What is electrochemistry?
Electrochemistry is primarily concerned with the use of an electrode to effect chemical reactions, with single electron transfer processes initiated at the surface of the electrode dominating any reaction pathways [1]. Although electrochemistry has been known to chemists for nearly 200 years, there has been an apathy toward use within mainstream organic chemistry that has been attributed to the lack of electrochemistry within undergraduate education, lack of resources for cell assembly, the high cost of electrodes and the limited number of reactions reported in the literature [2].
Scheme 1: General overview of an electrochemical reaction showing mass transfer from the bulk solvent to the electrode surface.
However, electrochemistry has recently witnessed a renaissance within organic chemistry due to the ability to perform reactions only using electrons, the possibility of deriving electricity from renewable sources and the development of readily-available electrochemical equipment, particularly in relation to flow chemistry. It should be noted that electrochemical reactions are considered mild as they can often be completed at ambient temperature and can be controlled, with reaction selectivity adjusted by nature of the electrode, the potential at the working electrode, and the nature of the electrolyte [2].
Key considerations
Electrochemical reactions can be thought of as being heterogeneous reactions, where substrates and electrons need to be transferred from the bulk solution to the electrode surface. A typical mechanism involves mass transfer of a substate from the bulk solution to the electrode surface, electron transfer, and then mass transfer of the product back into the bulk solution. The reaction rate relies upon either the rate of transfer of electrons or the mass transfer to the electrode surface [1]. An electrochemical reactor can be easily inserted into a continuous flow chemistry set-up, with heating and cooling both available, as well as a range of electrode materials.
Continuous electrochemical reactions
Electrosynthesis is performed by passing an electric current through a reagent solution, causing oxidation and reduction of organic molecules by the addition or removal of electrons. Electrosynthesis in continuous flow has a number of advantages: It is possible to generate reactive species without the need for hazardous oxidising and reducing agents; reactions are often highly selective and electrochemical reactions can be carried out using mild conditions. Electrochemistry defines the electron energy directly via over-potential, helping to avoid the formation of undesired by-products. By the principles of ‘Green Chemistry, electrochemistry has a high atom economy and low waste.
Electrochemistry is not a routine technique for the organic chemistry lab. This is because equipment has never been in an easy-to-use format and because batch electrosynthesis requires high concentrations of electrolytes. During the past 10 years, there has been increased interest in electrochemistry generated by the drive toward green, atom-efficient chemistry. Integrating electrochemistry with continuous flow offers a powerful combination. The requirement for electrolytes can be eliminated and reactions have improved selectivity as the reaction products are removed from the reactor and are not allowed to mix with unreacted starting materials.
Continuous flow electrochemistry in detail
As noted above, an electrochemical reaction requires transfer of the substrate from the bulk to the electrode surface either through diffusion or migration. Flow chemistry and microfluidics are perfectly placed to exploit this. In a microreactor, mass transport is largely dominated by diffusion, and because microreactors, by their very nature, contain small channels, electrochemical reactions can happen more quickly than when compared to a larger batch reaction [1]. In addition, temperature (or pressure) build-up caused by electrical current running through the solution (Joule heating) can be controlled due to the excellent heat transfer characteristics of a flow system, leading to improved selectivity, a lower likelihood of unwanted side-reactions and better reproducibility [2].
Examples of electrochemistry in continuous flow
Several uses of electrochemistry in continuous flow will be outlined, and reviews by Noël [1, 3] and Lam [2] provide an excellent overview of the field.
Selective C–H oxidation
Monoxidation of benzylic C(sp3)–H bonds using continuous flow reactors was achieved by Xu and co-workers, with a broad range of substrates and exceptional selectivity observed, alongside short reaction times and no over-oxidation, Scheme 2 [4]. Primary, secondary and tertiary alcohols were rapidly prepared, and in one example, 147 g of Celestolide was passed through twenty parallel flow cells over 4 h, resulting in 115 g (74%) yield of the desired secondary alcohol. The reaction also had high site-selectivity in substrates with multiple benzylic centres, favouring the most electron rich and sterically accessible sites.
Scheme 2: Selective C–H oxidation of C(sp3)–H bonds was achieved using an electrochemical flow reactor.
Electrochemical fluorination
Fluorination is an extremely powerful tool, particularly within medicinal chemistry where addition of a fluorine atom can increase lipophilicity, improve membrane permeability, address metabolism issues and improve a drug’s therapeutic properties. However, the fluorinating agents used can be costly, may require use of fluorine gas and have significant toxicity limiting their scale. Using flow electrolysis, in situ generation of unstable (difluoroiodo)toluene from 4-iodotoluene led to a range of fluorination reactions including fluorocyclisation of N-allylcarboxamides, vicinal difluorination of alkenes, fluorocyclisation of carboxylic acids and ring contraction [5]. In addition, reaction yields were improved using flow, and in some cases products that could not be synthesised using batch were readily accessible, Scheme 3.
Scheme 3: Fluorination of substrates using hypervalent iodine mediators using flow chemistry.
N-Nitrosation of Secondary Amines
Generation of N-nitrosyl compounds from secondary amines with sodium nitrite was achieved in flow at ambient temperatures without the need for toxic nitrosating agents by Wirth and co-workers [6]. In some cases, flash column chromatography could be avoided and an in-line acidic work-up protocol using a liquid-liquid extractor was used, Scheme 4. A diverse range of N-nitrosamines was prepared, which can be converted into other useful functionalities such as diazo compounds, hydrazines and N-nitramines, as well as their use in some industries as nitric oxide (NO) donors.
Scheme 4: N-nitrosylation of secondary amines using flow electrochemistry.
Photoelectrochemistry
In recent years, the combination of photoredox catalysis and electrochemistry has seen great activity, which might be attributable to the development of flow chemistry and the advantages offered by this set-up. Although they are often compared, there are key differences in the activation modes and the way that electron transfer occurs. Within electrochemistry, single electron transfer (SET) occurs at the electrode surface with the applied voltage tuned using a potentiostat. Photocatalysis uses photons as the energy carrier, leading to an excited state that can engage with SET-processes with other organic molecules [7]. In addition, photoelectrochemistry can expand the window of redox tranformations available and decrease the waste of additional redox reagents and photocatalysts. In particular, the combination of photochemistry and electrochemistry in flow can facilitate the technological challenges to allow for consistent reaction illumination and electron delivery.
References
[1] The Fundamentals Behind the Use of Flow Reactors in Electrochemistry (T. Noël, Y. Cao and G. Laudadio, Acc. Chem. Res., 2019, 52, 2858 – 2869) https://doi.org/10.1021/acs.accounts.9b00412
[2] Bridging Lab and Industry with Flow Electrochemistry (N. Tanbouza, T. Ollevier and K. Lam, iScience, 2020, 23, 101720) https://doi.org/10.1016/j.isci.2020.101720
[3] A field guide to flow chemistry for synthetic organic chemists (L. Capaldo, Z. Wen and T. Noël, Chem. Sci., 2023, 14, 4230 – 4247) https://doi.org/10.1039/d3sc00992k
[4] Continuous Flow Electrochemistry Enables Practical and Site-Selective C–H Oxidation (T.-S. Chen, H. Long, Y. Gao and H.-C. Xu, Angew. Chem. Int. Ed., 2023, 62, e202310138) https://doi.org/10.1002/anie.202310138
[5] Flow electrochemistry: a safe tool for fluorine chemistry (B. Winterson, T. Rennigholtz and T. Wirth, Chem. Sci., 2021, 12, 9053 – 9059) https://doi.org/10.1039/d1sc02123k
[6] Flow Electrochemistry for the N-Nitrosation of Secondary Amines (R. Ali, R. Babaahmadi, M. Didsbury, R. Stephens, R. L. Melen and T. Wirth, Chem. Eur. J., 2023, 29, e202300957) https://doi.org/10.1002/chem.202300957
[7] Technological Innovations in Photochemistry for Organic Synthesis: Flow Chemistry, High-Throughput Experimentation, Scale-up, and Photoelectrochemistry (L. Buglioni, F. Raymenants, A. Slattery, S. D. A. Zondag and T. Noël, Chem. Rev., 2022, 122, 2752 – 2906) https://doi.org/10.1021/acs.chemrev.1c00332
