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Pyrazole

Pyrazole is a five-membered heterocyclic aromatic with the molecular formula C₃H₄N₂, characterized by a ring structure composed of three carbon atoms and two adjacent atoms, where one is pyrrole-like (with a ) and the other is pyridine-like. It exists primarily as the 1H-tautomer but exhibits tautomerism with 3H- and 4H-pyrazole forms, contributing to its chemical versatility. Pyrazole appears as a colorless crystalline solid with a pyridine-like and acts as a with a pK_b of 11.5; it has a of approximately 69–70 °C, a of 187–188 °C, and is partially soluble in (about 19.4 g/L at 25 °C). Its aromatic 6π-electron system makes it resistant to oxidation and reduction, though the C4 position is particularly susceptible to , while the ring can open under strong basic conditions or electrolytic oxidation. Pyrazole also forms hydrogen-bonded dimers in concentrated solutions and has a pK_a of 2.48, indicating moderate acidity for the N-H proton. The compound is commonly synthesized through the condensation of 1,3-dicarbonyl compounds or their equivalents (such as α-enones or alkynes) with , often yielding high efficiency (up to 93% with catalysts like Sc(OTf)₃), and alternative routes include ring transformations or reactions with ketene acetals. In applications, pyrazole serves as a key building block in , particularly for pharmaceuticals with antimalarial, anticancer, , and antitubercular properties, as well as agrochemicals, dyes, and bleaching agents. It functions as a bifunctional chelating in metal catalysts and is noted for biological relevance, including as an and a natural component in plants like Glycyrrhiza glabra, though evidence for teratogenicity in animal models remains equivocal.

Structure and Properties

Molecular Structure

Pyrazole is a five-membered with the molecular formula C_3H_4N_2, consisting of three carbon atoms and two adjacent atoms at positions 1 and 2 in the ring. The is 1H-pyrazole, while the systematic name is 1,2-diazole; it is identified by number 288-13-1 and number 206-017-1, with a molecular weight of 68.08 g/mol. The pyrazole ring exhibits through a delocalized 6 π-electron system, satisfying (4n + 2, where n = 1), which arises from two double bonds contributing 4 electrons and the on the pyrrole-like nitrogen providing the remaining 2. This aromatic character is evident in the planar geometry of the ring, as confirmed by , where the atoms deviate by less than 0.01 Å from the mean plane. Bond lengths reflect this delocalization: C–N bonds are approximately 1.33 Å (ranging from 1.326(3) to 1.344(3) Å), and C–C bonds are around 1.37 Å (1.366(3) to 1.389(3) Å), with the N–N bond at about 1.35 Å (1.351(2) to 1.354(2) Å). Pyrazole undergoes tautomerism between the 1H-pyrazole and 2H-pyrazole forms, involving proton migration between the two atoms; the 1H-tautomer predominates in both gas and due to greater stability, often by a ratio of about 3:1 in aqueous media at 25°C. This tautomerism influences the electronic distribution but preserves the overall aromatic π-system in both forms.

Physical Properties

Pyrazole is a colorless crystalline solid at with a pyridine-like , melting to a colorless above its of 68–70 °C. Its is 186–188 °C at . The exhibits moderate in , approximately 19.4 g/L at 25 °C, and is freely soluble in organic solvents such as and . The density of the phase is 1.026 g/cm³ at 70 °C. Pyrazole behaves as a , with a pK_b value of 11.5 at 25 °C, reflecting the basicity of its pyrrole-like . The molecular is approximately 2.2 D, attributable to the asymmetric arrangement of the two atoms in the five-membered ring. Under standard laboratory conditions, pyrazole remains stable, but it undergoes at temperatures exceeding 300 °C, consistent with the high (298 kJ/mol) required for ring breakdown.

Chemical Properties

Pyrazole exists in a tautomeric between the 1H-pyrazole and 2H-pyrazole forms, with the 1H-tautomer predominating at approximately 75% in at 25°C, influencing in reactions. This equilibrium arises from the mobility of the NH proton between the two nitrogen atoms, leading to indistinguishable 3- and 5-positions in unsubstituted pyrazole and directing electrophilic attacks to the electron-rich C4 position. As an amphoteric heterocycle, pyrazole exhibits weak basic character, with its conjugate acid having a pKa of approximately 2.5 due to protonation at the pyridine-like N1 nitrogen. The NH group imparts very weak acidity, with a pKa of about 14.2, allowing it to act primarily as a under typical conditions. Electron density distribution favors electrophilic substitution at C4, the most activated carbon, as seen in reactions that yield 4-nitropyrazole as the major product. Conversely, the electron-deficient C3 and C5 positions are susceptible to , while the lone pairs on the atoms enable coordination to metal centers. The structural features of pyrazole confer strong hydrogen bonding capabilities, with the NH functioning as a donor and the unprotonated N as an acceptor, facilitating intermolecular associations in solid and states. Pyrazole demonstrates resistance to mild oxidation due to its aromatic stability but undergoes reduction via catalytic to form pyrazoline.

History and Development

Discovery and Early Synthesis

The exploration of derivatives in the late , spurred by Emil Fischer's synthesis of in and Theodor Curtius's isolation of itself in 1887, laid the groundwork for advances in heterocyclic chemistry. In 1883, Ludwig Knorr achieved the first synthesis of pyrazole-containing compounds by condensing with β-keto esters, such as , to form pyrazolone derivatives like antipyrine (). This reaction introduced the pyrazole ring system—a five-membered heterocycle with adjacent nitrogen atoms—and Knorr coined the term "pyrazole" to describe it, marking the initial recognition of its structure as a 1,2-diazole isomer distinct from the 1,3-diazole . Knorr's work demonstrated the potential of hydrazine derivatives in forming stable aromatic heterocycles, with the pyrazolone products exhibiting antipyretic properties that spurred further interest. Although these early compounds were substituted pyrazoles rather than the unsubstituted parent, they established the core reactivity patterns, including cyclocondensation and tautomerism between and forms. The synthesis of unsubstituted pyrazole followed soon after. In 1889, Eduard Buchner prepared it via of pyrazole-3,4,5-tricarboxylic acid, providing the first access to the parent compound. Building on this, Hans von Pechmann reported in 1898 a direct route involving the 1,3-dipolar of to , yielding pyrazole albeit in low yield due to the challenges in handling the volatile reactants. This method underscored the role of diazoalkanes in pyrazole formation and influenced subsequent synthetic strategies within the evolving field of hydrazine-based heterocyclization.

Naming and Characterization

The term "pyrazole" was first coined by the German chemist Ludwig Knorr in 1883 to describe the core heterocyclic nucleus obtained from derivatives, reflecting its structural relation to with an additional atom replacing a carbon and the removal of the carbonyl group from pyrazolone. This naming established pyrazole as a distinct class of five-membered azoles, distinguishing it from related diazoles like . In the , the International Union of Pure and Applied Chemistry (IUPAC) formalized the through its recommendations on heterocyclic compounds, designating the preferred name as 1H-pyrazole to denote the predominant tautomeric form with the hydrogen attached to the nitrogen at position 1. Early characterization of pyrazole relied on spectroscopic methods to confirm its structure following initial syntheses. Infrared (IR) spectroscopy revealed a characteristic N-H stretching band at approximately 3200 cm⁻¹, shifted lower due to intermolecular hydrogen bonding in the solid state or solutions, which helped verify the presence of the NH group in the ring. Ultraviolet (UV) spectroscopy provided further evidence through absorption maxima around 210 nm, attributable to π-π* transitions in the aromatic heterocycle. Modern analytical techniques have refined pyrazole's characterization with greater precision. (¹H NMR) spectroscopy typically shows signals for the ring protons (H-3, H-4, and H-5) in the range of δ 6.3-8.0 ppm in deuterated solvents like DMSO-d₆ or CDCl₃, with the deshielded H-3 and H-5 protons appearing around 7.5-7.6 ppm due to the electron-withdrawing effects of adjacent s. confirms the molecular formula via the molecular ion peak at m/z 68 [M]⁺, often with characteristic fragmentation patterns involving loss of or . Pyrazole exhibits a of 66-70 °C and undergoes preferentially at the 4-position.

Synthesis

Classical Methods

The Knorr pyrazole synthesis, developed in the late , involves the condensation of s with 1,3-dicarbonyl compounds, such as β-diketones or β-ketoesters, often under acidic or basic conditions, leading to the formation of pyrazoles through cyclization and dehydration. This method provides a direct route to 3,5-disubstituted pyrazoles, where the substituents at the 3- and 5-positions originate from the carbonyl groups of the 1,3-dicarbonyl precursor. A representative example is the reaction of with hydrazine hydrate, yielding 3,5-dimethylpyrazole in 73–77% yield after recrystallization, typically conducted at low temperatures around 15°C in aqueous alkali to control the addition. The general reaction can be represented as: \mathrm{R-CO-CH_2-CO-R' + H_2N-NH_2 \rightarrow \begin{pmatrix} \text{pyrazole} \\ (1-\mathrm{H}, 3-\mathrm{R}, 5-\mathrm{R'}) \end{pmatrix} + 2 \mathrm{H_2O}} However, when the substituents R and R' differ, the Knorr synthesis often suffers from challenges, producing mixtures of 3,5- and 1,3-isomers that require chromatographic or fractional separation, with ratios depending on the electronic and steric properties of the groups. Another classical approach, the Pechmann pyrazole synthesis introduced in 1898, utilizes a 1,3-dipolar between and or other alkynes to form pyrazolines, which are subsequently oxidized to pyrazoles. This method is particularly hazardous due to the explosive nature of diazomethane and typically affords low yields, limiting its practical utility despite its historical significance in preparing unsubstituted pyrazole. Pyrazoles can also be synthesized classically from α,β-unsaturated carbonyl compounds via initial Michael addition of to the , followed by intramolecular cyclization to a pyrazoline and dehydrogenation, often using oxidants like or air. This route is versatile for 3- or 5-monosubstituted pyrazoles but similarly encounters issues, yielding isomeric mixtures that necessitate purification, and is best suited for derivatives where the unsaturated system bears electron-withdrawing groups to enhance reactivity.

Modern Variations

Since the , modern synthetic strategies for pyrazoles have focused on enhancing efficiency, , and environmental compatibility through techniques like irradiation and multicomponent reactions. -assisted cyclization of hydrazines with chalcones has emerged as a rapid method, dramatically reducing reaction times from hours to minutes while achieving high yields. One-pot multicomponent reactions have further streamlined pyrazole synthesis by integrating multiple steps without isolation of intermediates, often employing acids for . The reaction of enaminones with hydrazines in the presence of or related zinc complexes in enables regioselective formation of 1,3-disubstituted pyrazoles with yields exceeding 80%, proceeding via enamine-imine tautomerism and cyclocondensation at . These protocols improve and scalability, addressing classical challenges in a single vessel. Analogs of , particularly 1,3-dipolar cycloadditions involving compounds or nitrile imines derived from hydrazonoyl precursors with alkynes, provide efficient access to N-substituted pyrazoles. These metal-free or copper-catalyzed cycloadditions yield 1,4-disubstituted pyrazoles with excellent (>95:5) under mild conditions, such as in aqueous media at ambient temperature, facilitating the incorporation of diverse N-protecting groups for downstream functionalization. Sustainability has driven the development of green methods, including solvent-free and aqueous protocols that eliminate volatile organic solvents. Solvent-free microwave or grinding-assisted reactions of hydrazines with 1,3-dicarbonyl equivalents produce pyrazoles in 85–95% yields, while aqueous variants using recyclable catalysts like Amberlyst-70 enable room-temperature synthesis with minimal waste. Emerging enzymatic approaches, such as lipase-mediated resolutions of hydrazine intermediates or bio-inspired catalysts, offer stereoselective variants, though they remain less common for direct cyclization. Post-2000 advances include palladium-catalyzed couplings for introducing functionalized substituents on pyrazole rings. Suzuki-Miyaura cross-couplings of pyrazole triflates or boronic acids with aryl halides, using Pd₂(dba)₃ ligands, afford 4- or 5-arylated pyrazoles in 70–90% yields with high , enabling late-stage diversification. In the 2020s, focus has shifted to asymmetric synthesis of chiral pyrazole derivatives, such as axially chiral heterobiaryls via organocatalytic arylation of 5-aminopyrazoles with naphthoquinones, achieving enantioselectivities up to 96% ee for bioactive scaffolds. A representative regioselective is the reaction of alkynyl ketones with hydrazines, forming 1,3-disubstituted pyrazoles: \begin{align*} &\ce{R-C#C-C(=O)-CH3 + H2N-NH-R' ->[base][rt]} \\ &\quad \ce{(1R',3R')-1-methyl-3-R-5-R'-1H-pyrazole} \end{align*} This base-mediated process proceeds via initial formation followed by 5-exo-dig cyclization, yielding >85% of the desired regioisomer without mixtures.

Natural Occurrence

Sources in Nature

Pyrazoles occur rarely in nature, with the first derivative being 1-pyrazolylalanine, isolated in 1959 from the seeds of ( lanatus). This analog was obtained through acid hydrolysis of seed proteins, marking the initial documentation of a naturally occurring pyrazole scaffold. Subsequent discoveries have pyrazole alkaloids in select plant species. In , the roots yield withasomnine, a (3-methyl-1-phenyl-1H-pyrazol-5(4H)-one), first reported in 1966. () contains pyrazole alkaloids such as 3,5-dimethyl-1-phenylpyrazole, which are present in mainstream smoke and undergo thermal degradation via pathways. Microbial sources include bacteria of the genus Pseudomonas, where pyrazolotriazine alkaloids such as pseudoiodinine have been isolated from Pseudomonas mosselii. This compound, characterized in 2023, represents a recent example of pyrazole-containing metabolites in prokaryotes. Trace pyrazole alkaloids occur in marine organisms, particularly sponges of the genus Cinachyrella, from which cinachyrazoles A–C (1,3,5-trimethylpyrazole variants) were isolated in 2017. No significant pyrazole forms have been reported in minerals or terrestrial animals. Isolation of natural pyrazoles typically involves solvent extraction of followed by purification via on or reversed-phase (HPLC), often guided by liquid chromatography-mass spectrometry (LC-MS) for detection. Yields are generally low, frequently below 1% of the dry weight, due to the rarity and low abundance of these compounds.

Biosynthetic Pathways

Pyrazoles occur rarely in nature, primarily as components of certain microbial and analogs, with their typically involving the formation of an N-N bond from -derived precursors. In bacteria such as candidus, the pyrazole ring of the C-nucleoside pyrazomycin is assembled through a pathway initiating with N-hydroxylation of L-lysine by the flavin-dependent monooxygenase PyrM to yield N^6-hydroxy-L-lysine. This intermediate then undergoes N-N bond formation with L-glutamate (or its D-enantiomer in related pathways), catalyzed by the PLP-dependent synthase PyrN, producing a lysine-glutamate conjugate that is further processed by saccharopine dehydrogenase-like PyrL into 2- acid, which cyclizes to form the pyrazole core. Similar mechanisms operate in the of formycin A and pyrazofurin in strains, where synthetases (ForJ/PyfG) couple N^6-hydroxy-L-lysine with D-glutamic acid, followed by reduction, cryptic N-acylation with (e.g., or L-threonine), and dehydrogenation to yield the pyrazole moiety, as revised in recent studies. In plants, particularly Cucumis sativus (cucumber), the pyrazole ring is generated from 1,3-diaminopropane, a degradation product derived from or . The pyrazole catalyzes the cyclization of 1,3-diaminopropane to 2-pyrazoline, followed by dehydrogenation to pyrazole; this pathway is stimulated by exogenous 1,3-diaminopropane or pyrazole itself, leading to incorporation into the non-proteinogenic amino acid β-pyrazol-1-yl-L-alanine via conjugation with O-acetyl-L-serine by β-pyrazol-1-ylalanine . Although no -like enzymes have been directly implicated in plant pyrazole formation, the overall route contrasts with microbial pathways by relying on cyclization rather than condensation. Fungal and additional bacterial routes, as seen in pyrazofurin production, involve oxidative transformations rather than intermediates, with a Rieske oxygenase triggering nonenzymatic ring contraction of a precursor to the pyrazole, though diazo-like transients may arise transiently during dehydrogenation steps. Biosynthetic clusters for pyrazole-containing compounds were identified in the through genome mining of actinomycetes; for instance, the ~28 pyr cluster in S. candidus encodes the core enzymes for pyrazomycin (pyrM, pyrN, pyrL), while the for and pyf clusters in other species govern formycin and pyrazofurin assembly, respectively. Natural pyrazole abundance remains low due to the toxicity of hydrazine intermediates, which disrupt cellular balance and limit flux through these pathways. Overexpression studies post-2020 have enhanced bioproduction; for example, overexpression of the cluster-situated PyrR in the pyr cluster increased pyrazomycin titers by approximately 10-fold to 10 mg/L in engineered hosts. An illustrative enzymatic step in plant metabolism is the conversion of 1,3-diaminopropane to pyrazole: \text{1,3-diaminopropane} \xrightarrow{\text{pyrazole synthase}} \text{2-pyrazoline} \xrightarrow{\text{dehydrogenation}} \text{pyrazole} This two-step process underscores the reliance on amine cyclodehydrogenation for pyrazole formation in eukaryotes.

Applications and Derivatives

Pharmaceutical Uses

Pyrazole derivatives have emerged as a privileged scaffold in pharmaceutical design due to their ability to mimic key pharmacophores and engage in favorable interactions with biological targets. One prominent example is celecoxib (Celebrex), approved by the FDA in 1998 for the management of osteoarthritis and rheumatoid arthritis symptoms, which features a 1,5-diarylpyrazole core as a selective cyclooxygenase-2 (COX-2) inhibitor. This compound exerts its anti-inflammatory effects by blocking prostaglandin synthesis primarily through COX-2 inhibition, offering reduced gastrointestinal side effects compared to non-selective NSAIDs. In the realm of , pyrazole-based compounds target epigenetic regulators and kinases. Tazemetostat, an inhibitor containing a pyrazole moiety, received FDA approval in 2020 for treating adults and pediatric patients with locally advanced or metastatic . This drug modulates gene expression by inhibiting EZH2-mediated trimethylation of lysine 27, thereby promoting tumor cell death in EZH2-mutated cancers. Beyond and cancer, pyrazoles contribute to treatments for metabolic and cardiovascular conditions. (Viagra), approved in 1998, incorporates a fused pyrazolo[4,3-d] system and functions as a phosphodiesterase-5 ( to treat and pulmonary arterial by elevating levels and promoting . , another key derivative, inhibits and was approved for treating or , preventing the formation of toxic metabolites. The pyrazole NH group commonly enables hydrogen bonding within active sites, enhancing binding affinity. Structure-activity relationship () studies reveal that substitutions at the and positions of the pyrazole ring often improve potency and selectivity, as seen in optimized COX-2 and inhibitors. By 2025, more than 40 pyrazole-containing drugs have been approved by the FDA, underscoring the scaffold's versatility across therapeutic areas.

Applications

Pyrazole derivatives have found significant application in agrochemicals as , fungicides, and herbicides, leveraging the heterocycle's ability to enhance target specificity and efficacy against pests while minimizing off-target effects. One prominent example is , a phenylpyrazole introduced in 1996, which acts as a GABA-gated antagonist, disrupting the of . This compound is particularly effective for control in structural and agricultural settings, where the pyrazole ring contributes to its high selectivity for insect receptors over mammalian ones, resulting in lower toxicity to non-target vertebrates. Due to its high toxicity to pollinators and persistence in the environment, fipronil has been banned for agricultural use in the since 2017 and faces restrictions or bans in several other countries, including parts of and . In development, pyrazole scaffolds enable novel modes of action against pathogens. Fluoxapiprolin, proposed for registration by the U.S. EPA in 2025, is a pyrazole-containing piperidinyl-thiazole-isoxazoline that inhibits oxysterol-binding proteins (OSBPs) in oomycetes, disrupting homeostasis and thereby inhibiting pathogen and growth. This provides effective control of diseases such as late blight on potatoes and on grapes and , offering a new tool for managing resistant strains in crops like potatoes. Pyrazole-based herbicides target key biosynthetic pathways in weeds, with pyrazosulfuron-ethyl serving as a representative derivative for . This compound inhibits acetolactate synthase (), an essential for synthesis in plants, effectively suppressing broadleaf and sedge weeds without significant impact on crops. The pyrazole moiety enhances binding affinity to the , promoting selective herbicidal activity. The versatility of pyrazoles in agrochemicals stems from the nitrogen atoms in the ring, which facilitate coordination with metal ions or hydrogen bonding in target enzymes, stabilizing interactions that underlie their modes of action across classes. For instance, in ALS inhibitors, these nitrogens contribute to precise docking within the enzyme's catalytic pocket. Pyrazole agrochemicals represent a growing segment of the global pesticide market, with fipronil alone projected to contribute around USD 300 million in value by 2025 amid broader adoption of pyrazole scaffolds in integrated pest management. Resistance management strategies emphasize rotating pyrazole-based products with those of differing modes of action, alongside cultural practices like crop rotation, to delay the evolution of resistant pest populations. Environmentally, pyrazole pesticides generally exhibit moderate , with biodegradation half-lives varying from several days to several months in under aerobic conditions, depending on the compound and environmental factors, facilitating their breakdown by microbial activity. They are characterized by low mammalian , often with oral LD50 values exceeding 90 mg/kg in , due to reduced affinity for receptors. This profile supports their use in while necessitating monitoring for aquatic impacts from runoff.

Coordination Chemistry and Ligands

Pyrazole and its serve as versatile ligands in coordination chemistry due to the atoms in the five-membered ring, which provide strong σ-donation capabilities through their lone pairs. These ligands are particularly valued for forming stable complexes with transition metals, enabling applications in and . Poly(pyrazolyl)borate ligands, known as scorpionates, exemplify this role, acting as tridentate N-donor systems that mimic coordination environments found in metalloproteins. Scorpionate ligands, such as hydrotris(pyrazolyl) (Tp), are synthesized by heating pyrazole with a , typically (KBH₄), at elevated temperatures around 200 °C. The reaction proceeds via stepwise and B–N formation, releasing gas, as shown in the equation for the : $3 \text{ pyrazole} + \text{KBH}_4 \rightarrow \text{K[HB(pz)}_3\text{]} + 3 \text{H}_2 This method, originally developed by Trofimenko, yields the tridentate κ³-HB(pz)₃ , where pz denotes the pyrazolyl group, providing three donors in a arrangement. Substituted variants, like hydrotris(3,5-dimethylpyrazolyl) (Tp*), enhance steric protection and tunability for specific metal centers. Hydrotris(pyrazolyl)methane (HOMOpy) ligands represent a class of carbon-centered homoscorpionates, HC(pz)₃, which offer similar tridentate N₃ coordination but with a methine pivot instead of boron. These neutral ligands are prepared by condensing pyrazole with orthoformate esters or related reagents, providing a facially coordinating environment suitable for asymmetric catalysis. For instance, rhodium complexes of chiral HOMOpy derivatives have been employed in enantioselective transformations, leveraging the ligand's ability to create sterically defined chiral pockets around the metal. In metal complexes, pyrazolyl ligands primarily engage through σ-donation from the pyrrole-like lone pairs, forming strong M–N bonds that stabilize high oxidation states. Additionally, the pyridine-like can participate in π-backbonding with electron-rich metals, enhancing transfer and influencing reactivity. This dual bonding mode contributes to the ligands' robustness in catalytic cycles. Pyrazolylborate complexes have found applications as catalysts in olefin , where group 4 metal derivatives, such as TpZrCl₃ activated by methylaluminoxane (MAO), promote and with high activity and control over polymer microstructure. These systems benefit from the tridentate ligation, which prevents β-hydride elimination and supports single-site behavior akin to metallocene catalysts. In , Tp and Tp* zinc complexes serve as models for enzymes like and , replicating the His₃ of the and enabling studies of and mechanisms under mild aqueous conditions. Recent advancements in the have incorporated pyrazole-based linkers into metal-organic frameworks (MOFs) for gas storage applications. For example, aluminum pyrazolate frameworks like MOF-303 exhibit high uptake capacities for and CO₂ due to coordinatively unsaturated sites and hydrogen-bonding motifs from the pyrazole units, achieving reversible storage exceeding 0.4 g/g for . These structures demonstrate enhanced selectivity and stability compared to carboxylate-based MOFs, with ongoing developments focusing on mixed-linker designs for and adsorption.