Name: enolate ions: stability and reaction sites
Uploaded: 2023-04-30T10:23:40.000Z
Duration: 1 min 23 s
Channel: JoVE

α wodory karbonylków mają charakter kwaśny, ponieważ ich sprzężone zasady są stabilizowane rezonansowo. Tak więc jony enolanowe są często bardziej przydatne w reakcjach niż enole, ze względu na ich stabilność roztworu i lepszą nukleofilowość.
Podobnie jak anion allilowy, jon enolanowy zachowuje się jak trzyatomowy układ sprzężony z czterema elektronami. Zastąpienie węgla tlenem obniża energię dwóch zajmowanych π orbitali molekularnych i zniekształca je.
Na najniżej zajętym orbicie π elektrony są zdelokalizowane w trzech atomach składowych, z większym udziałem elektroujemnego tlenu. To dodatkowe nakładanie się i stabilizacja sprawia, że wodór karbonylowy α jest bardziej kwaśny niż wodory allilowe alkenów.
HOMO ma znaczący charakter α-węglowy, z węzłem na wiązaniu węgiel-tlen. Podczas gdy reakcje zdominowane przez oddziaływanie z HOMO mają tendencję do zachodzenia na α węgla, prowadząc do α-podstawienia, te napędzane oddziaływaniami elektrostatycznymi mają tendencję do zachodzenia na tlenie, tworząc pochodne enolu.
Ponieważ enolany mają dwa odrębne reaktywne centra nukleofilowe, są to nukleofile ambidentowe.

<ol>
	<li>Solomons, G., & Fryhle, C. & Snyder, S. (2015). Chemia organiczna. New Jersey, NJ: Wiley, 822.</li>
	<li>Loudon, M. i Parise, J. (2016). Chemia organiczna. Nowy Jork, NY: Macmillan Publishers, 1103.</li>
	<li>Clayden, J., & Greeves, N., & Warren, S. (2012). Chemia organiczna. Oxford: Oxford University Press, 449.</li>
	<li>Carey, F. A. (2000). chemia organiczna McGraw-Hill, 702.</li>
	<li>McMurry, J. (2016). Chemia organiczna. Zaangażuj się w naukę. Boston. MA. Rozdział 728.</li>
	<li>Smith, J. G. (2008) Chemia organiczna, McGraw Hill, 884.</li>
</ol>

reaktywność jonów enolanowych

Jony enolanowe powstają w wyniku reakcji kwasowo-zasadowej związku karbonylowego z zasadą. Prowadzi to do deprotonowania atomu wodoru α, co prowadzi do powstania stabilizowanego rezonansowo jonu enolanowego, w którym jedną ze struktur przyczyniających jest oksyanion, co nadaje dodatkową stabilność. Dlatego proton na węglu α ma charakter bardziej kwaśny niż w innych wiązaniach C–H z hybrydyzacją sp_3, ale mniej kwaśny niż w wiązaniach O–H, gdzie ładunek ujemny w zasadzie koniugatu jest zlokalizowany na atomie tlenu. Znajduje to odzwierciedlenie w ich trendzie wartości pK_a. Na przykład kwas octowy, etanol, aceton, 1-propen i etan mają wartości pK_a odpowiednio 4,8, 16, 19,2, 43 i 50.

Jon enolanowy jest przykładem ambidentnego nukleofila, tj. nukleofila z dwoma miejscami reaktywnymi. Struktury przyczyniające się do jonów enolanowych pokazują, że zarówno atomy węgla, jak i tlenu mogą przenosić ładunek ujemny. Zatem jon enolanowy jest zasadą sprzężoną zarówno w postaci ketonowej, jak i enolowej. Teoretycznie może reagować z określonym elektrofilem, tworząc dwa różne produkty poprzez utworzenie wiązania w dwóch różnych miejscach. Jednakże jon enolanowy zwykle reaguje na końcu węglowym, ponieważ jest on bardziej nukleofilowy niż miejsce tlenowe.

Ponieważ jony enolanowe są zasadami Brønsteda, reagują z kwasami Brønsteda, jak protony. Prowadzi to do wymiany wodoru w pozycji α związków karbonylowych z rozpuszczalnikiem, co prowadzi do wymiany izotopów w obecności D_2O i wodnej zasady. Optycznie aktywny aldehyd lub keton ulega racemizacji, jeśli w cząsteczce znajduje się asymetryczny węgiel α. Utrata stereogeniczności wynika z utworzenia achiralnego enolanowego związku pośredniego, w którym wszystkie trzy atomy są płaskie trygonalne w wyniku hybrydyzacji sp_2 i koniugacji poprzez nakładanie się orbitali p. Ponieważ pK_a wodoru α jest bardzo wysoka w przypadku estrów, różne konsekwencje tworzenia jonów enolanowych obserwuje się szczególnie w przypadku aldehydów i ketonów.

Jony enolanowe reagują również jako zasady Lewisa, gdzie działają jako nukleofile. Dlatego mogą ulegać dwóm typom reakcji prowadzących do powstania nowych wiązań przy węglu α:

<ol style="display: flex; flex-direction: column; gap: 10px;">
 <li>Reakcje podstawienia z elektrofilami prowadzące do produktów halogenowanych i alkilowanych z cząsteczkowym halogenem (X_2) w obecności odpowiednio kwasu lub zasady i halogenku alkilu (RX) lub estru sulfonianowego (RSO_3-).</li>
 <li>Reakcje addycji z grupami karbonylowymi w elektrofilowym centrum węgla, po których następują reakcje nukleofilowego podstawienia acylowego w zależności od struktury grupy karbonylowej.</li>
</ol>

Reaktywność jonów enolanowych

Jony enolanowe powstają w wyniku reakcji kwasowo-zasadowej związku karbonylowego z zasadą. Prowadzi to do deprotonacji α atomu wodoru, ...

Education

JoVE Core

Organic Chemistry

Chemia organiczna

Unit 1

Jednostka 1

&alpha;-Carbon Chemistry: Enols, Enolates, and Enamines

Chemia węgla $\alpha$: enole, enolany i enaminy

carbon-chemistry-enols-enolates-and-enamines

KEY TERMS AND CONCEPTS

Kluczowe terminy i pojęcia

Reactivity of Enolate Ions

enolate ions: stability and reaction sites

Enolate ions form when a base removes the alpha hydrogen from a carbonyl compound. This acid-base reaction gives a resonance-stabilized ion, and one contributing form places the negative charge on oxygen. That oxygen-containing form adds extra stability.

The alpha hydrogen in a carbonyl compound is more acidic than other sp3 C-H bonds, but it is less acidic than O-H bonds. This difference appears in pKa values. Acetic acid has a pKa of 4.8, ethanol 16, acetone 19.2, 1-propene 43, and ethane 50.

Enolate ions are ambident nucleophiles, which means they have two reactive sites. Their resonance structures show that the negative charge can be on carbon or oxygen. So an enolate can, in theory, form different products by reacting at either site.

In practice, enolates usually react at the carbon end because it is more nucleophilic than the oxygen site. They also behave as Brønsted bases and can react with protons. This can cause hydrogen exchange at the alpha position with the solvent, including isotope exchange in D2O with aqueous base.

Optically active aldehydes or ketones can also racemize if they have an asymmetric alpha carbon. Racemization means loss of optical activity. It happens because the enolate intermediate is achiral, and the atoms around it are trigonal planar with sp2 hybridization and p-orbital overlap.

These effects are seen mainly with aldehydes and ketones, since alpha hydrogens in esters have very high pKa values. Enolates also act as Lewis bases and nucleophiles. They can form new bonds at the alpha carbon through substitution with electrophiles, such as halogenation with X2 in acid or base, alkylation with alkyl halides or sulfonate esters, and through addition to carbonyl groups followed by nucleophilic acyl substitution when the carbonyl structure allows it.

Enolate Ions: Stability and Reaction Sites

enolate-ions-stability-and-reaction-sites

reactivity of enols

Enol Reactions at the Alpha Carbon

Enols are compounds with a hydroxyl group attached to a carbon-carbon double bond. They are also called vinyl alcohols. In carbonyl compounds that have an alpha hydrogen, the keto form and the enol form stay in equilibrium through keto-enol tautomerism. In most cases, the keto tautomer is more common than the enol tautomer. This is because a C=O bond has higher bond energy than a C=C bond. The balance can shift when conjugation, intramolecular hydrogen bonding, or aromatic stability favors the...

reactivity of enolate ions

Enolate ions form when a base removes the alpha hydrogen from a carbonyl compound. This acid-base reaction gives a resonance-stabilized ion, and one contributing form places the negative charge on oxygen. That oxygen-containing form adds extra stability. The alpha hydrogen in a carbonyl compound is more acidic than other sp3 C-H bonds, but it is less acidic than O-H bonds. This difference appears in pKa values. Acetic acid has a pKa of 4.8, ethanol 16, acetone 19.2, 1-propene 43, and ethane 50.

types of enols and enolates

Enol Stability and Enolate Formation

Enol stability and enolate formation depend on the carbonyl compound. Aldehydes and ketones can form enols, but for simple monocarbonyl compounds only about 1% is present at equilibrium. The enol form is undetectable for acetaldehyde, is only 1.5 × 10 −4 % of acetone, and is only 1.2% of cyclohexanone. Unsymmetrical ketones can form two regioisomeric enols, and their total amount is still near 1% at equilibrium. This low amount reflects the lower bond energy of a C=C bond compared with a C=O...

enolate mechanism conventions

Drawing Enolate C-Attack Pathways

Enolate C-attack pathways show how a carbonyl compound reacts after the alpha position is deprotonated by a strong base. This forms an enolate, a resonance-stabilized intermediate. The enolate has two nucleophilic sites, so it is an ambident nucleophile. That means it can attack an electrophile in more than one place because the negative charge is spread between the alpha carbon and oxygen. When the oxygen atom attacks an electrophile, the process is called O-attack. When the attack happens...

regioselective formation of enolates

Kinetic vs Thermodynamic Enolate Formation

Unsymmetrical ketones can form two enolates, and the reaction conditions decide which one appears. One enolate comes from the less substituted alpha-carbon, and the other comes from the more substituted alpha-carbon. These pathways are linked to acid-base chemistry and to regioselectivity, which means choosing one position in the molecule over another. The enolate from the more substituted alpha-carbon is the thermodynamic enolate. It has lower energy, so it is more stable. The enolate from...

stereochemical effects of enolization

Racemization During Enol Formation

Racemization can happen when a carbonyl compound forms an enol. In these molecules, the chiral alpha-carbon is the stereocenter. When the molecule changes under acidic or basic conditions, the original chiral center can be lost. In acidic solution, the carbonyl oxygen is protonated first. At the same time, the alpha-hydrogen is removed, and an enol forms. In basic solution, removal of the alpha-hydrogen gives a resonance-stabilized enolate. The enolate oxygen is then protonated to make an enol.

acid-catalyzed &alpha;-halogenation of aldehydes and ketones

acid-catalyzed-halogenation-of-aldehydes-and-ketones

Alpha Halogenation Through Enol Formation

Acid-catalyzed alpha-halogenation changes an alpha-hydrogen in an aldehyde or ketone into a halogen. The result is a monohalogenated product. This reaction starts with acid protonation of the carbonyl oxygen, which creates a resonance-stabilized cation. The cation then loses an alpha-hydrogen and forms an enol tautomer. An enol is a molecule that can shift between a double bond and an alcohol group. The C=C bond in the enol is highly nucleophilic. That means it donates electrons easily. The...

base-promoted &alpha;-halogenation of aldehydes and ketones

base-promoted-halogenation-of-aldehydes-and-ketones

How Carbonyls Gain Halogens at the α-Carbon

Base-promoted α-halogenation of aldehydes and ketones is a reaction that replaces α hydrogens with halogens. The α carbon is the carbon next to the carbonyl group. A base starts the process by removing an α hydrogen and forming a nucleophilic enolate ion. The enolate then reacts with the halogen in a nucleophilic substitution step. This gives a monohalogenated carbonyl compound. If the starting molecule has more than one α hydrogen, the reaction is hard to stop after one substitution. That...

multiple halogenation of methyl ketones: haloform reaction

multiple-halogenation-of-methyl-ketones-haloform-reaction

Methyl Ketone Halogenation to Carboxylic Acid

Methyl ketones can be converted into carboxylic acids by a reaction called the haloform reaction. It uses excess base and a halogen. The process starts when the alpha hydrogen is removed to form an enolate ion, which then reacts with the electrophilic halogen. Halogenation continues at the alpha carbon until a trihalomethyl ketone is formed. This intermediate is unstable in hydroxide base. It then undergoes nucleophilic acyl substitution, which pushes out a trihalomethyl carbanion and forms a...

&alpha;-halogenation of carboxylic acid derivatives: overview

halogenation-of-carboxylic-acid-derivatives-overview

Making α-Haloacids from Carboxylic Acids

Making α-haloacids from carboxylic acids requires steps that differ from the usual halogenation of aldehydes and ketones. Carboxylic acids do not readily take part in α halogenation through enols or enolate intermediates. Instead, chemists use other routes to install a halogen on the α carbon. One common route is the Hell–Volhard–Zelinsky, or HVZ, reaction. In this method, the carboxylic acid is treated with a halogen in the presence of PBr3. The acid is first converted to an acid halide,...

&alpha;-bromination of carboxylic acids: hell&ndash;volhard&ndash;zelinski reaction

bromination-of-carboxylic-acids-hellvolhardzelinski-reaction

Making α-Bromo Carboxylic Acids

The Hell–Volhard–Zelinski reaction makes α-brominated carboxylic acids. It uses a mixture of phosphorus tribromide and bromine. This method is a standard way to add bromine at the alpha position of a carboxylic acid. Phosphorus tribromide can be used directly in the reaction. It can also be formed in situ, which means made inside the reaction mixture, from red phosphorus and bromine. The phosphorus tribromide helps turn the acid into an acid bromide and produces hydrogen bromide. The acid...

reactions of &alpha;-halocarbonyl compounds: nucleophilic substitution

reactions-of-halocarbonyl-compounds-nucleophilic-substitution

SN2 Reactions of α-Halocarbonyls

α-Halocarbonyl compounds can undergo nucleophilic substitution by an SN2 pathway. In this reaction, a nucleophile replaces the halogen on the carbon next to the carbonyl group. This is the main route described for these compounds. For α-haloketones, the reaction is usually carried out with less basic nucleophiles. Strong basic nucleophiles can instead form α-haloenolate ions. These ions often take part in side reactions, so they are not the preferred path. α-Haloacids behave differently and...

nitrosation of enols

Nitrosation to Make 1,2-Diketones

Nitrosation of enols is a route for making 1,2-diketones. In this reaction, the enol tautomer of a ketone reacts with sodium nitrite in hydrochloric acid. After hydrolysis, the product is a 1,2-diketone. The reaction begins when hydrochloric acid converts sodium nitrite into an oxonium ion. The loss of a water molecule from this intermediate forms the nitrosonium ion. This ion is the electrophile, meaning it accepts electrons in the next step. The enol tautomer then attacks the nitrosonium...

c&ndash;c bond formation: aldol condensation overview

cc-bond-formation-aldol-condensation-overview

Aldol Addition and Dehydration Steps

Aldol condensation forms a new carbon-carbon bond in synthetic organic chemistry. It can occur under basic or acidic conditions. The reaction shown here includes an aldol addition step followed by dehydration. Aldol addition reactions are reversible. They can happen by self-addition or crossed-addition. In self-addition, two identical carbonyl compounds react with each other. In crossed-addition, two different carbonyl compounds react. In that case, one carbonyl compound acts as the...

base-catalyzed aldol addition reaction

Aldol Product Formation from Aldehydes

Base-catalyzed aldol addition forms a beta-hydroxy carbonyl compound from two carbonyl compounds in aqueous sodium hydroxide. The reaction is most favorable with simple aldehydes, especially when the alpha carbon is monosubstituted. When the aldehydes or ketones are disubstituted, steric crowding at the alpha carbon can push the equilibrium back toward the reactants. Trisubstituted aldehydes, which do not have an alpha hydrogen atom, are not suitable for this reaction. The mechanism happens in...

acid-catalyzed aldol addition reaction

Ketone Aldol Condensation Under Acid

Ketone aldol condensation under acidic conditions leads to an unsaturated carbonyl product. The reaction starts with acid protonating the ketone to form a protonated ketone. Then the conjugate base of the acid removes the alpha carbon proton and forms the enol, a neutral molecule with a carbon-carbon double bond and an alcohol group. The enol acts as the nucleophile in the next step. It attacks a second protonated ketone molecule and forms a positively charged intermediate. Loss of a proton...

dehydration of aldols to enals: base-catalyzed aldol condensation

dehydration-of-aldols-to-enals-base-catalyzed-aldol-condensation

Aldol Condensation: Making Enals by Dehydration

Aldol condensation can turn a β-hydroxy aldehyde into an enal when the mixture is heated in the presence of base. An enal is an unsaturated carbonyl product. The β-hydroxy aldehyde first forms during a base-catalyzed aldol addition reaction. The reaction follows a two-step mechanism. First, the base removes the mildly acidic hydrogen on the α carbon, which is the carbon next to the carbonyl group. This forms an enolate ion intermediate. Next, hydroxide leaves through an E1cB elimination...

dehydration of aldols to enones: acid-catalyzed aldol condensation

dehydration-of-aldols-to-enones-acid-catalyzed-aldol-condensation

Acid-Driven Dehydration of β-Hydroxy Ketones

Acid-driven dehydration of β-hydroxy ketones turns them into enones. In this reaction, a β-hydroxy ketone loses water under acidic conditions. The process follows an E1 elimination reaction. The mechanism happens in steps. First, the acid protonates the hydroxyl group on the β-hydroxy ketone. This makes it a hydrated hydroxyl group that can leave more easily. After that group departs, a tertiary carbocation intermediate forms. Next, a hydrogen atom is removed from the α carbon. This final...

intramolecular aldol reaction

Ring Formation in Intramolecular Aldol Reactions

Intramolecular aldol reactions happen in dicarbonyl compounds such as dialdehydes, diketones, and keto-aldehydes. In these molecules, a base can remove a proton from more than one alpha carbon. This forms an enolate, which is the nucleophilic species that starts the ring-forming step. Symmetrical diketones can form four enolates because they have four alpha carbons. But the symmetry makes some of these enolates equivalent. For example, the enolate from carbon 1 matches the one from carbon 6,...

c&ndash;c bond cleavage: retro-aldol reaction

Retro-Aldol Reaction: Bond Breakage in Carbonyls

The retro-aldol reaction breaks a carbon–carbon bond in an aldol product. It is the reverse of aldol addition. Under acidic or basic conditions, this cleavage produces two carbonyl compounds. The mechanism follows three steps. First, a base removes the proton from the hydroxyl group of a β-hydroxy ketone. This forms an alkoxide ion. Next, the carbon–carbon bond breaks and gives a ketone molecule and an enolate ion. In the final step, the enolate ion picks up a proton. This forms a second...

crossed aldol reactions: overview

Limiting Side Products in Crossed Aldol

Crossed aldol addition joins two different carbonyl compounds under acidic or basic conditions. In this reaction, each carbonyl compound can act as both a nucleophile and an electrophile. That flexibility helps form new carbon-carbon bonds, but it also creates product mixtures. Without control, the reaction can give four products. Two come from self-condensation, where one carbonyl compound reacts with itself. The other two come from crossed-condensation, where the two different carbonyl...

crossed aldol reaction using weak bases

Selective Crossed Aldol Products with Weak Bases

Selective crossed aldol products can be formed by using weak bases. In this reaction, an aldehyde that has an alpha hydrogen is added slowly to a mixture of formaldehyde and a weak base such as hydroxide or alkoxide. Slow addition helps prevent the aldehyde from self-condensing, so one main crossed product can form. As the aldehyde is added, the base removes a proton from the alpha carbon. This creates an enolate, which is a reactive carbon-based ion. The enolate then attacks formaldehyde to...

ketones with nonenolizable aromatic aldehydes: claisen&ndash;schmidt condensation

ketones-with-nonenolizable-aromatic-aldehydes-claisenschmidt

Crossed Aldol Reactions with Benzaldehyde

Benzaldehyde can take part in a crossed aldol reaction with a ketone in basic solution. Because benzaldehyde has no alpha hydrogen, it cannot enolize to form an enolate. That feature helps the reaction give one main crossed product. This reaction is called Claisen-Schmidt condensation. In basic conditions, ketones usually do not self-condense strongly, so the self-condensed products are generally not formed when a ketone reacts with benzaldehyde. The result is a more selective reaction pathway.

crossed aldol reaction using strong bases: directed aldol reaction

crossed-aldol-reaction-using-strong-bases-directed-aldol-reaction

LDA-Controlled Crossed Aldol Product Formation

LDA-controlled crossed aldol product formation uses a strong base to guide a reaction between two different carbonyl compounds that both have alpha hydrogens. In a directed aldol reaction, this setup helps form one main crossed aldol product instead of a mixture. A simple aldehyde and ketone reaction with aqueous sodium hydroxide can give several products. That happens because both carbonyl compounds can self-condense. Replacing sodium hydroxide with lithium diisopropylamide, or LDA, reduces...

aldol condensation with &beta;-diesters: knoevenagel condensation

aldol-condensation-with-diesters-knoevenagel-condensation

Knoevenagel Condensation Mechanism in Aldol Reactions

The Knoevenagel condensation is an aldol-type reaction that joins aldehydes or ketones with active methylene compounds such as beta-diesters. It forms substituted olefins, which are compounds with a carbon-carbon double bond. In this reaction, an amine base acts as the catalyst. The amine base removes the acidic alpha hydrogen from the activated methylene group. This creates a resonance-stabilized enolate ion. The base is not strong enough to form the enolate of an aldehyde or ketone. Instead,...

esters to &beta;-ketoesters: claisen condensation overview

esters-to-ketoesters-claisen-condensation-overview

Base Choice in Claisen Condensation

Claisen condensation uses a base to join two identical esters that each have two alpha hydrogens. The reaction forms a beta-ketoester. It is a nucleophilic acyl substitution reaction. In this reaction, the base removes an alpha hydrogen from one ester. That ester becomes a nucleophilic enolate ion. The other ester acts as the electrophile, or the electron-poor partner that gets attacked. The choice of base matters. The reaction needs a nonaqueous base, such as an alkoxide. The alkoxide should...

esters to &beta;-ketoesters: claisen condensation mechanism

esters-to-ketoesters-claisen-condensation-mechanism

Claisen Condensation: Building Beta-Ketoesters

Claisen condensation is a reaction that builds beta-ketoesters from ester molecules. It uses an alkoxide base and works best with identical esters that have two alpha hydrogens. These alpha hydrogens are important because the base removes one of them to start the reaction. The first step forms a resonance-stabilized ester enolate. An enolate is a nucleophilic ion, which means it can attack an electron-poor center. In this reaction, the enolate attacks the carbonyl carbon of a second ester...

aldol condensation vs claisen condensation

aldol-condensation-vs-claisen-condensation

Aldol and Claisen Condensation Paths

Aldol condensation and Claisen condensation are two carbonyl reactions that begin in a similar way but end with different products. Aldol condensation can happen with aldehydes or ketones and is acid- or base-catalyzed. Claisen condensation is a base-promoted reaction between ester molecules that forms a β-ketoester. In both reactions, base removes the acidic alpha hydrogen to form an enolate. An enolate is a nucleophilic ion made from a carbonyl compound. The enolate then attacks a...

intramolecular claisen condensation of dicarboxylic esters: dieckmann cyclization

intramolecular-claisen-condensation-dicarboxylic-esters-dieckmann

Dieckmann Cyclization to Form Cyclic β-Ketoesters

Dieckmann cyclization is a base-driven reaction that forms cyclic β-ketoesters from diesters. It is an intramolecular Claisen condensation, which means the reaction happens within one molecule. The product is a ring-shaped β-ketoester. In this reaction, 1,6-diesters and 1,7-diesters are often used. These substrates are preferred because they can form five-membered and six-membered cyclic β-ketoesters. Those ring sizes are especially stable. The base removes a proton from the α carbon, which...

&beta;-dicarbonyl compounds via crossed claisen condensations

dicarbonyl-compounds-via-crossed-claisen-condensations

Controlling Crossed Claisen Products

Crossed Claisen condensations make β-dicarbonyl compounds by reacting two different esters under base-promoted conditions. These reactions can be useful in organic synthesis, but the choice of reagents strongly affects the product mix. When both esters have α hydrogens, the reaction can give a mixture of four products. That mixture is hard to separate, so the reaction becomes less useful. One common fix is to use an ester with no α hydrogen, such as an aryl ester. Other reagent choices also...

&alpha;-alkylation of ketones via enolate ions

Enolate Attack in Ketone Alkylation

Ketone alkylation with enolate ions starts when a strong base such as lithium diisopropylamide, or LDA, removes an alpha proton. This forms an enolate ion, which is stabilized by resonance. In the resonance hybrid, negative charge is shared between the carbonyl oxygen and the alpha carbon. An enolate is an ambident nucleophile, which means it can react at two different sites. It can attack through the carbonyl oxygen, called O-attack, or through the alpha carbon, called C-attack. In this...

factors affecting &alpha;-alkylation of ketones: choice of base

factors-affecting-alkylation-of-ketones-choice-of-base

Ketone Enolate Formation Depends on Base

Ketone α-alkylation depends on how the base forms the enolate ion. The reaction uses alkyl halides and a base. The enolate then acts as a nucleophile and undergoes nucleophilic substitution. The base is the key factor in the reaction outcome. A base such as EtO− has a conjugate acid, EtOH, with pKa 15.9. That value is higher in strength than the ketone, which has a pKa of 19.2, so the reaction stays as an equilibrium mixture with more ketone present. When that happens, side reactions can...

alkylation of &beta;-ketoester enolates: acetoacetic ester synthesis

alkylation-of-ketoester-enolates-acetoacetic-ester-synthesis

Ketone Formation by Acetoacetic Ester Synthesis

Acetoacetic ester synthesis is a way to make ketones from alkyl halides and β-keto esters. It uses an alkoxide base to remove the acidic proton from the β-keto ester. That forms an enolate ion, which is doubly stabilized. The enolate then reacts with an alkyl halide by an SN2 process. This step creates a new carbon-carbon bond and gives an alkylated ester intermediate. The intermediate is then hydrolyzed and acidified to form an alkylated β-keto acid. When the β-keto acid is heated, it loses...

alkylation of &beta;-diester enolates: malonic ester synthesis

alkylation-of-diester-enolates-malonic-ester-synthesis

Malonic Ester Synthesis for Carboxylic Acids

Malonic ester synthesis is a way to make alpha-substituted carboxylic acids from beta-diesters such as diethyl malonate and alkyl halides. It builds a new carbon-carbon bond and then turns the product into a carboxylic acid. The reaction starts by removing the acidic alpha hydrogen from the beta-diester. This forms a doubly stabilized enolate ion, which is a nucleophile, meaning it can attack an electron-poor partner. The enolate reacts with the alkyl halide by an SN2 mechanism. That step...

conjugate addition to &alpha;,&beta;-unsaturated carbonyl compounds

conjugate-addition-to-unsaturated-carbonyl-compounds

1,2- vs 1,4-Addition in Carbonyl Compounds

α,β-Unsaturated carbonyl compounds contain a carbonyl group and an alkene in conjugation. This conjugation creates three resonance forms. As a result, the molecule has two likely electrophilic sites: the carbonyl carbon and the β carbon. A nucleophile can attack either site. Attack at the carbonyl carbon gives an alkoxy intermediate. After protonation, this pathway forms the direct, or 1,2-addition, product. When the nucleophile attacks the β carbon instead, it forms an enolate ion...

conjugate addition (1,4-addition) vs direct addition (1,2-addition)

conjugate-addition-14-addition-vs-direct-addition-12-addition

Choosing the Product in Carbonyl Addition

Alpha,beta-unsaturated carbonyl compounds can react at two electrophilic sites. The carbonyl carbon and the beta carbon can both attract a nucleophile. This gives two possible outcomes: conjugate addition, also called 1,4-addition, and direct addition, also called 1,2-addition. Conjugate addition gives the more thermodynamically stable product. In this pathway, the stronger C=O bond is kept, while the weaker C=C pi bond is lost. The beta carbon is less electrophilic than the carbonyl carbon,...

conjugate addition of enolates: michael addition

conjugate-addition-of-enolates-michael-addition

Michael Addition by Enolate Donors

Michael addition uses enolate donors to build new carbon-carbon bonds in conjugate addition reactions. In this reaction, a nucleophile attacks the beta carbon of an alpha,beta-unsaturated carbonyl compound. The beta carbon is part of the conjugated system and serves as the electrophile, or Michael acceptor. The donors in a Michael addition are active methylene compounds. These include beta-diketones, beta-keto esters, beta-keto nitriles, and alpha-nitro ketones. A base starts the reaction by...

cyclohexenones via michael addition and aldol condensation: the robinson annulation

cyclohexenones-via-michael-addition-aldol-condensation-robinson

Building Cyclohexenones with Robinson Annulation

Robinson annulation is a base-catalyzed ring-forming reaction that builds 2-cyclohexenone derivatives. It combines a 1,3-dicarbonyl donor, such as a cyclic diketone, a beta-ketoester, or a beta-diketone, with an alpha,beta-unsaturated carbonyl acceptor. This reaction is named after Sir Robert Robinson, who discovered it. The process forms a six-membered ring and creates three new carbon-carbon bonds. Two of these are sigma bonds, and one is a pi bond. The ring forms in two main stages: Michael...

synthesis of &alpha;-substituted carbonyl compounds: the stork enamine reaction

synthesis-of-substituted-carbonyl-compounds-the-stork-enamine-reaction

Enamine Reactions for Carbonyl Functionalization

Enamine reactions can be used to make alpha-substituted ketones and aldehydes. This chemistry is known as the Stork enamine reaction, named after Gilbert Stork. It gives students a clear example of how a carbonyl compound can be modified at the alpha carbon, which is the carbon next to the carbonyl group. Enamines are useful synthetic intermediates because the lone pair on nitrogen is in conjugation with the C=C bond. Their resonance forms give them a nucleophilic alpha carbon. Enamines...

nonenolizable aldehydes to acids and alcohols: the cannizzaro reaction

nonenolizable-aldehydes-to-acids-and-alcohols-the-cannizzaro-reaction

Cannizzaro Reaction for Aldehyde Redox

The Cannizzaro reaction is a base-promoted redox reaction for nonenolizable aldehydes. It turns two aldehyde molecules into a primary alcohol and a carboxylic acid. A nonenolizable aldehyde is one that cannot form an enol under the reaction conditions. The reaction begins when the anionic form of the base attacks the carbonyl carbon. This forms a tetrahedral alkoxide intermediate. The base then removes a proton from this intermediate and creates an unstable dianionic species. That species...

key terms and concepts

Explore how enolate ions form, why alpha hydrogens are acidic, and how enolates react at carbon or oxygen in substitution and addition reactions.

Enolate Ions: Stability and Reaction Sites | JoVE K12

organic chemistry

JoVE Core Organic Chemistry explains basic concepts of stereochemistry, reactions, and mechanisms using concise and easy-to-understand animated video lessons. Additionally, the scientist-in-action videos demonstrate the application of related concepts in classical and original research experiments performed in today's laboratories worldwide.

Enolate Ions: Stability and Reaction Sites

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