oe CHAPTER 16 ents on benzene can be grouped into: Electrophilic Attack on Derivatives eeOpeeoooeobhgepaagerocon of Benzene: Substituents Control Regioselectivity 16-1 Activation or Deactivation by Substituents on a Benzene Ring ve donors and acceptors oatnactane8nsg8pgnheaents6eemneayn Ttetoaeeth9gpsoiecto oa2gw CieraPearte8tn.Carta&ano,nroand p以 一家 Reeonictoobeateataaee Taeaoyc ntains groups such as-NRR,and the 3-5-5-d a28ogoa2525ndng.hdcanoen ye 1
1 CHAPTER 16 Electrophilic Attack on Derivatives of Benzene: Substituents Control Regioselectivity The identity of the substituent on a monsubstituted benzene affects the reactivity and regioselectivity of a subsequent electrophilic substitution reaction. Substituents on benzene can be grouped into: Activators: Electron donors which generally direct a second electrophilic attack to the ortho and para positions; Deactivators: Electron acceptors which generally direct a second electrophilic attack to the meta positions. Activation or Deactivation by Substituents on a Benzene Ring 16-1 The electronic influence of any substituent is determined by two factors, inductance and resonance. Inductance occurs through the σ framework, tapers off rapidly with distance and is governed mostly by the relative electronegativity of the atoms. Resonance takes place through π bonds, is longer range and is particularly strong in charged systems. O X F CH2 C O O H Cl C C C δ− δδ+ δ+ δδδ+ Inductive donors and acceptors: Simple alkyl groups are donating due to hyperconjugation. The trifluoromethyl group is electron-withdrawing due to its electronegative fluorines. Directly bound heteroatoms (N, O, halogens) are electronwithdrawing due to their electronegativities. Positively polarized atoms (carbonyl, cyano, nitro and sulfonyl) are also electron-withdrawing. Substituents capable of resonance with the ring: Resonance donors bear at least one electron pair capable of delocalization into the benzene ring. This category contains groups such as –NR2, -OR, and the halogens. These groups are also electron-withdrawing. Inductance and resonance oppose each other. The effect that wins out depends upon the relative electronegativity of the heteroatoms, and the ability of their respective p-orbitals to overlap the π system. Resonance overrides induction for amino and alkoxy groups, while induction is more important for the halogens, making them weak electron acceptors
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2 Groups such as carbonyl, cyano, nitro and sulfonyl are all electron withdrawing through resonance. They all contain a polarized double or triple bond whose partially positive end is attached to the benzene nucleus. In these cases, resonance reinforces induction. Electron-donating groups increase the electron density in the benzene ring (red) while electron-withdrawing groups decrease the electron density in the ring (blue). Since the attacking species is an electrophile, the more electron rich the arene, the faster the reaction. Electrons donors activate the ring: Electron acceptors deactivate the ring. 16-2 Directing Inductive Effects of Alkyl Groups Groups that donate electrons by induction are activating and direct ortho and para. The electrophilic bromination of methylbenzene is considerably faster than the bromination of benzene itself. The reaction is also regioselective: Virtually no meta product is formed. Nitration, sulfonation and Friedel-Crafts reactions of methylbenzene all give similar results: mainly ortho and para substitutions. The regioselectivity depends upon the nature of the substituent, not on the reagent. The methyl substituent is said to be activating and ortho- and para-directing. The transition states for addition at the ortho, meta and para positions account for the differences in regioselectivity: In ortho and para attack, the transition state is stabilized by a resonance form having the positive charge on a tertiary carbon atom
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3 In meta attack, all of the resonance forms of the transition state place the positive charge on the secondary carbon atom. Ortho and para isomers are often not obtained in equal amounts, primarily due to steric effects. Para products often predominate over their ortho isomers. Groups that withdraw electrons inductively are deactivating and meta-directing. The trifluoromethyl group is electron-withdrawing due to its strongly electronegative fluorine atoms. When carrying this substituent, the benzene ring becomes deactivated and reaction with electrophiles becomes very sluggish. When substitution does occur (stringent conditions, such as heating), substitution occurs only at the meta positions. The trifluoromethyl group is both deactivating and metadirecting. The transition states for addition at the ortho, meta, and para positions account for the differences in regioselectivity: Ortho and para attack place positive charge next to the electron withdrawing CF3 group. Meta attach results in a transition state, which is more stable than either the ortho or para isomer since it does not place positive charge directly on the carbon atom bearing the electronwithdrawing group. The meta transition state, although lower in energy than that of the para or ortho isomer, is still of higher energy than the transition states in the case of an activating substituent. The trifluoromethyl group is both deactivating and meta-directing. Directing Effects of Substituents in Conjugation with the Benzene Ring 16-3 Groups that donate electrons by resonance activate and direct ortho and para. The groups –NH2 and –OH strongly activate the benzene ring. Halogenations of aniline and phenol take place in the absence of a catalyst and are difficult to stop at single substitution. Substitution occurs exclusively at the ortho and para positions. Modifying the amino and hydroxy substituents provides better control of non-substitution. The substituents in N-phenylacetamide and methoxybenzene are ortho- and para-directing but less strongly activating than benzenamine and phenol
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4 The activation and regioselectivity of aromatic electrophilic substitution by the amino group can be explained by examining the resonance forms for the intermediate cations: The ortho or para transition state is stabilized through resonance (compared to benzene). The transition state for meta attack is not resonance-stabilized by the amino group and the electronegative nitrogen atom withdraws electrons from the ring (deactivates). Little meta product is formed. Groups that withdraw electrons by resonance deactivate and direct meta. An example of a group that deactivates the benzene ring by resonance is the carboxy group. Nitration of benzoic acid, C6H5CO2H, occurs at 1/1000th the rate of benzene nitration and gives predominately the meta isomer. The CO2H group is deactivating and meta directing. The resonance structures of the intermediate cations show why the meta isomer is favored. The ortho and para transition states each have only two important resonance structures. The meta transition state has three important resonance structures. The carboxy group is therefore a deactivator (the carboxy group is electron-withdrawing) and a meta director (it deactivates the meta cation intermediate less than the ortho or para). There is always an exception: Halogen substituents, although deactivating, direct ortho and para. Halogen atoms are capable of donating electrons to the benzene ring through resonance and withdrawing electrons inductively (electronegativity). The overall effect is that halogens are deactivating but ortho- and para-directing
Ih8epengtanketwenhdctoaandresonaneexphinsthis -888-圆 不- 百--圆- hena6cggsgcoehfnsae98tea9ao8ho2maea A halogen atom is deactivating,yet ortho-and para-directing. a8 dop 血e-e流贵 16-4 Electrophilic Attack on Disubstituted Benzenes The strongest activator wins out. Within a group.substituents compete to oive isomer mixture 5
5 The competition between induction and resonance explains this unexpected result. Ortho and para attacks allow the positive charge of the transition state to be delocalized on the halogen. This outweighs the electron-withdrawing effect. In the case of meta attack, the positive charge cannot be delocalized. The inductive effect of the halogen is strong enough to make all three cations less stable than that derived from benzene itself. A halogen atom is deactivating, yet ortho- and para-directing. 16-4 Electrophilic Attack on Disubstituted Benzenes The strongest activator wins out. A set of simple guidelines allows the product of electrophilic attack on a disubstituted benzene to be predicted: Members of the higher-ranking groups override the effect of members of lower rank. Within a group, substituents compete to give isomer mixtures