Terphenyl

Terphenyls are polycyclic aromatic hydrocarbons with the molecular formula C₁₈H₁₄, composed of three benzene rings connected linearly or angularly via single bonds.^[1] They exist primarily as three isomeric forms—ortho-terphenyl (1,2-diphenylbenzene), meta-terphenyl (1,3-diphenylbenzene), and para-terphenyl (1,4-diphenylbenzene)—distinguished by the relative positions of the outer phenyl groups on the central ring.^[2] These colorless to light-yellow solids are characterized by high thermal stability, low volatility, and insolubility in water, with vapor pressures around 0.01 mm Hg at 20°C and flash points ranging from 163–207°C.^[3] Mixtures of terphenyl isomers are industrially significant as heat storage and transfer agents in high-temperature applications, including nuclear reactors and solar thermal systems, due to their boiling points exceeding 300°C and compatibility with closed-loop systems.^[3][1] They also serve as textile dye carriers to enhance dye penetration and as intermediates in lubricant production; their derivatives like polychlorinated terphenyls (PCTs) were historically used as dielectric fluids before being banned for environmental persistence and toxicity.^[3][4] The para-isomer specifically exhibits a melting point of 212–213°C, a boiling point of 376°C, and a density of 1.23 g/cm³, making it suitable for organic synthesis, electronics, and as a scintillator in radiation detection.^[1] In research, meta-terphenyl-based scaffolds are utilized as ligands in catalysis, while terphenyl structures more broadly serve as polymer additives and in anion exchange membranes, leveraging their rigid aromatic structure for enhanced conductivity and stability.^[5] Additionally, natural p-terphenyl derivatives from fungi and plants display notable biological activities, including antimicrobial and anticancer properties, inspiring pharmaceutical development.^[6]

Structure and Isomers

Ortho-Terphenyl

Ortho-terphenyl, also known as 1,1':2',1''-terphenyl, consists of three phenyl rings connected via single bonds, with the outer two rings attached to adjacent (ortho) positions 1 and 2 of the central phenyl ring, resulting in an angular arrangement and the molecular formula C₁₈H₁₄. This configuration leads to significant steric hindrance between the adjacent phenyl groups, causing the molecule to adopt a non-planar, twisted conformation that contrasts with the more extended planarity observed in the para isomer.^[7] Key physical characteristics of ortho-terphenyl include a melting point of 56–59 °C, a boiling point of 337 °C at standard pressure, and a density of 1.1 g/cm³ at 20 °C. These properties reflect its solid state at room temperature and relatively high thermal stability, though it remains insoluble in water and soluble in organic solvents like benzene.^[8] Commercially, ortho-terphenyl is available as a pure compound from chemical suppliers and is frequently included as a component in mixed terphenyl formulations employed as plasticizers for materials like polystyrene in thermoplastic applications.^[9]

Meta-Terphenyl

Meta-terphenyl, also known as 1,3-diphenylbenzene or [1,1':3',1'']-terphenyl, features a central benzene ring with two phenyl substituents attached at the meta positions (1 and 3), forming a bent, non-linear molecular framework with the formula C₁₈H₁₄. This arrangement results in an asymmetric π-conjugated system, differing from the more compact ortho isomer and the linear para isomer, which influences its packing and intermolecular interactions.^[10] Physically, meta-terphenyl appears as a white to pale yellow crystalline solid with a melting point of 86–87 °C and a boiling point of 365 °C at atmospheric pressure. Its density is approximately 1.195 g/cm³, and it is insoluble in water but shows enhanced solubility in common organic solvents like benzene, chloroform, acetone, ethanol, and ether compared to the para isomer, owing to the reduced symmetry that disrupts efficient crystal lattice formation. This solubility profile makes it more amenable to solution-based processing than the highly crystalline para-terphenyl.^[10][11][12]

Para-Terphenyl

Para-terphenyl, also known as 1,4-diphenylbenzene, features a central benzene ring with phenyl substituents attached at the 1 and 4 positions, forming a linear and planar molecule with the molecular formula C$_{18}$18​H$_{14}$14​. This arrangement results in fully extended π-conjugation across the three aromatic rings, which contrasts with the twisted, less conjugated structure of ortho-terphenyl due to steric hindrance between adjacent phenyl groups. The planarity of para-terphenyl enhances electron delocalization, contributing to its distinct physical and optical characteristics.^[13][14] Physically, para-terphenyl is a white crystalline solid with a melting point of 212–213 °C and high thermal stability, decomposing only above approximately 400 °C under inert conditions. Its boiling point is around 376 °C at atmospheric pressure, reflecting the strength of its intermolecular interactions. These properties make it suitable for applications requiring robustness at elevated temperatures.^[15][16][1] In commercial contexts, para-terphenyl serves as a major component in mixed terphenyl formulations, often comprising a significant portion of heat-transfer fluids and other industrial blends derived from biphenyl pyrolysis. It is also valued as a reference standard in spectroscopy for its reproducible behavior and purity.^[13][17] The compound exhibits superior optical properties, including strong fluorescence emission peaking at around 330 nm when excited near 276 nm, owing to its rigid, conjugated π-system that minimizes non-radiative decay pathways. This emission is notably more efficient and blue-shifted compared to the asymmetric meta-terphenyl isomer, enabling applications in scintillators and optoelectronic materials.^[18][19]

Physical and Chemical Properties

Thermal and Thermodynamic Properties

Terphenyl, commonly referring to the commercial mixture of its three isomers, has a boiling point of 389 °C at atmospheric pressure and demonstrates thermal stability with decomposition occurring above 400 °C under inert conditions.^[17][20] This mixture's thermodynamic properties, including low vapor pressure and high heat capacity in the liquid phase (approximately 2.1 J/g·K near 300 °C), make it suitable for high-temperature applications without phase change complications.^[21] The thermal properties vary significantly among the isomers due to differences in molecular packing and conformational flexibility. Ortho-terphenyl (o-terphenyl) melts at 58–59 °C and boils at 332 °C, with a heat of fusion of 17.2 kJ/mol at its melting point.^[22][23] Meta-terphenyl (m-terphenyl) exhibits a lower melting point of 86–87 °C and a boiling point of 363 °C, accompanied by a heat of fusion of 31.0 kJ/mol.^[24] Para-terphenyl (p-terphenyl), benefiting from its linear structure that enables efficient crystal lattice formation, has the highest melting point at 212–213 °C and boils at 375 °C, with a heat of fusion of 35.3 kJ/mol.^[14][25] Thermodynamic parameters further characterize these isomers. Heat capacities for the solid phase at 298 K are approximately 275 J/mol·K for o-terphenyl, 300 J/mol·K for m-terphenyl, and 279 J/mol·K for p-terphenyl.^[22] Enthalpies of vaporization range from 84 kJ/mol for o-terphenyl to 102 kJ/mol for p-terphenyl at their boiling points, reflecting increasing intermolecular forces with linearity.^[24][26] Vapor pressure data for p-terphenyl, for instance, follow correlations derived from effusion methods, showing log P (Pa) ≈ -A/T + B over 400–600 K, with very low values (<1 Pa at 300 K) indicative of high thermal stability.^[26] Pure terphenyl isomers undergo standard solid-liquid and liquid-vapor phase transitions without intermediate mesophases, though their high melting entropies (around 70–80 J/mol·K for p- and m-isomers) highlight ordered-to-disordered structural changes.^[27]

Optical and Spectroscopic Properties

Terphenyl isomers exhibit characteristic ultraviolet-visible (UV-Vis) absorption spectra dominated by π-π* electronic transitions arising from their extended conjugated systems. The ortho- and meta-terphenyl isomers display absorption maxima in the 230–290 nm range, with prominent bands at approximately 232 nm (ε ≈ 26,300 M⁻¹ cm⁻¹) and 251 nm (ε ≈ 11,500 M⁻¹ cm⁻¹) for ortho-terphenyl in ethanol, and at 247 nm (ε ≈ 39,000 M⁻¹ cm⁻¹) and 291 nm (ε ≈ 1,740 M⁻¹ cm⁻¹) for meta-terphenyl under similar conditions.^[23][10] In contrast, para-terphenyl shows a bathochromic shift due to enhanced conjugation, with a primary absorption maximum at 276 nm (ε = 33,800 M⁻¹ cm⁻¹) in cyclohexane, extending the absorption into the 280–300 nm region.^[28] The fluorescence properties of terphenyls are particularly pronounced in the para isomer, which serves as a standard for laser dyes owing to its high efficiency and well-defined emission. Para-terphenyl fluoresces with a maximum emission wavelength around 340 nm in solvents like ethanol or cyclohexane, following excitation at 290–295 nm, and exhibits a high quantum yield of approximately 0.93.^[19][29] This near-unity quantum yield reflects minimal non-radiative decay pathways in the excited state, making it ideal for reference measurements in fluorescence spectroscopy.^[30] Nuclear magnetic resonance (NMR) spectroscopy provides key insights into the structural distinctions among terphenyl isomers through the chemical shifts and coupling patterns of their aromatic protons. In ¹H NMR spectra (typically recorded in CDCl₃), the 14 aromatic protons of all isomers resonate in the 7.2–7.6 ppm range as complex multiplets, reflecting the symmetric or asymmetric environments influenced by phenyl ring orientations. Isomer differentiation is achieved via coupling constants: para-terphenyl shows symmetric AA'BB' patterns with ortho couplings (³J ≈ 8 Hz) and smaller meta couplings (⁴J ≈ 2 Hz), while ortho- and meta-terphenyl exhibit more deshielded protons near the inter-ring junctions (up to 7.5–7.6 ppm) and distinct vicinal couplings (³J ≈ 7–8 Hz) due to steric crowding and reduced planarity.^[31] Infrared (IR) spectroscopy of terphenyls highlights the vibrational modes associated with their aromatic frameworks. The C–H stretching vibrations for aromatic protons appear as medium-intensity bands in the 3000–3100 cm⁻¹ region, distinguishing them from aliphatic C–H stretches below 3000 cm⁻¹. Conjugated C=C stretching modes are observed between 1450–1600 cm⁻¹, often as multiple weak to medium peaks reflecting ring deformations and inter-ring interactions, with para-terphenyl showing slightly shifted bands (e.g., around 1480 and 1580 cm⁻¹) compared to the ortho and meta isomers due to planarity differences.^[32][33]

Reactivity and Stability

Terphenyls, consisting of three phenyl rings linked by single bonds, exhibit reactivity typical of polyaromatic hydrocarbons in electrophilic aromatic substitution (EAS) reactions, with substitution occurring preferentially at positions ortho and para to the phenyl substituents due to the activating and ortho-para directing effects of the phenyl groups.^[34] In protodedeuteriation, a kinetic model for EAS, the partial rate factors for the isomers reveal significant activation: for p-terphenyl, the 4-position shows a factor of 273 and the 2-position 176, while the meta-directing influence is minimal at the 3-position (1.54); for m-terphenyl, the 4′ position in the terminal ring is highly reactive (4690), reflecting strong phenyl activation; and for o-terphenyl, overall reactivity is lower (e.g., 89.5 at the 4-position), partly due to steric hindrance from adjacent rings.^[34] Nitration of terphenyls proceeds under standard conditions to yield mono- and polynitro derivatives, with multiple nitrations possible owing to the persistent activation by phenyl groups, though steric effects in the o-isomer limit polysubstitution compared to the p- and m-isomers.^[35] Terphenyls demonstrate high chemical stability, resisting hydrolysis under acidic or basic conditions due to the absence of hydrolyzable functional groups and their non-polar, aromatic structure.^[36] They also possess good oxidation stability in mild environments, but under strong oxidizing conditions, the o-terphenyl isomer undergoes transformation to cyclized products resembling fluorenone through ring closure and dehydrogenation, facilitated by the proximal phenyl rings.^[37] This contrasts with the linear m- and p-isomers, which require harsher conditions for oxidative cleavage or degradation, highlighting isomer-specific reactivity influenced by steric proximity. The p-terphenyl isomer exhibits superior photostability under UV irradiation compared to its o- and m-counterparts, with low photodegradation rates attributed to extended π-conjugation that delocalizes excited-state energy and reduces susceptibility to photochemical bond cleavage.^[38] In crystalline matrices or as dopants, p-terphenyl maintains structural integrity over extended exposure, enabling applications in UV-sensitive environments without significant decomposition.^[39] Halogenation of terphenyls, particularly chlorination, readily occurs via free-radical or electrophilic pathways to form polychlorinated terphenyls (PCTs), with up to ten chlorine atoms incorporated depending on conditions and isomer.^[40] Technical mixtures of terphenyl isomers are chlorinated to produce complex PCT congeners, which exhibit remarkable environmental persistence due to their high thermal and chemical stability, resisting biodegradation and persisting in ecosystems.^[40] This persistence arises from the chlorinated aromatic framework's resistance to metabolic and abiotic degradation processes.^[41]

Synthesis

Industrial Production

Commercial terphenyl is primarily produced as a by-product during the thermal dehydrocondensation (pyrolysis) of benzene at high temperatures, yielding biphenyl as the main product and terphenyls in the high-boiling fractions of the reaction mixture.^[1] This process operates at temperatures around 700–900 °C, often involving catalytic conditions to enhance selectivity toward polyphenyls, including terphenyl isomers. An alternative industrial route involves the pyrolysis of biphenyl itself, either alone or in a mixture with benzene, under similar high-temperature conditions to favor terphenyl formation over further polymerization.^[42] In commercial grades from the late 1970s, such as heat-transfer mixtures, terphenyl was supplied as a mixture of isomers, comprising approximately 2–10% ortho-terphenyl, 45–49% meta-terphenyl, and 25–35% para-terphenyl, reflecting the thermodynamic distribution from the pyrolysis processes.^[43] This mixture is suitable for many bulk applications without further separation, though individual isomers can be isolated via purification techniques when required. Historical production of terphenyl peaked in the 1970s, driven largely by demand for precursors to polychlorinated terphenyls (PCTs), with global PCT output estimated at around 60,000 metric tonnes between 1955 and 1980.^[44] Production of terphenyl for PCT precursors declined sharply due to environmental regulations banning PCTs by the mid-1980s; however, manufacturing of non-chlorinated terphenyls continues for applications such as heat transfer fluids and electronics, with a global market valued at approximately $300 million as of 2025.^[45] Purification of crude terphenyl mixtures commonly employs vacuum distillation to remove higher polyphenyls and, if needed, to fractionate the isomers based on their differing boiling points (ortho: ~332 °C, meta: 365 °C, para: 376 °C at atmospheric pressure).^[23][10][13]

Laboratory Methods

Laboratory synthesis of terphenyl isomers typically employs selective cross-coupling reactions to construct the triarylated framework with high purity and control over isomer distribution, contrasting with industrial approaches that often produce mixtures. The Suzuki-Miyaura coupling stands out as a versatile method, particularly for the para isomer, involving the reaction of 1,4-dibromobenzene with two equivalents of phenylboronic acid in the presence of a palladium catalyst such as Pd/C under ligand-free conditions in aqueous media. This protocol affords p-terphenyl in excellent yields of 78-91%, enabling the incorporation of substituents while maintaining operational simplicity at analytical scales.^[46] For ortho- and meta-terphenyls, consecutive Suzuki couplings using halobromobenzenes and boronic acids provide regioselective access, with yields exceeding 80% for purified isomers when employing phase-transfer catalysis in biphasic systems. These reactions proceed under mild heating (50-80°C) with base such as K2CO3, allowing isolation via chromatography for research purposes.^[47] Cyclization routes offer alternative pathways for terphenyl construction from stilbene derivatives, leveraging intramolecular bond formation to build the central ring connectivity. Photocyclization of appropriately substituted stilbenes, such as 1,2-bis(2-biphenylyl)ethene, under UV irradiation with iodine as oxidant yields dihydro intermediates that aromatize to ortho-terphenyl upon dehydrogenation, achieving moderate yields of 50-70% after purification. Acid-catalyzed variants employ polyphosphoric acid or BF3·OEt2 to promote electrophilic cyclization of stilbene-tethered biphenyls, providing access to angular isomers in 60-80% yields under reflux conditions, though selectivity requires careful substituent control to avoid side products.^[48] Isomer-selective syntheses utilize organometallic directing groups for precise substitution patterns. For ortho-terphenyl, directed ortho-lithiation of biphenyl with n-BuLi in THF at -78°C, followed by transmetalation to a zinc reagent and Negishi coupling with iodobenzene, delivers the 2-phenylbiphenyl in yields up to 85%, exploiting the inherent directing effect of the phenyl substituent. This method ensures high regioselectivity for the ortho position, with quenching and extraction yielding analytically pure product.^[49] Meta-terphenyl synthesis employs Grignard reagents derived from m-dibromobenzene, where selective monometalation with Mg in ether, followed by nickel-catalyzed Kumada coupling with phenyl bromide, constructs the 1,3-diphenylbenzene framework in 70-90% yields. The reaction tolerates the remaining bromide for further functionalization, making it suitable for small-scale preparations.^[50] Recent advances include metal-free carbanion-induced ring transformations for para-terphenyls, reported in 2025, wherein 6-biphenyl-2H-pyran-2-ones react with pyruvate acetal dimethyl aldehyde under base mediation (e.g., NaH in DMF at room temperature) to afford substituted p-terphenyls in good to excellent yields (75-95%). This approach avoids transition metals, proceeds without inert atmosphere, and accommodates alkoxy substituents, providing a sustainable route for optoelectronic precursors.^[51]

Applications

Heat Transfer and Storage

Terphenyls, particularly their hydrogenated forms, have been utilized as high-temperature heat transfer fluids in industrial applications due to their exceptional thermal stability, allowing operation up to 345–350 °C without significant degradation.^[52] This stability, combined with low vapor pressure that minimizes evaporation losses and non-corrosive behavior toward common metals in heat transfer systems, makes them suitable for closed-loop liquid-phase operations where uniform heat distribution is essential.^[52][53] These properties enable efficient heat transfer in processes requiring precise temperature control, such as those in chemical manufacturing. Historically, terphenyl-based fluids, including chlorinated variants like polychlorinated terphenyls (PCTs), served as Therminol-like media in chemical plants for heating reactors and in early solar thermal energy storage systems for concentrated solar power (CSP) installations.^[54][55] However, the use of PCTs was discontinued in the 1980s following regulatory bans due to their environmental persistence and toxicity risks, similar to those of PCBs, with phase-out deadlines set in regions like the European Community by 1986 for heat-transfer applications.^[56] Non-chlorinated terphenyls, such as those in Therminol 66, continued in these roles, supporting heat recovery in petrochemical refining and diurnal storage in CSP plants.^[57] Commercial terphenyl-based heat transfer fluids are typically formulated as blends of the ortho-, meta-, and para-isomers to optimize physical properties like viscosity, which affects pumpability and flow efficiency at operating temperatures.^[58] These mixtures ensure reliable operation across a wide temperature range, from low pour points for startup to high bulk temperatures without fouling. As of 2025, the market for hydrogenated terphenyls is projected to grow, reflecting sustained demand in high-temperature industrial processes.^[59] Following the regulatory phase-out of PCTs, the industry shifted toward non-chlorinated synthetic oils, including hydrogenated terphenyls and alternatives like alkylated aromatics or silicone-based fluids, which offer comparable thermal stability with improved environmental profiles and lower maintenance needs.^[60] This transition has sustained terphenyls' relevance in modern high-temperature processes while favoring fluids with enhanced fouling resistance for long-term system reliability.^[61]

Optoelectronics and Scintillators

Terphenyls, particularly the para isomer (p-terphenyl), serve as primary scintillators in plastic radiation detectors due to their efficient conversion of ionizing radiation into detectable light pulses. In these applications, p-terphenyl is incorporated into polystyrene matrices, where it absorbs energy from excited base material and re-emits fluorescence peaked at approximately 420 nm, closely matching the sensitivity of silicon photomultipliers and other photodetectors.^[62] This emission wavelength enables high light yield, with values around 33,000 photons per MeV for alpha and beta particles, facilitating precise particle identification and energy measurement in high-energy physics experiments.^[63] The short decay time of about 4-6 ns further supports fast timing applications, such as time-of-flight detectors.^[64] In optoelectronics, terphenyl derivatives are employed as blue emitters and host materials in organic light-emitting diodes (OLEDs), leveraging their rigid conjugated structures to achieve high color purity and efficiency. For instance, twisted diphenylamino-substituted terphenyls function as deep-blue fluorescent emitters, exhibiting electroluminescence with Commission Internationale de l'Eclairage coordinates near (0.15, 0.10) and external quantum efficiencies exceeding 5% in doped devices.^[65] Ortho-terphenyl (o-terphenyl) scaffolds, when functionalized with cyano groups, serve as bipolar hosts for blue thermally activated delayed fluorescence (TADF) emitters, providing high triplet energy levels that minimize non-radiative quenching and enable stable device operation with external quantum efficiencies up to 25% and low efficiency roll-off at high brightness.^[66] These hosts promote balanced charge transport and exciton confinement, essential for full-color displays and lighting. The photophysical properties underpinning these applications include p-terphenyl's high fluorescence quantum yield of 0.93 in solution, which ensures minimal energy loss to non-radiative pathways, and a triplet energy level of approximately 2.66 eV, sufficient to host blue phosphors or TADF molecules without back energy transfer.^[19][67] This triplet energy, derived from phosphorescence measurements, supports efficient intersystem crossing management in OLEDs, while the structured fluorescence spectrum—peaking in the UV-blue region—aligns with wavelength-shifting needs in scintillators, as briefly noted in optical property analyses.^[19] B,N-bridged p-terphenyl variants enhance luminescence efficiency through rigidified π-conjugation and reduced aggregation-induced quenching. These ladder-type structures exhibit solid-state fluorescence quantum yields up to 0.45, significantly higher than unmodified terphenyls, due to the boron-nitrogen bridge stabilizing the excited state and promoting through-space charge transfer.^[68] Such modifications enable brighter, more stable emission in both scintillator composites and OLED layers, with applications in high-resolution imaging and energy-efficient displays.^[69]

Other Industrial Uses

Terphenyls serve as additives in polymer formulations, particularly as plasticizers to enhance flexibility in polyvinyl chloride (PVC) materials. Hydrogenated terphenyls, valued for their thermal stability, are employed as intermediates in lubricant production, supporting high-temperature applications in industrial machinery.^[70][3][71] In pharmaceutical synthesis, o-terphenyl derivatives act as key intermediates for producing immunosuppressants, exemplified by their role in constructing the core structure of terprenin, a potent immunoglobulin E antibody suppressant isolated from Aspergillus candidus. The total synthesis of terprenin involves regioselective coupling to build the oxygenated p-terphenyl skeleton, highlighting terphenyls' utility in accessing bioactive scaffolds with antiproliferative effects on lymphocytes.^[72] Mesomorphic terphenyl derivatives, such as dialkoxyterphenyls, exhibit liquid crystalline properties suitable for display technologies. These compounds form smectic phases that enable alignment in ferroelectric liquid-crystalline polymer compositions, facilitating applications in electro-optic devices like twisted nematic displays.^[73] Terphenyls contribute to nanomaterials through surface-assisted polymerization, where dibromo-o-terphenyl precursors undergo on-surface coupling and cyclodehydrogenation to yield armchair graphene nanoribbons (AGNRs). This bottom-up approach on metal substrates like Au(111) produces atomically precise ribbons with tunable electronic properties, advancing integration into nanoelectronics.^[74]

Occurrence and Biological Role

Natural Sources

Terphenyls occur rarely in nature and are predominantly found as secondary metabolites in microbial organisms, particularly fungi, with limited reports from plants.^[6] In fungi, p-terphenyl derivatives are the most common natural forms, isolated from species such as Aspergillus candidus and Thelephora ganbajun. For instance, atromentin, a reddish-brown pigment and key intermediate in terphenylquinone biosynthesis, has been identified in various mushrooms belonging to the orders Agaricales and Thelephorales, including species like Serpula lacrymans. These fungal metabolites often exhibit biological activities, such as antimicrobial effects, contributing to the organisms' ecological roles.^[6][75][76] m-Terphenyl derivatives are less prevalent but have been reported in certain plants, including mulberrofuran R, isolated from the root bark of the cultivated mulberry tree (Morus lhou Koidzumi). This compound, featuring a meta-linked terphenyl core within a 2-arylbenzofuran structure, was extracted from ethyl acetate fractions of the plant material.^[77] Isolation of natural terphenyls typically involves solvent extraction, such as with ethyl acetate or methanol, from fungal cultures or plant tissues, followed by purification via column chromatography or high-performance liquid chromatography (HPLC). Structural identification relies on techniques like high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) spectroscopy. In the 2020s, studies have highlighted terphenyl antibiotics from deep-sea Aspergillus species, such as new p-terphenyl derivatives (phenylcandilides C–F) from Aspergillus candidus HNNU0546 isolated from a cold seep, showing antibacterial activity (e.g., MIC 21.6 μM against Staphylococcus aureus) and antifungal activity (e.g., EC₅₀ 3.0 μM against Alternaria sp.).^[78]

Biosynthesis in Organisms

In fungi, terphenyl biosynthesis predominantly proceeds via polyketide synthase (PKS)-dependent pathways that incorporate malonyl-CoA and phenylacetate units, derived from primary metabolism through the shikimate-chorismate route. The process initiates with the transamination and deamination of L-phenylalanine or L-tyrosine to form arylpyruvic acids, such as phenylpyruvic acid or 4-hydroxyphenylpyruvic acid, which undergo oxidative dimerization to establish the central biaryl linkage, yielding terphenylquinones like atromentin or polyporic acid as key intermediates. In basidiomycetes, dedicated quinone synthetases, such as HapA1 and HapA2 from Hapalopilus rutilans, facilitate this symmetric dimerization through Claisen-type condensations, with heterologous expression confirming their specificity for polyporic acid production.^[76][6] Subsequent tailoring steps diversify the terphenyl scaffold, including reduction, dehydration, methylation, and prenylation. For example, in the ascomycete Aspergillus ustus, a biosynthetic gene cluster orchestrates the reductive dehydration of atromentin to a terphenyl triol intermediate via the dual-function enzymes TerB (reductase) and TerC (dehydratase), followed by O-methylation, prenylation, and spontaneous cyclization to dibenzofurans; gene inactivation studies have validated these sequential transformations. Non-reducing iterative PKS enzymes play a central role in assembling the polyketide-derived portions, often in conjunction with accessory oxidoreductases and transferases.^[79] Genomic mining in the 2010s has illuminated the genetic underpinnings, identifying clusters with core genes like terA in Aspergillus species, which encodes a multifunctional enzyme initiating terphenyl core formation from phenylacetate starters, and atrA (atromentin synthetase) plus atrD in Tapinella panuoides, responsible for arylpyruvic acid dimerization. These genes, often clustered with regulators and tailoring enzymes, were pinpointed through comparative genomics and heterologous reconstitution in model hosts like Aspergillus nidulans.^[6] In plants, meta-terphenyls occur sporadically as natural products, with biosynthesis proposed to involve the phenylpropanoid pathway, where cinnamic acid derivatives undergo coupling reactions to form meta-linked isomers, though specific enzymes and pathways remain poorly characterized compared to fungal systems.^[80] Terphenyls fulfill evolutionary roles as pigments offering UV protection in fungal fruiting bodies and as antimicrobial defenses against competing microbes, with their quinone structures enabling reactive oxygen species scavenging and inhibition of bacterial or fungal pathogens.^[81][82]

Safety, Toxicity, and Environmental Impact

Terphenyls are classified as slight health hazards, with a NFPA health rating of 1. They are combustible solids that may burn but do not readily ignite, and exposure to fire can produce toxic gases including carbon monoxide. Incompatible with strong oxidizing agents such as perchlorates and peroxides, which may cause violent reactions.^[3] Acute exposure to terphenyls can irritate and burn the skin and eyes upon contact, while inhalation may irritate the nose, throat, and lungs, causing coughing and shortness of breath. Chronic or repeated exposure may lead to skin drying and cracking, and potential effects on the liver and kidneys. Terphenyls have low acute toxicity compared to their polychlorinated derivatives (PCTs), but they are moderately toxic like other aromatic hydrocarbons, potentially causing nausea, vomiting, and diarrhea if ingested. They are not classified as carcinogens, though some safety data sheets note suspected carcinogenic potential in specific contexts or for deuterated forms. Occupational exposure limits include an OSHA PEL of 9 mg/m³ (ceiling), NIOSH REL and ACGIH TLV of 5 mg/m³ (ceiling), and an IDLH of 500 mg/m³. Personal protective equipment such as gloves, goggles, and respirators is recommended during handling.^[3][83][84] Environmentally, terphenyls exhibit low water solubility and can bioaccumulate in aquatic organisms such as fish. They are classified as toxic to aquatic life with long-lasting effects (EU H413 or GHS Category Chronic 3), and releases should be prevented to avoid contamination of water bodies. Hydrogenated terphenyls are similarly noted for chronic aquatic toxicity. Waste containing terphenyls may require disposal as hazardous material under EPA or local regulations.^[3][84][85] Plain terphenyls are regulated under occupational safety standards by OSHA, NIOSH, and ACGIH, and listed on the New Jersey Right to Know Hazardous Substance List. In contrast, polychlorinated terphenyls (PCTs), historically used as dielectric fluids, have been banned since 1979 in Canada, the United States, and restricted in the European Economic Community since 1988 due to their environmental persistence, bioaccumulation, and toxicity similar to PCBs. PCTs are prohibited under the Stockholm Convention on Persistent Organic Pollutants and various national toxic substances lists. As of 2025, no such bans apply to unsubstituted terphenyls, though their use is subject to general chemical handling and environmental release regulations.^[3][86][87]