Water-based reactions conjugated synthesis

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Michael Addition. The Michael reaction is a typical base-catalyzed reaction used in organic chemistry to form a C—C bond. It is usually a consecutive side reaction accompanying the base-catalyzed synthesis of a, -unsaturated ketones, aldehydes, nitriles, or carbo lic acid derivatives. The reaction between an Q ,)S-unsaturated compoimd and an activated methylene compoimd is known as the Michael addition Scheme 9. The reaction is the nucleophilic addition of a car-banion intermediate to the ft carbon of the C—C double bond in the conjugated system (49) without releasing a water molecule. The carbanion is provided by the activated methylene compoimd, and contrarily to the Knoevenagel condensation the product retains the substituents of both reactant molecules. 

The use of base-catalysed reactions for the template synthesis of co-ordinated, often macrocyclic ligands was discussed in the introduction to this chapter. " Chromium(m) Complexes.—Studies of the base hydrolysis of chromium(ra) complexes at high pH are relatively rare, probably because of the ease with which polymeric hydroxy-complexes can be precipitated. Studies of aqua-chromium(m) complexes even at low pH invariably show that conjugate-base formation is important owing to the acidity of the co-ordinated water molecules. Conjugate-base formation is apparent when the observed pseudo-first-order rate constant, k, varies with acidity according to the equation A =A o+ -x/[H+]. Recent examples include studies of the [Cr(HaO)6(NHs) + and [Cr(ox)2(N3)(H20)]2- ions." ... 

The El reaction, here called dehydration because it results in the loss of a molecule of water (Figure 9-1, breaking bonds b and c see also Sections 9-3 and 9-7), is one of the methods for the synthesis of alkenes (Section 11-7). Rather than the nncleophilic acids HBr and HI, so called because the conjugate base is a good nucleophile, nonnucleophihc acids, such as H3PO4 or H2SO4, are employed. 

Note that the synthesis of this terminal alkyne requires a total of rAree equivalents of base. The double dehydrohalogenation itself requires two equivalents. However, a third equivalent is required because, as the alkyne forms, its acidic hydrogen atom reacts with the amide ion to convert the alkyne to its conjugate base. Without the extra equivalent of amide ion, the reaction would not go to completion. The water in the workup step acts as an acid to protonate the alkynide and to convert any excess amide ion to ammonia. 

Now, let s draw out the forward scheme. This multi-step synthesis uses three equivalents of ethylene (labeled A, B, C in the scheme below) and one equivalent of acetic acid (labeled D). Ethylene (A) is converted to 1,2-dibromoethane upon treatment with bromine. Subsequent reaction with excess sodium amide produces an acetylide anion which is then treated with bromoethane [made tfom ethylene (B) and HBr] to produce 1-butyne. Deprotonation with sodium amide, followed by reaction with an epoxide [prepared by epoxidation of ethylene (C)] and water workup, produces a compound with an alkyne group and an alcohol group. Reduction of the alkyne to the cis alkene is accomplished with H2 and Lindlar s catalyst, after which the alcohol is converted to a tosylate with tosyl chloride. Reaction with the conjugate base of acetic acid [produced by treating acetic acid (D) with NaOH] allows for an Sn2 reaction, thus yielding the desired product, Z-hexenyl acetate. 

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