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 NH 2 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 KMnO 4 or Na 2 Cr 2 O 7 and are converted into carboxyl groups – CO 2 H Net conversion of an alkylbenzene into a benzoic acid Ar-R Ar-CO 2 H Oxidation of butylbenzene into benzoic acid 9.10Oxidation 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

Reduction of Aryl Akyl Ketones Aromatic 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 9.11An 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 – CH 3 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

Strategy 1. 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

Strategy 3. Recall how each group can be introduced separately A bromine can be introduced by bromination with Br 2 /FeBr 3, a methyl group can be introduced by Friedel-Crafts alkylation with CH 3 Cl/ AlCl 3, and a nitro group can be introduced by nitration with HNO 3 /H 2 SO 4 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

Strategy 1. 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

Strategy 3. Recall how each of the three can be introduced A chlorine can be introduced by chlorination using Cl 2 /FeCl 3, a propyl group can be introduced by Friedel-Crafts acylation with CH 3 CH 2 COCl/ AlCl 3 followed by reduction with H 2 /Pd, and a sulfonic acid group can be introduced by sulfonation with SO 3 /H 2 SO 4 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 AlCl 3 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