Amines
Amines are nitrogen-based compounds. Just as water is related to alcohols which are
related to ethers, etc., amines follow a similar pattern:
R
O
O
O
O
R
R
R
H
R
R
H
H
Water
Alcohol
Ether
Trialkyloxonium salt
(unstable, quite rare)
R
R N R
R
R
R
H
R
R
H
H
R
Primary
Secondary
ammonia
Tertiary
Quaternary
amine
amine
amine
ammonium salt
(stable & very common)
There are of course major differences between the way oxygen-based compounds and
nitrogen-based compounds react. The main thing to remember is that amines have a very “active”
lone pair - they are much more basic, and much more nucleophilic than alcohols or ethers.
One thing amines do have in common with alcohols – hydrogen bonds. Amines form
GREAT hydrogen bonds. Massive supramolecular networks have been constructed based on
nitrogen hydrogen bonding in compounds like:
O
H
H
(dashed lines = hydrogen bonds)
N
N
H
N
N
O
H
H
N
N
N
H
H
Let me re-emphasize that if not for hydrogen bondage, we would all fall apart into little
pools of disorganized sludge (sorta the way I feel on Monday mornings...)
Amides: Recall that amides are not particularly reactive. The carbonyl group of an amide
is significantly less reactive than that of any other carbonyl compound, for the simple fact that this
resonance predominates:
H
N
H
N
R
N
H
N
O
H
N
O
O
H
N
O
Result: The nitrogen in an amide is essentially NONBASIC and NON-NUCLEOPHILIC,
and the carbonyl carbon is ONLY MARGINALLY ELECTROPHILIC. Remember also how
amides are prepared - reaction of an acid chloride with ammonia or just about any other
primary or secondary amine
Synthesis
Yeah, you knew you couldn't get away with it for long. There are a LOT of ways to make
amines, some of which you’ve already seen. Here is a review of new and old:
The most obvious way to prepare amines is by the alkylation of ammonia (or other amine)
with an alkyl halide. Unfortunately, it is VERY difficult to stop at mono-alkylated product;
mixtures are obtained (as shown from the attempted preparation of ethylamine), and ORGANIC
CHEMISTS HATE MIXTURES!!!!:
H
N
+ NH3
Br
+
H
H
N
+
+
N
N
The only time you can simply mix an alkyl halide and an amine is when you are trying to
make a quaternary salt (which we occasionally do in order to make a big organic molecule more
water-soluble):
Big
Ugly
Organic
Molecule
Br
N
Big
Ugly
Organic
Molecule
Water Insoluble
Br
N
Charged (ionic) compound Water Soluble!
But how do we make “normal” amines? You already know of several methods. The reduction of
amides and nitriles with LiAlH4, for example:
O
R
NH2
LiAlH4
or
R
NH2
R C N
There are some other methods that are particularly good for making primary amines: The
Azide Synthesis, and the Gabriel Synthesis.
The azide synthesis takes advantage of the fact that azides are great nucleophiles, and can
be easily converted (again, by LAH reduction) to amines. Here’s the scheme:
1) LiAlH4
NaN3
R N N N
R Br
R NH2
EtOH
2) H2O
This scheme works quite well with just about any primary or secondary amine.
The Gabriel synthesis is a much older method, but works just as well. This method uses a
sort of “protected” ammonia, and relies on “blocking” two of the reactive sites on ammonia leading
to mono-alkylation. Removal of the “protecting” groups leads to the primary amine:
O
O
N H
O
KOH
N K
O
O-
O
O
R Br
N R
O
O-
KOH
+
O
R NH 2
Succinamide is deprotonated with a decent base to yield the stabilized anion. This anion
can then react with a primary or secondary alkyl halide, to lead to the substituted succinamide.
“Deprotection” with concentrated base gives the amine and phthalate.
A very useful method for the preparation of amines from ketones and aldehydes is called
reductive amination. It is often simplest to think of this as the formation of an imine, followed
by hydrogenation (although your text gives a very good example of what really happens). This
method can be used to prepare primary, secondary AND tertiary amines. Here are a few examples:
R
O
RNH2
R
R'
R
N
R
H2 / cat.
R'
R
NH
R'
OH
O
H2 / Pt
EtOH
NH2
NH
+
HO
Reductive amination is a very mild and versatile method for preparing amines (especially
secondary amines).
Rearrangements
Okay, this is where everybody gets lost. It is possible, under the correct conditions, to get
a rearrangement to occur which turns an amide (or amide-like molecule) into an amine. These
methods are quite general for the preparation of primary amines, and partiuclarly good for the
preparation of vinyl, aryl and tertiary amines (which cannot be formed by the azide or Gabriel
methods!). These rearrangements are the Hofmann and the Curtius rearrangements, and they
both proceed through a similar mechanism - basically, the rearrangement of a deprotonated amide
with a good leaving group:
O
H2O
L.G.
NH2
+ CO2
N C O
R
N
R
R
Now let’s look at each of these reactions more specifically.
The Curtius rearrangement requires you to start with an acid chloride. Addition of sodazide
(NaN3) leads to the acyl-azide. This rearranges thermally (the leaving group being nitrogen [N2])
to an unstable intermediate isocyanate (that’s what we call the NCO group), which decomposes to
give the amine and CO2. Here’s a real live example:
O
O
O
Cl NaN3
SOCl2
OH
O H
N C O
H
ON C
N N N
proton
transfer
H
N C
O
NH
+ CO2
H2O
O
H
NH 2
O H
H
The Hofmann rearrangement proceeds by nearly the same mechanism. The main difference
is that you start with an amide, which is then brominated on nitrogen . . . here’s the same example,
using a Hofmann
O
H
N
H
O
KOH
Br2
H
N
OH
O
H
N
O
N Br
N C O
Br
OH
Br Br
Again, we get the same isocyanate intermediate, which decomposes to the amine by the
same pathway. These rearrangements are the best way to make amines from “delicate” substrates.
Phase Transfer Catalysis
One of the cool things about quaternary ammonium salts is that they can be used to carry all
sorts of negatively charged species into apolar (hydrophobic) regions. Whether it is to carry base
into chloroform (as your book says), or polyphosphates through a lipid membrane, we’ll talk a bit
about this in class ( I wouldn’t want to encourage anyone to skip lecture, now, would I....)