Organic Chemistry III
19.20 The Synthesis of Trisubstituted Benzenes
If both substituents direct the third substituent to the same
position, the product is easily predicted.
Steric hindrance makes the position between the
substituents less accessible, so only a very samll amount of
the third product will be formed.
A strongly activating substituent will win over an weakly
activating substituent or deactivating substituent.
If the two substituents have similar activating properties, neither will
dominate and a mixture of products will be obtained.
19.21 The Synthesis of Substituted Benzenes using Arenediazonium Salts
Displacing the leaving group of a diazonium ion by a nucleophile
occurs readily because it results in formation of nitrogen gas,
which is very stable.
Some displacements involve phenyl cations, whereas others involve radicals; the actual mechanism
depends on the particular nucleophile.
Analine can be converted into an arenediazonium salt by
treatment with nitrous acid (HNO2), which is very unstable so it
must be formed in situ at 0 °C.
Sandmeyer reaction = reaction of an arenediazonium salt with a
copper(I) salt
The nucleophiles -C≡N, Cl- and Br- will replace the diazonium group
if the appropriate copper(I) salt is added to the solution containing
the arenediazonium salt.
KCl and KBr cannot be used in place of CuCl and CuBr.
Sandmeyer reaction is a useful alternative
for direct halogenation, because only the
desired product is formed instead of e.g.
both the ortho and para isomers.
An iodo substituent will replace the diazonium group if potassium iodide (KI) is added to the solution
containing the diazonium ion.
Schiemann reaction = fluoro substitution on the
arenediazonium salt when this is heated with
fluoroboric acid (HBF4)
If the acidic aqueous solution in which the diazonium salt has been
synthesized is allowed to warm up, then an OH group will replace the
diazonium group; water is the nucleophile.
A better yield of phenol is obtained if aqueous copper(I) oxide and
copper(II) nitrate are added to the cold solution.
A hydrogen will replace a diazonium group
if the arenediazonium salt is treated with
1
,hypophosphorous acid (H3PO2); useful if an amino group or a nitro group is needed for directing
purposes and subsequently must be removed.
19.22 The Arenediazonium Ion as an Electrophile
Arenediazonium ions can be used as electrophiles in electrophilic aromatic substitution reactions that
can be carried out well below room temperature; only highly activated benzene rings (phenols, anilines
and N-alkylanilines).
azo compound = product of electrophilic aromatic
substitution reaction with arenediazonium ion electrophiles
azo linkage = the N=N linkage of the azo compound
The electrophile is very large, so substitution takes place
preferentially at the less sterically hindered para position.
If the para position is blocked, then substitution will occur at
an ortho position.
Mechanism for electrophilic aromatic substitution using an arenediazonium ion electrophile
This mechanism is the same as for electrophilic aromatic substitution with any other electrophile.
Azo compounds can exist in cis and trans forms; the trans isomer is more
stable because the cis isomer has steric strain.
Prontosil is an azo compound that is a prodrug; only becomes an active
drug after it undergoes a reaction in the body.
19.23 The Mechanism for the Reaction of Amines with Nitrous Acid
Conversion of an NH2 group to a diazonium group
requires a nitrosonium ion, which is formed when
water is eliminated from protonated nitrous acid.
Mechanism for formation of a diazonium ion from aniline
Aniline shares an electron pair with nitrosonium ion, after which N is deprotonated to form nitrosamine.
Delocalization of N’s lone pair and protonation on O form a protonated N-hydroxyazo compound,
which is in equilibrium with its nonprotonated form and can be reprotonated on N (the reverse
reaction) or protonated on O (the forward reaction).
Elimination of water forms the diazonium ion.
2
, 19.24 Nucleophilic Aromatic Substitution
Aryl halides do not react with nucleophiles because the π electron cloud repels the approach of a
nucleophile.
If the aryl halide has one or more substituents that strongly
withdraw electrons from the ring by resonance, a nucleophilic
aromatic substitution reaction can take place.
The electron-withdrawing groups must be positioned ortho or para to the halogen.
The greater the number of electron-withdrawing substituents ortho and para to the halogen, the more
easily the nucleophilic aromatic substitution reaction occurs.
SNAr reaction = nucleophilic aromatic substitution reaction
General mechanism for nucleophilic aromatic substitution
The nucleophile attacks the carbon bearing the leaving group from a trajectory that is nearly
perpendicular to the aromatic ring, forming a resonance-stabilized carbanion intermediate called a
Meisenheimer complex.
The leaving group is eliminated, restoring the aromaticity of the ring.
The incoming nucleophile must be a stronger base than the substituent that is being replaced,
because the weaker of the two bases will be the one eliminated from the intermediate.
The electron-withdrawing substituent must be ortho or para to the site
of nucleophilic attack because the electrons of the attacking
nucleophile can be delocalized onto the substituent only if the
substituent is in one of those positions.
Strongly electron-withdrawing substituents activate the benzene ring toward nucleophilic aromatic
substitution, but deactivate the ring toward electrophilic aromatic substitution.
Making the ring less electron rich makes it more reactive toward a nucleophile but less reactive toward
an electrophile.
19.25 The Synthesis of Cyclic Compounds
Cyclic compounds are formed from intra molecular reactions; favoured if the reaction forms a
compound with a five- or a six-membered ring.
A cyclic ketone will form in a Friedel-Crafts reaction of a compound that
contains both a benzene ring and an acyl chloride.
A cyclic ester (lactone) can be prepared form a reactant that has a
carboxylic acid group and an alcohol group in the same molecule separated
by the appropriate number of carbons.
A cyclic ether can be prepared by an intramolecular
Williamson ether synthesis.
A cyclic ether can also be prepared by an
intramolecular electrophilic addition reaction.
The products obtained from an
intramolecular reaction can undergo further
reactions.
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19.20 The Synthesis of Trisubstituted Benzenes
If both substituents direct the third substituent to the same
position, the product is easily predicted.
Steric hindrance makes the position between the
substituents less accessible, so only a very samll amount of
the third product will be formed.
A strongly activating substituent will win over an weakly
activating substituent or deactivating substituent.
If the two substituents have similar activating properties, neither will
dominate and a mixture of products will be obtained.
19.21 The Synthesis of Substituted Benzenes using Arenediazonium Salts
Displacing the leaving group of a diazonium ion by a nucleophile
occurs readily because it results in formation of nitrogen gas,
which is very stable.
Some displacements involve phenyl cations, whereas others involve radicals; the actual mechanism
depends on the particular nucleophile.
Analine can be converted into an arenediazonium salt by
treatment with nitrous acid (HNO2), which is very unstable so it
must be formed in situ at 0 °C.
Sandmeyer reaction = reaction of an arenediazonium salt with a
copper(I) salt
The nucleophiles -C≡N, Cl- and Br- will replace the diazonium group
if the appropriate copper(I) salt is added to the solution containing
the arenediazonium salt.
KCl and KBr cannot be used in place of CuCl and CuBr.
Sandmeyer reaction is a useful alternative
for direct halogenation, because only the
desired product is formed instead of e.g.
both the ortho and para isomers.
An iodo substituent will replace the diazonium group if potassium iodide (KI) is added to the solution
containing the diazonium ion.
Schiemann reaction = fluoro substitution on the
arenediazonium salt when this is heated with
fluoroboric acid (HBF4)
If the acidic aqueous solution in which the diazonium salt has been
synthesized is allowed to warm up, then an OH group will replace the
diazonium group; water is the nucleophile.
A better yield of phenol is obtained if aqueous copper(I) oxide and
copper(II) nitrate are added to the cold solution.
A hydrogen will replace a diazonium group
if the arenediazonium salt is treated with
1
,hypophosphorous acid (H3PO2); useful if an amino group or a nitro group is needed for directing
purposes and subsequently must be removed.
19.22 The Arenediazonium Ion as an Electrophile
Arenediazonium ions can be used as electrophiles in electrophilic aromatic substitution reactions that
can be carried out well below room temperature; only highly activated benzene rings (phenols, anilines
and N-alkylanilines).
azo compound = product of electrophilic aromatic
substitution reaction with arenediazonium ion electrophiles
azo linkage = the N=N linkage of the azo compound
The electrophile is very large, so substitution takes place
preferentially at the less sterically hindered para position.
If the para position is blocked, then substitution will occur at
an ortho position.
Mechanism for electrophilic aromatic substitution using an arenediazonium ion electrophile
This mechanism is the same as for electrophilic aromatic substitution with any other electrophile.
Azo compounds can exist in cis and trans forms; the trans isomer is more
stable because the cis isomer has steric strain.
Prontosil is an azo compound that is a prodrug; only becomes an active
drug after it undergoes a reaction in the body.
19.23 The Mechanism for the Reaction of Amines with Nitrous Acid
Conversion of an NH2 group to a diazonium group
requires a nitrosonium ion, which is formed when
water is eliminated from protonated nitrous acid.
Mechanism for formation of a diazonium ion from aniline
Aniline shares an electron pair with nitrosonium ion, after which N is deprotonated to form nitrosamine.
Delocalization of N’s lone pair and protonation on O form a protonated N-hydroxyazo compound,
which is in equilibrium with its nonprotonated form and can be reprotonated on N (the reverse
reaction) or protonated on O (the forward reaction).
Elimination of water forms the diazonium ion.
2
, 19.24 Nucleophilic Aromatic Substitution
Aryl halides do not react with nucleophiles because the π electron cloud repels the approach of a
nucleophile.
If the aryl halide has one or more substituents that strongly
withdraw electrons from the ring by resonance, a nucleophilic
aromatic substitution reaction can take place.
The electron-withdrawing groups must be positioned ortho or para to the halogen.
The greater the number of electron-withdrawing substituents ortho and para to the halogen, the more
easily the nucleophilic aromatic substitution reaction occurs.
SNAr reaction = nucleophilic aromatic substitution reaction
General mechanism for nucleophilic aromatic substitution
The nucleophile attacks the carbon bearing the leaving group from a trajectory that is nearly
perpendicular to the aromatic ring, forming a resonance-stabilized carbanion intermediate called a
Meisenheimer complex.
The leaving group is eliminated, restoring the aromaticity of the ring.
The incoming nucleophile must be a stronger base than the substituent that is being replaced,
because the weaker of the two bases will be the one eliminated from the intermediate.
The electron-withdrawing substituent must be ortho or para to the site
of nucleophilic attack because the electrons of the attacking
nucleophile can be delocalized onto the substituent only if the
substituent is in one of those positions.
Strongly electron-withdrawing substituents activate the benzene ring toward nucleophilic aromatic
substitution, but deactivate the ring toward electrophilic aromatic substitution.
Making the ring less electron rich makes it more reactive toward a nucleophile but less reactive toward
an electrophile.
19.25 The Synthesis of Cyclic Compounds
Cyclic compounds are formed from intra molecular reactions; favoured if the reaction forms a
compound with a five- or a six-membered ring.
A cyclic ketone will form in a Friedel-Crafts reaction of a compound that
contains both a benzene ring and an acyl chloride.
A cyclic ester (lactone) can be prepared form a reactant that has a
carboxylic acid group and an alcohol group in the same molecule separated
by the appropriate number of carbons.
A cyclic ether can be prepared by an intramolecular
Williamson ether synthesis.
A cyclic ether can also be prepared by an
intramolecular electrophilic addition reaction.
The products obtained from an
intramolecular reaction can undergo further
reactions.
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