Aziridine

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IUPACName = Aziridine
OtherNames = Azacyclopropane, Ethylene imine
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CASNo = 151-56-4
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Formula = | C=2 | H=5 | N=1
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Aziridines are a group of organic compounds sharing the aziridine functional group which is a three membered heterocycle with one amine group and two methylene groups. ["Heterocyclic chemistry" T.L. Gilchrist ISBN 0-582-01421-2] ["Epoxides and aziridines - A mini review" Albert Padwaa and S. Shaun Murphreeb Arkivoc (JC-1522R) pp 6-33 [http://www.arkat-usa.org/ark/journal/2006/I03_Coxon/1522/JC-1522R.asp Online article] ] The parent compound of the aziridines is called aziridine (or ethylene imine) with molecular formula C₂H₅N.

Structure

The bond angles in aziridine are around 60° which is considerably less than the bond angle of 109.5° found in ordinary hydrocarbons and this results in angle strain just like in the comparable cyclopropane and oxirane molecules. Bonding in this type of compound can be explained by invoking a banana bond model. 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. Increased angle strain in aziridine is also responsible for increased barrier for nitrogen inversion. This barrier is high enough for the isolation of separate invertomers for instance the "cis" and "trans" invertomers of "N"-chloro-2-methylaziridine.

Synthesis

Aziridines can be prepared in organic synthesis in several ways.

Cyclization of haloamines and amino alcohols

An amine functional group displaces the adjacent halide in an intramolecular nucleophilic substitution reaction to generate an aziridine. Amino alcohols have the same reactivity but it is required to convert the hydroxy group into a good leaving group first. The cyclization of an amino alcohol is called a Wenker synthesis (1935) and that of a haloamine the Gabriel ethylenimine method (1888) [ [http://www.drugfuture.com/OrganicNameReactions/ONR153.htm Gabriel Ethylenimine Method ] ]

Nitrene addition

Nitrene addition to alkenes is a well established method for the synthesis of aziridines. Photolysis or thermolysis of azides are a good way to generate nitrenes. Nitrenes can also be prepared in-situ from iodosobenzene diacetate and sulfonamides or the ethoxycarbonylnitrene from the "N"-sulfonyloxy precursor. ["Addition reactions of ethoxycarbonylnitrene and ethoxycarbonylnitrenium ion to allylic ethers" M. Antonietta Loreto, Lucio Pellacani, Paolo A. Tardella, and Elena Toniato Tetrahedron Letters, Volume 25, Issue 38, 1984, Pages 4271-4274 [http://www.sciencedirect.com/science?_ob=ArticleURL&_aset=V-WA-A-W-AV-MsSAYZW-UUW-U-AAWZCZYECB-AAWVAVEDCB-WYWCZUAZV-AV-U&_rdoc=11&_fmt=summary&_udi=B6THS-42H2CKG-1YM&_coverDate=12%2F31%2F1984&_cdi=5290&_orig=search&_st=13&_sort=d&view=c&_acct=C000051225&_version=1&_urlVersion=0&_userid=1065764&md5=781fe50f70e6397001e321945b9fd3db Abstract] ]

Triazoline decomposition

On thermal treatment or photolysis of triazolines, nitrogen is expelled and an aziridine remains. The required triazoline is generated from reaction of an azide with an alkene in a cycloaddition reaction.

From epoxides

One methods involves the ring-opening reaction of an epoxide with sodium azide followed by organic reduction of the azide with triphenylphosphine accompanied by expulsion of nitrogen gas: [Readily Available Unprotected Amino Aldehydes Ryan Hili and Andrei K. Yudin J. Am. Chem. Soc.; 2006; 128(46) pp 14772 - 14773; (Communication) DOI|10.1021/ja065898s]

The other method involves the ring-opening reaction of an epoxide with amine followed by ring closing with Mitsunobu reaction. [Aravinda B. Pulipaka, Stephen C. Bergmeier. Synthesis 2008, No. 9, 1420-1430]

From oximes

The Hoch-Campbell ethylenimine synthesis describes aziridine synthesis from reaction of certain oximes with Grignard reagents [Hoch, Compt. rend., 196, 1865 (1934); (a), ibid., aOS, 799 (1936); (e), ibid., 204, 358 (1937).] ["The action of Grignard reagents on oximes. i. The action of phenylmagnesium bromide on mixed ketoximes" Kenneth N. Campbell, James F. Mckenna J. Org. Chem.; 1939; 4(2); 198-205. DOI|10.1021/jo01214a012] ["The reaction of Grignard reagents with oximes. ii. The action of aryl grignard reagents with mixed ketoximes" Kenneth N. Campbell, Barbara Knapp Campbell, Elmer Paul Chaput J. Org. Chem.; 1943; 8(1); 99-102. DOI|10.1021/jo01189a015] ["The action of Grignard reagents on oximes. iii. The mechanism of the action of arylmagnesium halides on mixed ketoximes. A new synthesis of ethyleneimines" Kenneth N. Campbell, Barbara K. Campbell, James F. Mckenna, and Elmer Paul Chaput J. Org. Chem.; 1943; pp 103 - 109; DOI|10.1021/jo01189a016] :

Reactions

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. Effective nucleophiles are also carbon nucleophiles such as organolithium reagent and organocuprates.

One application of a ring-opening reaction in asymmetric synthesis is that with trimethylsilylazide TMSN₃ and an asymmetric ligand ["De Novo Synthesis of Tamiflu via a Catalytic Asymmetric Ring-Opening of meso-Aziridines with TMSN3" Yuhei Fukuta, Tsuyoshi Mita, Nobuhisa Fukuda, Motomu Kanai, and Masakatsu Shibasaki J. Am. Chem. Soc.; 2006; 128(19) pp 6312 - 6313; [http://dx.doi.org/10.1021/ja061696k Abstract] ] in "scheme 2" [The catalyst is based on yttrium with three isopropyloxy substituents, the ligand is a phosphine oxide (Ph = phenyl). with 91% enantiomeric excess (ee) ] in an organic synthesis of oseltamivir:

Other

N-unsubstituted aziridines can be opened with olefins in the presence of strong Lewis acid B(C6F5)3. [Aravinda B. Pulipaka and Stephen C. Bergmeier. J. Org. Chem. 2008, 73, 1462-1467] Certain N-substituted azirines with electron withdrawing groups on both carbons form azomethine ylides in an electrocyclic ring opening reaction. These ylides can be trapped with a suitable dipolarophile in a 1,3-dipolar cycloaddition.

Human toxicology

The toxicology of any specific aziridine compound will depend on its own structure and activity although sharing the general characteristics of the aziridine group. As an electrophile, aziridines are subject to attack and ring-opening by endogenous nucleophiles such as nitrogenous bases in DNA base pairs, resulting in potential mutagenicity [L. Kanerva, H. Keskinen, P. Autio, T. Estlander, M. Tuppurainen, R. Jolanki Occupational respiratory and skin sensitization caused by polyfunctional aziridine hardener Clinical & Experimental Allergy 1995; 25 (5), 432–439.] [Sartorelli P, Pistolesi P, Cioni F, Napoli R, Sisinni AG, Bellussi L, Passali GC, Cherubini Di Simplicio E, Flori L. Skin and respiratory allergic disease caused by polyfunctional aziridine Med Lav. 2003;94(3):285-95.] [Mapp CE, Agents, old and new, causing occupational asthma Occup. Environ. Med. 2001;58;354-60] .

Exposure

Inhalation and direct contact. It is noted in some reports that even when gloves have been used these have not prevented permeation of aziridine. It is therefore important that users check the breakthrough permeation times for gloves and pay scrupulous attention to avoiding contamination when degloving.

Carcinogenicity

The International Agency for Research on Cancer (IARC) has reviewed aziridine compounds and classified them as possibly carcinogenic to humans (Group 2B). http://monographs.iarc.fr/ENG/Monographs/vol9/volume9.pdfIn 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.

Irritancy

Irritant effects are caused to mucosal surfaces e.g. eyes, nose, respiratory tract and skin.

Sensitisation

Aziridine rapidly penetrates skin on skin contact.

Skin sensitiser - causing allergic contact dermatitis and urticaria.

Respiratory sensitiser - causing occupational asthma

References