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18.4: Preparation of Phenols: Nucleophilic Aromatic Substitution

  • Page ID
    201287
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    Objectives

    After completing this section, you should be able to

    1. identify the conditions necessary for an aryl halide to undergo nucleophilic aromatic substitution, and give an example of such a reaction.
    2. write the detailed mechanism for a nucleophilic aromatic substitution reaction.
    3. compare the mechanism of a nucleophilic aromatic substitution reaction and the SN1 and SN2 mechanisms discussed earlier.
    4. identify the product formed when a given nucleophile reacts with a given aryl halide in a nucleophilic aromatic substitution reaction.
    Key Terms

    Make certain that you can define, and use in context, the key terms below.

    • Meisenheimer complex
    • nucleophilic aromatic substitution
    Study Notes

    A nucleophilic aromatic substitution reaction is a reaction in which one of the substituents in an aromatic ring is replaced by a nucleophile.

    A Meisenheimer complex is a negatively charged intermediate formed by the attack of a nucleophile upon one of the aromatic-ring carbons during the course of a nucleophilic aromatic substitution reaction. A typical Meisenheimer complex is shown in the reaction scheme below. Notice how this particular complex can be formed from two different starting materials by using a different nucleophile in each case.

    reaction scheme showing Meisenheimer complex

    Figure 16.2: The formation of a typical Meisenheimer complex

    A Nucleophilic Aromatic Displacement Reactions of Aryl Halides

    The carbon-halogen bonds of aryl halides are like those of alkenyl halides in being much stronger than those of alkyl halides (see Table 4-6). The simple aryl halides generally are resistant to attack by nucleophiles in either SN1 or SN2 reactions (Table 14-6). However, this low reactivity can be changed dramatically by changes in the reaction conditions and the structure of the aryl halide. In fact, nucleophilic displacement becomes quite rapid

    1. when the aryl halide is activated by substitution with strongly electron-attracting groups such as NO2, and
    2. when very strongly basic nucleophilic reagents are used.

    Addition-Elimination Mechanism of Nucleophilic Substitution of Aryl Halides

    Although the simple aryl halides are inert to the usual nucleophilic reagents, considerable activation is produced by strongly electron-attracting substituents provided these are located in either the ortho or para positions, or both. For example, the displacement of chloride ion from 1-chloro-2,4-dinitrobenzene by dimethylamine occurs readily in ethanol solution at room temperature. Under the same conditions chlorobenzene completely fails to react; thus the activating influence of the two nitro groups amounts to a factor of at least 108:

    BPOCchapter14-6-6b-3.pngBPOCchapter14-6-6b-4.png

    A related reaction is that of 2,4-dinitrofluorobenzene with the amino groups of peptides and proteins, and this reaction provides a means for analysis of the N-terminal amino acids in polypeptide chains. (See Section 25-7B.)

    In general, the reactions of activated aryl halides closely resemble the SN2-displacement reactions of aliphatic halides. The same nucleophilic reagents are effective (e.g., CH3O⊖, HO⊖, and RNH2); the reactions are second order overall (first order in halide and first order in nucleophile); and for a given halide the more nucleophilic the attacking reagent, the faster the reaction. However, there must be more than a subtle difference in mechanism because an aryl halide is unable, to pass through the same type of transition state as an alkyl halide in SN2 displacements.

    The generally accepted mechanism of nucleophilic aromatic substitution of aryl halides carrying activating groups involves two steps that are closely analogous to those briefly described in Section 14-4 for alkenyl and alkynyl halides. The first step involves attack of the nucleophile Y:⊖ at the carbon bearing the halogen substituent to form an intermediate carbanion 4 (Equation 14-3). The aromatic system is destroyed on forming the anion, and the carbon at the reaction site changes from planar (sp2 bonds) to tetrahedral (sp3 bonds).

    BPOCchapter14-6-6b-5.png

    In the second step, loss of an anion, X⊖ or Y⊖, regenerates an aromatic system, and, if X⊖ is lost, the overall reaction is nucleophilic displacement of X by Y (Equation 14-4).

    BPOCchapter14-6-6b-51.png

    In the case of a neutral nucleophilic reagent, Y or HY, the reaction sequence would be the same except for the necessary adjustments in the charge of the intermediate:

    BPOCchapter14-6-6b-7.png

    Why is this reaction pathway generally unfavorable for the simple aryl halides? The answer is that the intermediate 4, which we can express as a hybrid of the valence-bond structures 4a-4c, is too high in energy to be formed at any practical rate. Not only has 4 lost the aromatic stabilization of the benzene ring, but its formation results in transfer of negative charge to the ring carbons, which themselves are not very electronegative:

    BPOCchapter14-6-6b-9.png

    However, when strongly electron-attracting groups are located on the ring at the ortho-para positions, the intermediate anion is stabilized by delocalization of electrons from the ring carbons to more favorable locations on the substituent groups. As an example, consider the displacement of bromine by OCH3 in the reaction of 4-bromonitrobenzene and methoxide ion:

    BPOCchapter14-6-6b-91.png

    The anionic intermediate formed by addition of methoxide ion to the aryl halide can be described by the valence-bond structures 5a-5d. Of these structures 5d is especially important because in it the charge is transferred from the ring carbons to the oxygen of the nitro substituent:

    BPOCchapter14-6-6b-10.png

    Substituents in the meta positions have much less effect on the reactivity of an aryl halide because delocalization of electrons to the substituent is not possible. No formulas can be written analogous to 5c and 5d in which the negative charges are both on atoms next to positive nitrogen, BPOCchapter14-6-6b-11.png and BPOCchapter14-6-6b-12.png

    BPOCchapter14-6-6b-13.png

    In a few instances, stable compounds resembling the postulated reaction intermediate have been isolated. One classic example is the complex 7 (isolated by J. Meisenheimer), which is the product of the reaction of either the methyl aryl ether 6 with potassium ethoxide, or the ethyl aryl ether 8 and potassium methoxide:

    BPOCchapter14-6-6b-14.png

    Exercises

    Questions

    Q16.7.1

    Propose a mechanism for the following reaction:

    16-7-1qu.png

    Solutions

    S16.7.1

    16.7.png

    Contributors and Attributions

    John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic Chemistry, second edition. W. A. Benjamin, Inc. , Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted under the following conditions, "You are granted permission for individual, educational, research and non-commercial reproduction, distribution, display and performance of this work in any format."

    Objectives

    After completing this section, you should be able to

    1. identify the reagents and conditions required to produce phenol from chlorobenzene on an industrial scale.
    2. write the mechanism for the conversion of an alkyl halide to a phenol through a benzyne intermediate.
    3. discuss the experimental evidence which supports the existence of benzyne intermediates.
    4. discuss the bonding in benzyne, and hence account for its high reactivity.
    Key Terms

    Make certain that you can define, and use in context, the key terms below.

    • benzyne
    • elimination-addition mechanism
    Study Notes

    An elimination-addition mechanism involves the elimination of the elements of a small molecule from a substrate to produce a highly reactive intermediate, which then undergoes an addition reaction.

    The elimination-addition mechanism of nucleophilic aromatic substitution involves the remarkable intermediate called benzyne or arynes.

    14-6C Elimination-Addition Mechanism of Nucleophilic Aromatic Substitution. Arynes

    The reactivities of aryl halides, such as the halobenzenes, are exceedingly low toward nucleophilic reagents that normally effect displacements with alkyl halides and activated aryl halides. Substitutions do occur under forcing conditions of either high temperatures or very strong bases. For example, chlorobenzene reacts with sodium hydroxide solution at temperatures around \(340^\text{o}\) and this reaction was once an important commercial process for the production of benzenol (phenol):

    Roberts and Caserio Screenshot 14-6-4.png

    In addition, aryl chlorides, bromides, and iodides can be converted to areneamines \(\ce{ArNH_2}\) by the conjugate bases of amines. In fact, the reaction of potassium amide with bromobenzene is extremely rapid, even at temperatures as low as \(-33^\text{o}\) with liquid ammonia as solvent:

    Roberts and Caserio Screenshot 14-6-5.png

    However, displacement reactions of this type differ from the previously discussed displacements of activated aryl halides in that rearrangement often occurs. That is, the entering group does not always occupy the same position on the ring as that vacated by the halogen substituent. For example, the hydrolysis of 4-chloromethylbenzene at \(340^\text{o}\) gives an equimolar mixture of 3- and 4-methylbenzenols:

    Roberts and Caserio Screenshot 14-6-6.png

    Even more striking is the exclusive formation of 3-methoxybenzenamine in the amination of 2-chloromethoxybenzene. Notice that this result is a violation of the principle of least structural change (Section 1-1H):

    Roberts and Caserio Screenshot 14-6-7.png

    The mechanism of this type of reaction has been studied extensively, and much evidence has accumulated in support of a stepwise process, which proceeds first by base-catalyzed elimination of hydrogen halide \(\left( \ce{HX} \right)\) from the aryl halide - as illustrated below for the amination of bromobenzene:

    Elimination

    Roberts and Caserio Screenshot 14-6-8.png

    The product of the elimination reaction is a highly reactive intermediate \(9\) called benzyne, or dehydrobenzene, which differs from benzene in having two less hydrogen and an extra bond between two ortho carbons. Benzyne reacts rapidly with any available nucleophile, in this case the solvent, ammonia, to give an addition product:

    Addition

    Roberts and Caserio Screenshot 14-6-9.png

    The rearrangements in these reactions result from the attack of the nucleophile at one or the other of the carbons of the extra bond in the intermediate. With benzyne the symmetry is such that no rearrangement would be detected. With substituted benzynes isomeric products may result. Thus 4-methylbenzyne, \(10\), from the reaction of hydroxide ion with 4-chloro-1-methylbenzene gives both 3- and 4-methylbenzenols:

    Roberts and Caserio Screenshot 14-6-10.png

    In the foregoing benzyne reactions the base that produces the benzyne in the elimination step is derived from the nucleophile that adds in the addition step. This need not always be so, depending on the reaction conditions. In fact, the synthetic utility of aryne reactions depends in large part of the success with which the aryne can be generated by one reagent but captured by another. One such method will be discussed in Section 14-10C and involves organometallic compounds derived from aryl halides. Another method is to generate the aryne by thermal decomposition of a 1,2-disubstituted arene compound such as \(11\), in which both substituents are leaving groups - one leaving with an electron pair, the other leaving without:

    Roberts and Caserio Screenshot 14-6-11.png

    When \(11\) decomposes in the presence of an added nucleophile, the benzyne intermediate is trapped by the nucleophile as it is formed. Or, if a conjugated diene is present, benzyne will react with it by a [4 + 2] cycloaddition. In the absence of other compounds with which it can react, benzyne will undergo [2 + 2] cycloaddition to itself:

    Roberts and Caserio Screenshot 14-6-12.png

    Exercises

    Questions

    Q16.8.1

    When p-chlorotoluene is reacted with NaOH, two products are seen. While when m-chlorotoluene is reacted with NaOH, three products are seen. Explain this.

    Solutions

    S16.8.1

    You need to look at the benzyne intermediates. The para substituted only allows for two products, while the para produces two different alkynes which give three different products.

    16.8.png

    Contributors and Attributions

    John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic Chemistry, second edition. W. A. Benjamin, Inc. , Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted under the following conditions, "You are granted permission for individual, educational, research and non-commercial reproduction, distribution, display and performance of this work in any format."


    18.4: Preparation of Phenols: Nucleophilic Aromatic Substitution is shared under a not declared license and was authored, remixed, and/or curated by LibreTexts.

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