EAS on Substituted Benzenes How do we know where E + will substitute? In general, consider: 1. Orientation Z is either an ortho,para-director or a meta-director 2. Rate Z is either activating (the rate of reaction is faster than benzene) or deactivating (the rate of reaction is slower than benzene)

Example 1 Nitration of nitrobenzene Is –NO 2 (the existing substituent) an ortho,para-director or a meta-director? Is –NO 2 an activator or a deactivator?

Example 2 Bromination of anisole Is –OCH 3 an ortho,para-director or a meta-director? Is –OCH 3 an activator or a deactivator? Why more para product than ortho?

Activating vs. Deactivating Substituents What structural features do activating substituents have in common? What structural features do deactivating substituents have in common? Electron-donating groups vs. electron-withdrawing groups Activating/DeactivatingSubstituent Strongly activating-NR 2, -OR (R = H or alkyl) Moderately activating-NHC(O)R, -OC(O)R Weakly activating-R, -Ph Weakly deactivating-X Moderately deactivating-C≡N, -SO 3 H, -C(O)Z (Z = H, R, N, O) Strongly deactivating-NO 2, -NR 3 + Remember, no F-C reactions with these substituents

Activators Electron-donating groups Have lone pair on atom next to benzene, or can donate electrons through induction (-R, -Ph) More electron density on ring makes benzene a better nucleophile Deactivators Electron-withdrawing groups Have + or  + on atom next to benzene Less electron density on ring makes benzene less nucleophilic Activating vs. Deactivating Substituents

Induction Electrons moving toward or away from ring through bonds Based on partial charges; electronegativity Resonance Substituent on ring can participate in resonance structures Electron Donating and Withdrawing

Directing Effects Which of these substituents are ortho,para-directors? Which of these substituents are meta-directors? Why? Activating/DeactivatingSubstituent Strongly activating-NR 2, -OR (R = H or alkyl) Moderately activating-NHC(O)R, -OC(O)R Weakly activating-R, -Ph Weakly deactivating-X Moderately deactivating-C≡N, -SO 3 H, -C(O)Z (Z = H, R, N, O) Strongly deactivating-NO 2, -NR 3 + ↑ o,p ↓ m↓ m

Directing Effects Relationship between structure and orientation effects? o,p-Directors Electron-donating groups m-Directors Electron-withdrawing groups Why? Look at how the intermediates (o,p and m) are stabilized through resonance or induction

Example Nitration of anisole See benzene worksheet questions o,p-Intermediates have more resonance structures (4) than m-intermediate (3)

Example Nitration of nitrobenzene See benzene worksheet questions m-Intermediate has more stable resonance structures (3) than o,p- intermediates (3 structure, but 1 is unlikely to form)

Summary Electron-donating groups: activators and o,p-directors Electron-withdrawing groups: deactivators and m-directors Exception: halogens Deactivators (EWG due to electronegativity and inductive effect) o,p-Directors (EDG through resonance)

Summary

EAS on Disubstituted Benzenes Example 1:

EAS on Disubstituted Benzenes Example 2:

EAS on Disubstituted Benzenes Example 3:

Predict the major product(s) a) b) c) d) e) f)

Synthesis Example 1 How would you prepare m-bromonitrobenzene from benzene? Process: 1. Identify steps that need to occur Bromination Nitration 2. Figure out the order in which the steps need to occur Which reaction comes first? Look at directing effects of the two substituents to decide Synthetic scheme:

Synthesis Example 2 Target molecule: Look at possible precursors

Synthesis Example 2, cont. Then, look at possible precursors to that target

Synthesis Example 2, cont. Finally, create synthesis scheme:

Synthesis Example 3 From McMurry, Organic Chemistry, 8 th ed., 2012

Synthesis Example 3, cont.

Synthesis Problems a) b) c)