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Xanthone

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Xanthone
Skeletal formula
Ball-and-stick model
Names
Preferred IUPAC name
9H-Xanthen-9-one
Other names
9-Oxoxanthene
Diphenyline ketone oxide
Identifiers
3D model (JSmol)
140443
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.001.816 Edit this at Wikidata
EC Number
  • 201-997-7
166003
UNII
  • InChI=1S/C13H8O2/c14-13-9-5-1-3-7-11(9)15-12-8-4-2-6-10(12)13/h1-8H checkY
    Key: JNELGWHKGNBSMD-UHFFFAOYSA-N checkY
  • InChI=1/C13H8O2/c14-13-9-5-1-3-7-11(9)15-12-8-4-2-6-10(12)13/h1-8H
    Key: JNELGWHKGNBSMD-UHFFFAOYAA
  • O=C1c2ccccc2Oc3ccccc31
Properties
C13H8O2
Molar mass 196.205 g·mol−1
Appearance white solid
Melting point 174 °C (345 °F; 447 K)
Sl. sol. in hot water
-108.1·10−6 cm3/mol
Hazards
GHS labelling:[1]
GHS06: Toxic
Danger
H301
P264, P270, P301+P310, P321, P330, P405, P501
Related compounds
Related compounds
 xanthene
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Xanthone is an organic compound with the molecular formula C13H8O2. It is a white solid.

In 1939, xanthone was introduced as an insecticide and it currently finds uses as ovicide for codling moth eggs and as a larvicide.[2] Xanthone is also used in the preparation of xanthydrol, which is used in the determination of urea levels in the blood.[3] It can also be used as a photocatalyst.[4]

Synthesis

[edit]

Xanthone can be prepared by the heating of phenyl salicylate:[5]

Various other methods of synthesis given are:[5]

Derivatives

[edit]

Multiple methods have been reported for synthesizing xanthone derivatives:[6]

Xanthone derivatives

[edit]

Xanthone forms the core of a variety of natural products, such as mangostin or lichexanthone. These compounds are sometimes referred to as xanthones or xanthonoids. Over 200 natural xanthones have been identified. Many are phytochemicals found in plants in the families Bonnetiaceae, Clusiaceae, and Podostemaceae.[7] They are also found in some species of the genus Iris.[8] Some xanthones are found in the pericarp of the mangosteen fruit (Garcinia mangostana) as well as in the bark and timber of Mesua thwaitesii.[9]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Xanthone

View on Grokipedia
from Grokipedia
Xanthone, systematically named 9H-xanthen-9-one, is a heterocyclic organic compound with the molecular formula C₁₃H₈O₂, featuring a tricyclic aromatic structure composed of two benzene rings fused to a central pyrone ring.[1][2] This white solid serves as the parent scaffold for the xanthone class, which encompasses over 250 naturally occurring and synthetic derivatives characterized by variations in oxygenation, prenylation, and glycosylation.[3][4] Xanthones are widely distributed in nature, primarily as secondary metabolites in higher plants from families such as Gentianaceae, Clusiaceae, and Moraceae (over 100 species), as well as in fungi (19 species), lichens (5 species), and certain marine organisms.[4] Their biosynthesis proceeds via a mixed shikimate-acetate pathway, involving phenylalanine-derived m-hydroxybenzoic acid coupled with acetate units to form a benzophenone intermediate, followed by oxidative cyclization to yield the characteristic xanthone nucleus.[4] Notable examples include mangiferin, a C-glycosylated xanthone abundant in mangoes and mangosteens, and simple oxygenated variants like 1,3,5-trihydroxyxanthone.[5] Beyond their ecological roles, xanthones and their derivatives exhibit diverse pharmacological properties, including potent antioxidant, anti-inflammatory, antimicrobial, antifungal, anticancer, antidiabetic, and neuroprotective activities, attributed to their ability to modulate oxidative stress, inhibit enzymes like COX-2, and interfere with signaling pathways such as NF-κB.[3][2] Historically introduced as an insecticide in 1939, xanthone's core structure has inspired synthetic modifications for drug discovery, particularly in targeting kinase networks for cancer therapy and enhancing insulin sensitivity in diabetes management.[1][6][7] These attributes position xanthones as versatile lead compounds in medicinal chemistry, with ongoing research exploring their bioavailability and clinical potential.[8]

Properties

Physical properties

Xanthone has the molecular formula C₁₃H₈O₂ and a molar mass of 196.20 g/mol.[9] It appears as a white to off-white powder.[10] The compound melts at 172–174 °C.[9] Xanthone exhibits low solubility in water, with a log₁₀ water solubility value of -8.24, indicating it is practically insoluble at room temperature but slightly soluble in hot water.[11] It is soluble in organic solvents such as acetone, ethyl acetate, and toluene, with solubilities exceeding 12 mg/mL in acetone and ethyl acetate at ambient temperature; solubility in ethanol is lower at less than 4 mg/mL.[12] The crystal structure of xanthone consists of a planar tricyclic arrangement, featuring two benzene rings fused to a central pyrone ring containing an ether linkage and a ketone group.[12] This structure belongs to the monoclinic space group P2₁/c, with consistent packing observed across temperatures from 130 to 300 K.[12]

Chemical properties

Xanthone exhibits a tricyclic aromatic structure consisting of two fused benzene rings sharing a central pyrone ring, which imparts significant aromatic character to the molecule due to the delocalized π-electron system across the fused framework.[13] This aromaticity is evident in its planar conformation and contributes to its stability and reactivity patterns.[14] As a white solid, xanthone demonstrates high stability under standard laboratory conditions, remaining intact without decomposition at ambient temperatures and pressures.[15] It is incompatible with strong oxidizing agents, which can lead to oxidative degradation, but shows no significant reactivity under neutral or mildly acidic/basic environments.[15] Spectroscopic analysis provides key signatures for identification. In UV-Vis spectroscopy, xanthone displays characteristic absorption bands in the 240–320 nm and 350–420 nm regions, attributable to π-π* transitions within the conjugated aromatic system.[16] The IR spectrum features a prominent carbonyl stretching band at around 1660 cm⁻¹, indicative of the conjugated ketone in the pyrone ring.[17] In ¹H NMR spectroscopy (CDCl₃), the nine aromatic protons appear as multiplets between δ 7.35 and 8.32 ppm, reflecting the symmetric aromatic environment with typical ortho and meta couplings (J ≈ 7.9–8.0 Hz).[18] Xanthone undergoes electrophilic aromatic substitution primarily at positions 2 and 4 (or equivalently 7 due to symmetry), as these are activated by the ether oxygen despite the electron-withdrawing carbonyl.[13] For instance, nitration under mild conditions yields predominantly 2-nitroxanthone.[19]

Synthesis

Classical methods

One of the earliest and simplest classical methods for synthesizing xanthone involves the thermal cyclization of phenyl salicylate (also known as salol). In this approach, phenyl salicylate is heated to temperatures between 275–355°C, leading to the elimination of phenol and formation of the xanthone core through an intramolecular Fries rearrangement-like mechanism. This process, detailed in early organic synthesis procedures, typically yields xanthone in 61–63% after distillation and purification steps such as treatment with sodium hydroxide and methanol recrystallization.[20] Another significant classical route, developed by Grover, Shah, and Shah in 1955, utilizes the condensation of a salicylic acid derivative with a suitable phenol to form an o-hydroxybenzophenone intermediate, followed by cyclodehydration to yield hydroxyxanthones. The reaction employs zinc chloride as a catalyst and phosphoryl chloride as the solvent, with heating to facilitate the initial condensation; cyclization proceeds efficiently if an additional hydroxyl group is positioned ortho to the carbonyl in the benzophenone, enabling direct formation of the xanthone skeleton in moderate to good yields depending on substituents.[21][22] These methods gained industrial relevance in the early 1940s when xanthone was prepared on a larger scale for use as an ovicide and larvicide against the codling moth (Cydia pomonella), with preliminary evaluations confirming its efficacy in disrupting egg hatch and larval development. Despite their historical importance, classical xanthone syntheses suffer from limitations including moderate yields (often below 70%), requirement for harsh conditions such as high temperatures or corrosive reagents like phosphoryl chloride, and challenges in scalability due to side reactions and purification demands.[20][21]

Modern methods

Since the mid-20th century, synthetic strategies for xanthone have evolved toward catalytic processes that enhance yield, reduce waste, and enable scalability, often incorporating transition metals and alternative energy sources. Palladium-catalyzed cross-coupling reactions represent a key advancement, allowing for the construction of the xanthone core through sequential bond formations. A carbonylative Suzuki-Miyaura coupling in a one-pot fashion from iodophenols and (2-methoxyphenyl)boronic acids yields xanthones with up to 95% efficiency using a pincer Pd complex as catalyst and a CO surrogate.[23] This method's efficiency stems from the orthogonal reactivity of the coupling and cyclization steps, minimizing side products and enabling late-stage diversification. Oxidative cyclization of 2-phenylphenol derivatives has also gained prominence, utilizing metal catalysts to facilitate dehydrogenative aromatization. Palladium-catalyzed oxidative double C-H functionalization/carbonylation of diaryl ethers or biphenyls, for example, directly assembles the xanthone framework by sequential C-H activation and CO insertion, achieving yields of 50–90% with Pd(OAc)2, oxidants like Cu(OAc)2 or O2, and additives such as Ag2CO3 in solvents like DMF at 120°C.[24] One-pot methods have streamlined classical condensations, notably through microwave-assisted protocols that accelerate reaction rates and boost yields. The condensation of salicylic acid with phenols under acidic conditions, enhanced by microwave irradiation (300–800 W for 5–15 min), using Lewis acids like SnCl2·2H2O in neat conditions or polyphosphoric acid, delivers polyhydroxylated xanthones in 70–90% yields, far surpassing conventional heating (which often requires hours and yields <50%).[25] This technique's rapidity and solvent-free nature align with green chemistry principles, allowing scalable preparation of derivatives without isolation of intermediates. Post-2000 advancements incorporate photoredox catalysis for selective functionalization and core assembly, leveraging visible light to drive radical pathways. Metal-free photoredox oxidation of 9H-xanthenes using riboflavin tetraacetate under blue LED irradiation (with O2 as oxidant in acetonitrile at room temperature) converts the central CH2 to carbonyl, yielding xanthones in 60–99% efficiency while enabling precise control over substitution patterns.[26] Visible-light-promoted, transition-metal-free photoredox catalysis has also been applied to the intramolecular cyclization of precursors for thioxanthone synthesis, providing high regioselectivity (yields up to 80%) with minimal byproducts; this approach is adaptable to xanthone scaffolds.[27] These light-driven methods reduce energy input and catalyst loading, marking a shift toward sustainable synthesis. Recent advancements as of 2024 emphasize catalytic green methods for xanthone synthesis, transitioning from stoichiometric reagents to more efficient catalytic processes.[28]

Occurrence and derivatives

Natural occurrence

Xanthones occur naturally in higher plants, predominantly within the families Clusiaceae, Bonnetiaceae, Podostemaceae, Gentianaceae, and Moraceae (over 100 species).[29] A prominent example is the mangosteen fruit (Garcinia mangostana) from the Clusiaceae family, where xanthones accumulate in the pericarp.[29] Over 600 xanthone-based natural products have been identified across these and other sources.[30] Xanthones are also found in fungi, with approximately 19 species reported, particularly in genera such as Aspergillus, Penicillium, and Emericella.[2] In marine organisms, xanthones have been isolated from marine-derived fungi associated with sponges, algae, and bacteria, including examples like those from Aspergillus species in marine environments.[31] The parent xanthone scaffold is also present in lichens, often as lichexanthone (1-hydroxy-3,6-dimethoxy-8-methylxanthone), a key compound in species such as Pyxine consocians and Heterodermia leucomelos.[32] More than 100 xanthones, including lichexanthone derivatives, have been isolated from lichens overall.[32] In plants, xanthone biosynthesis proceeds via the shikimate pathway, which supplies benzoyl-CoA, combined with malonyl-CoA from the acetate pathway to form benzophenone intermediates through benzophenone synthase activity.[33] These intermediates undergo polyketide cyclization, often regioselective oxidative coupling, to yield the core xanthone structure, such as 1,3,5-trihydroxyxanthone.[33] Xanthones serve ecological roles as defense metabolites in plants, protecting against microbial pathogens and herbivores.[34] For instance, in Hypericum perforatum, they inhibit fungal pathogens like Phomopsis obscurans and exhibit antimicrobial activity enhanced by elicitors.[34] They also deter herbivory, as seen in Chionochloa species where xanthones reduce grazing by ruminants.[34]

Derivatives

Xanthone derivatives constitute a diverse class of compounds, with over 600 naturally occurring variants identified and classified primarily by their substitution patterns, including simple oxygenated, glycosylated, prenylated, and miscellaneous forms.[30] These derivatives arise through modifications to the core xanthone scaffold, influencing their chemical properties and biological roles. Synthetic derivatives further expand this family, often designed to enhance specific activities. Among natural derivatives, prenylated xanthones represent a prominent subclass. α-Mangostin, a prenylated xanthone isolated from the mangosteen fruit (Garcinia mangostana), exhibits notable antioxidant properties by modulating oxidative stress pathways, such as Nrf2 activation in inflamed macrophages.[35] Lichexanthone, a lichen pigment characterized by a 1-hydroxy-3,6-dimethoxy-8-methyl-9H-xanthen-9-one structure, is produced via the polyacetate pathway in lichenized fungi and contributes to the yellow pigmentation observed in species like Pyxine consocians.[32] Gentisein, a trihydroxyxanthone (1,3,7-trihydroxy-9H-xanthen-9-one), occurs in plants of the Gentiana genus, such as Gentiana lutea, and is biosynthesized from acetate-shikimate precursors through oxidative coupling of benzophenone intermediates.[36] Synthetic derivatives include reduced and halogenated analogs tailored for analytical and therapeutic applications. Xanthydrol, the 9-hydroxy-reduced form of xanthone, serves as a reagent in colorimetric assays for urea quantification in biological fluids due to its reactivity with urea to form a colored complex.[37] Halogenated xanthones, such as 6-chloro-1-hydroxy-7-methyl-9H-xanthen-9-one, demonstrate enhanced bioactivity, including inhibition of aromatase in breast cancer cell lines (IC50 = 50 μM against MCF-7 cells), attributed to improved interactions with enzyme active sites.[38] Key structural variations in xanthone derivatives involve modifications at positions 1–8 on the tricyclic core, which modulate lipophilicity and reactivity. Prenylation, often at positions 2 or 3, introduces isoprenoid chains that increase lipophilicity, facilitating membrane permeation and enhancing bioavailability, as seen in α-mangostin.[39] Glycosylation, typically at hydroxyl groups in positions 1, 3, or 7, improves water solubility and stability, exemplified by O-glycosides like rutinosylxanthone. Halogenation at positions 5–8, such as chlorination, alters electron density and steric properties, boosting reactivity toward biological targets like enzymes.[40] These modifications collectively enable tailored functionalities while preserving the core's planar aromatic system.

Applications

Insecticidal uses

Xanthone was introduced as an insecticide in the late 1930s, specifically as an ovicidal and larvicidal agent targeting the codling moth (Cydia pomonella) in apple orchards.[41] Field trials conducted in Washington state demonstrated its effectiveness, achieving 94.9% to 98.4% clean fruit (U.S. No. 1 grade) when applied as cover sprays following lead arsenate treatments, outperforming traditional arsenicals in residue safety and plant compatibility.[41] Preliminary laboratory and orchard studies from 1940–1941 reported ovicidal activity of 33.7% against deposited eggs and larvicidal efficiencies ranging from 12% to 69%, depending on concentration and application timing.[42] The primary mechanism of xanthone's insecticidal action involves functioning as a stomach poison, ingested by larvae feeding on treated foliage or fruit surfaces, leading to mortality without significant phytotoxicity or human health risks at applied rates.[41] While specific LD50 values for codling moth larvae were not detailed in early investigations, toxicity assays indicated rapid larval death within 10 days at concentrations as low as those yielding 77% mortality in controlled settings.[41] Certain xanthone derivatives, such as α-mangostin isolated from the mangosteen pericarp (Garcinia mangostana), exhibit enhanced insecticidal activity against agricultural and vector pests. α-Mangostin inhibits mosquito sterol carrier protein-2, disrupting lipid transport essential for development, with an LC50 of 2.2–2.5 μg/ml (95% CI: 1.9–2.7 μg/ml) for third-instar Aedes aegypti larvae, demonstrating greater potency than parent xanthone.[43] Xanthone use declined significantly as an agricultural agent following the introduction of more effective synthetic insecticides in the mid-20th century. Recent research has sparked a resurgence in interest for xanthone derivatives in eco-friendly pest management, leveraging their targeted toxicity and low environmental persistence to address resistance and non-target impacts in integrated systems.[44]

Other applications

In analytical chemistry, xanthydrol, a derivative of xanthone, serves as a reagent for the colorimetric determination of urea in biological samples such as blood. The method involves the reaction of urea with xanthydrol under acidic conditions to form a colored complex, typically pink-red, which is quantified spectrophotometrically at around 520 nm, enabling microdetermination with high sensitivity for clinical diagnostics.[45][46] Natural xanthone derivatives, such as α-mangostin isolated from the mangosteen fruit (Garcinia mangostana), exhibit significant biological activities beyond pest control. These compounds demonstrate potent antioxidant effects by enhancing superoxide dismutase activity and reducing reactive oxygen species levels in cellular models of oxidative stress.[47] Additionally, α-mangostin displays anti-inflammatory properties through suppression of pro-inflammatory cytokines like TNF-α and IL-6, as well as inhibition of key pathways such as NF-κB and MAPK in macrophages and intestinal cells.[48] In potential cancer therapies, α-mangostin inhibits COX-2 expression and activity, promoting apoptosis in colon and hepatocellular carcinoma cells while attenuating tumor progression in animal models at doses of 10–30 μM in vitro and 30 mg/kg in vivo.[49] Xanthone functions as an effective photosensitizer in organic synthesis, particularly for facilitating C-H bond activation under UV irradiation. In nickel-catalyzed photoredox reactions, xanthone absorbs UV light to generate triplet excited states, enabling hydrogen atom transfer (HAT) that activates benzylic C(sp³)-H bonds for carboxylation with CO₂, achieving yields up to 80% under mild conditions without additional reductants. This approach has been applied to functionalize various alkylarenes, highlighting xanthone's role in sustainable, metal-mediated photocatalytic transformations.[50] Emerging applications of xanthone and its derivatives span bioimaging and materials science. Modified sulfone-xanthone chromophores have been engineered as fluorescent probes with enhanced Stokes shifts (>4000 cm⁻¹) and near-infrared emission (>700 nm), enabling tumor-targeted imaging in hepatocellular carcinoma models via conjugation to peptides like LS301, with quantum yields up to 17% in physiological buffers for real-time surgical navigation.[51] In textiles, derivatives such as euxanthone serve as natural yellow colorants, providing vibrant hues and fluorescence for dyeing fabrics, with synthetic yields optimized to 69–74% for scalable production.[52] Safety profiles indicate low toxicity at therapeutic or applied doses; for instance, xanthone exhibits an LD₅₀ >2000 mg/kg in rodent models, classifying it as non-toxic for low-dose exposures in bioimaging and dyeing contexts per PubChem data.[1]

References

  1. Xanthone | C13H8O2 | CID 7020 - PubChem - NIH
  2. Naturally Occurring Xanthones and Their Biological Implications - NIH
  3. Xanthones, A Promising Anti-Inflammatory Scaffold - PMC - NIH
  4. (PDF) Naturally Occurring Xanthones: Chemistry and Biology
  5. Biological Activities and Bioavailability of Mangosteen Xanthones
  6. focus on kinase target network and biomedical properties - Frontiers
  7. Exploring the therapeutic potential of xanthones in diabetes ...
  8. Bioavailability and Antioxidant Effects of a Xanthone-Rich ...
  9. Xanthone 97 90-47-1
  10. https://www.medchemexpress.com/xanthone-standard.html
  11. Xanthone (CAS 90-47-1) - Chemical & Physical Properties by Cheméo
  12. Elucidating the Polymorphism of Xanthone: A Crystallization and ...
  13. Xanthone - an overview | ScienceDirect Topics
  14. Xanthone (C13H8O2) properties
  15. Xanthone | 90-47-1
  16. Cytotoxic Prenylated Xanthones from the Pericarps of Garcinia ...
  17. 974. Oxidative Coupling. Part VI? Synthesis of Xanthones.
  18. Xanthone(90-47-1) 1H NMR spectrum - ChemicalBook
  19. xanthone - Organic Syntheses Procedure
  20. https://doi.org/10.1039/JR9550003982
  21. [PDF] Synthesis of Xanthones: An Overview - Sigarra
  22. One‐Pot Synthesis of Xanthone by Carbonylative Suzuki Coupling ...
  23. Palladium-catalyzed oxidative double C-H functionalization ...
  24. Hypervalent iodine reagent-mediated reactions involving ...
  25. An efficient and convenient microwave-assisted chemical synthesis ...
  26. Synthesis of Xanthones, Thioxanthones and Acridones by a Metal ...
  27. Photoredox Catalysis with Visible Light for Synthesis of ...
  28. A Review of the Influence of Various Extraction Techniques ... - PMC
  29. Xanthones of Lichen Source: A 2016 Update - PMC - PubMed Central
  30. Xanthone Biosynthetic Pathway in Plants: A Review - PubMed Central
  31. Xanthones: Biosynthesis and Trafficking in Plants, Fungi and Lichens
  32. Xanthone Biosynthetic Pathway in Plants: A Review - Frontiers
  33. Natural and Synthetic Xanthone Derivatives Counteract Oxidative ...
  34. Biogenesis of xanthones in Gentiana lutea - RSC Publishing
  35. Anti-Bacterial and Anti-Fungal Activity of Xanthones Obtained ... - NIH
  36. One-pot two-component synthesis of halogenated xanthone, 3-o ...
  37. An Update on the Anticancer Activity of Xanthone Derivatives - MDPI
  38. Modular Synthesis of Halogenated Xanthones by a Divergent ...
  39. US2347377A - Organic insecticide - Google Patents
  40. Xanthone as an Ovicide and Larvicide for the Codling Moth
  41. The Biological Activity of α-Mangostin, a Larvicidal Botanic Mosquito ...
  42. Organophosphorus Compounds at 80: Some Old and New Issues
  43. Isolation, Biosynthesis, and Biological Activity of Polycyclic ... - NIH
  44. The colorimetric microdetermination of urea nitrogen by ... - PubMed
  45. https://doi.org/10.1016/j.trac.2023.117345
  46. https://doi.org/10.1021/jf052649z
  47. α-Mangostin Is a Xanthone Derivative from Mangosteen with Potent ...
  48. https://doi.org/10.3748/wjg.v17.i16.2086
  49. https://doi.org/10.1039/D4RA06475E
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