Chem 2/24

Bromopropyl and Heptahexanol Reaction

• Reaction Overview

  • Using bromopropyl as the electrophile and heptahexanol’s anion as the nucleophile.

  • Nucleophilic substitution occurs via an SN2 mechanism.

  • Clean displacement of bromide leading to the desired product.

• Synthesis Method

  • Begin with cyclohexanol, treat with sodium hydride to generate alkoxide.

  • Sodium hydride (NaH) considered a common base for this transformation.

  • Alkoxides are not only strongly basic but also nucleophilic.

Steric Effects and Reaction Pathways

• Alkoxides vs Nucleophiles

  • Alkoxides: Highly basic, tend to favor E2 elimination reactions over SN2 at secondary and tertiary centers.

  • Useful Rule: Alkoxides favor E2 versus SN2 reactions at secondary centers.

• Complicated Synthetic Considerations

  • Experienced synthetic chemists may find ways to facilitate SN2 reactions at secondary centers despite preferential E2 reactions.

• Sulfur Nucleophiles

  • Sulfur nucleophiles are nucleophilic but not strongly basic, useful for SN2 mechanisms even at a primary carbon center (e.g., bromoethane with thiolate nucleophile).

  • Stereochemistry can remain unchanged in some cases while inversion occurs in others during SN2 mechanisms.

Test Solutions in the Lab

• Sodium Iodide and Acetone Solution for SN2

  • Sodium iodide (NaI) is an excellent nucleophile but non-basic.

  • Acetone serves as a polar aprotic solvent, enhancing the nucleophile’s reactivity during SN2.

  • Visual test: formation of precipitate through insoluble sodium halides when nucleophiles displace leaving groups.

• Silver Nitrate and Ethanol for SN1

  • Silver nitrate (AgNO3) in ethanol provides conditions conducive to SN1 through carbocations.

  • Ethanol is polar and solvates carbocations without being a strong nucleophile, favoring SN1 reactions.

  • Visual cue: silver halides precipitate confirming reaction took place.

Examples of SN2 Reactions

• Benzyl Chloride with Sodium Cyanide

  • Cyanide is a strong, non-basic nucleophile facilitating SN2 at both primary and secondary centers.

  • Result: products are expected to retain certain groups unchanged where no leaving group is present.

• Reaction on Tertiary Centers

  • Tertiary centers and their corresponding reactivity constraints; often result in no reaction for SN2 due to sterics.

Structural Factors Affecting SN2 Reactivity

• Primary, Secondary, and Tertiary Centers

  • Primary centers are most reactive in SN2; secondary centers less so.

  • Tertiary centers typically do not undergo SN2 reactions due to steric hindrance.

• Beta-Center Effects

  • Presence of bulky groups adjacent to the reactive center decreases reactivity.

  • Neopentyl centers are significantly unreactive due to steric hindrance from adjacent alkyl groups.

Allylic and Benzylic Centers

• Favorable Reactivity

  • Allylic and benzylic centers exhibit enhanced reactivity due to resonance stabilization and favorable orbital overlap.

  • Overview of mechanisms suggests that these configurations enhance both SN2 and E2 reactions significantly.

• Unfavorable Cases

  • Direct substitution on sp2 carbons is unfavorable, highlighting limitations in performing SN2 reactions at certain orientations.

  • Geometric impossibility restricts SN2 from proceeding in specific configurations like those adjacent to a benzene ring.

Transition State Considerations

• Impact of Methyl Substitution

  • Data suggests each additional methyl group substitutes increases activation energy, slowing the SN2 reaction.

  • Rate assessments indicate that secondary structures encounter more significant barriers compared to primary configurations.

Transition to SN1 Reactions

• Mechanisms and Competitors

  • SN1 reactions are defined by the formation of stable carbocations, favored by polar solvents like methanol.

  • Occurrence of both substitution and elimination reactions with varying preferences based on carbon stability and solvent properties.