Substitution reactions

Introduction

Nucleophilic substitution reactions occur when a nucleophile (Lewis base) attacks a polar carbon and causes a more electronegative group to leave (Leaving group)

Nucleophiles are structures that contain a pair of unshared electrons which are attracted to positive centers.

Resource: Three classes of nucleophiles

Resource: Nucleophile/Base strength

The leaving group should be considered a weaker base than the nucleophile, thus the reason for the substitution. These need to be stable in solution.

-Both Cl^- and Br^- are conjugate bases of strong acids, therefore are negligible bases (makes them stable).

Mechanisms: S_N1 vs S_N2

 S_N2 (Hughes-Ingold mechanism)

• this mechanism occurs in one step- no intermediates are formed

• an unstable transition state forms as the nucleophile begins to form a coordinate covalent bond with the carbon and the leaving group undergoes heterolysis

• this is shows second order (2^o) reaction kinetics because both the substrate and nucleophilic concentrations affect the overal rate (1^o for both)

  • Rate = k [substrate][Nu:]

The reaction is largely exergonic (-DG^o) and commonly have large K_eq, which favors product formation

 S_N2 mechanisms cause a change in conformation- due to nucleophilic attack from the backside of the leaving group

S_N1

• These have rate equations that are unimolecular--dependent only on the concentration of the substrate (halogenalkane)

  • Rate = k [substrate]   --> notice the [Nu:] is not part of the rate law equation

• This mechanism involves a multistep process where an elementary step limits the product formation.

• The first step is the slow step because the leaving group must leave without assistance of the nucleophile binding (S_N2 )

• The intermediate is a carbocation which has sp2 hybridization, leaving an empty, unhybridized p-orbital. This allows for racemic mixtures.

• These reactions are susceptible to solvent attack, especially if the solvent is more polar.

  • Solvolysis- condition where the solvent can act as the nucleophile- H₂O (hydrolysis), CH₃OH (methanolysis)

Factors that affect S_N1 vs S_N2 mechanisms

Two separate mechanisms exist for nucleophilic substitution reactions. These are dependent upon the following

1. structure of the substrate (halogenalkane)-- identify the degree of substitution (1^o, 2^o or 3^o)

2. The strength of the nucleophile

3. the stability of the leaving group

4. the type of solvent

1. Structure of the substrate

• S_N2 - less substituted halogenalkanes proceed more readily than more substituted.

• More substituted halogenalkanes exhibit greater steric hindrances- restriction of nucleophile attack on halogen-bearing carbon

  • The kinetic molecular theory of reactions- activation energy is dependent upon the minimum kinetic energy needed to intiate a reaction.

  • Steric hindrance decreasees the number of collisions with correct orientations--seen as an increase in activation energy and decrease in rate.

• S_N1- The carbocation stability is the principle factor that affects rates

  • only substrates that form stable carbocations undergo S_N1 mechanisms--commonly 3^o halogenalkanes

  • allylic halides (allyl group) and benzylic halides are also capable of S_N1 mechanisms

  • 3^o carbocations are stabilized by hyperconjugation and the allylic/benzylic halides are stabilized through pi-bond conjugation.

2. Nucleophile strength

• Only the S_N2 mechanism rates are affected by the strength of the nucleophile.

  • remember for S_N2 rate equations:  Rate = k [substrate][Nu:], whereas for  rate equations: Rate = k[substrate]

• Nucleophile strength is dependent upon the following:

  • negatively charged nucleophiles are always stronger than its conjugate acid.

    • OH^- is stronger than H₂O and RO^- is greater than ROH  (RO^- is an alkoxide)

  • the basicity of a nucleophilic atom parallels the nucleophile strength

    • RO^- > OH^- >> RCOO^- > ROH > H₂O

3. Leaving group

• The best leaving groups form stable anions or neutral molecules--typically weak bases (conjugates of strong acids)

  •  TsO^- & NH₃ >I^- & H₂O > Br^-  > Cl^- >>  F^- > OH^- & NH₂^- (TsO^- is the tosylate ion)

  • These acquire and hold onto negative charge (weak bases), which stabilizes the intermediate, decreases activation energy and increases rates

  • trifluoromethanesulfonate ion (CF₃SO₃^-) is one of the best leaving groups

• S_N1 reactions speed up with better leaving groups-

4. Solvent effects

• protic solvents are defined where a hydrogen is bonded to a highly electronegative element (such as oxygen)

  • readily form hydrogen bonds with nucleophiles, which can inhibit both S_N reactions

  • The strength of the hydrogen bonding is dependent upon the size of the nucleophile

    • smaller nucleophiles are solvated to a greater extent (form stronger attractions) and therefore reduce nucleophilic character

    • ex. fluoride is smaller, solvated to a greater extent and therefore is a weaker nucleophile as compared to bromide or iodide

    • sulfur atoms are stronger nucleophiles than oxygen species-- thiols are stronger than alcohols and sulfides are stronger than alkoxides

• polar aprotic solvents (lack hydrogen bonded to highly e.n. atom) are used in S_N2 mechanims

  • They dissolve ionic salts, specifically by strongly attracting to cations but not the anions, due to the lack of hydrogen bonds

  • the anions are free to function as strong nucleophiles

  • by using aprotic polar solvents, nucleophilicity of halides change-- F^- >  Cl^- > Br^- > I^- 

  • The rates of  reactions greater increase in the presence of polar aprotic solvents-- up to 10⁶ x's.

Functional group transformation

• S_N2 reactions provide a framework for reactions which allow for converting from one functional group to another.

• This forms the basis for retrosynthetic analysis

Resource: Notes on Functional group interconversions

Image: Reaction map for functional group interconversion (from LearnChemistry)

Resource: Substitution vs Elimination reactions

20.1h- Write the equation for the conversion of nitrobenzene to phenylamine via a two-stage reaction.