Reaction of Amines with Nitrous Acid (produced in situ by mixing sodium nitrite, NaONO, with HCl)

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1 Reaction of Amines with Nitrous Acid (produced in situ by mixing sodium nitrite, NaONO, with HCl) Qualitative testes: 1 -Amines + HONO (cold acidic solution) Nitrogen Gas Evolution from a Clear Solution 2 -Amines + HONO (cold acidic solution) An Insoluble Oil (N- Nitrosoamine) 3 -Amines + HONO (cold acidic solution) A Clear Solution (Ammonium Salt Formation) => 1

2 Reactions of Aryl Diazonium Salts Synthesis, 2007, J. Org. Chem., 2006, 71, Arenediazonium Salts Stable in solution at 0 10 C. The - + N N group is easily replaced by many different groups. Nitrogen gas, N 2, is a by-product. => 2

3 Sandmeyer Reaction 3

4 Schiemann Reaction 4

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8 Azo compounds Substitution and Elimination Reactions of Amines Amine functions don t usually act as leaving groups in nucleophilic substitution or base-catalyzed elimination reactions. tetraalkyl ammonium salts are efficient leaving groups in eliminations and in some S N 2 substitutions. C 6 H 5 N(CH 3 ) 3 (+) Br ( ) + R-S ( ) Na (+) R-S-CH 3 + C 6 H 5 N(CH 3 ) 2 + NaBr 8

9 Hofmann Elimination Hofmann Mechanism (1) N-H protons of amide are abstracted. Rearrangement forms an isocyanate. => 9

10 Hofmann Mechanism (2) Isocyanate reacts with water to form carbamic acid, which loses CO 2. => simple amines are easily converted to the necessary 4º-ammonium salts by exhaustive alkylation methyl has no beta-hydrogens and cannot compete in the elimination reaction. the major product may be the less substituted alkene. The tendency of Hofmann eliminations to give the less-substituted double bond isomer is commonly referred to as the Hofmann Rule, and contrasts strikingly with the Zaitsev Rule formulated for dehydrohalogenations and dehydrations. 10

11 Oxidation States of Nitrogen Oxidation State _ 3 _ 2 _ Formulas names R 3 N Amines R 2 N NR 2 Hydrazine RN=NR azo cpd. N 2 nitrogen R N=O nitroso R-NO 2 Nitro R 4 N (+) Ammoniu C=N R Imines C N nitriles C=N NR 2 Hydrazones R 2 NOH hydroxyl amine R 3 NO amine oxide R N 2 (+) diazonium RO N=O nitrite ester Amine Oxides Amine oxides are prepared by oxidizing 3º-amines or pyridines with hydrogen peroxide or peracids Cope Elimination 11

12 Aromatic Five-Membered Heterocycles 12

13 Pyrrole is an extremely weak base The dipole moment in pyrrolidine (left) is attributed to the electron-withdrawing property of the nitrogen atom 13

14 Pyrrole, furan, and thiophene undergo electrophilic substitution preferentially at C-2 14

15 Electrophilic aromatic substitution reactions Structures of the intermediates that can be formed from the reaction of an electrophile with pyrrole at C-2 and C-3 15

16 If both positions adjacent to the heteroatom are occupied, electrophilic substitution occurs at C-3 16

17 The relative reactivities of the five-membered-ring heterocycles in Friedel Crafts reaction The resonance hybrid of pyrrole indicates that there is a partial positive charge on the nitrogen Pyrrole is unstable in strongly acid solution because the protonated pyrrole polymerizes 17

18 Pyrrole is more acidic than the analogous saturated Its acidity is increased due to its conjugated base being stabilized by resonance!!!!!!!!!!!!! 18

19 Aromatic Six-Membered-Ring Heterocycles The pyridinium ion is a stronger acid than a typical ammonium ion 19

20 Pyridine Reacts Like a Tertiary Amine Pyridine Is Aromatic 20

21 Pyridine undergoes electrophilic aromatic substitution at C-3 21

22 Protonation of pyridine decreases its reactivity 22

23 Pyridine is less reactive than benzene toward electrophilic aromatic substitution, but is more reactive toward nucleophilic aromatic substitution Pyridine undergoes nucleophilic aromatic substitution at C-2 and C-4 23

24 If the leaving groups at C-2 and C-4 are different, the incoming nucleophile will preferentially substitute for the weaker base Bromination and Oxidation of Substituted Pyridine 24

25 Diazotization of Aminopyridine 25

26 The α-hydrogens of alkyl substituents can be removed by base to generate nucleophiles Quinoline and isoquinoline are known as benzopyridines 26

27 Some Biologically Important Heterocycles Imidazole 27

28 Purine and Pyrimidine 28

29 Porphyrin 29

Electrophilic Aromatic Substitution Reactions

Electrophilic Aromatic Substitution Reactions, Course Notes Archive, 1 Electrophilic Aromatic Substitution Reactions An organic reaction in which an electrophile substitutes a hydrogen atom in an aromatic