最常用的酸催化酯化反應----Fischer-Speier酯化反應

羧酸跟醇在酸催化（ Lewis酸或Br?nstedt 酸）下加熱合成酯的反應被稱為Fischer-Speier酯化反應。Fischer和Speier在1895年最早報道。此反應是最經典的酯化反應，是平衡反應，所以如果想要得較高的產率的話就必須使得平衡往產物方向進行。通常的方法是加入過量的其中一種原料，并且用Dean-Stark（分水器）除水或者加入分子篩吸水。經典的酯化條件是利用強Br?nstedt 酸, 條件比較劇烈，后期主要發展出了很多Lewis酸催化條件的酯化反應，擴大了應用范圍。

酯和醇作為原料在相同條件下反應的話，可以發生酯交換反應，機理相同。

反應機理

酸的羰基氧上加成上一個質子形成氧鎓離子，其具有很強的親電性，醇作為親核試劑進攻羰基得到含有兩個羥基的四面體中間體，通過質子轉移，消除一分子水生成酯。

相關實例

一、反應實例

【Chem. Commun.,1997, 351-352】

【 Tetrahedron ,2002, 58, 8179-8188】

【 Tetrahedron ,2003, 59, 3627-3633】

【 J. Am. Chem. Soc. ,2005, 127, 4168-4169】

【 Synthesis ,2008, 3407-3410】

【 J. Org. Chem. ,2005, 70, 8625-8627】

The α-bromoacid was treated with a solution of concentrated sulphuric acid (30 μL/mmol) in methanol (2 mL/mmol) and refluxed for one hour. The solution was cooled to room temperature and concentrated in vacuo. Et2O was added and the organic layer was washed with 5% aqueous solution of NaHCO3 followed by brine, dried over MgSO4 and concentrated in vacuo.

【 J. Org. Chem. ,2006, 71, 3332-3334】

【 J. Org. Chem. ,2009, 74, 5967-5974】

【 Synlett ,2017, 28, 981-985】

二、實例操作

1、硫酸作催化劑的酯化反應示例：

4-Amino-3-nitrobenzoic acid (200.0 g) was suspended in ethanol (1030 g).Conc. sulfuric acid (120.0 g) was added dropwise to the mixture over 0.5 h.After the dropwise addition, the mixture was refluxed under heating for 15 h. Apart (422 mL) of ethanol was distilled away at atmospheric pressure, and water(660 mL) was added dropwise to allow precipitation of crystals. To this suspension were added 25% aqueoussodium hydroxide solution (50 mL) and then 2.5% aqueous sodium hydroxidesolution (262 mL), and pH was adjusted to 6.5. The precipitated crystals werecollected by filtration, washed successively with ethanol (531 mL) and water(1069 mL), and dried under reduced pressure to give ethyl4-amino-3-nitrobenzoate (200.6 g)。

2 、鹽酸（氯化氫）作催化劑的酯化反應示例：

3,4-Diaminobenzoic acid (152 g, 1.0 mol) was stirred with ethanol (2000mL) in a Morton flask. Hydrogen chloride gas was passed through the stirredsuspension for about 2 h. As the gas was absorbed, the slurry became gel-likein character. Ethanol (500 ml.) was added to the reaction mixture to dispersethe gel. The reaction mixture was refluxed 24 h. The mixture was filtered andthe filtrate was evaporated to dryness in vacuo. The filter cake and thefiltrate residue were dissolved in water (9 L). Theaqueous solution was made basic by the addition of solid sodium carbonate. Theproduct precipitated from the basic solution. The material was filtered anddried to yieldethyl 3,4-diaminobenzoate (130 g, 72.14%)。

3 、氯化亞砜作催化劑的酯化反應示例：

To a suspension of 6-chloropyridine-2-carboxylic acid (8.3 g, 0.0525mol) in dioxane (25 mL), thionyl chloride (9.4 mL, 0.13 mol) was added and theresulting mixture was stirred at 70 ℃ for 4 h. The reaction mixture was concentrated invacuo and a mixture of dioxane (8.3 mL) and ethanol (16.6 mL) was added. Thereaction mixture was heated to 70 ℃ for 2 h, triethylamine (8.3 mL), ethanol (4.1 mL) andwater (8.3 mL) were added and the reaction mixture was again concentrated. Theresidue was distributed between diethyl ether (28 mL) and water (18 mL) and thephases were separated. The aqueous layer was extracted with diethyl ether (30mL) and the combined organic layers were dried over MgSO4, filteredand evaporated in vacuo to afford 6-chloropyridine-2-carboxylic acid ethylester (8.82 g, 91%) as oil。

4 、乙酰氯作催化劑的酯化反應示例：

Acetyl chloride (15.3 mmol) was added dropwise to ethanol (50 mL) at 0 ℃ . After 30 min, the acid (7.69 mmol) was added and thereaction mixture was heated at reflux for 15 h. The reaction mixture wasconcentrated and the residue was partitioned between dichloromethane (20 mL)and saturated sodium bicarbonate (10 mL). The aqueous layer was furtherextracted with dichloromethane (20 mL × 2) and the combined organic layers were dried(magnesium sulfate) and concentrated to provide the ester in 94% yield as brown oil。

主要起作用的應該是乙酰氯和乙醇反應生成的HCl。

5、 對甲苯磺酸作催化劑的酯化反應示例：

對甲苯磺酸作酯化催化劑只比硫酸稍弱，仍是一個強酸，其用量與使用硫酸相等，其作用相近，使用對甲苯磺酸作為酯化催化劑主要是為了避免硫酸帶來的焦化和其他副反應。

A 300-mL, one-necked,round-bottomed flask was equipped with a magnetic stirrer, Dean-Stark trap, and a reflux condenser. The flask was charged with 3.0 g (20 mmol) of L-(+)-tartaric acid, 6.5 g (60 mmol) of benzyl alcohol, 47.5 mg (0.25 mmol) of p-toluenesulfonic acid monohydrateand 40 mL of toluene. The mixture washeated under reflux in an oilbath (about 130 ℃ ) for 13 hr.During this period the theoretical amount of water (0.62 mL) was collected. Themixture was allowed to cool to ambient temperature, diluted with ether, and poured into 50 mL of aqueous, saturated sodium bicarbonate. Theorganic phase was separated and the aqueous phase was extracted twice with 20 mL of ether. The combinedorganic phases were dried over sodiumsulfate. The solvent was removed with a rotary evaporator, and the resulting crudeproduct was triturated with hexane-ether (20:1, 210 mL) to give white crystals of (?)-dibenzyl tartrate.The precipitate was collected by filtration and washed with hexane-ether (20:1). Thefiltrate was further concentrated to give a second crop. The total yield was 6.2 g (94%), mp 49–50 ℃

三、酯交換

【 J. Org. Chem. ,1991, 56, 5307-5311】

【 ACS Catal. ,2011, 1, 1178–1182】

相關文獻

1. Fischer, E.; Speier, A. Ber. Dtsch. Chem. Ges. 1895, 28, 3252-3258.

2. Hardy, J. P.; Kerrin, S. L.; Manatt, S. L. J. Org. Chem. 1973, 38, 4196-4200.

3. Fujii, T.; Yoshifuji, S. Chem. Pharm. Bull. 1978, 26, 2253-2257.

4. Pcolinski, M. J.; O’Mathuna, D. P.; Doskotch, R. W. J. Nat. Prod. 1995, 58, 209-216.

5. Kai, T.; Sun, X.-L.; Tanaka, M.; Takayanagi, H.; Furuhata, K. Chem. Pharm. Bull. 1996, 44, 208-211.

6. Birney, D. M.; Starnes, S. J. Chem. Educ. 1996, 76, 1560-1561.

7. Cole, A. C.; Jensen, J. L.; Ntai, I.; Tran, K. L. T.; Weaver, K. J.; Forbes, D. C.; Davis, J. H., Jr. J. Am. Chem. Soc. 2002, 124, 5962-5963.

8. Li, J. in Name Reactions for Functional Group Transformations, Li, J. J., Ed., Wiley: Hoboken, NJ, 2007. pp 458-461.

9. Saavedra, H. M.; Thompson, C. M.; Hohman, J. N.; Crespi, V. H.; Weiss, P. S. J. Am. Chem. Soc. 2009, 131, 2252-2259.

參考資料

一、 Name Reactions （A Collection of Detailed Reaction Mechanisms）, Jie Jack Li, Fischer-Speier esterification，page 252.

二、Organic Chemistry Portal：https://www.organic-chemistry.org/namedreactions/fischer-esterification.shtm

三、化學空間：https://cn.chem-station.com/reactions/2016/01/post-8092.html