Nucleophilic bases softness

The thermodynamic tendency of a substance to act as a Lewis base. The strength of a Lewis base depends on the nature of the acid with which the Lewis base forms a Lewis adduct. Hence, comparative measures of Lewis basicities are given by equilibrium constants for the formation of the adducts by a common reference acid. See Lewis Base Nucleophilicity Hard Bases Soft Bases Donor Number... 

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. 

It is appropriate at this point to summarize the tendency of various nucleophiles to add to the carbonyl group. In general, the strong bases (organometallics, hydrides, negative ions) are most effective among the neutral nucleophiles, the soft ones, for example the sulfur bases, tend to be more effective in addition than the hard ones, for example the oxygen bases. 

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. 

The properties of dimethyl carbonate, (MeO)2CO, as an ambident electrophile have been investigated by analysis of the products of its reaction with various nucleophiles having different hard-soft character. Results were in good agreement with the Hard-Soft Acid-Base theory, hard nucleophiles attacking the hard C=0 group and soft nucleophiles the soft Me group (Scheme ll).37... 

Figure 3.5 Solvent shells surround hard bases rendering them less reactive nucleophiles than soft bases.

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

General base catalysis of the Sn2 reaction is not generally observed, for various reasons. Amine nucleophiles do not need it, and hydroxy groups are very weakly nucleophilic towards soft, polarisable centers like sp -carbon. The only well-authenticated example of an intermolecular general base catalyzed nucleophilic displacement at sp -hybridized carbon is the trifluoroethanolysis of the benzylsul-... 

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. 

The asymmetric conjugate addition of sulfur-based nucleophiles to Michael acceptors has been achieved using enantiomerically pure metal-based catalysts and organocatalysts. Sulfur nucleophiles are soft, and preferentially react by conjugate addition with a, p-unsaturated carbonyl compounds. Only catalytic amounts of the lithium thiolate (11.65) are required, since addition to the enone (11.66) generates the enolate (11.67). The enolate is then able to deprotonate thiol (11.68), regenerating thiolate (11.65) with formation of the product (11.69). 

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). 

Nonaqueous Bases Nonaqueous Nucleophiles Organometallic Catalytic Reduction Acidic Reduction Basic or Neutral Reduction Hydride Reduction Lewis Acids Soft Acids Radical Addition Oxidizing Agents... 

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