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Aromatic and Heterocyclic Chemistry 1
Aromatic and Heterocyclic Chemistry 4 Lectures, Michaelmas 2014
[email protected] handout at: http://burton.chem.ox.ac.uk/teaching.html
Advanced Organic Chemistry: Parts A and B; Francis A. Carey, Richard J. Sundberg Organic Chemistry; Jonathan Clayden, Nick Greeves, Stuart Warren, Peter Wothers Advanced Organic Chemistry: Reac7ons, Mechanisms and Structures; J. March Fron7er Orbitals and Organic Chemical Reac7ons; I. Fleming Heterocyclic Chemistry; J. Joule, K. Mills, G. Smith Aroma7c Heterocyclic Chemistry; D. Davies Reac7ve Intermediates; C. Moody and G. Whitham Aroma7c Chemistry; M. Sainsbury The Chemistry of C-‐C π-‐Bonds – Lecture notes; Dr MarFn Smith
Osugar
O
HO NHCO2Me
SOsugar
O
HO NHCO2Me
S
Osugar
O
HO NHCO2Me
S
•
•
DNA
Osugar
O
HO NHCO2Me
S
Bergmancyclisation
DNA diradicalO2
DNA damage
+
Aromatic and Heterocyclic Chemistry 2
Synopsis The Origin of AromaFcity and General CharacterisFcs of AromaFc Compounds
Examples of AromaFcity
Nucleophilic AromaFc SubsFtuFon
Arynes
ReacFons with Metals: Ortho MetallaFon
IntroducFon of FuncFonal Groups
Pyridine: Synthesis and ReacFons
Pyrrole, Thiophene and Furan: Synthesis and ReacFons
Indole: Synthesis and ReacFons
ReducFon of AromaFcs
Aromatic and Heterocyclic Chemistry 3
retains aromaFc sextet of electrons in subsFtuFon reacFons does not behave like a “normal” polyene or alkene benzene is both kine7cally and thermodynamically very stable
typical reacFons of alkenes
typical reacFons of benzene
heats of hydrogenaFon
ΔHohydrog = -‐120 kJmol-‐1
ΔHohydrog= 3 x -‐120 = -‐360 kJmol-‐1
(hypotheFcal, 1,3,5-‐cyclohexatriene)
ΔHohydrog= -‐210 kJmol-‐1
benzene ≈150 kJmol-‐1 more stable than expected – (represents stability over hypotheFcal 1,3,5-‐cyclohextriene) – termed the empirical resonance energy (values vary enormously) we know that delocalisaFon is stabilising, but how much more stabilising is the delocalisaFon in
benzene – should compare benzene with a real molecule – we will use 1,3,5-‐hexatriene require a theory which explains the stability of benzene
Me + Br2
fast
Me
Br
Braddition
MeBr not substitution
+ Br2FeBr3 catalyst Br
substitution
+ HBr not additionBr
Br
H2/Pt catalyst H2/Pt catalyst
H2/Pt catalyst
Aromatic and Heterocyclic Chemistry 4
Understanding Aroma2city
Hückel’s Rule: planar, monocyclic, completely conjugated hydrocarbons will be aroma%c when the ring contains (4n +2) π-‐electrons (n = 0, 1, 2….posi7ve integers)
Corollary planar, monocyclic, completely conjugated hydrocarbons will be an%-‐aroma%c when the ring contains (4n) π-‐
electrons (n = 0, 1, 2….posi7ve integers)
Hückel Molecular Orbital Theory (HMOT) applicable to conjugated planar cyclic and acyclic systems
only the π-‐system is included; the σ-‐framework is ignored (in reality σ-‐framework affects π-‐system)
used to calculate the wave funcFons (ψk) and hence rela7ve energies by the LCAO method
i.e. ψk = c1φ1 + c2φ2 + c3φ3 + c4φ4 + c5φ5 …..
HMOT solves energy (Ek) and coefficients ck there are now many more sophisFcated methods for calculaFng the stabilisaFon energy in conjugated systems;
however, HMOT is adequate for our purposes.
ø1ø2
ø3 ø5ø4
Aromatic and Heterocyclic Chemistry 5
Understanding Aroma2city HMOT in Ac2on For cyclic and acyclic systems: molecular orbital energies = Ek = α + mjβ
α = coulomb integral -‐ energy associated with electron in an isolated 2p orbital (albeit in the molecular environment) – α is negaFve (stabilising) and is the same for any p-‐orbital in π-‐system β = resonance integral – energy associated with having electrons shared by atoms in the form of a covalent bond – β
is negaFve (stabilising) and is set to zero for non-‐adjacent atoms.
(all overlap integrals S assumed to be zero, electron correlaFon ignored)
linear polyenes mj = 2cos[jπ/(n+1)] j = 1, 2……n (n = number of carbon atoms in conjugated system)
cyclic polyenes mj = 2cos(2jπ/n) j = 0, ±1, ±2……±[(n-‐1)/2] for odd n, ±n/2 for even n
Ethene
mj = 2cos(π/3) and 2cos(2π/3) = 1 or -‐1 E = α ± β α
α + β
α -‐ β
stabilisaFon energy Estab = 2α + 2β
two 2p atomic orbitals give 2π molecular orbitals
Aromatic and Heterocyclic Chemistry 6
six 2p atomic orbitals give 6π molecular orbitals; n = 6, j = 1, 2, 3, 4, 5, 6
1,3,5-‐hexatriene vs benzene
MO no. nodes energy HMOT MO (calculated)
ψ6 5 α -‐ 1.80β
ψ5 4 α -‐ 1.25β
ψ4 3 α -‐ 0.45β
ψ3 2 α + 0.45β
ψ2 1 α + 1.25β
ψ1 0 α + 1.80β
stabilisaFon energy = Estab= 2(3α + 3.5β) = 6α + 7β
α
mj = 2cos(π/7) = 1.80 2cos(2π/7) = 1.25 2cos(3π/7) = 0.45...... and the corresponding negaFve values
energy E = α + 1.80β α + 1.25β α + 0.45β α – 0.45β…..etc
stabilisaFon energy ethene = 2α + 2β
Aromatic and Heterocyclic Chemistry 7
Benzene mj = 2cos(2jπ/n) j = 0 ±1, ±[(n-‐1)/2] for odd n; ±n/2 for even n
MO no. nodes energy HMOT MO (calculated)
ψ6 6 α -‐ 2β
ψ4,5 4 α -‐ β
ψ2,3 2 α + β
ψ1 0 α + 2β
stabilisaFon energy = Estab= 2(α + 2β) + 4(α + β) = 6α + 8β; stabilisaFon energy w.r.t. 1,3,5-‐hexatriene = β
α
six 2p atomic orbitals give 6π molecular orbitals; n = 6, j = 0 ±1, ±2, ±3 mj = 2cos(0) = 2, 2cos(±2π/6) = 1, 2cos(±4π/6) = -‐1, 2cos(±6π/6)= -‐2 energy E = α + 2β, α + β, α -‐ β, α – 2β
HMOT predicts benzene is more stable than 1,3,5-‐hexatriene aroma7c compounds are those with a π-‐system lower in energy than that of acyclic counterpart an7-‐aroma7c compounds are those with a π-‐system higher in energy than that of acyclic counterpart
Aromatic and Heterocyclic Chemistry 8
E
α
2β 2β
α
cyclobutadiene benzene
α"+"β
α"$"β
α"$"2βα"$"2β
α"+"2β α"+"2β
Frost-‐Musulin Diagram – Frost Circle simple method to find the energies of the molecular orbitals for an aromaFc compound
General CharacterisFcs of AromaFc Compounds planar fully conjugates cyclic polyenes
inscribe the regular polygon, with one vertex poinFng down, inside a circle of radius 2β, centred at energy α
each intersecFon of the polygon with the circumference of the circle corresponds to the energy of a molecular orbital
more stable than acyclic analogues bonds of nearly equal length i.e. not alternaFng single and double bonds undergo subsFtuFon reacFons (rather than addiFon reacFons) support a diamagneFc ring current -‐ good test for aromaFc character of a compound
H HδH = 5-6 ppm δH = 7.26 ppm
aromatics δH = 7-8 ppm
HB0
applied field
> >
> >
>
ring current
induced magnetic field
Aromatic and Heterocyclic Chemistry 9
ClNu Nu
Cl
SbCl5(Lewis acid)
SbCl6
H
H
H
Examples of AromaFc and AnF-‐AromaFc Compounds Hückel’s rule [(4n +2) π-‐electrons for aromaFc compounds [4n π-‐electrons for anF-‐aromaFc compounds] holds for
anions, caFons and neutrals
Cyclopropenium caFon (4n +2), n = 0, 2π electrons; stabilisaFon energy = 2α + 4β – stabilisaFon energy of allyl caFon = 2α + 2.8β
insoluble in non-‐polar solvents; 1 signal in 1H NMR δH = 11.1 ppm -‐ aromaFc and a caFon compare with cyclopropyl caFon which is subject to rearrangement to the allyl caFon
Cyclopropenium anion (4n), n = 1, 4π electrons – anF-‐aromaFc stabilisaFon energy Estab= 4α +2β; stabilisaFon energy of allyl anion = 4α +2√2β
rate of proton exchange: cyclopropane/cyclopropene = 10000
E
α!+!2β
α!$!β
Ph Ph
Ph H
Ph Ph
Ph
- H+ E
α!+!2β
α!$!β Ph Ph
NC H
Ph Ph
NC H
Aromatic and Heterocyclic Chemistry 10
N
H δ = 7.46H δ = 7.01
H δ = 8.50
1.40 Å
1.39 Å
1.34 Å
2.2 D
Benzene (4n +2), n = 1, 6π electrons δH = 7.26 ppm, planar molecule; bond length = 1.39 Å
isoelectronic with pyridine
Cyclopentadienyl Anion (4n +2), n = 1, 6π electrons
H
pKa = 16 pKa = 43 pKa < -‐2
C-‐C sp3-‐sp3 1.54 Å
C-‐C sp3-‐sp2 1.50 Å
C-‐C sp3-‐sp 1.47 Å
C-‐C sp2-‐sp2 1.46 Å
C-‐C benzene 1.39 Å
C=C 1.34 Å
C≡C 1.21 Å
H H H
CF3F3C
F3CCF3CF3
Hbase
B:
E
pKa H2O = 15.74 pKa HNO3 = -‐1.3
Aromatic and Heterocyclic Chemistry 11
Examples of aromaFc and anFaromaFc compounds (4n +2), n = 1, 6 electrons cyclopentadienide anion is isoelectronic with furan pyrrole and thiophene
in each case the (one of the) lone pair(s) is parallel to the p-‐orbitals and part of the π-‐system
all 3 are aromaFc, show ring currents and undergo electrophilic aromaFc subsFtuFon
S O NH X
thiophene furan pyrrole
0.66 D0.55 D 1.74 D
NH
pyrrolidine
X X X
Aromatic and Heterocyclic Chemistry 12
Examples of AromaFc and AnF-‐AromaFc Compounds cyclopentadienyl caFon (4n), n = 1, 4π electrons – anF-‐aromaFc
cyclopentadienone
I I
XAgClO4
CH3CH2CO2HAgClO4
CH3CH2CO2H
OO
Br
Et2NH O
anti-aromatichighly reactive compoundreadily dimerises
O
O
heat-CO
O
O
O
Diels-Alderreaction
O
Ph
PhPh
Ph CO2Me
O
CO2Me
H
Ph Ph
PhPh
Aromatic and Heterocyclic Chemistry 13
O O
hνO
O hν, 4 K -CO2 warm
Diels-Alder
Examples of AromaFc and AnF-‐AromaFc Compounds cyclobutadiene (4n), n = 1, 4π electrons – anF-‐aromaFc
cyclobutadiene can be stabilised with very bulky subsFtuents stable up to 150 °C but very reacFve towards O2
HMOT predicts triplet ground state for cyclobutadiene – cyclobutadiene is actually a singlet ground state and is rectangular not square
only possible to isolate at very low temperatures in an argon matrix
1.567 Å
1.346 Ådistorts
CO2Me
CO2Me
Me
MeMe Me
MeMe
Me
MeMe
H
Aromatic and Heterocyclic Chemistry 14
HPh
Ph PhBF4
+
trityl tetrafluoroborate(hydride acceptor)
Examples of AromaFc and AnF-‐AromaFc Compounds tropylium caFon (4n +2), n = 1, 6π electrons – aromaFc
cyclooctatetraene non-‐aromaFc, alternaFng bond lengths, distorts to avoid planar anF-‐aromaFc conformaFon, normal reacFvity of polyene
ionic compound mp 205 °C insoluble in non-‐polar solvents
1.33 Å
1.46 Å
D2dtub shaped
Br Br
Aromatic and Heterocyclic Chemistry 15
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
6.3 D
Ph
Ph
Ph
Ph
Ph
Ph
reduced barrierto rotation
0.8$D
6π 6π
Examples of AromaFc and AnF-‐AromaFc Compounds
Azulene
[18]-‐Annulene (4n+2), n = 4, 18π electrons –aromaFc ring large enough to be planar without steric congesFon of inner protons 2 signals in 1H NMR consistent with ring current
Lactarius indigo, the indigo milk cap
6π 2π
6π-‐aromaFc 2π-‐aromaFc
δH = 9.3
δH = -3.0
18 π electronsbright red
HH
B0
applied field> >
>
>
>
ring current
induced magnetic field
HH
decreased fieldlower chemical shift
Aromatic and Heterocyclic Chemistry 16
electron donaFng groups acFvate the aromaFc ring (i.e. substrate reacts faster than benzene) and are ortho and para direcFng
electron withdrawing groups deacFvate the aromaFc ring (i.e. substrate reacts slowed than benzene) and are meta direcFng
halogens are mildly deacFvaFng and direct ortho and para
Y YE
Y
E
Y
E
E
ACTIVATING group means that the reacFon of the subsFtuted benzene is faster than that of benzene itself Typical acFvaFng groups include: OH, O-‐, , ,OR, NH2, NR2, alkyl, Ph O R
O
HN R
O
OR
O
NR2
O
R
ODEACTIVATING group means that the reacFon of the subsFtuted benzene is slower than that of benzene itself Typical deacFvaFng groups include: R3N+, CF3, NO2, SO3H, CN, O-‐, , ,
OMe
Br2, AcOH
OMe
Br
OMeBr
98 2
kanisole / kbenzene = 109
Electrophilic AromaFc SubsituFon -‐ SubsFtuent Effects subsFtuent Y affects both the rate and regiochemistry of the reacFon
Aromatic and Heterocyclic Chemistry 17
Halogens
mildly deacFvaFng as they are electronegaFve and withdraw electron density from the ring through the σ-‐framework (falls off with distance) halogens direct ortho and para as they have lone pairs in high energy orbitals which stabilise the intermediates for
ortho/para a�ack
MeO – overall electron donaFng on benzene ring Cl – overall electron withdrawing on benzene ring
with chlorobenzene the σ-‐electron withdrawing of the chlorine is greater than the π-‐donaFon of the chlorine 3p lone pair and chlorobenzene is deacFvated with respect to benzene
OMe: OMe
1.2 D
Cl: Cl
1.6 D
2p –lone pair
good 2p -‐2p overlap
3p –lone pair
poor 2p -‐3p overlap
both oxygen and chlorine are electronegaFve with anisole the σ-‐electron withdrawing of the oxygen is less than the π-‐
donaFon of the oxygen 2p lone pair and anisole is acFvated with respect to benzene
N O F
P S Cl
Se Br
Te I
Po At
increasin
g electron
ega7
vity
increasin
g siz
e of p-‐orbita
ls
increasing electronega7vity
OMe
Cl
Aromatic and Heterocyclic Chemistry 18
product distribuFon % kArX/kbenzene ortho meta para
PhF 12 -‐ 87 0.18
PhCl 30 0.9 69 0.064
PhBr 37 1.2 62 0.060
PhI 38 1.8 60 0.12
Xconc. HNO3, conc. H2SO4 X
NO2
NitraFon of halobenzenes
why does fluorobenzene react faster than than the other halobenzenes? why does fluorobenzene give the largest amount of the para isomer?
NitraFon of toluene
Me is an electron donaFng group and hence an acFvaFng group Wheland intermediate for ortho / para a�ack is stabilised by hyperconjugaFon – σCH → π
CH3
HNO3 / H2SO4
CH3NO2
CH3
NO2
CH3
NO259% <4% 37%
H
HH
+H
O2N
NO2
H
H
HH
+
deactivatingm directing
NitraFon of dimethyl aniline strongly activatingand o/p directing
NMe2 H2SO4,HNO3
NMe2
NO2
NMe2
NO2
H
Aromatic and Heterocyclic Chemistry 19
Ipso aMack and reversible reacFons electrophilic aromaFc subsFtuFon is generally an irreversible process all of the above arguments with regard to
ortho, meta and para raFos have been based on the irreversibility of the process i.e. the reacFons are under kineFc control -‐ but there are some excepFons
not all electrophilic aromaFc subsFtuFon reacFons are under kineFc control
sulfonaFon -‐ usual reacFon condiFons: conc. H2SO4 with SO3
sulfonyl group is electron withdrawing so we only have mono-‐subsFtuFon
at high temperatures with dilute H2SO4 – sulfonaFon is reversible
a�ack by an electrophile at a posiFon which already carries a non-‐hydrogen subsFtuent is termed ipso-‐subs7tu7on
OHBr SO3H
SO3H
H2SO4
OHBr
ipso a�ack
we can use an SO3H group as a blocking group
SOO
O
H SOHO
O HO3S HHO3S
OHBr SO3H
SO3H
H
OHBr SO3H
SH
OO
OH
OHBr SO3H
H
OHBr H
H
Aromatic and Heterocyclic Chemistry 20
Ipso aMack – aXack at posi7on already carrying a subs7tuent
10000 Fmes faster than proton exchange in benzene Si stabilises a β-‐caFon – see organoelement course in Hilary SiMe3
H
SiMe3
ClH
+ Me3SiCl
Cl
Me
tBuCl / AlCl3
Me
low temperature
tBuCl / AlCl3
Me
high temperatureMe
MeMe
Me
MeMe
MeMeMe
kineFc control thermodynamic control
Me
H
Me
HMe Me
MeMe Me
Me
Me
Me
MeMeH
Me
Me
MeMe
Me
Me
MeMe
Me
MeMe
Aromatic and Heterocyclic Chemistry 21
Nucleophilic Aroma2c Subs2tu2on SNAr – AddiFon – EliminaFon Mechanism for halogens as leaving groups, rate of reacFon usually follows kF > kCl > kBr (c.f. rate of SN2 reacFons kI > kBr > kCl > kF)
rate determining step is generally a�ack of nucleophile on aromaFc ring therefore bond strength to leaving group is not so important in influencing the rate fluorine is the most electronegaFve element and enhances the electrophilicity of the carbon being a�acked
increasing the rate of a�ack by the nucleophile
MeO
NO2
50 °C
NO2X OMe X = F Cl Br I
krel 2810 3.1 2.1 1
1st step usually rate determining
leaving group ability does depend on the nucleophile, nevertheless leaving groups can broadly be divided into three classes:
good: F, NO2, Me3N+, OTs, Me2S+ medium: Cl, Br, I, OR, OAr, SR, SO2R poor: NMe2, H
rate = k[substrate][nucleophile] N
F
OO
Nu
NF
OO
Nu
NNu
OO
Aromatic and Heterocyclic Chemistry 22
Cl
Y
OMe
Y
O2N O2NMeO
Y NO2 Me3N+ SO2Ph O=CPh CF3 H
krel 114000 2130 18400 2700 800 1
Nucleophilic Aroma2c Subs2tu2on electron withdrawing groups ortho/para to leaving group enhance rate electron donaFng groups ortho/para to leaving group retard rate subsFtuents meta to the leaving group have less influence
the acFvaFng group
Cl
Y
HN
+
N
Y
O2N O2NH
Y CN OMe Br
krel 6000 0.25 10
Aromatic and Heterocyclic Chemistry 23
vicarious Nucleophilic SubsFtuFon -‐ (nucleophilic subsFtuFon of hydrogen)
mechanism
LG = Cl, Br, PhO, PhS, RO-‐ etc; EWG = SO2Ph, SO2NR2, SO2OPh, POPh2, CN, CO2Et
for VNS require a nucleophile which
carries a leaving group
LG EWG
Cl SO2Ph
KOH, DMSO
O2N
SO2Ph
O2N
H
O2NH
HPhO2S
rate determining step
rate determining step is eliminaFon of H-‐X (HCl) from σ-‐adduct
N
H
O
O
Cl
SO2Ph
NO
O
HCl
SO2Ph
NO
O
SO2Ph
NO
O
SO2Ph
NO
O
SO2PhHO
Aromatic and Heterocyclic Chemistry 24
Vicarious Nucleophilic SubsFtuFon
orientaFon of addiFon depends on: structure of the carbanion; structure of the arene; reacFon condiFons
for a�ack on nitrobenzene, as the bulk of the nucleophile increases the amount of para isomer increases
NO2
F
Cl SO2Ph
KOH, DMSO
NO2
FSO2Ph
18%
X R yield / % ortho para
F H 63 74 26
Cl H 75 53 47
Cl Et 68 100
Cl Ph 93 100
NO2
X SO2Ph
KOH, DMSO
NO2
SO2Ph
NO2
PhO2SR
R R
low yield due to compeFng SNAr of fluoride
Aromatic and Heterocyclic Chemistry 25
•
•
ortho-benzyne(benzyne)
relative energy = 0 kJmol-1
•
•
best represented
as
meta-benzynerelative energyca. 64 kJmol-1
•
•
para-benzynerelative energyca. 130 kJmol-1
Br
H
NaNH2, NH3(I)NH2
H
NH2 NH2
NH2
Arynes removal of two hydrogen atoms from benzene leaving two electrons to be distributed between two orbitals gives
rise to the various arynes
ortho-‐benzyne Synthesis
Evidence IR spectrum of benzyne in an argon matrix shows C-‐C bond is 0.05 Å shorter than in benzene Roberts isotope labelling experiment – disproves direct subsFtuFon or SNAr addiFon/eliminaFon mechanism
1:1 mixture • = 14C
ClKNH2NH3(l) •• NH2• •+
NH2
Aromatic and Heterocyclic Chemistry 26
O
O
Diels-Alder reaction
Arynes trapping experiments
isolaFon of complexes
Structure of ortho-‐benzyne best represented as an alkyne with a very strained triple bond
benzyne has a very small HOMO-‐LUMO gap (the “triple” bond is very weak)
the LUMO energy is very low and arynes are very electrophilic; they are uncharged their reacFons tend to be
dominated by orbital control (i.e. they are very “so�”) carbene like – two electrons in two orbitals
oxidaFve addiFon then ligand subsFtuFon
PNi
P
Cy Cy
CyCy
LiCl
Br
Br
Br
NiP
PCy
Cy
CyCy
Cl
Na/Hg
reduction
PNi
P
Cy Cy
CyCy
•
•
Aromatic and Heterocyclic Chemistry 27
SiMe3
I+Ph TfO-
Bu4N FOSO2CF3
SiMe3
F
X
Br
RLi X r.d.s
Arynes GeneraFon relaFve reacFvity for formaFon of benzyne with alkyl lithiums by deprotonaFon is F > Cl > Br > I; actual rate of
generaFon of benzyne depends on solvent, base and leaving group
lithium halogen exchange is very fast for Br and I and loss of X-‐ is r.d.s. hence rate is Br>Cl>F
mildest method of benzyne generaFon involves hypervalent iodine intermediate
F
H
RLiF E1CB
F
most acidic proton (inductive effect)
anion in sp2 orbitaltherefore mesomericeffects far less importantthen inductive effects
R
exceptionalleaving group
Aromatic and Heterocyclic Chemistry 28
EWGX base
EWG
Nu
EWG
Nu
EWG(-)
Nu(-)
EDGX base
EDGNu
EDGNu
EDGNu(-)
(-)
Arynes OrientaFon of a�ack on arynes from ortho-‐disubsFtuted substrates can be raFonalised by a charge-‐control model
– recently a more sophisFcated model involving aryne distorFon has been proposed.
Note: EWG and EDG in the above examples refer to induc7ve effects aryne orbitals are orthogonal to the aromaFc π-‐system hence subsFtuents exert influence inducFvely through σ-‐
framework
major product
developing negativecharge distal fromEDG
major product
EWG stabilisesdeveloping negativecharge
Aromatic and Heterocyclic Chemistry 29
EDG
base
EDG
Nu
EDG EDG
(-)XH
Nu Nu(-)
EWG
base
EWG
Nu
EWG
Nu
EWG
Nu(-)X
H
H
(-)
Arynes OrientaFon of a�ack on arynes from meta-‐disubsFtuted substrates
Note: EWG and EDG in the above examples refer to induc7ve effects
major product
most acidic
EWG stabilisesdeveloping negativecharge
developing negativecharge distal fromEDG
major productbut lowerselectivity
most acidic
Aromatic and Heterocyclic Chemistry 30
OMe
Br
N- Li+OMe OMe OMe
NN
N- Li+53:47
Arynes Examples
R = mild inducFve EDG but when R = iPr, sterics win
OMeBr KNH2, NH3
OMe
NH2high selectivity
OMe
inductive EWG
Cl
Cl
NaNH2, NH3
Cl Cl
NH2
high selectivity
H
inductive EWG
inductive EWG
RN- Li+
R R R
N
N- Li+Br N R = Me, 34:66R = iPr, 4:96
Aromatic and Heterocyclic Chemistry 31
+
+
Arynes CycloaddiFon reacFons of benzyne
2+2 of benzyne is not completely stereospecific – probably a diradical mechanism
anthracene
Cl
Cl
Cl
Cl
+
Cl
Cl
Cl Cl
major product minor product
minor product major product
Aromatic and Heterocyclic Chemistry 32
Osugar
O
HO NHCO2Me
SOsugar
O
HO NHCO2Me
S
Osugar
O
HO NHCO2Me
S
•
•
DNA
Osugar
O
HO NHCO2Me
S
Bergmancyclisation
DNA diradicalO2
DNA damage
+
H
H
•
•
CCl4
Cl
Cl
ClCl
Cl
Cl
H
H
D
D
D
D
•
•
200 °Ct1/2 = 30 s
D
D
H
HD
D
•
•
N2
O
O
heatMe
MeHMe
Me
Arynes ene reacFon (a group transfer reacFon)
para-‐benzyne the Bergman cyclisaFon
mechanism of acFon of calicheamicin γ1I
Aromatic and Heterocyclic Chemistry 33
OMeH BuLi
OH
Me LiBu O
Me
Li
O
NMe2H
DMF
MeO
NMe2
H OLi MeO
NMe2
H OH, H2O
H
H
MeO
H
O
Aroma2c organometallics Ortho-‐directed electrophilic aromaFc subsFtuFon
ortho-‐lithiaFon by lithium halogen exchange – faster then deprotonaFon and generally requires an organolithium base an aryl / alkenyl bromide or iodide.
mechanism involves a�ack of alkyl lithium at the halogen via an intermediate “ate” complex
via “ate” complex
OMeBrBu
reacFon is an equilibrium process which favours the more stable anion (remember, anion order is sp3>sp2>sp – the stability of the anion is in the order of the pKa of the corresponding hydrocarbon)
in the above example an sp3 anion (butyl lithium) gives an sp2 anion
anion in an sp2 orbital anion in an sp3 orbital
directed ortho-‐lithiaFon
use amides as electrophiles: reac7ve formyl group is not unmasked un7l the reac7on is
quenched with acid
OMeBr
OMeLi
+ BuBrBu Li
Aromatic and Heterocyclic Chemistry 34
O O
NR2
SR O
OR2N O
SR2N
OO
RN O
NO
MeMe
O NR2
O
RNStBuO
CF3
X
NR2
OR
NR2( )n
O O
N
O
OtBu
increasing ability to direct ortho-‐lithiaFon
temperature (°C) of ortho-‐lithiaFon with RLi in THF or ether
-‐78 °C -‐78 °C -‐78 °C -‐78 °C -‐50 °C -‐20 °C 0 °C >0 °C >20 °C
condiFon dependent order
O-‐carbamates 3° amides
sulfoxides
sulfonamides sulfones
2° amides imines
oxazloines MOM ethers ethers halogens benzylic alkoxides
anilines
aminomethyl
trifluoromethyl
remote amines
N-‐carbamates
Adapted from: J. Clayden in “Organolithiums: Selec7vity for Synthesis”, Pergamon, Oxford 2002.
most powerful directors
Aromatic and Heterocyclic Chemistry 35
COClHO NH2
MeMe
then dehydrate
NO
Me Me
BuLi
NO
Me Me
Li Br R
NO
Me Me
R
normal selectivityfor SN2
Aroma2c organometallics Directed ortho-‐lithiaFon
applicaFon: ortho-‐allylaFon
cooperaFon between two ortho-‐directors
Et2N O
HH
HF
BuLithen PhCHO
Et2N O
H
F
Ph
OHputs electrophile in
most difficult positionbetween two groups
Aromatic and Heterocyclic Chemistry 36
MeMe
Me Me
H
Me Me
MeMe
Me MeMe Me
Introduc2on of Func2onal Groups –Synthesis Friedel Cra�s AlkylaFon polyalkylaFon and rearrangement predominate
with one equivalent of alkylaFng agent mixtures of products result as the iniFally formed monoalkyl arene is more reacFve than the unalkylated arene – alkyl groups are electron donaFng
AlCl3, cat. MeCl Me Me
Me
MeMe
+
more reacFve than benzene
more reacFve than toluene
more reacFve than toluene
excess MeCl, cat. AlCl3
MeMeMe
Me MeMe
ClHHH
AlCl3
Aromatic and Heterocyclic Chemistry 37
Br AlBr3H
MeMe Me
MeBr: AlBr3 Me
MeH
Me
Me
Introduc2on of Func2onal Groups –Synthesis Friedel Cra�s AlkylaFon polyalkylaFon and rearrangement predominate with primary alkyl halides rearrangement occurs
cat. AlBr3
MeBr Me Me
+
Me
major minor
of monoalkylated products
1,2-‐hydride shi�
primary carbocaFons are very unstable rearrangement to the secondary carbocaFon occurs
Aromatic and Heterocyclic Chemistry 38
MeCl
O
AlCl3 MeO
OMe
H
OMe AlCl3
OMe
AlCl3
Introduc2on of Func2onal Groups –Synthesis Friedel Cra�s AcylaFon requires a full equivalent of the Lewis acid mono-‐subsFtuFon predominates as introduced group is electron-‐withdrawing and deacFvates aromaFc ring
carbonyl group can then be removed if required (Clemensen reducFon, Zn/HCl; Wolf-‐Kishner reducFon, NH2NH2 then KOH, heat; dithiane than Raney Ni) giving products of a selecFve Friedel-‐Cra�s alkylaFon
para-‐isomer generally favoured by steric hindrance
monosubsFtuFon Me
Cl
O OMe
1 equivalent AlCl3
MeOMe
O
O Me
O+
AlCl3, toluene
MeO
Me
O
93% yield
Aromatic and Heterocyclic Chemistry 39
O
Me
OH
O
MeO
AlCl3solvent-separated
ion pair
polar solvent
O
AlCl3
O
MeH
AlCl3
OMe
O
AlCl3
Introduc2on of Func2onal Groups –Synthesis Friedel Cra�s AcylaFon Fries rearrangement can give access to either the ortho-‐ or para-‐isomer
Friedel Cra�s summary Alkyla2on Acyla2on AlCl3 cataly7c stoichiometric Rearrangement possible no, but loss of CO from R-‐C≡O+ if R+ stable, e.g. Ph3C+ subsFtuFon order poly mono
HOMe
O
O Me
O+ pyridine
OMe
O
O
AlCl3
O
Me
inside solvent cage - tight ion pair
non-polarsolvent
O
O
Me
Cl3Al
major product in non polar solvents
workup
HO
O
Me
major product in polar solvents e.g. PhNO2
workup
HO
Me
O
Aromatic and Heterocyclic Chemistry 40
Introduc2on of Func2onal Groups –Synthesis Synthesis of benzyl halides
free radical brominaFon
mechanism
good radical iniFator Blanc chloromethylaFon – related to Fiedel-‐Cra�s reacFons
OMe
O
Me
Me
(CH2O)n,conc. HCl
OMe
O
Me
Me
ClCl
Me1 equivalent
N
O
O
Br
BrNBS, hv, or heat or AIBN
BrAIBN = azobisisobutyronitrile
NN
Me Me
CNNC
Me Me
OH
H
HOH
HHCl Cl
Aromatic and Heterocyclic Chemistry 41
Introduc2on of func2onal groups
halogenaFon – standard method is by electrophilic aromaFc subsFtuFon using a source of posiFve halogen generally in the presence of a Lewis acid
with acFvated aromaFcs Lewis acid acFvaFon of the electrophile is not required,
with benzene and with deacFvated aromaFcs Lewis acid acFvaFon of the electrophile is required
NO2
Me
Br2, FeBr3
NO2
MeBr
halogenaFon can frequently be best achieved using Sandmeyer reacFons (parFcularly good for introducing I and F as well as Cl, Br and CN)
conc. HNO3conc. H2SO4
NO2Sn, HClor H2Pd/C NH2 N
HX, NaNO2,0 °C N
X
Aromatic and Heterocyclic Chemistry 42
Ar N NX
HOHO N
N Ar
Introduc2on of Func2onal Groups –Synthesis diazonium salts -‐ reacFons
Ar N NX
H2O, 100 °CAr OH Ar N N
BF4
heatAr F
Ar N NX
cat. CuX,KX
X = Br, Cl, CNAr X Ar N N
XAr X
KI
Ar N NX
Ar HH3PO2
Ar N NX
Me
O
OR
O
Me
O
OR
O
NNHAr
SN1 reacFon via carbenium ion
v. high energy intermediate, offset by the formaFon of N2 carbenium not stabilised by π-‐system as is orthogonal to π-‐system
empty sp2 orbital
SN1 reacFon via carbenium ion – Balz Schiemann reacFon
radical reacFon
radical reacFon
radical reacFon
electrophilic aromaFc subsFtuFon
via enol
NH2
NaNO2,HX 0 °C N
N -N2
slow
Aromatic and Heterocyclic Chemistry 43
•
X
NN•
N •NNNI
NN
IKI, 0 °C I
MX
XCuIX
CuI Xstart here
XCuII
X
•
N2
NN
SET
XCuII
X
Introduc2on of Func2onal Groups –Synthesis HalogenaFon / cyanaFon Sandmeyer -‐ X = Br, Cl, CN
IodinaFon Sandmeyer – no copper salt required
NN
X
cat. Cu(I) XMX, 0 °C X
I I
I• I I+
Aromatic and Heterocyclic Chemistry 44
Br Bu Li I I I
NN
BF4
MeO
MeOOMe
OH I ClMeO
MeOOMe
OH
I
Me Me
Me Me
I2HIO4
Me Me
Me Me
I
NN
BF4
heat solid F+ BF3
Introduc2on of Func2onal Groups –Synthesis FluorinaFon from diazonium salts – Baltz-‐Schimann reacFons
IodinaFon other methods
Iodine less reacFve electrophile than bromine or chlorine, therefore require acFvated substrate or presence of an oxidising agent (maybe generaFng I+), or more reacFve interhalogen e.g. I-‐Cl
examples
metal halogen exchange
FB
F FF
Aromatic and Heterocyclic Chemistry 45
HNOH
HF HNOH2
F
NH
HF
H
N
F
N
OP
O HH
N
F
NOPO
H H
N
F
NOPO
H H
N
F
N•
F
•
NH2
F
OP
HO HH
H
F
N
F
i) SnCl2, HClii) NaNO2, HCl
NNO
O
NO2
Bu4N F NO
O
NO2F
NO
O
F
Introduc2on of Func2onal Groups –Synthesis FluorinaFon – Halex reacFon – SNAr-‐type
example
Bamberger reacFon to give para-‐fluoroanilines
Aromatic and Heterocyclic Chemistry 46
O
MeF3C O
OOH O
OHMe
O
CF3O
O
OH
MeO Me
O
MgBr OHB(OMe)3then HCl B(OMe)2 H2O2, NaOH
Br Mg MgBr O2OH
N2 Cl heat, SN1
water
H2O OH
Introduc2on of Func2onal Groups –Synthesis Phenols Diazonium route
OxidaFon of Grignard reagents
OxidaFon of organoboranes
Baeyer Villiger OxidaFon
Aromatic and Heterocyclic Chemistry 47
MeMeH
O2
OMeMe
OH
HOH
+O
Me Me
OH
OH
O
O
Me
O
O
OOMeHO
O
OOH
Me
O Me
OH
H2O2, NaOH
then H3O
OH
OH
Introduc2on of Func2onal Groups –Synthesis Dakin reacFon – usually used on phenolic substrates
Aerial oxidaFon of iso-‐propylbenzenes followed by cumenehydroperoxide rearrangement
Aromatic and Heterocyclic Chemistry 48
Br BuLi Li
O
NMe2H NMe2
LiO HH3O O
H
MgBr
O
NMe2H NMe2
BrMgO HH3O O
H
O
H
NaBH4 OH
Br Mg MgBr (CH2O)n OH
Introduc2on of Func2onal Groups –Synthesis Benzyl alcohols via Grignard reagents
reducFon of benzaldehydes
Benzaldehydes Organometallic route
Aromatic and Heterocyclic Chemistry 49
O
N HMe
Me
OP
Cl ClCl Me
NMe
OPO
ClCl
Cl
MeNMe
Cl
H
OR
Me
Me
OR
Me
Me
HNMe
Me
H
OR
Me
Me
HNMe
Me
OR
Me
Me
OH2NMe
Me
H2O
OR
Me
Me
OHNHMe
Me
OR
Me
Me
O
Me
MeOR
POCl3,then H3O
O
NMe2H Me
MeOR
OH
Introduc2on of Func2onal Groups –Synthesis Vilsmeir reacFon – requires acFvated aromaFcs – very good with furan, thiophene, pyrrole and indole
Vilsmeir reagent
Aromatic and Heterocyclic Chemistry 50
C NH H/Zn NH
Cl
H/Zn
reactive electrophileArH
NH2Cl
Ar H
MeO
MeO
Zn(CN)2, HClthen H3O MeO
MeO
O
H
Introduc2on of Func2onal Groups –Synthesis formyl chloride is too unstable to partake in Friedel Cra�s reacFons as it readily decomposes to CO and HCl
Ga�ermann-‐Koch formylaFon – good for alkyl benzenes, generally an industrial method
Ga�ermann aldehyde synthesis Neither the Ga�ermann nor the Ga�ermann-‐Koch reacFons can be used with aromaFc amines
C OH AlCl4 C OClCu
may involve intermediates such as
Me
CO, HCl, CuCl, AlCl3
high pressure Me
O
H
Aromatic and Heterocyclic Chemistry 51
O O
Cl
ClH H
OHHO
O
Cl
Cl
O
ClOH
O
Cl
OH
OH
O
H
O
OH
H
O
Cl Cl
O
Cl
Cl
HCl
ClClHO
Cl
ClCl
ClCl
dichlorocarbene
HN CHCl3, NaOH N
Cl
Cl
HHO
N
Cl
OHCHCl3, NaOH
OH
H
O
OH
H
O+
major minor
Introduc2on of Func2onal Groups –Synthesis Reimer-‐Tiemann Synthesis – requires a phenolic substrate
Pyrrole gives 3-‐chloropyridine under Reimer-‐Tiemann reacFon condiFons
Aromatic and Heterocyclic Chemistry 52
NO2
OMe
Me
Me
KMnO4, heat
NO2
OMe
COOH
HOOC
MgBrCO2 (g) or (s)H3O workup
O
OH
Introduc2on of Func2onal Groups –Synthesis Carboxylic acids Grignard route
OxidaFon of alkyl benzenes
NitraFon standard nitraFng mixture conc. sulfuric acid and conc. nitric acid is very harsh NO2
+ BF4-‐ is non-‐oxidizing and non-‐acidic – compaFble with many more funcFonal groups SulfonaFon reversible process – sulfonated product formed with conc. H2SO4 desulfonaFon can be achieved using dilute H2SO4
Aromatic and Heterocyclic Chemistry 53
NH
O
O
OOOONH3
NH2 ON
Hetroaroma2cs Pyridine properFes – pyridine is polarised by the presence of the nitrogen atom both through the π-‐system and σ-‐
framework the lone pair on nitrogen is orthogonal to the π-‐system, and is the HOMO of pyridine; the LUMO of pyridine is an
anF-‐bonding π-‐orbital pyridine is electron poor and undergoes EARS only very slowly
synthesis of pyridines and derivaFves – generally aim to make dihydropyridine and then oxidise it to the corresponding pyridine dihydropyridines are readily prepared by the condensaFon of ammonia with 1,5-‐dicarbonyl compounds
1,5-‐dicarbonyl compounds are readily prepared by addiFon of an aldehyde or ketone to an α,β-‐unsaturated
carbonyl compound
pyridine is electron deficient at C-‐2 and C-‐4 and it is prone to a�ack by nucleophiles
HOMO of pyridine is nitrogen lone pair in sp2 orbital
N N N
Aromatic and Heterocyclic Chemistry 54
N
CO2MeMeO2C
Me Me
Ph
-H2O
tautomerise x 2
NH2
CO2MeMeO2C
Me O
Ph
MeMe
NH2
OMe
O
PhCO2Me
OHMe
r.d.sMe
O
OMe
O
Ph
-H2O(Knoevenagel)
PhCHO
Me
O
OMe
O
Ph OH
Me
HN
OMe
OH
tautomerise
Me
NH
OMe
O
NH3, -H2O
Me
O
OMe
O2
NH3, 1 equiv.
PhCHO, 2 equiv. NH
CO2MeMeO2C
Me Me
Ph
HNO3
oxdidationN
CO2MeMeO2C
Me Me
Ph
N NH
NH2 O OONH3
OO O
O
Heteroaroma2cs Hantzsch pyridine synthesis
other oxidants to convert dihydropyridines to pyridines include: (NH4)2Ce(NO3)6 (CAN), MnO2, DDQ
O
O
CN
CN
Cl
Cl
Aromatic and Heterocyclic Chemistry 55
N
NMe Me
Ph Cl
O
then NaBPh4N
NMe Me
OPh
BPh4
v. slowNE
E E
NE
N
E
H
NOH
H
MeNH2OH•HCl,
heat
Me
O
170 °CO
Me
O
Me
O
NMe2
O
+
Heteroaroma2cs Pyridine synthesis with hydroxylamine – no oxidant required
Electrophilic subsFtuFon with pyridines
NMe
high energy intermediate -‐ electrophile reacFng with posiFvely charged nucleophile
E
N
E
N
E
v. poor yielding low concentraFon of free pyridine meta-‐posiFon least deacFvated
Pyridines are nucleophilic (on nitrogen)
Aromatic and Heterocyclic Chemistry 56
-H2SO3
N SO3H
NO2
[2,3]-sigmatropicrearrangement
H
N SO3H
O
NO
[2,3]-sigmatropicrearrangementN
N
SO3H
OO
HSO3N
NO2 NO3
NO O
N
NO2
N
N2O5, MeNO2then NaHSO3
77%
Heteroaroma2cs NitraFon of pyridine
nitraFon of pyridine with N2O5 plausible mechanism
1
2
3 2
3
1
2 2
1 1
N
c. HNO3, c. H2SO4, 300 °C, 24 h
N
NO2
6% NH
Aromatic and Heterocyclic Chemistry 57
PCl3
N
O
MeNO2
PClCl
Cl
N
MeNO2
+ POCl3
N
O
MeHNO3, H2SO4,100 °C
N
O
MeNO2
N
H2O2, CH3CO2H
N
O
2
34
Heteroaroma2cs pyridine N-‐oxides – much more suscepFble to electrophilic a�ack at 2 and 4 posiFons (and to nucleophilic
addiFon at 2 and 4 posiFons)
nitraFon of pyridine N-‐oxide
promotes electrophilic subsFtuFon at 2 and 4 posiFons N
O
N
O
N
O
NO2
66% yield, c.f. nitraFon of pyridine in acid (6% yield)
N
O
MeH NO2
N
O
MeNO2
Aromatic and Heterocyclic Chemistry 58
N
Me
H
O
Me
O
O Me, 100 °C
O
N
Me
O Me
O
N
Me
H
O
Me
O
O
MeO N
Me
O
Me
O
Heteroaroma2cs pyridine N-‐oxides – N-‐deoxygenaFon with rearrangement
pyridine N-‐oxides – conversion to chloro compounds
N
R
O
OP
Cl ClCl
N
R
OPO
Cl Cl
N
R
OPO
Cl Cl
H
Cl N
R
ClCl
3 2 1
3 2
1
Aromatic and Heterocyclic Chemistry 59
N
ONO2
PCl
OCl
H
ClPOCl3
N
ONO2
PCl
OCl
H
Cl
N
ONO2
H
H
Heteroaroma2cs pyridones
nitraFon
NH
O N OH NH
O
N
OH
N
O
HNO3, H2SO4
NH
ONO2
N
ClNO2POCl3 NaBH4
N
NO2
H
NO2
NH
ONO2
N
NO2Cl
NaBH4
Aromatic and Heterocyclic Chemistry 60
N Cl
MeO Na
N Cl
OMeN OMeN
HO
POCl3
Heteroaroma2cs and Nucleophilic subs2tu2on
nucleophilic aromaFc subsFtuFon
R Cl
O MeOR OMe
Ocompare with
Chichibabin reacFon
pyridine is electron deficient at C-‐2 and C-‐4 and is prone to a�ack by nucleophiles N N N
HOMO of pyridine is nitrogen lone pair
N
NaNH2
N
NaNH2
N
Na
NH2
HN N
H
H100 °C
-NaH
NNH
HN NH2
HNHNN NH2
+
Aromatic and Heterocyclic Chemistry 61
N
OH2
H
N
OHH
H
N
OH
H
tautomerise+ H
NH
H
OH
OH
HO OH
H
HO OHOH2
NH2
HO OHOH
H2SO4, PhNO2,heat+
N
Heteroaroma2cs quinolines and isoquinolines
Synthesis – Skraup synthesis
NN
quinolines isoquinolines
HO OH
N H
H
N
H
NH
H
NPhO
O
Aromatic and Heterocyclic Chemistry 62
Heteroaroma2cs synthesis of isoquinolines Bischler-‐Napieralski
Pictet-‐Spengler
quinoline and isoquinoline undergo EArS more readily than pyridine, with reacFon occurring on the benzenoid ring
NH2
R Cl
O
NHO
R
POCl3
N
Pd
N
POCl3
NCl
R
H N
R
HClH
N
R
HCl
NH2H H
O
NH NHN HH
HCl
N
HNO3, H2SO4
N
NO2
NNO2
+ N
HNO3, H2SO4
N
NO2
Aromatic and Heterocyclic Chemistry 63
order of aromaFcity is: thiophene > pyrrole > furan (enol ether like) sulfur is the largest atom and hence is be�er matched for bonding to sp2-‐hybridised carbon atoms in a 5-‐membered
ring leading to thiophene being the most aromaFc
Heteroaroma2cs
pyrrole, thiophene and furan all three have aromaFc properFes
in each case the (one of the) lone pair(s) is parallel to the p-‐orbitals and part of the π-‐system
the aromaFc heterocycles are electron rich
S O NH X
thiophene furan pyrrole
0.66 D0.55 D 1.74 D
NH
pyrrolidine
1
23
αβ
pyridine is electron poor
X X X
NNu
Aromatic and Heterocyclic Chemistry 64
XE
XH
EXH
EXH
EXE
Heteroaroma2cs Reac2ons electrophilic subsFtuFon – kineFc reacFon at the 2-‐posiFon is favoured over reacFon at the 3-‐posiFon
more reacFve than benzene – e.g. pyrrole similar reacFvity to aniline
more delocalised intermediate ∴ more stable ∴ 2-‐subsFtuFon favoured
less delocalised intermediate ∴ less stable ∴ 3-‐subsFuFon disfavoured
subsFtuents already present on the aromaFc heterocycle exert less direcFng effect than the corresponding subsFtuents in benzene
with EWG at α-‐posiFon β’-‐subsFtuFon favoured
with EDG at α-‐posiFon α’-‐subsFtuFon favoured
X
E
X
HE
X
HE
X
E
XE XH
EEDG EDG XH
EEDG X EDGE
X X
HE
XEWG EWG EWG
EE
Aromatic and Heterocyclic Chemistry 65
HN
HN
83%
O
N H, POCl3, RTMe
H
O
then hydrolysisMe
S
O
OMeN
O
O
AcOH, 0 °C
S NO2 +S
NO260% trace
HN
O
ClCl3CHN
CCl3
O
90% HNO3, -50 °CHN
CCl3
O
O2N
α'
β'
Heteroaroma2cs Reac2ons nitraFon
addiFon product acylaFon and formylaFon
β’ > α’ or β for α-‐EWG
O
O
OMeN
O
O
AcOH,-25 °C
O NO2O NO2
HMe O
O
O NO2H
AcON
HN
O
OMeN
O
O
AcOH, -10 °C
HN NO2 +
HN
NO251% 13%
S
O
NS
78%
H, POCl3, 35 °CPh
H
O
then hydrolysis
Me
Aromatic and Heterocyclic Chemistry 66
lithiaFon of 5-‐membered heterocycles
lithiaFon occurs preferenFally α to the heteroatom due to inducFve effect of heteroatom with, in some instances a DOM effect
furan and thiophene can be readily metalled α to the metal
S n-BuLi S Li O n-BuLi O Li
-10 °C, ether ether, reflux
with pyrrole itself, the N-‐deprotonaFon occurs first – the more ionic the N-‐metal bond the greater the percentage a�ack at nitrogen
with a more covalent N-‐M bond C-‐a�ack occurs.
HN NaNH2 N Na Me I N
MeNMe
BuLi Et I NMe
Et
HN EtMgBr N N
HN
MgBr O
H OEtO
H
H Oworkup
Aromatic and Heterocyclic Chemistry 67
with pyrroles bearing an N-‐EWG on nitrogen α-‐metallaFon occurs
SO2PhN
then HCl, water
SO2PhN B(OH)2
LDA, then B(OMe)3
selecFvity can be achieved using LDA or butyllithium
no lithium halogen exchange with LDA as would make weak N-‐Br bond most acidic proton removed by directed metallaFon S
Br
Bu LiS
Li
S
E
ES
Br
LiN
Li
iPriPr
H
Bu LiO Br O Li R X O R
NSO2Ph
I
INSO2Ph
I
NSO2Ph
MeLDA, I2 tBuLi, MeI
lithium halogen exchange occurs with aromaFc heterocycles
Aromatic and Heterocyclic Chemistry 68
S
Heteroaroma2cs indole
more enamine-‐like than pyrrole a�ack of electrophiles at the β posiFon is the lowest energy pathway
a�ack at β posiFon retains aromaFc sextet of benzenoid ring
benzofuran benzothiophene
minor
major
NH
E
NH
EH N
H
E
NH
E
NH
NH
EH E
NH
α
β
2
3
1 NH
O
Aromatic and Heterocyclic Chemistry 69
Heteroaroma2cs indole
if the β-‐posiFon is blocked α-‐a�ack occurs α-‐a�ack can occur via β-‐a�ack followed by rearrangement (● = CT2 i.e. a triFated methylene group)
NH
α
β
2
3
1 NH
O Sbenzofuran benzothiophene
1:1 mixture direct a�ack at α-‐posiFon would give solely
NH
NH
OH NH
OF3B
H NH
NH
H NH
BF3•OEt2
NH
NH
H NH
Aromatic and Heterocyclic Chemistry 70
Heteroaroma2cs Synthesis pyrrole -‐ synthesis from 1,4-‐dicarbonyls, Paal-‐Knorr synthesis
from α-‐amino ketones and carbonyl compounds with acFvated α-‐methylene groups – Knorr synthesis
HN N NH2
ONH
OOO + NH3
1,4-dicarbonyl
OOMeMe
NH3, benzene, heat OO
MeMeNH3 ±H
HOOMeMe
NH2O
MeMeNH-H2O
OMeMe
NH2
tautomerise
HN MeMe
HOHN MeMe
H2N MeMe
O±H-H2O
HN Me
CO2RMe
NH2
Me O
Me
CO2R
O+
-H2OMe
CO2R
N
OMe
tautomeriseMe
CO2R
HN
OMe
N Me
CO2RMeHO
tautomerise
HN Me
CO2RMeHO
H
HN Me
CO2RMe
H
H
Aromatic and Heterocyclic Chemistry 71
O
R1
X
R2
R3
O
OR4
O
X = Br, ClR1 = H, alkylR2 = alkyl
R3, R4 = alkyl
R1 = H
baseR1
X
R2
O
O R3
OR4O ±H
R1
X
R2
HO
O R3
OR4O O
R3
R4O2C
R1
R2
H
-H2OO
R3
R4O2C
R1
R2OH
Cl
Me O O Me
CO2Et NH3+Cl
Me O H2N Me
CO2Et
NH2Me
O Me
CO2EtH
NH
MeHO
CO2Et
Me
NH
Me
CO2Et
Me
-H2O
Heteroaroma2cs Hantzsch pyrrole synthesis –from α-‐chloroketones and carbonyl compounds
Furans – Paal-‐Knorr synthesis
Furans – from α-‐halocarbonyls and acFve methylene compounds
OOMeMe
acid catalyst O MeMe
R R' R' R'
R1 = alkyl
baseR2 R1
O R3
OR4OR2
OH
R1
O R3
OHR4O O
R3
R4O2C
R2
R1
H
-H2OO
R3
R4O2C
R2
R1
O
H
HO
Aromatic and Heterocyclic Chemistry 72
Heteroaroma2cs thiophenes – from 1,4-‐dicarbonyl compounds
from 1,2-‐dicarbonyl compounds – Hinsberg synthesis
from 1,3-‐dicarbonyl compounds
OOPh Ph
P2S5 SSPh Ph
-H2S
heat
S PhPh
Ph
OO
PhEtO2C S CO2Et+
EtONa, EtOHS
Ph Ph
CO2HEtO2C
OO
H
HSOMe
O
cat. H2SO4
OS
CO2Me
MeONa, MeOH
S CO2Me
Aromatic and Heterocyclic Chemistry 73
-NH3 HN
PhNH2
NH NH2
PhH
HHNNH2
Ph
HNNH
Ph
HNN
PhH
Heteroaroma2cs Indoles – the Fischer indole synthesis
[3,3]-‐sigmatropic rearrangement
unsymmetrical ketones give mixtures of indoles: strong acids favour indole formaFon from the less subsFtuted ene-‐hydrazine; weak acids favour indole formaFon from the more subsFtuted ene-‐hydrazine
HN
NH2Me
O Ph+
protic or Lewis acid
heat
HN
Ph
HN
Me
Me
HN
Me
HN
NH2Me
OMe
acid+ +
10022
078
AcOHMeSO3H, P4O10
H
Aromatic and Heterocyclic Chemistry 74
CO2
H
HEtO H
H OEt
•
CO2
H
H
H OEt MeOH
H OEt
HMeO
•
HMeO
•
SET add electron
•
•MeO MeO
•
MeO
Na or Li in liquid NH3, EtOHMeO MeO O
O
H3Omild
H3Ostronger or
longer
Reduc2on of Aroma2cs Birch reducFon – covered with Dr Smith
protonaFon at site of highest charge to give most stable radical
protonaFon at site of highest charge and largest HOMO coefficient
protonaFon at site of highest charge and largest HOMO coefficient
Na or Li in liquid NH3, EtOH
H
SET add electron
HMeO
protonaFon at site of highest charge and largest HOMO coefficient
Na or Li in liquid NH3, EtOH
CO2H CO2H
deprotonation SET add electron
••
•
CO2 CO2 CO2
SET add electron
CO2
H
Aromatic and Heterocyclic Chemistry 75
SET add electron
•
•
•O
RO
R
•
SET add electron
Reduc2on of Aroma2cs Birch reducFon examples
Birch reducFon with C-‐X bond cleavage
naphthalene
Na, NH3, EtOH
OMe
HO
Li, NH3, tBuOH OMe
HO
OMe
O
OR Na or Li, NH3
with or without ROHROH
"H ""H "
further reduction
NH
OHN
MeO
OMe
O
OH
O
Me
O
Li, NH3, THF NH
OHN
MeO
OMe
OH
OH
OH
Me
Aromatic and Heterocyclic Chemistry 76
SET add electron
HN N NMeI
MeN •N
Li, NH3, EtOH •HN
H OEt
Reduc2on of Aroma2cs Birch reducFon – heteroaromaFcs pyridine -‐ in the absence of added alcohol dimerisaFon of the intermediate radical anion occurs
pyridine -‐ in the presence of added alcohol dimers are not formed
with sufficient electron withdrawing groups, the addiFon of a further electron to the iniFally formed radical anion occurs to give a dianion
•N N•N N NLi, NH3
MeN NMeMeI
N
OOiPr
OiPrO
Na, NH3 N
OOiPr
OiPrO
add one electronthen another electron
then NH4ClNH
OOiPr
OiPrO
MeMe I
reaction at mostbasic site
Aromatic and Heterocyclic Chemistry 77
Me Iadd one electron
then another electron
N
OtBuO
N
OtBuO
Na, NH3 N
OtBuO
basic enoughto deprotonate
ammonia
N
OtBuO
NH3
NO
NO O
N
MeO
N
add one electronthen another electron
NO
OiPr
OtBuO
MeN
O
OiPr
OtBuONa, NH3 N
O
OiPr
OtBuO
basic enoughto deprotonate
ammonia
NO
OiPr
OtBuO
NH3 Me I
Reduc2on of Aroma2cs Birch reducFon – pyrroles, furans, thiophenes electron rich and hence require an electron withdrawing group
with enough electron withdrawing groups further reducFon of the intermediate radical anion occurs to give a dianion
cf. dianion of alkyl acetoacetates reacts with electrophiles at most basic site to leave most stable, conjugated enolate
N MeMe Na, NH3, MeOH N MeMepreferenFal reducFon of benzenoid aromaFc
H
OMe
O O
OMe
O O
Aromatic and Heterocyclic Chemistry 78
NMe
H NMe
H NMe
H NMe
H H
HBH
HH Na
H OEt
HBH
HH Na
NMe I
EtOH NMe
H OEt
H NMe
H NMe
H H
HBH
HH Na
HBH
HH Na
Reduc2on of Aroma2cs Hydride reducFons – pyridinium salts
major
minor
Simple pyrroles are only reduced by hydride reducing agents in the presence of acid
NSO2Ph
HBCNH
HNa
O
OH,F3C NSO2Ph
H NSO2Ph
HHH +NSO2Ph
minor
“Ionic hydrogenaFon” of furan and thiophene gives the saturated derivaFves
X Me Et3SiH, TFA X Me X = O, 72%X = S, 80%
Aromatic and Heterocyclic Chemistry 79
Reduc2on of Aroma2cs HydrogenaFon – complete reducFon of the aromaFc ring hydrogenaFon of aromaFc ring occurs most readily with Pt, Rh and Ru catalysts; Pd is less acFve
alkynes/alkenes and many other funcFonal groups can be readily reduced in the presence of aromaFc rings
Hydrogenolysis of benzylic heteroatoms readily occurs under palladium catalysis; a cartoon mechanism is shown
Pyridines are more easily hydrogenated than benzenoid aromaFcs
hydrogenaFon of pyrrole and furan is relaFvely straigh�orward; hydrogenaFon of thiophene is complicated by catalyst poisoning and the hydrogenolysis of the C-‐S bond with complete removal of sulfur
OH
Me
MeMe
H2, Ru/C, i-PrOH OH
Me
MeMe
55% cis
H2, Ru/C
92% cis
COOHHOOC COOH
COOHHOOC COOH
OR H2, Pd/C
HOR
+
H ORH H
catalyst surface
N
H2, Ru/C
NH
95% cisMe
HO HO
Me
HNMeO2C (CH2)2CO2Me
H2, Rh/Al2O3,
AcOHHNMeO2C (CH2)2CO2Me
S MeMe
(CH2)3CO2H
Raney Ni,H2O,
100 °C MeMe
(CH2)3CO2H