1) Electrophilic and nucleophilic aromatic substitution reactions can occur on both carbon and nitrogen atoms in heterocycles, with positions of reactivity depending on ring size and substitution. 2) Directed metalation techniques like lithiation and Grignard reactions allow for functionalization of heterocycles at specific positions. Metal derivatives can then undergo cross-coupling, substitution, or other transformations. 3) Five-membered rings are generally more reactive than six-membered rings towards electrophiles due to their electron-rich nature. The reverse is true for nucleophilic aromatic substitution.

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

11. 6-Membered rings N N N N N
R H
N R N
R H
R
N H
R
R
N
H N

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