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Friday, July 15, 2005

Creating Amphetamines by Tosylation of Alcohols

The picture above shows a few of the steps in the creation of amphetamines. In these steps, tosyl chloride is added to (2,5-dimethoxyl-4-methylphenyl)-2-propanol to create the tosylate. After this step, the reaction can proceed in one of two ways. If the chirality of the amphetamine is not important, ammonia is added to the tosylate to give 2,5-dimethoxy-4-methylamphetamine. This reaction has an 80% yield, but has a racemic mixture of products because it is thought to be an SN1 reaction. If the chirality is important, the tosylate is converted into an azide with sodium azide, then hydrogenated using a paladium catalyst to form 2,5-dimethoxy-4-methylamphetamine. Forming the amphetamine using this method gives a final yield of about 77%. The chirality of the original alcohol is inverted by the tosylation, so reacting an (S)-alcohol with the tosyl-azide-hydrogen sequence would give an (R)-amphetamine, and vice versa.

For the full text of the article describing this process, see this report.


  • Full Marks. Well done. Just correct the spelling mistake in the title. Here is an open question to anyone: Why would the reaction with ammonia proceed via SN1 while azide favors SN2?

    By Blogger Jean-Claude Bradley, at 5:33 AM  

  • The azide ion is an excellent nucleophile, which can displace the leaving group of tosylates via SN2 mechanism. Amonia, on the other hand is a weak nucleophile, which is why it favors the SN1 reaction.
    One explanation for this could be that simply comparing the two: the azide ion has a negative charge, as opposed to the neutral amonia molecule, making it[azide ion] a better neuclephile.

    By Blogger Petia, at 2:30 PM  

  • Petia - that makes sense. Is there anything that could have been done to make the reaction with ammonia favor SN2?

    By Blogger Jean-Claude Bradley, at 3:05 PM  

  • If a good ionizing solvent (a very polar one) is used, could we have made the anion of amonia and used the rule that a species with a negative charge is always a stronger nucleophile than the similar neutral species. However I am not sure if this would make the ion so strong a neucleophile that the reaction would favor SN2 or simply speed up the slow step of the SN1 reaction?!

    By Blogger Petia, at 11:16 PM  

  • Petia,
    It is probably true that the anion of ammonia would be a better nucleophile than ammonia but it will also be a stronger base, which will be a problem - why?
    Also, the slow step of the SN1 reaction does not involve the nucleophile.

    By Blogger Jean-Claude Bradley, at 1:38 PM  

  • A non-polar solvent would make it more difficult for the leaving group to come off, which would favor the SN2 mechanism. Though once ammonia would attach to the cation, a proton would have to be removed from it to yield a neutral amine molecule (another ammonia molecule could perform that task).
    Also, if ammonia is given a negative charge, it will have to convert into an ammide ion, which is extremely basic. Therefore it will seak to gain back a proton, and will acheve that by capturing a proton from a carbon adjecent to the cation (probably from the benzylic position , since that C-H bond is the weakest due to resonance stablization), which will lead to an ellimination reaction, instead of substitution, forming a double bond.

    By Anonymous Anonymous, at 9:38 PM  

  • Exactly, E-2 is the old nemesis of the SN2 reaction.

    By Blogger Jean-Claude Bradley, at 4:49 AM  

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