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Topic: Boc protection of cystamine  (Read 1277 times)

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Offline steph90

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Boc protection of cystamine
« on: February 28, 2023, 08:12:54 AM »
I am looking for confirmation of how I understand the selective synthesis of mono-BOC-cystamine.
I have already successfully synthesized the product, however, am lacking a few of the details to completely understand the reaction.

A referral of the mechanism: https://www.jkchemical.com/post/556

1. 1 mol. eq. of cystamine dihydrochloride in MeOH was brought to 0.5 celsius (what is the purpose of this solution being so cold?)
2. Taken off the ice, 3 mol. eq. of triethylamine (TEA) was stirred in the cold solution for 30 min. allowing it to come to room temperature (are 2 mol. eq. of the TEA used up here to deprotonate the primary amine salt?)
3. Boc2O was added dropwise over 3 hours. To describe the mechanism, is this a nucleophilic attack of the amine nitrogen to the carbonyl carbon?
4. Following the amine attack of Boc2O, an electron transfer occurred from the nitrogen to carbonyl oxygen. Can you say that this formed a carbamate intermediate or a tetrahedral intermediate? The extra electron pair then transfers to the sp3 hybridized C-O bond and further to the next internal C-O bond, cleaving tert-butyl carbonate.
5. The result of the cleavage leaves a protonates mono-BOC-amine, where the last molar equivalent of TEA deprotonates this.
6. If the above use of TEA as a base is correct, then I don't understand why the protocol I followed uses 1 M of NaOH for the extraction with DCM. Originally, I thought that the NaOH was basifying (or free-basing) any salt form of amine left (or maybe this is still true)?



Offline rolnor

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Re: Boc protection of cystamine
« Reply #1 on: March 12, 2023, 02:45:31 PM »
Cystamine is unstable as free base, so cooling is for avoiding heat I think. 1Mole is a large amount so it could evolve heat when TEA is added.. The TEA only partially makes the free base, its a equilibrium. I dont see if you make the di-BOC compound or mono-Boc? The NaOH is for washing salts away.
Here you see the mechanism. Its nuc attack on the carbonyl, carbondioxide+t-BuOH is formed as byproduct.

https://en.wikipedia.org/wiki/Nucleophilic_acyl_substitution

Offline steph90

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Re: Boc protection of cystamine
« Reply #2 on: May 13, 2023, 09:10:25 AM »
Thanks for your response rolnor.

The purpose was to make mono-BOC-cystamine. After purchasing the pure product to make an HPLC-MS standard curve, I calculated my purity to be only 17.6%.

Maybe it would have made more sense if I also had mentioned that Boc2O was added in 1 molar equivalent. So 1 part cystamine to 1 part Boc2O. Then there were 3 parts TEA.

Also, thanks for clarifying the mechanism.

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