Heterocyclic Flashcards
(41 cards)
Why do 1,3-azoles undergo slower electrophilic substitution than pyrrole
added inductive effects
also lone pair on the nitrogen can have side reactions
Electrophilic substitution of 1,3-azoles always occurs on the _ position and why
5
1) heteroatom
2) positive divalent nitrogen
3) Heteroaton
4) 2 resonance forms
5) 3 resonance forms
Electrophilic substitution of 1,2-azoles always occurs on the _ position and why
4 1,2) heteroatom 3) divalent N+ 4) 2 resonance forms 5) divalent N+
How do you synthesise a 1,3 azole
nitrile + alpha-amino carbonyl in acidic environment
How do you synthesise a 1,2-azole
a) condensation (start with 1,3-dicarbonyl and add NH2NHR or NH2OH)
b) cycloaddition with nitrile oxides and alkyne
How do you attempt selectivity of cycloaddition between a nitrile oxide and an alkyne (2)
a) electronically: one R group on alkyne electron withdrawing; O- will attack that side
b) sterically: one large R one small 2
How do you make tetrazoles
One nitrile RCN, NaN3 NH4Cl DMF and heat (cycloaddition)
CN attacks pi bond not N-
What sort of diazoles can you not use anion chemistry for and why
1,2-azoles
When you deprotonate, the negative charge delocalises onto the oxygen and creates an enolate which attacks RX itself rather than at the original deprotonated place
1,3 azoles proceed like normal
What are indoles
Benzene ring + pyrrole
pi excessive
pyrrole dominates chemistry
What are the 2 electrophilic substitution mechanisms of indoles and which is preferred and why
C2 and C3
C3 is preferred because C2 involves a breaking of aromaticity whereas C3 doesn’t
However this is just a preference and they can both proceed
Under what conditions can the benzene part of the molecule react and which positional atom reacts
VERY acidic. Need sulfuric acid C5 reacts (remember the connecting carbon is not counted)
What is the Heck reaction
Substitution of an aromatic Halogen or OTf with an alkene chain catalysed by Pd(0) and base
What are the reagents for oxidative Heck reaction
Pd(II)X2 and alkene
Give 5 ways to synthesise indoles
Reissert synthesis (+Leimgruber modification) Bischev reaction Fischer Indole reaction Bartoli Indole synthesis Larock Indole synthesis
What are the reagents in Reissert synthesis of Indoles
H2/Pd/C or Fe/AcOH
Describe Bischler reaction
Aromatic NH2 lone pair attacks alpha halo carbonyl at the carbon and halogen leaves. Then N lone pair moves electron density onto bond with aromatic ring and 1 carbon later on the ring attacks the carbonyl (which is protonated) to make the 5 mr then H2O leaves to make the double bond
Describe Fischer Indole reaction
Aromatic NHNH2 reacts with aldehyde under acidic conditions and heat
How do you make the aromatic starting material for Fischer Indole reaction
Aromatic NH2 react with HONO –> Aromatic N2+ react with Na2SO3 –> aromatic NHNH2
What is a selectivity problem in Fischer Indole synthesis and how is it solved
If you have a carbonyl which can form two enamines you can form two products
Add an electron withdrawing group to one side such as SPh to make the proton there more acidic such that that carbon is more enolisable
Why is an ortho substituent critical to the Bartoli Indole synthesis
It causes NO2 to twist out of the plane and make it more reactive because otherwise it is conjugated with the aromatic ring
Reaction does not proceed without an ortho R group
Why is Fischer indole better than Bartoli indole
Broader range of substrates
What does the mechanism of Bartoli Indole synthesis start with
Grignard attack of the O in NO2 to create N-O-alkyl
How many equivalents of grignard reagent do you need for Bartoli indole synthesis
3
- attacks NO2 at the start (@ =O atom)
- attacks resulting PhN-O atom (@ O)
- removes proton to finish
What are the reagents for Larock indole synthesis
alkyne, base, Pd(OAc)2 which forms Pd(0) in situ
