Balz-Schiemann反應(yīng)

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四氟硼酸的芳香重氮鹽(ArN2+BF4-)熱分解得到芳香氟化物的反應(yīng)稱為 Balz-Schiemann反應(yīng) 。一般的重氮鹽不穩(wěn)定，但四氟硼酸鹽的重氮鹽很穩(wěn)定，而且制備產(chǎn)率很高。四氟硼酸鹽的芳香雜環(huán)重氮鹽也可發(fā)生此反應(yīng)。重氮鹽可以在四氟硼酸存在下對(duì)芳胺進(jìn)行重氮化得到。一般情況下將重氮鹽轉(zhuǎn)變?yōu)椴蝗苡谒呐鸱猁}ArN2BF4，或直接在硼氟酸存在下重氮化，再加熱分解重氮鹽，便得到氟化物。當(dāng)用六氟磷酸鹽(PF6-)或六氟銻酸鹽(SbF6-)而不是四氟硼酸鹽作為平衡離子時(shí)，由于這兩種鹽溶解性更小，芳香氟化的產(chǎn)率可以提高。此反應(yīng)有一個(gè)缺點(diǎn)是，當(dāng)大量的六氟硼酸的重氮鹽熱分解時(shí)，有爆炸的危險(xiǎn)。對(duì)一些熱穩(wěn)定性差的化合物，也可以通過(guò)光解或超聲波分解得到相應(yīng)的氟化物。這個(gè)反應(yīng)的另一個(gè)改進(jìn)方法就是直接用HF/NaNO2進(jìn)行重氮化，或在一些堿如吡啶，2－羥基吡啶，哌啶等存在下重氮化，然后熱解生成相應(yīng)的氟化合物，苯胺類化合物和氨基取代的雜環(huán)化合物，如吡啶，嘧啶等都能發(fā)生這種反應(yīng)，在吡啶氟化氫溶液中分解時(shí)，大量的底物可以溫和的進(jìn)行。當(dāng)制備有極性取代基(OH, OMe, CF3, etc.)的芳香氟代物時(shí)，此方法非常有用。

反應(yīng)機(jī)理

反應(yīng)機(jī)理中包含正離子中間體，此正離子是被BF4-進(jìn)攻而不是氟離子。此反應(yīng)中四氟硼酸鹽的重氮鹽熱分解和光分解分解速率相同，這正證明了芳基正離子的存在。分解遵循一級(jí)反應(yīng)速率理論，因此是SN1反應(yīng)。

反應(yīng)實(shí)例

【J. Org. Chem.1969, 34, 1396-1399】

【J. Med. Chem.1990, 33, 937-942】

【J. Fluorine Chem.1994, 68, 141-144】

【J. Org. Chem.1989, 54, 3091-3096.】

【J. Med. Chem. 1990, 33, 789-808】

【J. Fluorine Chem. 2001, 107, 147-152】

【Org. Lett.2003, 5, 5023-5025】

光催化的Schiemann反應(yīng)。

【J. Fluorine Chem. 2007, 128, 674-678】

【Synthesis2008, 2333-2336】

A. o-Bromobenzenediazonium hexafluorophosphate. A solution of 95 mL of 12N hydrochloric acid in 650 ml. of water is added with stirring to 60 g. of o-bromoaniline (0.35 mole; in a 2-L. three-necked flask equipped with stirrer and thermometer. Solution is effected by heating the mixture on a steam bath. A solution of 29 g. (0.42 mole) of sodium nitrite in 75 ml. of water is added with stirring while the mixture is maintained at ?5° to ?10° by means of a bath of ice and salt or of dry ice and acetone. At the end of the addition there is an excess of nitrous acid, which can be detected with starch iodide paper. Seventy-four milliliters (134 g., 0.60 mole) of 65% hexafluorophosphoric acid is added in one portion, with vigorous stirring, to the cold solution of the diazonium salt. Cooling and slow stirring are continued for an additional 30 minutes, and the precipitated diazonium hexafluorophosphate is then collected on a Büchner funnel. The diazonium salt is washed on the funnel with 300 ml. of cold water and with a solution of 80 ml. of methanol in 320 ml. of ether. The salt is partly dried by drawing air through the funnel for 2 hours. It is then transferred to a pile of several filter papers, powdered with a spatula, and dried at about 25°/1 mm. for at least 12 hours. The dried o-bromobenzenediazonium hexafluorophosphate is cream-colored; weight 108–111 g. (94–97%); m.p. 151–156° (dec.).

B. 1-Bromo-2-fluorobenzene. Caution! This step should be carried out in a hood because the PF5 evolved on thermal decomposition of the diazonium salt is poisonous. The apparatus consists of a 1-L, three-necked, round-bottomed flask equipped with a thermometer, a condenser, a magnetic stirrer (optional), and a 250-mL Erlenmeyer flask that is attached by means of a short rubber Gooch connecting tube. The dry powdered hexafluorophosphate salt is placed in the Erlenmeyer flask, and 300 mL of heavy mineral oil is placed in the round-bottomed flask. The mineral oil is heated to 165–170° by means of an oil bath or electric heating mantle and maintained at this temperature while the salt is added rapidly in portions over a period of 30 minutes. The flask is cooled rapidly to room temperature, the side flask is removed, and 400 mL of 10% aqueous sodium carbonate is added slowly through the condenser. The mixture is steam-distilled until no more oil is visible in the distillate.

The oil, which is heavier than water, is separated, and the aqueous layer is extracted with three 50-mL portions of methylene chloride. The oil and extracts are combined, dried over anhydrous sodium sulfate, and distilled from a Claisen flask with an indented neck. Colorless 1-bromo-2-fluorobenzene is collected at 58–59°/17 mm. or 156–157°/760 mm.; weight 45–47 g. (73–75% based on o-bromoaniline); nD25 1.5320–1.5325.

In a 100-mL PFA made reactor equipped with a reflux condenser, 4-aminopyridine (470 mg, 5mmol) was added to HF/Pyridine (70% HF, 10 mL) at 0oC. The mixture was allowed to stand at room temperature until 4-aminopyridine was completely dissolved. After cooling down to –78oC, NaNO2 (380 mg, 5.5 mmol) was added to a solution of 4-aminopyridine in HF, the stirred solution was allowed to stand at 0oC for 30 min and then stand at 60oC for 15-30 min. By quenching the resultant solution with ice water, followed by the neutralization with cold saturated NaHCO3, the resulting mixture was extracted with CH2C12, the combined organic phase was dried over MgSO4, and evaporated under reduced pressure to give the crude product, which was distilled to give the desired product (460 mg, 95%).

Günther Schiemann生于德國(guó)的弗羅茨瓦夫，1925年獲得弗羅茲瓦夫大學(xué)的博士學(xué)位，并出任副教授。1950年出任伊斯坦布爾大學(xué)的化工學(xué)院主席，在那里他著重研究氟化學(xué)。

相關(guān)文獻(xiàn)

1. Balz, G.; Schiemann, G. Ber. 1927, 60, 1186-1190.

2. Roe, A. Org. React. 1949, 5, 193-228. (Review).

3. Sharts, C. M. J. Chem. Educ. 1968, 45, 185-192. (Review).

4. Montgomery, J. A.; Hewson, K. J. Org. Chem. 1969, 34, 1396-1399.

5. Laali, K. K.; Gettwert, V. J. J. Fluorine Chem. 2001, 107, 31-34.

6. Dolensky, B.; Takeuchi, Y.; Cohen, L. A.; Kirk, K. L. J. Fluorine Chem. 2001, 107, 147-152.

7. Gronheid, R.; Lodder, G.; Okuyama, T. J. Org. Chem. 2002, 67, 693-720.

8. Heredia-Moya, J.; Kirk, K. L. J. Fluorine Chem. 2007, 128, 674-678.

9. Gribble, G. W. Balz-Schiemann reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Ed.; Wiley: Hoboken, NJ, 2007, pp 552-563. (Review).

10. Pomerantz, M.; Turkman, N. Synthesis 2008, 2333-2336.

參考資料

一、Strategic Applications of Named Reactions in OrganicSynthesis, László Kürti and Barbara Czakó, Balz-Schiemann reaction, page34-35.

二、Name Reactions （A Collection of Detailed Reaction Mechanisms）, Jie Jack Li, Schiemann reaction，page 537-538.