In this organic chemistry series, we’ve learned a handful of name reactions.
These are reactions with synthetic utility that are named after their discoverers or
developers, and their names act as a shorthand to make them easy to refer to.
Apart from the fact that many name reactions will show up on organic chemistry exams, chemists
tend to refer to these reactions by name, so it is important to be aware of as many
as possible in order to follow chemistry research.
We’ve already talked about Williamson ether synthesis, Robinson annulation, Claisen condensation,
Friedel-Crafts reactions, Clemmensen reduction, the Grignard reaction, the Wittig reaction,
Beckmann rearrangement, and Baeyer-Villiger oxidation.
These are all named after chemists.
And now for the next significant portion of this series we are going to investigate many
more important name reactions.
First up is the Gabriel synthesis, which is a method of generating primary amines.
Primary amine synthesis was problematic at one time.
One could suggest that the SN2 reaction of ammonia with a primary alkyl halide should
give the corresponding primary amine.
However, ammonia is not only nucleophilic but also rather basic.
If the alkyl halide has β-hydrogens, elimination will compete, and large amounts of alkenes
will be obtained via E2, alongside low yields of the desired amine.
Even if the alkyl halide has no β-hydrogens, the reaction still works poorly, because the
primary amine that is produced is also rather nucleophilic, and will engage in sequential
alkylations, yielding complex mixtures of primary, secondary, and tertiary amines, and
even some quaternary ammonium salts.
The first general solution to this problem was discovered by German chemist Siegmund
Gabriel, and published in Chemische Berichte in 1887.
The reaction is still of synthetic importance, so let’s get a closer look.
Gabriel reacted a primary alkyl halide, in particular almost always alkyl bromides, although
alkyl iodides can also be used, with the potassium salt of phthalimide in a highly dipolar solvent
like DMSO or DMF.
This reaction follows a typical SN2 mechanism.
Phthalimide can be seen as a doubly protected version of ammonia.
This “protection” avoids multiple alkylations and imparts reduced basicity onto the nucleophile,
which makes E2 eliminations unlikely.
The reason this substrate is less basic than a primary amine is because it has its negative
charge delocalized across two carbonyl groups, which means it is highly stabilized and therefore
less prone towards acting as a base.
Once the substitution process has taken place, the phthalimide moiety has to be hydrolyzed
away.
This can be done under very strongly acidic or basic conditions.
However, if the amine has sensitive functionalities, it is best to carry out the deprotection under
modified conditions, using hydrazine as a nucleophile.
These nitrogen atoms attack these two carbonyls, which will eventually push this nitrogen out
of the ring to produce the amine.
This process is milder and yields a phthalyl hydrazide along with the desired primary amine,
the latter of which can be extracted into an aqueous acidic phase, whereas the hydrazide,
being a neutral compound, stays in the organic layer or precipitates out and can be filtered
off.
Now this synthesis is generally performed on primary alkyl halides.
With secondary alkyl halides, other methods must be used, because these substrates are
much less reactive in SN2 reactions, which is the first step of the synthesis.
There are very few side reactions, but one problem is the potential formation of the
O-alkylation product.
Phthalimide is referred to as an ambident nucleophile, because the negative charge which
does the attacking is localized on both the nitrogen and the carbonyl oxygen, given the
resonance.
Normally, the more stable N-alkylation product is obtained, but it is always wise to look
out for the isomeric O-alkylation product.
It is actually very difficult to distinguish between these two isomeric alkylation products,
because they have similar spectral characteristics.
The distinction requires complex carbon-13 NMR methods, which we will not discuss.
However, hydrolysis of the O-alkylated product ultimately yields an alcohol, which is neutral
and can be readily distinguished from the desired amine.
Now it is certainly the case that this synthetic concept has been fine-tuned by chemists over
the many decades since its development.
One useful variation consists of using differentially protected ammonia surrogates.
Here we see an example involving the use of this benzyl tert-butyl imidodicarbonate.
In the presence of strong base this compound can be alkylated just as in the Gabriel synthesis.
Then the benzyloxy carbonyl group can be removed under mild conditions using palladium-catalyzed
hydrogenolysis, which involves loss of CO2.
A second alkylation can be carried out in similar fashion, and then the tert-butoxycarbonyl
group can be removed under mildly acidic conditions, yielding a secondary amine with two different
alkyl groups, thus considerably expanding the scope of the Gabriel synthesis.
While such modifications are excellent tools to be aware of, the original Gabriel primary
amine synthesis is a classic reaction with great utility in modern synthesis, and every
organic chemist should be familiar with this important reaction.