Meldrum's acid

{{chembox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 442244479

| Name = Meldrum's acid

| ImageFile = meldrum's_acid.png

| ImageName = Meldrum's Acid

| PIN = 2,2-Dimethyl-1,3-dioxane-4,6-dione

| OtherNames = Isopropylidene malonate

|Section1={{Chembox Identifiers

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 15418

| PubChem = 16249

| InChI1 = 1/C6H8O4/c1-6(2)9-4(7)3-5(8)10-6/h3H2,1-2H3

| InChIKey1 = GXHFUVWIGNLZSC-UHFFFAOYAM

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C6H8O4/c1-6(2)9-4(7)3-5(8)10-6/h3H2,1-2H3

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = GXHFUVWIGNLZSC-UHFFFAOYSA-N

| CASNo_Ref = {{cascite|correct|CAS}}

| CASNo = 2033-24-1

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = DD139RP1SC

| SMILES = O=C1OC(OC(=O)C1)(C)C

| InChI = 1/C6H8O4/c1-6(2)9-4(7)3-5(8)10-6/h3H2,1-2H3

| InChIKey = GXHFUVWIGNLZSC-UHFFFAOYAM

}}

|Section2={{Chembox Properties

| C=6 | H=8 | O=4

| Density =

| MeltingPtC = 94 to 95

| MeltingPt_notes = (decomposes){{cite encyclopedia

| title = Meldrum's Acid

| encyclopedia = The Merck Index

| series = 14th

| volume = edition

| pages = 1005

| publisher = Merck Research Laboratories

| year = 2006

| isbn =978-0-911910-00-1}}

| pKa = 4.97

}}

Meldrum's acid or 2,2-dimethyl-1,3-dioxane-4,6-dione is an organic compound with formula {{chem2|C6H8O4}}. Its molecule has a heterocyclic core with four carbon and two oxygen atoms; the formula can also be written as {{chem2|[\sO\sC(CH3)2\sO\s(C\dO)\sCH2\s(C\dO)\s]}}.

It is a crystalline colorless solid that is sparingly soluble in water and which decomposes on heating to carbon dioxide, acetone, and a ketene.{{cite journal | last1 = McNab | first1 = Hamish | year = 1978 | title = Meldrum's acid | journal = Chemical Society Reviews | volume = 7 | issue = 3 | pages = 345–358 | doi = 10.1039/CS9780700345 }} Its synthesis was first reported in 1908 by Andrew Norman Meldrum, for whom it is named. Meldrum incorrectly concluded that it was a carboxylic acid based on its acidity; the correct bislactone structure was not reported until 1948.

Properties

=Acidity=

The compound can easily lose a hydrogen ion from the methylene ({{chem2|CH2}}) in the ring (carbon 5); which creates a double bond between it and one of the adjacent carbons (number 4 or 6), and a negative charge in the corresponding oxygen. The resulting anion {{chem2|[C6H7O4](-)}} is stabilized by resonance between the two alternatives, so that the double bond is delocalized and each oxygen in the carbonyls has a formal charge of −1/2.

File:Meldrum-anion-resonance.png

The ionization constant pK_a is 4.97; which makes it behave as a monobasic acid even though it contains no carboxylic acid groups. In this and other properties, the compound resembles dimedone and barbituric acid. However, while dimedone exists in solution predominantly as the mono-enol tautomer, Meldrum's acid is almost entirely as the diketone form.

The unusually high acidity of this compound was long considered anomalous—it is 8 orders of magnitude more acidic than the closely related compound dimethyl malonate. In 2004, Ohwada and coworkers determined that the energy-minimizing conformation structure of the compound places the alpha proton's σ*_CH orbital in the proper geometry to align with the π^*_CO, so that the ground state poses unusually strong destabilization of the C-H bond.{{cite journal | last1 = Nakamura | first1 = Satoshi | last2 = Hirao | first2 = Hajime | last3 = Ohwada | first3 = Tomohiko | journal = J. Org. Chem. | year = 2004 | volume = 69 | pages = 4309–4316 | title = Rationale for the Acidity of Meldrum's Acid. Consistent Relation of C−H Acidities to the Properties of Localized Reactive Orbital | pmid = 15202884 | issue = 13 | doi = 10.1021/jo049456f }}

Preparation

=Original synthesis=

The compound was first made by Meldrum by a condensation reaction of acetone with malonic acid in acetic anhydride and sulfuric acid.

File:Meldrum-acid-original-synthesis.png

=Alternative syntheses=

As an alternative to its original preparation, Meldrum's acid can be synthesized from malonic acid, isopropenyl acetate (an enol derivative of acetone), and catalytic sulfuric acid.

A third route is the reaction of carbon suboxide {{chem2|C3O2}} with acetone in the presence of oxalic acid.

Uses

Like malonic acid and its ester derivatives, and other 1,3-dicarbonyl compounds, Meldrum's acid can serve as a reactant for a variety of nucleophilic reactions.

= Alkylation and acylation =

The acidity of carbon 5 (between the two carbonyl groups) allows simple derivatization of Meldrum's acid at this position, through reactions such as alkylation and acylation. For example, deprotonation and reaction with a simple alkyl halide ({{chem2|R\sCl}}) attaches the alkyl group ({{chem2|R\s}}) at that position:

File:Meldrum-anion-alkylation.png

The analogous reaction with an acyl chloride ({{chem2|R\s(C\dO)\sCl}}) attaches the acyl ({{chem2|R\s(C\dO)\s}}) instead:

File:Meldrum-anion-acylation.png

These two reactions allow Meldrum's acid to serve as a starting scaffold for the synthesis of many different structures with various functional groups. The alkylated products can be further manipulated to produce various amide and ester compounds. Heating the acyl product in the presence of an alcohol leads to ester exchange and decarboxylation in a process similar to the malonic ester synthesis. The reactive nature of the cyclic-diester allows good reactivity even for alcohols as hindered as t-butanol,{{cite journal | doi = 10.1021/jo00404a066 | last1 = Oikawa | first1 = Yuji | last2 = Sugano | first2 = Kiyoshi | last3 = Yonemitsu | first3 = Osamu | journal = J. Org. Chem. | year = 1978 | volume = 43 | issue = 10 | pages = 2087–2088 | title = Meldrum's acid in organic synthesis. 2. A general and versatile synthesis of β-keto esters}} and this reactivity of Meldrum's acid and its derivatives has been used to develop a range of reactions.{{cite journal |last1=Ghosh |first1=Santanu |last2=Purkait |first2=Anisha |last3=Jana |first3=Chandan K. |title=Environmentally benign decarboxylative N -, O -, and S -acetylations and acylations |journal=Green Chemistry |date=2020 |volume=22 |issue=24 |pages=8721–8727 |doi=10.1039/D0GC03731A|s2cid=229195097 }}{{cite journal |last1=Li |first1=Jiang-Sheng |last2=Da |first2=Yu-Dong |last3=Chen |first3=Guo-Qin |last4=Yang |first4=Qian |last5=Li |first5=Zhi-Wei |last6=Yang |first6=Fan |last7=Huang |first7=Peng-Mian |title=Solvent-, and Catalyst-free Acylation of Anilines with Meldrum's Acids: A Neat Access to Anilides |journal=ChemistrySelect |date=13 February 2017 |volume=2 |issue=5 |pages=1770–1773 |doi=10.1002/slct.201601965}}{{cite journal |last1=Davis |first1=Garrett J. |last2=Sofka |first2=Holly A. |last3=Jewett |first3=John C. |title=Highly Stable Meldrum's Acid Derivatives for Irreversible Aqueous Covalent Modification of Amines |journal=Organic Letters |date=3 April 2020 |volume=22 |issue=7 |pages=2626–2629 |doi=10.1021/acs.orglett.0c00597|pmid=32191483 |pmc=7679203 }}{{cite journal |last1=Heard |first1=David M. |last2=Lennox |first2=Alastair J. J. |title=Dichloromeldrum's Acid (DiCMA): A Practical and Green Amine Dichloroacetylation Reagent |journal=Organic Letters |date=7 May 2021 |volume=23 |issue=9 |pages=3368–3372 |doi=10.1021/acs.orglett.1c00850|pmid=33844547 |s2cid=233223351 |url=https://research-information.bris.ac.uk/en/publications/89034a97-d592-4fcb-925d-459b9efd9a40 |hdl=1983/89034a97-d592-4fcb-925d-459b9efd9a40 |hdl-access=free }} Ketoesters formed from the reaction of alcohols with Meldrum's acid derivatives are useful in the Knorr pyrrole synthesis.

= Synthesis of ketenes =

At temperatures greater than 200 °C{{cite journal |last1=Gaber |first1=Abd El-Aal M. |last2=McNab |first2=Hamish |title=Synthetic Applications of the Pyrolysis of Meldrum's Acid Derivatives |journal=Synthesis |date=2001 |volume=2001 |issue=14 |pages=2059–2074 |doi=10.1055/s-2001-18057}} Meldrum's acid undergoes a pericyclic reaction that releases acetone and carbon dioxide and produces a highly reactive ketene compound:{{cite journal|last1 = Dumas|first1 = Aaron M.|last2 = Fillion|first2 = Eric|year = 2009|title = Meldrum's Acids and 5-Alkylidene Meldrum's Acids in Catalytic Carbon–Carbon Bond-Forming Processes|journal = Acc. Chem. Res.|volume = 43|issue = 3|pages = 440–454|doi = 10.1021/ar900229z|pmid = 20000793}}

File:Meldrum-derivative-pyrolysis.png

These ketenes can be isolated using flash vacuum pyrolysis (FVP). Ketenes are highly electrophilic and can undergo addition reaction with a range of other chemicals, particularly ketene cycloadditions, or dimerisation to diketene. With this approach it is possible to form new C–C bonds, rings, amides, esters, and acids:

File:Ketene-amine-addition.png

File:Ketene-enol-addition.png

File:Ketene-water-addition.png

Alternately, the pyrolysis can be performed in solution, to obtain the same results without isolating the ketene, in a one-pot reaction. The ability to form such diverse products makes Meldrum's acid a very useful reagent for synthetic chemists.{{cite journal | last1 = Oikawa | first1 = Yuji | last2 = Hirasawa | first2 = Hitoshi | last3 = Yonemitsu | first3 = Osamu | year = 1978 | title = Meldrum's acid in organic synthesis. 1. A convenient one-pot synthesis of ethyl indolepropionates | journal = Tetrahedron Letters | volume = 19 | issue = 20| pages = 1759–1762 | doi = 10.1016/0040-4039(78)80037-9 }}{{cite journal|last1 = Lipson|first1 = Victoria V.|last2 = Gorobets|first2 = Nikolay Yu.|year = 2009|title = One hundred years of Meldrum's acid: Advances in the synthesis of pyridine and pyrimidine derivatives|journal = Mol. Divers.|volume = 13|issue = 4|pages = 399–419|doi = 10.1007/s11030-009-9136-x|pmid = 19381852|s2cid = 20523615}}{{cite journal | last1 = Bonifácio | first1 = Vasco D. B. | year = 2004 | title = Meldrum's Acid | journal = Synlett | volume = 2004 | issue = 9| pages = 1649–1650 | doi = 10.1055/s-2004-829539 | doi-access = free }}

History

File:Meldrum-acid-wrong-structure.png

The compound is named after Andrew Norman Meldrum who reported its synthesis in 1908.{{cite journal | last1 = Meldrum | first1 = Andrew N. | authorlink = Andrew Norman Meldrum | year = 1908 | title = A β-lactonic acid from acetone and malonic acid | url = https://books.google.com/books?id=PMM3AAAAMAAJ&pg=PA598 | journal = Journal of the Chemical Society, Transactions | volume = 93 | pages = 598–601 | doi = 10.1039/CT9089300598 }} He misidentified its structure as a carboxylic acid based on its unusually high acidity, identifying it as the β-lactone of β-hydroxyisopropylmalonic acid; the correct structure, the bislactone of 1,3-dioxane was reported in 1948.{{cite journal | last1 = Davidson | first1 = David | last2 = Bernhard | first2 = Sidney A. | year = 1948 | title = The Structure of Meldrum's Supposed β-Lactonic Acid | journal = Journal of the American Chemical Society | volume = 70 | issue = 10| pages = 3426–3428 | doi = 10.1021/ja01190a060 | pmid = 18891879 }}