Org Prep Daily

September 27, 2006

2-(2′,6′-dichlorophenyl)-propionic acid

Filed under: procedures — milkshake @ 6:33 pm

 

diclhgh.gif

To a solution of o,o-dichlorophenylacetonitrile 18.60g (100mmol) in dichloromethane 100mL, 3.40g of Bu4NHSO4 (10mmol) and 25mL of iodomethane (400mmol) was added, followed by 50% aq. NaOH 100mL. The mixture was refluxed on oil bath (70-80C) for 18 hours (overnight). The reaction mixture was diluted with water 100mL with cooling (exothermic), ether 200mL and dichloromethane 100mL was added, shaken and separated. The aqueous layer was re-extracted with ether-dichloromethane 1:1 mixture (300mL). The org. extracts were washed with brine, combined, dried (MgSO4) and evaporated. The residue was suspended in ether 220mL, stirred for 1 hour, the insoluble Bu4NI (3.22g) was removed by filtration and washed with additional ether, the filtrates were evaporated and the residue dried on highvac. Y=20.105g (100%) of the pure propionitrile product as a white crystalline solid.

1H(CDCl3, 400MHz): 7.355(dAB, 7.8Hz, 2H), 7.214(ddAB, 8.6Hz, 7.4Hz, 1H), 4.833(q, 7.5Hz, 1H), 1.694(d, 7.5Hz, 3H); 13C(CDCl3, 100MHz): 134.83, 132.00, 129.91(2C), 129 (2C), 119.44, 27.47, 17.12

60% sulfuric acid 550g (obtained from 96% H2SO4 343g and 206mL of water) was combined with o,o-dichlorophenyl-2-propionitrile 10.076g (50.36mmol) and the mixture was refluxed with vigorous stirring on oil bath (160C) for 10 hours. The cooled mixture was diluted with water (0.5L) and stirred at R.T. for 1 hour to complete the crystallization of the crude product. The crude product was collected by filtration, washed with water. The material was suspended in water 0.5L, made strongly alkaline with 15% NaOH and stirred until complete dissolution (1 hour). A small spoon of charcoal was added, the mixture was filtered through a medium-porosity frit and the filtrate was acidified with excess of 4M HCl. The mixture was stirred for 10 min, the product was collected by filtration, washed with water, dried by suction and on highvac. Y=10.194g (92.5%) od a white crystalline solid.

1H(CDCl3, 400MHz): 7.299(d, 7.8Hz, 1H), 7.126(ddAB, 8.6Hz, 7.6Hz, 2H), 4.578(q, 7.0Hz, 1H), 1.532(d, 7.0Hz, 3H); 13C(CDCl3, 100MHz): 179.18, 136.78, 135.23, 128.79(2C), 128,76(2C), 42.17, 14.47

I believe the reason why no double-methylation occured is that Bu4NOH is probably not basic enough to deprotonate the 2-aryl-propionitrile. (The clash of o-Cl with the Me group of the nitrile anion causes the C=C=N(-)  to be out of plane of the aryl group, which means that unlike in the staring arylacetonitrile, the propionitrile anion is not stabilised by the conjugation with Ar.)

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