21-1 heterocyclic aromatics heterocyclic compound: heterocyclic compound: a compound that contains...

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Heterocyclic AromaticsHeterocyclic Aromatics

Heterocyclic compound:Heterocyclic compound: A compound that contains more than one kind of atom in a ring. • In organic chemistry, the term refers to a ring with one

or more atoms that differ from carbon.

Pyridine and pyrimidine are heterocyclic analogs of benzene; each is aromatic.

Pyridine

N

N

N••••

Pyrimidine

12

34

5

61

2

3 4

5

6

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Database for unknown compoundsDatabase for unknown compounds

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PyridinePyridine

• The nitrogen atom of pyridine is sp2

hybridized.• The unshared pair of

electrons lies in an sp2 hybrid orbital and is not a part of the six pi electrons of the aromatic system (the aromatic sextet).

• Resonance energy of pyridine is134 kJ (32 kcal)/mol.

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Furan and PyrroleFuran and Pyrrole

• The oxygen atom of furan is sp2 hybridized.• one unshared pairs of electrons on oxygen lies in an

unhybridized 2p orbital and is a part of the aromatic sextet.

• The other unshared pair lies in an sp2 hybrid orbital and is not a part of the aromatic system.

• The resonance energy of furan is 67 kJ (16 kcal)/mol.

O NH

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Other HeterocyclicsOther Heterocyclics

Purine

Indole

N

N

NN

N

H

H

N

H

CH2CH2NH2

Serotonin(a neurotransmitter)

HO

Caffeine

N

NN

N

O

O

H3CCH3

CH3

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Aromatic Hydrocarbon IonsAromatic Hydrocarbon Ions

Any neutral, monocyclic, unsaturated hydrocarbon with an odd number of carbons must have at least one CH2 group and, therefore, cannot be aromatic.

• Cyclopropene, for example, has the correct number of pi electrons to be aromatic, 4(0) + 2 = 2, but does not have a closed loop of 2p orbitals.

Cyclopropene Cyclopentadiene Cycloheptatriene

CH2 CH2CH2

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Cyclopropenyl CationCyclopropenyl Cation

• If, however, the CH2 group of cyclopropene is transformed into a CH+ group in which carbon is sp2 hybridized and has a vacant 2p orbital, the overlap of orbitals is continuous and the cation is aromatic.

Cyclopropenyl cation represented as a hybrid of three equivalent contributing structures

+

H

H

H

H

H

H

H

H

H+

+

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Cyclopropenyl CationCyclopropenyl Cation

• When 3-chlorocyclopropene is treated with SbCl5, it forms a stable salt.

• This chemical behavior is to be contrasted with that of 5-chloro-1,3-cyclopentadiene, which cannot be made to form a stable salt.

+

Cyclopropenyl hexachloroantimonate

+

3-Chloro-cyclopropene

HH

ClSbCl5 SbCl6

-

Antimony(V) chloride(a Lewis acid)

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Cyclopentadienyl CationCyclopentadienyl Cation

• If planar cyclopentadienyl cation were to exist, it would have 4 pi electrons and be antiaromatic.

• Note that we can draw five equivalent contributing structures for the cyclopentadienyl cation. Yet this cation is not aromatic because it has only 4 pi electrons.

Cyclopentadienyltetrafluoroborate

++

5-Chloro-1,3-cyclopentadiene

H

ClHAgBF4 BF4

- + AgCl

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Cyclopentadienyl Anion, CCyclopentadienyl Anion, C55HH55--

To convert cyclopentadiene to an aromatic ion, it is necessary to convert the CH2 group to a CH group in which carbon becomes sp2 hybridized and has 2 electrons in its unhybridized 2p orbital.

••

• • H

HH

H

H

the origin of the 6 pi electronsin the cyclopentadienyl anion

Cyclopentadienyl anion (aromatic)

HH

HH

H:

H

HH

HH

n = 1

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• As seen in the Frost circle, the six pi electrons of cyclopentadienyl anion occupy the 1, 2, and 3 molecular orbitals, all of which are bonding.

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The pKa of cyclopentadiene is 16.• In aqueous NaOH, it is in equilibrium with its sodium

salt.

• It is converted completely to its anion by very strong bases such as NaNH2 , NaH, and LDA.

pKa 15.7pKa 16.0

Na+ + H2OH

H

H

H

H

CH2 + NaOH :

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Cycloheptatrienyl Cation, CCycloheptatrienyl Cation, C77HH77++

Cycloheptatriene forms an aromatic cation by conversion of its CH2 group to a CH+ group with its sp2 carbon having a vacant 2p orbital.

+

Cycloheptatrienyl cation (Tropylium ion) (aromatic)

H

HH

H

H

HH

H

HH

H

H

HH

+

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NomenclatureNomenclature

Monosubstituted alkylbenzenes are named as derivatives of benzene.• Many common names are retained.

Toluene CumeneEthylbenzene Styrene

Phenol Aniline Benzoic acid Anisole

COOHNH2 OCH3OH

Benzaldehyde

CHO

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NomenclatureNomenclature

Benzyl and phenyl groups

(Z)-2-Phenyl-2-butene

4-(3-Methoxyphenyl)-2-butanone

1-Phenyl-1-pentanone

O OH3CO

Ph

BenzenePhenyl group, Ph- Toluene Benzyl group, Bn-

CH3 CH2

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Disubstituted BenzenesDisubstituted Benzenes

Locate two groups by numbers or by the locators orthoortho (1,2-), metameta (1,3-), and parapara (1,4-).• Where one group imparts a special name, name the

compound as a derivative of that molecule.

CH3

Br

COOHNO2

Cl

NH2

CH3

CH3

2-Nitrobenzoic acid

(o-Nitrobenzoic acid)

3-Chloroaniline(m-Chloroaniline)

4-Bromotoluene(p-Bromotoluene)

m-Xylene

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Disubstituted BenzenesDisubstituted Benzenes

• Where neither group imparts a special name, locate the groups and list them in alphabetical order.

CH2CH3

Cl

NO2Br

1-Bromo-2-nitrobenzene (o-Bromonitrobenzene)

1-Chloro-4-ethylbenzene (p-Chloroethylbenzene)

12

3

4 2

1

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Polysubstituted DerivativesPolysubstituted Derivatives

• If one group imparts a special name, name the molecule as a derivative of that compound.

• If no group imparts a special name, list them in alphabetical order, giving them the lowest set of numbers.

CH3

NO2

OH

Br

Br

NO2

CH2CH3

Br

4

2

1

6

4

21

4

1 2

4-Chloro-2-nitro-toluene

2,4,6-Tribromo-phenol

2-Bromo-1-ethyl-4-nitrobenzene

Br

Cl

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PhenolsPhenols

The functional group of a phenol is an -OH group bonded to a benzene ring.

1,2-Benzenediol(Catechol)

1,4-Benzenediol(Hydroquinone)

3-Methylphenol(m-Cresol)

Phenol

OH OHOHOH

OHCH3

OH

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Acidity of PhenolsAcidity of Phenols

Phenols are significantly more acidic than alcohols.

OH H2O

CH3CH2OH H2O

O-

CH3CH2O-

H3O+

H3O+

pKa = 9.95+

+

+

+ pKa = 15.9

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Separation of water-insoluble phenols from water-insoluble alcohols.

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Acidity of Phenols (Resonance)Acidity of Phenols (Resonance)

• The greater acidity of phenols compared with alcohols is due to the greater stability of the phenoxide ion relative to an alkoxide ion.

These 2 Kekuléstructures areequivalent

HH

OO O O

H

O

These three contributing structuresdelocalize the negative chargeonto carbon atoms of the ring

H

OO O O

H

O

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Phenol Subsitituents (Inductive Effect)Phenol Subsitituents (Inductive Effect)

Alkyl and halogen substituents effect acidities by inductive effects:• Alkyl groups are electron-releasing.• Halogens are electron-withdrawing.

p-ChororophenolpKa 9.18

m-ChlorophenolpKa 8.85

PhenolpKa 9.95

m-CresolpKa 10.01

p-CresolpKa 10.17

OH OH OH OH OH

CH3

CH3

ClCl

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Phenol Subsitituents(Resonance, Inductiion)Phenol Subsitituents(Resonance, Inductiion)

• Nitro groups increase the acidity of phenols by both an electron-withdrawing inductive effect and a resonance effect.

OH

NO2

OH OH

NO2PhenolpKa 9.95

p-NitrophenolpKa 7.15

m-NitrophenolpKa 8.28

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• Part of the acid-strengthening effect of -NO2 is due to its electron-withdrawing inductive effect.

• In addition, -NO2 substituents in the ortho and para positions help to delocalize the negative charge.

+ +

delocalization of negativecharge onto oxygen furtherincreases the resonancestabilization of phenoxide ion

O

O O

NO

O

NO

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SynthesisSynthesis: Alkyl-Aryl Ethers: Alkyl-Aryl Ethers

Alkyl-aryl ethers can be prepared by the Williamson ether synthesis:• but only using phenoxide salts and haloalkanes.• haloarenes cannot be used because they are

unreactive to SN2 reactions.

no reaction+X RO-Na

+

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SynthesisSynthesis: Alkyl-Aryl Ethers: Alkyl-Aryl Ethers

OH CH2=CHCH2ClNaOH, H2O, CH2Cl2

OCH2CH=CH2

Phenyl 2-propenyl ether(Allyl phenyl ether)

+

Phenol 3-Chloropropene(Allyl chloride)

OH

O

O

CH3OSOCH3NaOH, H2O, CH2Cl2

OCH3 Na2SO4+

Methyl phenyl ether(Anisole)

+

Phenol Dimethyl sulfate

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SynthesisSynthesis: Kolbe Carboxylation: Kolbe Carboxylation

Phenoxide ions react with carbon dioxide to give a carboxylate salt.

OH

NaOHH2O

O-Na

+

CO2

H2O

OHCO

-Na

+O

HClH2O

OH O

COH

Phenol Sodiumphenoxide

Sodium salicylate Salicylic acid

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Mechanism: Mechanism: Kolbe CarboxylationKolbe Carboxylation

• The mechanism begins by nucleophilic addition of the phenoxide ion to a carbonyl group of CO2.

O

C

O

O

OC

H

OO OH

CO

O

A cyclohexadienoneintermediate

+

Sodium phenoxide

Salicylate anion

keto-enoltautomerism

(1) (2)

Go back to aromatic structure

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Synthesis: Synthesis: QuinonesQuinones

Because of the presence of the electron-donating -OH group, phenols are susceptible to oxidation by a variety of strong oxidizing agents.

H2 CrO4

Phenol 1,4-Benzoquinone(p-Quinone)

O

O

OH

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QuinonesQuinones

OHOH K2Cr2O7

OH

OH

H2SO4

K2Cr2O7

H2SO4

O

O

OO

1,4-Benzoquinone (p-Quinone)

1,2-Benzenediol (Catechol)

1,2-Benzoquinone (o-Quinone)


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QuinonesQuinones

Readily reduced to hydroquinones.

1,4-Benzoquinone(p-Quinone)

(reduction)


O

O

OH

OH

Na2S2O4, H2O

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Coenzyme QCoenzyme Q

Coenzyme Q is a carrier of electrons in the respiratory chain.

O

O

MeO

HMeO MeO

MeO

OH

OH

Hn n

Coenzyme Q(oxidized form)

Coenzyme Q(reduced form)

reduction

oxidation

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Benzylic OxidationBenzylic Oxidation

Benzene is unaffected by strong oxidizing agents such as H2CrO4 and KMnO4

• Halogen and nitro substituents are also unaffected by these reagents.

• An alkyl group with at least one hydrogen on its benzylic carbon is oxidized to a carboxyl group.

2-Chloro-4-nitrotoluene 2-Chloro-4-nitrobenzoic acid

H2CrO4

O2N Cl

CH3

O2N Cl

COOH

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Benzylic OxidationBenzylic Oxidation

• If there is more than one alkyl group on the benzene ring, each is oxidized to a -COOH group.

1,4-Dimethylbenzene (p-xylene)

1,4-Benzenedicarboxylic acid (terephthalic acid)

CH3 H2 SO4

K2Cr2O7H3C COH

O

HOCO

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Benzylic ChlorinationBenzylic Chlorination

Chlorination and bromination occur by a radical chain mechanism.

CH3

Cl2+

CH2Cl

HCl+

Toluene

heat or light

Benzyl chloride

(PhCO2)2, CCl4

NBS

Br

Ethylbenzene 1-Bromo-1-phenylethane(racemic)

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Mechanism: Mechanism: Benzylic ReactionsBenzylic Reactions

Benzylic radicals (and cations also) are easily formed because of the resonance stabilization of these intermediates.• The benzyl radical is a hybrid of five contributing

structures.

C

C

C

C C

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Benzylic HalogenationBenzylic Halogenation

• Benzylic bromination is highly regioselective.

• Benzylic chlorination is less regioselective.

(PhCO2)2, CCl4

NBS

Br

Ethylbenzene 1-Bromo-1-phenylethane(the only product formed)

Cl

Cl2 +

heat or light

1-Chloro-2-phenylethane

(10%)

Ethylbenzene

+

1-Chloro-1-phenylethane

(90%)

Cl

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HydrogenolysisHydrogenolysis

Hydrogenolysis:Hydrogenolysis: Cleavage of a single bond by H2

• Benzylic ethers are unique in that they are cleaved under conditions of catalytic hydrogenation.

O H2Pd/C

OHMe

+

Benzyl butyl ether Toluene1-Butanol

+

this bondis cleaved

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Synthesis, Protecting Group: Synthesis, Protecting Group: Benzyl EthersBenzyl Ethers

The value of benzyl ethers is as protecting groups for the OH groups of alcohols and phenols.• To carry out hydroboration/oxidation of this alkene,

the phenolic -OH must first be protected; it is acidic enough to react with BH3 and destroy the reagent.

OH

1. ClCH2Ph

O Ph

2. BH3•THF

Et3N 3. H2O2/NaOH

H2

Pd/CO Ph

OH

OH

OH

2-(3-Hydroxypropyl)phenol

2-(2-Propenyl)phenol(2-Allylphenol)

21-1 heterocyclic aromatics heterocyclic compound: heterocyclic compound: a compound that contains...

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