Aldol reaction

The aldol reaction is a reaction in organic chemistry that combines two carbonyl compounds to form a new β-hydroxy carbonyl compound. Its simplest form might involve the nucleophilic addition of an enolized ketone to another:
These products are known as aldols, from the aldehyde + alcohol, a structural motif seen in many of the products. The use of aldehyde in the name comes from its history: aldehydes are more reactive than ketones, so that the reaction was discovered first with them.
The aldol reaction is paradigmatic in organic chemistry and one of the most common means of forming carbon–carbon bonds in organic chemistry. It lends its name to the family of aldol reactions and similar techniques analyze a whole family of carbonyl α-substitution reactions, as well as the diketone condensations.

Scope

Aldol structural units are found in many important molecules, whether naturally occurring or synthetic. The reaction is well used on an industrial scale, notably of pentaerythritol, trimethylolpropane, the plasticizer precursor 2-ethylhexanol, and the drug Lipitor. For many of the commodity applications, the stereochemistry of the aldol reaction is unimportant, but the topic is of intense interest for the synthesis of many specialty chemicals.

Aldol dimerization

In its simplest implementation, base induces conversion of an aldehyde or a ketone to the aldol product. One example involves the aldol condensation of propionaldehyde:
Featuring the RCHCHR'CR" grouping, the product is an aldol. In this case R =, R' =, and R" = H. Such reactions are called aldol dimerization.

Cross-aldol

With a mixture of carbonyl precursors, complicated mixtures can occur. Addition of base to a mixture of propionaldehyde and acetaldehyde, one obtains four products:
The first two products are the result of aldol dimerization but the latter two result from a crossed aldol reaction. Complicated mixtures from cross aldol reactions can be avoided by using one component that cannot form an enolate, examples being formaldehyde and benzaldehyde. This approach is used in one stage in the production of trimethylolethane, which entails crossed aldol condensation of butyraldehyde and formaldehyde:

Reactions of aldols

Aldols dehydrate:
Because this conversion is facile, it is sometimes assumed. It is for this reason that the aldol reaction is sometimes called the aldol condensation.

Mechanisms

The aldol reaction has one underlying mechanism: a carbanion-like nucleophile attacks a carbonyl center.
If the base is of only moderate strength 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.
Although only a catalytic amount of base is required in some cases, the more usual procedure is to use a stoichiometric amount 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.
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. Some may also dehydrate past the intended product to give the unsaturated carbonyl compound through aldol condensation.

Crossed-aldol reactant control

Despite the attractiveness of the aldol manifold, there are several problems that need to be addressed to render the process effective. The first problem is a thermodynamic one: most aldol reactions are reversible. Furthermore, the equilibrium is also just barely on the side of the products in the case of simple aldehyde–ketone aldol reactions.
A key distinction is whether the conditions dehydrate the product to an enone. In mild conditions, the product is a aldol, and the base catalyzes retro-aldol cleavage of the product. The reaction must be driven by e.g. distillation. Under harsher conditions, the product dehydrates practically irreversibly, and the reaction completes spontaneously. Hydration followed by retro-aldol cleavage is possible, but rare without dedicated catalysis. Dehydration is also the catalytic strategy of class I aldolases and numerous small-molecule amine catalysts.
When a mixture of unsymmetrical ketones are reacted, four crossed-aldol products can be anticipated: To obtain only one product, one must control which carbonyl becomes the nucleophilic enol/enolate and which remains in its electrophilic carbonyl form.
The simplest control occurs when only one reactant has acidic protons: that molecule must enolize. For example, the addition of diethyl malonate into benzaldehyde produces only one product:
If one group is considerably more acidic than the other, the most acidic proton is abstracted by the base. An enolate is formed at that carbonyl while the less-acidic carbonyl remains electrophilic. This type of control works only if the difference in acidity is large enough and base is the limiting reactant. A typical substrate for this situation is when the deprotonatable position is activated by more than one carbonyl-like group. Common examples include a CH₂ group flanked by two carbonyls or nitriles.
Otherwise, the most acidic carbonyls are typically also the most active electrophiles: first aldehydes, then ketones, then esters, and finally amides. Thus cross-aldehyde reactions are typically most challenging because they can polymerize easily or react unselectively to give a statistical mixture of products.
One common solution assumes kinetic control. In that case, the forward aldol addition is significantly faster than the retro-aldol reverse and faster than enolate transfer from one partner to another. Thus one can first form the desired partner's enolate quantitatively, then simply add the other partner. Common kinetic control conditions involve ketone enolization with LDA at −78 °C, followed by the slow addition of an aldehyde.

Stereoselectivity

The aldol reaction unites two relatively simple molecules into a more complex one. Increased complexity arises because each end of the new bond may become a stereocenter. Modern methodology has not only developed high-yielding aldol reactions, but also completely controls both the relative and absolute configuration of these new stereocenters.
To describe relative stereochemistry at the α- and β-carbon, older papers use saccharide chemistry's erythro/threo nomenclature; more modern papers use the following syn/''anti convention. When propionate nucleophiles add to aldehydes, the reader visualizes the R'' group of the ketone and the R' group of the aldehyde aligned in a "zig zag" pattern on the paper. The disposition of the formed stereocenters is deemed syn or anti, depending if they are on the same or opposite sides of the main chain:
The principal factor determining an aldol reaction's stereoselectivity is the enolizing metal counterion. Shorter metal-oxygen bonds "tighten" the transition state and effects greater stereoselection. Boron is often used because its bond lengths are significantly shorter than other cheap metals. The following reaction gives a syn:anti ratio of 80:20 using a lithium enolate compared to 97:3 using a dibutylboron enolate.
Where the counterion determines stereoinduction strength, the enolate isomer determines its direction. E isomers give anti products and Z give syn:

Zimmermann–Traxler model

If the two reactants have carbonyls adjacent to a pre-existing stereocenter, then the new stereocenters may form at a fixed orientation relative to the old. This "substrate-based stereocontrol" has seen extensive study and examples pervade the literature. In many cases, a stylized transition state, called the Zimmerman–Traxler model, can predict the new orientation from the configuration of a 6-membered ring.

On the enol

If the enol has an adjacent stereocenter, then the two stereocenters flanking the carbonyl in the product are naturally syn:
The underlying mechanistic reason depends on the enol isomer. For an E enolate, the stereoinduction is necessary to avoid 1,3-allylic strain, while a Z enolate instead seeks to avoid 1,3-diaxial interactions:
However, Fráter & Seebach showed that a chelating Lewis basic moiety adjacent to the enol will instead cause anti addition.

On the electrophile

E enolates exhibit Felkin diastereoface selection, while Z enolates exhibit anti-Felkin selectivity. The general model is presented below:
Since the transition state for Z enolates must contain either a destabilizing syn-pentane interaction or an anti-Felkin rotamer, Z-enolates are less diastereoselective:

On both

If both the enolate and the aldehyde contain pre-existing chirality, then the outcome of the "double stereodifferentiating" aldol reaction may be predicted using a merged stereochemical model that takes into account all the effects discussed above. Several examples are as follows:

Oxazolidinone chiral auxiliaries

In the late 1970s and 1980s, David A. Evans and coworkers developed a technique for stereoselection in the aldol syntheses of aldehydes and carboxylic acids. The method works by temporarily appending a chiral oxazolidinone auxiliary to create a chiral enolate. The pre-existing chirality from the auxiliary is then transferred to the aldol adduct through Zimmermann-Traxler methods, and then the oxazolidinone cleaved away.
Commercial oxazolidinones are relatively expensive, but derive in 2 synthetic steps from comparatively inexpensive amino acids. First, a borohydride reduces the acid moiety. Then the resulting amino alcohol dehydratively cyclises with a simple carbonate ester, such as diethylcarbonate.
The acylation of an oxazolidinone is informally referred to as "loading done".
Anti adducts, which require an E enolate, cannot be obtained reliably with the Evans method. However, Z enolates, leading to syn adducts, can be reliably formed using boron-mediated soft enolization:
Often, a single diastereomer may be obtained by one crystallization of the aldol adduct.
Many methods cleave the auxiliary: