Reactions of Alcohols, Ethers, Epoxides, Amines, Sulfur-Containing Compounds, and Introduction to Organometallic Compounds

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

Overview

This chapter explores the chemical reactivity and transformation of alcohols, ethers, epoxides, amines, and sulfur-containing compounds, with an introduction to organometallic chemistry. Understanding these reactions is essential for organic synthesis and mechanistic reasoning in organic chemistry.

Alcohols: Substitution and Elimination Reactions

Leaving Group Basicity and Reactivity

• Leaving group ability is related to the basicity of the group: weaker bases are better leaving groups.

• Order of leaving group ability (from best to worst): alkyl halide > sulfonate ester > alcohol > ether > amine > quaternary ammonium ion > sulfonium ion.

• pKa of the conjugate acid of the leaving group is a key indicator: lower pKa means better leaving group.

Compound	pKa of Conjugate Acid	Leaving Group Ability
Alkyl halide (X = Cl, Br, I)	-10 to 3.2	Excellent
Alcohol	~15	Poor
Ether	~15	Poor
Amine	~40	Very Poor
Sulfonate ester	~-10	Excellent
Sulfonium ion	~-4	Excellent

Activation of Alcohols

• Alcohols are poor leaving groups and must be activated (usually by protonation) before substitution or elimination can occur.

• Acid converts the hydroxyl group into a better leaving group (water).

• Only weakly basic nucleophiles can be used in acidic conditions; strongly basic nucleophiles will react with the proton.

Conversion of Alcohols into Alkyl Halides

• Alcohols react with hydrogen halides (HX) to form alkyl halides.

• Primary and secondary alcohols require heat; tertiary alcohols do not.

• Mechanism depends on the structure of the alcohol:

  • Secondary and tertiary alcohols: $S_N1$ mechanism (carbocation intermediate).

  • Primary alcohols: $S_N2$ mechanism (direct displacement).

Carbocation Rearrangements

• In $S_N1$ reactions, carbocation intermediates may rearrange (e.g., hydride or methyl shifts) to form more stable carbocations, affecting product distribution.

Alternative Methods for Alkyl Halide Formation

• Alcohols can be converted to alkyl halides using:

  • Phosphorus tribromide (PBr3)

  • Phosphorus trichloride (PCl3)

  • Thionyl chloride (SOCl2)

• Pyridine is often used as a solvent and base.

• These methods avoid carbocation rearrangements and are useful for sensitive substrates.

Sulfonate Esters as Activated Alcohols

• Alcohols can be converted to sulfonate esters (e.g., tosylates) using sulfonyl chlorides and pyridine.

• Sulfonate esters are excellent leaving groups due to electron delocalization.

• Reactions:

  • Primary alkyl tosylates: substitution products.

  • Secondary alkyl tosylates: substitution and elimination products.

  • Tertiary alkyl tosylates: elimination products.

Product Configuration

• The stereochemistry of the product depends on the activation method and reaction mechanism ($S_N1$ vs. $S_N2$).

Dehydration of Alcohols

Acid-Catalyzed Dehydration

• Alcohols undergo elimination reactions to form alkenes (dehydration).

• Mechanism:

  • Protonation of the alcohol

  • Loss of water to form a carbocation

  • Deprotonation to yield the alkene

• Regioselectivity: The major product is the more stable (more substituted) alkene (Zaitsev's rule).

• Stereoselectivity: The major product is the stereoisomer with the largest groups on opposite sides of the double bond (E-alkene).

Relative Ease of Dehydration

• Tertiary alcohols > secondary alcohols > primary alcohols (in terms of ease of dehydration).

• Rate depends on carbocation stability.

Mechanistic Variations

• E1 mechanism: For secondary and tertiary alcohols (carbocation intermediate).

• E2 mechanism: For primary alcohols (concerted elimination).

• Dehydration under mild conditions (e.g., POCl3/pyridine) avoids carbocation rearrangements and does not require heat.

Oxidation of Alcohols

Oxidation Reactions

• Secondary alcohols are oxidized to ketones.

• Primary alcohols are oxidized to aldehydes (with PCC or Swern/Dess-Martin) or further to carboxylic acids (with H2CrO4).

• Tertiary alcohols cannot be oxidized to carbonyl compounds (no hydrogen on the carbon bearing the OH group).

Common Oxidizing Agents

• Chromic acid (H2CrO4)

• PCC (Pyridinium chlorochromate)

• Swern oxidation (DMSO, oxalyl chloride, triethylamine)

• Dess-Martin periodinane

• Hypochlorous acid (HOCl)

Mechanisms

• Oxidation typically involves formation of a chromate ester or similar intermediate, followed by elimination to form the carbonyl compound.

• Swern and Dess-Martin oxidations are mild and compatible with sensitive functional groups.

Ethers and Epoxides

Activation and Cleavage of Ethers

• Ethers must be activated by protonation before cleavage.

• Cleavage can proceed via $S_N1$ (if carbocation is stable) or $S_N2$ (if not).

Epoxide Synthesis and Reactivity

• Epoxides are three-membered cyclic ethers, highly strained and reactive.

• Epoxides react with nucleophiles:

  • Under acidic conditions: nucleophile attacks the more substituted carbon (due to partial positive charge).

  • Under basic/neutral conditions: nucleophile attacks the less hindered carbon.

Condition	Site of Nucleophilic Attack
Acidic	More substituted carbon
Basic/Neutral	Less hindered carbon

Amines and Sulfur-Containing Compounds

Amines

• Amines are poor leaving groups and do not undergo substitution/elimination easily.

• They are common organic bases and nucleophiles.

• Hofmann elimination: Quaternary ammonium ions can undergo elimination with strong base, yielding the less substituted alkene (anti-Zaitsev product).

Thiols and Thioethers

• Thiols (mercaptans) are more acidic than alcohols (pKa ~10 vs. ~15).

• Thiolate ions are good nucleophiles in protic solvents.

• Thioethers and sulfonium salts are important in organic synthesis and biological methylation reactions.

Introduction to Organometallic Compounds

Organolithium and Grignard Reagents

• Organometallic compounds contain a carbon-metal bond.

• Carbon in these compounds acts as a nucleophile.

• Organolithium: Formed by lithium-halogen or lithium-hydrogen exchange.

• Grignard reagents: Formed by reaction of alkyl halide with magnesium in ether solvent.

Reactivity and Applications

• Organolithium and Grignard reagents react as carbanions, attacking electrophiles such as carbonyl compounds.

• Transmetallation: Organometallic compounds can exchange metals with more electronegative metals.

• Organocuprates (Gilman reagents): Formed from organolithium and copper(I) iodide; used for substitution reactions, especially with alkyl halides and vinylic halides.

• Reactions with Gilman reagents are stereospecific.

Summary Table: Methods to Convert Alcohols into Alkyl Halides

Alcohol	Reagent	Product
ROH	HBr (Δ)	RBr
ROH	HI (Δ)	RI
ROH	HCl (Δ, ZnCl2)	RCl
ROH	PBr3 (pyridine)	RBr
ROH	PCl3 (pyridine)	RCl
ROH	SOCl2 (pyridine)	RCl

Key Equations and Mechanisms

• Alcohol to Alkyl Halide ($S_N1$): $R{-}OH + HBr \xrightarrow{\Delta} R{-}Br + H_2O$

• Alcohol to Alkyl Halide ($S_N2$): $R{-}OH + HBr \xrightarrow{\Delta} R{-}Br + H_2O$

• Dehydration of Alcohol: $R{-}OH \xrightarrow{H_2SO_4,\ \Delta} R=R + H_2O$

• Oxidation of Secondary Alcohol: $R_2CH{-}OH \xrightarrow{H_2CrO_4} R_2C=O$

• Oxidation of Primary Alcohol: $RCH_2OH \xrightarrow{PCC} RCHO$ $RCH_2OH \xrightarrow{H_2CrO_4} RCOOH$

• Swern Oxidation: $RCH_2OH \xrightarrow{(COCl)_2, DMSO, Et_3N} RCHO$

• Epoxide Reaction (Acidic): $\text{Epoxide} + NuH \xrightarrow{H^+} \text{Nu attacks more substituted carbon}$

• Epoxide Reaction (Basic): $\text{Epoxide} + Nu^- \xrightarrow{\text{base}} \text{Nu attacks less hindered carbon}$