chemistry of carbonyl compounds (mcm 19-12) nucleophilic addition / substitution may also be acid...
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Chemistry of Carbonyl Compounds (McM 19-12)
O
Hδ+
δ-
Nucleophile
ElectrophileBase
Nucleophilic addition / substitution
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
O
R R'
H
O
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 L
O 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 (McM 19.13)
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
+R
HO
H
H
2 Aldehyde Carboxylic acid + prim. alcohol
N
N N
N
NH2
O
ORHO
OP
O
O
OH
P
OO
OHHO
N
O
HO
O
NH2
N
N N
N
NH2
O
ORHO
OP
O
O
OH
P
OO
OHHO
N
O
HO
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 (McM 19.14)
O
R
O
R
O
R
O
R
1,2-addition, Ex: •Alchohols•Organolithium
1,4-addition, Ex: •Amines•Organocuprates
O
Rδ+
δ+
δ-
δ-
Nu
1,2-addition
1,4-addition(conjugate addition / MIchael addition)
Michael reaction (McM 23.11)
Michael acceptorEWG
O O
R
O
ORN S
ON
O
O O
R
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
R
OR
O
R
Robinson Annulation (McM 23.13)
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
O
R
O R
- H2O
O
OH
R
O R
O
O R
R
Aldol condensation
Ring forming react.annulus (lat.) = ring
O
Hδ+
δ-
Nucleophile
ElectrophileBase
O
H
BaseO O
Enolate anionNucleophilic species
O
E
OE
E
O
EE: - Alkyl halides
- Carbonyl compounds (Aldol, Claissen condens.)- Halides
EWG
O O
R
O
ORN S
ON
O
O O
R
CN NO2 SO2R
Michael acceptor
Enolizable
Alkylation of enolate anions (McM 22.8)
O
HBase
O O
R-X
O
RX
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
ORRO
R-X O O
ORRO
R
BaseR-X
O O
ORROR R
H+/H2O O O
OHO
R
H O
C
O
OH
OH
R
+O
OHR
O
OHR
R
O O
R'RO
O O
R'RO
R
H+/H2O O O
RO
R
H
´- CO2
O
R'R
Enamines as enolate equivalents (McM 23.12, Lab ex. 11)
Synthesis of enamines (cf McM 19.9)
O
ketone / aldehyde
R-NH2
prim. amine
O NH2-R HO NH-R
H
NRH
- H
NR
ImineIminium ion
O
ketone / aldehyde
sec. amine
NRR'
Iminium ion
R
NHR'
HH
Base 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 N
E
R R'
O E O
E
H2OH2O N
R'
RHO N
R'
RH OH
+ RR'NH
O
E EEE
Halogenation of enolate anions (McM 22.7)
O
RH
H
O
R
H
O
R
H
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 (McM 22.3)
O
H
H OH
X-XO
X
H
X
O
X + HX
Aldehyde or ketone
(acid, ester, amide - not enolization)
H H HH
E2- HX
O
mainly monohalogenated prod.
α-Bromination of acids (McM 22.4)
O
OHH
PBr
BrBr
O
OH
P
Br
Br
H
Br
O
BrH
+
HO PBr
Br
P-O bondcf Wittig
OH
Br
Acid bromide generated in situEnolize more easily than acid
Br2O
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 (McM 21.8, 23.14)
Acetyl-CoA (Acetyl co-enzyme A)
N
N N
N
NH2
O
OHPO3
OP
OP
O
HN
O OO OOH
O
HN
SH3C
O
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
O
OH
Citric acid
Citrate cycle Energy
CO2
Carbohydrates
* +
CoAS
ODegradation / oxidation of fatty acids
Metab. with little carbohydrates(Diabetes, starvation, diets)
CoAS
OO O
SCoA
Acetoacetyl-CoA
BiosynthesisSteroids, Lipids etc
Acetone
≈ Claissencondes.
Polyesters, polyamides etc (McM 21.9)
OHHO
OOOO *O
n
+ n HXO
X
O
X
Polyester
NH2H2N
OO HN
HN *H
N
n
+ n HXO
X
O
X
Polyamid
OHHO
Polycarbonate
O
O OR R
Carbonate
OHHO OO
O
O O
O
*
n
+ 2n ROH
Acyl subst react
Step-Growth polymers (Chain-Growth polymers: Polyenes)
OHHO NN NH
O
OO
n
Polyurethane(Carbamide)
C OCO
isocyanate
NH
O