[AlphaScent]

Hey All,

Do we think I can produce the methyl ester of 12-hydroxy-7-heptadecynoic acid cleanly when put under the following conditions: 1.2 eq. potassium carbonate, 2.0 eq. Methyl Iodide, refluxing acetone. 

These are my standard conditions for making a methyl ester.  My question lies in do we think under refluxing acetone that there would be more than a trace of the Me-O-R ether formed at the 12-OH?

pKa seems to dictate that it wont easily.  Just wanted some thoughts on the matter.  Thanks for any input.

pKa bicarbonate = 10 ish
pKa carbonic acid = 6 ish
pKa secondary alcohol = 16 ish

[OrganicDan96]

probably not, if you could make the alcoxide it would just reprotonate from the bicarbonate i would think

[hollytara]

So - what is nucleophilicity of alcohol vs. carboxylate.  Alcohol is nucleophilic, if it reacts with iodide it will then be deprotonated to give the ether.  But it will come down to relative rate of SN2 with the two nucleophiles.

It usually goes as the pKa of conjugate acid, but what you want to compare is carboxylic acid (pKa about 4.5) and the protonated alcohol, (pKa about -2.4).  That is about 10^6 times more acidic (for the protonated alcohol) so conjugate base and nucleophile (alcohol vs carboxylate) should be a lot less reactive.

[wildfyr]

Why not just dissolve it in methanol with a bit of sulfuric acid?

No danger of methylation of the phenol.

[AlphaScent]

Thanks all for the input. Really appreciated.

I ended just doing what wildfyr said (methanol and sulfuric acid, Fischer) and it worked cleanly and gave 93% yield. 

Appreciate it all!!

Also...had ether ignite when boiling on a hot plate yesterday.  Pretty scary.  First time for everything I guess.

I was boiling to recrystallize 12-hydroxy-7-dodecynoic acid.  Have never had that happen.

Be safe all!

[hypervalent_iodine]

Glad you've had success using Fischer esterification. I have made esters using Cs₂CO₃ and alkyl iodides in the past, though I used DMF as the solvent. It worked well, though I did have issues with certain substrates and over-alkylation at some especially acidic alpha positions. It could be fixed with careful control of conditions, but it was a pain. Your substrate would quite possibly form the ether, as others have noted. For trickier ones our group has also used diazomethane a lot. It's a very clean reaction and has worked wonders for us where other methods were unsuccessful, but you do have to go through the hassle of making diazomethane.

[wildfyr]

Methanol + a drop of sulfuric acid is my esterification homeboy. Pretty mild all things considered, and it even works well with undried benchtop methanol. Workup is rotovap and sodium bicarb (aq)/organic LL extraction. Doesn't get any easier.

I learned it, oddly enough, in the synthesis of a mechanophore that didn't work, but that's because the previous step involved adding KOH, indene and a lactone to a steel bomb, sealing it, and cooking at 250°C for a few days. Awful tarry mess. The procedure was the esterify whatever would dissolve in organivs so you could column it. Hardly any real product to esterify. Smashing black/brown tar out of a narrow steel bomb with a scupula for a few hours gets old by the third time you run the reaction at 0-2% yield.