Section 6.1     Substitution reactions involve bond making between a nucleophile and electrophile with the loss of a leaving group. These processes are prevalent in physiological and metabolic processes and in the manufacture of drugs.

Section 6.2     A nucleophile is a Lewis base that can donate an electron pair in the formation of a new bond. Nucleophilicity refers to the relative reactivity of a nucleophile in reaction with electrophiles. It is determined by several factors including electronegativity, basicity, and polarizability.

Section 6.3     Electrophiles are Lewis acids that can accept an electron pair in the formation of a new bond. The polarization of bonds produces electrophilic sites in molecules. A strong electrophile possesses a weak bond to a good leaving group, such as in the molecule methyl iodide (CH₃–I).

Section 6.4     Leaving groups are species that can readily accept and stabilize an electron pair upon the breaking of a bond to the leaving group. Weak bases (the conjugate bases of strong acids) generally make good leaving groups.

Section 6.5     The bimolecular nucleophilic substitution reaction (S_N2) is a concerted process in which bond making occurs concurrently with bond breaking. These reactions occur with backside attack of the nucleophile on the breaking bond, resulting in inversion of configuration at the reacting center. The rate of the S_N2 reaction is also affected by the steric environment around the reacting carbon center.

Section 6.6     The S_N1 reaction occurs via discreet steps and involves a carbocation intermediate. The rate-determining step in an S_N1 reaction is the formation of a carbocation intermediate. The reaction rate is highly impacted by the nature of the electrophilic carbon center and leaving group but less so by the nature of the nucleophile.

Section 6.7     Substitution reactions can be significantly accelerated when an internal nucleophile is positioned to promote loss of a leaving group and/or stabilization of a carbocation intermediate. This effect is known as neighboring group assistance and can affect both the rate and stereochemical outcome of the reaction.

Section 6.8     Nucleophilic aromatic substitution (S_NAr) involves a slow, rate-determining addition step to form an anionic Meisenheimer complex, followed by a rapid elimination step. The aromatic electrophile must be activated by one or more electron-withdrawing substituents such as nitro or cyano positioned ortho or para to the leaving group.

Section 6.9     The addition reaction of HBr across an unsymmetrical alkene occurs according to Markovnikov’s rule to produce the more highly substituted bromide product. This results from preferential formation of the more stabilized carbocation intermediate. The addition of nucleophiles to highly polarized double bonds is known as the Michael reaction.

Section 6.10   E1 and E2 elimination reactions are conceptually the reverse of addition reactions. Both reactions follow Zaitsev’s rule, which states that the more highly substituted alkene product will predominate when multiple regioisomeric alkene products are possible.

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