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An introduction to penicillin

Despite having been discovered almost 90 years ago, penicillins remain one of the most widely-used antibiotics in the world, accounting for nearly 60% of all total drug consumption along with cephalosporins. From 2000 to 2010 global antibiotic use rose by 36%, and research and study into antibiotics and resistant bacteria continues as an essential and evolving science.

To understand how penicillins work we will first explore their general structure followed by their original synthesis.

Structure

There are many types of penicillin, all of which belong to a larger family of antibiotics called β-lactams. The name is derived from their central ring structure, consisting of a cyclic amide known as a lactam. β is the second letter of the Greek alphabet and is placed as a prefix due to the nitrogen of the cyclic amide being bonded to the second carbon attached to the carbonyl.

penicillin structure

Meanwhile the α carbon of the β-lactam ring bonds to the nitrogen of a second amide group. After the carbonyl the symbol R is shown. R stands for a range of different structures, each of which results in a slightly different analogue of the penicillin family of compounds.

Bonded to the β-lactam ring is another ring structure – a thiazolidine. This five-membered ring contains a sulfur atom, from which we can start numbering. Counting to the third point of the ring we see a nitrogen atom. Attached to the thiazolidine ring are two methyl groups (CH3) and a carboxylic acid group (COOH).

Synthesis

Now that we know the general structure of penicillins, we will consider how to make them in the lab. With so many functional groups, chiral centres, and two linked rings, this is not straightforward. Particularly, when we consider how strained the four-membered ring is – try making a molecular model and you will see how tricky it is to join the atoms together.

We will look at part of the first ever laboratory synthesis of penicillin V by a research group lead by John Sheehan. Penicillin V contains a phenoxymethyl group, (PhOCH2)–, as its variable R group.

penicillin G

It was relatively easy to make the penicilloic acid, but the difficult step in the synthesis and the part that baffled scientists who worked on penicillin production during World War II was the closure of the β-lactam ring. The strained four-membered ring is susceptible to breaking apart in even slightly acidic or basic conditions. Therefore, Sheehan and his team had to develop a very mild method for forming the amide bond at room temperature and at neutral pH.

You will see that we need to lose water from penicilloic acid (in a dehydration reaction) to make the four-membered ring. To achieve this, Sheehan used N,N’–dicyclohexylcarbodiimide or DCC.

penicilloic acid precursor

This compound was found to activate the carboxylic acid group in the penicilloic acid by converting the OH group into a good leaving group. First DCC removes H+ from the carboxylic acid. The resulting carboxylate ion acts as a nucleophile and attacks the electrophilic carbon atom of DCC.

DCC reaction pathway

The lone pair of the amide then attacks the electrophilic carbon of the carbonyl group, and then expulsion of the leaving group occurs, in a nucleophilic acyl substitution reaction. This is a complicated reaction mechanism and we will look at the underlying principles of nucleophilic acyl substitution in the next section.

At the time, this method of forming amide bonds, using DCC was state of the art and it was a groundbreaking discovery in synthesising penicillins. Although not useful for the mass production of penicillins (the overall synthesis is too long and inefficient), this approach allowed the formation and biological screening of penicillin analogues (with different R groups).

Since 1957, most penicillins are made on an industrial scale using fermenters, where penicillin-producing fungi are incubated. Penicillin producing Penicillium chrysogenum fungi are isolated and placed into a fermenter. A source of nutrients is added in the form of carbon containing sugars, such as glucose, and nitrogen containing ions, such as nitrates (NO3). Sterile oxygen is pumped into the fermenter in order to encourage aerobic respiration of the fungi (a series of reactions, that requires oxygen, in which energy is released from glucose). The fungi will grow initially and then begin to produce penicillin. These are extracted from any additional waste products and any impurities removed.

Preventing any other microbes from entering the fermenters is paramount and after a batch of fungi have reached their optimum penicillin yield the tank is sterilized and re-seeded for a fresh colony of fungi.

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This article is from the free online course:

Exploring Everyday Chemistry

University of York

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