Isocyanide

The C-N distance in isocyanides is 115.8 pm in methyl isocyanide. The C-N-C angles are near 180°.{{cite journal| last = Kessler | first = M. |author2=Ring, H. |author3=Trambarulo, R. |author4=Gordy, W. | title = Microwave Spectra and Molecular Structures of Methyl Cyanide and Methyl Isocyanide| journal = Physical Review | year = 1950 | volume = 79 | issue = 1 | pages = 54–56 | doi = 10.1103/PhysRev.79.54|bibcode=1950PhRv...79...54K }}

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. They are susceptible to polymerization.{{cite journal | last = Ramozzi | first = R. |author2=Chéron, N. |author3=Braïda, B. |author4=Hiberty, P. C. |author5=Fleurat-Lessard, P. | title = A Valence Bond View of Isocyanides' Electronic Structure | journal = New Journal of Chemistry | year = 2012 | volume = 36 | issue = 5 | pages = 1137–1340 | doi = 10.1039/C2NJ40050B}}

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

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.{{cite journal | last = Stephany | first = R. W. |author2=de Bie, M. J. A. |author3=Drenth, W. | title = A ¹³C-NMR and IR study of isocyanides and some of their complexes | journal = Organic Magnetic Resonance | year = 1974 | volume = 6 | issue = 1 | pages = 45–47 | doi = 10.1002/mrc.1270060112}}

Isocyanides have a very disagreeable odour. Lieke remarked that "{{lang|de|italic=invert|Es besitzt einen penetranten, höchst unangenehmen Geruch; das Oeffnen eines Gefässes mit Cyanallyl{{sic}} 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 cyanide{{sic}} is enough to foul up the air in a room for several days]...."{{rp|319}} 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."{{cite journal | last = Ugi | first = I. |author2=Fetzer, U. |author3=Eholzer, U. |author4=Knupfer, H. |author5=Offermann, K. | title = Isonitrile Syntheses | journal = Angewandte Chemie International Edition | year = 1965 | volume = 4 | issue = 6 | pages = 472–484 | doi = 10.1002/anie.196504721 }} Isocyanides have been investigated as potential non-lethal weapons.{{cite journal | last = Pirrung | first = M. C. |author2=Ghorai, S. |author3=Ibarra-Rivera, T. R. | title = Multicomponent Reactions of Convertible Isonitriles | journal = The Journal of Organic Chemistry | year = 2009 | volume = 74 | issue = 11 | pages = 4110–4117 | doi = 10.1021/jo900414n | pmid = 19408909 }}

Some isocyanides convey less offensive odours such as malt, natural rubber, creosote, cherry or old wood. Non-volatile derivatives such as tosylmethyl isocyanide do not have an odor.B. E. Hoogenboom, O. H. Oldenziel, and A. M. van Leusen "Toluenesulfonylmethyl isocyanide" Organic Syntheses, Coll. Vol. 6, p.987 (1988).

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".

Many routes to isocyanides have been developed.

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.{{cite journal |author=R. E. Schuster |author2=J. E. Scott | title = Methyl isocyanide |journal=Organic Syntheses | year = 1966 | volume = 46 | pages = 75 | doi = 10.15227/orgsyn.046.0075|title-link=Methyl isocyanide}}{{cite journal | author1 =Ivar Karl Ugi | author-link =Ivar Karl Ugi |author2 =R. Meyr| title = Neue Darstellungsmethode für Isonitrile | journal = Angewandte Chemie | year = 1958 | volume = 70 | issue = 22–23 | pages = 702–703 | doi = 10.1002/ange.19580702213| bibcode =1958AngCh..70..702U }}{{cite journal | author1 =Siobhan Creedon| author2 =H. Kevin Crowley| author3 =Daniel G. McCarthy| title = Dehydration of formamides using the Burgess Reagent: a new route to isocyanides| journal = J. Chem. Soc., Perkin Trans. 1 | year = 1998 | issue = 6 | pages = 1015–1018 | doi = 10.1039/a708081f}}{{cite journal |last1=Basoccu |first1=Francesco |last2=Cuccu |first2=Federico |last3=Casti |first3=Federico |last4=Mocci |first4=Rita |last5=Fattuoni |first5=Claudia |last6=Porcheddu |first6=Andrea |title=A trustworthy mechanochemical route to isocyanides |journal=Beilstein Journal of Organic Chemistry |date=22 June 2022 |volume=18 |pages=732–737 |doi=10.3762/bjoc.18.73|pmid=35821692 |pmc=9235834 |doi-access=free }}

:{{chem2|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,{{Cite journal|last1=정선호|last2=안진희|last3=Park, Sang-Kyu|last4=최중권|date=2002-01-20|title=A Practical and Convenient Procedure for the N-Formylation of Amines Using Formic Acid|journal=Bulletin of the Korean Chemical Society|volume=23|issue=1|pages=149–150|doi=10.5012/BKCS.2002.23.1.149|doi-access=free}} or from the Ritter reaction of alkenes (and other sources of carbocations) and hydrogen cyanide.{{Cite journal|date=1964|title=a,b-DIMETHYL-b-PHENETHYLAMINE|url=http://orgsyn.org/demo.aspx?prep=CV5P0471|journal=Organic Syntheses|volume=44|pages=44|doi=10.15227/orgsyn.044.0044}}

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.{{cite journal|author1=G. W. Gokel|author2=R. P. Widera|author3=W. P. Weber| title = Phase-transfer Hofmann Carbylamine Reaction: tert-Butyl Isocyanide| journal = Organic Syntheses| volume=55|doi=10.15227/orgsyn.055.0096| pages = 232| year = 1988}}

:{{chem2|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.

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.{{cite journal | author =W. Lieke| title = Über das Cyanallyl | journal = Annalen der Chemie und Pharmacie | year = 1859 | volume = 112 | issue = 3 | pages = 316–321 | doi = 10.1002/jlac.18591120307 | url = https://books.google.com/books?id=NYs8AAAAIAAJ&q=Cyanallyl++%22Es+besitzt+einen+penetranten%22&pg=RA1-PA319}}

:RI + AgCN → RNC + AgI

Another route to isocyanides entails deprotonation of oxazoles and benzoxazoles in the 2-position.{{cite journal |author1=Pirrung, M. C. |author2=Ghorai, S. | title = Versatile, Fragrant, Convertible Isonitriles | journal = Journal of the American Chemical Society | year = 2006 | volume = 128 | issue = 36 | pages = 11772–11773 | doi = 10.1021/ja0644374 | pmid = 16953613}} The resulting organolithium compound exists in chemical equilibrium with the 2-isocyanophenolate, which can be captured by an electrophile such as an acid chloride.

File:Benzoxazole-isocyanide synth.png

In some cases, a phosphonite ester-amide can desulfurize thiocyanates to isocyanides.{{cite journal|url=https://www.organic-chemistry.org/Highlights/2011/07November.shtm|date=7 Nov 2011|first=Douglass F.|last=Taber|title=The Rawal synthesis of N‑methyl­welwitindolinone D isonitrile|journal=Organic Chemistry Highlights}}

Isocyanides have diverse reactivity.

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:

:{{chem2|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.{{cite journal | last1 = Deming | first1 = T. J. | last2 = Novak | first2 = B. M. | year = 1993 | title = Mechanistic Studies on the Nickel Catalyzed Polymerization of Isocyanides | journal = J. Am. Chem. Soc. | volume = 115 | issue = 20 | page = 9101 | doi = 10.1021/ja00073a028 }}

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.{{cite journal | last = Imming | first = P. |author2=R. Mohr |author3=E. Müller |author4=W. Overheu |author5=G. Seitz | title = [4 + 1]Cycloaddition of Isocyanides to 1,2,4,5-Tetrazines: A Novel Synthesis of Pyrazole | journal = Angewandte Chemie International Edition | year = 1982 | volume = 21 | issue = 4 | pages = 284 | doi = 10.1002/anie.198202841}} Depending on the degree of substitution of the isocyanide, this reaction converts isocyanides into carbonyls or gives stable cycloadducts.{{cite journal | last = Stöckmann | first = H. |author2=A. Neves |author3=S. Stairs|author4=K. Brindle|author5=F. Leeper| title = Exploring Isonitrile-Based Click Chemistry for Ligation with Biomolecules | journal = Organic & Biomolecular Chemistry | year = 2011 | volume = 9 | issue = 21 | pages = 7303–7305 | doi = 10.1039/C1OB06424J | pmid = 21915395}} 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.{{cite journal | author = Lang, S. | title = Unravelling the labyrinth of palladium catalysed reactions involving isocyanides | journal = Chemical Society Reviews | year = 2013 | volume = 42 | issue = 12 | pages = 4867–4880 | doi = 10.1039/C3CS60022J | pmid = 23443313}}

Much like nitriles, isocyanides are electron-withdrawing and easily deprotonate at the α position. For example, benzyl isocyanide has a pK_a of 27.4 and benzyl cyanide has a pK_a of 21.9, but toluene has a pK_a in the 40s.{{Cite web|url=https://www.chem.wisc.edu/areas/reich/pkatable/|title=Bordwell pKa Table (Acidity in DMSO)|website=www.chem.wisc.edu|access-date=2018-12-20}} In the gas phase, {{chem2|CH3NC}} is 1.8 kcal/mol less acidic than {{chem2|CH3CN}}.{{Cite journal|last1=Filley|first1=Jonathan|last2=DePuy|first2=Charles H.|last3=Bierbaum|first3=Veronica M.|date=1987-09-01|title=Gas-phase negative-ion chemistry of methyl isocyanide|journal=Journal of the American Chemical Society|volume=109|issue=20|pages=5992–5995|doi=10.1021/ja00254a017|issn=0002-7863}}

Chlorination of isocyanides gives isocyanide dichlorides.

{{main|Transition metal isocyanide complexes}}

File:Tc CNCH2CMe2(OMe) 6Cation.png is a commercial isocyanide complex that is used in medicine for imaging.]]

Isocyanides form coordination complexes with most transition metals.{{cite journal | last1 = Singleton | first1 = Eric | last2 = Oosthuizen | first2 = Hester E. | year = 1983 | title = Metal Isocyanide Complexes | journal = Advances in Organometallic Chemistry | volume = 22 | pages = 209–310 | doi = 10.1016/S0065-3055(08)60404-9 | isbn = 9780120311224 }} They behave as electron-rich analogues of carbon monoxide. For example tert-butyl isocyanide forms {{chem2|Fe2(tBuNC)9}}, which is analogous to {{chem2|Fe2(CO)9}}.{{cite journal | last1 = Bassett | first1 = J.M. | last2 = Barker | first2 = G.K. | last3 = Green | first3 = M. | last4 = Howard | first4 = J.A. | last5 = Stone | first5 = G.A. | last6 = Wolsey | first6 = W.C. | title = Chemistry of low-valent metal isocyanide complexes | journal = Journal of the Chemical Society, Dalton Transactions | volume = 1981 | pages = 219–227 }} Although structurally similar, the analogous carbonyls differ in several ways, mainly because t-BuNC is a better donor ligand than CO. Thus, {{chem2|Fe(tBuNC)5}} is easily protonated, whereas its counterpart {{chem2|Fe(CO)5}} is not.{{cite journal | last1 = Bassett | first1 = J.-M. | author-link3 = F.G.A. Stone | last2 = Farrugia | first2 = L. J. | last3 = Stone | first3 = F.G.A. | year = 1980| title = Notes. Protonation of pentakis(t-butyl isocyanide)iron| journal = Journal of the Chemical Society, Dalton Transactions| volume = 1980 | issue = 9 | pages = 1789–1790 | doi = 10.1039/DT9800001789 }}

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.{{cite journal | author = Scheuer, P. J. | title = Isocyanides and Cyanides as Natural Products | journal = Accounts of Chemical Research | year = 1992 | volume = 25 | issue = 10 | pages = 433–439 | doi = 10.1021/ar00022a001}}

:File:Xantocillin.svg is a rare natural product that contains two isocyanide groups.]]

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,[http://www.acdlabs.com/iupac/nomenclature/79/r79_510.htm IUPAC Nomenclature of Organic Compounds (Recommendations 1993)] whereas an isocyanide has only one single and one multiple bond.

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

{{Reflist}}

{{Functional Groups}}

Category:Functional groups