Organic Synthesis I: Lecture Notes

Introduction

• Welcome to the lecture on Organometallics.
• Video cast by Sandra and the Rcast team throughout the semester.
• This lecture is part one; part two on catalytic organometallics will be in summer.

Overview of Organometallics

• The periodic table has numerous metals, which can make selection challenging for synthesis.
• Despite the challenge, there is a suitable organometallic reagent for nearly any synthetic problem.
• Reactivity can be enhanced by adding ligands.

Example Reactions

• Alic Organometallic Species Reaction:
  • React an alic organometallic species with CO2.
  • Hydrolysis yields:
    • Carboxylic acid (90:10 ratio with potassium).
    • Different metal (Grignard reagent) yields 1:99 ratio.
  • Observation:
    • Potassium species is more reactive than Grignard, but Grignard yields a thermodynamically stable product due to kinetic control.

Structure and Reactivity

• Potassium Species:
  • Highly reactive system with a polar bond.
  • CO2 attacks terminal carbon due to less steric hindrance.
  • Forms a stable compound.
• Grignard Reagent:
  • Covalent bond with terminal carbon.
  • Electrophilic magnesium center (Lewis acid) interacts with CO2, forming a six-membered transition state.

HSAB (Hard-Soft Acid-Base) Concept

• Introduced by Pearson in the 1960s as an extension of the Lewis acid-base concept.
• Definitions:
  • Hard Acids: Small, high charge density, weakly polarizable (e.g., H+, Li+, Mg2+, Fe3+).
  • Soft Acids: Larger, low charge density, strongly polarizable (e.g., Ni+, Pd2+, Ag+).
• Bases:
  • Hard Bases: e.g., F-, OH-.
  • Soft Bases: e.g., I-, thiolates, phosphines.

Core Statement of HSAB Principle

• Soft acids react faster and form stronger bonds with soft bases.
• Hard acids react faster and form stronger bonds with hard bases.

Kinetics vs. Thermodynamics

• The HSAB principle does not differentiate between kinetics and thermodynamics, leading to oversimplifications.

Examples of HSAB Concept

• Example with a hard base (alcoholate) and hard acid:
  • Produces an ester, showcasing the stability of the product.
• Reactions involving soft bases (iodide, thiolate) yield more reactive products (carboxylic acid iodide).
• Stability of carboxylic acid fluorides vs. chlorides – fluorides more stable against hydrolysis.

Reactions with Carbonyl Compounds

• Demonstrating the concept with carbonyl compounds and soft nucleophiles:
  • Reactivity influenced by the nature of the electrophile and nucleophile.
  • Observed selectivity based on hardness/softness of the systems involved.

Enolates as Ambident Nucleophiles

• Enolates have two nucleophilic sites: oxygen (hard) and carbon (soft).
• The HSAB principle can predict selectivity but exceptions exist.

Influence of Reaction Conditions

• Solvent choice significantly affects product ratios in enolate reactions.
• Example with different leaving groups influences the ratio of O-alkylation to C-alkylation.

Summary of Key Points

• Organometallic species, including various metals, play crucial roles in synthetic reactions.
• The HSAB concept serves as a qualitative guideline despite its limitations.
• Selectivity in reactions is influenced by hardness/softness of acids and bases, sterics, and reaction conditions.

Conclusion

• The next lecture will discuss basic reaction types in organometallic chemistry.
• Thank you for attending!