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By James Ashenhurst

Common Mistakes with Carbonyls: Carboxylic Acids… Are Acids!

Last updated: March 26th, 2019 |

Carboxylic acids… are acids.

I know that seems obvious. But it’s a near certainty that students taking Org 2 for the first time will forget this occasionally.

Here are two common mistakes that I see *all the time*.

1) Reactions of Grignard reagents with carboxylic acids.

Grignard reagents (with the general structure RMgBr) are great nucleophiles. They add to ketones, aldehydes, esters (twice), acid halides (twice), epoxides, and a number of other carbonyl-containing compounds.

For students getting their feet wet with carbonyl chemistry, it can be tempting to also draw Grignard reagents adding to carboxylic acids.

They don’t.

That’s because carboxylic acids are… acids, and Grignard reagents are very strong bases. So instead of adding to the carbonyl  carbon, the Grignard is simply protonated first. And the resulting conjugate base of the carboxylic acid (a carboxylate) is too unreactive to react further.

1-carboxacids

2) Reaction with alkoxides (deprotonated alcohols)

Carboxylic acid derivatives like esters, anhydrides, and acid halides react well with good nucleophiles like HO- and RO- . The pattern becomes familiar quite quickly: 1,2 addition, followed by 1,2 elimination. Seeing this pattern, students get lulled into a false sense of security that carboxylic acids will react this way as well.

They don’t – for the same reasons that Grignard reagents don’t. Carboxylic acids are acids. They protonate strong bases (such as alkoxides) and leave behind the carboxylate, which – again – is unreactive.

2-grignard

It seems silly to repeat this a third time, but it happens *all the time*. You might not think you will do this. Chances are, at some point, you will. It’s an easy mistake to make. So let’s say it one last time:

Carboxylic acids…. are acids!

———-

Note below: It’s a pretty good rule of thumb to assume that acid-base reactions will happen faster than reactions that involve nucleophilic attack, such as addition to carbonyls. If you’re keen, there’s a name for this: the principle of least motion.  That’s why we see protonation of the Grignard reagent before it has time to add to the carbonyl carbon.

Comments

Comment section

27 thoughts on “Common Mistakes with Carbonyls: Carboxylic Acids… Are Acids!

  1. So is there a way to add alkyl groups to carboxylic acids? Lets say I wanted to go from a carboxylic acid to a tertiary substituted alcohol.

    1. If you use organolithium reagents you can add alkyl groups to carboxylic acids to form ketones. These will also deprotonate the carboxylic acid to the carboxylate, but are powerful enough to add to subsequently form the C-C bond. However I believe that the intermediate that is formed is fairly stable and will not eliminate to give the ketone until workup. To get the tertiary alcohol you’d have to submit the ketone to another equivalent of organolithium (or Grignard if you prefer). Hope this answers your question.

  2. Carboxylic acids + amines is another common proton transfer example that students miss. I don’t know how many RC(=NR)OH products I’ve seen – it’s a lot.

  3. thanks that’s a lot of help so how could you prepare an ester from a carboxylic acid without carrying out fischer esterification?

  4. Hi James!

    Great post, I had understood it when I saw it last semester but recently I came across that Organolithium reaction you had mentioned in the comments. I’m a little confused as to why if you add the 2 equivalents of Organolithium you can use the first to deprotonate and the 2nd to add on but you can’t do the same thing with 2 equivalents of Grignard reagents. Is it simply that the Grignard is weaker? I had always thought the two were extremely powerful nucleophiles/bases and didn’t differ too much.

    -Confused But Would Love To Be Enlightened (Frank W.)

  5. This is Matt, I’m a tutor that works through Master Organic. To answer your question frank, I will start by agreeing that it does seem a bit crazy at first glance that a grignard will simply deprotonate a carboxylic acid while the the alkyl lithium irreversibly forms a dianion through sequential deprotonation/addition. In most context grignards and alkyl lithiums react in the same way, although alkyl lithiums are more often used when deprotonation is the specific goal, I have noticed (ylide formation, for example). If you study enough mechanisms you will eventually come upon many of these frustratingly inconsistent examples that must be rationalized by some hand waving. It’s possible that nobody knows the answer for sure it probably has something to with either:

    1) Slightly stronger lewis acidity of Li+ cation in this context
    2) Slightly higher nucleophilicity of the C-Li bond compared to the C-Mg bond

    This may be an oversimplification though, and I welcome anyone who knows of experimental data or computational studies that explain this. The mechanism itself could be entirely different, as these reagents do sometimes do funky things such as single electron transfer (SET) radical mechanisms.

    1. Matt – I would say your answer (1) is good, but your answer (2) is redundant. By definition, if the R-Li is more reactive it is because it means it has “higher nucleophilicity.”

      But back to the Li Lewis acidity. You can compare it to the difference between LiAlH4 and NaAlH4 or NaBH4 and LiBH4. In both cases, the Li salts are more reactive. A lot of the difference is likely due to the Lewis acidity, but there could also be solvation differences that affect reactivity as well. In fact, solvation/Lewis acidity pretty much accounts for the difference in reactivity between LAH and NaBH4. Thermochemical studies of the bare ions AlH4- and BH4- show that there is no difference in the hydride binding energies, and the activation energies for reduction of CO2 in the absence of solvent and counter-ion are the same for AlH4- and BH4-.

      It’s not always easy to think about the structures of things like organometallics or inorganic salts in organic solution. Even subtle differences in structure like diethyl ether and THF can change solvation properties, and these things can have large effects on reactivity. Fortunately, we have folks like Hans Reich and Dave Collum to help us understand it better.

    1. Generally not, unless the acid chloride is extraordinarily hindered. C-H bonds don’t deprotonate as quickly as O-H bonds since 1) there has to be reorganization (rehybridization) of the bonds, and 2) the acidity of C-H is dependent on its alignment with the carbonyl.

    1. Hydroxyl groups (OH), thiols (SH), and generally any other mildly acidic functional groups. Carboxylic acids are by far the most common situation one encounters.

  6. Please explain: Grignard reagent + carboxylic acid chloride –> ketone + Mg-halides.

    Is the C-Cl bond so reactive as to preclude simple protonation of said Grignard?

    1. By “carboxylic acid chloride” it’s meant, “acid chloride” which in fact does not contain an acidic hydrogen. So protonation of the Grignard is not an issue here, although it would be with carboxylic acids.

  7. A carboxylate actually has the charge delocalized between the two oxygens, This might explain why it isn’t keen on behaving like a carboxyl compound.

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