EAS:Retrosynthesis: Videos & Practice Problems

Proposing aromatic synthesis involves transforming benzene or its derivatives into more complex molecules using knowledge of substituent effects. For instance, converting acetophenone to a target molecule requires understanding the roles of ortho- and para-directors versus meta-directors. Key transformations include nitration to introduce a nitro group and subsequent conversion of a ketone to a benzoic acid. Mastery of these concepts is essential for effective organic synthesis, emphasizing the importance of sequence groups and regioselectivity in achieving desired products.

Aromatic synthesis starting with benzene/benzene derivatives

In the context of aromatic synthesis, transforming benzene or its derivatives into more complex molecules requires a solid understanding of the directing effects of substituents and the sequence of reactions involved. A key concept is the distinction between ortho/para and meta directors, which influence the position of new substituents added to the aromatic ring.

For instance, when starting with acetophenone, which is a ketone derivative of benzene, the goal may be to synthesize a target molecule that includes both a nitro group and a carboxylic acid (benzoic acid). The challenge lies in the fact that acetophenone acts as a meta director due to the electron-withdrawing nature of the carbonyl group. This means that if you were to nitrate acetophenone directly, the nitro group would be added in the meta position rather than the desired para position.

To achieve the desired substitution pattern, one must first convert the ketone into a substituent that can direct further reactions appropriately. This often involves a series of transformations. For example, one strategy could be to first convert the acetophenone into an ortho/para directing group, such as a hydroxyl group, through a reduction or substitution reaction. Once the ortho/para director is in place, nitration can be performed to add the nitro group in the para position.

After introducing the nitro group, the next step would be to convert the ketone into a carboxylic acid. This can typically be achieved through oxidation reactions, which will transform the ketone functional group into a carboxylic acid while maintaining the nitro group in the desired position.

In summary, the synthesis of complex aromatic compounds from simpler precursors like acetophenone involves careful planning of the reaction sequence, taking into account the directing effects of substituents and the transformations required to achieve the target structure. Understanding these principles allows for the strategic addition of functional groups in the desired positions on the aromatic ring.

Synthesize the target molecule

In this multi-step organic synthesis, the transformation of a ketone into nitrobenzoic acid is achieved through a series of carefully chosen reactions. The process begins with the conversion of the ketone into an alkylbenzene, specifically ethylbenzene, using a Clemensen reduction. This reaction employs a zinc-mercury amalgam as the reducing agent, which effectively removes the carbonyl group, resulting in the formation of an ortho-para directing group.

Once ethylbenzene is obtained, the next step involves nitration to introduce a nitro group at the para position. This is accomplished using a mixture of nitric acid (HNO₃) and sulfuric acid (H₂SO₄), which generates the active electrophile necessary for electrophilic aromatic substitution. The ortho-para directing nature of the ethyl group ensures that the nitro group predominantly occupies the para position, leading to the formation of nitroethylbenzene.

The final transformation to benzoic acid can be achieved through oxidation. This step utilizes potassium permanganate (KMnO₄) in the presence of a base and heat, often referred to as "chamino 4." This oxidation process converts the ethyl group into a carboxylic acid, yielding benzoic acid while leaving the nitro group intact. The overall reaction sequence can be summarized as follows:

1. Ketone → Ethylbenzene (Clemensen reduction with zinc-mercury amalgam)
2. Ethylbenzene → Nitroethylbenzene (Nitration with HNO₃ and H₂SO₄)
3. Nitroethylbenzene → Nitrobenzoic acid (Oxidation with KMnO₄ in base and heat)

Thus, the final product of this synthetic route is nitrobenzoic acid, demonstrating the importance of reagent selection and reaction order in organic synthesis. Each step is crucial, as altering the sequence or reagents could lead to different products or failed reactions.

Synthesize the target molecule

In this synthesis process, we focus on achieving specific substitutions on a benzene ring, particularly para and ortho positions. The goal is to introduce a methyl group in the para position and an aniline group in the ortho position. To facilitate this, we must consider the directing effects of substituents on the benzene ring. Generally, ortho substitution is less favored, so we need to strategically block the para position to encourage ortho substitution. This can be accomplished by first introducing a methyl group or another substituent that can act as a blocking agent.

To achieve the desired substitution, we can utilize a meta director that can later be converted into an ortho/para director. A common method to introduce an aniline group is through the reduction of a nitro group, which can be synthesized via nitration of the benzene ring. Therefore, we must first nitrate the benzene after establishing a meta director.

The initial step in this synthesis is a Friedel-Crafts acylation, where we use an acid chloride that contains the appropriate number of carbons for the desired product. For instance, if we want to add a single carbon, the acid chloride should have one carbon, resulting in an aldehyde attached to the para position of the benzene ring. This step is crucial as it sets up the necessary conditions for subsequent reactions.

Once we have the acylated product, we can proceed with nitration using a mixture of nitric acid and sulfuric acid. This introduces a nitro group, which, along with the existing substituents, directs further reactions towards the desired positions on the benzene ring.

After establishing the nitro and acyl groups, we need to perform two reductions: a Clemmensen reduction and a nitro reduction. The Clemmensen reduction, which utilizes zinc and hydrochloric acid, will convert the carbonyl group into a methylene group. Following this, we can reduce the nitro group to an aniline using stannous chloride (SnCl₂) and water, which selectively reduces the nitro group without affecting other functional groups.

This multi-step synthesis highlights the importance of understanding the directing effects of substituents and the sequence of reactions in organic chemistry. By carefully planning each step, we can achieve the desired final product through a series of strategic transformations.

Provide the reaction for each of the following reaction steps

In organic chemistry, transforming benzene into ethylbenzene involves an alkylation reaction, where a two-carbon chain is added without rearrangements. This process typically utilizes an alkyl group connected to bromine in the presence of a Lewis acid catalyst, such as aluminum chloride. The formation of a primary carbocation occurs, which remains stable without rearrangement.

Next, to introduce a bromine (Br) group to the ethylbenzene, the reaction can proceed via either N-bromosuccinimide (NBS) or bromine (Br₂) under UV light, targeting the benzylic carbon, which is directly attached to the benzene ring.

For the conversion of ethylbenzene to a carboxylic acid, a strong oxidizer like potassium permanganate (KMnO₄) in acidic conditions (H⁺) is employed. This side-chain oxidation is effective when the benzylic carbon has at least one hydrogen atom, resulting in the formation of a carboxylic acid.

To replace the bromine with a hydroxyl group (OH), sodium hydroxide (NaOH) can be used. To favor an SN2 substitution over an E2 elimination, it is crucial to conduct the reaction at a temperature lower than room temperature, which promotes the nucleophilic substitution mechanism.

Converting an alcohol to a carboxylic acid can be achieved through a two-step process. Initially, concentrated sulfuric acid (H₂SO₄) and heat are applied to dehydrate the alcohol, forming an alkene. Subsequently, KMnO₄ in acidic conditions oxidizes the alkene, converting it into a carboxylic acid, particularly if the alkene has a hydrogen atom on one of the carbons involved in the double bond.

To transform an alkyl halide into an alkene, an elimination reaction (E2) can be performed using a strong base like tert-butoxide. This reaction involves the removal of a beta hydrogen from the beta carbon adjacent to the alpha carbon bearing the halogen, resulting in the formation of a double bond.

In the case of adding H and Br across a double bond, the reaction can proceed via anti-Markovnikov addition by using peroxides. For instance, when HBr is reacted in the presence of a peroxide, the bromine atom attaches to the more substituted carbon, while the hydrogen atom attaches to the less substituted carbon. This principle also applies when converting an alkene to an alcohol through hydroboration-oxidation, where borane (BH₃) in tetrahydrofuran (THF) followed by hydrogen peroxide (H₂O₂) and hydroxide (OH^-) results in the addition of an OH group to the less substituted carbon, again demonstrating anti-Markovnikov behavior.

Understanding these mechanisms and the conditions that favor either Markovnikov or anti-Markovnikov addition is crucial for predicting the products of organic reactions.

Beginning from Benzene, synthesize the following compound.

When synthesizing a compound starting from benzene, it is crucial to identify the directing effects of substituents. In this case, we have an alkyl group and a halogen, both of which are ortho-para directors. However, the challenge arises because these groups are positioned meta to each other in the final compound. This suggests that one of the groups must have been a meta director initially, which was later transformed into an ortho-para director.

To achieve the desired synthesis, we first recognize that the alkyl group must have acted as a meta director before bromination occurred. The bromination process introduces the bromine atom at the meta position relative to the original alkyl group. Following this, we need to convert the acyl group into an alkyl group. This transformation can be accomplished through two well-known methods: Clemensen reduction or Wolff-Kishner reduction. Both methods effectively reduce the carbonyl group to a methylene group (–CH₂).

In summary, the synthesis involves a sequence of steps: first, the introduction of a meta-directing acyl group via acylation, followed by bromination to add the bromine at the meta position, and finally, the reduction of the carbonyl to an alkyl group. Understanding the nature of the directing groups and their spatial relationships is essential for successful synthesis from benzene.

Beginning from Benzene, synthesize the following compound. 
1-Phenylethanol

To synthesize 1-phenylethanol starting from benzene, we first need to understand the structure of the target compound. 1-phenylethanol consists of a phenyl group (a benzene ring) attached to a two-carbon chain with a hydroxyl (–OH) group on the first carbon. This means we need to add a carbon chain to benzene that is directly connected to an oxygen atom.

The first step in this synthesis involves an acylation reaction, where we introduce an acyl group to benzene. The acyl group we need is two carbons long, corresponding to the ethanol structure. In this reaction, a carbonyl group (C=O) is formed, resulting in a ketone. The acylation can be achieved using an acyl chloride and a Lewis acid catalyst, such as aluminum chloride (AlCl₃), which facilitates the reaction by forming a complex with the acyl chloride, allowing the carbon chain to attach to the benzene ring.

Once we have the ketone structure, the next step is to reduce this ketone to form the desired secondary alcohol, 1-phenylethanol. For this reduction, we can use reducing agents such as sodium borohydride (NaBH₄) or lithium aluminum hydride (LiAlH₄). Sodium borohydride is a milder reducing agent that selectively reduces aldehydes and ketones, while lithium aluminum hydride is a stronger reducing agent capable of reducing a wider range of carbonyl compounds, including carboxylic acids and esters. Either of these agents will effectively convert the ketone into the corresponding secondary alcohol.

In summary, the synthesis of 1-phenylethanol from benzene involves an initial acylation to introduce a carbonyl group, followed by reduction to convert the ketone into a secondary alcohol. Understanding the similarities between functional groups and the reactions that can be performed on them is crucial for successfully navigating organic synthesis.

Beginning from Benzene, synthesize the following compound.

In organic synthesis, starting from benzene, one can explore various pathways to create a desired compound. The first step involves recognizing that benzene is directly connected to one carbon atom. To add a carbon to benzene, an alkylation reaction can be employed. This can be achieved by using a methyl group (CH₃) connected to a halogen, in the presence of a Lewis acid catalyst. During this process, the halogen (Br) leaves, forming a methyl carbocation that attaches to the benzene ring without rearrangement, resulting in a substituted benzene.

Next, to replace one of the hydrogen atoms on the benzene with a hydroxyl group (OH), one can utilize N-bromosuccinimide (NBS) or bromine (Br₂) under UV light (HV). This step replaces a benzylic hydrogen with bromine, yielding a primary alkyl halide. Since primary alkyl halides favor an SN2 reaction mechanism, the hydroxide ion (OH^-) can attack the carbon bonded to bromine, displacing the bromine and forming the desired alcohol.

Alternatively, acylation can be performed, where an aldehyde is added to the benzene ring. In this case, the chlorine atom leaves and bonds with aluminum, facilitating the introduction of the carbonyl group. The resulting aldehyde can then be reduced to a primary alcohol using reducing agents such as lithium aluminum hydride (LiAlH₄) or sodium borohydride (NaBH₄).

Both pathways—alkylation followed by substitution or acylation followed by reduction—ultimately yield the same product. However, the acylation route is often more efficient due to fewer steps involved. This illustrates that in synthetic organic chemistry, multiple strategies can lead to the same outcome, and understanding the reasoning behind each method is crucial for effective problem-solving.

When approaching synthesis questions, whether in fill-in-the-blank or multiple-choice formats, it is essential to evaluate the proposed steps critically. Ensure that they adhere to established rules and limitations of organic reactions to determine the most viable synthetic route.

Here’s what students ask on this topic:

What is the role of ortho-para directors and meta directors in EAS reactions?

In Electrophilic Aromatic Substitution (EAS) reactions, substituents on the benzene ring influence the position where new groups are added. Ortho-para directors, such as alkyl groups and hydroxyl groups, activate the ring and direct incoming electrophiles to the ortho and para positions relative to themselves. Meta directors, like nitro groups and carbonyl groups, deactivate the ring and direct electrophiles to the meta position. Understanding these directing effects is crucial for planning the sequence of reactions in aromatic synthesis to achieve the desired substitution pattern.

How do you convert a ketone to a benzoic acid in aromatic synthesis?

To convert a ketone to a benzoic acid in aromatic synthesis, you typically use an oxidation reaction. A common reagent for this transformation is potassium permanganate (KMnO₄) under acidic or basic conditions. The reaction proceeds as follows:

$R_{\mathrm{CO}}+{\mathrm{KMnO}}_4\to R_{\mathrm{COOH}}$

This reaction converts the ketone group (R-CO) to a carboxylic acid group (R-COOH), resulting in benzoic acid.

What are sequence groups in aromatic synthesis?

Sequence groups in aromatic synthesis refer to the order in which substituents are introduced to the benzene ring to achieve the desired product. The sequence is crucial because the first substituent affects the reactivity and position of subsequent substituents. For example, if you need a para-substituted product, you might first introduce an ortho-para director before adding the second group. Understanding the directing effects and reactivity of each substituent helps in planning the correct sequence of reactions to synthesize complex aromatic compounds.

How do you introduce a nitro group into a benzene ring?

To introduce a nitro group into a benzene ring, you typically use a nitration reaction. This involves treating benzene with a mixture of concentrated nitric acid (HNO₃) and concentrated sulfuric acid (H₂SO₄). The reaction proceeds as follows:

$C{6}_H+{\mathrm{HNO}}_3+H_2\to C_6{\mathrm{NO}}_2+H_2$

This reaction introduces a nitro group (NO₂) into the benzene ring, typically at the meta position if the ring is already substituted with a meta-directing group.

What is the importance of regioselectivity in aromatic synthesis?

Regioselectivity in aromatic synthesis is crucial because it determines the position at which new substituents are added to the benzene ring. This is important for achieving the desired structure and properties of the final product. Regioselectivity is influenced by the nature of existing substituents, which can be ortho-para directors or meta directors. Proper understanding and control of regioselectivity allow chemists to design efficient synthetic routes and avoid unwanted by-products, making the synthesis process more predictable and efficient.