1. Amines Chapter 23

2. C H 3 C H - N H C H - N H C H - N 3 2 3 3 C H C H 3 3 : : : Methylamine Dimethylamine Trimethylamine (a 1° amine) (a 2° amine) (a 3° amine) 23.1 Structure & Classification • Amines are classified as: • 1°, 2°, or , 3° amines: amines in which 1, 2, or 3 hydrogens of NH3 are replaced by alkyl or aryl groups.

3. C H C H 3 3 N H N - H C H - N - C H 2 2 3 Aniline N-Methylaniline B enzyldimethylamine (a 1° aromatic amine) (a 2° aromatic amine) (a 3° aliphatic amine) Structure & Classification • Amines are further divided into aliphatic, aromatic, and heterocyclic amines: • aliphaticamine: an amine in which nitrogen is bonded only to alkyl groups. • aromatic amine: an amine in which nitrogen is bonded to one or more aryl groups. : : :

4. Structure & Classification • heterocyclic amine: an amine in which nitrogen is one of the atoms of a ring.

5. C H 3 H H N C O O C H 3 N ( a ) ( b ) ( c ) N H C H C H 3 6 5 ( S ) - C o n i i n e ( S ) - N i c o t i n e C o c a i n e N O O Structure & Classification Example: classify each amino group by type.

6. Structure & Classification • Aliphatic amines: replace the suffix -e of the parent alkane by –amine.

7. 22.2 A.Nomenclature • The IUPAC system retains the name aniline.

8. Nomenclature • Among the various functional groups discussed in the text, -NH2 is one of the lowest in order of precedence.

9. B. Nomenclature • Common names for most aliphatic amines are derived by listing the alkyl groups bonded to nitrogen in one word ending with the suffix –amine.

10. Nomenclature • When four groups are bonded to nitrogen, the compound is named as a salt of the corresponding amine.

11. 22.3 Chirality of Amines • if we consider the unshared pair of electrons on nitrogen as a fourth group, then the arrangement of groups around N is approximately tetrahedral. • an amine with 3 different groups bonded to N is chiral and exists as a pair of enantiomers and, in principle, can be resolved.

12. Chirality of Amines • in practice, however, they cannot be resolved because they undergo pyramidal inversion, which converts one enantiomer to the other.

13. Chirality of Amines • pyramidal inversion is not possible with quaternary ammonium ions, and their salts can be resolved.

14. 22.4 Physical Properties • Amines are polar compounds, and both 1° and 2° amines form intermolecular hydrogen bonds. • N-H- - -N hydrogen bonds are weaker than O-H- - -O hydrogen bonds because the difference in electronegativity between N and H (3.0 - 2.1 =0.9) is less than that between O and H (3.5 - 2.1 = 1.4).

15. Hydrogen Bonding in Amines

16. 22.5 Basicity • All amines are weak bases, and aqueous solutions of amines are basic. • it is common to discuss their basicity by reference to the acid ionization constant of the conjugate acid.

17. + - p K = - 5 . 8 8 + C H N H C H C O O H C H N H + C H C O O e q 3 2 3 3 3 3 p K 4 . 7 6 p K 1 0 . 6 4 5 K = 7 . 6 x 1 0 a a e q ( s t r o n g e r ( w e a k e r a c i d ) a c i d ) Basicity • using values of pKa, we can compare the acidities of amine conjugate acids with other acids.

18. p K p K A m i n e S t r u c t u r e a b A m m o n i a 9 . 2 6 4 . 7 4 N H 3 P r i m a r y A m i n e s m e t h y l a m i n e 1 0 . 6 4 3 . 3 6 C H N H 3 2 3 . 3 4 e t h y l a m i n e 1 0 . 8 1 3 . 1 9 C H C H N H 3 2 2 c y c l o h e x y l a m i n e 1 0 . 6 6 C H N H 6 1 1 2 S e c o n d a r y A m i n e s d i m e t h y l a m i n e 1 0 . 7 3 3 . 2 7 ( C H ) N H 3 2 d i e t h y l a m i n e 1 0 . 9 8 3 . 0 2 ( C H C H ) N H 3 2 2 T e r t i a r y A m i n e s t r i m e t h y l a m i n e 9 . 8 1 4 . 1 9 ( C H ) N 3 3 t r i e t h y l a m i n e 1 0 . 7 5 3 . 2 5 ( C H C H ) N 3 2 3 A. Basicity-Aliphatic Amines, Table 23.2 • Aliphatic Amines:

19. B. Basicity-Aromatic Amines, Table 23.2

20. Basicity-Aromatic Amines • aromatic amines are considerably weaker bases than aliphatic amines.

21. Basicity-Aromatic Amines • Aromatic amines are weaker bases than aliphatic amines because of two factors. • 1. Resonance stabilization of the free base, which is lost on protonation.

22. Basicity-Aromatic Amines • 2. The greater electron-withdrawing inductive effect of the sp2-hybridized carbon of an aromatic amine compared with the sp3-hybridized carbon of an aliphatic amine also decreases basicity. • Electron-releasing, such as alkyl groups, increase the basicity of aromatic amines. • Electron-withdrawing groups, such as halogens, the nitro group, and a carbonyl group decrease the basicity of aromatic amines by a combination of resonance and inductive effects.

23. Basicity-Aromatic Amines • 4-nitroaniline is a weaker base than 3-nitroaniline.

24. C. Basicity-Aromatic Amines • Heterocyclic aromatic amines are weaker bases than heterocyclic aliphatic amines.

25. Basicity-Aromatic Amines • in pyridine, the unshared pair of electrons on N is not part of the aromatic sextet. • pyridine is a weaker base than heterocyclic aliphatic amines because the free electron pair on N lies in an sp2 hybrid orbital (33% s character) and is held more tightly to the nucleus than the free electron pair on N in an sp3 hybrid orbital (25% s character).

26. Basicity-Aromatic Amines • Imidazole.

27. D. Basicity-Guanidine • Guanidine is the strongest base among neutral organic compounds. • its basicity is due to the delocalization of the positive charge over the three nitrogen atoms.

28. 22.6 Reaction with Acids • All amines, whether soluble or insoluble in water, react quantitatively with strong acids to form water-soluble salts.

29. Extraction Flow Sheet

30. Extraction Flow Sheet A = carboxylic acid B = phenol C = amine

31. 22.7 Preparation of Amines • We have already covered these methods: • nucleophilic ring opening of epoxides by ammonia and amines (11.9B). • addition of nitrogen nucleophiles to aldehydes and ketones to form imines (Section 16.8). • reduction of imines to amines (16.8A). • reduction of amides by LiAlH4 (18.10B). • reduction of nitriles to a 1° amine (18.10C). • nitration of arene2 followed by reduction of the NO2 group to 1° amines (22.1B).

32. A. Preparation • Alkylation of ammonia and amines by SN2. • unfortunately, such alkylations give mixtures of products through a series of proton transfer and nucleophilic substitution reactions.

33. B. Preparation via Azides • Attaching an alkyl group to an azide (alkylation) followed by reduction.

34. Preparation via Azides • Formation of an alkylazide then reduction.

35. 22.8 Reaction of amines with HNO2 • Nitrous acid, a weak acid, is most commonly prepared by treating NaNO2 with aqueous H2SO4 or HCl. • In its reactions with amines, nitrous acid • participates in proton-transfer reactions • is a source of the nitrosyl cation, NO+, a weak electrophile.

36. Formation of NO+ • NO+ is formed in the following way. • we study the reactions of HNO2 with 1°, 2°, and 3° aliphatic and aromatic amines.

37. A. & B. 3o Amines with HNO2 • 3° aliphatic amines, whether water-soluble or water-insoluble, are protonated to form water-soluble salts. • 3° aromatic amines: NO+ is a weak electrophile and, as such, participates in EAS. • 2° aliphatic and aromatic amines react with NO+ to give N-nitrosoamines.

38. C. 2o Amines with HNO2 • Reaction of a 2° amine to give an N-nitrosamine. • Step 1: reaction of the 2° amine (a nucleophile) with the nitrosyl cation (an electrophile). • Step 2: proton transfer.

39. D. 1o Amines (RNH2) with HNO2 • 1° aliphatic amines give a mixture of unrearranged and rearranged substitution and elimination products, all of which are produced by way of a diazonium ion and its loss of N2 to give a carbocation. • Diazonium ion: an RN2+ or ArN2+ ion. • Aromatic diazonium ions are more stable than aliphatic ones.

40. keto-enol tautomerism R - N = N - O - H R - N H R - N - N = O 2 A 1° aliphatic A n N-nitrosamine amine 1° RNH2 with HNO2 • Formation of a diazonium ion: Step 1: reaction of a 1° amine with the N=O+. Step 2: protonation followed by loss of water. H + : : : : : : : : : : + N O : : A diazotic acid

41. C l O H N a N O , H C l O H N H 2 2 o 0-5 C 1° RNH2 with HNO2 • Aliphatic diazonium ions are unstable and lose N2 to give a carbocation which may: 1. lose a proton to give an alkene. 2. react with a nucleophile to give a substitution product. 3. rearrange and then react by 1 and/or 2. (5.2%) + (25%) (13.2%) + (25.9%) (10.6%)

42. 1° RNH2 with HNO2 • Tiffeneau-Demjanov reaction: treatment of a -aminoalcohol with HNO2 gives a ketone and N2.

43. O - H O H - N H N O 2 2 C H C H N H 2 2 2 proton transfer to H O 2 C H C H 2 2 1° RNH2 with HNO2 • reaction with NO+ gives a diazonium ion. • concerted loss of N2 and rearrangement followed by proton transfer gives the ketone. : : : : + : N N (A diazonium ion) : : : : + O O H O H + Cycloheptanone A resonance-stabilized cation

44. E. 1° ArNH2 with HNO2 • The -N2+ group of an arenediazonium salt can be replaced in a regioselective manner by these groups. The aromatic diazonium salt is more stable than the aliphatic due to resonance.

45. 1° ArNH2 with HNO2 • A 1° aromatic amine can be converted to a phenol.

46. 1° ArNH2 with HNO2 Problem:what reagents and experimental conditions will bring about this conversion ?

47. 1° ArNH2 with HNO2 • Problem: Show how to bring about each conversion.

48. C H - I 3 H O + 2 A g O C H - N - C H + 2 2 3 C H 3 S ilver (Cyclohexylmethyl)trimethyl- oxide ammonium iodide C H - O H 3 + A g I + C H - N - C H 2 3 C H 3 (Cyclohexylmethyl)trimethyl- ammonium hydroxide 22.9 Hofmann Elimination • Hofmann elimination: thermal decomposition of a quaternary ammonium hydroxide to give an alkene. Step 1: formation of a 4° ammonium hydroxide.

49. Hofmann Elimination • Step 2: thermal decomposition of the 4° ammonium hydroxide.

50. Hofmann Elimination • Hofmann elimination is regioselective - the major product is the least substituted alkene. • Hofmann’s rule:any -elimination that occurs preferentially to give the least substituted alkene as the major product is said to follow Hofmann’s rule.