Introduction

The synthesis of complex molecules like Cardura (doxazosin) depends heavily on basic organic reactions. This chapter focuses on two types of reactions: nucleophilic substitution and base-induced elimination. These reactions are important in the lab and also play key roles in biological systems. As we explore the synthesis of doxazosin, we will see how these reactions, especially those involved in building the chiral benzodioxin core, are essential building blocks.

The benzodioxin part of doxazosin poses an intriguing synthetic challenge. Its chirality is important for the drug's effectiveness, and creating it requires a solid understanding of how to introduce and manipulate substituents. We will start by discussing the basic principles of nucleophilic substitution and elimination since these reactions form the foundation for more complex synthetic methods. Grasping these basic ideas will help us appreciate the skill and creativity behind the reactions used to create doxazosin.

Nucleophilic substitution and base-induced elimination often compete under similar reaction conditions. Both involve a molecule interacting with a nucleophile or a base. The key difference lies in how these reagents behave: nucleophiles try to form new bonds, while bases typically remove protons. This duality, where a species can act as either a nucleophile or a base, depends on the specific molecular environment. Thus, it’s important to study these reactions together to fully understand their strategic connection in organic synthesis.

• Nucleophilic Substitution: In nucleophilic substitution, one atom or group (the nucleophile) replaces another (the leaving group) within a molecule.  As we will see, the halides (Br-, Cl- and I-) are considered leaving groups so these will involve reactions of alkyl halides.  Recall that alkyl halides are be good electrophiles.  Nucleophilic substitution can proceed through a one-step concerted mechanism (SN2) or a two-step mechanism (SN1).
  
  Sn2 Mechanism (1 Step)
  In an SN2 reaction, the leaving group is displaced by the nucleophilic attack.  This occurs is a single step (i.e. concerted - all bond breaking and formation occurs at the same time). 
  
  SN1 Mechanism (2 Step)
  In an SN1 reaction, the leaving group is expelled in the first slow step and the nucleophile attacks the carbocation in the second faster step. 
  

• Elimination Reactions: Elimination reactions involve the removal of a hydrogen atom by a base, which triggers the departure of another group from an adjacent atom. This process generates a new double (𝜋) bond. Like substitution, elimination can occur in one step (E2) or two steps (E1).
  
  E2 Mechanism (1 step)
  The E2 mechanism is a concerted (single step) mechanism, in which a proton (H+) is removed by a base at the same time as the leaving group is expelled.
  
  
  E1 Mechanism
  The E1 mechanism is a two-step process where the leaving group first departs, forming a carbocation intermediate. In a subsequent, faster step, a base then removes a proton (H+) from an adjacent carbon, leading to the formation of a new 𝜋 bond.