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AromaticandHeterocyclicChemistry

65

Hetroaromatics

Pyridine

properties–pyridineispolarisedbythepresence

ofthenitrogenatom

both

throughthep-system

ands-

framework

thelonepaironnitrogenisorthogonalto

thep-system,andistheHOMOofpyridine;theLU

MOofpyridineisan

anti-bondingp-orbital

pyridineiselectronpoorandundergoesEARSonlyvery

slowly

synthesisofpyridinesandderivatives–generallyaim

tomake

dihydropyridineandthenoxidiseitto

the

correspondingpyridine

dihydropyridinesare

readilypreparedbythecondensationofammoniawith1,5-dicarbonylcompounds

1,5-dicarbonylcompoundsare

readilypreparedbyadditionofanaldehydeorketoneto

ana,b-unsaturated

carbonylcompound

N

AromaticandHeterocyclicChemistry

66

Heteroaromatics

Hantzschpyridinesynthesis

Me

NH2

OMe

O

Ph

CO2Me

OH

Me

r.d.s

otheroxidantsto

convertdihydropyridinesto

pyridinesinclude:(NH4) 2Ce(NO3) 6(CAN),MnO2,DDQ

AromaticandHeterocyclicChemistry

67

Heteroaromatics

Pyridinesynthesiswithhydroxylamine–nooxidantrequired

Electrophilicsubstitutionwithpyridines

E

N

E

AromaticandHeterocyclicChemistry

68

Heteroaromatics

Nitrationofpyridine

nitrationofpyridinewithN2O5

plausiblemechanism

N

NO2NO3

NO

O

NSO3H

NO2

[2,3]-sigmatropic

rearrangement

H

AromaticandHeterocyclicChemistry

69

Heteroaromatics

PyridineN-oxides–much

more

susceptibleto

electrophilicattack

at2and4positions(andto

nucleophilic

additionat2and4positions)

nitrationofpyridineN-oxide

N O

N O

promotesE+addition

at2and4positions

AromaticandHeterocyclicChemistry

70

Heteroaromatics

pyridineN-oxides–N-deoxygenationwithrearrangement

pyridineN-oxides–conversionto

chloro

compounds

N

Me

H

O

Me

O

Cl

AromaticandHeterocyclicChemistry

71

Heteroaromatics

pyridones

nitration

POCl 3

NO

NO2

PCl

OCl

H

AromaticandHeterocyclicChemistry

72

Heteroaromatics

pyridines–nucleophilicsubstitution

Chichibabinreaction

AromaticandHeterocyclicChemistry

73

Heteroaromatics

quinolinesandisoquinolines

Synthesis–Skraupsynthesis

HO

OH

OH2

NOH

H

tautomerise

+H

NOH2

H

AromaticandHeterocyclicChemistry

74

Heteroaromatics

synthesisofisoquinolines

Bischler-Napieralski

POCl 3 N

Cl

R

H

Pictet-Spengler

quinolineandisoquinolineundergoEArS

more

readilythanpyridine,withreactionoccurringonthebenzenoidring

AromaticandHeterocyclicChemistry

75

orderofaromaticity

is:thiophene>pyrrole>furan(enoletherlike)

sulfuristhelargestatom

andhence

isbettermatchedforbondingto

sp2-hybridisedcarbonatomsina5-m

embered

ringleadingto

thiophenebeingthemostaromatic

Heteroaromatics

Pyrrole,ThiopheneandFuran

allthreehave

aromaticproperties

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thearomaticheterocyclesare

electronrich

Reactions

electrophilicsubstitution–kineticreactionatthe2-positionisfavouredoverreactionatthe3-position

more

reactivethanbenzene–e.g.pyrrolesimilarreactivityto

aniline

AromaticandHeterocyclicChemistry

76

Heteroaromatics

electrophilicsubstitutionofpyrrole,thiopheneandfuran

substituentsalreadypresentonthearomaticheterocycleexertlessdirectingeffectthanthecorresponding

substituentsinbenzene

nitration

AromaticandHeterocyclicChemistry

77

Heteroaromatics

acylationandform

ylation

directedlithiation

AromaticandHeterocyclicChemistry

78

Heteroaromatics

lithium

halogenexchange

metallationofpyrrole

N-m

etallatedpyrrolescanreacteitheratnitrogenorcarbon

generally,themore

ionicthemetal-nitrogenbondthemore

N-alkylationproductsare

form

ed

thiophene

AromaticandHeterocyclicChemistry

79

Heteroaromatics

indole

more

enamine-likethanpyrrole

attack

ofelectrophilesatthebpositionisthelowestenergypathway

iftheb-positionisblockeda-attack

occurs

a-attack

canoccurviab-attack

followedbyrearrangement

N H

2

3

1

attack

atbpositionretains

aromaticsextetofbenzenoid

ring

AromaticandHeterocyclicChemistry

80

Heteroaromatics

Synthesis

pyrrole-synthesisfrom1,4-dicarbonyls,Paal-Knorrsynthesis

froma-aminoketonesandcarbonylcompoundswithactivateda-m

ethylenegroups–Knorrsynthesis

AromaticandHeterocyclicChemistry

81

Heteroaromatics

Hantzschpyrrolesynthesis–froma-chloroketonesandcarbonylcompounds

Furans–Paal-Knorrsynthesis

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AromaticandHeterocyclicChemistry

82

Heteroaromatics

thiophenes–from1,4-dicarbonylcompounds

from1,2-dicarbonylcompounds–Hinsberg

synthesis

from1,3-dicarbonylcompounds

AromaticandHeterocyclicChemistry

83

Heteroaromatics

Indoles–theFischerindolesynthesis

H N

Ph

NH2

[3,3]-sigmatropic

rearrangement

unsymmetricalketonesgivemixturesofindoles:strongacidsfavourindoleform

ationfromtheless

substituted

ene-hydrazine;weakacidsfavourindoleform

ationfromthemore

substitutedene-hydrazine

AromaticandHeterocyclicChemistry

84

H

HOEt

MeO

protonationatsite

ofhighestcharge

andlargestHOMOcoefficient

H

ReductionofAromatics

Birch

reduction–coveredwithDrSmith

SET

addelectron

•

•MeO

MeO

•

MeO

protonationatsite

ofhighestcharge

togivemoststableradical

protonationatsite

ofhighestcharge

andlargestHOMOcoefficient

CO2

H

HEtO

H

protonationatsite

ofhighestcharge

andlargestHOMOcoefficient

AromaticandHeterocyclicChemistry

85

"H"

further

reduction

ReductionofAromatics

Birch

reductionexamples

Birch

reductionwithC-X

bondcleavage

"H"

naphthalene

AromaticandHeterocyclicChemistry

86

ReductionofAromatics

Birch

reduction–heteroaromatics

pyridine-intheabsence

ofaddedalcoholdim

erisationoftheinterm

ediate

radicalanionoccurs

pyridine-inthepresence

ofaddedalcoholdim

ersare

notform

ed

withsufficientelectronwithdrawinggroups,theadditionofafurtherelectronto

theinitiallyform

edradicalanion

occursto

giveadianion

reactionatmost

basicsite

AromaticandHeterocyclicChemistry

87

ReductionofAromatics

Birch

reduction–pyrroles,furans,thiophenes

electronrich

andhence

requireanelectronwithdrawinggroup

withenoughelectronwithdrawinggroupsfurtherreductionoftheinterm

ediate

radicalanionoccursto

givea

dianion

cf.dianionofalkylacetoacetates

reactswithelectrophilesatmostbasicsite

toleavemoststable,conjugatedenolate

AromaticandHeterocyclicChemistry

88

ReductionofAromatics

Birch

reduction–pyrroles,furans,thiophenes

Hydridereductions–pyridinium

salts

major

minor

AromaticandHeterocyclicChemistry

89

ReductionofAromatics

Hydridereduction–pyridines–bestwithanattachedEWG

Sim

plepyrrolesare

onlyreducedbyhydridereducingagentsinthepresence

ofacid

“Ionichydrogenation”offuranandthiophenegivesthesaturatedderivatives

AromaticandHeterocyclicChemistry

90

ReductionofAromatics

Hydrogenation–complete

reductionofthearomaticring

hydrogenationofaromaticringoccursmostreadilywithPt,RhandRucatalysts;Pdislessactive

alkynes/alkenesandmanyotherfunctionalgroupscanbereadilyreducedinthepresence

ofaromaticrings

Pyridinesare

more

easilyhydrogenatedthanbenzenoidaromatics

hydrogenationofpyrroleandfuranisrelativelystraightforw

ard;hydrogenationofthiopheneiscomplicatedby

catalystpoisoningandthehydrogenolysisoftheC-Sbondwithcomplete

removalofsulfur

Hydrogenolysisofbenzylicheteroatomsreadilyoccursunderpalladium

catalysis;acartoonmechanism

isshown

AromaticandHeterocyclicChemistry

91

AromaticChemistryinAction

SynthesisofLavendamycinanalogues

AromaticandHeterocyclicChemistry

92

AromaticChemistryinAction

SynthesisofLavendamycinanalogues

AromaticandHeterocyclicChemistry

93

AromaticChemistryinAction

SynthesisofLavendamycinanalogues

NHBocN

Me

F

Cl

Me

AromaticandHeterocyclicChemistry

94

AromaticChemistryinAction

SynthesisofLavendamycinanalogues

AromaticandHeterocyclicChemistry

95

AromaticChemistryinAction

Synthesisofathrombininhibitor

Route

1to

fluoro

pyridine

AromaticandHeterocyclicChemistry

96

AromaticChemistryinAction

Synthesisofathrombininhibitor

Route

2to

fluoro

pyridine

AromaticandHeterocyclicChemistry

97

AromaticChemistryinAction

Synthesisofathrombininhibitor

preparationofthepyrazone

AromaticandHeterocyclicChemistry

98

AromaticChemistryinAction

preparationofthepyrazone

AromaticandHeterocyclicChemistry

99

AromaticChemistryinAction

completionofthesynthesis

completedhandoutat:http://burton.chem.ox.ac.uk/teaching.htm

AromaticandHeterocyclicChemistry

100

Problemsfrom

past1Apapers

Providemechanisms,andwhere

appropriate

products,forthefollowingreactions:

AromaticandHeterocyclicChemistry

101

Problemsfrom

past1Apapers

Providemechanisms,andwhere

appropriate

products,forthefollowingreactions:

AromaticandHeterocyclicChemistry

102

Problemsfrom

past1Apapers

Providemechanisms,andwhere

appropriate

products,forthefollowingreactions:

AromaticandHeterocyclicChemistry

103

Problemsfrom

past1Apapers

Providemechanisms,andwhere

appropriate

products,forthefollowingreactions:

Forthreeofthefollowingcompounds,suggestasynthesisfromtheunsubstitutedaromaticparentstatedin

parentheses;more

thanonestepmayberequiredineach

case.In

onecase,providemechanismsto

explainthe

transform

ationsusedinyourproposedsynthesis.

Suggestsynthesesofthreeofthefollowingfromeitherbenzeneortoluene(from1Bpaper)