22-1 Di- and Polysubstitution  Orientation on nitration of monosubstituted benzenes.

22-2 Directivity of substituents

22-3

22-4 Di- and Polysubstitution  Two characteristics of a substituent Orientation: Certain substituents direct preferentially to ortho & para positions; others to meta positions. ortho-para directing meta directingSubstituents are classified as either ortho-para directing or meta directing toward further substitution. Rate Certain substituents cause the rate of a second substitution to be greater than that for benzene itself; others cause the rate to be lower. activatingdeactivatingSubstituents are classified as activating or deactivating toward further substitution.

22-5 Di- and Polysubstitution -OCH 3 is ortho-para directing. -COOH is meta directing.

22-6 Di- and Polysubstitution Recall the polysubstitution in FC alkylation.

22-7 Di- and Polysubstitution  Generalizations: Directivity: Alkyl, phenyl, and all substituents in which the atom bonded to the ring has an unshared pair of electrons are ortho-para directing. All other substituents are meta directing. Activation: All ortho-para directing groups except the halogens are activating toward further substitution. The halogens are weakly deactivating.

22-8 Di- and Polysubstitution. Example The order of steps is important. Note the key point: transformation of o,p director into m director. o,p m m

22-9 Theory of Directing Effects  The rate of EAS is limited by the slowest step in the reaction.  For almost every EAS, the rate-determining step is attack of E + on the aromatic ring to give a resonance-stabilized cation intermediate.  The more stable this cation intermediate, the faster the rate-determining step and the faster the overall reaction.

22-10 Theory of Directing Effects  The orientation of the subsitution is controlled by the stability of the carbocation being formed by attack of the electrophile. Different carbocations formed depending on position of substitution.  Products are formed under kinetic control. In some cases, equilibrium can be established leading to different products. (FC alkylation)

22-11 Theory of Directing Effects -OCH 3 is directing: assume ortho-para attack. Here only para attack is shown. Very stable resonance structure. Why?

22-12 Theory of Directing Effects -OCH 3 is directing; assume meta attack. No corresponding very stable resonance structure. o, p preferred!

22-13 Theory of Directing Effects -CO 2 H is directing; assume meta attack.

22-14 Theory of Directing Effects -CO 2 H is directing: assume ortho-para attack.

22-15 Activating-Deactivating (Resonance)  Any resonance effect  Any resonance effect, such as that of -NH 2, -OH, and -OR, that delocalizes the positive charge on the cation has an activating effect toward further EAS.  Any resonance effect  Any resonance effect, such as that of -NO 2, -CN, - C=O, and -SO 3 H, that decreases electron density on the ring deactivates the ring toward further EAS. Next inductive

22-16 Activating-Deactivating (Inductive Effects)  Any inductive effect  Any inductive effect, such as that of -CH 3 or other alkyl group, that releases electron density toward the ring activates the ring toward further EAS.  Any inductive effect  Any inductive effect, such as that of halogen, -NR 3 +, -CCl 3, or -CF 3, that decreases electron density on the ring deactivates the ring toward further EAS.

22-17 Activating-Deactivating (halogens) For the halogens, the inductive and resonance effects run counter to each other, but the former is somewhat stronger. The net effect is that halogens are deactivating but ortho-para directing.

22-18 Nucleophilic Aromatic Substitution  Aryl halides do not undergo nucleophilic substitution by either S N 1 or S N 2 pathways.  They do undergo nucleophilic substitutions, but by two mechanisms quite different from those of nucleophilic aliphatic substitution. Nucleophilic aromatic substitutions are far less common than electrophilic aromatic substitutions.

22-19 Benzyne Intermediates (strong base)  When heated under pressure with aqueous NaOH, chlorobenzene is converted to sodium phenoxide. Neutralization with HCl gives phenol. Halogen reactivity: I > Br > Cl > F

22-20 Benzyne Intermediates (strong base) The same reaction with 2-chlorotoluene gives ortho- and meta-cresol. The same type of reaction can be brought about using sodium amide in liquid ammonia. mixture (!)

22-21 Benzyne Intermediates  -elimination of HX gives a benzyne intermediate, that then adds the nucleophile to give products.

22-22 Benzyne Intermediates  -elimination of HX gives a benzyne intermediate, that then adds the nucleophile to give products.

22-23 Benzyne Intermediates But wait, do we believe this crazy idea? We need some evidence…. A B

22-24 Benzyne Intermediates C next The deuterated fluoride below exchanges the D with solvent ammonia although the deuterated bromide does not. This indicates a relatively rapid exchange process for the fluoro compound.

22-25 Benzyne Intermediates explanation

22-26 Benzyne Intermediates D Get same product Explation next

22-27 Benzyne Intermediates explanation

22-28 Addition-Elimination (nitro groups) When an aryl halide contains electron-withdrawing NO 2 groups ortho and/or para to X, nucleophilic aromatic substitution takes place readily. Neutralization with HCl gives the phenol.

22-29 Meisenheimer Complex Reaction involves formation of reactive intermediate called a Meisenheimer complex. Similar to nucleophilic subsititution on carboxylic acid derivatives.