Picture it…



Poppy (Papaver somniferum)

Poppy flower (Papaver somniferum) in a glass condenser, together with the structure of morphine, one of its key ingredients.

Poppy flower (Papaver somniferum) in a glass condenser, together with the structure of morphine, one of its key ingredients.

Having recently observed Remembrance Day, people everywhere are wearing a poppy on their chest to remember the death and suffering that occurred in 1914. Today however, despite being the symbol of ultimate sacrifice, this poppy is merely a common weed in Europe. In this post we explore another member of the poppy family that has multiple applications as both a medicine and as highly addictive recreational drugs.

1. The image above shows a member of the poppy family known as the Opium poppy or Papaver somniferum. The family contains approximately 770 species of flowering plants and is of great economic importance. Today this is the only poppy species that is grown on a large scale as an agricultural crop, mainly in the Middle East and parts of Asia. In this image the poppy is fed into a condenser within a fume cupboard. A condenser is an important piece of laboratory kit used to cool hot vapours or liquids. It is used f0r reflux, which involves heating a reaction mixture so the solvent boils; this can be useful to speed up chemical reactions. The condenser is a large glass tube containing a smaller tube that allows gases to cool down when they come in contact with the outer compartment, which is cooled by running cold water through it. On cooling, the gases condense and return to their former, liquid state. Without the condenser, the gases would evaporate and disappear before the reaction was complete. Rather than evaporating off the solvent, it condenses in the condenser and is returned to the reaction vessel.

Poppy flower, morphine and an appropriate warning!

Poppy flower, morphine and an appropriate warning!

Cultivation of opium poppies (named ‘the flower of joy’ by the Sumerians) for food, anaesthesia and ritual purposes, dates back to 3,400 B.C. in Southwest Asia.  Despite a rather labour intensive method used for harvesting opium from poppies, the demand for the plant increased as people learned of its power. Opium is mentioned numerous times in the most important medical texts of the ancient world. Ancient surgeons used opium during prolonged surgical procedures and its widespread use as the most potent pain relief available continued throughout the American Civil war before the introduction of morphine.

Morphine is an alkaloid, the name given to a class of compounds of plant origin which have pronounced physiological effects in humans. It is the principal active ingredient in opium, making up about 12% of the total dry weight extracted, and was discovered in 1804 in Germany by a pharmacist named Friedrich Sertürner. Morphine was not only the first alkaloid to be extracted from opium, but the first ever alkaloid to be isolated from any plant. Prior to this discovery, research on plant alkaloids was virtually ignored. Sertürner’s breakthrough was therefore instrumental in the discovery of several other very important plant alkaloids, including caffeine, nicotine and cocaine, some of which we plan to cover in future posts.

On its discovery, morphine, named after the Greek God of dreams ‘Morpheus’, was hailed as a miracle drug due to its high potency (ten times higher than that of processed opium). Throughout the mid-1800s it was widely prescribed, not only as an analgesic but also as a treatment for opium and alcohol addiction. It was only discovered many years later that morphine was even more addictive and its extensive use during the American Civil War caused over 400,000 sufferers to develop a morphine addiction known as “soldier’s disease”. Today, morphine is isolated from opium in large quantities of over 1000 tons per year and is one of the most powerful analgesics known.

Structural drawing of Morphine.

Structural drawing of morphine.

2. Despite its discovery in 1804, the basic structure of morphine, chemical name 7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol, was not correctly determined until over 100 years later. Its key structural features are shown in the structural drawing on the left and include five rings, three of which are approximately in the same plane with the remaining two rings lying perpendicular to the trio.

The human body indicates that it is suffering intense pain by producing chemicals that bind with a specific receptor of nerve cells. Morphine inhibits these chemicals from binding to the receptors, which are mainly found in the spinal cord, and thus blocks the pain signals from reaching the brain. The architecture of the morphine molecule is therefore fundamental, as it is the molecule’s ability to fit exactly into and block the active site on the specific receptor that leads to its powerful analgesic properties. The body still recognizes the pain and tries to heal itself, but it no longer relays the actual sensation.

Structural drawing of Codeine

Structural drawing of codeine

Today, most commercial opium extracted from poppies is converted to codeine, also known as 3-methylmorphine, by methylation of morphine. Codeine is the second-most predominant alkaloid in opium, contributing up to 3% by weight. As shown in the structures, replacing the –OH group attached to one of the benzene rings in morphine with -OCH3 produces codeine which is used to control mild-to-moderate types of pain and works by binding to opioid receptors in the brain.

Structural drawing of Heroin

Structural drawing of heroin

The most infamous derivative of morphine, however, is heroin, also known as diamorphine when used in a medical environment. Heroin is formed by acetylation of both hydroxyl (OH) groups on morphine using acetyl anhydride. By replacing the –OH groups with –OCOCH3, the hydrogen bonding of the molecule is significantly reduced, making heroin much less soluble in water than morphine, but more soluble in oils and fats. It is for this reason that heroin must be injected into the bloodstream and is consequently twice as powerful. However, the effects do not last as long. Once the heroin molecule enters the bloodstream, it is broken down naturally by the body by removal of the acetyl groups, giving morphine.

3. The biosynthesis of morphine taking place in the opium poppy involves many complexities. The first total synthesis of the alkaloid morphine was completed by an American chemist called Marshall D. Gates Jr. in 1952 (described in J. Am. Chem. Soc., 1956, 78 (7), 1380–1393) and since then at least 18 more total syntheses have been described. The original total synthesis has 29 steps in total, giving a small yield of 0.0014%. The key step in the synthesis is a high-pressure Diels-Alder reaction with butadiene to establish the fused ring core of the system as shown below. This is one of the first examples of the Diels-Alder reaction used in the context of a total synthesis.synthesis 1

Another key disconnection that synthetic chemists have attempted is the reductive amination. As seen in the diagram below, reductive coupling occurs between the hydroxyl and cyano groups to form an ethylamine bridge and the “Gates Intermediate” is formed after further reactions, including a strenuous epimerisation of the stereocentre.

synthesis 2

The synthesis leads to codeine and, after addition of pyridine and HCl, morphine is produced. It was a landmark synthesis that confirmed the structural determination made some 27 years prior. Improvements have been made to it from then onwards, with particular attention being paid to the final steps. Other syntheses include those proposed by Rice, Evans and Parker.

Contributors: Louisa Gayford (research and writing), Ben Mills (ideas and research), Jenny Slaughter (photography), Natalie Fey (3D structure and editing)