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

8

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, ArN=NAr

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 cm1 Amine absorption bands are sharper and less intense

than hydroxyl bands Protonated amines show an ammonium band in

the range 2200 to 3000 cm1

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