Aldol reactions
| Aldol Reactions | |||||||||
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| Temperature | Variable[1]
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| Catalyst | -OH or H+
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In organic chemistry, aldol reactions are acid- or base-catalyzed reactions of aldehydes or ketones.
Aldol addition or aldolization refers to the addition of an enolate or enolation as a nucleophile to a carbonyl moiety as an electrophile. This produces a β-hydroxyaldehyde or β-hydroxyketone. In an aldol condensation, water is subsequently eliminated and an α,β-unsaturated carbonyl is formed. The aldol cleavage or Retro-aldol reaction is the reverse reaction into the starting compounds.
The name aldehyde -alcohol reaction derives from the reaction product in the case of a reaction among aldehydes, a β-hydroxy aldehyde.
Aldol reactions are important reactions for carbon-carbon bond formation and a fundamental reaction principle in organic chemistry.
Mechanisms
[edit]Aldol reactions may proceed by two distinct 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, being carbon 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'.
Despite the attractiveness of the aldol manifold, there are several problems that need to be addressed to render the process catalytic and 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.[2] If the conditions are particularly harsh (e.g.: NaOMe/MeOH/reflux), condensation may occur. However if an Aldol addition is desired, this can usually be avoided with mild reagents and low temperatures (e.g., LDA (a strong base), THF, −78 °C). Although 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.[3] This is the basis of the catalytic strategy of class I aldolases in nature, as well as numerous small-molecule amine catalysts.[4]
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. Then aldol, the aldol addition product itself is then formed.
After which it may undergo dehydration to give a unsaturated carbonyl compound, the aldol condensation product. The scheme shows a simple mechanism for the base-catalyzed aldol reaction of an aldehyde with itself.
Base-catalyzed aldol reaction
Base-catalyzed dehydration
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.
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 under the right conditions can then dehydrate to give the unsaturated carbonyl compound, the aldol condensation product.
- Acid-catalyzed aldol addition
Mechanism for acid-catalyzed aldol reaction of an aldehyde with itself - Acid-catalyzed aldol dehydration
Intramolecular reaction
[edit]
Aldol addition product; bottom right
Aldol condensation product; top right
Intramolecular aldol condensation is between two aldehyde groups or ketone groups in the same molecule. Five- or six-membered α, β-unsaturated ketone or aldehydes are formed as products. This reaction is an important approach to the formation of carbon-carbon bonds in organic molecules containing ring systems. As an example, under strong basic conditions (e.g. sodium hydroxide), hexane-2,5-dione (compound A in Figure 1) can cyclize via intramolecular aldol reaction to form the 3-methylcyclopent-2-en-1-one (compound B).
The mechanism of the intramolecular aldol reaction involves formation of a key enolate intermediate followed by an intramolecular nucleophilic addition process.
First, hydroxide abstracts the α-hydrogen on a terminal carbon to form the enolate. Next, a nucleophilic attack of the enolate on the other keto group forms a new carbon-carbon bond (red) between carbons 2 and 6. This forms the Aldol addition product.
Then, usually under heating conditions, the elimination of water molecule yields the cyclized α,β-unsaturated ketone, the aldol condensation product.
Intramolecular aldol reactions have been widely used in total syntheses of various natural products, especially alkaloids and steroids. An example is the application of an intramolecular aldol reaction in the ring closure step for total synthesis of (+)-Wortmannin by Shigehisa, et al.[5] (Figure 2).
References
[edit]- ^ Klein, David R. (December 22, 2020). Organic chemistry (4th ed.). Hoboken, NJ: Wiley. p. 1014. ISBN 978-1-119-65959-4. OCLC 1201694230.
- ^ Molander, G. A., ed. (2011). Stereoselective Synthesis 2: Stereoselective Reactions of Carbonyl and Imino Groups (1 ed.). Stuttgart: Georg Thieme Verlag. doi:10.1055/sos-sd-202-00331. ISBN 978-3-13-154121-5.
- ^ Guthrie, J.P.; Cooper, K.J.; Cossar, J.; Dawson, B.A.; Taylor, K.F. (1984). "The retroaldol reaction of cinnamaldehyde". Can. J. Chem. 62 (8): 1441–1445. doi:10.1139/v84-243.
- ^ Molander, ed. (2011). Stereoselective Synthesis 2: Stereoselective Reactions of Carbonyl and Imino Groups (1 ed.). Stuttgart: Georg Thieme Verlag. doi:10.1055/sos-sd-202-00331. ISBN 978-3-13-154121-5.
- ^ Shigehisa, H.; Mizutani, T.; Tosaki, S. Y.; Ohshima, T.; Shibasaki, M, Tetrahedron 2005, 61, 5057-5065.