The lecture series provides a foundational understanding of ionic reactions at polar sigma bonds in organic chemistry.

Structure, Properties, and Reactions at Alkyl Halides

For alkyl halides, the video series explain the origins of reactivity and propose mechanisms for substitution (SN1/SN2) and elimination (E1/E2) reactions. Key SN2 concepts include the concerted (single-step) backside attack resulting in inversion of configuration, with reactivity governed by substrate steric bulk (methyl > primary > secondary), strong nucleophiles, and polar aprotic solvents. E2 reactions are concerted beta-eliminations demonstrating regioselectivity (Zaitsev product with unhindered bases, Hoffman product with bulky bases) and stereospecificity, requiring an anti-coplanar transition state. SN1 and E1 reactions are step-wise, unimolecular processes characterized by the rate-determining formation of a carbocation intermediate, which can undergo rearrangements. These reactions are favored by polar protic solvents and good leaving groups. The video series explain how to predict plausible products and major outcomes by analyzing the reagent's function (base strength, nucleophilicity, steric bulk) and the alkyl halide's classification (primary, secondary, tertiary), while also considering regiochemical and stereochemical requirements.

Structure, Properties, and Reactions at Alcohols

Building on these foundations, the lectures cover alcohols, defined by a hydroxyl group connected to an sp3 carbon, and their characteristically high boiling points due to strong hydrogen bonding. The video series reveal how to convert the poor hydroxide leaving group into better ones—such as sulfonates, or by activation via protonation with Bronsted acids or coordination with Lewis acids—to enable substitution and elimination reactions. 

Structure, Properties, and Reactions at Ethers and Epoxides

The discussion then introduces ethers as generally unreactive solvents with low boiling points, lacking hydrogen bond donors themselves. Two main preparation methods are taught: acid-catalyzed SN2 reactions (yielding symmetrical ethers) and the Williamson ether synthesis (an alkoxide reacting with an alkyl halide). The sole significant reaction for ethers is acid-catalyzed cleavage with strong hydrogen halides, which can proceed via SN1 or SN2 mechanisms. Lastly, epoxides, a highly reactive subset of ethers due to ring strain and strong dipole moments, are explored. The video series show how to prepare epoxides via peroxidation of alkenes or intramolecular Williamson ether synthesis from halohydrins, both being stereospecific reactions. The ring opening of epoxides is detailed, with regiochemical outcomes differing under basic (nucleophile attacks less substituted carbon) versus acidic conditions (nucleophile attacks less substituted unless a tertiary carbon is present, then more substituted), with both leading to inversion of configuration at the attacked chiral center.

Student Learning Outcomes

Alkyl Halide Substitutions and Eliminations:

• Explain the origins of reactivity in alkyl halide substitutions and eliminations.

• Propose plausible mechanisms and transition states for substitution (SN1/SN2) and elimination (E1/E2) reactions.

• For SN2 reactions:

  • Predict the product and explain the stereochemical outcomes, specifically the inversion of configuration at the chiral center.

  • Identify the factors governing the rates, including substrate steric bulk (methyl > primary > secondary), nucleophile strength (stronger nucleophiles lead to faster reactions), and solvent effects (polar aprotic solvents increase reaction rate).

• For E2 reactions:

  • Predict the product and explain the regiochemical outcomes, favoring the Zaitsev product (more substituted alkene) with unhindered bases and the Hoffman product (less substituted alkene) with bulky bases.

  • Explain the stereochemical outcomes, noting the stereoselectivity where trans-alkenes are generally favored over cis-alkenes.

  • Understand the stereospecificity requiring an anti-coplanar transition state for the beta hydrogen and leaving group.

• For SN1 and E1 reactions:

  • Understand their unimolecular, step-wise nature characterized by a rate-determining carbocation formation.

  • Recognize that carbocations are prone to rearrangements, which can lead to multiple products and affect regiochemistry.

  • Identify factors affecting rates, such as polar protic solvents stabilizing intermediates and good leaving groups accelerating the reaction.

  • Explain the stereochemical outcomes of SN1, leading to an almost racemic mixture with a slight preference for inversion of configuration.

  • Predict plausible products, considering both substitution and elimination pathways from the carbocation intermediate.

• Overall, for alkyl halides, determine the function of reagents (strong/weak nucleophile, strong/weak base), analyze the substrate classification (primary, secondary, tertiary), and use this information to determine the expected mechanism(s) (SN1, SN2, E1, E2) and predict the major and plausible products, considering regiochemical and stereochemical requirements.

Alcohols:

• Rationalize the acidity of alcohols and differences in acidity among various alcohols (pKa values typically 15-18).

• Convert a poor hydroxide leaving group into a better leaving group through methods such as converting alcohols to sulfonate esters, or activating them using Bronsted acids (protonation) or Lewis acids (e.g., ZnCl2, SOCl2, PBr3).

• Utilize activated alcohols for substitution and elimination reactions, understanding that they follow the same rules as alkyl halides.

Ethers and Epoxides:

• Identify the ether functional group and explain its properties, particularly its generally low reactivity and low boiling points due to the lack of hydrogen bond donors, making them useful as solvents.

• Prepare ethers through two main methods:

  • Acid-catalyzed SN2 reactions between alcohols (efficient for symmetrical ethers, works best with primary alcohols).

  • Williamson ether synthesis, involving deprotonation of an alcohol with a strong base followed by an SN2 reaction with a primary or methyl alkyl halide.

• Predict reagents and products and propose mechanisms for the acid-catalyzed cleavage of ethers, which occurs only under strong acidic conditions (excess hydrogen halides and heat), typically yielding two alkyl halides and water, with SN1 favored if a tertiary carbon is present.

• Understand epoxides as a highly reactive subset of ethers due to significant ring strain and strong dipole moments.

• Prepare epoxides using two synthesis strategies:

  • Peroxidation of alkenes with a peroxy acid, a stereospecific reaction where cis alkenes yield cis epoxides and trans alkenes yield trans epoxides.

  • Intramolecular Williamson ether synthesis from halohydrins, also a stereospecific reaction where cis alkenes lead to cis epoxides and trans alkenes lead to trans epoxides via anti-addition in the halohydrin formation and subsequent intramolecular SN2.

• Predict reagents and products for the ring opening of epoxides and propose curved arrow mechanisms for this reaction under both basic and acidic conditions.

• For basic ring opening of epoxides:

  • Understand the regiochemical outcome: the nucleophile preferentially attacks the less substituted carbon in an SN2 fashion.

  • Explain the stereochemical outcome: inversion of configuration occurs at the attacked chiral center due to backside attack.

• For acidic ring opening of epoxides:

  • Understand the regiochemical outcome:

    • If a primary and secondary carbon are involved, the nucleophile attacks the less substituted carbon due to steric effects (SN2-like).

    • If a tertiary carbon is involved, the nucleophile attacks the more substituted (tertiary) carbon due to carbocation character stabilization (SN1-like).

  • Explain the stereochemical outcome: inversion of configuration occurs at the attacked chiral center due to backside attack (even in SN1-like scenarios at the tertiary center).