Committee Members Information

• Ph.D. Advisor Name: Professor Magnus Rueping (Chemistry, KAUST)
• External Examiner Name: Professor Carsten Bolm ( University....) 
• Committee Chair Name: Professor Javier Ruiz-Martinez (Chemical Engineering, KAUST)
• 4th Committee Member Name: Professor Luigi Cavallo (Chemistry, KAUST)

Abstract:  The development of sustainable synthetic methods has become a central goal in modern 
chemistry, driven by the need to reduce solvent use, energy consumption, and chemical waste. 
Resonant Acoustic Mixing (RAM) is a non-contact mechanochemical technology that uses low frequency acoustic energy to promote efficient mixing throughout a reaction vessel without milling balls, offering a flexible platform for solvent-free or solvent-minimized reactions with strong 
potential for scale-up. This thesis presents the development and application of RAM across three bond-forming reactions in organic synthesis and catalysis, establishing it as a versatile platform for sustainable mechanochemical synthesis. 

The first research chapter describes the development of a high-throughput mechanochemical experimentation platform combining RAM with a 96-well plate format for rapid parallel reaction screening. This platform was applied to nickel-catalyzed C–N cross-coupling amination, affording products in yields of up to 97% across a broad substrate scope, including pharmaceutically relevant molecules. Direct scale-up to 30 mmol was demonstrated without reoptimization. Process mass intensity analysis confirmed a substantial reduction in material consumption compared with solution-based protocols. 

The second research chapter presents a solvent-less amide coupling protocol for Fmoc based solid-phase peptide synthesis enabled by RAM. Conventional peptide synthesis relies heavily on more toxic polar aprotic solvents at each step of the synthesis cycle. The developed 
protocol eliminates bulk solvent from the coupling step, using only residual solvent retained in the Alice Nanni - PhD Thesis Abstract, 2026 pre-swollen resin to enable reagent activation. The method was validated on peptide targets of increasing complexity, delivering high yields and purities, and showed a five-fold reduction in process mass intensity relative to microwave-assisted solid-phase peptide synthesis. Scale-up to 10 mmol was achieved without re-optimization. 

The final research chapter describes a solvent-free Fischer-type esterification enabled by RAM using a premixing–aging strategy. Silica gel served as both support for concentrated sulfuric acid and an in-situ drying agent. After a brief RAM premixing step, the reaction proceeded during static aging. The silica-supported acid catalyst was recovered and reused over multiple cycles, and direct scale-up to 60 mmol was demonstrated. 
Together, these studies establish RAM as a broadly applicable and scalable platform for sustainable mechanochemical synthesis across diverse reaction classes.