Reactions With Substituent Effects Electrophilic Aromatic Substitutions
In an EAS reaction, an e lectrophile reacts with an aromatic ring and substitutes it for o ne hydrogen. General Mechanism
There are five types of EAS reactions 1. 2. 3. 4. 5.
Halogenation
Nitration Sulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation
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1. Halogenation Reagents are X2 and FeX3 (catalyst) where X is a halogen (generally Cl o r 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 part ially positive will react with the benzene ring, while the partially negative will join with the cata lyst to form a new ion.
b. Reaction b. Reaction of electrophile with benzene
2. Nitration + Reagents are H NO3 and H2SO4 with the electrophile being NO2 a. Generation of electrophile in which the H NO3 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 b. Reaction of electrophile with benzene
3. Sulfonation 1 + Reagents are SO3 and H2SO4 (fuming sulfuric acid) with the electrophile being HSO3 a. Generation of electrophile in which the SO3 acts like like a base and accepts a proton pro ton 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 b. Reaction of electrophile with benzene
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Reaction can be reversible depending on the [fuming sulfuric acid]. High [FSA] forward sulfonation sulfonation producing benzene sulfonic acid. Dilute [FSA] reverse desulfonation reaction reaction to produce benzen e
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Friedel-Crafts Alkylation Reagents vary, as there are three ways to produce the electro phile²a carbocation; the overall reaction remains the same. Because this th is requires the formation of carbocation, rearrangements are always possible. 4.
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 proto n 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
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Aromatic (aryl) halides and vinylic halides do not react because the carbocations are too high in energy (too stable) to form and react
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Doesn¶t succeed on aromatic aro matic rings that are substituted either by a strongly electronwithdrawing group (such as carbonyl C=O) or by an amino group (-NH2, NHR, -NR 2)
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It is often difficult to stop the reaction after a fter a single substitution (creates an activator group) and therefore polyalkylation usually occurs²as happened in the laboratory
5. Friedel-Crafts Acylation + Reagents are an acyl ac yl 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 cata lyst to form a new ion (AlX4 ) and the positive acyl group will react with the benzene benze ne ring.
b. Reaction with the benzene ring
Example
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Electrophilic Addition of Styrenes
Electrophilic Addition Reactions ²Alkenes or alkynes bond and electrophile ( 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-), H2O Produces a carboxylic acid and an alcohol
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Substit uent
Effects
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Reactions Without Substituent Effects Nucleophilic Aromatic Substitution
Benzene ring must have two t wo substituents with characteristics: 1. One must be an EWG by resonance 2. One must be a leaving group (usually halogen) that is ortho- or para para- to the EWG by resonance
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+
Reagent: CH3O Na (nucleophile)
General Mechanism
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Benzyne Reaction Two criteria associated with Benzene ring r ing 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 E lectrophilic Reagent Strong Base NaNH2 (Sodimamide) NH2 NaOH (OH )
Electrophilic Reagent HBr (hydrohalous acid) X2 + H3O
Lithium di-isopropyl amide (LDA)
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 specific atoms ato ms (C,N,S) within molecule - Decrease in the bonds to H and/or increase bonds to O
Two types of oxidations of benzylic atoms 1. K MnO MnO4
2. NBS, hv
ato m that requires to presence of at least one H KMnO4 Oxidation is the oxidation of benzylic atom atom
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Examples
It is a strong oxidizer but does not oxidize alkene/alkynes to produce diols
bonds of benzene rings but will oxidize
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NBS Oxidation is the oxidation of benzylic/allylic carbons with at least o ne H atom. It is a radical reaction that produces benzylic/allylic bromide
Radical Reaction has three steps st 1. Initiation-formation Initiation-formation of o f 1 radical species of a reaction 2. Propagation-reaction of a radical with a nonradical/neutral species to produce a nonracial and radical; This is the rate rat e determining step 3. 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 radicals 1 allylic 1 benzylic 2 allylic > 2 benzylic BUT There is no difference between the t he 1°, 2°, or 3° end molecule result
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Kinetic Reaction (under kinetic conditions) Major Product ²forms the fastest²derived 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 ²most stable product, regardless of stability of the reaction intermediate Therefore, 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 reduction 1. 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- K ishner ishner (Basic conditions) Reagents: Hydrozine (H2 N-NH2) and K OH
Why three different reagents to accomplish acco mplish the same conversion? 1. Catalytic hydrogenation a. Reduces benzylic carbonyl and nitro groups b. Reduces alkenes and alkynes 2. Clemenson Reduction a. Reduces benzylic carbonyl and nitro groups b. HCl can react with alkenes and a lkynes in electrophilic addition 3. Wolf-Kishner a. Reduces benzylic carbonyl and nitro groups b. K OH can induce hydrolysis (base-catalyzed) of esters
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