Aldol reaction

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The aldol reaction is a means of forming carbon–carbon bonds in organic chemistry.^[1][2][3] Discovered independently byCharles-Adolphe Wurtz^[4][5][6] and Alexander Borodin in 1872,^[7] the reaction combines two carbonyl compounds (the original experiments used aldehydes) to form a new β-hydroxy carbonyl compound. These products are known as aldols, from thealdehyde + alcohol, a structural motif seen in many of the products. Aldol structural units are found in many important molecules, whether naturally occurring or synthetic.^[8][9][10] For example, the aldol reaction has been used in the large-scale production of the commodity chemical pentaerythritol^[11] and the synthesis of the heart disease drug Lipitor (atorvastatin, calcium salt).^[12][13]

The aldol reaction unites two relatively simple molecules into a more complex one. Increased complexity arises because up to two new stereogenic centers (on the α- and β-carbon of the aldol adduct, marked with asterisks in the scheme below) are formed. Modern methodology is capable of not only allowing aldol reactions to proceed in high yield but also controlling both the relative and absolute stereochemical configuration of these stereocenters. This ability to selectively synthesize a particular stereoisomer is significant because different stereoisomers can have very different chemical and biological properties.

For example, stereogenic aldol units are especially common in polyketides, a class of molecules found in biological organisms. In nature, polyketides are synthesized by enzymes that effect iterative Claisen condensations. The 1,3-dicarbonyl products of these reactions can then be variously derivatized to produce a wide variety of interesting structures. Often, such derivitization involves the reduction of one of the carbonyl groups, producing the aldol subunit. Some of these structures have potent biological properties: the immunosuppressant FK506, the anti-tumor agent discodermolide, or the antifungal agent amphotericin B, for example. Although the synthesis of many such compounds was once considered nearly impossible, aldol methodology has allowed their efficient synthesis in many cases.^[14]

A typical modern aldol addition reaction, shown above, might involve the nucleophilic addition of a ketone enolate to analdehyde. Once formed, the aldol product can sometimes lose a molecule of water to form an α,β-unsaturated carbonyl compound. This is called aldol condensation. A variety of nucleophiles may be employed in the aldol reaction, including theenols, enolates, and enol ethers of ketones, aldehydes, and many other carbonyl compounds. The electrophilic partner is usually an aldehyde or ketone (many variations, such as the Mannich reaction, exist). When the nucleophile and electrophile are different, the reaction is called a crossed aldol reaction; on the converse, when the nucleophile and electrophile are the same, the reaction is called an aldol dimerization.

Mechanisms[edit]

The aldol reaction may proceed via two fundamentally different mechanisms. Carbonyl compounds, such as aldehydes and ketones, can be converted to enols or enol ethers. These species, being nucleophilic at the α-carbon, can attack especially reactive protonated carbonyls such as protonated aldehydes. This is the 'enol mechanism'. Carbonyl compounds, beingcarbon acids, can also be deprotonated to form enolates, which are much more nucleophilic than enols or enol ethers and can attack electrophiles directly. The usual electrophile is an aldehyde, since ketones are much less reactive. This is the 'enolate mechanism'.

If the conditions are particularly harsh (e.g.: NaOMe/MeOH/reflux), condensation may occur, but this can usually be avoided with mild reagents and low temperatures (e.g., LDA (a strong base), THF, −78 °C). Although the aldol addition usually proceeds to near completion under irreversible conditions, the isolated aldol adducts are sensitive to base-induced retro-aldol cleavage to return starting materials. In contrast, retro-aldol condensations are rare, but possible.^[15]

Enol mechanism[edit]

When an acid catalyst is used, the initial step in the reaction mechanism involves acid-catalyzed tautomerization of the carbonyl compound to the enol. The acid also serves to activate the carbonyl group of another molecule by protonation, rendering it highly electrophilic. The enol is nucleophilic at the α-carbon, allowing it to attack the protonated carbonyl compound, leading to the aldol after deprotonation. This usually dehydrates to give the unsaturated carbonyl compound. The scheme shows a typical acid-catalyzed self-condensation of an aldehyde.

Acid-catalyzed aldol mechanism

Acid-catalyzed dehydration

Enolate mechanism[edit]

If the catalyst is a moderate base such as hydroxide ion or an alkoxide, the aldol reaction occurs via nucleophilic attack by the resonance-stabilized enolate on the carbonyl group of another molecule. The product is the alkoxide salt of the aldol product. The aldol itself is then formed, and it may then undergo dehydration to give the unsaturated carbonyl compound. The scheme shows a simple mechanism for the base-catalyzed aldol reaction of an aldehyde with itself.

Base-catalyzed aldol reaction (shown using ⁻OCH₃ as base)

Base-catalyzed dehydration (frequently written incorrectly as a single step, see E1cB elimination reaction)

Although only a catalytic amount of base is required in some cases, the more usual procedure is to use a stoichiometricamount of a strong base such as LDA or NaHMDS. In this case, enolate formation is irreversible, and the aldol product is not formed until the metal alkoxide of the aldol product is protonated in a separate workup step.

Zimmerman–Traxler model[edit]

More refined forms of the mechanism are known. In 1957, Zimmerman and Traxler proposed that some aldol reactions have "six-membered transition states having a chair conformation."^[16] This is now known as the Zimmerman–Traxler model. E-enolates give rise to anti products, whereas Z-enolates give rise to syn products. The factors that control selectivity are the preference for placing substituents equatorially in six-membered transition states and the avoidance of syn-pentane interactions, respectively.^[17] E and Z refer to the cis-trans stereochemical relationship between the enolate oxygen bearing the positive counterion and the highest priority group on the alpha carbon. In reality, only some metals such as lithium and boron reliably follow the Zimmerman–Traxler model. Thus, in some cases, the stereochemical outcome of the reaction may be unpredictable.

Crossed-aldol reactant control[edit]

The problem of "control" in the aldol addition is best demonstrated by an example. Consider the outcome of this hypothetical reaction:

In this reaction, two unsymmetrical ketones are being condensed using sodium ethoxide. The basicity of sodium ethoxide is such that it cannot fully deprotonate either of the ketones, but can produce small amounts of the sodium enolate of both ketones. This me