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Topic: Synthesis of 5-methyl-3-hexen-2-one  (Read 668 times)

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Offline BjornS

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Synthesis of 5-methyl-3-hexen-2-one
« on: February 12, 2021, 06:42:08 AM »
Hello,

For a schoolproject, I have to synthesize 5-methyl-3-hexen-2-one (see picture, 4). To synthesize this chemical I wanted to use an Aldol addition reaction with acetone (1) and isobutyraldehyde (2) and after that condensate (Aldol condensation) the intermediate (3).

In school I have learned the best way to do synthesize the intermediate is with LDA (litium diisopropylamide). This way you get a directed Aldol reaction. Firstly I would make a litium enolate of acetone and add isobutylaldehyde to form the intermediate.

However, after looking down the internet I couldn't find an article which describes a reaction with LDA in this way. I could only find articles which uses NaOH (for example: Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 5906−5925.). This article describes a 49% yield of 5-methyl-3-hexen-2-one (step 1 (Aldol addition) 69%, step 2 (Aldol condensation) 71%).

I was wondering if you think using LDA would make a greater yield? I think it would because less by-products would be synthesized in step 1 but I can't find any evidence online. I have checked other starting products and products if I could find evidence there but also without any results. I have to admit that I'm still in school and my searching skills might not be good.

I hope you can help me.

Kind regards,
Bjorn

P.S. I am sorry if my English is not perfect. English is my second language and I am not the best in it...

Offline AWK

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Re: Synthesis of 5-methyl-3-hexen-2-one
« Reply #1 on: February 12, 2021, 11:26:15 AM »
Check different method from EP0457911B1.
AWK

Offline BjornS

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Re: Synthesis of 5-methyl-3-hexen-2-one
« Reply #2 on: February 12, 2021, 12:48:28 PM »
Check different method from EP0457911B1.

Thank you for your help. So you don't think the reaction with LDA,THF,-78*C would work?

Offline rolnor

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Re: Synthesis of 5-methyl-3-hexen-2-one
« Reply #3 on: February 12, 2021, 01:09:39 PM »
I think its important to av 1 equiv. of acetic acid directly when the reaction is finished, you can get byproducts if not. The reaction is very fast.

Offline sjb

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Re: Synthesis of 5-methyl-3-hexen-2-one
« Reply #4 on: February 12, 2021, 01:23:09 PM »
I would be surprised if you were using LDA at school, as well, to be honest.

Offline rolnor

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Re: Synthesis of 5-methyl-3-hexen-2-one
« Reply #5 on: February 12, 2021, 02:27:55 PM »
Yes, you need dry solvent an inert atmosphere like N2 och argon, do you have this?

Offline BjornS

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Re: Synthesis of 5-methyl-3-hexen-2-one
« Reply #6 on: February 16, 2021, 04:00:20 PM »
I'm sorry for the late reply. I was a little busy.

In school I can work in a N2 or Argon atmosphere. I didn't know it has to be completely water free. I think it's hard to do this reaction with LDA than. I have never worked in such an atmosphere. I'll talk about it with my teacher. Maybe he lets us use it or not.

In my book it says you can use this technique. But I guess theoretically it is easier than practically.

I want to thank you for your help

Offline rolnor

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Re: Synthesis of 5-methyl-3-hexen-2-one
« Reply #7 on: February 17, 2021, 02:50:50 AM »
Its not difficult if you have some training. But the fact that you did not know that you need inert atmosphere says that you probably will have som problem with chemistry on this high level. If you do a search in scifinder or reaxys you can probably find a procedure how to make this compound, this could be helpfull.

Offline BjornS

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Re: Synthesis of 5-methyl-3-hexen-2-one
« Reply #8 on: February 17, 2021, 10:28:30 AM »
I've only done 1 project before. This is going to be my second. Maybe it's too hard but I'll talk about it with my teacher. Once has to be the first time, right?

I use scifinder quite often and I've seen multiple procedures there. I didn't see the use of LDA on SciFinder, although I can find it in a lot of different organic chemistry books. I was wondering why nobody has done this to make the chemical above. That's why I came here. I guess sciencists were satisfied with a 50% yield.

I have used Reaxys before. Maybe I can give that site a go as well. Thanks for the tip.

In the article AWK sent I saw they use Pyrrolidine which has a pka of 11.3 (according to PubChem). In the article I have send earlier they use NaOH which has a pka around 13. Why Pyrrolidine works better than NaOH is a mystery to me because I thought a strong alkali favours enolates and the more acidic (11.3 is not acidic by far but more than NaOH) should favour ketones. I have to do more research on that before I can discuss this.

Offline AWK

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Re: Synthesis of 5-methyl-3-hexen-2-one
« Reply #9 on: February 17, 2021, 11:05:48 AM »
You have chosen a very ambitious synthesis method (low temperature, noble gas, perfectly anhydrous synthesis conditions). I doubt whether the beginning chemistry student will be allowed to work on such a line.
In addition, this method, although ambitious, does not guarantee a very high yield at all.
The method according to patent EP0457911B1 gives an aldol yield of over 80% from a very cheap ethyl acetoacetate and is carried out in a water-organic solution for 2 hours at 30 C.
What do you need more for happiness?
AWK

Offline BjornS

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Re: Synthesis of 5-methyl-3-hexen-2-one
« Reply #10 on: February 18, 2021, 03:15:20 AM »
Yes, you are right. I think I'm going to use pyrrolidine over NaOH or LDA. I'll just add LDA as a recommendation or a ''other way to synthezise this molecule''.

Offline kriggy

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Re: Synthesis of 5-methyl-3-hexen-2-one
« Reply #11 on: February 18, 2021, 04:36:56 AM »

In the article AWK sent I saw they use Pyrrolidine which has a pka of 11.3 (according to PubChem). In the article I have send earlier they use NaOH which has a pka around 13. Why Pyrrolidine works better than NaOH is a mystery to me because I thought a strong alkali favours enolates and the more acidic (11.3 is not acidic by far but more than NaOH) should favour ketones. I have to do more research on that before I can discuss this.

Pyrrolidine works by creating enamine which is kind of enolate instead of acting as a base.
https://en.wikipedia.org/wiki/Enamine

their reactivity is bit different compared to enolates

Offline BjornS

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Re: Synthesis of 5-methyl-3-hexen-2-one
« Reply #12 on: February 18, 2021, 07:23:04 AM »
Ah okay thank you Kriggy! That makes it more clear to me.

Offline rolnor

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Re: Synthesis of 5-methyl-3-hexen-2-one
« Reply #13 on: February 18, 2021, 09:07:30 AM »
I am wondering why the enamine does not form on the aldehyde? That should be faster?

Offline BjornS

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Re: Synthesis of 5-methyl-3-hexen-2-one
« Reply #14 on: February 18, 2021, 10:31:10 AM »
In the patent it describes adding pyrrolidine to acetone and after that isobutylaldehyde was dropped over an hour. I think there is plenty of acetone which has to compete with 1 drop of isobutylaldehyde. Pyrrolidine would find an acetone molecule earlier than an isobutylaldehyde. This is my guess. Maybe Kriggy can confirm or deny this? Or do you (rolnor) still think it would attack the aldehyde first?

I was wondering if the acetone molecules will react to each other. It is the same principle as I describe above. The enamine would find an acetone molecule earlier than isobutylaldehyde. Or does pyrrolidine react with ~100% (theoretically) of the acetone and makes ~100% enamine?

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