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Topic: Avoiding unwanted conjugate reduction of 3-methyl-2-cyclohexen-1-one  (Read 4394 times)

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Offline dew.be.dew.be.dew.

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I am trying to directly reduce the ketone in 3-methyl-2-cyclohexen-1-one to produce 3-methyl-2-cyclohexen-1-ol.  Sodium borohydride and cerium trichloride in methanol are being used for the reduction, and the reaction is stirred under n2 for 10-12 hrs (although sometimes it is left for closer to 24 hrs).  The problem is that there ends up being a significant amount of product from a conjugated ketone reduction, so I still get the alcohol, but I lose the alkene.  My professor told me that the addition of CeCl3 to the reaction favors direct addition although she is not sure why.  I have read that lithium aluminum hydride gives almost a 90%: 10% direct:conjugate product, but I think LiAlH4 is something my prof is trying to avoid.
So, I was wondering if anyone was familiar with or has any ideas on how to promote the direct reduction vs the conjugate reduction.  Do you think temperature would have an impact?  Or the alcohol used?  Or does anyone know of any other 'magic' compounds like CeCl3 that might help?
Thanks for any advice/suggestions!

Ryan

Offline lavoisier

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Re: Avoiding unwanted conjugate reduction of 3-methyl-2-cyclohexen-1-one
« Reply #1 on: June 30, 2006, 01:52:47 PM »
March gives LaCl3 and CeBr3 as additives which direct the reduction by NaBH4 or LiAlH4 to the C=O.
Other possible reagents: AlH3, Et3SiH, NaBH3(OAc), LiB(Bu)H3, DIBALH.

I guess that when you write 'conjugate reduction', you actually mean 'double' reduction, because it seems that you end with both the C=C and the C=O bonds reduced.
If that's the case, in principle you don't know which is reduced first (although one path is more likely to be correct). So in theory if you quench a sample of your reaction mixture you can have variable amounts of: C=CH-C=O, CH-CH2-C=O, C=CH-CH-OH and CH-CH2-CH-OH.
If you monitor these species, you may understand something more about the kinetics and then vary your reaction conditions accordingly.
If you only look at the result after 12 or 24 h, i.e. a single point, it's harder to optimise the method.

Btw, why doesn't she want you to use LiAlH4, if I may ask?

Offline dew.be.dew.be.dew.

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Re: Avoiding unwanted conjugate reduction of 3-methyl-2-cyclohexen-1-one
« Reply #2 on: July 01, 2006, 03:43:42 AM »
My prof explained the mechanism for the conjugate addition or double reduction as the C=CH-C=O being converted to CH-C=C-O, with the O having a (-) charge.  Since this isn't stable, it ends up as CH-CH2-C=O, which will then be reduced again (sorry if thats hard to follow, it's tough explaining it without pictures).  If the ketone is reduced first, then the double bond by itself is not favored to be reduced because it no longer has the stability of the conjugation.

Anyway, analyzing the mixture every hour or so is a good suggestion, I will run it by the prof and try to set something up.  As far as the LiAlH4, I found a journal article written by Johnson and Rickborn in like 1970 that showed the reduction of the same starting material I am using with LiALH4 and the results were 100% C=CH-CH-OH.  I assumed my prof would have already been aware that LiAlH4 works better than NaBH4 so I just thought maybe she thought it was too volatile or something and didn't want to use it.  But when I mentioned to her the possibility of using LiAlH4 she said that it would give worse results than the NaBH4, so I went back to make sure I read the article correctly, which I am pretty sure I did.  So I went to show her the article and she had left for the day so I will have to talk to her on Monday.

Well thanks for the help, I might also have to try LaCl3 and CeBr3 vs CeCl3.

Offline lavoisier

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Re: Avoiding unwanted conjugate reduction of 3-methyl-2-cyclohexen-1-one
« Reply #3 on: July 03, 2006, 02:28:25 PM »
I think you're pretty good at working out yourself how the chemistry works. I believe your prof. would appreciate your initiative, so my advice is don't make her think that you can't go on without her approval for each single detail.
You have a paper with the right conditions for your specific substrate: if I were you I would just try it. LiAlH4 is not the most dangerous stuff in chemistry, you just need to take some additional care.

Just a quick note about the reduction of CH=CH-CH2OH. March says that LiAlH4 can reduce allylic alcohols in some cases, so although I believe the mechanism you described is the right one, I wouldn't be too dogmatic about that. Let's leave the experimental evidence decide.

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