Electrophilic Aromatic Substitution

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Lesley Roberts
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1 Electrophilic Aromatic Substitution Electrophilic substitution is the typical reaction type for aromatic rings. Generalized electrophilic aromatic substitution: E E Electrophile Lewis acid: may be or neutral. Nucleophile Lewis base. Shorthand: Ar Product: neutral if electrophile is ; if electrophile is neutral. Shorthand: ArE 1. Nitration Ar N 3 2 S 4 Ar 2 1

Generalized electrophilic aromatic substitution: E E Electrophile Lewis acid: may be or

2 Mechanism (1) 2 2 S S 4 σ bond a nitronium ion, cf. BF 4 (2) =N= slow This intermediate carbocation is sometimes called a σ complex. Addition of a basic group, eg S 4, to the σ complex would result in formation of a nonaromatic compound, whereas expulsion of results in an aromatic product. (3) S 3 fast 2 S 4 Since the nitro group can often be reduced to the amine group (tin or iron and are frequently used to effect this reduction), Ar > ArN 2, nitration is often used to ultimately make an aryl amine. 2

Addition of a basic group, eg S 4, to the σ complex would result in formation of a nonaromatic compound, whereas expulsion of

3 2. Sulfonation Ar 2 S 4 S 3 ArS 3 2 Mechanism (1) 2 2 S 4 3 S 4 S 3 3 S (2) S σ complex 3 S S 3 (3) S 4 2 S 4 (4) ArS 3 3 ArS 3 2 strong acid 3

4 Note the following Sulfonic acids (eg, ArS 3 ), derivatives of sulfuric acid, are strong acids and are highly ionized in water. Each step in the sulfonation mechanism is an equilibrium; therefore, the entire reaction is an equilibrium. Thus, Ar can be sulfonated using fuming sulfuric acid, 2 S 4 CS 3, and ArS 3 can be desulfonated (to Ar) by boiling it in a dilute solution of sulfuric acid. Sulfonation of an aromatic ring can provide a route to a phenol, Ar. If a sulfonic acid is fused with solid K, the S 3 group is replaced by. [wing to the vigorous reaction conditions, there are limitations with regard to which substituents may be present on the ring.] Sulfonation of an aromatic ring provides a highly polar site capable of hydrogen bonding; this gives rise to water solubility. Dyes are sometimes made water soluble in this way. Some synthetic detergents have the structure R S 3 Na, where R is a longchain alkyl group. The ionic "head" is hydrophilic and the long "tail" is hydrophobic. This combination enables this material to disperse oily material in water. 4

Thus, Ar can be sulfonated using fuming sulfuric acid, 2 S 4 CS 3, and ArS 3 can be desulfonated (to Ar) by boiling it in a dilute solution of sulfuric acid.

5 3. alogenation Ar 2 Fe Ar Mechanism 2 Fe Fe 3 (1) 2 Fe 3 Fe 4 catalyst complex (2) Fe 4 electrophile slow Fe 4 (3) Fe 4 Fe 3 5

6 4. FriedelCrafts Alkylation Ar R anhydrous Al 3 or F ArR = halogen, R = alkyl, NT vinyl, NT aryl Ar R Ar C C BronstedLowry acid, eg F BronstedLowry acid, eg F ArR 2 Ar C C eg Ar C C BronstedLowry acid, eg F Ar C C NT Ar C C 6

BronstedLowry acid, eg F BronstedLowry acid, eg F ArR 2

7 Mechanism (1) R Al 3 Al 4 R catalyst sometimes a complex, sometimes not R R (2) electrophile slow Al 4 R R (3) Al 4 Al 3 Since a carbocation can be the electrophile in this mechanism, a variety of carbocation precursors could be used: alkenes, for example. Since aryl and vinyl carbocations are unstable, Ar and vinyl cannot be used as precursors for these species. 7

this mechanism, a variety of carbocation precursors could be used: alkenes, for example.

8 Limitations on FriedelCrafts Alkylation The alkyl group may rearrange. Any group which deactivates an aromatic ring more than the halogens (vide infra) cannot be present on the ring prior to FC alkylation, nor can N 2, NR, or NR 2. Alkyl groups activate aromatic rings toward electrophilic substitution; therefore, polyalkylation is a problem. 8

cannot be present on the ring prior to FC alkylation, nor can N 2, NR, or NR 2.

9 5. FriedelCrafts Acylation Ar RC acid chloride or RCCR acid anhydride Al 3 or 3 P 4 ArCR aryl ketone or RC carboxylic acid Mechanism (1) RC Al 3 catalyst R C R C resonance stabilized acylium ion Al 4 RC (2) R C electrophile RC slow R C Al 4 (3) Al 4 Al 3 9

Mechanism (1) RC Al 3 catalyst R C R C resonance stabilized

10 Limitations Any group which deactivates an aromatic ring more than the halogens (vide infra) cannot be present on the ring prior to FC acylation, nor can N 2, NR, or NR 2. owever, the acylium ion does not rearrange and polyacylation is not a problem because the acyl group deactivates the ring toward further electrophilic substitution. 10

11 Effect of Substituents Already on the Ring Reactivity: Activating or Deactivating If we allow toluene and benzene to react with mixtures of nitric and sulfuric acids under the same conditions and the toluene reacts 25 times faster than the benzene, we say it is 25 times more reactive. We would also say that the methyl group activates the aromatic ring toward nitration. Since the other electrophilic aromatic substitutions have mechanisms similar to nitration, we might expect the methyl group to activate the aromatic ring toward these reactions; usually, it does. C 3 N 3 2 S 4 ortho C 3 para C 3 C 3 meta Major Minor If we nitrate toluene, we find that the major products are pnitrotoluene and onitrotoluene; only a small amount of mnitrotoluene is formed. We say the methyl group is an ortho, para director for electrophilic substitutions. 11

Since the other electrophilic aromatic substitutions have mechanisms similar to nitration, we might expect the methyl group to activate the aromatic ring toward these reactions; usually, it does.

12 The table below shows the effect of some common aromatic ring substituents on electrophilic substitution Activating; rtho, Para Directing Strongly activating: N 2, NR, NR 2,. Moderately activating: R, NCR. Weakly activating: C 6 5, R. Deactivating; Meta Directing, N R 3, C/N, C, S 3, C, CR. Deactivating; rtho, Para Directing Weakly deactivating: F,, Br, I. Except for the halogens, activating groups activate all positions of the ring, but have greater effect on o & p; deactivating groups deactivate all positions of the ring, but have greater effect on o & p. The rate of formation of o, m or p isomers depends on the rate of formation of the precursor carbocations (σ complexes). 12

Deactivating; rtho, Para Directing Weakly deactivating: F,, Br, I.

13 rtho Attack N 3 2 S 4 Para Attack N 3 2 S 4 Meta Attack N 3 2 S 4 Boxed resonance structures make an especially large contribution if is electron releasing; they make an especially small contribution if is electron withdrawing. Note: ortho and para attack form carbocations with one boxed structure; the carbocation resulting from meta attack has no boxed structures. 13

small contribution if is electron withdrawing.

14 K. Electron withdrawing groups on the ring destabilize the transition state leading to the σcomplex, and electron donating ones stabilize the transition state, so reaction occurs faster with electron donating groups. And the effect is greatest at the ortho and para positions so an electron withdrawing group is meta directing because it deactivates the o and p positions. BUT, two questions. 1) Why are some groups which appear to be electron withdrawing, for example, deactivating and meta directing as expected, while others, N 2 for example, are activating and o, p directing? 2) Why are the halogens deactivating and o, p directing? K. 1) Note that all the groups which would seem to be deactivating meta directors and turn out to be activating o, p directors, and N 2, for example, carry at least one pair of unshared electrons. These unshared electrons are delocalized into the ring as the σcomplex intermediate forms if attack is at the ortho or para position. 14

1) Why are some groups which appear to be electron withdrawing, for example, deactivating and meta directing as expected, while others, N 2 for example, are activating and o, p directing?

15 Para Attack N 3 2 S 4 N 2 N 2 N 2 N 2 N 2 Meta Attack N 3 2 S 4 N 2 N 2 N 2 N 2 The red resonance structure makes a minor contribution: there is an electronegative element attached to the positively charged carbon; the positive charge is intensified by inductive electron withdrawal. The boxed resonance structure makes a major contribution. Although positive charge resides on an electronegative element, every atom (except hydrogens) has an octet of electrons. 2) When halogen is the ring substituent it seems that its ability to donate electrons via resonance determines the preferred orientation of attack by the electrophile, while reactivity is controlled by its inductive electron withdrawing effect. Causes halogens to deactivate ring. Causes halogen to be para (and ortho) director. 15

Although positive charge resides on an electronegative element, every atom (except hydrogens) has an octet of electrons.

16 Position of Electrophilic Attack for Disubstituted Benzenes 1) Where two groups reinforce each other, the outcome is obvious. N 2 C C In cases of opposing effects prediction is more difficult and mixtures may result. 2) Strongly activating groups usually win out over deactivating or weakly activating groups. 2 N N 3 2 S 4 2 N 2 N 3) The is usually little substitution between two groups which are meta to each other. C 3 C 3 C 3 C 3 N 3 2 S 4 2 N 32% 59% 9% 16

2) Strongly activating groups usually win out over deactivating or weakly activating groups.

Electrophilic Aromatic Substitution Reactions

Electrophilic Aromatic Substitution Reactions, Course Notes Archive, 1 Electrophilic Aromatic Substitution Reactions An organic reaction in which an electrophile substitutes a hydrogen atom in an aromatic