Aldol reaction acid-catalyzed mechanism

In the aldol reaction,the a carbon of one aldehyde or ketone molecule adds to the carbonyl carbon of another. Although acid-catalyzed aldol reactions are known,the most common form of the reaction uses a base. There is evidence that an SET mechanism can intervene when the substrate is an aromatic ketone. " Although hydroxide was commonly used in early versions of this reaction, stronger bases, such as alkoxides (RO ) or amides (R2N ), are also common. Amine bases have been used. Hydroxide ion is not a strong enough base to convert substantially all of an aldehyde or ketone molecule to the corresponding enolate ion, that is., the equilibrium lies well to the left, for both aldehydes and... 

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

The carbon-carbon bond-forming step of the acid-catalyzed aldol reaction has an enol (allylic source) attacking a protonated carbonyl (which is just a lone-pair-stabilized carbocation). With those hints, give a mechanism for the acid-catalyzed aldol reaction. 

The mechanism of an acid-catalyzed aldol reaction involves three steps, the first two of which are preparation of the aldehyde or ketone for formation of the new carbon-carbon bond. The key step is attack of the enol of one molecule on the protonated carbonyl group of a second molecule. 

The mechanism of the acid-catalyzed aldol reaction involves an initial acid-catalyzed keto-enol tautomerization to provide the enol form protonation of a second molecule on the carbonyl oxygen creates an electrophilic oxonium ion that is then attacked by the nucleophilic enol, followed by loss of a proton to give the j8-hydroxy aldehyde or ketone product. 

Propose a mechanism for this acid-catalyzed aldol reaction and the dehydration of the resulting aldol product. 

The detailed mechanism of this enantioselective transformation remains under investigation.178 It is known that the acidic carboxylic group is crucial, and the cyclization is believed to occur via the enamine derived from the catalyst and the exocyclic ketone. A computational study suggested that the proton transfer occurs through a TS very similar to that described for the proline-catalyzed aldol reaction (see page 132).179... 

Aldehydes and ketones also undergo acid-catalyzed aldol condensations. Devise a mechanism for this reaction in which an enol is an intermediate. 

For the proline- and proline congener-catalyzed aldol reaction [23, 24], a mechanism based on enamine formation is proposed [25], Scheme 7. The catalytic process starts with condensation of the secondary amino group of proline with a carbonyl substrate leading to a nucleophilic enamine intermediate, which mimics the condensation of the active-site lysine residue with a carbonyl substrate in type I aldolases. The adjacent carboxylic acid group of the enamine intermediate... 

It was suggested73 that the most probable mechanism of this reaction is an initial aldol condensation of the starting ketone leading to the a,/ -unsaturated ketone 100 or to the /Miydroxyketone 101 which serve as precursors to the tertiary carbenium ions 102, which reacts in turn with nitriles by an acid-catalyzed Ritter reaction to give 103 (equation 36). This suggestion is confirmed by the results of a cross-reaction experiment of benzaldehyde and diethyl malonate with acetonitrile to give 14 (equation 37). 

Computational studies suggest that the mechanism of the proline catalyzed aldol cyclization is best described by the nucleophilic addition of the neutral enamine to the carbonyl group together with hydrogen transfer from the proline carboxylic acid moiety to the developing alkoxide. A metal-free partial Zimmerman-Traxler-type transition state involving a chair-like arrangement of enamine and carbonyl atoms and the participation of only one proline molecule has been established [118,119]. On the basis of density functional theory (DFT) calculations Cordova and co-workers [120,121] have studied the primary amino acid intermolecular aldol reaction mechanism. They demonstrated that only one amino acid molecule is involved in the... 

Problem 21.12 In acid-catalyzed aldol condensations acid is believed to perform two functions to catalyze conversion of carbonyl compound into the enol form, and to provide protonated carbonyl compound with which the enol can react. The reaction that then takes place can, depending upon one s point of view, be regarded either as acid-catalyzed nucleophilic addition to a carbonyl group, or as electrophilic addition to an alkene. On this basis, write all steps in the mechanism of acid-catalyzed aldol condensation of acetaldehyde. In the actual condensation step, identify the nucleophile and the electrophile. 

The mechanism of the amino acid-catalyzed Mannich reactions is depicted in Scheme 4.14. Accordingly, the ketone or aldehyde donor reacts with the amino acid to give an enamine. Next, the preformed or in situ- generated imine reacts with the enamine to give after hydrolysis the enantiomerically enriched Mannich product, and the catalytic cycle can be repeated. It is important to bear in mind that N-Chz-, N- Boc-, or A-benzoyl-protected imines are water-sensitive. Thus, they can hydrolyze and thereby decrease the yield of the transformation. Moreover, in the case of cross-Mannich-type addition with aldehydes as nucleophiles the catalytic self-aldolization pathway can compete with the desired pathway and lead to nonlinear effects [63]. 

The mechanism involves an aldol reaction with dehydration, followed by a Michael addition, and then an intramolecular aldol with dehydration (all base catalyzed). Loss of the two ester groups begins with an acid-catalyzed hydrolysis, followed by decarboxylation of each of the resulting carboxylic adds. 

Although such reactions may be catalyzed by either acid or base, base catalysis is more common. The key step in a base-catalyzed aldol reaction is nucleophilic addition of the enolate anion of one carbonyl-containing molecule to the carbonyl group of another to form a tetrahedral carbonyl addition intermediate. This mechanism is illustrated by the aldol reaction between two molecules of acetaldehyde. Notice in this three-step mechanism that OH is a catalyst an OH is used in Step 1, but another OH is generated in Step 3. 

You might compare the mechanisms of the acid- and base-catalyzed aldol reactions. Under base catalysis, the carbon-carbon bond-forming step involves attack of an enolate anion (a nucleophile) on the uncharged carbonyl carbon (an electrophile) of a second molecule of the aldehyde or ketone. Under acid catalysis, it involves attack of the enol (a nucleophile) of one molecule on the protonated carbonyl group (an electrophile) of the second molecule. 

When acetaldehyde is treated with aqueous acid, an aldol reaction can occur. In other words, aldol reactions can also occur in acidic conditions, although the intermediate is different than the intermediate involved in the base-catalyzed reaction. Draw a mechanism for the acid-catalyzed process. 

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]. 

The mechanism of the cycloaddition reaction of benzaldehyde 2a with Danishefsky s diene 3a catalyzed by aluminum complexes has been investigated theoretically using semi-empirical calculations [14]. It was found that the reaction proceeds as a step-wise cycloaddition reaction with the first step being a nucleophilic-like attack of Danishefsky s diene 2a on the coordinated carbonyl compound leading to an aldol-like intermediate which is stabilized by interaction of the cation with the oxygen atom of the Lewis acid. The next step is the ring-closure step, giving the cycloaddition product. 

Judging from these findings, the mechanism of Lewis acid catalysis in water (for example, aldol reactions of aldehydes with silyl enol ethers) can be assumed to be as follows. When metal compounds are added to water, the metals dissodate and hydration occurs immediatdy. At this stage, the intramolecular and intermolecular exchange reactions of water molecules frequently occur. If an aldehyde exists in the system, there is a chance that it will coordinate to the metal cations instead of the water molecules and the aldehyde is then activated. A silyl enol ether attacks this adivated aldehyde to produce the aldol adduct. According to this mechanism, it is expected that many Lewis acid-catalyzed reactions should be successful in aqueous solutions. Although the precise activity as Lewis acids in aqueous media cannot be predicted quantitatively... 

The mechanism A very detailed mechanistic study of this phosphoramide-catalyzed asymmetric aldol reaction was conducted by the Denmark group (see also Section 6.2.1.2) [59, 60], Mechanistically, the chiral phosphoramide base seems to coordinate temporarily with the silicon atom of the trichlorosilyl enolates, in contrast with previously used chiral Lewis acids, e.g. oxazaborolidines, which interact with the aldehyde. It has been suggested that the hexacoordinate silicate species of type I is involved in stereoselection (Scheme 6.15). Thus, this cationic, diphosphoramide silyl enolate complex reacts through a chair-like transition structure. 

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