Lactone

β-propiolactone, formed from β-hydroxypropionic acid

In chemistry, a lactone is a cyclic ester^[1] which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule. It is characterized by a closed ring consisting of two or more carbon atoms and a single oxygen atom, with a ketone group =O in one of the carbons adjacent to the other oxygen.

Nomenclature

Lactone nomenclature: α-acetolactone, β-propiolactone, γ-butyrolactone, and δ-valerolactone

Lactones are usually named according to the precursor acid molecule (aceto = 2 carbons, propio = 3, butyro = 4, valero = 5, capro = 6, etc.), with a -lactone suffix and a Greek letter prefix that specifies the number of carbons in the heterocyle — that is, the distance between the relevant -OH and the -COOH groups along said backbone. The first carbon atom after the carbon in the -COOH group on the parent compound is labelled α, the second will be labeled β, and so forth. Therefore, the prefixes also indicate the size of the lactone ring: α-lactone = 3-membered ring, β-lactone = 4-membered, γ-lactone = 5-membered, etc.
The other suffix used to denote a lactone is -olide, used in substance class names like butenolide, macrolide, cardenolide or bufadienolide.

Etymology

The name lactone derives from the ring compound called lactide, which is formed from the dehydration of 2-hydroxypropanoic acid (lactic acid) CH₃-CH(OH)-COOH. Lactic acid, in turn, derives its name from its original isolation from soured milk (Latin: lac, lactis). An internal dehydration within the same molecule of lactic acid would have produced alpha-propiolactone, a lactone with a 3-membered ring.

Natural sources

Lactones (specifically 3-methyl-4-octanolide) are found in oak trees as well as many other plants, and impart flavour to whisky.^{[citation needed]}

Synthesis

Many methods in ester synthesis can also be applied to that of lactones. In one industrial synthesis of oxandrolone the key lactone-forming step is an organic reduction - esterification:^[2][3]

In halolactonization, an alkene is attacked by a halogen via electrophilic addition with the cationic intermediate captured intramolecularly by an adjacent carboxylic acid (See also iodolactamization), for example in this iodolactonization:^[4]

Specific methods include Yamaguchi esterification and nucleophilic abstraction.
A recent study has isolated β-lactones from bromination of 2,3-dimethylmaleate and/or 2,3-dimethylfumarate disodium salts, under ambient and aqueous conditions. The carboxylate groups of the maleate and fumarate moieties exhibit neighbouring group effects and alpha-lactones are proposed in the detailed mechanism.^[5]

Reactions

The most stable structure for lactones are the 5-membered γ-lactones and 6-membered δ-lactones because, as in all organic cycles, 5 and 6 membered rings minimize the strain of bond angles. γ-lactones are so stable that, in the presence of dilute acids at room temperature, 4-hydroxy acids (R-CH(OH)-(CH₂)₂-COOH) immediately undergo spontaneous esterification and cyclisation to the lactone. β-lactones do exist, but can only be made by special methods. α-lactones can be detected as transient species in mass spectrometry experiments.^[6]
The reactions of lactones are similar to those of esters, as exemplified by gamma-lactone in the following sections:

Hydrolysis

Heating a lactone with a base (sodium hydroxide) will hydrolyse the lactone to its parent compound, the straight chained bifunctional compound. Like straight-chained esters, the hydrolysis-condensation reaction of lactones is a reversible reaction, with an equilibrium. However, the equilibrium constant of the hydrolysis reaction of the lactone is lower than that of the straight-chained ester i.e. the products (hydroxyacids) are less favored in the case of the lactones. This is because although the enthalpies of the hydrolysis of esters and lactones are about the same, the entropy of the hydrolysis of lactones is less than the entropy of straight-chained esters. Straight-chained esters give two products upon hydrolysis, making the entropy change more favorable than in the case of lactones which give only a single product.

Reduction

Lactones can be reduced to diols using lithium aluminium hydride in dry ether. The reduction reaction will first break the ester bond of the lactone, and then reduce the carboxylic acid group (-COOH) to the alcohol group (-OH). For instance, gamma-lactones will be reduced to butan-1,4-diol, (CH₂(OH)-(CH₂)₂-CH₂(OH).

Aminolysis

Lactones also react with ethanolic ammonia, which will first break the ester bond and then react with the acidic -COOH group, because of the basic properties of ammonia, to form a difunctional group, i.e. alcohol and amide. Gamma-lactones will react to yield CH₂(OH)-(CH₂)₂-CO-NH₂.

Michael reaction

Sesquiterpene lactones, found in many plants, can react with other molecules via a Michael reaction.

Industrial Uses

Biofilm prevention

Brominated furanones have been shown to be somewhat effective at preventing the formation of biofilm. One species has specifically been shown to increase Salmonella enterica serovar Typhimurium's susceptibility to antimicrobial treatments.^[7]

Examples

• 
  

β-propiolactone

• 
  

γ-butyrolactone (GBL)

• 
  

D-glucono-δ-lactone (E575)

• 
  

ε-caprolactone

• Macrolides

dilactones

• Ellagic acid (Hexahydroxydiphenic acid dilactone)
• Flavogallonic acid dilactone can be found in Rhynchosia volubilis seeds and in Shorea laeviforia
• Lactide
• Tergallic acid dilactone can be found in Rhynchosia volubilis seeds
• Valoneic acid dilactone can be isolated from the heartwood of Shorea laeviforia

  

Synthesis of lactones and related compounds

Related:

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		Synthesis of     Butenolides Phthalides Recent Literature Silver(I) triflate catalyzes intramolecular additions of hydroxyl or carboxyl groups to olefins in good to excellent yields for a range of substrates under relatively mild conditions. This reaction is one of the simplest methods to construct cyclic ethers or lactones. C.-G. Yang, N. W. Reich, Z. Shi, C. He, Org. Lett., 2005, 7, 4553-4556. A new copper-catalyzed oxidative [3 + 2] cycloaddition of alkenes with anhydrides using oxygen as the sole oxidant affords γ-lactones in good to excellent yield. This catalyzed cyclization process has a broad substrate scope. L. Huang, H. Jiang, C. Qi, X. Liu, J. Am. Chem. Soc., 2010, 132, 17652-17654. A new and reliable method for the direct construction of biologically important aryl lactones and phthalides from carboxylic and benzoic acids is based on selective benzylic C-H abstraction in the presence of hypervalent iodine(III) reagents and KBr. T. Dohi, N. Takenaga, A. Goto, A. Maruyama, Y. Kita, Org. Lett., 2007, 9, 3129-3132. The hypervalent iodine reagent PIFA promotes the efficient intramolecular electrophilic cyclization of easily accessible alkynylamides and alkynyl carboxylic acids, leading to pyrrolidinone and lactone skeletons, respectively. A synthetic study and a mechanistic proposal for these transformations are presented. I. Tellitu, S. Serna, M. T. Herrero, I. Moreno, E. Domínguez, R. SanMartin, J. Org. Chem., 2007, 72, 1526-1529. Homogeneous carboamination, carboalkoxylation and carbolactonization of terminal alkenes are realized via oxidative gold catalysis, providing expedient access to various substituted N- or O-heterocycles. Deuterium-labeling studies established the nature of the alkene functionalization and the indispensible role of Au(I)/Au(III) catalysis. G. Zhang, L. Cui, Y. Wang, L. Zhang, J. Am. Chem. Soc., 2010, 132, 1474-1475. Several Pd-catalyzed oxidative cyclizations proceed in excellent yield under simple aerobic conditions. Importantly, this system provided entry into enatioselective catalysis with a readily available Pd-sparteine complex. R. M. Trend, Y. K. Ramtohul, E. M. Ferreira, B. Stoltz, Angew. Chem. Int. Ed., 2003, 42, 2892-2895. In the presence of CuI/trans-N,N′-dimethylcyclohexane-1,2-diamine as catalyst, a number of carboxylic acids underwent efficient intramolecular O-vinylation with vinyl bromides leading to the corresponding five- and six-membered enol lactones. The same catalytic system also enabled an efficient cycloisomerization of alkynoic acids. C. Sun, Y. Fang, S. Li, Y. Zhang, Q. Zhao, S. Zhu, C. Li, Org. Lett., 2009, 11, 4084-4087. C. Sun, Y. Fang, S. Li, Y. Zhang, Q. Zhao, S. Zhu, C. Li, Org. Lett., 2009, 11, 4084-4087. A general, efficient, and convenient cyclization of alkynes bearing carboxylic acids to the corresponding γ-alkylidene-γ-butyrolactones in the presence of commercially available Au2O3 shows a high degree of chemo-, regio-, and stereoselectivity. The 5-exo mode of cyclization and anti auration are a general trend for the Au2O3 catalyst. P. Y. Toullec, E. Genin, S. Antoniotti, J.-P. Genêt, V. Michelet, Synlett, 2008, 707-711. A highly efficient gold-catalyzed cyclization reaction of various functionalized acetylenic leads to γ-lactones in good to excellent yields. The reaction conditions are compatible with several functional groups, such as ester, alkene, alkyne, chloro, and free or protected alcohol. E. Genin, P. Y. Toullec, S. Antioniotti, C. Brancour, J.-P. Genêt, V. Michelet, J. Am. Chem. Soc., 2006, 128, 3112-3113. Imidazolinium-derived carbenes catalyze an efficient ring-expansion lactonization of oxacycloalkane-2-carboxaldehydes to give various functionalized five-, six-, and seven-membered lactones under mild reaction conditions. The electronic nature of the carbene catalyst plays a crucial role for the success of this method. L. Wang. K. Thai, M. Gravel, Org. Lett., 2009, 11, 891-893. A mechanistic investigation on the effect of substrate on stereoselectivity in the triflic acid-catalyzed allylboration reaction between 2-alkoxycarbonyl allylboronates and aldehydes confirms the involvement of a carbocation intermediate as the source of stereochemical inversion. This methodology allows a facile access to β,γ-disubstituted five-membered ring lactones. T. G. Elford, Y. Arimura, S. H. Yu, D. G. Hall, J. Org. Chem., 2007, 72, 1276-1284. T. G. Elford, Y. Arimura, S. H. Yu, D. G. Hall, J. Org. Chem., 2007, 72, 1276-1284. Depending on the strength of a Lewis or Brønsted acid catalyst, borate intermediates resulting from the crotylboration of aliphatic aldehydes with ester-containing crotylboronates form either γ-substituted-α-alkylidene-γ-butyrolactones via oxonia cope rearrangement-lactonization or β,γ-disubstituted-α-methylene-γ-butyrolactones via lactonization. P. V. Ramachandran, D. Pratihar, Org. Lett., 2007, 9, 2087-2090. P. V. Ramachandran, D. Pratihar, Org. Lett., 2007, 9, 2087-2090. The Reformatsky reaction of α-hydroxy ketones with indium enolates furnished highly diastereoselective lactones, while α-alkoxy ketones gave acyclic esters in moderate selectivities. A boat-type of chelated bicyclic transition state involving highly diastereoselective construction of three contiguous stereogenic centers is proposed. S. A. Babu, M. Yasuda, Y. Okabe, I. Shibata, A. Baba, Org. Lett., 2006, 8, 3029-3032. Treatment of 3-[(alkoxycarbonyl)alkyl]-substituted conjugated cycloalkenones with diisobutylaluminum hydride at -78 °C followed by acid quenching furnishes spiro ethers, whereas the corresponding 3-(carboxyalkyl)-substituted cycloalkenones generate spiro lactones upon reaction with sodium borohydride at 30 °C followed by acid quenching. M.-C. P. Yeh, Y.-C. Lee, T.-C. Young, Synthesis, 2006, 3621-3624. A mild, enantioselective hetero-Diels-Alder (HDA) reaction of the Brassard diene with aldehydes in the presence of a chiral titanium(IV) tridentate Schiff-base complexe has been developed. The mechanism is discussed. Q. Fan, L. Lin, J. Liu, Y. Huang, X. Feng, Eur. J. Org. Chem., 2005, 3542-3552. The Brønsted acid catalyzed formal insertion of an isocyanide into a C-O bond of various acyclic and cyclic acetals can be applied to form α-alkoxy imidates. Functional groups, such as nitro, cyano, halogen, ester, and alkoxy groups, are tolerant to the reaction conditions employed. The course of the reaction is highly dependent on the structure of the isocyanide. M. Tobisu, A. Kitajima, S. Yoshioka, I. Hyodo, M. Oshita, N. Chatani, J. Am. Chem. Soc., 2007, 129, 11431-11437. The synthesis of a planar-chiral bisflavin catalyst (1) and its use in asymmetric Bayer-Villiger-Oxidations is described. S. Murahashi, S. Ono, Y. Imada, Angew. Chem. Int. Ed., 2002, 41, 2366-2368. A quinine tethered Co(III)-salen complex promotes as a Lewis acid-Lewis base (LA*-LB*) bifunctional catalyst a rapid asymmetric [2+2] cycloaddition reaction between ketene and aldehydes to produce C4-substituted β-lactones in uniformly >99% ee and high isolated yields. S. Chidara, Y.-M. Lin, Synlett, 2009, 1675-1679. Chiral N-hetereocyclic carbenes are efficient catalysts for the formal [2 + 2] cycloaddition reactions of alkyl(aryl)ketenes with 2-oxoaldehydes to afford highly substituted β-lactones in high yields with good diastereoselectivities and excellent enantioselectivities. Both alkyl(aryl)ketenes and diarylketene worked well in this reaction. L. He, H. Lv, Y.-R. Zhang, S. Ye, J. Org. Chem., 2008, 73, 8101-8103. The regioselective opening of Bn2N-α-methylserine-β-lactone with organocuprates gave enantiopure α-methyl amino acids in excellent yields. N. D. Smith, A. M. Wohlrab, M. Goodman, Org. Lett., 2005, 7, 255-258. A new Pd-catalyzed oxidation reaction for the stereospecific conversion of enynes into cyclopropyl ketones proceeds with net inversion of geometry with respect to the starting olefin. This result is consistent with a mechanism in which the key cyclopropane-forming step involves nucleophilic attack of a tethered olefin onto the PdIV-C bond. L. L. Welbes, T. W. Lyons, K. A. Cychosz, M. S. Sanford, J. Am. Chem. Soc., 2007, 129, 5836-5837.