Nucleophiles hard/soft nucleophile concept

According to the concept of the hard-soft acid base, the carbon is considered more nucleophilic than the oxygen, thus more likely to react than the oxygen atom because the leaving... 

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. 

Carbon - heteroatom bonds can be cleaved by an appropriate combination of a hard acid and a soft nucleophile. Synthetically useful selective C-0 bond cleavage in the presence of other C-0 bond(s) is described. Reductive dehalogenation of a-haloketones is presented as an example that illustrates the concept of hard-soft affinity inversion. Finally, regio- and stereoselective functionalization of 1,3-di-enes is demonstrated by the thienium cation Diels-Alder cyclization involving the C-S bond cleavage. 

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. 

To the extent that the N+ correlation is successful it means that the pattern of nucleophilic reactivity is not influenced by the nature of the electrophilic center at which substitution takes place. On the other hand, according to the concepts of the theory of hard and soft acids and bases (HSAB) as applied to nucleophilic substitution reactions (Pearson and Songstad, 1967) one would expect that a significant change in the HSAB character of the electrophilic center as an acid should lead to changes in the pattern of nucleophilic reactivity observed. Specifically, in substitutions occurring at soft electrophilic centers, soft-base nucleophiles should be more reactive relative to other nucleophiles than they are in substitutions at harder electrophilic centers, and in substitutions at hard electrophilic centers hard-base nucleophiles should appear relatively more reactive compared to other nucleophiles than they do in substitutions at softer electrophilic centers. 

Pyridones are normally resistant to nucleophilic attack at ring carbon atoms, but the pyrones react rather readily. There is a useful correlation between the position of attack and the hardness or softness of the nucleophile, and the situation for the pyrones is summarized in Schemes 12 and 13. Representative transformations illustrating these concepts are shown in equations (45)-(51). ANRORC reactions are also very common and examples are given in equations (52)—(55). 

Nucleophilic Displacement of Halogens at Saturated Carbon Atoms Box 13.1 The Concept of Hard and Soft Lewis Acids and Bases (HSAB) Illustrative Example 13.2 Some More Reactions Involving Methyl Bromide Illustrative Example 13.3 1,2-Dibromoethane in the Hypolimnion of the Lower Mystic Lake, Massachusetts Polyhalogenated Alkanes — Elimination Mechanisms... 

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. 

Richard, the Marcus analysis, allied to the concept imbalance of bond making and charge development at the transition state, has provided an effective framework for tackling one of the outstanding problems for a general interpretation of reactivity. A reasonable conclusion might be that further measurements of equilibrium constants will be required to support and test the level of understanding achieved so far, and to probe more deeply the interpretation of hard and soft nucleophilicity in its application to reactions of electrophilic carbon atoms. 

The energy of the HOMO (EHomo) is directly related to the ionization potential and characterizes the susceptibility of the molecule to attack by electrophiles. On the other hand, EHOMO is directly related to the electron affinity and characterizes the susceptibility of the molecule toward attack by nucleophiles. Both the E, IOMO and LUMO energies are important in radical reactions. The concept of hard and soft nucleophiles and electrophiles has... 

The concept of soft and hard acids and bases (7), which is in effect an extension of the Chatt-Ahrland classification (2) of A and B metals, is applied in the 1963 paper by Pearson (7) particularly to equilibria involving mainly inorganic systems. This paper follows an earlier discussion by Edwards and Pearson (3) of the Swain-Edwards equation (4) (1) for nucleophilic reactivity. 

Taking into account the fact that the solvation of ambident anions in the activated complex may differ considerably from that of the free anion, another explanation for the solvent effect on orientation, based on the concept of hard and soft acids and bases (HSAB) [275] (see also Section 3.3.2), seems preferable [366]. In ambident anions, the less electronegative and more polarizable donor atom is usually the softer base, whereas the more electronegative atom is a hard Lewis base. Thus, in enolate ions, the oxygen atom is hard and the carbon atom is soft, in the thiocyanate ion the nitrogen atom is hard and the sulfur atom is soft, etc. The mode of reaction can be predicted from the hardness or softness of the electrophile. In protic solvents, the two nucleophilic sites in the ambident anion must interact with two electrophiles, the protic solvent and the substrate RX, of which the protic solvent is a hard and RX a soft acid. Therefore, in protic solvents it is to be expected that the softer of the two nucleophilic atoms (C versus O, N versus O, S versus N) should react with the softer acid RX. 

Systematic exploitation of the different susceptibilities of the different positions of perfluoroaromatic compounds can be used as a tool for combinatorial synthesis of (fluoro)aromatic compounds. The feasibility of this concept was recently demonstrated by R. D. Chambers and coworkers who used the pentafluoropyridine system as an example [99] (Scheme 2.43). Further differentiation of the reactivity toward hard and soft nucleophiles was achieved by partial replacement of fluorine by bromine in this system. 

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