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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)