Meldrum's acidor2,2-dimethyl-1,3-dioxane-4,6-dione is an organic compound with formula C6H8O4. Its molecule has a heterocyclic core with four carbon and two oxygen atoms; the formula can also be written as [−O−(C(CH3)2)−O−(C=O)−(CH2)−(C=O)−].
It is a crystalline colorless solid, sparingly soluble in water. It decomposes on heating with release of carbon dioxide and acetone.[2][3]
The compound can easily lose a hydrogen ion from the methylene (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[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.
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.[4]
As an alternative to its original preparation, Meldrum's acid can be synthesized from malonic acid, isopropenyl acetate (anenol derivative of acetone), and catalytic sulfuric acid.
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 (R−Cl) attaches the alkyl group (R−) at that position:
The analogous reaction with an acyl chloride (R−(C=O)−Cl) attaches the acyl (R−(C=O)−) instead:
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,[5] and this reactivity of Meldrum's acid and it's derivatives has been used to develop a range of reactions.[6][7][8][9] Ketoesters formed from the reaction of alcohols with Meldrum's acid derivatives are useful in the Knorr pyrrole synthesis.
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:
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.[12][13][14]
^Nakamura, Satoshi; Hirao, Hajime; Ohwada, Tomohiko (2004). "Rationale for the Acidity of Meldrum's Acid. Consistent Relation of C−H Acidities to the Properties of Localized Reactive Orbital". J. Org. Chem.69 (13): 4309–4316. doi:10.1021/jo049456f. PMID15202884.
^Oikawa, Yuji; Sugano, Kiyoshi; Yonemitsu, Osamu (1978). "Meldrum's acid in organic synthesis. 2. A general and versatile synthesis of β-keto esters". J. Org. Chem.43 (10): 2087–2088. doi:10.1021/jo00404a066.
^Ghosh, Santanu; Purkait, Anisha; Jana, Chandan K. (2020). "Environmentally benign decarboxylative N -, O -, and S -acetylations and acylations". Green Chemistry. 22 (24): 8721–8727. doi:10.1039/D0GC03731A. S2CID229195097.
^Li, Jiang-Sheng; Da, Yu-Dong; Chen, Guo-Qin; Yang, Qian; Li, Zhi-Wei; Yang, Fan; Huang, Peng-Mian (13 February 2017). "Solvent-, and Catalyst-free Acylation of Anilines with Meldrum's Acids: A Neat Access to Anilides". ChemistrySelect. 2 (5): 1770–1773. doi:10.1002/slct.201601965.
^Gaber, Abd El-Aal M.; McNab, Hamish (2001). "Synthetic Applications of the Pyrolysis of Meldrum's Acid Derivatives". Synthesis. 2001 (14): 2059–2074. doi:10.1055/s-2001-18057.
^Dumas, Aaron M.; Fillion, Eric (2009). "Meldrum's Acids and 5-Alkylidene Meldrum's Acids in Catalytic Carbon–Carbon Bond-Forming Processes". Acc. Chem. Res.43 (3): 440–454. doi:10.1021/ar900229z. PMID20000793.
^Oikawa, Yuji; Hirasawa, Hitoshi; Yonemitsu, Osamu (1978). "Meldrum's acid in organic synthesis. 1. A convenient one-pot synthesis of ethyl indolepropionates". Tetrahedron Letters. 19 (20): 1759–1762. doi:10.1016/0040-4039(78)80037-9.
^Davidson, David; Bernhard, Sidney A. (1948). "The Structure of Meldrum's Supposed β-Lactonic Acid". Journal of the American Chemical Society. 70 (10): 3426–3428. doi:10.1021/ja01190a060. PMID18891879.
