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Quinuclidine

Quinuclidine is a bicyclic tertiary amine with the molecular formula C₇H₁₃N and the systematic name 1-azabicyclo[2.2.2]octane, characterized by a rigid, cage-like structure formed by three ethylene bridges connecting a nitrogen atom to a carbon atom.^[1]^[2] This compound, with CAS number 100-76-5, appears as a white to light yellow crystalline solid, possessing a melting point of 157–160 °C and a boiling point of 149.5 °C at 760 mmHg, and it exhibits solubility in alcohols, diethyl ether, and water (though only slightly in the latter).^[1]^[3] As a strong organic base with a pKa of approximately 11.0 for its conjugate acid, quinuclidine's constrained geometry enhances its nucleophilicity and provides steric hindrance compared to acyclic amines like triethylamine, making it valuable in synthetic applications. It serves as a model for studying nucleophilic catalysis due to its rigid structure.^[4] It is commonly employed as a catalyst in reactions such as the osmium tetroxide-mediated dihydroxylation of alkenes and enantioselective carboxylations, as well as a ligand in coordination chemistry and a building block for more complex molecules.^[2]^[4] In pharmaceutical synthesis, quinuclidine is a core structure in alkaloids like quinine, which exhibits antimalarial properties, and its derivatives are used in developing drugs for cardiac conditions and cancer therapies.^[2]^[4] Radiolabeled quinuclidine derivatives are prepared via N-[¹¹C]methylation for use in medical imaging, such as PET ligands.^[4] Despite its utility, quinuclidine is toxic if swallowed and fatal in contact with skin; it causes skin irritation and serious eye damage, necessitating careful handling under controlled conditions.^[2]

Nomenclature and overview

Chemical identifiers

Quinuclidine is systematically named 1-azabicyclo[2.2.2]octane according to IUPAC nomenclature.^[5] This bicyclic tertiary amine is also commonly referred to by its trivial name quinuclidine or by the synonym 1,4-ethanopiperidine.^[1] Its molecular formula is C₇H₁₃N, corresponding to a molar mass of 111.188 g/mol.^[1]^[6] The canonical SMILES notation for quinuclidine is C1CN2CCC1CC2.^[3] Key registry identifiers include the CAS number 100-76-5 and the PubChem Compound ID (CID) 7527.^[6]^[1]

Historical context

Quinuclidine, known chemically as 1-azabicyclo[2.2.2]octane, was first proposed as a structural unit in 1904 by Koenigs in the context of substituted derivatives, but the unsubstituted compound was synthesized for the first time in 1909 by Löffler and Stitzel through a multi-step process involving pyridine derivatives.^[7] However, their product was impure, and it was not until 1920 that Meisenheimer isolated quinuclidine in pure form by improving the yield of the key intramolecular rearrangement step in the synthesis.^[7] The name "quinuclidine" originates from its structural resemblance to the bicyclic amine moiety present in quinine, a natural alkaloid derived from the bark of the Cinchona tree, which had long been recognized for its antimalarial properties.^[7] In the mid-20th century, quinuclidine gained recognition as a prototypical model compound for studying the properties of bridged bicyclic amines due to its rigid, symmetric structure that constrains the nitrogen lone pair in a fixed orientation, facilitating investigations into basicity, reactivity, and steric effects in tertiary amines.^[8] This period saw increased interest spurred by the structural role of the quinuclidine unit in cinchona alkaloids like quinine and cinchonine, whose chemotherapeutic potential drove synthetic and analytical efforts. Early reductions of quinuclidone precursors, such as those reported by Clemo and Metcalfe in 1937, further established reliable preparative routes, enabling broader chemical exploration. By the 1960s, systematic studies on quinuclidine's chemistry and biological activity intensified, particularly in the Soviet Union, where researchers examined its derivatives for pharmacological applications, including ganglion-blocking and cholinomimetic effects that led to compounds like aceclidine.^[7] These investigations, building on the foundational syntheses and structural insights from earlier decades, were comprehensively reviewed in 1969, highlighting quinuclidine's versatility as a scaffold in organic synthesis and its relevance to alkaloid chemistry.

Structure and properties

Molecular geometry

Quinuclidine features a bicyclic framework described as 1-azabicyclo[2.2.2]octane, in which a nitrogen atom occupies the bridgehead position at carbon 1, connected by three ethylene (-CH₂-CH₂-) bridges to a methylene carbon at the opposite bridgehead.^[9] This rigid cage-like structure enforces a symmetric arrangement with approximate C_{3v} point group symmetry in the gas phase.^[9] The molecule adopts a chair-like conformation in each of the three equivalent six-membered rings formed by the bridges, with the methylene hydrogens in an eclipsed orientation due to the constraints of the bicyclic system.^[9] Quantum chemical calculations at the B3LYP/6-311+G(d,p) level confirm this conformation as the energy minimum, with torsional oscillations allowing limited flexibility around the C₃ axis.^[9] The nitrogen atom exhibits sp³ hybridization, with its lone pair directed along the molecular C₃ symmetry axis away from the carbon framework. The C-N-C bond angle is approximately 109°, specifically 109.4° as determined by B3LYP calculations, reflecting the tetrahedral geometry typical of tertiary amines.^[9] Gas-phase electron diffraction studies yield consistent N-C bond lengths of 1.469(3) Å and C-C bond lengths of 1.534(3) Å in the ethylene bridges.^[9] In the solid state, quinuclidine crystallizes in a plastic cubic phase at 295 K, characterized by orientational disorder of the molecules. X-ray diffraction reveals a face-centered cubic unit cell with space group Fm\overline{3}m and lattice parameter a = 8.913 Å (Z = 4). Quinuclidine can be viewed as a "tied-back" analogue of triethylamine, where the flexible ethyl groups are constrained into a rigid bicyclic scaffold, enhancing steric accessibility of the nitrogen lone pair while maintaining similar basicity influenced by the fixed geometry.^[9]

Physical and chemical properties

Quinuclidine is a white to light yellow crystalline solid with a density of 0.97 g/cm³.^[10] It has a melting point of 157–160 °C and an estimated boiling point of 198 °C.^[3]^[2] The compound exhibits slight solubility in water, as well as solubility in organic solvents such as ethanol and chloroform.^[11]^[3] As a tertiary amine, quinuclidine acts as a strong organic base, with the pKa of its conjugate acid measured at 11.0.^[12] It readily forms stable adducts with Lewis acids, such as the quinuclidine-trimethylborane complex and the quinuclidine-boron trifluoride adduct.^[13] In ¹H NMR spectroscopy, the bridgehead proton appears at approximately 3.1 ppm, reflecting the symmetric bicyclic structure.^[14] The infrared (IR) spectrum lacks the characteristic N–H stretching band around 3300 cm⁻¹, consistent with its tertiary amine functionality.^[1] Quinuclidine is air-stable under normal conditions but is highly toxic, classified under GHS hazard statements H301 (toxic if swallowed), H310 (fatal in contact with skin), H315 (causes skin irritation), and H318 (causes serious eye damage).^[15]

Synthesis

Classical methods

The classical synthesis of quinuclidine relies on the reduction of 3-quinuclidinone (also known as quinuclidone), a key bicyclic ketone precursor. This method, established in the early 1950s, employs the Wolff-Kishner reduction (using hydrazine hydrate and base) or Clemmensen reduction (Zn/Hg in HCl) as the reducing agent to convert the carbonyl group at the 3-position to a methylene group, yielding quinuclidine in good efficiency while preserving the rigid 1-azabicyclo[2.2.2]octane framework. Typical conditions involve heating in ethylene glycol or aqueous HCl, followed by workup, with overall yields often exceeding 80% from the ketone.^[7] A foundational route to quinuclidine incorporates the Dieckmann condensation for constructing the bicyclic core, followed by reduction. In this approach, ethyl piperidine-1-acetate-4-carboxylate undergoes base-catalyzed intramolecular cyclization using metallic potassium in toluene at elevated temperatures (around 100–130°C), forming ethyl 3-oxoquinuclidine-2-carboxylate as the β-keto ester intermediate. Subsequent hydrolysis, acidification, and high-temperature decarboxylation (typically 150–200°C) afford 3-quinuclidinone, which is then reduced as described above to give quinuclidine. This sequence, originally reported by Clemo and Metcalfe in 1937, achieves typical overall yields of 50–70% but requires careful control to minimize side reactions during the decarboxylation step.^[7] These early methods, while effective for laboratory-scale preparation, suffer from inherent limitations inherent to multi-step organic transformations. The processes exhibit low atom economy due to the generation of byproducts from ester hydrolysis and decarboxylation, along with the need for protecting groups to handle the amine functionality during cyclization. Additionally, the reliance on harsh conditions and stoichiometric bases limits scalability and introduces challenges in purification.^[7]

Modern synthetic routes

Modern synthetic routes to quinuclidine emphasize catalytic processes that enhance stereoselectivity, reduce steps, and improve yields compared to earlier labor-intensive methods. A prominent example is the palladium-catalyzed intramolecular allylic alkylation of ketone enolates, which enables diastereoselective construction of the bicyclic [2.2.2] system. In this approach, an acyclic precursor bearing an allylic acetate and a ketone is treated with a palladium catalyst to form the C3–C4 bond, yielding 3-vinylquinuclidine derivatives with high regio- and diastereocontrol (dr >20:1). This method, developed in 2006 as part of efforts toward cinchona alkaloid analogues, demonstrates the power of transition-metal catalysis for precise ring assembly in the quinuclidine core.^[16] Catalytic hydrogenation plays a central role in contemporary routes, particularly for saturating pyridine-derived precursors or deoxygenating N-oxides to access the fully reduced quinuclidine scaffold. For instance, selective hydrogenation of quinuclidine N-oxide using 10% Pd/C under 1 atm H₂ in methanol proceeds cleanly to quinuclidine in 95% yield, preserving the bicyclic integrity while removing the oxygen functionality. In another application, Pt/C-catalyzed hydrogenation of 4-substituted pyridine intermediates, such as 1-(pyridin-4-yl)nonan-2-ol, in MeOH/AcOH at room temperature affords the corresponding piperidine products in 40–50% yields, which undergo subsequent cyclization. These platinum- and palladium-based reductions are noted for their mild conditions, high atom economy, and compatibility with bis(2-cyanoethyl)amine-like precursors, where nitrile groups are reduced to amines en route to cyclization. Such strategies have been refined post-2000 to minimize byproducts and enable multi-gram production.^[17] Scale-up efforts prioritize green chemistry principles, avoiding heavy metals where possible while maintaining efficiency for pharmaceutical intermediates. A modified version of the classical approach starts with 4-methylpyridine, which is deprotonated and reacted with paraformaldehyde to form a hydroxyethyl intermediate, followed by catalytic hydrogenation (Pt/C, AcOH) and acid-mediated cyclization. This sequence delivers quinuclidine in 53% overall yield on a 5 g scale, with straightforward purification via distillation. The method's scalability stems from its use of inexpensive starting materials and recyclable catalysts, making it industrially viable for producing quinuclidine as a building block in drug synthesis.^[17]

Applications

Role in organic chemistry

Quinuclidine serves as a versatile reagent in organic synthesis, particularly as a hindered tertiary amine base that facilitates deprotonations and eliminations while exhibiting reduced steric hindrance at the nitrogen lone pair compared to acyclic analogues like triethylamine. Its rigid bicyclic structure positions the alkyl groups away from the nitrogen, enhancing nucleophilicity despite a conjugate acid pKa of 11.0, higher than triethylamine's 10.8; this allows quinuclidine to react with methyl iodide 50 times faster and isopropyl iodide 700 times faster than triethylamine. In practice, quinuclidine promotes E2 eliminations, such as the dehydrohalogenation of 3-(β-chloroethylidene)quinuclidine to form 3-vinyl-Δ²-dehydroquinuclidine, and supports intramolecular acylations in the synthesis of 2-quinuclidones by deprotonating enolates in the presence of acid chlorides. As a ligand, quinuclidine forms stable adducts with borane (BH₃), yielding quinuclidine-borane complexes that act as mild, selective reducing agents in organic transformations, including hydroboration-related reductions. These adducts enable the stereoselective reduction of vinyl epoxides to allylic alcohols, providing a route for resolution and recycling in asymmetric synthesis by leveraging the chiral environment around the bicyclic framework. Unlike more reactive boranes like BH₃·THF, quinuclidine-borane offers controlled reactivity, avoiding over-reduction and facilitating high-yield conversions in sensitive substrates.^[18] Quinuclidine is employed as a co-catalyst in osmium tetroxide-mediated dihydroxylation of alkenes, enhancing reaction rates through electronic effects on the osmium complex.^[19] Quinuclidine excels as a nucleophilic catalyst in the Morita-Baylis-Hillman (MBH) reaction, promoting the coupling of activated alkenes like acrylates with aldehydes to form α-methylene-β-hydroxy carbonyl compounds via carbon-carbon bond formation. Studies correlating catalyst pKa with reactivity identified quinuclidine as the optimum among quinuclidine-based variants, balancing nucleophilicity and basicity to expand substrate scope to non-aromatic aldehydes and achieve reaction rates up to 100 times faster than with DABCO. The mechanism involves quinuclidine addition to the β-position of the acrylate, forming a zwitterionic enolate that adds to the aldehyde; kinetics reveal autocatalysis by the MBH product, enhancing rates through proton shuttling, while stereoselectivity favors anti addition products in up to 95% ee when chiral variants are employed. This catalytic role has been pivotal in synthesizing complex intermediates for natural products.^[20]

Pharmaceutical and biological uses

Quinuclidine derivatives demonstrate significant anticholinergic activity, primarily functioning as antagonists at muscarinic acetylcholine receptors. This property is exemplified in aclidinium bromide, a quaternary ammonium compound incorporating a quinuclidine core, which is approved as an inhaled long-acting muscarinic antagonist (LAMA) for the maintenance treatment of chronic obstructive pulmonary disease (COPD). By competitively binding to M3 muscarinic receptors in airway smooth muscle, aclidinium bromide inhibits acetylcholine-mediated bronchoconstriction, promoting bronchodilation and reducing exacerbations in COPD patients.^[21]^[22] Several quinuclidine-based compounds have been explored as cholinesterase inhibitors, targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for potential therapeutic applications in Alzheimer's disease. For instance, N-alkyl quaternary quinuclidine derivatives exhibit potent inhibition of human AChE and BChE, with IC₅₀ values ranging from 0.5 to 10 μM, and maintain cell viability in SH-SY5Y neuronal models at concentrations up to 100 μM, suggesting a favorable safety profile for central nervous system applications. Similarly, quinuclidinium carbamates display selective BChE inhibition (IC₅₀ ≈ 1-5 μM) over AChE, enhancing cholinergic neurotransmission without excessive peripheral effects, positioning them as candidates for mitigating cognitive decline in neurodegenerative disorders.^[23]^[24] The quinuclidine motif contributes to antimalarial activity in compounds like quinine, where it forms part of the bicyclic amine structure that disrupts heme detoxification in Plasmodium falciparum. Quinine inhibits the polymerization of ferriprotoporphyrin IX (heme) into non-toxic hemozoin, leading to accumulation of cytotoxic heme monomers that damage parasite membranes and proteins. This mechanism underlies quinine's efficacy against erythrocytic stages of malaria, with clinical doses achieving parasitemia reduction through heme aggregation blockade.^[25]^[26] Quinuclidine derivatives have also been investigated for cardiovascular applications, such as antihypertensive agents that reduce blood pressure through smooth muscle relaxation.^[27] Certain quinuclidine-based compounds show potential in cancer therapies, including cytotoxicity against breast cancer cell lines.^[28] Quinuclidine itself presents a notable toxicity profile, with an acute oral LD₅₀ of 81.2 mg/kg in rats, classifying it as highly toxic upon ingestion. Under Globally Harmonized System (GHS) guidelines, it is designated as causing skin irritation (Category 2) through direct contact-induced erythema and edema, persisting up to 24 hours, and serious eye damage (Category 1) via corrosive effects that provoke severe inflammation, opacity, and potential irreversible corneal injury. These hazards stem from its basic amine nature, which protonates in biological environments to form irritant cations disrupting epithelial barriers.^[29]

Derivatives and analogues

Natural derivatives

Quinine, a prominent natural derivative of quinuclidine, is an alkaloid isolated from the bark of Cinchona species, such as Cinchona officinalis and Cinchona ledgeriana.^[30] Its structure incorporates a quinuclidine ring at the C8' position, bearing a vinyl substituent and a 6-methoxyquinolyl group linked via a carbinol bridge, which contributes to its pharmacological properties, including antimalarial activity.^[31] Quinine has been a cornerstone in treating malaria since its discovery, highlighting the significance of quinuclidine-containing natural products in medicine.^[32] Closely related alkaloids, cinchonine and cinchonidine, are also extracted from Cinchona bark and share the quinuclidine core with quinine but lack the methoxy group on the quinoline ring. These compounds differ from quinine and each other primarily in stereochemistry at the C8 and C9 positions, resulting in pseudoenantiomeric pairs that influence their biological interactions.^[33] Quinidine, the 9-epimer of quinine, similarly originates from the same plant source and exhibits related therapeutic uses.^[34] The quinuclidine moiety in these cinchona alkaloids features three chiral centers at C3', C4', and C8', which are conserved across the natural variants and define their three-dimensional architecture essential for bioactivity.^[35] While C3' and C4' maintain consistent configurations, variations at C8' and the adjacent C9 position account for the stereoisomeric diversity observed in quinine, quinidine, cinchonine, and cinchonidine.^[36] Biosynthetically, these quinuclidine-containing alkaloids are derived from the condensation of tryptophan (via tryptamine) and secologanin, an iridoid glucoside, in Cinchona plants, leading to the formation of strictosidine as a key intermediate before elaboration into the final structures.^[37] This pathway underscores the plant's ability to assemble complex polycyclic systems, with tryptophan providing the indole-derived quinoline precursor and secologanin contributing the terpenoid components.^[38]

Synthetic analogues and isoquinuclidines

Synthetic analogues of quinuclidine encompass a range of laboratory-synthesized compounds designed to modify its bicyclic structure for enhanced pharmacological or chemical properties. Prominent examples include solifenacin, a quinuclidine derivative featuring a tetrahydroisoquinoline moiety, which acts as a selective M3 muscarinic antagonist for treating overactive bladder symptoms such as urinary incontinence, urgency, and frequency.^[39]^[40] Similarly, aceclidine, known chemically as 3-acetoxyquinuclidine, serves as a cholinergic agonist for glaucoma management by reducing intraocular pressure with minimal impact on accommodation compared to pilocarpine.^[41] Other key modifications involve N-oxides and quaternary ammonium salts, which alter quinuclidine's basicity and reactivity while maintaining thermal stability akin to the parent tertiary amine. Quinuclidine N-oxide, for instance, exhibits properties similar to its quaternary counterparts, resisting ring-opening under heating.^[42] These salts, often formed via alkylation, enhance solubility and antimicrobial potential, as seen in quinuclidin-3-ol-based derivatives quaternized with alkyl chains.^[43] Functionalized variants further diversify applications; 3-hydroxyquinuclidine, with its amine pKa of 9.9, demonstrates reduced basicity relative to unsubstituted quinuclidine (pKa 11.3) due to the electron-withdrawing hydroxyl group at the 3-position, influencing catalytic reactivity in reactions like Baylis-Hillman.^[20] Bisquaternary ammonium compounds (bisQACs) derived from quinuclidine, particularly those incorporating amide linkages (e.g., via acylation of 3-aminoquinuclidine with fatty acid anhydrides followed by quaternization), improve biodegradability through protease susceptibility, such as trypsin-mediated hydrolysis, while retaining potent antibacterial activity (MICs 4–8 µM against Gram-positive and Gram-negative strains).^[44] Isoquinuclidines represent structural isomers of quinuclidine, notably 3-azabicyclo[3.2.2]nonane, which features a rearranged bridge system leading to distinct ring strain and conformational rigidity compared to the [2.2.2] scaffold of quinuclidine. This isomer's synthesis often employs aza-Prins cyclization, involving intramolecular reactions of homoallylic amines with aldehydes under acidic conditions to form the bicyclic core efficiently from acyclic precursors.^[45] The basicity of isoquinuclidine, with a pKa approximately 10.5 for the conjugate acid, is slightly lower than quinuclidine's due to altered nitrogen hybridization and strain effects, impacting its utility in antimalarial analogs like chloroquine mimics.^[46]^[47] Recent developments in the 2020s include patents and studies on quinuclidine-based anticholinesterases, such as N-alkyl quaternary derivatives inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values in the low micromolar range, showing promise for neurodegenerative disorders while assessing cell viability impacts. Antimicrobial bisQACs from quinuclidine scaffolds have also advanced, with 3-substituted quaternary salts (e.g., via reductive amination and alkylation) exhibiting MICs of 4–8 µM against resistant strains like MRSA, low resistance induction, and biofilm inhibition exceeding 70%, alongside favorable biodegradability profiles.^[23]^[48]^[49]

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**Summary:**
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