Functional Group Chemistry 1

MPharm Programme - PHA111 Functional Group Chemistry 1

• Lecturer: Dr. Stephanie Myers
• Date: Dale 1.21
• Email: [email protected]
• Phone: 0191 5152760

Learning Objectives

• Appreciate the importance of functional group chemistry for pharmacy students
• Define diverse mechanistic terms to deduce and explain reaction mechanisms
• Identify nucleophiles, electrophiles, and determine leaving groups in organic molecules
• Identify functional groups in drug molecules and understand their properties, focusing on alkanes in the lecture
• Use accurate curly arrows to denote bond-making and breaking processes, focusing on alkane chemistry
• Explain product distribution patterns based on radical stability via hyperconjugation and resonance stabilisation

Functional Groups

• Understanding functional group chemistry allows for analysis of drug properties like:
  • Chemical structure
  • Ionisation
  • Solubility (lipid vs. aqueous)
  • Absorption, Distribution, Metabolism, Excretion (ADME)

Functional Groups (continued)

• Understanding how receptor binding produces a therapeutic effect and design new medicines for specific purposes
• Understanding how physiochemical properties affect analytical choices

What is a Functional Group?

• Most drugs are simple organic molecules composed of two parts:
  • A hydrocarbon part (usually unreactive)
  • A functional group (FG) where most reactions occur
• Molecules with the same functional group typically have similar properties and characteristic reactivities.
  • Examples of functional groups in the slides include: primary amine, secondary amide, phenol, lactam (cyclic amide), carboxylic acid, and an example of a drug containing some of these functional groups is amoxicillin

Chemical Similarity

• Emergency!!! Extreme Bronchospasm in asthma sufferer!
• The slides display several chemical structures related to the concept.

What is a Functional Group? (continued)

• Defining various types of hydrocarbons:
  • Alkanes (straight, branched, cyclic)
  • Alkenes (terminal, internal, cyclic)
  • Alkynes (terminal, internal)
  • Alcohols (primary, secondary, tertiary, phenol)

What is a Functional Group? (continued)

• Alkyl halides (primary, secondary, tertiary)
• Amines (primary, secondary, tertiary, quaternary)
• Amides (primary, secondary, tertiary)
• Aldehydes and Ketones

3D Representations

• Sp3 hybridised carbon atoms have a tetrahedral shape.
• Representations use wedged and hashed bonds.
  • Wedge bonds point towards the viewer
  • Hashed bonds point away from the viewer
• Plain bonds are in the plane of the screen
• Crucial for understanding chiral molecules and chiral centers (carbon atom with four different groups attached).

Reactivity and Reaction Mechanisms

• Mechanisms are detailed step-by-step descriptions of chemical processes.
• They involve the movement of electrons as bonds are made or broken.
• Reactions can be classified as ionic/polar (movement of two electrons in turn) or radical (movement of one electron in turn).

Nucleophile

• Defined as "nucleus-loving"
• Electron-rich molecules, usually with a negative charge or lone pairs of electrons, with curly arrows starting at the electron rich center.
• Double bonds can act as nucleophiles.

Electrophile

• Described as "electron-loving"
• Electron-poor molecules, often with a positive charge or polarisable atoms, with curly arrows ending at the electron poor center
• Polarisation by proximity can occur.

Leaving Groups

• Terminology for ions or neutral molecules displaced from a reactant during mechanistic sequences.
• Normally a consequence of a nucleophile attacking an electrophile.
• Good leaving groups form stable ions or neutral molecules.
• Students are expected to practice writing mechanisms involving nucleophiles, electrophiles, and leaving groups.

Bond Cleavage

• Heterolysis: Both electrons in a bond go to one atom.
• Homolysis: Each atom in a bond receives one electron.

Curly Arrows - Polar Mechanisms

• Double-headed arrows indicate movement of two electrons.
• Arrow placement is crucial for determining reaction pathways.
• These arrows visually represent the movement of electron pairs between electron-rich and electron-poor centers.

Curly Arrows - Radical Mechanisms

• Single-headed arrows represent the movement of one electron.
• Two radicals form a bond by donating electrons to each other.
• A bond breaks in a similar way, except each atom receives one electron.

Transition States and Intermediates

• Mechanisms might include predicted structures such as charged species or radicals.
• Diagrams illustrating the change in energy during reactants -> products are helpful visuals of the reaction processes.
• Energy difference between reactants and products is the standard free energy change ( $\Delta G^{\circ} $).
• High energy peaks represent transition states (or activated complexes).
• Energy minima between transition states indicate intermediates (structures in the pathway).

Why Study Mechanisms?

• Pharmacists need to understand how drugs are manufactured.
• Drugs covalently bind to biological targets through chemical mechanisms.
• Understanding metabolic processes helps predict drug stability.
• Understanding degradation mechanisms can improve drug stability.

Penicillins MOA

• Amoxicillin: Example of a covalent inhibitor, reacting through electrons within an active enzyme site by forming esters.
• Describes the reaction mechanism of Amoxicillin and relates it to the concept of covalent inhibitors.

Hydrocarbon Compounds

• Classification of hydrocarbons as aliphatic (linear, cyclic, saturated, unsaturated) or aromatic.
• Alkanes: Definition focusing on structure (containing only single bonds, C-C and C-H bonds) and properties (very unreactive, low reactivity with ionic or polar substances).

Alkanes: Physical Properties

• Melting and boiling points increase with increasing chain length and molecular weight due to weaker London dispersion forces.

Alkanes: Reactivity

• Alkanes are generally unreactive.
• Combustion reactions (reacting with oxygen to produce CO2, H2O and heat) and halogenation (reacting with halogens at high temperatures) are discussed.

Alkanes: Halogenation

• Radical mechanism for halogenation is outlined, including initiation, propagation, and termination steps

Alkanes: Halogenation (continued)

• Chlorine radical (Cl∙) is a chain carrier in propagation steps, leading to free-radical substitution for H with Cl.
• Example reaction of monochlorination of methane

Radical Stability

• Factors determining the substituted product distribution include probability and radical stability.
• Stability relates to the number of carbons bonded to the carbon with the unpaired electron (methyl, primary, secondary, tertiary).

Radical Stability (continued)

• More stable radicals form more stable products.
• Benzyl and allyl radicals are unusually stable due to resonance.

Hyperconjugation

• Hyperconjugation is a stabilising interaction resulting from interaction of σ bonds (of C-H alkyl groups) with the unfilled p orbital.
• Stabilises alkyl radicals by extending the electron system

Resonance Contributors and Hybrids

• Resonance contributors (e.g., unicorn and dragon) are different possible structures for a molecule connected by double-headed arrows.
• Resonance hybrid (rhinoceros) is the overall representation of the molecule as a combination of contributors.

Resonance Structures

• Being able to draw resonance structures is crucial for drawing and understanding reaction mechanisms.
• Resonance forms are not isomers or different compounds.
• Resonance structures are represented using double-headed arrows.

Resonance

• Resonance describes delocalization of electrons and/or charges.
• sp3 hybridised atoms cannot accept electrons during resonance.
• Resonance structures only exist on paper; they represent different extreme possibilities of the locations of electrons).

Resonance Structures (continued)

• The same number of paired and unpaired electrons exist in each resonance form.
• Atoms must be in the same plane, which requires overlap of p orbitals.
• The most stable form of resonance makes the largest contribution to the overall structure.

Resonance Stabilisation of Radicals

• The relative stability of different radicals is explained with examples and diagrams.
• Important resonance contributors of radicals like benzyl are represented and discussed.

Oxidation - AutoOxidation

• Oxidation (radical process) is a reaction that increases the number of bonds to oxygen and decreases the number of bonds to hydrogen.
• Auto-oxidation leads to drug degradation.
• Typical conditions that trigger autoxidation mechanisms include light, heat, and some metal ions, and these reactions are explained with diagrams and example structures.

Explore the significance of functional groups in pharmacy through this quiz. Understand the roles of nucleophiles, radical stability, and drug design principles that are essential for predicting the properties of drug molecules. Test your knowledge of key organic chemistry concepts critical for pharmacy students.