chemistry of carbonyl compounds€¦ · chemistry of carbonyl compounds •nucleophilic addition...
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Chemistry of Carbonyl Compounds
•Nucleophilic addition (1,2-add) / substitution•Conjugate addition (1,4 add)•Robinson annulation (McM 23.12)
•Alkylation of enolate anions•Enamines as enolate equivs. (McM 23.11)
•Halogenation of enols / enolates
•Related react. in nature
OH
δ+
δ-
Nucleophile
ElectrophileBase
Chemistry of Carbonyl Compounds
OH
δ+
δ-
Nucleophile
ElectrophileBase
Nucleophilic addition / substitutionAldehydes / Ketones
O
R'R
R, R': H, alkyl, aryl - Not good leaving groups
NuR R'O Nu H
R R'HO Nu
Addition reactions
O
R R'
HO
R'RNu-H
H
R R'HO Nu
H
HR R'HO Nu
_
Acid catalyzed
Better electrophileWeaker nucleophile
Carboxylic acid derivatives
Substitution
O
LR
L - Good leaving groups
Nu
-X > -OCOR > -OR > -NR2X: Halogen, R: H, alkyl, aryl
R LO Nu
- L
O
NuR May also be acid cat.
Aldehydes / Ketones
O
R'R
R, R': H, alkyl, aryl - Not good leaving groups
NuR R'O Nu H
R R'HO Nu
Addition reactions
The Cannizzarro reaction Hydride as leaving group!
O
R H
R: No acidic α-Hex -H, -Ph. -But
OH
R H
O OH
O
R HO
R OH
H
+RHO
H
H
2 Aldehyde Carboxylic acid + prim. alcohol
N
N N
NNH2
O
ORHO
OP
O
OOH
P
OO
OHHO
N
OHO
O
NH2
N
N N
NNH2
O
ORHO
OP
O
OOH
P
OO
OHHO
N
OHO
O
NH2
NADH
H H
Nicotinamid adenine dinucleotide
NADR=H
R=Phosphate: NADP+, NADPH
R-OH
prim or sec.
Alchohol dehydrogenase(NAD cont.)
aldehyde / ketone
R
O
H
Aldehyde dehydrogenaseR
O
OH
Conjugate Addition
O
R
O
R
O
R
O
R
1,2-addition, Ex: •Alcohols•Organolithium
1,4-addition, Ex: •Amines•Organocuprates
Termodyn. prod,
O
Rδ+
δ+
δ-
δ-
Nu
1,2-addition
1,4-addition(conjugate addition / MIchael addition)
Michael reaction
Michael acceptorEWG
O O
R
O
ORN S
ONO
O OR
CN NO2 SO2R
R' R
O OBase
R' R
O O
H H H
NB! resonance formsWell stabilized enolate anion
O
R''O
R''
HO
R''
OR
O
ROR
O
R
Identity of NuSterical factors
HSAB theory (not in McM)
HSAB : Hard and soft acids and bases
Lewis bases / nucleophiles Lewis acids / electrophiles
Donor atom - hard bases:•high electroneg.•low polarizability•hard to oxidize
Donor atom - soft bases:•low electroneg.•high polarizability•easy to oxidize
Hardness
F- > Cl- >Br- >I-
F- > OH- > NH2- > CH3
-
Acceptor atom - hard acid•small•high positive charge•no unchared e- pair in valence shell•high electroneg.•low polarizability
Acceptor atom - soft acid•large•low positive charge•unchared e- pair in valence shell•low electroneg.•high polarizability
Hard acids prefer to bind to hard basesSoft acids prefer to bind to soft bases
O
R
Hardest electrophilic site
Softest nucleophilic site
O
R
Harder Nu
HO Nu
1,2 addition
O
R
Softer Nu
O
Nu
1,4 addition
But also•Kin. / termodyn. control•Steric shielding
Robinson Annulation (McM 23.12)
R' R
O OBase
R' R
O O
H H H
O O
OR
O
R
H H
1,5-diketoneacidic α-H
Michael react.
Base
O
OR
O
R
O
OR
O R
- H2O
O
OHR
O R
O
O R
R
Aldol condensation
Ring forming react.annulus (lat.) = ring
OH
δ+
δ-
Nucleophile
ElectrophileBase
OH
BaseO O Enolate anion
Nucleophilic species
O
E
O E
E
OE
E: - Alkyl halides- Carbonyl compounds (Aldol, Claissen condens.)- Halides
(React with hard E+)
(React. with soft E+)
Regioselectivity in enolate anion formation (not in McM)
O
Acidic protons
Kinetic control
sterically hidered base
Low temp
O
termodynamiccontrol
O
O
O
Electrophilic addition to conjugated dienes
Termodyn prod: High activation barrier, most stable prod. Vigorous cond. (high temp), reversibleKinetic prod: Low activation barrier, less stable prod. Mils cond, (low temp,) irreversible
H-Br
sec, allylic cation
prim. cat.
BrBr
H
H H
1,2-add. prod.kinetic prod.
+H
Br
1,4-add. prod.termodyn. prod.
EWG
O O
R
O
ORN S
ONO
O OR
CN NO2 SO2R
Michael acceptor
Enolizable
Alkylation of enolate anions
OHBase
O O
R-X
OR
X
Ketones, esters, nitriles(Aldehydes: condensation)
Base: Strong, sterical hindrance
N H + n-Bu-LI N Li + n-BuH
Litium Diisopropyl AmidepKa ca 40
EWG
O O
R
O
ORCN NO2 SO2R
H
HHHHHH
1019 2517 25ca pKa: 30
Alkylation of 1,3-dicarbonyl compounds followed by decarboxylation
O O
ORROBase O O
ORROR-X O O
ORRORBaseR-X
O O
ORROR R
H+/H2O O O
OHOR
H OCO
OH
OHR
+OOHR
OOHR
R
O O
R'RO
O O
R'ROR
H+/H2O O O
ROR
H
´- CO2
OR'R
Enamines as enolate equivalents (McM 23.11, Lab ex. 11)
Synthesis of enamines
O
ketone / aldehyde
R-NH2
prim. amine
O NH2-R HO NH-R
H
N RH
- H
N R
ImineIminium ion
O
ketone / aldehyde
sec. amine
N RR'
Iminium ion
RNHR'
HHBase NR R'
Enamine
Neutral imine
Reactivity of enamines
•Alkylation (alkyl halides)•Conjugate addition (Michael acceptors)•Acylation (acid halides)
•Monoalkylation•No strong base
NR R'
Enamine
E NE
R R'
O E OE
H2OH2O N R'
RHO N R'
R H OH
+ RR'NH
O
E EEE
Halogenation of enolate anions
O
RH
H
O
RH
O
RH
X-BX
O
RX
HX
Reacts further in the presence of base and halgen source
H H
H
H
OH
O
RX
XX
OH
OHX
XX
O R
O
HO RCX3Fairly good leaving group +
O
O RHCX3 +
pKa X=I: 14
Halogenation of neutral enols
OH
H O HX-X O
X
H
X
OX + HX
Aldehyde or ketone
(acid, ester, amide - not enolization)
H H HH
E2- HX
O
mainly monohalogenated prod.
α-Bromination of acids
O
OHH
PBrBr
BrO
OH P
Br
BrH
Br
O
BrH
+
HO PBr
Br
P-O bondcf Wittig
OH
Br
Acid bromide generated in situEnolize more easily than acid
Br2 O
BrBr
H2O
O
OHBr
cf McM 17.7
Hell Volhart Zelinskii React.Intro of Cl also possible
R-OH + PBr3 R-Br
Carbonyl condensations in nature
Acetyl-CoA (Acetyl co-enzyme A)
N
N N
NNH2
O
OHPO3
OPOPOHN
O OO OOH
O
HNSH3CO
O
Acetyl-CoA
Nu
BaseNature's
O
Clor
O
O
O
Synthesis of Acetylcholine (neurotransmittor)
NOH
Choline
Acetylcholineesterase
CoAS
O
NO
O
Acetylcholine
Acyl-CoA
CoAS
ODegradation / oxidation of fatty acids +
O
HO2CCO2H
Oxaloacetic acid
≈ Aldol Hydrol.Acyl-CoA
OH
HO2CCO2H
OOH
Citric acid
Citrate cycle Energy
CO2
Carbohydrates
* +
CoAS
ODegradation / oxidation of fatty acids
Metab. with little carbohydrates(Diabetes, starvation, diets)
CoAS
OO O
S CoA
Acetoacetyl-CoA
BiosynthesisSteroids, Lipids etc
Acetone
≈ Claissencondes.