Acid-catalysed aldol condensation

For acid-catalysed aldol condensations (which are less frequent), the homogeneous mechanism [371] can again be accepted. The enol form of the hydrogen donor interacts with the protonated form of the hydrogen acceptor, viz. 

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). 

The most important side reaction in heterogeneously catalysed MPVO reactions is the acid-catalysed aldol condensation. Aldol products are usually observed during the Oppenauer oxidation of alcohols, when a surplus of ketone or aldehyde is used as the oxidizing agent and the solvent. The low amount of by-products formed when Ti-beta was used as the catalyst, demonstrates the advantage of the titanium system over Al-beta. This is probably caused by the much weaker Brpnsted acidity of the solvated titanium site [8] compared with the strong H -acidity of the aluminium site in Al-beta. As we have shown earlier Ti-beta has a high tolerance towards water, which further shows the catalytic potential of Ti-beta in MPVO reactions [9]. 

The isomeric 2-deoxy-2-C-methyl-pentonic acids (34) have been prepared by Lewis acid-catalysed aldol condensation of the thioester silyl ketene acetal (35) with 2,3-di-O-benzyl-D-glyceraldehyde either epimer can be obtained as the major product depending on the precise experimental procedure adopted. 

Use of quinine as catalyst induces chirality in the aldol condensation shown in Scheme (98) partial kinetic resolution of the starting material is observed when the reaction is stopped before completion. The acid-catalysed aldol condensation of ketones with their enol ethers has been reported. ... 

Examples are reactions initiated by the protonation, as for example carbenium ion formation from — for example—olefins (Bronsted acidic centres) or deprotonation reactions like base-catalysed aldol condensation. 

Mammals produce sialic acid by aldolic condensation of phosphoenolpyruvate and Ai-acetylmannosamine 6-phosphate (reaction 12.1). A kinase enzyme catalyses the phosphorylation of A -acetylmannosamine and a phosphatase catalyses the hydrolysis of the phosphate of sialic acid. These phosphorylation and dephosphorylation steps are irreversible, such that the synthesis can be total even with low concentrations of the substrate. A variation of reaction (12.1), observed with the bacterium Neisseria meningitidis, uses non-phosphated /-acetylmannosamine. However, these were not the enzymes used in the preparative synthesis, which used instead a microbial aldolase which catalyses equilibrium (12.2). This enzyme probably plays a catabolic role in these organisms, but it functions in the synthetic sense in the presence of an excess of pyruvate. 

The biosynthesis of the aromatic amino acids proceeds via shikimic acid. [56] The starting point is erythrose-4-phosphate, which is produced in the Calvin cycle. The enzyme-catalysed aldol condensation with phosphoenol pyruvate leads to a heptulose, 3-deoxy-(D)-arahino-heptulonic add 7-phosphate. Elimination of phosphate produces an enol, which is converted hy a further aldol condensation into 3-dehydroquinic acid. Elimination of water and reduction then yield shikimic add. 

Hydroformylation of oct-l-ene is catalysed by [M( -C6H5)(CO)2]2 (activity M = Fecyclopentadienyl ring is displaced. Basic aqueous alcoholic solutions of Ru3(CO)i2 catalyse the hydroformylation of pent-l-ene to n-hexanal (selectivity=97%) unfortunately the basic reaction medium also catalyses aldol condensation. Ruthenium compounds, e.g. Ru(acac>3, in the presence of iodide and acid promoters, also catalyse the reactions. ... 

Chain Extension. - Aldolase-catalysed aldol condensation reactions used in the synthesis of sialic acids and aza-sugars have been reviewed (38 refs.). Addition of 2-thiazolyl reagents to the nitrone 2, available from the D-galacto-dialdose 1, featured in syntheses of destomic acid 3 and... 

An investigation of the structure of threitol, which includes n.nLr. studies, is referred to in Charter 22 (section 3.9). The (/2)-stereocheniistry at C-5 of the 7-deoxy-4-heptulose 2, obtained in an enzyme-catalysed aldol condensation (see Chapter 2) has been ascertained by extensive n.nu . experiments, especially n.O.e. studies." The stmaural properties of the alkali metal salts of D-gluconic acid in the crystalline state and in solution have been examined by F.t.i.r. and "C-n.mjr. spectroscopy."... 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

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). 

Diastereomeric excesses of up 56% have been claimed for the preparation of a-amino-P-hydroxy acids via the aldol condensation of aldehydes with f-butyl N-(diphenylmethylene)glycinate [63]. It might be expected that there would be thermodynamic control of the C-C bond formation influenced by the steric requirements of the substituents, but the use of cinchoninium and cinchonidinium salts lead to essentially the same diastereoselectivity. The failure of both tetra-n-butylammo-nium and benzyltriethylammonium chloride to catalyse the reaction is curious. 

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. 

For the preparation of a-ionone, citral and acetone are reacted in an aldol condensation catalysed by a base to form so-called pseudo-ionone (Scheme 13.2). The pseudo-ionone can be cyclised to form a-ionone catalysed by an acid. 

Aldol condensation reaction may be either acid or base catalysed. However, base catalysis is more common. The product of this reaction is called an aldol, i.e. aid from aldehyde and ol from alcohol. The product is either a P-hydroxyaldehyde or P-hydroxyketone, depending on the starting material. For example, two acetaldehyde (ethanal) molecules condense together in the presence of an aqueous base (NaOH), to produce 3-hydroxybutanal (a P-hydroxyaldehyde). 

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 reaction is very slow in acetic acid alone, and accelerated as acetate by the addition of bases [59]. These two isomers undergo Pd-catalysed allylic rearrangement with each other. 3-Acetoxy-l,7-octadiene (139) is converted to the allylic alcohol 157 and to the enone 158, which is used as a bisannulation reagent [60], Thus Michael addition of 158 to 2-methylcyclopentanedione (159) and aldol condensation give 160. The terminal alkene is oxidized using PdCl2/CuCl/02 to the methyl ketone 161. After reduction of the double bond in 161, aldol condensation affords the tricyclic system 162. 

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,... 

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. 

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