Org Prep Daily

September 5, 2012

S-tritylthioacetic acid

Filed under: procedures — milkshake @ 6:53 pm

Neat mercaptoacetic acid 24.0g (260 mmol, about 18 mL) was added in one portion to a solution of trityl chloride 58.0g (208.0 mmol) in benzene 200mL (non-anhydrous, ACS grade). The flask was equipped with a gas outlet Drierite tube and the mixture was stirred for 17 hours: The HCl gas evolution ceased at this point and a heavy white material precipitated out from the reaction mixture. The reaction mixture was stirred under mild vacuum (50 Torr) for about 20 minutes to remove dissolved HCl. The solids were collected by filtration, washed with a small volume of benzene (2×10 mL) and with copious amount of hexane, then dried by suction.

The crude product (57.7g) was dissolved at reflux in benzene 250mL (100C oil bath) and the solution was left undisturbed for 1 day at ambient temperature. The supernatants were decanted off and the obtained crystalline mass was suspended in a small volume of benzene. The solids were collected by filtration, washed sequentially with benzene, cyclohexane and hexane and dried by suction, then on highvac. Y= 54.19g (78% based on Trit-Cl) of white coarse chunky crystals.

1H(CDCl3, 400MHz): 9.96(very br s, 1H), 7.32(m, 6H), 7.19(m, 6H), 7.12(m, 3H), 2.93(s, 2H); 13C(CDCl3, 100MHz): 176.1, 144.0(3C), 129.6(6C), 128.2(6C), 127.1(3C), 67.4, 34.6; TLC: CHCl3-MeOH 10:1 detected with UV and CAM, Rf=0.6

Note: The thiol reactant does not need to be present in excess but mercaptoacetic acid is cheap and its odor is quite tolerable – and adding more helps to improve the crude product purity and yield. This base-free thiol tritylation proceeds faster in more polar solvents like dichloromethane or dichloroethane but the reaction is then accompanied by a promptly vigorous HCl evolution and could be difficult to control on large scale. In benzene, the product gradually precipitates from the reaction mixture in a fairly pure form – this makes aqueous workup and evaporation unnecessary.

Benzene as a reaction solvent can be replaced with benzotrifluoride PhCF3 (400mL for a 58g scale experiment. Cooling on ambient water bath, 4 hours at RT) but PhCF3 alone does not work for recrystallization of Ph3CSCH2CO2H because the product is poorly soluble in it. Also, attempts at replacing benzene with toluene for recrystallization provided product of somewhat inferior purity so two recrystallizations from toluene (2 x 0.5L) were required.

Update: 2-mercaptopropionic acid can be tritylated without a base under similar condition but at elevated temperature: PhCF3 as a solvent, R.T. to reflux (distilled off a small volume of solvent until HCl evolution ceased, then at R.T. overnight. The precipitated crude product was collected by filtration, washed with hexane, dried and re-crystallized from PhCF3 to yield a pure product in 85% yield). 1H(CDCl3, 400MHz): 7.47(m, 6H), 7.29(m, 6H), 7.22(m, 3H), 3.05(q, 7.2 Hz, 1H), 1.211(d, 7.2Hz, 3H); 13C(CDCl3, 100MHz): 179.6, 144.3(3C), 129.8(6C), 128.1(6C), 127.1(3C), 68.4, 42.6, 18.6; TLC: CHCl3-MeOH 10:1 detected with UV and CAM, Rf=0.65

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