Di- and Polysubstitution

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

2. Directivity of substituents

3. Directivity of substituents

4. Di- and Polysubstitution • Two characteristics of a substituent • Orientation: • Certain substituents direct preferentially to ortho & para positions; others to meta positions. • Substituents are classified as either ortho-para directingor 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. • Substituents are classified as activating or deactivating toward further substitution.

5. Di- and Polysubstitution • -OCH3 is ortho-para directing. • -COOH is meta directing.

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

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.

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

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.

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)

11. Theory of Directing Effects • -OCH3 is directing: assume ortho-para attack. Here only para attack is shown. Very stable resonance structure. Why?

12. Theory of Directing Effects • -OCH3 is directing; assume meta attack. No corresponding very stable resonance structure. o, p preferred!

13. Theory of Directing Effects • -CO2H is directing; assume meta attack.

14. Theory of Directing Effects • -CO2H is directing: assume ortho-para attack.

15. Activating-Deactivating (Resonance) • Any resonance effect, such as that of -NH2, -OH, and -OR, that delocalizes the positive charge on the cation has an activating effect toward further EAS. • Any resonance effect, such as that of -NO2, -CN, -C=O, and -SO3H, that decreases electron density on the ring deactivates the ring toward further EAS. Next inductive

16. Activating-Deactivating (Inductive Effects) • Any inductive effect, such as that of -CH3 or other alkyl group, that releases electron density toward the ring activates the ring toward further EAS. • Any inductive effect, such as that of halogen, -NR3+, -CCl3, or -CF3, that decreases electron density on the ring deactivates the ring toward further EAS.

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.

18. Nucleophilic Aromatic Substitution • Aryl halides do not undergo nucleophilic substitution by either SN1 or SN2 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.

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

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 (!)

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

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

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

24. Benzyne Intermediates 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. C next

25. Benzyne Intermediates explanation

26. Benzyne Intermediates D Get same product Explation next

27. Benzyne Intermediates explanation

28. Addition-Elimination (nitro groups) • When an aryl halide contains electron-withdrawing NO2 groups ortho and/or para to X, nucleophilic aromatic substitution takes place readily. • Neutralization with HCl gives the phenol.

29. Meisenheimer Complex • Reaction involves formation of reactive intermediate called a Meisenheimer complex. Similar to nucleophilicsubsititution on carboxylic acid derivatives.