【Org. Process Res. Dev】只需萃取？亚硫酸氢钠如何有效除去反应体系中的醛？

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亚硫酸氢钠可以和醛、和某些活泼的酮发生羰基的加成反应，生成稳定的亚硫酸氢钠加成物(addition product of sodium bisulfite), 这主要得益于硫的强亲核性。

有机化学教科书中就讲过，用过量的饱和亚硫酸氢钠溶液和醛一同振荡, 就可以发生亲核加成反应, 把全部的醛变为加成物，亚硫酸氢钠加成物是一个盐，不溶于乙醚, 但溶于水中，所以可利用这个反应把醛从其他不溶于水的有机化合物中分离出来。但是具体的反应后处理的实际操作中，通常差强人意。2017年Maria M. Boucher和Cheyenne S. Brindle 等人对于此萃取纯 化方法 进行了系统研究 ，找到了一种可以 高效 除去混合物中醛或高活性酮的 液- 液 萃取 方法 ， 并发表在 在美国化学会学术期刊《 Org . Process Res . Dev .》上【 Org. Process Res. Dev. 2017 , 21 , 1394–1403 】 。

有机合成很多醛参与的反应，如，，，，，等等。过量的原料醛利用此方法除去，省去了很多不必要的纯化步骤。

开始作者先用乙醚溶解混合物，然后用加入饱和亚硫酸氢钠水溶液振荡，萃取，发现效果不佳。

通过试验发现加入甲醇后混合物中醛的含量明显降低。于是开发出了标准的萃取纯化方法：将混合溶于少量甲醇中，加入饱和亚硫酸氢钠，振荡30秒，然后利用有机溶剂萃取。发现大部分芳香醛都可以高效率的除掉。对于一些在甲醇中溶解度较差的芳醛（如对硝基苯甲醛），则用DMF代替甲醇，也可以高效除去。另外一些醛的 亚硫酸氢钠加成物溶解度较差，会在体系中析出，则可以直接过滤除去。

a：Benzyl butyrate (250 μL, 1.4 mmol) and aldehyde (1.4 mmol) were dissolved in 5 mL MeOH, 25 mL saturated NaHSO3(aq) added, shaken for approximately 30 s, diluted with 25 mL H2O, and extracted with 25 mL 10% EA/hexanes. b：DMF instead of MeOH used. Organic layer washed two times with 15 mL water. c：Required filtration to remove solid bisulfite adduct.

作者发现脂肪醛利用芳醛的萃取纯化方法，则效果不是很好，通过重复萃取，利用长时间搅拌代替振荡和增加甲醇的量都可以，明显提高纯化效率。

作者尝试了其他水溶性溶剂代替甲醇，发现DMF的代替效果较好，两倍量效果更佳。

利用DMF作为水溶性促溶溶剂，验证脂肪醛的纯化效果。

a：Aldehyde (1.4 mmol) and benzyl butyrate (250 μL, 1.4 mmol) were dissolved in 10 mL DMF, 25 mL saturated NaHSO3(aq) added, shaken for approximately 30 s, diluted with 25 mL H2O, and extracted with 25 mL hexanes. The aqueous layer was extracted once with hexanes and the combined organics were washed three times with water to remove DMF (25 mL, 10 mL, 5 mL). b：Required filtration to remove solid bisulfite adduct. c：Pentane used in place of hexanes. d：10% EA/hexanes used in place of hexanes. e：MeOH used in place of DMF. f：CHCl3 used in place of hexanes.

作者验证了一下，底物范围，发现此方法官能团耐受度很高，底物应用范围很广，但由于亚硫酸氢钠是酸性的，对于脂肪仲胺的纯化效果不佳。

另外一些高活性的酮，也可以通过此方法除去。

醛形成 亚硫酸氢钠加成物 是一个可逆的体系,把存在于体系中微量的亚硫酸氢钠用酸或碱不断地除去，其结果是加成物又分解成为原来的醛，因此也可以通过此方法回收醛或纯化醛。

标准操作

Standard work-up procedure for aldehyde and ketone removal.

Substrate (1.4 mmol) and aldehyde (1.4 mmol) were dissolved in 5 mL MeOH, 25 mL saturated NaHSO3(aq) added, shaken for approximately 30 s, diluted with 25 mL H2O, and extracted with 25 mL 10% EA/hexanes. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to yield the recovered substrate.

Work-up procedure for non-polar aldehyde and ketone removal.

Substrate (1.4 mmol) and aldehyde (1.4 mmol) were dissolved in 10 mL DMF, 25 mL saturated NaHSO3(aq) added, shaken for approximately 30 s, diluted with 25 mL H2O, and extracted with 25 mL 10% EA/hexanes. The aqueous layer was extracted with 25 mL of 10% EA/hexanes. The combined organic layers were washed three times with H2O (25 mL, 10 mL, 5 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to yield the recovered substrate.

Work-up procedure for isolation of both aldehyde and ketone.

Benzyl butyrate (250 μL, 1.4 mmol) and aldehyde 20 (275.0 mg, 1.4 mmol) were dissolved in 10 mL DMF, 25 mL saturated NaHSO3(aq) added, shaken for approximately 30 s, diluted with 25 mL H2O, and extracted with 25 mL 10% EA/hexanes. The aqueous layer was extracted with 25 mL of 10% EA/hexanes three times. The organic layers were washed three times with H2O (25 mL, 10 mL, 5 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to yield recovered benzyl butyrate (261.3 mg, 98% recovery). The combined aqueous layers were basified with 50% sodium hydroxide and extracted with 25 mL of 10% EA/hexanes three times. The organic layers were washed three times with H2O (25 mL, 10 mL, 5 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to yield recovered aldehyde 20 (261.3 mg, 95% recovery).

参考资料

Liquid–Liquid Extraction Protocol for the Removal of Aldehydes and Highly Reactive Ketones from Mixtures，Org. Process Res. Dev. 2017, 21, 9, 1394–1403