The Discovery of Nucleophilic Substitution Reactions

Introduction

• Nucleophilic substitution reactions: A fundamental type of reaction in organic chemistry.
• Initially discovered by Paul Walden in 1896.
• Walden demonstrated the interconversion of enantiomeric (+)- and (−)-malic acids through substitution reactions.

Key Discoveries

• Treatment of (−)-malic acid with PCl5 resulted in (+)-chlorosuccinic acid.
• This was converted back to (+)-malic acid using wet Ag2O.
• Similarly, the inverse process was used to convert (+)-malic acid to (−)-malic acid.
• Figure 11.2 depicts Walden's cycle of reactions.

Reaction Mechanism Insights

• Inversion of configuration occurs at the chirality center in some reactions.
• These reactions are termed nucleophilic substitutions as they involve replacing one nucleophile with another (Cl⁻ or OH⁻).

Historical Context

• Emil Fischer highlighted the significance of Walden's discoveries, comparing them to Pasteur's work.

Further Investigations

• Studies continued through the 1920s and 1930s to explore these reactions' mechanisms.
• Example: Interconversion of enantiomers of 1-phenyl-2-propanol via nucleophilic substitution of tosylate, as shown in Figure 11.3.
• Tosylate group acts like a halogen in these reactions.

Mechanism of Inversion

• In a three-step reaction involving tosylate and acetate ions, the inversion occurs during the substitution of tosylate by acetate.
• This observation led to the conclusion that primary and secondary alkyl halides or tosylates undergo nucleophilic substitution with inversion.

Worked Example 11.1

• Problem: Predict the product of a reaction between (R)-1-bromo-1-phenylethane and cyanide ion.
• Solution: Inversion of configuration results in the formation of (S)-2-phenylpropanenitrile.

Summary

• Nucleophilic substitution reactions are versatile and common in organic chemistry.
• Walden’s pioneering work laid the foundation for understanding these reactions.
• Inversion of configuration is a critical component in the stereochemistry of these reactions.

Additional Problems

• Explore further with exercises like the nucleophilic substitution of (S)-2-bromohexane with acetate ion.