Organic Chemistry - Chapter 18 Notes

Chapter 18: Reactions of Benzene and Substituted Benzenes

Introduction

• Benzene (C6H6) has a cyclic, planar structure with an uninterrupted cloud of π-electrons.
• Many substituted benzenes are found in nature and pharmaceuticals.
• Over 2/3 of the top 400 drugs contain benzene rings.

Aromaticity

• Criteria for aromaticity:
  • Cyclic, planar, uninterrupted cloud of π- electrons (π cloud).
  • π-cloud must contain an odd number of electron pairs (a “Hückel number” of π-electrons).

Other Aromatic Compounds

• Heterocyclic compounds like pyridine, pyrrole, furan, and thiophene.
• Lone pairs of electrons that are delocalized are pi electrons.
• Examples: quinoline, indole, imidazole, purine, pyrimidine, naphthalene, phenanthrene, chrysene

Aromatic Ions

• Cations can be $sp^2$-hybridized with an empty p-orbital.
• Anions might be $sp^2$-hybridized; check for delocalization.

Naming Monosubstituted Benzenes

• Some are named by adding the substituent name to "benzene."
• Some have common names that must be memorized.

Naming Disubstituted Benzenes

• Relative positions can be indicated by numbers or prefixes:
  • ortho = adjacent
  • meta = separated by one carbon
  • para = opposite each other

Naming Polysubstituted Benzenes

• Use numbers when more than two substituents are present.
• The incorporated substituent is given the 1-position.

General Mechanism for Electrophilic Aromatic Substitution (EAS)

1. Benzene acts as a nucleophile and attacks an electrophile.
2. The electrophile needs to be very reactive.
3. Steps:
   1. Generation of the electrophile (sometimes)
   2. Nucleophilic attack by the benzene ring
   3. Deprotonation to restore aromaticity
   4. Some EAS reactions have additional work-up steps

• The first step is slow because a carbocation is generated, and the aromaticity of the ring is lost.

Effect of Substituents

• The benzene ring itself is the nucleophile in an EAS reaction.
• Electron-donating substituents increase benzene’s nucleophilicity and stabilize the carbocation intermediate (activating substituents).
• Electron-withdrawing substituents decrease benzene’s nucleophilicity and destabilize the carbocation intermediate (deactivating substituents).
• Electron donation can occur through hyperconjugation or resonance.
• Electron withdrawal can occur through induction or resonance.

Directing Effects of Substituents

• When an EAS reaction occurs on a substituted benzene, the new substituent's attachment is determined by the directing effects of existing substituents.
• Electron-donating substituents push electron density onto the ortho and para positions, making them more nucleophilic.
  • Substituents that donate electrons through resonance or induction direct incoming electrophiles to the ortho and para positions (including halogens, which donate electrons through resonance).
• Electron-withdrawing substituents pull electron density away from the ortho and para positions, making the meta position most nucleophilic.
  • Substituents that withdraw electrons through resonance or induction direct incoming electrophiles to the meta position.
• Halogens are weakly deactivating but are ortho, para directors.
  • They withdraw electrons inductively, making the ring less nucleophilic (deactivated).
  • They donate electrons through resonance, directing incoming electrophiles to ortho/para positions.

Table 18.1 The Effect of Substituents on the Reactivity of a Benzene Ring Toward Electrophilic Aromatic Substitution

• Activating groups increase the reaction rate compared to benzene, while deactivating groups decrease it.
• Directing effects: ortho/para directing or meta directing.

The Ortho-Para Ratio

• Smaller substituents lead to more ortho product.
• Steric hindrance of larger substituents leads to more para product.
• Ortho and para products typically have different physical properties to allow them to be easily separated.

Halogenation of Benzene

• Bromination or chlorination of benzene requires a Lewis acid catalyst (e.g., $FeBr<em>3$ or $AlCl</em>3$) because benzene’s aromaticity causes it to be less reactive than an alkene.
• The catalyst and electrophile are generated in situ.

Iodination of Benzene

• Requires an oxidizing agent like $H<em>2O</em>2$ to generate the electrophile ($I^+$).
• $I<em>2 + H</em>2O<em>2 + 2H</em>2SO<em>4 \rightarrow 2I^+ + 2H</em>2O + 2HSO_4^−$

Nitration of Benzene

• Sulfuric acid protonates nitric acid.
• Protonated nitric acid loses water to form the electrophile (the nitronium ion, $NO_2^+$).

Sulfonation of Benzene

• Uses sulfuric acid, which gets protonated, then loses water to form the electrophile (the sulfonium ion, $SO_3H^+$).
• Fuming sulfuric acid ($SO<em>3$ in $H</em>2SO_4$) is also used.
• Sulfonic acids are strong acids because their conjugate base is particularly stable due to the delocalization of the negative charge over three oxygens.
• Sulfonation of benzene is reversible. The sulfonic acid group can be used to "block" the para-position, forcing the next substituent to add to the ortho-position.

EAS Reaction Summary

• Lists reagents and products for bromination, chlorination, nitration, sulfonation, Friedel-Crafts alkylation, and Friedel-Crafts acylation.
• Also lists reagents for side chain reactions such as benzylic bromination, oxidation, and reduction.

Forming a Carbon-Carbon Bond to Benzene

• Coupling reactions involving organometallic reagents can form new carbon-carbon bonds to the $sp^2$ carbon atoms of benzene.

Friedel-Crafts Substitutions

• Friedel–Crafts acylation places an acyl group on a benzene ring.
• Friedel–Crafts alkylation places an alkyl group on a benzene ring.
• Friedel-Crafts reactions are the slowest EAS reactions, and do not work if the ring is deactivated (if meta-director is present).

Friedel-Crafts Acylation

• An acyl chloride or an acid anhydride is the source of the acyl group.
• A Lewis acid ($AlCl_3$) is usually required.
• Mechanism involves generation of the acylium ion electrophile.
• More than one equivalent of $AlCl_3$ must be used, and a water work-up step is required to liberate the product from the complex.

Gatterman-Koch Reaction to Form Benzaldehyde

• Benzaldehyde cannot be made by Friedel–Crafts acylation because the needed acyl chloride (formyl chloride) is unstable.
• Formyl chloride is generated in the reaction mixture.

Friedel-Crafts Alkylation

• An alkyl halide is the source of the alkyl group.
• A Lewis acid ($AlCl_3$) is required.

Notes: Friedel–Crafts Alkylation

1. Reaction will not work if the ring is too deactivated.
2. Polyalkylations can occur because the alkylated benzene is more reactive than benzene itself. A large excess of benzene starting material is needed to avoid multiple alkylations.
3. The electrophile is a carbocation and prone to rearrangements.
4. Aniline and N-substituted anilines do not undergo either type of Friedel-Crafts reaction because the amine complexes with the Lewis acid catalyst.

Alkylation by Acylation-Reduction

1. Add the correct number of carbons with a Friedel–Crafts acylation reaction.
2. Reduce the carbonyl group to a methylene group.

Wolff-Kishner Reduction Converts Carbonyl of Ketone to Methylene Group

• Will reduce all ketones, not just aromatic ketones.
• Occurs under strongly basic conditions.
• Other reactions that will reduce ketone to methylene: Catalytic hydrogenation and reduction of a thioacetal with Raney Ni.

Reactions of Benzene Side Chains- Benzylic Bromination

• NBS (N-bromosuccinimide) is used to introduce a benzylic bromine, which allows for substitution and elimination reactions.

Reactions of Benzene Side Chains- Oxidation

• Oxidation occurs only if there is a benzylic hydrogen. Common oxidizing agents include $KMnO_4$.

Additional Considerations- Aniline Protection

• Aniline cannot undergo Friedel-Crafts reactions or nitration reactions ($-NH_2$ is easily oxidized, and nitric acid and aniline can be an explosive combination).
• Conversion to the amide protects the aniline group.

Aromatic Synthesis

• Things to consider: directing effects, reaction restrictions.
• The directing effects of both substituents must be considered in deciding where the third group will add. Addition between two substituents is a minor product because of steric hindrance.
• The effect of strongly activating substituents will dominate over weakly activating or deactivating groups. If the two substituents have similar activating properties, a mixture of products will be obtained.

Synthesizing Substituted Benzenes Using Arenediazonium Salts

• Certain nucleophiles can substitute for the diazonium group. Arenediazonium salts are synthesized at 0 °C and used immediately.
• Sandmeyer Reactions (Reactions of Arenediazonium Ions with Cu(I) Salts)
  • Allows a halogen or nitrile group to be placed at a specific location on the benzene ring.
  • Recall that nitriles and be reduced to amines, or hydrolyzed to carboxylic acids.
• Aryl Fluorides and Alkyl Iodides Can Be Made from Arenediazonium Salts via Schiemann reaction with $HBF_4$ or reaction with $KI$.
• Phenols Can Be Made from Arenediazonium Salts by warming an acidic aqueous solution of a diazonium salt.
• Replacing a Diazonium Group with a Hydrogen uses $H<em>3PO</em>2$.

Azobenzenes

• The arenediazonium ion is an electrophile and can react with highly activated benzene rings to form an azobenzene.
• The $N=N$ linkage is called an azo linkage. Para product is major product.
• The extended conjugation in azobenzenes causes them to absorb visible light, making them useful as dyes.

Nucleophilic Aromatic Substitution (SNAr)

• Aryl halides do not undergo $S_N2$ reactions because the nucleophile is repelled by the π electron cloud.
• If the aryl halide has one or more strongly electron-withdrawing groups (ortho or para), an $S_NAr$ reaction can take place.
• The two-step mechanism involves addition (slow) followed by elimination (fast).
• Electron-withdrawing substituents at the ortho and para positions stabilize the Meisenheimer complex intermediate.
• Requirements:
  1. Aryl halide with EWG ortho and/or para.
  2. Incoming group should be a stronger base than the leaving group (this is why we can replace $F^-$ in this substitution).

Elimination-Addition Reactions: Benzyne

• With a very strong base ($NaNH_2$) or forceful conditions (NaOH, high temperature), aryl halides can undergo a different type of substitution reaction.
• Two-step mechanism: elimination to form benzyne, followed by addition of a nucleophile to the benzyne.