Organic chemistry question

[Anonymous No.6660010]

Any chemists here?

Why can alkyllithium compounds react with carboxylic acids to form ketones, when Grignard reagents will just give an acid-base reaction? And why isn't the product a tertiary alcohol, like when reacting with esters?

[Anonymous No.6660037]

Look up the mechanisms. An organolithium reagent basically acts like a carbanion which knocks electrons up onto the carbonyl carbon, where it then slams down to reform the carbonyl and eject the best leaving group.

Grignard reagent forms a cyclic intermediate about the carbonyl and its oxygen, leaving the carbonyl as a -O-MgBr that provides a good leaving group in reaction workup as it doesn't have a lone pair with enough energy to eject the -OH

[Anonymous No.6660039]

>>6660010
Oh fug.
IIRC the organolithium reagent will undergo the expected acid/base reaction with a carboxylic acid.
One expects (reasonably, naively?) the carboxylate to be non-electrophilic, but the (hard) Li cation is maybe better at counteracting this than the (softer) Mg cation. Thus the Li-carboxylate is more electrophilic than the MgX-carboxylate.
As always with Li: aggregation matters. I'll bet it doesn't work well in the absence of something like TMEDA or HMPA.
Looking at the wikipedia entry (I know, but it is referenced - to lazy/drunk to actually pull out Francis/Carey or the Rubottom paper right now), the use of TMSCl is advantageous. LiO- sounds like a shit leaving group, TMSO- eh, IDK but if there's enough TMSCl to make (TMS)2O things look a bit better.

Finally: who fucking cares? Use the Weinreb amide to make ketones.

[Anonymous No.6660040]

>>6660010
My organic chemistry is a little rusty, but I think that alkyllithium compounds will be quenched by the acidic carboxylic acid in the same way that the Grignard reagents are quenched.

Grignard reagents are really good nucleophiles but are also really basic, so they are neutralized by taking the acidic hydrogen from the carboxylic acid before they can react with the carbonyl.
I think this reaction is quiet violent so adding two equivalents of the Grignard is not only wasteful but also dangerous.
The double addition happens with esters because their is no acidic hydrogen to quench the Grignard, so the Grignard reagent attacks the carbonyl forming the tetrahedral intermediate. Then the carbonyl reforms kicking off the O-R substituent, forming a ketone. Ketones are more reactive than esters, so they react with the Grignard reagents before the rest of the esters. When the Grignard reagent attacks the ketone, it forms the tetrahedral intermediate, but because their is nothing to kick off, it can't collapse back into a carbonyl.
If only one equivalent of the Grignard reagent is used then you get a messy mix of products, which includes the tetrahedral alcohol (after workup).

[Anonymous No.6660043]

>>6660010
My organic chemistry is a little rusty, but I think that alkyllithium compounds will be quenched by the acidic carboxylic acid in the same way that the Grignard reagents are quenched.

Grignard reagents are really good nucleophiles but are also really basic, so they are neutralized by taking the acidic hydrogen from the carboxylic acid before they can react with the carbonyl.
I think this reaction is quiet violent so adding two equivalents of the Grignard is not only wasteful but also dangerous.
The double addition happens with esters because their is no acidic hydrogen to quench the Grignard, so the Grignard reagent attacks the carbonyl forming the tetrahedral intermediate. Then the carbonyl reforms kicking off the O-R substituent, forming a ketone. Ketones are more reactive than esters, so they react with the Grignard reagents before the rest of the ester in the solution. When the Grignard reagent attacks the ketone, it forms the tetrahedral intermediate, but because their is nothing to kick off, it can't collapse back into a carbonyl.
If only one equivalent of the Grignard reagent is used then you get a messy mix of products, which includes the tetrahedral alcohol (after workup).

[Anonymous No.6660075]

Here's the Rubottom paper (it's 20 years old)
anonfiles /file/995bfc0e314a8b492709311210210caf

The first sentence:
One of the major problems associated with the transformations of carboxylic acids 1 into the corresponding methyl ketones 2 using methyl lithium has been the coproduction of unwanted tertiary alcohols 3.

[Anonymous No.6660096]

>>6660075
>20 years
30, like I said too drunk to deal with it

[Anonymous No.6661626]

Instead of wasting 1 equivalent of dangerous and expensive alkyllithium to turn the acid into a salt, couldn't you just use a premade lithium salt? Or does it even have to be a lithium salt?

[Anonymous No.6661666]

>>6661626
Look at reference 4 of the Rubottom paper.

[Anonymous No.6662779]

>>6660039
>Finally: who fucking cares? Use the Weinreb amide to make ketones.
N,O-Dimethylhydroxylamine doesn't grow on trees and making the amide from it isn't as simple as just adding it to the acid. But that doesn't matter since the question was purely theoretical.

>>6661666
Why wouldn't Na or K carboxylates work?

[Anonymous No.6662784]

>>6661626
>dangerous and expensive alkyllithium
You can get 1L of the 2.5 M in hexane for less than 100 bucks. That shit is dirt cheap.

[Anonymous No.6662813]

>>6662784
Plus how much for shipping? Assuming someone will even sell it to you.

[Anonymous No.6662822]

>>6662813
>Plus how much for shipping? Assuming someone will even sell it to you.
Oh, you're one of those kitchen scientists. Shipping to my lab is usually nothing since we buy in bulk. Also, i don't have to pay for it naturally so i have no idea.
We also got a whole fridge full of donations from Rockwood lithium, like 10 liters of different alkyllithiums and 5 different bottels of all kinds of gringards (seriously, there's like 2 liters of cyclohexyl magnesium bromide that nobody in this lab is ever going to use)

[Anonymous No.6663455]

>>6662779
>N,O-Dimethylhydroxylamine doesn't grow on trees and making the amide from it isn't as simple as just adding it to the acid.
No shit, just like every other amidation...

>Why wouldn't Na or K carboxylates work?
They might, but why mix cations (eg Na carboxylates and alkyllithiums)? Just one more potential complication.
Note that ref 4b of the Rubottom paper does mention someone using sodium carboxylates and Grinard reagents to give low yields of ketones w/o observation of carbinols.

[Anonymous No.6663496]

>>6663455
Re cations: maybe I shouldn't have been so fast to dismiss, see Schlosser's base.

Re: Weinreb amide: unless you're broke (can't afford acid activators/peptide coupling agents), illegitimate, or working on process scale...

[Anonymous No.6663627]

>>6661626
Alkyllithiums are readily prepared by reduction of lithium metal (eg. from Li batteries) with haloalkanes (you should have a source of DCM or similar anyway, if your reaction needs something more elaborate/non-OTC you can prepare haloalkanes a million ways (eg. suitable alcohol + HCl + ZnCl)).

[Anonymous No.6663644]

>>6663455
>using sodium carboxylates and Grinard reagents to give low yields of ketones w/o observation of carbinols.
How low yields? Are we talking about 10% or 0,0001%?

[Anonymous No.6663667]

>>6663496
>unless you're broke (can't afford acid activators/peptide coupling agents), illegitimate, or working on process scale...
i.e anyone NOT working in a research lab, having a shelf full of funky reagents paid by his employer.