Periodic Reporting for period 1 - FlowHAT (Site-selective C(sp3)–H functionalization with gaseous reagents using Hydrogen Atom Transfer photocatalysis in flow)
Reporting period: 2022-09-01 to 2025-02-28
The aim of FlowHAT is to develop novel synthetic approaches based on a continuous-flow photocatalytic Hydrogen Atom Transfer (HAT) that uses cheap decatungstate or other HAT photocatalysts to activate C(sp3)–H bonds selectively. The approach should enable the functionalization of strong C(sp3)–H bonds in both gaseous alkanes and biologically active molecules and solve important chemical and technological issues (i.e. reproducibility, generality and applicability) associated with it.
At the mid-term reporting period, the implementation of the project is successful and globally on time.
1. New synthetic methodologies based on activation of volatile alkanes (WPs 1-2)
During the FlowHAT project, we have developed and investigated four impactful transformations that demonstrate the utility of flow technology in enabling challenging chemical reactions, particularly involving gaseous reagents and photocatalysis.:
A) Carbonylation chemistry using gaseous CO: We established a general, mild, and scalable protocol for the direct C(sp3)–H carbonylation of saturated hydrocarbons, including natural products and light alkanes. This transformation employs photocatalytic hydrogen atom transfer (HAT) combined with gaseous carbon monoxide (CO). Flow technology proved essential to achieve high gas-liquid mass transfer rates and fast reaction kinetics, thereby overcoming deleterious side reactions.
B) Sulfinylation chemistry using gaseous SO2: We developed a practical and efficient method that utilizes HAT photocatalysis to activate volatile alkanes. The resulting nucleophilic radicals react with sulfur dioxide (SO2) to produce sulfinates, versatile intermediates for synthesizing sulfur-containing compounds (e.g. sulfones, sulfonamides, and sulfonate esters). Flow technology provided a robust, scalable, and safe platform for activating these challenging gaseous alkanes and transforming them into valuable sulfinates.
C) Arylation using metallaphotoredox reaction conditions: We achieved the previously elusive coupling between gaseous alkanes and (hetero)aryl bromides by combining HAT photocatalysis with nickel-catalyzed cross-coupling at room temperature. Flow technology enabled reduced reaction times and a scalable process, enhancing the practicality of this novel coupling reaction for both academia and industry.
2. Generation of gaseous reagents on demand (related to WPs 1-2)
During the execution of this ERC CoG research, it became evident that many gaseous reagents are extremely valuable for synthetic organic chemistry. However, their procurement is often challenging, particularly when only small quantities are required. To address this limitation, we developed a generator concept capable of producing these reagents on demand from bulk chemicals. This approach democratizes the use of such gases by enabling safe and controlled generation in precise quantities.
So far, we have established three impactful approaches:
A. Generation of sulfuryl fluoride: SuFEx click chemistry has emerged as a powerful tool for rapidly and efficiently linking chemical structures. Despite significant advancements, installing the critical -SO2F handle remains challenging due to reliance on expensive, non-atom-economical reagents. The use of SO2F2, the most obvious reagent, has been hindered by difficulties in handling its toxicity and its perceived low reactivity with amino functionalities. We developed a modular flow platform capable of generating SO2F2 on demand and safely dosing it into reactions.
(ii) High reactivity and an exceptional reaction scope. The platform’s effectiveness was demonstrated through the synthesis of a diverse array of fluorosulfates and sulfamoyl fluorides, including those derived from biorelevant compounds, peptides, and proteins.
B. Generation of thionyl fluoride: We developed a strategy for generating thionyl fluoride (SOF2) from the commodity chemicals thionyl chloride (SOCl2) and potassium fluoride (KF). This process employs a microfluidic device that efficiently produces and doses this toxic gaseous reagent under extremely mild and safe conditions. The in situ generated thionyl fluoride was successfully reacted with a wide range of structurally and electronically diverse carboxylic acids, leading to the direct synthesis of highly desirable acyl fluorides.
C. Generation of trifluoromethyl-heteroatom anions: The trifluoromethyl group (CF₃) is a crucial functionality in pharmaceutical and agrochemical development, significantly enhancing the efficacy and properties of target compounds. We developed a modular flow platform that enables the streamlined synthesis of heteroatom-CF₃ motifs. This strategy eliminates the need for perfluoroalkyl precursor reagents, offering a safer and more environmentally friendly approach to the synthesis of trifluoromethyl(heteroatom)-containing molecules. Additionally, the platform’s inherent scalability makes it suitable for manufacturing processes facilitated by flow technology.
4. Development of an Accelerated reaction optimization platform (WP3)
In this work, we introduced a versatile, all-in-one robotic platform for the autonomous optimization, intensification, and scaling-up of photocatalytic reactions in flow, which we coined RoboChem. The system's capabilities were validated through a series of challenging photocatalytic transformations (including Hydrogen Atom Transfer photocatalysis). Additionally, the platform was tested on previously reported flow-optimized reactions from the literature, where it delivered substantial improvements in both yield and space-time yield.
1. New synthetic methodologies based on activation of volatile alkanes (WPs 1-2)
During the FlowHAT project, we have developed and investigated four impactful transformations that demonstrate the utility of flow technology in enabling challenging chemical reactions, particularly involving gaseous reagents and photocatalysis.:
A) Carbonylation chemistry using gaseous CO: We established a general, mild, and scalable protocol for the direct C(sp3)–H carbonylation of saturated hydrocarbons, including natural products and light alkanes. This transformation employs photocatalytic hydrogen atom transfer (HAT) combined with gaseous carbon monoxide (CO). Flow technology proved essential to achieve high gas-liquid mass transfer rates and fast reaction kinetics, thereby overcoming deleterious side reactions.
B) Sulfinylation chemistry using gaseous SO2: We developed a practical and efficient method that utilizes HAT photocatalysis to activate volatile alkanes. The resulting nucleophilic radicals react with sulfur dioxide (SO2) to produce sulfinates, versatile intermediates for synthesizing sulfur-containing compounds (e.g. sulfones, sulfonamides, and sulfonate esters). Flow technology provided a robust, scalable, and safe platform for activating these challenging gaseous alkanes and transforming them into valuable sulfinates.
C) Arylation using metallaphotoredox reaction conditions: We achieved the previously elusive coupling between gaseous alkanes and (hetero)aryl bromides by combining HAT photocatalysis with nickel-catalyzed cross-coupling at room temperature. Flow technology enabled reduced reaction times and a scalable process, enhancing the practicality of this novel coupling reaction for both academia and industry.
2. Generation of gaseous reagents on demand (related to WPs 1-2)
During the execution of this ERC CoG research, it became evident that many gaseous reagents are extremely valuable for synthetic organic chemistry. However, their procurement is often challenging, particularly when only small quantities are required. To address this limitation, we developed a generator concept capable of producing these reagents on demand from bulk chemicals. This approach democratizes the use of such gases by enabling safe and controlled generation in precise quantities.
So far, we have established three impactful approaches:
A. Generation of sulfuryl fluoride: SuFEx click chemistry has emerged as a powerful tool for rapidly and efficiently linking chemical structures. Despite significant advancements, installing the critical -SO2F handle remains challenging due to reliance on expensive, non-atom-economical reagents. The use of SO2F2, the most obvious reagent, has been hindered by difficulties in handling its toxicity and its perceived low reactivity with amino functionalities. We developed a modular flow platform capable of generating SO2F2 on demand and safely dosing it into reactions.
(ii) High reactivity and an exceptional reaction scope. The platform’s effectiveness was demonstrated through the synthesis of a diverse array of fluorosulfates and sulfamoyl fluorides, including those derived from biorelevant compounds, peptides, and proteins.
B. Generation of thionyl fluoride: We developed a strategy for generating thionyl fluoride (SOF2) from the commodity chemicals thionyl chloride (SOCl2) and potassium fluoride (KF). This process employs a microfluidic device that efficiently produces and doses this toxic gaseous reagent under extremely mild and safe conditions. The in situ generated thionyl fluoride was successfully reacted with a wide range of structurally and electronically diverse carboxylic acids, leading to the direct synthesis of highly desirable acyl fluorides.
C. Generation of trifluoromethyl-heteroatom anions: The trifluoromethyl group (CF₃) is a crucial functionality in pharmaceutical and agrochemical development, significantly enhancing the efficacy and properties of target compounds. We developed a modular flow platform that enables the streamlined synthesis of heteroatom-CF₃ motifs. This strategy eliminates the need for perfluoroalkyl precursor reagents, offering a safer and more environmentally friendly approach to the synthesis of trifluoromethyl(heteroatom)-containing molecules. Additionally, the platform’s inherent scalability makes it suitable for manufacturing processes facilitated by flow technology.
4. Development of an Accelerated reaction optimization platform (WP3)
In this work, we introduced a versatile, all-in-one robotic platform for the autonomous optimization, intensification, and scaling-up of photocatalytic reactions in flow, which we coined RoboChem. The system's capabilities were validated through a series of challenging photocatalytic transformations (including Hydrogen Atom Transfer photocatalysis). Additionally, the platform was tested on previously reported flow-optimized reactions from the literature, where it delivered substantial improvements in both yield and space-time yield.
Several of the significant achievements in this project represent breakthroughs that advance the field of synthetic organic chemistry well beyond the current state-of-the-art.
1. RoboChem and Self-Driving Labs (SDLs): The development of RoboChem marks a transformative breakthrough, fulfilling a longstanding goal of automating and optimizing complex chemical processes. By leveraging machine learning, flow technology, and automation, this work surpasses expert chemists in reaction optimization. The platform’s ability to autonomously generate clean, structured datasets positions it as a game-changer for reaction discovery and data-driven predictive chemistry. While the initial outcomes were anticipated, the exceptional success of RoboChem and the subsequent interest from industry and policymakers exceeded expectations, underscoring its societal and practical impact.
2. Safe On-Demand Generation of Gaseous Reagents: The work on SuFEx chemistry and trifluoromethyl-heteroatom anions showcases how flow technology can unlock the safe and efficient use of hazardous yet valuable reagents. The ability to bypass PFAS-based reagents and generate SO2F2 and CF₃N anions on demand is a clear advancement with significant implications for sustainability and safety in synthetic chemistry. This approach was further validated through industrial collaborations (e.g. AstraZeneca), demonstrating both unexpected practical versatility and real-world applicability.
3. Activation of Volatile Alkanes: Our work on the photocatalytic activation of volatile alkanes addresses what has been considered one of the biggest challenges in synthetic organic chemistry. By combining decatungstate photocatalysis with flow technology, we achieved transformations at room temperature that were previously inaccessible.
1. RoboChem and Self-Driving Labs (SDLs): The development of RoboChem marks a transformative breakthrough, fulfilling a longstanding goal of automating and optimizing complex chemical processes. By leveraging machine learning, flow technology, and automation, this work surpasses expert chemists in reaction optimization. The platform’s ability to autonomously generate clean, structured datasets positions it as a game-changer for reaction discovery and data-driven predictive chemistry. While the initial outcomes were anticipated, the exceptional success of RoboChem and the subsequent interest from industry and policymakers exceeded expectations, underscoring its societal and practical impact.
2. Safe On-Demand Generation of Gaseous Reagents: The work on SuFEx chemistry and trifluoromethyl-heteroatom anions showcases how flow technology can unlock the safe and efficient use of hazardous yet valuable reagents. The ability to bypass PFAS-based reagents and generate SO2F2 and CF₃N anions on demand is a clear advancement with significant implications for sustainability and safety in synthetic chemistry. This approach was further validated through industrial collaborations (e.g. AstraZeneca), demonstrating both unexpected practical versatility and real-world applicability.
3. Activation of Volatile Alkanes: Our work on the photocatalytic activation of volatile alkanes addresses what has been considered one of the biggest challenges in synthetic organic chemistry. By combining decatungstate photocatalysis with flow technology, we achieved transformations at room temperature that were previously inaccessible.