus, the confinement of the catalytic site and the substrates in a single cavity should lead to a high catalytic activity and a high enantioselectivity.
Furthermore, this project is based on a strong and constant interaction between theory and experience, in order to solve the important issues mentioned above.