The story behind the Science paper – How our team created RoboChem

When I embarked on my independent academic career, my mission was clear: to push the boundaries of synthetic organic chemistry through technological innovation. One of my most audacious dreams was to create a chemical robot capable of working alongside human chemists, alleviating the burden of arduous and time-consuming tasks, such as reaction optimization. However, from the outset, I knew that this endeavor would be anything but easy. The examples I found in the literature appeared prohibitively expensive, requiring a diverse team with a wide range of skills, and the assembly process would be a time-consuming challenge in itself. Could we realistically pull this off? At the dawn of our research group, the answer was a resounding ‘no.’ Our team was small (1-5 PhD students in the first five years), resources were limited, and the risks loomed large: the potential for burning through funds and human capital without any publication to show for it. At that time, this was a risk we simply couldn’t afford to take.

The assembly of the team

Confidence in embarking on robotic projects began to take shape gradually after we successfully published an automated strategy for conducting Stern-Volmer experiments.[1] This platform, while relatively simple and cost-effective, made a significant scientific impact by delivering highly reproducible results for these notoriously finicky kinetic experiments.

Enter Zhenghui Wen: When I welcomed in September 2018 Zhenghui Wen, a skilled chemical engineer from China, to our team, I explained our ambitious vision. Zhenghui’s immediate enthusiasm ignited a flurry of activity. He began 3D-printing a multitude of reactors and liquid handlers while also diving into programming Arduino drivers. However, it soon became evident that the RoboChem project couldn’t be a one-person endeavor — though Zhenghui did exceptional work. We made the challenging decision to temporarily halt the project.

Around 2020, the tides began to turn in our favor. Our success in securing funding improved substantially, and our research group underwent remarkable growth. Additionally, I received a valuable startup package at the University of Amsterdam, enabling the purchase of a benchtop NMR, a pivotal yet costly instrument that would provide critical data on yield and selectivity.

Aidan Slattery Joins the Team: Around September 2020, Aidan Slattery, an Irish chemist with invaluable flow experience gained at SnapDragon, became a vital addition to our team. His dedication was fully committed to realizing the RoboChem vision.

Pauline Tenblad’s Expertise: Just a few months later, we were fortunate to welcome our first Swedish PhD student Pauline Tenblad. Her expertise in chemical engineering was crucial for the machine learning efforts required to enable self-optimization within the RoboChem platform.

Dr. Diego Pintossi Takes the Helm: Joining the team alongside Pauline was Dr. Diego Pintossi, a versatile, Italian chemical engineer. His role involved mentoring, coordinating efforts, and ensuring a seamless and productive journey toward our objectives.

Picture 1. Meet the Pioneers: The Original RoboChem Team in Front of the Platform (left to right): Aidan Slattery, Zhenghui Wen, Pauline Tenblad, and Diego Pintossi.

Assembling Hardware and Seamlessly Integrating it with Code: Bringing the RoboChem Vision to Life

These four exceptional researchers embarked on the formidable task of assembling the intricate hardware components and executing the essential coding for our project. The challenges we encountered during this phase were nothing short of daunting.

One major challenge we grappled with was the need for precise control over every piece of equipment through software integration (Figure 1). This necessitated the development of a sophisticated control system to ensure precise functionality of each component. Hardware-related hurdles further compounded our efforts, with compatibility issues and the need for meticulous fine-tuning of mechanical components becoming recurring challenges. For instance, we faced ‘lost in translation’ moments between our 64-bit software control and 32-bit hardware. Switching between these applications took Pauline a few days to untangle. There were countless other small, not-so-glorious issues to resolve, many of which won’t even make it into the final paper.

As progress proved slow and tangible results were limited, the paramount task at hand became maintaining focus and motivation. Tim den Hartog, a visiting researcher from Zuyd University of Applied Sciences, and I took it upon ourselves to keep the team’s spirits high throughout this challenging phase. Together, we actively participated in the biweekly ‘RoboChem meetings,’ where we discussed our ongoing progress and offered suggestions to overcome some of the hurdles that we encountered.

The combined effort of coding and hardware installation stretched over an arduous 2-3 year period, emphasizing the monumental nature of our undertaking. You might wonder why we didn’t opt for readily available off-the-shelf units. The answer, though deceptively simple, lies in the flexibility required for our highly specific applications. Most commercial units function as black boxes, lacking the adaptability needed for our unique project demands. Tailoring such units to our requirements would have presented nearly insurmountable challenges.

Figure 1. Embarking on the First Automated Steps: Taking the initial strides in automating syringe pumps and mass flow controllers, and implementing Arduino controllers.

The First Test: From Stress to Relief, A Remarkably Smooth Journey

But once all the bugs were meticulously ironed out of our system, we stood on the precipice of a crucial milestone—the first test (Figure 2). Our focus honed in on photocatalysis, a domain in which our group has ample experience. We decided to implement one of our versatile photochemical flow reactors within RoboChem, complete with a set of high-intensity LEDs.[2] This allows us to tune the light intensity meticulously, a feature we think might be important for the optimization of photocatalytic transformations.

Figure 2. The RoboChem Platform: Fully Assembled and Primed for Inaugural Testing.

I must admit that during this critical phase, I took a step back from the lab, preferring not to add any additional stress to my dedicated team. However, behind that cautious facade, I was filled with eager anticipation. You see, the stakes were exceptionally high. If this inaugural test failed to yield results, it would have meant a significant investment of time wasted, not to mention the daunting task of restoring the team’s confidence. [The specter of potential failure loomed heavily over us.]

On July 21, 2022, as I went about my day, a notification chimed on my phone—a WhatsApp message from Aidan. It was a moment that would define our journey (See Figure 3). The message held the key to our hopes and fears. The results were nothing short of astonishing: the experiment worked seamlessly, and we achieved an unprecedented level of optimization. We had successfully executed a photocatalytic hydrogen atom transfer-induced Giese-type radical addition to benzalmalonitrile. The euphoria that swept through our team was palpable, and in that instant, we knew we were on the cusp of something remarkable.

Figure 3. WhatsApp message from Aidan, filled with excitement, prompts an exuberant response from Tim, signaling a groundbreaking moment in the RoboChem project [pardon the F-bomb from Tim].

Progressing Forward: Exploring Diverse Case Studies

Once we obtained those initial results, and I assure you, this was truly a first result (no joke), we realized that we held something incredibly valuable in our hands. We also understood the importance of showcasing the full potential of the RoboChem platform. If we could achieve that, we knew we might be holding the key to a top-tier paper. I instructed the RoboChem team to explore the system thoroughly, with the understanding that once we comprehended its capabilities, we would be able to devise a strategic plan for our next steps.

Around November 2022, I reached out to Zhenghui and Aidan, suggesting that we select a diverse array of photocatalytic synthetic methods and initiate a small-scope optimization, typically with around five examples per method. It was at this stage that our Spanish postdoc Jesus Orduna, who was already a year in our NRG team, joined the RoboChem team, bringing his expertise to assist in chemistry selection, results analysis, and compound isolation.

Our working hypothesis was that while chemists often develop a single set of conditions and apply them universally across the substrate scope, individual AI refinements tailored to each molecule could yield superior results. Additionally, we were well aware of the challenges associated with photocatalysis. This activation mode is notoriously complex, involving intricate photophysics and poorly understood mechanisms. Moreover, technological issues, such as setup variability and irradiation profiles, contribute to interlaboratory irreproducibility, making it a time-consuming endeavor to achieve consistent and reliable results. In other words, the ideal testcase to validate RoboChem!

To our delight, we found that across all examples, spanning hydrogen atom transfer photocatalysis and photoredox catalysis, the RoboChem platform either matched or significantly surpassed yields reported in the literature. It often surprised us by making nuanced choices, such as opting for very low light intensity when beneficial for a specific molecule, while favoring higher intensities in other cases. The data yields more intriguing conclusions, all of which are elaborated in the paper. Notably, for each substrate, we compiled comprehensive data sets with results spanning from low to high yields, providing a clear picture of the parametric sensitivity for each molecule. This approach, we believe, sets our research apart as in literature typically only the best results are highlighted.

The importance of reproducibility

While the results exceeded our wildest dreams, it was imperative to eliminate any room for error. To achieve this, we implemented a rigorous quality assurance process. We utilized the best reaction conditions and ran them consistently in the same photochemical flow reactor, yielding up to 5 mmol of product in each case. Aidan, Zhenghui, and Jesus took on the demanding task of isolating all the compounds, with the obtained yields closely mirroring those achieved with the inline benchtop NMR (Picture 2). Subsequently, each compound underwent comprehensive characterization through NMR, MS, and other analytical techniques. Although time-consuming (we believe that this human isolation and characterization phase served as the rate-determining step, as the entire optimization protocol was fully automated and hands-off), it provided us with unwavering confidence that the results delivered by RoboChem were genuine and not a mere fluke.

Picture 2. Capturing Dedication: Jesus and Aidan, sleeves rolled up, diligently isolating the final compounds.

Paper Submission: The Waiting Game Begins…

Once we had gathered all the data, the exciting journey of crafting our paper began. The initial draft took shape in the hands of Aidan and Pauline, while Zhenghui worked his magic to create the graphics that would highlight our findings. When they presented me with their rough draft, I couldn’t help but feel a surge of enthusiasm. This phase, where you take the collective hard work and start shaping the narrative, is one of the most enjoyable aspects for me.

Typically, I maintain very close contact with the team during this process, bombarding them with multiple questions every day, whether in person or via WhatsApp. We delve into intricate details and fine-tune the storyline. This collaborative refinement process, however, demands time and dedication. For a paper as multifaceted as this one, integrating various disciplines such as chemistry, chemical engineering, programming, machine learning and robotics, it takes me at least two weeks to craft a narrative that we can all take immense pride in.

During the revision process, the team dedicated themselves to creating a comprehensive Supporting Information section, meticulously detailing procedures, characterizations, and optimization tables.

Once everyone was satisfied with the manuscript, we submitted it to ChemRXiv[3] and I began presenting it at conferences. The first opportunity arose at the 6th Flow Chemistry and Continuous Processing Conference in Boston (May 2-3, 2023). The prospect of sharing our work in the city where my journey began, learning flow chemistry at the Buchwald Research Group at MIT, just a 5-minute walk away, filled me with excitement. After my presentation, I was inundated with questions, particularly about RoboChem. The enthusiasm from the audience remained consistent throughout subsequent talks. I even made a playful remark to the RoboChem team that, while I was joking, held some truth: if I wanted questions on other parts of my talk, I’d have to remove RoboChem from the slides.

This overwhelmingly positive feedback boosted our confidence to aim high and submit the paper to the most prestigious journals in our field. We set our sights on Science (See Figure 4A). The submission was met with anticipation and nervous excitement. A promising sign emerged when the paper was sent out for review, spotted in the portal by Aidan (See Figure 4B). Then, on July 31, an email from the Science editor arrived, containing the feedback from the referees. The feedback was predominantly positive, and I couldn’t contain my excitement when I shared the news with the RoboChem team (See Figure 4C). Two referees had provided feedback with an acceptance recommendation, while one referee had a few specific requests, the most notable being, ‘Can you explore dual catalytic pathways, as these are notoriously challenging to optimize?’

Figure 4. Snapshot of key WhatsApp conversations between Tim (in green) and Aidan (white): (A) Should we try to submit to Science? [June 10, 2023] (B) Paper sent out for review, excitement gets built up. [July 7, 2023] (C) Feedback is in, two yes and one conditional feedback. We are in business, however, more work to do! [July 31, 2023]

The Final Stretch: Let’s Ace This One…

When you receive such exceptional feedback, two emotions intertwine: excitement and nerves. On one hand, the excitement of receiving fantastic feedback and the prospect of a potential paper in Science ignite your spirits. On the other hand, the nerves creep in; you realize you can’t afford to squander this remarkable opportunity. The twist was that we were all on vacation when this happened, so we couldn’t dive into action right away. Aidan and Jesus had to handle things in the lab, and Zhenghui, who had been an integral part of our team, had returned to China, become a father and was applying for jobs. In fact, he even pondered, ‘Should I come back? I am willing to do this!’ This underscores the unwavering dedication of our team to see this through.

Once our vacation ended, and we had some time during the break to strategize, we swiftly concurred that we needed to perform the experiments requested by referee 3. We opted for a photocatalytic cross-electrophile coupling, a realm we had recently explored and understood well.[4] This familiarity instilled confidence that we could execute it successfully. However, our initial attempt didn’t yield promising results; our NMR showed virtually nothing. It was at this point that Jesus’s background in organometallic chemistry came to our rescue. He suspected the interference of paramagnetic nickel, which was muddling the NMR signals. Indeed, by introducing a slight excess of ligand, we managed to prevent the formation of this nickel species and finally observed the NMR signals essential for quantification.

At this stage, we decided to go all out, exploring an extensive chemical space, incorporating both continuous and discrete variables. To our astonishment, the results were nothing short of spectacular, surpassing our original conditions by substantial yield margins and offering a plethora of unique insights (thank you referee 3! Your suggestion proved one of the most compelling cases we carried out on RoboChem). We once again meticulously isolated the compounds to validate the RoboChem results and submitted a revised version along with a rebuttal addressing all the questions. And then, the waiting game commenced.

While our confidence was high upon submission (we had diligently fulfilled all their requests), with each passing week, our anxiety grew (Had we truly covered everything? Why was it taking so long?). Aidan and Zhenghui kept refreshing the portal incessantly; minor updates appeared, but no email landed in my inbox. Sleep became elusive, as I frequently woke up (considering the 6-hour time difference with the USA, could the email arrive during our night?). Finally, on November 20th, while I was aboard the TGV to Lyon, I opened the long-awaited email from the editor. The news was favorable; referee 3 acknowledged that the new results were indeed compelling, albeit referee 2 had some additional questions. Fortunately, these seemed to revolve around textual changes, sparing us from further experimental work. We invested ample time to address them to the best of our ability and submitted the revised version within two weeks. On December 13th, the ultimate acceptance letter from the editor arrived, and it was an immensely gratifying moment (see Figure 5). While we had anticipated the acceptance by then, receiving the final verdict was still a heartening relief.

Figure 5. The Elation of the Final Acceptance Letter and the Joyous Forward to the RoboChem Team.

Some last remarks…

As we stand here today, a few weeks after the fact, our paper has been published online by Science.[5] The sense of accomplishment still lingers, and our team is tirelessly working on exploiting and expanding the RoboChem platform for new applications. We sincerely hope that you find our paper and the story behind its creation as enjoyable as we do.

While the conclusion is a happy one, the journey to reach this point was marked by numerous ups and downs. We encountered setbacks, moments of stress, and challenges that tested our resolve. By offering you this behind-the-scenes account, we aim to provide you with a genuine glimpse into the genesis of this work and our approach to projects within our research group. It’s crucial to recognize that this success was the result of dedicated individuals, each possessing unique and complementary skills. We embarked on this journey without full foresight of how it would unfold, and it was during the assembly of various components that the platform revealed its true potential.

Tim Noël
Amsterdam, 25/01/2024

[1] Kuijpers K.P.L.; Bottecchia, C.; Cambié, D.; Drummen, K.; Koenig, N. and Noël, T. A fully automated continuous‐flow platform for fluorescence quenching studies and Stern‐Volmer analysis. Angewandte Chemie International Edition 2018, 57(35), 11278-11282 DOI: 10.1002/anie.201805632.

[2] Wan, T.; Wen. Z.; Laudadio, G.; Capaldo, L.; Lammers, R.; Rincón, J. A.; García-Losada, P.; Mateos, C.; Frederick, M. O.; Boroersma, R. and Noël, T. Accelerated and Scalable C(sp3)–H Amination via Decatungstate Photocatalysis Using a Flow Photoreactor Equipped with High-Intensity LEDs. ACS Central Science 2022, 8 (1), 51-56 DOI: 10.1021/acscentsci.1c01109

[3] Slattery, A; Wen, Z; Tenblad, P.; Pintossi, D.; Sanjose-Orduna, J.; den Hartog, T. and Noël, T. An all-in-one multipurpose robotic platform for the self-optimization, intensification and scale-up of photocatalysis in flow. ChemRxiv, 2023, DOI: 10.26434/chemrxiv-2023-r0drq

[4] Luridiana, A.; Mazzarella, D.; Capaldo, L.; Rincón, J. A.; García-Losada, P.; Mateos, C.; Frederick, M. O.; Nuño, M.; Buma, W. J.and Noël, T. The Merger of Benzophenone HAT Photocatalysis and Silyl Radical-Induced XAT Enables Both Nickel-Catalyzed Cross-Electrophile Coupling and 1,2-Dicarbofunctionalization of Olefins. ACS Catalysis 2022, 12 (18), 11216–11225 DOI: 10.1021/acscatal.2c03805

[5] Slattery, A; Wen, Z; Tenblad, P.; Sanjose-Orduna, J.; Pintossi, D.; den Hartog, T. and Noël, T. Automated self-optimization, intensification and scale-up of photocatalysis in flow. Science 2024, DOI: 10.1126/science.adj1817

My personal story to obtain an ERC grant – 7 submissions, 4 interviews and 6 heartbreaks

Every young academic will sooner or later take a shot at applying for an ERC grant. ERC grants are considered to be amongst the most prestigious grants out there. It provides you sufficient funding to establish a high risk/high gain research line. Obtaining one is considered a game changer in your academic career: it is a prestigious award, it greases the wheels for getting tenure and it can even be used as a bargaining chip to secure a position elsewhere.

In this blog article, I aim to give you a -as honestly as my memory allows it- recollection of all the attempts I undertook to obtain an ERC grant in the past decade. I guess most of you will think it has always worked out for me the first time right; well, I can tell you that has rarely been the case. In life like in science, failures are rarely reported (although I always honestly mention it in my personal discussions with colleagues and young academics). However, failures happen frequently to me, as you will read below; my story is far from unique if you ask around. My hope is that this account provides young academics with some more insight into my ERC journey and gives them hope for their own ERC mission.


The Starting Grant

Like many, I was eager to roll the dice and try early on in my independent academic career to apply for the Starting Grant (ERC-2013-StG). I prepared by collecting as many successful proposals as I could get my hands on and trying to discover an underlying structure for what a winning proposal might look like. I brainstormed with colleagues about potential ideas I had, and after a few sessions, I felt confident that I had a bold idea that fit the high risk/high gain category.

I focused for the next few weeks, fervently writing the proposal and I even managed to rope in some colleagues for proofreading duty. Either they were just too nice or didn’t have the heart to say otherwise, but the feedback was unanimous that it was at least good enough to get an interview. Full of confidence, I submitted both B1 and B2 parts and I waited …

A few months later I got an email … from the ERC. Excited and nervous, I opened it and my face immediately dropped: shit … a B grade, indicating that the proposal was of high quality but not sufficient to be invited for an interview. Back then, you still had to wait longer to get the evaluation reports so I couldn’t even tell why it is was deemed “not good enough” (thankfully, that has changed in the meantime and now the decision and the reports are sent together). After a few weeks of waiting, I got the feedback. “The project targets the development and implementation of photo-redox catalysis to be used in microreactors, which is argued to improve the efficiency of the photochemical processes. The ideas are interesting and reasonably well based on state-of-the-art. Unfortunately, the panel finds that the project is described in a rather generic fashion.

OK, I thought, this feedback is actually not so bad. So I’ll try again next year and in the intervening time upgrade the proposal. I worked really hard to get more details in the proposal to avoid the “generic” criticism. After seeking further advice from a growing list of colleagues, I was happy with the upgrades and submitted it online (ERC-2014-StG).

A few months later, the verdict was again negative: another B grade! What the f*** I thought. The feedback left me equally confused: “The proposal clearly reports very clever and very ambitious objectives, with an impact on large range of fields. The proposal is therefore high risk and high gain. However, it does not go beyond the state of the art”. Re-reading this feedback today, it still sounds contradictory: ambitious but does not go beyond the state of the art… huh???

I must admit that the second time, the psychological blow was much harder to take. The amount of time I had invested into this project was significant and the feedback although it seemed kind of good, it clearly wasn’t good enough. It certainly was hard to accept, but at the end of the day what can you do?…

I had a long, fruitful discussion with my colleague (Dr. Martin Timmer, may he rest in peace) about what to do next. Resubmitting seemed like it was not an option and anyway, I was now restricted from submitting for one year (a new ERC rule: a B grade means excluded for one year, a C grade for two). We came to the conclusion that the proposal was good enough and that maybe the problem was that many of the details were in section B2. Which is -no joke- not even read if you do not reach the interview stage (I always felt frustrated about that, especially because it was the longest, most labor-intensive part).

We decided to repackage the proposal and submitted it to VIDI, a personal grant scheme from the Dutch Research Council (€800,000  vs €1,5 M from ERC StG). To my delight, it got great referee feedback and following a good interview the funding was approved on the first try! This process also gave me the confidence that the original ERC proposal was in fact not bad and the ideas were good enough to compete in prestigious grant schemes.

So, after sitting for one year on the ERC sidelines, I had one final chance for an ERC Starting Grant (ERC-2016-STG). Since my previous version was granted by NWO, I had to come up with a new idea and thus rewrite the entire proposal. The idea was to develop a new type of microreactor which could harvest solar energy efficiently to drive photocatalytic transformations. The reactor was made of a light-harvesting and light-guiding material, called luminescent solar concentrator. Once this reactor was developed we also wanted to develop an integrated reactor design, where all equipment (pumps, computers, etc.) were using solar energy as well, and thus could be utilized off-grid. This time we also had some preliminary results which demonstrated the feasibility of the concept.

After submitting the proposal, I got the news from ERC a few months later. Yet again, the news was negative, the result a B; thus no interview and another penalty of a one year-ban from submitting. “The panel found the ideas proposed in the project interesting; however questions were raised about the project neglecting the difficulties in using the solar radiation concentration. The stability of the luminescent solar concentrators under direct sunlight was also considered a critical issue.” This verdict meant that my chances to obtain an ERC starting grant were over…

However, since I was convinced of the strength of this research idea, I doubled down on it and tried to carry it out with other funding sources, which were however, less royal. Together with my PhD student Dario Cambié (MSCA ITN Photo4Future funding), we carried out the ERC idea and everything worked exactly as described in the proposal leading to one of the most successful research lines in my group: the luminescent solar concentrator-based photomicroreactor concept1,2,3.

Once the idea was executed, we had one of the few solar-driven reactors in the world. Funnily enough, due to this unique expertise, we are now asked by various consortia to contribute to their proposals, leading to a substantial amount of funding which has now eclipsed the initial ERC StG budget.


The Consolidator Grant

After failing the ERC StG three times and even not getting a single interview, one could get pretty demotivated. I must admit that I was frustrated, but only for a few hours/days after I received the news. However, as time passes, you get better at putting these things in perspective. As said above, there was always a silver lining: the feedback was not bad, the panel said nice things about my career, I was able to get backup funding via a different grant scheme and the ideas were fine resulting in new cutting-edge research lines. And like I jokingly told my group: I am going to get an ERC, or die trying!

So after my one year penalty was over, I decided to write a new proposal (ERC-2018-COG) for the Consolidator scheme (making it €2 M instead of €1.5 M). The idea was to develop synthetic methods and technology for the photocatalytic modification of peptides and proteins. I thought this idea was reasonable, as my student Cecilia Bottecchia had worked on some interesting methods for peptide modification (up to 20 residues, fully unprotected)4,5,6. She actually helped me a lot with getting the proposal ready in time!

This time, the news that came from Brussels was nicer: I got my first interview! I was really excited and I actually started with my preparations right away: studying the literature, asking colleagues for potential questions, reading books about presentation skills and even following a training from Yellow Research (an organization that specializes in preparing candidates for the interview). Everything I could control, I did and I was ready for the battle!

The day of the presentation I was excited but not nervous. I went to Brussels by train, was a bit too early and just went upstairs to the floor where the interviews were to be held. I even met a friend who was also there for an interview so we chatted and I felt really relaxed. Then it was my turn, I went in and I thought my presentation went pretty smooth: proper pace, well-timed hand movements and perfectly within time. The first questions went really well. I still remember that after 10 min I was really proud and I thought it was in the bag. But then the questions about selectivity issues started and despite my answers, the same question was returned to several times. It seemed that the panel was rushing to ask them and I felt I barely had time to answer the questions properly. The final question was about the fact that I asked for specialized equipment and thus exceeded the budget (FYI, I asked for > 2.6 million, which is allowed if you need something special to carry out the research). When giving my answer, one panel member sighed loudly and said in an annoyed tone “everybody wants more money”. I stayed firm and said I needed it to be able to do the experiments.

You might wonder, how the h*** does he still know those details. Well, on the train back, I wrote in my notebook every single question I received and how I answered it (I even wrote the time I arrived by train, when I went in, etc.). I can really recommend that you do this, it is helpful for analyzing your performance when the final verdict comes in.

And yes, the final verdict came a few weeks later … I still remember that day vividly. I was coming back by car from a seminar in Münster and my phone was not loading any emails while driving. Maybe for the better as the news was negative. I think it was one of the hardest blows in my career. I had to lie down the rest of the day and I was literally in tears. How could it be?, I had done everything right: I worked for months to prepare those 25 minutes (10 minutes speech + 15 minutes questions), even on the beach in summer I was reading papers/books in preparation…

After a day or two being completely down, I once again found my fighting spirit. I knew a person who was in the panel and I contacted him after a week. The information I received was extremely valuable, these panel members can give you a lot of insight in the decision making process and they know the exact reasons why your specific case could not be retained. He also encouraged me to try again and he was even willing to read my proposal.

So the year thereafter, I tried again (ERC-2019-COG): same proposal and all the criticisms were addressed, which was confirmed by that former panel member. And yes, I got another interview. This time, I am ready… I thought. To my surprise, I received the same questions all over again: issues with selectivity… I remember thinking: Did I not fix this, did I not detail that properly this time?

At that stage, I already knew the decision. It was confirmed a few weeks later: again a no… But yet again, I knew one of the panel members so I asked again for personal feedback. This feedback was a game-changer. Two issues were clear to him. Firstly, the selectivity remained an issue and this could only be dealt with by way of proof-of-concept results. Secondly, I am not a specialist of protein modification. There was a doubt that I would be the right candidate to do this work; this criticism was espoused by half of the referees and thus it could not be ignored by the panel even though my past research in general was regarded as strong. For me it was now crystal clear, the first criticism I could potentially be able to fix but I would have difficulties in fixing the second. The latter would take me years to address as I needed to gather both the papers and the credibility in that space. So the only conclusion I could come to was to abandon this proposal for now (currently I am repackaging it and I am trying to get it funded in a consortium with chemical biologists).

I had to write a new proposal which was closer to what we were doing in the group. Maybe it is good to reflect here again. A proposal closer to your expertise seems obvious. However, if you are too close to what you do already, referees might question why the ERC should invest so heavily in something that you already do. From my personal interactions with ERC holders, I often received the feedback that you need to push the boundaries. However, from my own experience, if you push too far, you also do not get funded as it is not seen as credible. So, it’s really a tight balance between high risk/high gain and staying realistic.

We wrote another proposal, called FlowHAT (ERC-2020-COG) aiming to develop synthetic methods and technological tools that would provide a breakthrough in the selective functionalisation of strong carbon–hydrogen (C–H) bonds present in small organic molecules and biologically active molecules. We had some proof of concept results which were published in Science after the submission of the proposal7. So I felt confident the work was definitely high gain-material.

And yes, for the third year in a row, I got an interview. As in the years before, I meticulously prepared every detail of the interview: gathering questions from my team and colleagues, preparing the talk and doing a number of mock defenses. On the interview day itself (which was on zoom due to the Covid pandemic), I felt the presentation went well (which was without slides this time, this felt weird but ok you can prepare for it) and also I felt the defense was pretty good. The questions I got were easy to rebut and my feeling afterwards was extremely positive. I wrote in my notebook: “Panel members were nice to me and very positive about the proposal. I have confidence we will be close to being funded.”

To my shock, it was not funded once again. The feedback was formulated as follows “The panel considers the proposal of high quality and fundable; however it is not in a sufficiently high position in the ranking order to be retained for funding.” I could not disagree more with the final decision, especially because I felt the overall feedback was the most positive I had ever received and maybe we could have been funded with a bit of good-will. To me, the only problem seemed to be that the proposal was “medium-risk/high-gain”, as mentioned by one referee.


ERC CoG – The last chance

I had one final chance to get a consolidator grant (ERC-2021-COG) and after that I would be “too old”. The feedback from the previous year was the best I had ever received and I was wondering what could I still improve? I disagreed that the proposal was medium risk, so why did referees say that? Can I sway the referee opinion in the right direction by making some minor adjustments?

So this is what I did. First, I pushed the risk a bit further. Not too much as I thought we were close to getting funded. Second, I made risk assessment tables for each work package, in those tables I provided for every task: the risk level (low-medium-high), the contingency plan, and the scientific impact. My hope was that I could steer the referee’s opinion in the direction that I had in mind, i.e. a good balance between doable research and high risk/high gain goals.

And yes, I got another interview, which was to be held online on January, 18th 2022. As usual, I wanted to take no risks and I blocked my agenda for the two weeks before the defence. However, the closer we came to the interview date, the more nervous and cranky I became. I guess it was mainly because it was my final chance. In my head, the lines “don’t f*** it up” were on repeat which, of course, did nothing to help the situation.

On the day itself, the presentation went really well; I think it is the one part which one can actually control and therefore I like it. However, this time, I remained nervous. During the questions, which I could answer pretty well, I always had the feeling I had to work hard to get my answers out. Of the four years, this time I couldn’t accurately tell how I had done. I’d had too much bad luck in the past years to feel confident afterwards. In the weeks thereafter, I tried my best not to think about it anymore. I even had a nightmare in which I woke up in the middle of the night bathing in sweat: in my dream, I had again screwed it up.

The final answer came on Wednesday March 9. As Figure 1 shows, nothing can be found in the email itself. You had to login on the portal. And I dared not click on the link… When I did, I had to fill in my password, which of course, I did not remember. So I had to request another one. Time was ticking and my heart was going like crazy.

Figure 1. Email received from the European Commission.

Finally, I got in. And I started reading (Figure 2), I got an A and the proposal was ranked for funding. But I really didn’t like the “if sufficient funds are available” line. What did it mean? Is it now funded or not? The panel comment seemed to be going in the direction of funded: “The panel therefore recommends the proposal to be retained for funding with a grant not exceeding 2,000,000 Euro.” But I was still not sure, so I opened the president letter (Figure 3): it starts with a lot of generic information but then I read “I am pleased to inform you that your proposal was ranked at a sufficiently high position to allow it to be funded.”  I was now sure that it was granted and I let out a scream of pure joy!

Figure 2. Screenshot from the Evaluation Letter

Figure 3. The so-called president letter with the clear message: Proposal funded.



We are now one week after the fantastic news and I still cannot believe it. After 7 submissions, 4 interviews and 6 heartbreaks, I had finally got an ERC proposal funded. It is a story of six downs and one final, glorious up. I am grateful to the many people who helped me in the past years, including my research group members, my colleagues and all those who were prepared to give advice.

I hope that this story might be useful to you too in obtaining a grant, whether it is ERC or something else. My main advice is: never give up and keep trying, you always have a chance to get it. And even if you do not get it first time, or the second, or the xth time… you always learn from the experience and sooner or later you will nail it. Trust me, you will get it!

Good luck!


Timothy Noel, March 17, 2022


(1) Cambié, D.; Zhao, F.; Hessel, V.; Debije, M. G.; Noël, T. A leaf-inspired luminescent solar concentrator for energy-efficient continuous-flow photochemistry. Angewandte Chemie International Edition 2017, 56 (4), 1050-1054 DOI: 10.1002/anie.201611101
(2) Cambie, D.; Dobbelaar, J.; Riente Paiva, P.; Vanderspikken, J.; Shen, C.; Seeberger, P.; Gilmore, K.; Debije, M. and Noël, T. Energy-Efficient Solar Photochemistry with Luminescent Solar Concentrator-Based Photomicroreactors. Angewandte Chemie International Edition 2019, 58 (40), 14374-14378 DOI: 10.1002/anie.201908553
(3) Masson, T. M.; Zondag, S. D. A.: Kuijpers, K. P. L.; Cambié, D.; G. Debije, M. and Noël, T. Development of an off-grid solar-powered autonomous chemical mini-plant for producing fine chemicals. ChemSusChem 2021, 14 (24), 5417-5423 DOI: 10.1002/cssc.202102011
(4) Bottecchia, C.; Rubens, M.; Gunnoo, S.; Hessel, V.; Madder, A.; Noël, T. Visible Light-Mediated Selective Arylation of Cysteine in Batch and Flow. Angewandte Chemie International Edition 2017, 56 (41), 12701-12707, DOI: 10.1002/anie.201706700
(5) Bottecchia, C.; Erdmann, N.; Tijssen, P. M. A.; Milroy, L-G.; Brunsveld, L.; Hessel, V.; Noël, T. Batch and flow synthesis of disulfides by visible light induced TiO2­ photocatalysis. ChemSusChem 2016, 9 (14), 1781-1785 DOI: 10.1002/cssc.201600602
(6) Bottecchia, C.; Wei, X-J.; Kuijpers, K. P. L.; Hessel, V.; Noël, T. Visible light-induced trifluoromethylation and perfluoroalkylation of cysteine residues in batch and continuous flow. Journal of Organic Chemistry 2016, 81 (16), 7301-7307 DOI: 10.1021/acs.joc.6b01031
(7) Laudadio, G.; Deng, Y.; van der Wal, K.; Ravelli, D.; Nuño, M.; Fagnoni, M.; Guthrie, D.; Sun, Y. and Noël, T. C(sp3)–H Functionalizations of Light Hydrocarbons Using Decatungstate Photocatalysis in Flow. Science 2020, 369 (6499), 92-96 DOI: 10.1126/science.abb4688

Leaving Eindhoven University of Technology, Joining University of Amsterdam

I have some very exciting news to share with you: The Noel Research Group will move up North and join the Van ‘t Hoff Institute for Molecular Sciences (HIMS) at the University of Amsterdam, where I will be promoted to Full Professor and be the chair of Flow Chemistry. The move is planned for September 1st of this year, so quite rapidly.

What can you expect from us at UvA? Our mission has always been to extend the available chemical space by embracing technology to the fullest extent. For sure, we will keep doing that using our key technology, flow chemistry! But we would not move if there were no exciting new opportunities. HIMS has a strong hub of homogeneous catalysis with a.o. the groups of Profs. Joost Reek, Bas de Bruin, Tati Fernández-Ibáñez and Francesco Mutti. We foresee some strong interactions with their teams in the years to come. So keep an eye on our website and social media channels.

Via this way, I also would like to thank the colleagues at Eindhoven University of Technology. They gave me the chance to kick start my academic career and supported me all the way, even now with the transfer to Amsterdam. Needless to say that I will miss the colleagues and the great atmosphere in the Chemical Engineering and Chemistry department.

Finally, thank you to everyone for the support and faith that has brought us to this moment.


July 30, 2020

Amsterdam, The Netherlands

Turning on the Light Alkanes: from Fuel to Valuable Reagents

Hot off the press! Our latest work on photochemical activation of light alkanes just appeared in Science ( We are stoked to present our group’s first Science paper to the community. In this blog article, we would like to discuss the human story behind this amazing project.

New project, new challenge

After our first project on the C(sp3)–H oxidation using decatungstate-photocatalysis, published almost two years ago in Angewandte Chemie (, we were looking for a new challenge where we could exploit the potential of this potent hydrogen atom transfer (HAT) catalyst. The NRG-TBADTeam (nickname of the subgroup dedicated to TBADT chemistry) focused its attention to a valuable -yet absent in organic synthesis- class of gasses which could benefit from continuous-flow microreactor technology: the volatile alkanes, such as methane, ethane, propane and butane. These compounds are mostly burned to release its energy for heating applications or propulsion, while in the chemical industry they are used as inexpensive starting materials for the synthesis of haloalkanes or polymer monomers (e.g. ethylene). Hence, we wondered if we could activate these inert and insoluble gasses with TBADT and immediately engage them in synthetically-useful transformations of interest to the organic chemistry community. Such a strategy would allow us to bypass the current toxic halogenation industry.

We commenced our investigations with propane and borrowed a bottle of high purity propane from our TU/e colleague Prof. F. Gallucci. To our delight, we could immediately spot some interesting reactivity. We were particularly delighted by the excellent selectivity provided by decatungstate for the most substituted carbon of propane (86:14 ratio for the instalment of a secondary propyl versus primary propyl moiety). At that point, master student Klaas van der Wal joined the group and together with him the real optimization commenced. Klaas did an amazing job, especially in the design of the flow setup, which was crucial to bring the gaseous reactants into contact with the soluble catalyst and substrates, and the initial reactivity screening. He received a great score for his MSc defense (Figure 1). However, we were not done yet!

Figure 1. TU/e M.Sc. student Klaas in action: left) at the Master thesis presentation and defence; right) graduation ceremony.

Shine brighter

Even if an extensive optimization was already conducted at that point, we managed to run our reactions only in stop-flow mode to reach full conversion. We realized that a more powerful light source was needed to reduce the reaction time. More photons were going to be crucial in order to move to a continuous operation of the flow reactor. For this reason, we decided to employ a Vapourtec setup, which was provided to us by Vapourtec’s CEO Duncan Guthrie and Dr. Manuel Nuño. Thanks to this photochemical flow system equipped with a powerful 365 nm LED set (60 W or 150 W, the latter high power 365 nm light source was even a prototype which proved crucial in our reaction discovery), we could easily move to a continuous-flow mode and complete our last screening.

At that point, Tim asked Yuchao Deng, who was a visiting Chinese PhD student in our lab, to join the TBADTeam. With her hard work and dedication, we were able to rapidly carry out the propane optimization and to identify the substrate scope. During the scope exploration, the input from Profs. Maurizio Fagnoni and Davide Ravelli was of great value to make rapid progress. They have been working with this catalyst for many years and TBADT has essentially no secrets for them anymore.

Next, we evaluated a variety of different alkane gases, starting with isobutane. Activation of isobutane led to a new methodology which allowed to introduce tert-butyl groups in a straightforward and selective fashion (96:4, tert butyl versus isobutyl).

Figure 2. Gabriele and Yuchao working with the Vapourtec setup.

Methane? Yes, we can!

We must acknowledge that at point we were quite satisfied with the results but we were still anxious as two formidable challenges laid ahead of us: the activation of ethane and methane. These alkanes possess the strongest C(sp3)–H bonds known in Nature and we were not sure whether decatungstate would be able to cleave those selectively… Methane for example has been a daunting challenge for many decades, occupying many researchers without much success so far. Cleaving methane’s C(sp3)–H bonds requires extremely high temperatures (> 500 C) and is only industrially done for a few processes.

For ethane, we needed to crank up the pressure a bit to get it into a liquid state. However, overall the activation went pretty smooth and only minor optimization was required to obtain a satisfactory scope.

Finally, we were ready to take on the challenge of methane. If this one would work, we knew it would be a big deal. And … we had probably a good shot to get it into a true top journal. In our first attempts, we could spot the right product only in traces. We realized that the major products obtained were propylated adducts or compounds derived from the activation of acetonitrile. The presence of propylated compounds puzzled us for a while. However, we realized that the gas line might still contain some propane from our previous experiments. Indeed, by applying vacuum on the gas lines, we could remove traces of condensed propane fairly quickly. With propylation being resolved, we saw that the HAT on acetonitrile was still prominent, and only a low yield was observed for the desired methylated product. We then realized that activation of acetonitrile was favoured over the activation of methane. Even if this result could be expected based on BDE, we originally thought that the polarity mismatch of the C-H bonds of acetonitrile would prevent this side reaction. This was indeed the case for butane, propane and ethane but not for the strongest C–H bonds present in methane. To circumvent this, we employed d3-acetonitrile. Once we did that, we finally obtained the desired products in synthetically useful yields. After isolating our first methylated molecule, Yuchao and I were so happy that I cannot even describe it in words. We repeated at least a thousand times “WE DID IT!” jumping all over the lab. Definitely, that was not a quiet day for our labmates.

Hard times, high hopes

When we were wrapping up our experiments, the pandemic crisis was advancing very fast. As an Italian, I was extremely aware of the potential threat of COVID-19. Yuchao was even more scared than I was, especially because her time in the NRG group was almost over and she would not be able to go back to China as her flights got systematically cancelled. Despite the COVID stress, we completed all the necessary experiments. Tim wrote the paper and submitted it to Science on February 26, a couple of weeks before the inevitable lockdown of our group (March 13, 2020). Then we waited, isolated at home.

On April 7, we got news! We received a request to submit a revision, so not rejected. What a relief! After reading the feedback from the referees, we were cautiously optimistic. Yet we were also scared! We felt we could smell our first paper in Science and we did not want to mess it up. After some Zoom calls with all co-authors, we submitted a carefully revised version and waited again, all of us still sheltered in place. On May 6, 2020, we finally got the acceptance letter (Figure 3, Top). As the email came in quite late in Europe, Tim was already sleeping. On May 7 at 6.20 AM, he send me via WhatsApp some very exciting messages (Figure 3, Bottom).

Figure 3. Top: Email with the long awaited final decision. Our first paper in Science is a fact. Bottom: WhatsApp conversation between Tim and myself (Gabriele Laudadio).

We are now July 2nd, almost two months later. The paper just got published in the latest issue of Science. But I still need to pinch myself regularly to know I am not dreaming. I will cherish these memories forever.




The paper discussed in this blog was published as “C(sp3)–H functionalizations of light hydrocarbons using decatungstate photocatalysis in flow”. by Gabriele Laudadio, Yuchao Deng, Klaas van der Wal, Davide Ravelli, Manuel Nuño, Maurizio Fagnoni, Duncan Guthrie, Yuhan Sun, and Timothy Noël, Science 2020, DOI: 10.1126/science.abb4688.

Tim Presented a Commemoration of Prof. Jun-ichi Yoshida’s Work at the Flow Chemistry Europe 2020 in Cambridge

During the Flow Chemistry Europe 2020 (Cambridge), Tim has used his speaker slot to commemorate our colleague and friend Prof. Jun-ichi Yoshida, who passed away on Saturday, September 14, 2019.  He was one of our regional editors at Journal of Flow Chemistry. He also served as the president of the National Institute of Technology Suzuka College and was emeritus professor of Kyoto University. Most of all we will remember Prof. Yoshida for his excellent work in Flow Chemistry. He coined the term “Flash Chemistry” for ultrafast reactions which can be done selectively in microreactors by taking advantage of the fast mixing and the excellent heat control. He also pioneered the so-called “cation pool” method, which allowed to accumulate anodically radical cations at low temperature. These could be subsequently converted in the presence of nucleophiles in a very controlled and reliable fashion.

Generally, one cannot overstate the achievements of Prof. Yoshida in Flow Chemistry. He can rightfully be called one of the pioneers and legends of the field. Many of us, including myself, have found inspiration in his early work and have tried to follow his lead at the outset of our career.

On a personnel level, I always enjoyed talking to Jun-ichi. He was very supportive to young flow chemists. He was very social and loved drinking a good glass of wine or sake.

Prof. Yoshida’s death is a great loss for the scientific community and we will miss him dearly.

The lecture can be downloaded as pdf using the following link: Talk_YoshidaMemorial

Timothy Noël

Flow Chemistry Europe 2020, Cambridge (UK); March 3, 2020

Making Sulfonamides via Electrochemistry by Activating Commodity Chemicals

Our most recent paper dealing with the electrochemical synthesis of sulfonamides was just published in Journal of American Chemical Society (DOI: 10.1021/jacs.9b02266). For our group, it was the first paper in this prestigious journal and we are particularly proud of the work itself. It has been an interesting project which required a lot of hard work by many co-authors and we are happy to take you today behind the scenes and providing you with some insights in the discovery process.

Figure 1. Graphical abstract of our “Sulfonamide synthesis through electrochemical oxidative coupling of amines and thiols”.

In search of inspiration

Our group is mostly known for its work on flow photochemistry but about three years ago, we started getting interested in electrochemistry. For us, electrochemistry seemed like a complementary activation mode compared to photoredox catalysis, both allowing to generate synthetically useful radicals. In addition, electrochemical setups are often affected by process-related problems, like mass- and heat-transfer limitations, which was for us the proof that a technological solution would of great added value.

After our first paper on the electrochemical oxidation of thioethers and thiols,1 we decided to design a new electrochemical flow microreactor to carry out our chemistry in a more reliable and scalable way.2 In the meantime, we started thinking about new electrochemical transformations that we could develop. The group’s aim is to develop new, useful synthetic methodology and utilize cutting-edge technology to give a further boost to the chemistry. At that time, our experience on electrochemistry was still very rudimentary and we were reading a lot of different publications to get a bit an image of the field. Ultimately, we found an amazing review entitled “Nonaromatic Aminium Radicals”.3 After reading this review carefully, we had an idea: what if we try to make sulfenamides electrochemically and then further oxidize these species to make sulfonamides? We had already some expertise with the oxidation of thioethers and if we could combine both the S–N coupling with the subsequent oxidation of the sulfur, we had a great method that allowed us to activate commodity chemicals, such as thiols and amines. Moreover, sulfonamides are interesting moieties which are quite common in pharmaceuticals and agrochemicals. Recently, a couple of interesting methods to prepare or functionalize sulfonamides appeared in the literature, incl. the work of Willis4 and MacMillan.5 Taken all of this information together, we had the feeling that this project would be both challenging and of high interest to the synthetic community.

Figure 2. Original idea for the synthesis of sulfonamides.

A working reaction = A wedding present for Gabriele

At that time, Lisa Struik joined our group for her master thesis. Initially, she worked on the experimental validation of our electrochemical flow reactor.2 When that project was finalized, we suggested her to try this idea we had on the synthesis of sulfonamides. Eager to work on this new project, she started with the experiments. One of the first things she said was the following: “We have a huge problem: the reaction is forming a solid and crashes out in pure acetonitrile. I can NOT carry this out in flow!” Our answer to this was “It is probably just the acid-base adduct, just add a bit of water and it will be fine”. Indeed that solved the issue pretty well and not only that, it really boosted the reactivity significantly. To our delight, the results were almost immediately perfect. You cannot imagine how excited we were when we saw that the major product was not the sulfenamide, but the sulfonamide directly!!! This gave us the confidence to increase our research efforts: We started right away with the further optimization and got some help from Christiane Schotten. Christiane was a visiting PhD student coming from the Browne group at Cardiff University and she helped us to test different reaction conditions, residence times, mediators and acids.

Once we had the optimal reaction conditions in hand, Christiane and Lisa started working on the substrate scope. Gabriele had to take a short break at that point as he got married and went on honeymoon on a cruise. Gabriele still remembers that every time they went on land he was anxious to check his emails to know if there was any progress. Upon his return, we had to say goodbye to Christiane and Lisa and for a while, Gabriele had to work alone on the scope. Luckily, Efstathios Barmpoutsis (AKA Stathis), another master student, joined the project, rolled up his sleeves and got immediately to work. It was at that point that we realized how crucial it was to clean the electrodes thoroughly in between reactions. If you don’t do that, yields drop gradually and the results are difficult to reproduce. However, with the proper cleaning, as we described in detail in the Supporting Information of our manuscript, this issue is completely overcome and highly reproducible results are obtained. A little bit later another issue arose: heterocyclic arenes were completely unreactive under our reaction conditions (Figure 3). After some optimization of the reaction conditions, we found that the reaction could be carried out when 1 equiv. of pyridine was added to the reaction mixture. We surmise that pyridine functions mainly as an electron mediator. To be sure, we also evaluated whether its presence was required in the other reactions we already screened but there it did not prove to be essential.

Figure 3. Optimization of heteroaromatic compounds

While Stathis and Gabriele were working on the reaction scope, an Erasmus student Sebastian Govaerts joined the team. (Basically, he returned to our group as he previously worked with Gabriele on the sp3 C–H oxidation project.6) He focused mainly on the batch scope as we wanted a thorough comparison with the results obtained in flow. In most cases, the yields were lower in batch and the reaction required 24 h and 100 mol% of supporting electrolyte to reach full conversion. In flow, the reaction was done within 5 min and needed only 10 mol% of supporting electrolyte. However, batch does have its advantages. For those reactions that were very slow or resulted in precipitate formation, we preferred the batch procedure.


Figure 4. (Left) Electrochemical batch reactor; (Right) Electrochemical flow reactor

With the finish line in sight – What is the mechanism?

Within sight of the finish line, it was time to gain some mechanistic understanding. Kinetic experiments revealed that the thiol dimerizes within 20 seconds to the corresponding disulfide. This observation indicates that some of the most odorous thiols can be replaced by their corresponding disulfide, a feature most chemists will be happy about. Next, Gabriele started with some quenching experiments and he was able to rapidly trap the aminium radical. With that preliminary result in hand, we were almost sure that the sulfenamide was one of the intermediates in our transformation. Indeed, we were able to isolate some sulfenamide and when subjected to our reaction conditions, the targeted sulfonamide was obtained in quantitative yield.

Finally, we had to do some cyclic voltammetry. Using a potentiostat, Gabriele recorded spectra of all relevant starting materials, including amines, thiols and disulfides. Despite some hints, it proved to be not enough evidence to pinpoint the entire mechanism. Then he decided to “titrate” thiophenol with cyclohexylamine and recorded different spectra. We firmly believe in the famous Latin maxim “Fortuna audaces iuvat”, which means literally “fortune favours the bold”. Indeed, at a certain moment, we found some white precipitate in the cell. It was a Friday evening, around 8 pm. Gabriele filtered the precipitate and ran to the NMR: indeed, it was the cyclohexylammonium thiophenolate (Figure 5), as was also observed by Lisa. And, when we tried to record the cyclic voltammogram of that compound, we knew that we had finally found the missing piece (Figure 6). We still carried out some additional control experiments to be 100% sure (you can find them in the supporting information of the paper) but from that moment on we knew the work in the lab was basically done.

Figure 5. Picture of the white solid and its 1H NMR spectrum

Figure 6. CV of cyclohexylammonium thiophenolate

A final word

The possibility to obtain complex moieties, such as sulfonamides, simply by stitching two commodity chemicals together using electrons is, in our opinion, a key feature of our electrochemical methodology. Moreover, we saw that microflow technology really made a difference in this transformation providing the experimentalist with practical reaction conditions and operational flexibility to rapidly investigate the reaction scope. This can be attributed to the small interelectrode gap (250 μm), the high mass transfer to the electrodes and the large electrode surface to volume ratio.

Currently, we are working hard to finish some more electrochemical methods of which we are really excited. So stay tuned and keep an eye on our group website and twitter accounts.


Gabriele and Tim

The paper discussed in this blog was published as “Sulfonamide synthesis through electrochemical oxidative coupling of amines and thiols”. by Gabriele Laudadio, Efstathios Barmpoutsis, Christiane Schotten, Lisa Struik, Sebastian Govaerts, Duncan L. Browne, and Timothy Noël, Journal of American Chemical Society 2019, DOI: 10.1021/jacs.9b02266


[1] Laudadio, G.; Straathof, N. J. W.; Lanting, M. D.; Knoops, B.; Hessel, V.; Noël, T. Green Chem. 2017, 19 (17), 4061–4066.

[2] Laudadio, G.; de Smet, W.; Struik, L.; Cao, Y.; Noël, T. J. Flow Chem. 2018, 8 (3–4), 157–165.

[3] Chow, Y. L.; Danen, W. C.; Nelsen, S. F.; Rosenblatt, D. H. Chem. Rev. 1978, 78 (3), 243–274.

[4] Chen, Y.; Murray, P. R. D.; Davies, A. T.; Willis, M. C. J. Am. Chem. Soc. 2018, 140, 8781-8787.

[5] Kim, T.; McCarver, S. J.; Lee, C.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2018, 57, 3488-3492.

[6] Laudadio, G.; Govaerts, S.; Wang, Y.; Ravelli, D.; Koolman, H. F.; Fagnoni, M.; Djuric, S. W.; Noël, T. Angew. Chem. Int. Ed. 2018, 57, 4078-4082.