Next Generation Photo- and Electrochemical Methodologies and their Applications to Sustainable Synthesis and Manufacturing

Active pharmaceutical ingredients (APIs) are becoming more structurally complex, with increased saturation. Multi-step approaches using harsh reaction conditions have traditionally been employed to form such C(sp2)–C(sp3) and C(sp3)–C(sp3) bonds. Photochemistry can provide access to these complex molecules with high selectivity via milder and greener reaction conditions. In this talk, we will highlight the screening and optimization of a Ni/photoredox-catalyzed crosselectrophile coupling reaction to access the core structure of an API. Multiple rounds of highthroughput screening were performed to replace more commonly used Ir-based photocatalysts with a cheaper organic photocatalyst and silane reductants with amine reductants. The best conditions from the batch screening reactions were then optimized for scale-up in continuous flow.

Benzene, in the excited state, is a remarkably reactive chemical motif. The year 2025 marks the 200-year anniversary of Faraday’s discovery of benzene, and in this talk I will explore how its excited-state behavior offers a unique platform for photochemical transformations. The talk begins with a quick introduction to Baird’s rule, the reversal of the Hückel electron-counting rule for aromaticity and antiaromaticity in the lowest ππ* states of annulenes. I will then highlight computational explorations from our group over the past decade on how relief of excited-state antiaromaticity in benzene derivatives and heteroarenes can drive diverse photochemical transformations, including proton transfer, electron transfer, π-bond activation, tunable Lewis interactions, and photo-HF elimination.

Decarboxylative functionalization of aliphatic carboxylic acids has emerged as a powerful platform for accessing alkyl radicals from abundant, stable, and structurally diverse feedstocks. Because such acids are prevalent in natural products and pharmaceuticals, they serve as attractive substrates for late-stage diversification. However, many existing decarboxylative methodologies rely on metal catalysts, specialized additives, or homogeneous photocatalysts that are costly, difficult to recover, and challenging to reuse, limiting their sustainability. Herein, we report the development of a recyclable polymeric photocatalyst incorporating three complementary chromophores that operate cooperatively under visible light irradiation. This multichromophoric design enhances light absorption and promotes efficient charge separation, enabling the generation of alkyl radicals via smooth decarboxylation. The resulting strategy facilitates metal-free sulfonylation and fluorination of aliphatic carboxylic acids across a broad substrate scope, delivering good yields while maintaining excellent tolerance to sensitive functional groups under mild conditions. Importantly, the polymer photocatalyst is synthesized in a single step, can be readily recovered, and retains its photocatalytic efficiency over multiple cycles with minimal loss of activity. This work highlights the potential of multichromophore polymer photocatalysts as robust, reusable platforms for sustainable decarboxylative radical chemistry, offering a practical alternative to conventional small-molecule and metal-based photocatalysts.

Photochemistry continues to increase in popularity in the design of small molecules. Visible-light photochemistry typically offers mild reaction conditions and high selectivity, both hallmarks of greenness and sustainability, making it an attractive option for the commercial manufacturing of active pharmaceutical ingredients (APIs). Even with the increasing number of photochemical transformations and methodologies available in the literature, scaling up photochemical reactions for commercial manufacturing remains a significant challenge in the pharmaceutical industry. Proper scale-up of photochemical reactions requires understanding of the reaction kinetics, the rate of photon absorption in the system, thermodynamics, and other transport phenomena. Per the famous Beer-Lambert law, the attenuation of light in chemically reacting systems imposes scale-up challenges for all photochemical reactions. Myriads of reactor-light source configurations and permutations are possible from lab to commercial scales, making replication of literature and bench protocols across scales challenging without the proper understanding of the key scale-up factors and considerations.
This talk will discuss fundamental aspects of photochemical reaction engineering, applications to flow photochemistry using laser-driven CSTRs as a platform, and general perspectives on scaling up photochemical reactions in the pharmaceutical industry. Flow systems offer high throughput in a small footprint, providing an effective, scalable solution for the attenuation of light in photochemical reactions. This talk will highlight how application of fundamental principles of photochemical reaction engineering can achieve kilogram-scale throughput in laboratory-scale equipment using a laser as a high intensity light source. This methodology easily extends to scalable reactor design for commercial manufacturing. The talk will conclude with perspectives on photochemical reaction engineering in the pharmaceutical industry, including how to approach process modeling, suggested best practices, and other considerations.

Electrochemistry is rapidly transforming the logic of synthetic design, yet the ability to precisely and sustainably programreaction pathways from a single substrate remains unprecedented. Herein, we disclose a fundamentally new strategy in which engineered reaction media dictate electrochemical fate, enabling propargyl alcohols to be selectively converted into either stereodefined Z -allylic alcohols or synthetically versatile allenes under mild, transition metal-free conditions. In aqueous micellar media derived from our designer surfactant PS-750-M, propargyl alcohols undergo a precious-metal-free electrosemihydrogenation, delivering water-sensitive allylic alcohols with perfect 100% Z -selectivity, and in water! The micelle functions simultaneously as a nanoscopic reaction compartment and a dynamic extraction shuttle, rapidly removing the product from the electrode interface to prevent over-reduction. This environmentally preferred platform eliminates the need for hydrogen gas, organic solvents, and stoichiometric reductants, establishing micellar electroreduction as a powerful tool for sustainable synthesis. In striking contrast, switching to a preferred organic solvent containing a catalytic proton source triggers a mechanistically distinct pathway leading to allenes. Under anodic polarization, the acid reorganizes at the electrode to form a surface-immobilized, glassy phosphate film acting as a strong, non-nucleophilic, confined Brønsted acid catalyst. This microenvironment weakens the C–O bond, stabilizes propargylic cationic character, and promotes a rapid dehydration–rearrangement sequence via a fleeting electrochemically generated enyne intermediate, directly observed in the control NMR study. The result is a clean, selective route to allenes while suppressing conventional side reactions.
Together, these studies introduce media-programmed electrochemical reactivity as a generalizable design principle—one in which nanostructured environments and electrode surface catalysis serve as tunable levers to access divergent molecular architectures from a single starting material. This platform opens new retrosynthetic logic for sustainable organic synthesis, demonstrating how precision-engineered microenvironments can unlock reactivity inaccessible by traditional chemical means.

Electrochemistry and photochemistry can enable new and different bond disconnections, with the potential to streamline synthesis and provide access to new regions of chemical space. Moreover, both electrosynthesis and photochemistry offer greener alternatives to traditional approaches by avoiding the use of stoichiometric and potentially hazardous redox reagents, thereby advancing sustainable chemistry goals. However, realizing the full potential of these activation modes in the pharmaceutical industry requires not only the development of new synthetic methods but also the design of suitable reactor technologies and workflows. This presentation will highlight our efforts in implementing electrochemical and photochemical transformations in process chemistry, focusing on the development of an ideal workflow for reaction scale-up in continuous flow. Case studies for both electrochemical and photochemical reactions will be used to illustrate the scaling strategy and the reactors employed, including the transition from lab-scale results to kilogram-scale demonstrations.

Hydrogen is often viewed as an ideal terminal reductant for electrosynthesis because it is abundant, atom-economical, and avoids the waste associated with sacrificial metal reductants. In practice, however, direct anodic H2 oxidation is difficult to pair with reductive electrosynthesis in organic media, owing to both the kinetic limitations of non-aqueous HOR and the complications that arise from proton and water transport in conventional hydrogen-anode formats.
This presentation will describe a quinone-mediated hydrogen anode that couples off-electrode Pd/C-catalyzed hydrogenation of an anthraquinone mediator with anodic oxidation of the corresponding hydroquinone, enabling nickel-catalyzed cross-electrophile coupling under non-aqueous conditions. The fundamental advantages of mediated electrosynthesis for this application will be described, followed by analytical assays to identify the capabilities and limitations of this anodic system. Particular emphasis will be placed on the application of an external voltage to supplement the intrinsic reductive potential of H2 and enable more challenging reductions. Operando UV–vis analysis of mediator speciation and polarization curves of the fully constituted cell will be analyzed to identify an operating regime that supports productive cathodic chemistry. Attention will also be given to proton management in the recirculating anode, where protons are retained, neutralized, and exchanged for Li+, suppressing proton crossover and allowing H2 to function as an effectively proton-free source of electrons.