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Aziridines
Aziridines
Aziridines
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Mitomycin C, an aziridine, is used as a chemotherapeutic agent by virtue of its antitumour activity.[1]

In organic chemistry, aziridines are organic compounds containing the aziridine functional group (chemical structure (R−)4C2N−R), a three-membered heterocycle with one amine (>NR) and two methylene bridges (>CR2).[2][3][4] The parent compound is aziridine (or ethylene imine), with molecular formula C2H4NH. Several drugs feature aziridine rings, including zoldonrasib, thiotepa, mitomycin C, porfiromycin, and azinomycin B (carzinophilin).[5]

Structure

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The bond angles in aziridine are approximately 60°, considerably less than the normal hydrocarbon bond angle of 109.5°, which results in angle strain as in the comparable cyclopropane and ethylene oxide molecules. A banana bond model explains bonding in such compounds. Aziridine is less basic than acyclic aliphatic amines, with a pKa of 7.9 for the conjugate acid, due to increased s character of the nitrogen free electron pair. Angle strain in aziridine also increases the barrier to nitrogen inversion. This barrier height permits the isolation of separate invertomers, for example the cis and trans invertomers of N-chloro-2-methylaziridine.

Synthesis

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Several routes have been developed to synthesize aziridines (aziridination).

Besides the various classes listed below, the Johnson-Corey-Chaykovsky reaction also gives aziridines from an imine.[6]

Vicinal cyclization

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Haloamines, aminoalcohols and azidoalcohols

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The amine functional group in vicinal haloamines spontaneously displaces the adjacent halide to generate an aziridine. The reaction is an intramolecular nucleophilic substitution, similar to the base-induced cyclization of halohydrins to epoxides. With appropriate activating agents, vicinal cyclization is similarly possible with aminoalcohols, themselves efficiently produced from opening epoxides with amines.[7]

The parent aziridine is produced industrially from aminoethanol via two related routes. The Nippon Shokubai process requires an oxide catalyst and high temperatures to effect the dehydration. In the Wenker synthesis, the aminoethanol is converted to the sulfate ester, which undergoes base-induced sulfate elimination.[8]

In the laboratory, aminoalcohols can be induced to cyclize with the Mitsunobu reaction,[7] but Mitsunobu conditions more fruitfully apply to 2-azido alcohols. Trialkyl phosphines such as trimethylphosphine or tributylphosphine reduce azidoalcohols to an α‑alcohol phosphine imide, which then cyclizes to an aziridine.[9][10]

In the Blum-Ittah aziridine synthesis, the initial azidoalcohol forms when sodium azide opens an epoxide:[11]

Aziridine synthesis Hili 2006
Aziridine synthesis Hili 2006

Darzens-like reactions

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The De Kimpe aziridine synthesis allows for the generation of aziridines by reacting an α-chloroimine with a nucleophile, such as hydride, cyanide, or a Grignard reagent.[12][13]

The Hoch-Campbell ethylenimine synthesis involves the reaction of certain oximes with Grignard reagents, which affords aziridines:[14]

Hoch-Campbell Ethylenimine Synthesis
Hoch-Campbell Ethylenimine Synthesis

Nitrene addition and triazoline contraction

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Nitrene addition to alkenes is a well-established method for the synthesis of aziridines, and occurs for a wide variety of nitrenoid precursors.

Nitrenes can be prepared in situ when iodosobenzene diacetate oxidizes various amides, or from deprotonation of an aminoester:[15]

Nitrene addition
Nitrene addition

Rhodium(II) carboxylates catalyze nitrene formation from O-(2,4-dinitrophenyl)hydroxylamine [de] (DPH), which then aziridates a mono-, di-, tri- or tetra-substituted alkene (olefin):[16]

alkene + DPH aziridine

Alternatively, photolysis or thermolysis of organic azides are good ways to generate nitrenes. The same conditions also contract triazolines, expelling nitrogen and producing an aziridine.

Reactions

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Nucleophilic ring opening

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Aziridines are reactive substrates in ring-opening reactions with many nucleophiles due to their ring strain. Alcoholysis and aminolysis are basically the reverse reactions of the cyclizations. Carbon nucleophiles such as organolithium reagents and organocuprates are also effective.[17][18]

One application of a ring-opening reaction in asymmetric synthesis is that of trimethylsilylazide TMSN
3 with an asymmetric ligand[19] in scheme 2[20] in an organic synthesis of oseltamivir:

Synthesis of Tamiflu via a Catalytic Asymmetric Ring-Opening of meso-Aziridines with TMSN3
Synthesis of Tamiflu via a Catalytic Asymmetric Ring-Opening of meso-Aziridines with TMSN3

1,3-dipole formation

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Certain N-substituted azirines with electron withdrawing groups on both carbons form azomethine ylides in an electrocyclic thermal or photochemical ring-opening reaction.[21][22] These ylides can be trapped with a suitable dipolarophile in a 1,3-dipolar cycloaddition.[23]

Aziridine ring opening

When the N-substituent is an electron-withdrawing group such as a tosyl group, the carbon-nitrogen bond breaks, forming another zwitterion TsN−
–CH
2–CH+
2–R[24]

2-phenyl-N-tosyl-aziridine cycloadditions

This reaction type requires a Lewis acid catalyst such as boron trifluoride. In this way 2-phenyl-N-tosylaziridine reacts with alkynes, nitriles, ketones and alkenes. Certain 1,4-dipoles form from azetidines.

Other

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Lewis acids, such as B(C
6F
5)
3, can induce decomposition of the ring to a carbocation and linear azanide, which then attack unsaturated moieties in tandem.[25] Oxidation to the N-oxide instead induces nitroso compound extrusion, leaving an olefin.[26]

Safety

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As electrophiles, aziridines are subject to attack and ring-opening by endogenous nucleophiles such as nitrogenous bases in DNA base pairs, resulting in potential mutagenicity.[27][28][29]

The International Agency for Research on Cancer (IARC) classifies aziridine compounds as possibly carcinogenic to humans (IARC Group 2B).[30] In making the overall evaluation, the IARC Working Group took into consideration that aziridine is a direct-acting alkylating agent, which is mutagenic in a wide range of test systems and forms DNA adducts that are promutagenic. The features that are responsible for their mutagenicity are relevant to their beneficial medicinal properties.[5]

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Aziridines

View on Grokipedia
from Grokipedia
Aziridines are a class of organic compounds characterized by a three-membered heterocyclic ring composed of two carbon atoms and one atom, making them the smallest -containing heterocycles and structural analogs to oxiranes (epoxides) where oxygen is replaced by . The parent compound, (C₂H₅N), is a colorless, volatile, and toxic liquid first synthesized in 1888, while substituted aziridines feature various N- or C-substituents that modulate their reactivity. Due to the inherent ring strain of approximately 26-28 kcal/mol in their azacyclopropane framework, aziridines exhibit high reactivity, particularly toward nucleophilic ring-opening reactions, acid-catalyzed rearrangements, and cycloadditions, which render them versatile synthons in . This strain arises from the compressed bond angles and eclipsed conformations in the three-membered ring, facilitating transformations into a wide array of nitrogen-containing products such as amines, , and more complex heterocycles. Activated aziridines, bearing electron-withdrawing groups like sulfonyl or moieties on nitrogen or carbon, display enhanced and stereocontrol in reactions, often proceeding with inversion at the attacked carbon. Common synthetic routes to aziridines include the cyclodehydration of β-amino alcohols (e.g., the Wenker synthesis using ), nitrogen-transfer reactions to alkenes via intermediates, and carbon-transfer additions to imines using sulfur ylides or diazocompounds. Recent advances emphasize metal-catalyzed asymmetric methods and photocatalyzed processes to access enantiopure aziridines, addressing challenges in and tolerance. Aziridines play a pivotal role in and synthesis, serving as precursors to biologically active molecules including antitumor agents (e.g., derivatives) and antibiotics. In , they are monomers for polymers via , valued for applications in and . Their toxicity, stemming from alkylating properties, necessitates careful handling, but controlled reactivity has driven innovations in and synthetic methodology over the past decades.

Structure and Properties

General Structure

Aziridines are three-membered heterocyclic compounds consisting of one nitrogen atom and two carbon atoms, with the parent compound, aziridine (also known as ethyleneimine), having the molecular formula C₂H₅N. The ring structure imposes severe geometric constraints, resulting in bond angles of approximately 60°, far below the ideal tetrahedral angle of 109.5°, which generates significant angle strain comparable to that in epoxides and cyclopropanes, with a total ring strain energy of about 27 kcal/mol. This strain results in C–N bond lengths of approximately 1.47 Å, comparable to those in typical acyclic secondary amines (around 1.47 Å). The atom in adopts an sp³-like hybridization but exhibits increased s-character in the orbital as a consequence of the , which elevates the out-of-plane position of the and reduces the molecule's basicity relative to acyclic amines. For N-H , the pKₐ of the conjugate acid is approximately 8 (specifically 7.98 for ), compared to around 11 for typical secondary aliphatic amines, reflecting the poorer availability of the for . The strain also raises the barrier to inversion to about 19.5 kcal/mol in the parent , higher than the 5–6 kcal/mol in acyclic amines, allowing observation of inversion stereoisomers at in some substituted cases. Aziridines are classified based on the : N-unsubstituted (bearing N–H), N-alkylated (with alkyl groups like methyl), N-arylated (with aryl groups such as phenyl), and N-acylated (with acyl groups like tosyl or carbonyl derivatives), each influencing reactivity and stability. The ring adopts a puckered envelope conformation, with the atom displaced out of the carbon plane by about 0.4 , contributing to conformational flexibility. In disubstituted aziridines (e.g., 2,3-disubstituted), stereoisomers exist as cis (substituents on the same face) and trans (on opposite faces) configurations, with the trans often more stable due to reduced steric interactions, and interconversion possible via inversion or ring opening.

Physical and Spectroscopic Properties

, the parent compound of the aziridine class, is a colorless with an ammonia-like . It has a of 56 °C, a of -78 °C, and a of 0.83 g/mL at 20 °C. Due to its polar atom, exhibits high and is miscible with as well as many organic solvents such as and . In (NMR) , aziridines display characteristic signals influenced by the . The methylene protons in the parent appear at δ 1.2-1.5 ppm in ¹H NMR, while the ring carbons resonate around 20-30 ppm in ¹³C NMR. The angle strain in the three-membered ring contributes to these upfield shifts compared to larger cyclic amines. (IR) reveals a distinctive C-N absorption for aziridines in the 1000-1100 cm⁻¹ region, reflecting the strained ring bonds. Mass spectrometry of aziridines typically involves ring opening, leading to prominent ion fragments as a result of β-cleavage pathways. Substituted aziridines show variations in physical properties depending on the substituents; for instance, N-alkyl or N-aryl groups increase the due to enhanced molecular weight and intermolecular forces, with examples like N-methylaziridine boiling at 66 °C. Spectroscopic features also shift, such as downfield ¹H NMR signals for ring protons adjacent to electron-withdrawing groups.

Synthesis

Cyclization Methods

Cyclization methods represent a foundational approach to synthesis, involving the intramolecular closure of linear precursors bearing a atom and a suitable separated by one carbon atom, typically under basic conditions to facilitate . These reactions proceed via an S_N2 mechanism, with inversion of at the carbon bearing the and often delivering aziridines in moderate to high yields (50-90%) depending on the substrate and conditions. One of the earliest and most straightforward cyclization routes is the base-promoted closure of vicinal haloamines, such as 2-haloethylamines, first reported by in 1888. In this method, treatment of a compound like 2-bromoethylamine with a strong base (e.g., NaOH or KOH) effects , generating the ring through intramolecular attack of the amine nitrogen on the carbon-halogen bond. \mathrm{Br-CH_2-CH_2-NH_2 + base \rightarrow \overset{\begin{matrix} \small \text{H_2C} \\ \small | \\ \small \text{H_2C} \\ \small | \\ \small \text{NH} \end{matrix}}{\text{aziridine}} + HBr} This approach is particularly effective for unsubstituted or N-alkyl aziridines and is conducted in aqueous or alcoholic media at elevated temperatures, with yields typically ranging from 60-85% for simple substrates. The reaction's arises from the backside attack in the S_N2 step, inverting configuration at the reacting carbon center. Amino alcohols serve as versatile precursors for aziridines through activation of the hydroxyl group to a better . A classic method is the Wenker synthesis, involving treatment of β-amino alcohols with concentrated to form the cyclic , followed by basification (e.g., with NaOH) to promote cyclization via intramolecular nucleophilic attack by the amine, often with inversion at the carbon originally bearing the OH group. This two-step process, developed in the , provides NH-aziridines in 50-80% overall yields for simple substrates like 2-aminoethanol and is effective under heating, though it can lead to side products with sensitive groups. The provides a mild and stereocontrolled variant. In this process, β-amino alcohols are treated with (PPh_3) and (DEAD) or (DIAD) in an aprotic solvent like THF, promoting inversion at the alcohol carbon via formation of an alkoxyphosphonium intermediate that is displaced by the adjacent amine. For example, 2-aminoethanol under these conditions yields the parent in good efficiency. HO−CH2−CH2−NH2+PPh3/DEAD→[aziridine](/page/Aziridine)\mathrm{HO-CH_2-CH_2-NH_2 + PPh_3/DEAD \rightarrow \text{[aziridine](/page/Aziridine)}} Yields for this transformation often fall in the 45-82% range, with high diastereoselectivity when starting from chiral amino alcohols, making it suitable for accessing enantiopure s. The reaction is typically performed at and tolerates various N-protecting groups, though unprotected amines require careful control to avoid side reactions. Azido alcohols offer an orthogonal route via reductive cyclization, leveraging the to convert the to an iminophosphorane intermediate that undergoes intramolecular nucleophilic attack on the alcohol-activated carbon. Primary 2-azido alcohols, upon treatment with in a like or THF followed by mild acidification, form NH-s through loss of Ph_3P=O and cyclization. N3−CH2−CH2−OH→PPh3iminophosphorane→reduction/cyclizationaziridine\mathrm{N_3-CH_2-CH_2-OH \xrightarrow{PPh_3} \text{iminophosphorane} \xrightarrow{\text{reduction/cyclization}} \text{aziridine}}
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