Organic Chemistry: Concepts and Applications - Headley Allan D. 2020
Nucleophilic Substitution Reactions at Acyl Carbons
16.2 Mechanism for Acyl Substitution
For the general reaction given in Reaction (16-1), the substitution takes place at the acyl carbon and the leaving group, L, is replaced with the nucleophile, Nu. These types of reactions occur in two steps, in which the first step involves the attack of the nucleophile on the electrophilic carbon of the electrophile, converting it to a sp3 carbon, which is also called a tetrahedral intermediate, as shown in Reaction (16-2).
(16-2)
Since the tetrahedral intermediate contains a leaving group and there are lone pairs of electrons on the negatively charged oxygen, a favorable double bond will re-form with the carbon and the oxygen. Simultaneously, the leaving group leaves with its bonding electrons as shown in Reaction (16-3).
(16-3)
From the above general mechanism, the nucleophile first uses its unshared pair of electrons to bond to the electrophilic carbon of the acyl compound to form a tetrahedral intermediate. This intermediate is unstable since it contains a leaving group and has the possibility of reforming a very stable carbon—oxygen double bond, the overall reaction mechanism is shown in Reaction (16-4).
(16-4)
Before we actually start our examination of these substitution reactions, let us first refresh our understanding of leaving groups, electrophile and the nucleophile. The next sections examine the reaction of various acyl compounds with different nucleophiles.
16.2.1 The Leaving Group of Acyl Substitution Reactions
As we have pointed out in the previous chapter, one of the major factors for a substitution reaction is the ability of the leaving group to leave. For these reactions, the leaving group departs from the tetrahedral intermediate after the electrons from the oxygen return to re-form a carbon—oxygen double bond. The ability of a leaving group to leave is reflected by its ability to stabilize the negative charge after leaving. Weak conjugate bases are good leaving groups, while strong bases are poor leaving groups. Based on the pKa values shown in Table 7.1 of Chapter 7, the leaving group ability of a specific atom or group of atoms can be determined. Recall that strong acids, which have more negative pKa values result in conjugate bases that are weak conjugate bases, hence good leaving groups. For acyl substitution reactions that will be covered in this chapter, the groups that are bonded to the acyl carbon and are potential leaving groups as shown below.
This trend implies that some of the most reactive acyl compounds are the ones in which the carbonyl carbon is bonded to a halogen and the least reactive are acyl compounds that have hydrogen or alkyl groups bonded to the carbonyl carbon. In this chapter, we will examine compounds that have the following leaving groups: ─Cl−, ─Br−. ─OR−, ─OH− ─O2CR−, ─NH3+, ─OH2+. Note that the last two leaving groups of the list are protonated leaving groups. As we have discussed in Chapter 7, the H2O+ is a weaker base than OH− and the same is true for NH3+, compared to NH2.
16.2.2 Reactivity of Electrophiles of Acyl Substitution Reactions
As you can imagine, the size of the R group bonded to the electrophilic carbon that contains the leaving group will affect the stability of the tetrahedral intermediate since the ideal bond angles about a sp3 carbon are 109.5°. As a result, large alkyl R groups that are bonded to the carbonyl carbon of the acyl functionality will serve to destabilize the tetrahedral intermediate and small R groups will offer more stability to the tetrahedral intermediate. This factor will dictate the reactivity of the acyl compound. For example, acyl compounds where R is hydrogen is more reactive than an acyl compound in which the R group is a tert-butyl ─C(CH3)3 group. A trend for the reactivity of different acyl compounds is shown below.
Another factor that affects the reactivity of acyl compounds toward a substitution reaction is the electronegativity of the group bonded to the acyl carbon. A very electronegative atom or group makes the acyl carbon more electrophilic since it is already bonded to the electronegative oxygen. As a result, acyl compounds that contain an electronegative atom or groups bonded to the acyl carbon are more reactive than acyl compounds that do not have an electronegative atom or group bonded to the acyl carbon. Examples of different acyl compounds that demonstrate this concept are shown below.
Problem 16.2
Of the following pairs of acyl compounds, which is more reactive toward substitution reactions?
16.2.3 Nucleophiles of Acyl Substitution Reactions
As we have seen from the previous chapter, a nucleophile is defined as a species that has at least one unshared pair of electrons, which as you will recall is the same definition as a Lewis base. Nucleophiles are nucleus-loving species. As we have seen, nucleophiles can be neutral or can have a formal negative charge, and those that we will be examining in this chapter include the following: OH−, H2O; NH2−, NH3; RO−, and ROH (alcohols), which all have at least one lone-pair of electrons.