Even if the word is unfamiliar to you, we have examined a variety of heterocycles thus far
in this organic chemistry series. To refresh your memory, this refers to cyclic molecules
in which at least one of the atoms in the ring is not carbon. The other element present in the
ring is most commonly either oxygen, sulfur, or nitrogen, or some combination thereof.
Heterocycles are extremely common amongst biomolecules of all varieties.
Consider chlorophyll b, the essential catalyst for photosynthesis in plants, or the nitrogenous
bases as well as carbohydate units in DNA and RNA. They are also prevalent in man-made drugs. So it
will definitely be in our best interest to become familiar with the main classes of heterocycles,
how they are prepared, and what they do. The first heterocycle we will look at is furan.
This is a five-membered ring, with one oxygen atom and two pi bonds. We must understand that furan
is aromatic, given that one of oxygen’s lone pairs is part of the pi system, allowing it
to be fully conjugated, and there is a total of six pi electrons, which satisfies Huckel’s rule.
So it’s a little bit like benzene, just with an oxygen in there, though it is actually quite a
bit more reactive than benzene, given that its delocalization energy, or resonance energy,
is only 16 kcal per mole compared to benzene’s 36 kcal per mole. Let’s also
note the numbering system, which always labels the oxygen atom as number one,
and going around in either direction from there. So what does furan do? Furan will react readily
with electrophiles, in ways that resemble the electrophilic aromatic substitution
reactions we’ve learned, simply without the necessity for a catalyst since furan is
more reactive than benzene. For example, furan will react with bromine in carbon tetrachloride,
and it will do so at a rate that is hard to control, which tends to result in tetrabromofuran.
Friedel-Crafts reactions can also be performed, and these are a bit more selective, occurring
primarily at carbon two. This Friedel-Crafts acylation is an example of this kind of chemistry.
The regioselectivity here can be explained as follows. If we push a lone pair from oxygen
around the ring to pick up the electrophile, we are left with a conjugated cationic species
called an oxocarbenium ion. This would not occur if the electrophile ended up on carbon 3.
So resonance is the primary factor guiding the regioselectivity here.
Furan can also act as a diene in a Diels-Alder reaction. And because it is electron-rich,
it can easily react with any activated dienophile, such as diethyl fumarate,
even under moderate conditions involving slight heating, to generate the product we see here.
To quickly cover how furans are formed, it is possible to isolate furan from cellulose
via a complex catalytic process, but more interesting is the synthesis of substituted
furans from 1,4-dicarbonyl compounds. This occurs via acid-catalyzed dehydrative cyclization.
As you can see, one carbonyl is protonated, which prompts attack from the other carbonyl oxygen.
After further protonation, elimination of one proton kicks off water, and the elimination
of another proton neutralizes this oxygen atom, leaving us with a disubstituted furan.
This process is known as the Paal-Knorr reaction.
Now let’s move on to thiophene. This is the sulfurous analog of furan,
in that the molecule is almost the same, just with a sulfur atom instead of oxygen.
However, its resonance energy is 29 kcal per mole, so it is quite a bit less reactive than furan.
For example, looking at the same Friedel-Crafts chemistry we examined earlier,
much higher temperatures are required to carry out the reaction on the thiophene substrate.
In addition, thiophenes are not reactive enough to participate in Diels-Alders reactions.
Interestingly, they are prepared identically to the technique we learned a moment ago with furans,
starting with a 1,4-dicarbonyl compound, then simply replacing the oxygen atoms with sulfur
atoms through sulfurization with P4S10 to generate the thiocarbonyls. From there,
acid catalysis prompts the same mechanism we learned to generate furans.
Finally we have pyrrole, which is again similar to furan,
just with a nitrogen atom instead of oxygen, which is bound to a hydrogen atom.
With a resonance energy of 21 kcal per mole, its reactivity is similar to that of furan,
typically reacting at carbon two. For example, pyrrole tetrabrominates easily,
making the monobromination product difficult to attain even at low temperatures.
Also like furan, Friedel-Crafts acylation happens easily even without Lewis acid activation.
An interesting feature of pyrrole is that despite the nitrogen atom, it is not basic.
In fact, if protonated by a very strong acid, it actually occurs at carbon 2. This is because the
lone pair on the nitrogen is tied up in resonance to produce aromaticity, and is thus not readily
available as a proton acceptor. However, the nitrogen can be acylated under strongly basic
conditions. Using something like sodium hydride or butyllithium, deprotonation occurs at the nitrogen
atom, which will react with acetic anhydride to become acetylated. N-acylated pyrroles
can undergo smooth Diels-Alder reactions just like furans, so this can be of synthetic utility.
And finally, pyrroles can be synthesized by the Paal-Knorr scheme we have outlined twice now,
using primary amines or ammonia as the source of the nitrogen atom.
So with that we have covered three very important five-membered aromatic
heterocycles, furan, thiophene, and pyrrole, so let’s move forward and
take a look at just one more heterocycle with some slightly different properties.