Org Prep Daily

October 5, 2006

4-Fluorophenylmethanesulfonyl chloride

Filed under: procedures — milkshake @ 1:35 pm

p-Fluorobenzyl chloride 14.458g (100mmol) was added to a slurry of thiourea 7.612g (100mmol) in anh. ethanol 150mL and the mixture was stirred at reflux (oil bath 110C) for 1 day. The obtained solution was cooled and evaporated to dryness. The obtained solid residue was suspended in ethyl acetate 200mL, stirred for 15 min, the solids were collected by filtration, washed with ethyl acetate and dried on highvac. Y=21.84g(99%) of a white cryst solid

1H(d6-DMSO, 400MHz): 9.350(br s, 2H), 9.288(br s, 2H), 7.487(m, 2H), 7.208(m, 2H), 4.536(s, 2H); 19F(d6-DMSO, 376.5 MHz): -114.26(m, 1F)

The thiuronium salt 21.84g was suspended in 1M HCl 800mL. The slurry was cooled to 0C and a stream chlorine gas was introduced first at 0-5C for 15 min, then the cooling bath was replaced with ambient water bath and the chlorine bubbling was continued for additional 30 min. (The starting material dissolved and a new solid formed.) The precipitated crude product was collected by filtration, washed with 1M HCl and partially dried by suction. The material was dissolved in benzene 250mL (with stirring for 20 min), the obtained cloudy solution was dried with MgSO4 (20 min), filtered and evaporated to a small volume (about 50mL). The obtained solidified mixture was gently heated until complete re-dissolution, hexane 400mL was gradually added with heating and the obtained mixture was allowed to cool to RT undisturbed. The resulting cloudy solution was gently filtered through a medium-porosity filter (to avoid premature crystallization), the filtrates were inoculated mechanically and the mixture was allowed to crystallize overnight (12h).  The supernatants were decanted off, the obtained large crystals (10.329g) were washed with hexane and dried on highvac. Evaporating the supernatants and re-crystallizing the residue from a mixture of benzene 10mL and hexane 150mL provided the second crop of pure product (5.413g).  A third crop of pure product (0.950g) was obtained from the second supernatans in the same fashion. Combined Y=16.692g (81%) of large beautiful white needles.

1H(CDCl3, 400MHz): 7.452(app dd, 8.6Hz, 5.1Hz, 2H), 7.129(app t,  8.6Hz, 2H), 4.823(s, 2H); 19F(CDCl3, 376.5MHz): -109.90(m, 1F)


  1. I love this procedure for benzyl sulfonyl chlorides. In many cases the crude sulfonyl chloride is very clean and good to use “as is” after drying.

    However, I am a little concerned after stumbling across this reference:

    In short, they speculate that hydrolysis of the cyanamide by-product to ammonia led to the formation of nitrogen trichloride and explosions. However, this only happened when the chlorination was done for an extended time (10 hours to 2 days).

    Any thoughts on how easy it is form nitrogen trichloride using this type of procedure? Or how to tell if NCl3 might be starting to form? There is some mention of a greenish color and oily globules separting associated with explosive events. Maybe its safer to stick to thioacetates although they arent nice crystalline salts like the thiouroniums?


    Comment by Z — October 10, 2007 @ 2:18 pm

  2. NCl3 is a problem that I did not think of. Apparently, it is quite easy to obtain from NH4Cl and Cl2 excess – so it is likely to form here too, especially with extended passage of Cl2. This would be a serious hazard to consider, on larger scale.

    NCl3 is a volatile liquid – so if the sulfonyl chloride product is a low-volatility crystalline solid and crashing out of the mix, and isolated by filtration and dried by air suction, there might be a less severe hazard. (As opposed to extracting the react mixture and evaporating down an organic extract). On a large scale one should be able to control the amount of used chlorine – maybe this could supress the NCl3 formation. Maybe one could also purge the reaction mix with SO2 gas at the end to quench NCl3

    Comment by milkshake — October 10, 2007 @ 5:37 pm

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