Aldol reaction acid-catalysed

The aldol condensation of acetone to diacetone alcohol is the first step in a three-step process in the traditional method for the production of methyl isobutyl ketone (MIBK). This reaction is catalysed by aqueous NaOH in the liquid phase. (3) The second step involves the acid catalysed dehydration of diacetone alcohol (DAA) to mesityl oxide (MO) by H2S04 at 373 K. Finally the MO is hydrogenated to MIBK using Cu or Ni catalysts at 288 - 473 K and 3- 10 bar (3). 

Many of the enone substrates used in polyamino acid-catalysed epoxidation reactions can be made via a simple aldol condensation, which leads directly to the desired enone after in situ dehydration. Enones that cannot be synthesised by the above route may often be synthesised using standard Wittig chemistry, (Scheme 6). The above methods of substrate synthesis provide compounds with a variety of groups R and enabling the incorporation of both aliphatic and aromatic moieties into the enone structure. 

A similar aldol reaction is encountered in the Krebs cycle in the reaction of acetyl-CoA and oxaloacetic acid (see Section 15.3). This yields citric acid, and is catalysed by the enzyme citrate synthase. This intermediate provides the alternative terminology for the Krebs cycle, namely the citric acid cycle. The aldol reaction is easily rationalized, with acetyl-CoA providing an enolate anion nucleophile that adds to the carbonyl of oxaloacetic acid. We shall see later that esters and thioesters can also be converted into enolate anions (see Section 10.7). 

Aldol condensations were originally carried out in the liquid phase and catalysed homogeneously by acids or bases this way of operation is still predominant. Solid-catalysed aldol reactions can also be performed in the liquid phase (in trickle or submerged beds of catalyst), but in many cases vapour phase systems are preferred the factors determining the choice are the boiling points and the stability of the reactants at elevated temperatures. At higher temperatures, the formation of a, j3-unsaturated aldehydes or ketones [reactions (B) and (C)] is preferred to aldol (ketol) formation [reaction (A)]. A side reaction, which may become important in some cases, is the self-condensation of the more reactive carbonyl compound if a mixed condensation of two different aldehydes or ketones is occurring. The Cannizzaro reaction of some aldehydes or polymerisation to polyols or other resin-like products can also accompany the main reaction. 

The Cannizzaro reaction, that is, the base-catalysed disproportionation of a carbonyl compound to an alcohol and a carboxylic acid, has gained some importance as an economically viable alternative to the reduction with borohydrides. However, the reaction is restricted to carbonyl compounds without any a-hydrogen, which do not undergo competing aldol reactions. Thus, mainly aromatic aldehydes are used for this kind of transformation. The protocols developed for microwave applications typically involve solvent-free conditions using alumina as the solid support. Under these conditions, a significant acceleration of the reaction was achieved. 

Formyl hydrogen bonds, in which die C—H bond of a formyl group acts as an acceptor (typically to oxygen), have recently been identified in Lewis acid-catalysed reactions of aldehydes.523 An X-ray crystal structure of such a complex has been reported.5213 This type of hydrogen bond is now suggested as a likely organizing stereochemical element in a variety of enantioselective aldol, allylation, and Diels-Alder reactions catalysed by Lewis acids reported in the literature.520 Further examples of such reactions are also discussed.53... 

The CD-spiroacetal subunit of the spongistatins proved to be of an appropriate level of complexity that several different synthetic strategies were evaluated. Access to the desired spiroacetal 5 was readily achieved by acid catalysed equilibration of the mixture of spiroacetals in aprotic solvents, followed by separation and recycling of the undesired isomer. Furthermore, the 1,5-anti aldol reaction of methyl ketones proved invaluable for construction of certain portions of the target molecule. 

In a reaction which is mechanistically related to the Skraup reaction an a,/ -unsaturated carbonyl compound, generated by way of an acid-catalysed aldol condensation, reacts with a primary aromatic amine in the presence of acid to yield a quinoline derivative (Doebner-Miller reaction). For example, when aniline is heated with paraldehyde (which depolymerises to acetaldehyde during the reaction) in the presence of hydrochloric acid the final product is 2-methyl-quinoline (101) (quinaldine, Expt 8.40). Retrosynthetic analysis for the 1,2-dihydroquinoline reveals crotonaldedhyde as the unsaturated carbonyl component which is in turn formed from acetaldehyde (see Section 5.18.2, p. 799). 

Small peptides - simple di- and tri-peptides with a primary amine at the N-terminus -catalyse the aqueous aldol between unmodified ketones and aldehydes with up to 86% ee.121 This is dramatically different from the corresponding amino acid-catalysed reaction, suggesting that peptide formation may have been significant in the evolution of asymmetric synthesis. Addition of a-cyclodextrin raised the ee further through the hydrophobic effect. 

Diketone (72) undergoes an acid-catalysed Michael-aldol reaction to give tricyclic ketone (73).205... 

The presence of H3 0+ or HO may alter drastically the observed reaction rate either because they catalyse the reaction (acid or base catalysis, see Section 3.2.3 for the Aldol reaction, and Chapter 11) or because of ionic strength effects. Proper pH control in an aqueous solution will require a buffer system which is described by the appropriate version of the Henderson-Hasselbach equation, according to whether the acid or base is the charged species ... 

Fig. 24 (a, b) Chemo-enzymatic process for synthesis of tetrahydroxylated pyrrolizidines 1-epi-alexine, australine and 3-epi-australine utilising dihydroxyacetone phosphate (DHAP), stereospecific aldol reaction catalysed by fructose-1.6-diphosphate aldolase (FDPA) and acid phosphatase (Pase) [149]... 

A variety of Brpnsted acid sources - benzoic acid, silica gel, 3 A molecular sieves - catalyse vinylogous aldol reactions of O-silyl dienolates, under solvent-free conditions.140... 

Dihydropyran-4-ones are formed with good enantiomeric excess by a chiral Lewis acid catalysed reaction of aldehydes with Danishefsky s diene and cyclisation of the initial aldol product. The overal process equates to a hetero-Diels-Alder cycloaddition (95JOC5998). Lactams also react with the electron rich diene under the influence of a Lewis acid, yielding 7-aza-l-oxaspiroalkenones (95JOC7724). 

The observation by Corey again raises the question under which conditions a hetero Diels-Alder or a two-step aldol reaction takes place especially when using silyloxybutadienes. Thus, in several studies a clear structure determination of the intermediate cycloadducts was not performed, being directly transformed into the final pyrone by an acid-catalysed reaction. Under these conditions also a primarily formed aldol-adduct would yield the isolated pyrones. 

Primary amine catalysis (usually involving a lysine residue) has been recognised to play an important role in various enzyme-catalysed reactions. Examples are the conversion of acetoacetate to acetone catalysed by acetoacetate decarboxylase, the condensation of two molecules of S-aminolevulinic acid catalysed by -aminolevulinic deshydratase during the biosynthesis of porphyrins, and the reversible aldol condensation of dihydroxy-acetone phosphate with glyceraldehyde which in the presence of aldolase yields fructose-1-phosphate (64) (For reviews see, for example, Snell and Di Mari,... 

The elimination is even easier in acid solution and acid-catalysed aldol reactions commonly give unsaturated products instead of aldols. In this simple example with a symmetrical cyclic ketone, the enone is formed in good yield in acid or base. We shall use the acid-catalysed reaction to illustrate the mechanism. First the ketone is enolized under acid catalysis as you saw in Chapter 21. 

Then the aldol reaction takes place. Enols are less nucleophilic than enolates, and the reaction occurs because the electrophilic carbonyl component is protonated the addition is acid-catalysed. An acid-catalysed aldol reaction takes place. 

Acid-catalysed aldol reactions may give the aldol product, but usually give the enone or enal by an El mechanism... 

A simple example from the first report of this reaction by Gilbert Stork and his group in 1974 is the condensation of pentan-2-one with butanal to give the aldol and then the enone oct-4-en-3-one by acid-catalysed dehydration. The yields may seem disappointing, but this was the first time anyone had carried out a crossed aldol reaction like this with an unsymmetrical ketone and an enolizable aldehyde and got just one aldol product in any reasonable yield at all. 

Acylations of ketone enols with anhydrides are catalysed by Lewis acids such as BF3, This process will remind you of Friedel-Crafts acylation but a better analogy is perhaps the aldol reaction where metals such as lithium hold the reagents together so that reaction can occur around a six-membered ring. 

The mechanism obviously involves attack by the enol (or boron enolate ) of the ketone on the anhydride, catalysed by the Lewis acid. Probably BF3 or BF2 groups (fluoride can come and go from boron easily) hold the reagent together at all times, much like lithium in the aldol reaction (p. 698). 

The reaction of salicylaldehydes with a,P-unsaturated compounds which can lead to chromenes, chromans and other heterocycles has been reviewed <07OBC1499> and details of their reaction with allenic esters and ketones have been published <07CEJ3701>. A proline-catalysed benzoic acid-promoted asymmetric synthesis of chromene-3-carbaldehydes involves a domino oxa-Michael - aldol reaction with a,P-unsaturated aldehydes the ee range is 83-98% (Scheme 11) <07CEJ574>. 

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