Anisocyanide (also calledisonitrile orcarbylamine) is anorganic compound with thefunctional group –N+≡C−. It is theisomer of the relatednitrile (–C≡N), hence the prefix isisocyano.[1] The organic fragment is connected to the isocyanide group through thenitrogen atom, not via thecarbon. They are used as building blocks for the synthesis of other compounds.[2]
The C-N distance in isocyanides is 115.8 pm inmethyl isocyanide. The C-N-C angles are near 180°.[3]
Akin tocarbon monoxide, isocyanides are described by tworesonance structures, one with atriple bond between the nitrogen and the carbon and one with adouble 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 topolymerization.[4]
Isocyanides exhibit a strong absorption in their IR spectra in the range of 2165–2110 cm−1.[5]
The electronic symmetry about the isocyanide14N nucleus results in a slow quadrupolarrelaxation so that13C-14N nuclear spincoupling can be observed, with coupling constants ofca. 5 Hz for the isocyanide13C nucleus and 5–14 Hz for the13C nucleus which the isocyanide group is attached to.[5]
Isocyanides have a very disagreeable odour. Lieke remarked that "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]...."[6]: 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."[7] Isocyanides have been investigated as potentialnon-lethal weapons.[8]
Some isocyanides convey less offensive odours such as malt, natural rubber, creosote, cherry or old wood.[9] Non-volatile derivatives such astosylmethyl isocyanide do not have an odor.[10]
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".[7]
Many routes to isocyanides have been developed.[2]
Commonly, isocyanides are synthesized bydehydration offormamides. The formamide can be dehydrated withtoluenesulfonyl chloride,phosphorus oxychloride,phosgene,diphosgene, or theBurgess reagent in the presence of a base such as pyridine or triethylamine.[11][12][13][14]
The formamide precursors are, in turn, prepared from amines by formylation withformic acid or formyl acetyl anhydride,[15] or from theRitter reaction of alkenes (and other sources of carbocations) andhydrogen cyanide.[16]
In thecarbylamine reaction (also known as the Hofmann isocyanide synthesis) alkali base reacts withchloroform to producedichlorocarbene. The carbene then converts primaryamines to isocyanides. Illustrative is the synthesis oftert-butyl isocyanide fromtert-butylamine in the presence ofcatalytic amount of thephase transfer catalyst benzyltriethylammonium chloride.[17]
As it is only effective for primary amines, this reaction can be used as achemical test for their presence.
Of historical interest but not often of practical value, the first isocyanide,allyl isocyanide, was prepared by the reaction ofallyl iodide andsilver cyanide.[6]
Another route to isocyanides entails deprotonation ofoxazoles andbenzoxazoles in the 2-position.[9] The resulting organolithium compound exists inchemical equilibrium with the2-isocyanophenolate, which can be captured by anelectrophile such as anacid chloride.
In some cases, aphosphonite ester-amide can desulfurizethiocyanates to isocyanides.[18]
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 correspondingformamides:
This reaction is used to destroy odorous isocyanide mixtures. Some isocyanides can polymerize in the presence of Lewis and Bronsted acids.[19]
Isocyanides participate in manymulticomponent reactions of interest inorganic synthesis, two of which are: theUgi reaction and thePasserini reaction.
Isocyanides also participate incycloaddition reactions, such as the [4+1] cycloaddition with tetrazines.[20] Depending on the degree of substitution of the isocyanide, this reaction converts isocyanides intocarbonyls or gives stable cycloadducts.[21] They also undergo insertion into the C–Cl bonds of acyl chlorides in theNef 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.[22]
Much likenitriles, isocyanides are electron-withdrawing and easily deprotonate at the α position. For example,benzyl isocyanide has a pKa of 27.4 andbenzyl cyanide has a pKa of 21.9, but toluene has a pKa in the 40s.[23] In the gas phase,CH3NC is 1.8 kcal/mol less acidic thanCH3CN.[24]
Chlorination of isocyanides givesisocyanide dichlorides.
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Isocyanides formcoordination complexes with most transition metals.[25] They behave as electron-rich analogues of carbon monoxide. For exampletert-butyl isocyanide formsFe2(tBuNC)9, which is analogous toFe2(CO)9.[26] Although structurally similar, the analogous carbonyls differ in several ways, mainly becauset-BuNC is a better donor ligand than CO. Thus,Fe(tBuNC)5 is easily protonated, whereas its counterpartFe(CO)5 is not.[27]
Only few naturally occurring compounds exhibit the isocyanide functionality. The first was discovered in 1957 in an extract of the moldPenicillium notatum. The compoundxanthocillin later was used as anantibiotic. 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.[28]
IUPAC uses theprefix "isocyano" for the systematic nomenclature of isocyanides:isocyanomethane, isocyanoethane, isocyanopropane, etc.
The sometimes used old term "carbylamine" conflicts with systematic nomenclature. Anamine always has three single bonds,[29] whereas an isocyanide has only one single and one multiple bond.
Theisocyanamide functional group consists of an amino group attached to an isocyano moiety. The isonitrile suffix or isocyano- prefix is used depending upon priority table.