1858 年，Peter Griess首次发现了芳香重氮化合物。1884 年，德国化学家T.Sandmeyer在用乙炔铜和苯胺的重氮盐（PhN2Cl）合成苯乙炔时，得到的主产物却是氯苯，经过仔细研究，发现原来是由于反应中产生的CuCl催化使重氮基被氯取代。随后，Sandmeyer发现用CuBr和CuCN也能得到相应的溴苯和苯甲腈，因此我们把这一类反应称为Sandmeyer反应。1890 年，L.Gatterman发现直接用铜粉和盐酸或氢溴酸也能从苯胺得到相应的氯苯或溴苯，这种类型的反应称为Gatterman反应。1927 年，同样是德国的化学家G.Balz和G.Schiemann发现直接加热苯胺的硼氟酸重氮盐能得到氟苯，这就是Balz-Schiemann反应。1935 年，F.B.Dains 和 F.Eberly用KI去处理重氮盐，成功合成了碘代苯5。随后重氮化羟基取代和重氮化去胺反应也相继被发现，加上偶氮反应，形成了比较完善的芳香重氮化合物反应体系。

一百多年来，由于芳香重氮化合物活性高，容易制备，工艺成熟，使其在化学合成和化学工业中的应用非常广泛。Sandmeyer 反应，Gatterman 反应和Balz-Schiemann 反应是官能团转换的重要反应，也是经典的人名反应，见证了整个有机化学的发展历程。

重氮化反应的影响因素

3、反应温度      反应温度一般在0~5oC进行，因降低温度可降低重氮盐的分解速度，但实验表明当芳环上连有某些基团时，反应温度可提高。例如：对氨基苯磺酸可在10~15oC进行；1-氨基萘-4-磺酸可在35oC进行重氮化。从理论分析，已知重氮盐分解成苯正离子和氮气的反应是可逆的。当重氮基的邻、对位上有吸电子取代基时，苯环的电子密度变小，苯正离子的稳定性减小，反而使分解速度降低；间位吸电子基虽然降低苯环的电子密度，但间位降低的相对少一些，能使苯正离子稳定，从而使重氮盐分解的速度加快。邻对位上有给电子基的重氮盐，与邻对位上有吸电子取代基相似，也使分解速度变慢。因为这种取代基可以通过给电子共轭效应与重氮基共轭，使碳氮键的双键性质增加，因此碳氮键断裂较难，形成苯正离子的速度减慢。

反应机理

其反应机理还没有完全搞清楚，一般我们认为是一个自由基反应，苯环上的取代基（如羟基，烷氧基，酰基，羧基，硝基和卤素等），无论是吸电子基团还是供电子基团，对反应都没有特别的影响，氯代必须用 CuCl/HCl 体系，溴代则要用CuBr/HBr 体系，碘代则一般用盐酸做重氮盐，不用Cu 盐催化，直接加KI或NaI 就能得到碘苯。

反应实例

【Tetrahedron Lett. 1998, 39, 9567–9570】

【Tetrahedron Lett. 1999, 40, 7501-7505】

【Org. Proc. Res. Dev. 2004, 8, 1059–1064】

【Tetrahedron Lett. 2005, 46, 2437–2439】

【J. Org. Chem. 2007, 72, 8501–8505】

【J. Am.Chem. Soc. 2013, 135, 8436–8439】

A mixture of 127.5 g. (1 mole) of a good commercial grade of o-chloroaniline

and 300 ml. (2.5 moles) of 48% hydrobromic acid in a 2-l. flask set in an ice bath is cooled to 0° by the addition of ice. A solution of 70 g. (1 mole) of sodium nitrite in 125 ml. of water is added rapidly, with stirring, the temperature being kept below 10°C by the addition of small pieces of ice. When only about 5 ml. of the sodium nitrite solution remains, further additions are made cautiously until an excess of nitrous acid remains after the last addition.

In the meantime, a mixture of 79 g. (0.55 mole) of cuprous bromide (Note 3) and

80 ml. (0.6 mole) of 48% hydrobromic acid is heated to boiling in a 5-l. round-bottomed three-necked flask, equipped with a condenser set for distillation and

provided with a 2-l. receiving flask, a steam inlet tube closed by a screw clamp, and a separatory funnel. About one-fourth of the diazonium solution is transferred to the separatory funnel, without filtration, and immediately run into the cuprous

bromide-hydrobromic acid solution, which is kept boiling over a free flame, at such a rate that boiling is continuous. When the separatory funnel is nearly empty a further portion of the cold diazonium solution is transferred to it without interrupting the addition. All the diazonium solution is added in this way over a period of about 30 minutes, during which time much of the product steam-distils. When the addition is complete, the stopcock in the separatory funnel is closed, the screw clamp in the steam line is opened, and a vigorous current of steam is passed through the mixture until no more organic material distils. About 1–1.5 l. of distillate is collected.

The heavy organic layer is separated from the distillate and washed with 10-ml.

portions of concentrated sulfuric acid until the acid becomes only slightly colored

during the washings; four washings usually suffice. The oil is then washed with one 100-ml. portion of water, two 50-ml. portions of 5% aqueous sodium hydroxide, and finally with one 100-ml. portion of water. The product is dried over about 3 g. of calcium chloride and distilled from a 250-ml. distilling flask. The yield of pure, colorless o-chlorobromobenzene, boiling at 199–201°/742 mm., is 170–183 g. (89–95%).

【Hartwell, J. L. Organic Syntheses, Coll. Vol. 3, p.185; Vol. 24, p.22.】

Traugott Sandmeyer (1854-1922)生于瑞士韦廷根。师从Victor Meyer和Arthur Hantzsch，但没获得博士学位。他在 J. R. Geigy公司（现在属于诺华）工作31年。

参考文献

一、Name Reactions （A Collection of Detailed Reaction Mechanisms）, Jie Jack Li, Sandmeyer reaction，page 535-536.

二、药明宝典--《经典合成反应标准操作》。