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.
[Link]
• 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
[Link]
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.
[Link]
[Link]
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:
[Link]
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 cm1
Protonated amines show an ammonium band in the range 2200 to 3000 cm1
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