Organica

Hard/ soft acid/ base (HSAB) theory has been applied to many chemical reactions usually not classified as acid/base reactions, in an attempt to predict product distributions. Care should be exercised in nontrivial cases, but this approach may be of value in predicting the likelihood of a number of reactions in a synthetic plan. Several examples are illustrated below.
SUBSTITUTION. Saville showedthat nucleophilic displacement of alkyl halides can be characterized by HSAB theory. In general, the reaction works best when the R group and nucleophile partner are matched. The two major categories are:
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When R-C has a greater differential in hardness and softness, the reaction proceeds best. Table 2.6 shows that chloromethane is harder than iodomethane. Therefore, a hard base such asmethoxide will show a larger energy difference for iodomethane, which should react faster.
Ethoxide and malonate are about equal in basicity, but ethoxide is a much harder base than malonate. Reaction with 2-bromopropane and ethoxide gives primarily elimination, but malonate gives the substitution product (2.22). In general, hard bases give elimination and soft bases substitution. The contraiónhas a profound influence on this reaction. Reaction of 1-bromo-2-chloroethane with 2.23 gives only elimination (to bromo or chloromethane, leaving behind the neutral substrate 2.24), but the chloromagnesium salt (2.25) leads to nucleophilic displacement and formation of 2.26 after a second displacement by the enamine formed in the first substitution.
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EPOXIDATION. Peroxyacids such as 2.27contain an unusual soft-hard combination which leads to attack by a soft alkene (a soft base) on the soft oxygen of the peroxyacid.
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CARBONYLS. The carbon of a carbonyl is a hard acceptor and the oxygen is a hard donor.
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An example is 2.28 which reacts with the soft thiophenoxide (PhS-) at the tosylate center (C-OTs) to give 2.29. Reaction of 2.28 with the harder cyanide, however,gives 2.30, and subsequent ring closure generates 2.31.
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The soft base (thiophenoxide) reacts with the soft acid (CH2OTs), whereas the hard base (cyanide) reacts with the hard acid (the carbonyl). Reductive hydrogenolysis of α-bromoketones (2.32) by sodium borohydride is an example. The soft base (hydride) reacts with the carbonyl oxygen (reacting as a soft acid in this case), expellingthe halide (a soft base). The reaction works best when the metal (M+) is a soft acid. The sodium counterion in sodium borohydride is a hard acid and unacceptable. A soft acid such as copper or lead, however, will facilitate the reduction. The reduction with metal borohydrides will be discussed in chap. 4.
Conjugate reduction of α,β-unsaturades ketones can also be explained by HSAB theory. Theβ-carbon of a conjugated ketone (2.33) is softer than the carbonyl. A covalent M-H reagent such as hydride is soft, and lithium aluminum hydride reduction of cyclohexenone leads to 22% of conjugate reduction. Conversely, lithium trimethoxyaluminum hydride suppresses the soft conjugate addition, since the alkyl groups are hard. Only 5% of conjugate addition is ibserved in this case. The presence of analkyl group increases the softness of the borohydride. Sodium borohydride give mainly 1,2 addition, but potassium tri-sec-butylborohydride gives mainly 1,4 reduction. The B-H bond is more covalent than Al-H, and borohydrides are softer than aluminum hydrides. This accounts for the relative inertness of BH4- to the hard acid H+. Softer cations such as Na+ favor 1,4 reduction, and NaBH4 gives more1,4 reduction than LiBH4.
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Reaction of enones with organometallics also follows this pattern. Dialkyl cuprates (with the soft copper) are soft and give primarily 1,4 addition. When organolithiums (with the hard Li.) react with enones, the major products rises from 1,2 addition. The hardness of common organometallics follows the order
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The alkyl portion also plays an important...