Reactions aldol

Aldol reactions, in which no subsequent elimination occurs and which lead to /3-hydroxy carbonyl compounds (Aldol formation). 

The formation of afi-unsaturated carbonyl compounds, in which the initial addition reaction is followed by dehydration (Perkin, Knoevenagel, and Claisen-Schmidt condensations). 

Claisen condensations, in which -keto carbonyl compounds are formed by the loss of a negative ion from an incipient hemiketal (Claisen condensations, and Dieckmann ring closures). 

In addition to these reactions in which the carbanions are supplied from carbonyl compounds, we will discuss in this chapter Grignard reactions, the benzilic acid rearrangement, the benzoin condensation, and the Kolbe synthesis of hydroxy aromatic acids. These reactions illustrate the addition of other kinds of carbanions to carbonyl groups. The benzilic acid rearrangement is an example of the intramolecular addition of a group with its pair of electrons to a carbonyl carbon atom. 

Aldol reactions (as well as the initial steps in the formation of unsaturated carbonyl compounds and /3-ketoesters) proceed through the following sequence of reactions  

Aldol Reactions. - Seebach et al. have published a detailed study of the diasteroselective aldol reaction of boron enolates, generated from an ethyl ketone by treatment with boron trichloride or an alkoxydichloroborane in the presence of Hunig s base. The reaction was found to occur with ul topicity in selectivities from 90-99% 

Aluminium montmorilIonite and rhodium carbonyl have been reported as catalysts for the aldol reaction of enol silanes with aldehydes, but in neither case are the stereoselectives at all high. The reaction has also been found to occur without Lewis acid catalysis in water or in 1 1 water oxolane. Although the yields are not high, the method is of interest in that syn-products were 

The diazabicyclooctane (DABCO) catalysed aldol type reaction of acrylic esters with aldehydes has now been extended to use methyl 

Similar products may be synthesised using allenolates prepared by the 1,4- addition of iodide to acetylenic ketones. Several sources of iodide could be used including tetrabutylammonium iodide/titanium tetrachloride which gave high Z-stereoselectivity at -78° and largely E-products at 0°C (equation (57)].180 

Aldol Reactions.—N-(Trimethylsilyl)amino-acid trimethylsilyl esters, e.g. 

Me3SiNHCH2C02SiMe3, have been shown to be effective reagents for the 

Aldol reaction between a silyl enol ether and an aromatic or aliphatic aldehyde can be catalysed by tetrabutylammonium fluoride ketones and epoxides are not attacked by the enolates derived in this manner. Directed cross-aldol reactions have now been carried out by conversion of a methyl ketone into the intermediate (15) using 9-trifluoromethylsulphonyl-9-borabicyclo[3,3,l]nonane and t-amine prior to reaction with the second carbonyl compound.  

Cross-aldol reactions involving the enolate (16) (formed from mesityl oxide under kinetic control) and a number of aldehydes and ketones have been used as key steps in the syntheses of some simple, naturally occurring terpenes.  

Cross-aldol reactions involving the optically active keto-esters menthyl pyruvate and phenylglyoxylate and either silyl enol ethers or keten silyl acetals have been shown to result in appreciable asymmetric induction, considerably larger than that observed in the reactions of the same chiral a-keto-esters with Grignard 

This reagent is the best promoter of the aldol reaction of 2-(trimethylsiloxy)acry-late esters, prepared by the silylation of pyruvate esters, to afford y-alkoxy-a-keto esters (Eq. 80) [135] These esters occur in a variety of important natural products. 

5-Dicarbonyl compounds are formed by reaction of silyl enol ethers with methyl vinyl ketones in the presence of BF3 Et20 and an alcohol (Eq. 84) [139]. 

Tin(II) aza enolates have been used to prepare anti-aldol products with high e.e. The aza-enolates, which are prepared by the lithiation and transmetallation of the (-)-norephedrine- 

The aldol type condensation of aldehydes with the o-position of enones can be achieved directly using 

Buse and Heathcock have extended their work on the stereochemistry of aldol formation. They find that condensation of the aldehyde (7) with the enolate (8) gives only two of the four possible diastereomers [equation (14)]. The first 

There is apparently only one published example of a synthesis that includes an aldol reaction of a carbon- 14-labeled acetoacetate. In this example doubly deprotonated methyl 

Asymmetric C-C bond formation based on catalytic aldol addition reactions remains one of the most challenging subjects in synthetic organic chemistry. Although many successful nonbiological strategies have been developed [1355, 1356], most of them are not without drawbacks. They are often stoichiometric in auxiliary reagent and require the use of a metal or organocatalytic enolate complex to achieve stereoselectivity [1357-1360]. Due to the instability of such complexes 

With few exceptions, the stereochemical outcome of the aldol reaction is controlled by the enzyme and does not depend on the substrate structure (or on its stereochemistry). Therefore, the configuration of the carbon atoms adjacent to the newly formed C-C bond is highly predictable. Furthermore, most aldolases are very restricted concerning their donor (the nucleophile), but possess relaxed substrate specificities with respect to the acceptor (the electrophile), which is the carbonyl group of an aldehyde or ketone. This is understandable, bearing in mind that the enzyme has to perform an umpolung on the donor, which is a sophisticated task in an aqueous environment  

To date more than 40 aldolases have been classified, the most useful and more readily available enzymes are described in this chapter. Bearing in mind that the natural substrates of aldolases are carbohydrates, most successful enzyme-catalyzed aldol reactions have been performed with carbohydrate-like (poly)hydroxy 

The development of the full synthetic potential of DHA(P)-dependent aldolases into a general and efficient methodology for asymmetric aldol additions largely depends 

RAMA accepts a wide range of aldehydes in place of its natural substrate, allowing the synthesis of carbohydrates [1383-1386] and analogs such as 

Highly hindered bases such as (20) deprotonate the methyl group of methyl ketones specifically. In the presence of an aldehyde, aldol reaction occurs before enolate equilibration can take place. The same base promotes the addition of ester and lactone enolates to aldehydes and ketones. However, it has been noted that at low temperature (—70 °C), the more accessible lithium diethylamide deproto-nates only the methyl group of methyl ketones. Addition of a second aldehyde or ketone species at this temperature leads to the exclusive formation of jS-ketoIs derived from this enolate.  

In the presence of zinc, a-substituted j8-keto-acid 2,2,2-trichloroethyl esters (22) react with aldehydes at the a-position. Aqueous work-up causes decarboxylation, and aldols are obtained in high yield.  

Mukaiyama and T. Inoue, Cliem. Letters, 1976, 559 T. Mukaiyama, K. Saigo, and 

Banno and T. Mukaiyama, Chem. Letters, 1976, 279 K. Banno, Bull. Chem. Soc. Japan, 1976, 49, 2284. 

Kuwajima, T. Sato, M. Arai, and N. Minami, Tetrahedron Letters, 1976, 1817. 

Formaldehyde is a versatile reagent as one of the most highly reactive Q electrophiles in organic synthesis [9, 10] and dry gaseous formaldehyde has been required for many reactions. For example, the titanium tetrachloride (TiCl4)-promoted hydroxymethylation reaction of a silyl enol ether was carried out by using tri-oxane as an HCHO source under strictly anhydrous conditions [11, 12]. Formalde-hyde/water solution could not be used because TiCl4 and the silyl enol ether reacted with water rather than with HCHO in that aqueous solution. 

It was found that the hydroxymethylation reaction of silyl enol ethers with commercial formaldehyde solution proceeded smoothly when lanthanide triflates were used as Lewis acid catalysis (Eq. 1) [7, 13]. The reactions were first carried out in commercial formaldehyde solution THF media. 

Lanthanide triflates are more soluble in water than in organic solvents such as di-chloromethane. Very interestingly, almost 100% of the lanthanide triflate is quite 

The aldol reactions of silyl enol ethers with aldehydes also proceed smoothly in water/ethanol/toluene [17]. The reactions proceed much faster in this solvent than in water/THF (Eq. 2). Furthermore, the new solvent system involves continuous use of the catalyst by a very simple procedure. Although the water/ethanol/toluene (1 7 4) system is one phase, it easily becomes two phases by adding toluene after the reaction is completed. The product is isolated from the organic layer by a usual work-up. On the other hand, the catalyst remains in the aqueous layer, which is used directly in the next reaction without removing water. It is noteworthy that the yields of the second, third, and fourth runs are comparable with that of the first run. 

In the area of organocatalysis, proline has been utilised in various asymmetric reactions including direct asymmetric aldol reactions. Some such proline-catalysed aldol reactions, however, have serious limitations with respect to reactivity and selectivity. Although these problems were overcome through the development of new catalysts derived from proline, there is still an urgent need for structurally and electronically novel catalysts due to the difficulty in appropriate modification of proline. In this context, we have designed and prepared artificial amino acid catalyst (S)-l having a binaphthyl backbone as a frequently utilised chiral unit in asymmetric catalysts.  

In the case of proline catalyst, the s-trans-enamine intermediate is preferably formed due to a decrease in the steric repulsion between the carbojyl group at ot-position of the catalyst and the enamine moiety. On the other hand, (Sj-S can form both s-fra s-enamine and s-cts-enamine due to the lack 

In organocatalytic cross-aldol reactions of two different aldehydes through the enamine intermediate first reported by MacMillan and Northrop, the a d-cross-aldol adduct could be obtained in a highly stereoselective fashion. However, most such reactions required the use of sterically hindered aliphatic aldehydes, from which the enamine intermediates are rather difficult to form, or aromatic aldehydes as electrophile. In the direct aldol reaction between simple aliphatic aldehydes (enolisable aldehydes), both aldehydes can perform the double role of nucleophile and electrophile, and consequently, two cross-aldol adducts and two homo-aldol adducts would be possible products with each having four stereoisomers. To differentiate two 

The regio- and stereoselective formation of new carbon-carbon bonds plays a pivotal role in complex molecule synthesis. Impressive advances in modern diastereo- and enantioselective methods have brought the aldol addition reaction into a prominent position as one of the most powerful and versatile processes for the asymmetric synthesis of acyclic molecules [13-21]. 

The aldol reaction enjoys a longstanding history in synthetic organic chemistry for the facile formation of carbon-carbon bonds. The discovery of the aldol condensation is associated with the Russian composer and chemist Borodin, who reported the reaction of valeraldehyde with the extrusion of water in 1869 [1, 22]. The term aldol reaction was coined by Wurt2 in 1872 in the description of the self-addition product of acetaldehyde (Equation 1) [23]. This terminology was later applied to the analogous reactions of ketones, the first known example of which, namely that of acetone, was discovered in 1838 [24]. 

The Russian chemical society meeting in St. Petersburg on October 17, 1869 was busier, however. The most far-reaching topics discussed at this meeting included Borodin s discovery of the aldol reaction, while Mendeleev reported on ordering the elements into the periodic table [1]  

Classics in Stereoselective Synthesis. Erick M. Carreira and Lisbet Kvaerno Copyright 2009 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-32452-1 (Hardcover) 

Mechanistically, the stereoselective aldol reaction can be divided into several different subclasses. Aldol reactions of metal enolates follow some general mechanistic pathways that facilitate prediction of the relative configuration of the products. The reactions can be described as proceeding via chelated, closed, Zimmerman-Traxler transition states [33]. The positioning of substi- 

The asymmetric aldol reaction represents the most versatile protocol for the preparation of optically enriched (5-hydroxy ketones. During the last two decades, a number of observations have been made regarding asymmetric aldol and related reactions mediated by a cinchona-derived catalyst that affords high stereoselectivity. 

On the basis of encouraging work in the development of L-proline-DMSO and L-proline-ionic liquid systems for practical asymmetric aldol reactions, an aldolase antibody 38C2 was evaluated in the ionic liquid [BMIM]PF6 as a reusable aldolase-ionic liquid catalytic system for the aldol synthesis of oc-chloro- 3-hydroxy compounds (288). The biocatalytic process was followed by chemical catalysis using Et3N in the ionic liquid [BMIM]TfO at room temperature, which transformed the oc-chloro-(3-hydroxy compounds to the optically active (70% ee) oc, (3-epoxy carbonyl compounds. The aldolase antibody 38C2-ionic liquid system was also shown to be reusable for Michael additions and the reaction of fluoromethylated imines. 

Nucleophilic reactions of unmodified aldehydes are usually diiScult to control, affording complex mixture of products, often due to the high reactivity of the formyl group under either basic or acidic reaction conditions. The activity order of the supported amines was secondary primary tertiary, which may suggest the intervention of an enamine pathway the enals were exclusively obtained as ( ) isomers. Notably, FSM-16-(CH2)3-NHMe exhibited higher activity than conventional solid bases such as MgO and Mg-Al-hydrotalcite [hexanal self-aldol condensation FSM-16-(CH2)3-NHMe 97% conversion and 85% yield in 2h, MgO 56% conversion and 26% yield in 20 h, Mg-Al-hydrotalcite 22% conversion and 11% yield in 24 h]. 

The leaching test allowed exclusion of the possible migration of any active catalytic species in solution. The catalyst on recycling showed a decrease in 

In the presence of TCG (10 mol.%) under homogeneous conditions benzaldehyde was quantitatively converted after 2h, giving compound 19 with 94% yield, whereas 10 mol.% TCG encapsulated in zeolite Wessallth (12) afforded 19 with 8% yield accompanied by compound 18 in 48% yield. 

By using TCG supported on MCM-41 silica the total yield (18-1-19 products) ranged from 31% to 89%, and the amount of the addition product 18 depended on the alcohol solvent utUized (19/18 MeOH 89/0,1 r OI 1 40/22, Bu OI 1 20/11). 

This reaction could also afford the heptaldehyde self-condensation product, some benzyl alcohol and benzoic acid (from the Cannizzaro reaction) as byproducts authors reported that a higher temperature favours the jasminaldehyde formation. By slowly adding heptaldehyde, to keep its concentration low, a 99% 

So far in this chapter, we have learned how to make enolates, and we have used them to attack various electrophiles (including halogens and alkyl halides). In this section, we will explore what happens when an enolate attacks a ketone or aldehyde. 

Suppose we start with a simple ketone, and we subject it to basic conditions, using hydroxide as a base. We have already seen that an equilibrium will be established between the ketone and the enolate  

If we do this in the presence of an electrophile, the enolate can attack the electrophile. And then the equilibrium will produce more enolate to replenish the supply. But what if we do not add any other electrophiles to the reaction mixture What if we just treat the ketone with hydroxide  

It turns out that there actually is an electrophile present. We said that the enolate is in equilibrium with the ketone (and there is a lot of ketone present). Well, ketones are electrophilic, aren t they We devoted an entire chapter to the reactions that take place when ketones get attacked. So, what happens when an enolate attacks a ketone  

The enolate attacks the ketone, forming a tetrahedral intermediate. Now, our golden rule tells us to try and re-form the carbonyl, but don t expel H or C . In this case, we have no leaving groups that can be expelled. So, the only way to remove the charge is to protonate. In these basic conditions, the proton source is water (not H3O+, because the presence of HsO is insignificant in basic conditions)  

The reaction of enolates with aldehydes or ketones to produce /3-hydroxy carbonyl derivatives is a very common and a very useful way to make carbon-carbon bonds. A fundamental stereochemical feature of the reaction is diat two new chiral centers are produced from achiral starting materials. Hence syn and anti diastereomers will be produced, each as a pair of enantiomers. This is shown schematically for the reaction of a propionate enolate with isobutyraldehyde. Because they have different energies, the syn and anti diastereomers will be 

The stereoelectronic requirements for carbonyl addition are that electron donation occurs by interaction of die donor with the it orbital of the carbonyl group. To meet the stereoelectronic requirements and explain the diastereoselectivity, the Zimmerman-Traxler model is used. Interaction of the lithium cation with the oxygen of die enolate and of die carbonyl electrophile leads to a six-membered 

This model is extremely useful in understanding the stereochemical outcomes of aldol processes. It also provides a framework for influencing the diastereose-lectivity in a rational way. For instance, if the ethoxy group in the above example is changed to a much bulkier group, increased transannular interactions in the pseudoaxial transition state would make it even higher in energy and result in increased selectivity for the anti isomer (and it does ) 

Even greater diastereoselectivity in die aldol reaction can be achieved using boron etiolates as the carbon nucleophile. Boron etiolates are easily prepared from aldehydes and ketones, and the syn and die anti isomers can be separated as pure compounds. They react with aldehydes and ketones to give aldol products by a similar transition state. The difference is fliat boron oxygen bonds are shorter than lidiium oxygen bonds, and thus steric interactions in the transition state are magnified and result in greater diastereoselectivity. 

Recent Developments in Asymmetric Organoeatalysis By Helene Pellissier HH ne Pellissier 2010 

It must be noted that a remarkable improvement of both the chemical yield (from 6% to 82%) and the enantioselectivity (up to 99% ee) of L-proline-catalysed aldol reactions of a wide range of aldehydes with acetone was found by Liebscher et al. when hexasubstituted or pentasubstituted guanidinium salts were added as ionic liquids. Furthermore, this study showed that guanidinium salts could be advantageous over imidazolium salt-based ionic liquids. 

Cross-aldol reactions of cyclohexanone with P,y-unsaturated keto esters catalysed by trans-siloxy-L-proline. 

Highly diastereo- and enantioselective aldol reactions between aromatic aldehydes and cyclohexanone performed in water were developed by Tao et al. by using a novel simple amphiphilic proline-derived organoeatalyst bearing a 

In a similar area, Ludtke et al. have employed a robust cysteine-derived prolinamide as an organocatalyst to promote the asymmetric aldolisation of 

Seebach, R. Amstutz, and J. D. Dunitz, Helv. Chitn. Acta, 1981,64,2622. 

Under kinetic conditions, E-enolates produce predominantly r/ireo-products in aldol condensations, making erythro-oldols difficult to prepare from cyclic ketones. However, readily isolable titanium enolates show pronounced erythro-selectivity in their reactions with aldehydes, irrespective of enolate geometry, the diastereoselection being high for reactions of cyclic ketones [equation (66)]. Triphenyltin enolates react in an analogous manner.  

Mukaiyama, M. Murakami, T. Oriyama, and M. Yamaguchi, Chetn. Lett., 1981,1193. 

Boron enolates of chiral ketones (16) have been developed for asymmetric induction in the aldol condensation [equation (68)], and as a result of their additional high diastereoselectivity, have proved valuable in the stereocontrolled synthesis of 6-deoxyerythronolide 

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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. 

A probable mechanism of these base-catalysed aldol reactions may be written in gena-al terms as follows ... 

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

Li+, Mg 2+. AP+= enolates give comparable levels of diastereoselection for kinetic aldol reactions. 

Non-chelation aldol reactions proceed via an "open" transition state to give syn aldols regardless of enolate geometry. 

The use of indium in acpieous solution has been reported by Li and co-workers as a new tool in org nometallic chemistry. Recently Loh reported catalysis of the Mukaiyama-aldol reaction by indium trichloride in aqueous solution". Fie attributed the beneficial effect of water to a eg tion phenomena in connection with the high internal pressure of this solvenf This woric has been severely criticised by... 

The synthesis of 3-phenyl-]-(2-pyridyl)-2-propen-]-one (2.4c) via an aldol reaction of 2-acetylpyridine with benzaldehyde has been described in the literature ". O jmpound 2.4a-e have been prepared in high yields, using slightly modified versions of these literature procedures. 

The higjily water-soluble dienophiles 2.4f and2.4g have been synthesised as outlined in Scheme 2.5. Both compounds were prepared from p-(bromomethyl)benzaldehyde (2.8) which was synthesised by reducing p-(bromomethyl)benzonitrile (2.7) with diisobutyl aluminium hydride following a literature procedure2.4f was obtained in two steps by conversion of 2.8 to the corresponding sodium sulfonate (2.9), followed by an aldol reaction with 2-acetylpyridine. In the preparation of 2.4g the sequence of steps had to be reversed Here, the aldol condensation of 2.8 with 2-acetylpyridine was followed by nucleophilic substitution of the bromide of 2.10 by trimethylamine. Attempts to prepare 2.4f from 2.10 by treatment with sodium sulfite failed, due to decomposition of 2.10 under the conditions required for the substitution by sulfite anion. 

It turned out that the dodecylsulfate surfactants Co(DS)i Ni(DS)2, Cu(DS)2 and Zn(DS)2 containing catalytically active counterions are extremely potent catalysts for the Diels-Alder reaction between 5.1 and 5.2 (see Scheme 5.1). The physical properties of these micelles have been described in the literature and a small number of catalytic studies have been reported. The influence of Cu(DS)2 micelles on the kinetics of quenching of a photoexcited species has been investigated. Interestingly, Kobayashi recently employed surfactants in scandium triflate catalysed aldol reactions". Robinson et al. have demonshuted that the interaction between metal ions and ligand at the surface of dodecylsulfate micelles can be extremely efficient. ... 

Ketones, in which one alkyl group R is sterically demanding, only give the trans-enolate on deprotonation with LDA at —12°C (W.A. Kleschick, 1977, see p. 60f.). Ketones also enolize regioseiectively towards the less substituted carbon, and stereoselectively to the trans-enolate, if the enolates are formed by a bulky base and trapped with dialkyl boron triflates, R2BOSO2CF3, at low temperatures (D A. Evans, 1979). Both types of trans-enolates can be applied in stereoselective aldol reactions (see p. 60f.). 

A useful catalyst for asymmetric aldol additions is prepared in situ from mono-0> 2,6-diisopropoxybenzoyl)tartaric acid and BH3 -THF complex in propionitrile solution at 0 C. Aldol reactions of ketone enol silyl ethers with aldehydes were promoted by 20 mol % of this catalyst solution. The relative stereochemistry of the major adducts was assigned as Fischer- /ir o, and predominant /i -face attack of enol ethers at the aldehyde carbonyl carbon atom was found with the (/ ,/ ) nantiomer of the tartaric acid catalyst (K. Furuta, 1991). 

Stereoselectivities of 99% are also obtained by Mukaiyama type aldol reactions (cf. p. 58) of the titanium enolate of Masamune s chired a-silyloxy ketone with aldehydes. An excess of titanium reagent (s 2 mol) must be used to prevent interference by the lithium salt formed, when the titanium enolate is generated via the lithium enolate (C. Siegel, 1989). The mechanism and the stereochemistry are the same as with the boron enolate. 

In the last fifteen years macrolides have been the major target molecules for complex stereoselective total syntheses. This choice has been made independently by R.B. Woodward and E.J. Corey in Harvard, and has been followed by many famous fellow Americans, e.g., G. Stork, K.C. Nicolaou, S. Masamune, C.H. Heathcock, and S.L. Schreiber, to name only a few. There is also no other class of compounds which is so suitable for retrosynthetic analysis and for the application of modem synthetic reactions, such as Sharpless epoxidation, Noyori hydrogenation, and stereoselective alkylation and aldol reactions. We have chosen a classical synthesis by E.J. Corey and two recent syntheses by A.R. Chamberlin and S.L. Schreiber as examples. 

Thiazolecarboxaldehydes exhibit many reactions typical of aldehydes. However, they give no aldolization reaction (no a-hydrogen), but they do react with different compounds such as acetic anhydride, hippuric acid, acetylglycine, and so for (37, 101, 102). Thus 2-phenyl-4-fonnylthiazole (31) mixed with hippuric acid and treated with AcOa and anhydrous NaOAc gives the azalactone (32) (Scheme 32). 

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... 

This cleavage is a retro aldol reaction It is the reverse of the process by which d fruc tose 1 6 diphosphate would be formed by aldol addition of the enolate of dihydroxy acetone phosphate to d glyceraldehyde 3 phosphate The enzyme aldolase catalyzes both the aldol addition of the two components and m glycolysis the retro aldol cleavage of D fructose 1 6 diphosphate... 

Cleavage reactions of carbohydrates also occur on treatment with aqueous base for prolonged periods as a consequence of base catalyzed retro aldol reactions As pointed out m Section 18 9 aldol addition is a reversible process and (3 hydroxy carbonyl com pounds can be cleaved to an enolate and either an aldehyde or a ketone... 

The 0X0 and aldol reactions may be combined if the cobalt catalyst is modified by the addition of organic—soluble compounds of 2inc or other metals. Thus, propylene, hydrogen, and carbon monoxide give a mixture of aldehydes and 2-ethylhexenaldehyde [123-05-7] which, on hydrogenation, yield the corresponding alcohols. 

Aldehydes fiad the most widespread use as chemical iatermediates. The production of acetaldehyde, propionaldehyde, and butyraldehyde as precursors of the corresponding alcohols and acids are examples. The aldehydes of low molecular weight are also condensed in an aldol reaction to form derivatives which are important intermediates for the plasticizer industry (see Plasticizers). As mentioned earlier, 2-ethylhexanol, produced from butyraldehyde, is used in the manufacture of di(2-ethylhexyl) phthalate [117-87-7]. Aldehydes are also used as intermediates for the manufacture of solvents (alcohols and ethers), resins, and dyes. Isobutyraldehyde is used as an intermediate for production of primary solvents and mbber antioxidants (see Antioxidaisits). Fatty aldehydes Cg—used in nearly all perfume types and aromas (see Perfumes). Polymers and copolymers of aldehydes exist and are of commercial significance. 

Formaldehyde condenses with itself in an aldol-type reaction to yield lower hydroxy aldehydes, hydroxy ketones, and other hydroxy compounds the reaction is autocatalytic and is favored by alkaline conditions. Condensation with various compounds gives methylol (—CH2OH) and methylene (=CH2) derivatives. The former are usually produced under alkaline or neutral conditions, the latter under acidic conditions or in the vapor phase. In the presence of alkahes, aldehydes and ketones containing a-hydrogen atoms undergo aldol reactions with formaldehyde to form mono- and polymethylol derivatives. Acetaldehyde and 4 moles of formaldehyde give pentaerythritol (PE) ... 

Other multifunctional hydroxycarboxylic acids are mevalonic and aldonic acids which can be prepared for specialized uses as aldol reaction products (mevalonic acid [150-97-0] (13)) and mild oxidation of aldoses (aldonic acids). 

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. 

Some unsaturated ketones derived from acetone can undergo base- or acid-catalyzed exothermic thermal decomposition at temperatures under 200°C. Experiments conducted under adiabatic conditions (2) indicate that mesityl oxide decomposes at 96°C in the presence of 5 wt % of aqueous sodium hydroxide (20%), and that phorone undergoes decomposition at 180°C in the presence of 1000 ppm iron. The decomposition products from these reactions are endothermic hydrolysis and cleavage back to acetone, and exothermic aldol reactions to heavy residues. 

A number of other valuable aroma chemicals can be isolated from essential oils, eg, eugenol from clove leaf oil, which can also, on treatment with strong caustic, be isomerked to isoeugenol, which on further chemical treatment can be converted to vanillin (qv). Sometimes the naturally occurring component does not requke prior isolation or concentration, as in the case of cinnamaldehyde in cassia oil which, on dkect treatment of the oil by a retro-aldol reaction, yields natural ben2aldehyde (qv). This product is purified by physical means. 

Aldol reaction of the campholenic aldehyde with 2-butanone gives the intermediate ketones from condensation at both the methyl group and methylene group of 2-butanone (Fig. 6). Hydrogenation results in only one of the two products formed as having a typical sandalwood odor (160). 

Aldol reaction of campholenic aldehyde with propionic aldehyde yields the intermediate conjugated aldehyde, which can be selectively reduced to the saturated alcohol with a sandalwood odor. If the double bond in the cyclopentene ring is also reduced, the resulting product does not have a sandalwood odor (161). Reaction of campholenic aldehyde with -butyraldehyde followed by reduction of the aldehyde group gives the aHyUc alcohol known commercially by one manufacturer as Bacdanol [28219-61 -6] (82). 

In E. coli GTP cyclohydrolase catalyzes the conversion of GTP (33) into 7,8-dihydroneoptetin triphosphate (34) via a three-step sequence. Hydrolysis of the triphosphate group of (34) is achieved by a nonspecific pyrophosphatase to afford dihydroneopterin (35) (65). The free alcohol (36) is obtained by the removal of residual phosphate by an unknown phosphomonoesterase. The dihydroneoptetin undergoes a retro-aldol reaction with the elimination of a hydroxy acetaldehyde moiety. Addition of a pyrophosphate group affords hydroxymethyl-7,8-dihydroptetin pyrophosphate (37). Dihydropteroate synthase catalyzes the condensation of hydroxymethyl-7,8-dihydropteroate pyrophosphate with PABA to furnish 7,8-dihydropteroate (38). Finally, L-glutamic acid is condensed with 7,8-dihydropteroate in the presence of dihydrofolate synthetase. 

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. 

Butyraldehyde undergoes stereoselective crossed aldol addition with diethyl ketone [96-22-0] ia the presence of a staimous triflate catalyst (14) to give a predominantiy erythro product (3). Other stereoselective crossed aldol reactions of //-butyraldehyde have been reported (15). 

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. 

Aldol Additions. These reactions catalyzed by lyases are perhaps the most synthetically useful enzymatic reactions for carbon—carbon bond formation. Because of the broad synthetic utiUty of this method, the enzymatic aldol reactions have received considerable attention in recent years and have been extensively covered in a number of books and reviews (10,138—140). 

Protonated pyridazine is attacked by nucleophilic acyl radicals at positions 4 and 5 to give 4,5-diacylpyridazines. When acyl radicals with a hydrogen atom at the a-position to the carbonyl group are used, the diacylpyridazines are mainly converted into cyclo-penta[ f]pyridazines by intramolecular aldol reactions (Scheme 43). 

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. 

Aldol reaction is the condensation of an aldehyde to produce longer-chain hydroxy aldehydes... 

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