oberkarteufel
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Embarrassing question about Grignard reaction
Hi. Everyone knows Grignard reaction, many know other reactions of Grignard reagents.
As you know, chemicals with hydrogen that are acidic enough (acids, phenols, alcohols, alkynes, iirc some nitriles, etc.) react with Grignard reagents
in a simple acid-base deprotonation manner. OK, I asked myself, but what about ketoacids? Or, to be precise, salts of ketoacids, that shouldn't have
the acidic hydrogens? Do we get a substituted hydroxy carboxylate?
Let's say we start with sodium pyruvate and react it with some Grignard, say ethyl magnesium bromide. Do we get the alkylated lactate?
I searched my books and online bases of main chemistry editors (acs, rsc, wiley, elsevier) but I could only find the general info everyone already
knows, but not on this particular topic. All while the questions are flooding in.
Would such a reaction occur? What would be the potential side reactions and what are the factors for them to occur? How would behave alkyl,
allyl/benzyl, phenyl Grignards and alpha, beta, gamma-oxocarboxylates? Would the salt solubility be an issue and what solvent/solvent system would be
optimal?
To sum up, could you guys direct me where to find the answers for my niche questions?
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Pumukli
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Good questions.
Unfortunately I can't tell you the exact answers. I 'm guessing though  :
Grignards can be picky about the solvent. They require ethers for their stability. Not all ethers are appropriate. Diethyl-ether and THF are generally
good solvents, sometimes other ethers work as well (di-n-butyl e.g., even anisole in some cases.)
The solubility of the pyruvate salt would surely be an issue in the above mentioned solvents. Maybe a lithium salt in THF would do the trick.
(Li-stearate is soluble in THF afaik.)
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DraconicAcid
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I second the "not all ethers are appropriate" bit- I found out the hard way that MTBE doesn't work for Grignards.
I suspect that the keto group would be significantly more reactive than the carboxylate. It might be worth trying.
Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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chempyre235
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Agreed. In the case with ketones, alkyl magnesium halide addition should result in a tertiary alcohol. Acetone and methyl magnesium chloride, for
example, produces t-BuOH and Mg(OH)Cl. I'd expect pyruvate to act similarly, though I have no idea what effect the carboxyl group has on this
reaction.
[Edited on 8/14/2025 by chempyre235]
"However beautiful the strategy, you should occasionally look at the results." -Winston Churchill
"I weep at the sight of flaming acetic anhydride." -@Madscientist
"...the elements shall melt with fervent heat..." -2 Peter 3:10
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oberkarteufel
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Thank you for the answers. Well, I'll keep digging, maybe something pops out.
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Keras
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I would expect the reaction to take place on the carbonyl carbon which is the most electropositive. In this case, I would expect it to be the carboxyl
carbon, because of the presence of the two oxygens. However, even if this is the case, there will probably be a small portion of the Grignard which
will attack on the keto side, and I’m sure you can also get a double substitution, although steric hinderance might play a role too.
But don’t take my word for it.
Also, this is a good case where the answer simply is: well, go ahead, do it, and see what you get!
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oberkarteufel
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Since it bothered me this much, I dug deeper than the dwarves of Khazad-dûm and I'll share the answer provided by the maître Grignard himself.
In short - a reaction of:
α- ketoacid ester with 1 mole equivalent of Grignard reagent will result in α-substituted hydroxyacid esters. Or bi-tertiary glycol, when 3 mole
equivalents of Grignard reagent are used (tertiary hydroxy groups stemming from carbonyl and carboxyl group respectively). Yields are low, in the
25-35% range.
β-ketoacids provide basically nothing useful, due to the acidity of their α-protons.
γ-ketoacids provide upon workup γ-substituted γ-lactones, also with yields around 30%.
Also, apparently ketoacid salts, despite their low solubility in ethers, work as (in)effectively as esters.
Cited literature:
-V. Grignard, Action des combinaisons organomagnésiennes mixtes sur les èthers d'acides cètoniques (II), Comptes rendus, t. 135 (1902), p. 627-630.
-V. Grignard, Action des combinaisons organomagnêsiennes
sur les èthers β-cétoniques, Comptes rendus, t. 134 (1901), p. 849-851.
-P. K. Porter, The Action of the Grignard Reagent on Keto Acids, J. Am. Chem. Soc. 1923, 45, 4, 1086–1087, DOI 10.1021/ja01657a501
-W. A. Noyes, C. S. Marvel, CYANCARBOXETHYL 3,3-DIMETHYL CYCLOPENTANONE, J. Am. Chem. Soc. 1917, 39, 6, 1267–1271, DOI 10.1021/ja02251a015
-D. T. Jones, G. Tattersall, CLXX.—A new synthesis of isocaprolactone and certain derivatives, J. Chem. Soc., Trans., 1904,85, 1691-1694, DOI
10.1039/CT9048501691
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chempyre235
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So, it sounds like you'd get ethyl lactate, or 3,4 dihydroxy, 3,4 diethyl hexane with excess of Grignard?
Nice! I got a good laugh out of that. Might seem like riddles in the dark to some, though.
"However beautiful the strategy, you should occasionally look at the results." -Winston Churchill
"I weep at the sight of flaming acetic anhydride." -@Madscientist
"...the elements shall melt with fervent heat..." -2 Peter 3:10
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charley1957
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Just as long as you didn't disturb the Balrog.
You can’t claim you drank all day if you didn’t start early in the morning.
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oberkarteufel
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That's right.
♫We do not fear what lies beneath
We can never dig too deep ♫
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