Chapter 16: Chemistry of Benzene: Electrophilic Aromatic Substitution. Let us look at bromination: δ+ δ Br Br FeBr 3 Br Br FeBr 3

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1 Chapter 16: Chemistry of Benzene: lectrophilic Aromatic Substitution lectrophilic positively charged species searching for electron density Aromatic benzene ring with a high electron density Substitution the overall reaction is the replacement of by the electrophile S 3 Sulfonation Let us look at bromination: 3 itration Alkylation Benzene omobenzene, 80% X alogenation Acylation The Lewis Acid catalyst is required to create the strong electrophile The addition stage: δ δ 3 3 omine (a weak electrophile) Polarized bromine (a strong electrophile) resonance stabilized This can also simply be shown as 4 -

2 What does the energy profile look like for this reaction? The elimination stage: 4 3 substitution occurs rather than addition since the elimination of the proton recreates the aromatic ring, with its superior stability. The other halogenations 86% 3 I I 65% Cu I I 86% 3 for iodine, an oxidant is needed itration 3 85% S 4 60 fluorine does not work too reactive! S 3 S 4 3 i Sn, ii a itrobenzene Aniline, 95% 3 this is an important reaction in the synthesis of substituted benzenes we will discuss this (Ch 4) at the end of this segment

3 Sulfonation S 3 S 4 40 S 3 95% S S 3 S S 4 S B S 3 S 3 Benzenesulfonic acid one advantage of sulfonation is that it is readily reversed: it is therefore easy to perform this reaction in either direction: S 3 S 3 S S 3 no water; low temp 40 95% S 4 S 3 S 3 and: S 3 S 4 S 4 95% 100 lots of water; high temp ne useful synthetic transformation of sulfonic acids: Alkylation of benzene rings: the Friedel Crafts alkylation C 3 S 3 i a, 300 ii 3 C 3 p-toluenesulfonic acid p-cresol, 7% Al 3 85% Benzene -Chloropropane Cumene (isopropylbenzene)

4 Al 3 Al 4 Limitations: An electron pair from the aromatic ring attacks the carbocation, forming a C-C bond and yielding a new carbocation intermediate Al 4 Al 4 1 An aryl halide T reactive Why not? A vinyl halide Loss of a proton then gives the neutral alkylated substitution product Al 3 X Al 3 reaction where = - 3, -, -C -S 3, -C, -CC 3, -C, -C C 3, (-, -, - ) Limitations: Acylation of benzene rings: the Friedel Crafts acylation 3 C(C 3) 3 C(C 3) 3 (C 3) 3C Al 3 C(C 3) 3 Al 3 80 Major product Minor product Benzene Acetyl chloride Acetophenone, 95% 4 C 3C C C CC C 3 Al 3 0 C 3 C C C C 3 sec-butylbenzene 65% Butylbenzene 35% o rearrangements -- multiple substitutions BBut the same limitations apply on substituents in the ring u t Al 3 Al 4 Substituents already present in the ring affect the substitution An acyl cation Al 3 Al 4

5 rientation of itration in Substituted Benzenes Meta-directing deactivators (C 3 ) C 76 C C t CC C product (%) o- m- p- 3 S 4 5 product (%) o- m- p- rtho- and para-directing deactivators F I rtho- and para-directing activators C CC benzene S 3 C C F alkyl C 3 eactivity 3 C CC 3 CC 3 I Ph CC 3 Meta-directing deactivators rtho- and para-directing deactivators rtho- and para-directing activators Substituents have two types of electronic effects inductive δ δ X δ δ δ C δ δ X δ δ δ δ δ C resonance (X = F,,, I) the groups attached to the ring are inductively electronwithdrawing because of the polarity of their bonds ings substituted by a group with an electron-withdrawing resonance effect have this general structure otice that for these groups all carbonyl groups, nitro, nitrile and sulfonic acid both inductive and resonance effects have the same result deactivation of the ring by electron withdrawal. benzaldehyde What happens when the two effects do not work in the same direction? inductive -- withdrawal δ δ resonance donation (X =halogen) ings substituted by a group with an electron-donating resonance effect have this general structure X otice these all have at least one electron pair on the atom directly attached to the ring Basically the stronger one wins! C 3 Alkyl group; inductively electron-donating

6 Directing effects those groups which send to the ortho- and para- positions Activating and deactivating effects summarized: eactivity 50% ortho Most stable meta 0% withdraws electrons; carbocation intermediate is less stable, and ring is less reactive donates electrons; carbocation intermediate is more stable, and ring is more reactive para 50% Most stable Directing effects those groups which send to the meta- positions Substituent ffects in lectrophilic Aromatic Substitution ortho 19% C Least stable C C Substituent eactivity rientation Inductive ffect esonance ffect C 3 activating o-/pweak electron-donating none activating o-/p- weak electron-withdrawing strong electron-donating C meta 7% C C C F I (C 3) 3 deactivating deactivating o-/p- m- strong electron-withdrawing strong electron-withdrawing weak electron-donating none para C C C C CC 3 C C t C deactivating m- strong electron-withdrawing strong electron-withdrawing 9% Least stable lectrophilic aromatic substitution in multiply substituted rings % lectrophilic aromatic substitution in multiply substituted rings C 3 C 0 C 3 80% Priorities: activator takes precedence over deactivator Priorities: activator takes precedence over deactivator strong activator takes precedence over weaker activator

7 lectrophilic aromatic substitution in multiply substituted rings C 3 3 C 3 C 3 S 4 C 3 98% Priorities: activator takes precedence over deactivator strong activator takes precedence over weaker activator all else being equal, steric constraints will dominate ucleophilic Aromatic Substitution - only proceeds when there is an activating substituent - since the ring bears a negative charge in the intermediate, electron withdrawing groups will stabilize and facilitate the reaction - this is the opposite of electrophilic reactions (positive intermediates)

8 eactions at the side chain of aromatic compounds oxidation C C C C 3 KMn 4 C Industrially: C 3 C butylbenzene benzoic acid 85% C 3 Co(III) C also K Cr 7,,, heat p-xylene terephthalic acid a few more examples eactions at the side chain of aromatic compounds a Cr 7 bromination S 4 85% Co(Ac), Ac 91% propylbenzene C C C 3 (PhC) C4 CC C 3 (1-bromopropyl)benzene 97% Co(Ac), Ac 90% refer back to 10.5 allylic bromination Ph Ph Ph why only the benzylic position? Ph benzyl radical resonance stabilized

9 where did the come from? some other examples: C 3 BS C C 4 hν 90% C 3 BS C 4 hν C 59% hν can replace (PhC ) And finally, reduction reactions of aromatics C 3C 3C CC C 3 Pd C C C 3 C 3 C 3, Pt, t 000 psi, 5 C 3 C 3 Al 3 propiophenone 95% propylbenzene 100% o-xylene 1,-dimethylcyclohexane 100% Al 3 C 3C 3C - C C C 3 C 3 CC 3 mixture of two products C 3 C 3 C 3 4-t-butylphenol, h/c, t 1 atm, 5 C 3 C 3 C 3 4-t-butylcyclohexanol 100% C 3 m-nitroacetophenone Pd/C t C 3 m-ethylaniline Strategy in aromatic substitution Strategy in aromatic substitution Things to consider: -- order in which groups are introduced this is dependent on the orientation in the target -- you may need to block a certain position to get the desired substitution pattern -- you may need to introduce a group to get the desired orientation, then modify it to the desired one called Functional Group Interconversion, FGI Things to consider: -- order in which groups are introduced

10 Strategy in aromatic substitution Functional Group Interconversions Things to consider: -- you may need to introduce a group to get the desired orientation, then modify it to the desired one meta- director ortho- / para- director 3 S 4 Pd/C t can be in these examples FGI nitro and amino This is a reduction -- most common reducing agents will work FGI nitro and amino, i Me 9% We can do a selective reduction i, ii a 95% i Sn, S, 3 t 80% ii a 8% LA in TF will also work, but the above processes are much cheaper! FGI nitro and amino FGI carbonyl and alkyl we have seen this one: This is an oxidation -- there is a mild, and specific, reagent Pd/C t CF 3 C 3 C 0 to 5 90% and this one follows on from a recent reaction: BS C 4 hν

11 There are two practice syntheses in the text problems 16.4 and 16.5 C both groups are ortho-/para- directing, so that s K but, we will never be able to get two large groups to substitute ortho- to each other in good yield Let us look at two different ones therefore, we must block the para- position in order to achieve ortho- substitution S 3 3 S and are in the correct orientation, if is introduced first 3 S S 4 S 4 heat but the will not be introduced in the correct orientation unless is changed to a stronger o/p director to is easy, but there is a problem with the latter it is too reactive (polysubstitution) and can react with an acid catalyst (to give a meta- director) 3 S 4 heat Pd/C t Ac py Ac Ac CF 3 C 3 C

4/18/2011. 9.8 Substituent Effects in Electrophilic Substitutions. Substituent Effects in Electrophilic Substitutions

4/18/2011. 9.8 Substituent Effects in Electrophilic Substitutions. Substituent Effects in Electrophilic Substitutions 9.8 Substituent effects in the electrophilic substitution of an aromatic ring Substituents affect the reactivity of the aromatic ring Some substituents activate the ring, making it more reactive than benzene