General resonance structure of an 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 nitrile (–C≡N), hence the prefix is isocyano.[1] The organic fragment is connected to the isocyanide group through the nitrogen atom, not via the carbon. They are used as building blocks for the synthesis of other compounds.[2]

Properties

Structure and bonding

The C-N distance in isocyanides is 115.8 pm in methyl isocyanide. The C-N-C angles are near 180°.[3]

Akin to carbon monoxide, 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. The π lone pair of the nitrogen stabilizes the structure and is responsible of the linearity of isocyanides, although the reactivity of isocyanides reflects some carbene character, at least in a formal sense. Thus, both resonance structures are useful representations.[4] They are susceptible to polymerization.[4]

Spectroscopy

Isocyanides exhibit a strong absorption in their IR spectra in the range of 2165–2110 cm−1.[5]

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.[5]

Odour

Isocyanides have a very disagreeable odour. 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 only little delay 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, but this is heavily outweighed by the fact that isonitriles can be detected even in traces, and that most of the routes leading to the formation of isonitriles were discovered through the odor of these compounds."[6] Isocyanides have been investigated as potential non-lethal weapons.[7]

Some isocyanides convey less offensive odours such as malt, natural rubber, creosote, cherry or old wood.[8] Non-volatile derivatives such as tosylmethyl isocyanide do not have an odor.[9]

Toxicity

While some isocyanides (e.g., cyclohexyl isocyanide) are toxic, others "exhibit no appreciable toxicity for mammals". Referring to ethyl isocyanide, toxicological studies in the 1960s at Bayer showed that "oral and subcutaneous doses of 500-5000 mg/kg can be tolerated by mice".[6]

Synthesis

Many routes to isocyanides have been developed.[2]

From formamides

Commonly, isocyanides are synthesized by dehydration of formamides. The formamide can be dehydrated with toluenesulfonyl chloride, phosphorus oxychloride, phosgene, diphosgene, or the Burgess reagent in the presence of a base such as pyridine or triethylamine.[10][11][12][13]

RNHC(O)H + ArSO2Cl + 2 C5H5N → RNC + [C5H5NH]+[ArSO3]− + [C5H5NH]+Cl−

The formamide precursors are, in turn, prepared from amines by formylation with formic acid or formyl acetyl anhydride[14].or from the Ritter reaction of alkenes (and other sources of carbocations) and hydrogen cyanide.[15]

From dichlorocarbene

In the carbylamine reaction (also known as the Hofmann isocyanide synthesis) alkali base reacts with chloroform to produce dichlorocarbene. The carbene then converts primary amines to isocyanides. Illustrative is the synthesis of tert-butyl isocyanide from tert-butylamine in the presence of catalytic amount of the phase transfer catalyst benzyltriethylammonium chloride.[16]

Me3CNH2 + CHCl3 + 3 NaOH → Me3CNC + 3 NaCl + 3 H2O

As it is only effective for primary amines this reaction can be used as a chemical test for their presence.

Silver cyanide route

Of historical interest but not often of practical value, the first isocyanide, allyl isocyanide, was prepared by the reaction of allyl iodide and silver cyanide.[17]

RI + AgCN → RNC + AgI

Other methods

Another route to isocyanides entails deprotonation of oxazoles and benzoxazoles in the 2-position.[8] The resulting organolithium compound exists in chemical equilibrium with the 2-isocyanophenolate, which can be captured by an electrophile such as an acid chloride.

Reactions

Isocyanides have diverse reactivity.[2]

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:

RNC + H2O → RNHC(O)H

This reaction is used to destroy odorous isocyanide mixtures. Some isocyanides can polymerize in the presence of Lewis and Bronsted acids.[18]

Isocyanides participate in many multicomponent reactions of interest in organic synthesis, two of which are: the Ugi reaction and the Passerini reaction.

Isocyanides also participate in cycloaddition reactions, such as the [4+1] cycloaddition with tetrazines.[19] Depending on the degree of substitution of the isocyanide, this reaction converts isocyanides into carbonyls or gives stable cycloadducts.[20] They also undergo insertion into the C–Cl bonds of acyl chlorides in the Nef isocyanide reaction, a process that is believed to be concerted and illustrates their carbene character.

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.[21]

The α position of isocyanides have substantial acidity. For example, benzyl isocyanide has a pKa of 27.4. In comparison, benzyl cyanide has a pKa of 21.9.[22] In the gas phase, CH3NC is 1.8 kcal/mol less acidic than CH3CN.[23]

Chlorination of isocyanides gives isocyanide dichlorides.

Ligands in coordination chemistry

Technetium sestamibi is a commercial isocyanide complex that is used in medicine for imaging.

Isocyanides form coordination complexes with most transition metals.[24] They behave as electron-rich analogues of carbon monoxide. For example tert-butyl isocyanide forms Fe2(tBuNC)9, which is analogous to Fe2(CO)9.[25] Although structurally similar, the analogous carbonyls differ in several ways, mainly because t-BuNC is a better donor ligand than CO. Thus, Fe(tBuNC)5 is easily protonated, whereas its counterpart Fe(CO)5 is not.[26]

Naturally occurring isocyanides

Only few naturally occurring compounds exhibit the isocyanide functionality. The first was discovered in 1957 in an extract of the mold Penicillium notatum. The compound xanthocillin later was used as an antibiotic. Since then numerous other isocyanides have been isolated. Most of the marine isocyanides are terpenoid, while some of the terrestrial isocyanides originate from α-aminoacids.[27]

Xanthocillin is a rare natural product that contains an isocyanide group (two in fact).

Nomenclature

IUPAC uses the prefix "isocyano" for the systematic nomenclature of isocyanides: isocyanomethane, isocyanoethane, isocyanopropane, etc.

The sometimes used old term "carbylamine" conflicts with systematic nomenclature. An amine always has three single bonds,[28] whereas an isocyanide has only one single and one multiple bond.

The isocyanamide functional group consists of a amino group attached to an isocyano moiety. for nomenclature as suffix of isonitrile or prefix of isocyano is used depending upon priority table.

References

  1. ↑ IUPAC Goldbook isocyanides
  2. 1 2 3 Patil, Pravin; Ahmadian-Moghaddam, Maryam; Dömling, Alexander (2020-09-29). "Isocyanide 2.0". Green Chemistry. 22 (20): 6902–6911. doi:10.1039/D0GC02722G. ISSN 1463-9270.
  3. ↑ Kessler, M.; Ring, H.; Trambarulo, R.; Gordy, W. (1950). "Microwave Spectra and Molecular Structures of Methyl Cyanide and Methyl Isocyanide". Physical Review. 79 (1): 54–56. Bibcode:1950PhRv...79...54K. doi:10.1103/PhysRev.79.54.
  4. 1 2 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.
  5. 1 2 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.
  6. 1 2 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.
  7. ↑ 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.
  8. 1 2 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.
  9. ↑ B. E. Hoogenboom, O. H. Oldenziel, and A. M. van Leusen "Toluenesulfonylmethyl isocyanide" Organic Syntheses, Coll. Vol. 6, p.987 (1988).
  10. ↑ R. E. Schuster; J. E. Scott (1966). "Methyl isocyanide". Organic Syntheses. 46: 75. doi:10.15227/orgsyn.046.0075.
  11. ↑ Ivar Karl Ugi; R. Meyr (1958). "Neue Darstellungsmethode für Isonitrile". Angewandte Chemie. 70 (22–23): 702–703. Bibcode:1958AngCh..70..702U. doi:10.1002/ange.19580702213.
  12. ↑ Siobhan Creedon; H. Kevin Crowley; Daniel G. McCarthy (1998). "Dehydration of formamides using the Burgess Reagent: a new route to isocyanides". J. Chem. Soc., Perkin Trans. 1 (6): 1015–1018. doi:10.1039/a708081f.
  13. ↑ Basoccu, Francesco; Cuccu, Federico; Casti, Federico; Mocci, Rita; Fattuoni, Claudia; Porcheddu, Andrea (22 June 2022). "A trustworthy mechanochemical route to isocyanides". Beilstein Journal of Organic Chemistry. 18: 732–737. doi:10.3762/bjoc.18.73. PMC 9235834. PMID 35821692.
  14. ↑ 정선호; 안진희; Park, Sang-Kyu; 최중권 (2002-01-20). "A Practical and Convenient Procedure for the N-Formylation of Amines Using Formic Acid". Bulletin of the Korean Chemical Society. 23 (1): 149–150. doi:10.5012/BKCS.2002.23.1.149.
  15. ↑ "a,b-DIMETHYL-b-PHENETHYLAMINE". Organic Syntheses. 44: 44. 1964. doi:10.15227/orgsyn.044.0044.
  16. ↑ G. W. Gokel; R. P. Widera; W. P. Weber (1988). "Phase-transfer Hofmann Carbylamine Reaction: tert-Butyl Isocyanide". Organic Syntheses. 55: 232. doi:10.15227/orgsyn.055.0096.
  17. ↑ W. Lieke (1859). "Über das Cyanallyl". Annalen der Chemie und Pharmacie. 112 (3): 316–321. doi:10.1002/jlac.18591120307.
  18. ↑ Deming, T. J.; Novak, B. M. (1993). "Mechanistic Studies on the Nickel Catalyzed Polymerization of Isocyanides". J. Am. Chem. Soc. 115 (20): 9101. doi:10.1021/ja00073a028.
  19. ↑ Imming, P.; R. Mohr; E. Müller; W. Overheu; G. Seitz (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.
  20. ↑ Stöckmann, H.; A. Neves; S. Stairs; K. Brindle; F. Leeper (2011). "Exploring Isonitrile-Based Click Chemistry for Ligation with Biomolecules". Organic & Biomolecular Chemistry. 9 (21): 7303–7305. doi:10.1039/C1OB06424J. PMID 21915395.
  21. ↑ Lang, S. (2013). "Unravelling the labyrinth of palladium catalysed reactions involving isocyanides". Chemical Society Reviews. 42 (12): 4867–4880. doi:10.1039/C3CS60022J. PMID 23443313.
  22. ↑ "Bordwell pKa Table (Acidity in DMSO)". www.chem.wisc.edu. Retrieved 2018-12-20.
  23. ↑ Filley, Jonathan; DePuy, Charles H.; Bierbaum, Veronica M. (1987-09-01). "Gas-phase negative-ion chemistry of methyl isocyanide". Journal of the American Chemical Society. 109 (20): 5992–5995. doi:10.1021/ja00254a017. ISSN 0002-7863.
  24. ↑ Singleton, Eric; Oosthuizen, Hester E. (1983). "Metal Isocyanide Complexes". Advances in Organometallic Chemistry. 22: 209–310. doi:10.1016/S0065-3055(08)60404-9. ISBN 9780120311224.
  25. ↑ Bassett, J.M.; Barker, G.K.; Green, M.; Howard, J.A.; Stone, G.A.; Wolsey, W.C. "Chemistry of low-valent metal isocyanide complexes". Journal of the Chemical Society, Dalton Transactions. 1981: 219–227.
  26. ↑ Bassett, J.-M.; Farrugia, L. J.; Stone, F.G.A. (1980). "Notes. Protonation of pentakis(t-butyl isocyanide)iron". Journal of the Chemical Society, Dalton Transactions. 1980 (9): 1789–1790. doi:10.1039/DT9800001789.
  27. ↑ Scheuer, P. J. (1992). "Isocyanides and Cyanides as Natural Products". Accounts of Chemical Research. 25 (10): 433–439. doi:10.1021/ar00022a001.
  28. ↑ IUPAC Nomenclature of Organic Compounds (Recommendations 1993)
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