Enols, Enolates, Condensations

Enol

RC=COHR; acidic conditions

Enolate

RC=CO^-R; basic conditions

Keto-Enol

equilibrium with acid/base; keto form is prefered

Alcohol pK_a

15-16

Aldehydes/Ketones pK_a

18-20

amine pK_a

34-38

CH₃ pK_a

52

Base-Catalyzed for enolates

ketone → RC=CO^-R; ^-OH; ^-OH removes H on alpha carbon & resonance to get more preferred RC=CO^-R; reversible

Acid-Catalyzed for enols

ketone → C=COHR; H₃O⁺; O lone pairs remove an H, resonance & OH₂ remove an H; reversible

ester pK_a

25

tertiary amide pK_a

30

nitrile pK_a

25

RNO₂ pK_a

9 bc resonance

pK_a

tendency to remove a proton; the higher it is, the less acidic/less it wants to leave

What do Enols & Enolates act like in Reactions?

act as nucleophiles

What does a reaction with E⁺ do with the keto/alde-enol/ate equilibrium?

shifts equilibrium towards products as product is being removed as it reacts with E⁺ & product of enol/enolate and E⁺ is more stable

Water pK_a

16

LDA

Lithium diisopropyl amide; non-Nucleophilic base

LDA pK_a

34

Equilibrium/reaction proceeds to the _________ pK_a value

higher

^.OH as base in enol/enolate

equilibrium; 1 step

LDA as base in enol/enolate

non-equilibrium base; 2 steps

Halogenation

replace H on alpha carbon with halogen

Basic Halogenation

complete; all H on alpha carbon get replaced by Br bc resonance & induction; NaOH, Br₂, H₂O; enolate as intermediate; making enolate is reversible but last step is not

Acidic Halogenation

monhalogenation; only one Br bc resonance and induction; H₃O⁺, Br₂; make enol intermediate which is reversible but adding Br isn’t

Haloform Reaction

ketone → carboxylic acid + HCX₃; 1) NaOH, H₂O, Br₂ (xs) 2) H₃O⁺; ^-CX₃ removes H on OH of carboxylic acid & H₃O⁺ is then added to reprotonate the O

Alkylation

always use LDA bc OH can react with alkyl halide; only use enolates; ketone → ketone with methyl on alpha carbon; 1) LDA 2) CH₃X; irreversible first step; enolate intermediate; can do thermodynamic or kinetic product

Alkylation for Kinetic Product

Rketone-CH₂CH₃ → CH₃CH₂-ketone-CH₂CH₃; 1) LDA (1.05 equiv) 2) CH₃I, -78C; add methyl to less substituted side

Alkylation for Thermodynamic Product

Rketone-CH₂CH₃ → ketone-CH₂(CH₃)₂; 1) LDA (0.95 equiv) 2) CH₃I, 40C; add methyl to more substituted side

Alternate to LDA Alkylation

use enamines

Enamine Alkylation

ketone → enamine; 1) R₂NH (secondary), CH₃CO₂H 2) CH₃I 3) H₃O⁺; thermodynamic product so add methyl to more substituted side

Relative reactivities of enamine, enol, enolate

enolate > enamine > enol

Aldol Reaction

the electrophile is a aldehyde or ketone; get a bond between alpha carbon beta carbon of other carbonyl; condensation makes it a double bond

Aldol Product

2 aldehyde/ketone → beta-hydroxycarboxylic; NaOH, H₂O or H₃O⁺; alpha carbon makes bond with C on C=O (beta C) so O=C-CR-C=OH-R

Base Catalyzed Aldol Product

NaOH, H₂O; alpha double bond attacks C on C=O & that O gets protonated; made alpha-beta bond

Acid Catalyzed Aldol Product

H₃O⁺; O on C=O gets protonated to make enol; double bond attacks C on C=O of protonated aldehyde/ketone; makes alpha-beta bond

Aldol Condensation

heat promotes conversion of Aldol product to Aldol Condensation product (alpha, beta-unsaturated carbonyl) via dehydration; get double bond between alpha and beta carbon & remove OH; basic & acidic mechanisms; reagents → NaOH, H₂O, heat or H₃O⁺, heat

Basic Aldol Condensation

aldol product → HC=OC=CR; NaOH, H₂O, heat; enolate intermediate; ^-OH leaves

Acidic Aldol Condensation

aldol product → HC=OCCR; H₃O⁺, heat; OH gets protonated & leaves so OH₂ removes H on alpha carbon to make alpha-beta double bond

Crossed Aldol

different ketones/aldehydes react; choose reactants so only one can become enolated, one reactant is more acidic, directed aldol

Directed Aldol

make one reactant an enolate/enol first before reacting it with another reactant

Drawing Aldols

draw trans bc more stable