Organic Mechanisms. Xiaoping Sun

to dedicate my book to Dr. Jack Passmore, my former PhD supervisor, and to my organic chemistry and biochemistry students at University of Charleston. The book is also dedicated to my wife Cindy and my son Oliver.

      Xiaoping Sun, PhD

      Professor of ChemistryProfessor of Chemistry Charleston, West Virginia

ABOUT THE COMPANION WEBSITE

      This book is accompanied by a companion website: www.wiley.com\go\Sun\OrgMech_2e

      The website includes:

       Solution Manual

       PPT

1 FUNDAMENTAL PRINCIPLES

      1.1 REACTION MECHANISMS AND THEIR IMPORTANCE

      The microscopic steps in a chemical reaction which reflect how the reactant molecules interact (collide) with each other to lead to the formation of the product molecules are defined as mechanism of the reaction. The mechanism of a reaction reveals detailed process of bond breaking in reactants and bond formation in products. It is a microscopic view of a chemical reaction at molecular, atomic, and/or even electronic level.

      The structure of most organic compounds is well established by X‐ray crystallography and various spectroscopic methods with the accuracy of measurement in bond distances and angles being the nearest to 0.01 Å and 1°, respectively. Only effective molecular collisions, the collisions of the molecules with sufficient energy that take place in appropriate orientations, lead to chemical reactions. The extent of a chemical reaction (chemical equilibrium) is determined by the changes in thermodynamic state functions including enthalpy (ΔH), entropy (ΔS), and free energy (ΔG). The combination of kinetic and thermodynamic studies, quantum mechanical calculations, and geometry and electronic structure‐based molecular modeling has been employed to reveal mechanisms of various organic chemical reactions.

Reaction mechanisms play very important roles in the study of organic chemistry. The importance of mechanisms not only lies in that they facilitate an understanding of various chemical phenomena but also that mechanisms can provide guidelines for exploring new chemistry and developing new synthetic methods for various useful substances, drugs, and materials. In this regard, mechanistic studies will allow synthetic chemists to vary reaction conditions, temperatures, and proportions of chemical reagents to maximize yields of targeted pure products. For industrial chemists, mechanistic knowledge allows the prediction of new reagents and reaction conditions which may affect desired transformations. It also allows optimization of yields, reducing the costs on raw materials and waste disposals. It provides a tool for the chemists to make reactions occur in their desired ways and manufacture the ideal products. For biochemists and medicinal chemists, the microscopic view of organic reactions can help them better understand how the metabolic processes in living organisms work at molecular level, how diseases affect metabolism, and how to develop appropriate drug molecules to assist or prevent particular biochemical reactions [1].

      Overall, the goal of this book is to tie reaction mechanisms, synthetic and green chemistry methodology, and biochemical applications together to form an integrated picture of organic chemistry. While the book emphasizes mechanistic aspects of organic reactions, it is a practical textbook presenting the synthetic perspective about organic reaction mechanisms appealing to senior undergraduate‐level and graduate‐level students. The book provides a useful guide for how to analyze, understand, approach, and solve the problems of organic reactions with the help of mechanistic studies.

      In this chapter, fundamental principles that are required for studies and understanding of organic reaction mechanisms are briefly reviewed. These principles include basic theories on chemical kinetics, transition states, thermodynamics, and atomic and molecular orbitals.

1.2 ELEMENTARY (CONCERTED) AND STEPWISE REACTIONS

      Some chemical reactions only involve one microscopic step. In these reactions, the effective molecular collision, the collision of reactant molecules with sufficient energy in appropriate orientation, leads to simultaneous breaking of old bonds in reactants and formation of new bonds in products. This type of reactions is defined as elementary (or concerted) reactions. An elementary (concerted) reaction proceeds via a single transition state. The transition state is a short‐lived (transient) activated complex in which the old bonds are being partially broken and new bonds are being partially formed concurrently. It possesses the maximum energy level (in the free energy term) in the reaction profile (energy profile).

Many other chemical reactions involve many microscopic elementary (concerted) steps in the course of the overall reactions. These reactions are defined as stepwise (or multistep) reactions. A stepwise reaction proceeds via more than one transition state. Each microscopic concerted step proceeds through one transition state, giving a distinct product which is referred to as an intermediate. Each intermediate formed in the course of a stepwise reaction is metastable and usually highly reactive, possessing a relatively high energy level. Once formed, the intermediate undergoes a subsequent reaction eventually leading to the formation of the final product.

Figure 1.1 shows reaction profiles for concerted and stepwise reactions using examples of S_N2 and S_N1 reactions, respectively [1]. In a concerted reaction such as the S_N2 reaction of bromomethane (CH₃Br) with hydroxide (OH⁻) (Fig. 1.1a), as the reactant molecules start colliding effectively, namely that OH⁻ approaches (attacks) the carbon atom in CH₃Br from the opposite side of the –Br group, formation of a new bond (the O─C bond) and breaking of an old bond (the C─Br bond) occur simultaneously. At the same time, the hydrogen atoms in CH₃Br move gradually from the left side toward the right side. The reaction proceeds via a single transition state (activated complex) in which the old C─Br bond is being partially broken, coincident with the partial formation of a new O─C bond. The hydrogen atoms have moved to the “middle,” forming a roughly trigonal‐planar configuration. The transition state possesses the maximum energy level in the reaction profile. It is short‐lived and highly reactive. As the reaction further progresses, the transition state collapses (dissociates) spontaneously to lead to full breaking of the old C─Br bond in the reactant and concurrent complete formation of the new O─C bond in the product. Simultaneously, the hydrogen atoms move to the right side. The overall process is a one‐step transformation. The extent of the reaction is determined by the difference in free energy (ΔG) between reactants and products.

In contrast to a concerted reaction, a stepwise reaction proceeds via more than one transition state. It consists of two or more elementary (concerted) steps (Fig. 1.1b), and distinct reactive intermediate(s) is formed in the course of the reaction [1]. The S_N1 reaction of 2‐bromo‐2‐methylpropane (Me₃CBr) in Figure 1.1b demonstrates the general feature of a stepwise reaction. The first step is the dissociation of Me₃CBr to a reactive carbocation Me₃C⁺ intermediate. In the second step, Me₃C⁺ reacts with water to give a tertiary alcohol product (via a hydronium Me₃C–OH₂⁺ which is very often omitted as its subsequent deprotonation to Me₃C–OH is spontaneous and very rapid, and nearly simultaneous). Each concerted step proceeds via a transition state. The extent of a stepwise reaction is also determined by the difference in