Nucleophilic addition reaction acid catalysis

This is a further example of a carbonyl-electrophile complex, and equivalent to the conjugate acid, so that the subsequent nucleophilic addition reaction parallels that in hemiacetal formation. Loss of the leaving group occurs first in an SNl-like process with the cation stabilized by the neighbouring oxygen an SN2-like process would be inhibited sterically. It is also possible to rationalize why base catalysis does not work. Base would simply remove a proton from the hydroxyl to initiate hemiacetal decomposition back to the aldehyde - what is needed is to transform the hydroxyl into a leaving group (see Section 6.1.4), hence the requirement for protonation. 

In the remainder of this chapter, well look at specific examples nucleophilic addition reactions. In so doing, well be concerned both wl the reversibility of a given reaction and with the acid or base catalysis of that reaction. Some nucleophilic addition reactions take place reversibl) and some do not. Some occur without catalysis, but many others require acid or base to proceed. 

In the nucleophilic addition reactions of amines to substituted aromatic aldehydes where acid catalysis is required, the use of EAN seems to be convenient. The EAN can take part in an acid-base equilibrium with the aromatic aldehydes substituted by electron-withdrawing groups. The imine products from the selected aldehydes could be obtained, confirming the dual behaviour of EAN as Brbnsted acid and potential nucleophile in these type of processes (Fig. 13.7). 

Many of the most interesting and useful reactions of aldehydes and ketones involve trans formation of the initial product of nucleophilic addition to some other substance under the reaction conditions An example is the reaction of aldehydes with alcohols under con ditions of acid catalysis The expected product of nucleophilic addition of the alcohol to the carbonyl group is called a hemiacetal The product actually isolated however cor responds to reaction of one mole of the aldehyde with two moles of alcohol to give gem mal diethers known as acetals... 

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

Chromanoxylium cation 4 preferably adds nucleophiles in 8a-position producing 8a-substituted tocopherones 6, similar in structure to those obtained by radical recombination between C-8a of chromanoxyl 2 and coreacting radicals (Fig. 6.4). Addition of a hydroxyl ion to 4, for instance, results in a 8a-hydroxy-tocopherone, which in a subsequent step gives the /zara-tocopherylquinone (7), the main (and in most cases, the only) product of two-electron oxidation of tocopherol in aqueous media. A second interesting reaction of chromanoxylium cation 4 is the loss of aproton at C-5a, producing the o-QM 3. This reaction is mostly carried out starting from tocopherones 6 or /zora-tocopherylquinone (7) under acidic catalysis, so that chromanoxylium 4 is produced in the first step, followed by proton elimination from C-5a. In the overall reaction of a tocopherone 6, a [ 1,4] -elimination has occurred. The central species in the oxidation chemistry of a-tocopherol is the o-QM 3, which is discussed in detail subsequently. 

Acids that have weakly nucleophilic anions, e.g. HS04e from dilute aqueous H2S04, are chosen as catalysts, so that their anions will offer little competition to H20 any R0S03H formed will in any case be hydrolysed to ROH under the conditions of the reaction. Rearrangement of the carbocationic intermediate may take place, and electrophilic addition of it to as yet unprotonated alkene is also known (p. 185). The reaction is used on the large scale to convert cracked petroleum alkene fractions to alcohols by vapour phase hydration with steam over heterogeneous acid catalysts. Also under acid catalysis, ROH may be added to alkenes to yield ethers, and RCOzH to yield esters. 

For these and similar reactions recently a variety of Lewis acidic aluminium, rare earth metals, and titanium alkoxides have been applied. Alkoxides have the additional advantage that they can be made as enantiomers using asymmetric alcohols which opens the possibility of asymmetric catalysis. Examples of asymmetric alcohols are bis-naphtols, menthol, tartaric acid derivatives [28], Other reactions comprise activation of aldehydes towards a large number of nucleophiles, addition of nucleophiles to enones, ketones, etc. 

An interesting bifunctional system with a combination of In(OTf)3 and benzoyl-quinine 65 was developed in p-lactam formation reaction from ketenes and an imino ester by Lectka [Eq. (13.40)]. High diastrereo- and enantioselectivity as well as high chemical yield were produced with the bifunctional catalysis. In the absence of the Lewis acid, polymerization of the acid chloride and imino ester occurred, and product yield was moderate. It was proposed that quinine activates ketenes (generated from acyl chloride in the presence of proton sponge) as a nucleophile to generate an enolate, while indium activates the imino ester, which favors the desired addition reaction (66) ... 

Keywords Absolute configuration, Amines, Amino acids, Carbenes, Cascade reactions, 2-chloro-2-cyclopropylideneacetates. Combinatorial libraries. Cycloadditions, Cyclobutenes, Cyclopropanes, Diels-Alder reactions. Heterocycles, Michael additions. Nitrones, Nucleophilic substitutions, Peptidomimetics, Palladium catalysis. Polycycles, Solid phase synthesis, Spiro compounds. Thiols... 

The Mukaiyama Reaction. The Mukaiyama reaction refers to Lewis acid-catalyzed aldol addition reactions of enol derivatives. The initial examples involved silyl enol ethers.40 Silyl enol ethers do not react with aldehydes because the silyl enol ether is not a strong enough nucleophile. However, Lewis acids do cause reaction to occur by activating the ketone. The simplest mechanistic formulation of the Lewis acid catalysis is that complexation occurs at the carbonyl oxygen, activating the carbonyl group to nucleophilic attack. 

The hydrogen-bond complex 5 and ion pair 6 are activated form of the carbonyl compounds. The nucleophilic addihon of carbon nucleophile to carbonyl compounds and imines may be accelerated by acid catalysis. Nucleophilic attack to carbonyl compounds or imine took place either by way of 5 or 6 to furnish addihon product. If HX activates carbonyl compound by forming hydrogen-bond complex 5 and nucleophilic addition takes place to give an adduct, the reaction is a hydro-gen-bond catalyzed reaction (Scheme 2.5). In contrast, when ion pair 6 is formed and nucleophilic addihon occurs, the reachon is a Br0nsted-acid-catalyzed reachon. 

An alternative method for dialkyl peroxide synthesis is the nucleophilic addition of an alkyl hydroperoxide to an alkene under acid catalysis reported by Davies and coworkers (Scheme 31, path B) ". A similar reaction is the nucleophilic addition of alkylhy-droperoxides to vinyl ethers under acid catalysis, producing perketals. Perketals can be deprotected under mild conditions (THF/water/acetic acid) and this hydroperoxide protection-deprotection sequence has been used by Dussault and Porter as a means for the resolution of racemic hydroperoxides (see also Section II.A.2) . In this respect more detailed studies were carried out with the perketals 75, which were prepared via reaction of alkyl hydroperoxides with vinyl ethers (Scheme 33). Weissermel and Lederer reported that in the presence of teri-butyl hypochlorite, a-chlorodialkyl peroxides can be formed in yields between 12% and 45% (Scheme 31, path C)". a-Alkoxydialkyl peroxides and diperoxyacetals were prepared by Rieche and coworkers via acid catalyzed reaction of one or two equivalents of alkyl hydroperoxides with acetals, ketals or aldehydes (Scheme 31, path D)" or by methylation of the corresponding a-alkoxy hydroperoxides with diazomethane (yields 11%, 27%)" . The diperoxyacetals 76 were isolated in yields ranging from 39 to 77%. 

Nucleophilic addition to C=0 (contd.) ammonia derivs., 219 base catalysis, 204, 207, 212, 216, 226 benzoin condensation, 231 bisulphite anion, 207, 213 Cannizzaro reaction, 216 carbanions, 221-234 Claisen ester condensation, 229 Claisen-Schmidt reaction, 226 conjugate, 200, 213 cyanide ion, 212 Dieckmann reaction, 230 electronic effects in, 205, 208, 226 electrons, 217 Grignard reagents, 221, 235 halide ion, 214 hydration, 207 hydride ion, 214 hydrogen bonding in, 204, 209 in carboxylic derivs., 236-244 intermediates in, 50, 219 intramolecular, 217, 232 irreversible, 215, 222 Knoevenagel reaction, 228 Lewis acids in, 204, 222 Meerwein-Ponndorf reaction, 215 MejSiCN, 213 nitroalkanes, 226 Perkin reaction, 227 pH and, 204, 208, 219 protection, 211... 

There are an extremely large number of reactions of 2-oxetanones with nucleophilic reagents, and space will allow inclusion of only representative examples. /3-Lactones show the interesting Bal.2 mechanism for base-catalyzed hydrolysis and the Aal2 mechanism for acid-catalyzed hydrolysis, according to data on kinetics and optical rotation studies of optically active lactones. The mechanistic interpretations are complicated, however, by the possibilities for subsequent elimination and addition reactions to occur, so that both of the two sites for nucleophilic attack on the 0-lactone skeleton, C-2 and C-4, may become involved. In fact 0-lactones are unusually insensitive to base, as well as acid, catalysis, the slow reaction with neutral water predominating between pH 1 and 9 (74JCS(P2)377). 

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