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Topic: Williamson Ether Synthesis - Acetaminophen alkylation  (Read 9371 times)

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Offline DaiseyDoo

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Williamson Ether Synthesis - Acetaminophen alkylation
« on: May 23, 2015, 02:40:20 PM »
As an experiment, we first reacted acetaminophen with NaOH to deprotonate it at the alcohol position and create a good nucleophile. We then added iodo-butane for a SN2 reaction to occur and create 4-butoxyacetanilide.
One side reaction is the creation of butanol via SN2 attack of the NaOH at the electrophilic carbon.
My question is: How can we prevent the butanol side reaction from occurring?

My suggestion: when mixing NaOH and acetaminophen originally to create the nucleophilic oxygen  use an excess of acetaminophen. Next, extract the ionized acetaminophen (with the anionic nucleophilic oxygen) with water and then react the extracted solution, ideally containing no NaOH because it's all reacted and only ionized acetaminophen, with the iodo-butane.
Problem: is this even possible? I'm not sure if the acetaminophen and ionized acetaminophen actually have different even solubility properties to be separated in this way?!

Is there another way to prevent butanol as a side product?

Thank you!!

Online Babcock_Hall

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Re: Williamson Ether Synthesis - Acetaminophen alkylation
« Reply #1 on: May 23, 2015, 05:30:11 PM »
Your idea shows some creativity of thought, although I am not certain how practical it is.  What is the solubility of iodobutane in water?

Do you know the approximate pKa of the group you are trying to deprotonate?  That value might suggest another approach.

Offline DaiseyDoo

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Re: Williamson Ether Synthesis - Acetaminophen alkylation
« Reply #2 on: May 25, 2015, 07:23:23 PM »
Your idea shows some creativity of thought, although I am not certain how practical it is.  What is the solubility of iodobutane in water?

Do you know the approximate pKa of the group you are trying to deprotonate?  That value might suggest another approach.

The pka of acetaminophen is 9.38! I'm not sure how I could use that to prevent butanol side product though... Because butanol is created by the left over NaOH reacting with the iodo-butane reagent. Other than what I suggested, I'm very stuck!
According to Sigma-Alderich, iodo-butane is insoluble in water, but soluble in alcohol. Hmm...

Online Babcock_Hall

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Re: Williamson Ether Synthesis - Acetaminophen alkylation
« Reply #3 on: May 25, 2015, 10:16:22 PM »
I might consider using a base that is less nucleophilic than hydroxide, and/or one that is not quite as basic.

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