Chapter 9

1. Chapter 9 Second Half

2. 9.6 Reactions of Aromatic Compounds: Electrophilic Substitution Electrophilic aromatic substitution • electrophile (E+) reacts with an aromatic ring and substitutes for one of the hydrogens • The most common reaction of aromatic compounds • This reaction is characteristic of all aromatic rings

3. Many substituents can be introduced onto an aromatic ring through electrophilic substitution reactions Halogen (-Cl, -Br, -I) Nitro group (-NO2) Sulfonic acid group (-SO3H) Hydroxyl group (-OH) Alkyl group (-R) Acyl group (-COR) Reactions of Aromatic Compounds: Electrophilic Substitution

4. Reactions of Aromatic Compounds: Electrophilic Substitution Electrophilic alkene addition • Addition of a reagent such as HCl to an alkene • The electrophilic hydrogen approaches the p electrons of the double bond and forms a bond to one carbon, leaving a positive charge at the other carbon • The carbocation intermediate then reacts with the nucleophilic Cl- ion to yield the addition product

5. Reactions of Aromatic Compounds: Electrophilic Substitution Electrophilic aromatic substitution reaction begins in a similar way to electrophilic alkene addition reaction • FeBr3 catalyst is needed for bromination of benzene to occur • FeBr3 polarizes Br2 molecule making it more electrophilic • Polarization makes FeBr4-Br+ species that reacts as if it were Br+

6. Reactions of Aromatic Compounds: Electrophilic Substitution Comparison of alkene addition and aromatic substitution • Instead of adding Br- to give an addition product, the carbocation intermediate loses H+ from the bromine-bearing carbon • If addition occurred, the overall reaction would be endergonic • When substitution occurs, the stability of the aromatic ring is retained and the reaction is exergonic

7. Reactions of Aromatic Compounds: Electrophilic Substitution • The reaction occurs in two steps and involves a resonance-stabilized carbocation intermediate

8. Reactions of Aromatic Compounds: Electrophilic Substitution Aromatic Halogenation • introduce halogens into aromatic rings • Aromatic rings react with Cl2 in the presence of FeCl3 catalyst to yield chlorobenzenes • Reaction mechanism just like Br2 in the presence of FeBr3 • Reaction used in the synthesis of numerous pharmaceutical agents such as the antianxiety agent diazepam (Valium)

9. Reactions of Aromatic Compounds: Electrophilic Substitution Fluorine is too reactive to give mono-fluorinated products For Iodine, an oxidizing agent such as hydrogen peroxide or a copper salt such as CuCl2 must be added to the reaction • These substances oxidize I2 to the electrophilic species that reacts as if it were I+ • The aromatic ring reacts with the I+ to yield a substitution product

10. Electrophilic aromatic halogenations occur in the biosynthesis of numerous naturally occurring molecules, particularly those produced by marine organisms Thyroxine, synthesized in the thyroid gland in humans, is a thyroid hormone involved in regulating growth and metabolism Reactions of Aromatic Compounds: Electrophilic Substitution

11. Aromatic Nitration Aromatic rings can be nitrated with a mixture of concentrated nitric and sulfuric acids The electrophile is the nitronium ion, NO2+ The nitronium ion reacts with benzene to yield a carbocation intermediate, and loss of H+ Reactions of Aromatic Compounds: Electrophilic Substitution

12. Reactions of Aromatic Compounds: Electrophilic Substitution Aromatic nitration • Does not occur in nature • Important in the laboratory • The nitro-substituted product can be reduced by reagents such as iron or tin metal to yield an arylamine, ArNH2

13. Reactions of Aromatic Compounds: Electrophilic Substitution Aromatic Sulfonation • Aromatic rings can be sulfonated in the laboratory by reaction with fuming sulfuric acid, a mixture of H2SO4 and SO3 • The reactive electrophile is either HSO3+ or neutral SO3 • Substitution occurs by the same two-step mechanism seen for bromination and nitration • Aromatic sulfonation does not occur naturally • The sulfa drugs, such as sulfanilamide, were among the first clinically useful antibiotics

14. Reactions of Aromatic Compounds: Electrophilic Substitution • The mechanism of electrophilic sulfonation of an aromatic ring

15. Reactions of Aromatic Compounds: Electrophilic Substitution Aromatic Hydroxylation • Direct hydroxylation of an aromatic ring to yield a hydroxybenzene (a phenol) • Difficult and rarely done in the laboratory • Occurs much more freely in biological pathways • The reaction is catalyzed by p-hydroxyphenylacetate-3-hydroxylase and requires molecular O2 plus the coenzyme reduced flavin adenine dinucleotide (FADH2)

16. Reactions of Aromatic Compounds: Electrophilic Substitution

17. 9.7 Alkylation and Acylation of Aromatic Rings: The Friedel-Crafts Reaction Alkylation • Introduces a new C-C bond! • Called the Friedel-Crafts reaction after its discoverers • Very useful! • The reaction is carried out by treating the aromatic compound with an alkyl chloride, RCl, in the presence of AlCl3 to generate a carbocation electrophile, R+ • Aluminum chloride catalyzes the reaction by helping the alkyl halide to dissociate • Loss of H+ completes the reaction

18. Alkylation and Acylation of Aromatic Rings: The Friedel-Crafts Reaction

19. Alkylation and Acylation of Aromatic Rings: The Friedel-Crafts Reaction Friedel-Crafts alkylation has several limitations • Only alkyl halides can be used as electrophiles • Aromatic (aryl) halides and vinylic halides do not react because aryl and vinylic carbocations are too high in energy to form under Friedel-Crafts conditions • Vinylic means that a substituent is attached directly to a double bond, C=C-Cl

20. Alkylation and Acylation of Aromatic Rings: The Friedel-Crafts Reaction • Friedel-Crafts reactions do not succeed on aromatic rings that are substituted either by a strongly electron-withdrawing group such as carbonyl (C=O) or by an amino group (-NH2, NHR, -NR2)

21. Alkylation and Acylation of Aromatic Rings: The Friedel-Crafts Reaction 3. It is often difficult to stop the reaction after a single substitution • Polyalklation is observed • High yield of monoalkylation product is obtained only when a large excess of benzene is used

22. Alkylation and Acylation of Aromatic Rings: The Friedel-Crafts Reaction

23. Worked Example 9.2Predicting the Product of a Carbocation Rearrangement The Friedel-Crafts reaction of benzene with 2-chloro-3-methylbutane in the presence of AlCl3 occurs with a carbocation rearrangement. What is the structure of the product?

24. Worked Example 9.2Predicting the Product of a Carbocation Rearrangement Solution

25. Alkylation and Acylation of Aromatic Rings: The Friedel-Crafts Reaction An aromatic ring is acylated by reaction with a carboxylic acid chloride, RCOCl, in the presence of AlCl3 • An acyl group, -COR, is substituted onto an aromatic ring • The reactive electrophile is a stabilized acyl cation • Because of stabilization, no carbocation rearrangement occurs during acylation

26. Alkylation and Acylation of Aromatic Rings: The Friedel-Crafts Reaction Aromatic alkylations occur in numerous biological pathways • The carbocation electrophile is typically formed by dissociation of an organodiphosphate • It can be expelled as a stable diphosphate ion • The dissociation of an organodiphosphate in a biological reaction is typically assisted by complexation to a divalent metal cation such as Mg2+ to help neutralize charge

27. Alkylation and Acylation of Aromatic Rings: The Friedel-Crafts Reaction

28. 9.8 Substituent Effects in Electrophilic Substitutions 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 • Some substituents deactivate the ring, making it less reactive than benzene • Relative rates of aromatic nitration

29. The three possible disubstituted products – ortho, meta, and para – are usually not formed in equal amounts The nature of the substituent on the ring determines the position of the second substitution Substituents affect the orientation of the reaction Substituent Effects in Electrophilic Substitutions

30. Substituent Effects in Electrophilic Substitutions Substituents can be classified into three groups • ortho- and para-directing activators • ortho- and para-directing deactivators • meta-directing deactivators • There are no meta-directing activators All activating groups are ortho- and para- directing All deactivating groups other than halogens are meta-directing The halogens are unique in that they are deactivating but ortho- and para-directing

31. Substituent Effects in Electrophilic Substitutions

32. Substituent Effects in Electrophilic Substitutions Activating and Deactivating Effects • The common characteristic of all activating groups is that they donate electrons to the ring • Makes the ring more electron-rich • Stabilize the carbocation intermediate • Lower activation energy • The common characteristic of all deactivating groups is that they withdraw electrons from the ring • Makes the ring more electron-poor • Destabilizes the carbocation intermediate • Raising the activation energy for its formation

33. Substituent Effects in Electrophilic Substitutions The electron donation or electron withdrawal may occur by either an inductive effect or a “resonance effect” • Inductive effect • Due to an electronegativity difference between the ring and the attached substituent

34. Substituent Effects in Electrophilic Substitutions • Resonance effect • Due to overlap between a p orbital on the ring and an orbital on the substituent

35. Substituent Effects in Electrophilic Substitutions A Summary of Substituent Effects in Electrophilic Substitutions

36. Worked Example 9.3Predicting the Product of an Electrophilic Aromatic Substitution Reaction Predict the major product of the sulfonation of toluene.

37. Worked Example 9.3Predicting the Product of an Electrophilic Aromatic Substitution Reaction Solution