Basicity amines, aromatic, substituted

Arylamines contain two functional groups the amine group and the aromatic ring they are difunctional compounds The reactivity of the amine group is affected by its aryl substituent and the reactivity of the ring is affected by its amine substituent The same electron delocalization that reduces the basicity and the nucleophilicity of an arylamme nitrogen increases the electron density in the aromatic ring and makes arylamines extremely reactive toward electrophilic aromatic substitution... 

The C-nitrosation of aromatic compounds is characterized by similar reaction conditions and mechanisms to those discussed earlier in this section. The reaction is normally carried out in a strongly acidic solution, and in most cases it is the nitrosyl ion which attacks the aromatic ring in the manner of an electrophilic aromatic substitution, i. e., via a a-complex as steady-state intermediate (see review by Williams, 1988, p. 58). We mention C-nitrosation here because it may interfere with diazotization of strongly basic aromatic amines if the reaction is carried out in concentrated sulfuric acid. Little information on such unwanted C-nitrosations of aromatic amines has been published (Blangey, 1938 see Sec. 2.2). 

Subsequently, the scope of the reaction was extended to N-nucleophiles 82. Because the inherent basicity of the substitution products 83 imposed some problems concerning catalyst decomposition, the addition of catalytic amoimts of piperidine hydrochloride (pip-HCl) proved to be necessary. Under optimized reaction conditions different aromatic amines 82 were allylated with almost exclusive regioselectivites in favor of the ipso substitution products 83 (eq. 1 in Scheme 20) [64]. 

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... 

Arylcinnolin-4-amines 246 could be obtained from o-trifluoromethylphenyl hydrazones 245 via treatment with NaHMDS in THF at —78°C (Equation 60). The mechanism consists of quinine methide formation followed by electrocyclization and elimination of HF yielding 3-aryl-4-fluorocinnolines. Nucleophilic aromatic substitution of the fluorine atom with NaFlMDS gave, after basic hydrolysis, 3-arylcinnolin-4-amines 246 <1999TL5111>. 

An additional modification in the above synthetic scheme is possible by introducing the aromatic diamine in the form of its trimethylsilyl derivative [72]. Monotrimethylsilyl-substituted amines are readily prepared from the free amine with hexamethyldisilazane or trimethylsilyl chloride in the presence of a tertiary amine [73, 74] whereas bis(trimethylsilyl)-substituted amines require more aggressive reagents, such as butyllithium in conjunction with trimethylsilyl chloride [75]. As illustrated in Scheme 19, monotrimethylsilyl-substituted amines react with acyl chlorides to form the corresponding amides and liberate trimethylsilyl chloride. Monotrimethylsilyl-substituted amines are reported to display increased reactivity with acyl chlorides [76], This is of great synthetic importance since the increased reactivity allows for reaction with low basicity amines. Bis(trimethylsilyl)-substituted amines, on the other hand, react with acyl chlorides to form the corresponding JV-trimethylsilyl amides, see Scheme 20. The JV-trimethylsilyl amides are much more soluble in common organic solvents. However, they are hydrolytically unstable and readily convert back to the free amides. 

It is made by dimerizing cyanamide in basic aqueous solution, and is a colorless solid melting at 208°C. Dicyandiamide is soluble in polar solvents, but at room temperature is insoluble in bisphenol A epoxy resins. It can be made into a very fine powder and milled into epoxy resins to form stable dispersions. Because the dicy is insoluble in the epoxy, the only possible reaction sites are at the particle surfaces. Although some reaction certainly occurs over a short time, the adhesives easily can have a useful shelf life of six months. On heating to about 150°C, the dicyandiamide becomes soluble in the epoxy resin, and the adhesive polymerizes rapidly. Cure can be accelerated by incorporation of tertiary aromatic amines or substituted ureas. 

In al this we have estimated the stability of a carbonium ion on the same basis the dispersal or concentration of the charge due to electron release or electron withdrawal by the substituent groups. As wc shall see, the approach that has worked so well for elimination, for addition, and for electrophilic aromatic substitution works for still another important class of organic reactions in which a positive charge develops nucleophilic aliphatic substitution by the S l mechanism (Sec. 14.14). It works equally well for nucleophilic aromatic substitution (Sec. 25.9), in which a negative charge develops. Finally, we shall find that this approach will help us to understand acidity or basicity of such compounds as carboxylic acids, sulfonic acids, amines, and phenols. 

Another drawback to the use of amino-substituted benzenes in electrophilic aromatic substitution reactions is that Friedel—Crafts reactions are not successful (Section 16.3). The amino group forms an acid-base complex with the AICI3 catalyst, which prevents further reaction from occurring. Both drawbacks—high reactivity and amine basicity—can be overcome by carrying out electrophilic aromatic substitution reactions on the corresponding amide rather than on the free amine. 

The chemistry of amines is dominated by the lone-pair electrons on nitrogen, which makes amines both basic and nucleophilic. The base strength of arylamines is generally lower than that of aliphatic amines because the nitrogen lone-pair electrons are delocalized by interaction with the aromatic tt system. Electron-withdrawing substituents on the aromatic ring further weaken the basicity of a substituted aniline, while electron-donating substituents increase basicity. 

The propensity for C-N vs. N-H activation correlates well with substituent Hammet parameters groups that increase the basicity of aniline increase the relative rate of N-H activation, suggesting that nucleophilic attack by the amine at an empty d /dy orbital of Ta(silox)3 preceeds oxidative addition. On the other hand, electron-withdrawing substituents decrease the rate of N-H activation and increase the rate of C-N activation, similarly to the effects observed on electrophilic aromatic substitution. Nucleophilic attack by the filled d a orbital of Ta(silox)3 is expected to occur at the arylamine ipso carbon preceding C-N oxidative addition. The carbon-heteroatom cleavages can be accomodated by mechanisms using both electrophilic and nucleophilic sites on the metal center. 

---