Using LC-MS & GC-MS to Decode Photoredox Catalyst Stability

🎤Lindsay Repka 

Lindsay Repka is a chemistry professor at Middlebury College whose research explores photoredox chemistry, catalyst stability, and visible-light-driven transformations. Her lab emphasizes both mechanistic insight and hands-on student training in advanced analytical instrumentation.

In this episode of Concentrating on Chromatography, we sit down with Lindsay Repka to discuss how LC-MS and GC-MS transformed her lab’s approach to photoredox chemistry.

What began as a project to develop a visible-light photocrosslinking handle unexpectedly led to a major discovery: the solvent (DMF) was reacting with the photocatalyst itself. Using high-resolution LC-MS, Lindsay’s team observed multiple solvent adducts forming — sometimes with complete catalyst consumption. That discovery reshaped their research direction.

This episode is a rare deep dive into both LC-MS and GC-MS within the same research project, showing how chromatography-driven insight can turn unexpected degradation into productive new reactivity.

If you work in:

• Photoredox chemistry
• Reaction optimization
• Mass spectrometry method development
• Catalyst screening
• Academic synthetic chemistry

…this conversation will resonate.

Key Topics Covered

• Photocatalyst stability in DMF, DCE, and MeCN
• Demethylation under mild visible-light conditions
• High-resolution Q-TOF LC-MS quantitation
• Internal standard methodology in GC-MS
• Signal-to-noise improvement using extracted ion chromatograms
• Reaction reproducibility and quality control strategy

Video Transcription

In this interview, Lindsay Repka discusses the role of photoredox chemistry in method development, photocrosslinking, solvent activation, catalyst stability, and the use of LC-MS and GC-MS to understand reaction pathways.

What is photoredox chemistry?

Photoredox chemistry uses light to activate a photocatalyst, which can either donate or accept an electron from a substrate. This generates radical species that can undergo new types of reactivity.

Repka explains that one of the key advantages of photoredox chemistry is its ability to operate under mild conditions, often using visible light. This makes it attractive for sensitive molecules and biological systems, including potential applications in drug release, live-cell chemistry, and drug development.

Photocrosslinking and drug-target interactions

Repka’s group initially aimed to develop visible-light photocrosslinking methods to study drug interactions with biological targets. Photocrosslinking can covalently link a drug to its target, making it easier to identify the biological target of a compound.

Traditional photocrosslinking often uses UV light, but visible light offers milder and more biologically compatible conditions.

From photocrosslinking to solvent activation

The project shifted direction when the desired photocrosslinking reactions gave very low yields. Instead of reacting with amino acids as intended, the radical intermediate mainly reacted with itself.

The team explored different solvents to stabilize the radical, but found that some solvents, such as DMF, were not inert. Instead, the solvent reacted with the photocatalyst or radical species, revealing unexpected solvent activation chemistry.

Why LC-MS was critical

LC-MS became essential because the reaction mixtures were too complex and low-yielding for NMR or GC-MS. High-resolution LC-MS allowed the team to detect minor products, identify photocatalyst modifications, and observe solvent addition products with high confidence.

Repka emphasizes that LC-MS was both a qualitative and quantitative tool. It was used quantitatively to measure how much photocatalyst remained after light exposure, and qualitatively to identify degradation products and new reactivity pathways.

Photocatalyst stability workflow

The team developed a systematic workflow to evaluate photocatalyst stability under light exposure. Because catalyst degradation was time-sensitive, reproducibility required strict control of experimental conditions.

Key steps included using a glove box, commercial deoxygenated solvents, accurate weighing on a microbalance, controlled light exposure in a photoreactor, and temperature control with a chiller. These precautions helped reduce day-to-day variability and enabled reproducible measurements of catalyst remaining.

Quantifying catalyst remaining by LC-MS

Calibration curves were prepared using pure photocatalyst solutions and LC-MS ion areas. The team worked in the nanomolar range to maintain linearity.

Instead of relying only on total ion chromatograms, they used extracted ion chromatograms (EICs) to improve signal-to-noise for the photocatalyst signal. Baseline subtraction was also applied to reduce noise and improve quantitation at low concentrations.

Calibration curves and quality control samples were prepared and measured on the same day as the reaction samples, because LC-MS signal intensity can vary significantly from day to day.

Why GC-MS was used later

For demethylation studies, the group moved to GC-MS because the substrates and products were small and volatile enough for gas chromatography. GC-MS was better suited for rapidly screening many reaction conditions, including different photocatalysts, solvents, and oxidants.

Instead of generating full calibration curves for every experiment, the team used an internal standard to streamline analysis and determine percent conversion based on relative response factors.

Practical lessons from the project

Repka highlights the importance of careful sample preparation, especially when working with very small quantities of photocatalysts. A high-quality microbalance, stable granite platform, antistatic tools, and aluminum weigh boats improved weighing accuracy and reproducibility.

She also argues that mass spectrometry should be a standard part of photoredox method development because it can reveal minor products, support reaction optimization, and provide insights that may be difficult or impossible to obtain by NMR alone.

Final perspective

Beyond the chemistry, Repka emphasizes the importance of student training and mentoring. For her, research is not only about discovering new reactivity but also about giving students practical experience, helping them develop independence, and preparing them for future scientific careers.

This text has been automatically transcribed from a video presentation using AI technology. It may contain inaccuracies and is not guaranteed to be 100% correct.

Concentrating on Chromatography Podcast

Dive into the frontiers of chromatography, mass spectrometry, and sample preparation with host David Oliva. Each episode features candid conversations with leading researchers, industry innovators, and passionate scientists who are shaping the future of analytical chemistry. From decoding PFAS detection challenges to exploring the latest in AI-assisted liquid chromatography, this show uncovers practical workflows, sustainability breakthroughs, and the real-world impact of separation science. Whether you’re a chromatographer, lab professional, or researcher you'll discover inspiring content!

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