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氧化反应之醇氧化为醛酮2020-02-03

有机化学中的氧化反应是指有机物分子中碳原子的氧化,可以根据氧化数确定。氧化数升高为氧化下降为还原,氧化还原总是同时进行,但由于有机反应中我们更多关注的是反应底物,所以我们常常将底物中碳原子氧化数升高的反应称为氧化反应。有机反应中通常氧化反应表现为分子中氧的增加或氢的减少。

六价铬氧化剂

CrO3是一种深红色极易吸潮的固体,可以溶于水和一些有机溶剂,如叔丁醇,吡啶,醋酸酐等等,但在有机溶中不稳定易爆。其在水中的存在状态为

一、琼斯试剂Jones Reagent: CrO3/H2SO4/H2O/Acetone

主要活性成分为铬酸,机理如下:

琼斯试剂氧化伯醇时一般不会停留在醛这一步,将继续氧化为酸,机理如下:

琼斯试剂氧化的一般操作步骤:

A 0.15–0.40volume of H2SO4(c) isadded over one volume of a 1.5–4.5 M solution of CrO3in water. A fraction of the resulting redsolution is dropped over a 0.01–0.5 M stirred solution of the alcohol inacetone. The alcohol causes the reduction of the red Cr (VI) cations tochromium species with a greenish look. A complete oxidation of the alcohol in ashort time requires normally between 1.2 and 5.0 equiv. of CrO3. Whenthe reaction is finished, the oxidant is quenched by the addition of 0.1–0.4volumes of 2-propanol. If so desired, the reaction mixture can be neutralizedby the addition of saturated aqueous NaHCO3 or diluted NaOH. The resulting mixture isextracted with an organic solvent, such as EtOAc, DCM or Et2O. Thecollected organic solutions are washed with brine, dried (Na2SO4 or MgSO4).

应用实例:

二、沙瑞特试剂和柯林斯试剂Sarett and CollinsReagents::CrO3·2Py

沙瑞特试剂为CrO3·2Py的吡啶溶液,柯林斯试剂为CrO3·2Py的二氯甲烷溶液,制备这两种试剂时,应当是将三氧化铬加入到吡啶中,这个过程中伴随着大量的放热,反加可能会发生爆炸,得到的试剂也极其易爆,并有很强的吸水性,因此做反应时一般要求惰性气体保护。此类氧化中,用的溶剂一般是二氯甲烷,最好不要用没有文献报道的其他溶剂(可能会爆炸)。反应中常常会加入一些硅胶,这样可以减少铬酸盐沉淀对产品的吸附导致的损失。另外醇的β位含有杂原子时,容易发生β消除的副反应,加入乙酸酐可以有效阻止此副反应的发生。

由于整个体系中是无水环境,因此此类试剂可以把伯醇氧化为醛时,不能形成缩醛,因此不会继续氧化(机理见上方),可以停留在醛这一步。

氧化的一般操作步骤:

Oneequivalent of CrO3 is slowly added over a 0.2–2.0 M solution of2–2.03 equivalents of dry pyridine in dry DCM. Very often, ca. 2–7 g ofdry Celite per g of CrO3 are added-normally before the preparationof the CrO3·2Py complex-in order to avoid loss of product on thechromium precipitates during the work-up.

Veryfrequently,ca. 2–5 equivalents of acetic anhydride are added-normally after thepreparation of the CrO3·2Py complex-in order to facilitate a milderreaction, particularly in sugars and nucleosides. It is not common to add bothCelite and acetic anhydride in the same reaction.

Afterca. 15–20 min, a 0.02–0.70 M solution of the alcohol in dry DCM isslowly added. Normally, between 4 and 10 equivalents of the CrO3·2Pycomplex are used per equivalent of alcohol. When most of the starting alcoholis consumed, two alternative work-ups can be carried out.

Work-up A:

Thereaction mixture is filtered through a pad of silica, Florisil or Celite. Thefiltrate is washed with an organic solvent, like Et2O, EtOAc, orDCM. The collected organic phases may be optionally washed with diluted HCl,diluted aqueous base, brine or saturated CuSO4 solution. The resulting organic solutionis dried (Na2SO4 or MgSO4) and concentrated.

Work-up B:

Thereaction mixture is sequentially washed with NaOH (5%), HCl (5%), NaHCO3(5%) and brine. Adding some ether can help the fractioning. Optionally, theorganic phase can be subsequently filtered through Florisil. The resultingorganic solution is dried (Na2SO4 or MgSO4)and concentrated.

反应实例

三、PDCpyridinium dichromate

将吡啶加入到三氧化铬的水溶液中有亮黄色的PDC固体生成,PDC溶于有机溶剂,在空气中温度,易于储存和操作。在二氯甲烷的悬浮溶液中可以将醇氧化为醛酮。PDC用DMF当溶剂可以将伯醇氧化为酸。另外3Å分子筛,HOAc,PPTS,PTFA,Ac2O可以加快PDC的氧化速度。

氧化的一般操作步骤

Approximately,1.1–7 equivalents of solid PDC are added over a ca. 0.01–0.30 M solution of thealcohol in dry DCM. The resulting suspension is stirred at roomtemperature. Approximately, 0.5–4 g of activated MS-preferably finely ground 3ÅMS-per mmol of alcohol can be added in order to accelerate the oxidation. Thereaction can also be accelerated by the addition of ca. 0.9–4 equivalents of dryAcOH or 0.75–12 equivalents of acetic anhydride. The simultaneous use ofmolecular sieves and an organic acid has a synergistic accelerating effect. Theaddition of ca. 0.5–2.50 g of Celite or Florisil (magnesium silicate) per mmol of alcohol canfacilitate the work-up. Celite or Florisil can be added either at the beginningof the oxidation or ca. 30 min before the work-up. Two alternative work-ups canbe carried out.

Work-upA:

The most common workup. Et2Ois added and the precipitate is decanted and washed with ether. The collectedorganic phases are filtered through a pad of Celite, silica or Florisil.Alternatively, decanting the precipitate can be avoided and the mixture,resulting from the addition of ether, can be directly filtered through a pad ofsilica, Celite or Florisil. When the reaction is carried out under diluteconditions, the addition of diethyl ether can be avoided. The organic phase isconcentrated giving a residue that may need chromatographic purification. Whenthe reaction is

carried out in the presence of addedCelite or Florisil, a similar work-up is made in which the Celite or Florisilis filtered.

Work-upB:

Et2O is added and theresulting mixture is washed with aqueous phases. The aqueous phases used canbe: plain water, aqueous saturated NaHCO3 solution, diluted HCl or brine.The collected organic phases are dried (MgSO4 or Na2SO4)and concentrated, giving a residue that may need chromatographic purification.

注意事项:

  1.  惰性气体保护避免接触空气中的水。
  2.  可以用亚硫酸钠快速淬灭反应。

反应应用:

  • PCCpyridinium chlorochromate

将三氧化铬(1eq)加入到6M盐酸(1.1eq)中得到氯铬酸溶液,0℃下加入吡啶(1eq)得到橙黄色的PCC固体,PDC溶于有机溶剂,在空气中温度,易于储存和操作。在二氯甲烷的悬浮溶液中可以将醇氧化为醛酮。PDC用DMF当溶剂可以将伯醇氧化为酸。另外3Å分子筛,HOAc,PPTS,PTFA,Ac2O可以加快PCC的氧化速度。

氧化的一般操作步骤

Approximately, 1.1–7 equiv., typically1.5 equiv. of solid PCC are added over a ca. 0.01–0.25 M solution of thestarting alcohol in dry DCM. The resulting mixture is stirred at roomtemperature. Very often, ca. 0.2–1.2 g of activated MS per mmol of alcohol areadded in order to accelerate the reaction. In order to moderate the acidity ofPCC, it is very common to add ca. 0.3–1 equivalents of NaOAc. A solid support,such as silica gel, Celite, Florisil or magnesium sulfate, is added, very oftenin a proportion of ca. 0.3–2 g of solid support per mmol of alcohol, in orderto facilitate the work-up. Occasionally alumina, working both as a solidsupport-used to facilitate the work-up and as an accelerant, mixed with PCC isadded, in a

proportion of ca. 0.4–1.5 g of aluminaper mmol of alcohol. Normally, PCC is deposited over the alumina. Occasionally,ca. 10–20 equivalents of acetic acid are added in order to accelerate thereaction.

Sometimes, the reaction flask issonicated with ultrasound in order to fragment the surface of the PCC particlesand, therefore, accelerate the reaction.

Although in PCC oxidations, it is verycommon to add simultaneously to the reaction an accelerant, a buffer and awork-up-facilitator; it is not common to employ simultaneously two materialsbelonging to the same kind, with the exception of the combination of the twoaccelerants molecular sieve and acetic acid, which are very often usedtogether.

Work-up:

When a TLC analysis shows that most ofthe starting alcohol is consumed,

the solids suspended in the reaction andthe chromium species are removed by filtration through a pad of Florisil1,silica gel, alumina or Celite, and the pad is washed with an organic solvent,such as ether, DCM, or EtOAc. Sometimes, the solids can be removed bydecantation. Other times, it is advisable to add some diethyl ether to thereaction mixture before the filtration, in order to promote the separation ofreduced chromium species in a granular form. Occasionally, the reaction mixtureis concentrated before the addition of diethyl ether. Finally, the collectedorganic phases are concentrated at the rotary evaporator, giving a crudealdehyde or ketone that may need some further purification.

注意事项:

  1.  惰性气体保护避免接触空气中的水。
  2.  可以用亚硫酸钠快速淬灭反应。

反应应用:

总结

1. 琼斯试剂不要求无水环境,成本低,适用于大批量生产,但不能用于对酸敏感的反应,也不能大量制备醛。

2. 柯林斯试剂成本低,但要求无水环境,选择性不如PDC和PCC,但对于简单的制备醛酮的反应能达到很好的效果。

3. PCC和PDC成本较高,但可以得到很好反应结果。

参考文献:common oxidation reagents, Yue Xu, Sundia Meditech

在由醇制备醛酮的过程中,由于铬类氧化剂毒性较大,近年来发展了一类超价有机碘(V)氧化物。高价碘类氧化物有低毒,温和和选择性好等特点,其缺点就是有一定的爆炸性。比较常见的有DMP和IBX,其中IBX是制备DMP的一个前体,它的良性溶剂是DMSO。

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