tema 1.9 session3
TRANSCRIPT
Mòdul MD2301 - Formació general; 564497 – Química orgànica i inorgànica
MASTER ON DRUGS, COSMETICS AND FOOD QUALITYMASTER ON DRUGS, COSMETICS AND FOOD QUALITY
Dr. Antonio DelgadoUniversitat de BarcelonaOctober 2009
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Session 3
Electrophilic aromatic substitution. Benzene, substituted benzenes and their reactivity with electrophiles. Directing groups.
Organic synthesis. Linear versus convergent synthesis. Protecting groups in organic synthesis. Retrosynthetic analysis. Enantiopure compounds: chemical resolution of racemates.
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Hückel’s rule: (4n+2) electrons delocalized (conjugated) in a cyclic system
Electrophilic aromatic substitution
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Heterocyclic aromatic systems
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6
Stability of aromatic systems
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Electrophilic aromatic substitution
Halogenation
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Electrophilic aromatic substitution
Nitration
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Electrophilic aromatic substitution
Sulfonation
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Electrophilic aromatic substitution
Alkylation
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Electrophilic aromatic substitution
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Electrophilic aromatic substitution on benzene derivatives
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• Construction of the carbon skeleton• Functional group transformations• Functional group protection• Stereochemical control (stereogenic
centers)
Planning an organic synthesis
Basic steps
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Planning an organic synthesis Construction of the carbon skeleton
Linear vs convergent synthesis
Linear synthesis
Convergent synthesis
AB ABC ABCD ABCDE
ABCDEF ABCDEFG ABCDEFGH
E
G
rendimiento de cada etapa 80%
rendimiento global:0,87 x 100 = 21%
A
B C D
F H
E G
AB EF GH
ABCD EFGH
ABCDEFGHrendimiento de cada etapa 80%
rendimiento global:0,83 x 100 = 51%
(80%)
(80%)
(80%)A B C D F H
CD
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CH3
CH3C
OH
Nretrosíntesis
desconexión
CH3
CH3C
OH
N
sintones
CH3
CH3
O
reactivos
síntesis KCN
H
ReagentReal species
Synthon (“virtual”)Ionic or radical fragment arising from a disconnection
Construction of the carbon skeletonRetrosynthetic analysis:
Strategic disconnections and synthon generation
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CE2
CX
PR2
OR
O
R
O
CH3Li / CH3MgBr
MgBr
NC CH2 CN
EtOOC CH2 COOEt
OR
O
R
O
Cl
Sintón Reactivo Sintón Reactivo
C1
CN
CH3
KCN
CH3Br
(CH3)3S Br
(CH3)2PCl
Equivalence between synthons and reagents
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Functional group transformationReduction of carbonyl derivatives
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Functional group protection: protecting groups in peptide synthesis: Reactivity control
ROH
O
NH2
H
RO
O
NH3
H
zwitterion
R1 O
O
NH3
H
R2 O
O
NH3
H
R1 OH
O
NHH
P
R1 X
O
NHH
P
protección NH2
activación COOH
R2 O
O
NH2
HY
R1
O
NHH
P
NH
O
O
R2H
Y
protección COOH
AA1 AA2
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R1
O
NHH
P
NH
O
O
R2H
Y
R1
O
NH2
HNH
O
O
R2H
YR1
O
NHH
P
NH
OH
O
R2H
elongación
desprotección NHPdesprotección COOY
Protecting groups in peptide synthesisDirectionality in peptide bond formation
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Enantiomers and chirality
Stereochemical control
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Enantiomers can show different biological activity
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Resolution of racemic mixtures
Chiralchromatography
EnzymaticChemical
Diastereomeric saltformation
Kineticresolution
Racemic mixtures
Preferentialcrystallization
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Chemical resolution(diastereomeric salt formation)
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An example of diastereomeric salt formation
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Resolution of racemic mixtures Diastereomeric salt formation in “high throughput format”
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Resolution of racemic mixturesChiral chromatography