Reactions self aldol condensation

When a normal carbonyl compound is treated with catalytic acid or base, we have a small proportion of reactive enol or enolate in the presence of large amounts of unenolized electrophile. Aldol reaction (self-condensation) occurs. With 1,3-dicarbonyl compounds we have a small proportion of not particularly reactive unenolized compound in the presence of large amounts of stable (and hence unreactive) enol. No aldol occurs. 

Aldol reactions. Self-condensation of aldehydes as well as Robinson annulation are effected. The latter process is conducted in the presence of molecular sieves 4A in aprotic solvents such as toluene. 

Pseudoionones are produced commercially by the aldol condensation of citral and acetone catalyzed by aqueous or ethanolic solutions of bases. However, these liquid catalysts have potential problems related to undesirable side reactions (self-condensation of citral and secondary reactions of pseudoionones), catalyst separation and disposal (the catalyst caimot be reused and causes serious damage to the environment) as well as purification steps, which are laborious and costly [268]. These homogeneous processes also require a large excess of acetone, typically 10-20 moles per mole of citral, for a satisfactory yield, and a large and costly plant is needed for commercial production. 

The aldol-like self-condensation of acetyl chloride in the presence of AICI3 gives the Al-chelate of acetoacetyl chloride (467). Reaction of this with thiophene-2-carboxylic acid chloride gives (469) in 72% yield via (468) <92JCS(Pl)2985>. Use of malonyl chloride instead of acetylchloride gives (471) (78%) via (470). 

The conversion of 21 to 24 is a self-condensation because butanal forms an enolate that reacts with another molecule of butanal. This means that two identical molecules are joined together in the product. Mild acid workup simply protonates the alkoxide unit in 24 to give the aldol, 22. Self-condensation is also possible with symmetrical ketones such as 3-pentanone. In a selfcondensation, one is tempted to ask where the second molecule of 21 comes from. Remember that structure 21 represents one molar equivalent 1 mol of molecules) because this is an equilibrium reaction, both 21 and enolate anion 23 will be present, so unreacted 21 is available to react with 23. After one half-life (Chapter 7, Section 7.11.3), the solution will contain 21, enolate anion 23, and 24. Therefore, as 24 is formed by the reaction, there is still plenty of 21 available for reaction. 

In practice this reaction is difficult to carry out with simple aldehydes and ketones because aldol condensation competes with alkylation Furthermore it is not always possi ble to limit the reaction to the introduction of a single alkyl group The most successful alkylation procedures use p diketones as starting materials Because they are relatively acidic p diketones can be converted quantitatively to their enolate ions by weak bases and do not self condense Ideally the alkyl halide should be a methyl or primary alkyl halide... 

Ba.se Catalyzed. Depending on the nature of the hydrocarbon groups attached to the carbonyl, ketones can either undergo self-condensation, or condense with other activated reagents, in the presence of base. Name reactions which describe these conditions include the aldol reaction, the Darzens-Claisen condensation, the Claisen-Schmidt condensation, and the Michael reaction. 

Examples include acetaldehyde, CH CHO paraldehyde, (CH CHO) glyoxal, OCH—CHO and furfural. The reaction is usually kept on the acid side to minimize aldol formation. Furfural resins, however, are prepared with alkaline catalysts because furfural self-condenses under acid conditions to form a gel. 

Thus, various kmds of bases are effective in inducing the Henry reaction The choice of base and solvent is not crucial to carry out the Henry reaction of simple nitroalkanes v/ith aldehydes, as summarized in Table 3 1 In general, sterically hindered carbonyl or nitro compounds are less reactive not to give the desired ni tro-aldol products in good yield In such cases, self-condensation of the carbonyl compound is a serious side-reaction Several mochfied procedures for the Henry reaction have been developed... 

Trost s group reported direct catalytic enantioselective aldol reaction of unmodified ketones using dinuclear Zn complex 21 [Eq. (13.10)]. This reaction is noteworthy because products from linear aliphatic aldehydes were also obtained in reasonable chemical yields and enantioselectivity, in addition to secondary and tertiary alkyl-substituted aldehydes. Primary alkyl-substituted aldehydes are normally problematic substrates for direct aldol reaction because self-aldol condensation of the aldehydes complicates the reaction. Bifunctional Zn catalysis 22 was proposed, in which one Zn atom acts as a Lewis acid to activate an aldehyde and the other Zn-alkoxide acts as a Bronsted base to generate a Zn-enolate. The... 

Figure 1. Kinetic parameters for the selection of antibody-catalyzed aldol and retro-aldol reactions, reflecting the biocatalyst s ability to accept substrates that differ clearly with respect to their molecular geometry. No background reaction was observed for the self-condensation of cyclopentanone. The indicated value for cyclopentanone addition to pentanal was estimated using the published kuncat value of 2.28 X 10 M s for the aldol addition of acetone to an aldehyde. Reproduced with permission of the authors and the American Association for the Advancement of Science.

When self-condensation of one of the reactants competes with the desired inter-molecular reaction, such as, 2A C and A + B E, where E is the desired product, it is obvious that the rate of the second reaction is improved by increasing the availability (or solubility) of B in a solvent. The principle has been demonstrated with a cross aldol condensation reaction, as shown in Scheme 17 109). 

Several cross-aldol condensations have been performed with alkaline earth metal oxides, including MgO, as a base catalyst. A general limitation of the cross-aldol condensation reactions is the formation of byproducts via the self-condensation of the carbonyl compounds, resulting in low selectivities for the cross-aldol condensation product. For example, the cross-condensation of heptanal with benzalde-hyde, which leads to jasminaldehyde (a-K-amylcinnamaldehyde), with a violet scent... 

In this proper sense, aldol condensation includes reactions producing j3-hydroxyaldehydes or j3-hydroxyketones by self-condensation or mixed condensation of aldehydes and ketones these reactions are, in fact, additions of a C—H bond activated by the carbonyl to the C=0 bond of the other molecule, viz. 

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 effect of the basicity of aldol condensation catalysts on their activity was thoroughly investigated by Malinowski et al. [372—379]. The observed linear dependence of the rate coefficients of several condensation reactions on the amount of sodium hydroxide contained in silica gel (Figs. 12 and 13) supported the view that the basic properties of this type of catalyst were actually the cause of its catalytic activity, though the alkali-free catalyst was not completely inactive. The amphoteric nature of the catalysis by silica gel, which can act also as an acid catalyst, was demonstrated [380]. By a stepwise addition of sodium acetate to a HN03-pretreated silica gel catalyst the original activity for acetaldehyde self-condensation was decreased to a minimum (when an equivalent amount of the base was added) by further addition of sodium acetate, the activity increased again because of the transition to a base... 

Aldol condensations.1 Under usual conditions, 1 is not useful for crossed-aldol condensation because of predominant self-condensation. However in the presence of pyridine and acetic acid 1 undergoes aldol condensation with aromatic and a,p-unsaturated aldehydes. Yields are moderate to high if the concentration of 1 is kept low (inverse addition). This reaction can be used to obtain all-trans-19,19,19- and 20,20,20-trifluororetinal (2). 

Mixed aldol reactions may be broadly classified as the reaction between two different aldehydes or ketones, or the reaction of an aldehyde with a ketone. Apart from the concomitant self-condensation, not less than two possible crossed products can be envisaged. Such reactions are therefore only prepara-tively useful either if appropriate structural conditions are present, or if certain experimental conditions are used to effect a directed aldol condensation. 

Disconnection 37 again uses the natural polarity of the carbonyl group but at the next bond 37 since we hope to use some enolate derivative 38 in an alkylation reaction. But—and it is a big but—do not think for a moment that you can make 37 just by mixing the ketone 39 with an alkyl halide and some base. The problem is that the ketone is itself electrophilic and the self-condensation by the aldol reaction (chapter 19) is generally preferred to alkylation. 

Most of the examples in this chapter have been of molecules without selectivity. They have indeed all been self condensations. We hope this has established the basic disconnections and the chemistry but we must now turn to examples where selectivity is needed. So the ketone 46 was made to study aldol reactions with aromatic aldehydes.13 They found that, in acid or base, the enone 52 was the main product with the best yield from HCI in EtOH. The product 52 was isolated as its HCI salt. In this case it is easy to see that only the ketone can enolise, that the aldehyde is more electrophilic than the ketone and that the geometrical isomer shown is the more stable. Such considerations are the substance of the next chapter. 

They are useful for ketones too. Disconnection of the enone 99 reveals an aldol reaction between cyclopentanone 74 and the enolisable ketone 100. Control is needed solely to prevent self-condensation of the aldehyde. 

---