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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。芳基重氮盐被卤离子或类卤离子（氰负离子）取代得到芳基卤代物或芳基腈的反应，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。1935 年，F.B.Dains 和 F.Eberly用KI去处理重氮盐，无需加入铜盐，成功合成了碘代苯。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。现在比较常用的改进法：是利用亚硝酸异戊酯和卤化铜(II)或卤化亚铜，在乙腈中（无水条件下），室温下反应。此条件下不用在强酸条件下进行，条件温和。对于一些富电子的芳环不适合利用CuBr2进行反应，由于二价铜氧化性可以氧化Br负离子，可以对富电子芳环进行得到溴代产物。苯胺重氮化后，重氮盐不用分离，直接加入氯化亚铜，溴化亚铜或氰化亚铜制备得到相应的氯苯，溴苯或苯甲腈。
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 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
1、无机酸 在实验中，芳胺和无机酸的摩尔比大约为1：2.5~4，酸大大过量，酸除用于生成亚硝酸外，主要目的是稳定生成的重氮盐，若盐酸用量不足，生成的重氮盐容易和未反应的芳胺发生自偶合反应而影响下步的反应。但是如果酸性浓度增加，游离胺的浓度降低，反而使重氮化速度变慢。因此，反应介质的酸性应保持在pH值在2~3左右。
2、亚硝酸的用量 反应过程中，应保持亚硝酸过量，否则也会引起自偶合反应，但太过量的亚硝酸能氧化和亚硝基化等而引起一系列的副反应，对下一步偶合很不利。一般芳胺和亚硝酸钠的摩尔比为1:1，若胺的活性低，也可以多加，但最好小于1:2。在偶合反应前，如果测定仍有过量的亚硝酸（淀粉碘化钾试纸变蓝），需加入少量的尿素破坏。
3、反应温度 反应温度一般在0~5℃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10~15℃进行；1-氨基萘-4-磺酸可在35℃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。
4、铜盐催化 制备氯代芳烃和溴代芳烃，经典的方法一般需要加入相应的氯化亚铜和溴化亚铜，碘代芳烃可以不用加入铜盐。制备氟苯也可以不用铜盐。
反应机理
重氮化过程参考 。
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.】
2-Nitro-phenylamine (13.8 g) are dissolved in conc. H2SO4(75mL), H3PO4 (100 mL) and water (50 mL). The solution of NaNO2 (8.3 g) in water (25 mL) was slowly addeddropwise under ice-water cooling. The temperaturewas maintained at 10－15 oC. NH3-SO3H was added in batches to remove the extraformed HNO2. The reaction wascooled down to -10 oC, liquid SO2 (50 mL) was addeddropwise. The reaction mixture waspoured into another mixture of FeSO4.7H2O (55.7 g) and Cu (1 g). Half anhour later, the reaction was filtered, the residue cake was washed with mixtureof ether (750 mL) and CH2Cl2 (750 mL). The combined filtrate and washings were washed with brine, dried andconcentrated. The residue wasprecipitated in water (50 mL), then diluted ammonia was used to adjust pH equal9 under stirring. Filtered, the filtratewas acidified with HCl (6 N), the precipitate was collected by filtration and driedto afford desired 2-Nitro-benzenesulfonic acid, (9.4 g, 65% yield.)
To a suspension of4-amino-2-chloro-3-methyl-benzonitrile (500 mg, 3.00 mmol) in 1.8 mL of 6 N HClat room temperature was added 2 mL of water followed by a solution of NaNO2(220mg, 3.13 mmol) in 1 mL of water dropwise and the suspension stirred at roomtemperature for 20 min. The suspension was added to a solution of SO2inacetic acid (prepared by bubbling SO2 gas into acetic acid until saturation atroom temperature) and copper(II) chloride dihydrate (60 mg, 3.52 mmol) in 0.15mL of water. The suspension was stirred at room temperature for 1.25 h andextracted with EtOAc. The organic layer was washed with water and brine, dried(MgSO4), filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography (silica gel, CH2Cl2/Hexanes,50:50, 75:25 and 100:0) to afford the title compound (305 mg) as a white solid.
【Markley, Lowell. D.; J.Med. Chem.; EN; 29; 3; 1986; 427-433】
4-Iodopyridine (5). To 4 (6 g, 63.8 mmol) in 48% HBF4 (50 mL) at -10 ℃ was added under stirring NaNO2 (4.8 g, 69.5 mmol) so that no nitric oxide evolution was detected. After 30 min, the diazonium salt was filtered and added to KI (17 g, 102.4 mmol) in 100 mL of Me2CO:H2O (40:60). The mixture was decolorized with Na2S2O3, neutralized (Na2CO3) and extracted (Et2O). Evaporation afforded 9.2 g of 5 (70%).
【Syn. Comm., 1996, 26, 3143】
【J. Org. Chem.,2009, 74, 2578–2580】
2,6-Dibromo-9,10-dipropoxyanthracene (A). 2,6-Diaminoanthraquinone (2.9 g, 12 mmol), tBuONO (2.8 g, 27 mmol), CuBr2 (6.0 g, 27 mmol), CH3CN (50 mL) were added to a one-neck flask and the mixture was heated at 65 °C for 2hr. The reaction was quenched by adding 20 % HCl(aq) solution to the product mixture. The solution was filtered, washed with CH3CN, and the product was purified by recrystallization with 1,4-dioxane to obtain 2,6-dibromo-9,10-anthraquinone. Yield: 2.7 g (92 %); Mp: >300 °C.2 To a two neck flask, 2,6-dibromo-9,10-anthraquinone (2.0 g, 5.4 mmol), Bu4N+ Br (1.6 g, 4.9 mmol), Na2S2O4 (1.9 g, 11 mmol), and water (50 mL) were added under argon. The mixture was stirred for 10 min and CH2Cl2 (60 mL) was added. When the solution turned to green color, 20 % NaOH(aq) was added and stirred for 2 hr. To this solution, n-propyl bromide (6.6 g, 54 mmol) was added and stirred for 8 hr. The product was purified on a silica column using hexane/CH2Cl2 (5:1) as the eluent. Yield: 1.8 g (73 %); Mp: 134~135 °C; 1 H NMR (300 MHz, CDCl3): δ 8.41 (s, 2H), 8.15 (d, J = 9.0 Hz, 2H), 7.55 (dd, 2H, J = 9.0 Hz, 3.0 Hz), 4.11 (t, 4H, J = 7.0 Hz), 2.10 (m, 4H), 1.25 (t, 6H, J = 7.5 Hz). Anal. Calcd for C14H6Br2O2: C, 53.12; H, 4.46. Found: C, 53.14; H, 4.49.
【Org. Lett. 2005, 7, 323–326】
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。
参考资料
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》。
三、Strategic Applications of Named Reactions in OrganicSnthesis, László Kürti and Barbara Czakó, Sandmeyer reaction，page 394-395.
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