Since their discovery(1) in 1858, aryl diazonium salts have played a major role in organic synthesis. They have been widely employed as precursors to diazo dyes(2) and synthetic intermediates. Classical named applications developed prior to 1940 include the Sandmeyer reaction,(3) Balz–Schiemann fluorination, Gomberg–Bachmann reaction, Pschorr cyclization, and Meerwein arylation.(4,5) Aryl diazonium salts can also serve as highly reactive aryl halide surrogates, and over the past 40 years their use in palladium-catalyzed cross-couplings has been extensively explored.(6−9) Recently, there has been renewed interest in the use of aryl diazonium salts within the synthetic community,(10) particularly in catalytic cross-couplings and C–H bond activation / functionalization.(9) Exemplar recent developments and applications (Figure 1) include Suzuki–Miyaura cross coupling for the large scale (>500 g) preparation of an intermediate in the synthesis of angiotensin II inhibitors.(11) Additionally, our laboratory has recently disclosed a mild and selective Pd-catalyzed C–H arylation of tryptophan derivatives.(12) Furthermore, recent advances in Sandmeyer-type chemistries have been developed for the borylation, stannylation, phosphorylation, and trifluoromethylation of arenes.(13) For example, pinacol boronates can be prepared through eosin Y photocatalyzed borylation of aryl diazonium salts.(14) Figure 1. Selected recent applications of aryl diazonium salts in chemical synthesis. The great utility of aryl diazonium salts is, however, tempered by their potential instability,(15) which is often governed by the associated counterion. Many salts, including the common aryl diazonium chlorides, can undergo violent decomposition and even explosion upon isolation.(16) Diazo compounds tend to decompose at low temperatures with enthalpies of decomposition of −160 to −180 kJ/mol.(17) Indeed, there have been multiple recorded incidents involving the loss of life from diazonium salt explosions.(16,17) However, diazonium tetrafluoroborates, hexafluorophosphates, tosylates, and disulfonamides are often significantly more stable.(16,18) The tetrafluoroborates, in particular, have seen significant recent use (Figure 1); they can often be easily prepared and isolated as crystalline solids that can be stored in the dark at −20 °C for several years.(16,18) Indeed, a small selection of aryl diazonium tetrafluoroborate salts are commercially available from major chemical suppliers. Furthermore, an undergraduate chemistry experiment involving the synthesis and isolation of phenyl diazonium tetrafluoroborate has been run at the University of York for over 20 years without incident. There seems to be a growing belief that, by virtue of the choice of counterion, aryl diazonium tetrafluoroborate salts will always be stable. This is a dangerous assumption—we recently encountered the violent decomposition of approximately 1 g of 3-pyridyl diazonium tetrafluoroborate 1. Clearly, it is of vital importance that the researcher should not assume that such salts will always be stable. Our material was prepared according to a standard procedure detailed in Organic Letters in 2019.(19) A previous, almost identical preparation was published in 2016.(20) Both called for isolation of the salt by filtration, followed by washing with diethyl ether and drying under vacuum. In our hands, the dry salt violently decomposed at room temperature before it could be transferred to a freezer. While no injury or damage occurred, it is of major concern how often this material is prepared and used in academic research laboratories. In the past four years there have been 10 reports of the use of solid 1 (Figure 2),(19−28) three of which have been published in Organic Letters. Importantly, none of these papers detailed any specific hazards associated with this material, and only two (from the same laboratory) provide general warning information on diazonium salts.(25,27) However, this compound has been known to be hazardous for over 70 years.(15) Figure 2. Recent uses of 3-pyridyl diazonium tetrafluoroborate 1 In 1947 Roe reported that 1 “decomposes spontaneously and with considerable violence when the last trace of ether is removed”.(29) Furthermore, in 1967, a specific warning was published in Chemistry and Engineering News.(30) Dr. Robert P. Johnson and John P. Oswald of Abbot Laboratories synthesized 1 from 15 g of 3-aminopyridine, and the material spontaneously detonated. This warning states “Fortunately, the only injuries were temporary loss of hearing. Many other diazonium fluoroborates have been isolated and handled without difficulty. Although the Abbott preparation seems to be an exception to the general rule, Dr. Johnson suggests that all isolated diazonium salts be considered explosive until proved otherwise.” We wholeheartedly agree with Dr Johnson. Given the resurgence in interest in the use of aryl diazonium salts, we strongly suggest that researchers working in this area ascertain if any known salts they plan on preparing are unstable and to avoid all known dangerous diazonium salts when performing reaction scope studies.(15) We also refer readers to the article written by Sheng and co-workers on the “Reactive chemical hazards of diazonium salts”.(17) Their 12 cardinal rules for working with diazonium salts are reproduced below, with some minor modifications:

1.	Understand the explosive properties of diazonium salts. Always assume they are explosive unless proved otherwise.
2.	Use only a stoichiometric amount of sodium nitrite when generating diazonium salts, avoiding excess sodium nitrite (or quench with sulfamic acid in conjunction with nitrite indicator test).
3.	Check for the excess of nitrous acid by starch–potassium iodide papers and neutralize it.
4.	Minimize the presence of nitrous acid by combining amine and acid first, then subsequently adding the sodium nitrite.
5.	Keep the temperature below 5 °C (note: some diazonium salts are unstable at this temperature)
6.	Always vent the gases generated.
7.	Determine the thermal stability of diazonium compounds in your system.
8.	Never allow the undesired precipitation of diazonium salts out of solution.
9.	Analyze the residual diazo compounds in the final product, especially for new process conditions.
10.	Quench the remaining diazonium salts before any further treatments; quench solutions should be readily available.
11.	Isolate no more than 0.75 mmol of explosive diazonium salts at one time; also consider the addition of an inert material to stabilize the diazonium salts. Note: even on this scale extreme caution should be exercised (i.e., use of a protective blast shield).
12.	Use a plastic spatula when handling the solid. The dried powder should not be “scratched” with a metal spatula and should never be ground.

Understand the explosive properties of diazonium salts. Always assume they are explosive unless proved otherwise. Use only a stoichiometric amount of sodium nitrite when generating diazonium salts, avoiding excess sodium nitrite (or quench with sulfamic acid in conjunction with nitrite indicator test). Check for the excess of nitrous acid by starch–potassium iodide papers and neutralize it. Minimize the presence of nitrous acid by combining amine and acid first, then subsequently adding the sodium nitrite. Keep the temperature below 5 °C (note: some diazonium salts are unstable at this temperature) Always vent the gases generated. Determine the thermal stability of diazonium compounds in your system. Never allow the undesired precipitation of diazonium salts out of solution. Analyze the residual diazo compounds in the final product, especially for new process conditions. Quench the remaining diazonium salts before any further treatments; quench solutions should be readily available. Isolate no more than 0.75 mmol of explosive diazonium salts at one time; also consider the addition of an inert material to stabilize the diazonium salts. Note: even on this scale extreme caution should be exercised (i.e., use of a protective blast shield). Use a plastic spatula when handling the solid. The dried powder should not be “scratched” with a metal spatula and should never be ground. Additionally, we would like to highlight the potential incompatibility of diazonium salts with iodide salts due to formation of less stable diazonium iodides.(15) Furthermore, impurities such as bases, transition metals, or nitrous acid can lower the temperature at which decomposition occurs, potentially causing unpredictable and irreproducible decomposition behavior.(15,17) It is worth noting that solutions of diazonium salts with a pH of 5–6 can result in the formation and separation of diazoanhydrides (i.e., of the type RN₂ON₂R), many of which are violently explosive.(15) Thus, reactions employing diazonium salts might result in pH sensitivities, in addition to safety concerns. For the safety of all researchers in our community, we call on chemists to fully describe potential safety hazards in their experimental procedures.(31) More specifically, given the known instability of 1, the accepted best practice is always to keep the material moist and use it immediately, recognizing that it would be always best to avoid isolation of the diazonium salt where practically feasible.(15,32,33) Better still, it should be prepared in situ and never allowed to precipitate from the reaction mixture.(8) Furthermore, use of continuous flow technologies may help mitigate risk.(34) While we are unable to provide specific guidance for every single aryl/heteroaryl diazonium salt, we suggest that they are initially prepared on as small a scale as feasible and the thermal decomposition temperatures/stability are determined by independent means by an expert (e.g., using differential scanning calorimetry). This is the norm within the chemical industry but appears to be a less common practice in academic laboratories. It should also be noted that the other isomers of 1, 2- and 4-pyridine diazonium tetrafluoroborate are also known to be unstable.(29) Furthermore, Bretherick’s Handbook of Reactive Chemical Hazards lists four other hazardous aryl diazonium tetrafluoroborates (Figure 3)(15) including 2-chloro-3-pyridine diazonium tetrafluoroborate. Therefore, we advise particular caution in the preparation of analogues and isomers of 1. Figure 3. Known hazardous diazonium tetrafluoroborates. While it is worth highlighting that these hazardous diazonium tetrafluoroborate salts all have a high nitrogen content, we reiterate that the user should be cautious when preparing and using all little-known aryl diazonium salts, regardless of their structure. We call on the synthetic community to improve the reporting of any known or potential safety hazards, and encourage the routine inclusion of appropriate information in the Experimental Sections of publications. Views expressed in this editorial are those of the authors and not necessarily the views of the ACS. We thank EPSRC for funding (EP/S009965/1: “A Fully-Automated Robotic System for Intelligent Chemical Reaction Screening”). We are grateful to Dr. Moray Stark (Chemistry Department Safety Adviser, in York) for general advice and guidance. We greatly appreciate valuable industrial input on organo diazonium salt safety by Drs. George Hodges, Matthew Hughes, Ian Priestley, and Alan Robinson (Syngenta AG) and academic input from several colleagues from York Chemistry. This article references 34 other publications.

中文翻译：

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在合成和通用的芳基重氮四氟硼酸盐的制备和应用中需要谨慎。

自从1858年发现（1）以来，芳基重氮盐在有机合成中发挥了重要作用。它们已被广泛用作重氮染料（2）和合成中间体的前体。1940年之前开发的经典命名应用包括Sandmeyer反应，（3）Balz-Schiemann氟化，Gomberg-Bachmann反应，Pschorr环化和Meerwein芳基化。（4,5）芳基重氮盐也可以用作高反应性的芳基卤代用品，在过去的40年中，已广泛探索了其在钯催化的交叉偶联中的应用。（6-9）最近，人们对在合成社区中使用芳基重氮盐有了新的兴趣，（10）特别是在催化领域交叉偶联和C–H键激活/功能化。（9）示例性的最新发展和应用（图1）包括Suzuki-Miyaura交叉偶联，用于大规模制备（> 500 g）合成血管紧张素II抑制剂的中间体。（11）此外，我们的实验室最近还公开了一种轻度和选择性的Pd催化色氨酸衍生物的C–H芳基化。（12）此外，桑德迈型化学的最新进展已开发出芳烃的硼酸酯化，甲锡烷基化，磷酸化和三氟甲基化。（13）例如，频哪醇硼酸酯可以通过曙红Y光催化芳基重氮盐的硼化来制备。（14）图1.芳基重氮盐在化学合成中的近期应用。然而，芳基重氮盐的巨大用途因其潜在的不稳定性而受到限制，（15）通常由相关的抗衡离子控制。许多盐，包括常见的芳基重氮氯化物，在分离时会剧烈分解甚至爆炸。（16）重氮化合物在低温下易于分解，分解焓为-160至-180 kJ / mol。（17）实际上，有许多已记录的事故涉及重氮盐爆炸造成的生命损失。（16,17）然而，重氮四氟硼酸盐，六氟磷酸盐，甲苯磺酸盐和二磺酰胺通常要稳定得多。（16,18）特别是四氟硼酸盐具有近期有大量使用（图1）；它们通常可以很容易地制备和分离为结晶固体，可以在-20°C的黑暗环境中保存数年。（16,18）的确，少量的芳基重氮四氟硼酸盐可以从主要的化学供应商处商购获得。此外，约克大学已经进行了一项涉及合成和分离四氟硼酸苯基重氮鎓的本科化学实验，已有20多年没有发生任何事故。人们似乎越来越相信，通过选择抗衡离子，芳基重氮四氟硼酸盐将始终稳定。这是一个危险的假设-我们最近遇到了约1克3-吡啶基重氮四氟硼酸盐的剧烈分解 人们似乎越来越相信，通过选择抗衡离子，芳基重氮四氟硼酸盐将始终稳定。这是一个危险的假设-我们最近遇到了约1克3-吡啶基重氮四氟硼酸盐的剧烈分解 人们似乎越来越相信，通过选择抗衡离子，芳基重氮四氟硼酸盐将始终稳定。这是一个危险的假设-我们最近遇到了约1 g的3-吡啶基重氮四氟硼酸盐的剧烈分解。1。显然，至关重要的是，研究人员不应假设此类盐将始终稳定。我们的材料是根据2019年《有机快报》中详述的标准程序制备的。（19）先前几乎相同的制备方法于2016年发表。（20）两者均要求通过过滤分离盐，然后用乙醚和真空干燥。在我们手中，干盐在室温下会剧烈分解，然后才能转移到冰箱中。虽然没有发生伤害或损坏，但主要关心的是这种材料在学术研究实验室中的制备和使用频率。在过去的四年中，已经有10篇关于使用固体1的报告（图2），（19-28），其中3篇已发表在有机字母。重要的是，这些论文都没有详细介绍与该材料有关的任何具体危害，只有两份（来自同一实验室）提供了有关重氮盐的一般警告信息。（25,27）然而，已知该化合物对70多种有害。年。（15）图2.三吡啶四氟硼酸重氮鎓盐的最新用途1在1947年，罗伊（Roe）报告说1 “当去除最后一丝醚时，会自发分解，并且会遭受相当大的暴力”。（29）此外，在1967年，警告已发表在《化学与工程新闻》上。（30）Abbot Laboratories的Robert P. Johnson博士和John P. Oswald博士合成了1从15克3-氨基吡啶中提取出该物质，并自发爆炸。该警告指出：“幸运的是，唯一的伤害是暂时的听力丧失。许多其他氟硼酸重氮盐已被分离和处理，没有任何困难。尽管雅培制剂似乎是一般规则的一个例外，但约翰逊博士建议所有分离出的重氮盐都被认为具有爆炸性，除非另有说明。我们完全同意约翰逊博士。考虑到人们对使用芳基重氮盐的兴趣再次兴起，我们强烈建议从事这一领域的研究人员确定他们计划制备的已知盐是否不稳定，并在进行反应范围研究时避免使用所有已知的危险重氮盐。

1。	了解重氮盐的爆炸特性。除非另有说明，否则请始终假定它们具有爆炸性。
2。	生成重氮盐时，仅使用化学计量的亚硝酸钠，避免亚硝酸钠过量（或与亚硝酸盐指示剂测试一起用氨基磺酸淬灭）。
3。	检查淀粉-碘化钾纸中是否有过量的亚硝酸，并中和。
4。	首先将胺和酸混合，然后再加入亚硝酸钠，以减少亚硝酸的存在。
5，	保持温度低于5°C（注意：某些重氮盐在此温度下不稳定）
6。	始终排出产生的气体。
7。	确定系统中重氮化合物的热稳定性。
8。	切勿让重氮盐从溶液中意外沉淀出来。
9。	分析最终产品中残留的重氮化合物，尤其是在新工艺条件下。
10。	在进一步处理之前，将剩余的重氮盐淬灭；淬灭溶液应易于获得。
11。	一次分离不超过0.75 mmol的易爆重氮盐；还考虑添加惰性材料来稳定重氮盐。注意：即使在这种规模下，也应格外小心（即使用防爆防护罩）。
12	处理固体时，请使用塑料刮铲。干燥后的粉末不应用金属刮刀“刮擦”，并且切勿研磨。

了解重氮盐的爆炸特性。除非另有说明，否则请始终假定它们具有爆炸性。生成重氮盐时，仅使用化学计量的亚硝酸钠，避免亚硝酸钠过量（或与亚硝酸盐指示剂测试一起用氨基磺酸淬灭）。检查淀粉-碘化钾纸中是否有过量的亚硝酸，并中和。首先将胺和酸混合，然后再加入亚硝酸钠，以减少亚硝酸的存在。保持温度低于5°C（注意：某些重氮盐在此温度下不稳定）始终排出产生的气体。确定系统中重氮化合物的热稳定性。切勿让重氮盐意外地从溶液中沉淀出来。分析最终产品中残留的重氮化合物，特别是对于新工艺条件。在进一步处理之前，将剩余的重氮盐淬灭；淬灭溶液应易于获得。一次分离不超过0.75 mmol的易爆重氮盐；还考虑添加惰性材料来稳定重氮盐。注意：即使在这种规模下，也应格外小心（即使用防爆防护罩）。处理固体时，请使用塑料刮铲。干燥后的粉末不应用金属刮刀“刮擦”，并且切勿研磨。此外，我们还要强调重氮盐与碘盐的潜在不相容性，这是由于形成的重氮碘化物的稳定性较差。（15）此外，诸如碱，过渡金属或亚硝酸等杂质会降低分解发生的温度，₂ ON ₂ R），其中许多具有剧烈爆炸性。（15）因此，除了安全性问题外，使用重氮盐的反应还可能导致pH敏感性。为了保护我们社区中所有研究人员的安全，我们呼吁化学家在他们的实验程序中完整描述潜在的安全隐患。（31）更具体地说，鉴于已知的不稳定性1，公认的最佳实践是始终保持材料湿润并立即使用，并认识到在可行的情况下始终最好避免重氮盐的分离。（15,32,33）更好的是，应在（8）此外，使用连续流技术可能有助于降低风险。（34）虽然我们无法为每种芳基/杂芳基重氮盐提供具体指导，但我们建议他们最初以尽可能小的规模制备热分解物，并且热分解温度/稳定性由专家通过独立手段确定（例如，使用差示扫描量热法）。这是化学工业中的规范，但在学术实验室中似乎不太常见。1，2-和4-吡啶四氟硼酸重氮也已知是不稳定的。（29）此外，反应性化学危害Bretherick手册列出其他四个有害芳基重氮四氟硼酸盐（图3）（15），包括2-氯-3-吡啶重氮四氟硼酸盐。因此，我们在类似物的制备指教特别小心和异构体1。图3.已知的有害重氮四氟硼酸盐。值得强调的是，这些有害的重氮四氟硼酸盐均具有较高的氮含量，但我们重申，在制备和使用所有鲜为人知的芳基重氮盐时，无论其结构如何，用户都应谨慎行事。我们呼吁合成社区改进对任何已知或潜在安全隐患的报告，并鼓励在出版物的“实验部分”中例行包括适当的信息。本社论中表达的观点只是作者的观点，不一定是ACS的观点。我们感谢EPSRC的资助（EP / S009965 / 1：“用于智能化学反应筛选的全自动机器人系统”）。我们感谢Moray Stark博士（化学部安全顾问，在约克）以获取一般建议和指导。我们非常感谢Drs对有机重氮盐安全性的宝贵工业投入。乔治·霍奇斯（George Hodges），马修·休斯（Matthew Hughes），伊恩·普里斯特利（Ian Priestley）和艾伦·罗宾逊（Alan Robinson）（先正达公司）以及约克化学公司的几位同事的学术投入。本文引用了其他34个出版物。