Organic Chemistry: Concepts and Applications - Headley Allan D. 2020
Nucleophilic Substitution Reactions at sp3 Carbons
15.3 The Leaving Group
We have already pointed out that the bonding electrons for the carbon—halogen bond are not equally shared, but they are closer to the highly electronegative halogen. The halogens that we will encounter in this course are mostly chlorine, bromine, and iodine. As a result, if the carbon halogen bond were to be broken, it would break heterolytically with the halogen taking the bonding electrons. The atom or a group of atoms that takes the electrons when a bond breaks heterolytically is called a leaving group, as illustrated in Reaction 15-1 where chlorine is classified as the leaving group.
(15-1)
In this chapter, we will encounter not only halogens as leaving groups but also many other types of leaving groups, and we will need a method to determine the leaving group and their ability to leave in a heterolytic cleavage of a covalent bond. This information can be gained from our knowledge of acid—base reactions that was presented in Chapter 7. One important concept covered is the relationship between conjugate acids and bases and specifically that strong acids result in weak conjugate bases in an acid—-base reaction. For example, hydrobromic acid has a pKa of −9.0, which makes it a very strong acid, and as a result, its conjugate base in the form of the bromide anion (Br−) is a weak base since it is large and polarizable and hence can accommodate the negative charge. Weak conjugate bases are good leaving groups owing to the ability to stabilize the negative charge. You may recall that the negative charge can be stabilized not only by polarizability effect but also inductive and resonance effects. Thus, groups such as the acetate anion are good leaving groups. You will recall from Chapter 7 on acids and bases that the conjugate base of acetic acid, the acetate anion is resonance stabilized, making it a fairly stable base, hence fairly good leaving group as shown in Reaction 15-2.
(15-2)
15.3.1 Converting Amines to Good Leaving Groups
The R2N groups are extremely poor leaving groups. You will recall that the pKa value of R2NH is approximately 38. These groups can be converted to better leaving groups if protonated in the presence of an acid, which will result in neutral molecules after the leaving group has taken the bonding electrons, as shown in Reaction (15-3).
(15-3)
An alternate method of converting an amine into a good leaving group is to carry out a substitution reaction to convert the amine to an ammonium ion, which is a good leaving group as shown in Reaction 15-4. You will recall that the pKa of the ammonium salt is 9.4.
(15-4)
15.3.2 Converting the OH of Alcohols to a Good Leaving Group in an Acidic Medium
The ─OH group is an extremely poor leaving group. You will recall that the pKa value of water is approximately 15. On the other hand, the pKa of H3O+ is −1.7. The ─OH group of an alcohol can be converted to a better leaving group if protonated, which will result in a neutral molecule after the leaving group has taken the bonding electrons, as shown in Reaction (15-5).
(15-5)
Problem 15.2
i. Using the pKa table in Chapter 7, determine which of the following is the weakest base, and hence the best leaving group.
1. Cl−; Br−; F−; I−
2. CH3CO2−; CH3O−; C6H5O−
3. SCN−; H2O; NH3; OH−
ii. Of the following pairs of ions, which is the better leaving group?
1. I− and Cl−
2. CH3O− and CH3CO2−
3. OH− and H2O
15.3.3 Converting the OH of Alcohols to a Good Leaving Group Using Phosphorous Tribromide
As mentioned above, the ─OH group of alcohols is a poor leaving group, but can be converted to a much better leaving group like a bromide in the presence of phosphorous tribromide, as shown below in Reaction 15-6.
(15-6)
The mechanism for the reaction using 1-propanol with PBr3 is shown in Reaction 15-7.
(15-7)
In this reaction, the nucleophilic hydroxyl group attacks the highly electrophilic phosphorous displacing a bromide anion. Since the bromide anion is nucleophilic, it will displace the leaving group as shown in the mechanism.
15.3.4 Converting the OH of Alcohols to a Good Leaving Group Using Thionyl Chloride
Thionyl chloride is a highly reactive compound, which will convert the ─OH of alcohols to alkyl chlorides, the chloride anion is a much better leaving group than the ─OH group. An example of this conversion is shown in Reaction 15-8. These reactions will be discussed in more detail in the next chapter.
(15-8)
15.3.5 Converting the OH of Alcohols to a Good Leaving Group Using Sulfonyl Chlorides
Another method that is widely used to convert the ─OH of alcohols to a good leaving group is given in the example shown in Reaction 15-9, where 4-toluenesulfonyl chloride (TsCl) reacts with butanol to convert the OH to an extremely good leaving group (-OTS).
(15-9)-
As you can imagine, one of the driving forces for this reaction is that the nucleophilic hydroxide group reacts readily with the electrophilic sulfur displacing the chloride anion. The acidity of the conjugate acid of the leaving group, 4-toluenesulfonic acid, is −2.8 making the conjugate base shown in Reaction 15-9 an extremely good leaving group.