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Pyrazine

Pyrazine is a heterocyclic aromatic with the molecular formula C₄H₄N₂, featuring a six-membered ring in which two adjacent carbon atoms of are replaced by atoms at the 1 and 4 positions, making it a symmetrical . It serves as the parent scaffold for the pyrazine class of compounds, which are ubiquitous in natural and synthetic contexts due to their stability and reactivity. Physically, pyrazine manifests as a white crystalline solid with a strong, pungent reminiscent of nuts or corn, a of 54–56 °C, and a of 115–116 °C at standard . It exhibits high solubility in and , reflecting its polar atoms, and displays weak basicity compared to owing to the electron-withdrawing effects of the dual nitrogens, with a around 0.4 for its conjugate acid. Chemically, pyrazine participates in at carbon positions and is synthesized via methods like the condensation of 1,2-dicarbonyl compounds with α-diamines or . Pyrazines, including unsubstituted pyrazine, occur naturally in diverse biological systems such as , , and microorganisms, and are prominent in thermally processed foods like , , roasted meats, and baked goods, where they form through the involving and reducing sugars at temperatures of 120–150 °C. This reaction pathway, including Strecker degradation, generates pyrazines that impart characteristic roasted, nutty, or earthy flavors essential to and aroma profiles. In applications, pyrazine functions as a flavoring agent in the food industry, approved by regulatory bodies like the FDA for use at levels posing no safety concern based on current intake estimates. Derivatives of pyrazine are integral to pharmaceuticals, exemplifying antimicrobial properties—as in pyrazinamide, a frontline drug for tuberculosis treatment—and broader biological activities including anti-inflammatory, anticancer, and antifungal effects in various complexes and analogs. Additionally, pyrazines find utility in materials science for luminescent compounds and in fragrance formulations due to their volatile, odor-active nature.

Properties

Physical properties

Pyrazine has the molecular formula C₄H₄N₂ and consists of a six-membered heterocyclic ring with nitrogen atoms positioned at the 1 and 4 loci, forming a diazine structure analogous to benzene but with two CH groups replaced by N. It appears as colorless crystals and exhibits a pungent, nutty odor reminiscent of roasted foods. The compound melts at 52 °C, boils at 115 °C, has a of 1.031 g/cm³ at 20 °C, and a of 55 °C. Pyrazine is soluble in water (11 g/L at 20 °C), as well as in and . Its is about 20 mmHg at 25 °C, and the of the liquid is 1.52. At , pyrazine exists as a solid and shows a tendency to under vacuum conditions, with an of of 56.2 / at 303 K. Its relatively high compared to non-aromatic analogs of similar molecular weight can be attributed to its aromatic stability.

Thermodynamic properties

Pyrazine exhibits aromatic character due to its six delocalized π-electrons in a planar, cyclic, conjugated system, satisfying (4n + 2, where n = 1) for aromatic stability. crystallographic studies confirm this with average C-N bond lengths of approximately 1.33 and C-C bond lengths of about 1.38 , indicative of partial double-bond character consistent with delocalization across the ring. The basicity of pyrazine is notably lower than that of , with the pK_a of its conjugate acid (pyrazinium ion) measured at 0.65 in at 20°C. This reduced basicity arises from the electron-withdrawing of the second atom, which destabilizes the positive charge on compared to pyridine's pK_a of 5.23. Thermodynamically, pyrazine demonstrates reflective of its symmetric aromatic structure, with a (Δ_f H°) of +196.1 ± 1.5 kJ/mol in the gas phase at 298 K. Its is 0 D, attributable to the D_{2h} that results in cancellation of individual bond dipoles. Upon , the preferred site is one of the equivalent atoms, leading to a symmetric pyrazinium cation without significant of the ring planarity. Pyrazine lacks stable tautomers in its neutral form, as any hypothetical shift of a from carbon to would disrupt the aromatic π-system, rendering such forms energetically unfavorable. In aqueous media, pyrazine engages in bonding primarily as an acceptor via its lone pairs, with energies influenced by these interactions; calculations indicate binding energies for pyrazine-water complexes on the order of -20 to -30 kJ/mol for the , facilitating moderate despite its nonpolar character.

Synthesis

Classical synthesis methods

The first synthesis of unsubstituted pyrazine was reported in 1882 by Wilhelm Weith, involving the heating of with under conditions that promote and dehydrogenation. Synthetic and laboratory-scale preparations of pyrazine and its simple derivatives emerged in the late , establishing foundational techniques for its cyclocondensation from simple precursors. These classical methods relied on ammonia-mediated reactions of carbonyl or halo-carbonyl compounds, though they were limited by inefficient processes suitable only for small-scale synthesis. The Staedel–Rugheimer synthesis, introduced in , represents one of the earliest systematic approaches, involving the treatment of 2-chloroacetophenone with to form an intermediate α-amino , followed by cyclocondensation and oxidation to yield 2,5-diphenylpyrazine. The key step proceeds via the self-condensation of two equivalents of the halo ketone under ammoniacal conditions: \ce{2 ClCH2C(O)Ph + 2 NH3 ->[cyclocondensation/oxidation] PhC4H2N2Ph + HCl + H2O + NH4Cl} This method produces the pyrazine ring through and subsequent ring closure, but it is plagued by low yields typically ranging from 10% to 30%, owing to competing side reactions that generate pyridines and other nitrogen heterocycles. Harsh conditions, including elevated temperatures (around 100–150°C) and excess , are required to drive the reaction, exacerbating byproduct formation and complicating purification. A notable variation, the Gutknecht synthesis reported in 1879, modifies the approach by employing the self-condensation of α-halo ketones under ammoniacal conditions, often starting from oximino ketones to α-amino ketones for improved handling. This technique optimizes yield through controlled (e.g., using tin and HCl), achieving marginally better efficiency for symmetric pyrazines like tetramethylpyrazine, yet still limited to 15–25% overall due to incomplete cyclization and impurities. The method avoids some lachrymatory issues of the original but retains the need for high temperatures and excess , highlighting the challenges in selectivity for early pyrazine preparations. The Gastaldi method, developed in 1921, provides a direct route to unsubstituted pyrazine using diaminomaleonitrile precursors, such as condensing the dinitrile with suitable carbonyl equivalents like derivatives under heating. This cyclization forms the parent heterocycle via and , offering a simpler entry to pyrazine without aryl substituents, though yields hover at 10–20% amid side products from or . Like prior techniques, it demands harsh conditions, including in alcoholic media with excess reagents, underscoring the general limitations of classical approaches: modest efficiency (10–30% yields), propensity for and reduced heterocycle byproducts, and reliance on vigorous heating with surplus. These constraints confined their use to proof-of-concept syntheses, paving the way for later optimizations in yield and selectivity.

Contemporary synthesis routes

Contemporary synthesis routes for pyrazine emphasize efficient, catalytic, and approaches that improve upon earlier methods by enhancing yields, reducing reaction times, and minimizing hazardous reagents. One prominent strategy involves multicomponent condensations of 1,2-diketones, such as , with under metal catalysis. For instance, phosphine-supported nanoparticles catalyze the reaction of α-diketones with to form substituted pyrazines in yields greater than 80%, typically at 100–120°C in , avoiding the need for stoichiometric oxidants. Similarly, catalysts facilitate the cyclization of isonitrosoacetophenones and aminoacetonitriles followed by , achieving yields of 55–80% in refluxing . These methods represent a shift from classical thermal condensations, which often suffer from low selectivity and high energy demands. Another approach utilizes the cyclization of N-substituted enediamines under oxidative conditions to construct the pyrazine ring. Enediamines, derived from precursors like α-amino ketones, undergo dehydrogenation with reagents such as N-bromosuccinimide (NBS) in at , yielding pyrazines through aromatization of intermediate dihydropyrazines with efficiencies up to 70–90% for substituted variants. This oxidative strategy is particularly useful for functionalized pyrazines, enabling precise control over substitution patterns. Biocatalytic methods offer sustainable alternatives, leveraging enzymes from bacterial sources for selective steps. Transaminases, such as ATA-113 from Arthrobacter sp., mediate the conversion of 1,2-diketones to α-amino ketones, which then cyclize to pyrazines under mild aqueous conditions ( 8–9, 30°C), delivering yields up to 99% for 2,5-disubstituted pyrazines while avoiding organic solvents and harsh reagents. These enzymatic processes highlight principles, with recyclability of biocatalysts enhancing overall for pharmaceutical-scale production. Post-2000 advances include -assisted protocols that drastically shorten reaction times to minutes while maintaining high efficiency. For example, the condensation of with 1,2-diketones under microwave irradiation (150–300 W, 5–10 min) in yields pyrazine derivatives in 70–92%, followed by purification via under reduced to isolate pure products. Such techniques reduce energy consumption compared to conventional heating and facilitate rapid optimization. Scalability in contemporary routes focuses on transitioning lab-scale reactions to pilot-plant operations through continuous-flow systems and catalyst immobilization, circumventing hazardous intermediates like α-halo ketones. Continuous-flow aminolysis of pyrazine esters with amines using solvent-free conditions achieves >90% yields on multi-gram scales, with easy purification and minimal waste, making it suitable for industrial applications. Ruthenium-catalyzed dehydrogenative couplings from diols and further support large-scale production by operating under acceptorless conditions, yielding pyrazines up to 92% without byproduct accumulation.

Reactivity

Electrophilic reactions

Pyrazine's electron-deficient nature, arising from the two atoms in the ring, renders it significantly deactivated toward relative to and even . In acidic conditions, of one atom occurs, further reducing the electron density on the ring and exacerbating this deactivation. This basicity-influenced interferes with catalyst interactions in many electrophilic processes. Direct of unsubstituted pyrazine is challenging due to its electron-deficient nature; however, activated pyrazine derivatives can undergo under forcing conditions, such as treatment with concentrated nitric and mixtures, primarily at the 2-position. is relatively more feasible among electrophilic substitutions on pyrazines; for example, bromination of activated pyrazine derivatives with Br2 in acetic acid affords 2-bromopyrazine analogs as the major product, with directed to the 2-position due to coordination of the with the nitrogen lone pairs. Standard Friedel-Crafts acylation fails on pyrazine owing to poisoning of the Lewis acid catalyst by the ring nitrogens, which coordinate strongly to metals like AlCl3. For activated pyrazines, the Vilsmeier-Haack using POCl3 and DMF can introduce an group at the 2-position, bypassing the catalyst issue. The mechanism of on pyrazine involves initial formation of a π-complex followed by the rate-determining generation of the Wheland (σ-complex) intermediate, stabilized preferentially at positions meta-like to the nitrogens (i.e., C-2/C-5). Computational studies using DFT methods indicate that the for Wheland intermediate formation correlates with the Fukui function f(r) at the attack site, rather than HOMO energy, explaining the observed and low reactivity. Under strong electrophilic conditions, side reactions such as polymerization or ring oxidation can compete, particularly when excess reagent or high temperatures are employed, leading to complex mixtures.

Nucleophilic and redox reactions

Pyrazine exhibits susceptibility to nucleophilic aromatic substitution (SNAr) primarily at the 2-position, where leaving groups such as halogens are displaced by nucleophiles like amines or alkoxides, owing to activation by the electron-withdrawing ring nitrogens. This reactivity follows an addition-elimination mechanism, often proceeding via radical-nucleophilic (SRN1) pathways in halogenated pyrazines under light or electron-transfer initiation. For instance, 2-chloropyrazine undergoes efficient substitution with alkoxide nucleophiles derived from primary or secondary alcohols, yielding alkoxy-substituted derivatives in 70–90% yields under mild conditions with thionyl chloride catalysis at 60°C. The general reaction can be represented as: \ce{2-halopyrazine + Nu^- -> 2-Nu-pyrazine + X^-} where Nu⁻ denotes the and X⁻ the . Reduction of pyrazine proceeds via catalytic hydrogenation to afford (C₄H₁₀N₂), a saturated six-membered , typically using (Pd/C) as the catalyst under atmospheric hydrogen pressure. Conditions such as 10% Pd/C in enable high diastereoselectivity (up to 79%) for substituted pyrazines, with the reaction often requiring acidic to prevent over-reduction or side products. Partial reduction to dihydropyrazines, retaining partial , can be achieved electrochemically at controlled potentials, yielding 1,4-dihydropyrazines as stable intermediates. in the resulting piperazines is influenced by the catalyst; for example, iridium-based systems provide enantioselectivities up to 96% ee for chiral variants, though Pd/C variants favor cis diastereomers in aqueous solvents. Oxidation of pyrazine targets the atoms, forming N-oxides with meta-chloroperbenzoic acid (mCPBA) in a straightforward manner, typically in at , producing pyrazine 1-oxide or 4-oxide depending on . These N-oxides exhibit good stability under neutral conditions but are protonated at the unsubstituted or N-oxide oxygen in ic media, facilitating regioselective further reactions. The reaction equation is: \ce{pyrazine + mCPBA -> pyrazine N-oxide + mCBA} where mCBA is meta-chlorobenzoic ; the N-oxide serves as a versatile intermediate for nucleophilic displacement or deoxygenation to access substituted pyrazines. In contexts, pyrazine functions as a bridging bidentate in metal complexes, influencing processes; for example, in the binuclear complex [(edta)Ru^{III}(pz)Ru^{III}(edta)]^{2-} (edta^{4-} = ethylenediaminetetraacetate; pz = pyrazine), stepwise with ascorbic generates mixed-valence Ru^{II}-pz-Ru^{III} and fully reduced Ru^{II}-pz-Ru^{II} species, with the pyrazine bridge mediating outer-sphere at potentials of 0.0 V and -0.4 V vs. SHE, respectively. This reactivity highlights pyrazine's role in stabilizing mixed-valence states and facilitating relays in coordination environments. Pyrazine participates in radical reactions during the Maillard process, where pyrazinium radical cations form in early stages from interactions of pyrazine precursors with enediols or amines, contributing to non-enzymatic browning through dimerization or hydrogen abstraction pathways. These s, such as 1,4-disubstituted pyrazine radical cations detected by , exhibit a of about 10 minutes in aqueous media before converting to dihydrohydroxy derivatives, underscoring their transient role in radical-mediated heterocycle formation.

Derivatives and analogs

Simple substituted pyrazines

Simple substituted pyrazines are derived from the parent pyrazine by replacing one or more atoms with simple functional groups such as alkyl, , or amino substituents, which modify the properties and reactivity of the . These compounds serve as key building blocks in due to their straightforward preparation and tunable characteristics. Methylpyrazines, particularly 2-methylpyrazine, are commonly synthesized through the cyclocondensation of with 1,2-propanediol or over metal oxide catalysts such as copper-alumina or zinc-chromium oxide systems at elevated temperatures around 380 °C. This method yields 2-methylpyrazine with high selectivity when using crude as a sustainable feedstock alternative. The compound exhibits a of 135 °C at 761 mm and a nutty, cocoa-like , contributing to its role as a precursor. Its is -29 °C, and it shows good in water (up to 1000 mg/mL at 20 °C) and . Halopyrazines, exemplified by 2-chloropyrazine, are prepared via chlorination of pyrazin-2(1H)-one or routes, often involving oxychloride treatment of hydroxy precursors. 2-Chloropyrazine is a stable liquid at with a of 153-154 °C and of 1.283 g/mL at 25 °C, making it suitable for handling in synthetic applications. The chlorine substituent activates the ring toward (SNAr) reactions due to the electron-withdrawing nature of the , facilitating displacements with amines or alkoxides under mild conditions. Aminopyrazines, such as 2-aminopyrazine, are typically obtained by of the corresponding halopyrazines with anhydrous ammonia in or through reductive ring cleavage of pyrazolo[1,5-a]pyrazine intermediates. These derivatives enhance in polar solvents like , DMF, and DMSO compared to unsubstituted pyrazine, owing to the polar amino group, and are valued as versatile intermediates in heterocyclic synthesis. The amino increases the on the ring, promoting further reactivity at adjacent positions. Symmetrically polysubstituted pyrazines include 2,3,5,6-tetramethylpyrazine (also known as ligustrazine), which can be synthesized by of diacetone amine or butanedione monoxime with sources under thermal conditions, achieving high yields through optimized catalytic processes. Although naturally isolated from herbal sources like Ligusticum wallichii, provides scalable access without reliance on . This tetrasubstituted analog displays enhanced stability and modified physical properties, such as a higher relative to mono-substituted variants, due to the steric and electronic influences of the four methyl groups. In general, substituents on pyrazine influence its and basicity: electron-donating groups like alkyl or amino moieties increase the basicity by raising the on the atoms, as seen in pKa shifts for compared to unsubstituted pyrazine (pKa ≈ 0.6). Conversely, electron-withdrawing slightly decrease basicity but enhance reactivity toward nucleophiles, maintaining the overall aromatic character of the ring.

Complex pyrazine-based compounds

Complex pyrazine-based compounds encompass advanced derivatives featuring fused ring systems or multiple functional groups, which introduce significant structural diversity and synthetic challenges due to the electron-deficient nature of the pyrazine core. These structures often arise from strategic annulation or functionalization strategies that enhance rigidity, conjugation, or reactivity for specialized applications in organic synthesis. Pteridines represent a key class of biheteroaromatics formed by the fusion of a pyrazine ring to a pyrimidine ring, creating a bicyclic system with notable structural rigidity and electronic delocalization. Their synthesis typically involves condensation reactions, such as the Gabriel-Isay method, where 4,5-diaminopyrimidines react with 1,2-dicarbonyl compounds like glyoxal or benzil under acidic or basic conditions to form the pteridine scaffold with high regioselectivity at the fused bonds. This approach highlights the pyrazine moiety's role in providing the central six-membered ring, while the biochemical relevance of pteridines underscores their structural importance without delving into specific biological functions. Pyrazine dicarboxylates, particularly 2,3-pyrazinedicarboxylic acid, exemplify multifunctional derivatives where carboxylic groups are introduced at adjacent positions, enabling further or coordination. Preparation often proceeds via oxidation of precursors with , yielding the in moderate to high efficiency, though direct methods using under have also been reported for selective functionalization. These compounds exhibit enhanced acidity compared to simple pyrazine carboxylic acids, with pKa values of approximately 0.8 and 2.84 for the first and second , respectively, reflecting the influence of the adjacent atoms on . Organometallic pyrazines involve the pyrazine scaffold as a in metal complexes, where directed lithiation serves as a pivotal step for introducing metal centers while preserving the organic framework's integrity. Lithiation predominantly occurs at the 2-position due to the directing effect of the nitrogen lone pairs, facilitated by strong bases like in ethereal solvents at low temperatures. This reaction can be depicted as: \ce{C4H4N2 + nBuLi ->[THF, -78°C] 2-LiC4H3N2 + C4H10} Subsequent transmetalation with metal halides forms pyrazine-bridged complexes, such as those with or , emphasizing the scaffold's ability to coordinate via donors without disrupting the core . Fused pyrazine systems like s arise from the condensation of o-phenylenediamines with 1,2-diketones, resulting in a benzene-pyrazine that imparts extended π-conjugation and improved stability. The reaction proceeds via initial formation followed by cyclization and , often catalyzed by acids or metals, with regiochemistry controlled by the diketone's substitution pattern to favor the 2,3-disubstituted quinoxaline isomer in unsymmetrical cases. This method's versatility allows for diverse substituents on the pyrazine ring, addressing synthetic challenges posed by the heteroarene's reactivity. Post-2010 developments have introduced pyrazine- hybrids, such as pyrazinoporphyrins, which integrate the pyrazine unit into the for enhanced photophysical properties. These are synthesized via oxidative cyclization of dipyrazinyl-substituted porphyrin precursors using hypervalent iodine reagents, achieving yields of 20-50% depending on the peripheral substituents, or through Suzuki-Miyaura of pyrazine halides with porphyrin boronic acids followed by ring closure. The structural fusion promotes intramolecular charge transfer, central to their photochemical behavior.

Applications

Flavor and aroma chemistry

Pyrazines play a pivotal role in the flavor and aroma chemistry of thermally processed foods, primarily forming through the between and reducing sugars at temperatures ranging from 100 to 200 °C. This non-enzymatic browning reaction generates a variety of volatile heterocycles that impart characteristic roasted, nutty, and earthy sensory attributes. A key pathway for pyrazine formation involves the Strecker degradation, where α-dicarbonyl compounds react with free to produce α-aminoketones, which subsequently condense and oxidize. For instance, the formation of 2,5-dimethylpyrazine proceeds via the Strecker degradation of (CH₃CH(NH₂)COOH) with pyruvaldehyde (CH₃C(O)CHO), yielding (CH₃CHO) and aminoacetone (CH₃C(O)CH₂NH₂); two molecules of aminoacetone then condense to a dihydropyrazine intermediate, which spontaneously oxidizes to the aromatic pyrazine: \ce{2 CH3C(O)CH2NH2 ->[condensation] dihydro-2,5-dimethylpyrazine ->[oxidation] 2,5-dimethylpyrazine} This process exemplifies how specific precursors dictate the substitution pattern and resulting aroma profile. These compounds contribute significantly to roasted and nutty notes in foods, often at trace concentrations due to their low odor thresholds. For example, 2-methoxy-3-isopropylpyrazine exhibits an odor threshold of 0.002 ppb in wine, evoking green bell pepper and herbaceous qualities that enhance varietal character. Similarly, alkylpyrazines like 2,5-dimethylpyrazine, with thresholds around 80 ppb to 1.8 ppm in air, deliver intense roasted nut and cocoa-like aromas prevalent in coffee and baked goods. Sensory evaluation reveals structure-odor relationships where the length and position of alkyl substituents modulate perception; shorter chains (e.g., methyl groups) promote nutty, toasty notes, whereas longer chains (e.g., propyl or isopropyl) shift toward green, earthy, or vegetal tones, influencing overall flavor harmony in complex matrices. Analysis of pyrazines in food relies heavily on gas chromatography-mass spectrometry (GC-MS), which enables identification and quantification of these volatiles in roasted products like , , and . In roasted , GC-MS has detected around 10 distinct pyrazines, underscoring their diversity and contribution to the signature nutty . Pyrazines demonstrate favorable in food matrices, characterized by high that facilitates aroma release and sufficient heat resistance to endure processing conditions without significant degradation, ensuring sustained sensory impact.

Pharmaceutical and biological roles

Tetramethylpyrazine (TMP), a key pyrazine derivative isolated from the herb Ligusticum chuanxiong, serves as a vasodilator primarily used for treating cardiovascular diseases such as and ischemia. Its therapeutic mechanism involves inhibition of calcium channels in vascular cells, reducing cytosolic free calcium concentrations and thereby promoting and alleviating pressure. In clinical settings, TMP is administered at doses of 100 mg three times daily (300 mg/day) to improve cardiac function and reduce in patients with acute . Pyrazines occur naturally as microbial metabolites and plant constituents, contributing to biological signaling and defense mechanisms. For instance, BP25 produces 2,5-dimethylpyrazine, which enhances plant resistance against pathogens like mango anthracnose. In plants, such as Ligusticum wallichii, tetramethylpyrazine is present and utilized in . Biosynthesis of these pyrazines typically proceeds via condensation of with α-dicarbonyl compounds, such as the formation of tetramethylpyrazine from and through an α-hydroxyimine intermediate. Pyrazine hybrids exhibit promising anticancer potential through kinase inhibition, targeting pathways critical for tumor proliferation. For example, cinnamic acid–pyrazine derivatives inhibit Pim-2 kinase with IC₅₀ values of 10–13 nM, demonstrating activity against hepatocellular and lung cancer cell lines. Post-2015 studies have advanced pyrazinecarboxamide analogs, with certain hybrids like those combined with betulinic acid showing tumor inhibition rates up to 76% in vivo at 5 mg/kg doses, though specific phase I trials for pyrazinecarboxamides remain limited to preclinical evaluations. Pyrazines, particularly , display antioxidant activity by scavenging , including anions, and reducing production in neutrophils. This is attributed to the pyrazine scaffold's ability to directly trap free radicals via donation. studies report IC₅₀ values for scavenging in the range of 10–50 μM for TMP derivatives, highlighting their role in mitigating in biological systems. TMP undergoes rapid hepatic metabolism, with a short of approximately 1–2 hours due to extensive first-pass clearance in the liver, limiting its . No significant is observed at therapeutic levels, with acute oral LD₅₀ values of approximately 1.9 g/ in rats, indicating a favorable profile for clinical use.

Coordination and materials chemistry

Pyrazine serves as a versatile bidentate in coordination due to its two donor atoms, enabling the formation of bridging structures in metal complexes. In Hofmann-type clathrates, pyrazine links metal centers to create layered frameworks that host guest molecules, as exemplified by the complex (pyrazine)[M(CN)4] (where M = or ), which exhibits spin-crossover behavior influenced by the ligand's bridging geometry. Similar cadmium-based clathrates, such as those derived from Cd(NH3)2[Cd(NO3)4] with pyrazine incorporation, demonstrate host-guest inclusion properties suitable for selective adsorption. These structures highlight pyrazine's role in stabilizing extended networks through N-M-N coordination bonds with bond lengths typically around 2.1-2.3 . In metal-organic frameworks (MOFs), pyrazine acts as a pillar to connect paddle-wheel nodes, enhancing framework dimensionality and porosity. For instance, zinc-based MOFs incorporating pyrazine and 1,4-benzenedicarboxylic acid (BDC), such as Zn(BDC)(pyz)_{0.5} (MOF-45), feature microporous channels with BET surface areas exceeding 1000 m²/g and narrow pore size distributions centered at approximately 0.6-0.8 nm. These materials exhibit selective gas adsorption capacities, with CO2 uptake up to 4 mmol/g at 273 K and 1 bar, attributed to the ligand's ability to tune pore apertures and framework flexibility. Pyrazine's incorporation in such MOFs also improves thermal stability, maintaining structural integrity up to 300°C under . The electronic properties of pyrazine in coordination complexes arise from its π-acceptor capability, which stabilizes low-oxidation-state metals by delocalizing into the ligand's π* orbitals. In ruthenium(II) complexes like [Ru(bpy)2(pyrazine)]^{2+} (bpy = 2,2'-bipyridine), pyrazine's strong π-backbonding shifts metal-to-ligand charge transfer bands to higher energies, with potentials for the Ru^{II/III} couple around +0.5 V vs. in , reflecting enhanced electron withdrawal compared to analogs. This property facilitates applications in -active materials, where the ligand modulates electrochemical windows by up to 200 mV through substituent effects. Pyrazine-derived polymers, particularly those featuring pyrazine-diimide units, have emerged as n-type with tunable electronic properties. These materials are synthesized via condensation polymerization of pyrazine-dicarboxylic acids with diamines, yielding conjugated backbones that support efficient . For example, dithienylpyrazinediimide-based copolymers exhibit field-effect mobilities up to 0.1 cm²/V·s and conductivities on the order of 10^{-5} S/cm in thin films, owing to the diimide's electron-deficient core that lowers the LUMO to approximately -4.0 . Such polymers demonstrate ambient , retaining over 80% performance after 1000 bending cycles in flexible devices. In optoelectronic applications, pyrazine units contribute to electron-transport layers (ETLs) in organic light-emitting diodes (OLEDs) by providing wide bandgaps and balanced charge injection. Bipolar hosts like 2,6-bis(carbazol-9-yl)pyrazine (26PyzCz) feature a pyrazine core flanked by donors, enabling HOMO-LUMO gaps of about 4 as determined by UV-Vis absorption onset at ~310 , which supports efficient emission with external quantum efficiencies up to 5% in single-layer devices. The ligand's π-acceptor nature minimizes at the ETL , enhancing device lifetimes beyond 10,000 hours at 1000 cd/m² . Recent advancements in the 2020s have integrated pyrazine into cells as hole-transport materials (s), improving efficiency and stability. A pyrazine-based donor-acceptor , NBD-Pyz, employed as a dopant-free in MAPbI3 devices achieves power conversion efficiencies of 22.9% under standard AM 1.5G illumination, surpassing traditional spiro-OMeTAD due to better alignment ( at -5.3 ). These cells retain over 90% initial efficiency after 1000 hours of continuous light soaking at 85°C, attributed to the 's hydrophobic pyrazine units that suppress and moisture ingress.