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Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: Fmeub on October 30, 2009, 09:12:33 AM

Title: Hydroxy methylation with poor yield
Post by: Fmeub on October 30, 2009, 09:12:33 AM

By the way, is there a way in which I can import a structure, say from Chemdraw?

I have a C-8 chain with a secondary alcohol, a terminal alkyne and a double bond somewhere in the middle as well. I want to add a single carbon and another alcohol group to the terminal end of the alkyne. In pursuit of this purpose I use two equivalents of Butyl Lithium (first eq for the secondary alcohol), and paraformaldehyde, but I get very poor yield. I leave the reaction overnight at 30-35 degrees, and it is under Ar from the start of course. My supervisor doesn't think that leaving it any longer will improve the yield. I have tried with adding even up to 1.7 eq of paraformaldehyde (which I have ground and put on a vacuum pump to dry)
as well as slightly more than 2 eq BuLi, but if at all the extra BuLi only worsened it.

The dryness of the paraformaldehyde does have an influence, but it still gives a low yield even if I grind it very hard and leave it on the pump for at least a day. My supervisor has done a similar reaction, but in her case the secondary alcohol is protected by TBS, and this gives a respectable yield. Someone also suggested that the H on the terminal alkyne forms a bridge with the deprotonated secondary alcohol after the first equivalent of BuLi is added, and so it is not properly deprotonated by the second eq of BuLi. However, the mixture supposedly becomes a darker shade of yellow when the dianion is formed and this I have seen-it's not my imagination or over-eagerness.

This is the formula of the reagent:
This is the formula of the proposed product:

Any suggestions as to why I may be getting such a low yield? Also, what would be your gutt feeling, should I leave the reaction a bit longer or what? Do you agree with the theory of the bridged H?
Title: Re: Hydroxy methylation with poor yield
Post by: movies on October 30, 2009, 11:26:40 AM
By the way, is there a way in which I can import a structure, say from Chemdraw?

Yes!  Save your file as a pdf or a gif and then upload it as an attachment to your post.

For the reaction, at what temperature are you performing the deprotonation?  What is your order of addition?  I would start with a –78 oC solution of your alcohol in THF or ether (ca. 0.1 M) and then add the butyllithium dropwise to that cooled solution.  From your description, it sounds like the deprotonation is not really the problem though.  To confirm this, you might want to try quenching an aliquot of your dianion solution with D2O and checking the 1H and 2H NMR just to be sure.

I really don't think that reaction time is the problem in your case.  I have worked with paraformaldehyde in the past and for many reactions the polymer gave me very poor yield.  To get decent results I had to crack the solid to generate free formaldehyde gas and bubble that through my solution of Li-anion.  It is a real pain to do this, but it is the only thing that really worked in my case.  If you go this route, make sure the tube you use to connect the flask containing the paraformaldehyde to the reaction vessel has a relatively large diameter.  Paraformaldehyde tends to resolidify in the tube and it can get clogged.  Definitely don't use a cannula!

Another alternative to the lithium anion might be KOH in aqueous formaldehyde solution.  Have you tried that?  It would certainly be an easier reaction to run.  I would give it a go on 20 mg of your alcohol and see what you get.

The other thing that I see as a potential pitfall is the possibility of forming acetals off of your free alcohol.  That is a common side reaction with formaldehyde and it can be a real pain to deal with.  Sometimes these can be cleaved with an acidic workup, but before you go to the trouble of figuring that out, check the crude NMR of your product and see if there are peaks that look like acetals/hemiacetals.
Title: Re: Hydroxy methylation with poor yield
Post by: Fmeub on November 04, 2009, 01:09:02 PM

It seems my supervisor has tried cracking the paraformaldehyde, but without much success and a lot of frustration. Yeah, she mentioned that it clogged and got gunged-up in the tube.

Could you please give me more details about the KOH alternative? I'm not very experienced in the lab.


Title: Re: Hydroxy methylation with poor yield
Post by: movies on November 04, 2009, 02:33:48 PM
Well, I came across some scattered (old) reports of reactions of terminal alkynes with acetone in the presence of KOH.  Much more common is the reaction with an alkynyl metal (Li, Mg, Na).  Maybe the easy way doesn't work as well in practice as it does in my mind - lol!  If it were me, I would give it a shot with a little bit of material just because it is so easy to try.

You may want to try some other bases (like i-PrMgCl or NaHMDS) in your paraformaldehyde reactions to see if that has a substantial effect.  I would also suggest adding some TMEDA to your lithium reactions because that often has a substantial effect on the reactivity of Li reagents.
Title: Re: Hydroxy methylation with poor yield
Post by: orgopete on November 04, 2009, 04:55:28 PM
If it was failing with paraformaldehyde, my next try would have been with acetone. There are enough acetone examples that I would have used it to verify the successful formation of the dianion.

For all we know, the titer of the butyllithium has fallen and that is the reason for failure. I had done a number of metalation reactions in which my substrate formed a dianion. That was convenient as the dianion was highly colored so the metalation reaction served as a titration experiment as well. We commonly adjusted our butyllithium use based upon the amount needed to form the first anion.