Structure and properties Nomenclature Reactions (some review) Synthesis (some review)

1. Unit 4 Amines • Structure and properties • Nomenclature • Reactions (some review) • Synthesis (some review) • Spectroscopy – mass spec, IR, NMR

2. Amines-Introduction Amines and amine derivatives are found throughout biological systems. Amino acids (proteins) Bioregulators Neurotransmission Vitamins drugs

3. Amines-Introduction

4. Amines-Introduction caffeine Biologically active basic amines obtained from plants are called alkaloids.

5. Amines-Introduction There are many man-made drug that are amines. vasoconstrictor Nasal decongestant

6. Amine- Structures Amines are derivatives of ammonia NH3 Amines are classified based on the number of alkyl groups attached to nitrogen. R-NH2 primary amine (1°) R2-NH secondary amine (2°) R3-N tertiary amine (3°) R4-N+, X- quaternary ammonium salt(4°)

7. Amine- Nomenclature Common amines are named based on the alkyl groups attached to the nitrogen. Alkylamine ethylamine dialkylamine dimethylamine trialkylamine butyldiethylamine tetralkylamine tetraethylammonium chloride

8. Amine- Nomenclature Name and classify the following amines.

9. Amine- Nomenclature The amine is named as a substituent group when there is a higher priority group. 4-aminobutanoic acid 2-methylaminophenol 4-(ethylmethylamino)cyclohexanone 3-aminocyclohexene

10. Amine- Nomenclature (IUPAC) IUPAC names are based on the longest carbon chain. • Drop the –e of the alkane name and add-amine. • Substituents on nitrogen have N- prefix.

11. Aromatic Amines When the amino group is bonded to an aromatic ring the parent compound is called an aniline. aniline N,N-dimethylaniline 4-methylaniline or P-toluidine

12. Heterocyclic Amines pyrrole pyrrolidine pyridine aziridine purine pyrimidine piperidine piperazine

13. Structure of Amines Nitrogen atoms with 3 or 4 single bonds are sp3 hybridized. H-N-H bond angle is about 107° The steric interactions of larger substituents increases the bond angle C-N-C is about 108 °

14. Structure of Amines The nitrogen atom is potentially a stereocenter. However nitrogen inversion occurs rapidly at room temperature. Chiral Amines: Amines with a chiral carbon. Quaternary ammonium cpds with four different groups bonded to nitrogen. Amines that are unable to achieve the planar transition state (ie small rings). pp. 875

15. Structure of Amines Quaternary ammonium salt with four different groups bonded to nitrogen. The counter ion can be Cl-, Br-, OH- etc.

16. Physical properties of Amines Amines (1 °,2 ° and 3 °) are highly polar materials because of the lone pair of electrons on nitrogen. • The N-H bond is less polar than the O-H bond. • Weaker hydrogen bonding. • Tertiary amines cannot hydrogen bond but are hydrogen bond acceptors.

17. Physical properties of Amines The strength and number of hydrogen bonds found in an amine influence melting points, boiling points, and water solubility.

18. Physical properties of Amines type MW mp bp Methylamine 1° 31 -93 -7 ethylamine 1° 45 -81 17 n-propylamine 1° 59 -83 48 dimethylamine 2° 45 -96 7 diethylamine 2° 73 -42 56 trimethylamine 3° 59 -117 3.5 triethylamine 3° 101 -115 90

19. Physical properties of Amines • Amines up to about 6 carbons are water soluble. • Amines accept hydrogen bonds from water and alcohols. • Branching increases solubility. • Amines have very strong odors (rotting fish). • 1,5-pentanediamine (cadaverine). • 1,4-butanediamine (putrescine). • Pure amine are clear (liq. or solids) but oxidation from atmospheric oxygen often results in the materials being dark colored.

20. Physical properties of Amines Amines are bases, in the presence of acids the lone pair of electrons act as a proton acceptor (Bronsted-Lowry bases). The lone pair of electrons on nitrogen can also act as a nucleophile (Lewis base).

21. Physical properties of Amines Amines are weak bases: Kb = 10-3 - 10-10 Larger Kb is stronger base. pKb = 3 - 10 Smaller pKb is stronger base.

22. Physical properties of Amines type pKb ammonia 4.74 methylamine 1° 3.36 ethylamine 1° 3.36 n-propylamine 1° 3.32 dimethylamine 2° 3.28 diethylamine 2° 3.01 trimethylamine 3° 4.26 triethylamine 3° 3.24 aniline 1° 9.4 pyridine heterocyclic 8.75 see page 878

23. Physical properties of Amines • Amines are converted to the water soluble ammonium salt by treatment with an acid. Examples: HCl, HBr, H2SO4 and organic acids. • The salt can be converted back to the free amine by treatment with a strong base. Examples: NaOH, KOH, Na2CO3 and bicarbonate. • Amines are often isolated and purified using acid/base extraction. page 881 • Amine salts are more stable to air oxidation than the free amine and have little or no odor.

24. Physical properties of Amines

25. Spectroscopy of Amines

26. Spectroscopy of Amines • propylamine

27. Spectroscopy of Amines • piperidine

28. Spectroscopy of Amines • Benzylamine

29. Spectroscopy of Amines • N-methylaniline

30. Spectroscopy of Amines

31. Reactions of Amines (review) Primary amines react with ketones and aldehydes to give imines. Analogous products are obtained for hydroxylamine, hydrazine, semicarbazide and carbazide. Write the mechanism for this reaction. (Note: The acid conditions.)

32. Formation of Imines • The formation of an imine involves an initial nucleophilic attack by ammonia or a primary amine on the carbonyl carbon. Followed by subsequent loss of a water molecule. • The C=O becomes a C=N-R group where R= H, alkyl or aryl

33. Reactions of Amines (review) The aromatic ring of aniline derivatives are highly activated for electrophilic aromatic substitution reactions. As shown above the sigma complex is stabilized at the ortho and para positions by the non-bonding electron on the nitrogen. Is the ring activated in the presents of an acid?

34. Reactions of Amines (review) What function does the sodium bicarbonate serve in the above reaction? Give two reasons why anilines can not be nitrated directly using HNO3/H2SO4?

35. Reactions of Pyridine The pyridine ring is deactivated towards electrophilic aromatic substitution because of the electronegative nitrogen in the ring. Additionally the non-bonding electron on the nitrogen would react with the electrophile. Reaction only occurs under extreme conditions. Note: That substitution is in the 3-position.

36. Reactions of Pyridine The pyridine ring is activated towards nucleophilic aromatic substitution. With substitution occurring at either the 2- or 4- position. The sigma complex is stabilized by the negative charge being on nitrogen.

37. Alkylation of Amines Amines are good nucleophiles that react with alkyl halides via a Sn2 mechanism. Reaction with primary halides give alkylated ammonium halides. Secondary halides are less reactive than primary halides and often give poor yields or elimination products. Tertiary halides do not react because of steric hindrance. Note: The that °3 halides can still under go elimination.

38. Alkylation of Amines The above reaction gives an incomplete picture of the chemistry involved in the alkylation of an amine with an alkyl halide.

39. Alkylation of Amines The reaction of one mole of primary amine with one mole of alkyl halide will give a mixture of starting primary amine, secondary amine, tertiary amine and quaternary ammonium salts. There two methods that can be used to avoid obtaining mixtures of products when alkylating amines with alkyl halides.

40. Alkylation of Amines Exhaustive alkylation (methylation) involves reacting the amine with an excess of alkyl halide in the presence of an acid scavenger.

41. Alkylation of Amines The use of a large excess of ammonia results in monoalkylation. The excess ammonia is simply allowed to boil of at the end of the reaction. This synthetic approach is useful in many situations but is often limited by the cost of the alkyl halide.

42. Acylation of Amines Amides are produced by the treatment of primary and secondary amines with acid halides in the presents of a non-nucleophilic acid scavenger. The reaction involves the nucleophilic attack of the amine on the carbonyl carbon (the electrophilic center) of the acid halide followed by loss HX. Amides are far less basic and nucleophilic than amines. As a result mono-acylation product is normally produced. Why is the amide less basic and nucleophilic than the amine?

43. Acylation of Amines The base is typically pyridine, a tertiary amine or bicarbonate. The yields are generally very good ( > 90 %).

44. Acylation of Amines The acyl group in an amide can be easily removed by hydrolysis with aqueous acid. As a result acylation can be used as a means of temporary protecting the amine group as the amide while conducting other reactions that would produce undesired change in the amine. The acyl group acts as a Masking agent. Many reactions can not be done directly on the aromatic ring of aniline either because the amine will react with the reagents or multiple substitution occur.

45. Acylation of Amines The Friedel-Crafts acylation of the ring fails in the above reaction. However, if the amine of the aniline is acylation first then the ring can be acylated.

46. Acylation of Amines Why do we need to do a final pH adjustment?

47. Sulfonylation of Amines The reaction of amines with sulfonyl chlorides is analogous to that of acyl halides. The sulfa drugs are antibacterial agents that contain the sulfonamide group.

48. Elimination Reactions involving Amines Amines can under go two different types of elimination reactions that give alkenes. Hofmann elimination: An amine is exhaustively methylated to the quaternary ammonium salt. The halide salt is converted to the hydroxide salt by treatment with silver oxide. The quaternary ammonium hydroxide is then thermally decomposed via a conserted E2 mechanism to give the alkene. Cope Elimination: A tertiary amine is converted to the amine oxide by treatment with hydrogen peroxide or a peroxyacid. The amine oxide is then thermally decomposed to give an alkene. Both reactions generally give the least-substituted alkene.

49. Elimination Reactions involving Amines Hofmann elimination: For R = 2-butyl the product is 95 % 1-butene, the least substituted alkene. Onle 5% of the product is the Saytzeff product.

50. Hofmann elimination: Requirements an anti coplanar stereochemistry.