An isocyanide (also called isonitrile or carbylamine) is an
organic compound
In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...
with the
functional group
In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...
–. It is the
isomer
In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers.
Iso ...
of the related
nitrile
In organic chemistry, a nitrile is any organic compound that has a functional group. The prefix ''cyano-'' is used interchangeably with the term ''nitrile'' in industrial literature. Nitriles are found in many useful compounds, including met ...
(–C≡N), hence the prefix is ''isocyano''.
[IUPAC Goldboo]
''isocyanides''
/ref> The organic fragment is connected to the isocyanide group through the nitrogen
Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
atom, not via the carbon
Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent
In chemistry, the valence (US spelling) or valency (British spelling) of an element is the measure of its combining capacity with o ...
. They are used as building blocks for the synthesis of other compounds.
Properties
Structure and bonding
The C-N distance in isocyanides is 115.8 pm in methyl isocyanide
Methyl isocyanide or isocyanomethane is an organic compound and a member of the isocyanide family. This colorless liquid is isomeric to methyl cyanide (acetonitrile), but its reactivity is very different. In contrast to the faintly sweet, ethereal ...
. The C-N-C angles are near 180°.
Akin to carbon monoxide
Carbon monoxide (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simple ...
, isocyanides are described by two resonance structures
In chemistry, resonance, also called mesomerism, is a way of describing bonding in certain molecules or polyatomic ions by the combination of several contributing structures (or ''forms'', also variously known as ''resonance structures'' or '' ...
, one with a triple bond
A triple bond in chemistry is a chemical bond between two atoms involving six bonding electrons instead of the usual two in a covalent single bond. Triple bonds are stronger than the equivalent single bonds or double bonds, with a bond order o ...
between the nitrogen and the carbon and one with a double bond
In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
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
In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer, monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are ...
.
Spectroscopy
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
A coupling is a device used to connect two shafts together at their ends for the purpose of transmitting power. The primary purpose of couplings is to join two pieces of rotating equipment while permitting some degree of misalignment or end mov ...
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.
Odour
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 soyanide 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
Ivar Karl Ugi (9 September 1930 in Saaremaa, Estonia – 29 September 2005 in Munich) was an Estonian-born German chemist who made major contributions to organic chemistry. He is known for the research on multicomponent reactions, yielding the U ...
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."'' Isocyanides have been investigated as potential non-lethal weapon
Non-lethal weapons, also called nonlethal weapons, less-lethal weapons, less-than-lethal weapons, non-deadly weapons, compliance weapons, or pain-inducing weapons are weapons intended to be less likely to kill a living target than conventional ...
s.
Some isocyanides convey less offensive odours such as malt, natural rubber, creosote, cherry or old wood. Non-volatile derivatives such as tosylmethyl isocyanide
TosMIC (toluenesulfonylmethyl isocyanide) is an organic compound with the formula CH3C6H4SO2CH2NC. The molecule contains both sulfonyl and isocyanide groups. It is a colourless solid that, unlike many isocyanides, is odorless. It is prepared by de ...
do not have an odor.
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".
Synthesis
Many routes to isocyanides have been developed.[
]
From formamides
Commonly, isocyanides are synthesized by dehydration
In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
of formamide
Formamide is an amide derived from formic acid. It is a colorless liquid which is miscible with water and has an ammonia-like odor. It is chemical feedstock for the manufacture of sulfa drugs and other pharmaceuticals, herbicides and pesticide ...
s. The formamide can be dehydrated with toluenesulfonyl chloride
4-Toluenesulfonyl chloride (''p''-toluenesulfonyl chloride, toluene-''p''-sulfonyl chloride) is an organic compound with the formula CH3C6H4SO2Cl. This white, malodorous solid is a reagent widely used in organic synthesis. Abbreviated TsCl or To ...
, phosphorus oxychloride
Phosphoryl chloride (commonly called phosphorus oxychloride) is a colourless liquid with the formula . It hydrolyses in moist air releasing phosphoric acid and fumes of hydrogen chloride. It is manufactured industrially on a large scale from pho ...
, phosgene
Phosgene is the organic chemical compound with the formula COCl2. It is a toxic, colorless gas; in low concentrations, its musty odor resembles that of freshly cut hay or grass. Phosgene is a valued and important industrial building block, espe ...
, diphosgene
Diphosgene is an organic chemical compound with the formula ClCO2CCl3. This colorless liquid is a valuable reagent in the synthesis of organic compounds. Diphosgene is related to phosgene and has comparable toxicity, but is more conveniently handl ...
, or the Burgess reagent
The Burgess reagent (methyl ''N''-(triethylammoniumsulfonyl)carbamate) is a mild and selective dehydrating reagent often used in organic chemistry. It was developed in the laboratory of Edward M. Burgess at Georgia Tech.
The Burgess reagent is ...
in the presence of a base such as pyridine or triethylamine.
:
The formamide precursors are, in turn, prepared from amines by formylation with formic acid or formyl acetyl anhydride.or from the Ritter reaction of alkenes (and other sources of carbocations) and hydrogen cyanide.
From dichlorocarbene
In the carbylamine reaction The carbylamine reaction (also known as the Hoffmann isocyanide synthesis) is the synthesis of an isocyanide by the reaction of a primary amine, chloroform, and base. The conversion involves the intermediacy of dichlorocarbene.
Illustrative is the ...
(also known as the Hofmann isocyanide synthesis) alkali base reacts with chloroform
Chloroform, or trichloromethane, is an organic compound with chemical formula, formula Carbon, CHydrogen, HChlorine, Cl3 and a common organic solvent. It is a colorless, strong-smelling, dense liquid produced on a large scale as a precursor to ...
to produce dichlorocarbene
Dichlorocarbene is the reactive intermediate with chemical formula CCl2. Although this chemical species has not been isolated, it is a common intermediate in organic chemistry, being generated from chloroform. This bent diamagnetic molecule rapidly ...
. The carbene then converts primary amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
s to isocyanides. Illustrative is the synthesis of ''tert''-butyl isocyanide from ''tert''-butylamine in the presence of catalytic
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
amount of the phase transfer catalyst
In chemistry, a phase-transfer catalyst or PTC is a catalyst that facilitates the transition of a reactant from one phase into another phase where reaction occurs. Phase-transfer catalysis is a special form of heterogeneous catalysis. Ionic reac ...
benzyltriethylammonium chloride.
:
As it is only effective for primary amines this reaction can be used as a chemical test
In chemistry, a chemical test is a qualitative property, qualitative or Quantitative property, quantitative procedure designed to identify, quantify, or characterise a chemical compound or substituent, chemical group.
Purposes
Chemical testing m ...
for their presence.
Silver cyanide route
Of historical interest but not often of practical value, the first isocyanide, allyl
In organic chemistry, an allyl group is a substituent with the structural formula , where R is the rest of the molecule. It consists of a methylene bridge () attached to a vinyl group (). The name is derived from the scientific name for garlic, ...
isocyanide, was prepared by the reaction of allyl iodide
Allyl iodide (3-iodopropene) is an organic halide used in synthesis of other organic compounds such as ''N''-alkyl- 2-pyrrolidones, sorbic acid esters, 5,5-disubstituted barbituric acids, and organometallic catalysts. Allyl iodide can be synthesi ...
and silver cyanide
Silver cyanide is the chemical compound with the formula AgCN. It is a white solid that precipitated upon treatment of solutions containing Ag+ with cyanide, which is used in some schemes to recover silver from solution. Silver cyanide is used in ...
.
:RI + AgCN → RNC + AgI
Other methods
Another route to isocyanides entails deprotonation of oxazole
Oxazole is the parent compound for a vast class of heterocyclic aromatic organic compounds. These are azoles with an oxygen and a nitrogen separated by one carbon. Oxazoles are aromatic compounds but less so than the thiazoles. Oxazole is a weak ...
s and benzoxazole
Benzoxazole is an aromatic organic compound with a molecular formula C7H5NO, a benzene-fused oxazole ring structure, and an odor similar to pyridine. Although benzoxazole itself is of little practical value, many derivatives of benzoxazoles are co ...
s in the 2-position. The resulting organolithium compound exists in chemical equilibrium
In a chemical reaction, chemical equilibrium is the state in which both the reactants and products are present in concentrations which have no further tendency to change with time, so that there is no observable change in the properties of the sy ...
with the ''2-isocyanophenolate'', which can be captured by an electrophile
In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries ...
such as an acid chloride
In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group . Their formula is usually written , where R is a side chain. They are reactive derivatives of carboxylic acids (). A specific example o ...
.
Reactions
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
Formamide is an amide derived from formic acid. It is a colorless liquid which is miscible with water and has an ammonia-like odor. It is chemical feedstock for the manufacture of sulfa drugs and other pharmaceuticals, herbicides and pesticide ...
:
:
This reaction is used to destroy odorous isocyanide mixtures. Some isocyanides can polymerize in the presence of Lewis and Bronsted acids.
Isocyanides participate in many multicomponent reaction In chemistry, a multi-component reaction (or MCR), sometimes referred to as a "Multi-component Assembly Process" (or MCAP), is a chemical reaction where three or more compounds
react to form a single product. By definition, multicomponent reaction ...
s of interest in organic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than inorganic compounds, and their synthesis has developed into one o ...
, two of which are: the Ugi reaction
The Ugi reaction is a multi-component reaction in organic chemistry involving a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid to form a bis-amide.
The reaction is named after Ivar Karl Ugi, who first reported this reaction in ...
and the Passerini reaction
The Passerini reaction is a chemical reaction involving an isocyanide, an aldehyde (or ketone), and a carboxylic acid to form a α- acyloxy amide. This addition reaction is one of the oldest isocyanide-based multicomponent reactions (IMCR) and wa ...
.
Isocyanides also participate in cycloaddition
In organic chemistry, a cycloaddition is a chemical reaction in which "two or more Unsaturated hydrocarbon, unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of th ...
reactions, such as the +1cycloaddition with tetrazines. Depending on the degree of substitution of the isocyanide, this reaction converts isocyanides into carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...
s or gives stable cycloadducts. They also undergo insertion into the C–Cl bonds of acyl chlorides in the Nef isocyanide reaction
The Nef isocyanide reaction is an addition reaction that takes place between isocyanides and acyl chlorides to form imidoyl chloride products, a process first discovered by John Ulrich Nef.
The product imidoyl chloride can be hydrolyzed to giv ...
, 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.
The α position of isocyanides have substantial acidity. For example, benzyl isocyanide has a p''K''a of 27.4. In comparison, benzyl cyanide has a p''K''a of 21.9. In the gas phase, is 1.8 kcal/mol less acidic than .
Chlorination of isocyanides gives isocyanide dichlorides.
Ligands in coordination chemistry
Isocyanides form coordination complex
A coordination complex consists of a central atom or ion, which is usually metallic and is called the ''coordination centre'', and a surrounding array of bound molecules or ions, that are in turn known as ''ligands'' or complexing agents. Many ...
es with most transition metals. They behave as electron-rich analogues of carbon monoxide. For example tert-butyl isocyanide forms , which is analogous to . Although structurally similar, the analogous carbonyls differ in several ways, mainly because ''t''-BuNC is a better donor ligand than CO. Thus, is easily protonated, whereas its counterpart is not.
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
''Penicillium chrysogenum'' (formerly known as ''Penicillium notatum'') is a species of fungus in the genus ''Penicillium''. It is common in temperate and subtropical regions and can be found on salted food products, but it is mostly found in in ...
''. The compound xanthocillin
Xantocillin (INN), also known as xanthocillin X or ophthocillin, was the first reported natural product found to contain the isocyanide functional group. It was first isolated from ''Penicillium notatum
''Penicillium chrysogenum'' (formerly kn ...
later was used as an antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
. 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.
:
Nomenclature
IUPAC uses the prefix
A prefix is an affix which is placed before the Word stem, stem of a word. Adding it to the beginning of one word changes it into another word. For example, when the prefix ''un-'' is added to the word ''happy'', it creates the word ''unhappy'' ...
"isocyano" for the systematic nomenclature of isocyanides: isocyanomethane, isocyanoethane, isocyanopropane, etc.
The sometimes used old term "carbylamine" conflicts with systematic nomenclature. An amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
always has three single bonds,IUPAC Nomenclature of Organic Compounds (Recommendations 1993)
/ref> 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
{{Functional Groups
Functional groups