Chapter 24

Amines and Heterocycles

Intended learning outcomes:
1. To understand the structure and bonding of amines
2. To understand the methods for amine synthesis and know the
limitations of these methods
reduction of nitriles, nitro compounds, azides, and amides
SN2 alkylation of halides, Gabriel synthesis, reductive amination,
Hofmann rearrangement, Curtius rearrangement.
3. To understand the reactions of amines
Hofmann elimination, Diazotization, Sandmeyer reaction
4. To understand the synthesis, structure, and reactivity of simple
heterocycles, such as pyrrole and pyridine.
5. To understand the spectroscopic features of amines.
Amines – Organic Nitrogen Compounds

• Organic derivatives NH3

• The lone pair on N — both
basic and nucleophilic.

https://www.youtube.com/watch?v=YxQo_uXKP2Q

• Many Occur in plants

and animals.

• Natural amines are also

called alkaloids.
Classification

Primary amine － RNH2 Note

Secondary amine － R2NH

Tertiary amine － R3N
Quaternary amonium － R4N+

N with four R groups:

positively charged
IUPAC Names: Simple Amines

A. Suffix -amine is added to the name of the alkyl substituent

Phenylamine

B.
Alkane → Alkanamine
Alkane → Alkanediamine (No drop of “e” in case of diamine)
IUPAC Names－Amines with Multiple Groups

1. with multiple functional groups

• NH2 has lower priority than carbonyl groups
• Consider the －NH2 as an amino substituent

2. with multiple different alkyl groups

• Named as N-substituted primary amines
• Parent name: largest alkyl group
• Other alkyl groups: considered N-substituents
Common Names of Heterocyclic Amines

Each ring system has its own parent name

Properties of Amines

Bonding:
• Similar to NH3
• N is sp3-hybridized
• C–N–C bond angles are ~109°

Chirality:
• N with 3 different substituents is chiral: the lone pair is the 4th substituent.
• Most amines with 3 different substituents on N can not be separated:
the molecules interconvert by pyramidal inversion (rapidly at room temp).
Basicity of Amines
Basicity of Amines and Amides

Non-basic, pKb > 14

Basic, pKb = 3.4

To compare the acidity of the conjugate acids:

question?
is NH2-OH very basic?

Inductive destabilization
Inductive stabilization
lose resonance
Arylamines and N-Heterocyles

https://www.youtube.com/watch?v=0UglGmtjl0I
Basicity of Substituted Arylamines

EDG: increase the basicity (–CH3, –NH2, –OCH3, etc.)

EWG: decrease basicity (–Cl, –NO2, –CN, etc.)
Synthesis of Amines

Reduction
(nitrile, nitro, azide, amide, etc.)
SN2 Reactions of Alkyl Halides
Ammonia and other amines are good nucleophiles

A mixture of products will be formed: not practical

Azide reduction: only primary amine formed

Gabriel Synthesis

Tow steps: phthalimide alkylation, then removal of N-H imide

Question: How to make this compound?

Summary of Amine Synthesis from Alkyl Halides

1. Direct SN2 reactions (limited applications)

2. Azide synthesis (primary amines)

Better Nu

3. Nitrile synthesis (primary amines with one more carbon)

4. Gabriel amine synthesis (primary amines)

H2O
HO-
Reductive Amination of Aldehydes and Ketones

aldehyde or ketone + ammonia or an amine + reducing agent

Imine is the intermediate

Scope and Condition

1o, 2o, 3o amines

can be prepared.

Reducing Agent
NaBH3CN
OK for aldehydes and ketones
reduces C=N, but not C=O
stable in water

NaBH4
only good for ketones
aldehydes  alcohol
Hofmann Rearrangements

Primary amide  Primary amines, lose 1 carbon

pKa ~ 17
Curtius Rearrangement

Acyl chloride  Acyl azide  Primary amines, lose 1 carbon

Example

No base needed
Summary of Amine Synthesis (Not from Alkyl Halides)
Reductive Amination Amide Reduction

lose 1 carbon
Reactions of Amines – Alkylation and Acylation

Alkylation

Acylation
Hofmann Elimination

Amines  Alkenes

Ag2O can exchange OH- for I-, thus providing the base for elimination.

2 R-N(CH3)3+ I- + Ag2O + H2O

R-N(CH3)3+ -OH + 2 AgI
Orientation in Hofmann Elimination

• Expected: More substituted alkene (Zaitsev's rule for E2 of alkyl halide)

• Observed: Less substituted alkene predominates in Hofmann elimination
• Reason: large size of the trialkylamine leaving group, the base will approach
the most accessible (least hindered) H.
https://www.youtube.com/watch?v=lCHVfpWjnQk
https://www.youtube.com/watch?v=QaedbDXCzl0
Example
Reactions of Arylamines (Electrophilic Substitution)
Amino substituents are strongly activating (ortho- and para-directing).

Too reactive to be stopped

at mono-bromination step Can be controlled by conversion to amides
Ar－N2+: Diazonium Salts: Sandmeyer Reaction

Diazotization

Arylamines stable arenediazonium salts

Alkylamines fail

Sandmeyer Reaction

Most reactions use a Cu(I) salt via radical mechanism:

https://www.youtube.com/watch?v=9qWxwLu_Bp4
Ar-N2+: Useful Transformations
Diazonium Coupling Reactions
Arenediazonium salts + Activated aromatic rings (ArOH, ArNR2)

Usually occurs at the para- position,

but can be ortho if para is blocked.
Azo Dyes

Extended  conjugation visible light absorption (dyes)

Sudan red 1
Heterocycles

Pyrrole

Non-basic
Chemistry of Pyrrole
• Similar to activated benzene rings (more e-rich than benzene)
• Electrophilic substitution: at C2
Pyridine and Pyrimidine

less basic than alkylamines.

Low reactivity towards electrophilic substitution:

• Acid-base complexation of N lone pair.
• Decreased ring e density: induction effect.

worse substrate
Polycyclic Heterocycles
Polycyclic Heterocycles
Spectroscopy of Amines : IR
Characteristic N–H stretching absorptions 3300 to 3500 cm1

Protonated amines show an ammonium band in the range 2200 to 3000 cm1
NMR
• N–H: broad signal, no clear-cut coupling to neighboring H.
• D2O can exchange N–H to N–D, thus N–H signal disappears.

• N-CH3 gives a sharp three-H singlet at  2.2 to  2.6

• Carbons next to amine N are slightly deshielded

Mass Spectrometry of Amines
• Compounds with odd number of N: Odd-number molecular weight (M+)
• α-Cleavage: Cα–Cβ break, typically form R• and N-containing cation
Practice Problems

7th Ed.
24.30, 24.31, 24.34, 24.35, 24.37, 24.38, 24.39,
24.40, 24.42, 24.43, 24.44, 24.45, 24.46, 24.48,
24.49, 24.50, 24.51, 24.52, 24.55, 24.56, 24.58,
24.60, 24.61, 24.64, 24.66, 24.67, 24.69, 24.70,
24.72, 24.73

8th Ed.
24.30, 24.32, 24.45, 24.37, 24.39, 24.43, 24.41,
24.40, 24.46, 24.52, 24.34, 24.33, 24.54, 24.50,
24.53, 24.35, 24.57, 24.38, 24.60, 24.62, 24.58,
24.66, 24.65, 24.47, 24.67, 24.72, 24.70, 24.71,
24.49, 24.48