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A heterocyclic compound is a ring-structured molecule that contains at least two different elements as members of the ring. The sizes can vary, from highly strained, three-membered ring compounds, to larger molecules with eight, nine, or ten-membered ring structures. That being said, five and six-membered rings are usually the most common heterocyclic compounds, as they are less strained and thus more stable, especially in the case of aromatic heterocyclics. This structural variation in heterocycles (from ring size to the constituent elements) gives them a wide range of chemical properties and is a key reason what they have so many applications in organic chemistry.
Heterocyclic molecules make up many of the materials that are vital to life. For example, the fundamental building blocks of DNA (nucleic acids) are heterocyclic compounds, as are most naturally occurring antibiotics, vitamins, and pigments. In fact, heterocycles constitute nearly 50% of known organic compounds and almost 90% of active pharmaceuticals, making them one of the most indispensable classes of compounds today.
Given this, you can imagine the huge impact that heterocyclic molecules had on organic chemistry when the first methods to artificially synthesize them were developed. Early successes—like Brugnatelli isolating the heterocyclic compound alloxan from uric acid in 1818—later led to revolutionary syntheses such as the first industrial production of indigo dye. Subsequently, the late 1800s and early 1900s became a golden age for new heterocyclic syntheses. In this blog, we’ll outline five of the most important heterocyclic reactions from this golden age, and explore how they are still relevant over a century after their initial discovery.
In 1882, Arthur Rudolf Hantzsch was researching and developing new multi-component organic reactions. After much experimentation, he discovered that if he added an aldehyde together with two equivalents of a β-keto ester and a nitrogen donor (e.g. ammonia), a reaction occurred to form a dihydropyridine molecule. After this discovery, many more substituted dihydropyridine molecules began to be prepared by this revolutionary method.
However, the Hantzch dihydropyridine synthesis really sprang into prominence a century later in the 1980s, with the revelation that the dihydropyridine intermediates prepared from aromatic aldehydes are calcium channel blocking agents. It was found that inhibiting Ca2+ ion transport across cell membranes in this way can selectively relax muscle tissues without affecting the workings of the heart. Hence, high blood pressure can be thrown for a loop all thanks to Hantzch’s research.
A year after the Hantzsch dihydropyridine synthesis, the brilliant chemist Emil Fischer discovered a way to produce aromatic heterocyclic indoles. Fischer had earlier discovered the oily liquid phenylhydrazine as a PhD student, and he decided to test the reaction of this new compound with aldehydes and ketones under acidic conditions. The result was an elegant way to produce a variety of substituted indoles.
Many antimigraine drugs of the triptan class are synthesized by this method, as are drugs like indomethacin (a nonsteroidal anti-inflammatory). More recently, a whole series of useful compounds have been made using the Fischer indole synthesis and a single acid catalyst in a one-pot conversion. Proving that Fischer’s work is still ringing true to this day.
In 1886, Ludwig Knorr took two measures of ethyl acetoacetate, dissolved one of them in glacial acetic acid, then slowly added one equivalent of saturated aqueous sodium nitrite under cool conditions. He then stirred some zinc dust into the solution as a catalyst. What resulted was a pyrrole synthesis that formed the basis of countless chemical reactions that are still prominent today.
Pyrroles are incredibly useful in modern chemistry and are found in several drugs, including ketorolac (a common analgesic), atorvastatin (a lipid-lowering agent), and sunitinib (a treatment for many internal organ cancers). They also form the components of several complex macromolecules such as chlorophylls and hemoglobin groups. What’s more, Knorr’s pyrrole product is a precursor to the drug tolmetin, which reduces pain in many forms of arthritis!
A few years after the Knorr pyrrole synthesis (in 1893 to be exact), Cäsar Pomeranz and Paul Fritsch discovered the acid-promoted synthesis of isoquinoline from benzaldehyde and a 2,2-dialkoxyethylamine. This reaction subsequently opened the door for the preparation of many diverse isoquinolines. Despite being used for over 100 years, the exact mechanism via which the reaction proceeds is still uncertain.
Pomeranz-Fritsch reactions allowed for the many modern applications of isoquinolines. This includes their use in the manufacture of dyes, insecticides and antifungal drugs. They can also be employed in anesthetics such as papaverine, a common alkaloid used as an antispasmodic. Furthermore, they are needed in the synthesis of dimethisoquin, a drug that can be applied to skin reduce irritation. In other words, Pomeranz-Fritsch helps you ditch that itch.
In 1911, Amé Pictet and Theodor Spengler found that β-arylethylamines were able to undergo ring closure reactions after condensation with an aldehyde or ketone. In some cases, this innovative reaction was shown to proceed with no catalyst under mild conditions, while still giving good product yields. However, an acidic catalyst is often added by today’s chemists, and the mixture is heated to enable faster reaction times.
The Pictet-Spengler tetrahydroisoquinoline synthesis remains a significant reaction used during pharmaceutical development and is a useful way of making some important alkaloid natural products (indeed, it mimics the way nature makes them). Therefore, its products are often found in several drugs such as tubocuranine (a muscle relaxant), nomifensine and diclofensine (both antidepressants). The Pictet-Spengler reaction product of tryptophan and aldoses can even be found in things like ketchup. Saucy!
These five reactions are examples of syntheses that shaped the world of heterocycles today. If you’d like to find out more about the mechanisms behind these reactions, or are curious about the intricate nature of everything from the Fischer to the Pomeranz-Fritsch synthesis, check out our heterocyclic formation pages today.