- Diethyl azodicarboxylate
Diethyl azodicarboxylate Identifiers CAS number ChemSpider Jmol-3D images Image 1 Properties Molecular formula C6H10N2O4 Molar mass 174.15 g mol−1 Appearance Orange to red to orange liquid Density 1.11 g/cm3 Melting point
104.5 °C at 12 mm Hg
Refractive index (nD) 1.420 (20 °C) Hazards MSDS External MSDS R-phrases S-phrases Flash point 85 °C (what is: /?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Diethyl azodicarboxylate, conventionally abbreviated as DEAD and sometimes as DEADCAT, is an organic compound with the structural formula CH3CH2O2CN=NCO2CH2CH3. Its molecular structure consists of a central azo functional group, RN=NR, flanked by two ethyl ester groups. This orange-red liquid is a valuable reagent but also quite dangerous and explodes upon heating. Therefore, commercial shipment of pure diethyl azodicarboxylate is prohibited in the United States and is carried out either in solution or on polystyrene particles.
DEAD is an aza-dienophile and an efficient dehydrogenating agent, converting alcohols to aldehydes, thiols to disulfides and hydrazo groups to azo groups; it is also a good electron acceptor. While DEAD is used in numerous chemical reactions, it is mostly known as the principal component of the Mitsunobu reaction, which is daily carried out in chemical laboratories, and can be used for the synthesis of various natural products and pharmaceuticals. In particular, the resulting chemical zidovudine is a major drug against AIDS and FdUMP is a potent antitumor agent.
DEAD is an orange-red liquid which weakens its color to yellow or colorless upon dilution or chemical reaction. This color change is conventionally used for visual monitoring of the synthesis. DEAD dissolves in most common organic solvents, such as toluene, chloroform, ethanol, tetrahydrofuran and dichloromethane but has low solubility in water or carbon tetrachloride; the solubility in water is higher for the related azo compound dimethyl azodicarboxylate.
DEAD is a strong electron acceptor and easily oxidizes a solution of sodium iodide in glacial acetic acid. It also reacts vigorously with hydrazine hydrate producing diethyl hydrazodicarboxylate and evolving nitrogen. Linear combination of atomic orbitals molecular orbital method (LCAO-MO) calculations suggest that the molecule of DEAD is unusual in having a highly lying vacant bonding orbital, and therefore tends to withdraw hydrogen atoms from various hydrogen donors. Photoassisted removal of hydrogen by DEAD was demonstrated for isopropyl alcohol, resulting in pinacol and tetraethyl tetrazanetetracarboxylate, and for acetaldehyde yielding diacetyl and diethyl hydrazodicarboxylate. Similarly, reacting DEAD with ethanol and cyclohexanol abstracts hydrogen producing acetaldehyde and cyclohexanone. Those reactions also proceed without light, although at much lower yields. Thus, in general DEAD is an aza-dienophile and dehydrogenating agent, converting alcohols to aldehydes, thiols to disulfides and hydrazo groups to azo groups. It also joins pericyclic reactions with alkenes and dienes via Ene and Diels–Alder mechanisms.
Although available commercially, diethyl azodicarboxylate is often prepared fresh in the laboratory, especially if required in pure, non-diluted form. A two-step synthesis starts from hydrazine, first by alkylation with ethyl chloroformate, followed by treating the resulting diethyl hydrazodicarboxylate with chlorine (bubbling through the solution), hypochlorous acid, concentrated nitric acid or red fuming nitric acid. The reaction is carried out in an ice bath, and the reagents are added dropwise so that the temperature does not rise above 20 °C. Diethyl hydrazodicarboxylate is a solid with melting temperature of 131–133 °C which is collected as a residue; it is significantly more stable to heating than DEAD and is conventionally dried at a temperature of about 80 °C.
DEAD is an important reagent in the Mitsunobu reaction where it forms an adduct with phosphines (usually triphenylphosphine) and assists the synthesis of esters, ethers, amines and thioethers of alcohols. Reactions normally result in the inversion of molecular symmetry.
DEAD was used in the original 1967 article by Oyo Mitsunobu, and his 1981 review on the use of diethyl azodicarboxylate is a top-cited chemistry article. Mitsunobu reaction has several applications in the synthesis of natural products and pharmaceuticals.
In the above reaction, which is assisted either by DEAD or DIAD (diisopropyl azodicarboxylate), thymidine 1 transforms to the derivative 2. The latter easily converts to zidovudine 4 (also known as azidothymidine or AZT), an important antiviral drug, used among others in the treatment of AIDS. Another example of pharmaceutical application of DEAD-assisted Mitsunobu reaction is the synthesis of bis[(pivaloyloxy)methyll [PIVz] derivative of 2’-deoxy-5-fluorouridine 5’-monophosphate (FdUMP), which is a potent antitumor agent.
DEAD is an efficient component in Diels-Alder reactions and in click chemistry, for example the synthesis of bicyclo[2.1.0]pentane, which originates from Otto Diels. It has also been used to generate aza-Baylis-Hillman adducts with acrylates.
Another application is the use of DEAD as enophile in Ene reactions:
DEAD is toxic, shock and light sensitive; it can violently explode when its undiluted form is heated above 100 °C. Shipment of pure diethyl azodicarboxylate is prohibited in the United States and is carried out in solution, typically about 40% DEAD in toluene. Alternatively, DEAD is transported and stored on 100–300 mesh polystyrene particles at a concentration of about 1 mmol/g. The time-weighed average threshold limit value for exposure to DEAD over a typical 40-hour working week is 50 parts per million; that is, DEAD is half as toxic as, e.g., carbon monoxide. Safety hazards have resulted in rapid decline of DEAD usage and replacement with DIAD and other similar compounds.
- ^ Diethyl azo diformate. Webbook.nist.gov (1972-07-28). Retrieved on 2011-03-15.
- ^ a b Safety (MSDS) data for diethyl azodicarboxylate. Msds.chem.ox.ac.uk. Retrieved on 2011-03-15.
- ^ a b c d e f W. L. F. Armarego; Christina Li Lin Chai (22 May 2009). Purification of laboratory chemicals. Butterworth-Heinemann. pp. 124–. ISBN 9781856175678. http://books.google.com/books?id=PTXyS7Yj6zUC&pg=PA124. Retrieved 12 March 2011.
- ^ a b c Kauer, J. C., "Diethyl azodicarboxylate", Org. Synth., http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv4p0411 ; Coll. Vol. 4: 411
- ^ L19348 Diethyl azodicarboxylate, 97% – Alfa Aesar – A Johnson Matthey Company. Alfa.com (1972-07-28). Retrieved on 2011-03-15.
- ^ Caroline Cooper (23 July 2010). Organic Chemist's Desk Reference. CRC Press. pp. 109–. ISBN 9781439811641. http://books.google.com/books?id=ahbUc5M0I5AC&pg=PA109. Retrieved 12 March 2011.
- ^ DEAD is sometimes used for another chemical, diethyl acetylenedicarboxylate. P. N. Preston (1980). Benzimidazoles and congeneric tricyclic compounds. John Wiley and Sons. pp. 475–. ISBN 9780471081890. http://books.google.com/books?id=dZt_C5stw5kC&pg=PA475. Retrieved 12 March 2011.
- ^ a b Yoneda, Fumio; Suzuki, Kunio; Nitta, Yoshihiro (1967). Journal of Organic Chemistry 32 (3): 727. doi:10.1021/jo01278a049.
- ^ Kelmara K. Kelly (2009) Novel isotope effects and organic reaction mechanisms, PhD thesis, Texas A&M University, p. 81
- ^ Fumio Yoneda, Kunio Suzuki, Yoshihiro Nitta (1966). "A New Hydrogen-Abstracting Reaction with Diethyl Azodicarboxylate". J. Am. Chem. Soc. 88 (10): 2328. doi:10.1021/ja00962a051.
- ^ L. A. Paquette, ed (1995). Encyclopedia of Reagents for Organic Synthesis. 3. Chichester: Wiley. p. 1790.
- ^ Rabjohn, N., "Diethyl azodicarboxylate", Org. Synth., http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv3p0375 ; Coll. Vol. 3: 375
- ^ Mitsunobu, O.; Yamada, Y. (1967). "Preparation of Esters of Carboxylic and Phosphoric Acid via Quaternary Phosphonium Salts". Bull. Chem. Soc. Japan 40 (10): 2380–2382. doi:10.1246/bcsj.40.2380.
- ^ Mitsunobu, Oyo (1981). "The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products". Synthesis: 1–28.
- ^ More than 4,300 citations by March 2011 according to Web of Science
- ^ Czernecki, Stanislas and Valery, Jean-marc "Process for preparing AZT (3'-azido-3'-deoxy-thymidine) and related compounds" U.S. Patent 5,124,442 issued 23 June 1992
- ^ Czernecki, Stanislas; Valéry, Jean-Marc (1991). "An Efficient Synthesis of 3′-Azido-3′-deoxythymidine (AZT)". Synthesis 1991 (03): 239. doi:10.1055/s-1991-26434.
- ^ Dueholm, Kim L.; Aly, Youssef L.; Jørgensen, Per T.; El-Barbary, Ahmed A.; Pedersen, Erik B.; Nielsen, Claus (1993). "Convergent synthesis of 2′,3′-dideoxy-3′-methylthio and 2′,3′-dideoxy-3′-mercapto nucleosides and their disulfide analogues — Potential anti-HIV agents". Monatshefte für Chemie - Chemical Monthly 124: 37. doi:10.1007/BF00808508.
- ^ Farquhar, David; Khan, Saeed; Srivastva, Devendra N.; Saunders, Priscilla P. (1994). "Synthesis and Antitumor Evaluation of Bis[(pivaloyloxy)methyl] 2'-Deoxy-5-fluorouridine 5'-Monophosphate (FdUMP): A Strategy To Introduce Nucleotides into Cells". Journal of Medicinal Chemistry 37 (23): 3902. doi:10.1021/jm00049a009. PMID 7966151.
- ^ Comelles, C. et al. (2004). "Ionic and Covalent Copper(II)-Based Catalysts for Michael Additions. The Mechanism". J. Org. Chem. 69 (20): 6834. doi:10.1021/jo049373z.
- ^ Takeshi Uemura and Naoto Chatani (2005). "Copper Salt Catalyzed Addition of Arylboronic Acids to Azodicarboxylates". J. Org. Chem. 70 (21): 8631. doi:10.1021/jo051387x.
- ^ Gassman, P. G.;Mansfield, K. T., "Bicyclo[2.1.0]pentane", Org. Synth., http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv5p0096 ; Coll. Vol. 5: 96
- ^ Shi, Min and Zhao, Gui-Ling (2004). "Aza-Baylis–Hillman reactions of diisopropyl azodicarboxylate or diethyl azodicarboxylate with acrylates and acrylonitrile". Tetrahedron 60 (9): 2083–2089. doi:10.1016/j.tet.2003.12.059.
- ^ Vijay Nair, Smitha C. Mathew, Akkattu T. Biju, and Eringathodi Suresh (2007). "A Novel Reaction of the “Huisgen Zwitterion” with Chalcones and Dienones: An Efficient Strategy for the Synthesis of Pyrazoline and Pyrazolopyridazine Derivatives". Angew. Chem. Int. Ed. 46 (12): 2070–2073. doi:10.1002/anie.200604025. PMID 17286329.
- ^ G. C. Barrett (1999). Amino acid derivatives: a practical approach. Oxford University Press. pp. 119–. ISBN 9780198558538. http://books.google.com/books?id=DfyPvX57MP0C&pg=PA119. Retrieved 12 March 2011.
- ^ Diethyl Azodicarboxylate in Chemical Synthesis. Sigmaaldrich.com. Retrieved on 2011-03-15.
- ^ Livius Cotarca; Heiner Eckert (2004). Phosgenations—a handbook. Wiley-VCH. p. 42. ISBN 9783527298235. http://books.google.com/books?id=d-5PbJnbryMC&pg=PA443. Retrieved 12 March 2011.
Wikimedia Foundation. 2010.
Look at other dictionaries:
Diisopropyl azodicarboxylate — Diisopropyl azodicarboxylate … Wikipedia
Mitsunobu reaction — The Mitsunobu reaction is an organic reaction that converts an alcohol into a variety of functional groups, such as an ester, using triphenylphosphine and an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate … Wikipedia
Common reagents — This is a list of common inorganic and organic reagents often used in chemistry. Contents 1 Synopsis 2 Reagent Compounds 3 See also 4 References S … Wikipedia
Grupo activante — En química, especialmente en química orgánica, se dice que un grupo funcional es un grupo activante o grupo activador cuando aumenta la reactividad química de la molécula hacia un tipo de reacción química particular. La expresión grupo activante… … Wikipedia Español
Réaction de Mitsunobu — La réaction de Mitsunobu désigne, en chimie organique, la réaction de substitution nucléophile sur un alcool à l aide d un composé azo et d une phosphine. Elle tient son nom de chimiste japonais Oyo Mitsunobu qui a décrit en 1967 l acylation d un … Wikipédia en Français
Dead (disambiguation) — Dead refers to that which has experienced death. Dead may also refer to: In music: Dead (musician), Per Yngve Ohlin, Swedish black metal vocalist Grateful Dead, an American rock band Dead (album), an album by Obituary Dead! , a song by My… … Wikipedia
List of chemical compounds with unusual names — Chemical nomenclature, replete as it is with compounds with complex names, is a repository for some very peculiar and sometimes startling names. A browse through the Physical Constants of Organic Compounds in the CRC Handbook of Chemistry and… … Wikipedia
Ene reaction — The Ene reaction (also known as the Alder ene reaction) is a chemical reaction between an alkene with an allylic hydrogen (the ene) and a compound containing a multiple bond (the enophile), in order to form a new σ bond with migration of the ene… … Wikipedia
Mitsunobu-Reaktion — Reaktionsschema der Mitsunobu Reaktion Die Mitsunobu Reaktion ist eine organisch chemische Reaktion um Alkohole in eine Reihe von funktionellen Gruppen zu überführen. Sie wurde von Oyo Mitsunobu (1934−2003) entdeckt und nach ihm benannt. Sie… … Deutsch Wikipedia
Реакция Мицунобу — Реакция Мицунобу реакция в органической химии, в процессе которой под действием трифенилфосфина и диэтилового эфира азодикарбоновой кислоты (C2H5O2CN=NCO2C2H5, DEAD) происходит превращение гидроксильной группы спиртов в различные… … Википедия