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Topic: CDI coupling : solvent choice and acid workup alternatives.  (Read 16524 times)

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Offline endophytic

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CDI coupling : solvent choice and acid workup alternatives.
« on: April 27, 2013, 05:49:11 PM »
Hello board !

I'm planning on following the following methodologie  in order to form hydroxamate from a carboxylic acid :

Quote
CDI (4.5 mmol, 1.5 eq) was added to a solution of carboxylic
acid 1 (3.0 mmol) in dry tetrahydrofuran (THF) (5 ml). The reaction mixture was
stirred for 1 h. Powdered hydroxylamine hydrochloride (417 mg, 6 mmol) was added.
The resulting mixture was stirred overnight (ca. 16 h). The mixture was diluted with
5% aq. KHSO4 (30 ml) and extracted with EtOAc (230 ml). The combined organic
phase was washed with brine (30 ml) and dried over Na2SO4. The extract was filtered
and concentrated in vacuo to give the product 3.
(Usachova, N. et al. Synthetic Communications, 2010, 40(6), 927–935.)

Since the rxn mixture is further diluted with aq. KHSO4 I guess here solvent as EtOAc or DCM are not an alternative ?
I am a bit pertubated with the whole solvent choice thing. How do you guys orientate your choice ?
DMF, MeCN ? What would you choose in this case ?

Now regarding the acidic work up ? The 5% aq. KHSO4 dilution objective is what ? Reprotonate products of the reaction ? Now I have a question as a phytochemist I often do A/B extraction aiming to selectively isolate alkaloids. In my reaction there I'll have N-containing compounds. Generally acidification of the solution will lead to a greater water solubility an a decreased apolar solvent solubility. Now in this case since the next step is an EtOAc partition in't that an issue ?

Another thing (sorry for my obsession with alternatives but I'm in a natural products lab ... crucial lack of reagents here )  What alternative do I have for the 5% aq. KHSO4 dilution ? Will aq. HCl do the trick ? What proportion then ?

Thanks again for all feedback  :)

Offline Dan

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Re: CDI coupling : solvent choice and acid workup alternatives.
« Reply #1 on: April 28, 2013, 06:34:11 AM »
Since the rxn mixture is further diluted with aq. KHSO4 I guess here solvent as EtOAc or DCM are not an alternative ?

Fine in this case because it is just a partition of the reaction mixture between an aqueous and organic solvent.

Quote
I am a bit pertubated with the whole solvent choice thing. How do you guys orientate your choice ?
DMF, MeCN ? What would you choose in this case ?

You need to choose something that will dissolve the reagents but will not react with them. Basically, any dry aprotic solvent that will dissolve the reagents should be fine. Polarity of the solvent does affect reaction rates, but can be difficult to predict. I would probably go for DCM if you do not have THF, reason being I have used DCM as a solvent for similar reactions (with different coupling reagents) in the past and they worked well.

Quote
Now regarding the acidic work up ? The 5% aq. KHSO4 dilution objective is what ? Reprotonate products of the reaction ?

This will hydrolyse excess CDI and protonate the imidazole and leftover hydroxylamine and keep it in the aq layer.

Quote
Now I have a question as a phytochemist I often do A/B extraction aiming to selectively isolate alkaloids. In my reaction there I'll have N-containing compounds. Generally acidification of the solution will lead to a greater water solubility an a decreased apolar solvent solubility. Now in this case since the next step is an EtOAc partition in't that an issue ?

Amides are nowhere near as a basic as amines. The point is that the acid will protonate the more basic byproducts and leave the less basic amide in the organic layer.

Quote
Another thing (sorry for my obsession with alternatives but I'm in a natural products lab ... crucial lack of reagents here )  What alternative do I have for the 5% aq. KHSO4 dilution ? Will aq. HCl do the trick ? What proportion then ?

Yeah, HCl should be fine. You can calculate the molarity of 5% bisulfate and use a similar molarity of HCl - but something around 0.5-1 M should be fine.
My research: Google Scholar and Researchgate

Offline endophytic

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Re: CDI coupling : solvent choice and acid workup alternatives.
« Reply #2 on: April 28, 2013, 09:46:36 AM »
Hey Dan !

Again thank for the quick replies.


Fine in this case because it is just a partition of the reaction mixture between an aqueous and organic solvent.


You need to choose something that will dissolve the reagents but will not react with them. Basically, any dry aprotic solvent that will dissolve the reagents should be fine. Polarity of the solvent does affect reaction rates, but can be difficult to predict. I would probably go for DCM if you do not have THF, reason being I have used DCM as a solvent for similar reactions (with different coupling reagents) in the past and they worked well.


I don't get it. So here you tell me you'd use DCM. But this means that when you'll disolve with your aq. KHSO4 solution you'll have two phases right ? So how can you get to really have your acidic workup play his role whithout mixing with the org phase ?
And in this case this also means you skip the EtOAc extraction phase right ? You would just keep and concentrate your DCM phase ?
Would'nt Acetone (water miscible) be better for the acidic work up phase ?

Amides are nowhere near as a basic as amines. The point is that the acid will protonate the more basic byproducts and leave the less basic amide in the organic layer.

What if I have, let's say, an indolic moiety  on ther other part of my molecule. Would this be an issue here ?
How would you work this on ?


Thanks  for your attention  :) And sorry for my begginners questions :-\

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Re: CDI coupling : solvent choice and acid workup alternatives.
« Reply #3 on: April 28, 2013, 11:37:29 AM »
I don't get it. So here you tell me you'd use DCM. But this means that when you'll disolve with your aq. KHSO4 solution you'll have two phases right ? So how can you get to really have your acidic workup play his role whithout mixing with the org phase ?

There will be protonation reactions at the interface of the two phases - biphasic workups are routine.

Quote
And in this case this also means you skip the EtOAc extraction phase right ? You would just keep and concentrate your DCM phase ?

No, I would still do the extraction. My procedure would be to pour the reaction mixture into a separating funnel, add aqueous acid and ethyl acetate, shake, collect organic layer. I might then wash the organic fraction with aqueous acid a couple of times to make sure I got all the imidazole and other basic byproducts and salts out. I might also do a bicarbonate wash if I had reason to suspect (e.g. from TLC analysis) that there was unreacted carboxylic acid still present.

Quote
What if I have, let's say, an indolic moiety  on ther other part of my molecule. Would this be an issue here ?
How would you work this on ?

How basic do you think indoles are?
My research: Google Scholar and Researchgate

Offline endophytic

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Re: CDI coupling : solvent choice and acid workup alternatives.
« Reply #4 on: April 28, 2013, 04:40:38 PM »

There will be protonation reactions at the interface of the two phases - biphasic workups are routine.


OK.



No, I would still do the extraction. My procedure would be to pour the reaction mixture into a separating funnel, add aqueous acid and ethyl acetate, shake, collect organic layer. I might then wash the organic fraction with aqueous acid a couple of times to make sure I got all the imidazole and other basic byproducts and salts out. I might also do a bicarbonate wash if I had reason to suspect (e.g. from TLC analysis) that there was unreacted carboxylic acid still present.

OK. I'll do it this way.
So I guess I'll have a 3 phase system is that it ?
With DCM down my funnel, water in between and an upper EtOAc phase is that it ?


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Re: CDI coupling : solvent choice and acid workup alternatives.
« Reply #5 on: April 28, 2013, 05:57:35 PM »
DCM and ethyl acetate are miscible, there will only be two phases.
My research: Google Scholar and Researchgate

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