Medicinal Chemistry: Covalent Bonding Concepts

Fundamentals of Medicinal and Pharmaceutical Chemistry

• This presentation covers covalent bonding in physiologically important ions and molecules.
• Essential concepts are covered in Chang and Goldsby's "Essential Concepts" textbook (Section 9.1, 9.2, 9.4 - 9.9).

Learning Outcomes

• Construct Lewis dot structures for diatomic and triatomic molecules.
• Define resonance.
• Define bond order and its relation to bond strength/length.
• Define free radical.
• Identify nitric oxide, superoxide ion, and hydroxyl radical as free radicals.
• Define disproportionation (dismutation) reaction.
• Outline the equation for superoxide disproportionation and the role of superoxide dismutase.
• Outline the equation for the reaction of nitric oxide and superoxide to form peroxynitrite.
• Outline the neurotoxicity of peroxynitrite.

Lewis Dot Structures

• A Lewis dot symbol shows the element symbol and one dot for each valence electron.
• Valence electrons occupy the outermost shell and participate in bonding.
• Lewis dot structures represent bonding in molecules and ions.

Six-Step Procedure for Lewis Dot Structures

1. Count the valence electrons for each atom (considering ionic charge).
2. Arrange the atoms in the molecule; hydrogen is generally excluded from the central atom.
3. Connect each central atom to the other atoms using a single bond.
4. Complete the octet rule for most electronegative atoms first by adding lone pairs. Hydrogen follows the duet rule.
5. If the central atom doesn't have a full octet, use electrons from surrounding atoms to form multiple bonds (double or triple).
6. Show any possible resonance forms.

Electronegativity Trends

• Electronegativity increases across a period and decreases down a group in the periodic table.
• The table provides Pauling scale values for relative electronegativity.

Resonance and Resonance Structures

• Resonance involves using multiple Lewis structures to represent a molecule.
• A molecule's actual structure is a hybrid of its resonance structures.
• A double-headed arrow indicates resonance structures.

O-O Bond Properties in O₃

• The two oxygen-to-oxygen bonds in ozone are experimentally identical in length.
• The O-O bond lengths are 128 pm each, intermediate between a single and double bond.

Resonance Structures of O₃

• Ozone's structure is a hybrid of resonance structures, so the bond order of each O-O bond is 1.5.

Bond Order

• Bond order indicates the approximate bond strength.
• A higher bond order correlates with a stronger bond.
• Bond order is the number of connections between atoms.

Lewis Dot Structure for CO₃²⁻

• Calculate the total valence electrons.
• Arrangement of atoms and single bonds.
• Complete the octet rule in most electronegative atoms (O) first, then on the central atom (C).
• Determine any resonance structures.

Bond Order of C-O Bonds in CO₃²⁻

• The C-O bonds in CO₃²⁻ are identical.
• The actual structure is a hybrid of resonance structures, so the C-O bond order is 4/3.

Lewis Dot Structure for CO

• Count the valence electrons for carbon and oxygen.
• Arrange the atoms and form a single bond.
• Complete octet rule for the oxygen atoms, then the carbon atom.
• Check for any resonance structures.

Isoelectronic Structures

• Isoelectronic structures have the same number of valence electrons and the same connectivity.
• They share the same number of atoms and bonds.
• Examples include N₂, CO, and NO⁺.

Limitations of Lewis Dot Structures

• Lewis structures cannot always explain the paramagnetism observed in molecules like O₂.
• Molecular orbital theory provides a more accurate explanation.

NO (Nitric Oxide)

• NO is a molecule of the year 1992, a neurotransmitter, and involved in lowering blood pressure and antimicrobial defense.
• NO relaxes muscle cells in the cardiovascular system.

Reactive Oxygen Species (ROS)

• ROS are by-products of mitochondrial oxidation, including superoxide ion (O₂⁻), peroxide ion (O₂²⁻), and hydroxyl radical (OH).
• Hydroxyl radical (OH) is the most reactive ROS.

Superoxide Ion (O₂⁻) and Superoxide Dismutase

• Superoxide ion is a damaging reactive oxygen species that is removed by disproportionation (dismutation).
• This enzyme-catalyzed reaction involves the simultaneous oxidation and reduction of oxygen.

Exceptions to the Octet Rule

• Group 2A and 3A elements can form stable compounds with fewer than 8 electrons around the central atom (e.g., BeH₂).

Learning Outcomes (Recap)

• Draw Lewis dot structures for diatomic and triatomic molecules using simple rules.
• Define resonance, bond order, free radical, and disproportionation (dismutation).
• Identify key molecules as free radicals.
• Describe reactions related to peroxynitrite, superoxide dismutase and reactive oxygen species.