Unit 2: Alcohols, Phenols, and Ethers

1. Primary, Secondary, and Tertiary Alcohols: Preparation, Properties, and Relative Reactivity

Conceptual Foundation

Alcohols are organic compounds containing one or more hydroxyl (-OH) functional groups bonded to a saturated carbon atom. They are classified as primary (1°), secondary (2°), or tertiary (3°) based on the number of carbon atoms directly attached to the carbon bearing the hydroxyl group.

Primary Alcohol (1°): R-CH2-OH (Carbon attached to 1 alkyl group)
Secondary Alcohol (2°): R2CH-OH (Carbon attached to 2 alkyl groups)
Tertiary Alcohol (3°): R3C-OH (Carbon attached to 3 alkyl groups)

Methods of Preparation

• Hydration of Alkenes: Acid-catalyzed hydration yields alcohols following Markovnikov rule (or anti-Markovnikov via hydroboration-oxidation).
• Hydrolysis of Alkyl Halides: Reaction of alkyl halides with aqueous sodium hydroxide or potassium hydroxide.
  R-X + NaOH (aq) -> R-OH + NaX
• Reduction of Carbonyl Compounds:
  • Aldehydes reduce to 1° alcohols using LiAlH4 or NaBH4.
  • Ketones reduce to 2° alcohols using LiAlH4 or NaBH4.
  • Esters and carboxylic acids reduce to 1° alcohols using LiAlH4.
• Grignard Reaction: Nucleophilic addition of organometallic reagents (RMgX) to carbonyl compounds followed by acidic hydrolysis:
  • Formaldehyde + RMgX -> Primary Alcohol (1°)
  • Other Aldehydes + RMgX -> Secondary Alcohol (2°)
  • Ketones + RMgX -> Tertiary Alcohol (3°)

Relative Reactivity and Distinction Tests

The chemical behavior of 1°, 2°, and 3° alcohols depends on whether the reaction involves C-O bond cleavage or O-H bond cleavage.

• C-O Bond Cleavage Reactivity Order: 3° > 2° > 1° (governed by carbocation stability).
• O-H Bond Cleavage Reactivity Order: 1° > 2° > 3° (governed by steric hindrance and electron-donating inductive effect of alkyl groups).

Key Analytical Tests for Differentiation

1. Lucas Test

Reagent: Mixture of concentrated hydrochloric acid (HCl) and anhydrous zinc chloride (ZnCl2).

• 3° Alcohols: React immediately at room temperature, forming an insoluble alkyl chloride layer producing turbidity instantly.
• 2° Alcohols: React within 5 to 10 minutes to produce turbidity at room temperature.
• 1° Alcohols: Do not react at room temperature; turbidity appears only upon heating.

2. Victor Meyer Test

Process: Alcohol -> Alkyl Iodide (P/I2) -> Nitroalkane (AgNO2) -> Nitrolic Acid / Pseudonitrol (HNO2) -> Base Addition (NaOH).

• 1° Alcohols: Produce a blood-red color (formation of soluble sodium nitrolate).
• 2° Alcohols: Produce a deep blue color (formation of insoluble pseudonitrol).
• 3° Alcohols: Solution remains colorless (no reaction with nitrous acid due to lack of alpha-hydrogen).

3. Catalytic Dehydrogenation (Passing vapor over hot Cu at 573 K)

• 1° Alcohol: Undergoes dehydrogenation to form an aldehyde.
• 2° Alcohol: Undergoes dehydrogenation to form a ketone.
• 3° Alcohol: Undergoes dehydration (loss of water) to form an alkene.

2. Bouveault-Blanc Reduction

Definition and Reaction

The Bouveault-Blanc reduction is an organic reaction where an ester is reduced to primary alcohols using sodium metal in absolute ethanol as the reducing agent.

R-COOR' + 4 [H] --(Na / C2H5OH)--> R-CH2-OH + R'-OH

Reaction Mechanism

1. Single Electron Transfer (SET): Sodium transfers an electron to the carbonyl carbon of the ester to yield a radical anion intermediate.
2. Protonation: The radical anion abstracts a proton from ethanol, forming a neutral radical.
3. Second Electron Transfer: Sodium donates a second electron to the carbon radical, generating an alkoxide-type hemiacetal anion.
4. Elimination: Loss of an alkoxide ion (R'O-) converts the intermediate into an aldehyde (R-CHO).
5. Further Reduction: The aldehyde is rapidly reduced by two additional single electron transfers from sodium and proton transfers from ethanol to produce the primary alcohol (R-CH2-OH).

Exam Notes and Application

This method selectively reduces ester functions to primary alcohols while leaving non-conjugated carbon-carbon double bonds intact, making it valuable when chemoselectivity is required.

3. Preparation and Properties of Glycols

Definition

Glycols (1,2-diols or vicinal diols) are organic compounds containing two hydroxyl (-OH) groups attached to adjacent carbon atoms. The simplest member is ethylene glycol (ethane-1,2-diol).

Methods of Preparation

• Hydroxylation of Alkenes:
  • Syn-Hydroxylation: Oxidation of ethylene with cold, dilute, alkaline potassium permanganate (Baeyer's reagent) yields 1,2-diols.
    CH2=CH2 + H2O + [O] --(cold alkaline KMnO4)--> HO-CH2-CH2-OH
  • Anti-Hydroxylation: Reaction of alkenes with peroxy acids (e.g., RCO3H) forms an epoxide, followed by acid-catalyzed ring opening to give anti-1,2-diols.
• Hydrolysis of Ethylene Oxide (Epoxides): Industrial preparation by acidic or basic hydrolysis of ethylene oxide.
  C2H4O + H2O --(H+)--> HO-CH2-CH2-OH
• Hydrolysis of 1,2-Dihaloalkanes: Heating 1,2-dichloroethane with aqueous sodium carbonate.
  Cl-CH2-CH2-Cl + Na2CO3 + H2O -> HO-CH2-CH2-OH + 2 NaCl + CO2

Physical and Chemical Properties

Ethylene glycol is a sweet-tasting, viscous, hygroscopic liquid with high boiling point (197 °C) due to extensive intermolecular hydrogen bonding.

• Reaction with Sodium: Mono- and di-sodium derivatives are formed sequentially at elevated temperatures.
  HO-CH2-CH2-OH + 2 Na -> NaO-CH2-CH2-ONa + H2
• Reaction with Phosphorus Pentachloride (PCl5): Yields 1,2-dichloroethane.
  HO-CH2-CH2-OH + 2 PCl5 -> Cl-CH2-CH2-Cl + 2 POCl3 + 2 HCl
• Dehydration: Products depend on dehydrating conditions:
  • Heating with concentrated H2SO4 at 170 °C yields 1,4-dioxane.
  • Heating with anhydrous ZnCl2 yields acetaldehyde (via vinyl alcohol intermediate).

4. Oxidation of Glycols by Periodic Acid and Lead Tetraacetate

Oxidative cleavage of vicinal diols breaks the C-C bond between carbon atoms carrying the hydroxyl groups, converting them into carbonyl functional groups.

1. Periodic Acid Oxidation (Malaprade Reaction)

Treatment of 1,2-diols with periodic acid (HIO4) results in oxidative cleavage of the carbon-carbon single bond.

R-CH(OH)-CH(OH)-R' + HIO4 -> R-CHO + R'-CHO + HIO3 + H2O

Mechanism

The reaction proceeds via a cyclic periodate ester intermediate formed between the 1,2-diol and periodic acid. Concerted electron reorganization within this 5-membered ring leads to cleavage of the central C-C bond, producing carbonyl fragments and iodic acid (HIO3).

Product Rules

• Primary alcoholic carbon (-CH2OH) oxidizes to Formaldehyde (HCHO).
• Secondary alcoholic carbon (-CH(OH)R) oxidizes to an Aldehyde (RCHO).
• Tertiary alcoholic carbon (-C(OH)R2) oxidizes to a Ketone (R2CO).

2. Lead Tetraacetate Oxidation (Criegee Oxidation)

Lead tetraacetate [Pb(OAc)4] selectively cleaves vicinal diols into two carbonyl fragments under mild anhydrous conditions.

R-CH(OH)-CH(OH)-R' + Pb(OAc)4 -> R-CHO + R'-CHO + Pb(OAc)2 + 2 CH3COOH

Mechanism

The diol undergoes ligand exchange with lead tetraacetate to form a cyclic lead diester intermediate. Heterolytic cleavage of the C-C bond yields two carbonyl compounds, lead(II) acetate, and acetic acid.

5. Pinacol-Pinacolone Rearrangement

Definition and General Reaction

The Pinacol-Pinacolone rearrangement is an acid-catalyzed conversion of 1,2-diols (pinacols) into ketones or aldehydes (pinacolones) accompanied by a 1,2-alkyl or aryl shift.

(CH3)2C(OH)-C(OH)(CH3)2 --(H2SO4, heat)--> CH3-CO-C(CH3)3 + H2O
(2,3-dimethylbutane-2,3-diol -> 3,3-dimethylbutan-2-one)

Step-by-Step Mechanism

1. Protonation: One of the hydroxyl groups accepts a proton from the acid catalyst to form a oxonium ion (-OH2+).
2. Water Elimination: Loss of a water molecule leaves behind a stable tertiary carbocation.
3. 1,2-Shift (Migratory Step): An adjacent alkyl or aryl group migrates with its bonding electron pair to the carbocationic center. This shift forms a resonance-stabilized protonated ketone (oxocarbenium ion).
4. Deprotonation: Loss of a proton regenerates the acid catalyst and yields the final carbonyl product (pinacolone).

Migratory Aptitude

When unsymmetrical pinacols react, the migrating group follows a specific hierarchy based on nucleophilicity and electron density:

Migratory Order: Aryl > Alkyl > Hydrogen

Among substituted aryl groups: p-methoxyphenyl > p-tolyl > phenyl > p-chlorophenyl. Groups with greater electron-donating power migrate preferentially.

6. Phenols: Preparation and Physical Properties

Definition

Phenols are aromatic organic compounds containing a hydroxyl group directly bonded to an aromatic benzene ring (Ar-OH).

Methods of Preparation

• From Cumene (Industrial Hydroperoxide Process): Air oxidation of cumene (isopropylbenzene) forms cumene hydroperoxide, which undergoes acid-catalyzed cleavage to yield phenol and acetone as a commercially useful co-product.
  C6H5-CH(CH3)2 + O2 -> C6H5-C(CH3)2-OOH --(H+)--> C6H5OH + CH3COCH3
• From Chlorobenzene (Dow Process): Heating chlorobenzene with aqueous NaOH at high temperature (350 °C) and pressure (300 atm) forms sodium phenoxide, which upon acidification yields phenol.
• From Benzene Sulfonic Acid: Fusion of sodium benzenesulfonate with solid NaOH at 300 °C produces sodium phenoxide, followed by acidification with dilute acid.
• From Diazonium Salts: Hydrolysis of benzenediazonium chloride by warming with dilute sulfuric acid yields phenol and nitrogen gas.
  C6H5-N2+Cl- + H2O --(heat)--> C6H5OH + N2 + HCl

Physical Properties

• Phenol is a colorless, crystalline solid that turns pink over time due to slow atmospheric oxidation.
• Exhibits high boiling point (182 °C) compared to hydrocarbons of similar molar mass due to strong intermolecular hydrogen bonding.
• Moderately soluble in water due to hydrogen bonding with water molecules, but completely soluble in alcohol and ether.

7. Acidity of Phenols and Factors Affecting Acidity

Origin of Acidity

Phenols are significantly more acidic than aliphatic alcohols (pKa of phenol ≈ 10, whereas pKa of ethanol ≈ 16), reacting with aqueous NaOH to form sodium salts.

C6H5OH + H2O <=> C6H5O- + H3O+

The elevated acidity of phenol stems from the stabilization of the resulting phenoxide ion (C6H5O-) relative to the parent phenol molecule:

• In phenol, the oxygen atom is attached to an sp2 hybridized carbon which is more electronegative than the sp3 carbon of alcohols.
• The lone pair on oxygen delocalizes into the pi-system of the aromatic ring, placing partial negative charges on ortho and para positions.
• The phenoxide ion formed after deprotonation is stabilized by 5 resonance structures. Because the negative charge is delocalized across oxygen and three ring carbon atoms, the phenoxide ion is remarkably stable.

Factors Affecting Acidity

1. Electron-Withdrawing Groups (EWGs)

Substituents such as -NO2, -CN, -halo, and -COOH draw electron density away from the aromatic ring through inductive (-I) and mesomeric (-M) effects. This stabilizes the phenoxide ion, shifting the equilibrium toward ionization and increasing acidity.

• Nitrophenols show a marked increase in acidity. The effect is strongest at ortho and para positions where mesomeric delocalization is maximal.
• 2,4,6-Trinitrophenol (Picric acid, pKa ≈ 0.38) is an exceptionally strong organic acid due to three strongly electron-withdrawing nitro groups.
• Note on Ortho vs Para Nitrophenol: 2-Nitrophenol is slightly less acidic than 4-nitrophenol because intramolecular hydrogen bonding in 2-nitrophenol stabilizes the un-ionized molecule and hinders proton loss.

2. Electron-Donating Groups (EDGs)

Substituents such as -CH3, -OCH3, and -NH2 release electron density into the aromatic ring (+I or +M effects), destabilizing the phenoxide ion and decreasing acidity.

• Cresols (methylphenols) are less acidic than unsubstituted phenol.

8. Ring Substitution Reactions of Phenols

The hydroxyl group (-OH) is a powerful activating group and directs incoming electrophiles to the ortho and para positions due to strong resonance electron donation (+M effect).

1. Nitration

• Dilute Nitric Acid (298 K): Yields a mixture of ortho-nitrophenol and para-nitrophenol. The isomers are separated by steam distillation; ortho-nitrophenol is steam-volatile due to intramolecular hydrogen bonding, whereas para-nitrophenol is non-volatile due to intermolecular hydrogen bonding.
• Concentrated Nitric Acid (with H2SO4): Results in nitration at all active sites to form 2,4,6-trinitrophenol (Picric acid).

2. Halogenation

• In Non-Polar Solvent (CS2 or CCl4 at 273 K): Electrophilic bromination gives a mixture of ortho- and para-bromophenol (para is the major product).
• In Aqueous Medium (Bromine Water): The phenoxide ion forms readily in water, strongly activating the ring. Bromination occurs at all open ortho and para positions, immediately yielding a white precipitate of 2,4,6-tribromophenol.

3. Sulfonation

• Low Temperature (25 °C): Kinetic product dominates: o-phenolsulfonic acid.
• High Temperature (100 °C): Thermodynamic product dominates: p-phenolsulfonic acid.

4. Friedel-Crafts Reactions

Phenol reacts with alkyl or acyl halides in the presence of anhydrous AlCl3 to yield ortho- and para-alkylated or acylated phenols. Higher quantities of AlCl3 catalyst are required because oxygen forms a complex with AlCl3.

9. Reimer-Tiemann Reaction and Mechanism

Reaction Definition

Treatment of phenol with chloroform (CHCl3) in the presence of aqueous sodium hydroxide (NaOH) introduces a formyl group (-CHO) into the aromatic ring predominantly at the ortho position, producing salicylaldehyde (2-hydroxybenzaldehyde).

C6H5OH + CHCl3 + 3 NaOH -> o-HO-C6H4-CHO + 3 NaCl + 2 H2O

Detailed Reaction Mechanism

1. Electrophile Generation: The hydroxide ion abstracts a proton from chloroform to yield a trichloromethyl carbanion, which eliminates a chloride ion to form dichlorocarbene (:CCl2), an electron-deficient neutral electrophile.
   CHCl3 + OH- <=> :CCl3- + H2O
   :CCl3- -> :CCl2 + Cl-
2. Deprotonation of Phenol: Base deprotonates phenol to form nucleophilic phenoxide ion.
3. Electrophilic Addition: Phenoxide ion attacks the electrophilic dichlorocarbene at the ortho position, breaking ring aromaticity and forming a cyclohexadienone anion with a -CHCl2 group.
4. Tautomerization: Proton loss restores aromaticity, yielding a dichloromethyl phenoxide intermediate.
5. Nucleophilic Substitution / Hydrolysis: Hydroxide ions replace both chlorine atoms to generate an unstable gem-diol intermediate (-CH(OH)2), which spontaneously loses a water molecule to yield the aldehyde function (-CHO).
6. Acidification: Acidic workup converts sodium salicylaldehyde to salicylaldehyde.

10. Kolbe-Schmidt Reaction and Mechanism

Reaction Definition

Treatment of sodium phenoxide with carbon dioxide (CO2) at elevated temperature (125-140 °C) and pressure (4-7 atm), followed by acidic hydrolysis, yields salicylic acid (2-hydroxybenzoic acid).

C6H5ONa + CO2 --(125-140 °C, 4-7 atm)--> Sodium Salicylate --(H+)--> Salicylic Acid

Detailed Reaction Mechanism

1. Phenoxide Formation: Phenol reacts with NaOH to yield sodium phenoxide. Phenoxide is far more nucleophilic than neutral phenol.
2. Electrophilic Addition: The phenoxide ion attacks carbon dioxide (a weak electrophile) at the ortho position. The sodium cation coordinates with both oxygen atoms of carbon dioxide and phenoxide oxygen, guiding the addition stereoselectively to the ortho position.
3. Rearomatication: Proton transfer (tautomerization) from the ring restores aromaticity, yielding sodium salicylate.
4. Acidification: Protonation with aqueous mineral acid yields free salicylic acid.

11. Fries Rearrangement and Mechanism

Reaction Definition

The Fries rearrangement involves the conversion of phenolic esters (phenyl alkanoates) into acylphenols (ortho- and para-hydroxyacetophenones) in the presence of a Lewis acid catalyst such as anhydrous aluminum chloride (AlCl3).

C6H5-O-CO-R --(anhydrous AlCl3, heat)--> o-hydroxyacylphenol + p-hydroxyacylphenol

Temperature Control of Isomer Distribution

• Low Temperatures (< 60 °C): The reaction is under thermodynamic control and yields para-hydroxyacetophenone as the major product.
• High Temperatures (> 160 °C): The reaction yields ortho-hydroxyacetophenone as the major product, stabilized by intramolecular hydrogen bonding and chelation with aluminum.

Detailed Reaction Mechanism

1. Complex Formation: The oxygen atom of the ester carbonyl group coordinates with the Lewis acid AlCl3.
2. Cleavage to Acylium Ion: The ester carbon-oxygen bond cleaves, generating an acylium ion (R-C+=O) and an aluminum phenoxide complex.
3. Electrophilic Aromatic Substitution: The generated acylium ion attacks the electron-rich aromatic ring of the phenoxide at either the ortho or para position.
4. Rearomatication & Hydrolysis: Proton elimination restores ring aromaticity. Subsequent aqueous acidic hydrolysis produces the corresponding hydroxyacetophenone.

12. Claisen Rearrangement and Mechanism

Reaction Definition

The Claisen rearrangement is the thermal conversion of allyl aryl ethers into o-allylphenols upon heating (around 200 °C) without needing an external catalyst.

C6H5-O-CH2-CH=CH2 --(200 °C)--> o-allylphenol

Key Characteristics

• It is a classic example of a concerted [3,3]-sigmatropic rearrangement.
• Intramolecular transformation: The allyl group migrates directly to the ortho position.
• Inversion of the allyl group: The gamma-carbon of the original allyl chain bonds to the aromatic carbon atom.
• If both ortho positions are blocked, the allyl group migrates to the para position via two consecutive [3,3]-sigmatropic shifts.

Detailed Reaction Mechanism

1. Concerted Cyclic Transition State: Heating causes the allyl aryl ether to pass through a 6-membered cyclic chair-like transition state. The original O-C bond breaks while a new C-C bond forms simultaneously between the terminal gamma-carbon of the allyl group and the ortho-carbon of the ring.
2. Keto Intermediate Formation: This concerted electron movement forms a non-aromatic dienone intermediate (2-allylcyclohexa-2,4-dienone).
3. Tautomerization: Rapid keto-enol tautomerization takes place, shifting a hydrogen atom from the ring carbon back to oxygen, restoring aromaticity to form o-allylphenol.