Electrochemistry in Microreactors - Homogeneous Reactions II: Photochemistry and Electrochemistry and Radiopharmaceutical Synthesis - Microreactors in Organic Chemistry and Catalysis, Second Edition (2013)

Microreactors in Organic Chemistry and Catalysis, Second Edition (2013)

6. Homogeneous Reactions II: Photochemistry and Electrochemistry and Radiopharmaceutical Synthesis

6.2. Electrochemistry in Microreactors

Electroorganic synthesis also represents an efficient and “green” tool for the formation of complex molecular structures. The use of techniques has however been somewhat limited to small-scale syntheses because of the difficulties again associated with successful scale-up. Using microreactors, several groups have started to address the physical problems that have limited application of this technology, namely an inhomogeneous electric field and energy loss due to Joule heating; with the overall aim being to develop the technology to a stage that it can be used for production of chemicals. One of the most important aspects of electrochemical flow chemistry is efficient incorporation of electrodes into the reactors, an area that numerous authors have investigated with techniques ranging from plate electrodes [17] to micro-imprinted electrodes [18] or grooved electrodes [19].

Of the reactions studied, oxidations represent the most widely investigated, with early examples by Suga et al. [20] demonstrating the potential of the technique dubbed “cation flow” for the formation of CߝC bonds (Figure 6.1). As an example, methyl pyridinecarboxylate (21) in DCM (0.05 M), along with the supporting electrolyte, was passed through the electrochemical cell to generate the cationic intermediate (22) in situ, which could then be reacted with a wide variety of nucleophiles to afford the substituted pyridinecarboxylate (23) in typical yields of 50–70%.

Figure 6.1 Illustration of the reactor configuration used for the electrochemical generation of cations under continuous flow.


More recently, Yoshida and coworkers [21] have demonstrated the [4 + 2] cycloaddition of a series of N-acyl iminium ions derived from α-silyl carbamates, with the authors identifying the ability to react the cations (24) with a series of styrene-based dienophiles (25) (Scheme 6.9) to afford heterocycles (26) in high yield, without the formation of the polymeric products obtained in batch.

Scheme 6.9 Synthesis of [4 + 2] adducts under continuous flow.


In addition to those examples utilizing electrolytes, a series of examples have featured in the literature where reactions have been performed in the absence of added electrolytes [22–24]. One such example was the electrochemical reduction of 4-nitrobenzyl bromide (27) to afford the coupled product 1,2-bis(4-nitrophenyl)ethane (28) (Scheme 6.10) in 92% conversion with only 6% competing dehalogenation [25]. In an extension to this, the authors investigated the reductive coupling of benzyl bromide with a series of olefins to afford the CߝC coupling products in high yield and excellent selectivity [26].

Scheme 6.10 Electrochemical reduction of 4-nitrobenzyl bromide in a microreactor.


Hypervalent iodine reagents can be used in organic synthesis as mild, nontoxic, and highly selective reagents. However, their synthesis is not trivial and this most commonly involves a two-step synthesis protocol. Wirth [27] has reported a simple one-step synthesis within an electrochemical microreactor. Reaction of a variety of iodoarenes (29) with substituted benzene derivatives (30) afforded diaryliodonium hydrogensulfates (31), which were easily converted to the diaryliodonium iodides (32) using aqueous potassium iodide (Scheme 6.11). Conveniently, the iodides (32) were insoluble in the reaction mixture and could be easily isolated by filtration. A range of products was isolated in up to 72% yield.

Scheme 6.11 Electrochemical synthesis of hypervalent iodine reagents.


Amemiya [28] has reported the use of electrochemical flow allylation, between allylic halides (33) and aldehydes (34) (Scheme 6.12); where in batch it is incredibly difficult to control whether the γ-adduct (35) or α-adduct (36) is obtained. The authors report that by altering the order of reagent addition and cathode material, chemoselective control over product formation can be achieved. Pt and Ag worked effectively as the cathode material, whereby yields of 49–65% were obtained in up to 76% product selectivity.

Scheme 6.12 Electrochemical allylation between allylic halides and aldehydes.


Kashiwagi [29] has successfully demonstrated that a microreactor is very efficient for the electrochemical generation of the highly unstable o-benzoquinone intermediate. The authors have reported that a two-step reaction process may be efficiently conducted by first reacting catechol (37) within the electrochemical reactor to afford o-benzoquinone (38) in situ, before adding thiol (39) as a nucleophile, for example, to afford the product (40) in high yield (Scheme 6.13). Using a variety of thiols a library of products has been prepared in excellent yield (79–88%), whereas when the same reactions were performed in batch, yields were substantially lower (7–13%).

Scheme 6.13 In situ electrogeneration of o-benzoquinone in a microreactor.


Other recent examples of electrochemical synthesis in continuous flow systems include the TEMPO-mediated electrooxidation of primary and secondary alcohols in a microfluidic electrolytic cell [30]. Under the optimized reaction conditions, the authors report that primary alcohols could be oxidized to aldehydes in yields of up to 81% and that the secondary alcohols were oxidized to ketones in up to 85% yield. Using the same experimental approach, the group have also reported the methoxylation of N-formylpyrrolidine in very high conversion [31].