Nucleophilic bases hardness

Further examination of the results indicated that by invocation of Pearson s Hard-Soft Acid-Base (HSAB) theory (57), the results are consistent with experimental observation. According to Pearson s theory, which has been generalized to include nucleophiles (bases) and electrophiles (acids), interactions between hard reactants are proposed to be dependent on coulombic attraction. The combination of soft reactants, however, is thought to be due to overlap of the lowest unoccupied molecular orbital (LUMO) of the electrophile and the highest occupied molecular orbital (HOMO) of the nucleophile, the so-called frontier molecular orbitals. It was found that, compared to all other positions in the quinone methide, the alpha carbon had the greatest LUMO electron density. It appears, therefore, that the frontier molecular orbital interactions are overriding the unfavorable coulombic conditions. This interpretation also supports the preferential reaction of the sulfhydryl ion over the hydroxide ion in kraft pulping. In comparison to the hydroxide ion, the sulfhydryl is relatively soft, and in Pearson s theory, soft reactants will bond preferentially to soft reactants, while hard acids will favorably combine with hard bases. Since the alpha position is the softest in the entire molecule, as evidenced by the LUMO density, the softer sulfhydryl ion would be more likely to attack this position than the hydroxide. 

A similar picture holds for other nucleophiles. As a consequence, there might seem little hope for a nucleophile-based reactivity relationship. Indeed this has been implicitly recognized in the popularity of Pearson s concept of hard and soft acids and bases, which provides a qualitative rationalization of, for example, the similar orders of reactivities of halide ions as both nucleophiles and leaving groups in (Sn2) substitution reactions, without attempting a quantitative analysis. Surprisingly, however, despite the failure of rate-equilibrium relationships, correlations between reactivities of nucleophiles, that is, comparisons of rates of reactions for one carbocation with those of another, are strikingly successful. In other words, correlations exist between rate constants and rate constants where correlations between rate and equilibrium constants fail. 

We are going to look at these compounds briefly here. Pyrimidine is more important than either of the others because of its involvement in DNA and RNA—you will find this in Chapter 49. All three compounds are very weak bases—hardly basic at all in fact. Pyridazine is slightly more basic than the other two because the two adjacent lone pairs repel each other and make the molecule more nucleophilic (the a effect again see p. 588 of Chapter 23). 

Table 3-1 Some hard and soft acids (electrophiles) and bases (nucleophiles) Bases (Nucleophiles) Acids (Electrophiles)...

Nucleophiles with two sites that could react with electrophiles are called ambident nucleophiles. The Hard and Soft Acids and Bases (HSAB) principle applies because a hard electrophile reacts at the harder nucleophilic site and a soft electrophile at the softer nucleophilic site. For instance, the sulfenate ion 70 is an ambident nucleophile, because it reacts (a) with methyl fluorosulfonate, a hard electrophile, at the oxygen atom, where most of the negative charge is concentrated, to give the sulfenate ester 71 and (b) with methyl iodide, a soft electrophile, to give the sulfoxide 72. Sulfur atom is the softer of the two nucleophilic sites available in the sulfenate ion and, furthermore, it is rendered more nucleophilic by the a-effect arising from the adjacent oxygen atom. 

The HSAB theory of Pearson has been one of the key organizing concepts in the study of nucleophiles. This theory is applied and examined in Chapters 15 and 16. In Chapter 15, Fuji applies the HSAB principles to design nucleophilic reagents for cleaving C-X bonds. Fuji notes that all bonds are made of a combination of Lewis acid and Lewis base and have hard-soft dissymmetry for the typical C-X bond, the carbon is a soft acid and the X is a hard base. Thus, in accord with the HSAB principles, a soft base (the nucleophile) and a hard acid are required to cleave this bond selectively. Applying these ideas, Fuji then shows the utility of several soft base-hard acid reagents for cleaving various C-X bonds in complex molecules. 

The electrophiles or electrophilic intermediates that are or are postulated to be responsible for the carcinogenic action of chemicals include (i) positively charged carbonium, nitrenium, oxonium and episulfonium ions, (ii) free radicals, (iii) polarized double bonds, (iv) aldehydes, (v) strained rings such as epoxide, aziridine, lactones and sultones, and (vi) quinone/ quinoid/quinoneimine structures. Based on their reactivity (Table I), electrophiles may be graded from "soft" to "hard" similar to the concept of "soft" and "hard" acids and bases (18). In general, soft electrophiles react preferentially with soft nucleophiles whereas hard electrophiles react preferentially with hard nucleophiles. Thus, since the nucleophilic sites in the purine and pyrimidine bases in DNA are moderately hard nucleophiles, moderately hard electrophiles tend to have the greatest likelihood of covalent binding to DNA. Soft electrophiles often deplete the cellular pool of noncritical soft nucleophiles (such as GSH) before they can react with DNA. 

These equilibrium constants provide a measure of thermodynamic basicity, but we also need to have some concept of kinetic basicity. For the reactions in Scheme 4.3, for example, it is important to be able to generalize about the rates of competing reactions. The most useful qualitative approach for making predictions is the hard-soft-acid-base (HSAB) concept (see Section 1.1.6), which proposes that reactions occur most readily between species that are matched in hardness and softness. Hard nucleophiles prefer hard electrophiles, whereas soft nucleophiles prefer soft electrophiles. 

Turning to the good correlations of the actual scales, one may see that the highest order of CFD scheme, i.e., the spectral-like resolution chemical hardness-based aromaticity index is in best agreement with HOMA aromaticity, while the simpler scheme, i.e., the electrophi-licity-nucleophilicity chemical hardness gap (3.362), based aromaticity index A c correlating with REPE aromaticity. Both of these fits... 

Unsaturated sugars are useful synthetic intermediates (11). The most commonly used are the so-called glycals (1,5- or 1,4-anhydroalditol-l-enes). In the presence of a Lewis-acid catalyst, 3,4,6-tri-0-acetyl-l,5-anhydro-2-deoxy-D-arabinohex-l-enitol [2873-29-2] commonly called D-glucal triacetate, adds nucleophiles in both kineticaHy controlled and thermodynamically controlled (soft bases predominately at C-3 and hard bases primarily at C-1) reactions (11,13). 

Nucleophilic catalysis is also observed with iodide ions. Fluoride ion does not form nitrosyl fluoride under diazotization conditions, as is to be expected from Pearson s hard and soft acids and bases principle which was discussed briefly in Section 3.2. More recently, nucleophilic catalysis has also been shown to occur with thiocyanate ion (SCN ), thiosulfate ion (HS2Of), dimethyl sulfide, and thiourea (H2NCSNH2) or its alkyl derivatives (see below). 

Hammett equation(s) 78, 93, 148ff., 151 f., 153ff., 167f., 190, 193, 196, 297, 299, 308, 312, 375, 381, 392, see also Dual substituent parameter, and Quantitative structure-reactivity relationships Hammond postulate, in additions of nucleophiles to diazonium ions 157 Hard and soft acids/bases principle (Pearson) 49, 54, 109... 

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