Aromatic and Heterocyclic Chemistry

Lectures 1-6 2 nd Year Michaelmas 2009

Dr Jonathan Burton CRL Office 6, 1st floor E-mail: jonathan.burton@chem.ox.ac.uk

Synopsis
Lectures 1-6: J. W. Burton
1. The Origin of Aromaticity and General Characteristics of Aromatic Compounds a. kinetic and thermodynamic stability of benzene b. substitution not addition c. resonance energy by hydrogenation d. Hckel rule of linear and cyclic polyenes 1,3,5 hexatriene vs benzene e. cyclobutadiene and antiaromaticity 2. Examples of Aromaticity a. Frost circle b. examples of 3,4,5,6,7,8-membered aromatic compounds including cations and anions e.g. tropylium cation, acidity of cyclopentadiene, 18-annulene. 3. Electrophilic Aromatic Substitution a. Revision of 1st year b. Hammonds postulate to explain EAS c. mechanistic evidence for EAS i. isolation of arenium ion ii. Kinetic Isotope Effect (briefly) 4. Electrophilic Aromatic Substitution cont. a. Substituent effects including halogens b. Effects of two substituents c. Ispo attack and reversible reactions 5. Nucleophilic Aromatic Substitution a. Problems with SN1 and SN2 reaction on aromatics b. Diazonium salts and SN1 reactions radical mechanisms c. SNAr by addition/elimination mechanism d. Meisenheimer intermediates e. Substituent effects f. Vicarious Nucleophilic Substitution (briefly) g. SRN1 mechanism and examples (briefly) 6. Arynes a. Evidence for benzyne Roberts experiment, trapping experiments, etc. b. Structure of (ortho)-benzyne c. Generation of benzyne various methods d. Substituent effects e. meta- and para-benzynes (briefly)

Lectures 7-12: D. M. Hodgson

7. Reactions with metals: Ortho Lithiation, Palladium Catalysed Couplings, Chromium Complexes and Birch Reductions. 8. Introduction of Functional Groups 9. Pyridine: Synthesis and Reactions 2

10. Pyrrole, Thiophene and Furan: Synthesis and Reactions. 11. Indole: Synthesis and Reactions.

Suggested Reading
Advanced Organic Chemistry: Reactions Mechanisms, and Structures; J. March. Advanced Organic Chemistry Parts A and B; F. Carey and R. Sundberg. Aromatic Substitution Reactions; L. Stock Frontier Orbitals and Organic Chemical Reactions; I. Fleming. Aromatic Chemistry; M. Sainsbury. Reactive Intermediates; C. Moody and G. Whitham. Heterocyclic Chemistry; J. Joule, K. Mills and G. Smith. Aromatic Heterocyclic Chemistry; D. Davies. N.B. Other general organic texts also cover the basic chemistry of organic compounds.

Origin of Aromaticity
Typical reactions of alkenes

Typical reactions of benzene

benzene is kinetically stable retains aromatic sextet of electrons in substitution reactions does not behave like a normal polyene or alkene benzene is both kinetically and thermodynamically very stable how do we quantify this stability? Quantification of stability heats of hydrogenation

-1 H hydrog = -120 kJmol

-1 H hydrog =3 x -120 = -360 kJmol

(hypothetical, 1,3,5-cyclohexatriene)

-1 H hydrog = -210 kJmol

benzene 150 kJmol-1 more stable than expected (represents stability over hypothetical 1,3,5cyclohextriene) termed the empirical resonance energy (values vary enormously)

Energy

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 delocalisation is stabilising, but how much more stabilising is the delocalisation 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

Understanding Aromaticity - the Molecular Orbital Approach

Hckel Theory
Hckels Rule: planar, monocyclic, completely conjugated hydrocarbons will be aromatic when the ring contains (4n +2) -electrons (n = 0, 1, 2.positive integers) Corollary planar, monocyclic, completely conjugated hydrocarbons will be anti-aromatic when the ring contains (4n) -electrons (n = 0, 1, 2.positive integers)

Hckel Molecular Orbital Theory (HMOT)

applicable to conjugated planar cyclic and acyclic systems only the -system is included; the -framework is ignored (in reality -framework affects system) used to calculate the wave functions (i) and hence relative energies by the LCAO method i.e. i = c11 + c22 + c33 + c44 + c55 ..

HMOT solves energy (Ei) and coefficients ci there are now many more sophisticated methods for calculating the stabilisation energy in conjugated systems; however, HMOT is adequate for our purposes.

HMOT in Action
For cyclic and acyclic systems: Molecular Orbital Energies = Ei = + mj = coulomb integral - energy associated with electron in an isolated 2p orbital (albeit in the molecular environment) is negative (stabilising) and is the same for any p-orbital in -system = resonance integral energy associated with having electrons shared by atoms in the form of a covalent bond is negative (stabilising) and is set to zero for non-adjacent atoms. (all overlap integrals S assumed to be zero, electron correlation ignored) linear polyenes cyclic polyenes mj = 2cos[j/(n+1)] mj = 2cos(2j/n) j = 1, 2n (n = number of carbon atoms in conjugated system)

j = 0, 1, 2[(n-1)/2] for odd n, n/2 for even n 6

Examples
ethene

two 2p atomic orbitals give 2 molecular orbitals; n = 2, j = 1 or 2 mj = 2cos(/3) = 1 energy E = 2cos(2/3) = -1

stabilisation energy Estab = 2( + ) Note: the energy of two isolated p orbitals is 2 we have gained 2 of stabilisation allyl System

three 2p atomic orbitals give 3 molecular orbitals; n = 3, j = 1, 2 or 3 mj = 2cos(/4) = 2 energy E = + 2 2cos(/2) = 0 2cos(3 /4) = -2 - 2

E=

E=

E=

E=

allyl cation stabilisation energy Estab =2 + 2.8 i.e. more stable than ethene (Estab ethene =2 + 2) take home message conjugation is stabilising

allyl radical would have stabilisation energy Estab = 3 + 2.8

 1,3,5-Hexatriene vs Benzene

six 2p atomic orbitals give 6 molecular orbitals; n = 6, j = 1, 2, 3, 4, 5, 6 mj = 2cos(/7) = 1.80 2cos(2/7) = 1.25 and the corresponding negative values energy E = + 1.80 + 1.25 no. nodes 5 2cos(3/7) = 0.45...... + 0.45 0.45..etc

MO

energy

HMOT MO (calculated)

- 1.80

- 1.25

- 0.45

+ 0.45

+ 1.25

+ 1.80

stabilisation energy Estab= 2(3 + 3.5) = 6 + 7 stabilisation with respect to 3 x ethene = (6 + 7) 3(2 + 2) =

Benzene Cyclic polyenes mj = 2cos(2j/n) j = 0 1, [(n-1)/2] for odd n; n/2 for even n

six 2p atomic orbitals give 6 molecular orbitals; n = 6, j = 0 1, 2, 3 mj = 2cos(0) = 2, energy E = + 2, MO 2cos(2/6) = 1, + , 2cos(4/6) = -1, - , no. nodes energy 2 HMOT MO (calculated) 2cos(6/6)= -2

- 2

4,5

2,3

+ 2

stabilisation energy Estab= 2( + 2) + 4( + ) = 6 + 8 stabilisation energy with respect to 1,3,5-hexatriene = (6 + 8) (6 + 7) = stabilisation energy with respect to 3 x ethene = (6 + 8) 3(2 + 2) = 2 HMOT predicts benzene is more stable than hexatriene and than 3 x ethene aromatic compounds are those with a -system lower in energy than that of acyclic counterpart 9

 Cyclobutadiene vs 1,3-butadiene

four 2p atomic orbitals give 4 molecular orbitals; n = 4, j = 0 1, 2 mj = 2cos(0) = 2 energy E = + 2 2cos(2/4) = 0 cyclobutadiene MO no. nodes 4 energy 2 1,3-butadiene energy 2cos(4/4) = -2

- 2

1.62 0.62

2,3

+ 0.62 + 1.62

+ 2

Stabilisation energy Estab = 4 + 4 i.e. same as 2 x ethene

Stabilisation energy Estab = 4 + 4.4

cyclobutadiene is less stable than 1,3-butadiene anti-aromatic compounds are those with a -system higher in energy than that of acyclic counterpart

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Frost-Musulin Diagram Frost Circle

simple method to find the energies of the molecular orbitals for an aromatic compound inscribe the regular polygon, with one vertex pointing down, inside a circle of radius 2, centred at energy each intersection of the polygon with the circumference of the circle corresponds to the energy of a molecular orbital.

General Characteristics of Aromatic Compounds

i) planar fully conjugates cyclic polyenes ii) more stable than acyclic analogues iii) bonds of nearly equal length i.e. not alternating single and double bonds iv) undergo substitution reactions (rather than addition reactions) v) support a diamagnetic ring current magnetic field induces electrons in -system to circulate setting up a secondary magnetic field opposed to the first magnetic field aromatic protons of C6H6 see applied field plus induced field and hence require higher frequency to bring them into resonance and they appear at higher chemical shift ()

>

>
>

>

Good test for aromatic character of a compound 11

Examples of Aromatic and Anti-Aromatic Compounds

Hckels rule [(4n +2) -electrons for aromatic compounds; 4n -electrons for anti-aromatic compounds] holds for anions, cations and neutrals

Cyclopropenium cation
(4n +2), n = 0, 2 electrons

insoluble in non-polar solvents; 1 signal in 1H NMR H = 11.1 ppm - aromatic and a cation compare with cyclopropyl cation which is subject to rearrangement to the allyl cation

Synthesis

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Cyclopropenones

Cyclobutene dications
(4n +2), n = 0, 2 electrons H = 3.68 ppm all Me groups equivalent. Me groups to 2 positive charges H = 2.1 ppm

Benzene
(4n +2), n = 1, 6 electrons H = 7.26 ppm, planar molecule; C-C sp3-sp3 = 1.54 C-C sp3-sp2 = 1.50 bond length = 1.39 C-C sp3-sp = 1.47 C-C sp2-sp2 = 1.46 C=C sp2-sp2 = 1.34 isoelectronic with pyridine:

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Cyclopentadienyl Anion
(4n +2), n = 1, 6 electrons

quick reminder: pKa is a measure of the position 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

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Furan, pyrrole and thiophene

(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 -system

all 3 are aromatic, show ring currents and undergo electrophilic aromatic substitution

Tropylium Cation
(4n +2), n = 1, 6 electrons

ionic compound mp 205 C insoluble in nonpolar solvents

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Tropone (4n +2), n = 1, 6 electrons some aromatic character O O more basic than acetone

HBr OH OH Br pKa = -0.6 Tropolones (4n +2), n = 1, 6 electrons pKa = -6.2

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Cyclobutadiene
(4n), n = 1, 4 electrons anti-aromatic (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

Synthesis

Cyclobutadiene can be stabilised with very bulky substituents

stable up to 150 C but very reactive towards O2 H

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Cyclopropenium anion
(4n), n = 1, 4 electrons anti-aromatic

stabilisation energy Estab= 4 +2 stabilisation energy of allyl anion Estab= 4 +22

rate of proton exchange cyclopropane/cyclopropene = 10000

Cyclopentadienyl cation
(4n), n = 1, 4 electrons anti-aromatic

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Cyclopentadienone

Cycloheptatrienyl anion and Cyclooctatetraene

(4n), n = 2, 8 electrons anti-aromatic probably not planar similar pKa to normal 1,4-diene

non-aromatic, alternating bond lengths, distorts to avoid planar anti-aromatic conformation, normal reactivity of polyene

Other Examples

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[18]-Annulene
(4n+2), n = 4, 18 electrons aromatic Cu(OAc)2 pyridine, 85 C Glaser coupling hexadiyne

tBuOK base catalysed isomerisation (allene intermediates)

H2/Pd
H

= -3.0 H

= 9.3

18 electrons bright red ring large enough to be planar without steric congestion of inner protons 2 signals in 1H NMR consistent with ring current

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Benzene
model for arene reactions aromaticity makes benzene a thermodynamic sink Some isomers of C6H6

Numbering and Nomenclature

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Reactions
Electrophilic Aromatic Substitution (revision)

what does transition state look like for attack of E+ on aromatic ring? rates of chemical reactions are controlled by free energy of transition state therefore information about transition state structure is crucial transition states have transitory existence cannot make experimental measurements on them

Hammonds Postulate
If two states, as, for example, a transition sate and an unstable intermediate, occur consecutively during a reaction process and have nearly the same energy content, their interconversion will involve only a small reorganisation of molecular structure. The transition state resembles the structure (intermediate or substrate or product) to which it is closest in energy (i.e. transition state resembles intermediate arenium ion, therefore what stabilises the arenium ion stabilises the transition state.) 22

Mechanistic Evidence
Isolation of intermediates

Isotope Effects effect on rate of reaction by substitution of an element (most commonly H) for a heavier isotope (D or T) very useful mechanistic probe Example

transfer of H-atom 9 times faster than D 23

 examine potential energy curves for C-H(D) bond these are the same for C-H and C-D bonds (Morse potentials) due to lower zero point energy for vibration of C-D bond with respect to C-H bond, C-D bond is stronger than C-H bond stretching frequency of bond

m1m2 m1 m2

E0

1 h 2

C-H = 0.92 (ca. 1)

C-D = 1.72 (ca. 2)

Eo CH > Eo CD hence C-D bond stronger than C-H bond Crude analysis (which assumes bond 100% broken at transition state) gives kH/kD 7 (normally 2-7) primary kinetic isotope effect (more later)

potential energy

dissociation

C-H C-D bond distance take home message: expect kinetic isotope effect if break C-H bond in rate determining step

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Nitration of Benzene

kH/kD = 1 hence C-H bond not involved in r.d.s. - consistent with step 1 being rate determining no kinetic isotope for nitration of benzene excludes the following mechanisms

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 if there is a kinetic isotope effect there is some reversibility in step 1

normally 1st step is rate determining step lose aromaticity 2nd step is fast regain aromaticity

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Substituent Effects
substituent Y affects both the rate and regiochemistry of the reaction

electron donating groups activate the aromatic ring (i.e. substrate reacts faster than benzene) and are ortho and para directing

electron withdrawing groups activate the aromatic ring (i.e. substrate reacts slowed than benzene) and are meta directing

halogens are mildly deactivating and direct o/p

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 Y = electron donating group, ortho and para attack favoured i.e. the intermediate (and hence the transition state leading to the intermediate) is stabilised by electron donation from Y (not possible for meta attack)

Y = Electron withdrawing group o and p attack disfavoured i.e. the intermediate (and hence the transition state leading to the intermediate) is destabilised by electron withdrawing group Y (not possible for meta attack), and hence get meta attack by default

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 curly arrows (in a molecular orbital context) illustrate the electron distribution in the frontier orbital we are interested in the stability of the competing intermediates, and, although curly arrows give us the correct answer we really should compare the total energy of the -system we can do this using Hckel 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, 1, 2 and 3

MO

ortho

Eortho

meta

Emeta 0

para

Epara

0.45 E E

0.52

1.0 3 E 1.25 E 1.18 E

1.80 E 1.90 E Estab =(6) + 6.9 1.93

Estab =(6) + 7

Estab =(6) + 6.16

The intermediates from ortho and para attack are more stable than those from meta attack

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 Y = EWG - we will model these groups as the benzyl cation and will compare the energies of the sigma complexes - look at two filled MOs, 1 and 2

MO

ortho E

Eortho

meta

Emeta

para

Epara 1.0

1.18 1.25 E E

1.80 E 1.90 E 1.93

Estab =(4) + 6.1

Estab =(4) + 6.16

Estab =(4) + 5.86

intermediate from meta attack is more stable than those from ortho and para attack we will continue to use the curly arrow method. Halogens mildly deactivating as they are electronegative and withdraw electron density from the ring through the -framework (falls off with distances) halogens direct ortho and para as they have lone pairs in high energy orbitals which stabilise the intermediates for ortho/para attack

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 fluorobenzene has similar reactivity to benzene although it is the most electronegative of the halogens if has a 2p lone pair which overlaps efficiently with the benzene ring Examples

Two Substituents reinforcing

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 opposing - if similar reactivity will get mixtures of compounds; however, a strong activator beats a weak activator.

activating ability rough order

all other things being equal a 3rd group is least likely to enter between two groups meta to one another Ipso attack

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Reversible reactions electrophilic aromatic substitution is generally an irreversible process but there are some exceptions SO3H H / H2O + SO3

HO H

O S

Me tBuCl / AlCl3

Me

tBuCl / AlCl3 heat Me

tBu

tBu

tBu

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Nucleophilic Aromatic Substitution

SN2: aliphatic vs aromatic

Aliphatic

nucleophile attacks C-L * resulting in inversion of configuration Aromatic

no possibility of nucleophile attacking backside of C-L * (transition geometry impossible) LUMO is * not * attacking electron rich arene with electron rich nucleophile

SN1: aliphatic vs aromatic

Aliphatic

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Aromatic

Examples

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SNAr Addition Elimination Mechanism

nucleophile attacks LUMO, electron withdrawing groups lower energy of LUMO and stabilise the negative charge in the intermediate best to have electron withdrawing group(s), ortho and/or para to the leaving group

Evidence
Isolation of intermediates

for halogens as leaving groups, rate of reaction follows kF > kCl > kBr (c.f. rate of SN2 reacitons kI > kBr > kCl > kF)

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 r.d.s. is attack of nucleophile on aromatic ring therefore bond strength to leaving group is not so important in influencing the rate fluorine is the most electronegative element, polarises sigma bond, lowers LUMO, therefore fastest rate Example
H N + O 2N X O2N N NO2 NO2 X= F Cl Br I

relative rate 3300 4.3 4.3 1

NO2 H N + O2N X O 2N Ph

NO2 X= F relative rate 1 N Me Cl 15 Br 46

Ph

Me

Mechanism

d[P] k2 [I] d[t]

[I] k1[A][B] k-1 k2

d[I] k1[A][B] - k2 [I] - k-1[I] = 0 (steady state approximation) dt d[P] k1k2 [A][B] d[t] k1 k2

37

 if k2 >> k-1 step 1 is the rate determining step, if k-1 >> k2 i.e. the second step is rate loss of X- is faster than loss of R2NH determining intermediate reverts to starting material faster than progressing to product d[P] k1k2 [A][B] d[P] k1k2 [A][B] d[t] k2 d[t] k1 do not break C-X bond in r.d.s in r.d.s break C-X bond and hence fastest with weaker bond

k1 k1 k2 k-1 k2

A+B P piperidine is a worse leaving group then methyl aniline step 1 is r.d.s for piperidine

A+B P step 2 is r.d.s for methyl aniline

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Substitutent Effects electron withdrawing groups ortho/para to leaving group enhance rate electron donating groups ortho/para to leaving group retard rate substituents meta to the leaving group have less influence

Other Examples

Sangers Reagent N-terminus labelling of peptides

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Vicarious Nucleophilic Substitution - (nucleophilic substitution of hydrogen)

mechanism

LG = Cl, Br, PhO, PhS etc; EWG = SO2Ph, SO2NR2, CN, CO2Et Examples

SRN1 nucleophilic substitution by unimolecular radical mechanism

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Mechanism radical chain process

Nucleophile can be:

O , enolates, , O

electron donating and electron withdrawing groups are tolerated 1 electron reducible groups (e.g. NO2) are not tolerated h accelerates the initiation single electron transfer to aromatics facilitates other reactions

equivalent of SN2 at a tertiary centre 41

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 (benzyne) relative energy = 0 kJmol-1 meta-benzyne relative energy ca. 64 kJmol-1 best represented as para-benzyne relative energy ca. 130 kJmol-1

ortho-Benzyne
Synthesis

Evidence IR spectrum of benzyne in an argon matrix shows C-C bond is 0.05 shorter than in benzene Roberts isotope labelling experiment disproves direct substitution or SNAr addition/elimination mechanism

42

 trapping experiments

isolation of complexes

Stucture 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 reactions tend to be dominated by orbital control (i.e. they are very soft) carbene like two electrons in two orbitals Generation

relative reactivity for formation of benzyne with alkyl lithiums is F > Cl > Br > I; actual rate of generation of benzyne depends on solvent, base and leaving group

43

 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 generation involves hypervalent iodine intermediates

generation from zwitterions

NH2 OH O

N heat or h O + CO2 + N2

explosive

44

 thermal and photochemical fragmentations

oxidative fragmentation

45

Orientation of attack on arynes from ortho-disubstituted substrates

Note: EWG and EDG in the above examples refer to inductive effects aryne orbitals are orthogonal to the aromatic -system hence substituents exert influence inductively through -framework Orientation of attack on arynes from meta-disubstituted substrates

Note: EWG and EDG in the above examples refer to inductive effects

46

Orientation of attack on arynes from para-disubstituted substrates

Note: EWG and EDG in the above examples refer to inductive effects Examples

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Further examples

48

SiMe3 + OTf F-

O OEt

O CsF, MeCN 80 C

EtO2C OEt O + O O OEt

O EtO2C

OEt

O O Application to the total synthesis of (-)-quinocarcin an antitumour antibiotic O

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Cycloadditions benzynes readily undergo Diels-Alder reactions

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meta-Benzyne

para-Benzyne
the Bergman cyclisation

51

Mechanism of action of calicheamicin 1I

highly potent antitumour agent enediyne constrained in 10-membered ring ends of enediyne brought in close proximity by conformational change on conjugate addition of thiolate Bergman cyclisation occurs to give a diradical which abstracts hydrogen atoms from DNA causing DNA damage

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