# Aziridines

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For the parent compound, see [Aziridine](/source/Aziridine).

In [organic chemistry](/source/Organic_chemistry), **aziridines** (also sometimes called **ethyleneimines**) are [organic compounds](/source/Organic_compound) containing the aziridine [functional group](/source/Functional_group) ([chemical structure](/source/Chemical_structure) (R\s)4C2N\sR), a three-membered [heterocycle](/source/Heterocycle) with one [amine](/source/Amine) (>NR) and two [methylene bridges](/source/Methylene_bridge) (>CR2).[1][2][3] The parent compound is [aziridine](/source/Aziridine) (or ethylene imine), with [molecular formula](/source/Molecular_formula) C2H4NH. Several drugs feature aziridine rings, including [zoldonrasib](/source/RMC-9805), [thiotepa](/source/Thiotepa), [mitomycin C](/source/Mitomycin_C), [porfiromycin](/source/Porfiromycin), and [azinomycin B](/source/Azinomycin_B) (carzinophilin).[4]

## Structure

The [bond angles](/source/Bond_angle) in aziridine are approximately 60°, considerably less than the normal [hydrocarbon](/source/Hydrocarbon) bond angle of 109.5°, which results in [angle strain](/source/Ring_strain) as in the comparable [cyclopropane](/source/Cyclopropane) and [ethylene oxide](/source/Ethylene_oxide) molecules. A [banana bond](/source/Banana_bond) model explains bonding in such compounds. Aziridine is less [basic](/source/Base_(chemistry)) than [acyclic](/source/Open_chain_compound) [aliphatic](/source/Aliphatic) amines, with a [pKa](/source/PKa) of 7.9 for the [conjugate acid](/source/Conjugate_acid), due to increased [s character](/source/Orbital_hybridization) of the [nitrogen](/source/Nitrogen) [free electron pair](/source/Free_electron_pair). [Angle strain](/source/Angle_strain) in aziridine also increases the barrier to [nitrogen inversion](/source/Nitrogen_inversion). This barrier height permits the isolation of separate *invertomers*, for example the [*cis*](/source/Cis_isomer) and [*trans*](/source/Trans_isomer) invertomers of *N*-chloro-2-methylaziridine.

## Synthesis

Several routes have been developed to [synthesize](/source/Organic_synthesis) aziridines (**aziridination**).

Besides the various classes listed below, the [Johnson-Corey-Chaykovsky reaction](/source/Johnson-Corey-Chaykovsky_reaction) also gives aziridines from an [imine](/source/Imine).[5]

### Vicinal cyclization

#### Haloamines, aminoalcohols and azidoalcohols

The [amine](/source/Amine) functional group in vicinal haloamines spontaneously displaces the adjacent [halide](/source/Halide) to generate an aziridine. The reaction is an [intramolecular](/source/Intramolecular_reaction) [nucleophilic substitution](/source/Nucleophilic_substitution), similar to the base-induced cyclization of [halohydrins](/source/Halohydrin) to epoxides. With appropriate activating agents, vicinal cyclization is similarly possible with aminoalcohols, themselves efficiently produced from opening epoxides with [amines](/source/Amine).[6]

The parent aziridine is produced industrially from [aminoethanol](/source/Aminoethanol) via two related routes. The Nippon Shokubai process requires an oxide catalyst and high temperatures to effect the dehydration. In the [Wenker synthesis](/source/Wenker_synthesis), the aminoethanol is converted to the [sulfate ester](/source/Sulfate_ester), which undergoes base-induced sulfate elimination.[7]

In the laboratory, aminoalcohols can be induced to cyclize with the [Mitsunobu reaction](/source/Mitsunobu_reaction),[6] but Mitsunobu conditions more fruitfully apply to 2-azido alcohols. In a variant on the [aza-Wittig reaction](/source/Aza-Wittig_reaction), trialkyl phosphines such as [trimethylphosphine](/source/Trimethylphosphine) or [tributylphosphine](/source/Tributylphosphine) reduce azidoalcohols to an αalcohol [phosphine imide](/source/Phosphine_imide), which then cyclizes to an aziridine.[8][9]

In the [Blum-Ittah aziridine synthesis](/source/Blum-Ittah_aziridine_synthesis), the initial azidoalcohol forms when [sodium azide](/source/Sodium_azide) [opens](/source/Ring-opening_reaction) an [epoxide](/source/Epoxide):[10]

#### Darzens-like reactions

The [De Kimpe aziridine synthesis](/source/De_Kimpe_aziridine_synthesis) allows for the generation of aziridines by reacting an [α-chloroimine](/source/Imine) with a nucleophile, such as [hydride](/source/Hydride), [cyanide](/source/Cyanide), or a [Grignard reagent](/source/Grignard_reagent).[11][12]

The [Hoch-Campbell ethylenimine synthesis](/source/Hoch-Campbell_ethylenimine_synthesis) involves the reaction of certain [oximes](/source/Oxime) with [Grignard reagents](/source/Grignard_reagent), which affords aziridines:[13]

### Nitrene addition and triazoline contraction

[Nitrene](/source/Nitrene) addition to [alkenes](/source/Alkene) is a well-established method for the synthesis of aziridines, and occurs for a wide variety of [nitrenoid](/source/Nitrenoid) precursors.

Nitrenes (as [iminoiodinane](/source/Iminoiodinane) nitrenoids) can be prepared *in situ* when [iodosobenzene diacetate](/source/Iodosobenzene_diacetate) oxidizes various [amides](/source/Amide_(functional_group)), or from deprotonation of an [aminoester](/source/Aminoester_(functional_group)):[14]

[Rhodium(II) carboxylates](/source/Rhodium(II)_acetate) catalyze nitrene formation from [*O*-(2,4-dinitrophenyl)hydroxylamine](/source/O-(2,4-dinitrophenyl)hydroxylamine) (DPH), which then aziridates a mono-, di-, tri- or tetra-substituted alkene (olefin):[15]

- alkene + DPH ->[\ce{Rh2(CO2R)4}] aziridine

Alternatively, [photolysis](/source/Photolysis) or [thermolysis](/source/Thermolysis) of [organic azides](/source/Organic_azide) are good ways to generate nitrenes. The same conditions also contract [triazolines](/source/Triazoline), expelling [nitrogen](/source/Nitrogen) and producing an aziridine.

## Reactions

### Nucleophilic ring opening

Aziridines are reactive substrates in ring-opening reactions with many [nucleophiles](/source/Nucleophile) due to their [ring strain](/source/Ring_strain). Alcoholysis and aminolysis are basically the reverse reactions of the cyclizations. Carbon nucleophiles such as [organolithium reagents](/source/Organolithium_reagent) and [organocuprates](/source/Organocuprate) are also effective.[16][17]

One application of a ring-opening reaction in [asymmetric synthesis](/source/Asymmetric_synthesis) is that of [trimethylsilylazide](/source/Trimethylsilylazide) TMSN3 with an asymmetric ligand[18] in *scheme 2*[19] in an [organic synthesis](/source/Organic_synthesis) of [oseltamivir](/source/Oseltamivir_total_synthesis):

### 1,3-dipole formation

Certain N-substituted azirines with [electron withdrawing groups](/source/Electron_withdrawing_group) on both carbons form [azomethine ylides](/source/Azomethine_ylide) in an [electrocyclic](/source/Electrocyclic_reaction) thermal or photochemical [ring-opening reaction](/source/Ring-opening_reaction).[20][21] These ylides can be trapped with a suitable [dipolarophile](/source/Dipolarophile) in a [1,3-dipolar cycloaddition](/source/1,3-dipolar_cycloaddition).[22]

When the N-substituent is an [electron-withdrawing group](/source/Electron-withdrawing_group) such as a [tosyl](/source/Tosyl) group, the [carbon-nitrogen bond](/source/Carbon-nitrogen_bond) breaks, forming another [zwitterion](/source/Zwitterion) TsN-–CH2–CH2+–R[23]

This reaction type requires a [Lewis acid](/source/Lewis_acid) catalyst such as [boron trifluoride](/source/Boron_trifluoride). In this way 2-phenyl-*N*-tosylaziridine reacts with alkynes, [nitriles](/source/Nitrile), [ketones](/source/Ketone) and [alkenes](/source/Alkene). Certain 1,4-dipoles form from [azetidines](/source/Azetidine).

### Other

Lewis acids, such as B(C6F5)3, can induce decomposition of the ring to a [carbocation](/source/Carbocation) and linear [azanide](/source/Azanide), which then attack [unsaturated](/source/Saturated_and_unsaturated_compounds) moieties in [tandem](/source/Tandem_reaction).[24] Oxidation to the [N-oxide](/source/N-oxide) instead induces [nitroso](/source/Nitroso) compound extrusion, leaving an [olefin](/source/Olefin).[25]

## Safety

As [electrophiles](/source/Electrophile), aziridines are subject to attack and ring-opening by endogenous nucleophiles such as nitrogenous bases in DNA base pairs, resulting in potential mutagenicity.[26][27][28]

The [International Agency for Research on Cancer](/source/International_Agency_for_Research_on_Cancer) (IARC) classifies aziridine compounds as possibly [carcinogenic](/source/Carcinogenic) to humans ([IARC Group 2B](/source/List_of_IARC_Group_2B_carcinogens)).[29] In making the overall evaluation, the IARC Working Group took into consideration that aziridine is a direct-acting [alkylating agent](/source/Alkylating_agent), which is [mutagenic](/source/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.[4]

## See also

- [Binary ethylenimine](/source/Binary_ethylenimine), a dimeric form of aziridine

## References

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1. *Epoxides and Aziridines – A Mini Review* Albert Padwa and S. Shaun Murphree [Arkivoc](/source/Arkivoc) (JC-1522R) pp. 6–33 [Online article](http://www.arkat-usa.org/ark/journal/2006/I03_Coxon/1522/JC-1522R.asp)

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1. The catalyst is based on [yttrium](/source/Yttrium) with three [isopropyloxy](/source/Isopropyloxy) [substituents](/source/Substituent) and the [ligand](/source/Ligand) a [phosphine oxide](/source/Phosphine_oxide) (Ph = [phenyl](/source/Phenyl)), with 91% [enantiomeric excess](/source/Enantiomeric_excess) (ee)

1. Harold W. Heine & Richard Peavy (1965). "Aziridines XI. Reaction of 1,2,3-triphenylaziridine with diethylacetylene dicarboxylate and maleic anhydride". *[Tetrahedron Letters](/source/Tetrahedron_Letters)*. **6** (35): 3123–6. [doi:10.1016/S0040-4039(01)89232-7](https://doi.org/10.1016/S0040-4039(01)89232-7)

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Adapted from the Wikipedia article [Aziridines](https://en.wikipedia.org/wiki/Aziridines) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Aziridines?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.