enolates, enols, and enamines part 1
TRANSCRIPT
Enolates, Enols, and EnaminesPart 1
NaOHO
+
Ph H
ONaOH
H2O
OHO
PhH2O
O
Ph
Similar Structures cause Similar Reactions
Name Resonance contributors Resonance hybrid
Enolate
Enolalkene + alcohol
Enaminealkene + amine
Oδ−
δ−
HOδ+
δ−
R2Nδ+
δ−
α β
Reading: OCATSA Chapter 27
Nucleophilicat β-carbon
O O
HO HO
R2N R2N
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 1
Enolates: Formation
Recall the three C=O group fates:
•Nucleophilic attack at carbon
•Accept electrophile (usually H) at oxygenUsed extensively in C=O
addition and substitution reactions
•Form enolate:
H Base
O OO
Enolate
Important issues: •Which O=C-C-H is most acidic (removed first)?
•What base to use?
•How much enolate is formed?
Relative Acidity of H-C-C=O
Review: --OCATSA chapter 9
--Tutorials on course web site
--Chem 14C notes
Example:O
+
OO
+
OCH3
OBase
Which enolate is formed?
Most stableenolate
LowestpKa
comes from
indicated by
comes from
Example: H2SO4 pKa -9; H2O pKa 15.7
Most acidicH-C-C=O
Conjugate acidmost readilydeprotonated
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 2
Relative Acidity of H-C-C=O
•Keq ~ 10(pKa right acid – pKa left acid) = 10(15.7 – 19) = 10-3.3
•pKa values do not need to be memorized, but can be useful to know
•Enolate is often drawn as its most stable resonance contributor
Example: A ketone and its enolate
Ketones
Keq < 1 (more ketone than enolate) Keq > 1 (more enolate than ketone)
Equilibrium position?
•Acid/base equilibrium favors weakest (most stable) acid and weakest (most stable) base
pKa 19Weaker acid
pKa 15.7Stronger acid
O
+ HOO
+ H2O
Most acidic?
Ketone
β-diketone
Most stable enolate?
Ketone enolate
β-diketone enolate
More extensive delocalization?
Ketone enolate
β-diketone enolate
Relative Acidity of H-C-C=O
Keq ~
β-Diketones
Keq < 1 (more diketone than enolate) Keq > 1 (more enolate than diketone)
Ketone enolate:
β-diketone enolate:
O O
OO
+ CH3O
OO+ CH3OH
OO OO OO
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 3
Relative Acidity of H-C-C=O
Keq ~
Esters
Keq < 1 (more ester than enolate) Keq > 1 (more enolate than ester)
Ketone enolate:
Most acidic?
Ketone
Ester
Most stable enolate?
Ketone enolate
Ester enolate
Largest δ− charges?
Ketone enolate
Ester enolate
Ester enolate:CH3O
O
CH3O
O
CH3O
O
O O O δ−
δ−
CH3O
O
δ−δ+
δ−
CH3O
O
+ CH3O
CH3O
O
+ CH3OH
Relative Acidity of H-C-C=O
O
+
OO
+
OCH3
OBase
Which enolate is formed?
pKa 19 9 25
OO
•Most acidic proton removed first
CH3O
OO
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 4
Enolate Formation: A Potential ProblemProblem: Strong base is also usually strong nucleophile...
How to avoid addition, and get enolate formation only?
HO- is a base
HO- is a nucleophile
CH3O
O
+ HO
CH3O
O
CH3O
OHO
Competing pathways
Enolate Formation: A Potential ProblemHow to avoid addition, and get enolate formation only?
•Reduce nucleophilicity? Strong base usually also strong nucleophile
•Steric effects?
H
OBase/Nuc
Less hindered than C
More hindered than H
•Therefore use sterically hindered strong base to minimize attack at C=O
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 5
•LDA is a very strong base; equilibrium favors... enolate ester Keq ~ _________
Enolate Formation: A Potential ProblemSterically Hindered Base Minimizes Attack at C=O
•LDA favors deprotonation instead of addition
Lithium diisopropyl amideLDA
Li+ -N(iPr)2
N
Li
CH3O
O
H N(iPr)2
CH3O
O
+ H N(iPr)2
pKa 25 pKa 36
1011
Not formed
N
OCH3O
Example: Use of LDA to form ester enolate
What is an Enolate Good For?Now that I have an enolate, what do I do with it?
suggests
Less significant contributor:FC on carbon (EN = 2.5)
More significant contributor:FC on oxygen (EN = 3.0)
R
O
•Resonance suggests multiple spots to form new bonds
•Enolates accept most electrophiles at carbon
•Enolates useful to form new carbon-carbon bonds
R
O
Elec
R
O
Elec
Elec
R
OElec
Negative formal charge
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 6
Enolate Reactions: AlkylationEnolate (nucleophile) + alkyl halide (electrophile) SN2 reaction
Example:
New C-C bondnext to C=O
O
1. LDA
2. CH3I
O
CH3
Mechanism:
O O
CH3H N(iPr)2
O H3C I
SN2
O
CH3C
CH3H3C
Enolate Reactions: AlkylationEnolate (nucleophile) + alkyl halide (electrophile) SN2 reaction
•Enolate alkylation must meet usual SN2 requirements...
O
+ (CH3)3C-I
SN2 E2
O
+ CH2C CH3
CH3
Nuc + R3C–LGSolvent
Nuc–CR3 + LG
Enolates are usually
_________ nucleophiles
Enolate solventsOK for SN2
Not _______ Depends on electrophile
Example:
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 7
O
H OH
O
Ph H
O O
Ph
OH H OH O
Ph
OH
+ HO
Enolate Reactions: The Aldol ReactionEnolate + ___________________________
Another electrophileProduct?
Example: Predict product byworking out mechanism
Mechanism:•Strong base present so consider enolate pathways before addition/substitution
•PhCHO cannot form enolate
Keq = __________
Aldehyde more / less
electrophilic than ketone
O
Ph H
O
+NaOH
H2O
•HO- is ________________ and __________________.
Tetrahedral adduct...
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 8