Antimicrobials: phenols and chlorophenol


As antiseptics, phenols were first used in surgery, but they become even more deadly when chlorine atoms are attached to them.

Another substance (the first was hypochlorite) with a pungent odor is phenol, which also happened to play an important role in the prevention of infectious diseases. On August 12, 1865, professor of surgery Joseph Lister (1827-1912), who worked at the University of Glasgow, operated on a boy whose leg was run over by a car, as a result of which the child suffered an open fracture, with this type of fracture, the broken bone breaks the skin and comes out. Lister was aware of the high risk of developing gangrene, a condition in which a person’s tissue rots, emits a foul odor, and can result in the patient’s death.

But, like other doctors of that time, Lister did not know that the cause of this pathology is the Clostridium bacterium, which secretes a toxin that can destroy surrounding tissues, but nevertheless he decided to try a new way to prevent this most dangerous disease. The doctor compared the boy’s broken bone and wrapped it around the open wound with a bandage moistened with a phenol solution. Then this substance was known as carbolic acid, and it was obtained as one of the by-products of coal processing. Gangrene did not develop, the wound healed quickly, and six days later the boy was discharged home. From this moment begins the history of surgical antisepsis, thanks to which millions of lives have already been saved today. (By antiseptics are meant substances that destroy pathogens, but do not harm the patient’s tissues.)

It soon became clear that, although phenol is a powerful antiseptic and disinfectant, when it was used in high concentrations, it caused damage to those tissues that it was intended to protect. And in 1880, another product of the coal industry, creosol, replaced phenol in surgery. At that time, brown oil, also known as creosote, was produced in large quantities, which was originally simply burned as a liquid fuel. (The name «creosote» was given to a substance that the German Karl Reichenbeck isolated from beech wood in 1832 and which he later used to preserve meat.) In 1865, German chemists learned how to isolate creosote from coal, and subsequently found a way to obtain creosol from creosote.

The phenol molecule consists of a benzene ring with a hydroxyl group (OH) attached to it. Creosol is the same phenol, but with the benzene ring of which, in addition to the hydroxyl group, a methyl radical is attached. The hydroxyl group and the methyl radical in the creosol molecule can be attached to adjacent carbon atoms, through one atom, or located on opposite sides of the benzene ring. When three forms of creosol became known in 1869, an alternative commercial name for the substance, tricreosol, emerged. All three forms have the same antimicrobial efficacy. Although creosols are highly toxic (a tablespoon of this substance can kill a person), they are still not as dangerous as phenol, one gram of which is a lethal dose for humans. Both phenol and creosol are effective bactericidal agents, they are added to soap, resulting in varieties such as «creosol», «medical» and «tar». These substances have also been used in the manufacture of bottle disinfectants.

Phenol and creosol are poorly soluble in water, but inventor John Jace (1817-1892) from Northampton, England discovered that creosol could be made soluble by heating and adding sodium hydroxide (caustic soda) and rosin. Jace’s liquid was patented in 1877 and has become a world famous household cleaner.

Jace’s liquid was the ideal disinfectant for use in hospitals, farms, sewage treatment plants, food processing plants and public restrooms. She not only cleaned and disinfected, but also left behind a long and quite acceptable smell. This remedy is still produced in Norfolk, and was actively used by English farmers in 2001 during an outbreak of foot-and-mouth disease. It still continues to be popular in agriculture.

There are two forms of phenol-based disinfectants today: a black liquid containing 8% phenols and a white liquid containing 35% phenols. The first remedy is suitable for home use and to a lesser extent for commercial use. When black liquid is added to water, a cloudy white emulsion is formed. An alternative product is obtained by mixing phenol and soap, while the water remains clear, and the commercial name for such a product is «lysol». This disinfectant was popular until the thirties of the last century, until it was replaced by hypochlorite.

Although phenol has lost its role as a popular disinfectant, more than five million tons of the substance are produced annually worldwide, most of which goes to the synthesis of polymers such as nylon and polycarbonate. A small proportion of phenol still gets into antimicrobial agents, but only in the form of chemically modified, more selective and less dangerous molecules. Modification is achieved by attaching chlorine atoms to the phenol ring, which significantly increase the potential of the disinfectant. In terms of chemistry, phenol is a very reactive molecule that reacts very quickly with chlorine water with the addition of three chlorine atoms to the benzene ring — two on the sides of the hydroxyl group and a third on the opposite side of the benzene ring. The resulting substance, trichlorophenol, is a powerful antibacterial and antifungal agent. But even one chlorine atom enhances the properties of some phenol derivatives, for example, benzylchlorophenol has powerful antimicrobial properties. Dichlorophenol, containing two chlorine atoms, was used as an antiseptic, but more often it was used to disinfect seeds.

When four chlorine atoms are attached, tetrachlorophenol is formed, which is a preservative for leather and wood. Phenol with five chlorine atoms is called pentachlorophenol («penta»), it is an excellent disinfectant and fungicidal agent, it was also widely used for wood treatment. However, many chlorinated products have been actively opposed by environmentalists, resulting in some being banned and others being restricted.

Hexachlorophene is still used today as an antibacterial agent added to soaps, handwashes, and lotions. It consists of two benzene rings linked together, each containing three chlorine atoms. It is now popular as an over-the-counter acne treatment sold under the commercial name pHixo-Hex. It had a wider use in the past, adding it to soaps, shampoos, deodorants, and mouthwashes until the 1970s, but experiments on laboratory animals have shown that it can adversely affect the nervous system.

It is theoretically possible to synthesize thousands of chlorine-containing derivatives of phenol by including chlorine and various combinations of other groups in its molecule. In the last century, many similar substances were synthesized, followed by testing of their antibacterial properties. However, only a few of them combined the properties necessary for commercial success, which include safety for humans, ease of preparation, solubility in water, compatibility with other components of household chemicals. However, two substances from this group emerged from the shadows and gained wide popularity, which they still have to this day. These substances:

Parachlor-metaxylenol and triclosan

Parachloromethoxylenol is probably better known by its commercial name Dettol and is available from Reckitt Denckiser. Its active substance is chlorophenol, the production of which began in 1923 in Germany, then it was called chlorxylenol. Today it is called parachloromethoxylenol (PCMA). As an antiseptic, PCMA is sixty times more potent than phenol and is sold as a 5% solution, which also includes ingredients such as pine oil (5%), castor oil (14%) and isopropanol (12%), which help the disinfectant to be in dissolved state.

In the late 1920s, PCMC, in the form of Dettol, was being clinically tested at the Queen Charlotte’s Hospital in London, where its use as a general antiseptic halved the incidence of puerperal fever. «Dettol» was used in a diluted form, which made it safe to use as an antiseptic for washing wounds and abrasions, the remedy proved to be extremely effective in combating bacteria and fungi. Dettol has been at the service of medicine for half a century, it has also been used in many other ways: added to swimming pools, in laundries it was used to disinfect fabrics, in hospitals it was used along with ethanol (alcohol) for urgent disinfection of medical instruments.

Even when diluted 400 times, Dettol is able to kill most of the bacteria in just five minutes. And at the recommended fortyfold dilution, Dettol provides a log kill of five (kills 99.999% of bacteria) within one minute, even if the pathogen is in dirt or blood. For mushrooms, it takes a little longer, but in two minutes the Dettol solution successfully deals with them. And with a tenfold dilution, even viruses are not able to withstand its destructive effect. The herpes virus in such a solution is eliminated within one minute, the AIDS virus is more resistant to its effects, a logarithm of destruction equal to three is achieved per minute (only 99.9% of the virus will die).

Triclosan is a commonly used safe antibacterial agent found in products such as soaps, antimicrobial ointments, and toothpaste. It is also used to decontaminate plastic, especially cutting boards and other kitchen utensils. The Swiss company Ciba Specialty Chemicals (now known as Novartis) is the main manufacturer of triclosan. The molecule of this substance consists of phenol bonded to the benzene ring, in this structure two chlorine atoms are on the benzene ring and two on the phenol ring.

It is most likely that triclosan affects the bacterial cell in several ways at once. However, in 1998, a research team at Tufte University School of Medicine in Boston discovered that the mechanism of action of this substance is mainly due to the blockade of the enzyme enoyl acyl protein reductase (another name for FabI), which is necessary for bacteria to synthesize fatty acids. Theoretically, this means that bacteria can become resistant to triclosan if they mutate to form an alternative fatty acid synthesis enzyme. And the bacterium Sreptococcus pneumoniae has such an enzyme; instead of FabI, this bacterium uses FabK for the synthesis of fatty acids, which, apparently, is more resistant to triclosan. There are fears that triclosan-resistant bacteria may also appear by this mechanism.

Reassuringly, no evidence of triclosan-resistant bacteria has been identified to date. And in fifty years of widespread use of triclosan, no enzymes have been found that could save bacteria.

Source: based on the book by John Emsley «On the benefits and harms of the products we love to buy»

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