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Isoquinoline

Isoquinoline is a heterocyclic aromatic organic compound with the molecular formula C₉H₇N, characterized by a benzene ring fused to a pyridine ring at the 5,6-positions of the pyridine, making it a structural isomer of quinoline where the nitrogen atom is positioned in the heterocyclic ring away from the fusion site.^[1] This bicyclic structure classifies it as an ortho-fused heteroarene and a benzopyridine, contributing to its role as a fundamental scaffold in organic chemistry.^[1] Isoquinoline occurs naturally in coal tar, bone oil, and certain plants such as Lonicera japonica, from which it can be isolated.^[1] It is typically produced industrially through extraction from coal tar or via synthetic methods like the Pomeranz–Fritsch reaction, which involves the condensation of benzaldehyde with aminoacetaldehyde (or its diethyl acetal) followed by acid-catalyzed cyclization.^[2] Physically, isoquinoline appears as a colorless to pale yellow hygroscopic liquid with a melting point of 26.5 °C, a boiling point of 243.2 °C, a density of approximately 1.10 g/cm³, and limited solubility in water (about 4.5 g/L at 25 °C) but good solubility in organic solvents.^[1] Chemically, it exhibits basic properties with a pKa of 5.14 for its conjugate acid and is known for its reactivity in electrophilic substitutions, particularly at the 5- and 8-positions, due to the electron-donating effect of the benzene ring.^[1] Isoquinoline serves as the core structure for a diverse class of natural alkaloids, with over 2,500 known derivatives exhibiting significant biological activities, including antitumor, antimicrobial, anti-inflammatory, and antimalarial effects.^[3] Notable examples include morphine and codeine (from benzylisoquinoline pathways), berberine (a protoberberine with dyslipidemia-lowering properties), and trabectedin (an FDA-approved anticancer agent for soft tissue sarcoma derived from tetrahydroisoquinoline).^[3]^[4] These derivatives are synthesized in plants via pathways involving tyrosine decarboxylation and are widely studied for pharmaceutical applications, though isoquinoline itself is used in dyes, insecticides, rubber accelerators, and as a flavoring agent in food.^[1]^[4] Despite its utility, isoquinoline is toxic, causing irritation and potential systemic effects upon exposure.^[1]

Structure and Properties

Molecular Structure

Isoquinoline has the molecular formula C₉H₇N and a molecular weight of 129.16 g/mol.^[1] It is a heterocyclic aromatic compound consisting of a benzene ring fused to a pyridine ring at the 3,4-positions of the pyridine, forming an ortho-fused bicyclic system, with the nitrogen atom at position 2. The standard numbering system for isoquinoline begins at the carbon atom adjacent to the nitrogen (position 1), proceeds to the nitrogen (position 2), then to the next carbon (position 3), and continues around the pyridine ring to position 4 before entering the benzene ring at positions 5 through 8, with fusion bonds at 4a and 8a.^[1]^[5] Isoquinoline is a structural isomer of quinoline, the latter having the nitrogen atom at position 1 instead of 2, which places the heteroatom directly adjacent to the fusion site in quinoline but separated by a carbon in isoquinoline. This difference in nitrogen positioning affects the electron distribution and reactivity, though both maintain a similar overall fused-ring architecture.^[5]^[6] The molecule exhibits aromaticity across both rings due to a conjugated system of 10 π electrons, satisfying Hückel's rule (4n + 2, where n = 2), with delocalization over the bicyclic framework. The nitrogen lone pair occupies an sp² hybrid orbital in the plane of the ring and does not participate in the π system, preserving the aromatic character.^[5]^[1] This non-participating lone pair on nitrogen confers basic properties to isoquinoline, enabling protonation to form the isoquinolinium ion; the pKₐ of the conjugate acid is 5.42 (at 20 °C).^[1]

Physical Properties

Isoquinoline is a colorless, hygroscopic liquid at room temperature, forming platelets upon solidification.^[1] It has a melting point of 26–28 °C and a boiling point of 243.2 °C at standard pressure.^[1]^[7] The density of isoquinoline is 1.099 g/cm³ at 20 °C.^[8] Isoquinoline exhibits a refractive index of 1.623 at 20 °C and a viscosity of approximately 3.25 cP at 30 °C.^[9]^[10] In terms of solubility, isoquinoline is miscible with common organic solvents such as ethanol and diethyl ether, soluble in dilute acids due to its basic character, and has low solubility in water, approximately 0.5 g/100 mL at 25 °C.^[1]^[7] Spectroscopically, isoquinoline shows UV-Vis absorption maxima at approximately 268 nm and 319 nm in ethanol solution.

Chemical Properties

Isoquinoline exhibits weak basic character due to the nitrogen atom in its heterocyclic ring, with a pKb value of approximately 8.58 (corresponding to a pKa of 5.42 for its conjugate acid at 20 °C).^[1] This basicity allows it to form stable salts upon protonation with strong acids such as hydrochloric acid, yielding isoquinolinium chloride, which is commonly used in synthetic applications. In terms of reactivity, isoquinoline undergoes electrophilic aromatic substitution preferentially at positions 5 and 8 on the benzene ring, where electron density is highest due to the directing influence of the nitrogen atom.^[11] These positions mimic the behavior of naphthalene's alpha carbons, facilitating reactions like nitration or halogenation under forcing conditions. Oxidation of isoquinoline typically targets the nitrogen lone pair, forming isoquinoline N-oxide with reagents such as m-chloroperbenzoic acid (mCPBA) or hydrogen peroxide. Further oxidation can lead to quinolone-like derivatives under harsh conditions, though the N-oxide serves as a key intermediate for subsequent transformations. Reduction of isoquinoline proceeds via catalytic hydrogenation, often employing palladium on carbon (Pd/C) under hydrogen pressure to yield 1,2,3,4-tetrahydroisoquinoline, selectively saturating the pyridine ring while leaving the benzene ring intact.^[12] Isoquinoline demonstrates good stability in neutral aqueous or organic media, resisting hydrolysis or decomposition at ambient temperatures. However, it shows sensitivity to strong oxidants, readily forming N-oxides or undergoing ring cleavage under extreme conditions.^[13] Unlike certain enolizable heterocycles, isoquinoline lacks significant tautomerism, maintaining its aromatic structure akin to pyridine.

Natural Occurrence

In Plants and Alkaloids

Isoquinoline itself occurs naturally in certain plants, such as Lonicera japonica, though it is less common than its derivatives.^[14] Isoquinoline serves as the central scaffold in benzylisoquinoline alkaloids (BIAs), a diverse class of over 2,500 specialized metabolites produced by plants. These compounds are particularly abundant in the order Ranunculales, with key representatives in families such as Papaveraceae (e.g., opium poppy, Papaver somniferum), Ranunculaceae (e.g., goldthread, Coptis japonica), Berberidaceae, and Menispermaceae, though BIAs have been identified across more than 20 plant families including Magnoliaceae.^[15] The biosynthesis of BIAs begins with the amino acid tyrosine, which is decarboxylated to dopamine and condensed with 4-hydroxyphenylacetaldehyde to form (S)-norcoclaurine, the foundational tetrahydroisoquinoline structure. This intermediate undergoes N-methylation to yield norlaudanosoline, followed by further modifications including O-methylation and oxidation to produce reticuline, a pivotal branch-point intermediate. Enzymes such as the berberine bridge enzyme (BBE), an FAD-dependent oxidase, catalyze the formation of a methylenedioxy bridge in protoberberine alkaloids by converting (S)-reticuline to (S)-scoulerine, enabling downstream diversification.^[16]^[17] Notable BIA examples include papaverine, a non-narcotic alkaloid from Papaver somniferum that acts as a vasodilator, and berberine, an antimicrobial protoberberine found in species like Coptis japonica and Berberis plants. Morphine precursors, such as thebaine and codeinone, also derive from the reticuline pathway in opium poppy, contributing to the plant's pharmacologically significant alkaloid profile. These compounds are often extracted for pharmaceutical applications, such as analgesics and antimicrobials.^[16]^[15] BIAs play a crucial role in plant defense, exhibiting toxicity to herbivores and antimicrobial activity against pathogens. For instance, berberine deters insect feeding, while sanguinarine and chelerythrine disrupt microbial cell membranes and inhibit fungal enzymes, thereby protecting plant tissues from infection and herbivory. This defensive function underscores the ecological importance of BIA accumulation in specialized structures like laticifers and rhizomes.^[15]^[18]

In Animals and Environment

Isoquinoline occurs as a trace constituent in coal tar and petroleum, arising from the diagenetic and catagenetic transformation of nitrogen-rich organic matter during fossilization processes. These fossil fuel deposits represent major abiotic reservoirs, where isoquinoline is typically found at low concentrations relative to the total heterocyclic fraction in crude oils and coal tars.^[19] In animal systems, isoquinoline derivatives, particularly tetrahydroisoquinolines, form endogenously through the Pictet-Spengler reaction, involving the condensation of phenethylamines such as dopamine with aldehydes like formaldehyde or acetaldehyde under physiological conditions. This non-enzymatic process occurs in mammalian brain tissue and other organs, yielding bioactive tetrahydroisoquinolines that act as neuromodulators. Plant-derived isoquinoline alkaloids can also enter animal food chains via dietary intake, contributing to trace levels in higher trophic levels.^[20] Isoquinoline has been detected in marine sediments, often linked to anthropogenic inputs from oil spills and industrial discharges. In the atmosphere, it appears as a pollutant from incomplete combustion of fossil fuels, biomass, and organic materials, partitioning into both gas and particulate phases. Vehicle emissions contribute to urban atmospheric burdens. Due to its environmental persistence, with half-lives in water exceeding days under aerobic conditions, isoquinoline exhibits low bioaccumulation in aquatic organisms such as fish and invertebrates, with bioconcentration factors around 2, facilitated by sorption to sediments and uptake via gill diffusion.^[21]

Synthesis

Classical Methods

Isoquinoline was first isolated from coal tar in 1885 by Simon Hoogewerff and Willem Adriaan van Dorp through fractional crystallization of the acid sulfate, marking the initial discovery of this heterocycle as a natural product of coal distillation.^[22] This isolation provided the foundational material for early studies, though yields were low due to the compound's minor presence in coal tar fractions (typically less than 0.1% of the basic components).^[23] One of the earliest classical synthetic routes is the Pomeranz-Fritsch reaction, independently developed in 1893 by Cäsar Pomeranz and Paul Fritsch. This method involves the acid-catalyzed condensation of benzaldehyde with aminoacetaldehyde dimethyl acetal to form an imine intermediate, followed by cyclization to yield isoquinoline.^[24] The reaction typically proceeds under heating with acids such as HCl or H2SO4, producing isoquinoline in moderate yields of 30-50%, though it is limited by the instability of the aminoacetaldehyde acetal and sensitivity to substituents on the aromatic ring. The Bischler-Napieralski reaction, reported in 1893 by August Bischler and Bernard Napieralski, represents another cornerstone classical approach for isoquinoline construction. It entails the dehydration-cyclization of N-acylphenethylamines (β-phenethylamides) using phosphorus oxychloride (POCl3) or similar dehydrating agents to generate 3,4-dihydroisoquinolines, which are then aromatized via dehydrogenation with agents like Pd/C or sulfur.^[25] This two-step process affords isoquinolines in overall yields of 40-60%, but it requires electron-rich aromatic rings for efficient cyclization and often suffers from side reactions such as over-chlorination under harsh conditions.^[26] Overall, these classical methods are multi-step processes relying on traditional reagents and conditions, offering moderate efficiency (generally 30-60% overall yields) but limited scalability due to harsh reaction environments, poor functional group tolerance, and the necessity for subsequent purification steps.^[27]

Modern Methods

Modern methods for isoquinoline synthesis have advanced significantly since 2020, emphasizing efficiency, sustainability, and selectivity through innovative catalytic strategies that build on classical cyclization motifs in a single step. These approaches prioritize atom economy, mild conditions, and reduced waste, often achieving yields exceeding 80% in one-pot reactions. Key developments include transition metal catalysis, radical processes, and eco-friendly protocols, as highlighted in recent comprehensive reviews.^[28]^[29] Transition metal-catalyzed C-H activation has emerged as a cornerstone for constructing isoquinoline scaffolds via directed annulation reactions. Rhodium(III)-catalyzed protocols, such as the annulation of N-chloroimines with alkenes, enable mild synthesis of substituted isoquinolines with broad substrate scope and good functional group tolerance, typically proceeding through chelation-assisted C-H bond activation followed by migratory insertion and cyclization.^[30] Similarly, iridium(III)-catalyzed cyclizations of aryl ketoximes with internal alkynes provide efficient access to isoquinoline derivatives under solvent-minimized conditions, leveraging directing group strategies to achieve regioselectivity.^[31] These methods often incorporate one-pot three-component assemblies, as seen in Rh(III)-catalyzed reactions of benzamides, alkynes, and carboxylic acids to form benzoisoquinolin-3-ones in yields up to 92%.^[32] Radical-mediated cyclizations have gained traction for their compatibility with photoredox catalysis, offering metal-free alternatives to traditional pathways. Photoredox-catalyzed cascades, such as the visible-light-mediated addition/cyclization of N-(methacryloyl)benzamides, generate amide-functionalized isoquinolines via radical initiation and intramolecular trapping, with organic dyes serving as inexpensive photocatalysts to drive the process under ambient conditions.^[33] Xanthate-based radical additions, though less common for parent isoquinolines, have been adapted in photoredox systems for fused derivatives, enabling sequential radical transfer and cyclization with high efficiency.^[28] These strategies contrast with earlier thermal radical methods by utilizing light to control reactivity, often in solvent-free setups, and have been reviewed for their role in sustainable heterocycle assembly.^[34] Green chemistry principles underpin several recent innovations, including metal-free and solvent-free protocols enhanced by ionic liquids or microwave irradiation. Photoredox variants using recyclable heterogeneous catalysts further reduce metal loading, as in the dehydrogenation of tetrahydroisoquinolines to isoquinolines co-producing hydrogen.^[35] These approaches align with sustainability goals, avoiding toxic solvents and excess reagents. Enantioselective synthesis of chiral isoquinoline derivatives has advanced through the integration of chiral ligands in catalytic cycles, enabling asymmetric induction during key bond formations. Rh(III)-catalyzed C-H activations with chiral cyclopentadienyl ligands facilitate enantioselective annulations of benzamides with alkynes, producing axially chiral isoquinolines with ee values >90%.^[29] For tetrahydroisoquinoline precursors, photoredox-chiral Brønsted acid dual catalysis achieves dearomative cycloadditions of isoquinolinium salts with enones, yielding enantioenriched products via selective radical capture.^[36] These methods prioritize modular construction for pharmaceutical intermediates. Recent reviews from 2023 to 2025 underscore the prevalence of high-yield (>80%) one-pot reactions, such as Pd-catalyzed sequential annulations of 2-alkynylarylaldehydes with ketones, completing isoquinoline assembly in under 6 hours.^[37] A 2025 publication details sustainable protocols using visible-light photoredox in water, achieving 88-95% yields for diversely substituted isoquinolines while minimizing waste.^[28] These advancements reflect a shift toward scalable, eco-compatible syntheses poised for industrial adoption.^[38]

Derivatives

Tetrahydroisoquinolines

Tetrahydroisoquinolines represent a class of partially hydrogenated isoquinoline derivatives where the non-aromatic B ring is fully saturated, conferring distinct chemical behaviors compared to the fully aromatic parent compound. The prototypical member, 1,2,3,4-tetrahydroisoquinoline (THIQ), features a fused benzene ring with a piperidine-like heterocycle, resulting in a secondary amine structure that enhances reactivity and solubility in polar solvents.^[39] THIQ and its derivatives are commonly synthesized through reduction of the corresponding 3,4-dihydroisoquinolines, employing methods such as sodium borohydride (NaBH₄) for hydride delivery or catalytic hydrogenation under mild conditions with palladium or platinum catalysts.^[40] These reductions proceed selectively at the C3-C4 double bond, yielding the saturated heterocycle in high efficiency, often exceeding 90% yield under optimized protocols.^[41] In natural systems, tetrahydroisoquinolines arise biosynthetically via the Pictet-Spengler reaction, an acid-catalyzed cyclization of β-arylethylamines with aldehydes, mediated by Pictet-Spenglerase enzymes in alkaloid-producing organisms. This enzymatic process facilitates the formation of the tetrahydroisoquinoline core in various plant and microbial metabolites, incorporating chiral centers during iminium ion interception by the ortho-position of the aromatic ring.^[42] Substitutions at the C1 position introduce chirality, creating a stereogenic center that influences biological activity and requires enantioselective synthetic strategies for access to pure enantiomers. Enantioselective reductions of 1-substituted-3,4-dihydroisoquinolines utilize chiral catalysts, such as ruthenium-based complexes for hydrogenation or biocatalysts like imine reductases, achieving enantiomeric excesses often above 95%.^[40]^[41] Due to the saturation of the heterocyclic ring, tetrahydroisoquinolines exhibit reduced aromatic stability relative to isoquinoline, rendering them more susceptible to oxidation or electrophilic attack while increasing nucleophilicity at the nitrogen. Their basicity is notably higher, with the conjugate acid of THIQ displaying a pKa of approximately 9.5, facilitating protonation and salt formation under physiological conditions.^[43]^[44] Tetrahydroisoquinolines are prevalent structural motifs in natural alkaloids, exemplified by salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline), a dopamine-derived compound found in mammalian brain tissue and certain plants, formed via non-enzymatic Pictet-Spengler condensation.^[45]^[46]

Other Notable Derivatives

1-Benzyl-1,2,3,4-tetrahydroisoquinoline alkaloids, such as reticuline, represent a significant subclass of tetrahydroisoquinoline derivatives characterized by a benzyl group attached at the 1-position of the tetrahydroisoquinoline core. Reticuline, specifically (S)-reticuline, serves as a pivotal branch-point intermediate in the biosynthesis of numerous benzylisoquinoline alkaloids (BIAs) found in plants, enabling the formation of diverse structural scaffolds with pharmacological potential.^[47] These derivatives are derived from the condensation of dopamine and 4-hydroxyphenylacetaldehyde, highlighting their role in natural product pathways.^[48] N-oxides of isoquinoline, formed by oxidation of the nitrogen atom, exhibit enhanced polarity that improves water solubility compared to the parent compound, making them valuable in medicinal chemistry for better bioavailability.^[49] Similarly, quaternary isoquinolinium salts, generated through N-alkylation, possess charged nitrogen centers that confer high aqueous solubility and surfactant properties, facilitating their use in formulations requiring polar interactions.^[50] These modifications alter the electronic properties of the isoquinoline ring, influencing reactivity and stability in various applications. Halogenated isoquinoline derivatives, including compounds like 4-bromo-1-chloro-3,7-dimethylisoquinoline, are explored as building blocks in agrochemical synthesis due to the halogen atoms' ability to modulate bioactivity and enable further functionalization for pesticidal agents.^[51] The introduction of halogens such as chlorine, bromine, or fluorine at positions like C1 or C4 enhances metabolic stability and target specificity in crop protection compounds.^[52] Fused isoquinoline systems, exemplified by protoberberines, feature a tetracyclic architecture formed by additional ring closures on the isoquinoline framework, often derived from benzylisoquinoline precursors through oxidative coupling.^[53] Protoberberines, such as berberine, are prominent in this category and display a characteristic isoquinoline moiety fused with a benzyl unit, contributing to their widespread occurrence in plant alkaloids with antimicrobial and anti-inflammatory activities.^[54] Synthetic modifications of isoquinoline include electrophilic sulfonation at the C5 position using oleum, yielding isoquinoline-5-sulfonic acid, which serves as an intermediate in the manufacture of dyes and pigments due to its ability to form colored complexes and improve solubility in dye formulations.^[55] This regioselective sulfonation exploits the electron-rich nature of the benzene ring in isoquinoline, directing substitution to C5 under harsh acidic conditions with yields around 61%.^[55]

Applications

Pharmaceutical Uses

Isoquinoline derivatives have found significant applications in pharmaceutical therapy due to their diverse pharmacological properties, including enzyme inhibition and modulation of cellular processes. These compounds are integral to several approved drugs targeting cardiovascular, infectious, and neurological conditions.^[56] In the treatment of hypertension, quinapril serves as a prodrug angiotensin-converting enzyme (ACE) inhibitor that incorporates a tetrahydroisoquinoline moiety, effectively reducing blood pressure by blocking the conversion of angiotensin I to angiotensin II.^[57] For antiretroviral therapy, saquinavir, an HIV-1 protease inhibitor featuring an isoquinoline-3-carboxamide core, is used in combination regimens to suppress viral replication in patients with advanced HIV infection.^[58] As a topical anesthetic, dimethisoquin provides antipruritic effects by blocking nerve conduction, particularly useful for relieving skin irritation and minor pain.^[59] Papaverine, a naturally occurring benzylisoquinoline alkaloid derived from the opium poppy Papaver somniferum, acts as a non-selective phosphodiesterase inhibitor to promote vasodilation and smooth muscle relaxation, aiding in the management of cerebral and peripheral vasospasms.^[60] Recent advancements from 2020 to 2025 highlight isoquinoline derivatives as promising anticancer agents, particularly through topoisomerase I inhibition; for instance, indenoisoquinoline compounds like WN198 demonstrate potent antitumor activity by stabilizing topoisomerase-DNA cleavage complexes, leading to DNA damage in cancer cells.^[61] These derivatives often exert effects via DNA intercalation, inserting between base pairs to disrupt replication, or by binding to enzymes such as topoisomerases and kinases.^[62] In anti-inflammatory applications, isoquinoline alkaloids such as litcubanine A inhibit NF-κB pathway activation in macrophages, reducing pro-inflammatory cytokine production, as detailed in 2023 reviews of their therapeutic potential.^[63]

Industrial and Other Uses

Isoquinoline serves as a versatile solvent in organic synthesis owing to its high boiling point (243 °C) and ability to dissolve a range of organic compounds. It is particularly utilized in liquid-liquid extraction processes for isolating resins and terpenes from natural sources.^[64] Derivatives of isoquinoline, including phosphonates and quinolinium bromides, function as effective corrosion inhibitors in the petroleum industry. These compounds are incorporated into fuels such as gasoline, diesel, and jet fuel to mitigate corrosion in pipelines, storage tanks, and refining equipment by forming protective films on metal surfaces.^[65]^[66] Azo-isoquinoline compounds, synthesized by coupling diazonium salts with isoquinoline derivatives, are employed in the production of dyes and pigments. These heterocyclic azo dyes exhibit vibrant colors, enhanced solubility, and stability, making them suitable for applications in textiles and inks.^[67] Quaternary ammonium salts derived from isoquinoline demonstrate insecticidal properties and are used as pesticides to control agricultural pests. These cationic compounds disrupt microbial and insect physiology, providing broad-spectrum activity against bacteria, fungi, and insects.^[68] Isoquinoline derivatives serve as catalysts in polymerization reactions, such as the synthesis of polyimide films where isoquinoline promotes ordered layer structures. Additionally, they serve as key intermediates in agrochemical production, contributing to the formulation of pesticides and herbicides that account for about 25% of global isoquinoline demand. As of 2024, the global isoquinoline market is valued at approximately USD 270 million, with projections to reach USD 420 million by 2033, fueled by demand in agrochemicals and pharmaceuticals.^[69]^[70]

Biological Role

In Human Physiology

Tetrahydroisoquinolines (TIQs), a class of isoquinoline derivatives, are endogenously formed in human physiology through the Pictet-Spengler condensation reaction between dopamine and reactive aldehydes such as acetaldehyde or methylglyoxal.^[71] This non-enzymatic process occurs in dopamine-rich regions of the brain, including the striatum and substantia nigra, where dopamine concentrations drive the formation of these compounds.^[72] Specific TIQs like salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) result from dopamine reacting with acetaldehyde, a metabolite of ethanol or generated endogenously.^[71] TIQs function as neuromodulators in the central nervous system, influencing catecholaminergic neurotransmission. Salsolinol, in particular, acts within the mesolimbic dopamine reward pathways, binding to dopamine D3 receptors to modulate dopaminergic neuron activity and potentially reinforce behavioral responses.^[73] However, the neuromodulatory and neurotoxic roles of TIQs remain debated, with some evidence suggesting potential neuroprotective effects in certain contexts.^[74] It is detected in human brain tissue, particularly in areas associated with reward processing, suggesting a role in normal physiological regulation of motivation and locomotion.^[72] In human metabolism, isoquinoline alkaloids, including TIQs, are primarily processed in the liver by cytochrome P450 (CYP) enzymes. For instance, the isoquinoline alkaloid corynoline undergoes oxidative metabolism via CYP2C9 to form one major metabolite and CYP3A4 for another, as demonstrated in human liver microsomes.^[75] This hepatic biotransformation facilitates clearance and prevents accumulation under normal conditions. Dietary intake contributes to the pool of isoquinoline compounds in humans, primarily through plant-derived alkaloids such as berberine found in foods like barberries or herbal supplements.^[76] These exogenous sources can influence systemic levels alongside endogenous formation. Under physiological conditions, TIQs such as salsolinol and norsalsolinol are present at trace concentrations in human biological fluids, typically ranging from 0.1 to 29.5 ng/mL in urine and detectable but low levels in plasma.^[77] These baseline amounts reflect balanced endogenous synthesis and metabolic clearance without external influences.

In Disease and Toxicity

Isoquinoline, the parent compound, exhibits moderate acute toxicity in animal models, with an oral LD50 of 360 mg/kg in rats, classifying it as harmful if swallowed.^[78] It is also toxic upon dermal contact, potentially causing skin irritation and systemic effects due to its ability to penetrate biological membranes.^[1] Though human data remain limited, chronic exposure effects require further study. Certain isoquinoline derivatives, particularly tetrahydroisoquinolines (TIQs) such as 1,2,3,4-tetrahydroisoquinoline (TIQ) and salsolinol, form endogenously in the brain through the condensation of catecholamines like dopamine with aldehydes under oxidative stress. These compounds act as selective dopaminergic neurotoxins, inhibiting mitochondrial complex I activity in a manner analogous to the parkinsonism-inducing agent MPTP, thereby contributing to neurodegeneration in Parkinson's disease (PD).^[79] TIQ and its derivatives have been hypothesized to contribute to PD based on their neurotoxic properties, though direct evidence of elevated levels in patient tissue is lacking. They promote oxidative stress, protein aggregation, and apoptosis in dopaminergic neurons.^[80] This neurotoxic profile is supported by in vitro studies showing dose-dependent toxicity in PC12 cells and primary neuronal cultures, with IC50 values in the micromolar range for mitochondrial dysfunction.^[81] In addition to PD, certain plant-derived isoquinoline alkaloids pose toxicity risks, including potential nephrotoxicity in some contexts. Overall, while isoquinoline derivatives exhibit varied biological roles, their toxicity underscores the need for caution in pharmaceutical applications and environmental exposure assessments.^[82]

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nD30 1.62078. Viscosity (cP): 3.2528 (30°); 1.0230 (100°); 0.4223 (200°). bp743 242.2°; bp760 243.25°. Dipole moment: 2.49. More basic than quinoline, pKa (25°): ...
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The Synthesis of Isoquinolines by the Pomeranz‐Fritsch Reaction
Mar 15, 2011 · This reaction, first reported by Pomeranz and Fritsch, has been used in the synthesis of a variety of isoquinoline compounds.
[30]
Bischler-Napieralski Reaction - Organic Chemistry Portal
The Bischler-Napieralski Reaction allows the synthesis of 3,4-dihydroisoquinolines from the β-ethylamides of electron-rich arenes using condensation reagents.
[31]
Bischler-Napieralski Reaction - an overview | ScienceDirect Topics
The Bischler–Napieralski reaction is a significant strategy for the syntheses of isoquinolines. First, in 1893, this method was reported by August Bischler and ...Missing: date | Show results with:date
[32]
Friedlaender Synthesis - Organic Chemistry Portal
The starting materials for this quinoline synthesis are o-aminoaryl aldehydes or ketones and a ketone possessing an α-methylene group.
[33]
Syntheses of Isoquinoline and Substituted Quinolines in Charged ...
Oct 9, 2015 · Isoquinolines and quinolines can be synthesized in charged microdroplets during a flight time on the order of a few milliseconds without the addition of ...
[34]
Comprehensive Strategies for the Synthesis of Isoquinolines ...
Aug 18, 2020 · Isoquinoline is an N-heterocyclic aromatic organic compound, which is being a structural isomer of quinoline. Quinoline and isoquinoline belongs ...Missing: tautomerism | Show results with:tautomerism
[35]
Greener alternatives for synthesis of isoquinoline and its derivatives
Aug 26, 2025 · This review aims to bridge this gap by providing an in-depth analysis of the methodological innovations in the green synthesis of isoquinoline ...
[36]
Recent advances in the synthesis of nitrogen heterocycles via Rh(III)
Feb 17, 2025 · In this review, we mainly highlight the recent advances in the synthesis of nitrogen heterocycles via Rh(III)-catalyzed chelation-assisted C–H ...
[37]
Rh(III)-Catalyzed Mild Synthesis of Isoquinoline Derivatives from N ...
Aug 26, 2025 · The Rh(III)-catalyzed C-H activation/annulation protocol enables efficient assembly of isoquinoline derivatives from N-chloroimines and ...Missing: Ir( 2020-2025
[38]
Easy access to synthesize isoquinolines from aryl ketoximes and ...
May 31, 2019 · A highly efficient approach to synthesize isoquinoline derivatives through Iridium(III)-catalyzed cyclization of aryl ketoximes and internal ...
[39]
One-pot three-component synthesis of benzo[ h]isoquinolin-3-ones ...
One-pot three-component synthesis of benzo[ h]isoquinolin-3-ones via rhodium(III)-catalyzed C-H activation. Org Biomol Chem. 2025 Oct 29;23(42):9587-9591.
[40]
Synthesis of amide-functionalized isoquinoline derivatives by photo ...
This study developed a novel method to synthesize amide-functionalized isoquinoline derivatives by a cascade amidation/cyclization of N-(methacryloyl)benzamide ...Missing: xanthate photoredox 2020-2025
[41]
Recent developments for the synthesis of the dihydroisoquinolin-1(2H)
Apr 1, 2025 · The synthesis of substituted 3,4-dihydroisoquinolin-1(2H)-ones can be achieved via a radical addition/cyclization and deprotonation process ( ...
[42]
Photoredox-promoted co-production of 3,4-dihydroisoquinoline and ...
May 15, 2024 · The Pd-doped CdS catalyst co-produces 3,4-dihydroisoquinoline and H2 via photoredox, using a cation-exchange method for dehydrogenation of THIQ.
[43]
Photoredox catalytic asymmetric dearomative [3 + 2] cycloaddition of ...
Aug 13, 2025 · Herein, we report the asymmetric dearomative photocycloaddition reactions of isoquinolines, achieved through a synergistic photoredox and chiral ...
[44]
One-pot, two-step regioselective synthesis of isoquinolines
Mar 21, 2023 · A palladium-catalyzed one-pot, two-step sequential reaction of 2-alkynylarylaldehydes and ketones was established to access isoquinolines under mild conditions.
[45]
Greener alternatives for synthesis of isoquinoline and its derivatives
This review highlights green synthesis of isoquinolines via photocatalysis, microwave-assisted, metal-free, solvent-free methods, and recyclable catalysts, ...
[46]
1,2,3,4-Tetrahydroisoquinoline | C9H11N | CID 7046 - PubChem
H301 (69.5%): Toxic if swallowed [Danger Acute toxicity, oral]. H310 (69.5%): Fatal in contact with skin [Danger Acute toxicity, dermal].Missing: stability | Show results with:stability
[47]
synthesis of chiral 1-substituted-1,2,3,4-tetrahydroisoquinoline – a ...
The enantioselective reduction of 1-substituted-DHIQs was accomplished by using chiral hydride reducing agents, by hydrogenation with a chiral catalyst, by ...
[48]
synthesis of chiral 1-substituted-1,2,3,4-tetrahydroisoquinoline ... - NIH
The chirality introduced at the C1 position of 1-substituted-1,2,3,4-tetrahydroisoquinolines, obtained by four methods of enantioselective reduction of 1- ...
[49]
The Pictet-Spengler Reaction Updates Its Habits - PMC
The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores ...
[50]
Balancing pKa and Steric Effects in the Optimization of 3-Methyl-1,2 ...
Fluorination of the methyl group lowers the pKa of the THIQ amine from 9.53 (CH3) to 7.88 (CH2F), 6.42 (CHF2), and 4.88 (CF3). This decrease in pKa results in a ...
[51]
1,2,3,4-TETRAHYDROISOQUINOLINE | 91-21-4 - ChemicalBook
Jan 27, 2025 · pka, 9.66±0.20(Predicted). color, Clear yellow to brown. Water ... 1, 2, 3, 4-TETRAHYDROISOQUINOLINE belongs to tetrahydroisoquinoline compound ...
[52]
Salsolinol: an Unintelligible and Double-Faced Molecule—Lessons ...
Oct 23, 2017 · Salsolinol (SAL) is a tetrahydroisoquinoline derivative whose presence in humans was first detected in the urine of Parkinsonian patients on l- ...
[53]
Salsolinol, a naturally occurring tetrahydroisoquinoline ... - PubMed
Salsolinol (SAL) is a tetrahydroisoquinoline neurotoxin that has been speculated to contribute to pathophysiology of Parkinson's disease and chronic alcoholism.
[54]
Microbial production of plant benzylisoquinoline alkaloids - PNAS
These results indicate that microbial systems that incorporate plant genes cannot only enable the mass production of scarce benzylisoquinoline alkaloids but may ...
[55]
Benzylisoquinoline Alkaloid Metabolism: A Century of Discovery and ...
Benzylisoquinoline alkaloids (BIAs) are a structurally diverse group of plant specialized metabolites with a long history of investigation.
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Medicinal Chemistry of Drugs with N-Oxide Functionalities - PMC
N-Oxide groups can be used to increase the solubility of drugs and decrease membrane permeability. Many heteroaromatic and aniline-derived N-oxides are reduced ...
[57]
[PDF] SYNTHESIS OF THE ISOQUINOLINIUM SALTS DIFFERING IN THE ...
Jun 8, 2012 · Quaternary isoquinolinium salts differing in alkyl chain length are members of a cationic surfactant group with quaternary nitrogen in its ...
[58]
Cas no 2137581-11-2 (Isoquinoline, 4-bromo-1-chloro-3,7-dimethyl-)
4-Bromo-1-chloro-3,7-dimethylisoquinoline is a halogenated isoquinoline derivative with potential applications in pharmaceutical and agrochemical research.
[59]
Discovery of Potent Isoquinolinequinone N-Oxides to Overcome ...
Aug 2, 2024 · This work outlines the development of 20 potent IQQ N-oxide derivatives in two isomeric families, both exhibiting nanomolar GI 50 against human tumor cell ...
[60]
Protoberberine Alkaloids - ScienceDirect.com
Protoberberine alkaloids have a tetracyclic ring system derived from benzylisoquinolines. They include protoberberines, tetrahydroprotoberberines, and 14-oxo ...
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Protoberberine Isoquinoline Alkaloids from Arcangelisia gusanlung
Protoberberine alkaloids, which belongs to a isoquinoline alkaloid class, are widely distributed in many species of the Berberidaceae, Annonaceae, Fumariaceae, ...
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[PDF] Product Class 5: Isoquinolines - Thieme Connect
Scheme 153 Sulfonation of Isoquinoline at C5[304]. N. N oleum, 95 oC. 61%. 336. SO3H. Reaction of 3-methylisoquinoline with benzeneseleninic anhydride ...<|control11|><|separator|>
[63]
Synthesis, Reactions and Medicinal Uses of Isoquinoline
Medicinal Uses: Dimethisoquin (an anesthetic), debrisoquine, quinapril (an antihypertensive) and papaverine (a vasodilator) are some of these drugs.
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Quinapril: Uses, Interactions, Mechanism of Action | DrugBank Online
Quinapril is an ACE inhibitor prodrug used to treat hypertension, congestive heart failure, and slow rate of progression of renal disease.
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Saquinavir | C38H50N6O5 | CID 441243 - PubChem - NIH
An inhibitor of HIV-1 protease. It has a role as a HIV protease inhibitor and an antiviral drug. It is a member of quinolines and a L-asparagine derivative.
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Quinisocaine: Uses, Interactions, Mechanism of Action - DrugBank
Jun 23, 2017 · This compound belongs to the class of organic compounds known as isoquinolines and derivatives. These are aromatic polycyclic compounds ...
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Papaverine: A Miraculous Alkaloid from Opium and Its ...
Papaverine, also known by its IUPAC nomenclature 1-[(3,4-dimethoxy phenyl) methyl]-6,7-dimethoxyisoquinoline, is one of the principal benzylisoquinoline ...
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Synthesis and Biological Activity of a New Indenoisoquinoline ...
Sep 26, 2023 · Copper-derived indenoisoquinoline topoisomerase I inhibitor WN198 is a promising antitumorigenic agent for the development of future DNA-damaging treatments.
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Novel tetrahydroisoquinolines as DHFR and CDK2 inhibitors
Feb 16, 2024 · All tested compounds showed moderate to strong anti-cancer activity towards the two cell lines. Compound 7e exhibited the most potent cytotoxic ...<|separator|>
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Dual action anti-inflammatory/antiviral isoquinoline alkaloids as ...
Apr 11, 2023 · In addition to having strong antiviral activities, most of these alkaloids have significant anti-inflammatory effects which are often manifested ...
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Isoquinoline - Synthesis, Applications and Scope - ChemicalBook
Nov 21, 2019 · Isoquinoline was first obtained from coal tar by Hoogewerf and Van Dorp in 1985. They were able to isolate isoquinoline through fractional ...Missing: Hoogewerff 1885
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Use as corrosion inhibitors: quinoline and isoquinoline phosphonates
as additives to various petroleum fuels including gasoline, diesel fuel, jet fuels, etc. 4. as gasoline anti-icers and antistallers 5. as additives for sludging ...
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[PDF] Experimental and theoretical evaluation of (iso)quinolinium bromide ...
Jun 8, 2023 · were investigated for corrosion inhibition of mild steel E24 in H2SO4 by impedance spectroscopy and potentiodynamic polarization.
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Synthesis and pharmacological activities of azo dye derivatives ...
Sep 13, 2022 · Among the tested dyes, azo dye 107 and 108 exhibit good radical scavenging activity. The activities of these compounds were attributed to the ...
[75]
Cationic isoquinoline pesticide - US2435458A - Google Patents
The compounds used have marked antiseptic properties and are toxic to bacteria and myccpbyta. as well as to other micro-flora and micro-iauna. The compounds are ...
[76]
Effects of Catalyst Isoquinoline in Polymerization Process on the ...
Oct 21, 2005 · By adding the isoquinoline at the beginning of polymerization, two kinds of layer structures in the gel are developed. However, by adding the ...
[77]
Global Isoquinoline Market Poised for Steady Growth Amid Rising
Jun 20, 2025 · The agrochemical sector contributes approximately 25% of market demand, utilizing isoquinoline in pesticides and herbicides. ... chemical ...
[78]
Tetrahydroisoquinoline - an overview | ScienceDirect Topics
Tetrahydroisoquinoline derivatives are endogenously formed via condensation reactions between dopamine and aldehydes such as acetaldehyde and methylglyoxal, ...
[79]
A systematic regional study of dopamine and ... - ScienceDirect.com
The in vivo formation of tetrahydroisoquinoline alkaloids by the Pictet–Spengler reaction of catecholamines and aldehydes has been investigated since the early ...
[80]
Salsolinol—neurotoxic or Neuroprotective? - PMC - PubMed Central
Salsolinol (6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline), widely available in many edibles, is considered to alter the function of dopaminergic ...
[81]
Identification of cytochrome P450 (CYP) isoforms involved in the ...
The present study focused on its metabolism and metabolism-based herb-drug interactions. After corynoline was incubated with human liver microsomes (HLMs) ...
[82]
[PDF] ANSES OPINION on the “safety of use of berberine-containing ...
However, no maximum level of isoquinoline alkaloids is proposed for food supplements made with plants or plant preparations containing berberine. Moreover, food ...
[83]
Salsolinol and Norsalsolinol in Human Urine Samples - ScienceDirect
The tetrahydroisoquinoline alkaloids salsolinol and norsalsolinol were found in human urine samples in concentrations ranging from 0.1 to 29.5 ng/ml.
[84]
isoquinoline, 119-65-3 - The Good Scents Company
Flavouring agent Being an analog of pyridine, isoquinoline is a weak base, with a pKb of 8.6. It protonates to form salts upon treatment with strong acids ...
[85]
Isoquinoline: Uses, Interactions, Mechanism of Action - DrugBank
Jun 13, 2005 · Properties ; water solubility, 4520 mg/L (at 25 °C), PEARLMAN,RS ET AL (1984) ; logP, 2.08, HANSCH,C ET AL. (1995) ; logS, -1.45, ADME Research, ...
[86]
Isoquinoline derivatives as endogenous neurotoxins in the aetiology ...
The cause of neurodegeneration in Parkinson's disease (PD) remains unknown. However, isoquinoline derivatives structurally related to the selective ...
[87]
Isoquinoline neurotoxins in the brain and Parkinson's disease
Isoquinoline derivatives have neurochemical properties similar to those of MPTP and they are considered to be the endogenous neurotoxins which cause Parkinson's ...
[88]
Toxicity to PC12 cells of isoquinoline derivatives structurally related ...
Thus, the low toxicity of isoquinoline derivatives towards PC12 cells suggests that high concentrations of or prolonged exposure to these compounds may be ...
[89]
Cytotoxic activity of isoquinoline alkaloids and herbal extracts ... - NIH
When taken by mouth, Aristolochia is toxic to the kidneys and causes cancer. It can lead to kidney damage, kidney dialysis, the need for a kidney transplant, ...
[90]
Interactions of Isoquinoline Alkaloids with Transition Metals Iron and ...
Sep 29, 2022 · However, these interactions can have important consequences in the treatment of both Alzheimer's disease and cancer. As isoquinoline alkaloids ...
[91]
Selective dopaminergic neurotoxicity of isoquinoline derivatives ...
Selective dopaminergic neurotoxicity of isoquinoline derivatives related to Parkinson's disease: studies using heterologous expression systems of the dopamine ...