chapter 23. carbonyl alpha substitution reactions semester files...chapter 23. carbonyl alpha...
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Chapter 23. Carbonyl Alpha Substitution Reactions
Alpha-substitution reactions occur at the position NEXT to the carbonyl group- the α position- and involve substitution of the α-H by an electrophile E through either an ENOL or ENOLATE ION. The α-C of carbonyls can act as a nucleophile in a number of reactions via either the enol tautomer or via the enolate anion. Keto-Enol Tautomerization and Enol Reactivity • S. 8.5: A ketone with alpha H is in equilibrium with its corresponding enol tautomer: There is a rapid interconversion between the two forms which is a special kind of isomerism called: tautomerism (Greek: the same) Under most conditions the enol form is present in very small amounts. However, it is very important for synthetic reasons because they are so reactive. The formation of the enol component is catalyzed by both acids and bases such that it can be present in amounts that allow for synthetically useful reactions:
R
O OR'
H H!
no alpha-proton
R
OR'
H E
E+
O OH
ketone99.9999%
enol0.0001%
Alpha halogenation of enols One important reaction of enols: alpha halogenation Aldehydes and ketones can be halogenated with Cl2, Br2, and I2 under acidic conditions:
O H+ OH
H OH+ H+
Acid Catalyzed
Base Catalyzed
OH
B- O-H-B OH
+ B-
O
Br2/H+
O
Br
Mechanism:
R
O
H
H+
R
O
H
HOH
R CH2
Br-BrR
O H
R
OBr
Only ONE alpha-H is replaced by a halogen
Br
R
O H
Br
Br-
If a ketone is unsymmetrically substituted, the halogen is delivered to the more substituted side, via the more substituted and more nucleophilic enol: Alpha-halogenated ketones and aldehydes are easily converted in their corresponding α,β-unsaturated compounds by elimination:
Acidity of Alpha H: Enolate ion formation • Discuss pKa
• Lower pKa due to resonance stabilization :
O
Cl2/H+OH O
Cl
OBr2/H+
O H
Br
tBuOKE2 O
HA + H2O A- + H3O+
Ka = [A-][H3O+][HA] pKa = -logKa
H3C CH2H
pKa = 60
R C C HH
H
O
!
pKa = 17
R C C RH
H
O
!
pKa = 20
R
OR'
H HB
R
OR'
H R
OR'
enolate
Difference: ~40 pKa units ketone is 1040
times more acidic than alkane. (USA budget (2006) ~$2 trillion (1012) )
• Weaker bases, such as NaOH and NaOEt generate an equilibrium mixture of enolate and carbonyl compound: Even though the generated enolate is not much it can still be used in reactions. • A more powerful base, LDA, can be used to completely convert a ketone or aldehyde to their corresponding enolate:
pKa = 17pKa = 20
O
OH
pKa = 25
O
NHpKa = 30
O
ClHpKa = 16
O
H
O
HH
EDG, less enolate stabilization
NO2
H
pKa = 8.6
C NHpKa = 25
C CH
HC NN
pKa = 12
O
O OO O
H H2,4 pentane dione
pKa = 9Ethyl-3-oxobutyrate
pKa = 11
Why higher?Discuss
O
99.9 %
NaOEt
orNaOH
O
0.1 %
Enolates are more useful than enols for two reasons:
1. Unlike enols, enolates can be generated as stable, pure solutions
2. Due to their negative charge, enolates are more reactive nucleophiles than enols
OLDA: lithium
diisopropylamide
NLi
LDA
NH
+ nBuLi N
LipKa ~ 40bulky base
good base, bad nucleophileweak acid
conjugated base is strong
O
NH
+
~ 100%
Enolates can react either at the alpha carbon or at the oxygen carbon. (We will only study reactions at the alpha carbon)
R
OR'
R
OR'
E+ E+
R
OR'
ER
OER'
not discussed
reaction at ! carbon
reaction at oxygen
Two reactions of Enolates to discuss: 1. alpha Halogenation • Already saw enol halogenation (under acidic conditions): Compare to enolate halogenation (basic conditions):
So: Under basic conditions every alpha-H is replaced by a halogen:
OH+/Br2
OBr
NaOHBr2
OBr
BrBr
Br
monohalogenation
perhalogenation
H+
OHBr much less
nucleophilic enol due to EW bromine
O
NaOH
Br-BrO O
BrH
more acidic due to EW Br
OBr
BrBr
Br
H
ONaOHCl2 H
O
Cl Cl
Haloform Reaction: ONLY with methyl ketones, same conditions afford carboxylic acids.
2. Alkylation of Enolate Ions
• Aldehydes, Ketones, Lactones, Esters, Nitriles can all be alkylated on the alpha C this way.
O 1. Br2/NaOH2. H3O+ OH
O
R
O NaOHBr2 R CBR3
O NaOHR O
O
HCBr3
R O
OCHBr3
H3O+
R OH
O
Mechanism
O
LDA
O
Br
SN2O
O
Examples:
Kinetic vs Thermodynamic Enolate
O
HH LDA
O O
+
OO
more hindered
less hindered
fasterkinetic enolate
more stablethermodynamic enolate
O O
lactone
1. LDA2. CH3CH2Cl
O O
!-H
O
!-H!-H
1. LDA2.Ph I
O
symmetric
Ph
O
1. LDA2. CH3CH2Cl
O
!-H !-H
asymmetricor
O
• Dicarbonyl Compounds Remember:
So, dicarbonyl compounds will form enolates easier (no need for strong base like LDA, softer bases (NaOEt, NaOH) would do) Very useful synthetic indermediates
O
LDA (2 eq) O
O
fasterkinetic enolate
more stablethermodynamic enolate
LDA (<1 eq)
Cl
Cl
O
O
pKa = 17pKa = 20
O
H
O
HH
O
O OO O
H H2,4 pentane dione
pKa = 9Ethyl-3-oxobutyrate
pKa = 11
O O 1. NaOEt2. Ph Br
O O
Ph
Two useful reactions (need to memorize the names of the compounds): 1. The Malonic Ester synthesis (Provides Carboxylic Acids)
2. The Ethyl Acetoacetate synthesis (Provides Methyl Ketones)
EtO OEt
O O 1. NaOEt2. R Br EtO OEt
O O
R
H3O+
heat
O
O
O
OH
R
H
ester hydrolysis
-CO2O
OH
RExample
EtO OEt
O O1. NaOEt2.
3. H3O+ heat
Ph BrO
OH
Ph
diethyl malonate
EtO
O O 1. NaOEt2. R Br EtO
O O
R
H3O+
heat
O
O
O
R
H
ester hydrolysis
-CO2O
RExample
EtO
O O1. NaOEt2.
3. H3O+ heat
BrO
ethyl acetoacetate
Both reaction proceed through a decarboxylation rxn (loss of CO2) - 3-oxo-carboxylic acids can decarboxylate if heated under acidic or basic conditions:
O-
O + CO2
bad leaving group
O
O O O + CO2
enolate-stabilized
Example:
O
O O
NaOH, heat O
O O
CO2
O
Chapter 24. Carbonyl Condensation Reactions
Carbonyls can act as both Electrophiles and Nucleophiles, so:
• Self Aldol Condensation • Similar rxn with ketones affords beta-hydroxyketones
Nu R
O
R
electrophile
R R
OH
Nu
O
RRBase O
RR
nucleophile
E+ O
RR
E
O
HNaOH O
H
O
H
O
H
O-
H2O
O
H
OH
used to be carbonyl !
"C-C bond formation
"-hydroxyaldehyde
• Hydroxy compounds can dehydrate under acidic conditions, heat • Aldol products can dehydrate under acidic or basic conditions and heat easier, since the product is a conjugated system. Some Aldol products do not need heat. They dehydrate since they will have extra conjugation. For example, aromatic systems:
Dehydrated Aldols are called “Aldol Condensations”
NaOH
O O
OH
!-hydroxyketone
heatdehydration
O
",! unsaturated enone
O
-OH
O O
O O-O OHO
Oused to be carbonyl
Mixed (Crossed) Aldols When two non identical carbonyls are used in an aldol rxn Typically, what is isolated is a statistical mixture of four products: two self-aldol products and two mixed aldol products.
(If asymmetric ketones used, even worse mess!) Two possible solutions: 1. If one participant has no α−hydrogens
Two products, better yield of 1st if excess benzaldehyde used.
O
H
O
H+ NaOH
H
H
OH
H
O
H
OH
OOH O
OOH
O
H
H
O
NaOH
OH O
H
O
H
H
OH O++
2. Better solution: Generate the enolate of one carbonyl compound completely with LDS and then add the 2nd carbonyl compound.
Examples:
O1. LDA-78 oC
O O2.
3. H3O+
O
1. LDA-78 oC
2.
3. H3O+
Ocarbonyl
OOH O
H
O
O OH
O OOH
O
O O
1. LDA, -78 oC
2.
3. H3O+kinetic enolate
O O-H2O
O
• Intramolecular Aldol Reactions When the same molecule has two aldehydes or ketones Driving force: Formation of 5 or 6 membered rings. 23.8 Claisen Condensation Condensation of two esters: Example:
O
O
NaOHO
O
O
O
O1. NaOCH32. H+ O
O O
!-ketoster
O
O
O
O
1. NaOCH3
O
O- O
O
Note: Base has to be same as ester otherwise
transesterification
O OEt
O OEt
O
Mixed Claisens: 1. Useful only if one of the two esters has no α-H. That ester is used in excess to avoid homocoupling:
2. Works the best if you 1st generate one enolate and then add the second ester. 3. Useful if ester is used to condense with ketone/aldehydes (α-H pKa is less), use ester in excess
O
O
O
O 1. NaOMe2. H+
O
O
O
excess
O
O
1. LDA, -78oC
2.
O
O
Ph O
OEt
O
Ph
O
O
O
+ 1. CH3CH2ONa2. H+
O O
excess !-diketone
O
H O
O1. CH3CH2ONa2. H+
H
O O
!-ketoaldehyde
23.10 Dieckmann Condensation (Intramolecular Claisen) Diesters can cyclize to form cyclic β-keto esters (5 , 6 m. rings)
23.11 The Michael Reaction Remember addition to unsaturated compounds: 1,2 for strong bases (Grignard) 1,4 for weaker bases Michael Reaction combines enolate chemistry with the reactivity of α,β-unsaturated carbonyls. Works well with enolates of beta-dicarbonyls, since they are relatively acidic.
O OO
O1
2
3
45 NaOCH3 O
O
O
O
O O
O
O
O
OO
O OO
OHO
O
O
Examples: • 1,4 addition does not take place readily with enolates of ketones/aldehydes (too basic). (Weʼll see Stork Enamine Rxn for forming 1,4 diketones, dialdehydes )
Mechanism:
O
OH
H H
O O OH O OO
O
O
O
O
O
O
O O O
O
O
O
O
NaOCH3
H
O OCN
NaOH
O
CN
O
O O
NaOHno 1,4 product
O
O
beta-diketone
How to prepare α ,β unsaturated carbonyls a. Elimination of alpha halogen carbonyls (Not very good) b. Aldol c. BETTER WAY. Works well for ketones, esters, nitriles
OBr OH
O
O
1. LDA2. PhSeCl
OSePh
selene nylation
OSePh H2O2
OSePh
OO
O
O 1. LDA2. PhSeCl3. H2O2 O
O
23.12 The Stork Enamine Reaction Michael rxn with an enamine nucleophile instead of an enolate:
Enamines behave similarly to enolates in that they have a partial negative charge on their alpha-C.
N Nnucleophilic
!-C
NO
1.
2. H3O+
OO
O N O
protonates the enolate and
hydrolyzes the iminium
H3O+
N OHN
23.13 The Robinson Annulation Reaction Combination of a Michael Rxn followed by an intramolecular aldol Always makes six-membered rings, α,β-unsaturated ketones:
To analyze a Robinson annulation product: Cut between β, γ and through double bond
OO
NaOHO
mechanism
O
H
Michael
OH
O
O
O O
H O H
O O
HOH
O OAldol
O
O H O H
OH
OH
OH
O
O
!"
O
H
O
O
O O
O
O
!"
