Chem 234 Organic Chemistry II Professor Duncan J. Wardrop

2. Topics Covered: Aryl Halides - Bonding, Physical Properties and Reactions Nucleophilic Aromatic Substitution of Chlorobenzene Nucleophilic Aromatic Substitution: Addition-Elimination Floxcin - Application of Nucleophilic Aromatic Substitution Nucleophilic Aromatic Substitution: Elimination-Addition Benzyne: Generation, Bonding and Reactions

4. Chapter 23Aryl Halides

5. 23.1Bonding in Aryl Halides

9. 23.2Sources of Aryl Halides

14. 23.3Physical Properties of Aryl Halides

15. resemble alkyl halides are essentially insoluble in water less polar than alkyl halides

16. 23.4Reactions of Aryl Halides:A Review and a Preview

22. the SN2 is not reasonable because the aromatic ring blocks back-side approach of the nucleophile. Inversion is not possible.

26. 23.5Nucleophilic Substitution inNitro-Substituted Aryl Halides

27. Reaction 1 - electrophile interacts with the filled HOMO orbital of the aromatic ring Reaction 2 - nucleophile interacts with the empty LUMO orbital of the aromatic ring.Reaction 1 - electrophile interacts with the filled HOMO orbital of the aromatic ring Reaction 2 - nucleophile interacts with the empty LUMO orbital of the aromatic ring.

32. Reaction Rate Depends on X: I > Br > Cl > F

35. 23.6The Addition-Elimination Mechanismof Nucleophilic Aromatic Substitution

40. When there isn�t a good leaving group, this type on intermediate is stable and can be isolated and characterized - Meisenheimer complexesWhen there isn�t a good leaving group, this type on intermediate is stable and can be isolated and characterized - Meisenheimer complexes

42. Restoration of AromaticityRestoration of Aromaticity

43. carbon-halogen bond breaking does not occuruntil after the rate-determining step electronegative F stabilizes negatively charged intermediate

45. 23.7Related Nucleophilic AromaticSubstitution Reactions

48. Consider relationship between this process and the reaction of carboxylic acid chlorides and alcohols.Consider relationship between this process and the reaction of carboxylic acid chlorides and alcohols.

49. Consider relationship between this process and the reaction of carboxylic acid chlorides and alcohols.Consider relationship between this process and the reaction of carboxylic acid chlorides and alcohols.

50. Synthetic Application ofNucleophilic Aromatic Substitution Reaction works with a wide range of nucleophiles and electrophiles and does so under mild conditions. As a result, this type of chemistry has found widespread application in synthesis. In Chapter 23, we shall meet the Sanger reaction Reaction works with a wide range of nucleophiles and electrophiles and does so under mild conditions. As a result, this type of chemistry has found widespread application in synthesis. In Chapter 23, we shall meet the Sanger reaction

51. FLOXIN� Tablets (ofloxacin tablets) is a broad-spectrum quinolone antibiotic available in an oral dosage form. The drug is indicated for treatment of susceptible strains of designated microorganisms that cause a wide range of mild to moderate genitourinary tract infections, including cystitis, urinary tract infection, prostatitis, and sexually transmitted diseases including gonorrhea and chlamydia. FLOXIN is not indicated for the treatment of syphilis. In 1996, FLOXIN tablets became the first oral medication that could be used alone to treat acute pelvic inflammatory disease (PID)*, a condition that afflicts approximately one million women in the U.S. Group D (that inhibits the nucleic acid synthesis) contains substances such as quinolones, pyrimethamine, rifampin, sulfonamides and trimethoprim and so on and these have a different way of action compared to the other groups. Rifampin binds itself to a substance called RNA-polymeras inside the bacteria and by doing so it inhibits the RNA synthese (RNA is a nucleic acid). The bacteria can become resistent if there is a change in the RNA-polymeras so that the rifampin cannot bind itself to it. Rifampin also have a inhibiting effect against the poxviruses in a late stage of construction. All quinolones and fluoroquinolones stops the DNA synthese by blocking the DNA gyras. A very important substance is p-aminobenzoic acid, also called PABA. PABA is deeply involved in the folic acid synthesis, and folic acid is a part of the nucleic acid synthesis. (Folic acid is a substance that is commonly found in vitaminpills.) Sulfonamides are structural analogues of PABA and can therefore take the place of PABA in the folic acid synthesis - except that you get a structural analogue of folic acid which cannot take the place of the real folic acid and therefore have no function in the cell and the nucleic acid synthesis stops when there is no real folic acid left. Mammals cannot produce folic acid and are therefore not affected at all by sulfonamides, but many bacteria produce folic acid and are therefore sensitive to this medication. Unfortunately some bacteria produce much more PABA than they use up which means that they are less sensitive to sulfonamides. FLOXIN� Tablets (ofloxacin tablets) is a broad-spectrum quinolone antibiotic available in an oral dosage form. The drug is indicated for treatment of susceptible strains of designated microorganisms that cause a wide range of mild to moderate genitourinary tract infections, including cystitis, urinary tract infection, prostatitis, and sexually transmitted diseases including gonorrhea and chlamydia. FLOXIN is not indicated for the treatment of syphilis. In 1996, FLOXIN tablets became the first oral medication that could be used alone to treat acute pelvic inflammatory disease (PID)*, a condition that afflicts approximately one million women in the U.S. Group D (that inhibits the nucleic acid synthesis) contains substances such as quinolones, pyrimethamine, rifampin, sulfonamides and trimethoprim and so on and these have a different way of action compared to the other groups. Rifampin binds itself to a substance called RNA-polymeras inside the bacteria and by doing so it inhibits the RNA synthese (RNA is a nucleic acid). The bacteria can become resistent if there is a change in the RNA-polymeras so that the rifampin cannot bind itself to it. Rifampin also have a inhibiting effect against the poxviruses in a late stage of construction. All quinolones and fluoroquinolones stops the DNA synthese by blocking the DNA gyras. A very important substance is p-aminobenzoic acid, also called PABA. PABA is deeply involved in the folic acid synthesis, and folic acid is a part of the nucleic acid synthesis. (Folic acid is a substance that is commonly found in vitaminpills.) Sulfonamides are structural analogues of PABA and can therefore take the place of PABA in the folic acid synthesis - except that you get a structural analogue of folic acid which cannot take the place of the real folic acid and therefore have no function in the cell and the nucleic acid synthesis stops when there is no real folic acid left. Mammals cannot produce folic acid and are therefore not affected at all by sulfonamides, but many bacteria produce folic acid and are therefore sensitive to this medication. Unfortunately some bacteria produce much more PABA than they use up which means that they are less sensitive to sulfonamides.

52. Things to Note: 1. Amine not hydroxyl group adds to the electron-deficient alkene 2. Oxygen is a better leaving group than nitrogen Things to Note: 1. Amine not hydroxyl group adds to the electron-deficient alkene 2. Oxygen is a better leaving group than nitrogen

56. . .

57. Synthetic Application ofNucleophilic Aromatic Substitution Reaction works with a wide range of nucleophiles and electrophiles and does so under mild conditions. As a result, this type of chemistry has found widespread application in synthesis. In Chapter 23, we shall meet the Sanger reaction Reaction works with a wide range of nucleophiles and electrophiles and does so under mild conditions. As a result, this type of chemistry has found widespread application in synthesis. In Chapter 23, we shall meet the Sanger reaction

58. FLOXIN� Tablets (ofloxacin tablets) is a broad-spectrum quinolone antibiotic available in an oral dosage form. The drug is indicated for treatment of susceptible strains of designated microorganisms that cause a wide range of mild to moderate genitourinary tract infections, including cystitis, urinary tract infection, prostatitis, and sexually transmitted diseases including gonorrhea and chlamydia. FLOXIN is not indicated for the treatment of syphilis. In 1996, FLOXIN tablets became the first oral medication that could be used alone to treat acute pelvic inflammatory disease (PID)*, a condition that afflicts approximately one million women in the U.S. Group D (that inhibits the nucleic acid synthesis) contains substances such as quinolones, pyrimethamine, rifampin, sulfonamides and trimethoprim and so on and these have a different way of action compared to the other groups. Rifampin binds itself to a substance called RNA-polymeras inside the bacteria and by doing so it inhibits the RNA synthese (RNA is a nucleic acid). The bacteria can become resistent if there is a change in the RNA-polymeras so that the rifampin cannot bind itself to it. Rifampin also have a inhibiting effect against the poxviruses in a late stage of construction. All quinolones and fluoroquinolones stops the DNA synthese by blocking the DNA gyras. A very important substance is p-aminobenzoic acid, also called PABA. PABA is deeply involved in the folic acid synthesis, and folic acid is a part of the nucleic acid synthesis. (Folic acid is a substance that is commonly found in vitaminpills.) Sulfonamides are structural analogues of PABA and can therefore take the place of PABA in the folic acid synthesis - except that you get a structural analogue of folic acid which cannot take the place of the real folic acid and therefore have no function in the cell and the nucleic acid synthesis stops when there is no real folic acid left. Mammals cannot produce folic acid and are therefore not affected at all by sulfonamides, but many bacteria produce folic acid and are therefore sensitive to this medication. Unfortunately some bacteria produce much more PABA than they use up which means that they are less sensitive to sulfonamides. FLOXIN� Tablets (ofloxacin tablets) is a broad-spectrum quinolone antibiotic available in an oral dosage form. The drug is indicated for treatment of susceptible strains of designated microorganisms that cause a wide range of mild to moderate genitourinary tract infections, including cystitis, urinary tract infection, prostatitis, and sexually transmitted diseases including gonorrhea and chlamydia. FLOXIN is not indicated for the treatment of syphilis. In 1996, FLOXIN tablets became the first oral medication that could be used alone to treat acute pelvic inflammatory disease (PID)*, a condition that afflicts approximately one million women in the U.S. Group D (that inhibits the nucleic acid synthesis) contains substances such as quinolones, pyrimethamine, rifampin, sulfonamides and trimethoprim and so on and these have a different way of action compared to the other groups. Rifampin binds itself to a substance called RNA-polymeras inside the bacteria and by doing so it inhibits the RNA synthese (RNA is a nucleic acid). The bacteria can become resistent if there is a change in the RNA-polymeras so that the rifampin cannot bind itself to it. Rifampin also have a inhibiting effect against the poxviruses in a late stage of construction. All quinolones and fluoroquinolones stops the DNA synthese by blocking the DNA gyras. A very important substance is p-aminobenzoic acid, also called PABA. PABA is deeply involved in the folic acid synthesis, and folic acid is a part of the nucleic acid synthesis. (Folic acid is a substance that is commonly found in vitaminpills.) Sulfonamides are structural analogues of PABA and can therefore take the place of PABA in the folic acid synthesis - except that you get a structural analogue of folic acid which cannot take the place of the real folic acid and therefore have no function in the cell and the nucleic acid synthesis stops when there is no real folic acid left. Mammals cannot produce folic acid and are therefore not affected at all by sulfonamides, but many bacteria produce folic acid and are therefore sensitive to this medication. Unfortunately some bacteria produce much more PABA than they use up which means that they are less sensitive to sulfonamides.

59. 23.8 Benzyne & the Elimination-Addition Mechanismof Nucleophilic Aromatic Substitution

60. Amide (NH2-) is the conjugate base of ammonia, and is a much stronger base than hydroxide or alkoxide. It can be bought, or made by adding sodium to liquid ammonia It reacts rapidly and quantitatively with aldehydes and ketones to make the enolate and with alkynes to convert them to their conjugate bases (which are also good nucleophiles).Amide (NH2-) is the conjugate base of ammonia, and is a much stronger base than hydroxide or alkoxide. It can be bought, or made by adding sodium to liquid ammonia It reacts rapidly and quantitatively with aldehydes and ketones to make the enolate and with alkynes to convert them to their conjugate bases (which are also good nucleophiles).

61. new substituent becomes attached to eitherthe carbon that bore the leaving group orthe carbon adjacent to it

63. new substituent becomes attached to eitherthe carbon that bore the leaving group orthe carbon adjacent to it

66. compound formed in this step is called benzyne

68. Benzyne differs from alkynes in that the C-C triple bond is not linear. The set of two 2pz orbitals is part of the Pi system of the aromatic ring, while the sp2 orbitals on adjoining carbon atoms have a poor overlap Benzyne is an aromatic molecule, which indicates that the p orbitals of the triple bond are in conjugation.Benzyne differs from alkynes in that the C-C triple bond is not linear. The set of two 2pz orbitals is part of the Pi system of the aromatic ring, while the sp2 orbitals on adjoining carbon atoms have a poor overlap Benzyne is an aromatic molecule, which indicates that the p orbitals of the triple bond are in conjugation.

80. 23.9Cycloaddition Reactions of Benzyne

81. IUPAC Definition: Cycloaddition - a reaction in which two or more unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity. IUPAC Definition: Cycloaddition - a reaction in which two or more unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity.

87. Topics Covered: Aryl Halides - Bonding, Physical Properties and Reactions Nucleophilic Substitution of Chlorobenzene Nucleophilic Aromatic Substitution: Addition-Elimination Synthetic Application of Nucleophilic Aromatic Substitution Nucleophilic Aromatic Substitution: Elimination-Addition Benzyne: Generation, Bonding and Reactions