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Heterocyclic Aromatics
 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.
4
3
5
2
6
1N
••
Pyridine
4
3
N
2
1N
••
5
6
Pyrimidine
21-1
Database for unknown compounds
21-2
Pyridine
• 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.
21-3
Furan 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.
21-4
Other Heterocyclics
CH2 CH2 NH 2
HO
N
N
H
H
Serotonin
(a neurotransmitter)
Indole
N
N
N
H3 C
N
O
H
Purine
O
CH3
N
N
N
N
CH3
Caffeine
21-5
Aromatic 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.
CH2
Cycloprop ene
CH2
Cyclop entadien e
CH2
Cycloh eptatriene
• 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.
21-6
Cyclopropenyl 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.
H
H
H
+
+ H
H
H
H
+
H
H
Cycloprop enyl cation represented as a h yb rid
of three equ ivalen t contributin g s tru ctures
21-7
Cyclopropenyl Cation
• When 3-chlorocyclopropene is treated with SbCl5, it
forms a stable salt.
H
+
Cl
3-Chlorocyclopropene
Sb Cl 5
Antimony(V)
chloride
(a Lewis acid)
+
H Sb Cl 6
-
Cyclopropenyl
hexachloroantimonate
• This chemical behavior is to be contrasted with that of
5-chloro-1,3-cyclopentadiene, which cannot be made
to form a stable salt.
21-8
Cyclopentadienyl Cation
H
+ A gBF4
Cl
5-Chloro-1,3cyclopentadiene
+
H BF4
-
+ Ag Cl
Cyclopentadienyl
tetrafluoroborate
• 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.
21-9
Cyclopentadienyl Anion, C5H5 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 •
•
•
H
H
•
H
H
th e origin of th e 6 pi electrons
in the cyclopen tadienyl anion
H
H
H
:
H
H
H
H
H
H
H
Cyclopentad ienyl anion
(aromatic)
n=1
21-10
Cyclopentadienyl Anion, C5H5• As seen in the Frost circle, the six pi electrons of
cyclopentadienyl anion occupy the p1, p2, and p3
molecular orbitals, all of which are bonding.
21-11
Cyclopentadienyl Anion, C5H5 The
pKa of cyclopentadiene is 16.
• In aqueous NaOH, it is in equilibrium with its sodium
salt.
H
H
CH2 + NaOH
:
H
p K a 16.0
H
H Na+ + H2 O
pK a 15.7
• It is converted completely to its anion by very strong
bases such as NaNH2 , NaH, and LDA.
21-12
Cycloheptatrienyl Cation, C7H7+
 Cycloheptatriene
forms an aromatic cation by
conversion of its CH2 group to a CH+ group with
its sp2 carbon having a vacant 2p orbital.
H
H
H
H
H
H
H
+
H
H
+
H
H
H
H
H
Cyclohep tatrien yl cation
(Tropylium ion )
(aromatic)
21-13
Nomenclature
 Monosubstituted
alkylbenzenes are named as
derivatives of benzene.
• Many common names are retained.
Toluene
Ethylbenzene
OH
N H2
Phenol
Aniline
CHO
Benzaldehyde
Cumene
Styrene
COOH
Benzoic acid
OCH3
Anis ole
21-14
Nomenclature
 Benzyl
and phenyl groups
CH3
Benzene
Phenyl group, PhO
Toluene
CH2
Benzyl group, Bn-
O
H 3 CO
Ph
1-Phenyl-1-pentanone
4-(3-Methoxyphenyl)2-butanone
(Z)-2-Phenyl2-butene
21-15
Disubstituted Benzenes
 Locate
two groups by numbers or by the
locators ortho (1,2-), meta (1,3-), and para (1,4-).
• Where one group imparts a special name, name the
compound as a derivative of that molecule.
CH3
NH2
COOH
NO2
CH3
Cl
CH3
Br
4-Bromotolu ene 3-Chloroan iline
2-N itrobenzoic acid m-Xylene
(p-Bromotoluen e) (m-Chloroan iline) (o-N itrob enzoic acid )
21-16
Disubstituted Benzenes
• Where neither group imparts a special name, locate
the groups and list them in alphabetical order.
CH2 CH3
4
3
2
NO2
Br
1
2
1
Cl
1-Chloro-4-ethylben zene
(p-Ch loroethylbenzen e)
1-Bromo-2-nitrob enzene
(o-Bromon itroben zene)
21-17
Polysubstituted 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.
1 2
N O2
OH
CH3
N O2
Br
6
1
2
4
Br
2
4
4
Cl
Br
4-Chloro-2-nitrotoluene
2,4,6-Tribromophenol
1
Br
CH2 CH3
2-Bromo-1-ethyl-4nitrobenzene
21-18
Phenols
 The
functional group of a phenol is an -OH group
bonded to a benzene ring.
OH
OH
OH
OH
OH
CH3
Phenol
3-Methylphenol
(m- Cresol)
1,2-Benzenediol
(Catechol)
OH
1,4-Benzenediol
(Hydroquinone)
21-19
Acidity of Phenols
 Phenols
are significantly more acidic than
alcohols.
OH + H2 O
O- + H3 O+
CH3 CH2 OH + H2 O
CH3 CH2 O + H3 O
-
pK a = 9.95
+
pK a = 15.9
21-21
Acidity of Phenols
 Separation
of waterinsoluble phenols
from water-insoluble
alcohols.
21-22
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.
O
O
O
O
O
H
H
These 2 Kekulé
s tru ctures are
equivalent
H
These th ree con trib utin g s tru ctures
delocalize th e negative charge
on to carb on atoms of th e rin g
21-23
Phenol Subsitituents (Inductive Effect)
 Alkyl
and halogen substituents effect acidities by
inductive effects:
• Alkyl groups are electron-releasing.
• Halogens are electron-withdrawing.
OH
OH
OH
CH3
Phen ol
pK a 9.95
m-Cres ol
p Ka 10.01
OH
OH
Cl
CH3
p-Cres ol
pK a 10.17
Cl
m-Chlorop henol p-Chororophen ol
pK a 8.85
p Ka 9.18
21-24
Phenol Subsitituents(Resonance, Inductiion)
• Nitro groups increase the acidity of phenols by both an
electron-withdrawing inductive effect and a resonance
effect.
OH
OH
OH
NO2
Ph e no l
p K a 9.95
NO2
m - N itrop h e n ol p- N itrop h e n ol
p K a 8.28
p K a 7.15
21-25
Acidity 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.
O
O
O
N+
N+
O
O
delocalization of negative
charge onto oxygen further
increases the resonance
stabilization of phenoxide ion
O
21-26
Synthesis: 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.
X + RO - N a+
no reaction
21-29
Synthesis: Alkyl-Aryl Ethers
OH + CH2 = CHCH2 Cl
Phenol
3-Chloropropene
(Allyl chloride)
N aOH, H2 O, CH2 Cl 2
OCH2 CH= CH2
Phenyl 2-propenyl ether
(Allyl phenyl ether)
O
OH + CH3 OSOCH3
Phenol
O
D imethyl sulfate
N aOH, H2 O, CH2 Cl 2
OCH3 + N a2 SO 4
Methyl phenyl ether
(Anisole)
21-30
Synthesis: Kolbe Carboxylation
 Phenoxide
ions react with carbon dioxide to give
a carboxylate salt.
-
OH
O Na
+
CO2
NaOH
H2 O
Phenol
OH O
+
CO Na
H2 O
Sodiu m
phen oxid e
Sodium salicylate
HCl
H2 O
OH O
COH
S alicylic acid
21-31
Mechanism: Kolbe Carboxylation
• The mechanism begins by nucleophilic addition of the
phenoxide ion to a carbonyl group of CO2.
O
O
O
+
C
O
Sodium
phenoxide
O
C
(1)
O
keto-enol
tautomerism
H
OH
O
C
O
(2)
A cyclohexadienone
intermediate
Salicylate anion
Go back to aromatic
structure
21-32
Synthesis: Quinones
 Because
of the presence of the electron-donating
-OH group, phenols are susceptible to oxidation
by a variety of strong oxidizing agents.
OH
O
H2 Cr O 4
Phenol
O
1,4-Benzoquinone
(p-Quinone)
21-33
Quinones
O
OH
OH
O
K2 Cr2 O7
H2 SO4
1,2-Benzen ediol
(Catechol)
1,2-Benzoquin on e
(o-Qu inone)
OH
O
K2 Cr2 O7
H2 SO4
OH
1,4-Ben zenediol
(Hydroquin on e)
O
1,4-Benzoquin on e
(p-Qu inone)
21-34
Quinones
 Readily
reduced to hydroquinones.
O
OH
Na2 S2 O4 , H2 O
(reduction )
O
1,4-Benzoqu inone
(p-Qu inone)
OH
1,4-Benzen ediol
(Hydroq uinone)
21-35
Coenzyme Q
 Coenzyme
Q is a carrier of electrons in the
respiratory chain.
O
OH
MeO
MeO
reduction
MeO
O
Coenzyme Q
(oxid ized form)
n
H
oxidation
MeO
OH
Coenzyme Q
(redu ced form)
n
H
21-36
Benzylic 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.
CH3
O2 N
Cl
2-Chloro-4-nitrotoluene
COOH
H2 Cr O4
O2 N
Cl
2-Chloro-4-nitrobenzoic acid
21-38
Benzylic Oxidation
• If there is more than one alkyl group on the benzene
ring, each is oxidized to a -COOH group.
H3 C
CH3
1,4-Dimethylbenzene
(p-xylene)
K2 Cr 2 O 7
H2 SO 4
O
HOC
O
COH
1,4-Benzenedicarboxylic acid
(terephthalic acid)
21-39
Benzylic Chlorination
 Chlorination
and bromination occur by a radical
chain mechanism.
CH3
+
Cl2
h eat
or ligh t
Toluen e
CH2 Cl
+
HCl
Benzyl ch loride
Br
NBS
( PhCO2 ) 2 , CCl4
Ethylbenzen e
1-Bromo-1-p henylethan e
(racemic)
21-40
Mechanism: Benzylic 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
21-41
Benzylic Halogenation
• Benzylic bromination is highly regioselective.
Br
NBS
(PhCO2 ) 2 , CCl4
Eth ylb enzene
1-Bromo-1-phen yleth ane
(the only product formed )
• Benzylic chlorination is less regioselective.
Cl
+ Cl2
Eth ylb enzene
heat
or ligh t
Cl
+
1-Chloro-1p henylethan e
(90%)
1-Ch loro-2ph enylethan e
(10%)
21-42
Hydrogenolysis
 Hydrogenolysis:
Cleavage of a single bond by H2
• Benzylic ethers are unique in that they are cleaved
under conditions of catalytic hydrogenation.
this bond
is cleaved
O
Benzyl butyl ether
+ H2
Pd/ C
Me
OH +
1-Butanol
Toluene
21-43
Synthesis, Protecting Group: Benzyl 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.
2 . BH3 • THF
1 . ClCH2 Ph
OH
2-(2-Propen yl)p henol
(2-A llylp henol)
Et 3 N
O
OH
O
Ph
H2
Pd/ C
Ph
3 . H2 O2 / NaOH
OH
OH
2-(3-Hyd roxyprop yl)p henol
21-44