458 Reactions of Alcohols, Ethers, Epoxides, Amines, and Sulfur-Containing Compounds

• Chemists explore natural sources for compounds to develop new drugs.

• Example: Cocaine from Erythroxylon coca leaves is used to create anesthetics.

• Alkyl halides undergo substitution and/or elimination reactions due to their electron-withdrawing halogen atoms.

• Relative reactivity of compounds in Group II depends on the electron-withdrawing group (the leaving group).

Reactivity Based on Leaving Group Basicity

• Stronger Bases & Weaker Leaving Groups:

  • Leaving groups from alcohols and ethers (HO- , RO-) are stronger bases than those from alkyl halides.

  • Consequently, alcohols and ethers are less reactive than alkyl halides in substitution and elimination reactions.

  • Alcohols and ethers must be activated to undergo these reactions.

• Amines:

  • Amine leaving groups (-NH2) are very basic, thus inhibiting substitution and elimination reactions; however, they serve as important nucleophiles and bases.

Table of Compounds and Their Characteristics

10.1 Nucleophilic Substitution Reactions of Alcohols: Forming Alkyl Halides

• Alcohols have a strong basic leaving group (HO-) which hinders substitution reactions.

• If the OH group is converted into a better leaving group, a nucleophilic substitution can occur.

  • Protonation Method:

  • Adding acid converts the OH group from HO- to H2O, a better leaving group.

  • The substitution reaction is typically slow and requires heating.

Nucleophilic Substitution Mechanism:

• Reaction:
  ext{R-OH} + ext{HX}
  ightarrow ext{R-X} + ext{H}_2 ext{O}

• Reaction requires weakly basic nucleophiles like I-, Br-, Cl-.

• Moderately and strongly basic nucleophiles are ineffective in an acidic medium as they get protonated.

Reactivity of Alcohols

• All types of alcohols (primary, secondary, tertiary) react with hydrogen halides (HI, HBr, HCl) to form alkyl halides:

  • Primary: SN2 reaction.

  • Secondary & Tertiary: Favor SN1 reaction due to carbocation stability.

SN1 Mechanism for Secondary and Tertiary Alcohols

1. Protonation of the alcohol.

2. Leaving group (H2O) departs forming a carbocation.

3. Nucleophile (X-) attacks the carbocation.

   • Both substitution and elimination products can form, although elimination products are minimal due to further interactions with HBr.

SN2 Mechanism for Primary Alcohols

1. Protonation of the alcohol.

2. Nucleophile attacks from the back (SN2).

3. Only substitution products form, as E2 elimination requires a stronger base.

Lucas Test for Alcohol Classification

• Used prior to spectroscopy, it distinguishes between primary, secondary, and tertiary alcohols using HCl/ZnCl2.

  • **Results: **

  • Tertiary: Immediate cloudiness.

  • Secondary: Cloudiness in 1-5 min.

  • Primary: Requires heating.

10.2 Other Methods to Convert Alcohols to Alkyl Halides

• Standard method involves treating alcohol with hydrogen halides for conversion to alkyl halides.

• Efficiency can be improved using phosphorus trihalides (PCl3, PBr3) or thionyl chloride (SOCl2).

• These reagents aid in creating a better leaving group compared to the halide ion.

Mechanism for Phosphorus Trihalide Reaction:

• Step 1: SN2 reaction occurs on phosphorus.

• Pyridine neutralizes the intermediate, allowing halides to displace.

Mechanism for Thionyl Chloride Reaction:

1. Protonation of the alcohol.

2. Formation of an alkyl chloride when SO2 is a good leaving group.

Table 10.1 : Common Methods for Converting Alcohols into Alkyl Halides

10.3 Converting Alcohols into Sulfonate Esters

• Alcohols can also activate for nucleophilic substitutions as sulfonate esters.

• Reaction of alcohol with sulfonyl chloride (e.g., TsCl) leads to the formation of sulfonate esters.

Sulfonate Ester Formation Mechanism

1. Alcohol reacts with sulfonyl chloride in pyridine.

2. Formation of sulfonate ester as a good leaving group.

Advantages of Sulfonate Esters

• Sulfonate esters allow subsequent substitutions with various nucleophiles as they react via SN2.

• They can facilitate broader synthetic applications due to excellent reactivity.

Key Characteristics of Sulfonate Esters

• Display excellent leaving group properties due to the stability of negative charge through resonance fragmentation.

Problem 10: Reality of Configuration Change

• Alcohol to ether conversions via alkyl halides result in configurations opposing original alcohol.

• Inversion occurs during successive SN2 reactions, whereas tosylates maintain original configurations.

10.4 Elimination Reactions of Alcohols: Dehydration

• Dehydration involves the loss of a water molecule from an alcohol, leading to alkene formation.

• An acid catalyst (e.g. H2SO4) and heat are necessary.

Dehydration Mechanism - E1 and E2

1. E1 Mechanism (Secondary/Tertiary Alcohols):

   • Protonation leads to carbocation formation.

   • Loss of water creates a double bond.

Key Takeaway: Depending on the alcohol structure, dehydration mechanisms differ in the stability and arrangement of intermediary species.

2. E2 Mechanism (Primary Alcohol):

• Elimination occurs in a concerted manner with a base abstracting a proton, yielding alkenes.

Dehydration Products

• Major products are the more stable alkenes, following Zaitsev’s rule, which guides most highly substituted double bonds forming preferentially.

Influence of Carbocation Stability

• Carbocation intermediates influence the reactivity and selectivity pathways followed in dehydration, explaining primary, secondary, and tertiary alcohols’ distinct behavior.

10.5 Oxidation of Alcohols

• Alcohols can be oxidized to ketones and aldehydes using various oxidizing agents.

Common Oxidizing Agents

• Chromic Acid (H2CrO4):

  • Primary alcohols are oxidized to carboxylic acids.

  • Secondary to ketones.

  • Cannot oxidize tertiary alcohols.

• Pyridinium Chlorochromate (PCC): finer control halting oxidation at aldehyde levels for primary alcohols.

Novel Reagents

• HOCl as an alternative oxidizer provides a safer route for alcohol oxidation without toxic chromium byproducts.

Biological Reactions and Medical Applications

• In clinical practice, blood alcohol levels are assessed via reactions showing the stability of ethanol oxidization leading to chromic ion can positively correlate with breathalization levels.

• Antabuse aims to control alcoholism by blocking aldehyde dehydrogenase, causing unpleasant effects upon alcohol consumption.

Methanol Consideration

• Methanol can lead to formaldehyde formation, causing severe toxicity.

10.6 Nucleophilic Substitution Reactions of Ethers

• Ethers cannot undergo nucleophilic substitution without prior activation.

• Protonation with hydrogen halides enables substitution reactions via cleavage reactions similar to those observed in alcohols.

Mechanism of Ethers in Reactions

• Substitution reaction proceeds dependent on the ether structure.
  - Stable carbocation formation through protonation dictates the pathway for SN1 vs SN2 mechanisms respectively.

Summary of Reactions of Alcohols, Ethers, Epoxides, Amines, and Sulfur-Containing Compounds

• This extensive study of reactions provides foundational knowledge for understanding alcohols and derivatives in organic chemistry, specifically their reactivity, mechanisms, and practical applications.

• The knowledge elucidated here prepares students to tackle both theoretical and practical scenarios related to these compounds in both research and industrial applications.