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Topic: Ligand-Halogen Exchange - Paraformaldehyde  (Read 11030 times)

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Offline Nescafe

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Ligand-Halogen Exchange - Paraformaldehyde
« on: March 08, 2012, 08:10:02 PM »
Hi,

So I have a bit of a problem. I am trying to make benzyl alcohol from bromo benzene using Lithium-halogen exchange followed by treatment with paraformaldehyde (Simplifying the structure of my tarting material here but there is not much more complexity to the molecule I am actually working with than what I am stating here).

Starting with bromo benzene dissolved in anhydrous diethyl ether at -78C I added 1.5eq of n-BuLi. After stirring for 30minuts at -78 I add my electrophile,dried paraformaldehyde in great excess (5eq). I stir the reaction for another 2hrs at -78 and slowly bring it up to 0C which I stir at for 1hr and then stop the reaction. This whole time I keep the reaction under nitrogen. I do a water work-up and get a brilliant 0% of product. The reaction does not work. This whole time I am observing the reaction and can actually visually see the paraformaldehyde solids (White solid - Bought from Sigma) just stirring in solution (Et2O). Now I tried this reaction today with formaldehyde (%50Wt H20 - Sigma aldrich) and I do see minor product formation but I mainly just destroy the Lithium specie.

 After doing some research I realize that my current methodology which involves adding dry paraformaldehyde without trying to break it via heat is not ideal. Any suggestions? How does one properly carry out such a reaction?

Any advice would be highly appreciated.
« Last Edit: March 08, 2012, 08:21:57 PM by Nescafe »

Offline discodermolide

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Re: Ligand-Halogen Exchange - Paraformaldehyde
« Reply #1 on: March 08, 2012, 09:18:45 PM »
Hi,

So I have a bit of a problem. I am trying to make benzyl alcohol from bromo benzene using Lithium-halogen exchange followed by treatment with paraformaldehyde (Simplifying the structure of my tarting material here but there is not much more complexity to the molecule I am actually working with than what I am stating here).

Starting with bromo benzene dissolved in anhydrous diethyl ether at -78C I added 1.5eq of n-BuLi. After stirring for 30minuts at -78 I add my electrophile,dried paraformaldehyde in great excess (5eq). I stir the reaction for another 2hrs at -78 and slowly bring it up to 0C which I stir at for 1hr and then stop the reaction. This whole time I keep the reaction under nitrogen. I do a water work-up and get a brilliant 0% of product. The reaction does not work. This whole time I am observing the reaction and can actually visually see the paraformaldehyde solids (White solid - Bought from Sigma) just stirring in solution (Et2O). Now I tried this reaction today with formaldehyde (%50Wt H20 - Sigma aldrich) and I do see minor product formation but I mainly just destroy the Lithium specie.

 After doing some research I realize that my current methodology which involves adding dry paraformaldehyde without trying to break it via heat is not ideal. Any suggestions? How does one properly carry out such a reaction?

Any advice would be highly appreciated.

Have a look at the following;
Anionic, in Situ Generation of Formaldehyde:  A Very Useful and Versatile Tool in Synthesis
Geoffrey Deguest, Laurent Bischoff,* Corinne Fruit, and Francis Marsais
Laboratoire de Chimie Organique Fine et Hétérocyclique, CNRS UMR 6014, IRCOF-INSA Rouen, B.P. 08, 76131 Mont-Saint-Aignan, France
 Org. Lett., 2007, 9 (6), pp 1165–1167
DOI: 10.1021/ol070145b
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Offline Nescafe

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Re: Ligand-Halogen Exchange - Paraformaldehyde
« Reply #2 on: March 08, 2012, 09:25:18 PM »
Thank you for that. It definitely changed my mood.

Sometimes when you get stuck on a problem in lab you get tunnel vision and just can't snap out of it. I looked through scifinder for three hours and the only thing I found was a publication dating back to the 1960s with little detail on the exact steps involved. This publication you directed me to on the other hand is very detailed.

I will give it a shot,

Appreciate it.

Offline opsomath

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Re: Ligand-Halogen Exchange - Paraformaldehyde
« Reply #3 on: March 09, 2012, 10:21:57 AM »
Why are you making your own benzyl alcohol, if you don't mind my asking? It isn't that expensive.

Offline Mobius1988

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Re: Ligand-Halogen Exchange - Paraformaldehyde
« Reply #4 on: March 09, 2012, 12:58:38 PM »
Why are you making your own benzyl alcohol, if you don't mind my asking? It isn't that expensive.

He said he simplified his starting materials, he has other functionality on the molecule that he cant purchase.

Offline Mobius1988

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Re: Ligand-Halogen Exchange - Paraformaldehyde
« Reply #5 on: March 09, 2012, 01:08:34 PM »
Also Nescafe, you can make benzyl alcohols using Lithium Halogen Exchange, DMF, MeOH and NaBH4. Basically by forming an aldehyde and reducing in one pot.

Ive done this reaction a couple of times recently (mine didnt work well because my end product could dimerise) but its a nice reaction. I did this when I realised I couldnt use aqueous formaldehyde and I didnt know about that paper.

How to do the reaction (all under nitrogen):

Dissolve starting material in solvent, cool to -78.
Add 1-2 equiv nBuLi and stir at - 78
Add 5 equiv DMF (still at - 78) and stir at -78, warm to room temp 
Add 50 equiv MeOH
Add 1 equiv NaBH4
Stir until complete

At each point you can LC-MS to see your intermediates. If you want a paper on it let me know and ill see if i can dig it out.

Offline Nescafe

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Re: Ligand-Halogen Exchange - Paraformaldehyde
« Reply #6 on: March 10, 2012, 12:01:04 AM »
Why are you making your own benzyl alcohol, if you don't mind my asking? It isn't that expensive.

Exactly what Mobius1988 said! =)

Also Nescafe, you can make benzyl alcohols using Lithium Halogen Exchange, DMF, MeOH and NaBH4. Basically by forming an aldehyde and reducing in one pot.

Ive done this reaction a couple of times recently (mine didnt work well because my end product could dimerise) but its a nice reaction. I did this when I realised I couldnt use aqueous formaldehyde and I didnt know about that paper.

How to do the reaction (all under nitrogen):

Dissolve starting material in solvent, cool to -78.
Add 1-2 equiv nBuLi and stir at - 78
Add 5 equiv DMF (still at - 78) and stir at -78, warm to room temp 
Add 50 equiv MeOH
Add 1 equiv NaBH4
Stir until complete

At each point you can LC-MS to see your intermediates. If you want a paper on it let me know and ill see if i can dig it out.



I looked up the paper Discodermolide referred me to and it's definitely an interesting way of doing it. But I am going to make that my option number two after reading your post Mobius. I am very confident that the conditions you suggested will not touch the rest of the functional groups on my starting material. Plus, we already have all the materials required to carry out the reaction whereas to do what the paper suggests it will cost another $80-90 bucks. I am going to try this reaction over the weekend and if it works I will let you know!

Highly appreciate it,

Nescafe.

Offline Mobius1988

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Re: Ligand-Halogen Exchange - Paraformaldehyde
« Reply #7 on: March 11, 2012, 02:54:07 PM »
How did it go?

Offline Nescafe

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Re: Ligand-Halogen Exchange - Paraformaldehyde
« Reply #8 on: March 12, 2012, 11:32:00 PM »
How did it go?

Hi Mobius,

Perhaps I have under valued the importance of some of the other functionalities existing on my starting material. I followed your procedure and saw a smooth consumption of SM based on TLC and LC-MS. However, product peak was absent.

I have a benzyl ester functionality which is in very close proximity to a benzyl ester. Now I can't explain exactly what is going on. No SM, no product either but based on TLC there are a few new spots and it looks kinda ugly (EtoAC/Hexanes). I isolated most of them but none were my  desired product.

In your experience working with Lithium-Halogen exchange reactions, have you noticed any protecting groups being very sensitive to the conditions used? Benzyl esters, benzyl ethers etc.

I know NaBH4 wont do anything to esters as it is not nearly as strong enough as LiAlH4, but could the Li attack benzyl esters that are shielding by bulky neighbors? I am starting to feel that I need to re-construct my synthetic map.

Thanks,

Nescafe.
« Last Edit: March 12, 2012, 11:49:16 PM by Nescafe »

Offline discodermolide

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Re: Ligand-Halogen Exchange - Paraformaldehyde
« Reply #9 on: March 12, 2012, 11:59:12 PM »
Just a point, NaBH4 will reduce esters in a THF/Methanol mixture at around 55°C.
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Offline Nescafe

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Re: Ligand-Halogen Exchange - Paraformaldehyde
« Reply #10 on: March 13, 2012, 12:02:37 AM »
Just a point, NaBH4 will reduce esters in a THF/Methanol mixture at around 55°C.

I did not know that. Thank you.

The reaction does spend the last hour in THF/MeOH but it is at R.T.

Nescafe.

Offline Mobius1988

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Re: Ligand-Halogen Exchange - Paraformaldehyde
« Reply #11 on: March 14, 2012, 07:23:42 PM »
To be quite honest I have only conducted this reaction a couple of times and I dont know a great deal about its effect on protecting groups.

I would suggest you look for a LC-MS peak at - 126 (relative to your starting molecules mass ion) as this will indicate that you are losing your halogen and protonating in its place (i get a little bit of this is my reaction). Perhaps youre forming your lithiated species but it is just deprotonating somewhere else in your molecule before you add the DMF (next to the carbonyl of your ester maybe??). I dont have any particularly acidic areas in my molecule.

Did you LC-MS at each stage of the reaction? Were there any significant peaks with mass ions that you could use to work out what youre forming? As i said previously, I was able to observe my lithiated species ( m/z - 126 relative to starting material), followed by my aldehyde (m/z - 97) and finally the alcohol (m/z - 95) by clear LC-MS peaks.

I actually got about 8 or 9 spots in my TLC plate before my chromatography so the reaction can be messy but these all corresponded to tiny impurities and were easily removed on the column.

Offline Mobius1988

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Re: Ligand-Halogen Exchange - Paraformaldehyde
« Reply #12 on: March 14, 2012, 07:26:00 PM »
Just a point, NaBH4 will reduce esters in a THF/Methanol mixture at around 55°C.

Do you happen to have a paper on this or is it just your own knowledge?

Offline discodermolide

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Re: Ligand-Halogen Exchange - Paraformaldehyde
« Reply #13 on: March 14, 2012, 08:58:07 PM »
Just a point, NaBH4 will reduce esters in a THF/Methanol mixture at around 55°C.

Do you happen to have a paper on this or is it just your own knowledge?

My own knowledge and practical experience of running 1kmol reactions. The knowledge is propriety, so I can't say much more.
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Offline fledarmus

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Re: Ligand-Halogen Exchange - Paraformaldehyde
« Reply #14 on: March 15, 2012, 08:37:18 AM »
If you are worried about whether you are getting the halogen-metal exchange to work or if you are losing protecting groups in that process, take an aliquot of your solution after you have added your n-BuLi and quench it with D2O, then add some MeOH. The MS of the aliquot will tell you whether you are getting your halogen-metal exchange reaction to work. If the halogen-metal exchange product is being quenched from someplace else, you will see molecular weights from both protonated and deuterated species. You can also isolate the now-deuterated starting material from that aliquot and run an NMR to see if the intermediate is deprotonating some other point in your molecule. (The MeOH will take care of any rapidly exchanging protons that might be deuterated by the operation).

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