The project targets the design and preparation of immobilized organocatalysts to be employed in batch and flow modes. The selection of the more efficient catalytic system and the control of its activity after the immobilization procedure will be obtained by mass spectrometry experiments. As a starting point, the ESI-MS off-line reaction monitoring of catalytic systems allows the evaluation of catalytic efficiency (in terms of yield and reaction rate) and the identification of the involved intermediates. Once the most interesting system has been identified, the project involves the preparation of its heterogeneous version (with a supported catalyst) to be used in continuous flow reactions. Smaller equipments for flow reactions are very attractive at lab-scale, because they allow a fast screening and an easy on-line monitoring of processes to optimize their productivity. Meso-reactors (like a small HPLC column) and micro-reactors (like 3-D printed channels) are built and connected to the mass spectrometer to control the progress of catalytic reactions. Chiral organocatalysts bearing primary amino groups (such as 9-amino-9-epi-cinchona alkaloids and vicinal chiral diamines) or thiourea and amide functions (such as 9-amino-9-epi-cinchona alkaloid derivatives) will be exploited as privileged structures in the activation of carbonyl compounds providing new carbon-carbon bonds. These catalysts, their intrinsically charged intermediates (enamine or iminium ion), the active catalyst-substrate complexes (via noncovalent bonding) and products are easy ionizable and suitable to be explored by mass spectrometry. The project aims at creating a useful platform enabling catalyst selection and an early stage of process intensification (immobilized organocatalysts, flow mode reactions) with low material consumption.
Based on the experimental results carried out in the first phase of the project, the design of improved catalytic supports can be pursued in line with the process intensification concept but in more economical and ecological manners. In particular, the research will benefit in each step of the project:
- PA-1: knowledge of catalytic cycles. Activation of carbonyl groups via enamine/iminium ion or via hydrogen bond interaction represents an ideal candidate for MS investigation due to the presence of ionic and easy-ionizable intermediates. There are only few mechanistic studies investigating the activation mode of those catalysts, and ESI-MS approach has never been used in this context. Experimental data will be rationalized to select improved and refined catalytic machines.
-PA-2: deep characterization of immobilized catalyst will drive to the more active system. The development of immobilized catalyst will require considerable effort, but reusable systems can be obtained.
-PA-3: Micro and meso flow reactors in lab-scale are devices to rapidly screen reactions. The control of reaction progress by ESI-MS will provide indications in the optimization of working conditions for new unexplored reactions. In addition, in view of the intensification procedure, the devices can be employed to prepare in continuous a small library of products.
Moreover, a more ambitious purpose is the realization of a solid-supported synergic catalyst to address the stereocontrol of multiple stereogenic elements. The synergic effect can be obtained by mixing different organocatalysts as well organo- and metallo-catalysts or employing an active solid support.