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Synthesis 2023; 55(18): 2833-2842
DOI: 10.1055/a-2020-8923
short review
Special Issue Electrochemical Organic Synthesis

Recent Advances in Electro- or Photochemical Driven Transformations via Cleavage of the C–N Bond of Quaternary Ammonium Salts

Xiaohui Chen
a   School of Chemical Engineering and Materials, Changzhou Institute of Technology, No. 666 Liaohe Road, Changzhou 213032, P. R. of China
,
Neng-Zhong Wang
b   Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang, Hubei 443002, P. R. of China
,
Ya-Min Cheng
c   College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004, P. R. of China
,
Xianqiang Kong∗
a   School of Chemical Engineering and Materials, Changzhou Institute of Technology, No. 666 Liaohe Road, Changzhou 213032, P. R. of China
,
Zhong-Yan Cao∗
c   College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004, P. R. of China
› Author Affiliations

We thank the funding from the National Natural Science Foundation of China (NSFC) (22102012, 22202021, 22272011, and 22201062), Changzhou Science and Technology Plan Applied Basic Research Project (CJ20210159, CJ20210129, and CZ20220022), Natural Science Foundation of Henan Province (K22029Y), the Jiangsu Higher Education­ Institutions of China (22KJA150001, 21KJD530003, 21KJB530013), and the opening funding of Hubei Key Laboratory of Natural Products Research and Development, China Three Gorges University (2022NPRD02).
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Abstract

Selective functionalization via cleavage of the C–N bond of amines has proven to be challenging partly because of its relatively high bond dissociation energy, even though amines are abundant and readily available. To meet this challenge, many new transformations based on the pre-activation of the C–N bond before the cleavage have been developed. Among them, the conversion of amines into quaternary ammonium salts has certain advantages, such as easy preparation from primary, secondary, or tertiary amines, as well as stable storage and usage. Although transition metal catalysis has been frequently applied for developing new transformations via oxidative addition of the C–N bond of quaternary ammonium salts, recent studies have shown a new dimension by using green electro- or photochemical tools. In this short review, recent advances in electro-, photo-, or photoelectrochemical driven synthetic applications of quaternary ammonium salts have been summarized and discussed.

1 Introduction

2 Electrochemical Driven Transformations

3 Photochemical Driven Transformations

4 Photoelectrochemical Driven Transformations

5 Conclusion and Outlook


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Key words

quaternary ammonium salts - synthetic transformation - C–N bond cleavage - amines - electrochemistry - photochemistry
1

Introduction

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Xianqiang Kong received his BS degree from Nanjing Tech University in 2012 and his Master’s degree from Jiangsu Normal University in 2016. He received his Ph.D. degree from Donghua University in 2020 under the guidance of Professor Bo Xu. His research focuses on synthetic electrochemistry. Zhong-Yan Cao received his BS degree from East China Normal University in 2010 and completed his Ph.D. under the supervision of Prof. Jian Zhou at the same university. He joined Henan University as an appointed professor in 2020 after carrying postdoctoral research with Prof. Paolo Melchiorre (ICIQ) and Prof. Jianrong Steve Zhou (Nanyang Technological University), respectively. His research group focuses on radical-mediated methodology development.

The amine group is a fundamental functional group that is frequently found in natural products, drugs, dyes, pharmaceuticals, as well as many other functional molecules. In addition, a large number of amines bearing versatile functional groups are commercially available at reasonable cost.[1] Therefore, new chemical tools for the efficient transformation of these amines into high-value targets via the cleavage of C–N bonds under mild reaction conditions are high attractive, which will undoubtedly expand their synthetic utility and the chemists’ vision.[2] However, compared with the direct functionalization of inert C–H,[3] C–C,[4] or C–O[5] bonds, progress in the functionalization of the inert C–N bonds has been slow,[2] even though such kinds of transformations have been well-documented in life-related enzymatic processes (such as urea synthesis in metabolism and protein and nucleotide biosynthesis). This can be partly attributed to the relatively high bond dissociation energy of C–N bonds.[6]

One of most successful approaches for the effective manipulation of C–N bonds is by a pre-activation strategy by converting the amines into the corresponding diazonium[7] or Katritzky salts,[8] quaternary ammonium salts,[9] highly strained amides, and others.[2] Compared to diazonium or Katritzky salts (only from primary amines), and amides (only from both primary and secondary amines), the use of quaternary ammonium salts shows a broad scope as they can be easily prepared from primary, secondary, or tertiary amines in good to excellent yields on a gram scale on reaction with inexpensive alkyl electrophiles such as MeOTf. Furthermore, quaternary ammonium salts are easy to handle, as they are generally solid and stable towards air and moisture, enabling long-term storage in open vessels. In comparison to amines, the corresponding quaternary ammonium salts often exhibit much higher C–N reactivity due to the strong C–N bond polarity and release of electronically neutral amine molecule in the course of the reaction.[9b] These key characteristics make such quaternary ammonium salts facilely activated via oxidative addition by transition metal catalysts, opening a new avenue for synthetic applications.[9] For example, Wenkert and co-workers pioneered the nickel-catalyzed cross-coupling reaction of quaternary ammonium salts with Grignard reagents in 1988.[10] Inspired by this, many excellent methodologies with or without transition metal catalysts focusing on the manipulation of C–N bonds of quaternary ammonium salts have been developed in the last few decades, although these procedures often have harsh conditions and have relatively narrow functional group tolerance. This progress has been well documented in some excellent reviews.[9]

Electrochemical synthesis, which employs electrons as a green and environmentally benign redox reagent to promote the generation of reactive intermediates in a controllable manner in the absence of external chemical reducing or oxidizing agents under mild reaction conditions, has recently received considerable attention in both the academic and industry fields.[11] Although Emmert conducted the electrochemical reduction of aryltrimethylammonium salts as early as in 1909,[12] the synthetic advantages of such an activation model have been largely neglected. Delightfully, very recent studies have witnessed the renaissance of this field. The Theunissen group reported that both simple phenyl- and benzyltrimethylammonium triflate have a very negative reduction potential (–2.35 V vs. SCE).[13] The use of electrosynthesis provides a simple yet effective way for activation because of the tunable nature of the redox ability of such a synthetic tool. In addition, with the renaissance of photosynthesis,[14] recent progress has also shown that quaternary ammonium salts can be directly activated by light[15a] or photocatalyst,[15b] [c] enabling the development of C–N bond transformations under mild reaction conditions.

These latest achievements have not been covered by previous reviews,[9] and electricity- or photo-facilitated examples were only briefly mentioned in review articles by Yang[9b] and Zeng, respectively.[9e] Herein, in continuation of our interest in the development of new synthetic methodology,[16] we present a detailed discussion of these latest achievements, with the aim of further guiding new advances by highlighting the unique advantages of electrosynthesis and photosynthesis for the selective cleavage and functionalization of C–N bonds of both aryl and benzyl quaternary ammonium salts. This short review is categorized based on the following three activation models: electrosynthesis, photosynthesis, and photoelectrochemical driven transformations (Scheme [1]). Some highly selective reactions such as reduction, carboxylation with CO2, addition reactions to unsaturated compounds (aldehydes and alkenes), borylation, cyanation and cyanomethylation, decarboxylative cross-couplings, arylation, amino- and alkoxycarbonylation, etc. have been developed for the efficient construction of C–H, C–C, C–B, or C–P bonds. These useful transformations go through the formation of four carbon-based intermediates (radicals, anions, triplet cation, and nickel or cobalt-based aryl metallic species), further fueling the area. Interestingly, this area has become the platform for designing new electro- or photochemical methodologies guided by new concepts or new strategies.

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Scheme 1 Summary of content of this short review

# 2

Electrochemical Driven Transformations

Quaternary ammonium salts can be reduced to form radicals or anions via direct reduction at the cathode. As discussed in the introduction, the use of electricity to selectively reduce both aryl- and benzyltrimethylammonium salts to form arenes or bibenzyl was first reported in 1909.[12] The involvement of an aryl or benzyl radical intermediate for these transformations was later proposed in the 1960s.[17] Although this provides a new way for the generation of very useful aryl or benzyl radical intermediates under mild reaction conditions, these works mainly focus on mechanistic studies, and the synthetic potential was largely neglected. In 2019, Manthiram and co-workers revisited this subject and reported the direct electrochemical carboxylation of benzylammonium salts 1 through a sequence of the selective cleavage of the benzylic C–N bond and CO2 insertion (Scheme [2]).[18] Thanks to the power of using electrons to reduce 1 at room temperature, the use of a external stoichiometric reducing agents or sacrificial anode was not necessary. The use of –4.5 V constant cell voltage was essential in this case. Both primary and secondary benzyl carboxylic acids 2 bearing versatile functional groups, such as halogen, cyano, carboxylic acid, and ketone, were facilely prepared in moderate to good yields and on a gram-scale without column chromatography for purification. Mechanistic studies involving the utilization of differential electrochemical mass spectrometry (DEMS) indicate that the reaction initiates with the formation of benzylic radical I and trimethylamine via cathode reduction of 1. Subsequently, I obtains a further electron to form a more nucleophilic benzyl anion II, which is trapped by CO2 to deliver the 2-arylacetate anion III. Meanwhile, Me3N is oxidized at the anode giving radical cation IV; the loss of one proton and oxidation at the anode delivers the imine cation V, which can form an ion pair with III. Noteworthy, the anion from the benzylammonium salts is essential to achieve satisfactory results, and this counteranion effect is frequently used in the examples that follow.

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Scheme 2 Direct electrochemical carboxylation of benzylammonium salts

In 2021, Xu and co-workers reported that both aryl and benzyl radicals formed in this way were efficiently trapped by B2Pin2, providing a new route for rapid access to a variety of aryl- or benzylboronates, which have valuable synthetic applications in modern chemistry.[19] As shown in Scheme [3], electroreduction of ammonium triflates 1 in the presence of B2Pin2 in DMF/MeOH gives valuable boronates 3 bearing versatile functional groups in moderate to good yields even on a gram scale. Control experiments showed the essential role of MeOH, as its absence resulted in a dramatic decrease in yield. In addition, some nitrogen- or sulfur-based heterocyclic products were also compatible with these mild reaction conditions. A plausible mechanism is shown in Scheme [3], in which radical I along with Me3N is formed at the cathode by reduction of 1. Different from the mechanism of Manthiram,[18] which involves a counteranion species (Scheme [2]),[18] radical I reacts with B2Pin2 in the presence of base (MeO–) to form product 3 together with anion IV via species II and III. Meanwhile, anodic oxidation of the solvent makes the overall transformation redox neutral (not shown in Scheme [3]). Subsequently, species IV is quenched by a single electron transfer with the solvent to give MeOBPin. Similar to before, Me3N is oxidized to imine cation V at the anode.

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Scheme 3 Electrochemical borylation

Cyanations of amines are widely reported.[20] In 2022, we also found that the use of simple TsCN or 3-azido-2-methylbut-3-en-2-ol (4) to trap the electrochemically formed aryl radical enabled cyanation or cyanomethylation, respectively, under mild reaction conditions (Scheme [4]).[20a] Our method shows good functional group tolerance, as a variety of groups and heterocyclic substrates, were compatible and the reaction can be easily performed on a gram scale. Moreover, our cyanation protocol has been successfully applied in the modification of bioactive molecules. Benzyltrimethylammonium salts were also compatible substrates for the cyanation and cyanomethylation processes, albeit with relatively low efficiency.[20a]

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Scheme 4 Electrochemical cyanation and cyanomethylation

Detailed mechanistic studies indicate that the key aryl radical is facilely formed via electrochemical reduction at the cathode (Scheme [5]).[20a] Subsequent reaction with highly electrophilic TsCN or 4 gives species II or II′, respectively. As for the cyanation reaction, it is proposed that 5 and Ts• are formed via a Barton nitrile transfer. Dimerization of the Ts• delivers the observed byproduct Ts–Ts. It is noteworthy that although the reduction potential of these aryl nitriles 5 and 6 is higher than that of the corresponding trimethylammonium triflates 1 and the voltage used, the products 5 and 6 were isolated in good yields under the standard conditions, without the plausible over-reduction problem. This can be attributed to the fact that these nitriles exhibit reversible electron transfer (which was shown by CV spectra).[21] For the cyanomethylation process, II′ is transformed into III after the release of N2; III undergoes C–C bond cleavage to deliver 6 along with ketyl radical IV. Acetone is formed through deprotonation after oxidation of ketyl radical at the anode. In both cases, trimethylamine loses two electrons to form the imine cation and H+, similar to previous examples.[20a]

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Scheme 5 Proposed mechanism for cyanation and cyanomethylation

While the examples discussed so far are intriguing, the use of very strong electricity (generally less than –4 V) to directly reduce aryltrimethylammonium salts might inevitably limited further synthetic applications. Given that such aryltrimethylammonium salts could be effectively activated by transition metal catalysis, as pioneered by Wenkert,[10] it was postulated that the development of electricity-driven transition-metal-catalyzed methodologies, which combine the advantages of electrosynthesis and transition metal catalysis, will open new opportunities via the selective cleavage of the C–N bond of quaternary ammonium salts.

For example, carboxylic acids and their derivatives are inexpensive fundamental chemicals. The use these nucleophiles for decarboxylative cross-coupling has received tremendous attention since the pioneering work of Goossen.[22] Nevertheless, the requirement for expensive Pd catalysts, narrow substrate scope, as well as harsh conditions diminished its practical applications. Although photochemical tools[23] have been developed for challenging these drawbacks, it is still highly desirable to develop new catalysis models for this purpose. To meet these challenges, coupled with our experience in nickel catalysis,[16b] [c] we have developed a practically unified electrochemical strategy for Ni-catalyzed decarboxylative cross-coupling of aryltrimethylammonium salts.[24]

As shown in Scheme [6], decarboxylative cross-coupling of four types of α-oxocarboxylic acids 7 and their derivatives, which includes 2-oxocarboxylic acids, N,N-disubstituted oxamic acids, potassium oxoacetates, and glyoxylic acid monohydrate, with aryltrimethylammonium salts under mild conditions gave ketones, esters, amides, and aldehydes 8. Moreover, no external strong bases, oxidants, reductants, or activators were necessary. The reaction was easily performed on a gram scale and is compatible with various functional groups. In addition, this protocol has been applied to the modification of natural molecules and a concise preparation of fenfibrate, a cholesterol-modulating drug. Different from examples discussed so far (Schemes 2–5) where electricity was used for the reduction of aryltrimethylammonium salts, in our case mechanistic studies indicate that electricity promotes the formation of acyl radical I and the true Ni(0) catalyst II via oxidation at the anode, and reduction at the cathode, respectively. Meanwhile, Ni(0) species II undergoes an oxidative addition process with arylammonium triflates 1 to form Ar–Ni(II)–OTf intermediate III. Ni(III) complex IV is formed via the trapping of I by III. A final reductive elimination from IV gives product 8 as well as Ni(I)–OTf complex V, which undergoes cathodic reduction to regenerate Ni(0) species II; Me3N loses two electrons to form an imine cation via anodic oxidation.[24]

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Scheme 6 Electrochemical decarboxylative coupling

# 3

Photochemical Driven Transformations

Ammonium salts generally do not absorb visible light, so these salts can be activated either by direct irradiation with UV light or photocatalysts under visible light conditions. This brings new activation models, and three kinds of reactive intermediates, such as carbon-based radicals, triplet aryl cation species, and benzyl anions, can be formed in a mild way resulting in new avenues for reaction design.

In 1968, Kabi and Clay used γ irradiation for the deamination of benzyltrimethylammonium ions in aqueous solution by hydrated electrons.[25] In 2016, Larionov and co-workers reported that the direct irradiation of aryltrimethylammonium salts with ultraviolet light (at 254 nm) triggered homolytic or heterolytic cleavage of the C–N bond in what constitutes a third activation model.[15a] As shown in Scheme [7], photoinduced borylation of a variety of quaternary arylammonium salts 1 takes place under very mild reaction conditions to deliver arylboronic acids 9 in good to excellent yields. Although detailed studies are required, the authors proposed that the reaction goes through the formation of a transient aryl radical or triplet cation species, responsible for the subsequent borylation via homolytic substitution.

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Scheme 7 UV-light-mediated borylation

Considering that the activation model is limited to the use of UV light, it is reasonable to question whether the use of visible light is feasible for the activation of quaternary ammonium salts. The Theunissen group showed that both simple phenyl- and benzyltrimethylammonium triflate have a very negative reduction potential (–2.35 V vs. SCE), which reaches the reduction limit of the typical range of photocatalysts.[13] In order to achieve satisfactory efficiency, a substantial amount of an expensive Ir-based photocatalyst or light with high intensity are used, and the scope of quaternary ammonium salts is often limited to those bearing electron-withdrawing groups due to their relatively easy reduction.

In 2018, Yu and co-workers first reported the synthetic transformation of benzyltrimethylammonium salts via the cleavage of C–N bonds mediated by visible light.[15b] In this seminal contribution, they used benzyltrimethylammonium triflates 1 as electrophiles for coupling with other electrophiles such as aromatic aldehydes and CO2. By taking advantage of the in situ formed Me3N from 1, an external-reductant-free cross-coupling concept was established. This reductive cross-coupling took place smoothly promoted by photoredox catalysis to deliver secondary alcohols 10 or carboxylic acids 11 in good to excellent yields (Scheme [8]). Noticeably, benzyltrimethylammonium triflates with an unactivated aryl ring in the benzyl group often showed poor reactivity and required the use of up to 4 mol% Ir-based photocatalyst. Although further detailed mechanistic studies are necessary, they propose that under the irradiation of light the Ir-based photocatalyst plays multi roles. Initially, the excited state of [Ir(ppy)2(dtbbpy)]PF6 (E(IrIV/IrIII*) = –1.80 V vs. Ag/Ag+) reduces 1 to deliver the key benzyl radical I, Ir(IV) II, and Me3N. Meanwhile, both the excited state of the Ir(III) catalyst and Ir(IV) II are quenched or reduced by Me3N or its degraded species (such as Me2NH, α-amino radicals) to give Ir(II) intermediate III or Ir(III) catalyst, respectively. Subsequently, benzyl radical I (E ox = –1.43 V vs. SCE) is further reduced by Ir(II) III (E(IrIII/IrII) = –1.51 V vs. SCE) to deliver the Ir(III) catalyst, as well as key benzylic anion IV for the subsequent nucleophilic additions. Again, the carbanion is proposed to be a key intermediate, similar to Manthiram’s proposal (Scheme [2]).[15b]

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Scheme 8 Visible-light-mediated reductive couplings

During their study of the reductive activation of ammonium salts by visible-light-triggered photocatalysis, the Theunissen group noticed that the excited state of Ir(ppy)3 can be efficiently quenched by aryltrimethylammonium triflates bearing activating groups, such as aryl, ester, nitrile, and trifluoromethyl, on the phenyl rings; their reduction potentials range from –2.13 to –1.77 V vs. SCE which very close to the reduction potential of Ir(ppy)3* (E(IrIV/IrIII*) = –1.73 V vs. SCE).[13] Using this, they realized a hydrodeamination of aryltrimethylammonium triflates by the formation of key aryl radical under irradiation by blue light (Scheme [9]). The use of 2.5 mol% of Ir(III) photosensitizer together with a strong light source was necessary for satisfactory efficiency. Furthermore, radical couplings between a variety of arylammonium salts 1 and four radical acceptors (pyrrole, 1,1-diphenylethylene, B2Pin2, and P(OEt)3) were successfully developed, to construct C–C, C–B, and C–P bonds.

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Scheme 9 Visible-light-mediated reduction
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Scheme 10 Visible-light-mediated reduction of benzylic salts

Inspired by the work of Yu, the Theunissen group extend the scope of this reduction to benzyltrimethylammonium triflates 1, in this case the use of [Ir(ppy)2(dtbbpy)]PF6 was optimal (Scheme [10]).[13] The use of benzyltrimethylammonium triflates 1 with electron-withdrawing groups on the phenyl ring was necessary. Interestingly, and different from the above examples, Stern–Volmer quenching experiments imply that the excited state of [Ir(ppy)2(dtbbpy)]PF6 might be firstly quenched by i-Pr2NEt, to form the key Ir(II) species I. Such Ir(II) species (E(IrIII/IrII) = –1.51 V vs. SCE) is able to reduce 1, delivering the key benzylic radicals for the subsequent reduction.

From the examples discussed so far, it can be seen that the visible-light-mediated transformations based on the cleavage of C–N bonds or ammonium salts utilized expensive Ir-based photocatalysts with special light apparatus and both the scope and the reaction types were limited. To overcome these challenges, the invention of novel yet more powerful visible-light-trigger catalytic system guided by new activation models will be undoubtedly necessary. Recent studies have shown the possibilities, and three kinds of new activation models have been reported, enabling the promotion of the activation of ‘inert’ quaternary ammonium salts under visible light.

For instance, in 2019 Wenger and co-workers first reported that a water-soluble Ir(III)-based photocatalyst can execute such hypothesis (Scheme [11]).[26] Under irradiation by a self-designed inexpensive blue continuous wave laser, a new catalyst Irsppy (only 1 mol%) absorbed one photon to reach the excited state I. The transient formed species I absorbs a further photon and releases one electron to the media (D2O was used as solvent in this case), to form the so-called hydrated electron (eaq –) with a standard potential of –2.9 V vs. NHE. The hydrated electron effective reduced the benzyltrimethylammonium cation to a benzyl radical and Me3N, promoting the whole process in a catalytic way with triethanolamine (TEOA) as the terminal reductant. It is foreseeable that such activation model might soon result in new synthetic transformations.

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Scheme 11 Hydrated electron as the reductant

The second successful activation model comes from the Larionov group. Their new strategy was by proton-coupled electron transfer (PCET)-enabled borylation under the mediation of visible light (Scheme [12]).[15c] Under the catalysis of inexpensive N-unsubstituted organo-photocatalyst phenothiazine PTH,[27] the visible-light-mediated C–N borylation of aryltrimethylammonium salts 1 proceeded smoothly to deliver arylboronates 3 with generally good yields even on a gram scale. Key to the success is the use of PTH without a substituent on the nitrogen atom and the extra Cs2CO3 as base. This protocol shows good substrate scope, both electron-withdrawing and more challenging electron-donating groups on the aryl rings of 1 are suitable, and functional group tolerance. In addition, both 1H NMR and fluorescence quenching experiments imply that the presence of a PCET process arising from the PTH–carbonate interaction (exemplified as species I) results in the formation of a transient photocatalyst with enhanced reduction potential in its excited state compared to that of the simple excited state of PTH (E red = –2.60 V vs. SCE). Single electron reduction of aryltrimethylammonium salts 1 becomes more favorable from the singlet excited state of complex I, leading to the formation of the key aryl radical II and the oxidized photocatalyst complex III. As indicated by DFT calculations, the following homolytic substitution reaction with B2Pin2 gives products 3 along with boryl radical IV. The barrierless and exerogonic reaction of IV with III delivers the formation of I and PinBOCO2 – after exchange with CO3 2–.

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Scheme 12 PCET-mediated reduction

In 2022, similar to our electricity-driven transition metal catalysis strategy, Alexanian and co-workers reported an excellent light-facilitated transition metal catalysis strategy, which relies on the use of low valent Co to selectively promote the cleavage of the C–N bond of aryltrialkylammonium salts under very mild reaction conditions (Scheme [13]).[28] In 1981, Caubere and co-workers observed the formation of phenylacetic acid during a study of the carbonylation of organic halides catalyzed by Co under photostimulation (350 nm) using benzyltriethylammonium chloride as the phase transfer catalyst.[29] Inspired by this, Alexanian and co-workers reported a three-component deaminative amino- and alkoxycarbonylation of aryltrialkylammonium triflates 1 with CO, amines or alcohols with cheap Co2(CO)8 as the catalyst and 370 nm LED light. Primary and secondary amines and even simple (NH4)2CO3 were used as the amino source and gave aryl amides 17 or esters 18 with good functional group tolerance; this method was applied for the modification of bioactive molecules. Detailed mechanistic studies indicate that light promotes the formation of the key [Co(CO)3]– intermediate I via photodissociation of CO. Oxidative addition of this active cobaltate species I with a phenyltrimethylammonium ion via concerted S NAr forms intermediate II. The following migratory insertion of CO gives an acyl cobalt species III that undergoes ligand exchange with the amines. The final reductive elimination delivers the amide product 17 and regenerates I.[28]

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Scheme 13 Co-catalyzed three-component couplings

# 4

Photoelectrochemical Driven Transformation

Following the renaissances of electro- and photosynthesis, the combination the advantages of both methods has very recently received considerable attention,[11e] [30] even though photoelectrochemical synergistic catalysis was reported by Moutet and Reverdy in 1979.[31] Until now, four categories related to photoelectrochemical catalysis, namely electrochemically mediated photoredox catalysis,[32] decoupled photoelectrochemistry,[33] interfacial photoelectrochemistry,[34] and continuous-flow photoelectrochemistry,[35] have been reported. Wickens and co-workers have used the electrochemical activation of numerous conventional photocatalysts in the selective cleavage of the C–N bond of quaternary ammonium salts (Scheme [14]).[36] As discussed previously, the reduction potential of phenyltrimethylammonium salt is very low (–2.5 V vs. SCE),[13] which beyond the potential of most photosensitizers even in their excited state. Wickens and co-workers noticed that after reduction by electricity, some organic photocatalysts such as 4-DPAIPN 19 are reduced to the radical anion species I at the correct voltage (–1.6 V in this case). Irradiation of intermediate I at 405 nm enables the formation of the excited state II. Specifically, excited state II serves as powerful photoreductant and reduces a variety of aryltrialkylammonium salts 1 to the corresponding arenes 12 via an aryl radical intermediate in moderate to excellent yields. This electrochemically mediated photoredox catalysis promotes the formation of a far more reductive species without the need for harsh and strong voltage or light, providing opportunities for designing new methodologies with broad functional group tolerance.[11e] [30] Indeed, such synergistic catalysis has been successfully applied for the phosphonylation, borylation, and heteroarylation of phenyltrimethylammonium iodide (1a) via trapping the same key aryl radical species. It is anticipated that this activation model will lead to the development of new transformations that cannot be easily achieved using other tools.

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Scheme 14 Photoelectrochemical driven reduction and coupling

# 5

Conclusions and Outlook

This short review summarizes the latest achievement in the electro- or photochemical driven functionalization of quaternary ammonium salts via selective cleavage of C–N bonds, based on our experience in this area. The history and detailed mechanism of these interesting transformations have been discussed, enabling the construction of C–H, C–C, C–N, or C–P bonds in a site-selective manner thus opening new avenues for selective deamination.

However, although much progress has been made in this field, challenges still remain. We envisioned that further developments could be made to the following aspects: (1) The substrate scope is limited to aryl- or benzyl-substituted quaternary ammonium salts. This can be attributed to the fact that these substrates can easily and selectively cleave of one of the four C–N bonds to form the anticipated intermediates. Broadening the scope to simple quaternary ammonium salts remains a challenge. (2) After the selective cleavage of these quaternary ammonium salts, the tertiary amine moiety has often been ignored, leading to the low atom economy of the strategy. Reusing this part by clever reaction design is of great importance. (3) The reaction type is limited. Broadening the reaction types, such as for the construction of other C–X bonds, remains underdeveloped. More fundamentally novel reactions are necessary. One prerequisite lies in the development of novel catalytic systems guided by mechanistic studies. We believe these new and interesting transformations should find more practical applications in the future.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Authors

Xianqiang Kong
School of Chemical Engineering and Materials, Changzhou Institute of Technology
No. 666 Liaohe Road, Changzhou 213032
P. R. of China   

Zhong-Yan Cao
College of Chemistry and Chemical Engineering, Henan University
Kaifeng 475004
P. R. of China   

Publication History

Received: 30 December 2022

Accepted after revision: 26 January 2023

Accepted Manuscript online:
26 January 2023

Article published online:
01 March 2023

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Xianqiang Kong received his BS degree from Nanjing Tech University in 2012 and his Master’s degree from Jiangsu Normal University in 2016. He received his Ph.D. degree from Donghua University in 2020 under the guidance of Professor Bo Xu. His research focuses on synthetic electrochemistry. Zhong-Yan Cao received his BS degree from East China Normal University in 2010 and completed his Ph.D. under the supervision of Prof. Jian Zhou at the same university. He joined Henan University as an appointed professor in 2020 after carrying postdoctoral research with Prof. Paolo Melchiorre (ICIQ) and Prof. Jianrong Steve Zhou (Nanyang Technological University), respectively. His research group focuses on radical-mediated methodology development.
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Scheme 1 Summary of content of this short review
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Scheme 2 Direct electrochemical carboxylation of benzylammonium salts
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Scheme 3 Electrochemical borylation
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Scheme 4 Electrochemical cyanation and cyanomethylation
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Scheme 5 Proposed mechanism for cyanation and cyanomethylation
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Scheme 6 Electrochemical decarboxylative coupling
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Scheme 7 UV-light-mediated borylation
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Scheme 8 Visible-light-mediated reductive couplings
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Scheme 9 Visible-light-mediated reduction
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Scheme 10 Visible-light-mediated reduction of benzylic salts
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Scheme 11 Hydrated electron as the reductant
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Scheme 12 PCET-mediated reduction
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Scheme 13 Co-catalyzed three-component couplings
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Scheme 14 Photoelectrochemical driven reduction and coupling