18.7 Retrosynthesis with Aromatic Compounds | Organic Chemistry
TLDRThe video script focuses on the principles and strategies of retrosynthesis with aromatic compounds, specifically benzene derivatives. It begins by highlighting common patterns and considerations for electrophilic aromatic substitution (EAS) reactions, emphasizing the impact of electron-withdrawing groups on the reactivity of benzene rings. The tutorial then delves into six detailed examples, illustrating the step-by-step process of retrosynthetic analysis to transform simple benzene into various disubstituted benzene structures. Each example explores different directing effects, the importance of reaction sequence, and the use of crossover reactions to achieve desired regiochemistry. The script also touches on techniques like sulfonation to block certain positions and side chain oxidation to introduce functional groups. The instructor provides insights into common pitfalls and how to navigate them, preparing viewers for the complexities of organic synthesis problems. The summary concludes with an invitation to access additional study materials and practice problems for further learning.
Takeaways
- 🚫 Strongly deactivated benzene rings with electron withdrawing groups like nitro, cyano, or sulfonate are not suitable for Friedel-Crafts alkylation or acylation.
- ⚠️ When a carbonyl group is adjacent to a benzene ring, Friedel-Crafts reactions are not possible due to the strong deactivating effect.
- 🔄 Halogens like fluorine, chlorine, bromine, and iodine are weak electron withdrawing groups that allow for Friedel-Crafts reactions on benzene rings.
- 🔑 Ortho-directing groups can be selectively substituted using a sulfonation blocking group, which is reversible with dilute sulfuric acid.
- 🔄 Crossover reactions can change the directing effect of a substituent from ortho-para to meta (or vice versa), offering flexibility in electrophilic aromatic substitution (EAS) reactions.
- ➡️ The order of substitution on benzene rings matters and can be determined by considering the directing effects of substituents and the possibility of crossover reactions.
- 🔍 Retrosynthesis of aromatic compounds involves strategic planning to determine the correct sequence of reactions for adding substituents to a benzene ring.
- 🛠️ Friedel-Crafts alkylation and acylation are common reactions for introducing substituents to benzene rings, but must be considered within the context of other possible reactions and the directing effects of existing substituents.
- 🔬 Side chain oxidation and reduction techniques can be used to convert substituents like alkyl groups to carboxylic acids or amines, respectively, which changes their directing effects in subsequent EAS reactions.
- ⛔ Methyl chloride is often avoided in Friedel-Crafts alkylation due to its low reactivity and potential for side reactions.
- 📚 Understanding the directing effects of different substituents and the conditions under which they change is crucial for successful retrosynthesis of complex aromatic compounds.
Q & A
Why are Friedel-Crafts alkylation and acylation not possible for strongly deactivated benzene rings?
-Friedel-Crafts alkylation and acylation are not possible for strongly deactivated benzene rings because the presence of strong electron-withdrawing groups like nitro, cyano, or sulfonate groups deactivates the ring to such an extent that these electrophilic substitution reactions cannot occur.
What is the minimum requirement for a benzene ring to undergo Friedel-Crafts alkylation?
-The minimum requirement for a benzene ring to undergo Friedel-Crafts alkylation is the presence of a weak electron-withdrawing group such as a halogen (fluorine, chlorine, bromine, or iodine), which slightly deactivates the ring but still allows the reaction to proceed.
How can you ensure selective substitution at the ortho position of an ethyl benzene?
-Selective substitution at the ortho position of an ethyl benzene can be achieved by temporarily blocking the para position using a bulky sulfonate group. This is done by adding fuming sulfuric acid (SO3), which adds the sulfonate group directing subsequent reactions to the ortho position due to its size and steric hindrance.
What is a crossover reaction in the context of the video?
-A crossover reaction, as described in the video, is a sequence of reactions that can convert a meta director into an ortho-para director or vice versa. This provides flexibility in the placement of electrophilic aromatic substitution (EAS) reactions and allows for the synthesis of different regioisomers.
How does side chain oxidation affect the directing properties of a substituent on a benzene ring?
-Side chain oxidation can change the directing properties of a substituent. For example, an ethyl group (an ortho-para director) can be oxidized to a carboxylic acid, which is a meta director. This change can be used strategically to control the position of subsequent EAS reactions.
What is the role of the sulfonate group in the synthesis of a disubstituted benzene where one substituent is a bulky group?
-The sulfonate group acts as a temporary, bulky director that guides the addition of the second substituent to the desired position on the benzene ring. Due to its size, it predominantly directs the addition to the para position, which is useful when the para position is the target for substitution.
Why is it necessary to perform Friedel-Crafts alkylation before adding a strongly deactivating group like a nitro group?
-Performing Friedel-Crafts alkylation before adding a strongly deactivating group like a nitro group is necessary because once the nitro group is present, the benzene ring becomes too deactivated for further Friedel-Crafts reactions to occur. The nitro group acts as a strong electron-withdrawing group, which prevents the formation of the necessary carbocation intermediate for Friedel-Crafts alkylation.
What is the significance of the order of substitution in the synthesis of disubstituted benzene rings?
-The order of substitution is significant because it determines the final position of the substituents on the benzene ring. The directing effects of the substituents and the reactions used to add them dictate the possible positions for further substitutions. Strategic planning of the synthesis order is crucial for achieving the desired product.
How does the video script guide the viewer in planning a retrosynthesis of aromatic compounds?
-The video script guides the viewer through a step-by-step approach to retrosynthesis, emphasizing the importance of understanding the directing effects of different substituents, the limitations of Friedel-Crafts reactions on deactivated rings, and the strategic use of crossover reactions. It provides multiple examples to illustrate how to work through complex synthesis problems.
What are the common patterns to consider when attempting retrosynthesis problems with aromatic compounds?
-Common patterns to consider include the directing effects of substituents (ortho-para directors vs. meta directors), the limitations of Friedel-Crafts reactions on strongly deactivated rings, the use of bulky groups to block certain positions, and crossover reactions that can change the directing properties of a substituent. These patterns help in predicting the outcomes of reactions and planning the synthesis steps.
How does the video script address the issue of regioisomerism in the synthesis of aromatic compounds?
-The script addresses regioisomerism by discussing strategies to control the position of substitution, such as using bulky groups as blocking agents and performing crossover reactions. It also mentions the possibility of needing to purify specific isomers before proceeding with further reactions, acknowledging that in some cases, both major and minor products may need to be considered.
Outlines
🔍 Introduction to Retrosynthesis with Aromatic Compounds
The video begins with an introduction to the chapter on retrosynthesis with aromatic compounds. The speaker outlines a plan to discuss six examples of organic synthesis, emphasizing the importance of recognizing common patterns before attempting retrosynthesis problems. The video is part of an organic chemistry series released weekly throughout the school year. The content delves into the limitations of Friedel-Crafts reactions with strongly deactivated benzene rings and the conditions under which these reactions are possible. It also touches on the use of halogenated benzene rings in Friedel-Crafts alkylation and acylation.
🧩 Strategies for Ortho Substitution and Crossover Reactions
The second paragraph focuses on strategies for ortho substitution and crossover reactions. It discusses how to achieve ortho substitution using a bulky sulfonate group as a temporary blocking agent. The paragraph also explores the concept of crossover reactions, where the directing effect of a substituent can be altered to guide electrophilic aromatic substitution (EAS) reactions to different positions on the benzene ring. This is illustrated with examples involving the transformation of meta-directors into ortho-para directors and vice versa, using reactions such as side chain oxidation and reduction.
🎓 Retrosynthesis Examples Starting with Benzene
The third paragraph presents a series of retrosynthesis examples starting with benzene and aiming to produce disubstituted benzene. The speaker discusses the directing effects of different substituents and the logical order in which they should be added to the benzene ring. It covers the use of Friedel-Crafts alkylation and sulfonation to introduce substituents and emphasizes the importance of considering the directing effects and the bulkiness of groups when planning a synthesis route.
🚧 Addressing Synthesis Challenges with Crossover Reactions
The fourth paragraph continues with more retrosynthesis examples, highlighting challenges and how to address them using crossover reactions. The speaker explains situations where neither of the substituents can be added first due to their directing effects and how to use crossover reactions to overcome these issues. The paragraph also discusses the use of Friedel-Crafts acylation and side chain oxidation to introduce a carboxylic acid group and the strategic timing of EAS reactions before or after these processes.
🔬 Advanced Synthesis Strategies and Crossover Reactions
The fifth and final paragraph covers advanced strategies for synthesis, particularly focusing on situations where the traditional order of substituent addition does not work. The speaker discusses the use of nitration and reduction to introduce an amine group, which changes the directing effect from meta to ortho-para. The paragraph also explores the use of EAS bromination and the importance of performing EAS reactions before or after certain reduction reactions to control the final product's regiochemistry. The speaker concludes with a reminder to consider all possible isomers and the need for purification steps in complex syntheses.
Mindmap
Keywords
💡Retrosynthesis
💡Friedel-Crafts Alkylation
💡Electron Withdrawing Groups
💡Ortho-Para Director
💡Side Chain Oxidation
💡Sulfonation
💡Crossover Reactions
💡Electrophilic Aromatic Substitution (EAS)
💡Benzylic Carbon
💡Regioisomers
💡Catalytic Hydrogenation
Highlights
Introduction to retrosynthesis with aromatic compounds, focusing on key patterns for solving retrosynthesis problems.
Explanation of why Friedel-Crafts reactions are not possible with strongly deactivated benzene rings.
Introduction to substitution at the ortho position using sulfination to block the para position.
Detailed exploration of crossover reactions that can change a meta director to an ortho-para director and vice versa.
Strategies for selectively directing substituents to the ortho position in complex aromatic compounds.
Practical application of sulfination to direct electrophiles to desired positions in aromatic rings.
Examination of the practical reversibility of sulfonation and its implications for synthetic chemistry.
Step-by-step guide for conducting Friedel-Crafts acylation with a focus on regioselectivity.
Discussion of the impact of different substituents on directing outcomes in electrophilic aromatic substitution (EAS).
Illustration of the importance of the order of steps in synthetic routes, particularly for complex molecule construction.
Introduction to the concept of side chain oxidation to transform alkyl groups into carboxylic acids.
Overview of reduction techniques to convert nitro groups to amines, highlighting the transformation from meta to ortho-para directors.
Demonstration of multiple retrosynthesis examples, illustrating strategies to achieve desired structural outcomes.
Insights into how to approach disubstituted benzene synthesis starting from plain benzene.
Highlighting the practical challenges and solutions in synthesizing specific regioisomers in complex organic molecules.
Transcripts
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