Fiche de révision : Fundamental Organic Reactions and Syntheses

📋 Course Outline

1. Acetylation Name Reactions
2. Wurtz Fittig Reaction
3. Wurtz Reaction
4. Wolff-Kishner Reduction
5. Williamson's Reaction
6. Stephen Reaction
7. Schotten Baumann Reaction
8. Sandmeyer’s Reaction
9. Rosenmund Reaction
10. Reimer-Tiemann Reaction
11. Perkin Reaction
12. Liebermann’s Nitroso Reaction

📖 1. Acetylation Name Reactions

🔑 Key Concepts & Definitions

• Acetylation: A chemical reaction where an acetyl group (CH₃CO−) is introduced into an organic molecule, often to modify reactivity or protect functional groups.
• Acetyl Group (CH₃CO−): A functional group derived from acetic acid, commonly used in acetylation reactions.
• Acetyl Chloride (CH₃COCl): A reactive acetylating agent used to introduce acetyl groups into compounds.
• Acetic Anhydride ((CH₃CO)₂O): Another common acetylating agent, more reactive than acetic acid.
• Acetylation of Aromatic Compounds: Typically involves electrophilic substitution where the acetyl group attaches to aromatic rings, often facilitated by catalysts like Lewis acids.
• Protection Strategy: Acetylation is used to temporarily protect hydroxyl or amino groups during multi-step syntheses.

📝 Essential Points

• Purpose of Acetylation: To modify chemical reactivity, improve stability, or protect functional groups such as −OH and −NH₂.
• Common Reagents: Acetyl chloride, acetic anhydride, pyridine (as a base and solvent).
• Reaction Conditions: Usually carried out under mild conditions; pyridine acts as both solvent and base to scavenge HCl.
• Reactions Involved:
  • Alcohols and phenols react with acetyl chloride or acetic anhydride to form esters.
  • Amines react to form amides or N-acetyl derivatives.
• Applications:
  • Synthesis of acetylated derivatives for analytical purposes.
  • In pharmaceutical chemistry for modifying drug molecules.
  • In organic synthesis as a protective group.

💡 Key Takeaway

Acetylation is a fundamental reaction used to modify, protect, or activate functional groups in organic molecules, primarily employing acetyl chloride or acetic anhydride to introduce acetyl groups efficiently.

Additional Notes on Related Reactions (for context):

• Williamson's Reaction: An SN2 reaction to synthesize ethers, often involving alkyl halides.
• Friedel-Crafts Acylation: Aromatic substitution where an acyl group (including acetyl) is introduced onto benzene rings.
• Schotten-Baumann Reaction: Acylation of amines or alcohols using acyl chlorides in the presence of base.
• Reimer-Tiemann Reaction: Ortho-formylation of phenols, sometimes involving acetyl groups in subsequent steps.
• Sandmeyer’s Reaction: Used for diazotization and substitution, often in aromatic amines.

Remember: Acetylation is a versatile tool in organic synthesis, crucial for protecting groups and modifying molecular properties.

📖 2. Wurtz Fittig Reaction

🔑 Key Concepts & Definitions

• Wurtz Fittig Reaction: A coupling reaction where aryl halides (or aryl derivatives) are reacted with alkyl halides (or aryl halides) in the presence of a metal catalyst, typically sodium or potassium, to form biaryl or aryl-alkyl compounds.
• Aryl Halides: Aromatic compounds where hydrogen is replaced by halogens (Cl, Br, I).
• Coupling Reaction: A chemical process that joins two fragments to form a larger molecule.
• Metal Catalyst: Usually sodium or potassium, facilitating electron transfer for coupling.

📝 Essential Points

• The reaction involves the coupling of an aryl halide with an alkyl halide using sodium or potassium metal in dry ether.
• It is a variation of the Wurtz reaction, specifically designed for aryl compounds.
• The reaction is useful for synthesizing biaryl compounds, which are important in dyes, pharmaceuticals, and organic materials.
• The mechanism involves single-electron transfers leading to radical intermediates that couple to form new bonds.
• Limitations include possible formation of multiple products and sensitivity to functional groups.

💡 Key Takeaway

The Wurtz Fittig Reaction is a vital method for synthesizing biaryl and aryl-alkyl compounds through metal-mediated coupling of halides, playing a crucial role in aromatic compound synthesis.

📖 3. Wurtz Reaction

🔑 Key Concepts & Definitions

• Wurtz Reaction: A coupling reaction where two alkyl halides are reacted with sodium metal in dry ether to form a new alkane.
• Alkyl Halides (R-X): Organic compounds where a halogen (X = Cl, Br, I) is attached to an alkyl group.
• Sodium Metal (Na): Acts as a reducing agent, facilitating the formation of carbon-carbon bonds.
• Dry Ether: An inert solvent used to prevent side reactions and ensure the reaction proceeds smoothly.

📝 Essential Points

• Reaction Mechanism: Involves the formation of free radicals or carbanions from alkyl halides, which then couple to form a new C–C bond.
• Conditions: Requires dry, anhydrous conditions; typically performed in dry ether.
• Limitations: Only effective with primary alkyl halides; secondary and tertiary halides tend to undergo elimination or other side reactions.
• Applications: Used for synthesizing symmetrical alkanes and in organic synthesis to connect two alkyl groups.
• Side Reactions: Possible formation of alkenes via elimination, especially with secondary or tertiary halides.

💡 Key Takeaway

The Wurtz reaction is a fundamental method for forming carbon-carbon bonds between alkyl groups, primarily effective with primary halides under anhydrous conditions, but it has limitations regarding substrate scope and side reactions.

📖 4. Wolff-Kishner Reduction

🔑 Key Concepts & Definitions

• Wolff-Kishner Reduction: A chemical reaction that converts aldehydes or ketones into hydrocarbons (alkanes) using hydrazine (N₂H₄) and a strong base, typically under heating.
• Hydrazone: An intermediate formed when hydrazine reacts with a carbonyl compound (aldehyde or ketone).
• Reagent: Hydrazine hydrate (N₂H₄·H₂O) and a strong base such as potassium hydroxide (KOH).
• Mechanism: Involves formation of hydrazone, followed by base-induced decomposition to produce the alkane and nitrogen gas.
• Application: Used for the reduction of carbonyl groups that are sensitive to hydrogenation conditions.

📝 Essential Points

• The Wolff-Kishner reduction is a deoxygenation process, removing the carbonyl oxygen.
• It is compatible with other functional groups that are sensitive to hydrogenation, unlike catalytic hydrogenation.
• The reaction requires heating typically at high temperatures (~200°C).
• The process involves two main steps: formation of hydrazone and subsequent decomposition under basic conditions.
• It is preferable over Clemmensen reduction when the substrate contains acid-sensitive groups.
• Limitations include the requirement of harsh conditions and potential side reactions with sensitive functionalities.

💡 Key Takeaway

The Wolff-Kishner reduction is a valuable method for converting aldehydes and ketones into alkanes, especially when other reduction methods are incompatible with sensitive functional groups. It involves hydrazone formation followed by base-induced decomposition to remove oxygen as nitrogen gas.

📖 5. Williamson's Reaction

🔑 Key Concepts & Definitions

• Williamson's Reaction: An SN2 nucleophilic substitution reaction used to synthesize ethers from alkyl halides and alkoxides.
• Alkyl Halide: An organic compound containing a halogen atom attached to an alkyl group, serving as the electrophile.
• Alkoxide Ion: The conjugate base of an alcohol, acting as the nucleophile in Williamson's reaction.
• SN2 Mechanism: A bimolecular nucleophilic substitution where the nucleophile attacks the electrophilic carbon simultaneously as the leaving group departs, leading to inversion of configuration.

📝 Essential Points

• Reaction Conditions: Typically carried out in a polar aprotic solvent like acetone to favor SN2 mechanism.
• Reactivity Order: Methyl > primary > secondary > tertiary alkyl halides; tertiary halides do not favor SN2 due to steric hindrance.
• Stereochemistry: Inversion of configuration at the chiral center occurs during SN2.
• Limitations: Not suitable for tertiary alkyl halides; better with primary and methyl halides.
• Applications: Used to synthesize symmetrical and unsymmetrical ethers, important in organic synthesis.

💡 Key Takeaway

Williamson's Reaction is a versatile SN2 process for preparing ethers, emphasizing the importance of substrate structure and reaction conditions to favor nucleophilic substitution over elimination.

📖 6. Stephen Reaction

🔑 Key Concepts & Definitions

• Stephen Reaction: A chemical reaction involving the conversion of aromatic aldehydes (like benzaldehyde) into corresponding phenylhydrazones using phenylhydrazine.
• Phenylhydrazine: An organic compound used as a reagent to form hydrazones with aldehydes and ketones.
• Hydrazone: A compound formed by the reaction of hydrazine derivatives with aldehydes or ketones, characterized by a C=N-NH- linkage.
• Application: Used in qualitative analysis and in the synthesis of heterocyclic compounds.

📝 Essential Points

• The reaction involves the condensation of aromatic aldehydes with phenylhydrazine.
• It produces phenylhydrazones, which are often crystalline and can be used for identification purposes.
• The reaction is reversible; hydrazone formation can be driven forward by removing water.
• It is useful in differentiating aldehydes from ketones, as aldehydes form hydrazones more readily.
• The reaction is a key step in the synthesis of heterocyclic compounds like pyrazoles.

💡 Key Takeaway

The Stephen Reaction is a fundamental method for converting aldehydes into hydrazones, aiding in compound identification and serving as a precursor in heterocyclic synthesis.

📖 7. Schotten Baumann Reaction

🔑 Key Concepts & Definitions

• Schotten Baumann Reaction: A chemical reaction involving the acylation of aromatic amines (anilines) with acyl chlorides in the presence of a base, typically sodium hydroxide, to produce amides.
• Acylation: The process of introducing an acyl group (R–C=O) into an organic compound.
• Aniline: An aromatic amine (C₆H₅NH₂), primary substrate in the reaction.
• Acyl Chloride: A reactive acyl derivative (R–C=OCl) used as the acylating agent.
• Amide Formation: The main product, where the amino group of aniline reacts with acyl chloride to form an amide.

📝 Essential Points

• The reaction typically occurs under basic conditions, with sodium hydroxide neutralizing the HCl formed.
• It is used to synthesize acetanilide and other aromatic amides.
• The reaction is selective for amino groups on aromatic rings, with minimal substitution on the ring.
• The process involves nucleophilic attack of the amino group on the acyl chloride, followed by deprotonation.
• It is an important step in pharmaceutical and dye chemistry for modifying aromatic amines.

💡 Key Takeaway

The Schotten Baumann Reaction efficiently converts aromatic amines into amides via acylation with acyl chlorides under basic conditions, serving as a fundamental method in organic synthesis for modifying aromatic amines.

📖 8. Sandmeyer’s Reaction

🔑 Key Concepts & Definitions

• Sandmeyer’s Reaction: A chemical reaction where aromatic amines (anilines) are converted into aryl halides (chlorides, bromides, or iodides) using copper(I) halides (CuX) in the presence of hydrochloric acid (HCl), hydrobromic acid (HBr), or hydroiodic acid (HI).
• Aromatic Amines: Organic compounds containing an amino group (-NH₂) attached to an aromatic ring.
• Copper(I) Halides (CuX): Copper in the +1 oxidation state used as a catalyst and halogen source in the reaction.
• Diazonium Salt: An intermediate formed from aromatic amines reacting with nitrous acid (HNO₂), which then undergoes substitution.

📝 Essential Points

• Mechanism: Involves formation of diazonium salt from aromatic amine, followed by replacement of the diazonium group with halogen via a copper-mediated process.
• Reaction Conditions: Typically carried out at low temperatures (0–5°C) to stabilize diazonium salts.
• Applications: Used to synthesize aryl halides, which are important intermediates in dyes, pharmaceuticals, and organic synthesis.
• Limitations: Only works with aromatic amines that form stable diazonium salts; sensitive to heat and light.
• Variants: Can be extended to other nucleophiles (e.g., CN⁻, OH⁻) for different substitution reactions.

💡 Key Takeaway

Sandmeyer’s Reaction is a vital method for converting aromatic amines into aryl halides through diazonium intermediates, enabling the synthesis of diverse aromatic compounds with halogen substituents.

📖 9. Rosenmund Reaction

🔑 Key Concepts & Definitions

• Rosenmund Reaction: A catalytic hydrogenation process that selectively reduces acyl chlorides to aldehydes using hydrogen gas (H₂) in the presence of a poisoned catalyst.
• Catalyst: Typically palladium on barium sulfate (Pd/BaSO₄), poisoned with quinoline to prevent over-reduction.
• Poisoned Catalyst: A catalyst treated with a substance (quinoline) that moderates its activity, ensuring selective reduction.

📝 Essential Points

• The Rosenmund reaction is used to convert acyl chlorides (R–COCl) into aldehydes (R–CHO).
• The reaction employs hydrogen gas and Pd/BaSO₄ catalyst poisoned with quinoline.
• The poisoning prevents further reduction of aldehydes to primary alcohols.
• Conditions are mild; typically performed at room temperature and atmospheric pressure.
• Over-reduction to alcohols is minimized due to catalyst poisoning.
• The reaction is highly selective for aldehyde formation from acyl chlorides.

💡 Key Takeaway

The Rosenmund reaction provides a controlled method to synthesize aldehydes from acyl chlorides by using a poisoned palladium catalyst, preventing over-reduction to alcohols and ensuring selectivity.

📖 10. Reimer-Tiemann Reaction

🔑 Key Concepts & Definitions

• Reimer-Tiemann Reaction: A chemical reaction that synthesizes ortho-hydroxybenzaldehyde (salicylaldehyde) from phenol and chloroform in the presence of a strong base (usually sodium hydroxide).
• Phenol: An aromatic compound with a hydroxyl group attached directly to the benzene ring, serving as the substrate.
• Chloroform (CHCl₃): Acts as a source of dichlorocarbene intermediate in the reaction.
• Dichlorocarbene (CCl₂): A reactive intermediate generated during the reaction, which adds to phenol to form salicylaldehyde.
• Ortho-Position: The position adjacent to the hydroxyl group on the benzene ring where the aldehyde group is introduced.

📝 Essential Points

• The reaction selectively introduces an aldehyde group at the ortho-position of phenol.
• It requires phenol, chloroform, and sodium hydroxide.
• The mechanism involves formation of dichlorocarbene from chloroform under basic conditions, which then electrophilically adds to phenol.
• The product, ortho-hydroxybenzaldehyde (salicylaldehyde), is useful in synthesizing dyes, pharmaceuticals, and fragrances.
• The reaction is sensitive to substituents on the phenol ring; electron-donating groups facilitate the reaction.
• It is a classic example of electrophilic aromatic substitution with a carbene intermediate.

💡 Key Takeaway

The Reimer-Tiemann reaction is a valuable method for ortho-formylation of phenols, utilizing dichlorocarbene generated from chloroform and base, leading to salicylaldehyde formation.

📖 11. Perkin Reaction

🔑 Key Concepts & Definitions

• Perkin Reaction: An organic chemical reaction where aromatic aldehydes (commonly benzaldehyde) react with anhydrides (typically acetic anhydride) in the presence of a base or catalyst to produce α, β-unsaturated aromatic acids, such as cinnamic acid.
• Reactants: Aromatic aldehyde + Acid anhydride.
• Product: α, β-Unsaturated aromatic acid (e.g., cinnamic acid).
• Mechanism: Involves aldol condensation followed by dehydration, leading to the formation of a conjugated double bond system.

📝 Essential Points

• Reaction Conditions: Usually carried out with acetic anhydride and a catalyst like sodium acetate or other bases.
• Mechanism Steps:
  1. Formation of an enolate ion from the aldehyde.
  2. Nucleophilic attack on the acyl group of the anhydride.
  3. Dehydration to form the conjugated unsaturated acid.
• Applications: Used in synthesizing cinnamic acid derivatives, which are precursors for flavoring agents, perfumes, and pharmaceuticals.
• Limitations:
  • Mainly effective with aromatic aldehydes.
  • Sensitive to steric hindrance and electronic effects of substituents.
• Comparison: Similar to Knoevenagel condensation but specific to aromatic aldehydes with acetic anhydride.

💡 Key Takeaway

The Perkin reaction is a vital method for synthesizing α, β-unsaturated aromatic acids, especially cinnamic acid, through the condensation of aromatic aldehydes with acid anhydrides under basic conditions, forming conjugated double bonds essential in flavor and fragrance industries.

📖 12. Liebermann’s Nitroso Reaction

🔑 Key Concepts & Definitions

• Liebermann’s Nitroso Reaction: An organic reaction where phenols are converted into nitroso derivatives using nitrous acid (HNO₂) under specific conditions.
• Nitroso Compound: An organic compound containing the -NO group attached to an aromatic or aliphatic system.
• Phenol: An aromatic compound with a hydroxyl group (-OH) attached to a benzene ring, serving as the substrate in this reaction.
• Nitrous Acid (HNO₂): A weak, unstable acid used as a reagent to introduce nitroso groups into phenols.
• Reaction Mechanism: Involves electrophilic substitution where the phenol reacts with nitrous acid to form nitroso derivatives.

📝 Essential Points

• The reaction is typically performed by treating phenols with nitrous acid, generated in situ from sodium nitrite (NaNO₂) and acid.
• The product formed is a nitroso phenol, which can further undergo oxidation or rearrangement.
• The reaction is sensitive to pH; acidic conditions favor the formation of nitroso derivatives.
• It is used to synthesize nitroso compounds, which are important intermediates in dye and pharmaceutical industries.
• The reaction can be used to distinguish phenols from other aromatic compounds due to their specific reactivity with nitrous acid.
• The reaction mechanism involves electrophilic attack at the ortho or para position relative to the hydroxyl group.

💡 Key Takeaway

Liebermann’s Nitroso Reaction is a vital method for synthesizing nitroso phenols, leveraging the electrophilic nature of nitrous acid to modify phenolic compounds selectively under acidic conditions.

📊 Synthesis Tables

⚠️ Common Pitfalls & Confusions

1. Acetylation: Confusing acetylation with acylation; acetylation specifically introduces CH₃CO− groups.
2. Wurtz Reaction: Not suitable for secondary or tertiary halides; prone to side reactions like elimination.
3. Wurtz Fittig Reaction: Mistaking it for simple Wurtz; it involves aromatic halides and forms biaryl compounds.
4. Wolff-Kishner Reduction: Overlooking harsh conditions; sensitive to acid-sensitive groups.
5. Williamson's Reaction: Using tertiary halides, which do not undergo SN2; stereochemical inversion occurs.
6. Reaction Conditions: Many reactions require anhydrous, inert conditions—failure leads to side reactions.
7. Functional Group Compatibility: Not all functional groups tolerate reaction conditions (e.g., strong bases, high temperatures).
8. Side Products Formation: Multiple products in Wurtz reactions due to multiple coupling possibilities.
9. Misidentification of Mechanisms: Confusing SN1 with SN2 in Williamson's reaction; Williamson is SN2.
10. Reaction Reversibility: Some reactions (like acetylation) are reversible under certain conditions.

✅ Exam Mastery Checklist

• Understand the purpose and reagents of acetylation reactions.
• Differentiate between Wurtz and Wurtz Fittig reactions, including their mechanisms and products.
• Know the scope, limitations, and mechanism of the Wurtz reaction.
• Describe the Wolff-Kishner reduction, including its mechanism and suitable substrates.
• Explain Williamson's reaction, including SN2 mechanism and stereochemical implications.
• Recognize the typical conditions and functional group sensitivities for each reaction.
• Identify common side reactions and how to avoid them.
• Recall applications of each reaction in organic synthesis.
• Be able to predict products given reactants for each reaction.
• Distinguish between similar reactions based on reagents and conditions.
• Understand the role of catalysts and solvents in these reactions.
• Recall the significance of protecting groups like acetyl groups.
• Be prepared to troubleshoot reaction failures based on conditions and reagents.