220 px,

chemotherapeutic Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothera ...

agent by virtue of its antitumour activity. Aziridines are organic compounds containing the aziridine functional group, a three-membered heterocycle with one

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...

(-NR-) and two methylene bridges (--). The parent compound is

aziridine Aziridine is an organic compound consisting of the three-membered heterocycle . It is a colorless, toxic, volatile liquid that is of significant practical interest. Aziridine was discovered in 1888 by the chemist Siegmund Gabriel. Its derivati ...

(or ethylene imine), with

molecular formula In chemistry, a chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, ...

. Several drugs feature aziridine rings, including

mitomycin C Mitomycin C is a mitomycin that is used as a chemotherapeutic agent by virtue of its antitumour activity. Medical uses It is given intravenously to treat upper gastro-intestinal cancers (e.g. esophageal carcinoma), anal cancers, and breast ...

, porfiromycin, and azinomycin B (carzinophilin).

Structure

The

bond angle Bond or bonds may refer to: Common meanings * Bond (finance), a type of debt security * Bail bond, a commercial third-party guarantor of surety bonds in the United States * Chemical bond, the attraction of atoms, ions or molecules to form chemical ...

s in aziridine are approximately 60°, considerably less than the normal

hydrocarbon In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons are examples of group 14 hydrides. Hydrocarbons are generally colourless and hydrophobic, and their odors are usually weak or ...

bond angle of 109.5°, which results in

angle strain In organic chemistry, ring strain is a type of instability that exists when bonds in a molecule form angles that are abnormal. Strain is most commonly discussed for small rings such as cyclopropanes and cyclobutanes, whose internal angles are ...

as in the comparable cyclopropane and

ethylene oxide Ethylene oxide is an organic compound with the chemical formula, formula . It is a cyclic ether and the simplest epoxide: a three-membered Ring (chemistry), ring consisting of one oxygen atom and two carbon atoms. Ethylene oxide is a colorless a ...

molecules. A

banana bond In organic chemistry, a bent bond, also known as a banana bond, is a type of covalent chemical bond with a geometry somewhat reminiscent of a banana. The term itself is a general representation of electron density or configuration resembling a ...

model explains bonding in such compounds. Aziridine is less basic than acyclic

aliphatic In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated, like hexane, ...

amines, with a pKa of 7.9 for the

conjugate acid A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...

, due to increased s character of the

nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...

free electron pair In chemistry, a lone pair refers to a pair of valence electrons that are not shared with another atom in a covalent bondIUPAC '' Gold Book'' definition''lone (electron) pair''/ref> and is sometimes called an unshared pair or non-bonding pair. Lo ...

Angle strain In organic chemistry, ring strain is a type of instability that exists when bonds in a molecule form angles that are abnormal. Strain is most commonly discussed for small rings such as cyclopropanes and cyclobutanes, whose internal angles are ...

in aziridine also increases the barrier to

nitrogen inversion In chemistry, pyramidal inversion (also umbrella inversion) is a fluxional process in compounds with a pyramidal molecule, such as ammonia (NH3) "turns inside out". It is a rapid oscillation of the atom and substituents, the molecule or ion passi ...

. This barrier height permits the isolation of separate ''invertomers'', for example the ''cis'' and ''trans'' invertomers of ''N''-chloro-2-methylaziridine.

Synthesis

Several routes have been developed for the syntheses of aziridines (aziridination).

Cyclization of haloamines and amino alcohols

functional group displaces the adjacent halide in an intramolecular

nucleophilic substitution In chemistry, a nucleophilic substitution is a class of chemical reactions in which an electron-rich chemical species (known as a nucleophile) replaces a functional group within another electron-deficient molecule (known as the electrophile). The ...

reaction to generate an aziridine. The parent aziridine is produced industrially from

aminoethanol Aminoethanol may refer to: * 1-Aminoethanol * Ethanolamine (2-aminoethanol, ETA, or MEA) {{Short pages monitor

Nucleophilic ring opening

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 reagent In organometallic chemistry, organolithium reagents are chemical compounds that contain carbon–lithium (C–Li) bonds. These reagents are important in organic synthesis, and are frequently used to transfer the organic group or the lithium atom ...

s and organocuprates are also effective. One application of a ring-opening reaction in asymmetric synthesis is that of trimethylsilylazide with an asymmetric ligand in ''scheme 2'' in an organic synthesis of

oseltamivir Oseltamivir, sold under the brand name Tamiflu, is an antiviral medication used to treat and prevent influenza A and influenza B, viruses that cause the flu. Many medical organizations recommend it in people who have complications or are at high ...

1,3-dipole formation

Certain N-substituted azirines with

electron withdrawing group In chemistry, an electron-withdrawing group (EWG) is a substituent that has some of the following kinetic and thermodynamic implications: *with regards to electron transfer, electron-withdrawing groups enhance the oxidizing power tendency of ...

s on both carbons form

azomethine ylide Azomethine ylides are nitrogen-based 1,3-dipoles, consisting of an iminium ion next to a carbanion. They are used in 1,3-dipolar cycloaddition reactions to form five-membered heterocycles, including pyrrolidines and pyrrolines. These reactions ...

s in an

electrocyclic In organic chemistry, an electrocyclic reaction is a type of pericyclic rearrangement where the net result is one pi bond being converted into one sigma bond or vice versa. These reactions are usually categorized by the following criteria: * React ...

thermal or photochemical

ring-opening reaction A cyclic compound (or ring compound) is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where a ...

. These ylides can be trapped with a suitable dipolarophile in a 1,3-dipolar cycloaddition. : Aziridine ring opening

When the N-substituent is an

electron-withdrawing group In chemistry, an electron-withdrawing group (EWG) is a substituent that has some of the following kinetic and thermodynamic implications: *with regards to electron transfer, electron-withdrawing groups enhance the oxidizing power tendency of the ...

such as a

tosyl In organic chemistry, a toluenesulfonyl group (tosyl group, abbreviated Ts or Tos) is a univalent functional group with the chemical formula –. It consists of a Toluene, tolyl group, –, joined to a sulfonyl group, ––, with the open vale ...

group, the carbon-nitrogen bond breaks, forming another

zwitterion In chemistry, a zwitterion ( ; ), also called an inner salt or dipolar ion, is a molecule that contains an equal number of positively- and negatively-charged functional groups. : With amino acids, for example, in solution a chemical equilibrium wil ...

2-phenyl-N-tosyl-aziridine cycloadditions

This reaction type requires a

Lewis acid A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any sp ...

catalyst such as boron trifluoride. In this way 2-phenyl-''N''-tosylaziridine reacts with alkynes, nitriles, ketones and

alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...

s. Certain 1,4-dipoles form from

azetidine 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 ...

Other

N-unsubstituted aziridines can be opened with olefins in the presence of strong Lewis acid B(.

Safety

electrophile In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carrie ...

s, aziridines are subject to attack and ring-opening by endogenous nucleophiles such as nitrogenous bases in DNA base pairs, resulting in potential mutagenicity. The

International Agency for Research on Cancer The International Agency for Research on Cancer (IARC; french: Centre International de Recherche sur le Cancer, CIRC) is an intergovernmental agency forming part of the World Health Organization of the United Nations. Its role is to conduct and ...

(IARC) classifies aziridine compounds as possibly

carcinogenic A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive subs ...

to humans ( IARC Group 2B). In making the overall evaluation, the IARC Working Group took into consideration that aziridine is a direct-acting

alkylating agent Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effectin ...

, which is

mutagenic In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer i ...

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.

References

{{reflist, 30em Functional groups IARC Group 2B carcinogens