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P2P trough Meerwein Arylation of Aniline

Text & Pictures by Xicori

HTML by Rhodium

US Patent 5,811,586

Exampe 4: 1-(3-trifluoromethyl)-phenyl-propan-2-one

220 ml of water and 180 g of 37% (w/w) aqueous hydrochloric acid are put in a flask equipped with stirrer and dripping funnel. 97 grams (0.602 moles) of m-trifluoromethylaniline are added after having cooled to 10C with an ice bath and then at 5C, an aqueous solution containing 42.2 (0.612 moles) of sodium nitrite in 50 ml of water is slowly added. The reaction mixture is stirred for 30 minutes and then is added in 30 minutes to a mixture warmed at 40C made by 800 ml of water, 280 ml of methanol, 1.50 g (0.015 moles) of cupric chloride, 49.2 g (1.200 moles) of anhydrous sodium acetate and 75.2 (0.751 moles) of isopropenyl acetate. The reaction temperature goes up till a maximum value of 60C, the reaction mixture is kept under stirring for further 30 minutes at this temperature and then is cooled to 20C. 350 ml of heptane are added and the two layers are separated. The aqeuous layer is discarded while the organic layer is washed with water and concentrated under vacuum to remove the solvent. The obtained oil is distilled under vacuum at 10 mm Hg collecting the fraction that distills at 98-102C. 72 grams of pure ketone are obtained with a yield to 59.1% calculated on the starting m-trifluormethylaniline.


The reaction was performed on a 50% scale (based on the amounts of the above example).

Flask 1:

To a 500 ml single neck flask 100 ml tap water, 90 g (76 mol) conc. HCl and 28 ml aniline (brown coloured) were added, resulting in an exothermic reaction with smoke formation. The mixture was cooled in an ice-water-bath, the smoke disappeared.
When the internal temperature has reached 4C a cooled solution of 22.1 g NaNO2 in 40 ml tap water was added slowly via a pressured equalized addition funnel. During the addtion the mixture was stirred vigorously. The temperature was controlled carefully to hold in under 4-5C.

Flask 2:

Everything was mixed in the flask, and stirred. The mixture was heated to 40C, and the aniline mixture (Flask 1) was added over 45 minutes (1-2 drops per second) formation of red coloured reaction products. After finished addition the mixture was much clearer then during the addition of the diazonium salt solution.

After finished addition the flask was held at 60C for further 30 min.

After cooling to RT the mixture was extracted with 3x75 ml of petroleum ether (bp 50-90C), the pooled organic extracts were washed with 100 ml of water and evaporated under vacuo.

The first extract was analyzed by TLC (ethyl acetate:methanol, 4:1) and showed two spots. One sticking on the starting line and another one close to the front which had the same Rf-value as P2P from an authentic sample (made by another route).

The residue was distilled under aspirator vacuum (12mm Hg) to yield a fraction between 90C-100C, which was yellow in colour. - The weight of the fraction was 11g which is a ~25% yield calculated on the amount of aniline used.

Flask 1 - filled with smoke

Addition of the Sodium Nitrite solution

During the addition the solution became more orangish

Flask 1 after finished addition. Flask 2 is meanwhile heated to 40C.

Addition of the diazonium salt solution to flask 2 caused a red reaction product to appear.

After finished addition - back to room temperature

Extraction with petrol ether.

Product in the receiver (boiling @ 95C-100C/12mm Hg)

Closeup. The top seems to be much more orange (like a 2 phase system), but the phases were miscible without problems.

The P2P seems to bee much darker than it usually is (compared to the sample that was prepared via PAA/AAA), but the TLC seems to be clean - 1 single spot with the same Rf-Value than the authentic sample. Refractive index of the product will be checked within the next 2 weeks.

Discussion & further changes:


This method for P2P-synthesis out of cheap & non watched chemicals seems to be working, and can be done within one afternoon. The yield wasnt to good at the 1st try (25%), but I'm sure that we can modify this synthesis to improve the yield. Would be nice if any other bees would like to work together on this topic.