A General Electrochemical Strategy for Sandmeyer Reaction

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Chemical Science

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Chemical Science

化学科学

A General Electrochemical Strategy for Sandmeyer Reaction

桑德迈尔反应的通用电化学策略

Qianyi Liu, ${}^{a}$ Beiqi Sun, ${}^{a}$ Zheng Liu, ${}^{b}$ Yi Kao, ${}^{b}$ Bo-Wei Dong, ${}^{b}$ Shang-Da Jiang, ${}^{b}$ Feng Li, ${}^{c}$ Guoquan Liu, ${}^{c}$ Yang Yang ${}^{d}$ and Fanyang Mo ${ * }^{a}$

刘谦益，${}^{a}$ 孙北奇，${}^{a}$ 刘铮，${}^{b}$ 考毅，${}^{b}$ 董博伟，${}^{b}$ 蒋尚达，${}^{b}$ 李丰，${}^{c}$ 刘国权，${}^{c}$ 杨扬 ${}^{d}$ 和莫凡洋 ${ * }^{a}$

Herein we report a general electrochemical strategy for the Sandmeyer reaction. Using electricity as the driving force, this protocol employs simple and inexpensive halogen source, such as NBS, ${\mathrm{{CBrCl}}}_{3},{\mathrm{{CH}}}_{2}{\mathrm{l}}_{2},{\mathrm{{CCl}}}_{4}$ , LiCl and NaBr for the halogenation of aryl diazonium salts. In addition, we found these electrochemical reactions could be performed using anilines as the starting material in a one-pot fashion. Furthermore, the practicality of this process was demonstrated in the multigram scale synthesis of aryl halides using highly inexpensive graphite as the electrode. A series of detailed mechanism studies has been performed, including radical clock and radical scavenger study, cyclic voltammetry analysis and in situ electron paramagnetic resonance (EPR) analysis.

在此，我们报道了一种用于桑德迈尔反应的通用电化学策略。该方案以电为驱动力，使用简单且廉价的卤素源，如NBS、${\mathrm{{CBrCl}}}_{3},{\mathrm{{CH}}}_{2}{\mathrm{l}}_{2},{\mathrm{{CCl}}}_{4}$、LiCl和NaBr对芳基重氮盐进行卤化。此外，我们发现这些电化学反应可以以苯胺为起始原料一锅法进行。此外，该方法的实用性在使用高度廉价的石墨作为电极进行多克规模的芳基卤化物合成中得到了证明。我们进行了一系列详细的机理研究，包括自由基时钟和自由基清除剂研究、循环伏安分析和原位电子顺磁共振(EPR)分析。

Received 00th January 20xx, Accepted 00th January 20xx

于20xx年1月00日收到，20xx年1月00日接受

DOI: 10.1039/x0xx00000x

DOI: 10.1039/x0xx00000x

www.rsc.org/

www.rsc.org/

Introduction

引言

The Sandmeyer reaction represents a fundamentally important method to convert an aryl amine to an aryl halide via the intermediacy of a diazonium salt. ${}^{1}$ Discovered in ${}^{{1884},{}^{2,}{}^{3}}$ this century-old transformation is still being extensively used in modern organic synthesis in both academic and industrial settings. ${}^{4 - 8}$ To date, many synthetically useful variants of Sandmeyer reaction have been reported, including copper metal mediated process (Gattermann reaction), ${}^{9}$ diazotization in organic phases (Doyle diazotization), ${}^{{10},{11}}\mathrm{{Cu}}\left( \mathrm{I}\right)$ -catalyzed process ${}^{12}$ and acetate-facilitated metal-free halogenation. ${}^{13}$ Despite these valuable advances, ${}^{9 - {15}}$ the development of new strategy for Sandmeyer reaction is still of great importance.

桑德迈尔反应是一种通过重氮盐中间体将芳基胺转化为芳基卤化物的根本重要方法。${}^{1}$ 这个有百年历史的转化反应于${}^{{1884},{}^{2,}{}^{3}}$ 被发现，至今仍在学术和工业环境中的现代有机合成中广泛使用。${}^{4 - 8}$ 迄今为止，已报道了许多具有合成价值的桑德迈尔反应变体，包括铜金属介导的过程(加特曼反应)、${}^{9}$ 有机相中的重氮化反应(多伊尔重氮化反应)、${}^{{10},{11}}\mathrm{{Cu}}\left( \mathrm{I}\right)$ -催化的过程${}^{12}$ 以及乙酸盐促进的无金属卤化反应。${}^{13}$ 尽管取得了这些有价值的进展，${}^{9 - {15}}$ 开发桑德迈尔反应的新策略仍然非常重要。

The past decade has witnessed a resurging interest in organic electrochemistry that dramatically improved organic chemists’ ability for green and sustainable synthesis. ${}^{{16} - {29}}$ Our laboratory has been engaged in the development of organic electrochemistry to overcome unmet synthetic challenges. ${}^{{30},{31}}$ In this context, we have recently become interested in electrocatalytic transformations of diazonium salts (Scheme 1A). An efficient electrochemical method for Sandmeyer reaction is hampered by several factors. First, diazonium salts can engage in undesired two-electron reduction, ${}^{{32},} \; {}^{33}$ leading to the formation of an aryl anion that could be easily protonated to give the reduction product (Scheme 1Ba). Second, known as the Gomberg-Bachmann reaction, ${}^{34}$ the transient aryl radical intermediate can react with an arene or another aryl radical to give a biaryl side product (Scheme 1Bb). ${}^{35}$ Third, the well-documented reaction of diazonium salts with the electrode can alter its properties and reduce the efficiency of electrochemical processes (Scheme 1Bc). ${}^{{36} - {38}}$ We envision that the regulation of electric current to control the rate of aryl radical generation and the judicious choice of halogenation reagents to rapidly intercept the nascent aryl radical would be the key to this electrochemical Sandmeyer reaction (Scheme 1Bd). In this report, we demonstrate a general electrochemical strategy for the Sandmeyer halogenation of aryl diazonium salts. Scheme 1 Electrochemical Sandmeyer halogenation reaction.

在过去十年中，人们对有机电化学的兴趣再度兴起，这极大地提高了有机化学家进行绿色和可持续合成的能力。${}^{{16} - {29}}$ 我们实验室一直致力于有机电化学的开发，以克服未解决的合成挑战。${}^{{30},{31}}$ 在这种背景下，我们最近对重氮盐的电催化转化产生了兴趣(方案1A)。桑德迈尔反应的有效电化学方法受到几个因素的阻碍。首先，重氮盐可能会发生不期望的双电子还原反应，${}^{{32},} \; {}^{33}$ 导致形成芳基阴离子，该阴离子很容易被质子化生成还原产物(方案1Ba)。其次，瞬态芳基自由基中间体可与芳烃或另一个芳基自由基反应生成联芳基副产物(方案1Bb)，这一反应被称为贡伯格-巴赫曼反应。${}^{34}$ ${}^{35}$ 第三，重氮盐与电极的反应已被充分记录，这会改变电极性质并降低电化学过程的效率(方案1Bc)。${}^{{36} - {38}}$ 我们设想，调节电流以控制芳基自由基的生成速率，并明智地选择卤化试剂以快速捕获新生的芳基自由基，将是这种电化学桑德迈尔反应的关键(方案1Bd)。在本报告中，我们展示了一种用于芳基重氮盐桑德迈尔卤化反应的通用电化学策略。方案1 电化学桑德迈尔卤化反应。

A. Electrochemical Sandmeyer reaction

A. 电化学桑德迈尔反应

a. Department of Energy and Resources Engineering, College of Engineering, Peking University, Beijing 100871, China.

a. 能源与资源工程系，工程学院，北京大学，北京100871，中国。

b. Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.

b. 北京分子科学国家实验室，化学与分子工程学院，北京大学，北京100871，中国。

C. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China.

C. 天然药物及仿生药物国家重点实验室，药学院，北京大学，北京100871，中国。

${}^{d}$ Department of Chemistry, University of California, Berkeley, CA 94720, United States.

${}^{d}$ 化学系，美国加利福尼亚大学伯克利分校，加利福尼亚94720

Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/x0xx00000x

电子补充信息(ESI)可用:[应在此处包含任何可用补充信息的详细内容]。见DOI:10.1039/x0xx00000x

Results and discussion

结果与讨论

The electrochemical bromination of aryldiazonium tetrafluoroborate 1a was selected as the model reaction with $N$ - bromosuccinimide (NBS) as the halogen source. The results are depicted in Table 1 (entries 1-7). Acetonitrile and DMF were first evaluated due to the good solubility of substrates and electrolytes in these solvents. Under these conditions, the desired product ethyl 4-bromobenzoate (2a) formed in low yields (entry 1-2). The major byproduct was found to be ethyl benzoate as indicated by GC-MS analysis of the crude reaction mixture, showing that protonation or hydrogen abstraction ${}^{11}$ was the major undesired pathway. We then evaluated other solvents, and the use of a mixed solvent system consisting of MeOH and DMF (entries 3-6) provided higher yield of 2a. Under the optimized reaction conditions using a 5:1 (v:v) mixture of MeOH/DMF as the solvent, ${\mathrm{{Bu}}}_{4}{\mathrm{{NClO}}}_{4}$ as the electrolyte and a constant current of ${10}\mathrm{\;{mA}}$ and time of $3\mathrm{\;h}({3.7}\mathrm{\;F}/\mathrm{{mol}}$ electricity), the desired bromination product (2a) formed in 83% yield. Finally, control experiments were conducted without current (entry 7), and significantly lower yield of 2a was observed. This demonstrated that the desired product was predominantly obtained from the electrochemical process.

以四氟硼酸芳基重氮盐1a的电化学溴化反应作为模型反应，以$N$ - 溴代琥珀酰亚胺(NBS)作为卤素源。结果如表1所示(条目1 - 7)。由于底物和电解质在乙腈和N, N - 二甲基甲酰胺(DMF)中具有良好的溶解性，因此首先对这两种溶剂进行了评估。在这些条件下，所需产物4 - 溴苯甲酸乙酯(2a)的产率较低(条目1 - 2)。通过对粗反应混合物的气相色谱 - 质谱(GC - MS)分析发现，主要副产物是苯甲酸乙酯，这表明质子化或氢原子抽取${}^{11}$是主要的不期望发生的反应途径。然后我们评估了其他溶剂，由甲醇和DMF组成的混合溶剂体系(条目3 - 6)能提供更高产率的2a。在使用甲醇/ DMF体积比为5:1的混合物作为溶剂、${\mathrm{{Bu}}}_{4}{\mathrm{{NClO}}}_{4}$作为电解质、恒定电流为${10}\mathrm{\;{mA}}$且电解时间为$3\mathrm{\;h}({3.7}\mathrm{\;F}/\mathrm{{mol}}$的优化反应条件下，所需的溴化产物(2a)的产率为83%。最后，进行了无电流的对照实验(条目7)，观察到2a的产率显著降低。这表明所需产物主要是通过电化学过程获得的。

The iodination of 1a was next examined (entries 8-10). Compared with $N$ -iodosuccinimide (NIS) (entry 8), ${\mathrm{{CH}}}_{2}{\mathrm{I}}_{2}$ was found to be a better iodinating agent in this electrochemical reaction. The desired product (3a) was obtained in 87% isolated yield under the optimized conditions (entry 9). Again, this iodination was unambiguously driven by electricity as revealed by the control experiment (entry 10).

接下来研究了1a的碘化反应(条目8 - 10)。与$N$ - 碘代琥珀酰亚胺(NIS)相比(条目8)，发现${\mathrm{{CH}}}_{2}{\mathrm{I}}_{2}$在该电化学反应中是一种更好的碘化剂。在优化条件下(条目9)，所需产物(3a)的分离产率为87%。同样，对照实验(条目10)表明该碘化反应无疑是由电驱动的。

Compared with bromination and iodination, the electrochemical chlorination of diazonium salts was more challenging. Due to the higher electronegativity of chlorine, ${\mathrm{{NCS}}}^{39}$ and ${\mathrm{{TCCA}}}^{40}$ behaved more like oxidants rather than chlorine donors. Inspired by Lin’s recent work on the electrocatalytic chlorination of alkenes, ${}^{{41},{42}}$ we used anodic oxidation to generate chlorine radical from chloride anion. A series of alkali chlorides, cathode materials and solvents were evaluated. Ultimately, LiCI was found to be the optimal chlorine source with nickel as the cathode and acetonitrile as the solvent (entries 13-15).

与溴化和碘化相比，重氮盐的电化学氯化反应更具挑战性。由于氯的电负性较高，${\mathrm{{NCS}}}^{39}$和${\mathrm{{TCCA}}}^{40}$表现得更像氧化剂而不是氯供体。受Lin最近关于烯烃电催化氯化工作的启发，${}^{{41},{42}}$我们使用阳极氧化从氯离子生成氯自由基。评估了一系列碱金属氯化物、阴极材料和溶剂。最终发现，以氯化锂为最佳氯源，镍为阴极，乙腈为溶剂(条目13 - 15)。

With the optimal reaction conditions, we then surveyed the substrate scope (Table 2). For bromination using NBS, aryl diazonium salts with an electron-withdrawing group, including an ester (2a-2c), a nitro (2d-2g), a cyano (2h and 2i), a halogen (2j-2l), a trifluoromethyl (2m) and a sulfonyl group (2n), furnished the corresponding brominated products in good to excellent yields. For electron-neutral or electron-rich diazonium salts, the use of NBS led to polybromination as revealed by GC-MS analysis. In these cases, ${\mathrm{{CBrCl}}}_{3}$ proved to be a better brominating agent using DMF as the solvent (2o-2t).

在优化的反应条件下，我们接着考察了底物范围(表2)。对于使用NBS进行的溴化反应，带有吸电子基团的芳基重氮盐，包括酯基(2a - 2c)、硝基(2d - 2g)、氰基(2h和2i)、卤素(2j - 2l)、三氟甲基(2m)和磺酰基(2n)，能以良好到优异的产率得到相应的溴化产物。对于电子中性或富电子的重氮盐，气相色谱 - 质谱分析表明使用NBS会导致多溴化。在这些情况下，以DMF为溶剂时，${\mathrm{{CBrCl}}}_{3}$被证明是一种更好的溴化剂(2o - 2t)。

Moreover, under analogous electrochemical conditions, the iodination of aryl diazonium salts bearing an electron-withdrawing group, such as an ester (3a-3c), a cyano (3h and 3i), a halogen (3j- 3I), a trifluoromethyl (3m), a sulfonyl (3n) and an acetyl (3u, 3v), gave good yields (63-96%). Additionally, electron-neutral aryl diazonium salts were also suitable substrates for this procedure (3o-3q, 3s). Last, a range of diazonium salts (4a, 4k, 4m, 4n and 4o)

此外，在类似的电化学条件下，带有吸电子基团的芳基重氮盐的碘化反应，如酯基(3a - 3c)、氰基(3h和3i)、卤素(3j - 3l)、三氟甲基(3m)、磺酰基(3n)和乙酰基(3u，3v)，能得到良好的产率(63 - 96%)。此外，电子中性的芳基重氮盐也是该反应的合适底物(3o - 3q，3s)。最后，一系列重氮盐(4a，4k，4m，4n和4o)

could be efficiently chlorinated using LiCI as the electrochemical chlorine reagent. For instance, sulfone substituted product 4m was obtained in 64% isolated yield.

使用氯化锂作为电化学氯试剂能够有效地进行氯化反应。例如，砜取代产物4m的分离产率为64%。

Table 1 Reaction development and optimization

表1反应的发展与优化

${}^{a}$ Reaction conditions: 1a (0.3 mmol), halogenation reagent [X], electrolyte (0.25 mmol,0.83 equiv), solvent (3 mL),20°C,3 h. cc, constant current. Pt mesh electrodes $\left( {1{\mathrm{\;{cm}}}^{2}}\right.$ each, 52 mesh) were used. ${}^{b}$ GC-FID yields using decane as an internal standard. Isolated yields in parentheses. ${}^{c}{15}\mathrm{\;h}.{}^{d}$ MeCN (3 mL) as the solvent and nickel foam $\left( {1{\mathrm{\;{cm}}}^{2}}\right)$ as the cathode.

${}^{a}$反应条件:1a(0.3 mmol)，卤化试剂[X]，电解质(0.25 mmol，0.83当量)，溶剂(3 mL)，20°C，3小时。采用恒流。使用铂网电极($\left( {1{\mathrm{\;{cm}}}^{2}}\right.$各一个，52目)。${}^{b}$以癸烷为内标物的气相色谱 - 氢火焰离子化检测器产率。括号内为分离产率。${}^{c}{15}\mathrm{\;h}.{}^{d}$以乙腈(3 mL)为溶剂，泡沫镍$\left( {1{\mathrm{\;{cm}}}^{2}}\right)$作为阴极。

Anilines are broadly available starting materials for organic synthesis. Thus, it is highly desirable to perform in situ diazotization/electrochemical reaction to directly employ anilines as the precursors for halogenation. As shown in Table 3, a diverse array of aryl amines was successfully transformed to the corresponding halogenated products in good to excellent yields (42- 83%). This one-pot protocol tolerated a number of functional groups, such as a boronic ester (3aa), an amide (3ab-3ad) and an indole (3ae). In general, aryl amines with an electron-withdrawing group gave relatively higher yield. For instance, bromination of 4- cyanoaniline under the one-pot protocol gave 83% GC yield (2h); iodination of N-(4-aminophenyl)acetamide gave 78% isolated yield (3ab). Moreover, it is noteworthy that the aniline derived from Vitamin E was also iodinated in 59% isolated yield (3af).

苯胺是有机合成中广泛可得的起始原料。因此，非常希望进行原位重氮化/电化学反应，直接将苯胺用作卤化反应的前体。如表3所示，多种芳基胺成功转化为相应的卤化产物，产率良好至优异(42 - 83%)。此一锅法方案耐受多种官能团，如硼酸酯(3aa)、酰胺(3ab - 3ad)和吲哚(3ae)。一般来说，带有吸电子基团的芳基胺产率相对较高。例如，在一锅法方案下，4 - 氰基苯胺的溴化反应气相色谱产率为83%(2小时)；N - (4 - 氨基苯基)乙酰胺的碘化反应分离产率为78%(3ab)。此外，值得注意的是，源自维生素E的苯胺碘化反应分离产率也达到了59%(3af)。

${}^{a}$ Reaction conditions: 1 (0.3 mmol), ${\mathrm{{Bu}}}_{4}{\mathrm{{NClO}}}_{4}$ (0.25 mmol,0.83 equiv), ${\mathrm{{CH}}}_{3}\mathrm{{OH}}$ (2.5 mL), and DMF (0.5 mL), ${20}^{ \circ }\mathrm{C},3\mathrm{\;h}$ , constant current 10 mA. Pt mesh electrodes $\left( {1\mathrm{\;{cm}} \times 1\mathrm{\;{cm}}}\right)$ were used. Isolated yields were given. GC-FID yields in parentheses were given due to either product volatility or difficulty in isolation with by-product (e.g. ArH). ${}^{b}{\mathrm{{CH}}}_{3}\mathrm{{OH}}/\mathrm{{DMF}}{20} : 1$ (total ${3.0}\mathrm{\;{mL}}$ ). ${}^{c}1\mathrm{\;h}$ . ${}^{d19}\mathrm{\;F}$ NMR yields determined using 4- (trifluoromethoxy)anisole as an internal standard. ${}^{e}$ DMF (3 mL). ${}^{f}$ 4.5 h. ${}^{g}$ 2 h. ${}^{h}$ MeCN (3 mL), LiClO ${}_{4}$ (0.5 mmol) as electrolyte. ${}^{i}$ 20 mA, Ni foam cathode.

${}^{a}$反应条件:1(0.3 mmol)，${\mathrm{{Bu}}}_{4}{\mathrm{{NClO}}}_{4}$(0.25 mmol，0.83当量)，${\mathrm{{CH}}}_{3}\mathrm{{OH}}$(2.5 mL)，以及N, N - 二甲基甲酰胺(0.5 mL)，${20}^{ \circ }\mathrm{C},3\mathrm{\;h}$，恒流10 mA。使用铂网电极$\left( {1\mathrm{\;{cm}} \times 1\mathrm{\;{cm}}}\right)$。给出分离产率。括号内的气相色谱 - 氢火焰离子化检测器产率是由于产物挥发性或与副产物(如ArH)分离困难而给出的。${}^{b}{\mathrm{{CH}}}_{3}\mathrm{{OH}}/\mathrm{{DMF}}{20} : 1$(总计${3.0}\mathrm{\;{mL}}$)。${}^{c}1\mathrm{\;h}$。${}^{d19}\mathrm{\;F}$以4 - (三氟甲氧基)苯甲醚为内标物测定的核磁共振产率。${}^{e}$N, N - 二甲基甲酰胺(3 mL)。${}^{f}$4.5小时。${}^{g}$2小时。${}^{h}$乙腈(3 mL)，高氯酸锂${}_{4}$(0.5 mmol)作为电解质。${}^{i}$20 mA，泡沫镍阴极。

To further demonstrate the utility of this electrochemical protocol, gram-scale experiments were next carried out. Since the electrochemical reduction of diazonium salts takes place at the cathode, we applied inexpensive graphite plate electrodes with a large size to lower the current density $\left( {J = {2.78}\mathrm{{mA}}/{\mathrm{{cm}}}^{2}}\right)$ . By using the setup shown in Scheme 2, 2h was prepared from 1h on a three-gram scale (15 mmol) in 76% yield. Similarly, 3h was prepared on a three-gram scale in 80% yield.

为了进一步证明这种电化学方法的实用性，接下来进行了克级实验。由于重氮盐的电化学还原在阴极发生，我们应用了大尺寸的廉价石墨板电极以降低电流密度$\left( {J = {2.78}\mathrm{{mA}}/{\mathrm{{cm}}}^{2}}\right)$。通过使用方案2所示的装置，以1h为原料在3克规模(15 mmol)上制备2h，产率为76%。同样，以3克规模制备3h，产率为80%。

Table 3 One Pot Diazotization/Electrochemical Reaction. ${}^{a}$

表3一锅法重氮化/电化学反应。${}^{a}$

${}^{a}$ Reaction conditions: aryl amine (0.3 mmol), ${}^{t}$ BuONO (0.33 mmol, 1.1 equiv), HCl (5 M in ${\mathrm{{Et}}}_{2}\mathrm{O},{90\mu }\mathrm{L},{0.45}\mathrm{{mmol}},{1.5}$ equiv), ${\mathrm{{CH}}}_{3}\mathrm{{OH}} \; {2.5}\mathrm{\;{mL}}$ , DMF ${0.5}\mathrm{\;{mL}},0{}^{ \circ }\mathrm{C},{0.5}\mathrm{\;h}$ ; then ${\mathrm{{Bu}}}_{4}{\mathrm{{NClO}}}_{4}({0.25}\mathrm{{mmol}},{0.83}$ equiv), [X], 20 ${}^{ \circ }\mathrm{C}$ , 3 h, constant current 10 mA. Pt mesh electrodes (1cm $\times$ 1cm) were used. Isolated yields were given. GC-FID yields were shown in parentheses. For details, see ESI.

${}^{a}$反应条件:芳基胺(0.3 mmol)，${}^{t}$叔丁基亚硝酸酯(0.33 mmol，1.1当量)，HCl(5 M，${\mathrm{{Et}}}_{2}\mathrm{O},{90\mu }\mathrm{L},{0.45}\mathrm{{mmol}},{1.5}$当量)，${\mathrm{{CH}}}_{3}\mathrm{{OH}} \; {2.5}\mathrm{\;{mL}}$，N, N - 二甲基甲酰胺${0.5}\mathrm{\;{mL}},0{}^{ \circ }\mathrm{C},{0.5}\mathrm{\;h}$；然后${\mathrm{{Bu}}}_{4}{\mathrm{{NClO}}}_{4}({0.25}\mathrm{{mmol}},{0.83}$当量)，[X]，20${}^{ \circ }\mathrm{C}$，3小时，恒流10 mA。使用铂网电极(1cm$\times$1cm)。给出了分离产率。括号内为气相色谱 - 氢火焰离子化检测器产率。详情见补充信息。

To probe this electrically generated aryl radical species, we carried out a range of mechanistic experiments. First, a radical clock experiment was performed by using diazonium salt 5 derived from 2-(allyloxy)aniline as the substrate (Scheme 3A). We obtained only the cyclized product 6 in 37% yield as determined by ${}^{1}\mathrm{H}$ NMR spectroscopy, and the acyclic product was not detected by GC-MS and ${}^{1}\mathrm{H}$ NMR analysis. Next, electrochemical reaction of 1a with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was conducted, affording arylated product 7 in 62% isolated yield (Scheme 3B). This is well in accord with the Studer’s report. ${}^{43}$ In their paper, they have demonstrated that TEMPONa is capable of reducing diazonium salt to its aryl radical, thus facilitating the following transformation.

为了探究这种电生成的芳基自由基物种，我们进行了一系列机理实验。首先，以2 - (烯丙氧基)苯胺衍生的重氮盐5为底物进行了自由基钟实验(方案3A)。通过${}^{1}\mathrm{H}$核磁共振光谱测定，我们仅获得了环化产物6，产率为37%，并且通过气相色谱 - 质谱联用和${}^{1}\mathrm{H}$核磁共振分析未检测到开环产物。接下来，进行了1a与2,2,6,6 - 四甲基 - 1 - 哌啶氧基(TEMPO)的电化学反应，得到芳基化产物7，分离产率为62%(方案3B)。这与施图德的报告非常一致。${}^{43}$在他们的论文中，他们证明了四甲基哌啶醇钠能够将重氮盐还原为其芳基自由基，从而促进后续转化。

Scheme 2 Gram-Scale Electrochemical Sandmayer Reactions. A Pt mesh electrode $(1\mathrm{\;{cm}} \times 1\mathrm{\;{cm}},{52}$ mesh) as the anode, and 4 graphite plates $(4 \times 3\mathrm{\;{cm}} \times 3\mathrm{\;{cm}}$ immersed in the solution) as the cathodes.

方案2 克级电化学反应桑德迈尔反应。以铂网电极$(1\mathrm{\;{cm}} \times 1\mathrm{\;{cm}},{52}$网)作为阳极，4块石墨板$(4 \times 3\mathrm{\;{cm}} \times 3\mathrm{\;{cm}}$浸入溶液中)作为阴极。

A. Electrochemical clock reaction

A. 电化学钟反应

Scheme 3 Control experiments.

方案3 对照实验。

Figure 2 (A) Four in situ EPR electrochemical reactions. Photograph of EPR flat cell with home-made electrolysis setup is shown. (B) Time dependent EPR profile of reaction b. For the EPR profile of reactions a, c and d, see Figure S5 in Electronic Supplementary Information. (C) EPR signal at different time of reactions a-d. (D) Time evolution of double-integrated intensity of the signals of in situ EPR electrochemical reactions a-d. a. u., arbitrary unit.

图2 (A)四个原位电子顺磁共振电化学反应。展示了带有自制电解装置的电子顺磁共振扁平池照片。(B)反应b的随时间变化的电子顺磁共振谱图。反应a、c和d的电子顺磁共振谱图见电子补充信息中的图S5。(C)反应a - d在不同时间的电子顺磁共振信号。(D)原位电子顺磁共振电化学反应a - d信号的双积分强度随时间的变化。a.u.，任意单位。

Electron paramagnetic resonance (EPR) is a spectroscopic technique capable of detecting and identifying paramagnetic species, such as organic radicals, thus providing essential information on the nature of reactive intermediates in single electron transfer reactions. EPR spectroscopy has been extensively utilized to study the electrochemically generating organic radicals. ${}^{46}$ Here, we applied EPR spectroelectrochemistry to study the current electrochemical Sandmeyer reaction. In our setup, we combined a common Bruker Elexsys E580 spectrometer with a Super-high sensitivity probe head $\left( {\omega = {9.80}\mathrm{{GHz}}}\right)$ and a standard flat cell (0.3 mm in depth) with ultrathin Pt wires ( $\Phi$ 0.2 mm) for this in situ study (Figure 2A). Using this setup, electrolysis experiments and in situ EPR measurements were first performed on samples containing diazonium salt 1a and NBS in MeOH/DMF with $n - {\mathrm{{Bu}}}_{4}{\mathrm{{NClO}}}_{4}$ as the electrolyte. EPR signals were not observed, presumably due to the high reactivity and low concentration of these radical intermediates. Consequently, N-benzylidene-tert-butylamine N-oxide (PBN) was introduced to the experiments as a spin-trap. ${}^{47}$ Spin-traps react with short-living radicals and convert them to more stable, EPR detectable radical species. The choice of PBN is based on Bard’s report, ${}^{48}$ where they found that PBN is electroinactive between 1.5 and -2.4 V ( ${vs}$ . SCE). Thus, four electrochemical reactions a-d were followed by in situ EPR spectroscopy using PBN as the spin-trap (Figure 2A). The EPR spectrum was acquired in an interval of ${30}\mathrm{\;s}$ over the course of ${100}\mathrm{\;{min}}$ . These EPR signals were then compiled as a time dependent 2D profile (for reaction b, see Figure 2B; for reactions a, c and d, see Figure S5). Figure 2C shows the EPR signals of these reactions at different reaction time, and figure 2D shows time dependent double-integrated intensity of these in situ EPR signals.

电子顺磁共振(EPR)是一种光谱技术，能够检测和识别顺磁性物质，如有机自由基，从而提供有关单电子转移反应中反应中间体性质的重要信息。EPR光谱已被广泛用于研究电化学产生的有机自由基。${}^{46}$ 在这里，我们应用EPR光谱电化学来研究当前的电化学桑德迈尔反应。在我们的装置中，我们将一台普通的布鲁克Elexsys E580光谱仪与一个超高灵敏度探头 $\left( {\omega = {9.80}\mathrm{{GHz}}}\right)$ 和一个标准扁平池(深度为0.3毫米)以及用于原位研究的超薄铂丝($\Phi$ 0.2毫米)相结合(图2A)。使用该装置，首先在含有重氮盐1a和NBS的甲醇/二甲基甲酰胺溶液中以 $n - {\mathrm{{Bu}}}_{4}{\mathrm{{NClO}}}_{4}$ 作为电解质进行电解实验和原位EPR测量。未观察到EPR信号，可能是由于这些自由基中间体的高反应活性和低浓度。因此，将N-苄叉叔丁胺N-氧化物(PBN)作为自旋捕获剂引入实验。${}^{47}$ 自旋捕获剂与短寿命自由基反应并将它们转化为更稳定的、可通过EPR检测的自由基物种。PBN 的选择基于巴德的报告，${}^{48}$ 他们发现在该报告中PBN在1.5至 -2.4 V(${vs}$ . SCE)之间是电惰性的。因此，使用PBN作为自旋捕获剂，通过原位EPR光谱跟踪了四个电化学反应a - d(图2A)。在 ${30}\mathrm{\;s}$ 的时间间隔内采集EPR光谱，持续时间为 ${100}\mathrm{\;{min}}$ 。然后将这些EPR信号汇编为随时间变化的二维图谱(对于反应b，见图2B；对于反应a、c和d，见图S5)。图2C显示了这些反应在不同反应时间的EPR信号，图2D显示了这些原位EPR信号随时间变化的双积分强度。

In these reactions, no major EPR signal is observed until electricity is on. The isotropic $g$ factor and hyperfine coupling constants of these radical EPR signals were simulated using the least-squares fitting method with EasySpin’s function garlic (For details, see ESI). As expected, radicals in reactions a, b and c are different and in d resembles c (Figure 2C). The contrasting growth rates of intensity shown in Figure 2D provided valuable mechanistic information. By comparing reaction a and b, a rapid growth observed in reaction b indicated that diazonium salt 1a was rapidly reduced to an aryl radical upon electrolysis. The resulting aryl radical was trapped by PBN to afford an EPR active species. Based on a six-line EPR spectrum $\left( {g = {2.0039},{a}_{\mathrm{N}} = {13.02}\mathrm{G},{a}_{\mathrm{H}} = {2.37}\mathrm{G}}\right) {}^{{47},} \; {}^{48}$ and HRMS data, this radical could be likely attributed as compound 8. In reactions $c$ and $d$ , the intensity grow slowly as compared with reaction b, indicating that the addition of NBS changes the reaction pathway of electrically generated radicals. In reaction d, the intensity rapidly decayed when the current was turned off, also demonstrating an electricity driving radical generation process. These in situ EPR electrochemical experiments and previous cyclic voltammetry studies demonstrated that diazonium salts can readily undergo single electron reduction processes on the cathode, and the resulting aryl radical is a highly reactive species that can be trapped by many radical trapping reagents, such as NBS, ${\mathrm{{CH}}}_{2}{\mathrm{I}}_{2}$ , PBN and TEMPO. Meanwhile, the solvents (e.g. MeOH) can be oxidized on anode ${}^{49}$ to balance the overall transformation (Scheme 4).

在这些反应中，直到通电才观察到主要的EPR信号。使用EasySpin的函数garlic通过最小二乘法拟合模拟了这些自由基EPR信号的各向同性 $g$ 因子和超精细耦合常数(详细信息见ESI)。正如预期的那样，反应a、b和c中的自由基不同，反应d中的自由基与反应c中的相似(图2C)。图2D中显示的强度对比增长速率提供了有价值的机理信息。通过比较反应a和b，反应b中观察到的快速增长表明重氮盐1a在电解时迅速还原为芳基自由基。生成的芳基自由基被PBN捕获，得到一个具有EPR活性的物种。基于六线EPR光谱 $\left( {g = {2.0039},{a}_{\mathrm{N}} = {13.02}\mathrm{G},{a}_{\mathrm{H}} = {2.37}\mathrm{G}}\right) {}^{{47},} \; {}^{48}$ 和高分辨质谱数据，该自由基可能归因于化合物8。在反应 $c$ 和 $d$ 中，与反应b相比强度增长缓慢，表明加入NBS改变了电生成自由基的反应途径。在反应d中，当电流关闭时强度迅速衰减，也证明了电驱动自由基生成过程。这些原位EPR电化学实验和先前的循环伏安研究表明，重氮盐可以在阴极上容易地经历单电子还原过程，并且生成的芳基自由基是一种高反应活性的物种，可以被许多自由基捕获试剂捕获，如NBS、${\mathrm{{CH}}}_{2}{\mathrm{I}}_{2}$ 、PBN和TEMPO。同时，溶剂(如甲醇)可以在阳极 ${}^{49}$ 上被氧化以平衡整体转化(方案4)。

Scheme 4 Proposed reaction events on both electrodes and in solvent bulk.

方案4 提出的在两个电极和溶剂本体中的反应过程。

Conclusion

结论

In summary, we have developed a general electrochemical protocol for the Sandmeyer halogenation process. A diverse range of functional groups were compatible with this electrochemical reaction. Anilines can be directed employed as the starting material, further expanding utility of this method. Moreover, this method is amenable to the large-scale synthesis of aryl halides, and very inexpensive graphite can be employed instead of platinum as the cathode material for these large-scale preparation. Importantly, detailed mechanism studies, including the application of rarely used in situ EPR measurements, supports a single electron reduction mechanism for the halogenation of diazonium salts upon electrolysis. This electrochemical process could be a complementary method for the existing Sandmeyer halogenation reactions, and might inspire other Sandmeyer type transformations (e.g. noble metal free trifluoromethylation ${}^{{50} - {52}}$ ) in the near future.

总之，我们已经开发出一种用于桑德迈尔卤化反应的通用电化学方法。多种官能团与这种电化学反应兼容。苯胺可以直接用作起始原料，进一步扩展了该方法的实用性。此外，该方法适用于芳基卤化物的大规模合成，并且在这些大规模制备中，可以使用非常便宜的石墨代替铂作为阴极材料。重要的是，详细的机理研究，包括应用很少使用的原位电子顺磁共振测量，支持了电解时重氮盐卤化的单电子还原机理。这种电化学方法可能是现有桑德迈尔卤化反应的一种补充方法，并且可能在不久的将来启发其他桑德迈尔类型的转化(例如无贵金属的三氟甲基化${}^{{50} - {52}}$)。

Conflicts of interest

利益冲突

There are no conflicts to declare.

无需声明利益冲突。

Acknowledgements

致谢

The project is supported by the Natural Science Foundation of China (Grants 21502003 and 21772003). We also thank the “1000-Youth Talents Plan” and Peking University for start-up funds. Y.Y. thanks the Miller Institute for Basic Research in Science at UC Berkeley for a post-doctoral fellowship.

The project is supported by the Natural Science Foundation of China (Grants 21502003 and 21772003). We also thank the “1000-Youth Talents Plan” and Peking University for start-up funds. Y.Y. thanks the Miller Institute for Basic Research in Science at UC Berkeley for a post-doctoral fellowship.

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注释与参考文献

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In situ EPR electrochemical experiments

原位电子顺磁共振电化学实验