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Azetidine
Azetidine
Azetidine
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Azetidine
Names
Preferred IUPAC name
Azetidine[1]
Systematic IUPAC name
Azacyclobutane
Other names
Azetane
Trimethylene imine
1,3-Propylenimine
Identifiers
3D model (JSmol)
102384
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.007.240 Edit this at Wikidata
EC Number
  • 207-963-8
986
UNII
  • InChI=1S/C3H7N/c1-2-4-3-1/h4H,1-3H2 checkY
    Key: HONIICLYMWZJFZ-UHFFFAOYSA-N checkY
  • InChI=1/C3H7N/c1-2-4-3-1/h4H,1-3H2
    Key: HONIICLYMWZJFZ-UHFFFAOYAE
  • N1CCC1
Properties
C3H7N
Molar mass 57.09 g/mol
Appearance colorless liquid
Density 0.847 g/cm3 at 25 °C
Boiling point 61 to 62 °C (142 to 144 °F; 334 to 335 K)
miscible
Acidity (pKa) 11.29 (conjugate acid; H2O)[2]
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Somewhat strong base, combustible
GHS labelling:
GHS02: FlammableGHS05: Corrosive
Danger
H225, H314
P210, P233, P240, P241, P242, P243, P260, P264, P280, P301+P330+P331, P303+P361+P353, P304+P340, P305+P351+P338, P310, P321, P363, P370+P378, P403+P235, P405, P501
Related compounds
Other anions
 Oxetane, Phosphetane, Thietane
Related compounds
 Aziridine, Diazetidine, Pyrrolidine, Piperidine, Azepane, Azocane, Azonane
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Azetidine is a saturated heterocyclic organic compound containing three carbon atoms and one nitrogen atom. It is a liquid at room temperature with a strong odor of ammonia and is strongly basic compared to most secondary amines.

Synthesis and occurrence

[edit]
Mugineic acid, an iron-binding azetidine.

Azetidines can be prepared by reduction of azetidinones (β-lactams) with lithium aluminium hydride. Even more effective is a mixture of lithium aluminium hydride and aluminium trichloride, a source of "AlClH2" and "AlCl2H".[3] Azetidine can also be produced by a multistep route from 3-amino-1-propanol.[4]

Regio- and diastereoselective synthesis of 2-arylazetidines could be performed from appropriately substituted oxiranes via ring transformation. It is controlled by Baldwin's Rules with remarkable functional group tolerance.[citation needed]

The Paternò−Büchi reaction has an aza analogue.

Azetidine and its derivatives are relatively rare structural motifs in natural products. They are a component of mugineic acids and penaresidins. Perhaps the most abundant azetidine containing natural product is azetidine-2-carboxylic acid - a toxic mimic of proline.[5]

See also

[edit]
  • Azete, the unsaturated analog

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Azetidine

View on Grokipedia
from Grokipedia
Azetidine is a saturated four-membered with the molecular formula C₃H₇N, consisting of a cyclobutane ring in which one carbon atom is replaced by a atom, making it the smallest azacycloalkane after . This strained ring structure imparts significant reactivity, particularly toward nucleophilic ring-opening and transformations, due to bond angle deviations and nitrogen inversion. Azetidine exists as a clear, colorless, mobile that is miscible with , with a of 61–62 °C, a of −45 °C, and a of 0.84 g/mL at 25 °C; it is moisture- and air-sensitive and has a pKa of 11.29. As a versatile building block in , it is employed in reactions such as couplings, Ullmann-type couplings, and the preparation of polyamines like N,N'-bis-(3-amino-propyl)-propanediyldiamine. In pharmaceutical chemistry, azetidine derivatives are pivotal, notably as the core of β-lactam antibiotics including penicillins and cephalosporins, where the azetidin-2-one ring provides antibacterial activity through inhibition of bacterial cell wall synthesis. , a non-proteinogenic and homologue, influences conformations and has been implicated in studies of pathogenesis.

Structure and Properties

Molecular Structure

Azetidine is a saturated four-membered with the molecular formula C₃H₇N, consisting of three methylene (CH₂) groups and one atom arranged in a ring. The atom is positioned at one vertex, bonded to two adjacent carbon atoms, forming a structure analogous to cyclobutane but with one CH₂ replaced by NH. This configuration results in a puckered ring to alleviate strain, adopting a slightly folded envelope conformation similar to that of cyclobutane. The bond angles within the azetidine ring deviate significantly from the ideal tetrahedral geometry of 109.5°, with the C-N-C angle measured at approximately 91.2°. This compression arises from the geometric constraints of the small , forcing the angles to approach 90° for both C-C-C and C-N-C bonds, which contributes predominantly to angle strain. The carbon and nitrogen atoms are sp³ hybridized, with the bearing a in an sp³ orbital oriented in a pseudoaxial position due to the ring puckering. The ring exhibits puckering characterized by a of about 29.7°, as determined by gas-phase , allowing partial relief of the eclipsed interactions present in a planar conformation. This puckering amplitude is comparable to that in cyclobutane, though slightly reduced due to the heteroatom's influence on bond lengths and . The overall energy of azetidine is approximately 25.2 kcal/mol, primarily attributed to angle from the distorted bond angles, with lesser contributions from torsional .

Physical Properties

Azetidine is a colorless liquid with a characteristic . It has a of 61–62 °C at 760 mmHg, a of −70 °C, refractive index n_D^{20} = 1.432, and a of −21 °C. The is 0.847 g/mL at 25 °C. Azetidine is miscible with and common organic solvents such as . The (IR) of azetidine exhibits key absorption bands including the N-H stretch at approximately 3300 cm⁻¹ and C-H stretches in the 2900–3000 cm⁻¹ region. In the ¹H NMR spectrum (in CDCl₃), the methylene protons alpha to the appear around 3.2–3.5 ppm, while the beta protons resonate near 1.8 ppm. The ¹³C NMR shows signals at approximately 50 ppm for the carbons attached to and 25 ppm for the remote carbons. Thermodynamic data for azetidine include a standard of formation (ΔH_f) of approximately +4.7 kcal/mol (gas phase, estimated). The also influences its low relative to unstrained analogs.

Chemical Properties

Azetidine exhibits strong basicity characteristic of secondary amines, with the pKa of its conjugate acid measured at 11.29 in at 25°C. This value indicates that azetidine is a moderately strong base, comparable to other cyclic secondary amines such as (pKa 11.27) and (pKa 11.12). The inherent in the four-membered heterocycle influences the hybridization, compressing the C–N–C bond angle to approximately 93° and increasing the s-character of the orbital. This effect stabilizes the , reducing its availability for protonation and tending to lower basicity relative to less strained larger rings in the gas phase, where the of azetidine is 222.6 kcal/mol compared to 225.0 kcal/mol for . However, in , and inductive effects balance this strain, resulting in nearly equivalent basicities. Computational studies using methods, such as M06–2X/6–31+G(d), reveal that the on the atom in azetidine is modulated by , leading to a gas-phase basicity of 215.4 kcal/mol, slightly lower than in (216.3 kcal/mol) due to enhanced lone pair stabilization. This strain-induced hybridization shift imparts higher s-character to the lone pair compared to larger azacycles, where angles approach the ideal tetrahedral 109.5°. As a result, azetidine's lone pair is held more tightly to the nucleus, contributing to its distinct reactivity profile while maintaining overall basicity similar to acyclic dialkylamines like (pKa 10.73). Azetidine demonstrates reasonable thermal stability as a at but undergoes upon heating above approximately 200°C, potentially releasing irritating gases and vapors such as derivatives. It is sensitive to oxidative conditions, with the prone to forming oxidized species like N-oxides under prolonged exposure to air or oxidants, though the parent compound is typically handled under inert atmospheres to prevent such transformations. Due to its basic nature, azetidine readily forms salts with acids; for instance, the hydrochloride salt (azetidinium chloride) is a stable, crystalline solid commonly used in synthesis and storage. The alpha C–H bonds adjacent to the nitrogen exhibit enhanced acidity relative to alkanes (pKa ~50), with an estimated pKa around 40, attributable to relief upon formation, facilitating in strong bases.

Synthesis

Classical Methods

The first reported synthesis of azetidine dates to 1888, when and J. Weiner described its preparation via the base-promoted cyclization of 3-bromopropylamine, marking the initial isolation of the parent heterocycle. A closely related classical approach, also pioneered by that same year, utilized a variant of the . In this method, phthalimide reacts with 1,3-dibromopropane to form N-(3-bromopropyl)phthalimide, followed by hydrazinolysis to yield 3-bromopropylamine, which undergoes base-promoted cyclization to azetidine; the overall yield typically ranges from 20% to 30%. Another foundational technique involves the intramolecular cyclization of γ-aminopropyl halides under basic conditions. For instance, 3-chloropropylamine is treated with aqueous or , promoting nucleophilic displacement to form the four-membered ring and yielding azetidine in approximately 40% efficiency after and purification. This approach, initially explored in the late 19th century, relies on the of the to facilitate SN2 closure at the terminal carbon. Additional early routes include elimination reactions on ammonium salts derived from propylamine precursors. One such variant, reported by in 1890, entails the dry distillation of 1,3-diaminopropane dihydrochloride, which undergoes thermal elimination to generate azetidine, albeit in modest yields comparable to other period methods. These classical strategies, while instrumental in establishing azetidine as a viable synthetic target, are hampered by inherently low yields, often below 50%, owing to prevalent side reactions such as of the reactive intermediate or competing β-elimination to form acyclic byproducts like . The in the product exacerbates these challenges, favoring alternative pathways under forcing conditions like high temperatures or prolonged heating.

Modern Synthetic Routes

One prominent modern approach to azetidine synthesis involves the cyclization of sulfonamide-protected precursors, such as allylic sulfonamides, via electrocatalytic intramolecular . This method, developed in 2023, enables the formation of azetidines in good yields (typically 60-85%) under mild conditions using a catalyst and as the driving force, offering high and compatibility with diverse substituents. Another stereoselective route utilizes iodocyclization of homoallylamines, where derivatives are converted to azetidines with an iodomethyl group at the 2-position. Introduced in , this room-temperature process delivers cis-2-(iodomethyl)azetidines in high yields (70-95%) and excellent diastereoselectivity (>20:1 dr), facilitating subsequent functionalizations while avoiding competing formation through optimized iodine-mediated conditions. Metal-catalyzed methods have significantly advanced azetidine preparation, including palladium-catalyzed intramolecular C-H of γ- and δ-amines protected as picolinamides. This 2012 protocol achieves efficient ring closure for unactivated substrates, yielding azetidines in moderate to good yields (50-80%) with broad substrate scope, leveraging Pd(II) catalysis and an additive for selective β-methylene activation. Complementary ruthenium-catalyzed processes, such as oxidative β-elimination from azetidine benzoates, enable access to azetines as precursors, which can be further reduced to azetidines, though direct variants remain less common for this ring system. Enzymatic approaches have emerged since the 2010s as sustainable alternatives, particularly for of substituted azetidines. Engineered carbene transferase enzymes catalyze one-carbon ring expansion of to azetidines with high enantioselectivity (up to 99% ee) and yields (70-90%), providing access to chiral analogs not easily obtained via chemical means; transaminases have also been employed to generate chiral precursors for subsequent cyclization, enhancing overall stereocontrol in multi-step sequences. For industrial scalability, flow chemistry has been applied to the preparation of N-protected azetidines, exemplified by continuous-flow of 2-azetines using heterogeneous catalysts. This 2023 method achieves >95% purity and high throughput (gram-scale per hour) in green solvents like , minimizing side reactions and enabling efficient production of unsubstituted or N-Boc azetidines suitable for pharmaceutical intermediates.

Reactions

Ring-Opening Reactions

Azetidine's four-membered ring imparts significant strain, estimated at 25.2 kcal/mol, which drives ring-opening reactions by facilitating C-N bond cleavage and providing thermodynamic relief. This contrasts sharply with the minimal 5.8 kcal/mol in , rendering azetidine far more reactive toward opening compared to its five-membered analog. Such processes typically occur via SN2 mechanisms at the carbon adjacent to , yielding linear 1,3-functionalized amines as products. Nucleophilic ring-opening predominates, with nucleophiles targeting the C-N bond in azetidinium ions, often generated . For instance, aryl Grignard react with activated azetidines, such as those bearing electron-donating groups, to cleave the ring and form enantioenriched 1,3-amino derivatives, with the methoxy-substituted aryl system enhancing reactivity through stabilization of the . Similarly, other nucleophiles like alkoxides or amines attack unsubstituted or substituted azetidines regioselectively at the less hindered C-4 position, producing β-hydroxy or β-amino propylamines; in trisubstituted cases, attack shifts to C-2 for improved orbital overlap, as supported by DFT calculations. Thiols function analogously as soft nucleophiles in related systems but have been less explored for azetidines, though strain-driven SN2 opening yields 1,3-aminothioethers. Acid-catalyzed hydrolysis proceeds via protonation of the , enhancing electrophilicity and enabling SN2 attack by at the C-N bond to afford 3-aminopropanol from unsubstituted azetidine. This process is pH-dependent, with protonation serving as a key precursor to ring opening, and the reaction rate is markedly accelerated by the , occurring under milder conditions than for larger rings. In substituted variants, such as aryl azetidines, intramolecular nucleophilic attack follows protonation, leading to decomposed products like phenethylamines. Electrophilic ring-opening involves activation by halides or similar electrophiles, where alkyl or acyl halides attack protonated or activated azetidines, cleaving the ring to form extended γ-halo or γ-acyl amines with high enantioselectivity when using chiral catalysts like squaramide donors. Halogens promote N-coordination followed by C-N scission, while reactions with epoxides typically position azetidine as the nucleophile, though rare electrophilic variants extend the chain via formal addition. In chiral azetidines, ring-opening proceeds with inversion of configuration at the attacked carbon, consistent with the SN2 pathway, as observed in enantiopure azetidinium salts treated with or nucleophiles. Kinetically, the activation energy for azetidine ring-opening is lowered by approximately 20 kcal/mol relative to , attributable to the strain differential, enabling reactions at ambient temperatures where five-membered analogs remain stable.

Functionalization and Derivatives

Functionalization of azetidine typically involves modifications at the or carbon atoms while preserving the strained four-membered ring, enabling the of diverse scaffolds for synthetic and medicinal applications. N-substitution is a common strategy, where the secondary of unsubstituted azetidine undergoes with alkyl halides or conjugate to activated unsaturated systems to yield N-alkylazetidines. Acylation with acyl chlorides in the presence of bases like or triethylamine forms N-acyl derivatives, which can be further reduced to N-alkylazetidines using aluminum . These N-acylazetidines serve as precursors to β-lactams (2-azetidinones), key structural motifs in antibiotics such as penicillin, where the azetidinone ring is essential for their . C-functionalization often exploits the to facilitate at the α-position (C2 or C4), generating organolithium species for subsequent electrophilic . Treatment of N-protected azetidines with strong bases like s-BuLi at low temperatures induces α-lithiation, often via a β-elimination/re-lithiation sequence, allowing trapping with electrophiles such as methyl iodide to produce 2-substituted derivatives like 2-methylazetidine. This method enables stereoselective installation of alkyl, aryl, or other groups at the α-carbon, expanding the scope beyond simple N-modifications. Key derivatives include 3-azetidinone, a valuable intermediate featuring a at the 3-position, synthesized through gold-catalyzed oxidative cyclization of N-propargylsulfonamides with high enantioselectivity (>98% ee) and yields up to 82%. This compound acts as a building block for further azetidine elaboration, such as in spirocyclic systems for . Another notable derivative is azetidine-2-carboxylic acid, a four-membered ring homolog of that mimics its conformational properties but introduces altered rigidity due to the smaller ring size. Protecting group strategies are crucial for selective functionalization, with carbamates like tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz) commonly employed on the . Boc protection is readily installed and removed under acidic conditions, facilitating ring-opening or substitution reactions, as seen in conversions to pyrroles or iminosugars. Cbz groups provide orthogonal deprotection via hydrogenolysis, enabling multi-step syntheses such as Mitsunobu cyclizations in carbohydrate-derived azetidines. The synthetic utility of functionalized azetidines extends to cross-coupling reactions, particularly Suzuki-Miyaura couplings on 3-halo derivatives. Protected 3-iodoazetidines react with arylboronic acids under or catalysis, often with microwave assistance, to afford 3-arylated azetidines in good yields, serving as versatile motifs in . These transformations highlight azetidine's compatibility with modern C-C bond-forming methods while maintaining ring integrity.

Applications and Biological Role

Pharmaceutical Applications

Azetidin-2-ones, commonly referred to as β-lactams, represent a key structural motif in pharmaceutical applications, particularly as the core of monocyclic β-lactam antibiotics known as monobactams. These four-membered rings are central to natural products like nocardicins, isolated from actinomycetes such as Nocardia uniformis, which exhibit activity against Gram-negative bacteria through inhibition of cell wall synthesis. The synthetic analog aztreonam, featuring an azetidine-2-one sulfonate structure, was approved by the FDA in 1986 for treating infections caused by aerobic Gram-negative pathogens, including Pseudomonas aeruginosa, and remains a cornerstone therapy due to its resistance to many β-lactamases. In (CNS) therapeutics, azetidine derivatives serve as bioisosteres in designing ligands for nicotinic receptors. For instance, sazetidine-A, which incorporates a 2-azetidinylmethoxy group attached to a scaffold, acts as a selective and desensitizer at α4β2 nicotinic receptors, reducing self-administration in preclinical models and demonstrating potential as an aid for by alleviating withdrawal symptoms without reinforcing nicotine-seeking behavior. Azetidine scaffolds have also emerged in , where 3-aminoazetidine derivatives function as inhibitors of kinases such as kinases (JAKs). These compounds, often featuring the azetidine ring as a rigid linker or , exhibit potent and selective inhibition of JAK3, with applications in treating inflammatory and proliferative disorders including certain cancers; for example, azetidine-based JAK inhibitors have advanced to clinical evaluation since the mid-2010s for autoimmune conditions with oncogenic relevance. The compact, strained azetidine ring provides advantages over larger heterocycles like by enabling more rigid pharmacophores that enhance binding affinity, reduce conformational flexibility, and improve metabolic stability, thereby optimizing potency and pharmacokinetic profiles in drug candidates. Recent innovations incorporate azetidine motifs into proteolysis-targeting chimeras (PROTACs) for targeted protein degradation. Azetidine-containing linkers, such as those combining and azetidine units, facilitate the recruitment of ubiquitin ligases to disease-associated proteins, enabling sub-stoichiometric degradation; these designs have been patented in the 2020s for applications in and beyond, leveraging the ring's polarity and rigidity to fine-tune and selectivity.

Occurrence and Biological Activity

Azetidine derivatives, particularly azetidine-2-carboxylic acid (AZC), occur naturally in trace amounts in certain marine sponges and as components of bacterial metabolites. In the , AZC was isolated from the marine sponges Haliclona sp. and Chalinopsilla sp., where it contributes to antidermatophyte activity in their ethanolic extracts. Similarly, a β-lactam compound featuring an azetidine ring, (S)-alanyl-3-[α-(S)-chloro-3-(S)-hydroxy-2-oxo-3-azetidinylmethyl]-(S)-, was identified in 1975 from the fermentation broth of an unidentified species. AZC is also present in plants such as (Convallaria majalis) and sugar beets, as well as in bacterial natural products like azetidomonamides from and vioprolides from Cystobacter violaceus. The biosynthesis of AZC in bacteria proceeds through dedicated azetidine-2-carboxylic acid (AZE) synthases, such as AzeJ in P. aeruginosa and VioH in C. violaceus, which catalyze the intramolecular 4-exo-tet cyclization of S-adenosylmethionine (SAM). This reaction involves nucleophilic attack by the α-amine on the Cγ-carbon of SAM's aminocarboxypropyl moiety, forming the strained four-membered azetidine ring and releasing methylthioadenosine. These enzymes are distributed across bacterial phyla like Pseudomonadota and Actinomycetota, enabling AZC incorporation into non-ribosomal peptides such as bonnevillamides from Streptomyces sp. and clipibicyclenes from Streptomyces cattleya. AZC exhibits toxicity primarily through its role as a proline analog, leading to misincorporation into proteins by prolyl-tRNA synthetase, which disrupts folding and function, particularly in and basic protein. This mechanism contributes to neurotoxic effects, including damage, myelin blistering, and observed in mice at doses of 600 mg/kg, resulting in 60% mortality. In cellular models like cells and embryos, AZC induces , which can be partially rescued by proline supplementation, highlighting its proteotoxic impact. In biological systems, azetidine rings in AZC undergo rapid metabolic ring opening, often initiated by cytochrome P450-mediated α-carbon oxidation, leading to scission and formation of reactive intermediates like aldehydes and ketones. For instance, in human liver microsomes, azetidine-containing inhibitors produce metabolites such as Cys-Gly-thiazolidine conjugates via this pathway, which can be further trapped by glutathione. As a non-proteinogenic amino acid, AZC plays a role in the evolutionary refinement of translation fidelity, challenging aminoacyl-tRNA synthetases (AARSs) and driving the development of editing mechanisms. Human alanyl-tRNA synthetase rejects AZC via pre-transfer editing (>99% efficiency), while prolyl-tRNA synthetase incorporates it at proline sites (up to 13.8% in myelin basic protein), potentially contributing to immunogenic neo-epitopes in diseases like multiple sclerosis. This selective pressure underscores AZC's influence on the evolution of AARS specificity to exclude toxic analogs from primitive protein synthesis pathways.

References

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