Chapter 11: The Chemistry of Alcohols and Thiols – Study Notes

Chapter 11: The Chemistry of Alcohols and Thiols

Overview

This chapter explores the structure, properties, and reactivity of alcohols and thiols, focusing on their acid-base behavior, methods of preparation, and key reactions such as dehydration, substitution, and oxidation. The chapter also discusses the use of alcohols and thiols in organic synthesis and their transformation into other functional groups.

Alcohols and Thiols as Brønsted Acids and Bases

Acidity of Alcohols and Thiols

• Alcohols have acidity similar to water (pKa ≈ 15.9 for ethanol).

• Thiols are much more acidic than alcohols (pKa ≈ 10.5 for ethanethiol).

• The conjugate bases of alcohols are called alkoxides (e.g., sodium ethoxide), and those of thiols are thiolates (e.g., sodium methanethiolate).

Example:

• Ethanol: $\mathrm{CH_3CH_2OH}$, pKa = 15.9

• Ethanethiol: $\mathrm{CH_3CH_2SH}$, pKa = 10.5

Formation of Alkoxides and Thiolates

• Alkoxides require a stronger base than hydroxide for complete formation:

$\mathrm{CH_3CH_2OH} + \mathrm{NaH} \rightarrow \mathrm{CH_3CH_2O^-Na^+} + \mathrm{H_2}$

• Sodium metal can also be used to generate alkoxides:

$2\mathrm{R-OH} + 2\mathrm{Na} \rightarrow 2\mathrm{R-ONa} + \mathrm{H_2}$

• Thiols can be deprotonated by hydroxide or alkoxide to form thiolates (mercaptides):

$\mathrm{CH_3CH_2SH} + \mathrm{CH_3CH_2O^-} \rightarrow \mathrm{CH_3CH_2S^-} + \mathrm{CH_3CH_2OH}$

Polar Effects and Solvent Effects on Acidity

• Electronegative substituents (e.g., F) increase acidity, especially when close to the –OH group.

• Solvation stabilizes the conjugate base; large, branched alkyl groups decrease acidity by hindering solvation.

Alcohol	pKa	Alcohol	pKa
CH3CH2OH	15.9	(CH3)3COH	17.1
CH3OH	15.5	(CH3)2CHOH	17.1

Additional info: The order of acidity in aqueous solution is primary > secondary > tertiary alcohols. In the gas phase, the order is reversed.

Basicity and Amphoterism

• Alcohols and thiols can be protonated to form strong acids (conjugate acids), but their neutral forms are weak bases.

• Both alcohols and thiols are amphoteric: they can act as acids or bases (gain or lose a proton).

Example:

• Loss of a proton (acidic behavior): $\mathrm{EtOH} + \mathrm{OH^-} \rightleftharpoons \mathrm{EtO^-} + \mathrm{H_2O}$

• Gain of a proton (basic behavior): $\mathrm{EtOH} + \mathrm{H_3O^+} \rightleftharpoons \mathrm{EtOH_2^+} + \mathrm{H_2O}$

Thiols are less basic than alcohols.

Dehydration of Alcohols

General Reaction and Conditions

• Alcohols undergo dehydration (loss of water) in the presence of strong acids (e.g., H2SO4, H3PO4) to form alkenes.

• Heat and Lewis acids (e.g., Al2O3) can also catalyze dehydration.

$\mathrm{RCH_2CH_2OH} \xrightarrow{H_2SO_4,\ heat} \mathrm{RCH=CH_2} + \mathrm{H_2O}$

Mechanism of Dehydration (E1 Mechanism)

• Step 1: Protonation of the alcohol to form a better leaving group (–OH2+).

• Step 2: Loss of water to generate a carbocation intermediate.

• Step 3: Loss of a β-hydrogen to form the alkene.

Relative reactivity: Tertiary > Secondary > Primary alcohols (due to carbocation stability).

Regiochemistry and Rearrangements

• If multiple β-hydrogens are available, more than one alkene product can form (major and minor products).

• Carbocation rearrangements (hydride or alkyl shifts, ring expansions) can occur, leading to unexpected products.

Example: 3,3-dimethyl-2-butanol can rearrange to give 2,3-dimethyl-2-butene and 2,3-dimethyl-1-butene.

Reactions of Alcohols with Hydrogen Halides (HX)

Formation of Alkyl Halides

• Alcohols react with HX (HCl, HBr, HI) to form alkyl halides and water.

• Tertiary alcohols react via the SN1 mechanism; primary alcohols react via the SN2 mechanism.

$\mathrm{R_3COH} + \mathrm{HCl} \rightarrow \mathrm{R_3CCl} + \mathrm{H_2O}$

$\mathrm{RCH_2OH} + \mathrm{HBr} \rightarrow \mathrm{RCH_2Br} + \mathrm{H_2O}$

Mechanistic Details

• SN1 (Tertiary alcohols): Protonation, carbocation formation, nucleophilic attack by halide.

• SN2 (Primary alcohols): Protonation, concerted nucleophilic substitution by halide.

• Carbocation rearrangements can occur in SN1 reactions, leading to rearranged products.

Alcohol-Derived Leaving Groups: Sulfonate Esters

Activation of Alcohols

• Alcohols can be converted to sulfonate esters (e.g., tosylates, mesylates, triflates) to become better leaving groups for substitution and elimination reactions.

• Sulfonate esters are derivatives of sulfonic acids (R–SO3H).

Common Name	Structure	Abbreviation
Ethyl methanesulfonate	CH3SO3CH2CH3	OMs
sec-Butyl p-toluenesulfonate	p-TsOCH(CH3)CH2CH3	OTs

Preparation and Reactivity

• Prepared by reacting alcohols with sulfonyl chlorides (e.g., TsCl) in the presence of a base (e.g., pyridine).

• Sulfonate esters are excellent leaving groups due to the stability of the sulfonate anion.

• Triflate esters (OTf) are even better leaving groups than tosylates or mesylates.

Substitution and Elimination Reactions

• Sulfonate esters undergo SN2 and E2 reactions with nucleophiles and bases, respectively.

Reactions of Alcohols with SOCl2 and Ph3PBr2

Reactions with Thionyl Chloride (SOCl2)

• Alcohols react with SOCl2 (often with pyridine) to form alkyl chlorides, SO2 (gas), and HCl.

• Best for primary and secondary alcohols.

• Mechanism involves formation of a chlorosulfite intermediate, followed by SN2 displacement by chloride.

$\mathrm{RCH_2OH} + \mathrm{SOCl_2} \rightarrow \mathrm{RCH_2Cl} + \mathrm{SO_2} + \mathrm{HCl}$

Reactions with Triphenylphosphine Dibromide (Ph3PBr2)

• Alcohols react with Ph3PBr2 to form alkyl bromides via an SN2 mechanism.

• Inversion of configuration occurs at the chiral center.

• Works well for primary and secondary alcohols.

Oxidation and Reduction in Organic Chemistry

Definitions

• Oxidation: Addition of oxygen/heteroatom or removal of hydrogen.

• Reduction: Addition of hydrogen or removal of oxygen/heteroatom.

• Oxidation state increases with more bonds to oxygen or other electronegative atoms.

Oxidation of Alcohols

• Secondary alcohols are oxidized to ketones (e.g., 2-octanol to 2-octanone) using chromium-based reagents (e.g., Na2Cr2O7/H2SO4).

• Primary alcohols are oxidized to aldehydes (and further to carboxylic acids if water is present).

• Anhydrous conditions (e.g., PCC in CH2Cl2) stop oxidation at the aldehyde stage.

• Tertiary alcohols do not undergo oxidation (no α-hydrogen).

$\mathrm{RCH_2OH} \xrightarrow{[O]} \mathrm{RCHO} \xrightarrow{[O]} \mathrm{RCOOH}$

$\mathrm{R_2CHOH} \xrightarrow{[O]} \mathrm{R_2CO}$

Mechanism of Cr(VI) Oxidations

• Involves formation of a chromate ester intermediate and elimination to form the carbonyl compound.

• Requires at least one α-hydrogen on the alcohol carbon.

Oxidation of Thiols

• Thiols are oxidized at the sulfur atom, not the carbon.

• Oxidation can yield disulfides (R–S–S–R) or, with stronger oxidants, sulfonic acids (R–SO3H).

• Disulfide formation is important in protein structure and stability.

$2\mathrm{RSH} + [O] \rightarrow \mathrm{RSSR} + H_2O$

$\mathrm{RSH} + [O] \rightarrow \mathrm{RSO_3H}$

Summary Table: Key Reactions of Alcohols and Thiols

Reaction Type	Alcohols	Thiols
Acid-Base	Form alkoxides with strong base	Form thiolates with weaker base
Dehydration	Form alkenes (E1/E2)	Not typical
Substitution	Form alkyl halides (HX, SOCl2, Ph3PBr2)	Not typical
Oxidation	To aldehydes, ketones, acids	To disulfides, sulfonic acids

Additional info: Alcohols and thiols are important functional groups in organic synthesis, serving as intermediates for the preparation of a wide variety of compounds.