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1858 年，Peter Griess首次發(fā)現(xiàn)了芳香重氮化合物。1884 年，德國化學(xué)家T.Sandmeyer在用乙炔銅和苯胺的重氮鹽（PhN2Cl）合成苯乙炔時，得到的主產(chǎn)物卻是氯苯，經(jīng)過仔細研究，發(fā)現(xiàn)原來是由于反應(yīng)中產(chǎn)生的CuCl催化使重氮基被氯取代。隨后，Sandmeyer發(fā)現(xiàn)用CuBr和CuCN也能得到相應(yīng)的溴苯和苯甲腈。芳基重氮鹽被鹵離子或類鹵離子（氰負離子）取代得到芳基鹵代物或芳基腈的反應(yīng)，稱為Sandmeyer反應(yīng)。1890 年，L.Gatterman發(fā)現(xiàn)直接用銅粉和鹽酸或氫溴酸也能從苯胺得到相應(yīng)的氯苯或溴苯，這種類型的反應(yīng)稱為Gatterman反應(yīng)。1927 年，同樣是德國的化學(xué)家G.Balz和G.Schiemann發(fā)現(xiàn)直接加熱苯胺的硼氟酸重氮鹽能得到氟苯，這就是。1935 年，F(xiàn).B.Dains 和 F.Eberly用KI去處理重氮鹽，無需加入銅鹽，成功合成了碘代苯。隨后重氮化羥基取代和重氮化去胺反應(yīng)也相繼被發(fā)現(xiàn)，加上偶氮反應(yīng)，形成了比較完善的芳香重氮化合物反應(yīng)體系。現(xiàn)在比較常用的改進法：是利用亞硝酸異戊酯和鹵化銅(II)或鹵化亞銅，在乙腈中（無水條件下），室溫下反應(yīng)。此條件下不用在強酸條件下進行，條件溫和。對于一些富電子的芳環(huán)不適合利用CuBr2進行反應(yīng)，由于二價銅氧化性可以氧化Br負離子，可以對富電子芳環(huán)進行得到溴代產(chǎn)物。苯胺重氮化后，重氮鹽不用分離，直接加入氯化亞銅，溴化亞銅或氰化亞銅制備得到相應(yīng)的氯苯，溴苯或苯甲腈。

一百多年來，由于芳香重氮化合物活性高，容易制備，工藝成熟，使其在化學(xué)合成和化學(xué)工業(yè)中的應(yīng)用非常廣泛。Sandmeyer 反應(yīng)，Gatterman 反應(yīng)和 反應(yīng)是官能團轉(zhuǎn)換的重要反應(yīng)，也是經(jīng)典的人名反應(yīng)，見證了整個有機化學(xué)的發(fā)展歷程。

重氮化反應(yīng)的影響因素

1、無機酸 在實驗中，芳胺和無機酸的摩爾比大約為1：2.5~4，酸大大過量，酸除用于生成亞硝酸外，主要目的是穩(wěn)定生成的重氮鹽，若鹽酸用量不足，生成的重氮鹽容易和未反應(yīng)的芳胺發(fā)生自偶合反應(yīng)而影響下步的反應(yīng)。但是如果酸性濃度增加，游離胺的濃度降低，反而使重氮化速度變慢。因此，反應(yīng)介質(zhì)的酸性應(yīng)保持在pH值在2~3左右。

2、亞硝酸的用量 反應(yīng)過程中，應(yīng)保持亞硝酸過量，否則也會引起自偶合反應(yīng)，但太過量的亞硝酸能氧化和亞硝基化等而引起一系列的副反應(yīng)，對下一步偶合很不利。一般芳胺和亞硝酸鈉的摩爾比為1:1，若胺的活性低，也可以多加，但最好小于1:2。在偶合反應(yīng)前，如果測定仍有過量的亞硝酸（淀粉碘化鉀試紙變藍），需加入少量的尿素破壞。

3、反應(yīng)溫度 反應(yīng)溫度一般在0~5℃進行，因降低溫度可降低重氮鹽的分解速度，但實驗表明當芳環(huán)上連有某些基團時，反應(yīng)溫度可提高。例如：對氨基苯磺酸可在10~15℃進行；1-氨基萘-4-磺酸可在35℃進行重氮化。從理論分析，已知重氮鹽分解成苯正離子和氮氣的反應(yīng)是可逆的。當重氮基的鄰、對位上有吸電子取代基時，苯環(huán)的電子密度變小，苯正離子的穩(wěn)定性減小，反而使分解速度降低；間位吸電子基雖然降低苯環(huán)的電子密度，但間位降低的相對少一些，能使苯正離子穩(wěn)定，從而使重氮鹽分解的速度加快。鄰對位上有給電子基的重氮鹽，與鄰對位上有吸電子取代基相似，也使分解速度變慢。因為這種取代基可以通過給電子共軛效應(yīng)與重氮基共軛，使碳氮鍵的雙鍵性質(zhì)增加，因此碳氮鍵斷裂較難，形成苯正離子的速度減慢。

4、銅鹽催化 制備氯代芳烴和溴代芳烴，經(jīng)典的方法一般需要加入相應(yīng)的氯化亞銅和溴化亞銅，碘代芳烴可以不用加入銅鹽。制備氟苯也可以不用銅鹽。

反應(yīng)機理

重氮化過程參考 。

其反應(yīng)機理還沒有完全搞清楚，一般我們認為是一個自由基反應(yīng)，苯環(huán)上的取代基（如羥基，烷氧基，酰基，羧基，硝基和鹵素等），無論是吸電子基團還是供電子基團，對反應(yīng)都沒有特別的影響，氯代必須用 CuCl/HCl 體系，溴代則要用CuBr/HBr 體系，碘代則一般用鹽酸做重氮鹽，不用Cu 鹽催化，直接加KI或NaI 就能得到碘苯。

反應(yīng)實例

【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)生于瑞士韋廷根。師從Victor Meyer和Arthur Hantzsch，但沒獲得博士學(xué)位。他在 J. R. Geigy公司（現(xiàn)在屬于諾華）工作31年。

參考資料

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

二、藥明寶典--《經(jīng)典合成反應(yīng)標準操作》。

三、Strategic Applications of Named Reactions in OrganicSnthesis, László Kürti and Barbara Czakó, Sandmeyer reaction，page 394-395.