Basic centers

Dioxo compounds are deprotonated at C-2 and C-4 by two equivalents of strong bases (e.g. LDA or BuLi). Carbon atom C-4 of those dianions is much more nucleophilic than the less basic center C-2 (Hauser s rule C.R. Hauser, 1958 K.G. Hampton, 1965). The formation of some typical d -synthons and their pA values are given below. 

The use of a reagent bearing a basic center or the addition of a base to the reaction mixture was recognized as necessary to prevent the acid-catalyzed elimination of the elements of water from the intermediates. Since the publication of this work, a number of similar intermediates have been isolated from thioamides and a-halogeno carbonyl compounds (608, 609, 619, 739, 754, 801), and as a result of kinetic studies, the exact mechanism of this reaction has been well established (739, 821). 

That the ind-N atom in the anhydro-bases is the basic center is also obvious from a consideration of the ultraviolet absorption spectra of the anhydro-bases. In aqueous 0.1 A hydrochloric acid as well as in neutral alcoholic solutions each carboline anhydro-base gives rise to an ultraviolet absorption spectrum identical with that of the parent carbolinium salt. In alkaline solutions (pH above 11.5 in the case of the... 

The methods outlined, of course, are readily applicable to a wide variety of substituted heterocycles like the carboxyl, hydroxy and mercapto derivatives of pyridines, pyridine 1-oxides, pyrroles, etc. The application to amines and to diaza compounds such as pyrimidine, where the two centers are basic, is obvious except that now 23 takes the role of the neutral compound, 21 and 22 the roles of the tautomeric first conjugate bases, and 20 the role of the second conjugate base. Extensions to molecules with more than two acidic or basic centers, such as aminonicotinic acid, pyrimidinecarboxylic acids, etc., are obvious although they tend to become algebraically cumbersome, involving (for three centers) three measurable Kg s, four Ay s, and fifteen ideal dissociation constants (A ), a total of twenty-two constants of which seven are independent. 

Methyl- and 2,6-dimethylpyridine as catalysts with sterically hindered a-com-plexes give greater isotope effects (k2n/k2D up to 10.8). Such values are understandable qualitatively, since the basic center of these pyridine derivatives cannot easily approach the C-H group. The possibility of tunneling can be excluded for these reactions, as the ratio of the frequency factors 4h 4d and the difference in activation energies ED—EU (Arrhenius equation) do not have abnormal values. 

As seen from (Scheme 12-73) the primary product of arylazo substitution is the anion Ar - N2 - R . It is protonated in a subsequent step either at a basic center of the residue R (preferentially at an oxygen atom, for example, in coupling with phenol), or at the azo nitrogen next to the group Ar forming a hydrazone. The problem as to whether the final product is a hydroxyazo- or a quinonehydrazone-type... 

Transition metals have been used to complex Lewis-basic centers in metathesis substrates and to arrange the reacting olefins in such a way that cycliza-tion is facilitated. Olefin metathesis of 122, for example, proceeds with good yield to the bispyridine macrocycle 123 (Eq. 17) [115]. 

In yet a further variation on this scheme, the basic center in the molecule can be present as an... 

Incorporation of additional basic centers into the phenylpiperidinol nucleus leads to a molecule that shows local anesthetic rather than CNS activity. Condensation of the protected piperidone 106 with... 

It has been found subsequent to this that attachment of the basic center in the guise of a piperazine ring... 

The presence in the heterocycle of additional basic centers or those open to alkylation can lead to a change in reaction directions. It essentially limits the application of this method in the formation of a-methoxy nitrones. In such cases, it is reasonable to use diazomethane and, depending on the structure of hydroxamic acid (198-201) the yields of a-methoxy nitrones (197), (202-204) can rise from 17% up to 62% (Scheme 2.70) (353). 

The differences in reactivity between the nitrogen and the sulfur atom in OZTs reveal that most reactions can be interpreted with reference to Pearson s HSAB theory.56 In the case of l,3-oxazolidine-2-thiones, one may consider the nitrogen atom as a harder basic center than the softer sulfur atom. 

Extensive collections of pK values are available in the literature, e.g., [98-101]. It is also possible to predict pK values for a broad range of organic acids and bases using linear free energy relationships based on a systematic treatment of electronic (inductive, electrostatic, etc.) effects of substituents which modify the charge on the acidic and basic center. Quantitative treatment of these effects involves the use of the Hammett Equation which has been a real landmark in mechanistic organic chemistry. A Hammett parameter (a), defined as follows ... 

It is worth noting that anodic oxidations often give electrophilic and/or acidic centers, whereas cathodic reductions lead to nucleophihc and/or basic centers. Moreover, we must keep in mind that the mechanisms of many anodic and cathodic cyclizations are not accurately known. 

The removal of hydroxyl groups in proximity to the basic center may increase the basicity of imino sugars, whereas the introduction of strongly electronegative substituents, in particular fluorine atoms, may cause the free base to prevail, or at least be present in a comparably higher proportion in the equilibrium at the same pH value. 

On nitrided aluminophosphates, AlPON, Massinon et al. [206] observed on a series of six samples with increasing nitrogen contents a good correlation between the catalytic activity in the Knoevenagel condensation reaction and the amount of surface NH, species (1 < x < 4) quantified by the Kjeldahl method. The authors suggest that those species are not the only active species and evoke an additional role of the nitride ions in the reaction [206] on the other hand, Benitez et al. [207] suggest hydroxyls linked to aluminum cations in the vicinity of terminal P-NH2 groups as basic centers. 

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