Balz-Schiemann反應

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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稱為 Balz-Schiemann反應 。一般的重氮鹽不穩定，但四氟硼酸鹽的重氮鹽很穩定，而且制備產率很高。四氟硼酸鹽的芳香雜環重氮鹽也可發生此反應。重氮鹽可以在四氟硼酸存在下對芳胺進行重氮化得到。一般情況下將重氮鹽轉變為不溶于水的硼氟酸鹽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，由于這兩種鹽溶解性更小，芳香氟化的產率可以提高。此反應有一個缺點是，當大量的六氟硼酸的重氮鹽熱分解時，有爆炸的危險。對一些熱穩定性差的化合物，也可以通過光解或超聲波分解得到相應的氟化物。這個反應的另一個改進方法就是直接用HF/NaNO2進行重氮化，或在一些堿如吡啶，2－羥基吡啶，哌啶等存在下重氮化，然后熱解生成相應的氟化合物，苯胺類化合物和氨基取代的雜環化合物，如吡啶，嘧啶等都能發生這種反應，在吡啶氟化氫溶液中分解時，大量的底物可以溫和的進行。當制備有極性取代基(OH, OMe, CF3, etc.)的芳香氟代物時，此方法非常有用。

反應機理

反應機理中包含正離子中間體，此正離子是被BF4-進攻而不是氟離子。此反應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。分解遵循一級反應速率理論，因此是SN1反應。

反應實例

【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。

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

相關文獻

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.