Nucleophilic Aliphatic Substitution Reactions

The Sn2 Mechanism

Leaving Groups

Introduction

We have seen how chemical kinetics allows chemists to evaluate the impact that changing the substituents attached to the reaction center has on the rates of Sn2 reactions. We have also seen how the rates of bimolecular nucleophilic aliphatic substitution reactions change when the nucleophile is changed. Now we will take a brief look at the role of the leaving group in this process.

Scheme 1 reiterates the general description of nucleophilic aliphatic substitution reactions.

Scheme 1

Nucleophilic Aliphatic Substitution

Changing Leaving Groups

Like nucleophiles, leaving groups may be neutral or negatively charged. As Scheme 2 shows, the central atom of a leaving group that is negatively charged will be neutral while it is bonded to the substrate.

 

Scheme2

The Charge of the Light Bromine

Exercise 1 Draw a picture of the transition state for the reaction shown in Scheme 2. Use the d+/ d- symbolism to show the charge distribution.
Similarly, the central atom of a neutral leaving group will be positively charged while it is bound to the substrate. Scheme 3 illustrates this principle for the intermediate formed in the reaction of methanol with hydrobromic acid.

Scheme 3

The Charges Are Reduced

Exercise 2 Draw a picture of the transition state for the reaction shown in Scheme 3. Use the d+/ d- symbolism to show the charge distribution.

Exercise 3 Suggest a reason why the bromide ion doesn't bond directly to the positively charged oxygen atom in Scheme 3.

Exercise 4 The equilibrium constant for the reaction shown in Scheme 3 is approximately 1025 10-25 107 10-7

Among the halogens, the leaving group reactivity sequence is F < Cl < Br < I for reactions performed in protic solvents. The tendency of fluoride ion to act as a leaving group is so low that alkyl fluorides generally are not used as substrates in Sn2 reactions.

Exercise 5 The bond strengths of CH3F, CH3Cl , CH3Br and CH3I are 108, 84, 70, and 56 kcal/mol, respectively. State the correlation between the carbon-halogen bond strength and leaving group tendency for the halide ions in an Sn2 reaction.

Exercise 6 In protic solvents, the relative order of nucleophilicities of the halide ions is I > Br > Cl > F. The relative leaving group abilities is also I > Br > Cl > F. Considering factors such as bond strengths, electronegativities, and solvation, rationalize this paradox.

The general trend in leaving group tendencies for some of the more commonly encountered leaving groups is shown in Figure 1.

Figure 1

We Gotta Get Out of This Place, If It's the Last Thing We Ever Do

Most commonly alkyl bromides and chlorides are used in synthetic reactions, as are alcohols, from which alkyl bromides and chlorides are easily made by treatment with aqueous HBr and HCl. Triflates and tosylates are highly reactive substrates that are normally prepared from alcohols just before use. Equation 1 shows the preparation of methyl tosylate from methanol and p-toluenesulfonyl chloride, a highly reactive, but commercially available solid.

This is actually a nucleophilic substitution reaction in which methanol acts as the nucleophile displacing chlorine from the sulfur of the p-toluenesulfonyl chloride. Pyridine, C5H5N, acts as an acid trap, reacting with the HCl that is formed. The resulting salt, pryidine hydrochloride, C5H5N.HCl, is insoluble in the solvent, benzene. Its precipitation from the mixture insures complete conversion of the alcohol to the tosylate.

Exercise 7 Use curved arrows to depict the bond-making and bond-breaking that occurs in Equation 1. Draw the structure of the transition state that is formed when the oxygen bonds to the sulfur atom.

Exercise 8 Draw the structure of pyridine. Write an equation showing the acid-base reaction between pyridine and HCl to form pyridine hydrochloride.

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