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Quinoline

Quinoline is a heterocyclic aromatic organic compound with the molecular formula C₉H₇N, consisting of a benzene ring fused to a pyridine ring at the 2,3-positions of the pyridine.^[1] It was first isolated from coal tar in 1834 by German chemist Friedlieb Ferdinand Runge (initially named leukol). The name "quinoline" was introduced in 1842 by Charles Frédéric Gerhardt, who obtained it by distilling quinine with potassium hydroxide, due to its relation to quinine.^[2]^[3] Quinoline appears as a colorless, hygroscopic liquid that darkens upon exposure to light, with a melting point of -15.6 °C, a boiling point of 237.7 °C, a density of 1.095 g/cm³ at 20 °C, and limited solubility in water (6.11 mg/mL at 25 °C).^[1] As a weak tertiary base with a pKa of approximately 4.90, it exhibits basic properties similar to pyridine and is miscible with most organic solvents.^[1] Industrially, quinoline is primarily obtained from coal tar distillation, where it constitutes about 0.4% of the high-boiling fraction, or synthesized via methods such as the Skraup reaction, which involves the condensation of aniline with glycerol in the presence of sulfuric acid and an oxidizing agent like nitrobenzene.^[1] Quinoline and its derivatives are widely used as intermediates in the production of pharmaceuticals, dyes, and agrochemicals, with notable applications in antimalarial drugs such as chloroquine and primaquine, which incorporate the quinoline scaffold for their therapeutic efficacy.^[4] It also functions as a corrosion inhibitor in industrial processes and as a flavoring agent in certain foods, though its direct use is limited due to toxicity concerns.^[1] Naturally occurring in sources like coal tar, cigarette smoke, and certain plants, quinoline exhibits biological activities including antimalarial, antibacterial, and anticancer properties in derivatized forms, but it is classified as a possible human carcinogen (IARC Group 2B) with an oral LD50 of 331 mg/kg in rats.^[1]

Structure and Properties

Molecular Structure

Quinoline has the molecular formula C₉H₇N, consisting of a benzene ring fused to a pyridine ring at the b-position (between carbons 2 and 3 of the pyridine ring).^[1] This fused heterocyclic arrangement forms a bicyclic system with 10 π electrons delocalized across both rings, conferring aromatic character; the nitrogen atom in the pyridine portion contributes one π electron to the system via its p orbital, while its lone pair occupies an sp² hybrid orbital in the molecular plane, avoiding disruption of the aromatic sextet in the pyridine ring.^[5] The molecule is strictly planar, as evidenced by its conjugated π system and computational geometries, which show all atoms lying in a single plane to maximize orbital overlap.^[6] Density functional theory (DFT) optimizations at the B3LYP/6-31G(d,p) level yield representative bond lengths indicative of this delocalization, such as C–N bonds ranging from 1.318 Å (pyridine-like) to 1.367 Å and C–C bonds from 1.374 Å to 1.432 Å, with bond angles near 120° (e.g., 117.5°–123.0° around the rings), consistent with sp² hybridization and aromatic bonding.^[6] The systematic IUPAC name is 1-benzazine, reflecting its structure as a benzene ring fused to azine (pyridine); the conventional numbering starts at the heteroatom (nitrogen as position 1), proceeds along the pyridine ring to position 4, shares the fusion bond at 4a–8a, and continues through the benzene ring to position 8.^[7] Quinoline is stable in its neutral form, exhibiting no significant tautomerism, in contrast to hydroxyquinoline derivatives where keto-enol equilibria can occur; the parent structure lacks migratable hydrogens adjacent to the nitrogen for such transformations.^[1]

Physical Properties

Quinoline appears as a colorless, hygroscopic liquid with a pungent, penetrating odor that darkens to yellow or brown upon exposure to light or air.^[8] It boils at 237.4 °C and melts at -15.6 °C, with a density of 1.095 g/cm³ at 25 °C.^[1] These properties reflect its behavior as a stable, volatile liquid under standard conditions, suitable for use in organic synthesis and as a solvent.^[9] Quinoline is miscible with common organic solvents, including ethanol, diethyl ether, acetone, and benzene, facilitating its dissolution in nonpolar media.^[1] Its solubility in water is moderate, at approximately 0.6 g/100 mL at 20 °C, limiting its polarity despite the nitrogen heteroatom.^[10] Spectroscopically, quinoline shows strong UV-Vis absorption bands at 275 nm (log ε = 3.51), 299 nm (log ε = 3.46), and 312 nm (log ε = 3.52) in aqueous solution, arising from π-π* transitions within the fused aromatic ring system.^[1] Infrared spectroscopy reveals a characteristic C-N stretching band near 1580 cm⁻¹, indicative of the heterocyclic nitrogen's involvement in the ring. In ¹H NMR, the aromatic protons resonate between 7.4 and 8.9 ppm in CDCl₃, confirming the delocalized electron environment.^[1] Key thermodynamic parameters include a standard heat of combustion of -8710 cal/g, a low vapor pressure of 0.06 mmHg at 25 °C, and a dipole moment of 2.2 D, highlighting its energetic stability and moderate polarity.^[1]^[11]

Chemical Properties

Quinoline displays basic character arising from the lone pair of electrons on the nitrogen atom, which is available for protonation in the sp²-hybridized orbital without participating in the aromatic π-system. The pKa of its conjugate acid is 4.94, reflecting moderate basicity weaker than that of pyridine due to the electron-withdrawing effect of the fused benzene ring. This allows quinoline to form stable salts with strong acids, such as the hydrochloride, which are often soluble in polar solvents.^[1] Despite its basic nature, quinoline exhibits weak C-H acidity at the 2- and 4-positions of the pyridine ring, where deprotonation can occur under strong base conditions like sodium amide or butyllithium, generating reactive carbanions stabilized by the adjacent nitrogen. These positions are more acidic than typical aromatic C-H bonds owing to the electron-deficient character of the heterocycle, with the 4-position being preferentially deprotonated over the 2-position.^[12] Quinoline demonstrates good stability toward mild oxidizing agents, resisting degradation under conditions that affect many hydrocarbons, but it undergoes selective N-oxidation with hydrogen peroxide to yield quinoline N-oxide. This reaction targets the nitrogen lone pair, forming a polar N-O bond without disrupting the aromatic framework.^[13] In terms of reduction, quinoline can be catalytically hydrogenated over metals like platinum or ruthenium to afford 1,2,3,4-tetrahydroquinoline, selectively saturating the pyridine ring while leaving the benzene ring intact. This transformation is a key step in accessing partially reduced derivatives for pharmaceutical applications.^[14] The chemical reactivity of quinoline is governed by its resonance structures, which reveal an uneven electron density distribution across the fused rings: the pyridine portion is electron-deficient due to the electronegative nitrogen, while the benzene ring retains higher electron density. This delocalization, facilitated by the ortho-fused ring system, renders positions 2 and 4 electron-poor and highly susceptible to nucleophilic attack, whereas electrophilic substitution preferentially occurs in the carbocyclic ring.

Natural Occurrence and Isolation

Sources in Nature

Quinoline and its derivatives occur naturally in geological formations derived from ancient organic matter. Coal tar, obtained from the destructive distillation of bituminous coal formed from fossilized plant material, contains quinoline bases at concentrations typically around 0.3% by weight.^[15] These bases include quinoline itself and related compounds, contributing to the complex mixture of heterocyclic nitrogenous substances in such tars.^[16] In biological systems, quinoline derivatives are biosynthesized in certain plants as part of alkaloid pathways. Notably, the bark of Cinchona trees (family Rubiaceae) produces quinoline alkaloids such as quinine, where the quinoline moiety forms a key structural element derived from tryptophan metabolism.^[17] Quinoline alkaloids have also been isolated from tobacco leaves (Nicotiana tabacum).^[18] These plant-derived quinolines play roles in defense mechanisms against herbivores and pathogens. Quinoline is present in petroleum and shale oil deposits, originating from the thermal alteration of ancient marine and terrestrial organic matter, with trace concentrations (typically in the ppm range) of quinoline and related heterocycles.^[19] Microbial processes also contribute to quinoline occurrence in natural environments; certain soil bacteria, such as Pseudomonas species, can produce or transform quinoline during the degradation of organic pollutants, integrating it into biogeochemical cycles.^[20]

Isolation Methods

Quinoline was historically isolated from coal tar through fractional distillation, targeting the middle oil fraction with a boiling range of approximately 230–240°C, where quinoline concentrates due to its boiling point of 237°C. This process, first demonstrated in the 19th century following Friedlieb Runge's initial extraction of impure quinoline from coal tar in 1834 and Charles Gerhardt's purification in 1842, separates the tar into light, middle, and heavy oils. The middle oil fraction, rich in heterocyclic bases, undergoes acid-base extraction using sulfuric acid to form water-soluble quinoline salts, which are then neutralized with a base like sodium hydroxide to liberate the free base; this yields approximately 0.3% quinoline from the processed coal tar.^[1]^[21]^[22] Modern isolation techniques have advanced to include supercritical CO₂ extraction from coal tar fractions, such as methylnaphthalene oil, enabling selective recovery of quinoline bases under mild conditions (typically 40–60°C and 200–300 bar) with high efficiency and minimal solvent residue. For instance, semicontinuous processes using CO₂ with supported adsorbents like aluminum chloride-impregnated silica achieve over 90% recovery of quinolines by exploiting their polarity differences from non-basic aromatics. Additionally, steam distillation is employed for extracting quinoline from plant materials, where the compound's partial volatility allows co-distillation with water vapor at 100–150°C, followed by phase separation to isolate the organic layer.^[23] Purification of isolated quinoline often involves fractional crystallization as picrate salts, formed by adding picric acid in ethanol to form yellow crystalline derivatives (melting point ~203°C for quinoline picrate), which are then decomposed with alkali to regenerate pure quinoline; this method effectively separates it from impurities. Alternatively, column chromatography on neutral alumina elutes quinoline using hexane-ethyl acetate mixtures, providing high purity (>98%) for analytical or synthetic use. A key challenge in these isolations is separating quinoline from closely related azaarenes like isoquinoline (boiling point 243°C), which is addressed using selective solvents such as concentrated sulfuric acid, where quinoline forms a more soluble bisulfate salt, allowing differential extraction and precipitation.^[24]^[25]^[26]

Synthesis

Historical Methods

The inaugural synthetic route to quinoline emerged in 1880 through the work of Czech chemist Zdenko Hans Skraup, establishing the eponymous Skraup synthesis as a cornerstone of heterocyclic chemistry. This method entails heating aniline with glycerol in concentrated sulfuric acid alongside an oxidizing agent, such as nitrobenzene or ferric chloride, to facilitate dehydration and cyclization. The reaction proceeds as follows:

\ce{C6H5NH2 + C3H8O3 ->[H2SO4][oxidant] C9H7N + H2O + CO2 + other byproducts}

Yields typically range from 50% to 70%, though early implementations often suffered from lower efficiency owing to the formation of tarry side products.^[27]^[28] A key variant, the Doebner–Miller synthesis, was introduced in 1881 by Oskar Doebner and Wilhelm von Miller as a modification of the Skraup approach, enabling access to substituted quinolines. It involves condensing aniline with α,β-unsaturated aldehydes (or their equivalents) and a carboxylic acid under acidic conditions, bypassing glycerol to reduce complexity in substituent introduction. This method proved particularly useful for preparing 2- or 4-substituted derivatives but retained similar yield profiles to the Skraup reaction.^[27] Both historical syntheses were hampered by inherent limitations, including modest yields, generation of intractable byproducts like polymeric tars and isomeric quinolines, and the necessity of harsh, corrosive conditions such as high temperatures and strong acids. These drawbacks underscored the need for structural confirmation through alternative means; the Skraup synthesis itself served as a pivotal milestone by aligning with degradation studies from quinine, validating quinoline's fused benzene-pyridine architecture.^[27]^[28]

Modern Synthetic Routes

One prominent modern laboratory method for quinoline synthesis is the Combes reaction, which entails the acid-catalyzed condensation of aniline derivatives with 1,3-diketones, such as pentane-2,4-dione, to afford 2,4-disubstituted quinolines.^[29] This approach proceeds via enamine formation followed by electrophilic cyclization, with contemporary optimizations employing mild catalysts like p-toluenesulfonic acid or magnesium chloride at moderate temperatures (around 80°C) to achieve fair to good yields while minimizing side products.^[4] The Friedländer synthesis, developed in 1882, involves the base- or acid-catalyzed condensation of o-amino benzaldehydes or ketones with carbonyl compounds having an α-methylene group, providing a versatile route to substituted quinolines. The Pfitzinger reaction represents another efficient route, involving the base-mediated condensation of isatin with α-keto acids or their equivalents, yielding quinoline-4-carboxylic acids that can be decarboxylated to unsubstituted quinolines if desired.^[30] Recent advancements, including one-pot esterification-cyclization protocols under aqueous or solvent-free conditions, enhance regioselectivity and facilitate the preparation of functionalized derivatives suitable for pharmaceutical intermediates.^[31] Transition metal-catalyzed methods have gained prominence for their versatility and regioselectivity, particularly the palladium-catalyzed Larock annulation, which couples o-haloanilines (e.g., o-iodoanilines) with internal alkynes or propargyl alcohols via sequential carbopalladation and C-N bond formation. This intermolecular process, often conducted with Pd(OAc)₂ and phosphine ligands in the presence of a base, delivers 2,3- or 2,4-disubstituted quinolines in good to excellent yields (typically 70-95%) under mild conditions, making it ideal for late-stage diversification.^[32] On an industrial scale, while quinoline is primarily obtained from coal tar, synthetic routes such as the Skraup reaction and vapor-phase processes using aniline and carbonyl compounds over acid catalysts are employed for production and derivatives.^[1] Many modern routes emphasize green chemistry principles, with microwave-assisted variants accelerating reactions like the Combes or Pfitzinger syntheses in solvent-free environments using heterogeneous catalysts, achieving yields up to 90-92% in short times (10-40 minutes) while reducing energy consumption and waste.^[33] These scalable protocols, often employing recyclable nanocatalysts or aqueous media, align with sustainable manufacturing goals for quinoline production.^[34]

Chemical Reactions

Electrophilic Substitution

Quinoline's pyridine ring is generally deactivated toward electrophilic aromatic substitution (EAS) due to the electron-withdrawing inductive effect of the nitrogen atom, which reduces electron density across the ring, particularly in the protonated form where the positive charge on nitrogen further diminishes reactivity. As a result, EAS reactions preferentially occur on the more electron-rich benzene ring at positions 5 and 8 in the protonated species. However, under milder conditions with the free base, substitution can take place on the pyridine ring, primarily at the C3 position, as this site allows for relatively better stabilization of the Wheland intermediate compared to C2 or C4, where the nitrogen's influence is more direct and destabilizing. The mechanism involves initial addition of the electrophile to form a σ-complex (Wheland intermediate) at C3, followed by loss of a proton to restore aromaticity.^[12] Nitration of quinoline under standard acidic conditions (HNO3/H2SO4) directs the nitro group to the benzene ring, yielding a mixture of 5-nitroquinoline (52%) and 8-nitroquinoline (48%). However, to achieve substitution on the pyridine ring, milder nitrating agents like acetyl nitrate are employed, leading to addition at C3 followed by elimination to afford 3-nitroquinoline in good yield. This regioselectivity arises from the partial positive charge development at C3 in the transition state, which is tolerated better than at other pyridine positions.^[35] Halogenation reactions similarly favor the benzene ring under forcing conditions, but bromination on the pyridine ring at C3 can be achieved using Br2 in acetic acid or with FeBr3 as a Lewis acid catalyst, producing 3-bromoquinoline. The reaction proceeds via the same addition-elimination pathway, with the Wheland intermediate at C3 stabilized by the fused benzene ring's conjugation. This method highlights the role of solvent and catalyst in modulating regioselectivity toward the pyridine ring.^[36] The electron density distribution, influenced by the nitrogen, underscores why C3 emerges as the key site for pyridine ring EAS, enabling targeted functionalization for downstream applications.^[37]

Nucleophilic Addition

Quinoline, with its electron-deficient pyridine ring, is susceptible to nucleophilic attack primarily at the C2 and C4 positions, where the partial positive charge is highest due to resonance with the nitrogen lone pair. This reactivity enables both addition and substitution pathways, often facilitated by activation through N-protonation or quaternization, which enhances the electrophilicity of the ring. The basicity of the nitrogen, with a pKa of approximately 4.9 for its conjugate acid, aids in such activations under acidic conditions.^[38] Quinoline can also undergo oxidation to form quinoline N-oxide, typically by treatment with hydrogen peroxide in acetic acid or m-chloroperbenzoic acid (mCPBA) in dichloromethane, involving nucleophilic addition of the peroxy oxygen to the nitrogen lone pair.^[39] N-alkylation occurs readily at the nitrogen atom when quinoline is treated with alkyl halides, such as methyl iodide or benzyl bromide, typically in a solvent like acetonitrile under mild heating, yielding stable N-alkylquinolinium salts. These quaternary salts, for example, N-methylquinolinium iodide, serve as versatile intermediates for further transformations, including dearomatizing additions, due to their increased ring electrophilicity. The reaction proceeds via an SN2 mechanism at nitrogen, with yields often exceeding 80%.^[38] Nucleophilic substitution at C2 or C4 is prominent in activated derivatives like 2-chloro- or 4-chloroquinoline, where leaving groups are displaced by nucleophiles such as amines (e.g., aniline or piperidine) or alkoxides (e.g., sodium methoxide). For instance, 2-chloroquinoline reacts with aniline under microwave irradiation at 150°C to afford 2-anilinoquinoline in 95% yield via an addition-elimination (SNAr) mechanism, with the chloride at C2 being particularly labile due to stabilization of the Meisenheimer complex by the nitrogen. Similarly, alkoxides displace halides at C4 in 4-chloroquinoline, forming 4-alkoxyquinolines, often in quantitative yields under basic conditions in polar solvents like DMF. These reactions highlight the enhanced reactivity at C2/C4 compared to the benzene ring.^[40] Organometallic nucleophiles, such as Grignard reagents (e.g., phenylmagnesium bromide), add to quinoline or N-alkylquinolinium salts at C2, generating 1,2-dihydroquinolines as initial adducts. This 1,2-addition, often promoted by Lewis acids like BF₃·OEt₂, yields unstable intermediates that can be isolated or trapped; for example, addition to quinolinium bromide followed by hydrolysis gives 2-phenyl-1,2-dihydroquinoline in 70-90% yield. These dihydroquinolines frequently undergo elimination of the magnesium or proton to restore aromaticity, forming 2-substituted quinolines, or isomerize to 1,4-dihydroquinolines via a redox process involving hydride transfer.^[41]^[42] The Chichibabin reaction exemplifies direct C2 amination, where quinoline is treated with sodium amide (NaNH₂) or potassium amide (KNH₂) under forcing conditions, such as heating at 100-130°C in high-boiling aprotic solvents or in liquid ammonia at lower temperatures, often with an oxidant like KMnO4, producing 2-aminoquinoline in 50-70% yield. The mechanism involves nucleophilic addition of the amide anion to C2, forming a 1,2-dihydroquinolinide σ-complex, followed by elimination of hydride to restore aromaticity; minor 4-aminoquinoline (up to 10%) forms via C4 attack. This high-temperature process requires careful control to minimize side products like dihydro derivatives.^[43] Many nucleophilic additions to quinoline are reversible, driven by the thermodynamic stability gained from reforming the aromatic system, with equilibrium favoring the aromatic substrate under neutral or basic conditions. For example, 1,2-dihydroquinoline adducts from Grignard additions revert upon acidification or oxidation, underscoring the role of aromaticity in dictating reaction outcomes. This reversibility enables dynamic processes in synthetic applications, such as isomerizations between 1,2- and 1,4-dihydro isomers.^[38]

Other Reactions

Quinoline can undergo ring-opening reactions under specific conditions, such as treatment with low-valent titanium alkyl complexes, which cleave the heterocyclic ring to form open-chain titanium species that can be further functionalized.^[44] These transformations are particularly useful for synthetic applications, providing access to non-aromatic derivatives from the otherwise stable quinoline scaffold. Drastic conditions like high temperatures with hydriodic acid have been reported in alkaloid chemistry to open the quinoline ring, leading to fragments that include aniline-like structures, though such methods are less common for unsubstituted quinoline due to its aromatic stability. Photochemical reactions of quinoline, initiated by UV irradiation, often involve dearomatization and cycloaddition processes. For instance, quinoline participates in [2+2] photocycloadditions with alkenes, generating cyclobutane-fused adducts that can be thermally reversed via retro-Diels-Alder pathways to release modified quinolines or alkenes.^[45] Under UV light, quinoline N-oxides undergo rearrangement, including ring contraction or expansion, yielding products like acridine derivatives through dimerization or isomerization mechanisms, which highlight quinolines' utility in photoredox catalysis.^[46] These reactions are typically conducted in aprotic solvents to control selectivity and avoid competing protonation. In coordination chemistry, quinoline serves as a bidentate or monodentate ligand in metal complexes, particularly with ruthenium and palladium, facilitating catalytic processes. For example, ruthenium(II) p-cymene complexes bearing pyridine-quinoline ligands exhibit enhanced stability and activity in hydrogenation reactions, such as the selective reduction of quinolines to tetrahydroquinolines.^[47] Similarly, palladium complexes with 8-aminoquinoline motifs promote C-H activation and cross-coupling reactions, leveraging the ligand's nitrogen donors for directing group effects in arene functionalizations.^[48] These complexes are prized for their role in asymmetric catalysis, where the quinoline backbone influences stereoselectivity. Biotransformations of quinoline primarily involve cytochrome P450 enzymes, which catalyze regioselective hydroxylation. CYP3A4 predominantly hydroxylates at the 3-position of the quinoline ring, as seen in the metabolism of quinine derivatives, producing 3-hydroxyquinoline intermediates that are key detoxification products.^[49] Additional oxidation at C4 can occur via CYP1A2 or related isoforms, though less efficiently, underscoring the enzyme's preference for electron-rich sites in the pyridine ring.^[50] These enzymatic reactions mimic industrial oxidations but proceed under mild physiological conditions, aiding in the biodegradation of quinoline pollutants. Quinoline exhibits Diels-Alder reactivity as a diene, particularly in its benzene ring under high-pressure conditions, enabling cycloaddition with activated dienophiles like maleic anhydride. This dearomatization forms bicyclic adducts, which can be extruded to restore aromaticity or serve as scaffolds for further synthesis, though the reaction requires pressures exceeding 10 kbar to overcome the aromatic stabilization energy.^[45] Such high-pressure protocols expand quinoline's synthetic versatility beyond standard substitutions.

Applications

Industrial Uses

Quinoline is primarily obtained as a fraction from the refining of coal tar, a byproduct of metallurgical coke production, which accounts for the majority of its global supply. Significant production capacity is concentrated in regions with extensive coal processing industries, such as China.^[51] In the dye industry, quinoline acts as a key precursor for synthesizing quinoline-based dyes, which are applied in textile coloring for their vibrant hues and binding properties to fabrics like acrylic and polyester.^[52] These dyes contribute to the production of durable colorants used in clothing and industrial textiles, leveraging quinoline's heterocyclic structure to form stable chromophores.^[53] Quinoline finds application as a solvent in the processing of resins and polymers due to its ability to dissolve complex organic materials effectively. Quinoline and its derivatives function as corrosion inhibitors to protect metals such as aluminum and steel from degradation in various industrial processes, including cooling systems.^[54] Their high electron density enables adsorption onto metal surfaces, forming protective layers that mitigate pitting and general corrosion in chloride-containing environments.^[55] In agrochemicals, quinoline serves as an essential intermediate in the synthesis of herbicides, notably quinclorac, a quinoline carboxylic acid compound used for selective weed control in crops like rice and cereals.^[56] This derivative targets auxin-sensitive grasses and broadleaf weeds by disrupting plant growth hormones, with quinoline providing the core ring structure for its bioactivity.^[57]

Pharmaceutical Applications

Quinoline derivatives have played a pivotal role in pharmaceutical applications, particularly as antimalarial agents. Quinine, a natural quinoline alkaloid isolated from the bark of the cinchona tree in 1820 by Pierre Joseph Pelletier and Joseph Bienaimé Caventou, was the first effective treatment for malaria and served as the foundation for synthetic analogs.^[58] Synthetic derivatives like chloroquine, developed in the 1940s, revolutionized malaria therapy by offering improved efficacy and lower toxicity compared to quinine. These compounds exert their antimalarial action primarily by inhibiting the polymerization of toxic heme released during hemoglobin digestion by the Plasmodium parasite in infected red blood cells, leading to the accumulation of free heme that damages the parasite.^[59] This mechanism has enabled quinoline-based drugs to treat millions of malaria cases globally throughout the 20th century, significantly reducing mortality in endemic regions.^[60] Structure-activity relationship studies of quinoline antimalarials highlight the importance of specific substitutions for enhanced potency. The 7-chloro substitution on the quinoline ring, as seen in chloroquine and related 4-aminoquinolines, improves binding to heme and accumulation in the parasite's digestive vacuole, thereby boosting antimalarial activity while minimizing host toxicity. However, widespread use has led to resistance issues, with the first reports of Plasmodium falciparum resistance to chloroquine emerging in the 1950s in Southeast Asia and South America, complicating treatment efforts and necessitating combination therapies.^[61] For preventing malaria relapse caused by dormant liver-stage hypnozoites in Plasmodium vivax and Plasmodium ovale infections, 8-aminoquinoline derivatives such as primaquine are employed; primaquine targets these stages by generating reactive oxygen species that disrupt parasite metabolism.^[62] Beyond antimalarials, quinoline derivatives exhibit antibacterial properties, particularly certain 4-aminoquinolines that inhibit bacterial DNA gyrase and topoisomerase IV, essential enzymes for DNA replication in pathogens like Staphylococcus aureus.^[63] In anticancer applications, quinoline-based compounds have shown promise as topoisomerase inhibitors. For instance, tailor-made quinoline derivatives act as poisons of topoisomerase I, stabilizing the enzyme-DNA cleavage complex and inducing DNA damage that triggers apoptosis in cancer cells, with potent activity observed against various tumor lines in preclinical studies.^[64] Nitroxoline, a hydroxyquinoline derivative, demonstrates anticancer effects by inhibiting multiple pathways, including topoisomerase activity, and has been repurposed for its cytotoxicity against prostate and bladder cancer cells.^[65] These applications underscore the versatility of quinoline scaffolds in targeting critical biological processes for therapeutic benefit.

Safety and Toxicology

Health Effects

Quinoline demonstrates moderate acute toxicity via oral exposure, with a reported LD50 value of 331 mg/kg in rats.^[1] Direct contact with quinoline can cause irritation to the skin and eyes, potentially leading to redness, pain, and corneal damage upon prolonged or high-concentration exposure.^[66] In industrial production environments, workers may encounter quinoline through inhalation of vapors, resulting in irritation of the respiratory tract, including the nose, throat, and lungs, along with symptoms such as headache, nausea, and dizziness at elevated levels.^[66] Quinoline undergoes hepatic metabolism primarily through cytochrome P450-mediated oxidation, yielding 5,6-dihydroxy-5,6-dihydroquinoline as the major metabolite, with lesser amounts of 2- and 3-hydroxyquinoline, which are subsequently conjugated (often as a glucuronide) and excreted in the urine in small amounts in animal studies. Quinoline exhibits mutagenic potential, as evidenced by positive results in the Ames bacterial reverse mutation test using Salmonella typhimurium strains, particularly in the presence of metabolic activation. Regarding carcinogenicity, the International Agency for Research on Cancer (IARC) classifies quinoline as Group 2B, possibly carcinogenic to humans, based on sufficient evidence of carcinogenicity in experimental animals but limited evidence in humans. This risk arises from metabolic activation in the liver to reactive epoxides, such as the 5,6-epoxide, which can form DNA adducts and contribute to tumorigenesis.^[67]

Environmental Impact

Quinoline enters the environment primarily through anthropogenic sources, including coal tar processing, coking operations, petroleum refining, and effluents from pharmaceutical manufacturing. These activities release quinoline into wastewater, groundwater, and soil, particularly at contaminated industrial sites such as former coal gasification plants. Underground coal gasification and wood treatment using creosote also contribute to its environmental presence.^[68]^[69]^[70] In the environment, quinoline demonstrates variable persistence depending on the compartment. Atmospheric degradation occurs rapidly via reaction with hydroxyl radicals, with an estimated half-life of about 1.4 days.^[1] Limited data on soil persistence indicate potential for prolonged presence, with conservative biodegradation half-lives exceeding 100 days under certain conditions due to slow microbial activity. In water, photodegradation contributes to breakdown, with half-lives around 123 days in winter conditions. Quinoline undergoes microbial degradation under aerobic conditions, primarily by bacteria such as Pseudomonas and Rhodococcus species, which initiate breakdown through monooxygenation to form hydroxylated intermediates like 2-hydroxyquinoline, followed by ring opening and mineralization to simpler compounds.^[71]^[72]^[73]^[74]^[75] Quinoline has a low to moderate bioaccumulation potential in aquatic organisms, reflected by its octanol-water partition coefficient (log Kow) of 2.03. While it does not meet criteria for high bioaccumulation (BCF or BAF ≥ 5000), dietary exposure studies in fish such as rainbow trout demonstrate uptake and accumulation in tissues, though depuration occurs relatively quickly.^[70]^[76]^[77] Ecotoxicity assessments reveal adverse effects on aquatic life at moderate concentrations. For fish, the 96-hour LC50 is 77.8 mg/L in the fathead minnow (Pimephales promelas) under flow-through conditions. Quinoline also inhibits algal growth, with a 72-hour EC50 of 60.9 mg/L for Chlorella pyrenoidosa based on growth inhibition. These values indicate moderate toxicity to primary producers and vertebrates in freshwater systems.^[78]^[72] Under the European Union's REACH regulation, quinoline is registered for evaluation and risk management, with requirements for monitoring its release and concentrations in water bodies to safeguard aquatic ecosystems. Environmental quality guidelines, such as Canada's Federal Water Quality Guideline of 7 μg/L for the protection of aquatic life, further emphasize ongoing surveillance in surface and groundwater.^[72]

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Formula: C9H7N; SMILES: c1ccc2ncccc2c1; Molecular Weight: 129.16; CAS: 91-22-5; Other Names. 1-Azanaphthalene; 1-Benzazine; B 500; BENZOPYRIDINE; Benzo[b] ...
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Quinoline · Formula: C9H7N · Molecular weight: 129.1586 · IUPAC Standard InChI: InChI=1S/C9H7N/c1-2-6-9-8(4-1)5-3-7-10-9/h1-7H Copy · IUPAC Standard InChIKey: ...
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Sep 8, 2022 · Room temperature and selective hydrogenation of quinolines to 1,2,3,4-tetrahydroquinolines using a safe and clean hydrogen donor catalyzed ...
[14]
Appendix 1: Detailed Description of the Exposure Scenario for ...
Nov 10, 2022 · Fraction of quinoline in coal tar (w/w): 0.0011 and 0.005 65. These values bracket lower and higher limits for quinoline content of coal tar ( ...
[15]
[PDF] Quinoline - California Air Resources Board
Quinoline is a hygroscopic liquid with a penetrating odor. It absorbs as much as 22 percent water and is volatile with steam. Quinoline is slightly soluble ...
[16]
Biologically active quinoline and quinazoline alkaloids part I - PMC
With the development of natural product technology, quinine (1), a quinoline alkaloid, was isolated from the bark of the Cinchona tree in 1820. Due to its low ...
[17]
Quinoline Alkaloids from the Leaves of Cigar Tobacco and Their Anti ...
Aug 5, 2025 · Quinoline Alkaloids from the Leaves of Cigar Tobacco and Their Anti-Tobacco ... Compounds 1 and 2 are the first naturally occurring pterosin-type ...
[18]
[PDF] Induction Conditions and Kinetic Properties of Quinoline ...
Dec 16, 2019 · Concentrations of quinolone in wastewater generated during shale oil production reach 2-50 mgL-1. Concentrations of quinoline are about 10 mg/L ...
[19]
Recent advances in chemistry and therapeutic potential of ...
It possesses the ability to absorb water molecules from the environment. It is a colorless hygroscopic liquid, which when aged and exposed to light, changes ...<|separator|>
[20]
Quinolizidine-Type Alkaloids: Chemodiversity, Occurrence, and ...
Jul 28, 2023 · The basic structure of this type of QA is the matrine alkaloid (7), having the mentioned tetracyclic moiety formed by two quinolizidine moieties ...
[21]
Coal Tar and its Distillation Processes - IspatGuru
Dec 26, 2018 · Fractional distillation process is used for the distillation of coal tar. Fractional distillation of tar refers to the process by which ...
[22]
Method for extracting quinoline from coal tar wash oil - Google Patents
The invention relates to a method for extracting quinoline from coal tar wash oil, which belongs to the field of chemical separation.
[23]
Removal and Recovery of Quinoline Bases from Methylnaphthalene ...
Removal and Recovery of Quinoline Bases from Methylnaphthalene Oil in a Semicontinuous Supercritical CO2 Separation Apparatus with a Fixed Bed of Supported ...
[24]
Purification of Quinoline - Chempedia - LookChem
The method using the picrate is as follows: quinoline is added to picric acid dissolved in the minimum volume of 95% EtOH, giving yellow crystals which were ...Missing: salts | Show results with:salts
[25]
Studies Directed toward the Synthesis of Aspidophytine
Aug 15, 2016 · We have developed an efficient route for the synthesis of the perhydroquinoline core of the indole alkaloid aspidophytine (2), starting from commercially ...
[26]
Removal of tar base from coal tar aromatics employing solid acid ...
This study presents a feasible and effective method for removing tar bases such as quinoline from coal tar aromatics. Strong chemisorption of quinoline and ...
[27]
Recent Advances in Metal-Free Quinoline Synthesis - PMC - NIH
Jul 29, 2016 · A variation of the Skraup procedure, the Doebner–Von Miller reaction (C) was introduced in 1881 and uses α,β-unsaturated aldehydes or ketones to ...Missing: history Friedlieb Hofmann
[28]
On the Mechanism of the Skraup−Doebner−Von Miller Quinoline ...
In the early 1880s, Skraup described heating a mixture of nitroethane, aniline, and glycerol with concentrated sulfuric acid to form quinoline in a very low ...Missing: Hofmann confirmation
[29]
Current progress toward synthetic routes and medicinal significance ...
Sep 28, 2023 · This mini-review article highlights the traditional and green synthetic approaches of quinoline and its analogs, including multicomponent one-pot reactions and ...
[30]
The Synthesis of Quinolines by the Pfitzinger Reaction
The Synthesis of Quinolines by the Pfitzinger Reaction. Click to copy ... Pfitzinger quinoline synthesis. 2020https://doi.org/10.1002/9783527809080 ...
[31]
An improved Pfitzinger reaction for the direct synthesis of quinoline ...
Aug 8, 2018 · The improved Pfitzinger reaction involves esterification and cyclization in one-step process, and in situ formed a carboxylic ester/acid group ( ...
[32]
Synthesis of quinolines - Organic Chemistry Portal
The use of hydrazine under basic conditions enables an efficient and general construction of quinoline N-oxides from ortho-nitro chalcones via umpolung of ...Missing: properties pKa resonance<|control11|><|separator|>
[33]
US5700942A - Process for preparing quinoline bases
When conditions are optimized, the Skraup synthesis can give good yields of quinolines, e.g. 90% yield of8-methylquinoline (See, Synthesis 1989, 880-82).Missing: percentage | Show results with:percentage
[34]
Microwave assisted regioselective synthesis of quinoline appended ...
Jun 1, 2021 · The foremost supremacy of this method are transitory reaction times, facile workup, excellent yields (88–92%) with exorbitant purity and ...
[35]
Quinoline Synthesis: Nanocatalyzed Green Protocols An Overview
This review focuses on the published research articles on nanocatalysts to synthesize substituted quinoline derivatives.
[36]
Why does the nitration of quinoline occur at the 5 (and 8) position?
Jun 6, 2025 · It's worth note that nucleophilic substitution would take place only on the heterocycle side of quinoline at its C2 and C4 positions. For ...
[37]
Science of Synthesis: Best methods. Best results – Thieme Chemistry
... acetic acid[‌742‌] affords good yields of the corresponding 3-haloquinolines, as in the bromination of quinoline hydrochloride to 3-bromoquinoline (‌294‌).Missing: Br2 | Show results with:Br2
[38]
Recent advances in the synthesis of quinolines: a review
Apr 17, 2014 · This review article gives information about the green and clean syntheses using alternative reaction methods for the synthesis of quinoline derivatives.
[39]
Recent Strategies in the Nucleophilic Dearomatization of Pyridines ...
Jan 2, 2024 · The aim of this review, which covers the period from 2016 to 2022, is to update the state of the art of nucleophilic dearomatizations of pyridines, quinolines, ...
[40]
Efficient nucleophilic substitution reactions of quinolyl and ...
Nucleophilic substitution reactions of 2-chloroquinoline, 3-bromoquinoline and 4-bromoisoquinoline with thiolate, alkoxy ions and aniline were completed ...
[41]
Evidence for a Unique Redox Reaction between a 1,4- and a 1,2 ...
Addition of Grignard Reagents to Quinolinium Salts: Evidence for a Unique Redox Reaction between a 1,4- and a 1,2-Dihydroquinoline. Click to copy article ...
[42]
1,2-Dihydroquinolines: preparation and isolation as intermediates in ...
The preparation of 2-alkyl-1,2-dihydroquinolines by addi- tion of Grignard reagents to quinoline is illustrated in a recent paper (8) which also describes some ...
[43]
[PDF] Advances in the Study of the Chichibabin Reaction
The mechanism of the Chichibabin reaction has been studied much less than those of other nucleophilic substi- tution reactions and is still not entirely clear.Missing: source | Show results with:source
[44]
Ring-opening reactions of quinoline and isoquinoline with a low ...
Apr 7, 2017 · Herein, we report ring-opening reactions of quinoline and isoquinoline by a transient and low-valent titanium (II) alkyl complex. The ...
[45]
Photochemical Dearomative Cycloadditions of Quinolines and ...
Sep 15, 2022 · A method to achieve photochemical cycloaddition of quinolines and alkenes is shown. Emphasis is placed on generating sterically congested products.
[46]
Quinoline as a Photochemical Toolbox: From Substrate to Catalyst ...
Sep 9, 2025 · In the case of protonated quinoline, the typical reactive intermediate in Minisci-type transformations, Fukui indices for C2 and C4 are ...Missing: acidity | Show results with:acidity
[47]
Ruthenium-p-Cymene Complexes Incorporating Substituted ... - MDPI
This is the first report of ruthenium(II) p-cymene complexes incorporating substituted pyridine–quinoline ligands, with –Br and –C6H4OH groups in the 6-position ...
[48]
Synthesis of Quinoline-Based Pt–Sb Complexes with L- or Z-Type ...
Aug 13, 2024 · A series of Pt–Sb complexes with two or three L-type quinoline side arms were prepared and studied. Two ligands, tri(8-quinolinyl)stibane ...
[49]
CYP450 phenotyping and metabolite identification of quinine by ...
Jun 21, 2013 · In the present study, CYP 3A4 was identified as predominantly responsible for the production of 3-hydroxyquinine, and a second hydroxylation ...Chemicals Used · Cyp Incubations · Reactive Oxygen Species...<|control11|><|separator|>
[50]
The roles of cytochrome P450 3A4 and 1A2 in the 3-hydroxylation of ...
Cytochrome P450 3A4 is important for the 3-hydroxylation of quinine in vivo. On the other hand, CYP1A2 had no significant effect on this metabolic pathway.
[51]
Quinoline Market revenue to reach USD 545 Billion by 2035,
Their annual worldwide turnover is close to about 7999 tons. Understanding food colorants is a highly profitable endeavor since it has been demonstrated ...
[52]
Cyanine Dyes Containing Quinoline Moieties: History, Synthesis ...
Cyanine dyes carrying quinoline moieties are an important class of organic molecules that are of great interest for applications in many fields.
[53]
Studies on quinoline type dyes and their characterisation studies on ...
May 16, 2025 · In the dyeing and finishing industry, quinoline is the manufacture of dyes [6] [7][8][9], mainly used to prepare cyanine blue pigment and ...Missing: acriflavine | Show results with:acriflavine
[54]
Quinoline and its derivatives as corrosion inhibitors: A review
Quinoline derivatives show reasonable good effectiveness against metallic corrosion because of their association with high electron density.
[55]
Composition containing hydroquinone or quinoline for fuel cell coolant
The antifreeze solution composition of the present invention may include a pH adjusting agent, a dye, an antifoaming agent or a corrosion inhibitor. The pH ...
[56]
Quinclorac | C10H5Cl2NO2 | CID 91739 - PubChem - NIH
Quinclorac is a selective herbicide used primarily to control weeds in rice crops, but is also used on other agricultural crops and is found in some household ...
[57]
A review of recent studies on quinclorac - ScienceDirect
Quinclorac is a specific auxin herbicide with quinoline ring and chloro groups. · Ethylene, cyanide, and phytohormone were induced by quinclorac in plants.
[58]
Antimalarial Drug Discovery: From Quinine to the Dream of Eradication
Nov 13, 2013 · The first use of the bark in treating malaria is often attributed to Jesuit missionaries in 17th century Peru, though the indigenous population ...<|control11|><|separator|>
[59]
A common mechanism for blockade of heme polymerization by ...
Nov 20, 1998 · The antimalarial quinolines are believed to work by blocking the polymerization of toxic heme released during hemoglobin proteolysis in intraerythrocytic ...
[60]
The past, present and future of anti-malarial medicines
Mar 22, 2019 · Resistance to CQ was first reported in the 1950s and over the years many strains of malaria have developed resistance. Indeed, resistant ...
[61]
History of antimalarial drugs - Medicines for Malaria Venture
The bark was named cinchona in 1742 by Linnaeus. In 1820, two French chemists isolated quinine from the cinchona bark and quinine became a treatment of ...
[62]
Primaquine Therapy for Malaria | Clinical Infectious Diseases
Most cases of vivax malaria among travelers are relapses and are preventable with primaquine, the only currently available drug for therapy to prevent relapse.Primaquine Therapy For... · Tolerability And Toxicity · Relapse
[63]
Exploring Antibacterial Efficacy, MRSA Inhibition, and PBP2a ... - MDPI
This paper highlights the role of structural features in antibacterial efficacy and guides the future optimization of 4-aminoquinoline derivatives.
[64]
Discovery and Mechanistic Study of Tailor-Made Quinoline ...
Mar 21, 2019 · Here, we report the design, synthesis, mechanism study, and validation of a novel class of Top1 poisons based on the quinoline core, identified ...
[65]
Repurposing of nitroxoline as a potential anticancer agent against ...
Nov 24, 2015 · Nitroxoline induces anticancer activity through AMPK-dependent inhibition of mTOR-p70S6K signaling pathway and cyclin D1-Rb-Cdc25A axis, leading to G1 arrest ...
[66]
[PDF] Quinoline - Hazardous Substance Fact Sheet
Quinoline is hygroscopic. SPILL/LEAKS. PHYSICAL PROPERTIES. Isolation Distance: Spills: 50 meters (150 feet). Fires: 800 meters (1/2 mile). Absorb liquids in ...
[67]
On the metabolism of quinoline and isoquinoline - PubMed - NIH
These data are consistent with the hypothesis that formation of the 5,6-epoxide of quinoline is associated with its metabolic activation to a tumorigen.
[68]
A state-of-the-art review of quinoline degradation and technical ...
Dec 10, 2020 · Furthermore, quinoline widely exists in coal tar, mineral oil, petroleum and industrial wastewater, such as coking wastewater, pharmaceutical ...
[69]
[PDF] Quinoline and Groundwater - Minnesota Department of Health
Quinoline is a naturally occurring substance found in coal and is a component of coal tar and petroleum. It can also be formed when organic material is burned ...
[70]
[PDF] Quinoline - U.S. Environmental Protection Agency
However, quinoline breaks down quickly in water. (1). Assessing Personal ... Water solubility at 25°C is 6,110 milligrams per liter (mg/L). (1,3,7).
[71]
Toxicological Review of Quinoline (CAS No. 91-22-5)
The studies described below were designed to investigate the carcinogenic effects of quinoline following oral exposure, but none exposed animals for more than ...Missing: LD50 IARC Ames<|control11|><|separator|>
[72]
Federal environmental quality guidelines - Quinoline - Canada.ca
Aug 11, 2020 · A long biodegradation half-life of >100 000 years was selected as a conservative assumption due to limited biodegradation data for quinoline.
[73]
Photodegradation of quinoline in water - ResearchGate
Aug 10, 2025 · The calculated half-life in winter was about 123 calendar days. The photodegradation of quinoline was accelerated significantly by NaNO3 and ...
[74]
Isolation and characterization of quinoline-degrading bacteria from ...
Rapid aerobic mineralization of quinoline at concentrations as low as 0.002 microgram ml-1 indicates that these organisms possess a high-affinity uptake and ...
[75]
Biodegradation of Quinoline by a Newly Isolated Salt-Tolerating ...
Apr 9, 2022 · According to previous research reports, some strains in Rhodococcus can degrade quinoline under aerobic culture conditions, such as Rhodococcus ...
[76]
[PDF] Screening Assessment Quinoline 91-22-5 Environment ... - Canada.ca
Bioaccumulation criteria are a bioaccumulation factor (BAF) or bioconcentration factor (BCF) of ≥5000 or a log Kow of. ≥5.0. In summer, quinoline is not ...
[77]
[PDF] Mechanisms affecting the bioaccumulation of dietary quinoline by ...
quinoline, are relatively water-soluble and are readily taken up from the water by fish prey organisms, including small fish (Southworth et al., 1980; Bean ...
[78]
[PDF] Quinoline - NET
Oct 11, 2017 · Specific target organ toxicity (single exposure) : May cause respiratory irritation. Specific target organ toxicity (repeated exposure).