Aziridine

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Aziridine
Aziridine.svg Aziridine3d.png
Identifiers
CAS number 151-56-4 YesY
ChemSpider 8682 YesY
EC number 205-793-9
KEGG C11687 YesY
ChEBI CHEBI:30969 YesY
ChEMBL CHEMBL540990 YesY
Jmol-3D images Image 1
Properties
Molecular formula C2H5N
Molar mass 43.07 g mol−1
Appearance Clear colorless oily liquid[1]
Density 0.8321 g/mL 20 °C[2]
Melting point −77.9 °C (−108.2 °F; 195.2 K)
Boiling point 56 °C (133 °F; 329 K)
Solubility in water miscible
Hazards
Main hazards highly flammable, very toxic
NFPA 704
Flammability code 3: Liquids and solids that can be ignited under almost all ambient temperature conditions. Flash point between 23 and 38 °C (73 and 100 °F). E.g., gasoline) Health code 4: Very short exposure could cause death or major residual injury. E.g., VX gas Reactivity code 3: Capable of detonation or explosive decomposition but requires a strong initiating source, must be heated under confinement before initiation, reacts explosively with water, or will detonate if severely shocked. E.g., fluorine Special hazards (white): no codeNFPA 704 four-colored diamond
Flash point −11 °C (12 °F; 262 K)
Explosive limits 3.6–46%
Related compounds
Related heterocycles Borirane
Ethylene oxide
Thiirane
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 YesY (verify) (what is: YesY/N?)
Infobox references

Aziridines are organic compounds containing the aziridine functional group, a three-membered heterocycle with one amine group (-NH-) and two methylene bridges (-CH
2
-).[3][4] The parent compound is aziridine (or ethylene imine), with molecular formula C
2
H
5
N
.

Structure[edit]

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[edit]

There are several syntheses of aziridines (aziridination).

Cyclization of haloamines and amino alcohols[edit]

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 the hydroxy group must first be converted into a good leaving group. The cyclization of an amino alcohol is called a Wenker synthesis (1935), and that of a haloamine the Gabriel ethylenimine method (1888) [5]

Nitrene addition[edit]

Nitrene addition to alkenes is a well-established method for the synthesis of aziridines. Photolysis or thermolysis of azides are good ways to generate nitrenes. Nitrenes can also be prepared in situ from iodosobenzene diacetate and sulfonamides, or the ethoxycarbonylnitrene from the N-sulfonyloxy precursor.[6]

Nitrene addition

Triazoline decomposition[edit]

Thermal treatment or photolysis of triazolines expels nitrogen, producing an aziridine. Triazolines can be generated by cycloaddition of alkenes with an azide.

From epoxides[edit]

One method 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:[7]

Aziridine synthesis Hili 2006

The other method involves the ring-opening reaction of an epoxide with amines, followed by ring closing with the Mitsunobu reaction.[8]

From oximes[edit]

The Hoch-Campbell ethylenimine (Aziridine) synthesis is the reaction of certain oximes with Grignard reagents:[9][10][11][12]

Hoch-Campbell Ethylenimine Synthesis

Reactions[edit]

Nucleophilic ring opening[edit]

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.

One application of a ring-opening reaction in asymmetric synthesis is that of trimethylsilylazide TMSN
3
with an asymmetric ligand[13] in scheme 2[14] in an organic synthesis of oseltamivir:

Scheme 2. Synthesis of Tamiflu via a Catalytic Asymmetric Ring-Opening of meso-Aziridines with TMSN3

1,3-dipole formation[edit]

Certain N-substituted azirines with electron withdrawing groups on both carbons form azomethine ylides in an electrocyclic thermal or photochemical ring-opening reaction.[15][16] These ylides can be trapped with a suitable dipolarophile in a 1,3-dipolar cycloaddition.[17]

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
[18]

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[edit]

N-unsubstituted aziridines can be opened with olefins in the presence of strong Lewis acid B(C
6
F
5
)
3
.[19]

Human toxicology[edit]

The toxicology of a particular aziridine compound depends on its structure and activity, although sharing the general characteristics of aziridines. 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.[20][21][22]

Exposure[edit]

Inhalation and direct contact. Some reports note that the use of gloves has 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. Workers handling azidrine are expected to be provided with, and required to wear and use, a half-mask filter-type respirator for dusts, mists and fumes.[23]

There is relatively little human exposure data on aziridine. This is because it is considered extremely dangerous. In industrial settings, class A pressure suits are preferred when exposure is possible.

Carcinogenicity[edit]

The International Agency for Research on Cancer (IARC) has reviewed aziridine compounds and classified them as possibly carcinogenic to humans (IARC Group 2B).[24] 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.

Irritancy

Aziridines are irritants of mucosal surfaces including eyes, nose, respiratory tract and skin.

Sensitization

Aziridine rapidly penetrates skin on contact.

Skin sensitizer — causing allergic contact dermatitis and urticaria.

Respiratory sensitiser — causing occupational asthma

See also[edit]

References[edit]

  1. ^ "Aziridine". Re-evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 71. 1999. 
  2. ^ Weast, Robert C. et al (1978). CRC Handbook of Chemistry and Physics (59th ed.). West Palm Beach, FL: CRC Press. ISBN 0-8493-0549-8. 
  3. ^ Gilchrist, T.L. Heterocyclic chemistry. ISBN 0-582-01421-2. 
  4. ^ Epoxides and aziridines – A mini review Albert Padwaa and S. Shaun Murphreeb Arkivoc (JC-1522R) pp. 6–33 Online article
  5. ^ Gabriel Ethylenimine Method
  6. ^ M. Antonietta Loreto, Lucio Pellacani, Paolo A. Tardella, Elena Toniato (1984). "Addition reactions of ethoxycarbonylnitrene and ethoxycarbonylnitrenium ion to allylic ethers". Tetrahedron Letters 25 (38): 4271–4. doi:10.1016/S0040-4039(01)81414-3. 
  7. ^ Ryan Hili, Andrei K. Yudin (2006). "Readily Available Unprotected Amino Aldehydes". J. Am. Chem. Soc. 128 (46): 14772–3. doi:10.1021/ja065898s. 
  8. ^ B. Pulipaka, Stephen C. Bergmeier (2008). "Aravinda". Synthesis (9): 1420–30. 
  9. ^ Hoch, Compt. rend., 196, 1865 (1934); (a), ibid., aOS, 799 (1936); (e), ibid., 204, 358 (1937).
  10. ^ Kenneth N. Campbell, James F. Mckenna (1939). "The action of Grignard reagents on oximes. i. The action of phenylmagnesium bromide on mixed ketoximes". J. Org. Chem. 4 (2): 198–205. doi:10.1021/jo01214a012. 
  11. ^ Kenneth N. Campbell, Barbara Knapp Campbell, Elmer Paul Chaput (1943). "The reaction of Grignard reagents with oximes. ii. The action of aryl grignard reagents with mixed ketoximes". J. Org. Chem. 8 (1): 99–102. doi:10.1021/jo01189a015. 
  12. ^ Kenneth N. Campbell, Barbara K. Campbell, James F. Mckenna, Elmer Paul Chaput (1943). "The action of Grignard reagents on oximes. iii. The mechanism of the action of arylmagnesium halides on mixed ketoximes. A new synthesis of ethyleneimines". J. Org. Chem. 8: 103–9. doi:10.1021/jo01189a016. 
  13. ^ Yuhei Fukuta, Tsuyoshi Mita, Nobuhisa Fukuda, Motomu Kanai, Masakatsu Shibasaki (2006). "De Novo Synthesis of Tamiflu via a Catalytic Asymmetric Ring-Opening of meso-Aziridines with TMSN3". J. Am. Chem. Soc. 128 (19): 6312–3. doi:10.1021/ja061696k. 
  14. ^ The catalyst is based on yttrium with three isopropyloxy substituents and the ligand a phosphine oxide (Ph = phenyl), with 91% enantiomeric excess (ee)
  15. ^ Harold W. Heine, Richard Peavy (1965). "Aziridines XI. Reaction of 1,2,3-triphenylaziridine with diethylacetylene dicarboxylate and maleic anhydride". Tetrahedron Letters 6 (35): 3123–6. doi:10.1016/S0040-4039(01)89232-7. 
  16. ^ Albert Padwa, Lewis Hamilton (1965). "Reactions of aziridines with dimethylacetylene dicarboxylate". Tetrahedron Letters 6 (48): 4363–7. doi:10.1016/S0040-4039(00)71101-4. 
  17. ^ Philippe Dauban, Guillaume Malik (2009). "A Masked 1,3-Dipole Revealed from Aziridines". Angew. Chem. Int. Ed. 48 (48): 9026–9. doi:10.1002/anie.200904941. 
  18. ^ Ioana Ungureanua, Cristian Bologab, Saïd Chayera, André Mann (16 July 1999). "Phenylaziridine as a 1,3-dipole. Application to the synthesis of functionalized pyrrolidines". Tetrahedron Letters 40 (29): 5315–8. doi:10.1016/S0040-4039(99)01002-3. 
  19. ^ Aravinda B. Pulipaka, Stephen C. Bergmeier (2008). "A Synthesis of 6-Azabicyclo[3.2.1]octanes. The Role of N-Substitution". J. Org. Chem. 73 (4): 1462–7. doi:10.1021/jo702444c. 
  20. ^ Kanerva L, Keskinen H, Autio P, Estlander T, Tuppurainen M, Jolanki R (May 1995). "Occupational respiratory and skin sensitization caused by polyfunctional aziridine hardener". Clin Exp Allergy 25 (5): 432–9. doi:10.1111/j.1365-2222.1995.tb01074.x. PMID 7553246. 
  21. ^ Sartorelli P, Pistolesi P, Cioni F, Napoli R, Sisinni AG, Bellussi L, Passali GC, Cherubini Di Simplicio E, Flori L (2003). "Skin and respiratory allergic disease caused by polyfunctional aziridine". Med Lav 94 (3): 285–95. PMID 12918320. 
  22. ^ Mapp CE (2001). "Agents, old and new, causing occupational asthma". Occup. Environ. Med. 58 (5): 354–60. doi:10.1136/oem.58.5.354. PMC 1740131. PMID 11303086. 
  23. ^ Appendix E - OSHA Respirator Requirements for Selected Chemicals
  24. ^ Some Aziridines, N-, S- and O-Mustards and Selenium (PDF). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 9. 1975. ISBN 92-832-1209-6.