Nitrile anion
Encyclopedia
Nitrile anions are nitriles lacking a proton at the position α to the nitrile group. They undergo nucleophilic addition and substitution reactions with various electrophile
s.
Although nitrile anions are functionally similar to enolates, the extra multiple bond in nitrile anions provides them with a unique ketene
-like geometry. Additionally, deprotonated cyanohydrin
s can act as masked acyl anions, giving products impossible to access with enolates alone. The mechanisms of nitrile addition and substitution are well understood; however, strongly basic conditions are usually required, limiting the reaction's synthetic usefulness.
) or metal alkyls (such as butyllithium
) for effective deprotonation. In the latter case, competitive addition of the alkyl group to the nitrile takes place.
IR spectroscopy studies have demonstrated the existence of at least two tautomeric forms of the nitrile anion (see above).
Polyanions of nitriles can also be generated by multiple deprotonations, and these species produce polyalkylated products in the presence of alkyl electrophiles.
Alternative methods to produce nitrile anions include conjugate addition to α,β-unsaturated nitriles, reduction, and transmetallation.
involved. Simple alkylations take place by SN2 displacement and are subject to the usual stereoelectronic requirements of the process. Phase-transfer catalysis has been employed in alkylations of arylacetonitriles. Nitrile anions can also be involved in Michael
-type additions to activated double bonds and vinylation reactions with a limited number of polarized, unhindered acetylene derivatives.
Arylation of nitrile anions is also possible, and can take place through different mechanisms depending on the substrates and reaction conditions. Aryl halides lacking electron-withdrawing groups react through an addition-elimination mechanism involving benzyne intermediates. Aryl phosphates and ammoniums react through the SRN1
pathway, which involves the generation of an aryl radical anion, fragmentation, and bond formation with a nucleophile. Electron transfer to a second molecule of arene carries on the radical chain.
Electron-poor aromatic compounds undergo nucleophilic aromatic substitution
in the presence of nitrile anions.
s (the nearby negative charge of the opened epoxide wards off further alkylation) and alkylations with cyanomethylcopper(I) species. Side reactions may also present a problem; concentrations of the nitrile anion must be high in order to mitigate processes involving self-condensation, such as the Thorpe-Ziegler reaction. Other important side reactions include elimination of the alkyl cyanide product or alkyl halide starting material and amidine
formation.
The cyclization of ω-epoxy-1-nitriles provides an interesting example of how stereoelectronic factors may override steric factors in intramolecular substitution reactions. In the cyclization of 1, for instance, only the cyclopropane isomer 2 is observed. This is attributed to better orbital overlap in the SN2 transition state for cyclization. 1,1-disubstituted and tetrasubstituted epoxides also follow this principle.
Conjugated nitriles containing γ hydrogens may be deprotonated at the γ position to give resonance-stabilized anions. These intermediates almost always react with α selectitivity in alkylation reactions, the exception to the rule being anions of ortho-tolyl nitriles.
Formation of cyanohydrins from carbonyl compounds renders the former carbonyl carbon acidic. After protection of the hydroxyl group with an acyl or silyl group, cyanohydrins can function essentially as masked acyl anions. Because ester protecting groups are base labile, mild bases must be employed with ester-protected cyanohydrins. α-(dialkylamino)nitriles can also be used in this context.
Examples of arylation and acylation reactions are shown below. Although intermolecular arylations using nitrile anions result in modest yields, the intramolecular procedure efficiently gives four-, five-, and six-membered benzo-fused rings. Acylation can be accomplished using a wide variety of acyl electrophiles, including carbonates, chloroformates, ester
s, anyhdrides, and acid chlorides. In these reactions, two equivalents of base are used to drive the reaction towards acylated product—the acylated product is more acidic than the starting material.
Acylation is much more straightforward, as the resulting α-cyanocarbonyl compounds are much more acidic (and less nucleophilic) than corresponding starting materials. Monoacylated products can be obtained easily.
in 200 mL of anhydrous toluene
was added a mixture of 122 g (1.043 mol) of phenylacetonitrile and 150 g (1.095 mol) of isobutyl bromide. The mixture was heated at 65°, at which temperature the reaction commenced. The heating mantle was removed, and the flask was cooled in order to keep the reaction from becoming too vigorous during the initial 0.5-hour reaction period. The reaction mixture was refluxed for an additional 5 hours and permitted to stand overnight. Ethanol
(40 mL) was cautiously added dropwise, followed by the dropwise addition of 200 mL of water. The organic layer was separated, and the aqueous layer was extracted with benzene
. The combined organic layers were washed successively with dilute acid, water, sodium carbonate
solution, and water. After filtration through a layer of sodium sulfate
, the benzene was evaporated and the product was fractionally distilled
to afford 115 g (66%) of 2-phenyl-4-methylvaleronitrile, bp
130–134° (10 mm) [lit. (540) bp
136–138° (15 mm)].
Electrophile
In general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...
s.
Although nitrile anions are functionally similar to enolates, the extra multiple bond in nitrile anions provides them with a unique ketene
Ketene
A ketene is an organic compound of the form R'RC=C=O. The term is also used specifically to mean ethenone, the simplest ketene, where R' and R are hydrogen atoms.Ketenes were first studied as a class by Hermann Staudinger.-Formation:...
-like geometry. Additionally, deprotonated cyanohydrin
Cyanohydrin
A cyanohydrin is a functional group found in organic compounds. Cyanohydrins have the formula R2CCN, where R is H, alkyl, or aryl. Cyanohydrins are industrially important precursors to carboxylic acids and some amino acids...
s can act as masked acyl anions, giving products impossible to access with enolates alone. The mechanisms of nitrile addition and substitution are well understood; however, strongly basic conditions are usually required, limiting the reaction's synthetic usefulness.
Generation of Nitrile Anions
Nitrile anions are most often generated through the action of an appropriate base. However, the pKas of nitriles span a wide range—at least 20 pKa units. Thus, the proper choice of base is usually substrate dependent. Acetonitriles containing an extra stabilizing electron-withdrawing group (such as an aromatic ring) can usually be deprotonated using hydroxide or alkoxide bases. Unstabilized nitriles, on the other hand, usually require either alkali metal amide bases (such as NaNH2Sodium amide
Sodium amide, commonly called sodamide, is the chemical compound with the formula NaNH2. This solid, which is dangerously reactive toward water, is white when pure, but commercial samples are typically gray due to the presence of small quantities of metallic iron from the manufacturing process...
) or metal alkyls (such as butyllithium
N-Butyllithium
n-Butyllithium is an organolithium reagent. It is widely used as a polymerization initiator in the production of elastomers such as polybutadiene or styrene-butadiene-styrene...
) for effective deprotonation. In the latter case, competitive addition of the alkyl group to the nitrile takes place.
IR spectroscopy studies have demonstrated the existence of at least two tautomeric forms of the nitrile anion (see above).
Polyanions of nitriles can also be generated by multiple deprotonations, and these species produce polyalkylated products in the presence of alkyl electrophiles.
Alternative methods to produce nitrile anions include conjugate addition to α,β-unsaturated nitriles, reduction, and transmetallation.
Reactions of Nitrile Anions
The mechanisms of reactions involving nitrile anions depend primarily on the nature of the electrophileElectrophile
In general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...
involved. Simple alkylations take place by SN2 displacement and are subject to the usual stereoelectronic requirements of the process. Phase-transfer catalysis has been employed in alkylations of arylacetonitriles. Nitrile anions can also be involved in Michael
Michael reaction
The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an alpha, beta unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C-C bonds...
-type additions to activated double bonds and vinylation reactions with a limited number of polarized, unhindered acetylene derivatives.
Arylation of nitrile anions is also possible, and can take place through different mechanisms depending on the substrates and reaction conditions. Aryl halides lacking electron-withdrawing groups react through an addition-elimination mechanism involving benzyne intermediates. Aryl phosphates and ammoniums react through the SRN1
Radical-nucleophilic aromatic substitution
Radical-nucleophilic aromatic substitution or SRN1 in organic chemistry is a type of substitution reaction in which a certain substituent on an aromatic compound is replaced by a nucleophile through an intermediary free radical species:...
pathway, which involves the generation of an aryl radical anion, fragmentation, and bond formation with a nucleophile. Electron transfer to a second molecule of arene carries on the radical chain.
Electron-poor aromatic compounds undergo nucleophilic aromatic substitution
Nucleophilic aromatic substitution
right|300px|Aromatic nucleophilic substitutionA nucleophilic aromatic substitution is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring...
in the presence of nitrile anions.
Scope and Limitations
The primary difficulty for alkylation reactions employing nitrile anions is over-alkylation. In the alkylation of acetonitrile, for instance, yields of monoalkylated product are low in most cases. Two exceptions are alkylations with epoxideEpoxide
An epoxide is a cyclic ether with three ring atoms. This ring approximately defines an equilateral triangle, which makes it highly strained. The strained ring makes epoxides more reactive than other ethers. Simple epoxides are named from the parent compound ethylene oxide or oxirane, such as in...
s (the nearby negative charge of the opened epoxide wards off further alkylation) and alkylations with cyanomethylcopper(I) species. Side reactions may also present a problem; concentrations of the nitrile anion must be high in order to mitigate processes involving self-condensation, such as the Thorpe-Ziegler reaction. Other important side reactions include elimination of the alkyl cyanide product or alkyl halide starting material and amidine
Amidine
Amidines are a class of oxoacid derivatives.The oxoacid from which an amidine is derived must be of the form RnEOH, where R is a substituent...
formation.
The cyclization of ω-epoxy-1-nitriles provides an interesting example of how stereoelectronic factors may override steric factors in intramolecular substitution reactions. In the cyclization of 1, for instance, only the cyclopropane isomer 2 is observed. This is attributed to better orbital overlap in the SN2 transition state for cyclization. 1,1-disubstituted and tetrasubstituted epoxides also follow this principle.
Conjugated nitriles containing γ hydrogens may be deprotonated at the γ position to give resonance-stabilized anions. These intermediates almost always react with α selectitivity in alkylation reactions, the exception to the rule being anions of ortho-tolyl nitriles.
Formation of cyanohydrins from carbonyl compounds renders the former carbonyl carbon acidic. After protection of the hydroxyl group with an acyl or silyl group, cyanohydrins can function essentially as masked acyl anions. Because ester protecting groups are base labile, mild bases must be employed with ester-protected cyanohydrins. α-(dialkylamino)nitriles can also be used in this context.
Examples of arylation and acylation reactions are shown below. Although intermolecular arylations using nitrile anions result in modest yields, the intramolecular procedure efficiently gives four-, five-, and six-membered benzo-fused rings. Acylation can be accomplished using a wide variety of acyl electrophiles, including carbonates, chloroformates, ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
s, anyhdrides, and acid chlorides. In these reactions, two equivalents of base are used to drive the reaction towards acylated product—the acylated product is more acidic than the starting material.
Synthetic Applications
Alkylation of a nitrile anion followed by reductive decyanation was employed in the synthesis of the sex pheromone of Pazalobesia viteana.Typical Conditions
The most common bases used to deprotonate nitriles are the alkali metal amides, substituted amides, and hydrides. These reagents require inert, anhydrous conditions and careful handling. Polyalkylation is a significant problem for primary or secondary nitriles; however, a number of solutions to this problem exist. Alkylation of cyanoacetates followed by decarboxylation provides one solution. Acylation of primary or secondary nitriles provides a convenient entry to the starting materials for this sequence. Distillation and chromatography are only practical for the separation of mono- and di-alkylated material when the molecular weight difference between the two is large.Acylation is much more straightforward, as the resulting α-cyanocarbonyl compounds are much more acidic (and less nucleophilic) than corresponding starting materials. Monoacylated products can be obtained easily.
Example Procedure
To a suspension of 24.4 g (1.017 mol) of sodium hydrideSodium hydride
Sodium hydride is the chemical compound with the empirical formula NaH. It is primarily used as a strong base in organic synthesis. NaH is representative of the saline hydrides, meaning it is a salt-like hydride, composed of Na+ and H− ions, in contrast to the more molecular hydrides such as...
in 200 mL of anhydrous toluene
Toluene
Toluene, formerly known as toluol, is a clear, water-insoluble liquid with the typical smell of paint thinners. It is a mono-substituted benzene derivative, i.e., one in which a single hydrogen atom from the benzene molecule has been replaced by a univalent group, in this case CH3.It is an aromatic...
was added a mixture of 122 g (1.043 mol) of phenylacetonitrile and 150 g (1.095 mol) of isobutyl bromide. The mixture was heated at 65°, at which temperature the reaction commenced. The heating mantle was removed, and the flask was cooled in order to keep the reaction from becoming too vigorous during the initial 0.5-hour reaction period. The reaction mixture was refluxed for an additional 5 hours and permitted to stand overnight. Ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
(40 mL) was cautiously added dropwise, followed by the dropwise addition of 200 mL of water. The organic layer was separated, and the aqueous layer was extracted with benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....
. The combined organic layers were washed successively with dilute acid, water, sodium carbonate
Sodium carbonate
Sodium carbonate , Na2CO3 is a sodium salt of carbonic acid. It most commonly occurs as a crystalline heptahydrate, which readily effloresces to form a white powder, the monohydrate. Sodium carbonate is domestically well-known for its everyday use as a water softener. It can be extracted from the...
solution, and water. After filtration through a layer of sodium sulfate
Sodium sulfate
Sodium sulfate is the sodium salt of sulfuric acid. When anhydrous, it is a white crystalline solid of formula Na2SO4 known as the mineral thenardite; the decahydrate Na2SO4·10H2O has been known as Glauber's salt or, historically, sal mirabilis since the 17th century. Another solid is the...
, the benzene was evaporated and the product was fractionally distilled
Fractional distillation
Fractional distillation is the separation of a mixture into its component parts, or fractions, such as in separating chemical compounds by their boiling point by heating them to a temperature at which several fractions of the compound will evaporate. It is a special type of distillation...
to afford 115 g (66%) of 2-phenyl-4-methylvaleronitrile, bp
Boiling point
The boiling point of an element or a substance is the temperature at which the vapor pressure of the liquid equals the environmental pressure surrounding the liquid....
130–134° (10 mm) [lit. (540) bp
Boiling point
The boiling point of an element or a substance is the temperature at which the vapor pressure of the liquid equals the environmental pressure surrounding the liquid....
136–138° (15 mm)].