Hofmann Elimination and Amines

Overview

Lecture covers Hofmann elimination, polyalkylation of amines, and related reactions.
Emphasis on mechanism, regiochemistry (least substituted alkene), and examples.
Also touches on reductive amination and synthetic routes to primary amines.

Converts amine to quaternary ammonium salt, then to alkene upon base and heat.
Major product: the least substituted (less substituted) alkene — opposite of Zaitsev rule.
Mechanism: E2 anti-periplanar elimination where the quaternary ammonium is the leaving group.

Excess alkyl halide (e.g., methyl iodide) converts primary/secondary amines to quaternary ammonium salts.
Process: NHx → successive substitution replaces hydrogen(s) and lone pair with alkyl groups.
Result: quaternary ammonium ion (positively charged nitrogen) with halide counterion (I-).

Ag2O acts as Ag+2 and O2-; in water it produces hydroxide ions (OH-).
One Ag+ precipitates I- as AgI (insoluble), exchanging I- for OH- on the ammonium salt.
Net: quaternary ammonium iodide → quaternary ammonium hydroxide (anion exchange).
Heating required for elimination step.

Hydroxide deprotonates beta-hydrogen.
Electrons form a C=C between alpha and beta carbons.
Bond between alpha carbon and nitrogen breaks; nitrogen leaves with its substituents (as tertiary amine or related).
Result: alkene formed between alpha and beta carbons; leaving group is the tertiary amine (or neutral species upon deprotonation).

Hofmann elimination favors formation of the least substituted alkene (Hofmann product).
Contrast with Zaitsev rule (E2 typical): Zaitsev gives the most substituted alkene.
When multiple non-equivalent beta hydrogens exist, elimination can occur at different beta positions producing different alkenes.
Major product is from deprotonation at the beta position leading to the least substituted double bond.
If cis/trans stereoisomers available, trans is generally favored (but cis may be present in small amounts).

Standard procedure flagged by reagents: excess methyl iodide + Ag2O (imply Hofmann elimination).
Steps to analyze a substrate:
- Identify the nitrogen and label alpha carbon (attached to N) and all beta carbons.
- For each distinct beta position, draw product formed by removing a beta hydrogen and forming a double bond to alpha.
- Determine substitution level of each alkene; least substituted is major product.
- Count stereoisomers (cis/trans) where applicable; trans usually favored.
Example outcomes:
- Single beta type → single alkene product.
- Multiple distinct beta positions → multiple alkene products (major = least substituted).
- Include cis isomer counts if counting total possible products.

Elimination is concerted (E2) and requires an anti-periplanar arrangement between the beta-H and leaving group.
Leaving group: quaternary ammonium (very good leaving group as neutral amine after departure).
Heat necessary; reaction does not proceed at room temperature in typical exam scenarios.

Converts carbonyl compounds (aldehydes/ketones) to amines via imine formation then reduction.
Common reducing agents:
- H2 with Pd/C (hydrogenation).
- Sodium cyanoborohydride (NaBH3CN) — milder, selective for imine reduction.
Used to make secondary or tertiary amines depending on starting carbonyl and amine.

Street synthesis of methamphetamine: pseudoephedrine → reductive amination/reduction steps noted (discussion of legal/ethical concerns).
Converting bromopropyl (or similar) substrates to primary amines:
- Gabriel synthesis (phthalimide route) → hydrolysis to yield primary amine.
- SN2 with CN- to extend carbon chain → reduce nitrile (LAH) to amine.
- Reduce nitro group (e.g., Fe/HCl, H2/Pd/C, or LAH) to obtain amine.
- Reductive amination: aldehyde + NH3, then reduce imine to primary amine.

Quaternary Ammonium Ion: Nitrogen bearing four alkyl groups and a positive charge.
Hofmann Elimination: Elimination of a quaternary ammonium hydroxide to give the least substituted alkene.
Zaitsev Rule: Traditional E2 preference for the most substituted (more stable) alkene.
Polyalkylation: Sequential alkylation of amines leading to tertiary/quaternary amines.
Reductive Amination: Formation of amine via imine intermediate followed by reduction.
Anti-Periplanar: Required E2 geometry where the hydrogen and leaving group are opposite in the same plane.

Practice identifying alpha and all distinct beta carbons for substrates.
Draw all possible Hofmann products; determine which is least substituted.
Work assigned homework problems and compare to solutions manual.
Review Gabriel synthesis, nitrile reductions (LAH), nitro reductions, and reductive amination mechanisms and reagents.