aromatic and heterocyclic chemistry 4 lectures, michaelmas...

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

+


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


•

•

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


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

•

•


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


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


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


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


+

+

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


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


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


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


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


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


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


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


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


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


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


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


•

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+


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


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


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


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


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


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


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


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


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


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


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


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)


-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


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


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


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


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

+


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


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


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


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


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


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


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


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


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


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


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


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


-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


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


Na or Li in liquid NH3, EtOH

H

SET add electron

HMeO


Na or Li in liquid NH3, EtOH

CO2H CO2H

deprotonation SET add electron

••

•

CO2 CO2 CO2

SET add electron

CO2

H


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


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


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


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%


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

aromatic and heterocyclic chemistry 4 lectures, michaelmas...

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