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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
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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
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6 Synthetic Strategies toward Substituted Benzenes 16-5 To obtain substitutions in positions incompatible with the directing sense of substituents requires a couple of synthetic “tricks”. Among these are: •Chemical interconversions of ortho, para with meta directors (nitro ⇔ amino or carbonyl ⇔ methylene); •Additional knowledge about practicality of certain electrophilic substitutions; •Employment of reversible blocking strategies with sulfonic acid groups (-SO3H). The sense of the directing power of substituents can be changed. The simplest way to introduce a nitrogen substituent into an arene is by nitration. The nitro group (meta-directing, deactivating) can be easily converted into the amino group (ortho, para-directing, activating) by reduction: Catalytic hydrogenation or Exposure to acid in the presence of active metals (iron or zinc amalgam) Oxidation of the amino group back to a nitro group can be accomplished using trifluoroperacetic acid. To prepare 3-bromobenzamide, direct bromination of benzamide leads to ortho and para substitution. If nitrobenzene is used instead: A similar conversion strategy can be used for alkanoyl ⇔ alkyl. In the synthesis of 1-chloro-3-ethylbenzene from benzene, neither chlorobenzene nor ethylbenzene is suitable as the immediate precursor to the product; each is ortho-, paradirecting. Ethanoyl benzene is a meta director which can subsequently be reduced to the ethyl functional group
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7 Reduction of alkanoyl- to alkylarenes provides a synthetic path that does not suffer from overalkylation or alkyl group rearrangement. Butyl benzene is best synthesized by alkanoylation with butanoyl chloride followed by Clemmensen reduction. Direct Friedel-Crafts butylation of benzene results in di- and trialkylation, as well as the formation of a rearranged product. Friedel-Crafts electrophiles do not attack strongly deactivated benzene rings. Only one of the two synthetic paths below to 1-(3- nitrophenyl)ethanone actually succeeds. The second route fails primarily due to the extreme deactivation of the nitrobenzene ring. Another factor is the low electrophilicity of the acylium ion compared to other electrophiles in aromatic electrophilic substitution. As a general rule, neither Friedel-Crafts alkylations nor alkanoylations take place with benzene derivatives strongly deactivated by meta-directing groups. Reversible sulfonation allows the efficient synthesis of ortho-disubstituted benzenes. The synthesis of 1-(1,1-dimethylethyl)-2-nitrobenzene [o-(tbutyl)nitrobenzene] by direct nitration of t-butylbenzene results in very low yields. The para isomer is the dominant product in this and in most other electrophilic substitutions of an ortho, para director. The desired ortho isomer can be prepared in high yield by first sulfonating the t-butylbenzene, nitrating the p-product and then removing the sulfonate group. Because both the substituent and the electrophile are sterically bulky, sulfonation occurs almost entirely at the para position. Protection strategies moderate the activating power of amine and hydroxy groups. Electrophilic attack on benzenamine and phenol are difficult to stop at the monosubstitution stage and sometimes may involve the heteroatom rather than the aromatic ring. Protection groups, acetyl for benzenamine and methyl for phenol reduce the activating nature of the amino and hydroxy groups and protect them against reaction with the incoming electrophile. Deprotonation is by basic or acidic hydrolysis, respectively
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8 16-6 Reactivity of Polycyclic Benzenoid Hydrocarbons Naphthalene is activated toward electrophilic substitution. Naphthalene undergoes electrophilic substitution rather than addition. Naphthalene is activated with respect to electrophilic aromatic substitution. Bromination at C1 occurs without a catalyst under mild conditions. Nitration, as well as other electrophilic substitutions, occur readily and are highly selective for reaction at C1. The ease of reaction and preference for reaction at C1 for naphthalene can be explained on the basis of the resonance structures for the carbocation transition state: Note that there are 5 resonance structures, two of which contain the particularly stable benzene ring and one of which contains a stable tertiary carbocation. Attack at C2 also leads to a carbocation having 5 resonance structures, however, not one of these has the structure of an intact benzene. Attack at C1 leads to a more stable transition state than does attack at C2. Electrophiles attack substituted naphthalenes regioselectively. The naphthalene ring carrying a substituent is the ring most affected toward electrophilic attack. An activating group directs the incoming electrophile to the same ring; a deactivating group directs the incoming electrophile to the other ring. Deactivating groups direct electrophilic substitutions to the other ring, preferentially to position C5 and C8
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9 Resonance structures aid in predicting the regioselectivity of larger polycyclic aromatic hydrocarbons. Resonance, steric considerations and the directing power of substituents apply to larger derivatives of naphthalene, such as phenanthrene. Electrophilic attack in this system is at C9 and C10 because substitution at these positions leads to a carbocation resonance structure having two intact benzene rings. 16-7 Polycyclic Aromatic Hydrocarbons and Cancer Many polycyclic benzenoid hydrocarbons are carcinogenic. A particularly well-studied environmental carcinogenic pollutant is benzo[a]pyrene. This molecule is generated by gasoline and oil combustion, incineration of refuse, forest fires, cigarettes, cigars and in roasting meats. Benzo[a]pyrene is biologically converted into the ultimate carcinogen, an oxacyclopropane, diol derivative: The carcinogenic activity of the epoxide derivative of benzo[a]pyrene is believe to be due to its interaction with a guanine base in DNA. Other alkylating agents (1,2-dibromoethane and oxacyclopropane) also act as carcinogens, presumably by the same mechanism. The carcinogenicity in a number of organic compounds has necessitated their replacement in synthetic applications. A recent example is the chloro(methoxy)methane molecule, once commonly used for the protection of alcohols by ether formation. 16 Important Concepts 1. Benzene Substituent Classes – • Activating – Electron donors • Strong: amino, alkoxy • Weak: alkyl, phenyl • Deactivating – Electron Withdrawers • Strong: nitro, trifluoromethyl, sulfonyl, oxo, nitrile, cationic • Weak: halogens • Activation or deactivation mechanism is by resonance • Multiple substituents operate simultaneously to either reinforce or oppose each other
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10 16 Important Concepts 2. Activators – Direct electrophiles ortho and para; deactivators direct meta (but at a much lower rate). Halogens are an exception: deactivate but direct ortho and para. 3. Several Substituents – The strongest activator (or weakest deactivator) controls the regioselectivity of attack. • NR2, OR > X2 > R > meta directors 4. Synthesis Strategies – • Directing power of the substituents • Chemical manipulation of substituents to change the sense of direction • Use of blocking and protecting groups (sulfonation and desulfonation) 16 Important Concepts 5. Naphthalene – Preferred electrophilic substitution is at C1 due to the stability of the resulting carbocation. 6. Naphthalene Substituents – • Electron donating substituents direct electrophiles to ortho and para on the same ring • Electron withdrawing substituents direct electrophiles away from the same ring, mainly to C5 and C8 7. Benzo[a]pyrene – Actual carcinogen is an oxacyclopropanediol having C7 and C8 hydroxy groups and C9 and C10 bridged by oxygen. • Mutational mechanism: alkylation of one of the nitrogens on one of the DNA bases
