酰鹵的製備

有機合成 2020-08-25 19:00

酰鹵是有機合成中非常重要的中間體，可以由其製備酰胺和酯。酰氯主要通過二氯亞碸，草酰氯和三氯氧磷製備，另外Vilsmeier試劑也有用到。

Vilsmeier試劑較貴，在氯化亞碸中加入少量DMF催化會直接生成Vilsmeier試劑中間體，接著生成酰氯。

高沸點的底物來說，二氯亞碸是最合適的試劑；一般的酸在二氯亞碸回流數小時後，蒸掉過量二氯亞碸及溶劑後，再用些甲苯帶一下殘餘的二氯亞碸即可用於下步反應。對低沸點的底物來說，則使用三氯氧磷較為方便，主要由於低沸點很容易蒸餾出來。對於α-氨基酸，由於相應的酰氯在加熱會分解，因而一般不通過二氯亞碸和三氯氧磷的製備。當分子中有對酸敏感的官能團存在時，無法使用二氯亞碸，一般采用等當量的草酰氯和堿，一鍋發生酰氯再直接用於下步反應，最近也有文獻報道應用三氯均三嗪在堿存在下可一鍋將酸轉化為酰氯。由於酰氯的活性太高，一般很難鑒定，有時為了判斷酰氯是否生成，一般取出一點加入過量的苄胺或甲醇等，通過TLC 確認反應進行的程度，也可以蒸幹溶劑通過HPLC, LC-MS 或NMR 確認。α-氨基酰氯一般也通過以上兩種方法合成。芳香酰氯相對烷基酰氯要穩定的多，例如苯甲酰氯加入水中也要近半個小時才能分解完全。

酰氟要比酰氯穩定的，其對水和其他親核試劑都較為穩定，其可通過三氟均三嗪在吡啶的存在下製備(Tetrahedron lett. 1991,32（10)，1303)。並可以通過層析分離出來。酰氟對水和其他親核試劑，易於保存和使用方便，我們有時可以利用它進行酰胺類化合物庫的合成。

 

反應實例

1、應用二氯亞碸合成酰氯示例（Practical organic chemistry）

Fit a 100 mL two-necked flask with a dropping funnel and a reflux condenser connected at the top to a gas absorption trap. Place 36 g (21.5 mL, 0.3 mol) of redistilled thionyl chloride in the flask and 22 g (23mL, 0.25 mol) of butyric acid in the separatory funnel. Heat the flask gently on a water bath, and add the butyric acid during the course of 30-40 minutes. When all the acid has been introduced, heat was on a water bath for 30 minutes. Rearrange the apparatus and distillation: collect the crude acid chloride boiling between 70 and 110 ℃.

Finally, restil from a flask provided with a short fractionating column and collect the butyryl chloride at 100-101 ℃. The yield is 23 g (86 %).

Note: Wrap a piece of absorbent cotton wool around the stem of the reflux condenser above the joint of the reaction flask to prevent condensed。

 

2 、用草酰氯合成酰氯示例（J. Med. Chem. 1996, 39, 5183-5191.）

Compound 42 (4.19 g, 13.94 mmol) was dissolved in 20 mL CH2Cl2, oxalyl chloride (4.25 mL, 48.40 mmol) was added at room temperature, the resultant mixture was stirred at room temperature for 30 min and then the mixture was gently warmed under reflux for 30 min. After the mixture was concentrated in vacuo, the residue was dissolved in THF, and the solution was again concentrated in vacuo to offer quantitatively the crude chloride 43.

3、 用三氯均三嗪合成酰氯示例

To a mixture of P-nitrobenzoic acid (1.67g, 0.01 mol) and 2,4,6-Trichloro-[1,3,5]triazine 44 (1.84g, 0.01mol) in acetone (20 mL) was added TEA (1.01, 0.01 mol) and the mixture was stirred for 3hr, filtrated to remove the separated dichlorohydroxy-s-triazine derivative, and the filtrate concentrated under reduced pressure. The residue was extracted with CCl4 and the solvent removed to give the desired acid chloride 46 (yield 58 %). (Note: the residue insoluble in CCl4 was found to be the unreacted carboxylic acid).

4 、三氟均三嗪合成酰氟示例【Tetrahedron lett. 1991,32（10），1303】

Typical experimental detail: equimolecular amount of the amino acid, pyridine and cyanuryl fluoride are mixed and stirred for 3~4 hours in dichloromethane at room temperature. At that time, ice-water is added to the reaction mixture and the precipitated canuric acid is filtered off the organic phase is dried and evaporated to dryness, which generally leaves the pure amino acid fluoride in crystalline form.

 

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