Ch 21 - Alpha Carbon Chemistry: Enols and Enolates

alpha position

directly adjacent to a subject position

e.g. in relation to a carbonyl, the positions right next to the carbonyl (not the carbonyl itself)

designated by an α (alpha) symbol

enol

exists in equilibrium with a ketone in the presence of catalytic acid or base

the tautomer of a ketone

generally not favored at equilibrium, unless it is stabilized

very reactive; alpha position is very nucleophilic (lone pair with negative charge)

tautomers

rapidly interconverting constitutional isomers that differ from each other in the placement of a proton and the position of a double bond

note: NOT the same as resonance structures

e.g. ketones and their respective enols

tautomerization is catalyzed by trace amounts of acid or base, and is difficult to prevent

mechanism for acid-catalyzed tautomerization

proton transfer (protonation of carbonyl)

rearrangement of resonance-stabilized cation

proton transfer (deprotonation at alpha position)

mechanism for base-catalyzed tautomerization

proton transfer (deprotonation at alpha position)

rearrangement of resonance-stabilized anion

proton transfer (protonation of anion)

enolate

a resonance-stabilized intermediate that results from deprotonation of a ketone’s alpha position when treated with a strong base

possess two nucleophilic sites which can each attack an electrophile (thus, called ambident nucleophiles) (oxygen or carbon)

O bears the majority of negative charge, but C is more common to attack

more useful than enols because they possess a full negative charge (are more reactive), and can be isolated and stored for short periods of time

most reactions in this chapter will proceed via this intermediate

O-attack

when the oxygen atom of an enolate attacks an electrophile

less common than C-attack

C-attack

when the negative carbon atom of an enolate attacks an electrophile

more common than O-attack

note: when drawing the mechanism, draw the resonance charge with the negative charge on O, even though C is attacking (because O bears more negative charge than C)

typical pKa range of aldehydes and ketones

16-20

pKa of acetone

19.2

pKa of acetophenone

18.3

pKa of acetaldehyde

16.7

equilibrium between alkoxide base and ketone/aldehyde

pKa range of aldehydes and ketones is similar to the range of alcohols

when alkoxide ion is used as base, equilibrium is established where both alkoxide and enolate are present (usually there is less of the enolate present at equilibrium)

equilibrium favors the higher pKa

commonly used bases for irreversible enolate formation

sodium hydride (H^- is the nucleophile)

LDA (lithium diisopropylamide)

enolate formed by attack of a molecule with two beta carbonyl groups

protons sandwiched between the carbonyls are highly acidic

pKa is generally around 9

acidity is because of the highly stabilized anion formed upon deprotonation

negative charge in anion is spread over 2 oxygens and 1 C

nearly complete enolate formation can be completed with just hydroxide or alkoxide

mechanism for acid-catalyzed halogenation of ketones

part 1: enol formation

proton transfer (protonation of carbonyl)

rearrangement of resonance-stabilized cation

proton transfer (deprotonation of alpha position)

part 2: halogenation

nucleophilic attack by enol

proton transfer (deprotonation)

alpha halogenation

undergone by ketones and aldehydes under acid-catalyzed conditions

(does not occur readily with carboxylic acids, esters, or amides)

observed for Cl, Br, and I (not F)

variety of solvents can be used, e.g. acetic acid, water, chloroform, diethyl ether

rate is independent of concentration of identity of the halogen (halogen does not participate in the rate-determining step)

autocatalytic

occurs primarily at the more substituted side of the ketone/aldehyde if the starting material is unsymmetrical

autocatalytic

when the reagent necessary to catalyze a reaction is produced by the reaction itself

e.g. alpha halogenation; HBr is a byproduct, which is an acid and is capable of catalyzing the enol formation

Hell-Volhard-Zelinsky reaction

alpha halogenation of a carboxylic acid when treated with bromine in the presence of PBr3

sequence of Hell-Volhard-Zelinsky reaction

carboxylic acid reacts with PBr3 → forms acid halide

acid halide exists in equilibrium with enol

enol functions as nucleophile, undergoes halogenation at alpha position

hydrolysis regenerates carboxylic acid

haloform reaction

reaction in which a methyl ketone is converted into a carboxylic acid upon treatment with excess base and excess halogen, followed by aqueous acid

most efficient when the other side of the ketone has no alpha protons

(believed) mechanism for haloform reaction

alpha protons are removed and replaced with Br atoms, one at a time

tribromomethyl group functions as a leaving group → results in nucleophilic acyl substitution

resulting carboxylic acid is deprotonated → produces carboxylate and CHBr3 (bromoform)

formation of carboxylic drives the reaction to completion

(note: if performed with Cl or I instead of Br, chloroform or iodoform is the by-product)

reaction is followed by treatment with a proton source (acid) to protonate the carboxylate and form carboxylic acid

aldol addition

an aldehyde or ketone is attacked by enolate

product is (always) a beta-hydroxy aldehyde or ketone

product exhibits both aldehydic and hydroxyl groups

for most simple aldehydes, equilibrium favors aldol product

for most ketones, aldol product is not favored; poor yields are common

mechanism for aldol addition

proton transfer (deprotonation of alpha position to form enolate)

nucleophilic attack by enolate (attacks aldehyde)

proton transfer (protonation of alkoxide)

retro-aldol reaction

reverse process of aldol addition

beta-hydroxy ketone/aldehyde is converted back into a ketone/aldehyde

mechanism for retro-aldol reaction

proton transfer (deprotonation of beta-hydroxy group)

loss of leaving group (enolate is expelled)

proton transfer (protonation of enolate)

aldol condensation

reaction in which the product of aldol addition is heated in acidic or basic conditions and undergoes elimination to produce unsaturation between alpha and beta positions

two steps: aldol addition plus dehydration

condensation refers to the addition of two molecules accompanied by the loss of a small molecule, e.g. water, CO2, or N2

product is an alpha,beta-unsaturated ketone/aldehyde

if two stereoisomeric pi bonds can be formed, the product with fewer steric interactions is generally the major product

yields are generally much greater than yields for addition reactions

mechanism for aldol condensation

part 1: aldol addition

proton transfer (deprotonation to form enolate)

nucleophilic attack (enolate attacks aldehyde)

proton transfer (protonation of alkoxide)

part 2: elimination of H2O

proton transfer (deprotonation of alpha position)

loss of leaving group (hydroxide is ejected)

E1cb mechanism

an elimination reaction in which the leaving group only leaves after deprotonation occurs

occurs at the end of aldol condensation

cb stands for conjugate base

1 indicates that the reaction is first order

crossed aldol (aka mixed aldol) reaction

an aldol reaction that can occur between different partners

e.g. two starting materials may be treated with a base and produce four different aldol products

of little practical use

only efficient if they can be performed in a way that minimizes the number of possible products

ways to minimize the number of possible products in a crossed aldol reaction

1) one of the aldehydes lacks alpha protons and possesses an unhindered carbonyl group (e.g. formaldehyde)

2) LDA is used as a base (causes irreversible enolate formation)

directed aldol addition

a technique for performing a crossed aldol addition that produces one major product

success is limited by the rate at which enolate ions can equilibriate (function as a base and deprotonate a molecule of aldehyde)

intramolecular aldol reactions

may occur in compounds that possess two carbonyl groups

one end forms an enolate group, which attacks the carbonyl group

preference is for formation of five- and six-membered rings

(smaller rings are possible but not generally observed)

Claisen condensation

the reversible condensation of an ester

nucleophilic acyl substitution reaction in which the nucleophile is an ester enolate, electrophile is an ester

product is a beta-keto ester

ester is treated with 1) NAOEt and 2) H3O+ (workup)

differs from aldol reaction in the fate of the tetrahedral intermediate; tetrahedral can expel leaving group to reform carbonyl

hydroxide can NOT be used as base because it can cause hydrolysis of the starting ester

mechanism for Claisen condensation

proton transfer (deprotonation)

nucleophilic attack (enolate is nucleophile, attacks ester)

loss of leaving group (alkoxide ion gets ejected)

proton transfer (protonation of alpha position)

crossed Claisen condensation

a Claisen condensation that occurs between two different partners

produce a mixture of products, just like crossed aldol reaction

only efficient if one of the two criteria are met:

1) one ester has no alpha protons and cannot form an enolate

2) LDA is used as base to irreversibly form ester enolate (which then gets treated with a different ester)

Dieckmann cyclization

intramolecular Claisen condensation

product is a cyclic beta-keto ester

one carbonyl is the ester enolate (nucleophile), the other carbonyl is the electrophile

preference is for formation of five- and six-membered rings, just like intramolecular aldol reactions

alpha alkylation

alpha position of a ketone or aldehyde via formation of an enolate, followed by treatment of enolate with an alkyl halide

enolate functions as nucleophile, attacks alkyl halide in Sn2 fashion (usually restrictions for Sn2 apply)

choice of base is important: hydroxide or alkoxide ions cannot be used. stronger base, e.g. LDA, can be used

if ketone is unsymmetrical, two possible enolates can be formed (thermodynamic and kinetic)

how to choose the formation of either a thermodynamic or kinetic enolate

if kinetic enolate is desired, use LDA at low temperature (-78*C)

if thermodynamic enolate is desired, nonsterically hindered base (e.g. NaH) can be used at room temperature

acetoacetic ester synthesis

a three-step synthesis that converts an alkyl halide into a methyl ketone with the introduction of three new carbon atoms

(prepares substituted derivatives of acetone)

a way to avoid the issue of polyalkylation

ethyl acetoacetate gets deprotonated by strong base → forms highly stabilized enolate

enolate is alkylated by alkyl halide (via Sn2)

alkylated product is treated with aqueous acid, results in hydrolysis of ester group

if hydrolysis is performed at elevated temp, resulting carboxylic acid undergoes decarboxylation to produce a monosubstituted acetone derivative and CO2

malonic ester synthesis

an efficient method for creating substituted derivatives of acetic acid

enables the transformation of a halide into a carboxylic acid with the introduction of two new carbon atoms

diethyl malonate is deprotonated, then the resulting enolate is treated with an alkyl halide (best to use primary alkyl halide)

alkylated product is treated with aqueous acid, both ester groups are hydrolyzed to give a diacid

if hydrolysis is performed at elevated temp, diacid will undergo decarboxylation to produce an acetic acid derivative and CO2

Michael reaction

reaction in which a nucleophile attacks a conjugated pi system

results in a 1,4-addition (aka conjugate addition)

a diketone is deprotonated to form a highly stabilized enolate ion

the enolate serves as a nucleophile in 1,4-addition

Michael donor

the highly stabilized enolate in a Michael reaction

the nucleophile

Michael acceptor

the alpha,beta-unsaturated aldehyde in a Michael reaction

the electrophile

common Michael donors

only highly stabilized enolates

not regular enolates

common Michael acceptors

Stork enamine synthesis

a type of Michael reaction in which an enamine is the nucleophile

ketone is converted into enamine by treatment with secondary amine

enamine reacts with a suitable Michael acceptor and generates an intermediate that is both iminium ion and enolate ion

treated with aqueous acid, both groups get converted into carbonyls

three steps:

1) enamine formation

2) Michael addition

3) hydrolysis

Robinson annulation

two-step method to form a ring in which Michael addition is followed by intramolecular aldol condensation

often used for synthesis of polycyclic compounds

similarities and differences between aldol addition, Claisen condensation, and Stork enamine synthesis

all produce difunctionalized compounds, but the positioning is different

aldol addition and Claisen condensation produce 1,3-difunctionalized compounds

Stork enamine synthesis produces 1,5-difunctionalized compounds

aldol addition produces a carbonyl and a hydroxyl group, Claisen condensation produces an ester and a carbonyl group (oxidation states are different)

alkylation of alpha and beta positions

an enolate formed by Michael addition can be quenched with water to give the product

or the enolate can be treated with alkyl halide → get alkylated at alpha position

both alpha and beta positions can be alkylated in one reaction flask (the two alkyl groups do not need to be the same)