Aldol reaction

The aldol reaction (aldol addition) is a reaction in organic chemistry that combines two carbonyl compounds (e.g. aldehydes or ketones) 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.^[2][3][4]

The aldol reaction is

Aldol structural units are found in many important molecules, whether naturally occurring or synthetic.^[8][9] The reaction is used in several industrial syntheses, notably of pentaerythritol,^[10] trimethylolpropane, the plasticizer 2-ethylhexanol, and the drug Lipitor (atorvastatin, calcium salt).^[11] 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.

Mechanisms

The aldol reaction has one underlying mechanism, but it appears in different forms depending on pH:^[12]

α-carbon

, can attack another reactive carbonyl. 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.

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.^[13] 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.^[14] This is the basis of the catalytic strategy of class I aldolases in nature, as well as numerous small-molecule amine catalysts.^[15]

When a mixture of unsymmetrical ketones are reacted, four crossed-aldol (addition) products can be anticipated:

Thus, if one wishes to obtain only one of the cross-products, one must control which carbonyl becomes the nucleophilic enol/enolate and which remains in its electrophilic carbonyl form. The simplest control is if only one of the reactants has acidic protons, and only this molecule forms the enolate. 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 and 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

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 (or higher order) 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 (or screen). 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.^[18] Boron is often used^[19][20] because its bond lengths are significantly shorter than other cheap metals (lithium, aluminium, or magnesium). The following reaction gives a syn:anti ratio of 80:20 using a lithium enolate compared to 97:3 using a bibutylboron enolate.

Where the counterion determines stereoinduction strength, the enolate isomer determines its direction. E isomers give anti products and Z give syn:^[21]

Zimmermann-Traxler model

If the two reactants have carbonyls adjacent to a pre-existing stereocenter, then the new stereocenters may

If the enol has an adjacent stereocenter, then the two stereocenters flanking the carbonyl in the product are always syn:[23]

However, 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:^[24]

On the electrophile

E enolates exhibit

Since the

rotamer, Z-enolates are less diastereoselective:^[27][28]

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.[29] Several examples are as follows:^[28]

Oxazolidinone chiral auxiliaries

In the late 1970s and 1980s,

Commercial oxazolidinones are relatively expensive, but derive in 2 synthetic steps from comparatively inexpensive amino acids. (Economical large-scale syntheses prepare the auxiliary in-house.) 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:^[32]

Often, a single diastereomer may be obtained by one crystallization of the aldol adduct.

Many methods cleave the auxiliary:^[33]

Variations

A common additional chiral auxiliary is a

Crimmins thiazolidinethione aldol

In the Crimmins thiazolidinethione approach,^[35][36] a thiazolidinethione is the chiral auxiliary^[37] and can produce the "Evans syn" or "non-Evans syn" adducts by simply varying the amount of (−)-sparteine. The reaction is believed to proceed via six-membered, titanium-bound transition states, analogous to the proposed transition states for the Evans auxiliary.

"Masked" enols

A common modification of the aldol reaction uses other, similar functional groups as ersatz enols. In the

In the Stork enamine alkylation, secondary amines form enamines when exposed to ketones. These enamines then react (possibly enantio­selectively^[41]) with suitable electrophiles. This strategy offers simple enantioselection without transition metals. In contrast to the preference for syn adducts typically observed in enolate-based aldol additions, these aldol additions are anti-selective.

In aqueous solution, the enamine can then be hydrolyzed from the product, making it a small organic molecule catalyst. In a seminal example, proline efficiently catalyzed the cyclization of a triketone:

This combination is the

A Stork-type strategy also allows the otherwise challenging cross-reactions between two aldehydes. In many cases, the conditions are mild enough to avoid polymerization:[45]

However, selectivity requires the slow syringe-pump controlled addition of the desired electrophilic partner because both reacting partners typically have enolizable protons. If one aldehyde has no enolizable protons or alpha- or beta-branching, additional control can be achieved.

"Direct" aldol additions

In the usual aldol addition, a carbonyl compound is deprotonated to form the enolate. The enolate is added to an aldehyde or ketone, which forms an alkoxide, which is then protonated on workup. A superior method, in principle, would avoid the requirement for a multistep sequence in favor of a "direct" reaction that could be done in a single process step.

If one coupling partner preferentially enolizes, then the general problem is that the addition generates an alkoxide, which is much more basic than the starting materials. This product binds tightly to the enolizing agent, preventing it from catalyzing additional reactants:

One approach, demonstrated by Evans, is to silylate the aldol adduct.

TMSCl is added in the reaction, which replaces the metal on the alkoxide, allowing turnover of the metal catalyst:

The aldol dimerization of alpha-oxyaldehydes requires that the aldol adduct, itself an aldehyde, be inert to further aldol reactions.^[48] Earlier studies revealed that aldehydes bearing alpha-alkyloxy or alpha-

Biological aldol reactions

Examples of aldol reactions in biochemistry include the splitting of

Howard Zimmerman and Marjorie D. Traxler proposed their model for stereoinduction in a 1957 paper.^[22]

See also

• Aldol–Tishchenko reaction
• Baylis–Hillman reaction
• Ivanov reaction
• Reformatsky reaction
• Claisen-Schmidt condensation

Notes

References