Heterocyclic Flashcards
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
What are the steps of the Larock mechanism
1) oxidative addition - Pd inserts into C-I bond
2) carbometallation - insertion of alkyne (becomes alkene on coordination) into C-Pd bond
3) formation of palladocycle by N lp attack on C making I leave
4) reductive elimination makes Pd leave and N bonds to carbon
In the second step (carbometallation) of Larock synthesis, what is the selectivity involved
C-Pd reacts with least hindered carbon of alkyne and therefore the one with smaller R groups
Why can’t you make carbazoles (indole where the pyrrole double bond has another Ph ring fuzed to it) by Fischer Indole synthesis
The enolate starting material is phenol therefore no equilibrium; it is way too stable as an aromatic ring
How do you synthesise carbazoles
The nitrene pathway; 2 routes
1) A benzene ring with ortho Ph and N3 substituents. Heat or hv
2) A benzene ring with ortho Ph and NO2 substituents. react with P(OEt)3 and heat
You get two benzene rings connected by a bond and ortho to that bond on one of them is an ortho N
CH insertion of this N gives a carbazole
OR via benzotriazoles
What is the Grubbe-Ullman
Formation of carbazoles from triazoles
Radical pathway proceeds when you heat a triazole at 180*C OR hv
How do benzofurans react
Electrophilic substitution on the benzene ring and the acidic proton ortho to the oxygen of the furan
How do you synthesise benzofurans
- O-Aryl Ketoximes (analogous of Fischer Indole)
- via phenoxide which attacks the alpha carbon of an alpha bromo carbonyl such that the bromide leaves. Then the lone pair on the oxygen makes the C=C in the benzene ring attack the carbonyl (which is protonated) followed by dehydration to make the double bond in the pyrrole ring
Quinolines and isoquinolines are
pi-deficient because the heterocycle is less reactive than the benzene ring
What are the two types of chemistry by which quinolines and isoquinolines can react
nucleophilic addition at pyridine
electrophilic substitution at benzene
At what position does nucleophilic addition occur on the pyridine of a quinoline
1 position not 3 because it is closer to the benzene ring
If you reduce quinoline with LithAl what do you get
reduction at N=C bond only, N becomes NH
You get dihydroquinoline, H- attacks 2 position and is a potent nucleophile
If you reduce quinoline with H2/Pt and MeOH what do you get
Reduction of pyridine ring only
tetrahydroquinoline
If you reduce quinoline with H2/Pt and Conc HCl what do you get
reduction of benzene ring only
protonation of N results in protection of N and activation of the benzene ring otherwise stable
How do you synthesise quinolines
1) Skraup synthesis
- phenylalanine, triol molecule and H2SO4/H2O and PhNO2 (high boiling solvent) and heat
- Doebner-Miller modification uses alkyl groups on a ketone to add R groups to pyridine
2) Coombes synthesis
- Phenylalanine and 1,3-dione then remove water twice
What role does the triol compound play in Skraup synthesis of quinolines
It is a 3C building block which inserts between N and benzene
Cons of Coombes synthesis of quinolines (2)
- mild compared to Skraup/Doebner-Miller
- lack of selectivity but ok if R groups are the same otherwise you get isomers
(aniline attacks least hindered site therefore smaller R group)
How do you synthesise isoquinolines
1) Pictet-Spenglar
- makes tetrahydroisoquinoline (best method for fully saturated molecule)
2) Bischlev-Napieralski reaction
- makes dihydroisoquinoline; isolable but reactive
