Chapter 18 - Aromatic Substitution Reactions Flashcards
What are food colorings such as Red #40 and Yellow #6?
Compounds that are often aromatic and synthesized using electrophilic aromatic substitution reactions.
What type of reactions will the chapter focus on?
Electrophilic aromatic substitution reactions.
What is the significance of research on aromatic compounds in the early twentieth century?
It made significant contributions to the field of medicine.
What is the stability of benzene compared to alkenes?
Benzene is inert under the same conditions that cause alkenes to undergo addition reactions.
What role does iron play in the bromination of benzene?
Iron enhances the electrophilicity of bromine by forming iron tribromide (FeBr3).
What is the mechanism of electrophilic aromatic substitution?
- The aromatic ring functions as a nucleophile and attacks an electrophile to form a sigma complex. 2. The sigma complex is deprotonated to restore aromaticity.
What is a sigma complex?
A positively charged intermediate formed during electrophilic aromatic substitution.
What is the catalyst in the bromination of benzene?
Iron tribromide (FeBr3).
What is the difference between substitution and addition reactions in terms of energy?
Substitution is exergonic (downhill in energy), while addition is endergonic (uphill in energy).
What is the electrophilic agent in the chlorination of benzene?
A complex formed between chlorine (Cl2) and aluminum trichloride (AlCl3).
Fill in the blank: The reaction of benzene with fuming sulfuric acid results in the formation of ______.
benzene-sulfonic acid.
What makes sulfur trioxide (SO3) a powerful electrophile?
The sulfur atom is a site of low electron density.
What are azole antifungal agents?
A broad class of five-membered rings containing a nitrogen atom and at least one other heteroatom.
What is the significance of halogen positions in drug design?
Halogens positioned in the ortho and para positions are more easily halogenated and critical for drug activity.
What is the general mechanism for electrophilic aromatic substitution?
Nucleophilic attack followed by proton transfer.
True or False: Fluorination and iodination of aromatic rings are common.
False.
What happens during the sulfonation of benzene?
Benzene reacts with sulfur trioxide (SO3) to form a sigma complex and then benzene-sulfonic acid.
What is the role of the Lewis acid in electrophilic aromatic substitution?
It acts as a catalyst and is not consumed in the reaction.
What is the first step in the sulfonation mechanism?
The aromatic ring functions as a nucleophile, forming a sigma complex.
What is the result of the reaction between benzene and SO3?
The reaction is highly sensitive to the concentrations of the reagents and is reversible.
This reversibility will be re-examined later and utilized in the synthesis of polysubstituted aromatic compounds.
What process allows two aromatic rings to be joined by an azo group?
Azo coupling
This process involves an electrophilic aromatic substitution reaction.
What are azo dyes used for?
Azo dyes are used in paints, cosmetics, and food.
They represent more than 50% of the synthetic dye market.
What is the significance of sulfonic acid groups in azo compounds?
They are necessary for deprotonation to give anions, making the compounds water soluble.
What happens when benzene is treated with a mixture of nitric acid and sulfuric acid?
A nitration reaction occurs, forming nitrobenzene.
What is the electrophile believed to be in the nitration of benzene?
Nitronium ion (NO2+).
What is the mechanism of nitration of benzene?
It involves the formation of a sigma complex and subsequent deprotonation to restore aromaticity.
What is prontosil and its historical significance?
Prontosil is the first drug systematically used for treating bacterial infections, discovered for its antibacterial properties.
What compound is produced from the metabolism of prontosil?
Sulfanilamide.
What are prodrugs?
Pharmacologically inactive compounds converted by the body into active compounds.
What is the purpose of L-dopa in treating Parkinson’s disease?
L-dopa is a prodrug that is converted to dopamine in the brain.
What is the Friedel–Crafts alkylation reaction?
It allows the installation of an alkyl group on an aromatic ring using a Lewis acid.
What type of alkyl halides are readily converted into carbocations during Friedel–Crafts alkylation?
Secondary and tertiary alkyl halides.
What happens when primary alkyl halides are used in Friedel–Crafts alkylation?
They cannot form stable carbocations; however, a complex with AlCl3 can react.
Fill in the blank: The electrophilic agent in Friedel–Crafts alkylation with ethyl chloride is presumed to be a complex between ethyl chloride and _______.
AlCl3.
What is a common issue with primary alkyl halides in Friedel–Crafts reactions?
Their complexes with AlCl3 readily undergo rearrangement to form secondary or tertiary carbocations.
What is the primary limitation of Friedel–Crafts alkylation using primary alkyl halides?
They can undergo rearrangement to form secondary or tertiary carbocations, leading to a mixture of products.
For example, 1-chlorobutane can form a secondary carbocation via a hydride shift.
Under what conditions is a Friedel–Crafts alkylation considered efficient?
When the substrate cannot undergo rearrangement.
What type of hybridization must the carbon atom connected to the halogen have in Friedel–Crafts alkylation?
sp3 hybridized.
What is the effect of installing an alkyl group on the aromatic ring during Friedel–Crafts alkylation?
It activates the ring toward further alkylation, leading to polyalkylations.
What must be assumed about reaction conditions for Friedel–Crafts alkylation in this text?
They favor monoalkylation.
Which functional groups are incompatible with Friedel–Crafts reactions?
Nitro groups and others that deactivate the aromatic ring.
What is a Friedel–Crafts acylation?
A process that installs an acyl group on an aromatic ring using acyl chlorides and a Lewis acid.
What is an acylium ion?
A cationic species formed during Friedel–Crafts acylation.
Why do acylium ions not undergo rearrangement?
They are resonance stabilized, and rearrangement would lose the stabilization associated with full octets.
What is the product of a Friedel–Crafts acylation?
An aryl ketone.
What is the Clemmensen reduction used for in Friedel–Crafts acylation?
To reduce an aryl ketone to an alkyl group.
What is the significance of the acylation process compared to direct alkylation?
It avoids carbocation rearrangements due to the stability of acylium ions.
What is the role of electron-donating groups like methyl in electrophilic aromatic substitution?
They activate the aromatic ring and stabilize the positively charged sigma complex.
How much faster does toluene undergo nitration compared to benzene?
Approximately 25 times faster.
What are the major products formed during the nitration of toluene?
Ortho and para nitrotoluene.
Which product is formed in the least amount during toluene nitration?
Meta nitrotoluene.
Why does the ortho product predominate over the para product in the nitration of toluene?
There are two ortho positions and only one para position, making it statistically favored.
What is the effect of the methoxy group on the activation of an aromatic ring?
It is a more powerful activator than a methyl group, donating electron density via resonance.
How does the presence of a methoxy group affect the nitration rate of anisole compared to toluene?
Anisole undergoes nitration 400 times faster than toluene.
What phenomenon occurs when resonance and induction effects compete in substituents like methoxy?
Resonance generally dominates and overshadows inductive effects.
What is the effect of activating groups on an aromatic ring?
Activating groups stabilize the positively charged sigma complex and lower the energy of activation for its formation.
How does bromination of anisole demonstrate the ortho-para directing effect?
All three positions undergo bromination, with a preference for ortho and para positions.
What are the product distribution percentages for the nitration of anisole?
ortho-Nitroanisole (31%), meta-Nitroanisole (2%), para-Nitroanisole (67%)
What stabilizes the sigma complex obtained from ortho and para attacks in the nitration of anisole?
An additional resonance structure stabilizes the sigma complexes.
Which sigma complex is higher in energy during the nitration of anisole?
The sigma complex obtained from meta attack.
What factor contributes to the preference of the para product over the ortho product in nitration of anisole?
Steric consideration; the ortho sigma complex has greater steric interaction.
What is the general rule for the directing effects of activating groups?
All activators are ortho-para directors.
What is the effect of a nitro group on an aromatic ring?
It deactivates the ring toward electrophilic aromatic substitution.
Why does the nitro group deactivate the aromatic ring?
It is an inductively electron-withdrawing group and destabilizes the positively charged sigma complex.
How much less reactive is nitrobenzene compared to benzene toward nitration?
100,000 times less reactive.
What is the predominant product distribution for the nitration of nitrobenzene?
meta (93%), ortho (6%), para (1%)
Why does the meta product predominate in the nitration of nitrobenzene?
The sigma complex from meta attack is lower in energy compared to ortho and para attacks.
What is a notable exception to the general rule regarding the directing effects of substituents?
Halogens are ortho-para directors despite being deactivators.
Why are halogens considered weak deactivators?
Inductive effects dominate, withdrawing electron density from the ring.
What type of activators are characterized by a lone pair immediately adjacent to the aromatic ring?
Strong activators.
What defines a moderate activator?
A lone pair that is already delocalized outside of the ring.
What is the activation effect of alkyl groups on an aromatic ring?
Weak activators due to hyperconjugation.
What are examples of moderate deactivators?
Groups that exhibit a π bond to an electronegative atom, conjugated with the aromatic ring.
Fill in the blank: Activators are ______ directors.
ortho-para
Fill in the blank: Deactivators (except halogens) are ______ directors.
meta
What effect do halogens (Cl, Br, I) have on a benzene ring?
They deactivate the benzene ring
Halogens are considered weak deactivators due to their electronic effects.
What determines the electronic effects of halogens?
The competition between resonance and induction
Induction emerges as the dominant effect.
What are moderate deactivators?
Groups that exhibit a π bond to an electronegative atom, conjugated with the aromatic ring
Examples include groups like -O, -OH, -NH2.
What is the effect of strong deactivators?
They withdraw electron density from the ring via resonance or inductive effects
Examples include -NO2 and -CX3.
What is the unique position of halogens in terms of directing effects?
They are ortho-para directors, unlike typical deactivators that are meta directors.
What is the effect of a nitro group on a benzene ring?
It is a strong deactivator due to resonance and induction.
Fill in the blank: The common substituents that are strong deactivators include ______.
NO2, CX3
CX3 refers to groups with three electron-withdrawing halogens.
What is the general rule for the directing effects of activators?
Activators are ortho-para directors.
What are the expected directing effects of a strong activator?
Directs electrophilic substitution to the ortho and para positions.
What is the expected effect of a weak activator in the presence of a strong deactivator?
The strong deactivator will dominate the directing effects.
For monosubstituted aromatic rings, which product generally dominates?
The para product
This is due to steric considerations.
What is the impact of steric effects in 1,4-disubstituted aromatic rings?
Sterics favor substitution at the less hindered position.
What is the most sterically hindered position in a 1,3-disubstituted aromatic ring?
The position between the two substituents.
How can blocking groups be used in electrophilic aromatic substitution?
They can direct reactions to desired positions by occupying others.
What is one common method for introducing a blocking group?
Sulfonation
This process is reversible and allows for later removal.
What is the main purpose of a blocking group in synthetic reactions?
To direct a substitution reaction toward a specific position on the aromatic ring.
Fill in the blank: Steric hindrance raises the energy of activation (Ea) for attack at the ______ position.
ortho
This results in the para product being favored.
What happens when two substituents on a ring reinforce each other’s directing effects?
They direct substitution to the same location.
What is the expected outcome when a weak activator is present with a strong deactivator?
The strong deactivator controls the directing effects.
What is a common characteristic of ortho-para directors?
They enhance the reactivity of the aromatic ring.
In the presence of multiple substituents, what should be identified first?
The most powerful activator.
What is the role of steric effects in determining product distribution?
They influence which positions are more likely to undergo substitution.
What should be done to predict the site of an electrophilic aromatic substitution reaction?
Identify the nature of each group and their directing effects.
What are the reactive centers in a benzene ring with a methoxy group?
The unoccupied ortho and para positions.
Which position is more sterically hindered in a benzene ring with a methoxy group?
The ortho position.
What is expected to happen during a substitution reaction at the para position of a methoxy group?
A substitution reaction will take place.
What is required to install a group in the ortho position of a benzene ring?
A blocking group.
What contaminant can taint the flavor of beer?
Ortho-bromophenol.
What is needed to prepare certified beer flavor standards?
Pure samples of ortho-bromophenol.
What is the starting material for synthesizing ortho-bromophenol?
Phenol.
What is the first step in proposing a synthesis for a monosubstituted benzene ring?
Identify reagents that can be used to install the desired group.
How many different groups can be installed on an aromatic ring according to the text?
Ten different groups.
What type of reactions are used to install functional groups on a benzene ring?
Electrophilic aromatic substitution reactions.
What is the result of treating benzene with fuming sulfuric acid?
Formation of sulfonic acid.
What is the effect of a nitro group on directing effects?
It is a meta director.
What is a Friedel–Crafts reaction?
A reaction that installs alkyl or acyl groups on aromatic rings.
What limitations exist for performing Friedel–Crafts reactions?
Cannot occur on rings that are moderately or strongly deactivated.
What happens to the amino group during nitration?
It can be oxidized, leading to undesirable products.
What is a protecting group?
A group used to mask a reactive functional group during a reaction.
What is the main advantage of using a protecting group during nitration?
It prevents oxidation or protonation of the amino group.
What is the order of events for synthesizing a compound with an ortho-para directing group and a meta directing group?
Nitration, followed by chlorination, and then reduction.
What are the two possible routes for installing groups on a disubstituted benzene ring?
Using either a nitro group or an acyl group as a meta director.
Fill in the blank: Nitration cannot be performed on a ring that contains an _______.
[amino group].
What are the necessary steps to synthesize 2-nitroaniline from benzene?
Nitration followed by reduction.
What is the role of retrosynthetic analysis in synthesizing polysubstituted benzene rings?
It helps determine the last step of the synthesis.
What is a key consideration when proposing a synthesis for a polysubstituted benzene ring?
The order of installation of substituents based on their directing effects.
What is the effect of a bromine substituent on directing effects?
It is ortho-para directing.
What is the result of installing both a nitro group and a bromine group on a benzene ring?
The outcome depends on the order of installation to achieve the desired regioselectivity.
What does a retrosynthetic arrow indicate?
It indicates that the first compound might be made from the second compound.
What is the last step in the synthesis discussed?
Bromination reaction.
What is the challenge with bromination in the discussed synthesis?
The Br group would be installed meta to both the nitro and acyl groups, which is not the desired location.
What is the proposed last step of the synthesis after bromination?
Installation of the nitro group.
What is the desired outcome when installing the nitro group?
Both the Br group and the acyl group will direct the incoming nitro group to the desired location.
What is a Friedel–Crafts acylation?
A reaction where an acyl group is introduced to an aromatic ring.
What is the effect of the nitro group on the Friedel–Crafts acylation?
The ring is strongly deactivated by the presence of a nitro group, making the acylation reaction unattainable.
What is the significance of the order of group installation in synthesis?
It affects the regiochemical outcome of the reaction.
What is the role of the Br group in the discussed synthesis?
Bromine is an ortho-para director with a preference for para position.
What is the conclusion about the sequence of events in the proposed synthesis?
Bromination should be carried out first, followed by acylation.
What are the two main criteria for nucleophilic aromatic substitution?
- The ring must contain a powerful electron-withdrawing group (e.g., nitro group)
- The ring must contain a leaving group (usually a halide).
What is the third criterion for nucleophilic aromatic substitution?
The leaving group must be either ortho or para to the electron-withdrawing group.
What is the Meisenheimer complex?
A resonance-stabilized intermediate formed during nucleophilic aromatic substitution.
What is the difference between the Meisenheimer complex and a sigma complex?
The Meisenheimer complex has a negative charge, while the sigma complex has a positive charge.
What happens to the negative charge in the Meisenheimer complex?
It can reside on the nitro group, stabilizing the complex.
Why is the presence of the nitro group crucial in nucleophilic aromatic substitution?
It acts as a temporary reservoir for electron density.
What does the elimination-addition mechanism involve?
Formation of an unstable benzyne intermediate followed by nucleophilic attack.
What is benzyne?
A high-energy intermediate formed during elimination-addition reactions.
What experimental evidence supports the existence of benzyne?
The formation of Diels-Alder cycloadducts when furan is added to the reaction mixture.
What type of orbitals overlap in the benzyne intermediate?
sp2 orbitals.
What is the expected outcome when both R groups are nitro groups in nucleophilic aromatic substitution?
The reaction readily occurs at lower temperatures.
What happens when a fourth nitro group is added to the ring in nucleophilic aromatic substitution?
The temperature requirement is expected to be lowered further.
What is the main distinguishing feature of the three mechanisms for aromatic substitution?
The type of intermediate formed: Meisenheimer complex for nucleophilic substitution, sigma complex for electrophilic substitution, and benzyne for elimination-addition.
What is the intermediate formed in electrophilic aromatic substitution?
Sigma complex
What is the intermediate formed in nucleophilic aromatic substitution?
Meisenheimer complex
What is the intermediate formed in elimination-addition aromatic substitution?
Benzyne intermediate
In electrophilic aromatic substitution, what does the incoming substituent replace?
A proton
In nucleophilic aromatic substitution, what is expelled as a leaving group?
A negatively charged leaving group (such as a halide ion)
How do electron-withdrawing groups affect the reactivity in electrophilic aromatic substitution?
They deactivate the ring toward attack
What is required for nucleophilic aromatic substitution to occur?
An electron-withdrawing group
What is the first step in determining the mechanism of an aromatic substitution reaction?
Determine whether the reagents are electrophilic or nucleophilic
What must be satisfied for a nucleophilic aromatic substitution to be likely?
All three criteria must be met: a leaving group, an electron-withdrawing group, and the electron-withdrawing group must be ortho to the leaving group
What is the result of treating 2-ethyl-5-chlorotoluene with sodium hydroxide followed by H3O+?
Three constitutional isomers with the molecular formula C9H12O
What does Friedel-Crafts alkylation enable?
The installation of an alkyl group on an aromatic ring
What is generated when an alkyl halide is treated with a Lewis acid in Friedel-Crafts alkylation?
A carbocation
Why are carbocation rearrangements avoided in Friedel-Crafts alkylation?
When carbocation rearrangements cannot occur
What does Friedel-Crafts acylation enable?
The installation of an acyl group on an aromatic ring
What is a characteristic of the acylium ion generated in Friedel-Crafts acylation?
It is resonance stabilized and not susceptible to carbocation rearrangements
What happens when a Friedel-Crafts acylation is followed by a Clemensen reduction?
The net result is the installation of an alkyl group
How does a nitro group affect an aromatic ring?
It deactivates the ring and is a meta director
What is the role of a methyl group in aromatic substitution?
It activates the aromatic ring and is an ortho-para director
What is a unique characteristic of halogens in aromatic substitution?
They are deactivators but are ortho-para directors
What must be present for nucleophilic aromatic substitution to occur?
A powerful electron-withdrawing group, a leaving group, and the leaving group must be ortho or para to the electron-withdrawing group
What is the mechanism of nucleophilic aromatic substitution?
Formation of a Meisenheimer complex followed by loss of a leaving group
What defines an elimination-addition reaction in aromatic substitution?
It occurs via a benzyne intermediate
What distinguishes the three mechanisms for aromatic substitution?
The intermediate, the leaving group, and substituent effects
