Non-traditional Activation Methods for the Synthesis of Biologically Active Compounds and Fine Chemicals

Guoshu Xie, University of Massachusetts Boston

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Abstract

The major goal of this work was to address the need for new green processes and develop synthetic protocols that are environmentally superior to existing methods. Chemistry has made an enormous contribution to the development and well-being of human society. The chemical industry reached earlier unimaginable heights over the past century, however, the negative impacts of these rapid developments soon followed. The concept of green chemistry, which is not only aiming to make ‘benign by design’ products but also minimize the environmental impact of chemical processes, became the mainstream in laboratory and industrial practices. This thesis includes the following projects which are all focused on the development of green chemistry processes: The first project is focused on high pressure initiated solvent- and catalyst-free instant Paal-Knorr reactions. In this study, high hydrostatic pressure (HHP) has been found to be a highly efficient activation method in the synthesis of pyrroles which are important skeletons in organic synthesis due to their biological importance. The reactions were carried out at pressures from 1 bar (control) up to 3.8 kbar and the observed nearly quantitative yields and seconds-long reaction times indicate the usefulness of the developed methodology. The reaction rates have been increased by two orders of magnitude compared to the conventional synthesis. The second project is inspired by the green synthesis of Paal-Knorr reactions under high hydrostatic pressure (HHP). The HHP-assisted Paal-Knorr reactions were successfully scaled up from milligrams to kilograms. Four typical Paal-Knorr reactions were selected and carried out at large scale under HHP. The gradully increased scales were 30 g, 100 g and 250 g. The low density polyethylene bottle was used as reaction vessels that ensure uniform pressure distribution and prevent any leakage under high pressure. The third project describes Rh-catalyzed environmentally benign selective hydrogenation of a broad variety of functional groups using Al-water as a hydrogen source. The 5% Rh/Al2O3 and 5% Rh/C performed well in controlling the selective hydrogenation under the desired amount of time and temperature. In this regard, partially- and fully- hydrogenated products have been selectively prepared by controlling reaction time or temperature. Al-H2O system, activated by ultrasonic irradiation, in situ producing hydrogen and the excellent, controllable selectivity make this protocol environmentally benign and highly efficient compared to available alternatives. The fourth project is ultrasound-assisted catalyst-free synthesis of α,β-unsaturated amino acid esters and unsaturated amino ketones. The ultrasound-assisted catalyst and (mostly) solvent-free synthesis of α,β-unsaturated amino acid esters and amino ketones was found to be a highly efficient environmentally benign method for the preparation of the target compounds. The method aligns with green chemistry principles, reducing the need for hazardous solvents and reagents. The absence of catalysts minimized waste and the need for additional purification steps. The fifth project is an extended applictaion of the metal catalyst-Al-water system. In this project I used D2O instead of H2O to introduce deuterium to molecules without the need for explosive and quite expensive deuterium gas. Many substrates with hydrogenation sensitive groups (C=C, or C=O bonds) were deuterated in the Pd/C-Al-D2O reduction system with high yields and excellent selectivities. The sixth project is the investigation into high hydrostatic pressure (HHP)-initiated, solvent- and catalyst-free synthesis of 1,3-dihydrobenzimidazoles that reveals a novel and sustainable approach to chemistry. Our findings show that HHP can efficiently drive the formation of 1,3-dihydrobenzimidazoles without relying on conventional solvents or catalysts, thereby minimizing environmental impact and streamlining the synthetic procedure.