0
$\begingroup$

Various ethers are used for hydroxyl protection. My question is about their removal. I know that there are various methods but I want to specify on the use of acids.

Certain groups are removed easily like Trityl, by using aqueous acetic acid. If I'm not mistaken, the mechanism is Sn1, as the trityl carbocation is stabilised through delocalisation on the phenyl groups.

However, other similar groups like benzene or PMB are not removed that easily. Can't they follow the same logic, as the postive charge could again be delocalised in the aromatic ring? Is it because the delocalisation is not good enough, as in the case of trityl?

Also, I've noticed that in order to remove smaller groups like methyl, haloacids are mainly used. Why can't a more weak acid do the job?

$\endgroup$
  • 1
    $\begingroup$ PMB can be removed under acid conditions, but it needs strong acid as the benzyl cation is not as stable as the trityl - 20% TFA in DCM is the standard in our labs, though hydrogenation is a better and milder way. Phenyl ethers are not protecting groups, PhO- is a decent leaving group. To remove OMe you first need to protonate it and for that you require strong acid and you also need a good nucleophile as the counter ion. $\endgroup$ – Waylander Nov 6 '18 at 16:04
  • $\begingroup$ @Waylander My queastion about PMB or Bn is why it can't be removed by a weaker acid since the positive charge that would be formed (Sn1) can be delocalised just like in Tr removal. I didn't mention phenyl but benzene group as protecting. As for the OMe I asked why can't a weaker acid do the job. I'm already familiar with what is being used in general. The why is what $\endgroup$ – Αντώνιος Κελεσίδης Nov 6 '18 at 16:09
  • 1
    $\begingroup$ A weaker acid will not protonate PMB or Bn $\endgroup$ – Waylander Nov 6 '18 at 16:17
  • $\begingroup$ What would obstruct it? Sterically they are more open than triyl. $\endgroup$ – Αντώνιος Κελεσίδης Nov 6 '18 at 16:39
  • 1
    $\begingroup$ Protons are not really affected by steric factors being quite small $\endgroup$ – Waylander Nov 6 '18 at 17:07
1
$\begingroup$

You are right.In case of benzene and PMB, the delocalization is not good enough. So a strong acid is required.

As for the case of OMe, a strong acid as well as strong nucleophile will be needed. A weaker acid can't do the job. Let me explain why. Note that carbon oxygen bond is quite strong. So what we need is a strong nucleophile. But in case of OMe as a protecting group, even a stronger nucleophile will not work if the oxygen is not heavily protonated due to two reasons:- 1. Strength of C-O bond. 2. SN1 can't occur as methyl carbocation not stable.

Here acid is a stoichiometric reagent, not simply a catalyst. If a weaker acid is used, it will just establish a protonation-deprotonation equilibrium. However, a stronger acid will shift the equilibrium towards protonation. And haloacids are best suited.

Conclusion being that a weaker acid will render nucleophile incapable to cleave ether in case of OMe.

$\endgroup$

Your Answer

By clicking “Post Your Answer”, you agree to our terms of service, privacy policy and cookie policy

Not the answer you're looking for? Browse other questions tagged or ask your own question.