Reactions of Indoles

Question 1

pKa of indole hydrogen on N

Answer 1

16.7

Question 2

why are idoles good nucleophiles

Answer 2

10 pi-electrons over 9-centres so electron rich

Question 3

indole reactions with E+

Answer 3

attack at C3, most wheland intermediates

Question 4

halogenation

Answer 4

halogen and pyridine at 0C, adds at C3

Question 5

reactions with acid chloride/anhydride

Answer 5

adds at C3, acid chloride reactive and can add at N too but readily cleaved by NaOH

Question 6

vilsmeiner

Answer 6

indole with DMF and POCl3 gives enamine
basic aqueous work up hydrolyses enamine to aldehyde then loses proton to re-aromatise 5-membered ring

Question 7

conjugate addition

Answer 7

indoles are soft nucleophiles

Question 8

acidic nitration

Answer 8

conc H2SO4 and cons HNO3, OSO3H added to 5-membered ring, this is the deactivated so nitration occurs on 6-membered ring

Question 9

Mild nitration

Answer 9

indole with PhCOCl and AgNO3 gives nitration at C3, driven by AgCl ppt

Question 10

Indole anion chemistry

Answer 10

NH indoles do nucleophilic attack through N1 and C3
if have N-Directing group attach through C2 and C7

Question 11

Na/K with indoles

Answer 11

cationic, react through N1

Question 12

Mg/Zn with indoles

Answer 12

more covalent character, react through C3

Question 13

formation of zinc anions

Answer 13

transmetallation

Question 14

Li salts with less coordinating solvent (toluene)

Answer 14

no solvent coordination to N, shorter and stronger, more covalent N-Li bond, reacts like Mg/Zn

Question 14

Li salts with coordinating solvent (THF)

Answer 14

THF coordinates to N and donates electron density, weakens N-Li bond therefore more ionic character, reacts like Na/K

Question 15

How do lewis bases direct lithiation

Answer 15

lewis bases act as directing group, Lithium adds ortho to DG as it helps stabilisation, electrophile then replaces Li