Chapter 24. Amines and Heterocycles

1. Chapter 24. Amines and Heterocycles Based on McMurry’s Organic Chemistry, 7th edition

2. Amines – Organic Nitrogen Compounds • Organic derivatives of ammonia, NH3, • Nitrogen atom with a lone pair of electrons, making amines both basic and nucleophilic • Occur in plants and animals

3. Why this Chapter? • Amines and carbonyl compounds are the most abundant and have rich chemistry • In addition to proteins and nucleic acids, a majority of pharmaceutical agents contain amine functional groups

4. Common Names of Heterocyclic Amines • If the nitrogen atom occurs as part of a ring, the compound is designated as being heterocyclic • Each ring system has its own parent name

5. 24.2 Properties of Amines • Bonding to N is similar to that in ammonia • N is sp3-hybridized • C–N–C bond angles are close to 109° tetrahedral value

6. Chirality Is Possible (But Not Observed) • An amine with three different substituents on nitrogen is chiral (in principle but not in practice): the lone pair of electrons is the fourth substituent • Most amines that have 3 different substituents on N are not resolved because the molecules interconvert by pyramidal inversion

7. 24.3 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

9. 24.5 Biological Amines and the Henderson-Hasselbalch Equation • What form do amines exist at physiological pH inside cells

10. Selective Preparation of Primary Amines: the Azide Synthesis • Azide ion, N3 displaces a halide ion from a primary or secondary alkyl halide to give an alkyl azide, RN3 • Alkyl azides are not nucleophilic (but they are explosive) • Reduction gives the primary amine

11. Gabriel Synthesis of Primary Amines • A phthalimide alkylation for preparing a primary amine from an alkyl halide • The N-H in imides (CONHCO) can be removed by KOH followed by alkylation and hydrolysis

12. Reductive Amination of Aldehydes and Ketones • Treatment of an aldehyde or ketone with ammonia or an amine in the presence of a reducing agent

13. Mechanism of Reductive Amination

14. Reducing Step • Sodium cyanoborohydride, NaBH3CN, reduces C=N but not C=O • Stable in water

15. Hofmann and Curtius Rearrangements • Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and the Curtius rearrangement

16. 24.7 Reactions of Amines • Alkylation and acylation have already been presented

17. Hofmann Elimination • Converts amines into alkenes • NH2 is very a poor leaving group so it converted to an alkylammonium ion, which is a good leaving group

18. Orientation in Hofmann Elimination • We would expect that the more highly substituted alkene product predominates in the E2 reaction of an alkyl halide (Zaitsev's rule) • However, the less highly substituted alkene predominates in the Hofmann elimination due to the large size of the trialkylamine leaving group • The base must abstract a hydrogen from the most sterically accessible, least hindered position

19. 24.8 Reactions of Arylamines • Amino substituents are strongly activating, ortho- and para-directing groups in electrophilic aromatic substitution reactions • Reactions are controlled by conversion to amide

20. Arylamines Are Not Useful for Friedel-Crafts Reactions • The amino group forms a Lewis acid–base complex with the AlCl3 catalyst, preventing further reaction • Therefore we use the corresponding amide

21. Diazonium Salts: The Sandmeyer Reaction • Primary arylamines react with HNO2, yielding stable arenediazonium salts

22. Uses of Arenediazonium Salts • The N2 group can be replaced by a nucleophile

23. Reduction to a Hydrocarbon • By treatment of a diazonium salt with hypophosphorous acid, H3PO2

24. Mechanism of Diazonium Replacement • Through radical (rather than polar or ionic) pathways

25. Diazonium Coupling Reactions • Arenediazonium salts undergo a coupling reaction with activated aromatic rings, such as phenols and arylamines, to yield brightly colored azo compounds, ArN=NAr

26. How Diazonium Coupling Occurs • The electrophilic diazonium ion reacts with the electron-rich ring of a phenol or arylamine • Usually occurs at the para position but goes ortho if para is blocked

27. Azo Dyes • Azo-coupled products have extended  conjugation that lead to low energy electronic transitions that occur in visible light (dyes)

28. 24.9 Heterocycles • A heterocycle is a cyclic compound that contains atoms of two or more elements in its ring, usually C along with N, O, or S

29. Pyrole and Imidazole • Pyrole is an amine and a conjugated diene, however its chemical properties are not consistent with either of structural features

30. Chemistry of Pyrole • Electrophilic substitution reactions occur at C2 b/c it is position next to the N • A more stable intermediate cation having 3 resonance forms • At C3, only 2 resonance forms

31. Polycyclic Heterocycles

32. 24.10 Spectroscopy of Amines -Infrared • Characteristic N–H stretching absorptions 3300 to 3500 cm1 • Amine absorption bands are sharper and less intense than hydroxyl bands • Protonated amines show an ammonium band in the range 2200 to 3000 cm1

33. Nuclear Magnetic Resonance Spectroscopy • N–H hydrogens appear as broad signals without clear-cut coupling to neighboring C–H hydrogens • In D2O exchange of N–D for N–H occurs, and the N–H signal disappears

34. 13C NMR • Carbons next to amine N are slightly deshielded - about 20 ppm downfield from where they would absorb in an alkane