DCM+Methanol+10% Pd on Carbon generates HCl?

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Discussion Overview

The discussion revolves around the unexpected formation of a salt during the deprotection of a phenol and a secondary amine using 10% Pd on Carbon in a DCM and methanol solvent system. Participants explore the potential sources of acid that could lead to this salt formation, including the possibility of HCl generation and other acids from impurities or reaction byproducts.

Discussion Character

  • Exploratory
  • Technical explanation
  • Debate/contested

Main Points Raised

  • One participant describes the deprotection process and notes the formation of a salt, questioning the source of the acid responsible for this.
  • Another participant suggests that common impurities in methanol, such as formic acid, and the reaction of DCM with oxygen and light could produce HCl, which might react with amine moieties to form a salt.
  • A later reply acknowledges the presence of acids but argues that the amount formed from impurities would be insufficient to create a salt, proposing that carbonic acid from CO2 produced during the reaction could be a contributing factor.
  • One participant mentions the pKa values of phenol and methyl amine, indicating that secondary amines are stronger bases than primary ones, which may influence the acid-base interactions in the reaction.

Areas of Agreement / Disagreement

Participants express differing views on the source of the acid leading to salt formation. While some suggest impurities and reactions with DCM, others argue that these sources are insufficient, indicating a lack of consensus on the explanation for the observed salt.

Contextual Notes

The discussion highlights potential limitations regarding the assumptions about the purity of reagents and the conditions under which the reactions occur, as well as the implications of acid-base interactions in the formation of salts.

gravenewworld
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I've been trying to remove a benzyl protecting group of a phenol and also remove a CBZ protecting group on a secondary amine by standard hydrogenation of the material with 10% Pd on Carbon. My protected molecule is very lipophilic and soluble in DCM. The reason I added methanol was because the intermediates generated (the intermediate where the benzyl is removed but the CBZ still present and vice versa) are generally not soluble in DCM, but soluble in methanol. Deprotection of the two groups worked fine, but to my surprise, after working up the reaction, my material is a salt. I definitely know it is a salt because of the broadening of the NMR signals. I'm just not sure where the acid is coming from or even what acid it is.

I know a good way to dehalogenate material is by hydrogenation with Pd on carbon. Am I dehalogenating the DCM ,and with the presence of methanol as well, generating HCl which is reacting with the amine moities to generate a HCl salt?
 
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So you simultaneously deprotected a phenol and an amine, eh?

Do you see it yet? (you are going to kick yourself)

BTW, I'm sure that you know that common impurities in methanol include formic acid and that DCM in contact with oxygen and light produces HCL and phosgene provided there is no inhibitor, like methanol, in the DCM reagent. These acids are usually present in only trace amounts.
 
Last edited:
chemisttree said:
So you simultaneously deprotected a phenol and an amine, eh?

Yup. The phenol's acidity has never given me a problem with similar analogs before.


Do you see it yet? (you are going to kick yourself)


Yup, via NMR, LC/MS, and TLC. 99% pure by HPLC and the mass spec is spot on. You only know that it is a salt because it is obvious in the NMR.

BTW, I'm sure that you know that common impurities in methanol include formic acid and that DCM in contact with oxygen and light produces HCL and phosgene provided there is no inhibitor, like methanol, in the DCM reagent. These acids are usually present in only trace amounts.


I don't think that is the problem because there are 1-2 equivalents of acid that are forming salts with my compound. It would take much more acid than trace amounts to form a salt with my compound. The only other thing that I can think of is that the CO2 that is produced from the CBZ deprotection is forming carbonic acid and the molecule is salting with that.

Now that I think about it, I'm pretty certain that it can't be an HCl salt. Most compounds that have 2 HCl equivalents are incredibly hydroscopic. The salt of my compound doesn't seem to soak up a lot of water from the atmosphere at all if you leave it out.
 
pKa of phenol is 9.6. pKa of the acid form of methyl amine (ammonium) is 10.6. Secondary amines are stronger bases than primary ones.
 

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