Mannich Reaction Overview
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Questions and Answers

What is the ratio of anti to syn configurations for the reaction depicted with N,O acetals?

  • 78:22 (correct)
  • 65:35
  • 50:50
  • 45:55

    • Which compound is used to form silyl enol ethers in the presence of methylene iminium salts?

  • OSiMe3 (correct)
  • OBu2
  • OLi
  • NMe2

    • What type of reaction involves the use of boron enol ethers with aminals?

  • Condensation (correct)
  • Alkylation
  • Addition
  • Reductive amination

    • What is one of the reactants needed to create N,O acetals?

    <p>Ph</p> Signup and view all the answers

    What is the main functional group present in carbonyl compounds?

    <p>Aldehyde or Ketone</p> Signup and view all the answers

    What functional group is present in both fluoxetine and tramadol based on the structure?

    <p>Amine group</p> Signup and view all the answers

    Which molecule is indicated to be associated with HCl in the provided content?

    <p>Tramadol</p> Signup and view all the answers

    What is the primary ingredient of the synthetic pathway indicated for fluoxetine?

    <p>Me2 NH</p> Signup and view all the answers

    Which component is NOT present in the chemical structure of fluoxetine?

    <p>Methyl group</p> Signup and view all the answers

    What type of chemical reaction is likely involved in the formation of both fluoxetine and tramadol?

    <p>Amination</p> Signup and view all the answers

    What role does the base play in the formation of the copper acetylide?

    <p>It leads to the formation of a pi-alkyne complex.</p> Signup and view all the answers

    Which of the following amines is highlighted for its efficiency and reversibility in reactions with trans-RPdX(PPh3)2 complexes?

    <p>Piperidine</p> Signup and view all the answers

    What is a limitation of using a copper co-catalyst in reactions?

    <p>It can lead to the Glaser coupling reaction.</p> Signup and view all the answers

    Which application is NOT mentioned in relation to the copper cycle?

    <p>Energy generation</p> Signup and view all the answers

    What is necessary to avoid during a Sonogashira reaction with a copper co-catalyst?

    <p>Unwanted dimerization</p> Signup and view all the answers

    Who was Carl Ulrich Franz Mannich?

    <p>A German chemist</p> Signup and view all the answers

    What is the Mannich reaction primarily characterized by?

    <p>The formation of β-aminocarbonyl compounds</p> Signup and view all the answers

    During the Mannich reaction, which component is commonly used with formaldehyde?

    <p>An enolizable carbonyl compound</p> Signup and view all the answers

    What limitations are associated with the Mannich reaction?

    <p>Regio- and stereoselectivity control is often unsatisfactory</p> Signup and view all the answers

    What advantage do preformed Mannich reagents provide?

    <p>Fewer undesired side reactions</p> Signup and view all the answers

    What type of compounds can be used to replace carbonyl components in the Mannich reaction?

    <p>Enolates</p> Signup and view all the answers

    Which of the following best describes Mannich bases?

    <p>They are β-aminocarbonyl compounds.</p> Signup and view all the answers

    What are some of the reactions that can result from the Mannich reaction?

    <p>Side reactions and undesired products</p> Signup and view all the answers

    What type of copper salt is typically involved in the reaction with terminal alkynes?

    <p>Copper(I) iodide</p> Signup and view all the answers

    Which amine is commonly used as a base and solvent in the reaction?

    <p>Diethylamine</p> Signup and view all the answers

    What is the role of copper(I) in the coupling reaction?

    <p>It serves as a catalyst</p> Signup and view all the answers

    What is a necessary condition for the Sonogashira coupling reaction?

    <p>Basic conditions to neutralize hydrogen halide byproducts</p> Signup and view all the answers

    What is the first step in the palladium cycle for the reaction?

    <p>Reduction of palladium(II) to palladium(0)</p> Signup and view all the answers

    Which complex is produced during the transmetallation step?

    <p>Complex C</p> Signup and view all the answers

    What is believed to be the rate-limiting step in the palladium cycle?

    <p>Oxidative addition</p> Signup and view all the answers

    What type of geometry does complex D undergo during isomerization?

    <p>From trans to cis</p> Signup and view all the answers

    What is formed as a result of the Wittig reaction?

    <p>An alkene and triphenylphosphine oxide</p> Signup and view all the answers

    Which reaction type is involved in the Wittig reaction?

    <p>Nucleophilic Addition then Elimination</p> Signup and view all the answers

    What can influence the stereoselectivity of the Wittig reaction?

    <p>The choice of ylide, carbonyl compound, and reaction conditions</p> Signup and view all the answers

    What alternative reaction involves replacing the ylide with a phosphine oxide carbanion?

    <p>Horner reaction</p> Signup and view all the answers

    In which type of reaction does an enolate attack a carbonyl compound?

    <p>Aldol condensation</p> Signup and view all the answers

    The mechanism of the Wittig reaction involves which intermediates?

    <p>Betaine and/or oxaphosphetane</p> Signup and view all the answers

    What is the outcome when the ylide is replaced with a phosphonate carbanion?

    <p>Horner-Emmons-Wadsworth reaction</p> Signup and view all the answers

    What type of compound does the Wittig reaction use as an electrophile?

    <p>Carbonyl compound</p> Signup and view all the answers

    Study Notes

    The Mannich Reaction

    • The Mannich reaction is an aminoalkylation reaction.
    • It involves the condensation of an enolizable carbonyl compound with a nonenolizable aldehyde (like formaldehyde) and ammonia, or a primary or secondary amine.
    • This reaction forms a β-aminocarbonyl compound, often called a Mannich base.

    Background

    • Carl Mannich was a German chemist (March 8, 1877 – March 5, 1947).
    • He was a professor of pharmaceutical chemistry at the University of Berlin from 1927 to 1943.
    • His expertise included keto bases, alcohols, piperidine derivatives, papaverine, lactones, and digitalis glycosides.

    Background (Mechanism)

    • The reaction is best performed with methyl ketones.
    • Aldehydes other than formaldehyde can be used.
    • Diethyl amine - HCl is often used in excess (used as a base).
    • Other secondary amines can replace diethylamine.
    • A variety of R groups can be incorporated.

    Mechanism

    • Complex chemical reaction mechanisms are shown.

    Limitations

    • The Mannich reaction has limited applications.
    • It often creates undesired side products.
    • It often struggles to control regio- and stereoselectivity.

    Modifications

    • Preformed Mannich reagents increase reaction speed & efficiency.
    • Using a higher electrophile concentration lowers reaction temperatures, and decreases reaction times.
    • Sensitive substrates produce fewer side reactions.
    • Replacing the carbonyl component with a reactive synthetic equivalent like an enolate improves efficiency.
    • This reaction has an extended spectrum of application.

    Modifications (Cont.)

    • Imines
    • Aminals
    • N,O-acetals
    • Benzotriazole aminals
    • Iminium salts
    • Intermolecular amino-alkylation

    Modifications (cont.)

    • Carbonyl compounds (with iminium salts)
    • Enolates (with N,O acetals)
    • Boron enol ethers (with aminals)
    • Silyl enol ethers (with methylene iminium salts)

    Applications

    • Used in the synthesis of pharmaceuticals, natural products, organic materials, and nanomaterials.
    • Used to create tazarotene (a psoriasis & acne treatment) and SIB-1508Y (also known as Altinicline, a nicotinic receptor agonist).
    • Applicable in alkynylation, enynes, and enediynes reactions.

    Applications (Medical Compounds)

    • Produces various medicinally important compounds, like fluoxetine and Tramadol.

    Applications (Natural Product Synthesis)

    • Used in the synthesis of natural products.
    • Produces compounds like epibatidine, ferruginine, and anatoxin.

    Wittig Reaction

    • A chemical reaction to synthesize alkenes.
    • Involves reacting an aldehyde or ketone with a triphenylphosphonium ylide (a Wittig reagent).
    • The product is an alkene and triphenylphosphine oxide.
    • This reaction is nucleophilic addition then elimination.

    Wittig Reaction (Mechanism)

    • The reaction includes several steps.
    • Preparing the ylide through a reaction of triphenyl phosphine and alkyl halide.
    • Using organolithium compounds for deprotonation to create the ylide.

    Wittig Reaction (Mechanism - cont.)

    • Alkene formation from carbonyl compounds and phosphonium ylides.
    • This reaction primarily involves proposed betaine and/or oxaphosphetane intermediates.
    • The choice of ylide, carbonyl compound, and reaction conditions can control the stereoselectivity of the reaction.
    • If the ylide is replaced with a phosphine oxide carbanion, it is referred to as the Horner reaction.
    • If the ylide is replaced with a phosphonate carbanion, it is referred to as the Horner-Wadsworth-Emmons reaction.

    General Wittig Reaction

    • This reaction uses a carbonyl compound as an electrophile, attacked by the phosphorus ylide.
    • The Wittig reaction complements the aldol condensation.
    • The aldol condensation produces enones.
    • Wittig reactions are more flexible as the product carbonyl does not need to have an attached carbonyl.

    Sonogashira Reaction

    • A cross-coupling reaction in organic synthesis to create carbon-carbon bonds in terminal alkynes and aryl or vinyl halides.
    • Pd and Cu catalysts are used simultaneously.

    Sonogashira Reaction: Conditions and Solvents

    • Conducted under mild conditions (like room temperature and in aqueous media).
    • Typically uses amines such as diethylamine.
    • Diethylamine also acts as a solvent that neutralizes the hydrogen halide byproduct of this coupling reaction.

    Sonogashira Reaction: Catalysts

    • Needs zerovalent palladium complexes (like Pd(PPh3)4 or Pd(PPh3)2Cl2).
    • Bidentate ligand catalysts (like Pd(dppe)Cl, Pd(dppp)Cl2, and Pd(dppf)Cl2) are often used.
    • Needs copper(I) halide co-catalysts like copper iodide.
    • Palladium(II) is often used as a pre-catalyst.

    Sonogashira Reaction: Mechanism

    • A detailed description of the Pd and Cu catalytic cycle is present.

    Sonogashira Reaction: Complications

    • Specific amines must be added in excess as a reactant or solvent for the reaction process, as piperidine, morpholine, and diisopropylamine.
    • The equilibrium constant depends on R, X (factors for basicity) and the steric hindrance of the amine.

    Sonogashira Reaction: Applications

    • Used in synthesis of pharmaceuticals, natural products, organic materials, and nanomaterials.
    • Includes the synthesis of tazarotene (psoriasis and acne treatment), and SIB-1508Y (nicotinic receptor agonist).
    • Also used in alkynylation reactions, enynes, and enediynes.

    Sonogashira Reaction: Limitations

    • Copper co-catalysts form alkyne dimers, which is unwanted.
    • The presence of copper leads to Glaser coupling.
    • To prevent this, reactions need to be conducted in an inert atmosphere.
    • Copper-free Sonogashira reaction variations have recently been developed.

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    The Mannich Reaction PDF

    Description

    Explore the Mannich reaction, an important aminoalkylation process that forms β-aminocarbonyl compounds. Learn about the significant contributions of Carl Mannich and the key components and mechanisms involved in this reaction. Understand its applications and limitations in organic chemistry.

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