1. Electrophilic Reaction on Nitrogen
+ H + H
N N
N N H H
H
H
R = H: pKa 5,23 pKa - 0.27
H
N N
+ H
RX H2O2 N N
H H
N N N
R O pKa 6.95
RCOX
N
R O
2. Electrophilic Reaction on Carbon:
Electrophilic Aromatic Substitution
6-membered rings - electron deficient - ↓ reactivity
H E
E
N N
+ res. forms
•Both C and N may react
N
+ E •3/5 pos. most reactive C
•Diazines less reactive
N
E
H NO2 NO2
H / NO 2 H / NO 2
N N N N
H H
+ res. forms
Benzo ring most reactive
Much slower react. than naphthalene
3. 5-membered rings - electron rich - reactive i E-fil. Ar subst.
+ E E E E
X X H X H X H X E
E E H
H H
+ E
X X X X
React. in α-position generally preferred
Selectivity not always good
React.: Pyrrole > thiophene > furan
4. Nucleophilic Reaction on Carbon:
Nucleophilic Aromatic Substitution
X Nu X X X Nu
Nu Nu Nu
•SNAr
•SN1: Via diazonuim salts and arylic cation
•Benzyne
•SRN1: Involves radicals
•VNS: Vicarious nucl. Subst.
5. 6-membered rings - electron deficient - reactive in Nu-fil. Ar subst.
OMe
OMe
N Cl N Cl N OMe
+ res. form
2 / 4 Pos. reactive; electron def. C, neg. charge partly on N in intermed
3 / 5-Pos. much less reactive (benzenoid pos.)
5-membered rings - electron rich - not reactive in Nu-fil. Ar subst.
6. Radical Reactions
6-membered rings
HetAr H + R HetAr H + R HetAr R HetAr + H
R H
Electron deficient Electron rich
heterocycle radical
5-membered rings
HetAr H + R HetAr H + R HetAr R HetAr +H
R H
Electron rich Electron def.
heterocycle radical
7. Deprotonation NH
H + N N
N N N N N
H N N
H H
pKa 17.5
pKa ≈44 pKa 4.8
C-metallation
C-Litiation: a) Direct litiation (C-H →C-Met)
(“Metal-Hydrogen exchange”)
b) Metal-Halogen exchange (C-X →C-Met)
C-Met a) Transmetallation (C-Li→C-Met)
(Met≠Li) b) Insertion (C-X →C-Met-X)
8. Direct Litiation
R Li
+ R-H
X H X Li
N N
X H X H X H X H
Li
•Reactivity / Acidity / Anion Stability
•Other subst - Directed ortho metallation
•R-Li: Alkyllithium and lithium amides
9. Metal - Halogen Exchange
R Li
+ R-X
X Li
X: Br, I
R-Li: Alkyllithium, NOT LDA etc.
Metall - halogen exchange favored over direct litiation, low temp.
Formation of R-X may be avoided; 2 equivs. t-BuLi
Li
+ X
X Li
X + Li + H + LiBr
10. 5-Membered rings - examples
N N
LDA or BuLi LDA or BuLi
Li X X Li
X X
Li
BuLi BuLi
OLi O
X CO2H X X
O O Li
Br Br Li
LDA BuLi
X Li X low temp. X X Li
Br Br
BuLi
X Br X Li
12. Magnesium Derivatives
MgBr
Mg
X MgBr X Br X MgBr
Zinc Derivatives
Metal - Halogen Exchange Insertion
Zn ZnX2
X Br X ZnBr X Li
Insertion Transmetallation
Negishi coupling
Reformatski etc
Boron / Silicon / Tin Derivatives
Transmetallaton
1) B(OMe) 3 Suzuki coupling
2) H 2O
X B(OH) 2
Bu 3SnCl
Stille coupling
Ipso subst
X Li
X SnBu3
Me 3SiCl
Ipso subst
X SiMe3
13. Reactions on Metallated Heterocycles
Pd-Catalyzed coupling reactions (C-C bond): Zn, Sn, B
Pd(0) Ar-X
HetAr-Ar
reductive
elimination Oxidative
addition
+II +II
HetAr-Pd-Ar Ar-Pd-X
Met-X HetAr-Met
transmetallation
Ipso Substitution (react with E+): Si, Sn
Nu
SiMe3 E E
E SiMe3
+ Nu-SiMe3
X X X
+ res. form
14. Metallation in Alkyl Side Chains
N Acidic
n
H
Strong Base
N CH3 N CH2 N CH2
c.f. enolate anion
