Lecture 16 (CH 19-2) - Tagged

Chapter 19: Aldehydes and Ketones: Nucleophilic Addition Reactions

Nucleophilic Addition of HCN: Cyanohydrin Formation

  • Cyanohydrins: Products of nucleophilic reactions between aldehydes/unhindered ketones and HCN.

  • Addition of HCN is reversible and base-catalyzed, producing the nucleophilic cyanide ion (CN-).

  • Addition of CN- to C=O forms a tetrahedral intermediate that is then protonated.

  • Equilibrium favors the cyanohydrin adduct.

Uses of Cyanohydrins

  • Reduction: The nitrile group (R–C≡N) can be reduced with LiAlH4 to form a primary amine (RCH2NH2).

  • Can be hydrolyzed in hot acid to produce a carboxylic acid.

Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Alcohol Formation

  • Alcohol Preparation: Carbonyl compounds can be reduced to form alcohols.

    • Aldehydes reduced with NaBH4 yield primary alcohols.

    • Ketones yield secondary alcohols when reduced similarly.

  • Reduction occurs via a typical nucleophilic addition mechanism under basic conditions.

Mechanism of Alcohol Formation

  1. Grignard or hydride reagents react as donors of hydride ions.

  2. Protonation after addition yields the alcohol.

  3. Reaction is effectively irreversible.

Nucleophilic Addition of Amines: Imine and Enamine Formation

  • Imines: Formed when RNH2 adds to aldehydes and ketones (R2C=NR).

  • Enamines: Formed by R2NH addition resulting in structures (R2N–CR=CR2).

Mechanism of Imine/Enamine Formation

  1. Nucleophilic attack on the carbonyl by amine lone-pair electrons forms a dipolar tetrahedral intermediate.

  2. Proton transfer yields a carbinolamine.

  3. Hydrolysis and nitrogen lone-pair electrons expel water to yield an imine or enamine.

pH Dependence of Imine Formation

  • An acid catalyst is needed to protonate the intermediate carbinolamine.

  • Reaction conditions must be optimized for maximum rates.

Nucleophilic Addition of Hydrazine: The Wolff-Kishner Reaction

  • Hydrazine (H2NNH2) and KOH convert aldehydes/ketones to alkanes via a hydrazone intermediate:

    • Involves double-bond migration and loss of N2 gas.

  • Considered more useful than catalytic hydrogenation.

Nucleophilic Addition of Alcohols: Acetal Formation

  • Aldehydes/ketones react with alcohols in the presence of an acid catalyst to form acetals (R2C(OR’)2), or ketals if from ketones.

  • Initial addition forms hemiacetals, which are reversible.

Mechanism of Acetal Formation

  1. Protonation of carbonyl oxygen strongly polarizes the carbonyl group.

  2. Alcohol’s lone-pair electrons attack, forming a hemiacetal intermediate.

  3. Additional alcohol forms a protonated acetal, which loses a proton to yield a neutral acetal product.

Uses of Acetals

  • Acetals serve as protecting groups for aldehydes and ketones.

  • Easier synthesis using diols to form cyclic acetals.

Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

  • Conversion of aldehydes/ketones to alkenes via nucleophilic addition of phosphorus ylides leads to a four-membered cyclic intermediate (oxaphosphetane).

  • The intermediate decomposes to yield an alkene and triphenylphosphine oxide.

Biological Reductions

  • The Cannizzaro reaction demonstrates nucleophilic addition of OH- to aldehydes, leading to oxidation and reduction processes.

Conjugate Nucleophilic Addition to α,β-Unsaturated Aldehydes and Ketones

  • 1,2-addition: Direct addition of a nucleophile to the carbonyl group.

  • 1,4-addition: Nucleophile adds to the C=C double bond.

Summary

  • Key Reaction Type: Nucleophilic addition of HCN yields cyanohydrins; primary amines yield imines, and secondary amines yield enamines.

  • The Wolff-Kishner reaction converts aldehydes and ketones to alkanes.

  • Acetals are formed from alcohol additions and serve as protective groups.

  • The Wittig reaction gives alkenes; conjugate addition affects α,β-unsaturated carbonyl compounds.