Notes on Reactions of Carboxylic Acids and Carboxylic Acid Derivatives

Chapter 14: Reactions of Carboxylic Acids and Carboxylic Acid Derivatives

Introduction

  • Overview of carboxylic acids and derivatives, their structure, and related reactions.

The Families in Group III

  • Structure:
    • Carboxylic acids and derivatives can be represented generally as:
    • R−C(=O)ZR-C(=O)Z
    • Where Z = R or H or an atom more electronegative than carbon.

Carbonyl, Acyl, and Carboxyl Groups

  • Carbonyl Group: Characterized by the presence of a C=O bond.
  • Acyl Group: Contains a carbonyl group attached to an R group.
  • Carboxyl Group: Represented as −COOH-COOH and often abbreviated in formulas.

Classes of Carbonyl Compounds

  • Two Classes:
    • Substitutable Carbonyl Compounds: Can have a substituent replaced.
    • Non-Substitutable Carbonyl Compounds: Lack a substitutable group.

Naming Carboxylic Acids

  • Common Examples:
    • Methanoic acid (formic acid)
    • Ethanoic acid (acetic acid)
    • Propanoic acid (propionic acid)
    • Butanoic acid (butyric acid)
    • Pentanoic acid (valeric acid)
    • Hexanoic acid (caproic acid)
    • Propenoic acid (acrylic acid)
    • Pentanedioic acid (glutaric acid)

Identifying Chains in Carboxylic Acids

  • In systematic nomenclature:
    • Carbonyl carbon is considered C-1.
    • In common nomenclature, the adjacent carbon is the alpha (a) carbon.

Naming Carboxylic Acids Attached to Rings

  • Add "carboxylic acid" to the name of the cyclic compound.

Naming Salts of Carboxylate Ions

  • Common Names:
    • Sodium methanoate (sodium formate)
    • Potassium ethanoate (potassium acetate)
    • Sodium benzenecarboxylate (sodium benzoate)

Naming Acyl Chlorides

  • Systematic Names:
    • Ethanoyl chloride (acetyl chloride)
    • 3-Methylpentanoyl chloride
    • β-Methylvaleryl chloride
    • Cyclopentanecarbonyl chloride

Naming Acid Anhydrides

  • Formed from the loss of water from two molecules of a carboxylic acid.

Naming Esters

  • The substituent attached to the oxygen is stated first.
  • Change “ic acid” to “ate” in the name.

Naming Lactones (Cyclic Esters)

  • Examples include:
    • 2-Oxacyclohexanone
    • S-Valerolactone
    • 3-Methyl-2-oxacyclohexanone

Naming Amides

  • The substituent attached to nitrogen is named first.

Naming Lactams (Cyclic Amides)

  • Examples include:
    • 2-Azacyclohexanone
    • S-Valerolactam
    • 2-Azacyclopentanone

Formation of Carbonyl Groups

  • Discussion of the molecular orbitals involved in the formation of a carbonyl group.

Resonance Contributors of Carbonyl Compounds

  • Esters, carboxylic acids, and amides have two resonance contributors that stabilize their structures.

Physical Properties

  • Boiling Points (orderby):
    • Amide > Carboxylic Acid >> Ester ~ Acyl Chloride > Ketone > Aldehyde > Alcohol > Ether
  • Detailed boiling point data (example):
    • Carboxylic acid: bp=118°Cbp = 118 °C
    • Amide: bp=221°Cbp = 221 °C

High Boiling Points of Carboxylic Acids and Amides

  • Discussion on factors contributing to their relatively high boiling points compared to other compounds.

Carbonyl Carbon as an Electrophile

  • The carbonyl carbon is positive due to the electron-withdrawing effect of the oxygen.

Nucleophilic Acyl Substitution Reactions

  • General Mechanism:
    • Instability of sp3 hybridized carbons adjacent to electronegative atoms.

Bond Breaking During Nucleophilic Attacks

  • Nucleophile attacking:
    • Alkyl halide: breaks the sigma bond.
    • Carbonyl compound: breaks the pi bond.

Nucleophile Base Strength's Importance

  • If the incoming nucleophile (Z) is a weaker base than the reactant (Y):
    • The weakest base is eliminated from the tetrahedral intermediate.
    • Reactants may reform if Z is weaker.
  • If Z is stronger:
    • A new product forms.
  • If both have similar basicity:
    • A mixture of reactants and products is obtained.

Relative Reactivity Dependence on Basicity

  • Basicity of the substituent determines the reactivity of acyl compounds.

Tetrahedral Intermediate Formation and Collapse

  • Weaker bases in the reaction increase the electrophilicity of the carbonyl carbon, facilitating intermediate formation and elimination.

Reactivity Ladder of Carboxylic Acid Derivatives

  • Order of Reactivity:
    • Acid Chlorides > Acid Anhydrides > Esters > Amides > Carboxylic Acids > Carboxylate Anions

Carboxylic Acid Derivatives Reactivity

  • Conversion between derivatives only to less reactive forms.

Reactions of Acyl Chlorides

  • Reactions with nucleophiles explained.

Mechanism with Negatively Charged Nucleophile

  • Details on involving negatively charged nucleophiles in acyl substitution.

Mechanism with Neutral Nucleophiles

  • Description of how neutral nucleophiles interact during the same processes.

Requirements for Two Equivalents of Amine

  • One acts as the nucleophile; the other picks up excess protons post-reaction.

Reactions of Acid Anhydrides

  • Detailed reactions similar to acyl chlorides, showing the versatility of acid anhydrides.

Hydroxide-Ion-Promoted Hydrolysis of Esters

  • Analysis of reaction nature with water as a nucleophile.

Mechanism of Hydroxide Ion Action

  • Hydroxide ions facilitate reactions by functioning as a superior nucleophile compared to water.

Acid-Catalyzed Hydrolysis of Esters

  • How acids promote the hydrolysis process.

Mechanism for Acid-Catalyzed Hydrolysis

  • Description and stages involved in the catalyzed mechanic processes.

Use of Excess Water in Hydrolysis

  • Water’s effect on equilibrium shifts.

Protonation and Nucleophile Susceptibility

  • Protonation increases the susceptibility of the carbonyl for nucleophilic attack.

Improving Leaving Group Quality via Protonation

  • Protonation enhances the ability of leaving groups, impacting reaction rates.

Tertiary Alkyl Group Mechanism in Hydrolysis

  • Unique characteristics when dealing with tertiary structures during ester hydrolysis.

Comparison of Hydrolysis Types

  • Acid-catalyzed vs hydroxide-ion-promoted processes and their reversibility noted.

Alcohol Reactions with Esters

  • Transesterification detailed; how alcoholysis converts one ester to another.

Alcohol Reaction Catalyzation by Alkoxide Ions

  • Mechanisms highlighting the role of alkoxide ions in alcoholysis processes.

Reaction of Esters with Amines

  • Aminolysis described; reaction details with amines.

Saponification Process Explained

  • Ester hydrolysis breakdown into glycerol and sodium salts of fatty acids, forming soap.

Aspirin's Mechanism of Action

  • Role of cyclooxygenase, reaction with acetylsalicylate, and how it inhibits the enzyme's activity.

Micelle Formation by Soaps

  • Description of micelle structures formed by the interaction of soap molecules in water.

Relative Reactivity in Carboxylic Acids

  • Dependence on acidic form of carboxylic acids for nucleophilic acyl substitution.

Neutralization and Carboxylate Ion Reactivity

  • Insights on carboxylate ions not reacting with nucleophiles.

Fischer Esterification Process

  • Mechanism involving excess alcohol to drive equilibrium toward esterification.

Carboxylic Acids and Amines Reaction

  • Acid-base reactions leading to amide formation through heating.

Reactivity Comparison: Amides, Esters, and Carboxylic Acids

  • Overview of amide stability and reactivity properties.

Hydrolysis and Alcoholysis in Amides

  • Stressing the need for acidic environments for amide hydrolysis.

Gabriel Synthesis Overview

  • How amide groups are hydrolyzed to form primary amines.

Penicillin's Mechanism of Action

  • Involvement of penicillin in bacterial cell wall synthesis inhibition through acylation.

Penicillinase and Its Effects

  • Mechanism of action in penicillinase catalyzing penicillin hydrolysis.

Clinical Applications of Penicillins

  • List of penicillins in clinical use, showcasing their structural variations and targets.

Step-Growth Polymers Overview

  • Explanation of how these polymers form through functional group reactions.

Polyester and Polyamide Examples

  • Examples such as polyethylene terephthalate (Dacron) and nylon.

Nitriles Characteristics

  • Structural representation and naming conventions for nitriles and their hydrolysis properties.

Mechanism of Nitrile Hydrolysis

  • Outline of the acid-catalyzed hydrolysis mechanism for nitriles.

Synthesis of Carboxylic Acids and Amines from Nitriles

  • Conversion pathways of nitriles into desired products discussed.

Dicarboxylic Acids Overview

  • Structure, common names, and pKa values for various dicarboxylic acids.

Dicarboxylic Acid Behavior

  • Discussion of differences in pKa values and dehydration behavior on heating.

Anhydride Formation from Dicarboxylic Acids

  • Mechanism of cyclic anhydride formation via dehydration reactions.

Carboxylic Acids Activation to Acyl Chlorides

  • Discusses improving the leaving group quality to facilitate reactions.

Summary on Carboxylic Acid Derivatives

  • Activation methods discussed, including conversions facilitating diverse derivative synthesis.

Coenzyme A Role in Cells

  • Coenzyme A as an essential thiol in biochemical processes.