Thank you Sir Chesebrough

I have a lot of favourite chemicals, including caffeine and paracetamol. Lately, though, my favourite chemical has become soft paraffin. Soft paraffin (petroleum jelly or petrolatum) is a non-polar, hydrophobic hydrocarbon mixture. It is not one chemical structure but a mixture of hydrocarbon chains (around 25 carbons in length) with a melting point similar to that of the human body’s temperature.

Pentacosane

n-Pentacosane

I suffer from excruciatingly itchy legs, mostly in the winter months. It keeps me (and my poor other half) awake at night. I can even draw blood without realising. Various creams keep my itching at bay but what most of these creams/lotions/balms have in common is that they contain soft paraffin. This works by forming a layer that prevents loss of moisture from my skin and also protects my skin from harsh conditions.

This stuff saves me from having sleepless nights and scarred legs, so thank you Sir Chesebrough for devising the process of extracting these chemicals from oil (U.S. Patent 127,568) and believing wholeheartedly in your product.

Are there any chemists you wish to thank for an amazing or useful discovery? If so, who and why?

Advertisements

Taking Medicines

Is it just me, or do all chemists guess the structure of a medicine before they take it? After having a guess, I then Google it and look up the synthesis, where possible.

I am currently using Ketoconazole for a skin condition (over-share, sorry). Immediately I knew there was a ketone (keto) and a nitrogen containing heterocycle (azole = five-membered nitrogen ring containing at least one other heteroatom) in there.  Conazoles are a common type of fungicide containing an imidazole or triazole ring so that narrowed it down further for me. I could not predict any thing more so looked up the structure (DOI: 10.1021/jm00194a023). It is actually a lot more complex than I expected.

ChemDraw2

Ketoconazole

Similarly, a few years ago I took Metronidazole and, as usual, I tried to predict the structure from the name. I guessed there was a nitrogen heterocycle, probably an imidazole ring and possibly nitro group. I wasn’t far off this time! When looking up the structure, I was very surprised by the simplicity of the structure and the synthesis (DOI:10.1007/BF00764821).

photo (2)

Metronidazole

So, is it just me? Or do you all try and predict aspects of a drug molecule before you take it? Have you ever guessed close to the true structure? If so, share in the comments section below.

Chemistry makes me cry

A recent discussion on Twitter about lachrymators (from lacrima meaning tear in Latin) has got me to wondering about chemicals that we use in the lab and the effect they can have on our “emotional” state.  Clearly, lachrymators don’t change our emotional state but when they are released they do make us look like immensely sad.

The most common culprit in our undergraduate labs is benzyl bromide. On contact with the eye, the chemical stimulates sensory neurons creating a stinging, painful sensation which causes tears to be released from the tear glands to dilute and flush out the irritant. When this gets released in a lab, everyone knows about it, especially when there are dozens of undergraduates using it.

Benzyl bromide

More commonly found lachrymators are onions, which release syn-propanethial S-oxide on slicing. The release is due to the breaking open of the onion cells and their releasing enzymes called alliinases, which then break down amino acid sulfoxides, generating sulfenic acids. A specific sulfenic acid, 1-propenesulfenic acid, is rapidly rearranged by a second enzyme, called the lachrymatory factor synthase (LFS), giving syn-propanethial S-oxide.  

Syn-propanethial S-oxide

1-propenesulfenic acid

Lachrymators were commonly used in World War I as “tear gas”.  Extremely low concentrations of lachrymators caused an intense irritant action on the eyes. This caused tears and pain which then resulted in reduced vision which meant that the soldier became impaired. Benzyl bromide, bromoacetone, dibrommethylethylketone (which could prove fatal), ethyl iodoacetate and xylyl bromide were the common culprits.

There are also many other lachrymators that are used today for crowd control purposes. In the past, phenacyl chloride was used but this has mostly been replaced by 2-chlorobenzalmalononitrile (CS gas), dibenzoxazepine (CR gas) and pepper spray (OC gas) due to the toxicity of phenacyl chloride. Pepper spray contains capsaicin which is a capsaicinoid which is produced as a secondary metabolite by chili peppers. It is why you may ‘cry’ when you are chopping up chillies…you may notice it more acutely when you accidentally rub your eyes after cooking with chillis.

I have explained that chemicals can make us ‘cry’ (probably not as much as our PhDs did) but chemicals can also have the opposite effect and make us giddy with laughter. I have never experienced this but I am told it is quite pleasant!

Nitrous oxide, or laughing gas, was discovered in 1799 by British chemist Humphry Davy, is an example of a chemical that makes us feel happy. Inhalation of nitrous oxide for recreational use, with the purpose of causing euphoria and possibly slight hallucinations, began in 1799 and was commonly used by the upper class at ‘laughing gas parties’. Nitrous oxide abuse has even been documented (Emergency Medicine Australasia (2010) 22, 88–90). It is also used as an analgesic, particularly in the dental profession although my dentist always chooses to use the unpleasant Lidocaine.

Nitrous oxide

Nitrous oxide quickly enters the bloodstream through the alveoli in the lungs and is distributed quickly through the whole body, including to synapses in the brain. Nitrous oxide is an uncompetitive NMDA channel blocker which blocks the ion channel by binding to a site within it. The NMDA receptor is a receptor which allows for the transfer of electrical signals between neurons in the brain and in the spinal column. For electrical signals to pass, the NMDA receptor must be open but when nitrous oxide is used, it is blocked.

Obviously, the laughing gas is causing a change in the chemistry of our brains, unlike lachrymators, which just make us look like we are upset but I just wanted to show that chemistry can make us cry, but it can also make us happy.**

Interesting reads:

J. Carson, Food Reviews International, 1987, 3, 71-103
Nitrous Oxide: No Laughing Matter – D. Wuebbles, Science, 2009, 326, 56-57

** I am not condoning the use of laughing gas to make you happy. Eat some chocolate instead.

I am the captain of Team Fluorine

So..I thought it about time I joined in with #ToxicCarnival since I spent 3.5 years of my life playing with oh so scary elemental fluorine for my PhD.

According to gospel Wikipedia “above a concentration of 25 ppm, fluorine causes significant irritation while attacking the eyes, respiratory tract, lungs, liver and kidneys. At a concentration of 100 ppm, human eyes and noses are seriously damaged”. The MSDS of fluorine also states that fluorine gas is corrosive to exposed tissues and to the upper and lower respiratory tracts.  Fluorine penetrates deeply into body tissues and will continue to exert toxic effects unless neutralized.  Workers should have 2.5% calcium gluconate gel on hand before work with fluorine begins. Fluorine also reacts violently and decomposes to hydrofluoric acid (which has previously been described as part of #ToxicCarnival) on contact with moisture.  Fluorine is the most powerful oxidiser known.  It reacts with virtually all inorganic and organic substances.  Fluorine ignites in contact with ammonia, ceramic materials, phosphorus, sulfur, copper wire, acetone and many other organic and inorganic compounds.

As you can tell, it is pretty darn unpleasant. Thankfully, the very pungent odour is detectable at concentrations as low as 20 ppb so you have time to escape, should you come across a fluorine leak.

A little history lesson… Fluorine was isolated successfully over a century ago by Moissan (Ann. Chim. Phys., 1891, 19, 272.) who gained a Nobel Prize in 1906 for his achievement. He produced fluorine by electrolysing a solution of potassium hydrogen difluoride in non-conducting liquid anhydrous HF. The electrolytic cell was constructed from platinum/iridium electrodes in a platinum holder and the apparatus was cooled to -50 °C. Today, fluorine is still manufactured using this electrochemical process.

The first large-scale production of fluorine was actually associated with the Manhattan Project during World War II, where uranium hexafluoride (UF6) was used to allow separation of the 235U and 238U isotopes. The radioactive uranium was used for the construction of the first atomic bombs in 1945 and uranium refining for nuclear energy is still one of the major uses for elemental fluorine.

So..so far you have learnt that fluorine is scary stuff and can be used to make atomic bombs. Now I am going to tell you why we should all love fluorine a little more.

Organo-fluorine compounds are almost non-existent as natural products but these days 20–25 % of pharmaceuticals contain at least one fluorine atom with these drugs treating a huge variety of diseases. One of the earliest synthetic fluorinated drugs was the anti-neoplastic agent 5-fluorouracil, an anti-metabolite first synthesised in 1957 (Nature, 1957, 179, 663-666). It shows high anticancer activity by inhibiting the enzyme thymidylate synthase, thereby preventing the cellular synthesis of thymidine. Since 5-fluorouracil, fluorine substitution is commonly used in med. chem. to improve metabolic stability, bioavailability and protein–ligand interactions amongst other things. An increasing number of related fluorinated anti-tumour agents have now becoming available as cancer treatments, including 5-fluoro-2’- deoxyuridine and its derivatives (Frontiers Biosci., 2004, 9, 2484-2494).

5-Fluorouracil is synthesised by bubbling fluorine through a solution  of uracil in a high di-electric constant solvent. If used correctly and safely fluorine can be a cheap and easy reagent, especially in large scale synthesis. EASY PEASY! Other fluorinating agents (mainly N-F) are seen to be an easier and safer alternative but these reagents can be expensive and wasteful. Using elemental fluorine is really all about knowing how to use it, for example it is best when the reaction is carried out at around -10C as a low concentration mixture in nitrogen. The key is to stop the competing radical reaction and promote the electrophilic process by polarising the F-F bond.

So what have we learnt?

1) fluorine is toxic and smells bad

2) fluorine can be used to make life-saving drugs (cheaply and easily if the infrastructure is in place)

3) I love fluorine a little too much.

If you want to know more about elemental fluorine in synthesis then check out publications by R. D. Chambers, G. Sandford and S. Rozen. All legends in their own right.

If you want to know more about fluorine, then just get in touch. I may or may not know the answer but I will probably be able to point you in the right direction.

Chemistry at the hairdresser

So, very recently I spent four (yes, really) hours sat in my hairdresser’s chair. After having read all the trash about what all those celebrities were up to and what ridonculous items of clothing I should be wearing in this so called British summer, I got to thinking about chemistry, more specifically, what transformations were actually happening to me and my hair, other than me slowly but surely looking like an alien from the planet Foil.

So what chemical processes have my ~100000 strands of hair gone through?

Hair is mainly keratin, the same protein found in skin and fingernails. The natural colour of hair depends on the ratio and quantities of two proteins: eumelanin and pheomelanin. Eumelanin gives us the brown/black hair shades (my natural colour) whereas phaeomelanin is responsible for the red based colours. Conversely, the absence of either type of melanin protein produces white/gray hair. 1

Hair dyeing by oxidation been practiced for well over 100 years and came from the observation that colourless p-phenylenediamine (shown below) produces a coloured compound when subjected to oxidation, and that this reaction could be used to colour a variety of substrates. The first patent relating to oxidation dyeing of human hair was applied for in 1883 by Monnet (F.P. 158,558).2 More scientifically put, permanent hair colouring involves the in-fibre formation of indo-dyes from colourless precursors by oxidation with hydrogen peroxide, under alkaline conditions. The primary intermediates are p-phenylenediamines (shown below) or p-aminophenols which are easily oxidised by hydrogen peroxide to form p-benzoquinone imines. 3

The use of hydrogen peroxide to develop the colour also allows for bleaching of the natural pigment by one or two shades at the same  time as the synthetic  colour is being formed.

The mechanism of oxidation dyes involves three steps:

  • The first step shows the oxidation of p-phenylenediamine (or similar stuctures, below) to the quinonediimine derivative

  • The second step involves the attack of this quinonediimine on the coupler (with chosen colour properties) by electrophilic aromatic substitution.
  • In the third and final step, the product from the quinonediimine-coupler reaction oxidises to the final hair dye.


Hair can also be dyed by bleaching of the hair’s natural pigments only. Bleaching is simply the removal of colour from hair. Bleaching can be caused by the sun’s ultra violet rays breaking bonds in the pigment molecules but hair bleaching is most commonly achieved by using hydrogen peroxide. Typically, a low volume of peroxide (5-30%) is applied to hair and left until the required amount of colour is stripped from the hair, at which point it is rinsed out. Before the bleach can change the colour of the hair, however, it must first penetrate below the surface of the hair’s cuticle. This is achieved by mixing the peroxide bleach with an alkaline solution, most commonly ammonia. The ammonia swells the hair fibres causing the cuticles to separate and open allowing the bleach to penetrate the cortex of the hair. This cuticle opening effect is also important when colour is being added to or implanted into the hair.

Hydrogen peroxide reacts with the melanin within the hair and in an irreversible reaction, the peroxide oxidises the melanin which renders it colourless. Complete bleaching tends to leave hair a pale yellow colour rather than pure white, however.

A really good review on hair dye in the modern world has been written by Christie and Morel. Well worth a read if you want to know more about dyes.

1            J. F. Corbett, Dyes Pigments, 1999, 41, 127-136.

2            J. F. Corbett, J. Soc. Dyers Colour., 1976, 285-303.

3            C. Incorporated and A. Seminar, J. Soc. Cosmet. Chem., 1984, 310, 297-310.

4            O. J. X. Morel and R. M. Christie, Chem. Rev., 2011, 111, 2537-2561.

5            http://www.chem.shef.ac.uk/chm131-2003/cha02js/dye.html