Aryl halides that have electron-withdrawing substituents can undergo a nucleophilic substitution...

Aryl halides that have electron-withdrawing substituents can undergo a nucleophilic substitution reaction

9.9 Nucleophilic Aromatic Substitution

• Reaction of proteins with 2,4-dinitrofluorobenzene (Sanger’s reagent) attaches a “label” to the terminal NH2 group of an amino acid by a nucleophilic aromatic substitution reaction

Nucleophilic Aromatic Substitution

Mechanism of nucleophilic aromatic substitution reactions

Nucleophilic Aromatic Substitution

Nucleophilic aromatic substitution occurs only if the aromatic ring has an electron-withdrawing substituent in a position ortho or para to the leaving group to stabilize the anion intermediate through resonance

Nucleophilic Aromatic Substitution

Comparison of electrophilic and nucleophilic aromatic substitution reactions

• Electrophilic substitutions are favored by electron-donating substituents which stabilize the carbocation intermediate

• Nucleophilic substitutions are favored by electron-withdrawing substituents which stabilize a carbanion intermediate

• Electron-withdrawing groups that deactivate rings for electrophilic substitution (nitro, carbonyl, cyano, and so on) activate rings for nucleophilic substitution

Nucleophilic Aromatic Substitution

Alkyl substituents on aromatic rings containing a benzylic hydrogen react readily with common laboratory oxidizing agents such as aqueous KMnO4 or Na2Cr2O7 and are converted into carboxyl groups – CO2H

• Net conversion of an alkylbenzene into a benzoic acid

Ar-R Ar-CO2H• Oxidation of butylbenzene into benzoic acid

9.10 Oxidation and Reduction of Aromatic Compounds

• The mechanism of side-chain oxidation involves reaction of a C-H bond at the position next to the aromatic ring (the benzylic position) to form an intermediate benzylic radical

• Benzylic radicals are stabilized by resonance and thus form more readily than typical alkyl radicals

Oxidation and Reduction of Aromatic Compounds

Side chain oxidations occur in various biosynthetic pathways• The neurotransmitter norepinephrine is biosynthesized

from dopamine by a benzylic hydroxylation reaction • Radical reaction • Reaction catalyzed by the copper-containing enzyme

dopamine -monooxygenase

Oxidation and Reduction of Aromatic Compounds

Hydrogenation of Aromatic Rings• Alkene double bonds can be reduced selectively in the presence

of an aromatic ring

Oxidation and Reduction of Aromatic Compounds

• To hydrogenate an aromatic ring it is necessary to use a platinum catalyst with hydrogen gas at several hundred atmospheres pressure or a more effective catalyst such as rhodium on carbon

Oxidation and Reduction of Aromatic Compounds

Oxidation and Reduction of Aromatic Compounds

Reduction of Aryl Akyl KetonesAromatic ring activates a neighboring carbonyl group toward

reduction• An aryl alkyl ketone prepared by Friedel-Crafts acylation

of an aromatic ring can be converted into an alkylbenzene by catalytic hydrogenation over a palladium catalyst• Propiophenone is reduced to

propylbenzene by catalytic hydrogenation

There are many reasons for carrying out laboratory synthesis of an organic molecule• In the pharmaceutical industry, new molecules are

designed and synthesized in the hope that some might be useful drugs

• In the chemistry industry, syntheses are done to devise more economical routes to known compounds

• In biochemistry laboratories molecules synthesized to probe enzyme mechanisms

9.11 An Introduction to Organic Synthesis: Polysubstituted Benzenes

Planning a successful multistep synthesis of a complex molecule requires knowledge of the uses and limitations of numerous organic reactions

The trick to planning an organic synthesis is to work backward, often referred to as the retrosynthetic direction

• Keep starting material in mind and work backward to it• Look at the final product and determine possible immediate

precursors of that product• Work backward one step at a time

An Introduction to Organic Synthesis: Polysubstituted Benzenes

Examples of synthetic planning using polysubstituted aromatic compounds as the targets

• Electrophilic substitution on a disubstituted benzene ring is governed by the same resonance and inductive effects that affect monosubstituted rings• Must consider the additive effects of two groups

An Introduction to Organic Synthesis: Polysubstituted Benzenes

1. If the directing effects of the two groups reinforces each other, the situation is straightforward• In p-nitrotoluene both the methyl and the nitro group direct

further substitution to the same position (ortho to the methyl = meta to the nitro). A single product is thus formed on electrophilic substitution

An Introduction to Organic Synthesis: Polysubstituted Benzenes

2. If the directing effects of the two main groups oppose each other, the more powerful activating group has the dominant influence• Nitration of p-methylphenol yields primarily 4-methyl-2-

nitrophenol because –OH is a more powerful activator than –CH3

An Introduction to Organic Synthesis: Polysubstituted Benzenes

3. Further substitution rarely occurs between the two groups in a meta-disubstituted compound because this site is too hindered• Aromatic rings with three adjacent substituents must

therefore be prepared by some other route• The substitution of an ortho-disubstituted compound

An Introduction to Organic Synthesis: Polysubstituted Benzenes

Propose a synthesis of 4-bromo-2-nitrotoluene from benzene.

Worked Example 9.4

Synthesizing a Polysubstituted Benzene

Strategy1. Draw the target molecule

2. Identify the substituents• The three substituents on the ring are a bromine, a methyl

group, and a nitro group

Worked Example 9.4

Synthesizing a Polysubstituted Benzene

Strategy3. Recall how each group can be introduced separately

• A bromine can be introduced by bromination with Br2/FeBr3, a methyl group can be introduced by Friedel-Crafts alkylation with CH3Cl/ AlCl3, and a nitro group can be introduced by nitration with HNO3/H2SO4

4. Then plan retrosynthetically

Worked Example 9.4

Synthesizing a Polysubstituted Benzene

Solution• The final step will involve introduction of one of the three

groups – bromine, methyl, or nitro • Three possibilities:

Worked Example 9.4

Synthesizing a Polysubstituted Benzene

• Immediate precursors of p-bromotoluene• Toluene

• Because the methyl group would direct bromination to the ortho and para positions

• Bromobenzene • Because Friedel-Crafts methylation would yield a mixture of ortho

and para products

Worked Example 9.4

Synthesizing a Polysubstituted Benzene

• The immediate precursor of toluene• Benzene, which could be methylated in a Friedel-Crafts

reaction• The immediate precursor of bromobenzene

• Benzene, which could be brominated• Two valid routes possible from benzene to 4-bromo-2-

nitrotoluene

Worked Example 9.4

Synthesizing a Polysubstituted Benzene

Propose a synthesis of 4-chloro-2-propylbenzenesulfonic acid from benzene.

Worked Example 9.5

Synthesizing a Polysubstituted Benzene

Strategy1. Draw the target molecule

2. Identify the substituents• The three substituents on the ring are chlorine, a propyl

group, and a sulfonic acid group

Worked Example 9.5

Synthesizing a Polysubstituted Benzene

Strategy3. Recall how each of the three can be introduced

• A chlorine can be introduced by chlorination using Cl2/FeCl3, a propyl group can be introduced by Friedel-Crafts acylation with CH3CH2COCl/ AlCl3 followed by reduction with H2/Pd, and a sulfonic acid group can be introduced by sulfonation with SO3/H2SO4

4. Then plan retrosynthetically

Worked Example 9.5

Synthesizing a Polysubstituted Benzene

Solution• The final step will involve introduction of one of the three

groups – chlorine, propyl, or sulfonic acid• Three possibilities:

Worked Example 9.5

Synthesizing a Polysubstituted Benzene

• The immediate precursors to m-chloropropylbenzene• Because the two substituents have a meta relationship, the first

substituent placed on the ring must be a meta director so that the second substitution will take place at the proper position

• Because primary alkyl groups such as propyl cannot be introduced directly by Friedel-Crafts alkylation, the precursor of m-chloropropylbenzene is probably m-chloropropiophenone, which could be catalytically reduced

Worked Example 9.5

Synthesizing a Polysubstituted Benzene

• The immediate precursor of m-chloropropiophenone • Propiophenone, which could

be chlorinated in the meta position

• The immediate precursor of propiophenone• Benzene which could

undergo Friedel-Crafts acylation with propanoyl chloride and AlCl3

Worked Example 9.5

Synthesizing a Polysubstituted Benzene

• The final synthesis is a four-step route from benzene:

Worked Example 9.5

Synthesizing a Polysubstituted Benzene

Solution

Worked Example 9.3

Predicting the Product of an Electrophilic Aromatic Substitution Reaction