Basicity of amidines

The general topic of the basicity of amidines has been recently covered in a chapter74 in the book The Chemistry of Amidines and Related Compounds. Here, the general scheme rationalizing the dependence of basicity on the nature of the substituents is outlined. 

Basicity measurements of a great number of amidines have been conducted, both in solution and more recently in the gas phase. It was established that the basicity of amidines depends on the extent and type of substimtion at three sites at the amino and imino nitrogen atoms and at the functional carbon atom. Since the protonation occurs at the imino nitrogen atom, substitution at this site has the largest influence on the pK value of amidines, followed by the substitution at the functional carbon [45]. The pK values of alkyl-Al-substituted amidines measured in ethanol are presented in Table 2.3. Since these substituents show identical electronic effects, pK s are quite uniform along the series, and the values indicate a modest superbasicity at the lower part of the superbasicity scale. 

As shown by Koppel, solution basicity of amidines could be increased to some extent by OCH3 and NCH3 groups positioned at the end of an alkyl chain [47] (Table 2.4). Here, the... 

The basicity of compounds containing the amidino group N=C—N depends on the substituents at the three sites (both nitrogens and the amidino carbon atom) and the protonation site is the imino nitrogen atom75. It has been shown76 that, at any of the three sites, in the series of monosubstituted amidines, their pKa values obey Hammett s equation. 

The enhanced basicities of acetamidine [28] and amidines with conjugated double bonds linking the two nitrogen atoms [29] are... 

The alternative possibility of protonation of amidines on the amino-nitrogen depends on its basicity, after its lone pair of electrons has been localized. This localization energy is not known and neither is the inductive effect of the residue attached to the amino-nitrogen in [36], but an amino-nitrogen attached to an -hybridized carbon... 

The even greater basicity of guanidine (p/iLa = 13-6) as compared with amidines is due to an even greater resonance stabilization of the cation, since three equivalent resonance structures enter into resonance [6]. The base itself resonates between three nonequivalent structures [37], and has according to Pauling (1939,... 

The A-nitration of the furazan-based heterocycle (29) has been reported. The corresponding tetranitramine (30) is an unstable substance, but obtained on treating (29) with either trifluoroacetic anhydride (TFAA) in nitric acid or dinitrogen pentoxide in nitric acid. In this case the furazan rings stabilize the 1,4,5,8-tetraazadecalin structure and further reduce the basicity of the amidine amino groups. A number of other furazan and nitrogen-rich nitramines... 

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... 

Amidines are converted into 1,2,4-thiadiazoles by reaction with isothiocyanates, iminosulfenyl chlorides, di- and trichloromethyl sulfenyl chlorides, and carbon disulfide in the presence of sulfur <82AHC(32)285> for example, 5-mercapto-3-methyl-l,2,4-thiadiazole (205) is obtained by the treatment of acetamidine with carbon disulfide and sulfur under basic conditions (Equation (29)) <85JAP85255783>. A useful method for the synthesis of 5-chloro-l, 2,4-thiadiazole (206) (R = 6-methyl-2-pyridyl) involves the reaction of amidines with trichloromethylsulfenyl chloride (Equation (30)) <91JAP9183590>. 

A few scattered examples of hexahydro- and octahydro-l,3-diazocines have been reported, mainly in the context of studies on the effect of chain length on the cyclization of diamines. Reaction of the N- aryl-iV - aroyldiamines (194) with polyphosphoric ester gives the cyclic amidines (195) (77JCS(P2)2068). Yields of the diazocines (195 n =5) were about 40%, compared to 90% for the 1,3-diazepine (195 n =4). The basicities of the products decrease in the order of ring size 6 7>8 5, lower basicity reflecting non-planarity of the amidine system. 

In 1954, Goerdeler6 introduced a general synthesis of 1,2,4-thia-diazoles from amidines. This versatile method has since been widely extended and has made a great variety of 1,2,4-thiadiazole derivatives readily accessible. Basically, an amidine is converted into its i T-thio-cyanato derivative, which cyclizes spontaneously to the 5-amino-1,2,4-thiadiazole. 

Amidines are strongly basic compounds that often show interesting biological activity. Few preparations of amidines on insoluble supports have, however, been reported (Table 13.18). Linkers for amidines are considered in Section 3.9. 

The kinetics and mechanism of the phosphorus-catalysed dimerization of acrylonitrile to give 1,4-dicyanobut-l-ene and 2,4-dicyanobut-l-ene have been studied.114 The reactions of aryhminodimagnesium (138) with //-substituted p-cyanobenzophenones, l-cyano-9-fluorenenone, o-, m-, and p-dicyanobcnzcnes, and o-, m-, and p-nitrobenzonitriles have been examined.115 The effect of pressure on the reaction of 3 -methyl- l-(4-tolyl)triazene (139) and benzoic acid in chloroform and acetonitrile has been studied.116 The effect of acids on the rate of urethane formation from alcohols and isocyanates in the presence of alkyltin carboxylates has been examined.117 A Hammett a value has been reported for the amidine group N=CHNMe2 and used for the prediction of the basicity of sites in bifunctional amidines.118... 

An amidine is the nitrogen equivalent of an amide—a C=NH group replaces the carbonyl. Amidines are much more basic than amides, the p faHs of amidines are larger than those of amides by about 13 so there is an enormous factor of 1013 in favour of amidines. In fact, they are among the strongest neutral bases. 

A ring-closure reaction of amidine-containing pyrazoles 121 can be effected by treatment with diethyl carbonate under basic conditions to afford products 122 in almost quantitative yields (Scheme 77) <2000JME449, 2003BMC4093, CHEC-III(11.17.6.3.5)798>. 

The readiness of amidine formation in reactions of lactim ethers with amines has been used in the synthesis of 8,9-poly methylene-purines.97 Attempts to condense 2 (R = Me) with uramil and l,3-dimethyl-4,5-diaminouracil failed.97 Lactim ethers were also found not to react with derivatives of 5-aminouracil, probably due to the low basicity of the latter.97... 

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