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Lactone
Lactone
Lactone
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Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated.[1]

Lactones are formed by lactonization, the intramolecular esterification of the corresponding hydroxycarboxylic acids.[2]

Nomenclature

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Greek prefixes in alphabetical order indicate ring size.

Ring size
(number of atoms
in the ring) 		Systematic name IUPAC name Parent lactone Structure, comment
3 α-lactone Oxiran-2-one Acetolactone
4 β-lactone Oxetan-2-one
  • β-Propiolactone
  • Propiolactone
5 γ-lactone Oxolan-2-one γ-Butyrolactone
6 δ-lactone Oxan-2-one
7 ε-lactone Oxepan-2-one
  • ε-Caprolactone
  • Caprolactone
  • Hexanolide

Lactones are usually named according to the precursor acid molecule (aceto = 2 carbon atoms, propio = 3, butyro = 4, valero = 5, capro = 6, etc.), with a -lactone suffix and a Greek letter prefix that specifies the number of carbon atoms in the heterocycle — 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, δ-lactone = 6-membered, etc. Macrocyclic lactones are known as macrolactones.[3]

Look up macrolactone in Wiktionary, the free dictionary.

The other suffix used to denote a lactone is -olide, used in substance class names like butenolide, macrolide, cardenolide or bufadienolide.

To obtain the preferred IUPAC names, lactones are named as heterocyclic pseudoketones by adding the suffix 'one', 'dione', 'thione', etc. and the appropriate multiplicative prefixes to the name of the heterocyclic parent hydride.[4]

Etymology

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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). The name was coined in 1844 by the French chemist Théophile-Jules Pelouze, who first obtained it as a derivative of lactic acid.[5] An internal dehydration reaction within the same molecule of lactic acid would have produced alpha-propiolactone, a lactone with a 3-membered ring.

In 1880 the German chemist Wilhelm Rudolph Fittig extended the name "lactone" to all intramolecular carboxylic esters.[6]

Occurrence

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D-glucono-δ-lactone (E575)

Lactone rings occur widely as building blocks in nature, such as in ascorbic acid, kavain, nepetalactone, gluconolactone, hormones (spironolactone, mevalonolactone), enzymes (lactonase), neurotransmitters (butyrolactone, avermectins), antibiotics (macrolides like erythromycin; amphotericin B), anticancer drugs (vernolepin, epothilones), phytoestrogens (resorcylic acid lactones, cardiac glycosides).

5-Membered γ-lactones and 6-membered δ-lactones are prevalent. β-lactones appear in a number of natural products.[7] α‑Lactones can be detected as transient species in mass spectrometry experiments.[8]

Macrocyclic lactones are also important natural products.[9] Lactones are present in oak wood, and they contribute to the flavour profile of barrel-aged beers.[10]

Synthesis

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Oxandrolone synthesis

Many methods in ester synthesis can also be applied to that of lactones. Lactonization competes with polymerization for longer hydroxy acids, or the strained β‑lactones. γ‑Lactones, on the other hand, are so stable that 4-hydroxy acids (R-CH(OH)-(CH2)2-CO2H) spontaneously cyclize.

In one industrial synthesis of oxandrolone the key lactone-forming step is an organic reaction – esterification.[11][12]

iodolactonization

In halolactonization, an alkene is attacked by a halogen via electrophilic addition with the cationic intermediate captured intramolecularly by an adjacent carboxylic acid.[13]

Specific methods include Yamaguchi esterification, Shiina macrolactonization, Corey-Nicolaou macrolactonization, Baeyer–Villiger oxidation and nucleophilic abstraction.

γ-Lactone synthesis from fatty alcohols and acrylic acid

An alternative radical reaction yielding γ-lactones is the manganese-mediated coupling.

Reactions

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Lactones exhibit the reactions characteristic of esters.

Hydrolysis and aminolysis

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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 gives only a single product.

Lactones also react with amines to give the ring-opened alcohol and amide.

Reduction

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Lactones can be reduced to diols using lithium aluminium hydride. For instance, gamma-lactones is reduced to butane-1,4-diol, (CH2(OH)-(CH2)2-CH2(OH).

Polymerization

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Some lactones convert to polyesters:[14][15] For example the double lactone called lactide polymerizes to polylactic acid (polylactide). The resulting polylactic acid has been heavily investigated for commercial applications.[16][17]

Uses

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Flavors and fragrances

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Lactones contribute significantly to the flavor of fruit, and of unfermented and fermented dairy products,[18] and are therefore used as flavors and fragrances.[9] Some examples are γ-decalactone (4-decanolide), which has a characteristic peach flavor;[18] δ-decalactone (5-decanolide), which has a creamy coconut/peach flavour; γ-dodecalactone (4-dodecanolide), which also has a coconut/fruity flavor,[18] a description which also fits γ-octalactone (4-octanolide),[19] although it also has a herbaceous character;[18] γ-nonalactone, which has an intense coconut flavor of this series, despite not occurring in coconut,[20] and γ-undecalactone.

Macrocyclic lactones (cyclopentadecanolide, 15-pentadec-11/12-enolide) have odors similar to macrocyclic ketones of animal origin (muscone, civetone).[9]

Plastics

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Polycaprolactone is an important plastic. Its formation has even been considered in the context of the origin of life.[21]

Dilactones

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See also

[edit]
Look up lactone in Wiktionary, the free dictionary.

References and notes

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Lactone

View on Grokipedia
from Grokipedia
A lactone is a cyclic derived from the intramolecular reaction of a hydroxy , where the hydroxyl group reacts with the group to form a ring containing the linkage, eliminating in the process. These compounds are characterized by their ring structure, in which the functional group is integrated into the cycle, typically involving 4 to over 20 atoms, though smaller rings like β-lactones (four-membered) are less stable and larger macrolactones are common in natural products. Lactones exhibit diverse physical properties, including low volatility and characteristic odors, and are named according to the position of the hydroxy group relative to the , such as γ-lactones for five-membered rings and δ-lactones for six-membered rings, which are the most prevalent due to favorable and stability. Lactones occur widely in , contributing to the flavors and aromas of fruits, products, and essential oils, where they impart fruity, coconut-like, or peachy notes through their volatile structures. In , many natural lactones, such as lactones and macrocyclic variants, exhibit potent bioactivities including antibacterial, antiviral, , , and antitumor effects, often serving as plant defense compounds or prodrugs in pharmaceuticals like statins, which are lactone forms that hydrolyze to active hydroxy acids in vivo. Synthetic lactones, meanwhile, play key roles in ; for instance, ε-caprolactone undergoes to produce , a biodegradable used in , systems, and medical implants due to its and mechanical properties. Beyond these applications, lactones are valuable synthetic intermediates in , enabling the construction of complex molecules through , reduction, or ring-opening reactions, and their thermodynamic properties—such as enthalpies of formation and —have been extensively studied to understand strain energies in rings from C4 to C13. Commercially, they find use in fragrances, food additives, and agrochemicals, underscoring their versatility across industries while highlighting the need for careful handling of certain types due to potential or .

Fundamentals

Structure and Properties

Lactones are cyclic esters formed by the intramolecular esterification of hydroxycarboxylic acids, where the hydroxyl group reacts with the carboxylic acid group to eliminate water and form a closed ring structure. This cyclization typically occurs when the hydroxy and carboxy groups are positioned to form rings of 3 to 7 members, with the general connectivity involving an ester linkage (-O-C(=O)-) integrated into the cyclic framework. The molecular structure of lactones varies by ring size, influencing their stability and reactivity. For instance, γ-lactones, which feature a five-membered ring, have the general represented as a cycle with the sequence −O−C(=O)−CH2−CH2−CH2−-O-C(=O)-CH_2-CH_2-CH_2-, where the oxygen bridges the carbonyl carbon and the γ-carbon. plays a critical role: α-lactones (3-membered rings) and β-lactones (4-membered rings) exhibit high strain energies, approximately 85-87 kJ/mol greater for α- than β-lactones and around 22.8 kcal/mol for β-lactones, rendering them reactive transients rarely isolated under standard conditions. In contrast, γ-lactones (5-membered) and δ-lactones (6-membered) possess lower , making them thermodynamically stable and common in natural and synthetic contexts. Physically, lactones are typically colorless liquids or solids with boiling points elevated relative to analogous acyclic esters due to their cyclic nature; for example, γ-butyrolactone (a γ-lactone) boils at 204°C and is miscible with and most organic solvents. Similarly, δ-valerolactone (a δ-lactone) exhibits a of 230 °C and good solubility in polar solvents. In (IR) spectroscopy, the carbonyl (C=O) stretching frequency serves as a diagnostic feature, appearing at higher wavenumbers for smaller rings due to strain-induced s-character increase in the carbonyl carbon: approximately 1730-1750 cm⁻¹ for δ-lactones and up to 1770 cm⁻¹ for γ-lactones. Chemically, lactones display hydrolytic sensitivity that correlates inversely with ring size and directly with strain; smaller α- and β-lactones undergo rapid under mild conditions due to the energetic favorability of strain relief, while γ- and δ-lactones require harsher acidic or basic environments for ring opening. This reactivity stems from the strained ester bond, which facilitates nucleophilic attack at the carbonyl carbon, ultimately yielding the parent hydroxycarboxylic acid.

Classification and Nomenclature

Lactones are classified primarily according to the size of the cyclic ring formed by intramolecular esterification of hydroxy s. The most common uses Greek letter prefixes to denote the position of the hydroxyl group relative to the in the parent chain, which corresponds to specific ring sizes: α-lactones feature a three-membered ring, β-lactones a four-membered ring, γ-lactones a five-membered ring, δ-lactones a six-membered ring, and ε-lactones a seven-membered ring. Larger rings, typically those with more than twelve members, are designated as macrolactones and are often found in complex natural products. For smaller lactones, the Greek prefix system (α-, β-, γ-, etc.) remains widely used in both common and systematic nomenclature to indicate ring size and strain characteristics. In contrast, larger lactones are generally named using heterocyclic nomenclature, treating the ring as a substituted oxacycloalkane with the ester functionality incorporated. According to IUPAC recommendations, preferred names for lactones are derived by naming them as heterocyclic compounds with a , using suffixes such as "-one" for the lactone moiety. For example, γ-butyrolactone is systematically named oxolan-2-one, reflecting its five-membered ring with oxygen at position 1 and the carbonyl at position 2. This substitutive nomenclature prioritizes the heterocyclic parent structure and is applicable to both saturated and unsaturated variants. The term "lactone" was coined in 1844 by French chemist Théophile-Jules Pelouze, derived from "" combined with the suffix "-one" to describe the cyclic obtained from its . In 1880, German chemist Wilhelm Rudolf Fittig broadened the term to encompass all cyclic esters of hydroxy acids, formalizing its general application. Lactones were first recognized as a distinct class of compounds in the early through isolation from natural products, such as from tonka beans in 1820, which exemplified the δ-lactone structure fused to a ring. This period marked the initial structural elucidation of cyclic esters amid broader advances in from plant-derived substances.

Occurrence and Biological Significance

Natural Sources

Lactones are ubiquitous in nature, occurring across various organisms and contributing to diverse ecological and sensory roles. In plants, particularly those in the Asteraceae family, sesquiterpene lactones represent a major class of secondary metabolites, with over 5,000 distinct structures identified. These compounds are biosynthesized from farnesyl pyrophosphate and feature a characteristic α-methylene-γ-lactone moiety. A prominent example is artemisinin, a sesquiterpene lactone isolated from the leaves of sweet wormwood (Artemisia annua), used traditionally in herbal medicine. In animals and microorganisms, lactones appear in bioactive compounds essential for defense and . antibiotics, such as erythromycin produced by the bacterium Saccharopolyspora erythraea, contain a large 14-membered macrocyclic lactone ring attached to deoxy sugars, enabling their antibacterial properties. Similarly, glucono-δ-lactone, a six-membered lactone derived from glucose oxidation, is naturally produced by fungi like through enzymatic and occurs in trace amounts in , fruit juices, and wine. Lactones also impart characteristic flavors to food and beverages, enhancing sensory appeal. For instance, γ-decalactone, a five-membered lactone, is a key in peaches and strawberries, contributing peachy and fruity notes at concentrations up to several parts per million. In dairy products, δ-decalactone, its six-membered , provides a creamy, coconut-like flavor to , where it forms via β-oxidation of hydroxy fatty acids during processing. Beyond these, lactones feature in other natural products with unique functions. Ascorbic acid (), found in fruits and leafy greens, is a furanoid lactone essential for , biosynthesized in and most animals via the conversion of L-galactono-1,4-lactone. , a bicyclic lactone comprising up to 99% of ( cataria) essential , acts as an and feline attractant. The of lactones in typically involves enzymatic lactonization, where hydroxyl groups react with carboxylic acids under by lipoxygenases, P450s, or Baeyer-Villiger monooxygenases to form cyclic esters. This process, often part of or pathways, enables the structural diversity observed in natural lactones.

Biological Roles

Lactones play diverse roles in plant defense mechanisms, particularly sesquiterpene lactones, which serve as allelochemicals to deter herbivores and . These compounds, prevalent in the family, exhibit potent anti-herbivory activity by disrupting insect development, reproduction, and feeding behavior, thereby enhancing survival in herbivore-rich environments. For instance, sesquiterpene lactones like costunolide and parthenolide inhibit microbial growth by alkylating sulfhydryl groups in enzymes and disrupting cell walls, contributing to allelopathic effects that suppress competing and invading microbes. This defensive function is evolutionarily significant, as evidenced by the stereochemical variations in lactone ring junctions that modulate resistance levels against specific herbivores. In microbial interactions, γ- and δ-lactones demonstrate broad activity, primarily by disrupting bacterial cell membranes and inhibiting essential biosynthetic pathways. These smaller ring lactones interact with phospholipids in the , increasing permeability and leading to leakage of cellular contents, which compromises bacterial viability. A notable example is , a γ-lactone produced by species, which exhibits antibacterial properties against Gram-positive and , historically utilized in the 1960s for treating infections due to its ability to inhibit microbial proliferation. Such activities highlight lactones' ecological role in fungal-bacterial competition within natural environments. Sesquiterpene lactones also mediate anti-inflammatory and cytotoxic effects in biological systems through targeted inhibition of the NF-κB signaling pathway, a key regulator of immune responses. Compounds like helenalin directly alkylate the p65 subunit of NF-κB via Michael addition at the α-methylene-γ-lactone moiety, preventing DNA binding and transcriptional activation without affecting IκB degradation or nuclear translocation. This selective inhibition reduces pro-inflammatory cytokine production, as demonstrated in various cell types stimulated by TNF-α or other inducers, underscoring the lactones' potential in modulating inflammation. Similarly, parthenolide exhibits comparable NF-κB suppression, contributing to cytotoxic effects against aberrant cells by halting survival signaling. Beyond defense, lactones function in interspecies signaling, exemplified by , a lactone from (Nepeta cataria), which acts as a potent attractant for domestic cats by mimicking feline pheromones and eliciting euphoric behaviors in responsive individuals. In , various lactones serve as pheromones to coordinate social and reproductive activities; for example, unsaturated γ-lactones like buibuilactone function as sex attractants in scarab beetles, while macrocyclic lactones regulate queen-worker interactions in primitively eusocial wasps by suppressing ovarian development in subordinates. These signaling roles facilitate chemical communication essential for species-specific behaviors. In human physiology, endogenous lactones arise from , particularly through the lactonization of hydroxy fatty acids during β-oxidation processes. Enzymes such as serum paraoxonase 1 (PON1) catalyze the formation of lactones from substrates like 4-hydroxydocosahexaenoic acid (4-HDoHE), an oxidation product of , accounting for a significant portion of plasma lactonizing activity under calcium-dependent conditions. These metabolites influence homeostasis and may modulate inflammatory responses, linking lactone formation to broader metabolic regulation in health and disease.

Synthesis

Classical Methods

One of the most traditional approaches to lactone synthesis is the acid-catalyzed lactonization of hydroxy acids, where the hydroxyl group intramolecularly attacks the protonated , leading to and ring closure. This method, established in the late 19th and early 20th centuries, is particularly favorable for forming γ- and δ-lactones due to the stability of five- and six-membered rings, with reaction rates increasing dramatically for smaller rings compared to larger ones. For instance, γ-hydroxybutyric acid undergoes cyclization in the presence of concentrated or to yield γ-butyrolactone in high yields, often under heating to drive off water. The general reaction can be represented as: R-CH(OH)-(CH2)n-COOH→H+lactone + H2O\text{R-CH(OH)-(CH}_2)_n\text{-COOH} \xrightarrow{\text{H}^+} \text{lactone + H}_2\text{O}
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