The aldol reaction

The Aldol reaction (Equation 4.15) is an important synthetic prototype mentioned in Chapter 3 [16, 17]  

The final proton transfer will be extremely fast, so the rate of formation of product is effectively shown in Equation 4.16, i.e. the rate of the addition of the enolate anion to another molecule of aldehyde  

however, is not a legitimate rate law as it includes the concentration of an intermediate. We need to be able to express the concentration of the enolate in terms of the concentrations of acetaldehyde and the bases present. 

Substituting the SSA concentration of CH2CHO into Equation 4.16, the reaction rate is now given by Equation 4.17  

The aldol reaction is one of the most useful methods for the construction of carbon-carbon bonds. The products of aldol reactions are either (B-hydroxy carbonyl compounds or, after dehydration, a,P-unsaturated carbonyl compounds. The aldol reaction is useful not only for making C-C bonds, but also for providing two functional groups, the C=0 and a 3-OH, which can be further elaborated. 

In the strictest sense, the aldol reaction involves the condensation of an enolate derived from an aldehyde or a ketone with another aldehyde or ketone to give a (3-hydroxyaldehyde or a (3-hydroxyketone, respectively. In a broader sense, the aldol reaction encompasses reactions of enolates—usually derived from ketones, esters, or amides—with an aldehyde or a ketone. 

The aldol reaction is catalyzed by base or by acid. Both base- and acid-catalyzed condensations are reversible in the 1,2-addition step. The equilibrium constant for the addition step is usually unfavorable for ketones. 

The enol content of simple ketones is quite low under standard acid-catalyzed conditions (for acetone = 10 cyclohexanone = 10 ). The base-catalyzed aldol reaction for aldehydes is slightly exothermic while the reaction for ketones is somewhat endothermic. 

The P-hydroxy aldehydes and P-hydroxy ketones formed in aldol reactions are readily dehydrated to yield conjugated systems. These p-elimination reactions can be effected by either acid or base while heating during the condensation. 

The aldol reaction of aldehydes and ketones involves the attack of an enolate (or enol) nucleophile on a carbonyl electrophile. When the alpha (a) carbon of one compound bonds with the carbonyl carbon of another compound, a P-hydroxy carbonyl product is initially formed this product can undergo a further reaction to give an a,P-unsaturated carbonyl product. When either of these patterns is present in a target molecule, it is an indication that the TM might be the product of an aldol reaction, and an aldol disconnection will be one option for retrosynthesis. 

The aldol reaction is a reaction between two carbonyl-containing compounds. In a self-condensation aldol, the same carbonyl starting material is used as both the nucleophile and the electrophile. In other cases, it is possible to have a mixed aldol, which reacts one ketone/aldehyde with a different ketone/ aldehyde. Such reactions would require some means of controlling the regio-chemistry of the reaction. 

Introduction to Strategies for Organic Synthesis, First Edition. Laurie S. Starkey. 2012 John Wiley Sons, Inc. Published 2012 by John Wiley Sons, Inc. 

The aldol reaction involves the substitution of an ct-hydrogen by the carbonyl carbon of another carbonyl compound, thereby creating a 3-hydroxycarbonyl product. Eq. 11.13 shows the coupling of two aldehydes, while Eq. 11.14 shows the coupling of two ketones. The reaction is similar to the alkylation and halogenation of an enolate, except that now the electrophile is another carbonyl compound, and so we have nucleophilic addition to a carbonyl as well as substitution on an a-carbon. As with other reactions we have seen in this section, the aldol reaction can proceed via an enol or an enolate. However, the most common pathway, and the one we will emphasize here, makes use of an enolate and so is base-catalyzed. With prolonged treatment in acid or base, the p-hydroxycarbonyl products will dehydrate to form a,(3-unsaturated carbonyl structures. 

The aldol reaction is reversible cleavage of a p-hydroxycarbonyl is called the reverse aldol or retro-aldol. Equilibria between the p-hydroxycarbonyl products and the carbonyl reactants lie toward the products with alkyl aldehydes and toward the reactants with alkyl 

Chapter 24 concentrates on the second general reaction of enolates—reaction with other carbonyl compounds. In these reactions, one carbonyl component serves as the nucleophile and one serves as the electrophile, and a new carbon-carbon bond is formed. 

The presence or absence of a leaving group on the electrophilic carbonyl carbon determines the strucmre of the product. Even though they appear somewhat more complicated, these reactions are often reminiscent of the nucleophilic addition and nucleophilic acyl substitution reactions of Chapters 21 and 22. Four types of reactions are examined  

In the aldol reaction, two molecules of an aldehyde or ketone react with each other in the presence of base to form a 3-hydroxy carbonyl compound. For example, treatment of acetaldehyde with aqueous OH forms 3-hydroxybutanal, a P-hydroxy aldehyde. 

Many aldol products contain an a/dehyde and an alcoho/ hence the name aldol. 

The mechanism of the aldol reaction has three steps, as shown in Mechanism 24.1. Carbon-carbon bond formation occurs in Step [2], when the nucleophilic enolate reacts with the electrophilic carbonyl carbon. 

The classical aldol addition commonly uses a basic catalyst. However, the condensation reaction of various ketones with aryl aldehydes under basic conditions in water gave the expected aldol products along with the dehydration compounds. The presence of surfactants led mainly to dehydration products, whereas the use of a water/dioxane two-phase system gave good yields of aldol products with reactive aliphatic aldehydes. 

A microporous 1 2 polycondensate obtained by the treatment of anthracenebis (resorcinol) with La(0-i-Pr)3 was also successfully applied to this reaction in neat water at neutral pH with efficient recycling of the catalyst.  

Aldolization of unprotected glycolaldehyde in water in the presence of a Zn-proline catalyst at room temperature and in the absence of strong bases gave the corresponding tetroses and hexoses, but in low ee s.  

The catalytic activities of these lanthanide triflates were found to be mainly dependent on two parameters, the hydrolysis constant and the water exchange rate constant. Moreover, 

It was shown that the Lewis acid surfactant-combined catalyst scandium tris(dodecyl sulfate) was an excellent catalyst for the aldol reaction in water without any organic cosolvent, providing yields up to The much higher activity observed in water than in organic 

Lithium enethiolates react rapidly and at low temperature with aldehydes and afford good yields of 0-hydroxydithioesters (120, 331], This reaction 

The potential of this sequence was applied in Meyers s total synthesis of antibiotic maytansinoids such as (-)-maysine 1345). 

It is also of interest to note that high diastereofacial selectivity could be achieved. A 10 1 ratio of diastereomcric products (epimeric at C7) was obtained at 120°C, and the major isomer isolated in a 62% yield (liquid chromatography) is of syn stereochemistry, following Cram s rule. 

A good stereospecificity has also been demonstrated for the reaction of m-enethiolates with aldehydes [359,360], 

Stereocontrolled creation of three asymmetric centres yielding syn,syn products was realized as in the example given here [359]. 

In Chapter 24, we examine carbonyl condensations—that is, reactions between two carbonyl compounds—a second type of reaction that occurs at the a carbon of a carbonyl group. Much of what is presented in Chapter 24 applies principles you have already learned. Many of the reactions may look more complicated than those in previous chapters, but they are fundamentally the same. Nucleophiles attack electrophihc carbonyl groups to form the products of nucleo-phihc addition or substitution, depending on the stracture of the carbonyl starting material. 

Every reaction in Chapter 24 forms a new carbon-carbon bond at the a carbon to a carbonyl group, so these reactions are extremely useful in the synthesis of complex natural products. 

Reaction of enolates with other carbonyl compounds 

Enantiomerically pure boron-based Lewis acids have also been used successfully in catalytic aldol reactions. Corey s catalyst (7.10a) provides good enantioselectivity with ketone-derived silyl enol ethers, including compound (7.11). Other oxazaborolidine complexes (7.13) derived from a,a-disubstituted a-amino acids give particularly high enantioselectivity, especially with the disubstituted ketene 

Titanium complexes are often encountered in Lewis acid-catalysed reactions. This is certainly true for catalysed aldol reactions. Mikami and Matsukawa demonstrated that titanium/BINOL complexes e.g. complex (7.20) afforded high yield and enantioselectivity in the aldol reactions of thioester ketene silylacetals with a variety of aldehydes. In contrast to some of the aldol reactions described above, the stereochemistry of the adducts is dependant on the geometry of the enol ether. Thus, reaction of the (B)-enol ether (7.21) with aldehyde (7.22) yields the sy -aldol adduct (7.23) predominantly while the (Z)-e.no ether (7.24) results in isolation of the anti-adduct (7.25) as the major product. The authors invoke a closed silatropic ene transition state (structure (7.26) for syn-transition state), substantiated by suitable crossover experiments, to explain the diastereoselectivities 

The nickel(II) (BOX) complex (7.42) is an effective catalyst in the direct aldol reaction of thiazolidinethione (7.43). In this process, the enolate generated using 2,6-lutidine reacts with a range of aromatic and aliphatic aldehydes to give the syn-adduct (7.44) predominantly. 

An alternative use of copper(II) catalysts has been reported by Carreira. Using a fluoride counterion, they reason that the reaction proceeds via formation of a copper enolate rather than through Lewis acid-mediated activation of the aldehyde. Using TolBlNAP as the hgand, the catalyst affords high enantioselectivities. The reaction worked well with most of the aldehydes that were reported (65—95% ee), including the reaction of benzaldehyde (7.17). 

Palladium catalysts have also been reported to give good enantioselectivities in aldol reactions, again via catalytic formation of an enantiomerically pure enolate. 

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Here we will illustrate the method using a single example. The aldol reaction between an enol boronate and an aldehyde can lead to four possible stereoisomers (Figure 11.32). Many of these reactions proceed with a high degree of diastereoselectivity (i.e. syn anti) and/or enantioselectivity (syn-l syn-Tl and anti-l anti-lT). Bernardi, Capelli, Gennari,... 

Bernard A, A M CapeUi, A Comotti, C Gannari, J M Goodman and I Paterson 1990. Transltion-St Modeling of the Aldol Reaction of Boron Enolates A Force Field Approach. Journal of Orga Chemistry 55 3576-3581. 

The aldol reaction is an equilibrium which can be "driven" to completion. 

Some of the earliest studies of the aldol reaction were carried out by Aleksander Borodin Though a physician by training and a chemist by profession Borodin is re membered as the composer of some familiar works in Russian music See pp 326-327 in the April 1987 issue of the Journal of Chem ical Education for a biogra phical sketch of Borodin... 

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. 

In the presence of dilute sodium or potassium hydroxide, //-butyraldehyde undergoes the aldol reaction to form 2-ethyl-3-hydroxyhexanal [496-03-7] which, on continued heating, is converted iato 2-ethyl-2-hexenal [26266-68-2]. Hydrogenation of the latter gives 2-ethyl-1-hexanol/7 (94-7%., aptincipal plastici2er alcohol. 

Many commercially important isobutyraldehyde derivatives are prepared through aldol and/or Tischenko condensation reactions. For example, isobutyraldehyde undergoes the aldol reaction to form isobutyraldol (2,2,4-trimethyl-3-hydroxypentanal [918-79-6]) which, when hydrogenated, gives 2,2,4-trimethyl-1,3-pentanediol (TMPD) [144-19-4],... 

Neopentyl glycol (2,2-dimethyl-1-propanol [126-30-7]) another important iadustrial derivative of isobutyraldehyde, is obtained from the aldol reaction product of isobutyraldehyde with formaldehyde followed by hydrogenation. 

For the other broad category of reaction conditions, the reaction proceeds under conditions of thermodynamic control. This can result from several factors. Aldol condensations can be effected for many compounds using less than a stoichiometric amount of base. Under these conditions, the aldol reaction is reversible, and the product ratio will be determined by the relative stability of the various possible products. Conditions of thermodynamic control also permit equilibration among all the enolates of the nucleophile. The conditions that permit equilibration include higher reaction temperatures, protic solvents, and the use of less tightly coordinating cations. 

When the aldol reaction is carried Wt under thermodynamic conditions, the product selectivity is often not as high as under kinetic conditions. All the regioisomeric and stereoisomeric enolates may participate as nucleophiles. The adducts can return to reactants, and so the difference in stability of the stereoisomeric anti and syn products will determine the product composition. 

The fluoride anion has a pronounced catalytic effect on the aldol reaction between enol silyl ethers and carbonyl compounds [13] This reacbon proceeds at low temperature under the influence of catalytic amounts (5-10 mol %) of tetra-butylammonium fluoride, giving the aldol silyl ethers in high yields (equation 11). 

The aldol reactions of enamines may be formally considered to proceed via acyclic amino aldehyde or amino ketone forms, in spite of the fact that the cyclic enamine forms can also take part in aldol reactions. 

Furthermore, in analogy to the aldol reaction, a-chloro-a,3-unsaturated esters have been observed—likely the result of 3-elimination of water from the intermediate halohydrin. For example, when benzaldehyde is condensed with the enolate of 17, chloride 19 was obtained. ... 

In recent years, several modifications of the Darzens condensation have been reported. Similar to the aldol reaction, the majority of the work reported has been directed toward diastereo- and enantioselective processes. In fact, when the aldol reaction is highly stereoselective, or when the aldol product can be isolated, useful quantities of the required glycidic ester can be obtained. Recent reports have demonstrated that diastereomeric enolate components can provide stereoselectivity in the reaction examples include the camphor-derived substrate 26, in situ generated a-bromo-A -... 

The addition of the a-carbon of an enolizable aldehyde or ketone 1 to the carbonyl group of a second aldehyde or ketone 2 is called the aldol reaction It is a versatile method for the formation of carbon-carbon bonds, and is frequently used in organic chemistry. The initial reaction product is a /3-hydroxy aldehyde (aldol) or /3-hydroxy ketone (ketol) 3. A subsequent dehydration step can follow, to yield an o ,/3-unsaturated carbonyl compound 4. In that case the entire process is also called aldol condensation. 

The aldol reaction as well as the dehydration are reversible. In order to obtain the desired product, the equilibrium might have to be shifted by appropriate reaction conditions (see below). 

If the initially formed /3-hydroxy carbonyl compound 3 still has an a-hydrogen, a subsequent elimination of water can take place, leading to an o ,/3-unsaturated aldehyde or ketone 4. In some cases the dehydration occurs already under the aldol reaction conditions in general it can be carried out by heating in the presence of acid ... 

Several pairs of reactants are possible. The aldol reaction between two molecules of the same aldehyde is generally quite successful, since the equilibrium lies far to the right. For the analogous reaction of ketones, the equilibrium lies to the left, and the reaction conditions have to be adjusted properly in order to achieve satisfactory yields (e.g. by using a Soxhlet extractor). 

From a mixture of two different aldehydes, each with a-hydrogens, four different aldols can be formed—two aldols from reaction of molecules of the same aldehyde -I- two crossed aldol products not even considering possible stereoisomers (see below). By taking into account the unsaturated carbonyl compounds which could be formed by dehydration from the aldols, eight different reaction products might be obtained, thus indicating that the aldol reaction may have preparative limitations. 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

Besides the aldol reaction in the true sense, there are several other analogous reactions, where some enolate species adds to a carbonyl compound. Such reactions are often called aldol-type reactions the term aldol reaction is reserved for the reaction of aldehydes and ketones. 

Diketones 1 can be converted into the salt of an a-hydroxy carboxylic acid upon treatment with alkali hydroxide after acidic workup the free a-hydroxy carboxylic acid 2 is obtained. A well-known example is the rearrangement of benzil (R, R = phenyl) into benzilic acid (2-hydroxy-2,2-diphenyl acetic acid). The substituents should not bear hydrogens a to the carbonyl group, in order to avoid competitive reactions, e.g. the aldol reaction. 

Aldehydes 1 that have no a-hydrogen give the Cannizzaro reaction upon treatment with a strong base, e.g. an alkali hydroxide.In this disproportionation reaction one molecule is reduced to the corresponding alcohol 2, while a second one is oxidized to the carboxylic acid 3. With aldehydes that do have a-hydrogens, the aldol reaction takes place preferentially. 

The term Knoevenagel reaction however is used also for analogous reactions of aldehydes and ketones with various types of CH-acidic methylene compounds. The reaction belongs to a class of carbonyl reactions, that are related to the aldol reaction. The mechanism is formulated by analogy to the latter. The initial step is the deprotonation of the CH-acidic methylene compound 2. Organic bases like amines can be used for this purpose a catalytic amount of amine usually suffices. A common procedure, that uses pyridine as base as well as solvent, together with a catalytic amount of piperidine, is called the Doebner modification of the Knoevenagel reaction. 

The overall process is the addition of a CH-acidic compound to the carbon-carbon double bond of an o ,/3-unsaturated carbonyl compound. The Michael reaction is of particular importance in organic synthesis for the construction of the carbon skeleton. The above CH-acidic compounds usually do not add to ordinary carbon-carbon double bonds. Another and even more versatile method for carbon-carbon bond formation that employs enolates as reactive species is the aldol reaction. 

Certain starting materials may give rise to the non-selective formation of regioisomeric enolates, leading to a mixture of isomeric products. Furthermore a ,/3-unsaturated carbonyl compounds tend to polymerize. The classical Michael procedure (i.e. polar solvent, catalytic amount of base) thus has some disadvantages, some of which can be avoided by use of preformed enolates. The CH-acidic carbonyl compound is converted to the corresponding enolate by treatment with an equimolar amount of a strong base, and in a second step the a ,/3-unsaturated carbonyl compound is added—often at low temperature. A similar procedure is applied for variants of the aldol reaction. 

The stereochemical outcome of the Michael addition reaction with substituted starting materials depends on the geometry of the a ,/3-unsaturated carbonyl compound as well as the enolate geometry a stereoselective synthesis is possible. " Diastereoselectivity can be achieved if both reactants contain a stereogenic center. The relations are similar to the aldol reaction, and for... 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

Aldehydes and ketones with an a hydrogen atom undergo a base-catalyzed carbonyl condensation reaction called the aldol reaction. For example, treatment of acetaldehyde with a base such as sodium ethoxide or sodium hydroxide in a protic solvent leads to rapid and reversible formation of 3-hydroxybutanal, known commonly as aldol (aidehyde + alcohol), hence the general name of the reaction. 

Mechanism of the aldol reaction, a typical carbonyl condensation. 

Problem 23.1 Predict the aldol reaction product of the following compounds ... 

Strategy In the aldol reaction, H2O is eliminated and a double bond is formed by removing hvo hydrogens from the acidic a position of one partner and the carbonyl oxygen from the second partner. The product is thus an a,/3-unsaturated aldehyde or ketone. 

The aldol reaction yields either a /3-hydroxy aldehyde/ketone or an a, 3-unsatu-rated aldehyde/ketone, depending on the experimental conditions. By learning how to think backward, it s possible to predict when the aldol reaction might be useful in synthesis. Whenever the target molecule contains either a /3-hydroxy aldehyde/ketone or a conjugated enone functional group, it might come from an aldol reaction. 

The aldol reactions we ve seen thus far have all been intermolecular, meaning that they have taken place between two different molecules. When certain r/zcar-bonyl compounds are treated with base, however, an mtramolecular aldol reaction can occur, leading to the formation of a cyclic product. For example, base treatment of a 1,4-diketone such as 2,5-hexanedione yields a cyclopcntenone... 

Tire mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldeiwde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

The aldol reaction is a carbonyl condensation that occurs between two aldehyde or ketone molecules. Aldol reactions are reversible, leading first to a /3-hydroxy aldehyde or ketone and then to an cr,/6-unsaturated product. Mixed aldol condensations between two different aldehydes or ketones generally give a mixture of all four possible products. A mixed reaction can be successful, however, if one of the two partners is an unusually good donor (ethyl aceto-acetate, for instance) or if it can act only as an acceptor (formaldehyde and benzaldehyde, for instance). Intramolecular aldol condensations of 1,4- and 1,5-diketones are also successful and provide a good way to make five-and six-inembered rings. 

The aldol reaction is catalyzed by acid as well as by base. What is the reactive nucleophile in the acid-catalyzed aldoJ reaction Propose a mechanism. 

XVIII in a yield of 88 to 92%. It is here that the relationship between the Patemo-Buchi photocycloaddition process and the aldol reaction is most readily apparent. 

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