Electrophilic Reaction on Nitrogen R = H: pKa 5,23pKa pKa 6.95

Electrophilic Reaction on Carbon: Electrophilic Aromatic Substitution 6-membered rings - electron deficient -  reactivity Both C and N may react 3/5 pos. most reactive C Diazines less reactive Benzo ring most reactive Much slower react. than naphthalene

5-membered rings - electron rich - reactive i E-fil. Ar subst. React. in  -position generally preferred Selectivity not always good React.: Pyrrole > thiophene > furan

Nucleophilic Reaction on Carbon: Nucleophilic Aromatic Substitution S N Ar S N 1: Via diazonuim salts and arylic cation Benzyne SRN1: Involves radicals VNS: Vicarious nucl. Subst.

6-membered rings - electron deficient - reactive in Nu-fil. Ar subst. 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.

Radical Reactions 6-membered rings 5-membered rings Electron deficient heterocycle Electron rich radical Electron rich heterocycle Electron def. radical

Deprotonation NH 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)

Direct Litiation Reactivity / Acidity / Anion Stability Other subst - Directed ortho metallation R-Li: Alkyllithium and lithium amides

Metal - Halogen Exchange 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

5-Membered rings - examples

6-Membered rings

Magnesium Derivatives Boron / Silicon / Tin Derivatives Transmetallaton Zinc Derivatives

Reactions on Metallated Heterocycles Pd-Catalyzed coupling reactions (C-C bond): Zn, Sn, B Ipso Substitution (react with E + ): Si, Sn

Metallation in Alkyl Side Chains