Aldol-condensation

Condensation of a carbonyl with an enolate or an enol. A simple case is addition of an enolate to an aldehyde to afford an alcohol, thus the name aldol. 

Mahrwald, R. (ed.) Modem Aldol Reactions, Wiley—VCH Weinhekn, Germany, 2004. (Book). 

Aldol Condensation.— Russian authors report that in the presence of a stoicheiometric amount of methylcalciura iodide, acetone condenses rapidly to give mesityl oxide in high yield similar reactivity was shown by a range of carbonyl compounds. 

A number of methods of directing the orientation of aldol condensation have been described. In an extension to a patent, a procedure is given where 

Kinetic trapping is reported in the reaction of formaldehyde with un-symmetrical ketones in the presence of trifluoroacetic acid condensation at the more substituted carbon atom predominates, the /5-ketoIs formed being trifluoroacetylated more rapidly than they are produced. Controlled hydroxy-methylation of ketones can be achieved by reduction of the sodium salt of the corresponding hydroxy methylene derivative with aluminium hydride direct base-catalysed condensation with formaldehyde normally gives products of polycondensation. 

A reagent suitable for the specific detection of aldehydes in concentrations as low as 10 mol 1 is provided by the triazole (175). The immediate condensation product (176) is air-oxidized to the triazolotetrazine (177), whose 

Fries and J. K. Stille, Synthesis Inorg. Metal-org. Ghent., 1971,1, 295. 

The aldol condensation of benzaldehyde and acetophenone yields chalcone (Eq. 10-11) 

The aldol reaction is usually base-catalyzed, the results of the synthesis using different catalysts are demonstrated in Table 10-2. 

The base catalysts must be neutralized and/or washed out during the work-up procedure. The solid-acid Nafion H, on the other hand, can be reused. Table 10-2 shows that the most effective procedure with regard to mass efficiency and E factor can be carried out with catalyst d. Not only solvents and auxiliary materials can be saved, but the catalyst too, is reusable without having a negative effect on the yield. This leads to a further decrease in the E factor. In conclusion, Nafion H seems to be an efficient catalyst for performing aldol condensation to yield chalcone in an environmentally friendly manner, i.e. avoiding the use of water and reducing the amount of solvent. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 2, Springer-Verlag Berlin Heidelberg 2009 

Example 4, Intermolecular aldol reaction using organocatalyst 

Guillena, G. Najera, C. Ramon, D. J. Tetrahedron Asymmetry 2007,18, 2249—2293. (Review on enantioselective direct aldol reaction using organocatalysis.) 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applicaticms, DOI 10.1007/978-3-319-03979-4 2, Springer International Publishing Switzerland 2014 

The aldol condensation is considered to be one of the most important carbon-carbon bond forming reactions in organic synthesis in presence of basic reagents. The conventional aldol condensation involve reversible self-addition of aldehydes containing a a-hydrogen atom. The formed P-hydroxy aldehydes 

The above reactions are carried out under non-aqueous conditions. 

It has been found that the dehydration of the alcohols can be avoided in presence of complexes of Zn with aminoesters or aminoalcohols.  

The reaction of several silyl enol ethers with commercial formaldehyde solution catalysed by yb(OTf)3 were carried out and good yields (80-90%) of the products obtained. Several examples of the aldol condenstion in water have been cited using various aldehydes and silyl enol ethers. The products were obtained in good yield (80-90%). In all the above reactions the catalyst could be recovered and used again and again. The above methodology has been extensively reviewed. 

Certain aldol condensations have been also carried out in solid state (Sec. 13.2.5). 

There has been a quite limited number of reports of clay-catalysed aldol condensations. One of the more interesting of these is the aluminium-exchanged montmorillonite (Al3+-mont) catalysed cross-aldol reaction of silyl enol ethers with aldehydes (Reaction 6).34 The reaction proceeded smoothly under mild conditions to give the corresponding aldol adduct in good yield. 

The diastereoselectivity of the reaction was independent of the catalyst but was affected by the nature of the solvent. The threo isomer was preferentially formed in toluene, while the erythro isomer was formed in 1,2-dimethoxy-ethane. The proton-exchanged montmorillonite (H+-mont) showed similar activity and diasteroselectivity to Al3+-mont. This fact suggests that the exchangeable Al3+ cations in the montmorillonite do not function as Lewis acid sites and it is the Bronsted acid sites that are essential for catalysis of the aldol reaction. 

H+- and Na+-exchanged montmorillonite showed only very low catalytic activity towards the oxidation. 

The first nan of -this reaction is technically called aidof addition but is sometimes referred in as aldol condensation, T e aldol to enal step is actually tlie condensation part of Ihe reaction and almost always accompanies aidol addition. Although complicated this reaction is easy to remember if yo-i keen in mind the acidity T the a-uydrogens am the planar configuration of the carbonyl, v hich makes it susceptible jo nucleophilic attack. You must know this reaction for i-.ii.AT 

Halogens add to ketones at the alpha carbon in the presence of a base or an arid-When a base is used, it is dffieult to prevent haJogdnation at more than one of the alpha positions. The base is also consumed by the reaction with water as a by-product, whereas the acid acts as a true catalyst and is not consumed. 

When a base is used with a methy] ketone, the alpha carbon will become completely halogenated. This trihalo product reacts further with the base to produce a carboxylic acid and a haloform (chloroform, CHCI j bromoform, CHBr, or iodoform, CHIj). This is called the Haloform Reaction. 

A more complicated case would exist if the second group necessary to key the transform was totally absent. In the example below, the only functional substructure capable of keying a transform would be the olefin. To perform the Aldol 

ACS Symposium Series American Chemical Society Washington, DC, 1977. 

Subgoal requests can be combined and mixed according to the situation. Next to be added is PGI then INTRO since not all groups may be INTRO ed. 

Four ring forming transforms have been considered at length by the LHASA development group - the Diels Alder addition, the Robinson Annelation, the Simmons-Smith reaction, and iodo-lactonization. The first three of these have been fully implemented in LHASA and the fourth is completely flow charted and awaits only coding into the chemistry data base language. 

Jasminaldehyde can be obtained classically from heptanal and benzaldehyde in 70% yield within 3 days at room temperature (Eq. 41). By use of a 600-W domestic micro-wave oven, however, an enhanced yield of 82% was achieved in only 1 min. The amount of side-products (self condensation of w-heptanal) decreased from 30 to 18% when this technique was used [62], 

A second example of aldolization (Eq. 42) is the dry reaction of ferrocene carbal-dehyde with carbonyl compounds in the presence of potassium hydroxide, and Aliquat as catalyst [63]. Reactions which are too slow at room temperature are efficiently accelerated by use of microwaves, giving good yields within a few minutes. 

Microwave activation and solvent-free PTC have been shown to be of prime efficiency for the synthesis of new benzylidene cineole derivatives (UV sunscreens) by the Knoevenagel reaction. When performed classically by use of KOH in ethanol at room temperature for 12 h (Eqs. 43 and 44) the yield was 30%. This was improved to 90-94% within 2-6 min under PTC + MW conditions (Tabs 5.17 and 5.18) [27, 28], 

R R Multimode oven (250 W) Monomode reactor (90 W) Classical heating 

From the few examples summarized in Tab. 5.19, three important conclusions can 

The catalytic conversion of ethanol and glycerol produces short aldehydes or ketones, which can be converted to more suitable molecular weight products. Aldol condensation reactions of these molecules lead also to the formation of G-C bonds. These reactions are generally catalyzed by bases. These types of condensation over solid bases lead mainly to aldol, ketol, or a,p-unsaturated carbonyl compounds. 

The reaction of acetaldehyde has also been studied on CeOg-based catalysts. CeOg was chosen as a support because its reducibility and basicity favor aldolization reactions.Three C-C bond formation reactions from acetaldehyde were observed aldolization to cro-tonaldehyde and crotyl alcohol (more prominent on CeOg alone), 

In order to transform the oxygenated compounds derived from biomass into valuable compounds, Dumesic and collaborators studied the aldol condensation/hydrogenation reaction of 2-hex-anone (as A model molecule) over a Pd/CeZrO catalysts at 350°C under 5 bar (Table 13.17). 

The primary product of aldol condensation/hydrogenation is Ci2 ketone, with the formation of Cg and Cjg ketones as secondary products. The selectivity towards Cjg products (essentially 

Catalyst Surface area (m. g- ) Total acidic sites (pmol-m ) Total basic sites (pmol-m ) Selectivity to MIBK (%) 

In Chapter 1 we mentioned that efficient alkylation of aldehydes and ketones requires essentially quantitative formation of their enolates. When a low concentration of an enolate ion is generated, it may react more competitively with the parent aldehyde or ketone present in the reaction mixture than it does with an alkyl halide. The aldol condensation reaction is this acid- or base-catalyzed self-condensation of 

CHAPTER 2 REACTIONS OF CARBON NUCLEOPHILES WITH CARBONYI. GROUPS 

The mechanism of the base-catalyzed reaction involves, in the carbon-carbon bond-forming step, the nucleophilic addition of an enolate ion to a carbonyl group. 

Under conditions of acid catalysis it is the enol which acts as the nucleophile and the protonated carbonyl is the electrophile. 

Modem Synthetic Reactions, second edition, W. A. Benjamin, Menlo Park, California (1972), pp. 629-682. 

Aldehydes and ketones are deprotonated by strong bases to give enolates. These can then reaet with a seeond aldehyde or ketone, whieh ean then eliminate water, e.g. 

For unsymmetrieal ketones, two eondensation produets are possible. For example, intramolecular condensation of 2,7-octadione may lead to products which follow from the two possible enolates. 

Electrostatic potential map for 2,7-octadione shows positively charged regions (in blue) as likely acidic sites. 

Examine atomic charges and display the electrostatic potential map for 2,7-octadione. Are you able to say which hydrogens (at Ci or at C3) are more likely to be abstracted by base, and conclude which is the kinetically-favored enolate Which enolate (2,7-octadione, Cl enolate or C3 enolate) is the lower in energy What do you conclude is the thermodynamically-favored enolate Is this also the enolate in which the negative charge is better delocalized Compare electrostatic potential maps to tell. 

Finally, examine the transition states for closure of the Ci enolate to the 7-membered ring product, and of the C3 enolate to the 5-membered ring product. Calculate activation energy barriers from their respective enolates. Which ring closure (to the five or the seven-membered ring) occurs more readily  

There are several useful esters that cannot enolize and, thereby, cannot act as enol partner. The four shown below are the most important, of which first three are more electrophilic than most esters, so they should acylate an ester enolate faster than the ester being enolized  

Diethyl oxalate Ethyl formate Diethyl carbonate Ethyl benzoate 

Diamine-functionahzed mesoporous SBA-15 materials have been also synthesized and applied to Knoevenagel reaction of benzaldehyde with ethyl cyanoacetate to form the a,p-unsaturated compound [79]. The heterogeneous diamine-functionalized SBA-15 showed excellent catalytic activity compared to aminopropyl-functionahzed material in the Knoevenagel reaction due to two amine sites which might have a synergistic effect in the reaction. 

Aldol condensations are universal reactions in organic chemistry, from the synthesis of small molecules to the well-designed intermediates of drugs. Among the many organocatalysts for aldol condensation that have been developed so far are the aminofunctional group, i-proline, and ILs. lin and coworkers reported a new cooperative catalytic system comprising a series of bifunctionalized 

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Cannizzaro reaction Two molecules of many aldehydes, under the influence of dilute alkalis, will interact, so that one is reduced to the corresponding alcohol, while the other is oxidized to the acid. Benzaldehyde gives benzyl alcohol and benzoic acid. Compare the aldol condensation. 

Both precursors can be used as reactants in an aldol condensation. It has to be emphasized that the chlorine atom in 4 has to be considered as a representative for any electron-withdrawing group in particular, in the case presented here, it would best be taken as an OEt group. In order to verify this proposal, a reaction substructure search is initiated in the Chcmlnform reaction database of 1997. 

When a mixture of aniline, hydrochloric acid and acetaldehyde is heated (in the absence of an oxidising agent), a vigorous reaction occurs with the pro duction of quinaldine. In these circumstances, the main reactions are undoubtedly, (i) the acetaldehyde undergoes the aldol condensation, and the... 

With concentrated alkali, a resin is formed from repeated aldol condensations between aldol, crotonaldehyde and acetaldehyde. A similar condensation occurs with acetone (b.p. 56°), but the equilibrium mixture contains only a few per cent, of diacetone alcohol (III), b.p. 166° ... 

Clalsen aldol condensation. This consists in the condensation of an aromatic aldehyde and an ester R—CHjCOOCjHj in the presence of finely divided sodium and a trace of alcohol at a low temperature. The catalyst is the alkoxide ion aqueous alkalis caimot be employed since they will hydrolyse the resulting ester. The product is an ap-unsaturated ester, for example ... 

The mechanism of the reaction between aromatic aldehydes and esters probably involves the intermediate formation of an aldol (hence the name— Claisen aldol condensation) ... 

Diastereoselective Aldol Condensation with Boron Enolates... 

AJdoJ Condensation -Aldol condensation Initially give p-hydroxy ketones which under certain conditions readily eliminated to give a,p-unsaturated carbonyls. 

Robinson Annulation Sequential Michael addition/aldol condensation between a ketone enolate and an alkyl vinyl ketone (i.e. MVK) to give a cyclohex-2-en-l-one... 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

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. 

Ni(N03)2 6H20, Cu(N03)2 3H20, Zn(N03)2-4H20 and KNOj were of the highest purity available. Substituted 3-phenyl-l-(2-pyridyl)-2-propene-ones (2.4a-e) were prepared by an aldol condensation of the corresponding substituted benzaldehyde with 2-acetylpyridine, following either of two modified... 

A regioselective aldol condensation described by Biichi succeeds for sterical reasons (G. Biichi, 1968). If one treats the diaidehyde given below with acid, both possible enols are probably formed in a reversible reaaion. Only compound A, however, is found as a product, since in B the interaction between the enol and ester groups which are in the same plane hinders the cyclization. BOchi used acid catalysis instead of the usual base catalysis. This is often advisable, when sterical hindrance may be important. It works, because the addition of a proton or a Lewis acid to a carbonyl oxygen acidifies the neighbouring CH-bonds. 

The early Escherunoser-Stork results indicated, that stereoselective cyclizations may be achieved, if monocyclic olefins with 1,5-polyene side chains are used as substrates in acid treatment. This assumption has now been justified by many syntheses of polycyclic systems. A typical example synthesis is given with the last reaction. The cyclization of a trideca-3,7-dien-11-ynyl cyclopentenol leads in 70% yield to a 17-acetyl A-norsteroid with correct stereochemistry at all ring junctions. Ozonolysis of ring A and aldol condensation gave dl-progesterone (M.B. Gravestock, 1978 see p. 279f.). 

In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

Difunctional target molecules are generally easily disconnected in a re/ro-Michael type transform. As an example we have chosen a simple symmetrical molecule, namely 4-(4-methoxyphenyl)-2,6-heptanedione. Only p-anisaldehyde and two acetone equivalents are needed as starting materials. The antithesis scheme given helow is self-explanatory. The aldol condensation product must be synthesized first and then be reacted under controlled conditions with a second enolate (e.g. a silyl enolate plus TiCl4 or a lithium enolate), enamine (M. Pfau, 1979), or best with acetoacetic ester anion as acetone equivalents. 

Allyl aryl ethers are used for allylation under basic conditionsfh], but they can be cleaved under neutral conditions. Formation of the five-membered ring compound 284 based on the cyclization of 283 has been applied to the syntheses of methyl jasmonate (285)[15], and sarkomycin[169]. The trisannulation reagent 286 for steroid synthesis undergoes Pd-catalyzed cyclization and aldol condensation to afford CD rings 287 of steroids with a functionalized 18-methyl group 170]. The 3-vinylcyclopentanonecarboxylate 289, formed from 288, is useful for the synthesis of 18-hydroxyestrone (290)[I7I]. 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

Acetoxy-l,7-octadiene (40) is converted into l,7-octadien-3-one (124) by hydrolysis and oxidation. The most useful application of this enone 124 is bisannulation to form two fused six-membered ketonesfl 13], The Michael addition of 2-methyl-1,3-cyclopentanedione (125) to 124 and asymmetric aldol condensation using (5)-phenylalanine afford the optically active diketone 126. The terminal alkene is oxidi2ed with PdCl2-CuCl2-02 to give the methyl ketone 127 in 77% yield. Finally, reduction of the double bond and aldol condensation produce the important intermediate 128 of steroid synthesis in optically pure form[114]. 

The method was applied to the synthesis of (-t-)-l9-nortestosterone by the following sequence of reactions. Michael addition of the bisannulation reagent 124 to the optically active keto ester 129 and decarboxylation afforded 130, and subsequent aldol condensation gave 131. Selective Pd-catalyzed oxidation of the terminal double bond afforded the diketone 132 in 78% yield. Reduction of the double bond and aldol condensation gave ( + )-19-nortestosterone (133)[114]. 

The 3.8-nonadienoate 91, obtained by dimerization-carbonylation, has been converted into several natural products. The synthesis of brevicomin is described in Chapter 3, Section 2.3. Another royal jelly acid [2-decenedioic acid (149)] was prepared by cobalt carbonyl-catalyzed carbonylation of the terminal double bond, followed by isomerization of the double bond to the conjugated position to afford 149[122], Hexadecane-2,15-dione (150) can be prepared by Pd-catalyzed oxidation of the terminal double bond, hydrogenation of the internal double bond, and coupling by Kolbe electrolysis. Aldol condensation mediated by an organoaluminum reagent gave the unsaturated cyclic ketone 151 in 65% yield. Finally, the reduction of 151 afforded muscone (152)[123]. n-Octanol is produced commercially as described beforc[32]. 

Category Ih cyclizations effect closure of the C2 C3 bond. Scheme 3.1 depicts retrosynthetic transformations corresponding to syntheses in category lb. Included are three variations of the intramolecular aldol condensation and reductive coupling of o,/V-diacylanilines,... 

A number of aldehydes and ketones are prepared both m industry and m the lab oratory by a reaction known as the aldol condensation which will be discussed m detail in Chapter 18... 

Reactions in which two molecules of an aldehyde combine to form an a p unsat urated aldehyde and a molecule of water are called aldol condensations... 

Write the structure of the aldol condensation product of eacfT... 

Product of aldol condensation of pentanal (2 propyl 2 heptenal)... 

Aldol condensations of dicarbonyl compounds—even diketones—occur mtramo lecularly when five or six membered rings are possible... 

Aldol condensations are one of the fundamental carbon-carbon bond forming processes of synthetic organic chemistry Furthermore because the products of these aldol con densations contain functional groups capable of subsequent modification access to a host of useful materials is gamed... 

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