Benzylic and Aromatic Reactions of Substituted Benzene | Organic Chemistry 3

The benzylic and aromatic reactions of substituted benzene are studied in this chapter: reactivity of the benzylic position, benzylic oxidation and reduction, reduction of nitrobenzene, nucleophilic aromatic substitutions, elimination-addition via benzyne, reactivity of phenol, preparation and reactivity of diazonium salts.

Reactivity of the Benzylic Position

Benzylic Position:

The benzylic position refers to a carbon atom directly bonded to a benzene ring. Benzylic radicals, cations and anions are stabilized by resonance with the benzene ring.

Consequences:

⇒ relatively easy radical halogenations
⇒ substitution and elimination reactions
⇒ benzylic anion formation: H of the methyl substituent are slightly acidic (pKa = 41)

 

 

Radical halogenation:
 

Mechanism:

Radical process via an initiation step to activate Br2 then propagation steps.

  1. Initiation: homolysis of the Br-Br bond to form Br radicals.


     
  2. Propagation: hydrogen abstraction from the benzylic position to form a benzylic radical that reacts with Br2.


     
  3. Termination: reaction of 2 radicals to form a stable bond.

 

Substitution reactions:
 

Mechanism:

  • SN1 reaction (secondary and tertiary benzylic halides): loss of the leaving group to generate a benzylic carbocation, followed by attack of the nucleophile. The relative ease of the reaction is attributed to the stability of the carbocation intermediate.
  • SN2 reaction (primary benzylic halides): simultaneous attack of the nucleophile and displacement of the leaving group. Primary benzylic halides typically react via an SN2 pathway.

 

Elimination reactions:
 

Mechanism:

  • E1 reaction: loss of the leaving group to generate a benzylic carbocation, followed by loss of a proton H+ to form the π bond.
  • E2 reaction: simultaneous removal of the proton H+ by the base, loss of the leaving group, and formation of the π bond.

The relative ease of the reaction is attributed to the low energy of the transition state due to conjugation between the forming double bond and the aromatic ring.

 

Deprotonation reaction:
 

A strong base as BuLi is needed.

Benzylic Oxidation and Reduction

Benzylic oxidation:
 


Oxidation with chromic acid (Na2Cr2O7) or potassium permanganate (KMnO4) occurs selectively at the benzylic position of the alkylbenzene. The benzylic position must have at least one proton to be oxidized. The product is benzoic acid, regardless of the identity of the alkyl group.


Selective oxidation of a benzylic alcohol:

 

Benzylic reduction:

  • Clemmensen reduction:


Conversion of an aryl ketone to alkylbenzene using zinc and mercury in the presence of a strong acid.

 

  • Wolff-Kishner reduction:


Conversion of an aryl ketone to alkylbenzene using hydrazine (NH2NH2) and a strong base.

The benzylic reductions are useful for introducing an alkyl group to a benzene ring via Friedel-Crafts acylation followed by reduction. This two-step method avoids the overalkylation observed with Friedel-Crafts alkylation.

 

Benzyl ethers reduction:
 


Reduction via palladium-catalyzed hydrogenation to form an alcohol and toluene. Benzyl ethers are a common protecting group for the hydroxy function.

Reduction of Nitrobenzene

Reduction of nitro groups:


This process is particularly useful for adding an amino group to an aromatic ring to form an aniline. A nitro group is easily introduced to a benzene ring by nitration with a strong acid and is readily reduced to an amino group under a variety of conditions.

Nucleophilic Aromatic Substitution

Requirements for a SNAr:

  • The ring must contain a strong electron-withdrawing group (usually a nitro group).
  • The ring must contain a leaving group (usually a halide).
  • The leaving group must be either ortho or para to the electron-withdrawing group.

 

Nucleophilic aromatic substitution (SNAr):
 

Mechanism:

  1. Nucleophilic attack of the aromatic ring to form a Meisenheimer complex.


     
  2. Loss of a leaving group to regenerate the aromatic ring.

 

Meisenheimer complex:

A stabilized, negatively charged intermediate formed during nucleophilic aromatic substitution reactions.
The negative charge is resonance stabilized throughout the ring ⇒ the aromaticity is retained in the Meisenheimer complex explaining its stability.

Elimination-Addition via Benzyne

Elimination-addition:
 

Mechanism:

  1. Deprotonation of aromatic ring.


     
  2.  Loss of the leaving group to form a benzyne intermediate.


     
  3. Nucleophilic attack of the benzyne.


     
  4. Reprotonation of the aromatic ring.

 

Rearrangements can occur ⇒ the nucleophile can be added to one or the other of the carbons of the extra bond in the benzyne intermediate.
 

Properties and Reactivity of Phenol

There is a keto-enol equilibrium with phenol. The enol form is favored by aromaticity
The proton of the hydroxy function is acidic because the corresponding anion is stabilized by resonance


Reactivity of phenol:

  • Electrophilic Aromatic Substitution
  • SN reactions with the phenoxide ion:

Preparation of Diazonium Ions

Diazotization:
 

Mechanism:

Part 1 - Formation of an N-nitrosamine

  1. Formation of a nitrosonium salt from sodium nitrite (NaNO2) and HCl.
  2. Nucleophilic attack of a primary amine on the nitrosonium ion to form an ammonium ion.
  3. Deprotonation of the ammonium ion to form an N-nitrosamine.


     

Part 2 - Loss of H2O to form a diazonium ion

  1. Protonation of the oxygen atom.
  2. Deprotonation of the second proton of the starting amine to form a double bond between the nitrogen atoms.
  3. Protonation of the oxygen atom to form a good leaving group.
  4. Loss of the leaving group, H2O, to form a diazonium ion.


     

 

Stability of diazonium ions:

  • Alkyldiazonium ions:

The resulting alkyldiazonium salt is highly unstable and is too reactive to be isolated ⇒ it can spontaneously release nitrogen gas N2 to form a carbocation, which then reacts in a variety of ways to form a mixture of substitution, elimination, and rearrangement products.
 

 

  • Aryldiazonium ions:

The resulting aryldiazonium salt is stable enough to be isolated ⇒ it does not release nitrogen gas because this would involve the formation of a high-energy aryl cation. Aryldiazonium salt are useful synthetic intermediates.
 


Aryldiazonium ions are stabilized by resonance:
 

Substitution Reactions of Aryldiazonium Salts

General reactivity:

The diazo group of an aryldiazonium ion is a good leaving group and can be easily replaced by many different reagents ⇒ this is a simple procedure for installing a variety of groups on an aromatic ring.
 


 

Sandmeyer reactions:
 


Substitution of the diazo group with a halogen (Cl, Br, and I) or a cyano group using copper salts (CuX) to form an aryl halogen or benzonitrile, respectively.

 

Schiemann reaction:
 


Substitution of the diazo group with a fluorine using fluoroboric acid (HBF4) to form an aryl fluoride.

 

Other substitution reactions:
 


Substitution of the diazo group with a hydroxyl group using water under heating to form a phenol. This process is particularly useful because there are not many other ways to add an OH group to an aromatic ring.


 


Substitution of the diazo group with a hydrogen atom using hypophosphorus acid (H3PO2) to form a benzene. This reaction is useful for removing an amino group on a benzene previously used to manipulate the directing effects of a substituted aromatic ring. The amino group can then be converted to a diazo group which is removed with H3PO2.

Coupling Reactions of Aryldiazonium Salts

Azo coupling:
 

Mechanism:

Electrophilic aromatic substitution reaction to form an azo compound.

  1. Nucleophilic attack of an electron-rich benzene on the aryldiazonium ion to form a resonance-stabilized carbocation (sigma complex).
  2. Loss of a proton H+ to re-form the aromatic moiety into an azo compound.


     

 

The reaction works best with activated rings as nucleophiles, such as phenol or aminobenzene.
Para substitution occurs unless another substituent is already present.

Azo compounds are highly conjugated and therefore exhibit color ⇒ many are synthetic dyes.

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The high reactivity of the benzylic position in substituted benzene compounds is largely due to the stabilization of intermediates by resonance. The benzene ring allows for the delocalization of charge in reactive intermediates such as carbonium ions, radicals, or anions. Moreover, electron-donating groups increase reactivity towards electrophiles, and electron-withdrawing groups enhance reactivity towards nucleophiles.

The benzylic position is susceptible to various reactions, including radical halogenation, substitution, elimination, and deprotonation.

  • In radical halogenation, the benzylic hydrogen atom is abstracted by a halogen radical, leading to the formation of a benzylic radical.
  • Substitution reactions occur depending on the structure of the benzylic halide.
  • Elimination reactions such as E1 and E2 pathways are also feasible, with the aromatic ring providing stabilization to the transition state.
  • Furthermore, deprotonation reactions at the benzylic position require a strong base to form the corresponding benzylic anion.

Common reagents used in benzylic oxidation include chromic acid (CrO3 or Na2Cr2O7), potassium permanganate (KMnO4), and Jones reagent (CrO3-H2SO4). The benzylic position must have at least one proton to be oxidized. The product is benzoic acid, regardless of the identity of the alkyl group.

  1. Clemmensen reduction: This method involves the conversion of an aryl ketone to an alkylbenzene using zinc and mercury in the presence of a strong acid. The mechanism involves the formation of a carbanion intermediate, which then reacts with zinc amalgam to yield the reduced product.

  2. Wolff-Kishner reduction: In this process, an aryl ketone is converted to an alkylbenzene using hydrazine (NH2NH2) and a strong base. The mechanism involves the formation of a hydrazone intermediate, followed by deprotonation and elimination to produce the reduced product.

  3. Benzyl ethers reduction: This reduction occurs via palladium-catalyzed hydrogenation, resulting in the formation of an alcohol and toluene. Benzyl ethers are commonly used as protecting groups for the hydroxy function in organic synthesis.

 

The reduction of nitro groups in nitroaromatic compounds is important in organic chemistry because it facilitates the synthesis of various aromatic amines, such as anilines. Anilines serve as crucial intermediates in organic synthesis, finding applications in the production of pharmaceuticals, dyes, and agrochemicals.

Nucleophilic aromatic substitution (SNAr) is less common than electrophilic aromatic substitution (EAS) in benzene derivatives due to the structure of benzene itself. Benzene has a highly electron-rich π-system which tends to repel nucleophiles, making it difficult for them to approach and react with the ring. Conversely, this same electron-rich system is attractive to electrophiles, facilitating EAS. Additionally, SNAr typically requires more extreme conditions such as strong bases or nucleophiles and high temperatures, which are not necessary for many EAS reactions.

Nucleophilic aromatic substitution (SNAr) in substituted benzene rings typically requires the presence of a strong electron-withdrawing group, such as nitro (-NO2) or cyano (-CN), in the ortho or para position relative to the leaving group. This electron-withdrawing group stabilizes the negative charge in the intermediate Meisenheimer complex. Additionally, a good leaving group, like a halide, is necessary. The reaction is facilitated by high temperatures and the use of strong nucleophiles, often under basic conditions. SNAr is especially favorable in compounds where the aromatic ring is further activated by being part of a heteroaromatic system, like pyridine.

In the elimination-addition mechanism, the benzyne intermediate is formed by the elimination of hydrogen atoms from adjacent carbons on an aromatic ring, often facilitated by a strong base. This intermediate is highly unstable due to the introduction of a triple bond into the usually stable aromatic system, making it very reactive.

Once formed, the benzyne intermediate is open to addition reactions, such as the attack by a nucleophile, which can add across the triple bond to restore aromaticity, completing the substitution process. This mechanism allows for substitution at positions that are not normally reactive in electrophilic aromatic substitution reactions.

Phenol is distinctive due to its acidic hydroxyl group, which can stabilize the transition state during an aromatic substitution reaction. Since the oxygen in the hydroxyl group is electronegative, it withdraws electrons through the resonance effect, activating the ring towards electrophilic aromatic substitution (EAS) at the ortho and para positions. Additionally, the acidic nature of phenol allows it to form phenoxide ions under basic conditions, which further increases its reactivity towards EAS by delocalizing negative charge over the aromatic ring.

Phenol is more reactive than benzene towards electrophilic aromatic substitution because its hydroxyl group donates electron density to the ring through resonance. This makes the ortho and para positions more nucleophilic, favoring reaction with electrophiles. The resonance stabilization of the resulting carbocation intermediate further facilitates the reaction compared to benzene, which lacks this activating effect due to the absence of an electron-donating group.

Diazonium ions play a crucial role in the chemistry of aromatic compounds as intermediates for synthetic transformations. Containing the functional group -N2+, diazonium salts are highly reactive and can participate in substitution reactions where they are replaced by another group, such as a hydroxyl or halogen, to form various substituted aromatic compounds. They are also key in coupling reactions, where they react with electron-rich aromatic compounds, resulting in the formation of azo compounds, which are important dyes and pigments in industry.

Diazonium ions are prepared from aniline through a process called diazotization. The aniline is treated with a nitrosonium salt (generated in situ from sodium nitrite NaNO2 and hydrochloric acid), which leads to the formation of an N-nitrosamine. The protonation of N-nitrosamine followed by the loss of H2O results in the formation of a diazonium ion, which is stabilized by resonance within the aromatic ring, where the amine group (–NH2) of an aniline derivative is replaced by a diazonium group (–N2+). The cold temperature is necessary to maintain the stability of the diazonium ion, as they can decompose into nitrogen gas and a carbocation at higher temperatures.

 

The main types of substitution reactions involving aryldiazonium salts include Sandmeyer reactions, Schiemann reaction, and other substitution reactions: 

  • Sandmeyer reactions involve the substitution of the diazo group with a halogen or a cyano group using copper salts.
  • The Schiemann reaction substitutes the diazo group with a fluorine atom using fluoroboric acid.
  • Other substitution reactions include the substitution of the diazo group with a hydroxyl group using water to form a phenol, and with a hydrogen atom using hypophosphorus acid to regenerate benzene.

A coupling reaction involving aryldiazonium salts is a process where these salts react with electron-rich aromatic compounds or other nucleophiles to form a covalent bond between the aromatic rings, typically resulting in an azo compound (R-N=N-R'). These reactions are highly valuable in synthetic chemistry because they allow the formation of complex aromatic structures with relative ease.