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Author: Subject: Ozonelabs- Synthesis of Raspberry Ketone
Ozonelabs
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[*] posted on 3-9-2009 at 10:21
Ozonelabs- Synthesis of Raspberry Ketone


Our sincere thanks to Klute for the idea to conduct this synthesis and also for providing a good reduction procedure.

Comments are welcome as always.

Regards,

The Ozonelabs Team

Attachment: Rheosmin for pub.pdf (318kB)
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Klute
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[*] posted on 3-9-2009 at 10:36


Great! I am really pleased someone else tried this out! It's indeed a very fullfilling synthesis!

Not much I can say, recrystallization from water of the unsaturated ketone seems to work very well, perhaps better than the solvent system I used (EtOH/H2O IIRC). I could suggest using AcOEt/pet ether or DCM/pet teher to recrystallize the saturated ketone, it worked very well for me..

Are you planning on trying other reduction catalysts? NiB on CaCO3 for example? Or preparing analogues? (from vanilline, salicyladehyde, and their methyl or ethyl ethers, etc)

A few on my to-do's list are the 3,4-methylenedioxyphenyl, 4-fluorophenyl, 4-dimethylaminophenyl, etc

ANyway, great work as always, it was a pleasure to read.. I was so delighted when I saw a new thread on raspberry ketone! :)




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[*] posted on 3-9-2009 at 10:41


Thanks for the commemts klute.

We are planning to make some zingerone very soon and some other variants too.

Initially we tried the Sodium Dithionite reduction however this proved very unsuccessful for us as well as clouding any product we did make with an unpleasant sulphurous odour.

We did also try your recrystallisation method which did work, however the large yellow needles were absolutely lovely from water so we were very pleased.

Much obliged klute,
The Ozonelabs Team




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[*] posted on 3-9-2009 at 14:17


Very nice!
Did the unsaturated ketone have a smell?
Sorry if this is an obvious question, but how is reduction of the ketone prevented, or why is reduction of the alkene so selective? I tried looking it up but couldn't find anything right away. Are some of the side products the alcohol version?

Moved to Prepublication as it seems like a very decent piece of work!




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[*] posted on 3-9-2009 at 15:16


Actually, yes the unsaturated ketone did smell, personally I'd describe it as a 'bubblegum'/raspberry scent- not unpleasent by any means!

Catalytic hydrogenation of Carbonyl Groups is a slow reaction, though it does occur- the reduction of the alkene to the alkane is far more rapid. Information on the alcohol product (4-(3-hydroxybutyl)phenol) is sparse, though it is a reasonable possibilty as an impurity. We should hopefully be performing GS/MS, IR and HNMR on the product- so will report back with any further findings, thankyou for raising the point.





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[*] posted on 3-9-2009 at 17:07


The file does not open here (Acrobat 5).

Tim




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[*] posted on 5-9-2009 at 01:23


Im interested in the reduction of that double bond with hydrogen.
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[*] posted on 5-9-2009 at 18:39


See the raspberry ketone thread in Org Chem section for various catalysts capable of reducing the double-bond without reducing the carbonyl.. NiB supported on various supports, Cu/SiO2, CoB, Rh/C, Pd/C, etc

http://www.sciencemadness.org/talk/viewthread.php?tid=9706

[Edited on 6-9-2009 by Klute]




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[*] posted on 10-9-2009 at 05:55


Our apologies- it seems as though a part of our PDF wasn't published- Under the References heading-

Our sincere thanks to the School of Chemistry at the University of Southampton for help with analysis of the materials, and also for personal correspondence without which this project would not have become a reality.

Regards,

The Ozonelabs Team




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[*] posted on 15-1-2010 at 10:59


This is a beautiful synthesis with acetone, but I wanted to try with vanillin a variety of other ketones to create a variety of zingerone analogues.

But I am running into difficulty with my first variation.

2,6-dimethylheptan-4-one (diisobutyl ketone) is not water-miscible as is acetone, so the initial aldol condensation is slow. Stirring the mixture for two days only produced about 5% of a second product by TLC, and refluxing (at 163 degrees) produced a lot of tarry gunk.

I wonder if anyone has any recommendations.

Options might be to repeat with an excess of some solvent... methanol or ethanol, or maybe to try an acid-catalysed aldol. But I am unfamiliar with this route.
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[*] posted on 15-1-2010 at 11:26


Use NaOH in MeOH instead of NaOH in H2O, and only 3-fold excess of the ketone (instead of the ~6-fold in acetone example).

The reaction will have to be monophasic or else all the vanillin sticks in the aq. phase in the form of the phenoxide, and because diisobutyl ketone is not particularly soluble in water the reaction might never go anywhere. If you still have the reaction mixture you might try adding a quat PTC catalyst and stir vigorously at 40-60°C.

The product would be a compound not yet described in the literature, so I can not help you with a literature synthesis. Due to the alkyl branching, it is possible that the product will be either a viscous oil at room temperature or a hard to crystallize solid, in which case you will have to find an alternative work up instead of the recrystallization described above. Flash chromatography anyone?

"about 5% of a second product by TLC"
You must have supernatural powers to estimate conversion from a TLC?
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[*] posted on 15-1-2010 at 12:01


Right, so redo in a big excess of MeOH.

Do you have a review of acid-catalysed aldol, or can you offer any comments?

Well, the new spot (Rf 0.77) was only just visible as a UV-absorbing spot wheras vanillin (Rf 0.71) was huge. Solvent CHCl3/MeOH/H20 74/15/1. Calling it 5% is a guestimate.

Edit:-
5g vanillin, 4g NaOH, 50 ml DIBK and 500 ml MeOH formed a clear, very light yellow homogeneous mix. I'll check it daily and post any results.

[Edited on 15-1-2010 by Paddywhacker]
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[*] posted on 16-1-2010 at 07:11


though reaction involves simple methods of aldol followed by reduction, it's interesting. And these compounds had a range of biological activities like antiinflammatory, anticancer etc.

And regarding synthesis of unsaturated ketone, use of base KOH/NaOH (1.2 eq of ketone) in solvent system of MeOH/water (5:1) will work fine. And reduction of the alkene is possible by H2, pd/C.

Crystals of unsaturated chalcones are nice in appearance :D

BTW, are you synthesizing gingerone for any biological purposes or only synthesis? Just curious!

Good luck!




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[*] posted on 16-1-2010 at 14:08


Quote: Originally posted by Paddywhacker  
Do you have a review of acid-catalysed aldol, or can you offer any comments?

The only review I know of is the one in Organic reactions, 16. The whole volume 16, that is over 400 pages, is dedicated to the aldol reactions of all types, base or acid catalysed. This volume is unfortunately unavailable in electronic form, so you will have to visit a library to get it. It is from year 1968 though, but the best you can get. There are a bunch of new reviews about the asymmetric aldol reactions, but these are not really relevant to the topic. Neither are the directed aldol reactions for which there are also numerous reviews.

Quote:
Edit:-
5g vanillin, 4g NaOH, 50 ml DIBK and 500 ml MeOH formed a clear, very light yellow homogeneous mix. I'll check it daily and post any results.

I would stick to the original ratios if I were you. There is a reason for using 1.1-1.2 eq. of NaOH when using hydroxybenzaldehydes (1 eq. is lost in the deprotonation of the phenolic group + <0.2 eq. are needed to catalyse the aldol). Instead you used 3 eq. of NaOH which might cause troubles due to self condensation of DIBK and make the work up more of trouble that it should be (though at least this ketone is less reactive than acetone). Also using a 10-fold excess of the ketone is overkill - just an additional problem that will make the work up more troublesome.
Another advice is to do trial reactions at <10 mmol scale. There is no need to waste precious reagents just to try out if something works or not.




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[*] posted on 17-1-2010 at 01:46


[quote=169725&tid=12780&author=Nicodem]
Quote: Originally posted by Paddywhacker  
e
I would stick to the original ratios if I were you. There is a reason for using 1.1-1.2 eq. of NaOH when using hydroxybenzaldehydes (1 eq. is lost in the deprotonation of the phenolic group + <0.2 eq. are needed to catalyse the aldol). Instead you used 3 eq. of NaOH which might cause troubles due to self condensation of DIBK and make the work up more of trouble that it should be (though at least this ketone is less reactive than acetone). Also using a 10-fold excess of the ketone is overkill - just an additional problem that will make the work up more troublesome.
Another advice is to do trial reactions at <10 mmol scale. There is no need to waste precious reagents just to try out if something works or not.



I totally agree with this comment. :)

It's good to have small scale trial.
but in case of excess base, you can neutralize with 2N HCl after completion of reaction. It will be better option while doing workup. (If you are lucky you can get precipitate after neutralization with HCl, which will be easier to purify)


[Edited on 17-1-2010 by medchem]

[Edited on 17-1-2010 by medchem]




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[*] posted on 17-1-2010 at 13:14


Progress report. The yellow colour intensified over a day at ambient temperature, but seems not to have gotten any darker after another day. At 2 days there is still only vanillin by TLC (Rf 0.54 with hexane/EtOAC 50:50) by UV. Nothing by iodine stain. Should I wait longer or reflux, or try again?

I was interested to note that there was no sign of Cannizzaro with the aromatic aldehyde.

Thanks for the advice. This counts a small-scale to an oldschool chemist like myself, but I really should get with the microscale program.

Medchem, this zingerone analogue looked accessible, and was not listed according to chemspider, and SAR is an endlessly fascinating crapshoot, so this it was.

Methyl isobutyl ketone is less hindered then the DIBK that I used. Maybe I'll try next with that, but I don't like to be an early quitter.

Final report, 02 Feb 2010:- I figured that I was led astray by the compound co-eluting with vanillin on the TLC and worked it up.
The intermediate had a melting point of 74-76 Celcius.
In-situ reduction with zinc powder and acetic acid in ethanol with Pd/C catalyst gave an oil that recrystallised from ethanol in the freezer but remelted at room temperature. A dilute aqueous mouthwash did evoke a hint of ginger.

Without instrumental characterization, of course, I might have nothing except contaminated vanillin. I will try and get an IR spectrum once university starts.

[Edited on 1-2-2010 by Paddywhacker]

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[*] posted on 18-1-2010 at 11:58


In highschool, my first chemistry class failure smelled like a perfect banana ester. Thus, I'd love to do similar myself - thanks for the re-inspiration!



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[*] posted on 29-4-2011 at 10:16


All of the information above is interesting, thanks to all the contributors. I'm looking to find out any types of tests run about raspberry ketone altering lipid metabolism or increasing norepinephrine induced lipolysis. Can anyone point to studies?

Also, is there a better place to buy this? I've found it here: http://www.nutraplanet.com/product/nutraplanet/raspberry-ket... but didn't know if there was a better source. Thanks in advance for all of your help!
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