Hubbry Logo
EnolateEnolateMain
Open search
Enolate
Community hub
Enolate
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Enolate
Enolate
Enolate
View on Wikipedia
from Wikipedia
Resonance structures of an enolate anion.

In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl (RR'C=O) compounds. Rarely isolated, they are widely used as reagents in the synthesis of organic compounds.[1][2][3][4]

Bonding and structure

[edit]
Molecular orbitals of an enolate, showing the occupancy corresponding to the anion.
Molecular orbitals of an enolate, showing the occupancy corresponding to the anion.

Enolate anions are electronically related to allyl anions. The anionic charge is delocalized over the oxygen and the two carbon sites. Thus they have the character of both an alkoxide and a carbanion.[5]

Although they are often drawn as being simple salts, in fact they adopt complicated structures often featuring aggregates.[6]

Structure of the lithium enolate PhC(OLi)=CMe2(tmeda) dimer. H atoms omitted on the diamine.[7]

Preparation

[edit]

Deprotonation of enolizable ketones, aromatic alcohols, aldehydes, and esters gives enolates.[8][9] With strong bases, the deprotonation is quantitative. Typically enolates are generated from using lithium diisopropylamide (LDA).[10]

Often, as in conventional Claisen condensations, Mannich reactions, and aldol condensations, enolates are generated in low concentrations with alkoxide bases. Under such conditions, they exist in low concentrations, but they still undergo reactions with electrophiles. Many factors affect the behavior of enolates, especially the solvent, additives (e.g. diamines), and the countercation (Li+ vs Na+, etc.). For unsymmetrical ketones, methods exist to control the regiochemistry of the deprotonation.[11]

Deprotonation using LDA.[12]

The deprotonation of carbon acids can proceed with either kinetic or thermodynamic reaction control. For example, in the case of phenylacetone, deprotonation can produce two different enolates. LDA has been shown to deprotonate the methyl group, which is the kinetic course of the deprotonation. To ensure the production of the kinetic product, a slight excess (1.1 equiv) of lithium diisopropylamide is used, and the ketone is added to the base at −78 °C. Because the ketone is quickly and quantitatively converted to the enolate and base is present in excess at all times, the ketone is unable to act as a proton shuttle to catalyze the gradual formation of the thermodynamic product. A weaker base such as an alkoxide, which reversibly deprotonates the substrate, affords the more thermodynamically stable benzylic enolate.

Enolates can be trapped by acylation and silylation, which occur at oxygen. Silyl enol ethers are common reagents in organic synthesis as illustrated by the Mukaiyama aldol reaction:[13]

vereinfachte Übersicht mit einem Stereozentrum
vereinfachte Übersicht mit einem Stereozentrum

Role of Lewis acids on enolate formation

[edit]

In addition to the use of strong bases, enolates can be generated 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:

Stereoelectronic deprotonation requirements
Stereoelectronic deprotonation requirements

Geometry

[edit]

Extensive studies have been performed on the formation of enolates. It is possible to control the geometry of the enolate:[14]

Stereoselective enolate generation
Stereoselective enolate generation

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.

Effect of HMPA addition
Effect of HMPA addition

The stereoselective formation of enolates has been rationalized with the Ireland model,[15][16][17][18] 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.

The Ireland model
The Ireland model

In the Ireland model, the deprotonation is assumed to proceed by a six-membered or cyclic[19] monomeric transition state. The larger of the two substituents on the electrophile (in the case above, methyl is larger than proton) adopts an equatorial disposition in the favored transition state, leading to a preference for E enolates. The model clearly fails in many cases; for example, if the solvent mixture is changed from THF to 23% HMPA-THF (as seen above), the enolate geometry is reversed, which is inconsistent with this model and its cyclic transition state.

Regiochemistry of enolate formation

[edit]

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

Kinetic and thermodynamic enolates
Kinetic and thermodynamic enolates

The trisubstituted enolate is considered the kinetic enolate, while the tetrasubstituted 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 −78 °C, 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, conditions that give relatively ionic metal–oxygen bonding, and rapid deprotonation using a slight excess of a strong, sterically hindered base. The large base only deprotonates the more accessible hydrogen, and the low temperatures and excess base help avoid equilibration to the more stable alternate enolate after initial enolate formation. Thermodynamic enolates are favored by longer equilibration times at higher temperatures, conditions that give relatively covalent metal–oxygen bonding, and use of a slight sub-stoichiometric amount of strong base. By using insufficient base to deprotonate all of the carbonyl molecules, the enolates and carbonyls can exchange protons with each other and equilibrate to their more stable isomer. Using various metals and solvents can provide control over the amount of ionic character in the metal–oxygen bond.

Reactions

[edit]

As powerful nucleophiles, enolates react with a variety of electrophiles. The stereoselectivity and regioselectivity is influenced by additives, solvent, counterions, etc. When the electrophiles are alkyl halides, a classic problem arises: O-alkylation vs C-alkylation. Controlling this selectivity has drawn much attention. The negative charge in enolates is concentrated on the oxygen, but that center is also highly solvated, which leads to C-alkylation.[20]

Other important electrophiles are aldehydes/ketones and Michael acceptors.[21]

Sample aldol reaction with lithium enolate
Sample aldol reaction with lithium enolate

Synthesis of enones using regiospecific enolate formation and masked functionality

[edit]
"Masked functionality" for regiospecific enolate formation
Regiospecific enolate formation in the total synthesis of progesterone

Regiospecific formation is the controlled enolate formation by the specific deprotonation at one of the α-carbons of the ketone starting molecule. This provides one of the best understood synthetic strategies to introduce chemical complexity in natural product and total syntheses. A prominent example of its use is in the total synthesis of progesterone illustrated in Figure "Regiospecific enolate formation in the total synthesis of progesterone".

When ketones are treated with base, enolates can be formed by deprotonation at either α-carbon. The selectivity is determined by both the steric and electronic effects on the α-carbons as well as the precise base used (see figure ""Masked functionality" for regiospecific enolate formation" for an example of this). Enolate formation will be thermodynamically favoured at the most acidic proton which depends on the electronic stabilization of the resulting anion. However, the selectivity can be reversed by sterically hindering the thermodynamic product and therefore kinetically favouring deprotonation at the other α-carbon centre. Traditional methods for regioselective enolate formation use either electronic activating groups (e.g. aldehydes) or steric blocking groups (e.g. 1,2-ethanedithiol protected ketone).

An enone can also serve as a precursor for regiospecific formation of an enolate, here the enone is a "masked functionality" for the enolate. This process is first described by Gilbert Stork[22] who is best known for his contributions to the study of selective enolate formation methods in organic synthesis. Reacting an enone with lithium metal generates the enolate at the α-carbon of the enone. The enolate product can either be trapped or alkylated. By using "masked functionality", it is possible to produce enolates that are not accessible by traditional methods.

The "masked functionality" approach to regiospecific enolate formation has been widely used in the total synthesis of natural products. For example, in the total synthesis of the steroid hormone progesterone,[23] Stork and co-workers used the "masked functionality" to stereospecifically construct one of the quaternary carbons in the molecule.

Aza enolates

[edit]

Aza enolates (also known as imine anions, enamides, metallated Schiff bases, and metalloenamines) are nitrogen analogous to enolates.[24] When imines get treated with strong bases such as LDA, highly nucleophilic aza enolates are generated.

Formation of Aza enolate With LDA by deprotonation of the alpha-carbon hydrogen and the creation of an alpha-beta unsaturated bond

The major benefit of using aza enolates is that they don't undergo self-condensation (i.e. aldol reaction for aldehydes) in a basic or neutral solution, but rather they favor alkylation on the alpha-carbon.[25] This is mainly because imines contain carbon-nitrogen double bonds unlike aldehydes, which contain oxygen-carbon double bonds. Since oxygen is more electronegative than nitrogen, it withdraws more electron density from the carbonyl carbon, inducing a greater partially positive charge on the carbon. Therefore, with more electrophilic carbon, aldehydes allow for better nucleophilic addition to the carbon on the carbon-oxygen double bond.

On the other hand, imine has less electronegative nitrogen which induces a weaker partially positive charge on the carbonyl-carbon. As a result, while imines can still react with organolithiums, they don't react with other nucleophiles (including aza enolates) to undergo nucleophilic additions.[26]

Instead, aza enolates react similarly to enolates, forming SN2 alkylated products.[25] Through nitrogen lone pair conjugation, β-carbon becomes a nucleophilic site, permitting aza enolates to undergo alkylation reactions.[27] Thus, aza enolates can react with numerous electrophiles like epoxides and alkyl halides to form a new carbon-carbon bond on β-carbon.[24]

Two potential reaction mechanisms are shown below:

Alkylation of aza enolates via epoxide ring opening of oxetane [28]

Since epoxide is a three-membered ring molecule, it has a high degree of ring strain. Although the carbons in the ring system are tetrahedral, preferring 109.5 degrees between each atom, epoxide strains the ring angles into 60 degrees. To counter this effect, the nucleophilic aza enolates easily react with epoxides to reduce their ring strains.

Alkylation of aza enolates via allyl halide to generate Oulema melanopus [29]

Besides reacting with epoxides, aza enolates can also react with alkyl halides (or allyl halides as depicted above) to form a new carbon-carbon sigma bond. This reaction is one of the key steps in the synthesis of the male aggression pheromone, Oulema melanopus.[29] Aza enolate is generated by LDA reacting with pivaldehyde, which then reacts with an alkyl halide to form an Oulema melanopus intermediate.

Aza enolates can also be formed with Grignard reagents and react with other soft electrophiles, including Michael receptors.[24]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Enolate

View on Grokipedia
from Grokipedia
An enolate is an anionic species formed by the of a , such as an , , or , at the alpha carbon position adjacent to the , resulting in a resonance-stabilized structure where the negative charge is delocalized between the alpha carbon and the oxygen atom. Enolates are generated under basic conditions using bases ranging from moderate ones like or alkoxides, which establish an equilibrium with the parent carbonyl, to strong, non-nucleophilic bases such as (LDA) or , which drive complete . The stability of enolates arises from this delocalization, making the alpha C–H bond more acidic (pKa ≈ 20 for simple ketones like acetone) compared to typical hydrocarbons, and further enhanced in beta-dicarbonyl compounds (pKa 9–13) due to additional conjugation. In , enolates serve as versatile nucleophiles, enabling key carbon-carbon bond-forming reactions that are foundational to constructing complex molecules. Notable reactions include the , where an enolate adds to another carbonyl to form β-hydroxy carbonyls or α,β-unsaturated carbonyls after dehydration; the , involving ester enolates to produce β-keto esters; and alpha-alkylation, where enolates react with alkyl halides to introduce substituents at the alpha position. These processes, along with variants like the Dieckmann cyclization and , underscore enolates' role in stereoselective synthesis and the preparation of pharmaceuticals, natural products, and other fine chemicals.

Definition and Properties

Basic Definition

An enolate is the conjugate base formed by the of a , such as a , , or , at the alpha carbon position adjacent to the . This alpha generates an anion stabilized by the adjacent carbonyl functionality, distinguishing enolates as key reactive intermediates in . The stability of the enolate arises from delocalization of the negative charge between two primary contributing structures: one with the charge on the alpha carbon ( form) and the other with the charge on the oxygen atom (alkoxide-like enolate form), accompanied by a carbon-carbon in the latter. For simple cases, these resonance structures are represented as: \ceR−C(O−)=CH−R′<−>R−C(=O)−CH−−R′\ce{R-C(O^-)=CH-R' <-> R-C(=O)-CH^--R'} The enolate concept emerged in early 20th-century , particularly through mechanistic studies of aldol reactions by chemists like Arthur Lapworth, who employed early notations to describe enolate formation. This foundational understanding has since underscored enolates' importance in carbon-carbon bond-forming reactions central to synthesis.

Stability and Solvation

The stability of enolates is fundamentally tied to the acidity of the α-hydrogens in their parent carbonyl compounds, which determines the ease of and the resulting equilibrium position. For ketones, these pKa values typically fall in the range of 19–21, while aldehydes exhibit slightly higher acidity with pKa values around 16–18, owing to reduced steric bulk and enhanced electron-withdrawing effects of the formyl group compared to alkyl-substituted carbonyls in ketones. This difference in acidity directly influences enolate stability, as lower pKa values indicate a greater thermodynamic favorability for the enolate form in aldehydes versus ketones. In solution, enolate stability and behavior are profoundly affected by aggregation phenomena, where metal enolates—particularly those of —frequently form dimers, tetramers, or higher oligomers as contact pairs. These aggregates arise due to the coordination of the metal cation to multiple enolate oxygens, as observed in the lithium enolate of p-phenylisobutyrophenone in (THF), where both dimeric and monomeric species coexist, with the surprisingly dominating reactivity in certain alkylations. Such aggregation reduces the effective nucleophilicity of the enolate by shielding the carbanionic center but can also impart kinetic stability by limiting rates. Solvation plays a pivotal role in modulating enolate stability by influencing ion pair dissociation and aggregate disruption. In less polar aprotic solvents like THF, enolates maintain tight contact ion pairs, preserving aggregation and somewhat attenuating reactivity, whereas more polar aprotic solvents such as (DMSO) promote solvent-separated ion pairs through stronger of the cation, thereby increasing the free enolate concentration and enhancing nucleophilicity. This -dependent dissociation is evident in conductometric studies of alkali enolates, where DMSO facilitates greater ion separation compared to THF, leading to improved thermodynamic stability for the dissociated species. Enolates generally exhibit kinetic rather than thermodynamic stability, functioning as transient intermediates prone to rapid or reaction due to their strong basicity, though careful control of conditions can extend their persistence. Under kinetic protocols in aprotic media at low temperatures, enolates achieve short-term stability, while thermodynamic equilibration may favor the more substituted (stable) . In exceptional cases, certain enolates, such as those derived from anthracen-9-yl ketones, have been isolated as crystalline aggregates under strictly inert, conditions, allowing characterization of their solid-state structures and confirming their viability beyond solution-phase transients.

Structure and Bonding

Bonding and Resonance

Enolates are described as resonance hybrids of two primary canonical structures: the form, where the negative charge resides on the α-carbon adjacent to the , and the form, where the charge is localized on the oxygen atom. The form dominates the hybrid due to oxygen's higher , resulting in greater on oxygen, while the carbanion character enables preferential electrophilic attack at the carbon site. This delocalization results in partial negative charge on both the α-carbon and oxygen. Bond lengths in enolates reflect this delocalization, with the Cα-C(carbonyl) bond shortened relative to the parent carbonyl (indicating partial double-bond character) and the C=O bond elongated (indicating partial single-bond character). These changes are confirmed by crystallographic studies of metal-coordinated enolates and corroborated by computational geometry optimizations. further supports this, showing the C=O stretching frequency shifted to lower values (typically around 1550-1650 cm⁻¹ compared to 1710-1720 cm⁻¹ for ketones), due to the weakened carbonyl . In molecular orbital terms, the highest occupied (HOMO) of the enolate is a π-type orbital derived from the carbonyl π* orbital, but lowered in energy upon α-deprotonation, with significant on the α-carbon (larger coefficient than on oxygen). This HOMO distribution explains the enolate's ambident nucleophilicity, favoring C-alkylation under kinetic conditions. stabilizes the system by populating this delocalized orbital, enhancing reactivity compared to the neutral carbonyl precursor. Compared to enols, enolates represent the deprotonated anionic analogs, exhibiting greater charge delocalization without the charge-separated inherent in enols (where the minor contributor involves a C⁺-O⁻ ). This leads to enolates having enhanced stability and nucleophilicity, as the negative charge is more evenly distributed across the C=C-O framework, facilitating diverse synthetic transformations.

Molecular Geometry

Enolates adopt planar geometries at the α-carbon due to sp² hybridization, with stereochemical configurations designated as or based on the relative positions of the α-substituent and the carbonyl oxygen across the partial Cα–C(carbonyl) . This configuration arises from delocalization, which imparts double-bond character and restricts rotation. In enolates of ketones, the Z configuration predominates, stabilized by wherein the lithium cation coordinates to both the enolate oxygen and the carbonyl oxygen within oligomeric aggregates. For ester-derived enolates, the E configuration is typically favored under standard conditions due to minimized steric interactions between the alkoxy group and the α-substituent, though addition of (HMPA) shifts selectivity toward the Z isomer by solvating the lithium and disrupting aggregate formation. The model provides a framework for understanding through a cyclic chair-like during , where the bulky base approaches the α-proton anti to the larger substituent, predicting Z selectivity for most enolates and E for esters when the α-substituent is small. However, this monomeric model has limitations in modern contexts, as experimental evidence highlights the role of enolate aggregation and solvent effects in overriding simple predictions. Spectroscopic techniques confirm these configurations: multinuclear NMR reveals distinct chemical shifts and coupling constants for Z and E isomers, with the Z-lithium enolate of exhibiting dimeric or tetrameric aggregation in ethereal solvents at low temperatures, evidenced by line broadening and diffusion-ordered spectroscopy. further supports Z geometry in solid-state structures of lithium enolates, showing planar C–C–O units with bridged between oxygens in a chelated arrangement. Substituent effects introduce torsional strain around the Cα–C(carbonyl) bond, influencing planarity; bulky α- increase out-of-plane and pyramidality at the α-carbon, deviating from ideal trigonal geometry and affecting aggregate stability, as quantified by dihedral angles in computational models (e.g., O–C–C–H ≈ 10–15° in fused systems).

Formation

Deprotonation Methods

Enolates are typically generated through the of carbonyl compounds at the alpha position using bases of varying strength, which influences the extent of deprotonation and the of the process. Strong, non-nucleophilic bases such as (LDA) are commonly employed to achieve quantitative under kinetic control conditions, typically at low temperatures like -78°C in aprotic solvents such as (THF). This approach favors the formation of the less substituted enolate due to the steric bulk of LDA and the irreversibility of the , as the conjugate acid has a pKa around 36, higher than that of most alpha protons in ketones (pKa ~20). A representative example is the of acetone: \ceCH3C(O)CH3+LDA−>CH3C(O)CH2−Li++HN(iPr)2\ce{CH3C(O)CH3 + LDA -> CH3C(O)CH2^- Li^+ + HN(iPr)2} For thermodynamic control, weaker bases like sodium ethoxide (NaOEt) or potassium tert-butoxide are used at higher temperatures in protic solvents, allowing equilibration to the more stable, substituted enolate through reversible proton transfer. These conditions fully deprotonate the substrate only partially due to their basicity (pKa of EtOH ~16), promoting the thermodynamically favored species in solvents where enolate stability can be influenced by solvation effects. Weaker bases, such as alkoxides (e.g., , NaOEt), enable partial in protic solvents like , leading to an equilibrium mixture biased toward the thermodynamic enolate. The lower basicity of NaOEt (pKa of EtOH ~16) results in only a small of enolate formation, but the reversible nature allows interconversion, favoring the more substituted under ambient conditions. Metal enolates of , sodium, and are formed by with the corresponding metal amides or hydrides, yielding salts that differ in reactivity due to cation size and coordination properties; lithium enolates are often monomeric or dimeric in THF, while sodium and potassium variants tend to aggregate more extensively. Organocatalytic methods, such as phase-transfer using chiral quaternary ammonium salts, facilitate enolate generation from aqueous bases like NaOH by transferring the anion into organic phases, enabling efficient without strong aprotic bases.

Regioselectivity

In unsymmetrical carbonyl compounds, regioselectivity during enolate formation presents a significant synthetic challenge, as multiple alpha protons may be available, leading to mixtures of regioisomeric enolates. This control is essential for directing subsequent reactivity toward desired products in . The choice of conditions determines whether deprotonation favors the less substituted (kinetic) or more substituted (thermodynamic) enolate, exploiting differences in reaction rates or equilibrium stabilities. Kinetic enolates, which are less substituted and form more rapidly due to lower steric hindrance at the alpha site, are generated under conditions that promote irreversible . Strong, sterically hindered bases such as (LDA) at low temperatures (typically -78 °C in ) selectively abstract the more accessible proton, preventing equilibration. In contrast, thermodynamic enolates, which are more substituted and stabilized by greater alkyl substitution on the enolate double bond, predominate under equilibrating conditions, such as higher temperatures or weaker bases like , allowing proton exchange between regioisomers. The small pKa differences between alpha positions—approximately 1-2 units, as seen in 2-butanone where the methylene group's alpha proton has a pKa of ~26.5 in DMSO compared to ~27.6 for the —enable this kinetic bias, since the thermodynamic preference is modest and can be overridden by rate control. A representative example is 2-butanone (CH3C(O)CH2CH3), where kinetic deprotonation with LDA yields primarily the less substituted terminal enolate (CH2=C(O⁻)CH2CH3), while thermodynamic conditions favor the more substituted internal enolate (CH3C(O⁻)=CHCH3). In particularly hindered substrates, where standard bases like LDA may encounter steric issues, lithium 2,2,6,6-tetramethylpiperidide (LTMP)—a bulkier non-nucleophilic base—improves regioselectivity for the kinetic enolate by enhancing approach to congested alpha protons without promoting side reactions.

Role of Lewis Acids and Additives

Lewis acids, such as BF₃·OEt₂ and MgBr₂, coordinate to the oxygen atom of the carbonyl group in ketones and esters, thereby enhancing the acidity of the α-protons and enabling enolate formation using milder, weaker bases like Et₃N or i-Pr₂NEt under ambient conditions. This coordination activates the substrate by polarizing the C=O bond, lowering the pK_a of the α-hydrogen and promoting selective deprotonation without requiring strong bases like LDA, which can lead to over-deprotonation or side reactions. Such Lewis acid-mediated approaches are particularly valuable for generating "soft" enolates from esters, where the coordinated species reduce the tendency for self-condensation by stabilizing the enolate and suppressing nucleophilic attack on the ester carbonyl. Solvent choice plays a crucial role in modulating enolate reactivity through effects on and ion pairing. Polar aprotic solvents like HMPA or solvate or other cations strongly, promoting desolvation of the enolate anion and increasing its nucleophilicity by disrupting tight ion pairs or aggregates in THF. This enhancement is evident in reactions, where HMPA additives can shift selectivity toward C-alkylation by making the enolate more "naked" and reactive. Similarly, crown ethers such as 12-crown-4 or 18-crown-6 sequester cations, breaking down dimeric or higher-order enolate aggregates into more reactive monomeric species, thereby accelerating reactions and improving yields in non-polar media. A representative application involves the formation of enolates using TiCl₄ in conjunction with a like Bu₃N, which generates titanium-coordinated enolates suitable as precursors for crossed-Claisen condensations. In this process, TiCl₄ activates the by coordination, allowing selective and subsequent reaction with acid chlorides to afford β-keto esters in high yields (up to 95%) with minimal self-condensation, demonstrating the utility of such additives in synthetic planning.

Reactivity

Nucleophilic Additions

Enolates function as potent carbon nucleophiles in addition reactions with electrophilic π-systems, such as s and conjugated alkenes, while their ambident character allows for competing oxygen-centered reactivity depending on the electrophile's nature. These additions are fundamental in for constructing carbon-carbon bonds, with the enolate's nucleophilicity enhanced by the adjacent that stabilizes the negative charge. The reactivity often proceeds through a concerted or stepwise mechanism involving deprotonation of the initial . The exemplifies enolate , wherein the enolate attacks the carbonyl carbon of an to yield a β-hydroxy carbonyl compound. This process typically occurs under basic conditions and can be represented by the equation: \ce−CH2C(O)R′+RCHO−>[H+]RCH(OH)CH2C(O)R′\ce{^{-}CH2C(O)R' + RCHO ->[H+] RCH(OH)CH2C(O)R'} The stereochemical outcome of the aldol addition is rationalized by the Zimmerman-Traxler model, which posits a chair-like, six-membered cyclic structure coordinating the enolate's metal with the aldehyde oxygen. For or enolates, (Z)-enolates favor syn diastereoselectivity through a minimizing steric interactions, while (E)-enolates lead to anti products; experimental studies confirm preferences up to 50:1 for chair-like pathways over boat alternatives. In Michael additions, enolates undergo conjugate addition to the β-position of α,β-unsaturated carbonyl acceptors, forming enolates that protonate to 1,5-dicarbonyl compounds. This 1,4-addition exploits the electrophilic activation by the , with enolates typically adding efficiently to enones or enals under mild conditions. Seminal work demonstrated high yields for such additions using preformed enolates, establishing the reaction's utility for extending carbon chains. The ambident nature of enolates manifests in during nucleophilic additions, where the carbon terminus (softer nucleophilic site) predominates with soft electrophiles like primary alkyl halides in conjugate systems, yielding C-addition products. Conversely, hard electrophiles such as Meerwein trialkyloxonium salts promote O-attack, forming ethers. This dichotomy follows the hard-soft acid-base , with metal counterions and polarity modulating the C/O —lithium enolates in aprotic media favor C-addition by over 90% in many cases.

Alkylation and Acylation

Enolates act as carbon nucleophiles in alpha-alkylation reactions with primary alkyl halides, proceeding via an SN2 mechanism to forge new C-C bonds selectively at the alpha carbon. This process replaces an alpha hydrogen with an alkyl group and is favored with unhindered primary electrophiles such as methyl or ethyl iodides, which undergo clean backside displacement. To suppress polyalkylation—a common issue arising from the increased acidity of the monoalkylated product relative to the parent carbonyl—an excess of enolate is employed, ensuring high yields of the monoalkylated ketone or ester. Acylation of enolates with acid chlorides or anhydrides provides a direct route to 1,3-dicarbonyl compounds, particularly 1,3-diketones from ketone-derived enolates. The enolate carbon attacks the electrophilic carbonyl of the , displacing chloride or the to form the C-acylated product. These reactions exhibit excellent under kinetic control, often using lithium enolates to favor C-acylation over O-acylation, and are tolerant of various functional groups on the acyl component. The resulting 1,3-diketones are versatile synthons due to their enhanced acidity and content. Stereocontrol in these reactions is governed by the enolate geometry and conformational preferences, enabling diastereoselective outcomes. In enolates, such as those derived from 2-methyl, the preferentially approaches from the axial face of the planar enolate, leading to trans diastereomers in the 2,6-disubstituted products. This kinetic preference arises from minimized steric repulsion in the , where the incoming group aligns with the pseudo-axial trajectory, achieving diastereoselectivities often exceeding 90:10. Such control is critical for constructing stereodefined frameworks in synthesis. A classic illustration is the alkylation of the enolate of ethyl acetoacetate with methyl iodide, yielding ethyl 2-methyl-3-oxobutanoate as the alpha-methylated product. Generated using sodium ethoxide in ethanol, this enolate undergoes efficient SN2 alkylation at the activated methylene, setting the stage for further elaboration in the acetoacetic ester synthesis.

Synthetic Applications

Enolates play a pivotal role in target-oriented synthesis, particularly through masked variants such as silyl enol ethers, which enable regiospecific enone formation via Robinson annulation. In this approach, the silyl enol ether of a ketone undergoes Lewis acid-catalyzed Michael addition to methyl vinyl ketone (MVK), yielding a 1,5-diketone intermediate that cyclizes via intramolecular aldol condensation followed by dehydration to afford the α,β-unsaturated enone. This variation provides superior regioselectivity over classical base-mediated methods, avoiding competitive self-condensation and allowing access to fused cyclohexenone systems in high yields, as demonstrated in the synthesis of octalones from cyclohexanone-derived silyl enol ethers. A landmark application of enolate chemistry is found in the of progesterone, where sequential enolate alkylations build the steroidal carbon framework, complemented by an intramolecular to form the A-ring. Reported by Johnson and coworkers in 1971, this biomimetic route employs enolates for stereocontrolled C-C bond formations, culminating in a polyene cyclization and steps to deliver racemic progesterone in 18 steps from simple precursors, highlighting enolates' efficiency in constructing complex polycyclic structures. Modern synthetic applications leverage enolates for asymmetric synthesis, notably through chiral auxiliaries in aldol reactions. Evans' methodology uses N-acyl oxazolidinones to generate boron enolates, which add to aldehydes with high diastereoselectivity via a , enabling the preparation of syn-β-hydroxy carbonyls in enantiopure form after auxiliary cleavage. This approach has been instrumental in synthesizing fragments and natural products like discodermolide, achieving >95% in many cases. Complementing this, organocatalytic enolate equivalents, such as ammonium enolates from chiral tertiary amines, facilitate asymmetric alkylations and additions without metal mediators, as reviewed in methods generating centers with up to 99% . Enone synthesis can also proceed via kinetic enolates reacting with α-halo ketones to form 1,4-dicarbonyl compounds, followed by intramolecular . Under kinetic conditions with LDA at low temperature, the enolate of a methyl displaces the halide in an α-bromoacetone equivalent, affording the 1,4-dicarbonyl compound; subsequent acid-catalyzed dehydration yields the α,β-enone, providing a regioselective route to conjugated systems as utilized in precursors.

Aza-Enolates

Aza-enolates are nitrogen-containing analogs of enolates, specifically the conjugate bases of imines, exhibiting resonance structures such as R-CH⁻-CR'=N-R'' ↔ R-CH=CR'-N⁻-R''. These species share similarities with traditional oxygen-based enolates, allowing delocalization of the negative charge between the alpha carbon and the atom. Preparation of aza-enolates typically involves at the α-carbon of the corresponding precursor using strong bases such as (LDA). Alternative methods include transmetallation or activation with Lewis acids like . In terms of reactivity, aza-enolates preferentially undergo C-alkylation at the α-carbon due to the nucleophilic character of the carbanionic form, making them valuable for forming new carbon-carbon bonds. They are particularly effective in reactions with allyl halides, such as , yielding alkylated products in high yields (e.g., 62–91% with activated systems). Additionally, lithium aza-enolates can ring-open epoxides, including strained heterocycles like , which are often less reactive toward standard enolates. A representative synthetic application is the one-pot formation and of aza-enolates derived from secondary amines, such as , which has been employed in the expeditious synthesis of the male aggregation of the Oulema melanopus. In this process, oxidation of the amine generates an intermediate, followed by in situ to form the aza-enolate, which is then alkylated with an appropriate and hydrolyzed to the target .

Silicon and Other Enolates

Silyl enol ethers represent neutral, masked forms of enolate anions, where the enolate oxygen is silylated with a trimethylsilyl (TMS) group, offering enhanced stability and ease of isolation compared to reactive ionic enolates. They are typically generated by quenching kinetically formed lithium enolates—prepared from ketones and (LDA) at low temperatures—with chlorotrimethylsilane (TMSCl) in an aprotic solvent like . This approach ensures high , favoring the less substituted (kinetic) isomer due to the irreversible trapping under low-temperature conditions. An alternative metal-free protocol for kinetic employs N,O-bis(trimethylsilyl) (BSA) with catalytic tetrabutylammonium (TBAF), which promotes selective and silylation without strong bases, accommodating sensitive substrates. The primary advantages of silyl enol ethers lie in their greater thermal and chemical stability, allowing storage and purification by distillation or chromatography, unlike enolates which require generation in situ to avoid decomposition or side reactions. Upon activation with Lewis acids, they regenerate the enolate nucleophilicity in a controlled manner, minimizing competitive pathways like self-aldol condensation. A seminal application is the Mukaiyama aldol reaction, where silyl enol ethers couple with aldehydes under catalysis by titanium tetrachloride (TiCl4) or boron trifluoride etherate (BF3•OEt2) to afford β-hydroxy ketones with predictable syn/anti stereochemistry, often superior to traditional enolate aldols due to the neutral conditions. Beyond silicon-based masks, phosphonate-stabilized carbanions function as enolate equivalents in the Horner-Wadsworth-Emmons (HWE) olefination, providing a robust route to (E)-α,β-unsaturated esters from aldehydes and ketones. The reaction proceeds via base-mediated of a phosphonoacetate (e.g., with ), generating a resonance-stabilized anion that undergoes Wittig-like addition-elimination, with the leaving group ensuring high E-selectivity and yields often exceeding 80% for electron-deficient systems. This method's stability advantages stem from the electron-withdrawing , allowing milder conditions than unstabilized enolates and broad substrate tolerance in synthesis. Sulfur ylides, such as dimethylsulfoxonium methylide, serve as non-carbonyl enolate mimics through their carbanionic reactivity, particularly in the Corey-Chaykovsky epoxidation, where they act as nucleophilic methylene donors to aldehydes or ketones, forming epoxides as masked 1,2-diols analogous to enolate addition products. Generated from sulfoxonium salts and bases like , these ylides exhibit tunable reactivity—semi-stabilized variants favor of α,β-unsaturated carbonyls, extending carbon frameworks with high diastereocontrol—and offer handling ease due to their neutral precursors, though they require careful exclusion of protic impurities to prevent decomposition.

References

  1. https://employees.csbsju.edu/cschaller/Reactivity/carbonyl/COenolate.htm
  2. https://people.chem.ucsb.edu/neuman/robert/orgchembyneuman.book/18%20EnolateIonsEnols/18FullChapt.pdf
  3. https://www.masterorganicchemistry.com/2022/08/16/enolates-properties-reactions/
  4. https://www.chemistryworld.com/features/the-iconic-curly-arrow/3004840.article
  5. https://pubs.acs.org/doi/10.1021/ed075p78
  6. https://www.chem.ucalgary.ca/courses/351/Carey5th/Ch21/ch21-2.html
  7. https://kpu.pressbooks.pub/organicchemistry2/chapter/6-1-the-acidity-of-the-alpha-hydrogens/
  8. https://pubs.acs.org/doi/10.1021/ja00128a026
  9. https://pubs.acs.org/doi/10.1021/jo00120a006
  10. https://pubs.acs.org/doi/10.1021/ja00334a049
  11. https://pubs.acs.org/doi/10.1021/ja00952a005
  12. https://pubs.acs.org/doi/10.1021/jo990251u
  13. https://pubs.rsc.org/en/content/articlehtml/2024/dt/d4dt00211c
  14. https://www.utdallas.edu/~biewerm/19H-enolates.pdf
  15. https://research.cm.utexas.edu/nbauld/teach/ch610bnotes/ch19.htm
  16. https://ethz.ch/content/dam/ethz/special-interest/chab/chab-dept/department/images/Emeriti/Seebach/PDFs/386_ACI_1988.pdf
  17. https://research.rug.nl/files/3272043/1995HoubenWeylFeringa.PDF
  18. http://chemweb.bham.ac.uk/coxlr/Teaching/4th_Year/III/Enolate%20Chemistry.pdf
  19. https://pubs.acs.org/doi/10.1021/acs.orglett.0c01008
  20. https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Organic_Chemistry_(Morsch_et_al.)/22%3A_Carbonyl_Alpha-Substitution_Reactions/22.07%3A_Alkylation_of_Enolate_Ions
  21. https://pubs.acs.org/doi/10.1021/ja992062z
  22. https://www.masterorganicchemistry.com/2022/08/19/kinetic-versus-thermodynamic-enolates/
  23. https://macmillan.princeton.edu/wp-content/uploads/GCW_enolates.pdf
  24. https://pubs.acs.org/doi/10.1021/ja973174y
  25. https://chem.libretexts.org/Courses/University_of_Alberta_Augustana_Campus/AUCHE_252_-_Organic_Chemistry_II/05%3A_Aldehydes_and_Ketones/5.05%3A_Alkylation_of_Enolate_Ions
  26. https://organicchemistrydata.org/hansreich/resources/pka/
  27. https://pubs.acs.org/doi/10.1021/ja00025a023
  28. https://pubs.acs.org/doi/10.1021/cr068424k
  29. https://groups.chem.ubc.ca/chem330/11Oct02.pdf
  30. https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202203081
  31. https://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/special3.htm
  32. https://iopscience.iop.org/article/10.1070/RC1977v046n11ABEH002190
  33. https://pubs.acs.org/doi/10.1021/jo00815a037
  34. https://pubs.acs.org/doi/10.1021/ja00834a019
  35. https://pubs.acs.org/doi/10.1021/jo01349a070
  36. https://www.researchgate.net/publication/229982328_The_Alkylation_of_Esters_and_Nitriles
  37. https://doi.org/10.1021/jo00222a014
  38. https://doi.org/10.1021/ja20151a046
  39. https://onlinelibrary.wiley.com/doi/full/10.1002/adsc.202200262
  40. https://www.sciencedirect.com/science/article/abs/pii/S0040402012006588
  41. https://www.organic-chemistry.org/synthesis/O1Si/silylenolethers.shtm
  42. https://pubs.acs.org/doi/10.1021/ja00831a019
Add your contribution
Related Hubs
User Avatar
No comments yet.