Alpha-Carbon Chemistry & Carbonyl Condensation Reactions – Chapter 21 Review

21.1 Greek-Letter Nomenclature, Enol–Enolate Chemistry

• Greek letters & carbonyl proximity

  • Carbon next to carbonyl → α-carbon; next one → β-carbon; then γ, δ …

  • α-protons = hydrogens directly attached to the α-carbon.

• Enol–ketone tautomerism

  • In acid or base the C=O form interconverts with an enol (\text{C=C–OH}).

  • Equilibrium generally strongly favors the ketone/aldehyde (>99 %).

  • Significance: the enol places a π-bond at the α-position, rendering that carbon nucleophilic.

• Enolate formation

  • A strong base (e.g. \text{NaH}, \text{LDA}) removes an α-proton irreversibly → enolate (\text{O}^{–}–C= C).

  • Enolates are ambident nucleophiles (O-attack or C-attack) and key intermediates for C–C bond formation.

21.2 α-Halogenation & Specialized Transformations

• General α-halogenation

  • Aldehydes/ketones + X_2 in acid/base → halogen replaces an α-H.

  • Acidic variant is autocatalytic: HBr (or HCl) produced accelerates further protonation/enolization.

• Hell–Volhard–Zelinsky (HVZ) reaction

  • Carboxylic acid + \text{Br}2 / \text{PBr}3 → α-brominated acid.

  • \text{PBr}_3 converts acid → acyl bromide (more enolizable); bromine electrophilically halogenates; final hydrolysis regenerates acid.

• Haloform reaction

  • Scope: methyl ketones \text{RC(O)CH}_3.

  • Reagents: excess X_2 + excess base; work-up with acid.

  • Mechanism: successive α-halogenations → \text{RC(O)CBr}3 then base mediated cleavage → carboxylate \text{RCOO}^{–} + haloform \text{CHX}3 (e.g. \text{CHI}_3, yellow).

  • Synthetic utility: qualitative test for methyl ketones; preparation of carboxylic acids shortened by one carbon.

21.3 Aldol Chemistry

• Aldol addition

  • Aldehyde (or ketone) + \text{OH}^{–} (room T) → enolate of one molecule adds to carbonyl of another → β-hydroxy carbonyl (the “aldol”).

  • Aldehydes: equilibrium favors product (strong H-bonding, less steric hindrance).

  • Ketones: equilibrium favors starting material; reverse is retro-aldol.

• Aldol condensation

  • Heating β-hydroxy carbonyl in base eliminates \text{H}_2O via E1cb mechanism → \alpha,\beta-unsaturated carbonyl.

  • Conjugation provides large thermodynamic driving force.

• Crossed (mixed) aldol

  • Between two different carbonyl partners.

  • Efficient only if (i) one partner bears no α-H (e.g. benzaldehyde) or (ii) a directed aldol: pre-form specific enolate with LDA then add second carbonyl.

• Intramolecular aldol

  • Dicarbonyls (1,5- or 1,6-diketones/aldehydes) cyclize; five- and six-membered rings dominate (minimal strain).

21.4 Claisen Condensation & Dieckmann Cyclization

• Claisen condensation

  • Ester + matching alkoxide base → enolate adds to carbonyl of another ester → β-keto ester; final deprotonation drives equilibrium (requires ≥2 α-H on the donor ester).

  • Work-up with acid reprotonates the β-keto ester.

• Crossed Claisen

  • Mixed partners.

  • Practical when one ester lacks α-H (e.g. ethyl benzoate) or with directed enolate strategy.

• Dieckmann cyclization

  • Intramolecular Claisen of a diester → cyclic β-keto ester (again preferring 5/6-membered rings).

  • Economical route to cyclic ketones after decarboxylation.

21.5 Alkylation of Enolates & Ester Syntheses

• Direct α-alkylation

  • Generate enolate then add primary alkyl halide \text{RCH}_2X (SN2).

  • \text{LDA, −78 °C} → kinetic enolate (less substituted, faster deprotonation).

  • \text{NaH, rt} → thermodynamic enolate (more substituted, more stable).

• Acetoacetic ester synthesis

  • Start: ethyl acetoacetate (\text{Acetoacetic ester}).

  • Steps: (1) deprotonate α-H; (2) alkylate; (3) hydrolyze both esters + (4) decarboxylate ((\beta)-keto acid) upon heating ⇒ substituted acetone derivatives.

• Malonic ester synthesis

  • Start: diethyl malonate.

  • Same sequence gives substituted acetic acids after decarboxylation.

• Decarboxylation

  • Carboxylic acids with a \beta-carbonyl eliminate \text{CO}_2 on heating via a cyclic six-electron transition state.

21.6 Conjugate (Michael) Addition & Robinson Annulation

• Michael (1,4-) addition

  • \alpha,\beta-unsaturated carbonyl (Michael acceptor) + nucleophile (Michael donor) → attack at β-carbon → enolate.

  • Preference due to resonance stabilization: \ce{R2C=CH−C(=O)R'} \leftrightarrow \ce{R2C^{–}−CH=C(!O^{+})R'}.

• Michael donors

  • “Soft” nucleophiles: enolate of 1,3-dicarbonyls, \ce{CN^{–}}, \ce{RS^{–}}, cuprates, etc.

  • Ordinary ketone/ester enolates often too basic → employ Stork enamine.

• Stork enamine synthesis

  • Secondary amine + carbonyl → enamine (neutral, nucleophilic at α-C).

  • Enamine performs Michael addition; subsequent hydrolysis re-forms carbonyl → overall 1,5-difunctionalized product.

• Robinson annulation

  • Sequence: Michael addition → intramolecular aldol (with condensation) → bicyclic or fused rings.

  • Powerful for constructing steroid & terpene cores.

21.7 Product Patterns & Sequential Functionalization

• Functional-group distances produced

  • Aldol & Claisen condensations → 1,3-difunctionalization.

  • Michael / Stork → 1,5-difunctionalization.

• Tandem Michael–alkylation

  • The enolate generated after Michael attack can be trapped with an alkyl halide in the same pot → simultaneous α- and β-alkylation (efficient convergent synthesis).

Additional Mechanistic / Practical Notes

• E1cb elimination in aldol condensation:

  1. Base removes acidic proton → enolate (conjugate base).

  2. Leaving group (OH) departs as carbanion re-forms the C=O.

• Directed enolate generation avoids mixtures, enhances regio-selectivity in unsymmetrical ketones.

• Steric vs electronic control

  • Kinetic enolate favored by bulky, strong, non-nucleophilic base at low T.

  • Thermodynamic enolate favored by weaker base, reversible deprotonation, higher T.

• Ring-size preference (aldol & Dieckmann) follows Baldwin & Thorpe effects: 5/6-membered rings best balance enthalpy & entropy.

• Autocatalysis in α-halogenation: product acid increases electrophilicity of X_2 and protonates carbonyl, accelerating cycle.

• Ethical / safety considerations

  • \text{Br}2, \text{Cl}2, \text{PBr}_3 are corrosive and toxic; proper ventilation and PPE required.

  • Haloforms (especially \text{CHCl}_3) are carcinogenic; handle with care.

Key Equations & Numbers

• General enolate formation: \text{R–CO–CH}_2\text{R}' + \text{Base}^{–} \rightarrow \text{R–CO–CH}^{–}\text{R}' + \text{HB}

• Aldol condensation overall: 2\;\ce{CH3CHO} \xrightarrow[\Delta]{\text{OH}^{–}} \ce{CH3CH=CHCHO} + \ce{H2O}

• Claisen condensation: 2\;\ce{EtO–CO–CH2R} \xrightarrow{\text{EtO}^{–}} \ce{EtO–CO–CH2–CO–R} + \ce{EtOH}

• Decarboxylation: \ce{R–CO–CH2–CO2H} \xrightarrow{\Delta} \ce{R–CO–CH3} + \ce{CO2}

• Michael addition: \ce{\underset{donor}{CH2(CO2Et)2^{–}} + CH2=CH–C(=O)R} \rightarrow \ce{CH2(CO2Et)2–CH2–CH2–C(=O)R}

Conceptual Map

α-Halogenation (21.2) ↔ provides electrophilic centers usable in nucleophilic substitution → next step into carbon–carbon couplings.
Enolate chemistry (21.1) is the foundation → leads to Aldol (1,3 difunctionalization) & Claisen (β-keto esters).
Michael addition extends reach to 1,5 spacing; Robinson annulation merges Michael + Aldol → ring construction.
Ester syntheses (acetoacetic / malonic) exploit easy decarboxylation to reveal ketones/acids.

End of Study Notes – replicate content of Section 21 comprehensively.