Sciencemadness Discussion Board

Geosmin synthesis

TheServer201 - 10-8-2017 at 16:14

Hi.

Im trying to synthesis Geosmin (the molecule which give the rain odor).
So here what I have found :

tumblr_m5k2l3wzht1qzqb9o.png - 10kB

So I need for the synthesis :
- NaOEt
I made the sodium by sodium hydroxyde electrolysis and add some to dried ethanol.

- Reduction
From the Wolff_Kishner reduction page of Wikipedia I need hydrazine. Maybe hydrazine sulfate will work ? (NileRed, NurdRage and Doug's lab already covered the synthesis).

- Methyl vinyl ketone
From diethylammonium chloride and acetone.
Need to be stored with hydroquinone.

- Diethylammonium chloride
I have no idea xD

- Hydroquinone
Hydroxylation of phenol by hydrogen peroxide.

- 2-Methylcyclohexanone
Maybe from toluene by bromination ?

If anyone have a safer synthesis (less toxic reagent) and easy from household product it would be perfect.


[Edited on 11-8-2017 by TheServer201]

CharlieA - 10-8-2017 at 16:21

Just out of curiosity, do you have a reference for the molecule giving the rain odor?

Geocachmaster - 10-8-2017 at 17:30

Biosynthesis of the earthy odorant geosmin by a bifunctional Streptomyces coelicolor enzyme

Quote from the paper: "Geosmin (1), whose name means “earth odor”, is a volatile microbial metabolite that is responsible for the characteristic smell of moist soil or freshly plowed earth."

I would recommend not messing around with butenone (IUPAC name for MVK), considering you only have one post and are probably inexperienced. SDS: Methyl Vinyl Ketone. Short term exposure causes "irritation (possibly severe), nausea, vomiting, difficulty breathing, headache, symptoms of drunkenness, fainting, bluish skin color, lung congestion, coma, death".

CuReUS - 10-8-2017 at 19:09

Quote: Originally posted by TheServer201  
Maybe hydrazine sulfate will work ?

yes,since it will be converted to hydrazine in the basic environment required for wolf-kishner
Quote:
2-Methylcyclohexanone
Maybe from toluene by bromination ?

Why don't you directly methylate cyclohexanone ?

To avoid the vinyl ketone ,why don't you try a one pot reaction between 2-methylcyclohexanone,MEK and HCHO ?

And why do you need hydroquinone ?

[Edited on 11-8-2017 by CuReUS]

Texium - 11-8-2017 at 06:43

Just gonna point out that in the synthesis plan in the OP, ethyl vinyl ketone is used, not methyl vinyl ketone.

As for diethylamine HCl, the best method in an amateur setting would probably be careful alkylation of ammonia with ethyl bromide or iodide in dilute conditions and using stoichiometric amounts to avoid over-alkylation as much as possible, followed by freebasing the amine mixture produced and fractional distillation. The boiling points of ethylamine, diethylamine, and triethylamine are different enough to where separation shouldn't be too hard. Enjoy having your lab smell like rotting fish for weeks!

JJay - 11-8-2017 at 07:38

Quote: Originally posted by zts16  

As for diethylamine HCl, the best method in an amateur setting would probably be careful alkylation of ammonia with ethyl bromide or iodide in dilute conditions and using stoichiometric amounts to avoid over-alkylation as much as possible, followed by freebasing the amine mixture produced and fractional distillation. The boiling points of ethylamine, diethylamine, and triethylamine are different enough to where separation shouldn't be too hard. Enjoy having your lab smell like rotting fish for weeks!


This thread contains an outline of a very simple diethylamine HCl synthesis that is fully OTC. I think it would be less stinky and would produce a product that is easier to purify than one made by reacting an ethyl halide with aqueous ammonia, but bad smells are probably unavoidable if you require freebase diethylamine, and m-toluic acid is arguably less cool of a side product than ethylamine and triethylamine, not to mention any tetraethylammonium salt that might be formed: http://www.sciencemadness.org/talk/viewthread.php?tid=24131

CharlieA - 11-8-2017 at 15:59

@Geocachmaster: Thanks for the reference/link. I'm sure this will be an interesting read.:)

TheServer201 - 11-8-2017 at 16:40

Quote:

Why don't you directly methylate cyclohexanone ?

Does Methyl iodide would do the job ? Im afraid of multiple addition of the methyl group or at least not at position 2. (@CuReUS)
Quote:

And why do you need hydroquinone ?

It was to avoid the MVK to polymerise.
Quote:

Just gonna point out that in the synthesis plan in the OP, ethyl vinyl ketone is used, not methyl vinyl ketone.

Oups you are right (@zts16). So now I need to synthesis EVK.
A Convenient Preparation of Ethyl Vinyl Ketone

Any better idea ?

Thank for the reference on the Diethylammonium chloride (@zts16, @JJay).

[Edited on 12-8-2017 by TheServer201]

CuReUS - 12-8-2017 at 07:15

Quote: Originally posted by TheServer201  

Does Methyl iodide would do the job ? Im afraid of multiple addition of the methyl group or at least not at position 2

Yes -http://www.freepatentsonline.com/EP1810974A1.pdf (pg 6)
another way would be via the enamine.
Quote:
Any better idea ?

make EVK in situ

clearly_not_atara - 12-8-2017 at 09:16

Just wondering -- isn't geosmin one of the strongest odorants known? I'm guessing tiny amounts produce the rain smell; pure geosmin may render your home uninhabitable. Tread carefully...

TheServer201 - 13-8-2017 at 14:53

Quote:

another way would be via the enamine.

Prety good idea (@CuReUS).

From Method for the preparation of alpha-substituted organic carbonyl compounds US 2773099 A


From Odor sensitivity to geosmin enantiomers (@clearly_not_atara).
Quote:

The human nose is extremely sensitive to geosmin and is able to detect it at concentrations as low as 5 parts per trillion.
The natural occurring isomer, (−) geosmin had, on average an ×11 lower threshold than (+).


I still haven't found an EVK preparation which doesn't use gaz (ethylene).

CuReUS - 13-8-2017 at 19:15

Quote: Originally posted by TheServer201  
I still haven't found an EVK preparation which doesn't use gaz (ethylene).

You could do a grignard reaction between EtMgBr and acrylonitrile to get EVK
Quote:
Grignard reagents react with acrylonitrile by 1,2-addition and, after hydrolysis, give a,b-unsaturated ketones

http://reag.paperplane.io/00000035.htm
But I still think the in-situ method is the safest

kavu - 13-8-2017 at 23:57

Accessing the proposed aldol product using this method is difficult. The Robinson annulation will not stop at the aldol stage but does an E1cB to give a corresponding enone (10.1021/jo01342a008). Additionally a mixture of different diastereomers will form (10.1002/hlca.19900730607). However, using the E1cB product enone to access geosmin has been described in the literature (10.1016/S0040-4039(00)99122-6).

This basically means that running a Wolff-Kishner reduction on the aldol product would likely lead to a competing elimination of water and a mixture of elimination and reduction products as the end result. To optimize a reaction like this LC/MS and/or NMR would be needed.

With some modifications it is possible to access the aldol in 36% yield (as an uknown mixture of diastereomers) after extensive purification. This material has also been used to access geosmin via a route similar to what you propose (10.1021/jo01270a120 deoxygenation via a dithiane the formation of which does not compromise the tertiary alcohol):

"A solution containing 7.8 g of 2-methylcyclohexanone and 0.85 ml of 3 N ethanolic sodium ethoxide was maintained at -10°C and efficiently stirred while a solution of 5.9 g of ethyl vinyl ketone in 7.8 g of 2-methylcyclohexanone was added dropwise over a period of 5.5 hr. Stirring at -10°C was continued for 6.5 hr after addition was complete and the organic material was isolated by extraction with ether. The combined extracts were dried and distilled affording 8.9 g (57% recovery) of 2-methylcyclohexanone, bp 55-58°C (0.2 mm), and 9.3 g (68%) of ketol 11 and the corresponding conjugated ketone, bp 80-105°C (0.1 mm). The higher boiling fraction was crystallized from hexane affording 4.9 g (36%) of ketol 11, mp 70-77°C (lit.12 mp 88°C)."

[Edited on 14-8-2017 by kavu]

CuReUS - 14-8-2017 at 06:16

Quote: Originally posted by kavu  

This basically means that running a Wolff-Kishner reduction on the aldol product would likely lead to a competing elimination of water and a mixture of elimination and reduction products as the end result.

what about using cram's modification ;) -https://en.wikipedia.org/wiki/Wolff%E2%80%93Kishner_reductio...

kavu - 14-8-2017 at 06:41

Quote: Originally posted by CuReUS  
Quote: Originally posted by kavu  

This basically means that running a Wolff-Kishner reduction on the aldol product would likely lead to a competing elimination of water and a mixture of elimination and reduction products as the end result.

what about using cram's modification ;) -https://en.wikipedia.org/wiki/Wolff%E2%80%93Kishner_reductio...


Hydrazone alpha-protons can still be abstracted, giving E1cB products. This is how SAMP/RAMP alkylations work. This is of course down to which deprotonation occurs faster and is that fastness fast enough. What could be expected is that the hydrazone NH deprotonation will be faster than alpha-deprotonation, nevertheless both processes are possible. With a quick search I didn't find examples of situations where the Cram modification has been used for such aldol type structures.

[Edited on 14-8-2017 by kavu]

CuReUS - 14-8-2017 at 07:47

Quote: Originally posted by kavu  
Hydrazone alpha-protons can still be abstracted, giving E1cB products.

I don't think so,considering the extremely mild conditions and the use of a bulky base in cram's modification.Anyways,all these problems can be avoided by first making the enone,reducing the ketone,then hydrating the double bond to get geosmin