Cyanides aromatic nucleophilic substitution

BTF is a suitable solvent for conducting heterogeneous reactions with phase transfer catalysis. The reaction of benzyl chloride with sodium cyanide (in toluene and BTF) or potassium cyanide (in acetonitrile and BTF) using two different phase transfer catalysts [70] gave similar yields (12.1 12.2). Aromatic nucleophilic substitution of chloro-2,4-dinitro benzene using potassium fluoride and... 

Nucleophilic Substitutions of Benzene Derivatives. Benzene itself does not normally react with nucleophiles such as haUde ions, cyanide, hydroxide, or alkoxides (7). However, aromatic rings containing one or more electron-withdrawing groups, usually halogen, react with nucleophiles to give substitution products. An example of this type of reaction is the industrial conversion of chlorobenzene to phenol with sodium hydroxide at 400°C (8). 

Many different nucleophiles—halide, hydride, cyanide, and hydroxide among others—react with arenediazonium salts, yielding many different kinds of substituted benzenes. The overall sequence of (1) nitration, (2) reduction, (3) diazotization, and (4) nucleophilic substitution is perhaps the single most versatile method of aromatic substitution. 

Nuclear and side chain substitution in aromatics or substitution of a -hydrogen in alkylamines is — in most cases — best rationalized by postulating radical cations as intermediates. For anodic nuclear substitution of aromatics, especially for acyloxylation, cyanation or bromination a ECnECb3 -mechanism is assumed 37,4 9,50,226,227). jc-oxidation of the aromatic to the radical cation 28, which reacts with a nucleophile Nu, e.g., acetate, cyanide, alkoxide, followed by a second electron transfer and deprotonation (Eq. (98) ) ... 

Ambident anions are mesomeric, nucleophilic anions which have at least two reactive centers with a substantial fraction of the negative charge distributed over these cen-ters ) ). Such ambident anions are capable of forming two types of products in nucleophilic substitution reactions with electrophilic reactants . Examples of this kind of anion are the enolates of 1,3-dicarbonyl compounds, phenolate, cyanide, thiocyanide, and nitrite ions, the anions of nitro compounds, oximes, amides, the anions of heterocyclic aromatic compounds e.g. pyrrole, hydroxypyridines, hydroxypyrimidines) and others cf. Fig. 5-17. 

ROSgNMUND BRAUN AromaticCyanation u catalyaed nucleophilic substitution ol aromatic hatogen by cyanide (see UBman-Goldberg)... 

It is not possible to construct an invariant nucleophilicity order because different substrates and different conditions lead to different orders of nucleophilicity, but an overall approximate order is NH2 > PhaC > PhNH (aryne mechanism) > ArS > RO > R2NH > ArO > OH > ArNHi > NH3 > 1 > Br > Cl > H2O > ROH. As with aliphatic nucleophilic substitution, nucleophilicity is generally dependent on base strength and nucleophilicity increases as the attacking atom moves down a column of the periodic table, but there are some surprising exceptions, for example, OH, a stronger base than ArO , is a poorer nucleophile. In a series of similar nucleophiles, such as substituted anilines, nucleophilicity is correlated with base strength. Oddly, the cyanide ion is not a nucleophile for aromatic systems, except for sulfonic acid salts and in the von Richter (13-30) and Rosenmund-von Braun (13-8) reactions, which are special cases. 

As it is well known, nucleophilic substitution of a C-X bond, one of the key synthetic reactions with aliphatic compounds is severely limited with aromatic derivatives, where it occurs thermally only with electron-withdrawing substituted compounds and/or under severe conditions. Alternatives include time honored reactions involving the phenyl radical generated by decomposition of diazonium salts after a reductive step, such as the Meerwein and the Gomberg-Bachmann reactions, as well as the (often photoinitiated) SrnI reaction, where a (usually weak, e.g. carbon-iodine) bond is cleaved after monoelectronic reduction to give an aryl radical as the active inter-mediate that adds to an enolate, cyanide or other nucleophiles (and thus again with an aryl radical as the key intermediate. Scheme S). ... 

Cu catalyzed nucleophilic substitution of aromatic halogen by cyanide Ullman-Goldberg) (see 1st edition). (see also... 

ROSENMUND BRAUN AromaticCyanation Cu catalyzed nucleophilic substitution o( aromatic halogen by cyanide (see Ullman-GokJberg). 

Kinetic, steric, and thermodynamic results have been reviewed to argue that the rate-determining step in some aliphatic nucleophilic substitutions is the transfer of an electron. The same group carried out a systematic ranking of different nucleophiles with respect to their ability to stabilize the transition states of substitution reactions, acetonitrile and dimethyl sulfoxide being the solvents involved. The nucleophiles included enolates, phenolates, thiophenolates, hydroxide, and cyanide. The method is based on a comparison of the rate coefficient, ksm, for the substitution reaction between a given nucleophile and benzyl chloride with the rate coefficient, A et for the corresponding electron transfer from an aromatic radical anion to benzyl chloride. The ratio ksuB/ ET expresses the rate enhancement due to electronic interaction in the transition state of the substitution reaction. 

It has been known for a long time that the nucleophilic substitution of aromatic halides is strongly catalyzed by the presence of certain copper salts. Perhaps the most useful of the synthetic procedures based on this observation is the synthesis of aryl nitriles by reaction of aryl bromides with cuprous cyanide. The reaction is usually accomplished in dimethylformamide or a similar solvent. More recently. 

Nucleophilic aromatic substitutions involving loss of hydrogen are known. The reaction usually occurs with oxidation of the intermediate either intramoleculady or by an added oxidizing agent such as air or iodine. A noteworthy example is the formation of 6-methoxy-2-nitrobenzonitrile from reaction of 1,3-dinitrobenzene with a methanol solution of potassium cyanide. In this reaction it appears that the nitro compound itself functions as the oxidizing agent (10). 

When aromatic nitro compounds are treated with cyanide ion, the nitro group is displaced and a carboxyl group enters with cine substitution (p. 854), always ortho to the displaced group, never meta or para. The scope of this reaction, called the von Richter rearrangement, is variable. As with other nucleophilic aromatic substitutions, the reaction gives best results when electron-withdrawing groups are in ortho and para positions, but yields are low, usually < 20% and never > 50%. 

The initial discoveries of the extension of the aromatic ring of the ortho-phthalaldehyde (OPA) to a naphthalene-2,3-dicarboxaldehyde (NBA) and the substitution of cyanide (CN ) for 2-ME as the nucleophile have provided the Center with a much more versatile reagent system (5,11), which maintains the sensitivity for primary aliphatic amines and amino acids, and now is known to form fluorescent products with oligopeptides, proteins, and other related analytes that possess a primary amine function (Equation 1). 

Amongst the nucleophiles most used in the study of nucleophilic aromatic photosubstitution, the cyanide ion has proved of special interest (Letsinger and McCain, 1966, 1969 Letsinger and Hautala, 1969 Lok et al., 1970). In many instances it gives efficient substitution, promoted by presence of oxygen (air). With some... 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

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