Chemistry of Porphyrins

A Utility Player
The more you learn about chemistry, the more often you get amazed by the smart principles of nature. Nature impresses you with the intricacy and precision in her designs, and lessons you with the way she neatly applies a same basic concept to different situations. This molecule called porphyrin, is one of those compounds with unique characteristics that are utilized cleverly at important points.


Fig 1 porphyrin

As shown in Figure 1, a porphyrin is a rigid, square-planar molecule made of four pyrroles (a five-membered ring containing a nitrogen atom) connecting to form a larger ring. The molecule is stabilized by the aromatic character which extends over its entire structure.
A porphyrin has four of its nitrogen atoms facing the center, which can capture a metal ion to form a very stable organometallic complex. It turns out, that this property of the molecule is closely linked with the way it is used in living systems.
When forming a complex, many metal ions accept six coordinating ligands to assume an octahedral (a shape made of two pyramids attached at the bases) configuration (Figure 2).


Fig 2 octahedral structure

The nitrogen atoms of a porphyrin occupy the four sites on the square plane of an octahedron, leaving two empty sites on the top and the bottom (Figure 3). These two sites are then filled by the axial ligands, which are known to react in special ways. By using them, biological systems carry out a wide range of chemical reactions.


Fig 3 porphyrin complex

A Carrier of Oxygen
Letfs take a look at hemoglobin, a carrier of oxygen molecules in blood, as the first representative example. Hemoglobin has a structure in which the porphyrin part called heme is connected to a big protein (Figure 3.39). Positioned at the center of this heme is an iron atom, and a molecule of oxygen attaches to it as an axial ligand. An oxygen molecule is not a strong metal-binder naturally, so it usually doesnft form a stable complex with metal ions. But porphyrin makes it happen, showing its unique ability.


Fig 4 heme (red ball is oxygen atom)

Hemoglobins are designed to capture oxygen molecules actively in the places where there is an abundance of O2, and to release them when there is a shortage. A liter of human blood is said to have the capacity of carrying the same amount of oxygen contained in a liter of air, which tells you about the efficiency of the chemistry.

A Cleaner of Foreign Substances
Heme plays an important role not only in blood, but also as a component of an enzyme called cytochrome P-450 (abbreviated as CYP) in organs such as the liver. Unlike hemoglobin, to which a molecule of oxygen binds, it is the highly reactive single atom of oxygen that binds to the iron located in the center of CYP. When a CYP sees a potential target compound, the enzyme oxidizes it by transferring its oxygen atom to it. Widely spread in the biological world, the CYP enzymes come in many different types and their workplaces are diverse. One type plays a role in the synthesis of important molecules like hormones, while another type oxidizes foreign molecules to raise their water solubility, making their excretion easier. You could say that the latter function is essentially a detoxification process.
Medicinal molecules are foreign to a body, so they are also transported first to the liver to get metabolized by the CYP oxidation. The liver contains many kinds of CYPs, and their total and relative amounts depend on individual health and ethnicity. So a person with strong CYP activities breaks up the drug molecule quickly after he or she takes it, lowering the effectiveness of the drug as a result. This is one of the reasons why there is an individual difference on how people respond to a drug.

Chlorophylls and Vitamins
Like animals, plants also rely on an important compound with the porphyrin skeleton. The molecule found in plants is chlorophyll, which is responsible for the green pigment normally seen in leaves (Figure 5).


Fig 5 chlorophyll

Vitamin B12 also contains a similar structure called corrin, and it is an essential compound in the synthesis of nucleic acids (Figure 6). At the core of the corrin skeleton sits a cobalt atom, a relatively rare entry for biological molecules.


Fig 6 Vitamin B12

As you can see, the overall structure of vitamin B12 is exceptionally complicated. The chemical synthesis had been considered impossible, but it was accomplished by the collaboration between two extraordinary chemists, Professors R. B. Woodward and Albert Eschenmoser, with their report published in 1973. The left side half of the corrin structure was made by Woodward in the United States, and the right side half was done by Eschenmoser in Switzerland. The big project over the Atlantic Ocean was completed by joining the two parts together at the end. It was an incredible achievement that took over a hundred researchers in the two groups combined, more than ninety synthetic steps in total, and twelve years of effort. There is no report of the second total synthesis of this compound even today, when synthetic methods are so much more sophisticated. The synthesis is considered as a landmark achievement in the history of organic synthesis.
Woodward also developed a theory now known as the Woodward-Hoffmann rules by analyzing stereochemical observations made during a key step in the vitamin B12 synthesis. Professor Roald Hoffman, a collaborator of Woodward who did the theoretical calculations, received a Nobel Prize in Chemistry in 1981. Itfs amazing that a Nobel Prize was born as a side product, but this may be a good example where a great discovery was made by challenging a difficult research.

The Elegant World of Artificial Porphyrins
Learning from nature, organic chemists have been using porphyrin structures of their own for various purposes. Synthesizing a porphyrin itself is relatively simple, and many methods are known to prepare the ones with substituents at desired positions.
As evident in its main role in photosynthesis, porphyrins are expected to have photochemically and electrochemically interesting properties. Organic chemists can fine-tune these properties by introducing substituents, or changing the central metal ion. A number of porphyrin derivatives are continuously made, and among them the compounds composed of multiple porphyrin units are particularly fascinating. Putting difficult lectures aside, letfs enjoy looking at some of the structures as beautiful as stained-glass art (Figures 7-9).


Fig 7 porphyrin 21-mer


Fig 8 grid porphyrin complex


Fig 9 cyclic porphyrin pentamer

As a linearly joined molecule, a massive polymer of astonishing 1024 porphyrin units have been synthesized by Professor Atsuhiro Osuga of Kyoto University in Japan.
With a molecular weight of over a million and its length reaching 0.8 micrometer, this is probably one of the biggest single molecule created by mankind. These researches are expected to expand into the development of nanometer-scale electric wires and electronic devices, and are a very promising field.

Molecules with the Name of Jewels
Lastly, I am going to introduce beautiful molecules having the name of jewels. A porphyrin has a purple color, but the color changes depending on the number of pyrrole units and the number of carbon atoms connecting the pyrrole units. These molecules are therefore named after the jewel stones of corresponding color.
The molecule having five pyrrole units shown in Figure 10 displays a beautiful blue color, and is called sapphyrin. This is a compound made by chance during the synthesis of vitamin B12 mentioned earlier, and was named after the blue jewel sapphire. Similarly, the green-colored compound shown in Figure 11 and the red-colored compound shown in Figure 12 are named smaragdyrin (after a Latin smaragdus, for emerald) and rubyrin, respectively.


Fig 10 sapphyrin Fig 11 smaragdyrin Fig 12 rubyrin

The syntheses of more of these compounds are in progress. Figure 13 shows orange-colored orangarin, Figure 14 shows rose-red rosarin, and finally Figure 15 shows purple-colored amethyrin, which was named after amethyst.


Fig 13 orangarin Fig 14 rosarin Fig 15 amethyrin

The analogues of porphyrin in which oxygen and sulfur atoms replaced the pyrrole nitrogens, such as bronze-colored bronzaphyrin (Figure 16) and green-colored ozaphyrin (Figure 17, named after the Emerald City from the Wizard of Oz) have been synthesized as well. The structure of turquoise blue turcasarin shown in Figure 18 contains ten pyrrole units, and the molecule is twisted like the shape of number eight instead of being planar.


Fig 16 bronzaphyrin Fig 17 ozaphyrin Fig 18 turcasarin

As more and more types of these macrocyclic porphyrins are introduced, more systematic nomenclature systems have been suggested instead of using random names. Itfs probably better for academic or scholastic purpose, but I also feel that beautiful compounds really deserve to have beautiful names. Setting up a reaction thinking which color the next product will be and what name it will get must be one of joyful moments for an inventive chemist.

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