Aldol reaction

The aldol reaction is an important carbon-carbon bond forming reaction in organic chemistry involving the addition of an enol or enolate anion to an aldehyde or ketone. In the aldol addition, the reaction results in a β-hydroxy ketone (or aldehyde), also called an "aldol" (aldehyde + alcohol). In the aldol condensation, the initial aldol adduct undergoes dehydration (loss of water) to form an α,β-unsaturated ketone (or aldehyde).

The enol or enolate is itself generated from a carbonyl compound, often an aldehyde or ketone, using acid or base. If the enol or enolate is formed in situ, the process can be considered as an acid or base-catalyzed reaction of one carbonyl compound with another. This may involve one aldehyde or ketone reacting with itself. Alternatively two different carbonyl compounds may be used, in which case the reaction is known as a crossed aldol reaction. In the scheme shown, the enol or enolate of a methyl ketone reacts with an aldehyde.

If strong bases such as LDA are used, the enolate may be produced separately before the reaction, then an aldehyde slowly added at low temperature to produce the aldol product. Enolates of aldehydes can not be made using LDA, however, as they usually give side reactions.

In 1872, the aldol reaction was discovered independently by Charles-Adolphe Wurtz and by Alexander Porfyrevich Borodin. Borodin observed the formation of 3-hydroxybutanal from acetaldehyde under acidic conditions.

Mechanisms

If an aldehyde or ketone is converted to an enol or enolate, it becomes nucleophilic at the α-carbon. α,β-Unsaturated aldehydes or ketones can also be deprotonate to form vinylogous enolates. This allows it to attack an electrophilic component (a carbonyl or protonated carbonyl) to form the aldol. The aldol reaction may proceed under acidic or basic conditions, as shown above. If specific acid catalysis is used, the reaction involves a weak nucleophile (an enol) attacking a strong electrophile (the protonated carbonyl). Under basic conditions, a nucleophile (the enolate) is formed which is strong enough to react with the unprotonated carbonyl. Dehydration may or may not occur, depending on the conditions. If strong base and kinetic control (see below) are used, the intermediates do not equilibrate and the reaction becomes in effect irreversible.

Enol mechanism

When an acid catalyst is used, the initial step 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.

Enolate mechanism

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.

If a stronger base such as LDA or NaHMDS is used in stoichiometric amounts, the formation of the enolate becomes irreversible, and this helps to drive the reaction forward. In such cases the aldol product is not formed until a separate protonation step is performed. Otherwise, the mechanism can be regarded as the same.

More refined forms of the mechanism are known. In 1957, Zimmerman and Traxler proposed that some aldol reactions have "six-membered transition state^* having a chair conformation". This has become known as the Zimmerman-Traxler model. E-enolates give rise to anti products, whereas Z-enolates give rise to syn products. 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, with the result that the stereochemical outcome of the reaction may be unpredictable.

Control in the Aldol reaction

The problem

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. Effectively, this means that in addition to being potential aldol electrophiles, both ketones may also act as nucleophiles via their sodium enolate. Two electrophiles and two nucleophiles then potentially results in four possible products:

Thus, if one wishes to obtain only one of the cross-products, then one must "control" the aldol addition.

Acidity

If one partner is considerably more acidic than the other, then control may be automatic. For example, the addition of diethyl malonate into benzaldehyde would not be problematic:

In this case, the doubly activated methylene protons of the malonate would be preferentially deprotonated by sodium ethoxide and quantitatively form the sodium enolate. Since benzaldehyde has no acidic alpha-protons, there is only one possible nucleophile-electrophile combination; hence, control has been achieved. Note that this approach combines two elements of control: increased acidity of the alpha protons on the nucleophile and the lack of alpha protons on the electrophile.

Order of addition

One common solution is to form the enolate of one partner first, and then add the other partner under kinetic control . Kinetic control means that the forward aldol addition reaction must be significantly faster than the reverse retro-aldol reaction. For this approach to succeed, two other conditions must also be satisfied; namely, it must be possible to quantitatively form the enolate of one partner and the forward aldol reaction must be significantly faster than the transfer of the enolate from one partner to another. Common kinetic control conditions involve the formation of the enolate of a ketone with LDA at -78 °C, followed by the slow addition of an aldehyde.

Enolates

Formation

Enolization may be effected using a strong base ("hard conditions") or using a Lewis acid and a weak base ("soft conditions"):

For deprotonation to occur, the stereoelectronic requirement is that the alpha-C-H sigma bond must be able to overlap with the pi* orbital of the carbonyl:

Geometry

Extensive studies have been performed on the formation of enolates under many different conditions. It is now possible to generate, in most cases, the desired enolate geometry:

For ketones, most enolization conditions give Z enolates. For esters, most enolization conditions give E enolates. The addition of HMPA is known to reverse the stereoselectivity of deprotonation.

The stereoselective formation of enolates has been rationalized with the so-called Ireland model, although its validity is somewhat questionable. In most cases, it is not known which, if any, intermediates are monomeric or oligomeric in nature; nonetheless, the Ireland model remains a useful tool for understanding enolates.

Kinetic vs. thermodynamic enolates

If an unsymmetrical ketone is subjected to base, it has the potential to form two regioisomeric enolates (ignoring enolate geometry). For example:

The trisubstituted enolate is considered the kinetic enolate while the tetrasubstitued enolate is considered the thermodynamic enolate. The alpha hydrogen deprotonated to form the kinetic enolate is less hindered, and therefore deprotonated more quickly. In general, tetrasubstituted olefins are more stable than trisubstituted olefins due to hyperconjugative stabilization. The ratio of enolate regioisomers is heavily influenced by the choice of base. For the above example, kinetic control may be established with LDA at -78C, giving 99:1 selectivity of kinetic:thermodynamic enolate, while thermodynamic control may be established with triphenylmethyllithium at room temperature, giving 10:90 selectivity.

In general, kinetic enolates are favored by cold temperatures, relatively ionic metal-oxygen bonds, and rapid deprotonation using a slight excess of a strong, hindered base while thermodynamic enolates are favored by higher temperatures, relatively covalent metal-oxygen bonds, and longer equilibration times for deprotonation using a slight sub-stoichiometric amount of strong base. Use of a sub-stoichiometric amount of base allows some small fraction of unenolized carbonyl compound to equilibrate the enolate to the thermodynamic regioisomer by acting as a proton shuttle.

Stereoselectivity

E vs. Z enolates

There is no significant difference between the level of stereoinduction observed with E and Z enolates:

Metal ion

The enolate metal cation may play a large role in determining the level of stereoselectivity in the aldol reaction. Boron is often used because its bond lengths are significantly shorter than that of other metals such as lithium, aluminum, or magnesium. For example, boron-carbon and boron-oxygen bonds are 1.4-1.5 Å and 1.5-1.6 Å in length, respectively, whereas typical metal-carbon and metal-oxygen bonds are typically 1.9-2.2 Å and 2.0-2.2 Å in length, respectively. This has the effect of "tightening" the transition state:

Stereoselectivity: Alpha stereocenter on the enolate

The aldol reaction may exhibit "substrate-based stereocontrol", in which existing chirality on either reactant influences the sterochemical outcome of the reaction. This has been extensively studied, and in many cases, one can predict the sense of asymmetric induction, if not the absolute level of diastereoselectivity. If the enolate contains a stereocenter in the alpha position, excellent sterocontrol may be realized.

In the case of an E enolate, the dominant control element is allylic 1,3-strain whereas in the case of a Z enolate, the dominant control element is the avoidance of 1,3-diaxial interactions. The general model is presented below:

For clarity, the stereocenter on the enolate has been epimerized; in reality, the opposite diastereoface of the aldehyde would have be attacked. In both cases, the 1,3-syn diastereomer is favored. There are many examples of this type of stereocontrol:

Stereoselectivity: Alpha stereocenter on the electrophile

When enolates attacks aldehydes with an alpha stereocenter, excellent stereocontrol is also possible. The general observation is that E enolates exhibit Felkin diastereoface selection, while Z enolates exhibit anti-Felkin selectivity. The general model is presented below:

Since Z enolates must react through a transition state which either contains a destabilizing syn-pentane interaction or anti-Felkin rotamer, Z-enolates exhibit lower levels of diastereoselectivity in this case. Some examples are presented below:

Stereoselectivity: Merged model for stereoinduction

If both the enolate and the aldehyde both 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 the enolate facial bias, enolate geometry, and aldehyde facial bias. Several examples of the application of this model are given below:

Asymmetric aldol reaction

Modern organic syntheses now require the synthesis of compounds in enantiopure form. Since the aldol addition reaction creates two new stereocenters, up to four stereoisomers may result.

Many methods which control both relative stereochemistry (i.e., syn or anti, as discussed above) and absolute stereochemistry (i.e., R or S) have been developed.

Evans' oxazolidone chemistry

A widely used method is the Evans' acyl oxazolidinone method. Developed in the late 1970s and 1980s by David A. Evans and coworkers, the method works by temporarily creating a chiral enolate by appending a chiral auxiliary. The pre-existing chirality from the auxiliary is then transferred to the aldol adduct by performing a diastereoselective aldol reaction. Upon subsequent removal of the auxiliary, the desired aldol stereoisomer is revealed.

In the case of the Evans' method, the chiral auxiliary appended is an oxazolidinone, and the resulting carbonyl compound is an imide. A number of oxazolidinones are now readily available in both enantiomeric forms. These may cost roughly $10-$20 US dollars per gram, rendering them relatively expensive.

The acylation of an oxazolidinone is a convenient procedure, and is informally referred to as "loading done". Z-enolates, leading to syn-aldol adducts, can be reliably formed using boron-mediated soft enolization:

Often, a single diastereomer may be obtained by one crystallization of the aldol adduct. Unfortunately, anti-aldol adducts cannot be obtained reliably with the Evans method. Despite the cost and being limited to syn adducts, the method's superior reliability, ease of use, and versatility render it the method of choice in many situations. Many methods are available for the cleavage of the auxiliary:

Evans, D.A.; Bender, S.L.; Morris, J. J. Am. Chem. Soc., 1988, 110, 2506-2526.

Upon construction of the imide, both syn and anti-selective aldol addition reactions may be performed, allowing the assemblage of three of the four possible stereoarrays: syn selective: Evans, D.A.; Clark, J.S.; Metternich, R.; Sheppard, G.S. J. Am. Chem. Soc., 1990, 112, 866-868. anti selective: Evans, D.A.; Ng, H.P.; Clark, J.S.; Reiger, D.L. Tetrahedron, 1992, 48, 2127-2142.

In the syn-selective reactions, both enolization methods give the Z enolate, as expected; however, the stereochemical outcome of the reaction is controlled by the methyl stereocenter, rather than the chirality of the oxazolidinone. The methods described allow the synthesis of extensive polyketide stereoarrays to be assembled.

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