Reactions of Benzene & Its Derivatives

Transcription

1 rganic Lecture Series Reactions of Benzene & Its Derivatives Chapter 22 1 Reactions of Benzene rganic Lecture Series The most characteristic reaction of aromatic compounds is substitution at a ring carbon alogenation e 3 2 Chlorobenzene itration 2 S itrobenzene 2

2 Reactions of Benzene rganic Lecture Series Sulfonation S 3 2 S 4 S 3 Benzenesulfonic acid Alkylation RX AlX 3 R X An alkylbenzene Acylation RCX AlX 3 CR X An acylbenzene 3 rganic Lecture Series Carbon-Carbon Bond ormations R R Al 3 Arenes Alkylbenzenes 4

3 rganic Lecture Series Electrophilic Aromatic Substitution Electrophilic aromatic substitution a reaction in which a hydrogen atom of an aromatic ring is replaced by an electrophile E E In this section several common types of electrophiles how each is generated the mechanism by which each replaces hydrogen 5 EAS General Mechanism A general mechanism rganic Lecture Series Step 1 Step 2 E E Electro - phile fast slow, rate determining E Resonance-stabilized cation intermediate E Key question What is the electrophile and how is it generated? 6

4 rganic Lecture Series 7 Chlorination Step 1 formation of a chloronium ion rganic Lecture Series e Chlorine (a Lewis base) erric chloride (a Lewis acid) - - e e 4 A molecular complex An ion pair with a positive charge containing a on chlorine ch loronium ion Step 2 attack of the chloronium ion on the ring slow, rate determining Resonance-stabilized cation intermediate; the positive charge is delocalized onto three atoms of the ring 8

5 Chlorination rganic Lecture Series Step 3 proton transfer regenerates the aromatic character of the ring Cation intermediate - fast -e 3 e 3 Chlorobenzene 9 Bromination rganic Lecture Series ebr Br 3 Br 2 Br Bromobenzene This is the general method for Substitution of halogen onto a benzene ring (CAT be halogenated by ree Radical Mechanism) 10

6 rganic Lecture Series Bromination-Why not addn of Br 2? Regains Aromatic Energy 11 itration Generation of the nitronium ion, 2 Step 1 proton transfer to nitric acid rganic Lecture Series S 3 S 4 Sulfuric itric Conju gate acid acid pk a = -3 acid pk a = -1.4 of nitric acid Step 2 loss of 2 gives the nitronium ion, a very strong electrophile The nitronium ion 12

7 itration rganic Lecture Series Step 1 attack of the nitronium ion (an electrophile) on the aromatic ring (a nucleophile) Resonance-stabilized cation intermediate Step 2 proton transfer regenerates the aromatic ring itration rganic Lecture Series A particular value of nitration is that the nitro group can be reduced to a 1 amino group C C 3 2 i (3 atm) itrobenzoic acid 2 4-Aminobenzoic acid 14

8 Sulfonation rganic Lecture Series Carried out using concentrated sulfuric acid containing dissolved sulfur trioxide 2 S 4 S 3 S 3 Benzene B enzenesulfonic acid (S 3 in 2 S 4 is sometimes called fuming sulfuric acid.) 15 riedel-crafts Alkylation rganic Lecture Series riedel-crafts alkylation forms a new C-C bond between an aromatic ring and an alkyl group Al 3 Benzene 2-Chloropropane (Isoprop yl chlorid e) Cumene (Isopropylbenzene) The electrophilic partner is a carbocation; it will arrange to the most stable ion allylic>3 o >2 o >1 o 16

9 riedel-crafts Alkylation rganic Lecture Series Step 1 formation of an alkyl cation as an ion pair - R Al R Al R - Al 4 A molecular An ion pair containing comp lex a carbocation Step 2 attack of the alkyl cation on the aromatic ring R R Step 3 proton transfer regenerates the aromatic ring R A resonance-stabilized cation R R Al 3 R Al 3 17 riedel-crafts Alkylation rganic Lecture Series There are two major limitations on riedel-crafts alkylations 1. carbocation rearrangements are common Al 3 Benzene Isobutyl chloride tert-butylbenzene C 3 C 3 - C 3 CC 2 - Al 3 C 3 C- C 2 --Al 3 I sobutyl chloride amolecular complex C 3 C 3 C - Al 4 C 3 an ion pair 18

10 riedel-crafts Alkylation rganic Lecture Series 2. -C alkylation fails on benzene rings bearing one or more of these strongly electronwithdrawing groups Y RX Al 3 o reacti on When Y Equals Any of These Groups, the Benzene Ring Does ot Undergo riedel-crafts Alkylation C CR C CR S 3 C 2 R 3 C 2 C 3 C 3 19 rganic Lecture Series 20

11 rganic Lecture Series The De-activation of Aromatic Systems ote deactivation refers to the rate of EAS 21 riedel-crafts Acylation rganic Lecture Series riedel-crafts acylation forms a new C-C bond between a benzene ring and an acyl group C 3 C Al 3 Benzene Acetyl ch loride Acetophenone Al 3 4-Phenylbutanoyl chlorid e α-tetralon e 22

12 riedel-crafts Acylation The electrophile is an acylium ion rganic Lecture Series R-C An acyl chloride Al- Aluminum chloride (1) - R-C Al A molecular complex with a positive charge charge on chlorine (2) R-C - Al 4 A n ion pair containing an acylium ion 23 riedel-crafts Acylation rganic Lecture Series an acylium ion is a resonance hybrid of two major contributing structures complete valence shells R-C R-C The more important contributing structure -C acylations are free of a major limitation of -C alkylations; acylium ions do not rearrange. 24

13 riedel-crafts Acylation rganic Lecture Series A special value of -C acylations is preparation of unrearranged alkylbenzenes Al 3 2-Methylpropanoyl chloride 2 4, K diethylene 2-Methyl-1- glycol phenyl-1-propanone Isobutylbenzene 25 Di- and Polysubstitution rganic Lecture Series nly a trace 26

14 Di- and Polysubstitution rganic Lecture Series rientation on nitration of monosubstituted benzenes Substituent ortho meta para ortho para meta C trace C trace Br C C Di- and Polysubstitution rientation rganic Lecture Series certain substituents direct preferentially to ortho & para positions; others to meta positions substituents are classified as either ortho-para directing or meta directing toward further substitution 28

15 Rate Di- and Polysubstitution rganic Lecture Series 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 29 rganic Lecture Series 30

16 Di- and Polysubstitution rganic Lecture Series -C 3 is ortho-para directing C 3 C 32 C 3 3 C3 C 2 Anisole o-itroanisole (44%) -C 2 is meta directing 2 p- itroanis ole (55%) C C C C 2 S C 2 Ben zoic 2 acid o-itrobenzoic acid (18%) m-itrobenzoic acid (80%) p-itrobenzoic acid (2%) 31 Di- and Polysubstitution rganic Lecture Series rtho-para Directing Strongly activating 2 R R 2 Moderately activating Weakly activating Weakly deactivating CR R CAr CR Br I CAr R Meta Directing Moderately deactivating Strongly deactivating C CR C C 2 S CR C C 3 C 3 32

17 Di- and Polysubstitution rganic Lecture Series the order of steps is important C 3 C 3 K 2 Cr S 4 2 S 4 C p-itrobenzoic acid C C K 2 Cr S 4 2 S 4 2 m- itroben zoic acid 33 Theory of Directing Effects rganic Lecture Series The rate of EAS is limited by the slowest step in the reaction or almost every EAS, the ratedetermining step is attack of E on the aromatic ring to give a resonancestabilized cation intermediate The more stable this cation intermediate, the faster the ratedetermining step and the faster the overall reaction 34

18 Theory of Directing Effects rganic Lecture Series or ortho-para directors, ortho-para attack forms a more stable cation than meta attack ortho-para products are formed faster than meta products or meta directors, meta attack forms a more stable cation than ortho-para attack meta products are formed faster than ortho-para products 35 Theory of Directing Effects itration of anisole -C 3 ; examine the meta attack rganic Lecture Series C 3 2 slow C 3 C 3 C (a) (b) (c) fast - C

19 itration of anisole rganic Lecture Series -C 3 examine the ortho-para attack C 3 C 3 2 slow C 3 C 3 C 3 C (d) (e) (f) (g) 2 - fast This resonance structure accounts for the selectivity 37 Theory of Directing Effects rganic Lecture Series - 2 ; examine the meta attack C 2 slow itration of benzoic acid C C C C 2 2 (a) (b) (c) fast

20 itration of benzoic acid rganic Lecture Series - 2 assume ortho-para attack C slow 2 C C C C fast (d) (e) (f) The most disfavored contributing structure 2 This resonance structure accounts for the selectivity 39 Activating-Deactivating rganic Lecture Series Any resonance effect, such as that of - 2, -, and -R, that delocalizes the positive charge on the cation intermediate lowers the activation energy for its formation, and has an activating effect toward further EAS Any resonance effect, such as that of - 2, -C, -C, and -S 3, that decreases electron density on the ring deactivates the ring toward further EAS 40

21 Activating-Deactivating rganic Lecture Series Any inductive effect, such as that of - C 3 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, -R 3, -C 3, or -C 3, that decreases electron density on the ring deactivates the ring toward further EAS 41 Di- and Polysubstitution rganic Lecture Series Generalizations alkyl, phenyl, and all other substituents in which the atom bonded to the ring has an unshared pair of electrons are orthopara directing; all other substituents are meta directing all ortho-para directing groups except the halogens are activating toward further substitution; the halogens are weakly deactivating 42

22 Activating-Deactivating rganic Lecture Series 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 E E E 43 Di- and Polysubstitution rganic Lecture Series rtho-para Directing Strongly activating 2 R R 2 Moderately activating Weakly activating Weakly deactivating CR R CAr CR Br I CAr R Meta Directing Moderately deactivating Strongly deactivating C CR C C 2 S CR C C 3 C 3 44

23 rganic Lecture Series Medicinal Chemistry Benzodiazepins 1) Sedative-hypnotic 2) Anticonvulsant 3) Muscle relaxant Valium 4) Anxiolytic 45 Retrosynthetic Analysis 3 C rganic Lecture Series Medicinal Chemistry 3 C C riedel-crafts Acylation X 46

24 rganic Lecture Series Medicinal Chemistry Short Problem Using EAS the synthesis of p-aminochlorobenzene e S 4 2 Pt or Pd Separate o from p 47 rganic Lecture Series Medicinal Chemistry The Synthesis of the amide section 2 3 C 3 C C 3 a C 3 Br 48

25 rganic Lecture Series Medicinal Chemistry riedel Crafts Acylation 3 C C 3 3 C Al 3 Amide is activating & o p directing 49 3 C rganic Lecture Series Medicinal Chemistry 3 C 1) a 2) 3 C 3 3 C 2 loss 2 formation of imine 50

26 rganic Lecture Series Medicinal Chemistry treatment of schizophrenia and acute psychotic states and delirium. Chlorpromazine (Thorazine) The introduction (1950) of chlorpromazine into clinical use has been described as the single greatest advance in psychiatric care, dramatically improving the prognosis of patients in psychiatric hospitals worldwide the availability of antipsychotic drugs curtailed indiscriminate use of electroconvulsive therapy and psychosurgery, and was one of the driving forces behind the deinstitutionalization movement. 51 rganic Lecture Series Medicinal Chemistry 52

27 rganic Lecture Series Medicinal Chemistry C 3 C 2 1) LiAl 4 2) Michael Reaction in Context rganic Lecture Series Medicinal Chemistry 2eq C 2 C 3 2 C 2 C 3 C 2 C 3 54

28 rganic Lecture Series Medicinal Chemistry Dieckmann Condensation in Context C 2 C 3 C 2 C 3 ac 3 C 3 C 2 C 3 55 rganic Lecture Series Medicinal Chemistry C 2 C 3 1) a 2) 3 3) Δ 56

29 rganic Lecture Series Medicinal Chemistry 1) MgBr 2) 3 aloperidol 57 Al 3 C 1) / 2) S 2 rganic Lecture Series C 3 2 1) LiAl 4 2) 3 C 2 2eq C 2 C 3 C 2 C 3 C 2 C 3 ac 3 C 3 C 2 C 3 1) a 2) 3 3) aloperidol 1) 2) 3 MgBr 58