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Pyridazine
Pyridazine
Pyridazine
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Pyridazine
Skeletal formula with numbering convention
Pyridazine molecule
C=black, H=white, N=blue
Pyridazine molecule
C=black, H=white, N=blue
Names
Preferred IUPAC name
Pyridazine[1]
Systematic IUPAC name
1,2-Diazabenzene
Other names
1,2-Diazine
Orthodiazine
Oizine
Identifiers
3D model (JSmol)
103906
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.005.478 Edit this at Wikidata
EC Number
  • 206-025-5
49310
UNII
  • InChI=1S/C4H4N2/c1-2-4-6-5-3-1/h1-4H checkY
    Key: PBMFSQRYOILNGV-UHFFFAOYSA-N checkY
  • InChI=1/C4H4N2/c1-2-4-6-5-3-1/h1-4H
    Key: PBMFSQRYOILNGV-UHFFFAOYAA
  • n1ncccc1
Properties
C4H4N2
Molar mass 80.090 g·mol−1
Appearance Colorless liquid
Density 1.107 g/cm3
Melting point −8 °C (18 °F; 265 K)
Boiling point 208 °C (406 °F; 481 K)
miscible
Solubility miscible in dioxane, ethanol
soluble in benzene, diethyl ether
negligible in cyclohexane, ligroin
1.52311 (23.5 °C)
Thermochemistry
224.9 kJ/mol
Hazards
GHS labelling:[2]
GHS07: Exclamation mark
Warning
H302, H315, H319, H335
P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, P501
Flash point 85 °C (185 °F; 358 K)
Related compounds
Related compounds
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 ?)

Pyridazine is an aromatic, heterocyclic, organic compound with the molecular formula C4H4N2. It contains a six-membered ring with two adjacent nitrogen atoms.[3] It is a colorless liquid with a boiling point of 208 °C. It is isomeric with two other diazine (C4H4N2) rings, pyrimidine and pyrazine.

Occurrence

[edit]

Pyridazines are rare in nature, possibly reflecting the scarcity of naturally occurring hydrazines, common building blocks for the synthesis of these heterocycles. The pyridazine structure is a popular pharmacophore which is found within a number of herbicides such as credazine, pyridafol and pyridate. It is also found within the structure of several drugs such as cefozopran, cadralazine, minaprine, pipofezine, and hydralazine.

Synthesis

[edit]

In the course of his classic investigation on the Fischer indole synthesis, Emil Fischer prepared the first pyridazine via the condensation of phenylhydrazine and levulinic acid.[4] The parent heterocycle was first prepared by oxidation of benzocinnoline to the pyridazinetetracarboxylic acid followed by decarboxylation. A better route to this otherwise esoteric compound starts with the maleic hydrazide. These heterocycles are often prepared via condensation of 1,4-diketones or 4-ketoacids with hydrazines.[5]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Pyridazine

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Pyridazine is a six-membered heterocyclic with the molecular formula C₄H₄N₂, featuring two adjacent atoms at positions 1 and 2 in the ring (also known as 1,2-diazine). It appears as a clear yellow-brown at , with a molecular weight of 80.09 g/mol, a of -8 °C, a of 208 °C, and a of 1.103 g/mL at 25 °C. Miscible with , pyridazine acts as a that forms salts with acids such as hydrochloric or and exhibits stability toward oxidizing agents like . As a privileged scaffold in , pyridazine is commonly prepared through the condensation of 1,4-diketones or 4-ketoacids with , though modern methods include Lewis acid-mediated Diels-Alder reactions, copper-catalyzed cyclizations, and regioselective Reissert-type processes for substituted derivatives. Its derivatives serve as versatile building blocks in , often functioning as bioisosteres for phenyl or other heteroaromatic rings to enhance pharmacological profiles. In pharmaceuticals, pyridazine-based compounds are key intermediates for drugs like the antihypertensive and sulfonamide antibiotics such as sulfapyridazine, while also contributing to glycogen synthase kinase-3 (GSK-3) inhibitors. Beyond therapeutics, pyridazine derivatives play significant roles in agrochemicals, including herbicides that target phytoene desaturase to disrupt carotenoid biosynthesis in , nematicides for controlling soil-borne pests, and fungicides within the class. Additionally, pyridazine has applications as a catalyst in oxidation processes and in the development of , underscoring its broad utility across chemical disciplines. Safety considerations include moderate toxicity (LD50 intraperitoneal in mice: 2650 mg/kg) and the release of toxic vapors upon heating, necessitating careful handling.

Structure and properties

Molecular structure

Pyridazine is a six-membered heterocyclic with the molecular formula \ceC4H4N2\ce{C4H4N2}, featuring two adjacent atoms at positions 1 and 2 in the ring, also referred to as 1,2-diazine. The molecule adopts a planar C2vC_{2v} symmetric structure, where the ring consists of four carbon atoms and the two nitrogens, with hydrogen atoms attached to the carbons at positions 3, 4, 5, and 6. The aromatic character of pyridazine arises from its conjugated π-electron system, which contains 6 π-electrons—contributed by the p-orbitals of the four carbon atoms and the two atoms—satisfying for (4n + 2, where n = 1). This delocalization is supported by structures involving the ring nitrogens, where can shift to form partial double-bond character between the nitrogens (N=N) or distribute across C=N bonds, enhancing the stability of the system. Semi-experimental equilibrium structures, derived from of isotopologues and corrected with CCSD(T)/cc-pCVTZ quantum chemical calculations, reveal bond lengths indicative of this aromatic delocalization: the N-N bond measures 1.333 , shorter than a typical single N-N bond (1.45 ), while adjacent C-N bonds are 1.331 , slightly shorter than the 1.337 C-N bond in due to the electronic effects of the neighboring . C-C bonds exhibit alternation, with lengths of 1.393 and 1.377 , deviating from the uniform 1.39 in , and bond angles are close to 120° (e.g., ∠N-N-C = 119.3°, ∠C-C-C = 116.8°), reflecting minor distortions from ideal aromatic geometry. In comparison to and other diazines, pyridazine displays a higher dipole moment of 4.2 , attributed to the polarity induced by the adjacent nitrogens, contrasting with 's zero and the lower values of (1,3-diazine, ~2.3 ) and (1,4-diazine, 0 ) due to their greater . This polarity arises from the uneven charge distribution across the N-N unit, and while the ring lacks significant strain typical of smaller heterocycles, the adjacent nitrogens introduce subtle electronic repulsion that influences bond uniformity compared to the more symmetric diazines. Pyridazine does not exhibit tautomerism in its parent form, maintaining a fixed structure stabilized by the aromatic .

Physical properties

Pyridazine is a yellow-brown liquid at with a of 80.090 g/mol. Its is 1.103 g/mL at 25 °C. The compound has a melting point of −8 °C and a of 208 °C at 760 mmHg. Pyridazine exhibits high solubility in polar solvents, being miscible with , dioxane, and , while soluble in and ; it shows negligible solubility in nonpolar solvents such as and . The dipole moment of pyridazine measures 4.2 , reflecting its pronounced polarity arising from the vicinal atoms in the heterocyclic ring. Key spectroscopic characteristics include UV-Vis absorption maxima near 220 nm and 300 nm in the gas phase, an IR band for the N-N stretch around 1500 cm⁻¹, and ¹H NMR chemical shifts for the ring protons in the range of δ 7.1–9.5 ppm.

Chemical properties

Pyridazine is a , with the pKa of its conjugate acid measured at 2.1. This basicity is notably lower than that of , whose conjugate acid has a pKa of 5.2, primarily due to the electron-withdrawing of the two adjacent atoms, which diminishes the available on the ring for . Additionally, the close proximity of the nitrogen lone pairs in the protonated form leads to electrostatic repulsion, further destabilizing the conjugate acid and reducing overall basicity. As the parent compound, pyridazine is electrically neutral and lacks N-H protons, rendering it non-acidic; acidity arises only in certain derivatives, such as N-substituted or partially hydrogenated forms. In terms of oxidation stability, pyridazine resists reaction with mild oxidizing agents but undergoes N-oxidation when treated with strong oxidants to form mono- or di-N-oxides. These N-oxides serve as versatile intermediates in and photochemical applications, highlighting the compound's reactivity under forcing conditions. For reduction, pyridazine can be selectively partially reduced to dihydropyridazines, typically using amalgamated metals like or in acidic media, which adds two electrons to the heterocyclic ring and yields isomers such as 1,2- or 1,4-dihydropyridazine. Pyridazine demonstrates good thermal stability under ambient and standard conditions, remaining intact up to temperatures near its of 208 °C, though it undergoes at higher temperatures. In coordination chemistry, pyridazine functions as a bidentate , binding transition metals via its two atoms to form chelate complexes, with examples including (II) and (II) species. The molecule's significant dipole moment of 4.2 D, the largest among the series, influences the geometry and stability of these complexes by enhancing electrostatic interactions with metal centers.

Synthesis

Laboratory methods

The original laboratory synthesis of a pyridazine derivative was achieved by in 1886 through the condensation of with , yielding an intermediate that undergoes and to produce 3-methyl-6-phenylpyridazine along with byproducts such as and water. This multi-step process established the foundational route for accessing the pyridazine core in small-scale settings. The reaction scheme is as follows:

C₆H₅NHNH₂ + CH₃COCH₂CH₂COOH → [condensation, heat] intermediate [pyrazolone](/page/Pyrazolone) → [[hydrolysis](/page/Hydrolysis), [decarboxylation](/page/Decarboxylation)] 3-methyl-6-phenylpyridazine + CO₂ + H₂O

C₆H₅NHNH₂ + CH₃COCH₂CH₂COOH → [condensation, heat] intermediate [pyrazolone](/page/Pyrazolone) → [[hydrolysis](/page/Hydrolysis), [decarboxylation](/page/Decarboxylation)] 3-methyl-6-phenylpyridazine + CO₂ + H₂O

A versatile and commonly employed method for preparing pyridazines involves the -mediated cyclization of 1,4-diketones, which proceeds via formation of a dihydropyridazine intermediate followed by dehydrogenation. For instance, treatment of pentane-2,5-dione with hydrate in under reflux, followed by oxidation with , yields 3,6-dimethylpyridazine in approximately 70% overall yield. This approach is particularly suitable for substituted analogs and allows flexibility in substituent placement. The general reaction scheme is:

R-CO-CH₂-CH₂-CO-R' + H₂NNH₂ → [reflux, ethanol] 4,5-dihydropyridazine → [CrO₃, acetic acid] 3,6-disubstituted pyridazine

R-CO-CH₂-CH₂-CO-R' + H₂NNH₂ → [reflux, ethanol] 4,5-dihydropyridazine → [CrO₃, acetic acid] 3,6-disubstituted pyridazine

Pyridazine itself can be synthesized from maleic hydrazide by chlorination with phosphoryl chloride to yield 3,6-dichloropyridazine, followed by hydrogenolytic dechlorination using palladium on carbon under a hydrogen atmosphere. This method leverages the readily available maleic hydrazide precursor and is effective for small-scale production of the unsubstituted parent compound. Contemporary laboratory routes utilize [4+2] strategies, including inverse electron-demand Diels-Alder reactions between 1,2,4,5-tetrazines and alkynes, which generate pyridazines directly through extrusion of gas and aromatization, often in high and yields exceeding 80% under mild conditions such as heating in polar solvents. These methods are favored in research for their efficiency and compatibility with diverse substituents. Due to its boiling point of 209 °C at , pyridazine is commonly purified by under reduced pressure (typically 10–20 mmHg) to lower the distillation temperature and minimize .

Industrial production

Pyridazine is produced industrially on a limited scale, typically 10-100 tons per year globally, primarily as an intermediate for the synthesis of pharmaceutical and derivatives rather than the parent compound itself. The primary commercial route begins with the condensation of and hydrate to form maleic hydrazide (3,6-dihydroxypyridazine), followed by chlorination with to yield 3,6-dichloropyridazine, and concludes with hydrogenolytic dechlorination using hydrogen gas and catalyst to afford pyridazine. This multi-step process achieves overall yields optimized to greater than 80% through refined conditions, making it efficient and economically viable for scaled production. An alternative industrial approach involves the catalytic dehydrogenation of tetrahydropyridazine employing or similar heterogeneous catalysts under controlled heating to aromatize the ring system. While less prevalent than the route due to the availability of the saturated precursor, this method offers potential for integration with existing infrastructure in plants. Key challenges in include the safe handling of , a highly toxic and carcinogenic reagent that requires stringent ventilation, , and protocols to mitigate risks of skin irritation, respiratory damage, and long-term health effects. itself is sourced commercially via oxidation of using hypochlorite or oxidants, adding to considerations for cost and purity. Additionally, purification often necessitates high-temperature distillations to separate the product from chlorinated byproducts and catalyst residues, which increases energy consumption and operational expenses. These factors underscore the emphasis on process optimization for safety and economics in commercial settings.

Chemical reactions

Electrophilic substitution

Pyridazine, as an electron-deficient heteroaromatic system, exhibits significantly reduced reactivity toward (EAS) compared to due to the electron-withdrawing effects of the two adjacent atoms, which lower the in the π-system. The preferred site of substitution is the 3-position (equivalent to the 6-position by ), where the Wheland intermediate—a σ-complex formed during EAS—experiences better stabilization through involving the nitrogen lone pairs without placing excessive positive charge on the heteroatoms. This regioselectivity arises from the higher electron density at C3, as determined by considerations in azines. Nitration of pyridazine typically requires , such as through the 1-oxide , to overcome deactivation; of pyridazine 1-oxide with acyl yields 3-nitropyridazine 1-oxide as the major product, which can be subsequently deoxygenated to afford 3-nitropyridazine. The mechanism follows the standard SEAr pathway: electrophilic attack by the nitronium ion (NO₂⁺) at C3 forms the Wheland intermediate, followed by loss of a proton to restore . Halogenation, such as bromination, also occurs preferentially at the 3-position under mild conditions, though yields are moderate due to overall ring deactivation. The reaction proceeds via of Br⁺ to C3, generating a stabilized Wheland intermediate, with yielding 3-bromopyridazine. Friedel-Crafts acylation is particularly challenging on unsubstituted pyridazine, as the basic nitrogens coordinate to Lewis acid catalysts like AlCl₃, leading to deactivation and complexation rather than substitution; successful often requires prior protection of the atoms, such as through N-oxidation or quaternization, to prevent . Without protection, the reaction fails to proceed effectively, highlighting the need for modified conditions in systems.

Nucleophilic substitution

Nucleophilic aromatic substitution (SNAr) reactions on pyridazine occur readily at positions activated by the electron-withdrawing atoms, particularly in 3- or 4-halo derivatives, where the adjacent nitrogens reduce electron density at the carbon bearing the halogen . The reactivity is enhanced compared to but follows an addition-elimination mechanism typical of electron-deficient azines. Among halo-pyridazines, the order of reactivity for nucleophilic displacement is position 4 > 3 > 2, with the 4-position most favored due to maximal activation by both ring nitrogens. The mechanism proceeds via nucleophilic addition to form a negatively charged Meisenheimer complex, which is particularly stabilized at these positions by delocalization onto the adjacent nitrogen; subsequent elimination of the leaving group restores aromaticity. A representative example is the reaction of 3-chloropyridazine with , which displaces the to afford 3-aminopyridazine in high yield (typically 65–90%) under in or aqueous conditions. Similarly, treatment with hydrazines yields hydrazinyl derivatives, often used as intermediates for fused triazolo[4,3-b]pyridazines with yields ranging from 11–66%. Alkoxides react analogously to produce alkoxy-pyridazines, as seen in the conversion of activated halo variants to ethers in 69–82% yield. In comparison to , pyridazine exhibits lower reactivity in SNAr due to the adjacency of the two atoms, which introduces lone-pair repulsion and diminishes the net electron-withdrawing influence on the ring despite similar overall electron deficiency (evidenced by conjugate acid pKa values: pyridazine 2.3 vs. pyrimidine 1.3).

Other reactions

Pyridazine participates in inverse electron demand Diels-Alder reactions as a with electron-rich dienophiles such as alkenes and alkynes, leading to bridged bicyclic that can undergo subsequent . For instance, the reaction with proceeds under thermal conditions to afford the corresponding adduct, which rearranges to pyridazine-fused systems, providing a route to complex polycyclic structures. Reduction of pyridazine can achieve complete saturation to via catalytic using catalysts under elevated pressure and temperature, typically in acidic media to facilitate the process. Partial reduction to 1,4-dihydropyridazine is accomplished selectively with in protic solvents like at , yielding the non-aromatic intermediate useful for further transformations. N-oxidation of pyridazine occurs readily with (mCPBA) in at low temperatures, producing pyridazine N-oxide as the primary product; over-oxidation can lead to the N,N'-dioxide under prolonged reaction times or excess reagent. These oxides serve as versatile intermediates for subsequent rearrangements and substitutions. Directed metalation of pyridazine at the C3 position is achieved through treatment with in at -78 °C, generating the 3-lithio derivative that enables electrophilic for regioselective functionalization, such as introduction of alkyl, aryl, or carbonyl groups. This method exploits the inherent directing effect of the adjacent nitrogen atoms. Photochemical reactions of pyridazine under UV (typically 254-350 nm) induce dimerization, particularly for N-oxide , resulting in the formation of pyrazole-linked dimers via ring contraction and coupling pathways in solvents like . These processes are condition-dependent, with yields influenced by concentration and light intensity, offering access to novel fused heterocycles.

Applications

Pharmaceutical uses

Pyridazine have emerged as valuable scaffolds in due to their incorporation into various therapeutic agents, particularly in cardiovascular, , metabolic, and applications. The core pyridazine ring, a six-membered heterocycle with adjacent atoms, imparts unique electronic properties that facilitate interactions with biological targets, such as hydrogen bonding and π-π stacking. These often exhibit enhanced and metabolic stability compared to carbocyclic analogs, making them suitable for . In the realm of antihypertensives, , a phthalazine (a benzo-fused pyridazine), serves as a prototypical direct arterial vasodilator used in the management of and . Its mechanism involves relaxation of vascular , potentially through inhibition of intracellular calcium release and increased of from the , leading to reduced peripheral resistance without significant effects on venous capacitance. is typically administered orally or intravenously, often in combination with other agents to mitigate reflex . Pyridazine moieties also feature in agents, exemplified by cefozopran, a fourth-generation with broad-spectrum activity against Gram-positive and , including . The drug incorporates an imidazo[1,2-b]pyridazinium side chain at the 3-position of the cephem nucleus, which enhances β-lactamase stability and cellular penetration, contributing to its efficacy in treating severe infections such as and intra-abdominal . Cefozopran is administered intravenously and has been approved in several countries for hospital use. Pyridazinone derivatives, particularly those with carbonyl substitution at the 3-position, have shown promise as antidiabetic and anti-inflammatory agents through agonism of peroxisome proliferator-activated receptor gamma (PPARγ). For instance, benzenesulfonylurea-substituted pyridazinones activate PPARγ, promoting insulin sensitization and glucose uptake in adipocytes, akin to thiazolidinedione analogs like pioglitazone, while exhibiting reduced side effects such as weight gain in preclinical models. These compounds also inhibit pro-inflammatory cytokines like TNF-α and IL-6, positioning them as dual agents for type 2 diabetes management and associated inflammatory conditions. Structure-activity relationship (SAR) studies reveal that aryl substitutions at the 6-position optimize binding affinity to the PPARγ ligand-binding domain, enhancing transcriptional activity. In , 3,6-disubstituted pyridazines represent a novel class of (CDK) inhibitors, targeting CDK2 to disrupt progression in cancer cells. Compounds with phenyl or heteroaryl groups at the 3- and 6-positions demonstrate nanomolar values against CDK2, inducing G1/S arrest and in breast and cell lines. SAR analyses indicate that electron-withdrawing substituents at the 3-position improve selectivity and potency, while the high dipole moment of the pyridazine core (approximately 4.2 ) facilitates favorable interactions with polar residues in the ATP-binding pocket. These derivatives offer potential as alternatives to approved CDK inhibitors like , with ongoing efforts to optimize for clinical translation. The biological properties of pyridazine derivatives are underpinned by their high dipole moment, which promotes binding to polar protein pockets and enhances solubility in aqueous environments, as evidenced in numerous SAR investigations. This electronic feature, combined with tunable through substitutions, allows for targeted modulation of receptor affinity and selectivity across therapeutic classes.

Agrochemical applications

Pyridazine derivatives have found significant application in , particularly as for in various crops. Credazine, a pyridazine-based compound, was historically used as a selective herbicide to manage annual grasses such as crabgrass and barnyardgrass, as well as broadleaved weeds like and charlock, primarily in tomatoes, strawberries, and fields. Its mode of action involves inhibition of and , leading to disrupted growth in target weeds. Although now obsolete due to limited data on its environmental behavior, credazine exemplifies early pyridazine utilization in . More contemporary examples include pyridate and its primary metabolite, pyridafol, both pyridazine derivatives employed as post-emergence contact herbicides. Pyridate is applied to cereals like and , as well as crops including and , to control broadleaved weeds such as nightshade, cleavers, and chickweed, and grasses like barnyardgrass and foxtail. It functions by rapidly hydrolyzing to pyridafol, which inhibits photosynthetic electron transport at (HRAC Group C3), blocking the QB site and causing rapid degradation through toxic oxygen release. Pyridafol itself exhibits similar activity, targeting the same weeds in cereals, brassicas, alliums, and beet, with enhanced when combined with phenoxyacetic acids. In and applications, pyridazinone derivatives like pyridaben provide control against pests in crops. Pyridaben is a non-systemic and used on trees, , strawberries, and ornamentals to target mites, rust mites, , , and leafhoppers throughout their life stages, offering rapid knockdown and long residual effects. Its mode of action involves inhibition of mitochondrial complex I electron transport ( Group 21A), disrupting ATP production in pests. Recent studies have also demonstrated pyridaben's potential as a novel against powdery mildew (Sphaerotheca fuliginea) in crops like cucumbers. Insecticidal uses of pyridazine derivatives remain limited compared to herbicides, with some pyridazinones acting as acetylcholinesterase inhibitors. For instance, pyridaphenthion, a pyridazinone , exhibits insecticidal activity against agricultural pests, contributing to through disruption of nerve function in . Patents describe additional pyridazinone derivatives with miticidal and insecticidal properties, though commercial adoption is less widespread than in herbicidal applications. Environmental impacts of pyridazine-based agrochemicals include moderate persistence and specific degradation pathways that influence their . Pyridafol, for example, degrades in with a laboratory DT₅₀ of 2.2 days but persists longer in field conditions (DT₅₀ 97 days), showing high mobility (Koc 104 mL/g) and potential for leaching into . Pyridaben demonstrates moderate persistence (DT₅₀ 55 days typical) but undergoes rapid aqueous photolysis (DT₅₀ 0.005 days), limiting its mobility and (BCF 48 L/kg). Common degradation involves hydrolysis to pyridazinone intermediates, as seen with pyridate converting to pyridafol, which can affect non-target aquatic systems if runoff occurs. Overall, these compounds balance efficacy with environmental considerations through targeted application and rapid breakdown under light exposure.

Other industrial uses

Pyridazine derivatives function as bidentate N-N donor ligands in complexes, particularly with and , facilitating various catalytic processes. For instance, (II) complexes bearing pyridazine-based N-heterocyclic ligands demonstrate high efficiency in the aerobic oxidation of alkenes to diketones, achieving turnover numbers up to 1000 under mild conditions. These ligands enhance catalyst stability and selectivity by coordinating through the adjacent nitrogen atoms, mimicking bipyridine systems but offering unique electronic properties due to the pyridazine ring's electron-deficient nature. While direct applications in cross-coupling reactions like the Heck process are emerging through pyridazine-fused heterocycles, the core motif improves in related Pd-catalyzed couplings by stabilizing key intermediates. In the realm of dyes and pigments, azo-pyridazine compounds are valued for their vibrant colors and superior fastness properties in textile applications. Disperse azo dyes derived from 3-amino-1H-pyrazolo[3,4-c]pyridazine exhibit excellent exhaustion and fixation on polyester fabrics, yielding shades from orange to deep red with good to excellent wash and light fastness ratings (typically 4-5 on the ISO blue wool scale). These dyes' high colorfastness stems from strong hydrophobic interactions and minimal hydrolysis, making them suitable for durable coloration in synthetic textiles without significant fading during laundering or exposure to sunlight. Similarly, aminothienopyridazine-based azo dyes provide bright hues and resistance to sublimation, enhancing their utility in high-performance apparel and upholstery. Pyridazine's incorporation into polyheterocycles has enabled the development of conductive polymers and materials with tunable electronic properties. Poly(3,6-pyridazine), synthesized via chemical oxidation, displays electrical conductivity on the order of 10^{-3} S/cm in its undoped state, increasing significantly upon doping with iodine or AsF_5 to reach metallic regimes. This polymer's planar, nitrogen-rich structure promotes π-conjugation, facilitating charge transport suitable for and sensors. Poly(3,6-pyridazine ), a related variant, exhibits even higher intrinsic conductivity (up to 10 S/cm when electrochemically prepared), positioning it as a promising candidate for flexible conductive films and layers in thin-film transistors. These materials benefit from pyridazine's ability to form stable, electron-deficient backbones that enhance carrier mobility without requiring heavy doping. Fluorescent pyridazine derivatives have found applications in optical materials, particularly as emitters in organic light-emitting diodes (OLEDs) due to their tunable and high quantum yields. Compounds featuring pyridazine cores conjugated with phenoxazine or dihydroacridine units exhibit thermally activated delayed (TADF), enabling efficient harvesting of triplet excitons for to emission with external quantum efficiencies exceeding 20% in non-doped devices. The pyridazine ring's electron-accepting properties allow precise control over the highest occupied (HOMO) and lowest unoccupied (LUMO) energy levels, optimizing charge balance and reducing non-radiative decay. For example, pyridazine-carbazole hybrids serve as bipolar hosts in solution-processed OLEDs, achieving low turn-on voltages (around 3 V) and stable with Commission Internationale de l'Eclairage (CIE) coordinates suitable for display applications. Pyridazine-based compounds act as effective inhibitors for metals, primarily through adsorption onto surfaces to form protective barriers. Novel pyridazine derivatives, such as 6-(4-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carbohydrazides, inhibit mild corrosion in 1 M HCl with efficiencies up to 96% at low concentrations (10^{-3} M), attributed to and via lone pairs and π-electrons. These inhibitors outperform traditional ones by forming compact monolayers that block anodic and cathodic sites, as confirmed by electrochemical impedance showing increased charge transfer resistance. Pyridazinone derivatives similarly protect in acidic media, with inhibition efficiencies of 90-95% via mixed-type adsorption following Langmuir isotherms, making them eco-friendly alternatives for industrial formulations in oil pipelines and cooling systems.

Occurrence

Natural occurrence

Pyridazines and their derivatives are exceedingly rare in natural sources, likely owing to the instability and scarcity of hydrazine precursors required for their biosynthesis. This rarity is underscored by the fact that only a handful of confirmed examples exist, primarily as components of microbial metabolites or marine alkaloids. Among the earliest identified natural pyridazines are reduced forms known as hexahydropyridazines, first reported in 1971 from microbial origins by Hassall and colleagues. Aromatic pyridazines appear even less frequently; notable examples include pyridazomycin, an antifungal antibiotic isolated from the soil bacterium Streptomyces violaceusniger, which features a pyridazinium ring linked to a glutamic acid moiety. Another is azamerone, a phthalazinone meroterpenoid produced by the marine sediment-derived bacterium Streptomyces sp. CNQ-766, biosynthesized through a unique rearrangement of an aryl diazoketone intermediate in the nap pathway. Trace occurrences have also been detected in marine organisms, such as the cytotoxic zarzissine, a 4,5-guanidino-pyridazine isolated from the Mediterranean Anchinoe paupertas (syn. Phorbas paupertas). These compounds are typically identified in environmental or biological samples using sensitive techniques like liquid chromatography-mass spectrometry (LC-MS), which enables detection of low-abundance pyridazine-fused systems in complex matrices. Pyridazines are not biosynthesized in plants, where they occur only as minor, non-native components in metabolic pathways targeted by synthetic herbicides, rather than as endogenous metabolites. Microbial production, particularly by actinobacteria like species involved in hydrazine-related metabolism, represents the primary biogenic route, though such pathways remain uncommon in the broader .

In synthetic compounds

Pyridazine functions as a versatile in the synthesis of man-made chemicals, particularly within the pharmaceutical and sectors, where it enables the creation of diverse bioactive molecules. Its incorporation into molecular frameworks is evidenced by over 100,000 patents related to and more than 100,000 for applications, underscoring its role in enabling structural modifications that enhance potency and selectivity. These patents often highlight pyridazine's utility in forming fused heterocycles and substituted derivatives that mimic or improve upon existing pharmacophores. Among pyridazine derivatives, 3,6-disubstituted variants are prominently used in as bioisosteres for pyridines, offering comparable electronic profiles while potentially improving metabolic stability and receptor binding due to the adjacent atoms' influence on dipole moment and hydrogen bonding. This substitution strategy has been applied in designing inhibitors for enzymes like GSK-3 and in optimizing leads for various therapeutic targets, leveraging pyridazine's weak basicity and high polarity for better pharmacokinetic properties. In environmental contexts, pyridazine derivatives arise as degradation products from anthropogenic sources, notably herbicides like pyridate, which undergoes rapid in to form pyridafol (6-chloro-3-phenylpyridazin-4-ol) under aerobic, anaerobic, and dark conditions, persisting as a non-mobile residue that influences microbial activity. This breakdown contributes to the anthropogenic distribution of pyridazines, contrasting with their rarity in natural systems. Pyridazine scaffolds are routinely integrated into combinatorial libraries for in , facilitating the rapid generation of diverse analogs through multi-component reactions and facilitating lead identification for targets such as kinases and G-protein coupled receptors. Their prevalence in such libraries stems from efficient synthetic accessibility and the scaffold's ability to support parallel functionalization at multiple positions, accelerating the evaluation of structure-activity relationships.

History

Discovery

Pyridazine was first discovered in 1886 by during his investigations into the synthesis of indoles. While exploring reactions involving , Fischer identified a novel formed through the condensation of with . This unexpected product emerged as a in attempts to generate indoles, marking the initial identification of the pyridazine ring system. Early efforts to isolate the compound faced significant challenges, as the reaction mixtures yielded impure products contaminated by side reactions that preferentially formed indoles instead of the desired . work highlighted the competing pathways in condensations, requiring careful optimization to favor pyridazine formation. The discovery and initial characterization were detailed in a seminal in Justus Liebig's Annalen der Chemie. The unsubstituted pyridazine was first isolated in 1895 by Isidor Tauber through of a pyridazine derivative. The structure of pyridazine was rigorously confirmed in 1887 by Ludwig Knorr, who employed degradation techniques to break the compound down into known chemical fragments, thereby establishing its identity as a six-membered aromatic ring with adjacent atoms. Knorr proposed the name "," combining elements of "" and "" to denote its hybrid nature as a analog of .

Development

In the early , particularly during the and , significant progress was made in understanding the reactivity and substitution patterns of pyridazine, building on its initial synthesis in 1886. Chemists contributed to the elucidation of electrophilic and behaviors, establishing key reactivity profiles that distinguished pyridazine from other diazines like and . These studies laid foundational knowledge for later synthetic applications, with detailed compilations of such early work appearing in subsequent reviews. The 1950s marked the transition of pyridazine into practical applications, notably in pharmaceuticals, with the approval of in 1953 as an antihypertensive agent acting as a relaxant for treating and . This represented one of the first commercial uses of a pyridazine , highlighting its potential in due to favorable pharmacokinetic properties. By the and , pyridazine scaffolds gained traction in agrochemicals, exemplified by the development of credazine, an patented in the mid- for controlling grasses and broadleaf weeds, amid a broader boom in pyridazine-based pesticides. Comprehensive reviews such as Comprehensive Heterocyclic Chemistry II (1996) and III (2008) served as milestones, systematically compiling pyridazine reactivity, synthesis methods, and applications up to those periods, facilitating further research. In the onward, pyridazine emerged as a bioisostere in , leveraging its high dipole moment and hydrogen-bonding capabilities to mimic other heterocycles while improving and reducing liabilities like hERG binding in kinase inhibitors and allosteric modulators. Recent innovations include techniques, such as the 2025 method for direct pyridine-to-pyridazine conversion via azide-mediated carbon-to-nitrogen replacement, enabling access to diverse pyridazine analogs while preserving . This period has also seen a surge in , with over 1,000 patents filed since 2010 focused on pyridazine-based anticancer agents targeting pathways like EGFR and JNK1.

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