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


  1. It is always nice to see a new post here! I wonder whether benzene could be replaced by toluene. I am not that afraid of benzene, just curious. Also, why do you wash your filter cake with cyclohexane prior to hexane. Is there particular reason for that like impurity or sm removal? Thanks.

    Comment by Peter — September 6, 2012 @ 7:52 am

    • I tried toluene only once, for the product recrystallization and the resulting material was not as nice but I have not run the reaction in it. (I used PhCF3 as a solvent and the material precipitated from it). Benzene often works better for crystallizations than toluene but maybe I am prejudiced. I noticed that the crude material has some limited solubility in cyclohexane but n-hexane would crash out stuff from supernatants – I did not want this to happen with my pristine re-crystalized material so thats why the extra cyclohexane wash (but maybe it was unnecessary)

      Comment by milkshake — September 6, 2012 @ 10:33 am

  2. This looks like an interesting reagent. What are you using it for?

    Comment by subnaught — September 7, 2012 @ 4:44 pm

    • It is just a cheap way of putting thiol group into a molecule, by peptide coupling.

      Comment by milkshake — September 7, 2012 @ 5:17 pm

  3. I’ve had these papers in my files for ages, wanting to use them for a similar job.

    DOI: 10.1007/BF00954046
    DOI: 10.1055/s-2003-36252

    Comment by FleaTamer — September 12, 2012 @ 8:11 am

    • thank you for the references, this is very nice. Handling trityl-thio compounds have some advantages though (stability, ease of putification on silica, no smell, highly crystalline products) so I think I will still use this piece in a trityl protected form.

      Comment by milkshake — September 12, 2012 @ 11:37 am

  4. Hi Milkshake. I’m currently tritylating lots of stuff too (or rather, dimethoxytritylating – for oligonucleotide synthesis precursors). I had a question for you about my current synthetic scheme. I’m looking to install a terminal alkyne onto my molecule which contains an epoxide. The plan is to react sodium acetylide with cyclohexanone (or similar ketone) then quench the alkoxide with my epoxide. Do you have any recommendations for handling commercial sodium acetylide slurry (18% in xylene) and do you think the reaction will need heating to open the epoxide? Many thanks.

    Comment by NorthwesternChemist — September 13, 2012 @ 8:25 pm

    • Hi, first many of these tertiary alcohols (adducts of simple ketones with acetylene) are commercially available and reasonably inexpensive. They could be prepared from acetylene gas excess, KOH and ketone in a solvent like DMSO or diglyme at about 80C, thats how they are made industrially. For acetylide additions, please see these OrgSyn procedures:
      and the reference cited there. (J. Am. Chem. Soc., 67, 1053 (1945)
      Please note that typically one uses an excess of acetylene gas (dried by bubbling through sulfuric acid) to minimize the formation of bis-adducts of ketones

      Epoxide opening: I don’t understand what are you trying to open your epoxide with – an alkoxide (O- anion) or acetylide (C anion)?

      Comment by milkshake — September 13, 2012 @ 10:05 pm

      • Hi Milkshake
        Thanks for the response! I’d like to quench the reaction by adding in an epoxide (so, I would be opening it with the intermediate alkoxide of the tertiary alcohol). Do you think that’s feasible?

        Comment by NorthwesternChemist — September 14, 2012 @ 11:12 am

        • definitely not in one pot – make sure that you have pure alkynyl alcohol in hand before playing with it. Epoxide opening with a tertiary alcohol is possible (I did it accidentally with 2-ethyl-2-butanol and ethylene oxide) but it will be a very sluggish reaction and it will compete with epoxide anionic polymerization (because the ring opened product is also an alkoxide). Make sure you have K-alkoxide (in THF, RT, then gently heating) because Na and Li alkoxides are considerably less reactive for epoxide ring opening.
          My estimate is that your chance of succeeding with what you trying to do is pretty low, especially on a complex substrate like your nucleotide. A lots of things can go wrong under these strongly basic conditions (heating with K-alkoxide)

          Comment by milkshake — September 14, 2012 @ 11:26 am

  5. Hi MS,

    Off topic. I am trying to do Friedel Craft acylation of 2-thiophene acid chloride (other alpha positions is also substituted) with 4-halo toluene. I am not getting any desired product however the FC reaction of aromatic acid chloride on thiophene is working. What could be the reason for this reactivity? I am using AlCl3 in DCM at 0 and rt for FC. Please suggest me if you have any experience. If you have any related refs also please let me know.



    Comment by marto — February 6, 2013 @ 1:20 pm

    • I don’t know what exactly is in your molecule so I cannot give you a good advice. Lots of things can go wrong in Friedel-Crafts depending on the actrual functional groups. If I understand you correctly p-halogen-substituted toluene is the arene substrate and thiophene-2-carboxylic acid chloride is the acylating agent (with the 5-position of thiophene blocked) . From what the little I know about thiophenes is that they dislike AlCl3 – they tend to polymerize into black tar with AlCl3. People typically used milder Lewis acids like SnCl4 for Friedel-Crafts with thiophene (when unsubst thiophene is the arene substrate). I don’t know the exact structure of your thiophene carbonyl cloride but I guess it will be prone to decomposition under the reaction conditions because thiophene is pretty electron rich, especially since the reactivity of p-halogen-substituted toluene as a substreate in F-C is going to be fairly poor.

      So try the reaction with para-xylene first – and use SnCl4, to see if you can get a desired product. Then move to p-halo-toluene (at slightly higher reaction temperature to compensate for lower reactivity). Also, dichloromethane as a solvent may interfere in F-C so it would be much better to use excess of p-xylene or p-halo-toluene as the actual solvent – they are quite inexpensive (and having an excess of the other aromatic might suppress thiophene ring self-acylation). But definitely try SnCl4 instead of AlCl3

      Comment by milkshake — February 6, 2013 @ 3:07 pm

  6. Hi MS,

    Thanks very much for the suggestions.


    Comment by marto — February 7, 2013 @ 1:51 am

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