Nucleophilic Substitution Reaction of Benzene

10 Key excerpts on "Nucleophilic Substitution Reaction of Benzene"

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  eBook - ePub

  Essentials of Organic Chemistry

  For Students of Pharmacy, Medicinal Chemistry and Biological Chemistry

  • Paul M. Dewick(Author)
  • 2013(Publication Date)
  • Wiley

    (Publisher)

  6

  Nucleophilic reactions: nucleophilic substitution

  As the term suggests, a substitution reaction is one in which one group is substituted for another. For nucleophilic substitution, the reagent is a suitable nucleophile and it displaces a leaving group. As we study the reactions further, we shall see that mechanistically related competing reactions, eliminations and rearrangements, also need to be considered.

  6.1 The SN 2 reaction: bimolecular nucleophilic substitution

  The abbreviation SN 2 conveys the information ‘substitution–nucleophilic–bimolecular’. The reaction is essentially the displacement of one group, a leaving group, by another group, a nucleophile. It is a bimolecular reaction, since kinetic data indicate that two species are involved in the rate-determining step:

  where Nu is the nucleophile, RL the substrate containing the leaving group L, and k is the rate constant.

  In general terms, the reaction can be represented as below

  Differences in electronegativities (see Section 2.7) between carbon and the leaving group atom lead to bond polarity. This confers a partial positive charge on the carbon and facilitates attack of the nucleophile. As the nucleophile electrons are used to make a new bond to the carbon, electrons must be transferred away to a suitable acceptor in order to maintain carbon’s octet. The suitable acceptor is the electronegative leaving group.

  The nucleophile attacks from the side opposite the leaving group – electrostatic repulsion prevents attack in the region of the leaving group. This results in an inversion process for the other groups on the carbon centre under attack, rather like an umbrella turning inside out in a violent gust of wind. The process is concerted, i.e. the bond to the incoming nucleophile is made at the same time as the bond to the leaving group is being broken. As a consequence, the mechanism involves a high-energy transition state in which both nucleophile and leaving group are partially bonded, the Nu–C–L bonding is linear, and the three groups X, Y, and Z around carbon are in a planar array. This is the natural arrangement to minimize steric interactions if we wish to position five groups around an atom, and will involve three sp 2 orbitals and a p orbital as shown. The p orbital is used for the partial bonding; note that we cannot have five full bonds to a carbon atom. The energy profile for the reaction (Figure 6.1

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  Klein's Organic Chemistry

  • David R. Klein(Author)
  • 2020(Publication Date)
  • Wiley

    (Publisher)

  • When designing a synthesis for a polysubstituted benzene ring, it is often most efficient to utilize a retrosynthetic analysis. SECTION 19.13 • In a nucleophilic aromatic substitution reaction, the aromatic ring is attacked by a nucleophile. This reaction has three requirements: • The ring must contain a powerful electron-withdrawing group (typically a nitro group). • The ring must contain a leaving group. • The leaving group must be either ortho or para to the electron-withdrawing group. • Nucleophilic aromatic substitution involves two steps: • Formation of a Meisenheimer complex. • Loss of a leaving group to restore aromaticity. SECTION 19.14 • An elimination-addition reaction occurs via a benzyne inter- mediate. Evidence for this mechanism comes from isotopic labeling experiments as well as a trapping experiment. SECTION 19.15 • The three mechanisms for aromatic substitution differ in (1) the intermediate, (2) the leaving group, and (3) substituent effects. SKILLBUILDER REVIEW 19.1 IDENTIFYING THE EFFECTS OF A SUBSTITUENT DEACTIVATORS ACTIVATORS OH NH 2 WEAK WEAK MODERATE A lone pair immediately adjacent to the ring. STRONG STRONG MODERATE Examples: Examples: Example: Exception: Moderate activator OR A lone pair that is already participating in resonance outside of the ring. O O R NO 2 NR 3 CX 3 META DIRECTORS C N O R Br Cl R ORTHO-PARA DIRECTORS Alkyl groups: Halogens: A π bond to a heteroatom, where the π bond is conjugated to the ring. The following three groups: ⊕ Try Problems 19.16, 19.17, 19.40–19.42, 19.43a–c,f,h, 19.45, 19.46a–d, 19.47a,b,d–g, 19.56a,b, 19.63 19.2 IDENTIFYING DIRECTING EFFECTS FOR DISUBSTITUTED AND POLYSUBSTITUTED BENZENE RINGS STEP 1 Identify the nature of each group. HO NO 2 CH 3 Strong activator Strong deactivator Weak activator STEP 2 Select the most powerful activator and then identify the positons that are ortho and para to that group. HO NO 2 CH 3 STEP 3 Identify the unoccupied positions.

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  Organic Chemistry

  • David R. Klein(Author)
  • 2021(Publication Date)
  • Wiley

    (Publisher)

  Such reactions are called electrophilic aromatic substitution reactions. In this section, we consider reactions in which the ring is attacked by a nucleophile. Such reactions are called nucleophilic aromatic substitution reactions. In the following example, an aromatic compound is treated with a strong nucleophile (hydroxide), which displaces a leaving group (bromide): Br NO 2 OH NO 2 1) NaOH, 70°C 2) H 3 O + In order for a reaction like this to occur, three criteria must be satisfied: 1. The ring must contain a powerful electron-withdrawing group (typically a nitro group). 2. The ring must contain a leaving group (usually a halide). 3. The leaving group must be either ortho or para to the electron-withdrawing group. If the leav- ing group is meta to the nitro group, the reaction is not observed. Br NO 2 No reaction 1) NaOH, 70°C 2) H 3 O + In this example, the first two criteria are met, but the last criterion is not met. Any mechanism that we propose for nucleophilic aromatic substitution must successfully explain the three criteria. Mechanism 18.8 accomplishes this task and is called the S N Ar mechanism. MECHANISM 18.8 NUCLEOPHILIC AROMATIC SUBSTITUTION (S N Ar) In the first step, the aromatic ring is attacked by a nucleophile, forming the intermediate Meisenheimer complex In the second step, a leaving group is expelled to restore aromaticity Nucleophilic attack Loss of a leaving group N Cl O O OH N O O OH Meisenheimer complex N O OH OH OH OH Cl N N O O O Cl Cl N O Cl Cl – O O O + + + + + + - - - - - - - - - - - - 18.13 Nucleophilic Aromatic Substitution 867 Much like the reactions we have seen thus far, this mechanism also involves two steps, but take special notice of the resonance-stabilized intermediate, called a Meisenheimer complex. This intermediate exhibits a negative charge that is resonance stabilized throughout the ring.

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  Keynotes in Organic Chemistry

  • Andrew F. Parsons(Author)
  • 2013(Publication Date)
  • Wiley

    (Publisher)

  2 groups, respectively. This electrophilic substitution reaction (with the diazonium salt as the electrophile) produces highly coloured azo compounds.

  Steric effects and electrophilic substitution is discussed in Section 7.3.2.4

  7.7 Reduction of the Benzene Ring

  Harsh reaction conditions are required to reduce the aromatic benzene ring. This can be achieved by catalytic hydrogenation (using high temperatures or pressures and very active catalysts) or alkali metals in liquid ammonia/ethanol (in a Birch reduction ).

  Catalytic hydrogenation of alkenes and alkynes is discussed in Section 6.3.2.4

  Catalytic Hydrogenation

  In the chair conformation of a substituted cyclohexane, the substituent (R) sits in an equatorial position (Section 3.2.4)

  Birch Reduction

  Sodium or lithium metal (in liquid ammonia) can donate an electron to the benzene ring to form a radical anion (R√− ). On protonation (by ethanol, EtOH) and further reduction then protonation, this produces 1,4-cyclohexadiene.

  Addition of an electron to a neutral organic compound forms a radical anion; loss of an electron from a neutral organic compound forms a radical cation (Section 10.1.1) For a related reduction of an alkyne, see Section 6.3.2.4

  7.8 The Synthesis of Substituted Benzenes

  The following points should be borne in mind when planning an efficient synthesis of a substituted benzene.

  1. The introduction of an activating group on to a benzene ring makes the product more reactive than the starting material. It is therefore difficult to stop after the first substitution. This is observed for Friedel-Crafts alkylations. Activating groups donate electron density toward the benzene ring (Section 7.3.1)

  An alkyl group is an ortho -/para -directing activator

  The mechanism of Friedel-Crafts alkylation is discussed in Section 7.2.4

  2. The introduction of a deactivating group on to a benzene ring makes the product less reactive than the starting material. Therefore multiple substitutions do not occur, for example, in Friedel-Crafts acylations (to give ketones, e.g. ArCOR). The ketone (ArCOR) could then be reduced to give the mono-alkylated product (ArCH2 R) in generally higher yield than that derived from a Friedel-Crafts alkylation. The mechanism of Friedel-Crafts acylation is discussed in Section 7.2.5 The Clemmensen reduction is introduced in Section 7.6

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  Foundations of Chemistry

  An Introductory Course for Science Students

  • Philippa B. Cranwell, Elizabeth M. Page(Authors)
  • 2021(Publication Date)
  • Wiley

    (Publisher)

  When undergoing reaction with electrophiles, the electronic effects of ring substituents are important and have an impact upon where the electrophile reacts. 15.2 Reactions of benzene with electrophiles You will encounter four main reactions when studying the reactivity of benzene with electrophiles: 1. Halogenation 2. Friedel – Crafts alkylation 3. Friedel – Crafts acylation 4. Nitration 15.2.1 Halogenation Benzene can undergo halogenation by treatment with a halogen (usually bro-mine or chlorine) in the presence of a catalyst (usually aluminium(III) chloride or iron(III) bromide) (Figure 15.10). The catalyst is required because, as dis-cussed earlier in this chapter, benzene is much less reactive than an alkene. Therefore, for benzene to react with the halogen, the halogen itself needs to be activated or made more reactive. As a general rule, when undertaking chlo-rination, use aluminium(III) chloride as a catalyst; and for bromination, use iron(III) bromide. The equivalent reaction with an alkene is discussed in Chapter 13. F Fluorobenzene NO 2 H O O HO O O RO O R 2 N N Nitro group Nitrile C=O directly adjacent to a benzene ring OR Ether NR 2 Amine X X = Cl, Br or I R R = an alkyl chain Activating Deactivating Figure 15.9 Commonly encountered activating and deactivating substituents. 15.2 Reactions of benzene with electrophiles 477 The mechanism contains a few steps, but they are all logical. In addition, the mechanistic steps for this reaction are broadly similar to those for the other reac-tions of benzene with electrophiles. The first step involves activation of the chlorine molecule, so it is more electro-philic. This occurs by a lone pair of electrons on the chlorine atom attacking the electron-deficient aluminium centre, which is acting as a Lewis acid.

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  Synthesis of Aromatic Compounds

  • Kenneth E. Maly, Kenneth Maly(Authors)
  • 2022(Publication Date)
  • De Gruyter

    (Publisher)

  3  Nucleophilic aromatic substitution reactions

  3.1  Introduction

  In the previous chapter, we saw that aromatic rings themselves are usually nucleophiles, reacting with electrophiles in electrophilic aromatic substitution reactions. Furthermore, SN 2 reactions cannot take place at the sp2 hybridized carbon atoms of an aromatic ring. Nonetheless, as we will see in this chapter, nucleophilic displacements on aromatic rings can occur. We will explore the mechanistic scenarios for nucleophilic aromatic substitution with particular attention to the addition–elimination mechanism. We will also consider the chemistry of aryl diazonium salts, which bear superficial resemblance to nucleophilic aromatic substitution.

  3.2  Addition–elimination of nucleophiles (SN Ar)

  The most common type of nucleophilic aromatic substitution at an aromatic ring proceeds first by nucleophilic addition to the carbon bearing the leaving group to form a delocalized carbanion intermediate, followed by expulsion of the leaving group and rearomatization [1 ]. Because the reaction proceeds by an anionic intermediate, it usually involves electron-deficient aromatic rings. The rate-determining step is typically nucleophilic addition and the reaction usually requires electron withdrawing groups ortho or para to the site of nucleophilic attack (Figure 3.1 ).

  Figure 3.1: Generalized SN Ar mechanism.

  As shown in Figure 3.1 , initial nucleophilic attack at the carbon bearing the leaving group results in a delocalized carbanion intermediate, referred to as a Meisenheimer complex. The reaction often requires electron-withdrawing groups ortho or para to the leaving group in order to stabilize the negative charge of the intermediate. The most common electron-withdrawing groups used to activate compounds toward nucleophilic aromatic substitution are nitro groups, but other frequently used groups include cyano, carbonyl, and sulfonate groups. All of these groups can stabilize the negative charge by resonance. This direct resonance stabilization explains the importance of having electron-withdrawing at the ortho- and/or para-positions – groups in the meta-positions can only stabilize the negative charge inductively. As strong support for this mechanism, several Meisenheimer intermediates have been isolated and characterized (Figure 3.2 ) [2

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  Organic Chemistry

  A Mechanistic Approach

  • Penny Chaloner(Author)
  • 2014(Publication Date)
  • CRC Press

    (Publisher)

  E + E H + E H + Plus other resonance forms in which there is no intact benzene ring Plus other resonance forms in which there is no intact benzene ring E + E H + FIGURE 12.44 Mechanism.and.regiochemistry.of.electrophilic.substitution.of.naphthalene. Br 2 + Br – 12.16 12.11 –HBr, Δ Br Br H Br H Br H FIGURE 12.45 Bromination.of.anthracene. 528 12.4 Reactions of Polycyclic Aromatic Compounds PROBLEM 12.11 Predict the product(s) of the electrophilic substitution of 12.17 and 12.18: HO NO 2 HOOC OH 12.17 12.18 Solutions HO NO 2 NO 2 NO 2 E + HO HO E E The ring bearing the −OH group is more electron rich and hence more reactive with electro- philes. OH is ortho, para-directing and activating, but the para-position is blocked by the ring. Given that the 1-position of naphthalene is favored over the 2-position, the second product will probably predominate under conditions of kinetic control. E + HOOC HOOC OH OH E E OH HOOC O O Xylene, heat O O O O FIGURE 12.46 Diels–Alder.reaction.of.anthracene.and.maleic.anhydride. Chapter 12 – Electrophilic Aromatic Substitution 529 This problem is similar to the previous one. OH is electron donating and activating and COOH is electron withdrawing and deactivating, so the ring bearing the OH group is more elec- tron rich, and hence electrophilic reaction occurs in this ring. OH is ortho, para-directing, and the naphthalene substitutes preferentially at the 1-position, so the first product will predominate under conditions of kinetic control. In both problems, substitution at the less hindered posi- tion would predominate under conditions of thermodynamic control, because of the unfavorable peri-interaction in the kinetic products. 12.5 HETEROCYCLIC AROMATIC COMPOUNDS We refer to compounds as heterocycles when there is an atom other than carbon as part of the ring.

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  Practical Synthetic Organic Chemistry

  Reactions, Principles, and Techniques

  • Stéphane Caron(Author)
  • 2020(Publication Date)
  • Wiley

    (Publisher)

  231 4 Nucleophilic Aromatic Substitution Stéphane Caron and Emma McInturff Pfizer Worldwide R&D, Groton, CT, USA CHAPTER MENU Introduction, 231 Oxygen Nucleophiles, 232 Sulfur Nucleophiles, 234 Nitrogen Nucleophiles, 236 Halogen Nucleophiles, 241 Carbon Nucleophiles, 243 ortho-Arynes, 245 4.1 Introduction Nucleophilic aromatic substitution (S N Ar), which can operate through several different reaction mechanisms, is considered one of the preferred methods to derivatize arenes. As such, there are numerous examples of simple functionalization and complex fragment union. Despite great advances in transition metal-catalyzed arene function- alization, S N Ar remains an attractive option due to simplicity, low cost, and avoidance of metal contamination of the product. The scope of this reaction is guided by three basic principles: electron deficiency at the reactive carbon on the aromatic system, nature of the leaving group to be displaced, and reactivity of the nucleophile. 1 In general, more electron-deficient arenes will undergo more facile aromatic nucleophilic substitution in an addition/elimination sequence. Aryl halides, specifically fluorides, and diazonium compounds have proven to be the most successful substrates for this reaction. While the typical order of reactivity for an aliphatic nucleophilic substitution follows I − > Br − > Cl − ≫ F − , this trend is generally reversed for the nucleophilic aromatic substitution. The electron with- drawing nature of an aryl fluoride enhances the propensity for nucleophilic attack at the fluorine-bearing carbon. Primary and secondary amines, as well as alkoxides, are usually excellent nucleophiles for the reaction. A few types of carbon nucleophiles, including cyanide and malonate derivatives, are also commonly used. The preparation of ortho-arynes will also be briefly discussed in this chapter.

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  Reaction Mechanisms in Organic Chemistry

  • Metin Balcı(Author)
  • 2021(Publication Date)
  • Wiley-VCH

    (Publisher)

  However, the situation is somewhat dif- ferent in S N 2 ′ reactions. The nucleophile approaches the double bond on the side from which the leaving group departs, which is called a syn-attack. In such an attack, double-bond electrons open backward to remove the X-group. Thus, the electron density is increased at the back of the leaving group. Substitution occurs by the attack of electrons on the car- bon atom to which the leaving group is bonded. If the nucleophile attacks the double bond from the opposite direction (anti-attack), the electron density will increase at the side of the leaving group, which will not be suitable for a substitution reaction. 74 2 Nucleophilic Substitution Reaction C CH C X Nu syn-attack C HC C Nu The syn-attack can be nicely demonstrated in cyclic structures. In the example given below, the nucleophile attacks the molecule from the side of the leaving group and removes benzoate [19]. C(CH 3 ) 3 O O Ph N H C(CH 3 ) 3 N 2.3.4 Internal Nucleophilic Substitution Reaction, S N i In the previous sections, we have discussed S N 1 and S N 2 mechanisms. S N 2 reactions proceed through the formation of a transition state, resulting in configuration inversion of the product. There are still other reactions whose stereochemical outcome cannot be explained by S N 1 or S N 2 mechanisms. In some nucleophilic substitution reactions, although the reaction molecularity is bimolecular, retention of the configuration is observed instead of inversion. These and similar reactions are often observed by the reaction of chiral alcohol with thionyl chloride to give the corresponding alkyl halide. In the first step, the oxygen atom of alcohol attacks the sulfur atom of thionyl chloride and removes one of the chlorine atoms attached to the sulfur atom to form alkyl chlorosulfite, which can be isolated. At this stage, there is no configurational change at the chiral carbon atom as the nucleophilic substitution reaction takes place on the sulfur atom.

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  Organic Reaction Mechanisms 1978

  An annual survey covering the literature dated December 1977 through November 1978

  • A. C. Knipe, W. E. Watts, A. C. Knipe, W. E. Watts(Authors)
  • 2008(Publication Date)
  • Wiley

    (Publisher)

  Chem. Soc. Jpn., 51, 1163 (1978). CHAPTER 7 Electrophilic Aromatic Substitution A. R. BUTLER Department of Chemistry, The Purdie Building, The University, St. Andrews KY16 8ST General . Halogenation. . Hydrogen Exchange . Nitrosation . Nitration . Azo-coupling Reactions . Sulphonation . Friedel-Crafts and Related Reactions Metallation . Miscellaneous Reactions . 299 300 301 302 302 304 305 3 05 307 307 General Electrophilic aromatic substitution has been reviewed.lP2 Qualitative potential energy surfaces in this type of substitution have been calculated3 and the reactivity- selectivity principle has been considered in relation to electrophilic substitution in heteroaromatic compound^.^ The effect of polysubstitution in benzene compounds is not additive5 and an examination has shown that there are considerable differ- ences in the effect of substituents upon ring substitution and sidechain solvolysis for both benzene compounds and a number of aromatic heterocycles.6 With bromine hexahelicene (1) gives addition products at positions 5/6 and 11/12, but nitration and acetylation result in substitution at positions 5 and 12; the corre- lation with various reactivity parameters is not very su~cessful.~ With 2-(2-thienyl)- pyrimidine and 2-(3-thienyl)pyrimidine substitution occurs at all positions in the thiophen ring, indicating unusual directive effects of the pyrimidine group.* By 299

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