Date: 23 May 2025 | Category: News
Authors: José L. Nova-Fernández, Martín Fañanás-Mastral*
José L. Nova-Fernández and Martín Fañanás-Mastral from Ciqus – Universidad de Santiago de Compostela have recently used the Vapourtec R-Series flow chemistry system equipped with the UV-150 photoreactor with great success, achieving photocatalytic hydroalkylation of trifluoromethyl alkenes with both isobutane and n-butane in good yields with excellent regioisomeric selectivity (Figure 1) [1].
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Figure 1: Selected scope of the photocatalytic hydroalkylation reaction. Regioisomeric ratios in parentheses
Photochemistry with light alkanes
The conversion of light alkanes into value-added products is attracting significant interest within the scientific community, as exploiting these abundant feedstock chemicals avoids the use of pre-functionalised alkylating agents, meaning the reaction is highly atom efficient and sustainable. However, carrying out these reactions is non-trivial, due to difficulties in handling the gaseous alkane reagents, and their inertness characterised by high C–H bond dissociation energies and low solubilities in many organic solvents. Selectivity issues can also pose a challenge, as numerous, more reactive C–H bonds are often present in the reagents, products or even the solvent, leading to the activation of undesired bonds and competing side-reactions.
“Flowtochemistry” of light alkanes using HAT catalysis
In recent years, photoinduced hydrogen atom transfer (HAT) catalysis has emerged as a highly efficient approach for the activation of unsaturated alkanes under mild reaction conditions [2]. In particular, the functionalisation of gaseous alkanes has been achieved [3], leading to Giese-type additions to activated alkenes, sulfinylation reactions and (hetero)arylation under dual metal/photoredox catalysis [1].
In this context, flow chemistry is a highly useful and versatile tool in organic synthesis – it offers better mass and heat transfer, more efficient mixing, and significant safety advantages [4]. It is a particularly useful strategy when employing gaseous reagents, as the use of back-pressure regulators force short-chain alkanes into solution by virtue of pressure.
Combining technologies in a synergistic “flowtochemistry” approach with the addition of the UV-150 photochemical reactor, allows for efficient irradiation of the reaction mixture at a range of wavelengths, as well as the option to adjust the power, with fine-tuning of the flow-rate a convenient tool for amending the residence time and limiting the occurrence of undesired side-reactions.
Photochemistry as a tool for late-stage functionalisation of scaffolds
In this work, sodium decatungstate (NaDT) was employed as the HAT photocatalyst, with acetonitrile as the solvent at room temperature and residence times as low as 4 minutes. The reaction set up is shown in Figure 2. Both n-butane and isobutane could be coupled with either carbocyclic or N-heteroaromatic trifluoromethyl alkenes with excellent regioselectivity for the most substituted carbon in the alkane in both cases. With substrates bearing aryl rings or a pyrimidine core, the addition of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) was successfully added to limit competing β-fluoride elimination [5]. Pleasingly, a range of pharmaceutically relevant functional groups were well tolerated, including esters, nitriles, halides, sulfones and sulfonamides. Finally, the reaction was scaled up to 1 mmol with a 73% yield and no loss in selectivity, further highlighting the capabilities of the flow set-up.
Figure 2a: Detailed image of Vapourtec’s UV-150 photoreactor during the reaction
Figure 2b: Detailed image of the gas-liquid mixture at the beginning of the reaction. Flow chemistry: providing practical advantages when using gaseous reagents
In summary, the Vapourtec R-Series equipped with the UV-150 photochemical reactor enabled the development of an efficient protocol for the hydroalkylation of electron-deficient trifluoromethyl alkenes with gaseous alkanes using HAT photocatalysis in flow. Flow chemistry offered key advantages in this case, with the use of back-pressure regulators enabling both isobutane and n-butane to dissolve in the reaction solvent, providing significant practical advantage over the batch process in terms of reaction safety and efficacy, especially for larger scale applications.
References:
[1] Photocatalytic Hydroalkylation of Trifluoromethyl Alkenes with Gaseous Alkanes in Flow (J. L Nova-Fernández, M. Fañanás-Mastral, Synlett, 2025, ASAP). https://doi.org/10.1055/a-2603-8442
[2] (a) Homogeneous catalytic C(sp3)–H functionalization of gaseous alkanes. (A. Pulcinella, D. Mazzarella, T. Noël, Chem. Commun. 2021, 57, 9956). https://doi.org/10.1039/D1CC04073A; (b) Light-Promoted Organic Transformations Utilizing Carbon-Based Gas Molecules as Feedstocks. (B. Cai, H. W. Cheo, T. Liu, J. Wu, Angew. Chem. Int. Ed. 2021, 60, 18950). https://doi.org/10.1002/anie.202010710
[3] Light-Promoted Organic Transformations Utilizing Carbon-Based Gas Molecules as Feedstocks. (B. Cai, H. W. Cheo, T. Liu, J. Wu, Angew. Chem. Int. Ed. 2021, 60, 18950). https://doi.org/10.1002/anie.202010710
[4] Flow Chemistry Enabling Efficient Synthesis. (J.Naber, C. Kappe, J.Pesti, Org. Process Res. Dev. 2020, 24, 1779). https://doi.org/10.1021/acs.oprd.0c00406
[5] Chemodivergent alkylation of trifluoromethyl alkenes via photocatalytic coupling with alkanes. (P. Martínez-Balart, Á. Velasco-Rubio, S. Barbeira-Arán, H. Jiménez-Cristóbal, M. Fañanás-Mastral, Green Chem. 2024, 26, 11196). https://doi.org/10.1039/D4GC04176C
Learn more about the R-Series flow chemistry system