Organic Chemistry: Concepts and Applications - Headley Allan D. 2020
Aromaticity and Aromatic Substitution Reactions
17.12 Nucleophilic Aromatic Substitution
17.12.1 Nucleophilic Aromatic Substitution Involving Substituted Benzene
We have demonstrated that the benzene ring is nucleophilic owing to the pi (π) electrons that are present in the aromatic ring. The electron density of the aromatic ring can be reduced if electron-withdrawing groups are bonded to the ring. For example, the high acidity of picric acid is due to the reduced electron density of the aromatic ring, which is brought about by the electron withdrawing nitro groups pulling electrons from the aromatic system, as shown in the acid-base equilibrium below.
As you can imagine, if a good leaving group is bonded to a molecule that has a low electron density an electronic environment is generated for substitution reactions. In this case, the aromatic ring would be electrophilic if a substitution reaction were to occur. This type of reaction would be a nucleophilic aromatic substitution, as shown in the reaction given in Reaction (17-79).
(17-79)
2,4-Dinitrochlorobenzene has a good leaving group in the form of the chloride anion and the electron density of the aromatic ring is reduced owing to the presence of two electron withdrawing nitro groups. In the presence of a nucleophile, such as the methylamine, a reaction will occur and the mechanism is shown below.
Since the nitro groups are in the ortho and para positions to the chlorine, the negative charge is stabilized by the nitro groups as shown in the resonance example given in Reaction (17-80).
(17-80)
Note that the nitro groups in the ortho or para positions can assist in the stabilization of the negatively changed intermediate better than if it were in the meta positions to the leaving group.
Note that the unshared pair of electrons are not adjacent to the nitro group for this molecule, compared to 2,4-dinitrochlorobenzene, where stabilization can occur.
Problem 17.14
Which of the molecules shown below is more reactive toward nucleophilic aromatic substitution? Explain your answer.
It was shown that the reaction given in Reaction (17-81) could occur under extremely severe reaction conditions, such as extremely high temperatures (~300 °C) and using a good nucleophile, such as the hydroxide anion, even though there are no electron withdrawing groups on the benzene ring.
(17-81)
Using an even stronger nucleophile, such as the amide anion, the reaction requires less severe reaction conditions as shown in Reaction (17-82).
(17-82)
These reactions occur since the nucleophiles are extremely good (also very strong bases) and under more severe reaction conditions, compared to the reactions discussed earlier. Experiments that were carried out proved that the reaction pathway might not be as straightforward as the nucleophile attacking the electrophilic carbon that contains the leaving group to accomplish the substitution. It was shown that if labeled chlorobenzene, in which the carbon that contains the leaving group is labeled with C-14, were used as the reactant, there was scrambling to provide a 50 : 50 mixture in the products as shown in the reaction in Reaction (17-74).
(17-83)
A plausible explanation for this observation is that a symmetrical intermediate was formed throughout the course of the reaction. In the first step of the mechanism, the very strong base abstracts a proton adjacent to the carbon containing the leaving group and forms a triple bond as the chloride leaves as shown it Reaction (17-84).
(17-84)
The intermediate is called a benzyne intermediate and as you can imagine, this intermediate is very unstable due to the geometry of this highly strained intermediate. In the next step of the mechanism, the benzyne is attacked by the nucleophile. As you can imagine, there is an equal probability of attack coming at either carbon as shown in Reactions (17-85) and (17-86).
(17-85)
(17-86)
After attack of the nucleophilic amide anion on the benzyne intermediate, it is protonated by the solvent, ammonia, to form the product shown. Even though the benzyne intermediate has never been isolated and actually studied, this is a classic representation of using scientific reasoning to provide a plausible explanation, which does not violate the basic chemistry principles and knowledge, for a very unusual observation.
Problem 17.15
Would you expect scrambling for the reaction shown below, the star shows the point of carbon labeling? Explain your answer.
17.12.2 Nucleophilic Aromatic Substitution Involving Substituted Pyridine
As pointed out, pyridine has a dipole moment of 2.26 debyes and the direction of the dipole is away from the aromatic ring and toward the very electronegative nitrogen. This means that the electron density of the pyridine ring is less than that of benzene. Thus, pyridine is more susceptible to nucleophilic attack, compared to benzene. The resonance structures shown in Reaction (17-87) give an idea of the regions of the molecule of lowest electron density, and hence most electrophilic.
(17-87)
Thus, placing a leaving group in either of the positions that are electrophilic would result in a facile nucleophilic displacement reaction, as illustrated in Reactions (17-88) and (17-89).
(17-88)
(17-89)
A specific reaction involving 2-bromopyridine and the NH2− nucleophile is shown in Reaction (17-90).
(17-90)
Even though the hydride ion is possibly the strongest base, it can be made to be a leaving group if it leaves as hydrogen gas. Of course, the driving force is the formation of the gas, which is entropy favored. In the example given in Reaction (17-91), the nucleophile is the strongly basic nucleophilic NH2−, but extreme conditions, such as high pressure and temperature, are required.
(17-91)
As you can imagine, these nucleophilic substitution reactions work best if there is a good leaving group already bonded to the pyridine ring. Another example in which an organometallic reagent is used is given in Reaction (17-92).
(17-92)
Problem 17.16
Give the product for each of the following reactions.
