Amines cyclic basicities

The pyrrole molecule possesses the NH group typical of secondary amines. The basicity of pyrrole, pX a = -3.8 for the conjugated acid is, however, much less than that of dimethylamine (pX = 10.87). This large difference is due to the incorporation of the nonbonding electron pair of the N-atom into the cyclic conjugated system of the pyrrole molecule. The protonation, moreover, does not occur on the N-atom, but to the extent of 80% on C-2 and of 20% on C-3. 

Imidazole and its derivatives form an interesting and important class of hetero cyclic aromatic amines Imidazole is approximately 100 times more basic than pyndme... 

Photoelectron spectroscopic studies show that the first ionization potential (lone pair electrons) for cyclic amines falls in the order aziridine (9.85 eV) > azetidine (9.04) > pyrrolidine (8.77) >piperidine (8.64), reflecting a decrease in lone pair 5-character in the series. This correlates well with the relative vapour phase basicities determined by ion cyclotron resonance, but not with basicity in aqueous solution, where azetidine (p/iTa 11.29) appears more basic than pyrrolidine (11.27) or piperidine (11.22). Clearly, solvation effects influence basicity (74JA288). 

In aqueous solution, azetidine (p/sTa 11.29) is slightly more basic than pyrrolidine and larger-ring cyclic amines and appreciably more basic than aziridine. It forms an addition compound (m.p. - 9 to -6 °C) with trimethylboron which is more stable than that formed by pyrrolidine (50JA2926, 64HC(l9-2)885). Azetidinium salts are well known (Section 5.09.2.2.7). 

Delphonine shows an unusually high basic dissociation constant, and that of aconine is only a little less. In the case of tertiary vinyl cyclic amines, which prove to be unexpectedly strong bases, Adams and Mahan suggested that they exist in solution as equilibrium mixtures consisting of the tertiary unsaturated base and a quaternary arrangement in which the double bond has moved to the nitrogen, which may be represented thus —. . . +. . . +... 

Selective hydrolysis of the 3-carboxylate with 6N-HCl/AcOH was unsuccessful and instead the 4-carboxylate hydrolyzed to the corresponding acid, however, heating of 432 at 50 °C caused its hydrolysis and decarboxylation in one step. Subsequent reaction with either MnO or DDQ gave 433. The fluorine atom at 8-position could be replaced by cyclic amines to give the 8-pyrrolyl or 8-[l-methyl-4-piperazinyl] derivatives 436 which upon hydrolysis using either acidic or basic conditions afforded the... 

In a similar reaction, tertiary amines are converted to amides " and cyclic tertiary amines (e.g., 30) can be converted to lactams by oxidation with Hg —EDTA complex in basic solution. 

The abasic sites (3, Scheme 8.2) resulting from the loss of alkylated bases from DNA are both cytotoxic and mutagenic. " The cyclic acetal (3) exists in equilibrium with small amounts (—1%) of the open chain aldehyde (4). The acidic nature of a-proton in the aldehyde form of the abasic lesion facilitates 3-elimination of the 3 -phosphate residue to yield a strand break. " This reaction occurs with a half-life of about 200 h under physiological conditions (pH 7.4, 37°C), but can be accelerated by heat, basic conditions, or the presence of various amines. " ... 

On studying a series of ammonium 1,3,2,5-dioxaborataphosphorinane oxides (111), the dependence of the tautomeric equilibrium position on amine basicity was analyzed. The equilibrium position was estimated from chemical shift values of bis(oxymethyl)phenylphosphine oxide with 8 3IP of 35 ppm being used as a model of an acyclic form and 5-Ph-5-oxo-1,3,5-dioxaphosphorinane (107, R = H) with 8 3IP of 6 ppm used as a model of a cyclic compound. The chemical shift values (111, X = 0, R = H) and dissociation constants (pKa) of conjugate acids for amines are presented in Table V. 

The constants of ion pair formation of 33 amines with 2,4-dinitrophenol in benzene (Ab) have been compared with the pAa in water56. The effects of structural variations on basicity are larger in water than in benzene for primary and secondary cyclic amines, but similar for tertiary amines. The Taft and Hancock equation [where <7 has the usual meaning and E° (R ) is the steric effect of a component substituent]... 

The properties of natural macrocycles, the cyclodextrins, has stimulated interest in the preparation of synthetic macrocycles. Three basic types have been made macrocyclic amines, cyclophanes, and cyclic peptides. Hersh-field and Bender (33) prepared a bicyclic amine with hydroxamate sub-... 

Systematically increasing the size and lipophilic character of the tertiary amino group by replacing the dimethylamino substituent with acyclic and cyclic amines failed to produce much increase in activity, and the weakly basic pyrazole (11) and triazole (12) were both inactive. However, the N-imidazolyl compound (13) was unexpectedly found to be at least 10-times more potent (RVN pA2 7.61) than the parent dimethylamino derivative (10) and became a template for further elaboration. 

Basicity measurements on open-chain and cyclic enamines have led to apparently conflicting results. While Adams and Mahan (1942), Leonard et al., (1955) and Leonard and Hauck (1957), studying 6-membered cyclic enamines bearing alkyl groups in the 2-position [152], found them to be more basic than the corresponding saturated amines (e.g., [152], R = Me has a p/sTa-value of 11 4 as compared with lO S for a tertiary amine), Stcimhuis et al. (1965), studying open-chain tertiary enamines [153], found them to be less... 

Benzoyl-2,2,4,4-tetramethylbutyramide was obtained (84BAP335) only as the cyclic isomer, whereas both isomers were isolated for 4-benzoyl-3,3-dimethylbutyramide. The ring-chain equilibrium (A j 1) was rapidly attained in a solution of ether in the presence of traces of an acid catalyst, but this equilibration was accompanied by dehydration of the cyclic tautomer. The same equilibrium was reached, but more slowly, in the presence of basic catalysts, such as tertiary amines. 

Nicotine has two nitrogen atoms, one as a cyclic tertiary amine and one in a pyridine ring. The basicities are easily distinguished, in that a pyridine system is much less basic than a simple amine. This is essentially a hybridization effect, the nitrogen lone pair in pyridine being held in an sp orbital. This means the lone pair electrons are held closer to the nitrogen, and are consequently less available for protonation than in an sp -hybridized aliphatic amine. Hence, as mentioned above, pyridine has p Ta approximately 5. It follows that pA"a 8.1 is more appropriate for the pyrrolidine nitrogen. 

Quinine has two potentially basic centres, a cyclic tertiary amine at a ring junction, and one in a quinoline ring system. pAfa 8.5 is reasonably basic, and this is most likely from the aliphatic tertiary amine. We need to convince ourselves that the quinoline nitrogen is less basic. This is true. As far as reactivity is concerned, a quinoline ring system behaves as two separate parts, either pyridine or benzene, depending upon the reagent. Thus, quinoline has pATa very similar to that of pyridine, i.e. around 5. 

Nagao has disclosed bifunctional chiral sulfonamide 69 as being effective for the thiolytic ASD of meso-cyclic anhydrides in up to 98% ee when employed at the 5 mol% level for 20 h at room temperature in ether [228], Catalyst 69 is a 1,2-diamine derivative in which one of the nitrogens presents as an acidic NH group (part of an electron deficient aryl sulfonamide) and the other as a nucleophihc/basic teri-amine group with the intention to act synergistically in activation of the substrate carbonyl function and thiol nucleophile respectively (Fig. 16) [228],... 

The Knoevenagel reaction consists in the condensation of aldehydes or ketones with active methylene compounds usually performed in the presence of a weakly basic amine (Scheme 29) [116], It is well-known that aldehydes are much more reactive than ketones, and active methylene substrates employed are essentially those bearing two electron-withdrawing groups. Among them, 1,3-dicarbonyl derivatives are particularly common substrates, and substances such as malonates, acetoacetates, acyclic and cyclic 1,3-diketones, Meldrum s acid, barbituric acids, quinines, or 4-hydroxycoumarins are frequently involved. If Z and Z groups are different, the Knoevenagel adduct can be obtained as a mixture of isomers, but the reaction is thermodynamically controlled and the major product is usually the more stable one. 

The initiator used is important for copolymerizations between monomers containing different polymerizing functional groups. Basic differences in the propagating centers (oxonium ion, amide anion, carbocation, etc.) for different types of monomer preclude some copolymerizations. Even when two different monomer types undergo polymerization with similar propagating centers, there may not be complete compatibility in the two crossover reactions. For example, oxonium ions initiate cyclic amine polymerization, but ammonium ions do not initiate cyclic ether polymerization [Kubisa, 1996]. 

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