Reactions With Substituent Effects

Electrophilic Aromatic Substitutions

In an EAS reaction, an electrophile reacts with an aromatic ring and substitutes it for one hydrogen.

General Mechanism

There are five types of EAS reactions

1. Halogenation2. Nitration3. Sulfonation4. Friedel-Crafts Alkylation5. Friedel-Crafts Acylation

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1. HalogenationReagents are X2 and FeX3 (catalyst) where X is a halogen (generally Cl or Br)

a. Generation of electrophile in which the FeX3 induces a dipole causing one atom to become partially positive (electrophile) and one partially negative. The partially positive will react with the benzene ring, while the partially negative will join with the catalyst to form a new ion.

b. Reaction of electrophile with benzene

2. NitrationReagents are HNO3 and H2SO4 with the electrophile being NO2

+

a. Generation of electrophile in which the HNO3 acts like a base and accepts a proton from sulfuric acid to generate the conjugate acid of nitric acid which then releases a molecule of H2O to generate the electrophile NO2

+

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b. Reaction of electrophile with benzene

3. Sulfonation1 Reagents are SO3 and H2SO4 (fuming sulfuric acid) with the electrophile being HSO3

+

a. Generation of electrophile in which the SO3 acts like a base and accepts a proton from H2SO4 to generate a conjugate acid, which has a formal charge on the oxygen. The conjugate acid then rearranges in to give sulfur the formal charge and therefore forming the electrophile for the reaction

b. Reaction of electrophile with benzene

1 Reaction can be reversible depending on the [fuming sulfuric acid]. High [FSA] forward sulfonation producing benzene sulfonic acid. Dilute [FSA] reverse desulfonation reaction to produce benzene

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4. Friedel-Crafts AlkylationReagents vary, as there are three ways to produce the electrophile—a carbocation; the overall reaction remains the same. Because this requires the formation of carbocation, rearrangements are always possible.

1. R-X and AlX3 where X is either Br or Cl a. Generation of electrophile using an alkyl halide

Example

Alkyl halide may be 1°, 2°, or 3° and so there are varying degrees of stability (3 > 2 > 1 > CH3) and therefore with 1 and 2 alkyl halides, rearrangements (1,2 hydride shift or 1,2 methyl shift) may occur

- May occur of a more stable C(+) can be generated from original- Sometimes when an equally stable C(+) can be generated - No arrangement occur if C(+) is less stable than original

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Example when rearrangement may occur

Example when rearrangement is less likely to occur

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2. R-OH and H+ Acid (phosphoric, sulfuric, acetic) whose conjugate base are not strong Nu: because they are able to delocalize their charge and so not as strong to compete with the carbocation. a. Generation of electrophile using an alcohol in which the oxygen of the alcohol acts as a base and accepts a proton from an acid, forming an intermediate, which then looses a water molecule

3. Alkene, H+

a. Generation of electrophile using an alkene in which the alkene donates its pi electrons to an acid in order to generate a carbocation

- Aromatic (aryl) halides and vinylic halides do not react because the carbocations are too high in energy (too stable) to form and react

- Doesn’t succeed on aromatic rings that are substituted either by a strongly electron-withdrawing group (such as carbonyl C=O) or by an amino group (-NH2, NHR, -NR2)

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- It is often difficult to stop the reaction after a single substitution (creates an activator group) and therefore polyalkylation usually occurs—as happened in the laboratory

5. Friedel-Crafts Acylation Reagents are an acyl halide (R-C=O-X) and AlX3 in which the electrophile is R-C=O+

a. Generation of the electrophile in which the AlX3 induces a dipole, causing the halide of the acyl halide to become partially negative and the acyl group to become positive. The halide will the aluminum halide catalyst to form a new ion (AlX4

+) and the positive acyl group will react with the benzene ring.

b. Reaction with the benzene ring

Example

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Electrophilic Addition of Styrenes

Electrophilic Addition Reactions—Alkenes or alkynes π bond and electrophile (π bond of benzene ring do not react). The reaction of Styrenes include the reaction of the vinyl group of the benzene ring. Run under kinetic conditions, like all electrophilic addition reactants

Reagents: H3O+ (H++ H2O), HX, or X2

General Mechanism

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Substituent Effects of Styrenes

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Base-Catalyzed Hydrolysis of Benzoate Esters

Can occur through either a reaction with

Reagents: NaOH (OH-), H2OProduces a carboxylic acid and an alcohol

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Substituent Effects

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Reactions Without Substituent Effects

Nucleophilic Aromatic Substitution

Benzene ring must have two substituents with characteristics:1. One must be an EWG by resonance2. One must be a leaving group (usually halogen) that is ortho- or para- to the EWG by

resonance

Reagent: CH3O- Na+ (nucleophile)

General Mechanism

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Benzyne ReactionTwo criteria associated with Benzene ring

1. Must have a leaving group (usually a fluorine or other halogen)2. Hydrogen on carbon ortho- to carbon with leaving group

Reagents: Strong base and Electrophilic Reagent

Strong Base Electrophilic ReagentNaNH2 (Sodimamide) NH2

- HBr (hydrohalous acid)NaOH (OH-) X2

Lithium di-isopropyl amide (LDA)

H3O+

Sodium t-butoxide (other alkoxide that are sterically hindered produced by alcohols)

NaH (Sodium hydride) H--

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General Mechanism

Example

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Three possible products (ortho, meta, and para) but meta is major due to it being produced two times in the reaction

Oxidation of Substituents on Benzene Rings

Oxidation refers to specific atoms (C,N,S) within molecule- Decrease in the bonds to H and/or increase bonds to O

Two types of oxidations of benzylic atoms1. KMnO4

2. NBS, hv

KMnO4 Oxidation is the oxidation of benzylic atom that requires to presence of at least one H atom

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Examples

It is a strong oxidizer but does not oxidize 𝛑 bonds of benzene rings but will oxidize alkene/alkynes to produce diols

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NBS Oxidation is the oxidation of benzylic/allylic carbons with at least one H atom. It is a radical reaction that produces benzylic/allylic bromide

Radical Reaction has three steps1. Initiation-formation of 1st radical species of a reaction2. Propagation-reaction of a radical with a nonradical/neutral species to produce a nonracial

and radical; This is the rate determining step3. Termination-reaction of two radicals to produce a neutral species

Mechanism

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Example

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Reaction Energy Diagram

Stability of carbocation radicals1° allylic ~ 1° benzylic2° allylic > 2° benzylic BUTThere is no difference between the 1°, 2°, or 3° end molecule result

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Kinetic Reaction (under kinetic conditions)Major Product—forms the fastest—derived from the most stable reaction intermediate formed during the rate determining step (low ∆G≠)Therefore the 2° allylic bromide is the major kinetic product (the most stable reaction intermediate)

Thermodynamic Reaction (under thermodynamic conditions)Major Product—most stable product, regardless of stability of the reaction intermediateTherefore, the 1° allylic bromide is the major thermodynamic product because it is a disubstituted alkene

Reduction of Substituents on Benzene Rings

Reduction is the increase in the number of bonds with H and/or decrease in the number of bonds with O

Three types of reduction1. Catalytic Hydrogenation Reagents: H2(g) and heterogeneous catalyst (Pt or Pd)

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2. Clemenson Reduction (Acidic conditions) Reagents: Zn, HCl or Sn, HCl

3. Wolf-Kishner (Basic conditions) Reagents: Hydrozine (H2N-NH2) and KOH

Why three different reagents to accomplish the same conversion?

1. Catalytic hydrogenationa. Reduces benzylic carbonyl and nitro groupsb. Reduces alkenes and alkynes

2. Clemenson Reductiona. Reduces benzylic carbonyl and nitro groupsb. HCl can react with alkenes and alkynes in electrophilic addition

3. Wolf-Kishnera. Reduces benzylic carbonyl and nitro groupsb. KOH can induce hydrolysis (base-catalyzed) of esters

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