Acetoacetic Ester Synthesis
Acetoacetic Ester Synthesis (••••°) is a named reaction in organic chemistry that forms a methyl ketone from an alkyl acetoacetate. The reaction is named for the usefulness of the starting material and not in honor of the chemist who invented or discovered the best use for it.
Related: malonic ester synthesis; enolate alkylation
Counter to what you may have learned about name reactions this is unusual because: 1) this does not synthesize or create an acetoacetic ester. 2) The current IUPAC rules of nomenclature are grandfathered in here, and the archaic (or “trivial”) terminology is used since it’s been around, well, the whole time. It goes instead by the obsolete and tedious way of naming things.*
Mechanism of the Reaction:
This is 2nd semester organic chemistry. You will almost certainly see this toward mid-semester during Organic Chemistry II and it’s perhaps one of the more difficult (••••°) questions on the ACS Final exam (useful link) because of the final step.
Starting with an acetoacetic ester, a suitably strong base like sodium ethoxide (NaOEt) is added. The most acidic carbon is alpha to two carbonyl groups which means its conjugate base (a negatively-charged anion) is more stable than a regular ester or ketone by virtue of having more resonance forms. By adding an alkyl halide (R’-X), at this point, a carbon-carbon bond (important!) is formed by SN2 displacement of the leaving group (-X). The alkyl halide is almost always primary meaning the leaving group is attached to a carbon that is in turn attached to just one other carbon. You were indoctrinated to never attack the hindered backside of a tertiary carbon in an alkyl halide. (There are however, very specific exceptions to that general rule (…a white lie for the learner’s sake).
In the final transformation, the ester is hydrolyzed (by acid-catalyzed carbonyl substitution). The OR group leaves as an alcohol in the presence of heat (Δ) and aqueous acid catalyst (H3O+) to generate the corresponding carboxylic acid. Once formed, the carboxylate of the acid readily undergoes decarboxylation (or loss of CO2) accompanying the increase in entropy (disorder). Since there are more species than there were, the number of different possible orientations of species goes up and so does disorder which is universal law. Because the enol is a relatively stable tautomer (isomeric form) of a ketone (versus mesomeric which is another word for resonance). Overall, one is left with a ketone flanked on one side by the original methyl group and on the other with whatever alkyl (or R) group one attaches in the 2nd step of the mechanism (substitution of R‘-X) along with the what is now a carboxylic acid.
(Review: Keto-Enol Tautomerization from first semester.)
Acetoacetic Ester Synthesis : a named reaction in organic chemistry in which a methyl ketone product is made from the alkylation of the enolate anion (conjugate base) formed from an alkyl acetoacetate.
*A Word or Two About the Old School Naming System:
*In biochemistry or biology, these terms happen to occur all the time, since, unlike chemists, they do not necessarily update or adhere to nomenclature conventions that chemists would go nuts without (there are over 10 million organic compounds known. That doesn’t stop even some chemists from regressing to the term “acetate”. In organic chemistry, an acetate is any two carbon species possessing the proper oxidation state (-3) to undergo a condensation reaction. For example, a polyacetate synthesis of a molecule is one which the final target is made from successive condensations of two-carbon molecules to make a final product that has 4, 6, 8…etc. carbons. The fat you store in your body is a biosynthetic polyacetate synthesis.
So why not just change the name of the reaction to suit the current IUPAC nomenclature? Because it makes things harder. The actual point of using named reactions in the chemical vernacular is for convenience. It doesn’t improve the conversation by referring to the acetoacetic ester synthesis as the “alkyl 3-ketobutanoate synthesis.”
It may be not understood yet by the learner but chemists drop locant numbers in colloquial speech. For example, the common oxidant, DDQ is not called by it’s IUPAC name, 2,3-dichloro-5,6-dicyano-1,4-quinone. The reason for abbreviating this common reagent is to simplify and literally no one ever calls it “2,3-D-5,6-D-1,4-Q”.
People don’t call DNA, the genetic material, 2′-desoxyribonucleic acid (or “two prime deoxy“). The prefixes “de-” and “des-” are equivalent and mean “without“. Thus, DNA differs from ribonucleic acid (RNA) because it is without an oxygen at the 2′ position of the ribose sugar attached to the nitrogenous base.