Isocyanide
An isocyanide (also called isonitrile or carbylamine) is an organic compound with the functional group -N≡C. It is the isomer of the related cyanide (-C≡N), hence the prefix iso.[1] The organic fragment is connected to the isocyanide group via the nitrogen atom, not via the carbon.
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Nomenclature [edit]
Whereas in IUPAC nomenclature in most cases the suffix "nitrile" or "carbonitrile" is used for organic cyanides (R-C≡N),[2] names for isocyanides have the prefix "isocyano". IUPAC names become isocyanomethane, isocyanoethane, isocyanopropane, et cetera.
The use of the prefix "isonitrile" has a contradiction in the nomenclature. For example, ethanenitrile ( CH3CN) and ethaneisonitrile (C2H5NC) are not isomers, as the prefix "iso" suggests. In contrast, ethyl cyanide (C2H5CN) and ethyl isocyanide (C2H5NC) are isomers.
The sometimes used term "carbylamine" conflicts with systematic nomenclature. An amine always has three single bonds,[3] whereas an isocyanide has only one single and one multiple bond.
Physical properties [edit]
Isocyanides are described by two resonance structures, one with a triple bond between the nitrogen and the carbon and one with a double bond between. Surprisingly, the second one, with a carbenic character is the most important one and best describes the electronic structure. Nevertheless, the π lone pair of the nitrogen, responsible of the zwitterionic structure, stabilizes the structure and is responsible of the linearity of isocyanides. Isocyanides are best shown as a mixture of both resonance structures.[4] They are susceptible to polymerization.[4]
Odour of isocyanides [edit]
Their disagreeable odour is legendary. To quote from Lieke, "Es besitzt einen penetranten, höchst unangenehmen Geruch; das Oeffnen eines Gefässes mit Cyanallyl reicht hin, die Luft eines Zimmers mehrere Tage lang zu verpesten, ..." (It has a penetrating, extremely unpleasant odour; the opening of a flask of allyl [iso]cyanide is enough to foul up the air in a room for several days). Note that in Lieke's day, the difference between isocyanide and nitrile was not fully appreciated.
Ivar Karl Ugi states that "The development of the chemistry of isocyanides has probably suffered ... through the characteristic odor of volatile isonitriles, which has been described by Hofmann and Gautier as 'highly specific, almost overpowering', 'horrible', and 'extremely distressing'. It is true that many potential workers in this field have been turned away by the odour."[5] Isocyanides have been investigated as potential non-lethal weapons.[6]
Some isocyanides convey less offensive odours such as malt, natural rubber, creosote, mild cherry or old wood.[7]
Non-volatile derivatives such as tosylmethyl isocyanide do not have objectionable odors[citation needed].
Toxicity [edit]
While some isocyanides (e.g. cyclohexyl isocyanide) are toxic, others "exhibit no appreciable toxicity for mammals". Toxicological studies in the 1960s at Farbenfabriken Bayer AG showed that "oral and subcutaneous doses of 500-5000 mg/kg can be tolerated by mice".[5]
Spectroscopy [edit]
IR absorption: 2165–2110 cm−1[8]
The electronic symmetry about the isocyanide 14N nucleus results in a slow quadrupolar relaxation so that 13C-14N nuclear spin coupling can be observed, with coupling constants of ca. 5 Hz for the isocyanide 13C nucleus and 5–14 Hz for the 13C nucleus which the isocyanide group is attached to.[8]
Synthesis of isocyanides [edit]
The first isocyanide, allyl isocyanide was prepared in 1859 by the chemist Lieke from the reaction of allyl iodide and silver cyanide.[9] Normally the alkylation of an alkali metal cyanide gives a nitrile, but the silver ion protects the carbon end of the cyanide. Commonly, isocyanides are synthesized by the reaction of primary amines with dichlorocarbene or by dehydration of a formamide with phosphorus oxychloride.[10]
- RNH2 + :CCl2 + 2 NaOH → RNC + 2 NaCl + 2 H2O
- RNHC(O)H + POCl3 → RNC + "PO2Cl" + 2 HCl
The Hofmann isocyanide synthesis is a chemical test for primary amines based on their reaction with potassium hydroxide and chloroform as dichlorocarbene precursors to foul smelling isocyanides.
Another route to isocyanides is by reaction of organolithium compounds with oxazoles and benzoxazoles:[7]
The benzoxazole gets deprotonated at the 2-position by n-butyllithium. The lithium compound is in chemical equilibrium with the 2-isocyanophenolate which can be captured by an electrophile such as an acid chloride. Being an ester the formed isocyanate in the example above behaves uncharacteristically with reportedly a mild cherry smell.
Another synthetic route towards an isocyanide is 1) condensation of an amine with formic acid, yielding a formamide, and 2) dehydrating this formamide. Phosgene (or a synthon or precursor such as diphosgene) can be used in combination with formamide to yield isocyanides.
Reactions [edit]
Isocyanides are stable to strong base (they are often made under strongly basic conditions), but they are sensitive to acid. In the presence of aqueous acid, isocyanides hydrolyse to the corresponding formamides. However, some isocyanides can polymerize in the presence of acids. Acid hydrolysis is a convenient method for removing the obnoxiously odoriferous isocyanides.
Isocyanides are reactants in many multicomponent reactions of interest in organic synthesis, two of which are: the Ugi reaction and the Passerini reaction.
Isocyanides participate in cycloaddition reactions, such as the [4+1] cycloaddition with tetrazines.[11] Depending on the degree of substitution of the isocyanide, this reaction converts isocyanides into carbonyls or gives stable cycloadducts.[12]
Isocyanides have also been shown to be a useful reagent in palladium catalysed reactions with a wide variety of compounds being formed using this method.[13]
Naturally occurring isocyanides [edit]
Several organic molecules extracted from living organisms contain the isocyanide functionality. The first was discovered in 1957 in an extract of the mold Penicillium notatum Westling. The compound xanthocillin later was used as the antibiotic. Since then numerous other isocyanides have been isolated. Most of the marine isocyanides are terpenes, while some of the terrestrial isocyanides originate from α-aminoacids.[14]
References [edit]
- ^ IUPAC Goldbook isocyanides
- ^ IUPAC Nomenclature of Organic Compounds (Recommendations 1993)
- ^ IUPAC Nomenclature of Organic Compounds (Recommendations 1993)
- ^ a b Ramozzi, R.; Chéron, N.; Braïda, B.; Hiberty, P. C.; Fleurat-Lessard, P. (2012). "A Valence Bond View of Isocyanides' Electronic Structure". New Journal of Chemistry 36 (5): 1137–1340. doi:10.1039/C2NJ40050B.
- ^ a b Ugi, I.; Fetzer, U.; Eholzer, U.; Knupfer, H.; Offermann, K. (1965). "Isonitrile Syntheses". Angewandte Chemie International Edition 4 (6): 472–484. doi:10.1002/anie.196504721.
- ^ Pirrung, M. C.; Ghorai, S.; Ibarra-Rivera, T. R. (2009). "Multicomponent Reactions of Convertible Isonitriles". The Journal of Organic Chemistry 74 (11): 4110–4117. doi:10.1021/jo900414n. PMID 19408909.
- ^ a b Pirrung, M. C.; Ghorai, S. (2006). "Versatile, Fragrant, Convertible Isonitriles". Journal of the American Chemical Society 128 (36): 11772–11773. doi:10.1021/ja0644374. PMID 16953613.
- ^ a b Stephany, R. W.; de Bie, M. J. A.; Drenth, W. (1974). "A 13C-NMR and IR study of isocyanides and some of their complexes". Organic Magnetic Resonance 6 (1): 45–47. doi:10.1002/mrc.1270060112.
- ^ Lieke, W. (1859). "Über das Cyanallyl". Annalen der Chemie und Pharmacie (C.F. Winter'sche) 112 (3): 316–321. doi:10.1002/jlac.18591120307.
- ^ Ugi, I.; Meyr, R. (1958). "Neue Darstellungsmethode für Isonitrile". Angewandte Chemie 70 (22–23): 702–703. doi:10.1002/ange.19580702213.
- ^ Imming, P.; Mohr, R.; Müller, E.; Overheu, W.; Seitz, G. (1982). "[4 + 1]Cycloaddition of Isocyanides to 1,2,4,5-Tetrazines: A Novel Synthesis of Pyrazole". Angewandte Chemie International Edition 21 (4): 284. doi:10.1002/anie.198202841.
- ^ Stöckmann, H.; Neves, A.; Stairs, S.; Brindle, K.; Leeper, F. (2011). "Exploring Isonitrile-Based Click Chemistry for Ligation with Biomolecules". Organic & Biomolecular Chemistry 9 (21): 7303–7305. doi:10.1039/C1OB06424J.
- ^ Lang, S. (2013). "Unravelling the labyrinth of palladium catalysed reactions involving isocyanides". Chemical Society Reviews 42: Advanced Article. doi:10.1039/C3CS60022J.
- ^ Scheuer, P. J. (1992). "Isocyanides and Cyanides as Natural Products". Accounts of Chemical Research 25 (10): 433–439. doi:10.1021/ar00022a001.
