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NH2 N N N
H
primary
secondary
tertiary
quaternary
HO H3CO O
O
O O O
N N O N
HO HO O
morphine
codeine
heroin
Common names name the amine by indicating each alkyl substituent with amine suffix
NH2 N H
N
aniline
pyridine
pyrrolidine
These compounds, and others seen in aromatic compounds, use common names
N
4-methylpyridine
CH3
Structure
With a saturated amine, the lone pair resides in a sp3 hybridized orbital
N CH
H3 C 3
CH3
With conjugation, the lone pair will reside in a p orbital to allow overlap
O O
H3 C N C H3 C H3C
H3 C O N H N H
CH3 CH3
Nitrogen Inversion
N S-N-ethyl-N-methyl-1-propanamine
N N N
S configuration
Planar sp2 hybridization
R configuration
Nitrogen Inversion Changes the Chiralty
1) Create quaternary nitrogen nitrogen is prevented to invert with four covalent bonds
N N
will invert
cannot invert
2)
Strain prevents formation of sp2 hybridized nitrogen
N CH Net dipole
H3C 3
CH3
In addition, hydrogen bonding causes amines to have a relatively higher boiling point
N CH
H 3
CH3
N CH
H 3
CH3
Basicity
H Kb H H
R N H2O N OH
H R H
Can determine pKb values (just like pKa values for acids)
pKa + pKb = 14
Therefore strong bases are weak conjugate acids, and vice versa
Effects of Basicity
The base strength for amines follow many of the same trends as already observed
H H
H N R N
H H
pKb = 4.74
pKb = 3.36
A difference with amines, however, is that secondary and tertiary amines are
approximately the same basicity as primary amines due to hydration effects
Resonance Effects
NH2
pKb = 9.40
pKb = 15
As the percent s character increases for the orbital holding the lone pair of electrons,
the electrons are held more closely to the positively charged nucleus
Therefore a sp2 hybridized amine have the electrons closer to the nucleus
than a sp3 hybridized amine
Thus the sp2 hybridized amine is harder to protonate (and form a positive charge)
than a sp3 hybridized amine (other factors like resonance being equal)
N H3 C C N
NH2
pKb = 3.36
pKb = 8.75
pKb = 24
Amine Salts
First, the salt form of aniline changes the substituent from strongly activating
to strongly deactivating, therefore changing the regiochemistry and reactivity
NH2 NH3
H+
Amine salts are also used to catalyze a variety of organic reactions that feature two
components that are soluble in different liquid phases (e.g. organic and aqueous)
Br
Low rate in either organic
NaCN
or aqueous solutions
R
O N
H+
RNH2
H H
Many reactions do not work with pyridine due to the strongly deactivating system
NO2
HNO3
H2SO4
N N
Cl OCH3
NaOCH3
N N
Also remember leaving group ability for these nucleophilic aromatic substitution reactions
follow electronegativity trends ( F > Cl > Br > I )
Alkylation of Amines
NH2 CH3I N
H
N CH3I N
H
NH2 CH3I N
H
10 equivalents
The other option is to run the reaction with excess of alkyl halide
The amines can also be reacted with acid chlorides to generate amides
The amide does not generally react further because the lone pair of electrons is delocalized
Acylation to Modify Aromatic Reactivity
Once used, the acetyl group can be hydrolyzed off in either acidic or basic conditions
Thus the acetylation of aniline derivatives are quite useful to modify reactivity
Sulfonamides
For these reactions the Saytzeff was generally favored due to the more stable product
Hofmann was observed when the base was too bulky to abstract
the hydrogen from the more substituted carbon
The Hofmann product in these E2 reactions is named after amine elimination reactions
When an amine is alkylated with excess alkyl halide, a quaternary amine is obtained
NH2 CH3I N
excess
!
N N
base
When heated with base, the amine can leave to generate an alkene
When different alkenes can form, the less substituted alkene is preferred
N(CH3)3 Ag2O
HO HO
H H
H H CH3
H H H Steric bulk
N(CH3)3 N(CH3)3
Another method to have an amine elimination from a compound is the Cope elimination
oxidation
N N
O
(primary amines are oxidized to nitro and secondary amines are oxidized to hydroxylamines)
N HO N(CH3)2
H HO
Diazonium Salts
Primary amines will react with nitrous acid to form diazonium salts
The key step is that the nitrogen will leave to generate a carbocation
Arenediazonium Salts
N
NH2 NaNO2 N
HCl
The nitrogen leaving group (N2) can then be replaced in a second step
N
N H2SO4 OH
!
Briefly saw in aromatic substitution chapter that fluorine substituted aromatic rings
can be obtained through an arenediazonium pathway
N
N HBF4 F
N
N CuCl Cl
N
N CuBr Br
N
N CuCN CN
Common substituents to add are chlorine, bromine or cyano with this route
Replacing Diazonium group with Hydrogen
N
N H3PO2 H
Br Br
Br2 1) NaNO2, HCl
NH2 FeBr3 NH2 2) H3PO2
Br Br Br Br
Would not be able to synthesize bromines meta to each other without this type of method
Synthesis of Amines
OH
O NH2OH N LAH NH2
H+
O CH3NH2 N LAH HN
H+
Instead of reacting hydroxylamine, react with primary amine to form imine then reduce
Tertiary Amines
O (CH3)2NH N Na(CH3CO2)3BH N
H+
imminium salt
React carbonyl with secondary amine to form an imminium salt, the imminium salt is
unstable and must be reduced in situ, therefore a weaker reducing agent is used
Acylation-Reduction
O CH3NH2 O LAH
Cl N N
H H
With the amide functionality, reduction with LAH yields the amine
The problem with using alkyl halides with an amine was the issue of polyalkylation
O O O
base CH3Br NH2NH2
NH N NCH3 CH3NH2
O O O
There are a couple of other strong nucleophile that can be reduced to an amine
Azides
Nitriles
Realize that cyano (nitrile) route adds one additional carbon to framework
Reduction of Nitro Group
or
Use active metal with H+ source (e.g. Sn, H2SO4 or Zn, HCl)
Hofmann Rearrangement