21-21-11
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
21-21-33
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.
21-21-44
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
21-21-55
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
21-21-66
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
21-21-77
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+
+
21-21-88
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)
21-21-99
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
21-21-1010
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
21-21-1111
Cyclopentadienyl Anion, CCyclopentadienyl Anion, C55HH55--
• 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.
21-21-1212
Cyclopentadienyl Anion, CCyclopentadienyl Anion, C55HH55--
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 :
21-21-1313
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
+
21-21-1414
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
21-21-1515
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
21-21-1616
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
21-21-1717
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
21-21-1818
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
21-21-1919
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
21-21-2121
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
21-21-2222
Acidity of PhenolsAcidity of Phenols
Separation of water-insoluble phenols from water-insoluble alcohols.
21-21-2323
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
21-21-2424
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
21-21-2525
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
21-21-2626
Acidity of PhenolsAcidity of Phenols
• 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
21-21-2929
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
+
21-21-3030
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
21-21-3131
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
21-21-3232
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
21-21-3333
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
21-21-3434
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)
1,4-Benzenediol(Hydroquinone)
21-21-3535
QuinonesQuinones
Readily reduced to hydroquinones.
1,4-Benzoquinone(p-Quinone)
(reduction)
1,4-Benzenediol(Hydroquinone)
O
O
OH
OH
Na2S2O4, H2O
21-21-3636
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
21-21-3838
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
21-21-3939
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
21-21-4040
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)
21-21-4141
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
21-21-4242
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
21-21-4343
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
21-21-4444
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)