[Aeon]

Hi,

The acetylation of Cafeic acid with acetic anhydride has been conducted in aqueous 1M NaOH with excellent yield.

5,6 mmol of Cafeic acid were deprotonated in 19,0 mmol of cold 1M sodium hydroxide. 15,0 mmol of acetic anhydride were slowly added to the mixture resulting in precipitation of the product.

Why does the reaction work so well? I was skeptical of the efficiency of conducting an esterification in water, for obvious reasons, but I was proven wrong. Here is the likely mechanism:



What I have reasoned so far is that my reactant is in such excess that the reaction can still come close to 100% yield. But I'm still not exactly happy with this explanation. I'm also wondering how can all of the acidic protons be eaten by NaOH...

Here are my questions:

1) Why does the reaction work if it's conducted in water?
2) How can NaOH deprotonate the acid and BOTH alcohols?
3) How does the configuration of benzenic diols affect their acidity?
And more specifically
4) In the case of ortho diols, does deprotonation of a first one facilitate deprotonation of the second?

Thank you very much!

PS: ChemDraw doesn't seem to like PNG, hence the missing "OH" and misplaced "AcO" in the image above.

[Dan]

5,6 mmol of Cafeic acid were deprotonated in 19,0 mmol of cold 1M sodium hydroxide. 15,0 mmol of acetic anhydride were slowly added to the mixture resulting in precipitation of the product.

Can you clarify whether the alcohol ROH is also in this mixture, and can you give the structure of R?

[Nosterius]

Dan: Caffeic acid has two hydroxyl groups, which are shown as methyl groups on Aeon's scheme.

Aeon: I will try to answer some of your questions:

1. I ran myself some reactions in water, using supposedly "water sensitive" reagents such as benzenesulfonyl chloride. My personnal impression is that acetic anhydride and water are not miscible. This reaction probably occurs when caffeic acid diffuses in miscelles of Ac2O. NaOH and water are probably less soluble in acetic anhydride than caffeic acid, so the latter will happen much more rapidly.

2. NaOH is the strongest base in your system, and you have an excess of it. It should deprotonate easily the most acidic protons (carboxylic acid and one phenol, see points 3 and 4). Never forget that an acid-base reaction is an equilibrium.

3. Draw resonance forms. Also, notice that an accumulation of charges of the same sign in the same vicinity is destabilizing. If you take an ortho benzene diol (catechol) and deprotonate both hydroxyl groups, the negative charges will be close to each other.

4. Draw the structure of a catechol with one proton abstracted. Have you heard of hydrogen bonds? Look also for "proton sponge".

[Aeon]

My drawing was incorrectly rendered by ChemDraw: there should be OHs attached to the "methyl" groups.

Nosterius:

I have already drawn resonance forms, and seen that there is intramolecular hydrogen bonding in singly deprotonated catechol. That's exactly why I was a bit confused...

As for the reaction taking place in micelles of Ac2O... I am a bit skeptical. Let's assume that it's right: most Caffeic acid diffusing in the micelles would have to be protonated. And even if Ac2O can accommodate ions to a certain point (dielectric cst = 21 @66F), most likely the two phenols would be protonated. I cannot imagine a 3- charge inside a micelle of Ac2O living long enough to be of any use.

It's a tricky little question, the answer is not evident (at least to a second year undergrad).

Thanks!

[Doc Oc]

The answer to your questions are much simpler than they're being made out to be.  This reaction is driven forward by the huge excess of reagents, you have nearly 4x as much NaOH as caffeic acid in the reaction mixture and 3x as much acetic anhydride.  It's nothing more than LeChatelier's Principle.

1) The reaction is not just taking place in water, it's in basic aqueous media, that changes things.  The order of operations is also very important.  If you just threw everything together it probably wouldn't be as clean.  Pre-mixing the base with your caffeic acid and THEN adding the acetic anhydride allows this reaction to proceed as desired.

2) There's excess NaOH.

3-4) Phenols are slightly more acidic than other alcohols like ethanol or methanol, but their configuration is less of an issue here than the excess NaOH.

[Nosterius]

Aeon:

Great move for trying the resonance structures and figuring out the intramolecular hydrogen bond. I think that, for this reason, the second hydrogen would be less acidic than the second hydrogen in resorcinol. That's off the top of my head though, you might want to check the pka of these compounds.

Doc OC:

There are 3.39 eq of NaOH and 2.68 eq of acetic anhydride. Since caffeic acid has 3 acidic protons and 2 sites to be acetylated, there is not such a large excess of reagent.

However, I think you got it right with LeChatelier's principle: the product crashes out of the mixture. I would think this is the driving force of this reaction.

[Aeon]

I think I'll settle on the reaction taking place because of an excess of reactants (Ac2O) and being driven by Le Châtelier's principle, which makes sense, but still makes me wonder if there's more to it than that.

Thanks!

[orgopete]

I think this is simpler than being made out to be. I saw a similar question with a simple answer that could be applied here. A benzene ring with an NH2-group and an OH-group react with acetic anhydride. The poster asked why the NH2-group reacted faster.

Without belaboring the point, we should again conclude the phenolic OH groups simply reacted faster. Since that is the product, it must be correct. Because sufficient NaOH had been added to make the anion of the phenol, it should increase the rate of reaction compared with unionized water. Undoubtedly, water can and probably does also react with acetic anhydride. However, it simply reacts more slowly. Its reaction is so slow, that caffeic acid can be converted to the diacetate in high yield.

[AlbertoA]

I think this is simpler than being made out to be. I saw a similar question with a simple answer that could be applied here. A benzene ring with an NH2-group and an OH-group react with acetic anhydride. The poster asked why the NH2-group reacted faster.

Without belaboring the point, we should again conclude the phenolic OH groups simply reacted faster. Since that is the product, it must be correct. Because sufficient NaOH had been added to make the anion of the phenol, it should increase the rate of reaction compared with unionized water. Undoubtedly, water can and probably does also react with acetic anhydride. However, it simply reacts more slowly. Its reaction is so slow, that caffeic acid can be converted to the diacetate in high yield.

but why does the NH2 reacts faster? a better nucleophile perhaps?