Aldol addition reaction mechanism

Note also the stereochemistry. In some cases, two new stereogenic centers are formed. The hydroxyl group and any C(2) substituent on the enolate can be in a syn or anti relationship. For many aldol addition reactions, the stereochemical outcome of the reaction can be predicted and analyzed on the basis of the detailed mechanism of the reaction. Entry 1 is a mixed ketone-aldehyde aldol addition carried out by kinetic formation of the less-substituted ketone enolate. Entries 2 to 4 are similar reactions but with more highly substituted reactants. Entries 5 and 6 involve boron enolates, which are discussed in Section 2.1.2.2. Entry 7 shows the formation of a boron enolate of an amide reactions of this type are considered in Section 2.1.3. Entries 8 to 10 show titanium, tin, and zirconium enolates and are discussed in Section 2.1.2.3. 

Antibody Catalysis. Recent advances in biocatalysis have led to the generation of catalytic antibodies exhibiting aldolase activity by Lemer and Barbas. The antibody-catalyzed aldol addition reactions display remarkable enantioselectivity and substrate scope [18]. The requisite antibodies were produced through the process of reactive immunization wherein antibodies were raised against a [Tdiketone hapten. During the selection process, the presence of a suitably oriented lysine leads to the condensation of the -amine with the hapten. The formation of enaminone at the active site results in a molecular imprint that leads to the production of antibodies that function as aldol catalysts via a lysine-dependent class I aldolase mechanism (Eq. 8B2.12). 

Mikami has carried out a number of investigations aimed at elucidating mechanistic aspects of this Si-atom transfer process. In particular, when the aldol addition reaction was conducted with a 1 1 mixture of enoxysilanes 60 and 62, differentiated by the nature of the 0-alkyl and 0-silyl moieties, only the adducts of intramolecular silyl-group transfer 63 and 64 are obtained (Scheme 8B2.6). This observation in addition to results obtained with substituted enol silanes have led Mikami to postulate a silatropic ene-like mechanism involving a cyclic, closed transition-state structure organized around the silyl group (Scheme 8B2.6). 

A-7. Write out the mechanism, using curved arrows to show electron movement, of the following aldol addition reaction. 

The mechanisms for metal-catalyzed and organocatalyzed direct aldol addition reactions differ one from another, and resemble the mode of action of the type 11 and type I aldolases, respectively. Some metal-ligand complexes, for example, 1-4 and 9 are considered to have a bifunctional character [22], embodying within the same molecular frame a Lewis acidic site and a Bronsted basic site. Whereas base would be required to form the transient enolate species as an active form of the carbonyl donor, the Lewis acid site would coordinate the acceptor aldehyde carbonyl, increasing its electrophilicity. By this means, both transition state stabilization and substrates preorganization would be provided (see Scheme 5 for a proposal). 

Scheme 7. Proposed enamine mechanism of the proline-catalyzed direct aldol addition reaction of acetone [25].

The aldol addition reaction is one of the most versatile carbon-carbon bond forming processes available to synthetic chemists. The addition reaction involves readily accessed starting materials and can provide )9-hydroxy carbonyl adducts possessing up to two new stereocenters. The previous decade witnessed many substantive advances in the crossed aldol addition reaction as a result of the development of a variety of well-defined enolization protocols and the evolution of highly sophisticated understanding of the reaction mechanism. Moreover, the design of highly effective chiral auxiliary-based systems has allowed for impressive levels of stereocontrol in a number of asymmetric aldol processes. 

In contrast to the mechanism discussed in the previous section, catalytic, enantioselective aldol addition processes have been described which proceed through an intermediate aldolate that undergoes subsequent intermolecular silylation. Denmark has discussed this possibility in a study of the triarylmethyl-cation-catalyzed Mukaiyama aldol reaction (Scheme 10) [73]. The results of exploratory experiments suggested that it would be possible to develop a competent catalytic, enantioselective Lewis-acid mediated process even when strongly Lewis acidic silyl species are generated transiently in the reaction mixture. A system of this type is viable only if the rate of silylation of the metal aldolate is faster than the rate of the competing silyl-catalyzed aldol addition reaction (ksj>> ksi-aidoi Scheme 10). A report by Chen on the enantioselective aldol addition reaction catalyzed by optically active triaryl cations provides support for the mechanistic conclusions of the Denmark study [74]. 

Advances in the development of metal-catalyzed Mukaiyama aldol addition reactions have primarily relied on a mechanistic construct in which the role of the Lewis acidic metal complex is to activate the electrophilic partner towards addition by the enol silane. Alternate mechanisms that rely on metallation of enol silane to generate reactive enolates also serve as an important construct for the design of new catalytic aldol addition processes. In pioneering studies, Bergman and Heathcock documented that transition-metal enolates add to aldehydes and that the resulting metallated adducts undergo silylation by the enol silane leading to catalyst turnover. 

Aldolases are a group of C—C bond forming enzymes with widespread applications. The stereoselective aldol addition reaction catalyzed by aldolases represents an attractive alternative to conventional chiral organic chemistry methods for chemical and pharmaceutical industries. Aldolases are classified according to both their proposed catalytic mechanism and the structure of the donor substrate, their sources and microbial production processes being presented in this chapter. To design appropriate bioreactors for aldol synthesis, the characteristics of aldolase biocatalysts obtained after purification procedures in free and immobilized form are discussed. 

Dehydration of an aldol addition product leads to a conjugated a,)8-unsaturated carbonyl system. The overall process is called an aldol condensation, and the product can be called an enal (alk e < /dehyde) or enone (alk e kem ), depending on the carbonyl group in the product. The stability of the conjugated enal or enone system means that the dehydration equilibrium is essentially irreversible. For example, the aldol addition reaction that leads to 3-hydroxybutanal, shown in Section 19.4, dehydrates on heating to form 2-butenal. A mechanism for the dehydration is shown here. 

The product exhibits both an aldehydic group and a hydroxyl group, and it is therefore called an aldol aid for aldehyde and ol for alcohol ). In recognition of the type of product formed, the reaction is called an aldol addition reaction. Notice that the hydroxyl group is located specifically at the P position relative to the carbonyl group. The product of an aldol addition reaction is always a P-hydroxy aldehyde or ketone (Mechanism 22.4). 

The best way to draw the product of an aldol addition reaction is to consider the mechanism. In the first step, the a position of the aldehyde is deprotonated to form an enolate. 

The mechanism for an aldol condensation has two parts (Mechanism 22.6). The first part is just an aldol addition reaction, which has three mechanistic steps. The second part has two steps that accomplish the elimination of water. Normally, alcohols do not undergo dehydration in the presence of a strong base, but here, the presence of the carbonyl group enables the dehydration reaction to occur. The a position is first deprotonated to form an enolate ion, followed by expulsion of a hydroxide ion to produce a,p unsaturation. This two-step process, which is different from the elimination reactions we saw in Chapter 8, is called an Elcb mechanism. In an Elcb mechanism, the leaving group only leaves after deprotonation occurs. 

Denmark SE, Eklov BM, Yao PJ, Eastgate MD (2009) On the mechanism of lewis base catalyzed aldol addition reactions kinetic and spectroscopic investigations using rapid-injection NMR. J Am Chem Soc 131 11770-11787... 

The large number of research programs aimed at the syntheses of steroids produced a phenomenal wealth of reaction methods for organic synthesis. The development of the asymmetric proline-catalyzed Robinson annulation reaction for the preparation of the Wieland-Miescher ketone (36, Equation 3) in the early 1970s [41] is noteworthy and marks an important milestone for catalysis by small organic molecules. Asymmetric amine-catalyzed aldol reactions represent an additional variant of the stereoselective aldol addition reaction. The mechanism of the proline-catalyzed aldol addition reaction has been the subject of extensive debate, but the general consensus, based on recent mechanistic studies and quantum mechanical calculations, supports the notion of the involvement of a single amino acid molecule in the transition state structure (39, Scheme 4.4) [42]. 

List [86] and Jorgensen [87] have recently independently described a novel application of L-proline (107) for catalysis of enantioselective hydrazidation of aldehydes [88]. For example, when aldehyde 106 is allowed to react with di-tert-butyl azodicarboxylate (95) in the presence of 10 mol% 107, adduct 108 is isolated in > 90% yield and 93% ee (Scheme 10.18) [87]. The product hydra-zides can be transformed into protected amino acid derivatives through a sequence that involves oxidation of the aldehyde to the corresponding carboxylic acid, esterification, deprotection, and N-N bond cleavage with Raney-Ni [86, 87]. The observed selectivity has been attributed to the intervention of transition state 111 [86]. This structure incorporates a hydrogen bond between proline s carboxyl group and the azodicarboxylate as a key organizing feature. The transition state structure has parallels to that proposed for the proline-cata-lyzed aldol addition reactions and is supported by quantum mechanical studies by Houk [89]. 

These examples indicate that the (Z)-syn,(E)-antt correlation should be considered to be a rule with many exceptions. Two explanations may be given in order to rationalize the manifold stereochemical results in aldol additions. Firstly, it seems plausible that the many different reaction conditions and starting materials (e.g., various types of enolates, counterions, etc.) may cause the aldol addition to follow different reaction mechanisms, so that different types of transition states are involved. Secondly, in a single type of transition state model, the reactants may have different orientations to each other, so that the formation of different stereoisomers may result even for one and the same transition state model. 

Base-induced eliminative ring fission, in which both the double bond and the sulfone function take part, has been observed in thiete dioxides253. The reaction can be rationalized in terms of initial Michael-type addition to the double bond of the ring vinyl sulfone, followed by a reverse aldol condensation with ring opening. The isolation of the ether 270c in the treatment of 6c with potassium ethoxide (since the transformation 267 -> 268 is not possible in this case) is in agreement with the reaction mechanism outlined in equation 101253. 

Another example of a [4S+1C] cycloaddition process is found in the reaction of alkenylcarbene complexes and lithium enolates derived from alkynyl methyl ketones. In Sect. 2.6.4.9 it was described how, in general, lithium enolates react with alkenylcarbene complexes to produce [3C+2S] cycloadducts. However, when the reaction is performed using lithium enolates derived from alkynyl methyl ketones and the temperature is raised to 65 °C, a new formal [4s+lcj cy-clopentenone derivative is formed [79] (Scheme 38). The mechanism proposed for this transformation supposes the formation of the [3C+2S] cycloadducts as depicted in Scheme 32 (see Sect. 2.6.4.9). This intermediate evolves through a retro-aldol-type reaction followed by an intramolecular Michael addition of the allyllithium to the ynone moiety to give the final cyclopentenone derivatives after hydrolysis. The role of the pentacarbonyltungsten fragment seems to be crucial for the outcome of this reaction, as experiments carried out with isolated intermediates in the absence of tungsten complexes do not afford the [4S+1C] cycloadducts (Scheme 38). 

Efforts were made by Garcia Gonzalez and his coworkers to elucidate the mechanism of this reaction. In one of the working hypotheses, it was considered that the aldehydo form of the sugar and the 1,3-dicarbonyl compound undergo an aldol reaction to yield a 2-C-(alditol-l-yl)-l,3-dicar-bonyl compound, which is then dehydrated to form the furan. This hypothesis was supported by the isolation of the aldol-addition product of... 

The general mechanistic features of the aldol addition and condensation reactions of aldehydes and ketones were discussed in Section 7.7 of Part A, where these general mechanisms can be reviewed. That mechanistic discussion pertains to reactions occurring in hydroxylic solvents and under thermodynamic control. These conditions are useful for the preparation of aldehyde dimers (aldols) and certain a,(3-unsaturated aldehydes and ketones. For example, the mixed condensation of aromatic aldehydes with aliphatic aldehydes and ketones is often done under these conditions. The conjugation in the (3-aryl enones provides a driving force for the elimination step. 

In order to gain further insight into the reaction mechanism, the indicated oxygen-tethered keto-enone was subjected to basic hydrogenation conditions under 1 atmos. elemental deuterium. Deuterium incorporation is observed at the former enone / -position exclusively. In addition to mono-deuterated material (81% composition), doubly-deuterated (8% composition) and non-deuterated materials (11% composition) are observed. These data suggest reversible hydro-metallation in the case of keto-enone substrates. Consistent with the mechanism depicted in Scheme 22.4, deuterium is not incorporated at the a-position of the aldol product [24b] (Scheme 22.5). 

Lithium Enolates. The control of mixed aldol additions between aldehydes and ketones that present several possible sites for enolization is a challenging problem. Such reactions are normally carried out by complete conversion of the carbonyl compound that is to serve as the nucleophile to an enolate, silyl enol ether, or imine anion. The reactive nucleophile is then allowed to react with the second reaction component. As long as the addition step is faster than proton transfer, or other mechanisms of interconversion of the nucleophilic and electrophilic components, the adduct will have the desired... 

A plausible mechanism involves the reaction of the dihydride precursor with t-butylethylene to the 14-e complex [Ir(C6H3-2,6 CH2P-f-Bu2 2)]> which undergoes the oxidative-addition reaction of the alcohol to afford a hydride alkoxide complex. Further /i-hydride ehmination gives the alde-hyde/ketone and regenerates the dihydride active species [55]. In the particular case of 2,5-hexanediol as the substrate, the product is the cycHc ketone 3-methyl-2-cyclopenten-l-one. The formation of this ketone involves the oxidation of both OH groups to 2,5-hexanedione followed by an internal aldol reaction and further oxidation as in the final step of a Robinson annotation reaction [56]. 

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