Bimolecular aldol reactions

We have also examined the use of cyclodextrin-derived artificial enzymes in promoting bimolecular aldol reactions, specifically those of m-nitrobenzaldehyde (57) and ofp-t-butylbenzaldehyde (58) with acetone [141]. Here, we examined a group of mono-substituted cyclodextrins as catalysts (e.g. 59), as well as two disubstituted (3-cyclodextrins (e.g. 60) (10 catalysts in all). They all bound the aldehyde components in the cyclodextrin cavity and used amino groups of the substituents to convert the acetone into its enamine. An intracomplex reaction with 58 and hydrolysis of the enamine product then afforded hydroxyketone 61 (cf. 62). These catalysts imitate natural enzymes classified as Class I aldolases. 

BIMOLECULAR ASSOCIATIVE AND SUBSTITUTION PROCESSES 16. Aldol reactions continued... 

The base-catalysed Aldol reaction is shown in Equation 3.11 [3, 4], and a mechanism to account for the global process in Scheme 3.1. At low concentrations of acetaldehyde, reverse of the proton-abstraction steps is fast compared with the forward bimolecular enolate capture (k [CH3CHO] <rate limiting. Under these conditions, the kinetics are second order in [CH3CHO] and show specific base catalysis, i.e. the reaction is first order in [HCY ] and, even though B is involved in the mechanism, it does not appear in the rate law [5]. According to this mechanism, therefore, the overall rate law is given by Equation 3.12 ... 

Reymond and Chen88 have investigated the same set of antibodies for their ability to catalyze bimolecular aldol condensation reactions. The antibodies were assayed individually at pH 8.0 for the formation of aldol 111 from aldehyde 109 and acetone. None catalyzed the direct reaction, but in the presence of amine 110 three anti-52a and three anti-52b antibodies showed modest activity. In analogy with natural type I aldolase enzymes, the reaction is believed to occur by formation of an enamine from acetone and the amine, followed by rate-determining condensation of the enamine with the aldehyde. As in the previous example, the catalyst, which was characterized in detail, is not very efficient in absolute terms ( cat = 3 x 10-6 s 1 for the anti-52b antibody 72D4), but it is approximately 600 times more effective than amine alone. Moreover, the reactions with the antibody are stereoselective The enamine adds only to the si face of the aldehyde to give... 

Although attempts to catalyze bimolecular aldol condensations without resorting to enamine chemistry have not yet been successful, the Schultz group92 has prepared an antibody against the phosphinate hapten 115 that catalyzes the retro aldol reaction of 116 (kcJKm = 125 M-1 s l). The equilibrium in this case strongly disfavors the condensation product, and a histidine induced in response to the phosphinate may be involved in catalysis. Interestingly and in contrast to the previous examples, the stereoselectivity of the antibody is modest. The syn diastereomer of 116 was found to be the better substrate for the antibody by 2 1 over the anti diastereomer, but no evidence of enantioselectivity was observed. 

Metal oxides that have adjacent cations with coordination vacancies in certain common surface planes, like some Ti02 and ZnO surfaces, can catalyze ketoniz-ation. This suggests that a bimolecular surface reaction is rate determining. However, not all such catalysts are very selective for ketonization, especially at high conversion. Kuriacose and co-workers proposed a mechanism based on the condensation of two adsorbed carboxylates, or a carboxylate and a less ionic species, following an aldol condensation-type pathway (Scheme The aldol-... 

By far the most important activating group in synthesis is the carbonyl group. Removal of a proton from the a-carbon atom of a carbonyl compound with base gives the corresponding enolate anion. It is these enolate anions that are involved in many reactions of carbonyl compounds, such as the aldol eondensation, and in bimolecular nucleophilie displacements (alkylations, as depieted in Scheme 1.2). 

It is generally accepted that acid aldol condensations proceed bimolecularly between an activated carbonyl molecule adsorbed on a Br0nsted acid site and a mobile species and that formation of enols is involved in the reaction sequence. However, the way these species form and their nature, for example, surface or gas-phase species or the extent of the proton transfer in the activated molecule, is still a matter of controversy. 

If the concentration of acetaldehyde is high, the rate of the bimolecular reaction is faster (rate = 7[enolate] [acetaldehyde]), and acetaldehyde is not re-formed from the enolate. Under these conditions, it is the formation of the enolate that is the slow step in the reaction, the rate-determining step (p. 350). If the concentration of acetaldehyde is low, the enolate is reconverted to acetaldehyde, and in D2O this reversal results in exchange. When exchanged acetaldehyde goes on to form aldol, the product also contains deuterium attached to carbon. At low acetaldehyde concentrations it is the addition step itself that is the slower one, and therefore the ratedetermining step. 

We recall that the conjugate base of an aldehyde must react with the aldehyde, which is present in a significantly greater concentration, to make an aldol condensation possible. A similar condensation reaction, called the Claisen condensatioii, occurs when low concentrations of ester enolates react with esters (Section 22.15). If an ester reacts vdth a very strong base, such as hthium diisopro-pylamide (LDA), high concentrations of the ester enolate form, and no ester would remain for a bimolecular self-condensation reaction. The ester enolate yield is stoichiometric when LDA is used as the base because diisopropylamine is a much weaker acid than an ester. Furthermore, LDA is a sterically hindered nucleophile, so it does not react with the electroplulic carbon atom of the ester. 

We recall that intramolecular aldol condensation reactions can occur to give five- or six-membered ring compounds (Section 22.9). An intramolecular Claisen condensation, known as the Dieckmann condensation, can also occur to give five- or six-membered ring compounds. The Dieckmann condensation is more favorable than the bimolecular Claisen condensation because it converts a single molecule of reactant into two molecules of product. 

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