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

2 Amines – Organic Nitrogen Compounds Organic derivatives of ammonia, NH 3, 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

Properties of Amines Bonding to N is similar to that in ammonia N is sp 3 -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

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

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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, N 3  displaces a halide ion from a primary or secondary alkyl halide to give an alkyl azide, RN 3 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, NaBH 3 CN, 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

Reactions of Amines Alkylation and acylation have already been presented

17 Hofmann Elimination Converts amines into alkenes NH 2  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

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 AlCl 3 catalyst, preventing further reaction Therefore we use the corresponding amide

21 Diazonium Salts: The Sandmeyer Reaction Primary arylamines react with HNO 2, yielding stable arenediazonium salts

22 Uses of Arenediazonium Salts The N 2 group can be replaced by a nucleophile

23 Reduction to a Hydrocarbon By treatment of a diazonium salt with hypophosphorous acid, H 3 PO 2

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)

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

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 D 2 O exchange of N–D for N–H occurs, and the N– H signal disappears

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