[Diasjota]

Hello mates,
I'm a grad student from brazil doing my masters in medicinal chemistry (Unicamp - State University of Campinas) currently struggling to make a reaction work and im running out of time for my masters, any help/insight would be greatly appreciated. Here's the reaction i'm having trouble with:



So, the condition i'm trying are the following:

0,150g trytil batyl alcohol (reactant) dissolved in 1ml Ethyl 4-bromobutyrate and catalytic amount of TBAB (to act as the PTC - phase transfer catalyst) mixtured with 1 ml NaOH 50% (to produce the alkoxy from the alcohol).

I've tried:
 - 2 hours in ultrassound... nothing...
 - 1 hour in ultrassound (wam bath ~ 55°C) ... nothing...
 - heating overnight (55°c and ~70°C) stirring magnetically .. nothing...

Only time i was able to get some product was when i left it reacting over the weekend (magnetically stirring and ~55°C) but the yield was really bad and when i got to the lab on monday it was completly dry. So, Could it be too diluted? only time when it worked was when both phases evaporated so at some point the concentration might have reached the perfect condition.. ? that's the only thing i can think of...

I believe (from articles i've been following) ultrassound and microwave combined would be the key to make this reaction work but we don't have a working microwave in the lab so im limited to either ultrassound or warm bath and magnetic stirr.

Any thoughts would be greatly appreciated!!

[wildfyr]

Are you getting side or degradation products, or just no reaction?

[Diasjota]

No reaction at all

[rolnor]

There could be risc of forming a cyclopropyl from the bromoester?

[clarkstill]

I would try pre-stirring your SM in anhydrous DMF or THF with NaH, then adding your alkyl bromide. You might need to heat it for the SN2 but I'd just keep an eye on it by TLC and warm it if nothing is happening.

You might also consider adding catalytic NaI to try to increase the rate by finkelstein-type reactivity.

You definitely won't need ultrasound or microwave heating to make this go.

[pgk]

URGENT
Regardless the ultrasound or the microwave assistance, you cannot accomplish this kind of alkylation with NaOH and phase transfer catalyst!!
Only phenols can be alkylated that way. Not aliphatic alcohols.
So, you waste your time, in vain.
You use NaH in anhydrous DMF or anhydrous THF, as Clarkstill advices.
PS: If your NaH is supplied in petroleum ether, you preliminary decant the petroleum ether and then wash it with your selected, anhdrous reaction solvent and finally suspend it in your anhydrous reaction solvent and then use it.

[Diasjota]

First of all, thanks for all the answers, i really appreciate it.

I have found articles about this kind of reaction using PTC.

"The phase-transfer catalyst is tetrabutylammonium hydrogen sulfate (9), the alkyl halide is benzyl chloride,
and the nucleophile is the alkaxide of l-butanol..." - Chemical Education.

I believe the problem with NaH and without PTC my SM (c18 alcohol - lipid) will form
micelle-like structures and will be impaired to act as a nucleophile. What do you think about that?

[wildfyr]

Nothing wrong with phase transfer and NaH. Ok, well maybe NaH would cause it to eliminate to give butene and tributyl amine.

Do you have trimethylbenzyl ammonium chloride to use as your PTC? It won't eliminate.

[OrganicDan96]

try adding some KI and heating, the I will replace the Br to give a better leaving group

[Diasjota]

Nothing wrong with phase transfer and NaH. Ok, well maybe NaH would cause it to eliminate to give butene and tributyl amine.

Do you have trimethylbenzyl ammonium chloride to use as your PTC? It won't eliminate.

unfortunately not =x

try adding some KI and heating, the I will replace the Br to give a better leaving group

Thanks, will try that.

How can i check if the alkoxy is being formed? any ideas?

[Doc Oc]

I like Finkelstein reactions, but I find them most useful in converting an alkyl chloride to something else. Bromides and iodides are generally well-behaved in my experience and I don't think that's the problem in your reaction.

First glance I noticed what everyone else did, I would ditch NaOH. If you're not getting E2 elimination then you're likely substituting with the OH anion instead, which would be difficult to detect by any method besides mass spec. You also run the risk of hydrolyzing your ester to a carboxylic acid.

Alkoxide formation is generally accomplished with NaH in either THF or DMF as someone else noted. I default to THF because it's easier to remove, but if you're having solubility issues then DMF is a good choice. I also use the NaH dispersion in mineral oil (60%) and don't wash it first, I've had no problems following that method. Stir NaH with your alcohol for 30 min to 1h at low temp (try 0 degrees first, but if it is too reactive then -78 degrees). Add your alkyl bromide slowly and let it warm up to room temp.

[pgk]

From personal experience, unwashed NaH leads to slightly lower yield than preliminary washed NaH.
Anyway, after warming up to room temperature, you can stir for another 20-30 min at room temperature and then heat it up to reflux. But the essential is adding the (preferably, diluted in the anhydrous reaction solvent) alkyl bromide slowly, at or below 0oC, as Doc Oc advises.
PS: Don't worry about micelles. Both THF and DMF are strong lipid solvents.