Chemistry of Aromatic Compounds

1. Chemistry of Aromatic Compounds Department of Pharmaceutical Analysis Chalapathi Institute of Pharmaceutical Sciences

2. The Structure of Benzene • Because each  bond has two electrons, benzene has six  electrons.

3. In benzene, the actual bond length (1.39 Å) is intermediate between the carbon—carbon single bond (1.53 Å) and the carbon—carbon double bond (1.34 Å).

4. Spectroscopic Properties of Benzene

5. The resonance description of benzene consists of two equivalent Lewis structures, each with three double bonds that alternate with three single bonds. • The true structure of benzene is a resonance hybrid of the two Lewis structures, with the dashed lines of the hybrid indicating the position of the  bonds. • We will use one of the two Lewis structures and not the hybrid in drawing benzene. This will make it easier to keep track of the electron pairs in the  bonds (the  electrons).

6. Stability of Benzene • Benzene reacts slowly with Br2 to give bromobenzene (where Br replaces H) • This is a substitution reaction rather than the rapid addition reaction common to compounds with C=C.

7. Heats of Hydrogenation as Indicators of Stability • The addition of H2 to C=C normally gives off about 118 kJ/mol – 3 isolated double bonds would give off 356 kJ/mol • Two conjugated double bonds in cyclohexadiene add 2 H2 to release 230 kJ/mol • Benzene has 3 units of unsaturation but gives off only 206 kJ/mol on reacting with 3 H2 molecules • Therefore it has about 150 kJ more “stability” than an isolated set of three double bonds

8. Benzene is actually 24 kJ more stable than cyclohexadiene!

9. Hückel’s Rule(1931), based on quantum mechanics: • Any conjugated monocyclic polyene that is planar and has (4n+2)π and/or nonbonding electrons, with n = 0,1,2, etc., will exhibit the special stability associated with aromaticity. (1930) • n4n + 2 Pi electrons 0 4(0) + 2 = 2 1 4(1) + 2 = 6 2 4(2) + 2 = 10 3 4(3) + 2 = 14 4 4(4) + 2 = 18

10. Which are Aromatic???

11. Electrophilic Aromatic Substitution

12. Nitration

13. Nitration Mechanism

14. Sulfonation is Reversible

15. Desulfonation

16. Bromination / Chlorination

17. Bromination Mechanism

18. Reaction Profile

19. Friedel-Crafts Acylation

21. Friedel-Crafts Alkylation

22. Mechanism of Friedel-Crafts Alkylation

23. Bisubstitutions, directing Effects

24. Substituent Summary

25. Activating group Summary

26. Electron-Withdrawing Nitro Group effect

27. Deactivating group summary

28. Halogens are the AnomolyDeactivators and o,p-Directors By electron withdrawinginductive effect, halogens deactivates the rings. Resonance donation causes o, p direction

29. Di substitution reactions Nitration of toluene Acylation of p-methyl toluene

30. Reactions of rings with 2 or more substituents

31. Aryl Halides Ar-X Organic compounds with a halogen atom attached to an aromatic carbon are very different from those compounds where the halogen is attached to an aliphatic compound. Carbon-halogen bonds in aryl halides are shorter and stronger than carbon-halogen bonds in alkyl halides. Because the carbon-halogen bond is stronger, aryl halides react more slowly than alkyl halides when carbon-halogen bond breaking is rate determining. While the aliphatic compounds readily undergo nucleophilic substitution and elimination reactions, the aromatic compounds resist nucleophilic substitution, only reacting under severe conditions or when strongly electron withdrawing groups are present ortho/para to the halogen.

32. reactions of alkyl halidesAr-X • SN2 NR • E2 NR •  organo metallic compounds similar • reduction similar

34. Bond Lengths (Å) C—Cl C—Br CH3—X 1.77 1.91 C2H5—X 1.77 1.91 sp3 (CH3)3C—X 1.80 1.92 CH2=CH—X 1.69 1.86 C6H5—X 1.69 1.86 sp2

35. In aryl halides, the carbon to which the halogen is attached is sp2 hybrizided. The bond is stronger and shorter than the carbon-halogen bond in aliphatic compounds where the carbon is sp3 hybridized. Hence it is more difficult to break this bond and aryl halides resist the typical nucleophilic substitution reactions of alkyl halides. The same is true of vinyl halides where the carbon is also sp2 hybridized and not prone to nucleophilic substitution. In a manner analogous to the phenols & alcohols, we have the same functional group in the two families, aryl halides and alkyl halides, but very different chemistries.

36. Aryl halides, reactions: • Formation of Grignard reagent • EAS • Nucleophilic aromatic substitution (bimolecular displacement) • (Ar must contain strongly electron withdrawing groups ortho and/or para to X) • Nucleophilic aromatic substitution (elimination-addition) • (Ring not activated to bimolecular displacement)

37. 1)  Grignard reagent

38. EAS The –X group is electron-withdrawing and deactivating in EAS, but is an ortho/para director.

39. Nucleophilic aromatic substitution (bimolecular displacement) • Ar must contain strongly electron withdrawing groups ortho and/or para to the X.

42. bimolecular displacement (nucleophilic aromatic substitution) mechanism:

43. evidence for the bimolecular displacement mechanism: no element effect : Ar-I  Ar-Br  Ar-Cl  Ar-F (the C—X bond is not broken in the RDS)

44. Elimination-Addition, nucleophilic aromatic substitution. • When the ring is not activated to the bimolecular displacement and the nucleophile is an extremely good one.

45. Elimination-Addition mechanism (nucleophilic aromatic substitution)

46. While the concept of “benzyne” may appear to be strange, there is much evidence that this mechanism is correct.

47. benzyne intermediate has been trapped in a Diels-Alder condensation:

48. Amines.Organic derivatives of ammonia, NH3. Nitrogen atom have a lone pair of electrons, making the amine both basic and nucleophilic Amines Nomenclature. (please read) Amines are classified according to the degree of nitrogen substitution: 1° (RNH2), 2° (R2NH), 3° (R3N) and 4° (R4N+) alkylaminesarylamines primary (1°) amines secondary (2°) amines tertiary (3°) amines quarternary (4°) ammonium ion Note: Although the terminology is the same, this classification of amines is different from that of alcohols.

49. Structure and bonding. The nitrogen of alkylamines is sp3hybridized and tetrahedral. The nitrogen of arylamines (aniline) is slightly flatten, reflecting resonance interactions with the aromatic ring.

50. Physical Properties. (please read) Basicity of Amines.The lone pair of electrons on nitrogen makes amines basic and nucleophilic. They react with acids to form acid–base salts and they react with electrophiles The basicity is reflective of and is expressed as the pKa of the conjugate acid. The conjugate base of a weak acid is a strong base: Higher pKa= weaker acid = stronger conjugate base The conjugate base of a strong acid is a weak base Lower pKa = stronger acid = weaker conjugate base pKavalues of ammonium ions Alkyl ammonium ions, R3NH+ X-, have pKa values in the range of 10-11 (ammonium ion, H4N+ X-, has a pKa ~ 9.3) The ammonium ions of aryl amines and heterocyclic aromatic amines are considerably more acidic than alkyl amines (pKa < 5). The nitrogen lone pair is less basic if it is in an sp2 hybridized orbital (versus an sp3)