ELECTROCHEMICAL ORGANIC TRANSFORMATIONS: FROM THE DEVELOPMENT OF ENANTIOSELECTIVE STRATEGIES TO CONTINUOUS-FLOW METHODOLOGIES

Electroorganic synthesis has emerged as a powerful platform to replace stoichiometric redox reagents with electric current, offering improved safety, sustainability, and scalability. This thesis explores electrochemical strategies for C(sp2)-C(sp3) bond formation, rearrangements, and C-Cl bond construction in both aliphatic and (hetero)aromatic frameworks. In the first part, the enantioselective α-chlorination of aldehydes is revisited by replacing classical chemical oxidants with anodic oxidation. Cyclic voltammetry and control experiments identify CuCl2 as a key chlorinating agent for the enamine radical cation, enabling a potentiostatic protocol (1 V, GC electrodes) that delivers α-chlorinated aldehydes in high yields and enantioselectivities (up to 97% ee). Translation to a continuous-flow electrochemical reactor enhances productivity and space-time yield, reducing residence times to less than two minutes while maintaining stereocontrol. Building on this reactivity, a Ni-catalyzed electrochemical α-arylation of aldehydes via C(sp2)-C(sp3) cross-coupling with aryl iodides was developed. Two complementary protocols were identified: an organocatalytic variant and a base-mediated approach using 2,6-lutidine. Mechanistic studies support a Ni(I)/Ni(III) pathway, although current systems provide racemic products and motivate further ligand development for enantiocontrol. The second part focuses on scaling up the electrochemical Hofmann rearrangement of cyclic amides in continuous flow. Using NaBr as both electrolyte and bromine source, carbamates are accessed in almost quantitative yield on up to 100 g scale. These carbamates serve as versatile intermediates for the synthesis of nitrogen-containing heterocycles, including imidazolone and imidazolthione scaffolds. Finally, the electrochemical chlorination of aromatic and heteroaromatic substrates using inexpensive LiCl or NaCl is investigated. The study revealed efficient chlorination for activated systems such as protected resorcinols and electron-rich imidazoles, while electron-poor arenes and easily oxidized heterocycles like indoles undergo competitive anodic degradation.

Grantor dc:publisher

Università degli Studi di Milano

Year dc:date

2025

Author dc:creator

• ANDOLINA, STEFANO

Contributors dc:contributor

• tutor: S. Rossi ; co-tutor: M. Benaglia ; coordinatore: L. Prati
• S. Andolina
• ROSSI, SERGIO
• PRATI, LAURA

• Settore CHEM-05/A - Chimica organica
• Settore CHEM-04/A - Chimica industriale

Statement dc:rights

• info:eu-repo/semantics/embargoedAccess
• license:Creative commons
• license uri:http://creativecommons.org/licenses/by-sa/4.0/

Language dc:language

eng

Handle dc:identifier

https://hdl.handle.net/2434/1205780

OAI identifier oai:identifier

oai:air.unimi.it:2434/1205780