Jones Oxidation (CrO3 + H2SO4)

The Jones Oxidation allows a relatively inexpensive conversion of secondary alcohols to ketones and of most primary alcohols to carboxylic acids.  The Jones reagent is a mixture of chromic anhydride and dilute sulfuric acid (CrO₃ + H₂SO₄ + H₂O) in acetone. It is used in the oxidation of secondary alcohols, that do not contain acid sensitive groups, to corresponding ketones and also the oxidation of primary allylic and benzylic alcohols gives aldehydes.

Jones described for the first time a conveniently and safe procedure for a chromium (VI)-based oxidation, that paved the way for some further developments such as Collins Reaction and pyridinium dichromate, which also enabled the oxidation of primary alcohols to aldehydes.

How does it work:

The Jones Reagent is a mixture of chromic trioxide or sodium dichromate in diluted sulfuric acid, which forms chromic acid in situ.

The alcohol and chromic acid form a chromate ester that either reacts intramolecularly or intermolecularly in the presence of a base (water) to yield the corresponding carbonyl compound.

Aldehydes that can form hydrates in the presence of water are further oxidized to carboxylic acids.

Some alcohols such as benzylic and allylic alcohols give aldehydes that do not form hydrates in significant amounts; these can therefore be selectively oxidized with unmodified Jones Reagent to yield aldehydes. Although the reagent is very acidic, the substrate in acetone is essentially titrated with the oxidant solution and only very acid-sensitive groups are incompatible. For example esters, even tert-butyl esters, remain unchanged. The concentration of sulfuric acid can be decreased to minimize side reactions, although the oxidation power increases too.

Procedures:

The oxidation reagent is prepared by dissolving 70 g. (0.70 mole) of chromium trioxide in 100 ml. of water in a 500-ml. beaker. The beaker is immersed in an ice bath, and 112 g. (61 ml., 1.10 moles) of concentrated (18M) sulfuric acid followed by 200 ml. of water is added cautiously with manual stirring. The solution is cooled to 0–5°C. 

A solution of 110 g. (1.00 mole) of nortricyclanol (Note 1) in 600 ml. of acetone (AR grade) is cooled to 0–5°C in a flask immersed in an ice bath and equipped with an efficient mechanical stirrer, a thermometer, and a dropping funnel with a pressure-equalizing arm. The cooled oxidation reagent prepared above is poured into the dropping funnel, and the reagent is added with vigorous stirring, at a rate to maintain the temperature of the reaction mixture at about 20°. The stirring is continued for 3 hours after the addition is completed.

Work-up: Sodium bisulfite is added in small portions until the brown color of chromic acid is gone from the upper layer of the two-phase mixture. The top layer is decanted, and the dense, green, lower layer is extracted with 200 ml. of 30–60°C petroleum ether. Combination of this extract with the original upper layer causes a separation into two phases. The lower phase is drawn off and added to the original lower phase, which is then extracted with there 200-ml. portions of 30–60°C petroleum ether. The extracts are combined, washed successively with two 50-ml. portions of saturated sodium chloride, two 50-ml. portions of saturated sodium bicarbonate solution, and 50 ml. of saturated sodium chloride solution, and dried over magnesium sulfate. The solvent is removed by distillation through a short column containing glass helices, and the residue is distilled under reduced pressure to give 85–95 g. (79–88%) of nortricyclanone, b.p. 103–105° (77 mm).

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The chromic acid oxidizing reagent is prepared by dissolving 67 g. of chromium trioxide in 125 ml. of distilled water. To this solution was added 58 ml of conc sulfuric acid (sp. gr. 1.84), and the salts which precipitate are dissolved by addition of a minimum quantity of distilled water; the total volume of the solution usually does not exceed 225 ml.

A solution of 64 g. (0.5 mole) of cycloöctanol in 1.25 l. of acetone is added to a 2-l. three-necked flask fitted with a long-stem dropping funnel, a thermometer, and a powerful mechanical stirrer (Note 2). The vigorously agitated solution is cooled in a water bath to about 20°C. The chromic acid oxidizing reagent is added from the dropping funnel as a slow stream, and the rate of addition is adjusted so that the temperature of the reaction mixture does not rise above 35°. The addition is continued until the characteristic orange color of the reagent persists for about 20 minutes. The volume of reagent added is about 120 ml.  The stirrer is removed, the mixture is decanted into a 2-l. round-bottomed flask, and the residual green salts are rinsed with two 70-ml. portions of acetone. The rinsings are added to the main acetone solution and additional oxidizing agent is added, if necessary, to ensure complete reaction. The stirrer is replaced and isopropyl alcohol is added drop wise until the excess chromic acid is destroyed. In small portions and with caution was added 63 g. of sodium bicarbonate, and the suspension is stirred vigorously until the pH of the reaction mixture tests neutral. The suspension is filtered and the filter cake is washed with 25 ml. of acetone. The filtrate is concentrated by distillation through a 75-cm. length of Vigreux column until the pot temperature rises to 80° and a water film begins to develop in the lower portions of the distillation column. The cooled pot residue (about 110 ml.) is transferred to a 1-l. separatory funnel, 500 ml. of saturated sodium chloride solution is added, and the mixture is extracted with two 150-ml. portions of ether. The ether extracts are combined, washed with a total of 25 ml. water in several portions, dried over anhydrous magnesium sulfate, filtered, and the ether distilled at atmospheric pressure. The pot residue is distilled under reduced pressure, b.p. 76–77° (10 mm.). The yield of cycloöctanone is 58–60 g. (92–96%), m.p. 40–42°.

An additional 2.2 g. (4%) of cycloöctanone may be obtained by addition of 250 ml. of water to the green salts formed during the reaction, extraction of the mixture with ether, distillation of the ether, and addition of 12 ml. of acetone. To the acetone solution there is added sufficient chromic acid oxidizing reagent to permit the orange color of the reagent to persist , and the mixture is processed as above.

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1.06 grams  CrO3 are added to .92ml H2SO4, and distilled water is added to bring the total volume to 4ml. 2 grams of pseudoephedrine are dissolved in 20ml acetone, and cooled in an ice bath. The Jones reagent is slowly added to the pseudoephedrine, dropwise and with stirring. The mixture becomes a reddish brown.

The reaction will proceed slowly, but very smoothly as exact moles were added (mild conditions). Stir the solution warm over night.  About 12-18 hours later the reaction is complete, the color is now a very dark green. Add about 20mL of water, and chill in an ice bath. Drop wise and with stirring add about 1 gram of NaOH in a solution with as little water as possible (highly concentrated). Check the pH regularly, and stop at pH=12. The now basic solution is extracted with toluene (3 x 50ml), filter if any emulsions form.  Combine the three toluene extractions and evaporate to result in a impure ketone of pseudoephedrine, also know as methcathinione or ephedrone.

Purification: It is purified by adding just enough toluene to redissolve it.  The toluene is filtered to remove any additional particles, poured back into the separation funnel and shaken with an equal amount of distilled water. This removes any small amount of water solubles. The toluene is put into a clean RB flask and distilled again. The impurities are more soluble in acetone than the ephedrone, so a very small amount of acetone is added, and sloshed around. Filter this and the solids resulting are a little over 1 gram (about 60% yield) of relatively pure, slightly off-white methcathinone.

Note: The example given - Pseudoephedrine or Ephedrine to Methcatinone - is for illustrative purposes only. Oxidizing cold pills is illegal, and makes a lousy drug anyway.

Reactions to remember with Jones Reagent:

The secondary alcohols are oxidized to corresponding ketones in Jones reaction.

The primary alcohols are oxidized to carboxylic acids via aldehydes with Jones reagent.

Benzyl alcohol can be oxidized to benzaldehyde. Further oxidation to benzoic acid is not possible as the benzaldehyde cannot form stable hydrates in water.

In Jones reaction, the allylic alcohols are also selectively oxidized to aldehydes. The double bonds are intact in this reaction.

Tips:

• Disproportionations and single electron transfers lead to chromium (V) acid and stable Cr(III) hydroxide. The chromium (V) acid promotes a two-electron oxidation of an alcohol and becomes Cr(III). Any residues of toxic Cr(V) and Cr(VI) compounds can be destroyed by the addition of an excess of 2-propanol once the intended reaction is complete. The formation of Cr(III) is indicated by a color change to green.
• For the synthesis of aldehydes, the Collins Reaction or use of more modern - although more expensive - chromium (VI) reagents such as PCC and PDC can be an appropriate choice.
• Some newer protocols are available in which a catalytic amount of CrO3 in aqueous solution is used in tandem with a strong stoichiometric oxidant, which is able to reoxidize Cr(IV) but does not interfere with the organic compounds.
• The Jones reagent is prepared by adding chromic anhydride to dilute sulfuric acid in acetone and is added to the alcohol at 0-25C.
• The orange or yellow colored Cr(VI) is reduced to blue green Cr(III) species during the oxidation.
• Make sure the reaction mass is slightly acidic for it to progress.

Pyridinium Chlorochromate (PCC) Corey-Suggs Reagent

Pyridinium chlorochromate is a reddish orange solid reagent used to oxidize primary alcohols to aldehydes and secondary alcohols to ketones. Pyridinium chlorochromate, or PCC, will not fully oxidize a primary alcohol to the carboxylic acid as does the Jones reagent. A disadvantage to using PCC is its toxicity. PCC was developed by Elias James Corey and William Suggs in 1975.  Pyridinium dichromate has the advantage of being less acidic than its class of oxidizing agents.

Preparation:

First chlorochromic acid is prepared by the dissolution of chromium trioxide in 6M aq. hydrochloric acid. Addition of pyridine gives pyridinium chlorochromate as orange crystals.

The properties of PCC can be compared with those of PDC: it is not particularly hygroscopic, is stable, commercial available and can be stored. PCC is soluble in many organic solvents, and especially dichloromethane at room temperature has been used in most cases, whereas DMF promotes the over-oxidation of primary alcohols into carboxylic acids.

PCC is more acidic than PDC, but acid-labile compounds can be oxidized in the presence of sodium acetate or other buffers such as carbonates. Another drawback is the formation of viscous materials that complicate product isolation. Addition of Celite, powdered molecular sieves or magnesium sulfate to PCC oxidation reaction mixtures can simplify the work-up, because the reduced chromium salts and other reagent-derived byproducts are deposited onto these solids, which can then be readily removed by filtration.

How does it work?

Oxidation reactions of this sort are actually a kind of elimination reaction. We’re going from a carbon-oxygen single bond to a carbon-oxygen double bond. The elimination reaction can occur because we’re putting a good leaving group on the oxygen, namely the chromium, which will be displaced when the neighboring C-H bond is broken with a base.

Attention: Chromium (VI) compounds are toxic and must be handled with care as it is a known carcinogen. Other methods for oxidizing alcohols using less toxic reagents have been introduced and are more preferred by green chemists:

• DMSO-based oxidations (Swern oxidation, Moffatt oxidation)
• hypervalent iodine based oxidation (such as the Dess-Martin periodinane)

Procedures:

A 500-mL, round-bottomed flask equipped with a 4.5-cm, egg-shaped Teflon-coated magnetic stir bar is charged with 130 mL of CH₂Cl₂, the alcohol (10.4 g, 40.0 mmol), and 15 g of freshly powdered 3 Å molecular sieves. Pyridinium chlorochromate (21.5 g, 100 mmol) is added portionwise over 10 min and the resulting mixture is stirred at room temperature for 15 hr. Ether (200 mL) is added slowly with vigorous stirring and the solution is filtered under vacuum through a pad of 35 g of Celite. The solids remaining in the reaction flask are transferred to the Celite pad by scraping with a spatula and washing with three 50-mL portions of ether. The resulting cloudy brown filtrate is concentrated by rotary evaporation at room temperature to give a brown solid. To this solid is added 25 mL of 1:1 ether:hexane and the solids are scraped with a spatula. The mixture is then poured onto 60 g of Whatman 60 Å (230-400 mesh) silica gel packed in a 4-cm diameter chromatography column and the liquid is adsorbed onto the silica gel by gravity. The material remaining in the flask is further washed with 1:1 ether:hexane and transferred onto the silica gel; this process is repeated until all the material has been loaded onto the silica gel. The ketone is eluted using 500 mL of 1:1 ether:hexane and the eluent is concentrated by rotary evaporation to afford the crude ketone as a white solid. This material is dissolved in 40-45 mL of boiling hexane. Upon cooling the solution to room temperature, the ketone begins to crystallize. The flask is then cooled to −25°C for 2 hr. The resulting solids are collected by filtration, washed with three 25-mL portions of cold (−25°C) hexane, and dried to afford 8.84-9.08 g, (86-88%) of the ketone as a white solid.

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A flame-dried, 250-mL, three-necked, round-bottomed flask is equipped with a magnetic stir bar, rubber septum, glass stopper, and an argon inlet. The flask is charged with pyridinium chlorochromate (16.4 g, 76 mmol) and 75 mL of dichloromethane. A solution of crude (6R)-(+)-1,6-dimethylcyclohex-2-en-1-ol (4.79 g, 38 mmol) prepared as described above in 25 mL of dichloromethane  is transferred into the reaction mixture via cannula over 5 min, and the resulting mixture is stirred at ambient temperature for 3 hr. The reaction mixture is then diluted with 120 mL of diethyl ether, the solution is decanted, and the remaining black resinous polymer is thoroughly washed with three 50-mL portions of diethyl ether. The combined dark brown/black ether solution is washed successively with two 100-mL portions of 5% aqueous sodium hydroxide solution, 100 mL of 5% aqueous hydrochloric acid, and two 50-mL portions of saturated aqueous NaHCO3 solution, dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation at room temperature (50 mmHg) to give 4.42 g of the crude product as a yellow oil. Purification by column chromatography  yields 3.71-3.85 g (79-82% overall from 1) of (R)-(+)-3,4-dimethylcyclohex-2-en-1-one (3) as a colorless oil.

Tips:

In practice the chromium byproduct deposits with pyridine as a sticky black tar, which can complicate matters. Addition of an inert adsorbent such as crushed molecular sieves or silica gel allows the sticky byproduct to adsorb to the surface, and makes workup much easier.