Carboxylic Acids & Derivatives – Key Vocabulary

Abundance & Industrial Significance of Carboxylic Acids

• Found widely in natural products (amino-acids, fatty acids, metabolic intermediates).
• Pharmaceutical/industrial uses: preservatives, solvents, polymer precursors.
• Key industrial transformation: acetic acid \longrightarrow vinyl acetate (monomer for poly(vinyl acetate) adhesives & coatings).

IUPAC & Common Nomenclature Rules

• Monocarboxylic acids: base name + suffix “oic acid.”
  • Example: \ce{CH3CH2CO2H} \rightarrow propanoic acid.
• Dicarboxylic acids: base name + suffix “dioic acid.”
  • Example: \ce{HO2C(CH2)4CO2H} \rightarrow hexanedioic acid (adipic acid).
• Accepted historical (common) names remain permissible (formic, acetic, benzoic, succinic, etc.).

Physical Properties & Acid–Base Chemistry

• Two hydrogen-bond donors/acceptors \Rightarrow relatively high b.p. & water-solubility (up to ~4–5 carbons).
• Deprotonation with strong base (e.g. \ce{NaOH}) gives a carboxylate salt: \ce{RCO2H + NaOH -> RCO2^- Na^+ + H2O}.
  • Naming: replace “ic acid” with “ate.” (propanoate, benzoate, etc.)
• Typical acidity: \text{p}K_a \approx 4 – 5 (≈10\^5 times stronger than alcohols).
  • Reason: conjugate base is resonance-stabilized [(two equal C–O bond lengths, e⁻ delocalization)].
• Henderson–Hasselbalch: \mathrm{pH}=\mathrm{p}Ka+\log\frac{[\text{RCO}2^-]}{[\text{RCO}_2H]}.
  • At physiological pH (7.4) \Rightarrow log term ≈ 3.4 \Rightarrow >99.9 % exists as carboxylate.
• Inductive effects: Electron-withdrawing groups (EWGs) lower \text{p}Ka. • Magnitude falls off with distance ((\alpha > \beta > \gamma)-carbon). • Example: \ce{ClCH2CO2H} (chloroacetic acid, \text{p}Ka = 2.9) more acidic than acetic acid (4.76).

Laboratory Preparations of Carboxylic Acids

• Nitrile Hydrolysis: \ce{RCN + 2H2O + H^+ \xrightarrow[]{\Delta} RCO2H + NH4^+} (acidic) or \ce{RCN + OH^- \xrightarrow[]{\Delta} RCO2^- + NH3} (basic).
• Grignard Carboxylation: \ce{RMgBr + CO2 \xrightarrow[]{Et2O}\ RCO2^- \xrightarrow[]{H3O^+} RCO2H}.

Reduction of Carboxylic Acids

• LiAlH4 or BH3·THF \Rightarrow primary alcohols (BH3 is selective in presence of other carbonyls).
  \ce{RCO2H \xrightarrow[]{1) LiAlH4\;2) H2O} RCH2OH}.

Overview & Nomenclature of Carboxylic Acid Derivatives (Same Oxidation State)

• Acid halide: replace “ic acid” with “yl halide.” (acetyl chloride).
• Acid anhydride: replace “ic acid” with “anhydride.” (acetic anhydride).
• Ester: name alkyl of alcohol + acid part “ate.” (ethyl acetate).
• Amide: replace “ic/oic acid” with “amide.” (acetamide).
• Nitrile: replace “ic acid” with “nitrile.” (acetonitrile).

Reactivity Principles of Derivatives

• Relative reactivity toward nucleophilic acyl substitution:
  \text{Acid halide} > \text{Acid anhydride} > \text{Ester} \approx \text{Carboxylic acid} > \text{Amide} (driven by leaving-group ability & resonance).
• Amide C–N shows partial (\pi)-character \Rightarrow restricted rotation, higher barrier (≈15–20 kcal·mol⁻¹).
• Generic mechanism:
  1. Nucleophilic attack on carbonyl \rightarrow tetrahedral intermediate.
  2. Re-form C=O; expel leaving group (avoid H⁻/C⁻ as leaving groups).
  3. Several proton transfers fine-tune charges (context-dependent).
     • Guideline: never create a strong base in strongly acidic medium, nor a strong acid in basic medium.

Acid Chlorides – Preparation & Reactions

• Formation: \ce{RCO2H + SOCl2 -> RCOCl + SO2 + HCl} (chlorination).
• Hydrolysis: \ce{RCOCl + H2O -> RCO2H + HCl}.
• Alcoholysis (esterification): \ce{RCOCl + ROH \xrightarrow[]{pyridine} RCO2R + HCl}.
• Aminolysis: \ce{RCOCl + 2NH3 -> RCONH2 + NH4Cl} (2 equiv NH3).
• Reduction:
  • LiAlH4 (excess) \rightarrow \ce{RCH2OH} (two hydride deliveries).
  • LiAlH(OtBu)3 (selective) \rightarrow aldehyde.
• Organometallic additions:
  • Grignard (2 equiv) \rightarrow tertiary alcohol (adds twice).
  • Gilman reagent \ce{R'2CuLi} (1 equiv) \rightarrow ketone (single substitution).

Acid Anhydrides

• Preparation:
  • Self-condensation of acetic acid at high T \rightarrow acetic anhydride + H2O.
  • \ce{RCOCl + RCO2^- Na^+ -> (RCO)2O + NaCl}.
• Reactions parallel those of acid chlorides; leaving group is \ce{RCO2^-} instead of \ce{Cl^-}.

Ester Formation & Reactions

• Alkylation of Carboxylate: \ce{RCO2^- + R'X -> RCO2R'} (SN2; requires strong base e.g. \ce{NaH} then alkyl halide).
• Fischer Esterification (acid-catalyzed, reversible):
  \ce{RCO2H + R'OH \rightleftharpoons[H2O][H^+] RCO2R' + H2O}.
  • Driven forward by excess alcohol or removal of water (Dean–Stark).
• Alternative: acid chloride + alcohol (+ pyridine) \rightarrow ester (irreversible).
• Hydrolysis:
  • Acidic: reverse of Fischer.
  • Basic (saponification): \ce{RCO2R' + OH^- -> RCO2^- + R'OH}; product carboxylate must be acid-work-up to acid.
• Reduction:
  • LiAlH4 \rightarrow two-step to primary alcohol.
  • DIBAH (\approx -78\,^{\circ}!\mathrm{C}) \rightarrow aldehyde (one hydride).
• Grignard (2 equiv) \rightarrow tertiary alcohol (analogous to acid chloride case).

Amide Chemistry

• Synthesis: best via acid chloride + amine (or ammonia) because direct coupling with carboxylic acid is sluggish (requires \ge 200 °C).
• Hydrolysis (harsh):
  • Acidic (6 M HCl, heat): \ce{RCONH2 -> RCO2H + NH4^+}.
  • Basic (NaOH, heat): \ce{RCONH2 -> RCO2^- + NH3}.
• Reduction (excess LiAlH4) \rightarrow amine \ce{RCH2NH2} (C=O completely removed).

Nitrile Chemistry

• Preparations:
  • \ce{RBr + NaCN -> RCN + NaBr} (SN2).
  • Dehydration of amide: \ce{RCONH2 + P2O5 -> RCN + H2O}.
• Hydrolysis (acidic or basic) \rightarrow carboxylic acid (via amide).
• Grignard Addition + work-up \rightarrow ketone:
  \ce{RCN + R'MgBr -> RC(=N^-MgBr)R' \xrightarrow[]{H3O^+} RCOR'}.
• Reduction (LiAlH4) \rightarrow primary amine \ce{RCH2NH2}.

Functional-Group Interconversion & Synthetic Planning

• Flowchart concept: acid \leftrightarrow chloride \leftrightarrow anhydride \leftrightarrow ester \leftrightarrow amide \leftrightarrow nitrile.
  • Upward moves (toward more reactive) require activating reagents (e.g. \ce{SOCl2}).
  • Downward moves (to less-reactive) accomplished via nucleophilic acyl substitution.
• When building C–C bonds, choose a protocol that positions the new carbon skeleton adjacent to the correct functional group (e.g., Grignard on acid chloride for tertiary alcohol vs. Grignard on nitrile for ketone).

Spectroscopic Identification

• IR: carbonyl stretch 1650 – 1850\;\text{cm}^{-1}.
  • Exact frequency diagnostic:
  – Acid chloride: \sim 1800\,\text{cm}^{-1}.
  – Anhydride (two bands): 1820 & 1760.
  – Ester: \sim 1740.
  – Carboxylic acid: \sim 1710 (+ broad O-H 2500–3500).
  – Amide: \sim 1660 – 1690.
  • Conjugation drops \nu_{C=O} by ≈20–30 cm⁻¹.
• ^{13}\text{C} NMR:
  • Carbonyl carbons of derivatives: 160 – 185\;\text{ppm}.
  • Nitrile carbon: 115 – 130\;\text{ppm} (sp-hybrid).
• ^{1}\text{H} NMR: CO2H proton highly deshielded \approx 12\;\text{ppm}.