Functional Group Chemistry: Carbonyls, Carboxylic Acids, Aldehydes, and Ketones

Newcastle University Functional Group Chemistry

Instructor Details

  • Instructor: Dr. Jon Sellars
  • Email: jon.sellars@newcastle.ac.uk

Learning Outcomes

At the end of this lecture, students will be able to:

  • Identify the basic structure of a carbonyl in a complex molecule and appreciate the increased functional complexity of this group, showing this with appropriate molecular examples.
  • Understand the reactivity of carbonyl compounds and how to utilize this knowledge.
  • Relate the structural reactivity of the carbonyl compound to the reaction pathway of a nucleophilic reaction, recognizing that carbonyl groups act as electrophiles.

Introduction to Carbonyl Compounds

  • C=O as Functional Group:
    • The carbonyl group (C=O) is the most important functional group in organic chemistry.
    • It is present in various functional groups such as:
    • Aldehydes
    • Ketones
    • Carboxylic acids
    • Esters
    • Amides
  • Reactivity of Carbonyl Groups:
    • Carbonyl groups participate in numerous reactions due to their electrophilic nature, facilitating their inclusion in many molecular structures.

Example Drug Molecules Containing Carbonyl Compounds

  • Cocaine
  • Procaine
  • Lidocaine
  • Enalapril
  • Captopril
  • Podophyllotoxin
  • Penicillin N
  • Erythromycin
  • Vincristine
  • Dactinomycin

Carbonyl Structure

  • Trigonal Planar Geometry:

    • The carbon atom is sp² hybridized, leading to a trigonal planar structure with bond angles of approximately 120°.
    • The C=O bond consists of a sigma (σ) bond formed by the overlap of two sp² hybrid orbitals and a pi (𝜋) bond formed via parallel p orbitals on carbon and oxygen.

  • Comparative Bond Characteristics:

    • The C=O bond is shorter (1.23 Å), stronger (178 kcal/mol or 745 kJ/mol), and more polar than the C=C bond in alkenes (1.34 Å, 146 kcal/mol or 611 kJ/mol).

Hydrogen Bonding

  • Importance of Hydrogen Bonding:

    • Hydrogen bonding is the most critical non-covalent interaction, influencing properties such as the melting point (mpt), boiling point (bpt), and surface tension of water, and playing a significant role in drug-molecule interactions with receptors.

  • Hydrogen Bonding Mechanism:

    • Carbonyl compounds can act as hydrogen bond acceptors due to the presence of a significant dipole moment. The carbonyl oxygen can participate in hydrogen bonds by interacting with hydrogen bond donors (HBD).

Interactions at Binding Sites

  • Characteristics of Binding Sites:
    • Carbonyl-containing molecules are planar and possess a significant dipole moment.
    • They may interact with binding sites through:
    • Hydrogen bonding (carbonyl group as an acceptor)
    • Dipole-dipole interactions

Reactions of Carbonyl Groups

  • General Reactions at the Carbonyl Carbon:

    • Electron pairs from the C=O bond can move to the electronegative oxygen, forming a tetrahedral alkoxide ion intermediate.
    • This process increases steric crowding, potentially leading to the formation of a chiral center (conversion from sp² to sp³ carbon).
    • Nucleophiles such as hydrides, alkynyl anions, and alkoxides are good candidates for nucleophilic addition, with the nucleophile approaching from above or below the C=O plane.

  • Bürgi-Dunitz Angle:

    • Reactivity varies for ketones (more steric crowding) versus aldehydes (less steric crowding), influencing nucleophilic attack geometry.

Reactivity of Carbonyl Groups

  • Protonation Effects:

    • Protonation of the carbonyl oxygen enhances the electrophilicity of the carbonyl carbon, making it more susceptible to nucleophilic attack.

  • Mechanism of Nucleophilic Addition:

    • The carbonyl group's electrophilic nature helps it undergo efficient nucleophilic reactions under the right conditions.
    • Nucleophiles can attack the carbonyl carbon in both acidic and basic conditions:
    • In basic conditions:
      • Nucleophiles are often deprotonated, targeting the carbonyl.
    • In acidic conditions:
      • Easier reversibility occurs since nucleophiles may become protonated, thus enhancing leaving group properties in the reaction.

Carboxylic Acids

  • Acidity:

    • Carboxylic acids are classified as weak acids that donate protons. When protons are transferred to water, hydronium ions (H₃O⁺) and carboxylate anions (RCO₂⁻) are formed.
    • Acidity constants (a) for typical carboxylic acids range from 10^{-3} to 10^{-5} with pKa values typically between 3 and 5.

  • Resonance Stabilization:

    • The greater acidity of carboxylic acids compared to alcohols is attributed to the resonance stabilization of the carboxylate anion, which serves as the conjugate base of the acid.

Carboxylic Acid Derivatives

  • Classes of Carboxylic Acid Derivatives:
    • Identified by the group (X) bonded to the acyl carbon:
    • -OH: Carboxylic acid
    • -Cl: Acid chloride
    • -OC(O)R’: Anhydride
    • -OR’: Ester
    • -NR₂: Amide
    • These derivatives can be interconverted using nucleophilic acyl substitution mechanisms and can be converted back to the parent carboxylic acid through hydrolysis.

Reactivity Trends

  • Reactivity decreases as the leaving group becomes more basic, affecting the stability and reactivity of the acid derivative. The more effective the orbital overlap (via resonance), the more stable and less reactive the corresponding derivatives become.

Biological Relevance of Carboxylic Acid Derivatives

  • Examples include acetyl-Coenzyme A (acetyl-CoA) and adenosine-5'-triphosphate (ATP) which have functional roles in metabolic pathways and energy transfer.

Aldehydes and Ketones

  • Reactivity:

    • Aldehydes typically exhibit greater reactivity than ketones in nucleophilic addition reactions due to a less crowded transition state.
    • Aldehydes possess a higher partial positive charge on the carbonyl carbon, making them more electrophilic compared to ketones.

  • Oxidation and Reduction:

    • Aldehydes can be oxidized to carboxylic acids (e.g., using oxidizing agents: CrO₃, KMnO₄, HNO₃).
    • Ketones show relatively low reactivity towards oxidation.

Keto-Enol Tautomerization

  • Definition:
    • This reversible reaction involves the interconversion between the keto (C=O) and enol (C=C-OH) forms of carbonyl compounds.
  • Mechanism:
    • Catalyzed by either acid or base; the process involves proton transfers between carbon and oxygen during transformation.

Implications of Carbonyl Reactivity in Pharmacology

  • Examples:
    • Xenical (orlistat) functions as an anti-obesity drug, acting locally and preventing fat absorption.
    • Aspirin interacts with enzyme prostaglandin synthase and acts as an irreversible inhibitor impacting inflammation pathways.
    • Acetylcholine esterase inactivates neurotransmitters, further serving as a target for drug interactions.

Summary

Overall, the structure, reactivity, and biological implications of carbonyl compounds such as carboxylic acids, aldehydes, and ketones play a crucial role in organic chemistry and medicine.