Research Projects

Biaryls are fundamental motifs in pharmaceuticals, agrochemicals, and high-performance materials, accounting for more than 11% of C–C bond-forming reactions in drug candidates. The conventional cross-coupling strategies like Suzuki-Miyaura and Negishi reactions rely on preactivated organometallic nucleophiles such as boronic acids, Grignard or zinc reagents. Nucleophiles are generally unstable, costly, and sensitive to functional groups, constraining substrate diversity and green scalability. In addition, the use of stoichiometric metallic reagents results in waste and environmental and economic issues. This proposal aims to address these limitations by creating a modular and sustainable cross-electrophile coupling (XEC) platform that allows selective C(sp²)–C(sp²), C(sp²)–C(sp³), and C(sp³)–C(sp³) bond formation from two electrophilic partners—namely (hetero)aryl halides or pseudohalides—without the need for organometallic nucleophiles or reductants. The breakthrough is achieved by combining visible-light activation, rational ligand design, and machine learning (ML)-optimal catalyst design to facilitate redox-neutral coupling under mild conditions. The core hypothesis is that structurally tuned ligand-supported photoexcited Pd(0) and Ni(0) complexes can be subjected to single-electron transfer (SET) in order to discriminate between two analogous aryl halides depending on their C–X bond dissociation energy and orbital interactions. Ligand geometry and electronics will manage reactivity and selectivity, whereas ML models will be used to predict ideal ligand structures and reaction conditions based on molecular descriptors and experimental data. These platforms will be extended to encompass aqueous-compatible bioconjugation and asymmetric biaryl synthesis. Scientific Goals: 1. Establish a ligand-managed, Electro and photoinduced Pd-catalyzed XEC protocol for C(sp²)–C(sp²) coupling of (hetero)aryl iodides and bromides. 2. Design and implement chiral phosphine ligands for asymmetric XEC to access axially chiral biaryls. 3. Develop water-compatible XEC for bioconjugation of aryl halides with peptides and carbohydrates. 4. Use ML tools to inform ligand and reaction design on the Pd and Ni platforms. 5. Upscale optimized protocols through photo-flow reactors for pharmaceutical scaffold synthesis. Key Experiments: Synthesis and screening of new ligands (e.g., SudipPhos) Photophysical and mechanistic investigation (UV-Vis, EPR, kinetics) to confirm SET and radical intermediates. Optimization of substrate scope with electronically and sterically diverse (hetero)aryl halides. Training of ML model on structure–reactivity datasets to predict high-performing ligand scaffolds. Synthesis of water-soluble ligands and peptide substrates for bioconjugation trials. Asymmetric coupling tests for assessing enantioselectivity and atropostability. Photo-flow scale-up reactions to form drug-like biaryls on a multigram scale. Significance: This work will change how biaryl scaffolds are assembled—moving away from nucleophile–electrophile to electrophile–electrophile approaches—should the research prove successful. The method will eliminate the use of unstable or costly reagents, minimize metal waste, and create access to otherwise difficult-to-reach scaffolds, including heterobiaryls and axially chiral motifs. The application of ML for ligand design is a major methodological leap, simplifying catalyst discovery and permitting predictive catalysis in XEC. Aqueous bioconjugation greatly expands the scope to peptide therapeutics and chemical biology. Scalable flow chemistry platform will provide direct applicability to industry, especially medicinal chemistry, functionalization in late stages, and green manufacture. In general, this proposal combines state-of-the-art catalysis, photochemistry, computer modeling, and synthetic utility to provide a revolutionary effect on synthetic organic chemistry and drug and agrochemical discovery applications.