Alcohols, Ethers, Aldehydes and Ketones

Alcohols (R—OH) are compounds characterized by the hydroxyl functional group —OH bonded to a saturated (sp³) carbon. They are classified into:

• Primary (1°): R—CH₂OH (e.g., ethanol CH₃CH₂OH)
• Secondary (2°): R₂CH—OH (e.g., isopropanol (CH₃)₂CHOH)
• Tertiary (3°): R₃C—OH (e.g., tert-butanol (CH₃)₃COH)

Physical properties: alcohols have much higher boiling points than corresponding alkanes due to intermolecular hydrogen bonding. Ethanol (M=46) boils at 78°C, while ethane (M=30) boils at −89°C. Water solubility decreases as the carbon chain length increases (methanol, ethanol, and isopropanol are miscible with water; octanol is practically insoluble).

Acidity of alcohols: alcohols are very weak acids (pKₐ ≈ 15–18), but can be deprotonated by strong bases (NaH, NaNH₂, alkali metals) to form alkoxides RO⁻. Alkoxides are strong bases and excellent nucleophiles, used in the Williamson synthesis to produce ethers.

Ethers (R—O—R'): compounds with an oxygen atom bonded to two alkyl or aryl groups. They are polar aprotic solvents (diethyl ether, THF) with low boiling points compared to the corresponding alcohols (no intermolecular H-bonding). They are relatively inert, but the C—O bond can be cleaved by strong acids (HI, HBr).

Real-world applications: ethanol is the active ingredient of alcoholic beverages and a biofuel (E85). Isopropanol is a disinfectant. Methanol is a fuel and industrial precursor (formaldehyde, MTBE). THF and diethyl ether are essential laboratory solvents.

The carbonyl group (C=O) is one of the most important functional groups in organic chemistry. It is present in aldehydes, ketones, carboxylic acids, and their derivatives. Its structure and reactivity are determined by the polarization of the double bond:

• Oxygen, more electronegative than carbon, attracts both the $pi$ and $sigma$ bond electrons, creating a dipole: $mathrm{C^{delta+}=O^{delta-}}$
• The carbonyl carbon is electrophilic (partial positive charge) and can be attacked by nucleophiles
• The carbonyl oxygen is basic (lone pairs) and can be protonated in acidic medium, increasing the carbon's electrophilicity
• The carbonyl carbon has sp² hybridization: trigonal planar geometry, angles ≈ 120°

Difference between aldehydes and ketones: in aldehydes the carbonyl is terminal (at least one H bonded to the C=O), in ketones it is internal (two R groups bonded to C=O). Aldehydes are generally more reactive than ketones in nucleophilic additions for two reasons: (1) less steric hindrance, (2) more electrophilic carbon (the +I inductive effect of the two R groups in ketones reduces the positive charge).

Real-world applications: formaldehyde (HCHO) is used as a disinfectant and in resin production. Acetone ((CH₃)₂C=O) is a universal solvent. The carbonyl group is the central reactive site in countless biological and synthetic reactions.

The characteristic reaction of aldehydes and ketones is nucleophilic addition to the carbonyl. General mechanism:

1. The nucleophile (Nu⁻) attacks the electrophilic carbonyl carbon
2. The $pi$ electrons of C=O shift to oxygen, forming an alkoxide intermediate (RO⁻)
3. Protonation of the alkoxide in aqueous medium gives the final alcohol

Main addition reactions:

• Reduction to alcohols: NaBH₄ reduces aldehydes to 1° alcohols and ketones to 2° alcohols. LiAlH₄ (more powerful) does the same. Mechanism: transfer of H⁻ (hydride) as nucleophile.
• Grignard addition (RMgX): Grignard reagents (R—MgX, X=Cl,Br,I) are strongly basic nucleophiles. Addition to formaldehyde gives 1° alcohols, to aldehydes gives 2° alcohols, to ketones gives 3° alcohols.
• Addition of HCN (hydrogen cyanide): forms cyanohydrins (R₂C(OH)CN). Reversible reaction, base-catalyzed. Cyanohydrins are intermediates for $alpha$-hydroxyacid synthesis.

Formation of hemiacetals and acetals: reaction with alcohols under acidic conditions:

1. An alcohol (R'OH) adds to the carbonyl forming a hemiacetal (R₂C(OH)OR')
2. In excess alcohol, the hemiacetal reacts further losing H₂O and forming an acetal (R₂C(OR')₂)

Hemiacetals are unstable intermediates (except cyclic ones, e.g., in sugars). Acetals are stable and are used as protecting groups for the carbonyl in organic synthesis.

Real-world applications: acetal formation is fundamental for protecting the carbonyl group during reactions involving other parts of the molecule. Grignard reagents are among the most powerful tools in organic synthesis for forming C—C bonds.

The aldol condensation is one of the most important C—C bond-forming reactions in organic chemistry. It involves two molecules of aldehyde or ketone in the presence of base (or acid).

Mechanism in basic medium:

1. Enolate formation: the base abstracts an $alpha$ proton (adjacent to the carbonyl), forming an enolate ion, a resonance-stabilized intermediate (negative charge delocalized between C$alpha$ and O).
2. Nucleophilic addition: the enolate (nucleophile) attacks the carbonyl of a second aldehyde/ketone molecule, forming a new C—C bond.
3. Protonation: the alkoxide intermediate is protonated to give a eta-hydroxyaldehyde or eta-hydroxyketone (the aldol product).
4. (Optional) Dehydration: upon heating, the aldol loses H₂O forming an alpha,eta-unsaturated compound (enone or enal).

Variants:

• Self-condensation: two molecules of the same compound. Example: acetaldehyde → 3-hydroxybutanal (aldol) → 2-butenal (crotonaldehyde).
• Crossed (mixed) condensation: between two different carbonyl compounds. Requires that one of them has no $alpha$ H (e.g., formaldehyde, benzaldehyde) to avoid complex mixtures.
• Cannizzaro reaction: aldehydes without $alpha$ H (e.g., formaldehyde) in strong base undergo disproportionation: one molecule oxidizes to acid, the other reduces to alcohol.

Real-world applications: aldol condensation is central in organic synthesis (ring formation, drug and natural product synthesis). In biochemistry, glycolysis involves the reverse aldol condensation (cleavage of fructose-1,6-bisphosphate into two trioses). The perfume industry uses aldol condensation to synthesize $alpha$-amylcinnamaldehyde and other fragrant compounds.