无金属电化学C—H键活化构建C—N/C—O键的研究进展

罗辉; 王文权; 贺瑜; 王富强; 杨金会

doi:10.6023/cjoc202508020

有机化学 >

2026 , Vol. 46 >Issue 3: 697 - 724

DOI: https://doi.org/10.6023/cjoc202508020

综述与进展

无金属电化学C—H键活化构建C—N/C—O键的研究进展

罗辉 ,
王文权 ,
贺瑜 ,
王富强 ^,^* ,
杨金会 ^,^*

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宁夏大学化学化工学院银川 750021

收稿日期: 2025-08-23

修回日期: 2025-11-14

网络出版日期: 2025-12-10

基金资助

国家自然科学基金(U24A20485)

宁夏自然科学基金(2023AAC03016)

中国工程院院地合作(2023NXZX1)

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Research Progress in Metal-Free Electrochemical C—H Bond Activation for the Construction of C—N/C—O Bonds

Hui Luo ,
Wenquan Wang ,
Yu He ,
Fuqiang Wang ^,^* ,
Jinhui Yang ^,^*

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College of Chemistry and Chemical Engineering, Ningxia University, Yinchuan 750021

*E-mail: wangfuq@nxu.edu.cn;

yang_jh@nxu.edu.cn

Received date: 2025-08-23

Revised date: 2025-11-14

Online published: 2025-12-10

Supported by

National Natural Science Foundation of China(U24A20485)

Ningxia Natural Science Foundation(2023AAC03016)

Project of Sino-Government Cooperation of the Chinese Academy of Engineering(2023NXZX1)

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摘要

电化学C—H键活化以其优异的原子经济性、丰富的反应位点、环境友好性以及无需底物预官能团化等优势备受关注. C—N/C—O键广泛存在于许多天然产物和药物分子中, 是生命体系中重要的结构, 因此其高效构建方法的研究具有重要意义. 近年来, 随着绿色化学理念的深入, 无金属参与的电化学C—H键活化构建C—N/C—O键因其避免金属残留、成本低廉且环境友好等优势, 正日益成为研究热点. 该领域已开发出多种通过电化学C—H键活化构建C—N/C—O键策略. 系统总结了近五年来无金属电化学C—H键活化构建C—N/C—O键的重要进展, 涵盖直接C—N/C—O键的构建及非金属介导的C—N/C—O键的构建, 并重点阐述了相关反应机理.

关键词： 电化学; C—H键活化; 绿色化学; 无金属; 构建C—N/C—O键

本文引用格式

罗辉 , 王文权 , 贺瑜 , 王富强 , 杨金会 . 无金属电化学C—H键活化构建C—N/C—O键的研究进展[J]. 有机化学, 2026 , 46(3) : 697 -724 . DOI: 10.6023/cjoc202508020

Abstract

Electrochemical C—H bond activation has garnered significant attention due to its superior atom economy, abundant reaction sites, environmental friendliness, and the absence of substrate pre-functionalization requirements. C—N/C—O bonds, which are widely present in numerous natural products and pharmaceutical molecules, serve as crucial structural motifs in biological systems, making the development of efficient methodologies for their construction highly consequential. In recent years, with the growing emphasis on green chemistry principles, metal-free electrochemical C—H bond activation for C—N/C—O bond formation has emerged as a prominent research focus, owing to its advantages in avoiding metal residues, cost-effectiveness, and environmental compatibility. This field has witnessed the development of diverse strategies for constructing C—N/C—O bonds via electrochemical C—H activation. The key advancements in metal-free electrochemical C—H activation for C—N/C—O bond formation over the past five years are systematically reviewed, encompassing both direct C—N/C—O bond construction and non-metal-mediated approaches, with particular emphasis on elucidating the under- lying reaction mechanisms.

Key words： electrochemistry; C—H bond activation; green chemistry; metal-free; construction of C—N/C—O bonds

C—H键的选择性活化/官能团化是合成化学中备受关注的问题, 是现代有机合成化学领域一项革命性策略, 被誉为合成中的“圣杯”^[1-4]. 直接、高选择性的 C—H键官能团化, 可为活性与功能分子的构建提供高效手段^[5]. 从原理上看, C—H键的转化不依赖预官能团化的底物, 具有原子经济性与步骤简洁性, 并且广泛存在的C—H键为合成化学提供了丰富的反应位点, 为高效制备结构多样的化合物库和优化分子性能提供强大工具^[6-10]. 然而, C—H键的惰性与活化能垒使得活化这些键通常需要高活性催化剂、剧烈反应条件或特殊活化手段, 这可能导致副反应增多、官能团耐受性降低和底物适用范围受限, 并且产物的选择性难以控制^[11-14]. 传统C—H官能化通常指过渡金属催化的C—H键断裂反应, 但在实际应用中, 过渡金属催化的C—H官能化面临诸多挑战: (1)部分底物与过渡金属反应活性较低; (2)引入和去除导向基团需额外步骤; (3)过渡金属价格昂贵且非金属催化剂活性不足; (4)寻找匹配的催化剂和配体过程复杂. 这些制约了传统C—H键官能化技术的广泛应用^[15-19].

在绿色化学发展趋势的推动下, 电化学合成凭借其环保、温和的特点备受瞩目^[20-22]. 在有机电合成中, 电极电势作为驱动力, 电子则作为清洁试剂. 通过精准调控电子转移过程, 可以高效地协调氧化还原反应. 因此, 该技术已成为现代有机合成中极具价值的研究工具^[23-26]. 这种方法无需使用化学计量的氧化剂和还原剂, 多数电化学反应在室温或低温、常压下进行, 避免高温高压带来的能耗与安全风险. 并且通过精确控制电极电势, 能实现传统方法难以完成的复杂化学转化^[27-30]. 因此, 相较于传统过渡金属催化的C—H键官能团化反应, 电化学C—H键的官能团化具有诸多优势(表1). 同时, 电化学驱动具有独特的反应机制, 可与光催化、酶催化或连续流控制技术联用, 实现多机制协同的精准合成. 因此, 相较于传统的合成方法, 电化学展现出更优的反应效率、更高的原子利用率, 大大提高了反应的经济性和选择性^[31-32].

表1 过渡金属催化与无金属电化学C—H官能化的比较

Table 1 Comparison of transition metal-catalyzed and metal-free electrochemical C—H functionalization

Item compared	Transition metal-catalyzed C—H functionalization	Metal-free electrochemical C—H functionalization
Reaction mechanism	Using transition metals as catalysts, through elementary steps such as ligand exchange, oxidative addition, migration insertion, and reductive elimination, the activation and functionalization of C—H bonds are achieved.	Using electrons as clean oxidants or reductants, through electron transfer at the electrode surface, the substrate is transformed into active intermediates, thereby achieving the cleavage and functionalization of C—H bonds.
Reactive driving force	Chemical oxidants (such as Ag salts, Cu salts, peroxides, etc.) or reductants provide or consume electrons to complete the catalytic cycle.	Electric energy. By applying an external voltage or current, the redox potential of the reaction can be precisely controlled.
major advantage	(1) The method is mature and has a wide range of applications; (2) It offers strong selectivity and can be precisely controlled through ligand engineering; (3) The reaction conditions are relatively mild and facilitate large-scale production.	(1) Green and sustainable, reducing the use of metals and oxidants; (2) Economical in steps, without the need for pre-functionalization steps; (3) Unique reactivity, facilitating the generation of highly reactive free radical species; (4) High safety, capable of avoiding some dangerous chemical oxidants.
Main challenges and limitations	(1) The cost of metals is high and they may be toxic; (2) Metal residues affect the purity of the products, especially in the pharmaceutical industry; (3) They rely on chemical reagents for oxidation, generating chemical waste.	(1) Selective control (especially regional and stereoscopic selectivity) is a major challenge; (2) Reaction scaling is difficult due to limitations imposed by electrode area and mass transfer efficiency; (3) Special equipment (electrolytic cells, power supplies) is required; (4) Requirements exist for the conductivity of the substrate and solvent.
Catalyst and cost	(1) Expensive transition metal catalysts (such as Pd, Rh, Ir) are required; (2) It may involve the design and synthesis of complex ligands; (3) There is a problem of metal residue, which is not friendly to drug synthesis.	(1) No need for transition metal catalysts, and the cost is relatively low; (2) It may use inexpensive media (such as salts, acids, and bases) to facilitate conductivity; (3) No metal residues, especially suitable for the fields of medicine and materials.
Reaction selecti- vity	Regional selectivity: Usually precisely controlled through the spatial/electronic effects of directing groups or ligands, as well as catalysts. Stereoselectivity: High enantioselectivity can be achie- ved through chiral ligands.	Regional selectivity: It can be regulated by substrate structure (such as inherent electronic effects at the site), electrode potential, and medium, but precise activation of the distal C—H bond poses greater challenges. Stereoselectivity: It is relatively difficult to control and is currently a research difficulty.
Sustainability and “Green Chemis- try”	Using stoichiometric oxidants results in poorer atom economy. (1) Toxic or expensive metals may be used; (2) The process has high economic efficiency, but the environmental footprint is relatively large.	The atomic economy is high, and electrons act as “clean reagents”. (1) It is more in line with the principles of green chemistry (reducing waste and using renewable sources); (2) It can be combined with renewable energy sources (solar energy, wind energy).

与过渡金属催化的C—H官能化不同的是, 无金属电化学C—H官能化通常能在简单温和的反应条件下顺利进行, 使其被视为一类更环保高效的C—H键官能化方法^[33-36]. 无金属电化学C—H键的活化/官能团化, 在消除金属残留、提升原子经济性、拓展反应选择性方面突破传统合成瓶颈^[37-40]. 使其在合成化学领域, 尤其是对金属残留限量极为严格的药物化学领域展现出广阔应用前景^[42]. 其技术内核完美契合绿色化学原则, 为药物绿色合成、大宗化学品制备及CO₂资源化利用提供了可行性的解决方案, 是未来合成化学向低毒化、低碳化转型的核心方向^[43-46].

无金属电化学C—H键的活化/官能团化在反应机制上主要可分为两大类, 即直接电化学C—H键活化和非金属介导的间接电化学C—H键活化(Scheme 1)^[47-49]. 这两种策略共同构成了该领域的核心方法学, 但其作用原理和适用场景各有侧重. 直接电化学C—H键的活化是指底物直接在电极表面发生电子转移, 并在电极表面生成相应的自由基阳离子或阴离子的过程, 是异相过程^[50]. 直接电化学C—H键的活化注重效率提升、实现原子利用率最大化并减少不必要的原子浪费. 但也存在诸多问题, 例如直接电化学C—H键的活化只适用于特定基底的选择性电解, 在处理具有高氧化/还原电位的基底或复杂的底物时, 由于电极与基底之间存在异质性的电子传递特性, 过电位会导致官能团兼容性差. 并且电极表面会积累大量活性物质, 容易发生自由基二聚、过度氧化或与电极反应, 最终导致电极钝化^[27,51-54]. 非金属介导的间接电化学C—H键的活化, 使用氧化还原介质在电化学驱动下生成活性中间体, 随后与底物发生外层电子转移, 此外, 当反应层脱离电极时, 活性自由基阴离子/阳离子从电极的流动与电解液中底物的流动达到平衡, 这是均相过程^[55]. 添加有机介质可减少或避免电极钝化现象, 因为活性物质是在溶液中生成而非在电极表面. 此外, 不同有机介质能提供独特的选择性, 并为理想的电化学转化创造多种可能性^[41,56-59].

模态框（Modal）标题

摘要

本文引用格式

Abstract

表1 过渡金属催化与无金属电化学C—H官能化的比较

图式1 直接和间接电化学反应

1 无金属电化学C—H键活化构建C—N键

1.1 电化学直接C—H键活化构建C—N键

1.1.1 经由碳正离子中间体的直接胺化

图式2 电化学C(sp3)—H键直接异硫氰基化

图式3 电化学C(sp3)—H键直接胺化

1.1.2 Ritter反应构建酰胺键

图式4 无金属电化学催化芳烃邻位C—H键的双胺化

图式5 氰类化合物作为亲核试剂的电化学Ritter反应

图式6 酰胺类化合物作为亲核试剂的电化学Ritter反应

1.1.3 自由基路径与环化策略

图式7 醛腙电化学胺化反应

图式8 电化学C—H/N—H交叉偶联反应

图式9 电化学分子内C(sp3)—H/N—H环化策略

图式10 偶氮苯的苄位C(sp3)—H直接活化环化

1.2 非金属介导的电化学活化C—H键构建C—N键

图式11 电化学HAT过程活化C—H

图式12 杂原子自由基引发的HAT活化C(sp3)—H键

图式13 电化学烯丙位C(sp3)—H异硫氰基化反应

图式14 DDQ介导的电化学C—H键胺化

图式15 硫或碘介导的电化学C—H键胺化

图式16 胺介导的电化学C—H键胺化

2 无金属电化学C—H键活化构建C—O键

2.1 电化学直接活化C—H键构建C—O键

2.1.1 C—H键羟基化构建醇与酚

图式17 N-芳酰胺的对位选择性羟基化

图式18 电化学苄位C(sp3)—H键羟基化

2.1.2 C—H键氧化构建羰基化合物

图式19 电化学C—H键羰基化

图式20 电化学苄位C(sp3)—H键氧化

2.1.3 连续流电化学在C—O键构建中的应用

图式21 电化学连续流构建C—O键

2.1.4 C—H键烷氧基化与醚化

图式22 电化学构建烷氧键

图式23 自组装诱导的C—H键酰氧基化

图式24 电化学活化C—H键构建烷氧键

图式25 电化学C—H键构建三氟甲氧基和烷氧基

图式26 电化学极性翻构建烷氧键

图式27 通过极性反转策略实现电化学C—H键烷氧化和磺化

图式28 烷基芳烃及三氟乙酰胺中邻C—H键的直接酯化

2.2 非金属介导的电化学C—H键活化构建C—O键

图式29 奎宁环啶和氨基氧介导的电化学C—H键羰基化

图式30 TMSN3和NHPI介导的电化学C—H键氧化

3 总结与展望

参考文献

图式2 电化学C(sp³)—H键直接异硫氰基化

图式3 电化学C(sp³)—H键直接胺化

图式9 电化学分子内C(sp³)—H/N—H环化策略

图式10 偶氮苯的苄位C(sp³)—H直接活化环化

图式12 杂原子自由基引发的HAT活化C(sp³)—H键

图式13 电化学烯丙位C(sp³)—H异硫氰基化反应

图式18 电化学苄位C(sp³)—H键羟基化

图式20 电化学苄位C(sp³)—H键氧化

图式30 TMSN₃和NHPI介导的电化学C—H键氧化