Acid catalysts aldol condensations

In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

A mechanistically similar example is the Cannizzaro reaction, which is in essence a disproportionation between two aldehydes lacking a-hydrogen with a parallel addition of water to yield an alcohol and a carboxylic acid [144]. Aldol condensation cannot take place since the a-hydrogen is absent. Most likely the formation of aldehydrates takes place in the zeolite pores. NaX and NaY have been reported to be successful catalysts [150]. 

A number of methods that utilize enolsilanes directly in the aldol process with either aldehydes or acetals have been developed recently. These reactions are usually performed either in the presence of Lewis acids such as titanium tetrachloride (67) or with fluoride ion (68). Recently trimethylsilyl triflate (CF3S03SiMe3) was found to be an efficient acid catalyst for condensation... 

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]. 

An organocatalytic (j0rgensen-Hayashi catalyst 1) domino Micliael/Michael/aldol condensation was used to prepare a hexahydronaphtlialenone (+)-121 m route to the natural product (+)-galbulin (Scheme 7.22). In this case, it was proposed that an iminium salt 118 (activated from the re face) and an enamine species 117 were preformed. Following a kinetic asymmetric transformation (KAT) of the racemic precursor 115, the intermediate 119 is first formed through an intermolecular Michael reaction. A second intramolecular Michael reaction occurs and the intermediate 120 forms, and finally an acid-initiated aldol condensation... 

In contrast to phase-transfer catalytic allgrlation, aldol reactions are somewhat less common because it is difficult to control more than one concurrently generated stereocentre, and the retroaldol reaction leads to low chemical yields. In 1991, the first catalytic asymmetric synthesis of P-hydrmg -a-amino acids via aldol condensation under PTC reaction conditions in the presence of catalyst 7a was reported by the Miller group. The moderately optically enriched diastereomeric aldol adducts 77 obtained from heptanal and 5 were derivatised to 78 (Scheme 16.23). °... 

Boron trifluoride is a highly moisture-sensitive gas (31). It is utilized in esterification, ether formation, Friedel-Crafts alkylation and acylation, and Lewis acid-catalyzed Diels-Alder reactions. A more widely used, easy-to-handle and convenient liquid source of BF3 is boron trifluoride etherate [BF3-0(C2H5)2] (32). Its main usage as catalyst is in the direct esterification of all types of acids, rearrangements, aldol condensation, and Lewis acid-catalyzed Diels-Alder reactions. It is the most frequently used acid in epoxide ring opening and rearrangement (33). 

The most widely used catalysts for acid-catalyzed aldol condensations are the molecular sieve zeolites, for example, crystalline aluminosilicates of group I and II elements, in which the latter have been replaced by protons. The surface protons confer Br0nsted acidity. Among the acidic zeolites we can mention HZSM-5 (pentasil zeolite), HY (faujasite), or HM (mordenite). Recently, polystyrene-supported sulfonic acids such as those of the macroreticular strongly acidic cation-exchange resins (59) and acid-base functionalized mesoporous materials such as amine and sulfonic acid-containing SBA-15 (60) have been shown to promote the acid-catalyzed aldol condensation of aldehydes with ketones at low temperatures. 

The acid-catalyzed aldol condensation of acetone is probably the most studied reaction of this type. As shown in Scheme 2, self-condensation of acetone yields a number of different products depending on the operating conditions and catalyst used. In particular, on acidic catalysts, the products are mainly aliphatic and aromatic hydrocarbons. A summary of the product distribution as a function of the reaction temperature on acidic zeolites can be found in Ref (65). 

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. ... 

In an intramolecular case, it was shown that, in an aqueous medium, the nature of the acidic or basic catalyst had a dramatic effect on the outcome of the aldolisation (Denmark and Lee, 1992). Acid-induced aldol condensation of ketoaldehyde 1 provided the syn hydroxyketone 2, while the anti isomer 3 arose from base-catalyzed reactions ... 

Entry 4 in Scheme 2.1 depicts an acid-catalyzed aldol condensation with dehydration. In entry 5, the Lewis acid catalyst aluminum tri-rerf-butoxide is used in place of a proton donor. 

Reaction of one mole of acetaldehyde and excess phenol in the presence of a mineral acid catalyst gives l,l-bis(p-hydroxyphenyl)ethane [2081-08-5], acid catalysts, acetaldehyde, and three moles or less of phenol yield soluble resins. Hardenable resins are difficult to produce by alkaline condensation of acetaldehyde and phenol because the acetaldehyde tends to undergo aldol condensation and self-resinification (see Phenolic resins). 

Lithium Iodide. Lithium iodide [10377-51 -2/, Lil, is the most difficult lithium halide to prepare and has few appHcations. Aqueous solutions of the salt can be prepared by carehil neutralization of hydroiodic acid with lithium carbonate or lithium hydroxide. Concentration of the aqueous solution leads successively to the trihydrate [7790-22-9] dihydrate [17023-25-5] and monohydrate [17023-24 ] which melt congmendy at 75, 79, and 130°C, respectively. The anhydrous salt can be obtained by carehil removal of water under vacuum, but because of the strong tendency to oxidize and eliminate iodine which occurs on heating the salt ia air, it is often prepared from reactions of lithium metal or lithium hydride with iodine ia organic solvents. The salt is extremely soluble ia water (62.6 wt % at 25°C) (59) and the solutions have extremely low vapor pressures (60). Lithium iodide is used as an electrolyte ia selected lithium battery appHcations, where it is formed in situ from reaction of lithium metal with iodine. It can also be a component of low melting molten salts and as a catalyst ia aldol condensations. 

Citral reacts in an aldol condensation using excess acetone and a basic catalyst, usually sodium hydroxide. The excess acetone can be recovered for recycle. The resulting intermediate pseudoionone [141-10-6] (83) after cyclization with phosphoric acid gives predominantly a-ionone [127-41 -3] (84), which is the isomer commercially important in flavors and fragrances. A hydrocarbon solvent is generally necessary in order to get high yields. P-Ionone [14901-07-6] (85) is the predominant isomer if sulfuric acid is used as the catalyst but lower temperature than that for cyclization to a-ionone is required. y-Ionone [79-6-5] (86) is also produced. 

Neo acids are prepared from selected olefins using carbon monoxide and acid catalyst (4) (see Carboxylic Acids, trialkylacetic acids). 2-EthyIhexanoic acid is manufactured by an aldol condensation of butyraldehyde followed by an oxidation of the resulting aldehyde (5). Isopalmitic acid [4669-02-7] is probably made by an aldol reaction of octanal. 

Examples of commercially applied solid base catalysts are much fewer than for solid acids. Nevertheless, much attention is currently focused on the development of novel solid base catalysts for classical organic reactions such as aldol condensations, Michael additions, and Knoevenagel condensations, to name but a few. 

As in the case of homogeneous acids as catalyst, we would also benefit from using solid ba.ses instead of dissolved bases as catalyst. A number of industrially important reactions are carried out with bases as catalyst. A well know example is the aldol condensation of acetone to diacetone alcohol, where dissolved NaOH in ethyl alcohol is u.sed as a catalyst at about 200 to 300 ppm level. However, heterogeneous pelleted sodamide can be used as a catalyst for this reaction and it obviates the problem of alkali removal from the product, which would otherwise lead to reversion of diacetone alcohol to acetone during distillation of the product mixture. 

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). 

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

This possible mechanism should be evaluated in relation to the catalysts. If the catalytic action is to be ascribed to the acid character of the catalysts, the condensation under consideration may differ from the ordinary aldol condensation, which is catalyzed preferentially by basic agents. Nevertheless, many condensations of the aldol type are effected with the aid of acidic reagents. Moreover, the condensation of sugars with dicarbonyl compounds has been carried out in aqueous alcoholic media which are non-acidic hence, there also exists the possibility of a mechanism catalyzed simultaneously by acid and by base, somewhat like that suggested by Lowry46 in another connection. A transition state with an amphiprotic structure has been postulated. Its formation can be catalyzed by either acids or bases. 

This aldol condensation is assumed to proceed via nucleophilic addition of a ruthenium enolate intermediate to the corresponding carbonyl compound, followed by protonation of the resultant alkoxide with the G-H acidic starting nitrile, hence regenerating the catalyst and releasing the aldol adduct, which can easily dehydrate to afford the desired a,/3-unsaturated nitriles 157 in almost quantitative yields. Another example of this reaction type was reported by Lin and co-workers,352 whereas an application to solid-phase synthesis with polymer-supported nitriles has been published only recently.353... 

Figure 6. Synthesis of 9-0-acetyl-N-acetylneuraminic acid. The aldol acceptor was prepared from N-acetylmannosamine and isopropenyl acetate in DMF catalyzed by protease N obtained from Amano. The aldol condensation was carried out by using N-acetylneuraminic acid aldolase as catalyst.

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