1
Aromatic and Heterocyclic Chemistry
Aromatic and Heterocyclic Chemistry
8 Lectures, Trinity 2013
jonathan.burton@chem.ox.ac.uk
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 Aromatic and Heterocyclic Chemistry
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Synopsis ◾ The Origin of AromaGcity and General CharacterisGcs of AromaGc Compounds ◾ Examples of AromaGcity ◾ Electrophilic AromaGc SubsGtuGon ◾ Nucleophilic AromaGc SubsGtuGon ◾ Arynes ◾ ReacGons with Metals: Ortho LithiaGon, Palladium Catalysed Couplings, Chromium Complexes and Birch ReducGons ◾ IntroducGon of FuncGonal Groups ◾ Pyridine: Synthesis and ReacGons ◾ Pyrrole, Thiophene and Furan: Synthesis and ReacGons ◾ Indole: Synthesis and ReacGons ◾ ReducGon of AromaGcs ◾ AromaGc Chemistry in AcGon 3
Aromatic and Heterocyclic Chemistry
Origin of Aroma0city ◾ Typical reacGons of alkenes ◾ Typical reacGons of benzene ◾ retains aromaGc sextet of electrons in subsGtuGon reacGons ◾ does not behave like a “normal” polyene or alkene ◾ benzene is both kine7cally and thermodynamically very stable ◾ Heats of hydrogenaGon o
= -­‐120 kJmol-­‐1 ΔH hydrog
o
= 3 x -­‐120 = -­‐360 kJmol-­‐1 ΔH hydrog
(hypotheGcal, 1,3,5-­‐cyclohexatriene) o
= -­‐210 kJmol-­‐1 ΔH hydrog
◾ benzene ≈150 kJmol-­‐1 more stable than expected – (represents stability over hypotheGcal 1,3,5-­‐
cyclohextriene) – termed the empirical resonance energy (values vary enormously) ◾ empirical resonance energy is not the true resonance energy as this would be the difference between benzene and a symmetrical non-­‐delocalised cyclohexatriene unit which does not exist ◾ we know that delocalisaGon is stabilising, but how much more stabilising is the delocalisaGon 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 Aromatic and Heterocyclic Chemistry
Understanding Aroma0city ◾ 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 funcGons (ψi) and hence rela7ve energies by the LCAO method i.e. ψi = c1φ1 + c2φ2 + c3φ3 + c4φ4 + c5φ5 ….. ◾ HMOT solves energy (Ei) and coefficients ci ◾ there are now many more sophisGcated methods for calculaGng the stabilisaGon energy in conjugated systems; however, HMOT is adequate for our purposes. 4
5
Aromatic and Heterocyclic Chemistry
Understanding Aroma0city HMOT in Ac0on ◾ For cyclic and acyclic systems:
Molecular Orbital Energies = Ei = α + mjβ ◾ α = coulomb integral -­‐ energy associated with electron in an isolated 2p orbital (albeit in the molecular environment) – α is negaGve (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 negaGve (stabilising) and is set to zero for non-­‐adjacent atoms. ◾ (all overlap integrals S assumed to be zero, electron correlaGon ignored) ◾ linear polyenes ◾ cyclic polyenes
mj = 2cos[jπ/(n+1)]
mj = 2cos(2jπ/n)
j = 1, 2……n (n = number of carbon atoms in conjugated system) j = 0, ±1, ±2……±[(n-­‐1)/2] for odd n, ±n/2 for even n ◾ 1,3,5-­‐Hexatriene vs Benzene – linear polyene ◾ six 2p atomic orbitals give 6π molecular orbitals; n = 6, j = 1, 2, 3, 4, 5, 6 ◾ mj = 2cos(π/7) = 1.80 2cos(2π/7) = 1.25 2cos(3π/7) = 0.45...... and the corresponding negaGve values ◾ energy E = α + 1.80β α + 1.25β α + 0.45β α – 0.45β…..etc 6
Aromatic and Heterocyclic Chemistry
◾ 1,3,5-­‐Hexatriene vs Benzene ◾ six 2p atomic orbitals give 6π molecular orbitals; n = 6, j = 1, 2, 3, 4, 5, 6 ◾ mj = 2cos(π/7) = 1.80 2cos(2π/7) = 1.25 2cos(3π/7) = 0.45...... and the corresponding negaGve values ◾ energy E = α + 1.80β α + 1.25β α + 0.45β α – 0.45β…..etc MO no. nodes energy 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 α ◾ stabilisaGon energy = Estab= 2(3α + 3.5β) = 6α + 7β HMOT MO (calculated) 7
Aromatic and Heterocyclic Chemistry
◾ Benzene mj = 2cos(2jπ/n)
j = 0 ±1, ±[(n-­‐1)/2] for odd n; ±n/2 for even n ◾ 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 MO no. nodes energy ψ6 6 α -­‐ 2β ψ4,5 4 α -­‐ β ψ2,3 2 α + β 0 α + 2β HMOT MO (calculated) α ψ1 ◾ stabilisaGon energy = Estab= 2(α + 2β) + 4(α + β) = 6α + 8β; stabilisaGon energy w.r.t. 1,3,5-­‐hexatriene = β ◾ 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 8
Aromatic and Heterocyclic Chemistry
◾ Cyclobutadiene vs 1,3-­‐butadiene ◾ four 2p atomic orbitals give 4π molecular orbitals; n = 4, j = 0 ±1, ±2 ◾ mj = 2cos(0) = 2
2cos(±2π/4) = 0
◾ energy E = α + 2β α
α – 2β cyclobutadiene 1,3-­‐butadiene no. energy nodes MO ψ4 4 ψ2,3 2 2cos(±4π/4) = -­‐2 HMOT MO (calculated) α -­‐ 2β energy α -­‐ 1.62β α -­‐ 0.62β α α α + 0.62β ψ1 0 ◾ stabilisaGon energy = Estab = 4α + 4β α + 1.62β α + 2β ■ stabilisaGon energy Estab = 4α + 4.4β ◾HMOT predicts cyclobutadiene is less stable than 1,3-­‐butadiene ◾ an7-­‐aroma7c compounds are those with a π-­‐system higher in energy than that of acyclic counterpart 9
Aromatic and Heterocyclic Chemistry
Frost-­‐Musulin Diagram – Frost Circle ◾ simple method to find the energies of the molecular orbitals for an aromaGc compound ◾ inscribe the regular polygon, with one vertex poinGng down, inside a circle of radius 2β, centred at energy α ◾ each intersecGon of the polygon with the circumference of the circle corresponds to the energy of a molecular orbital α0202β
α0202β
E
α020β
α
α
2β
2β
α0+0β
α0+02β
cyclobutadiene
α0+02β
benzene
General CharacterisGcs of AromaGc Compounds ◾ planar fully conjugates cyclic polyenes ◾ more stable than acyclic analogues ◾ bonds of nearly equal length i.e. not alternaGng single and double bonds ◾ undergo subsGtuGon reacGons (rather than addiGon reacGons) ◾ support a diamagneGc ring current -­‐ good test for aromaGc character of a compound H
δH"="56"ppm
H
δH"="7.26"ppm
aroma.cs"δH"="78"ppm
10
Aromatic and Heterocyclic Chemistry
Examples of AromaGc and AnG-­‐AromaGc Compounds ◾Hückel’s rule [(4n +2) π-­‐electrons for aromaGc compounds; 4n π-­‐electrons for anG-­‐aromaGc compounds] holds for anions, caGons and neutrals Cyclopropenium caGon ◾ (4n +2), n = 0, 2π electrons; stabilisaGon energy = 2α + 4β – stabilisaGon energy of allyl caGon = 2α + 2.8β α"%"β
E
α"+"2β
◾ insoluble in non-­‐polar solvents; 1 signal in 1H NMR δH = 11.1 ppm -­‐ aromaGc and a caGon ◾ compare with cyclopropyl caGon which is subject to rearrangement to the allyl caGon Cyclopropenones 11
Aromatic and Heterocyclic Chemistry
Examples of AromaGc and AnG-­‐AromaGc Compounds Cyclopropenium anion ◾ (4n), n = 1, 4π electrons – anG-­‐aromaGc ◾ stabilisaGon energy Estab= 4α +2β; stabilisaGon energy of allyl anion = 4α +2√2β α"%"β
E
α"+"2β
◾ rate of proton exchange: cyclopropane/cyclopropene = 10000 Benzene ◾ (4n +2), n = 1, 6π electrons δH = 7.26 ppm, planar molecule; bond length = 1.39 Å
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 sp2-­‐sp2 = 1.34 Å isoelectronic with pyridine 1.40#A.
H δ#=#7.46
H#δ#=#7.01
1.39#A.
N
1.34#A.
H#δ#=#8.50
2.2#D
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Aromatic and Heterocyclic Chemistry
Examples of AromaGc and AnG-­‐AromaGc Compounds Cyclopentadienyl Anion ◾ (4n +2), n = 1, 6π electrons ◾ quick reminder: pKa is a measure of the posiGon of equilibrium between an acid and its conjugate base; pKa = -­‐log10Ka ◾ most important factor in acid strength is the stability of the conjugate base A-­‐ ◾ for a strong acid the conjugate base A-­‐ is stable the equilibrium lies to the RHS and the pKa is low δH&=4.14
H
BuLi
FeCl2
δH&=5.55&ppm
D5h&symmerty
(aroma4c&but&anion,
shielded)
Fe
ferrocene&1st&sandwich
compound&
undergoes&electrophilic
aroma4c&suns4tu4on
Aromatic and Heterocyclic Chemistry
Examples of AromaGc and AnG-­‐AromaGc Compounds Furan, pyrrole and thiophene ◾ (4n +2), n = 1, 6π 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 aromaGc, show ring currents and undergo electrophilic aromaGc subsGtuGon 13
Aromatic and Heterocyclic Chemistry
Examples of AromaGc and AnG-­‐AromaGc Compounds Cyclopentadienyl caGon ◾ (4n), n = 1, 4π electrons – anG-­‐aromaGc Cyclopentadienone 14
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Aromatic and Heterocyclic Chemistry
Examples of AromaGc and AnG-­‐AromaGc Compounds Cyclobutadiene ◾ (4n), n = 1, 4π electrons – anG-­‐aromaGc ◾ 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 O hν,$4$K$
'CO2
hν
O
◾ cyclobutadiene can be stabilised with very bulky subsGtuents ◾ stable up to 150 °C but very reacGve towards O2 O
O
warm
Diels'Alder
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Aromatic and Heterocyclic Chemistry
Examples of AromaGc and AnG-­‐AromaGc Compounds Tropylium caGon ◾ (4n +2), n = 1, 6π electrons – aromaGc
◾ ionic compound mp 205 °C insoluble in non-­‐polar solvents Cycloheptatrienyl anion ◾ (4n), n = 2, 8π electrons – anG-­‐aromaGc ◾ probably not planar, similar pKa to normal 1,4-­‐diene Cyclooctatetraene ◾ non-­‐aromaGc, alternaGng bond lengths, distorts to avoid planar anG-­‐aromaGc conformaGon, ◾ normal reacGvity of polyene 17
Aromatic and Heterocyclic Chemistry
Examples of AromaGc and AnG-­‐AromaGc Compounds 6π 2π Azulene 6π
6π
0.8$D
[18]-­‐Annulene ◾ (4n+2), n = 4, 18π electrons –aromaGc ◾ ring large enough to be planar without steric congesGon of inner protons ◾ 2 signals in 1H NMR consistent with ring current δH"="'3.0
H
H
δH"="9.3
18 π"electrons
bright"red
Lactarius indigo, the indigo milk cap 18
Aromatic and Heterocyclic Chemistry
ReacGons Electrophilic AromaGc SubsGtuGon (revision) σ!complex,*
Wheland*intermediate,*
arenium*ion
π!complex)
i.e.)posi-ve)electrophile)
a3racted)by)nega-ve)electron)density
usually&rate&determining
/&breaks&aroma3city
/&forma3on&of&σ/complex&least&likely&to&be&reversible&with&
reac3ve&electrophiles&i.e.&reac3ve&electrophiles&are&unstable&
therefore&proton&loss&is&preferable
◾ what does transiGon state look like for a{ack of E+ on aromaGc ring? ◾ rates of chemical reacGons are controlled by free energy of transiGon state therefore informaGon about transiGon state structure is crucial ◾ transiGon states have transitory existence cannot make experimental measurements on them 19
Aromatic and Heterocyclic Chemistry
Electrophilic AromaGc SubsGtuGon (revision) Hammond’s Postulate “If two states, as, for example, a transi7on sate and an unstable intermediate, occur consecu7vely during a reac7on process and have nearly the same energy content, their interconversion will involve only a small reorganisa7on of molecular structure.” ◾ The transiGon state resembles the structure (intermediate or substrate or product) to which it is closest in energy (i.e. transiGon state resembles intermediate arenium ion, therefore what stabilises the arenium ion stabilises the transiGon state.) MechanisGc Evidence ◾ IsolaGon of intermediates δH%=%5.6
H H
H H
SbF5%/%FSO3H
*120%°C%in%SO2FCl
SbF6
H
H
δH%=%9.7
H
δH%=%8.6
δH%=%9.3
Aromatic and Heterocyclic Chemistry
Electrophilic AromaGc SubsGtuGon (revision) ◾ Isotope effects Reminder: C-­‐D bond is stronger than C-­‐H bond due to lower zero-­‐point energy . Therefore expect to observe a kine7c isotope effect if a C-­‐H bond is broken in the rate determining step of the reac7on. Normally kH /kD in the range of 2-­‐7 Example NitraGon of benzene ◾ kH/kD = 1 ◾ hence C-­‐H bond not involved in r.d.s. – consistent with step 1 being rate determining ◾ no kineGc isotope for nitraGon of benzene excludes the following mechanisms 20
Aromatic and Heterocyclic Chemistry
Electrophilic AromaGc SubsGtuGon (revision) ◾ if there is a kineGc isotope effect there is some reversibility in step 1 ◾ normally 1st step is rate determining step – lose aromaGcity ◾ 2nd step is fast – regain aromaGcity 21
Aromatic and Heterocyclic Chemistry
SubsGtuent Effects ◾ subsGtuent Y affects both the rate and regiochemistry of the reacGon ◾ electron donaGng groups acGvate the aromaGc ring (i.e. substrate reacts faster than benzene) and are ortho and para direcGng ◾ electron withdrawing groups deacGvate the aromaGc ring (i.e. substrate reacts slowed than benzene) and are meta direcGng ◾ halogens are mildly deacGvaGng and direct o/p 22
Aromatic and Heterocyclic Chemistry
SubsGtuent Effects ◾ Y = electron donaGng group, ortho and para a{ack favoured i.e. the intermediate (and hence the transiGon state leading to the intermediate) is stabilised by electron donaGon from Y (not possible for meta a{ack) ◾ Y = Electron withdrawing group -­‐ o and p a{ack disfavoured i.e. the intermediate (and hence the transiGon state leading to the intermediate) is destabilised by electron withdrawing group Y (not possible for meta a{ack), and hence get meta a{ack by default 23
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Aromatic and Heterocyclic Chemistry
SubsGtuent Effects ◾ curly arrows (in a molecular orbital context) illustrate the electron distribuGon in the fronGer orbital ◾ we are interested in the stability of the compeGng intermediates, and, although curly arrows give us the correct answer we really should compare the total energy of the π-­‐system – we can do this using Hückel theory ◾ Y = EDG i.e. a group carrying a lone pair or a C-­‐H or C-­‐C bond – we will model these as the benzyl anion and will compare their energies – look at three filled MOs, ψ1, ψ2 and ψ3 MO ortho Eψortho meta α + 0.45β ψ3 Eψmeta para Eψpara α + 0β α + 0.52β α + 1.18β ψ2 α + 1.0β α + 1.25β α + 1.80β ψ1 α + 1.90β Estab = 6α + 7β Estab = 6α + 6.16β α + 1.93β Estab = 6α + 6.9β ◾ The intermediates from ortho and para a{ack are more stable than those from meta a{ack 25
Aromatic and Heterocyclic Chemistry
SubsGtuent Effects ◾ Y = EWG -­‐ we will model these groups as the benzyl caGon and will compare the energies of the sigma complexes -­‐ look at two filled MOs, ψ1 and ψ2 MO ortho Eψortho meta Eψmeta para α + 1.0β α + 1.18β ψ2 Eψpara α + 1.25β α + 1.80β ψ1 α + 1.90β Estab = 4α + 6.1β Estab = 4α + 6.16β α + 1.93β Estab = 4α + 5.86β ◾ intermediate from meta a{ack is more stable than those from ortho and para a{ack – we will conGnue to use the curly arrow method. 26
Aromatic and Heterocyclic Chemistry
Halogens ◾ mildly deacGvaGng as they are electronegaGve 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 2p'lone
pair
good'2p'0'2p
overlap
3p'lone
pair
OMe
: OMe
poor'3p'0'2p
overlap
MeO – overall electron donaGng on benzene ring : Cl
Cl
Cl – overall electron withdrawing on benzene ring ◾ fluorobenzene has similar reacGvity to benzene – although it is the most electronegaGve of the halogens it has a 2p lone pair which overlaps efficiently with the benzene ring. Examples CH3
CH3
HNO3&/&H2SO4
NO2
CH3
CH3
NO2
59%
<4%
37%
F
NO2
F
σ,withdrawal%
largest%for%ortho
posi:on
F
major%product
F
Cl
Cl2%/%AlCl3
Cl
25%
2%
73%
Cl
Aromatic and Heterocyclic Chemistry
Example Two SubsGtuents ◾ reinforcing 27
28
Aromatic and Heterocyclic Chemistry
◾ opposing -­‐ if similar reacGvity will get mixtures of compounds; however, a strong acGvator beats a weak acGvator. ◾ acGvaGng ability – rough order ◾ all other things being equal a 3rd group is least likely to enter between two groups meta to one another Ipso a{ack – aback at posi7on already carrying a subs7tuent 10000 0mes faster than proton exchange in benzene (Si stabilises a β-­‐ca0on) Aromatic and Heterocyclic Chemistry
Ipso a{ack Reversible reacGons ◾ electrophilic aromaGc subsGtuGon is generally an irreversible process but there are some excepGons 29
30
Aromatic and Heterocyclic Chemistry
Nucleophilic Aroma0c Subs0tu0on SN2: aliphaGc vs aromaGc AliphaGc ◾ nucleophile a{acks C-­‐L σ* resulGng in inversion of configuraGon AromaGc ◾ no possibility of nucleophile a{acking backside of C-­‐L σ* (transiGon geometry impossible) ◾ Lowest Unoccupied Molecular Orbital (LUMO) is π* not σ* ◾ a{acking electron rich arene with electron rich nucleophile SN1: aliphaGc vs aromaGc AliphaGc ◾ system stabilised by hyperconjugaGon Me
Me
Me
X
Me
Me
Me
3°(carboca.on
Nu
p
Me
Me
Me
Nu
AromaGc X
Nu7
Nu
v.$unstable
no$hyper$conjuga5on
ca5on$oribtal$orthogonal$to$π7system
(σC7Hsp2$lower$in$energy
than$σC7Hsp3)
Me
Me
H
σC2H
L
C#L$σ*$buried
in$aroma0c$ring
Aromatic and Heterocyclic Chemistry
Nucleophilic Aroma0c Subs0tu0on SNAr – AddiGon – EliminaGon Mechanism ◾ nucleophile a{acks LUMO, electron withdrawing groups lower energy of LUMO and stabilise the negaGve charge in the intermediate ◾ best to have electron withdrawing group(s), ortho and/or para to the leaving group Evidence ◾ isolaGon of intermediates 31
32
Aromatic and Heterocyclic Chemistry
Nucleophilic Aroma0c Subs0tu0on SNAr – AddiGon – EliminaGon Mechanism ◾ for halogens as leaving groups, rate of reacGon follows kF > kCl > kBr (c.f. rate of SN2 reacitons kI > kBr > kCl > kF) NO2
MeO$
50*°C
NO2
X*= F Cl Br I
rela7ve*rate
X
8.7 2.8 2
1
OMe
◾ r.d.s. is a{ack of nucleophile on aromaGc ring therefore bond strength to leaving group is not so important in influencing the rate ◾ fluorine is the most electronegaGve element, polarises sigma bond, lowers LUMO, therefore fastest rate SubsGtuent Effects ◾ electron withdrawing groups ortho/para to leaving group enhance rate ◾ electron donaGng groups ortho/para to leaving group retard rate ◾ subsGtuents meta to the leaving group have less influence Aromatic and Heterocyclic Chemistry
Nucleophilic Aroma0c Subs0tu0on SNAr – AddiGon – EliminaGon Mechanism ◾ Vicarious Nucleophilic SubsGtuGon -­‐ (nucleophilic subsGtuGon of hydrogen) mechanism ◾ LG = Cl, Br, PhO, PhS etc; EWG = SO2Ph, SO2NR2, CN, CO2Et Examples 33
34
Aromatic and Heterocyclic Chemistry
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 subsGtuGon or SNAr addiGon/eliminaGon mechanism 1:1 mixture • = 14C Aromatic and Heterocyclic Chemistry
Arynes ◾ trapping experiments ◾ isolaGon of complexes oxida0ve addi0on then ligand subs0tu0on 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 reacGons tend to be dominated by orbital control (i.e. they are very “so‚”) ◾ carbene like – two electrons in two orbitals 35
Aromatic and Heterocyclic Chemistry
Arynes GeneraGon ◾ relaGve reacGvity for formaGon of benzyne with alkyl lithiums by deprotonaGon is F > Cl > Br > I; actual rate of generaGon 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 generaGon involves hypervalent iodine intermediate 36
Aromatic and Heterocyclic Chemistry
Arynes ◾ OrientaGon of a{ack on arynes from ortho-­‐disubsGtuted substrates can be raGonalised by a charge-­‐control model – recently a more sophisGcated model involving aryne distorGon has been proposed. Note: EWG and EDG in the above examples refer to induc7ve effects ◾ aryne orbitals are orthogonal to the aromaGc π-­‐system hence subsGtuents exert influence inducGvely through σ-­‐
framework 37
Aromatic and Heterocyclic Chemistry
Arynes ◾ OrientaGon of a{ack on arynes from meta-­‐disubsGtuted substrates Note: EWG and EDG in the above examples refer to induc7ve effects 38
39
Aromatic and Heterocyclic Chemistry
Arynes Examples R = mild induc0ve EDG but when R = iPr, sterics win Aromatic and Heterocyclic Chemistry
Arynes ◾ CycloaddiGon reacGons of benzyne anthracene ◾ 2+2 of benzyne is not completely stereospecific – probably a diradical mechanism 40
Aromatic and Heterocyclic Chemistry
Arynes ◾ ene reacGon (a group transfer reacGon) para-­‐Benzyne ◾ the Bergman cyclisaGon ◾ mechanism of acGon of calicheamicin γ1I 41
Aromatic and Heterocyclic Chemistry
42
Aroma0c organometallics Ortho-­‐directed electrophilic aromaGc subsGtuGon ◾ ortho-­‐lithiaGon by lithium halogen exchange – faster then deprotonaGon ◾ directed ortho-­‐lithiaGon use amides as electrophiles: reac%ve formyl group is not unmasked un%l the reac%on is quenched with acid 43
Aromatic and Heterocyclic Chemistry
Aroma0c organometallics Directed ortho-­‐lithiaGon ◾ good directors
◾ applicaGon: ortho-­‐allylaGon ◾ cooperaGon between two ortho-­‐directors ◾ excellent directors Aromatic and Heterocyclic Chemistry
Aroma0c organometallics ◾ applicaGon to the synthesis of Merck’s anG-­‐HIV drug Efavirenz 44
Aromatic and Heterocyclic Chemistry
Aroma0c organometallics Palladium-­‐catalyzed cross-­‐coupling reacGons – SGlle (Sn) and Suzuki (B) reacGons excellent method for making a bond between two sp2-­‐hybridised carbon atoms, one which carries a leaving group (e.g. halide, or triflate), the other which carries a main group metal e.g. Sn or B. ◾ X = I, OTf (OSO2CF3), Br, (Cl) ◾ M = SnR3(SGlle reacGon), BR2, B(OR)2 (Suzuki reacGon) ◾ Examples SGlle ReacGon ◾ Examples Suzuki ReacGon 45
46
Aromatic and Heterocyclic Chemistry
Aroma0c organometallics SGlle ReacGon -­‐ mechanism LnPd(0) ◾ oxidaGve addiGon ◾ reducGve eliminaGon ◾ transmetallaGon 47
Aromatic and Heterocyclic Chemistry
Aroma0c organometallics Suzuki ReacGon – mechanism ◾ different transmetallaGon mechanism from SGlle reacGon ◾ boranes R3B, boronic acids RB(OH)2, boronic esters RB(OR)2, are “electrophilic” (empty orbital on boron) not “nucleophilic” organometallics ◾ reacGon with aqueous base gives the corresponding “ate” complex gives a “nucleophilic” organometallic capable of donaGng R– LnPd(0) ◾ oxidaGve addiGon ◾ reducGve eliminaGon ◾ transmetallaGon Aromatic and Heterocyclic Chemistry
Aroma0c organometallics Cross coupling reacGons -­‐ examples 48
49
Aromatic and Heterocyclic Chemistry
Aroma0c organometallics Arene chromium tricarbonyl complexes ◾ Cr(CO)6, example of an 18 electron complex ◾ Treatment of Cr(CO)6 with benzene gives the corresponding benzene chromium tricarbonyl complex Cr(CO)6,
hν (sunlight),2O2
heat
OC Cr CO
OC
or2I22or2Ce(IV)
◾ Due to back donaGon into the CO ligands the Cr(CO)3 is overall an electron withdrawing group. ◾ pKa, of aryl and benzylic protons lowered with respect to non-­‐complexed arenes BuLi
H
OC Cr CO
OC
OC Cr CO
OC
Me
H
OC Cr CO
OC
H
H
Me
N
Li
anion)in)sp2)orbital
orthogonal)to)π2system
stabilised)by)induc9ve)effect
of)Cr(CO)3)group
Me
H
H
Me
OC Cr CO
OC
anion%in%p%orbital
stabilised%by%delocalisa0on
H
H
H
OC Cr CO
OC
OC Cr CO
OC
H
Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ Friedel Cra‚s AlkylaGon ◾ polyalkylaGon and rearrangement predominate ◾ with one equivalent of alkylaGng agent mixtures of products result as the iniGally formed monoalkyl arene is more reacGve than the unalkylated arene ◾ with primary alkyl halides rearrangement occurs 50
Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ Friedel Cra‚s AcylaGon ◾ Require a full equivalent of the Lewis acid ◾ mono-­‐subsGtuGon predominates as introduced group is electron-­‐withdrawing and deacGvates aromaGc ring ◾ carbonyl group can then be removed if required (Clemensen reducGon, Zn/HCl; Wolf-­‐Kishner reducGon, NH2NH2 then KOH, heat; dithiane than Raney Ni) giving products of a selecGve Friedel-­‐Cra‚s alkylaGon ◾ para-­‐isomer generally favoured by steric hindrance 51
52
Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ Friedel Cra‚s AcylaGon ◾ Fries rearrangement can give access to either the ortho-­‐ or para-­‐isomer ◾ Friedel Cra‚s Summary Alkyla0on
AlCl3
cataly7c
Rearrangement
possible
subsGtuGon order
poly
Acyla0on stoichiometric no, but loss of CO from R-­‐C≡O+ if R+ stable, e.g. Ph3C+ mono Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ Synthesis of benzyl halides ◾ free radical brominaGon ◾ chloromethylaGon ◾ mechanism 53
Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ HalogenaGon – standard method is by electrophilic aromaGc subsGtuGon using a source of posiGve halogen generally in the presence of a Lewis acid; acGvated substrates do not require a Lewis acid ◾ HalogenaGon – by the Sandmeyer reacGon – good for introducing I and F (as well as Cl and Br) ◾ Diazonium salt preparaGon 54
Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ Diazonium salts -­‐ reacGons 55
Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ HalogenaGon / cyanaGon Sandmeyer -­‐ X = Br, Cl, CN ◾ IodinaGon Sandmeyer – no copper salt required 56
Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ FluorinaGon from diazonium salts – Baltz-­‐Schimann reacGons ◾ IodinaGon other methods ◾ Iodine less reacGve electrophile than bromine or chlorine, therefore require acGvated substrate or presence of an oxidising agent (maybe generaGng I+), or more reacGve interhalogen e.g. I-­‐Cl ◾ examples ◾ metal halogen exchange 57
Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ FluorinaGon – Halex reacGon – SNAr-­‐type example ◾ Bamberger reacGon to give para-­‐fluoroanilines 58
Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ Phenols ◾ Diazonium route ◾ OxidaGon of Grignard reagents ◾ OxidaGon of organoboranes ◾ Baeyer Villiger OxidaGon 59
Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ Dakin reacGon – usually used on phenolic substrates ◾ Aerial oxidaGon of iso-­‐propylbenzenes followed by cumenehydroperoxide rearrangement 60
61
Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ Benzyl alcohols ◾ via Grignard reagents ◾ reducGon of benzaldehydes ◾ Benzaldehydes ◾ Organometallic route O
Br
BuLi
Li
H
LiO
NMe2
H
H
NMe2
H3O
O
62
Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ Vilsmeir reacGon – requires acGvated aromaGcs – very good with furan, thiophene, pyrrole and indole Vilsmeir reagent 63
Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ Friedel-­‐Cra‚s formylaGon – use of formyl fluoride ◾ this is not a pracGcal method for the conversion of aromaGcs to the corresponding aldehydes ◾ formyl chloride is too unstable to partake in Friedel Cra‚s reacGons as it readily decomposes to CO and HCl ◾ Ga{ermann-­‐Koch formylaGon – good for alkyl benzenes, generally an industrial method ◾ Ga{ermann aldehyde synthesis ◾ Neither the Ga{ermann nor the Ga{ermann-­‐Koch reacGons can be used with aromaGc amines Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ Reimer-­‐Tiemann Synthesis – requires a phenolic substrate ◾Pyrrole gives 3-­‐chloropyridine under Reimer-­‐Tiemann reacGon condiGons 64
Aromatic and Heterocyclic Chemistry
Introduc0on of Func0onal Groups –Synthesis ◾ Carboxylic acids ◾ Grignard route ◾ OxidaGon of alkyl benzenes ◾ NitraGon ◾ standard nitraGng mixture conc. sulfuric acid and conc. nitric acid is very harsh ◾ NO2+ BF4-­‐ is non-­‐oxidizing and non-­‐acidic – compaGble with many more funcGonal groups ◾ SulfonaGon reversible process – sulfonated product formed with conc. H2SO4 ◾ ◾ desulfonaGon can be achieved using dilute H2SO4 65
66
Aromatic and Heterocyclic Chemistry
Hetroaroma0cs ◾ Pyridine ◾ properGes – 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 anG-­‐bonding π-­‐orbital ◾ pyridine is electron poor and undergoes EARS only very slowly N
lone&pair&in&sp2&orbital
perpendicular&to&plane&of&
π3system
N
N
pyridine&is&electron&deficient&
at&C32&and&C34
HOMO&of&pyridine&is&the&
nitrogen&lone&pair
◾ synthesis of pyridines and derivaGves – generally aim to make dihydropyridine and then oxidise it to the corresponding pyridine ◾ dihydropyridines are readily prepared by the condensaGon of ammonia with 1,5-­‐dicarbonyl compounds ◾ 1,5-­‐dicarbonyl compounds are readily prepared by addiGon of an aldehyde or ketone to an α,β-­‐unsaturated carbonyl compound Aromatic and Heterocyclic Chemistry
Heteroaroma0cs Hantzsch pyridine synthesis ◾ other oxidants to convert dihydropyridines to pyridines include: (NH4)2Ce(NO3)6 (CAN), MnO2, DDQ 67
Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ Pyridine synthesis with hydroxylamine – no oxidant required ◾ Electrophilic subsGtuGon with pyridines 68
Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ NitraGon of pyridine ◾ nitraGon of pyridine with N2O5 ◾ plausible mechanism 69
70
Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ Pyridine N-­‐oxides – much more suscepGble to electrophilic a{ack at 2 and 4 posiGons (and to nucleophilic addiGon at 2 and 4 posiGons) promotes E+ addi0on at 2 and 4 posi0ons ◾ nitraGon of pyridine N-­‐oxide Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ pyridine N-­‐oxides – N-­‐deoxygenaGon with rearrangement ◾ pyridine N-­‐oxides – conversion to chloro compounds 71
Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ pyridones ◾ nitraGon 72
Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ pyridines – nucleophilic subsGtuGon ◾ Chichibabin reacGon 73
Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ quinolines and isoquinolines ◾ Synthesis – Skraup synthesis 74
Aromatic and Heterocyclic Chemistry
75
Heteroaroma0cs ◾ synthesis of isoquinolines ◾ Bischler-­‐Napieralski ◾ Pictet-­‐Spengler ◾ quinoline and isoquinoline undergo EArS more readily than pyridine, with reacGon occurring on the benzenoid ring 76
Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ pyrrole, thiophene and furan ◾ all three have aromaGc properGes ◾ in each case the (one of the) lone pair(s) is parallel to the p-­‐orbitals and part of the π-­‐system ◾ the aromaGc heterocycles are electron rich β α
2
3
NH
X
NH
S1
O
thiophene
pyrrolidine
furan
pyrrole
0.556D
1.746D
0.666D
◾ order of aromaGcity 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 aromaGc Reac0ons ◾ electrophilic subsGtuGon – kineGc reacGon at the 2-­‐posiGon is favoured over reacGon at the 3-­‐posiGon ◾ more reacGve than benzene – e.g. pyrrole similar reacGvity to aniline X
X
X
less'delocalised
E
E
E
H
X
E
H
E
H
X
E
H
H
X
E
X
more(delocalised
77
Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ electrophilic subsGtuGon of pyrrole, thiophene and furan ◾ subsGtuents already present on the aromaGc heterocycle exert less direcGng effect than the corresponding subsGtuents in benzene E
X
EWG
H
EDG
X
E
EWG
E
◾ nitraGon X
X
E
H
EDG
E
EWG
H
X
X
EDG
E
X
EDG
with*EWG*at*α,posi0on
β',subsitu0on*favoured
E
with*EDG*at*α,posi0on
α',subsitu0on*favoured
78
Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ acylaGon and formylaGon H
N
O
Cl3C
H
N
Cl,'AlCl3
O
CCl3 90%'HNO3,'-50'°C
α'
O2N
H
N
O
CCl3
β''>'α''or'β'for'α-EWG
β'
◾ directed lithiaGon Li Bu
X
Bu Li
X
H
X
Li
directed,lith/a/on,to,the,α3posi/on
induc/ve,effect,aids,α3deprotona/on
more,stable,sp2,anion,formed
Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ lithium halogen exchange ◾ metallaGon of pyrrole ◾ N-­‐metallated pyrroles can react either at nitrogen or carbon ◾ generally, the more ionic the metal-­‐nitrogen bond the more N-­‐alkylaGon products are formed ◾ thiophene 79
80
Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ indole 3β
2α
N1
H
◾ more enamine-­‐like than pyrrole ◾ a{ack of electrophiles at the β posiGon is the lowest energy pathway akack at β posi0on retains aroma0c sextet of benzenoid ring ◾ if the β-­‐posiGon is blocked α-­‐a{ack occurs ◾ α-­‐a{ack can occur via β-­‐a{ack followed by rearrangement Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ Synthesis ◾ pyrrole -­‐ synthesis from 1,4-­‐dicarbonyls, Paal-­‐Knorr synthesis ◾ from α-­‐amino ketones and carbonyl compounds with acGvated α-­‐methylene groups – Knorr synthesis 81
Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ Hantzsch pyrrole synthesis –from α-­‐chloroketones and carbonyl compounds ◾ Furans – Paal-­‐Knorr synthesis ◾ Furans – from α-­‐halocarbonyls and acGve methylene compounds 82
Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾thiophenes – from 1,4-­‐dicarbonyl compounds ◾ from 1,2-­‐dicarbonyl compounds – Hinsberg synthesis ◾ from 1,3-­‐dicarbonyl compounds 83
84
Aromatic and Heterocyclic Chemistry
Heteroaroma0cs ◾ Indoles – the Fischer indole synthesis [3,3]-­‐sigmatropic rearrangement ◾ unsymmetrical ketones give mixtures of indoles: strong acids favour indole formaGon from the less subsGtuted ene-­‐hydrazine; weak acids favour indole formaGon from the more subsGtuted ene-­‐hydrazine 85
Aromatic and Heterocyclic Chemistry
Reduc0on of Aroma0cs ◾ Birch reducGon – covered with Dr Smith protona0on at site of highest charge and largest HOMO coefficient protona0on at site of highest charge to give most stable radical protona0on at site of highest charge and largest HOMO coefficient 86
Aromatic and Heterocyclic Chemistry
Reduc0on of Aroma0cs ◾ Birch reducGon examples naphthalene ◾ Birch reducGon with C-­‐X bond cleavage Aromatic and Heterocyclic Chemistry
Reduc0on of Aroma0cs ◾ Birch reducGon – heteroaromaGcs ◾ pyridine -­‐ in the absence of added alcohol dimerisaGon of the intermediate radical anion occurs ◾ pyridine -­‐ in the presence of added alcohol dimers are not formed ◾ with sufficient electron withdrawing groups, the addiGon of a further electron to the iniGally formed radical anion occurs to give a dianion 87
88
Aromatic and Heterocyclic Chemistry
Reduc0on of Aroma0cs ◾ Birch reducGon – pyrroles, furans, thiophenes ◾ electron rich and hence require an electron withdrawing group ◾ with enough electron withdrawing groups further reducGon 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 89
Aromatic and Heterocyclic Chemistry
Reduc0on of Aroma0cs ◾ Birch reducGon – pyrroles, furans, thiophenes stereoselec(ve*alkyla(on*
controlled*by*chiral*auxilliary
◾ Hydride reducGons – pyridinium salts major minor Aromatic and Heterocyclic Chemistry
Reduc0on of Aroma0cs ◾ Hydride reducGon – pyridines – best with an a{ached EWG ◾ Simple pyrroles are only reduced by hydride reducing agents in the presence of acid ◾ “Ionic hydrogenaGon” of furan and thiophene gives the saturated derivaGves 90
Aromatic and Heterocyclic Chemistry
Reduc0on of Aroma0cs ◾ HydrogenaGon – complete reducGon of the aromaGc ring ◾ hydrogenaGon of aromaGc ring occurs most readily with Pt, Rh and Ru catalysts; Pd is less acGve alkynes/alkenes and many other funcGonal groups can be readily reduced in the presence of aromaGc rings ◾ Hydrogenolysis of benzylic heteroatoms readily occurs under palladium catalysis; a cartoon mechanism is shown ◾ Pyridines are more easily hydrogenated than benzenoid aromaGcs ◾ hydrogenaGon of pyrrole and furan is relaGvely straighˆorward; hydrogenaGon of thiophene is complicated by catalyst poisoning and the hydrogenolysis of the C-­‐S bond with complete removal of sulfur 91
Aromatic and Heterocyclic Chemistry
Aroma0c Chemistry in Ac0on Synthesis of Lavendamycin analogues 92
Aromatic and Heterocyclic Chemistry
Aroma0c Chemistry in Ac0on Synthesis of Lavendamycin analogues 93
Aromatic and Heterocyclic Chemistry
Aroma0c Chemistry in Ac0on Synthesis of Lavendamycin analogues 94
Aromatic and Heterocyclic Chemistry
Aroma0c Chemistry in Ac0on Synthesis of Lavendamycin analogues 95
Aromatic and Heterocyclic Chemistry
Aroma0c Chemistry in Ac0on ◾ Synthesis of a thrombin inhibitor ◾ Route 1 to fluoro pyridine 96
Aromatic and Heterocyclic Chemistry
Aroma0c Chemistry in Ac0on ◾ Synthesis of a thrombin inhibitor ◾ Route 2 to fluoro pyridine 97
Aromatic and Heterocyclic Chemistry
Aroma0c Chemistry in Ac0on ◾Synthesis of a thrombin inhibitor ◾ preparaGon of the pyrazone 98
Aromatic and Heterocyclic Chemistry
Aroma0c Chemistry in Ac0on ◾ preparaGon of the pyrazone 99
Aromatic and Heterocyclic Chemistry
Aroma0c Chemistry in Ac0on ◾ compleGon of the synthesis completed handout at: hkp://burton.chem.ox.ac.uk/teaching.html 100