CHEM211-Ch.18

Organic Chemistry Principles and Mechanisms

Chapter 18: Nucleophilic Addition to Polar π Bonds

General Mechanism: Addition of Strong Nucleophiles

  • A nucleophile tends to form a bond with the atom at the positive end of a polar π bond.

    • Definition: A nucleophile is a species that donates an electron pair to form a chemical bond.

    • Characteristics:

    • Electron-rich nature: Nucleophiles possess a lot of electrons.

    • Electron-poor target: The atom at the positive end of a polar π bond is electron deficient.

  • The addition under basic conditions differs from low pH conditions.

General Mechanism Continued: Addition of Strong Nucleophiles

  • To avoid exceeding the octet for the atom attacked by the nucleophile, the π bond is broken.

    • The electrons from the π bond become a lone pair on the more electronegative atom of the π bond.

Compounds with Polar p Bonds

  • In compounds where the C atom of the polar π bond has a leaving group, the leaving group facilitates nucleophilic addition–elimination reactions.

  • Certain leaving groups are more effective than others based on their leaving group ability:

    • Factors include:

    • Stability of the leaving group after departure.

    • Resonance effects or inductive stabilization can enhance leaving group ability.

Relative Reactivity of Ketones and Aldehydes

  • Ketones and aldehydes exhibit similar behaviors due to structural similarities.

  • Differences arise in thermodynamics and kinetics of nucleophilic addition, influenced by:

    • Sterics: The spatial arrangement of groups around the carbonyl affects nucleophilic attack.

    • Electronics: The electronic properties can stabilize or destabilize intermediates.

Hydration Rate and Equilibrium Constants

  • Table 17-1 presents reaction rates and hydration equilibrium for carbonyl compounds (ketones and aldehydes):

    • Example data:

    • For a specific ketone, the reaction rate constant is given as 5 imes 10^5 resulting in over 99.9% hydration.

    • In contrast, another ketone has a hydration rate constant of 2 imes 10^3 with a hydration percentage of 57%.

    • Another example indicates a rate constant of 1 with less than 1% hydration.

Ketones

  • Steric repulsion from two alkyl groups on the carbonyl carbon complicates nucleophilic attack, thus destabilizing the hydrate formation.

Aldehydes

  • Aldehydes have only one alkyl group, reducing steric effects, thus facilitating easier nucleophilic attack.

Electronics: Inductive Effects

  • Increasing positive charge concentration at the carbonyl carbon enhances susceptibility to nucleophile attack.

  • Visual Representation:

    • The pictorial contrast shows different intensities of positive charge at the carbonyl carbon based on alkyl substitution.

    • Notably, ketones are more stabilized than aldehydes by inductive effects.

Hydride Reducing Agents: LiAlH4 and NaBH4

  • The hydride anion is represented as H:-, indicating a hydrogen atom with an extra electron, commonly abbreviated as H-.

  • Common hydride sources:

    • Sodium Borohydride (NaBH4)

    • Lithium Aluminum Hydride (LiAlH4) (LAH)

  • These agents are essential for reduction reactions of polar π bond containing compounds.

Reduction of the Ketone: Example 1

  • In the presence of a ketone, both NaBH4 and LiAlH4 effectively act as reducing agents, leading to the conversion of butan-2-one to butan-2-ol:

    1. Methodology:

    • LiAlH4 is used in ether and reflux conditions.

    • Example yields racemic butan-2-ol at 83% and 80% using different procedures.

Simplified Mechanism

  • A proton transfer converts the alkoxide anion into the final alcohol product, acknowledging the instability of free H-.

NaBH4 vs. LiAlH4 Reactivity with Proton Sources

  • NaBH4 can reduce in water (weak acid), allowing simultaneous protonation and reduction, making it more convenient than LiAlH4, which requires two reaction steps:

    1. Treatment with LiAlH4 in ether.

    2. Acid workup with aqueous acid.

LiAlH4 Reactivity with Proton Source

  • Reacts quickly deprotonating weakly acidic protons from water/alcohols, producing hydrogen gas, which is exothermic and can lead to explosive reactions.

NaBH4 Reactivity with Proton Source

  • Deprotonation occurs slowly for NaBH4, especially at slightly basic pH, thus being more user-friendly for reductions in protic solvents.

Other Functional Groups and Hydride Agents

  • Functional groups with polar π bonds (excluding carbonyls) exhibit hydride reactions similarly, such as imines (Schiff bases) in biochemistry.

LiAlH4 Reducing Nitriles

  • LiAlH4 can reduce nitriles to primary amines.

    • Introduced through appropriate functional group transformations.

Sodium Hydride (NaH)

  • Sodium hydride is a strong base but poor nucleophile.

    • Typically generates carbon nucleophiles via proton transfer processes.

Organometallic Compounds

  • Strong nucleophiles and bases: Organolithium and Grignard reagents react quickly with water, resulting in exothermic proton transfers.

R⁻ Donors

  • Free R⁻ does not normally exist but behaves as R⁻ donors in reaction scenarios.

Organolithium Reaction and Its Mechanism

  • Example:

    1. Reaction with CH3(CH2)3-Li/ether at -65 °C for 3 hours.

    2. Followed by H3O for acid workup producing a new C-C bond and giving a yield of 74%.

Grignard Reaction and Mechanism

  • Procedure:

    1. Nucleophilic addition via R–MgBr at reflux for 5 hours followed by proton transfer using CH3OH.

  • Example results in formation of new C-C bonds with a 70% yield through acid workup.

Grignard Reactions and Synthesis of Carboxylic Acids

  • Highlighting the environmentally friendly synthesis method using greenhouse gasses as electrophiles.

Wittig Reagents and the Wittig Reaction: Synthesis of Alkenes

  • Defined as compounds characterized by a C-P bond where the C has a ˗1 formal charge, and P holds a +1 formal charge.

Wittig Reaction Mechanism

  • Step 1: Nucleophilic attack leading to a betaine formation.

  • Step 2: Coordination step leading to the formation of oxaphosphetane.

    • Advantages include generation from common alkyl halide precursors.

Mechanism for Generating Wittig Reagents

  • Step 1: SN2 reaction (nucleophile is Ph3P, leaving group is halide).

  • Step 2: Deprotonation by alkyllithium species - conditions suitable for such reactions (why alkyllithium as a base?).

  • Alkyl halide must have at least one H at the C atom bonded to the leaving group.

Sulfonium Ylides: Formation of Epoxides

  • Similar to phosphonium ylides, characterized by opposite charges on adjacent atoms, with sulfur being positively charged.

Epoxide Formation Using Sulfonium Ylides

  • Reaction of sulfonium ylides with carbonyls results in epoxide formation via nucleophilic addition followed by an internal SN2 reaction.

Direct Addition vs. Conjugate Addition

  • In compounds with C=C double bonds conjugated to polar π bonds, two electrophilic sites exist:

    • Carbonyl carbon (1st electrophilic site)

    • Alpha carbon (2nd electrophilic site)

Direct 1,2-Addition Mechanism

  • Nucleophilic attack at the carbonyl carbon results in direct 1,2-addition. After protonation, adjacent atoms show addition in 1,2-positioning.

Conjugate 1,4-Addition Mechanism

  • Attack at the beta carbon leading to conjugate 1,4-addition.

1,2 vs. 1,4 Addition

  • Dominance of addition type depends on whether the nucleophile adds reversibly or irreversibly.

    • Weak nucleophiles typically yield 1,4-addition while strong nucleophiles yield 1,2-addition.

Reversible vs. Irreversible Nucleophilic Addition

  • Addition type dictates whether products are thermodynamically or kinetically controlled.

Observations

  • Nucleophiles adding reversibly yield conjugate products as major, while nucleophiles that irreversibly add yield direct products as major.

    • Examples of each type to be explored.

Trends in Reversibility

  • Weak or resonance-stabilized nucleophiles (e.g., amide bases, enolates) prefer 1,4-addition. - Enolate 1,4-addition is termed Michael Addition.

Irreversible vs. Reversible Examples

  • Major products illustrate distinct addition mechanisms influenced by solvent and nucleophile strength.

Thermodynamic vs. Kinetic Control

  • Control types can affect the product distribution based on reaction conditions, analogous to HBr addition to 1,3-butadiene.

Thermodynamic or Kinetic Products and Free Energy

  • The conjugate product is more stable, while the direct product forms more rapidly due to stabilization dynamics in the transition state.

Lithium Dialkyl Cuprates

  • Organocuprates (e.g., R2CuLi) show less reactivity than alkyllithium or Grignard reagents and primarily undergo conjugate addition.

Example Reaction

  • When treated with a,β-unsaturated carbonyls, R groups add at the beta carbon via conjugate addition.

Alkyllithium vs. Grignard Reagents

  • Alkyllithium reagents demonstrate a higher selectivity for direct 1,2-addition compared to Grignard reagents.

Organic Synthesis Overview

  • Notable reaction: Carbonyl compound (ketone/aldehyde) reacts with Grignard/alkyllithium.

  • Williamson ether synthesis is shown as a multistep route incorporating Grignard attacks.

Further Transformations

  • Alcohol to alkyl halide via PBr3 followed by reaction with alkoxide salt.

Synthesizing Alkenes: Wittig Reactions Advantage

  • Wittig reactions generally provide better syntheses of alkenes compared to elimination reactions due to selectivity and product formation.

Retrosynthetic Analysis

  • Assessing possible synthetical pathways and precursor suitability in organic synthesis problems.