Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: BjornS on February 12, 2021, 06:42:08 AM
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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...
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Check different method from EP0457911B1.
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Check different method from EP0457911B1.
Thank you for your help. So you don't think the reaction with LDA,THF,-78*C would work?
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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.
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I would be surprised if you were using LDA at school, as well, to be honest.
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Yes, you need dry solvent an inert atmosphere like N2 och argon, do you have this?
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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
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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.
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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.
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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?
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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''.
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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
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Ah okay thank you Kriggy! That makes it more clear to me.
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I am wondering why the enamine does not form on the aldehyde? That should be faster?
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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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Yes it likely reacts with acetone and then with the aldehyde which is present only in small amounts. I think there is no free pyrrolidine in the reaction or to be more clear: at first it all reacts with the acetone and by the time the aldol reaction happens and pyrrolidine is released, there is no aldehyde to react with it because its added slowly.
Im not sure about the self-aldor reaction with acetone but its going to be slowed compared to the reaction with the aldehyde. I think I saw a ytb video doing this and the reaction took a week at RT to run.
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OK, makes sense.
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I don't think a self-aldol reaction will occur here. The website below says tertiary enamines can not be coverted into the corresponding imine.
If you add acetone first, I think there would be (mostly) one product because the enamine converted from acetone is tertiary and symmetrical (assymetrical enamines would yield 50:50 both sides to isobutylaldehyde).
In short: I think ~100% (acetone) enamine would be formed because of these reasons.
Website: http://www.chemgapedia.de/vsengine/vlu/vsc/en/ch/12/oc/vlu_organik/keto_enol/aldolkondensation_aehnliche_reaktionen.vlu/Page/vsc/en/ch/12/oc/keto_enol/enamine/enamine.vscml.html