Bitter is the coffee

Many of us don’t go through the day without having at least one cup of coffee, and some hardcore enthusiasts I’ve met spend the whole day drinking coffee instead of water, only to finish strong with a 9pm espresso. No later so it won’t affect their sleep.

Our dependence on coffee is partially due to the functional addiction caffeine induces: once it leaves the body, we feel more tired than before, and we crave more. We believe we can’t function without it and see it as our means of coping with constant demands for performance.

To a large extent, however, we drink coffee because we have a lifestyle dependence on it. It fills many gaps in our often boring days and we like it for its taste and flavour, and for its bitterness. This latter liking is acquired, and many drown out the bitter taste with sugar and dairy products. But if you’re a true fan of coffee, you probably want the bitterness and appreciate the additives for the new experience they create.

I was intrigued when I found that in 2016 a US company called Senomyx claimed in patent number US 9.247,759 B2 a way to reduce consistently the perceived bitterness of coffee. The food and pharmaceutical industries have been masking out bitter tastes for a long time. The additives used are trivial – sugar, salt – or already widely used and derived from natural sources: gluconate, carboxymethylcellulose or beta-cyclodextrin. But early in the 2000s companies started looking at ways to block the taste, rather than just mask it. Some potential uses appeared sensible, for example to make very bitter drugs more palatable to patients.

Tasting bitter

We can taste many different compounds as bitter, but can’t tell them apart based on taste, i.e. we can’t discern different kinds of bitter. The intensity of the sensation determines how we react: coffee and tonic water earn our liking, but intensely bitter substances, such as denatonium benzoate, make us so strongly averse that they are used as deterrents to prevent accidental poisoning. Little was known about the molecular basis of our tasting bitter before a team of scientists (Elliot Adler, Mark Hoon, Ken Mueller, Jayaram Chandrashekar, Nicholas Ryba, Charles Szuker, Luxin Feng and Wei Guo) reported in the year 2000 the discovery of a type of taste receptor called T2R (Taste receptor type 2, also abbreviated as TAS2R) responsible for bitter taste detection in mammals.

The biology

Taste receptor cells are found on taste buds covering the surface of the tongue, and in other areas of the mouth. You can see an illustration of a taste bud here. Receptor cells contain structures which allow for interaction with a tastant (a chemical entity eliciting the sensation of taste). Sour and salty are detected by channels in the cell membrane, but sweet, bitter and umami are detected by TRs (type 1 deals with sweet and umami). Adler et al. showed that taste cells contain T2Rs and proved they function as bitter taste receptors. Some only responded to a single compound, like mT2R5 (m for mouse strain) which reacted to cycloheximide, while others were not so selective. Using cell experiments the researchers explained why mice with mutations in T2R5 were about 8 times less sensitive to the repulsive cycloheximide.

Adler’s team showed how a bitter compound can be detected by one or more receptors, and that by blocking those receptors it should be possible to reduce the sensation of bitterness experienced. They also predicted from genome analysis the existence of 40 to 80 different T2Rs in humans.

The chemistry

A study published in 2010 (by Wolfgang Meyerhof, Claudia Batram, Christina Kuhn, Anne Brockhoff, Elke Chudoba, Bernd Bufe, Giovanni Appendino and Maik Behrens) investigated the detection range of human T2Rs (25 known at the time) against a selection of 104 compounds from natural and synthetic sources. A complex picture emerged with most T2Rs detecting multiple compounds – hT2R14 (h for human) was the least selective in this study and responded to 33 compounds – and more than half of the compounds activating up to 3 receptors, with one (diphenidol) found to activate 15 different hT2Rs. This complex detection pattern probably emerged from the evolutionary process which shaped it into a sophisticated means of preventing poisoning. For example, the studies of Meyerhof et al. showed how hT2R46 detected the toxic compound strychnine and the very similar, but about 100-200 times less toxic, brucine. The sensitivity for strychnine over brucine was just about as high as the toxicity factor and orders of magnitude higher than required to detect the poison in food.

It is no surprise that with so many receptors responding to so many different compounds, we end up finding bitter things that are not toxic to us today. Caffeine itself is bitter, but not dangerous in the amount we usually ingest.

Senomyx reported that compound C (below) can be used in taste tests to reduce consistently the perceived bitterness of a coffee fraction (i.e. instant coffee, medium roast or medium-dark roast) to which it had been added. The receptors targeted were hT2R8 and hT2R14, found to respond to bitter compounds in coffee. Compound C was also found to block to different extents the response of 19 other T2Rs, indicating it could be used broadly to reduce the bitterness of products.

Reported synthesis of compound C by Senomyx.

The chemistry for making compound C is nothing to write home about. It’s a simple three step procedure. The sulfonyl chloride starting material is reacted with 4-methoxybenzyl amine to form a sulfonamide, which is then N-alkylated with benzyl bromide under basic conditions. This results in the carboxylic acid being benzylated as well, so the final step involves a base hydrolysis of the benzyl ester to give compound C.

Bitter is the coffee

Animals have developed complicated systems to detect bitter chemicals as a means to avoid poisoning. Although we are now far less reliant on these defense systems, should we try to block them out? I agree there is value in applying this strategy to medical products, especially if intended for children who are more sensitive to bitter taste than adults. But what about foods and drinks?

What got me thinking was the structure of compound C and others Senomyx exemplified. They look to me more like drug molecules than food additives. The compounds chosen would have to be approved by regulatory agencies, so I don’t think there is any real danger there, as far as the science is concerned.

My question regards the principle. Cheating your own senses to avoid disagreeable sensations covers a range from necessity to indulgence. Taking painkillers is a valid improvement to our quality of life made possible by modern science. It is necessary if we are to function normally. Numbing our tongues to eliminate disagreeable taste from a drink we consume for enjoyment is luxury.

Where do we draw the line between necessity and luxury? Is it wrong to make use of any opportunity to increase our satisfaction and make life as enjoyable as possible? No, if it doesn’t contravene legal and moral principles. Is there value in denying ourselves this then? I think the value is in pushing ourselves to pursue more elevated means of satisfaction. Rather than spend time and energy fixing every nuissance, we could be thinking of better ways to find joy in our lives. Or how to acquire a liking for the bitter things.

Turning red into gold

Quinacridone gold, also known as PO49, Pigment Orange 49, was a golden pigment used in the automotive and artist’s paint industries until 2001, when production reportedly stopped. The pigment had gathered somewhat of a following within the artists’ community. Artists such as Jane Blundell explored alternatives on the market, and others like Sandrine Maugy bemoaned the last supply of pigment having been used to mix lesser colours.

Quinacridone gold appears to have been special even by the standards of the quinacridone family of pigments, which Bruce MacEvoy at handprint described as follows: “Among the miracles of modern industrial chemistry […] one must include the discovery and development of the quinacridones.”

Quinacridone gold PO49 is described at The Color of Art Pigment Database as “a mixed crystal phase of Quinacridone & Quinacridonequinone; C.I.Pigment Violet 19 (C.I. 73900) and C.I.Pigment Red 206 (C.I. 73920) co-precipitated. The exact derivative has not been disclosed.” Bruce MacEvoy at handprint claims “PO49 is another mixed crystal form of PV19 alpha and beta.”

Not surprising that the formula was proprietary, but still, what is it? And what is PV19?

The discovery

PV19 stands for Pigment Violet 19 and is one of the forms of the original quinacridone, patented in parallel as alpha (bluish red), beta (violet) and gamma (bluish red) forms by DuPont in the 1950s.

Chemical structure of linear quinacridone

Let’s look at our glossary of terms before discussing further.

Polymorphism describes the existence of a solid compound (containing more than one type of atom) in different crystalline forms differing in the way molecules are arranged in the solid. Polymorphs have different properties, which is why controlling their formation is crucial in pigment manufacture. Polymorphs are often referred to as crystal phases.

Crystal phase refers to a form of a solid in which the comprising atoms or molecules are arranged in an orderly fashion throughout. The crystal is said to have long range order, i.e. it is possible to predict with a high certainty what atom will be found at a specified position.

Powder X-Ray diffraction pattern is a graphical representation of the crystal phase features still distinguishable in the powder, i.e. after the crystal has been ground up, or if only a collection of minute crystals is available. X-rays are diffracted through a crystal like visible light is diffracted through a prism. The X-ray diffraction experiment records where the light ends up and how intense it is.

Solid solution describes a homogeneous mixture with structure and properties different to those obtained by simply mixing the components in the same ratio. It shows an X-ray diffraction pattern different to the sum of the patterns of its components.

First (amusing) bit of information is the mention how better red pigments were needed in the 1950s due to it having recently become a popular colour for cars.

The alpha, beta and gamma crystal phases of quinacridone and the method for controlling their formation represents the scope of the three DuPont patents, together with the characteristic X-ray diffraction patterns each phase exhibits.

The crude quinacridone formed by oxidation of dihydroquinacridone (more on this later) is subjected to a milling process under defined conditions which generates a material fine enough to use as pigment, and with control over the crystal phase. The process looks deceptively simple: quinacridone is mixed with salt, mill balls or cylpebs (little cylinders) and nails (the latter to prevent caking), and the mixture rotated until the pigment particles are fine enough. The material is then washed with dilute sulfuric acid to remove the salt and any metal contamination introduced by the milling process. The quinacridone can then be used as a paste, or washed with methanol (to remove water) and xylene (to remove methanol) before drying to obtain the powder.

The chemistry

The control over phase formation is achieved using solvents. Milling without DMF (dimethylformamide) or xylene converts quinacridone to the alpha form. Adding 25% xylene with respect to quinacridone during milling results in the beta phase forming. Adding DMF during milling or stirring quinacridone in DMF either prevents the gamma phase from turning to alpha, or turns other phases to gamma. Long story short, the gamma phase is the most stable and will form (predominantly) when sparingly soluble quinacridone crystallises from solution.

Such crystallisation also occurs in the high temperature oxidation of dihydroquinacridone with nitrobenzene-m-sodium sulfonate under alkaline conditions in a water/alcohol mixture. DuPont patented their way of making dihydroquinacridone.

DuPont synthesis of dihydroquinacridone in Dowtherm A

The condensation of diethyl succinate was performed in Dowtherm A (23.5% biphenyl and 76.5% diphenylether) and after a quick water wash, the resulting diethyl succinyl succinate (name which I find terribly confusing) solution was treated with aniline and catalytic anyline hydrochloride and heated under vacuum (no further detail here). Another quick wash to get rid of the catalyst, a distillation to remove aniline and the resulting substituted dihydroterephthalate can be used as a suspension in Dowtherm. The discovery here is the closing of the quinacridone ring system by heating the dihydroterephthlate at a high temperature (which is why Dowtherm is used) in the absence of oxygen to give dihydroquinacridone. The last step is an oxidation to remove the extra two hydrogen atoms, which is preferably achieved using the soluble oxidant meta-nitrobenzenesodium sulfonate. The great thing about the (dihydro)quinacridones is they are so insoluble, and isolation by filtration provides pure products.

The background and chemistry covered, let’s return to the question of PO49.

Turning red into gold

A number of other developments made by DuPont over the following decade resulted in what is most likely PO49. This patent from 1964 describes a number of inventions which allowed for extending the range of colours quinacridone pigments can attain. First of them is the incorporation of a derivative of quinacridone called quinacridonequinone, which can be formed by extending the reaction time in the oxidation of dihydroquinacridone described above. This sounds like a cost effective solution – tweaking a known process rather than having to develop a whole new one.

Quinacridonequinone

A mixture of quinacridone and quinacridonequinone can be processed to form an intimate mixture either by milling or by co-precipitation from concentrated sulfuric acid in water (known as drowning). This mixture, on solvent treatment (DMF) converts to a solid solution. Solid solutions, having properties different to that of a simple mixture, can have a colour different to that of their components. A solid solution containing quinacridone and quinacridonequinone is reported to have a maroon colour, quite different to the reds that quinacridone alone can generate. By varying amounts of components and their nature (various other quinacridones) a whole range of colours shifting towards yellow or blue was reported. But no gold.

Finally, a technical improvement on the precipitation step from sulfuric acid afforded “a bright gold pigment.” This invention adds the sulfuric acid solution to a high velocity flow of water to form very fine particles, which is believed to favour solid solution formation. The resulting slurry is then heated to convert the solid mixture into the solid solution. There is no need for any solvent treatments, which makes the process even more attractive.

I would say the story of PO49 going out of production sounds plausible. For whatever reason, the automotive industry didn’t want PO49 anymore. No demand – I would imagine the amount of pigment used by industry is far greater than what artists go through – means no supply, even if to the outsider chemist the gold pigment does not stand out as anymore of a challenge than red. Quinacridones are still being produced, and since PO49 does not appear to have any special challenges associated, its demise really might be due to gold falling out of favour while red is still going strong. Perhaps PO49 was superseded; chemists are always mixing something up.

Squeezing a Mannich reaction in Haloperidol synthesis

I recently learned about the life of Dr Paul Adriaan Jan Janssen, the Belgian physician who founded Janssen Pharmaceutical Companies and contributed, directly or otherwise, to the development of 80 medications, 18 of which are on the WHO List of Essential Medicines.

I want to discuss one of his company’s early breakthrough discoveries: Haloperidol. The drug is used for its antipsychotic properties, and is prescribed for treating various conditions.

Haloperidol

Bernard Granger and Simona Albu discuss the story of the discovery in this article: The Story of Haloperidol, Ann. Clin. Psychiatry 2005; 17(3): 137-40. The compound is reported to have been synthesised in February 1958 during an intense screening campaign, not unlike those used in today’s medicinal chemistry.

One of the investigators’ early compounds R 951 is presented as follows: “. . . a Mannich base of meperidine would be much more active. The synthesis of such a product is achieved very easily by using meperidine, acetophenone and formalin, and takes 30 minutes. The Mannich base of meperidine, known as propiophenone, was synthesized under the code name R 951”

R 951 does certainly look like it could have been made by the Mannich reaction, but not from meperidine which is N-methylated. R 951 is a substituted propiophenone, but not propiophenone proper.

Top left: meperidine. Top right: propiophenone. Bottom: R 951.

The article does not indicate how haloperidol R 1625 might have been made. I went in search of the original procedure.

Paul Janssen reported the discovery in the Journal of Medicinal and Pharmaceutical Chemistry, but unfortunately I don’t have access to this article. I found the synthesis in this patent granted by the United States Patent Office.

It turns out to be a nice bit of chemistry many chemists have probably seen, most likely on an exam question, yet never knew where it originated. A Friedel-Crafts acylation of fluorobenzene generates intermediate A, which is used to alkylate the piperidine B to form Haloperidol. Three days at 120 °C, a real struggle with that chloride.

Two-step synthesis of Haloperidol

One thing caught my attention: of the two reported ways to make amine B one does involve conditions similar to a Mannich reaction: formaldehyde solution and ammonium chloride.

Synthesis of piperidine B

A mixture of reagents is prepared at 60 °C, and then the substituted methylstyrene is added. The exothermic reaction is allowed to proceed with cooling until temperature drops to 40 °C. I assume the reaction will be mostly done at this point and methanol is added to prevent the remaining partially alkylated ammonium salt from precipitating. The reaction is allowed to proceed overnight before methanol is removed. I assume this is mostly to prevent uncontrollable boiling in the next step, but perhaps also to prevent addition into the double bond. Speaking of the next step, this involves an intramolecular SN2 displacement of the ammonium leaving group, at 100 °C in concentrated HCl, to close the piperidine-to-be ring. Yes, not mild conditions. HBr gas is passed for 7 h through a solution of the alkene intermediate in acetic acid to form the corresponding bromide, which is easily hydrolysed with sodium hydroxide. It’s not obvious to me why this sequence from alkene to alcohol wasn’t performed as an acid-catalysed hydration. It must have given inferior results.

No yields are reported. I have a feeling that alkylation to form Haloperidol was terrible. The quality of the work is great, however, with purification either by distillation or crystallisation performed for every intermediate.

Chemistry lesson over, I think Granger and Albu’s little mishap discussing chemical structure is not a big deal. They have my appreciation for the effort. Collaboration between disciplines is in high demand today and researchers, motivated by pressure or curiosity, are venturing more often outside the boundaries of their training. Their slips of the tongue should be forgiven but not ignored. This is all the more important when the target audience does not have expertise on the matter. Passing information along in the style of an ‘oral tradition’ can result in some truly flawed statements forming. If you find it easy to roll something off the tongue, maybe take a closer look to see if it’s correct.

How Louis Pasteur discovered racemisation and resolution

You can familiarise yourselves with these terms using the following glossary for non-specialists:

Handedness (or chirality) is the same property describing molecules as describing hands: left and right. You can’t put a left glove on your right hand.

Racemisation is the process of converting a molecule of one handedness (left or right) to the opposite handedness, and it must involve some kind of breaking and putting back together. The result is a racemate, a mixture of equal amounts of molecules with left and right handedness.

Resolution is the process of separating molecules of one handedness from molecules of the other from a mixture of the two.

Stereochemistry is the branch of chemistry dealing with the 3D shape of molecules and their handedness.

Stereochemistry is even for today’s chemists a bit of a headache: organic chemists are familiar with the concepts of molecular chirality, but to a large extent unfamiliar with chirality on the macroscopic scale. Crystallisation scientists and crystallographers on the other hand are comfortable with the latter. It all began in 19th century France.

Ghislaine Vantomme and Jeanne Crassous recently published a good account on the intense activity in the field of stereochemistry that took place in that era. The report (free to read here) focuses on the work of Louis Pasteur in the area of molecular and crystal chirality, viewed from the perspective of the modern chemist.

But at the time it was all discussed in terms of crystalline properties and solution properties. No use of molecular structure. Pasteur uncovered racemisation and resolution 20 years before the tetrahedral structure of carbon was discovered. The story of his discovery is the kind of textbook novelty that gets me excited, but sadly few chemists remember.

I wanted to read Pasteur’s account for myself, so I went on a bit of a quest in search of the original publications. Fortunately, a list of them is available from the Pasteur foundation, together with links to the texts. The only problem is they are in French.

For this reason, I will only endeavour to discuss one of them: Transformation des acides tartriques en acide racémique – Découverte de l’acide tartrique inactif. Nouvelle méthode de séparation de l’acide racémique en acides tartriques droit et gauche C. R. T. 37 (1853) 162-166.

It is worth noting that Pasteur had been working in the area for 5 years, and his (or someone else’s) enthusiasm is obvious in this communication letter: L. Pasteur, dans une Lettre adressée à M. Biot, annonce qu’il est parvenu à transformer l’acide tartrique en acide racémique C. R. T. 36 (1853) 973, where the text is italicised.

Extract from Pasteur’s letter to M. Biot regarding his discovery.

So how does his article sound to the modern chemist? Let’s see. This is technical, so feel free to skip to number 8 on the list. If you’re a French-speaking chemist and disagree with my translation, please let me know in the comments. I’d like to know better!

  1. Chinconine tartrate (the L-(+) natural form) is gradually heated to convert to chinconicine (it looks to me like ring opening by hydride shift) tartrate. Prolonged heating at 170 °C results in the alkaloid decomposing (forming some tarry material called quinoidine), but more importantly results in some of the racemic tartrate being formed. Treating with calcium chloride in the workup allows for isolation of racemic calcium tartrate.
  2. The alkaloid salts are used as the free acid decomposes at such temperature. The transformation also works with a ‘tartrate ether’ which does not have another optically active component beside the tartrate.
  3. The racemic acid isolated has identical physical and chemical properties to an authentic sample, and furthermore can be separated into left and right tartaric acids (only later does he mention how he achieved this).
  4. It follows that the right tartaric acid was converted artificially into the left.
  5. The experiment was repeated with left tartaric acid to give racemic acid under the same conditions. The conclusion is immense: a collection of dissymetric molecules can be converted to their inverse solely under heating; and the racemic is a mixture of the two isomers.
  6. Another product was discovered in the tarry residue: inactive tartaric acid, what we now call meso. Pasteur extended the reaction time, and this time he kept the filtrate after removing the racemic calcium tartrate. After 24 h he had crystallised the inactive calcium tartrate.
  7. Pasteur concluded the meso was formed from the racemic, and like a good scientist, he heated the isolated racemic to prove he could form the meso without starting from optically active materials.
  8. The most exciting part: “le sel double de soude et d’ammoniaque. Les cristaux qui prennet naissance sont de deux sortes; je sépare manuellement ces cristaux d’après le caractère de leur forme hémiédrique : il n’y a rien là de général. Ce dédoublement s’offre ici comme un accident.”
    In my translation: “the double sodium and ammonium salt. The crystals prepared are of two kinds; I separated them manually using the form of their hemihedral shape: this is nothing but particular. This resolution opportunity is an accident.”
  9. And then in the summary he drops another bomb discovery: resolution by crystallisation of diastereomeric salts: he preferentially crystallised left tartrate of cinchonine from the racemate solution.

This was an immense discovery. Pasteur was aware of it, but he was even more aware of how lucky he had been to stumble on just the right compound to provide him with the experimental results to power his logic work.

The lack of experimental detail is shocking by modern standards. In spite of this, the science is solid and many of the same experiments are the foundation for chemical enquiry. Science was an honourable gentlemen’s enterprise, and there was nothing wrong with that. What I loved, however, was how reasoning and emotion (yes, look at all the exclamation marks in the original) were well at home in his scientific writing. Emotion, when existent in today’s scientific writing, is often weak and artificial, and reasoning restrained and implied. And you certainly don’t see many ‘I’s.

As a final note, Vantomme and Crassous reference the discovery of the meso form (entry 6 on my list) to 1858. I don’t have access to this material, but according to my understanding this discovery was reported in 1853.

You are free to do your own digging if you would like, but the important message is this: there is no better reference than the original report. Try and find it!

On and off topic – the disconnect between sodium ammonium tartrate and Gantt charts

Can I talk about chemistry? Can I be nerdy, veer off course and ramble?

Yes, I can. Unfortunately, it took me more than 15 years to learn this. In fact, I only had this revelation about 10 minutes before I started writing this post. The wonderful topic I was investigating was how could I make racemic sodium ammonium tartrate at home, crystallise it and separate the enantiomers the way Louis Pasteur did to make his way into history books in 1848. (Note: the series of reports made by Pasteur started in 1848 and culminated with this discovery in 1853. A list is available here)

My cause is not noble – I just wanted to make a Youtube video. But the flashback I had was of Proust eating his madeleine with jasmine tea proportions. Don’t worry, my prose is far more modest.

I was somewhat of a weirdo even in the chemistry enclave. My interests never lined up with those of others. Scientists, as you expect, tend to be pragmatic and think about the future, the next discovery. This is great, and necessary for their survival in today’s scientific environment. I, on the other hand, have always been inclined towards the past. I got excited about the stories of discovery usually reserved for textbooks and other materials made for the public.

If you’re not a scientist you might be thinking what is wrong with that? We learn from the past – that’s what history tells us. Scientists generally appreciate the teachings and will go searching the literature for information, but they don’t care that much about who did what and how they got there (not beyond the requirements of referencing anyway). And if the information is now common knowledge, any attempts to uncover the murky, distant past are scoffed at. This makes an onerous task a shameful one. Scientists don’t care much for the history of science.

Back to my experience; I remember working on my master’s project thesis. I had an intro that was a bit like a herpetologist touching on the likely anatomy of the biblical snake in the garden of Eden. Needless to say, it wasn’t well received by my supervisor. I had to cut out a lot of the work which made me so proud.

I was heartbroken and furious. That maybe some points were valid (the page count for example) is irrelevant. Always getting our work edited and aligned with the standards and interests of the majority is damaging. Yes, that is how we learn and improve. But in my case, that is how I completely lost direction.

I ended up being unhappy doing what I liked. I hated what I was doing because it was what someone else wanted. I always got told they wanted to help me. I eventually gave up on chemistry and tried doing something else.

I failed so far. I recently got sacked from a new job (not a chemistry one) after two weeks. But I am not bitter about it. I think it was actually the most honourable rejection I’ve ever received. There was objective evidence I couldn’t do it. I got given a chance for what I had to offer and for my dedication. This is opposite to what I had experienced in chemistry where what I had to offer and who I was never mattered. The only thing that mattered was whether I delivered exactly what was expected.

I am obviously being emotional and still bitter about my chemistry past. I can’t think of anything clever to say here to balance this statement. And the only problem is I feel I should. Here it comes (after hours of mulling). Part of being a scientist is seeing black and white at the same time. But no one cares about dull, grey complexities – Not even scientists.

And that’s a shame. I think part of the problem with modern science is that it’s focused on delivering scientific ‘products’ rather than knowledge. It’s focused on the future, on achievement. It’s creating solutions to predicted problems rather than current ones.

Problems are solved by experimentation, by study, by reflection. Solutions are always serendipitous. Asking scientists to plan their work and their discoveries is absolutely ridiculous. I remember I had to make a Gantt chart at the beginning of my PhD. I hadn’t even heard of one before – which is to say that the study experience doesn’t quite prepare you for this. What is worse, the work was planned around ideas that were already in place for my project. Ideas which were written before I had arrived.

How can you expect young scientists to develop the skill of coming up with ideas, if you waste all their time researching someone else’s ideas? Pasteur is famous for his statement: ‘In the field of observation chance favours only the prepared mind.’ I don’t think Gantt charts was what he had in mind.

Why is this relevant? Because scientists should care about what they are doing. If you kill their interest and their passion, you are losing your biggest asset: the scientist. I cared. I still want to care. It just bothers me seeing how few people care.

I probably can’t change that. I just hope I can find the strength and ability to convince other people how exciting science can be. To make them appreciate the story of sodium ammonium tartrate.

A Christmas card for organic chemists

Being the grinch that I am, I thought I might as well jump on the celebration boat following the obvious reasoning of ‘ I want to see the world burn’.

So, here is my take on the Christmas card/wishes business.

Having ’til not long ago worked as an organic chemist, I still find a connection to this world which provides me with plenty of inspiration. That is how this card came to be.

What about its meaning? I don’t want to risk it being misunderstood; I am sure it will be mostly ignored. But I have to try.

Here it is in the painful equivalent of explaining the joke.

  • If you’ve been naughty, did not follow proper protocol, and ended up with your beloved sample getting intimate with the Rotavap bath, then Santa has a great bottle of XquisitePhos ready for you
  • If you’ve been nice, followed proper protocol, and both optimised your eluent polarity and measured the Rf value for your sample, then Santa has a nice glassware brush waiting for you

You may be thinking ‘That makes no sense’. There are a couple of possible explanations: either I’ve mixed up my boxes or I planned this all along in a clever way; something that chemists call, use, and abuse: rational design.

Let’s assume it is the latter. I planned it this way. Why would the naughty chemist get the expensive present? Well, there is the old saying ‘Fortune favours the brave’, and as I have found for myself, playing by the rules gets you nowhere. Sometimes it goes wrong, but you have to take your chances if you want to get anything done.

There is one other clever interpretation of this metaphorical Christmas ‘wish-you-well’ item. There are a couple of things any organic chemist who’s been in the business for long enough cannot avoid: going on the Phos and having to clean glassware. Some, working on very well-funded projects, might have lab dishwashers (I actually don’t know what the proper name is for those). In that case I assume they would probably throw out the compromised glassware that can’t be cleaned this way. Maybe I was wrong.

It’s less likely that you can get away from the Phos. Which brings me to the label on the beloved expensive Christmas present:

XquisitePhos
ResplendentPlus grade
Purified by triple incantation
Immobilised onto unicorn tears

I am so proud of myself for coming up with this one that I won’t explain it. If you are a chemist and don’t get it, then I guess..you must be new? Good luck!

Happy holidays and may the Phos be with you!

The tightening restrictions on DMF use in the EEA from 2023

I have recently come across a woeful comment on the future ‘ban’ of one of the staple solvents in chemistry: N,N-dimethylformamide, usually referred to as DMF. I decided to take a look for myself into some of the legal proceedings of the European Union and this is what I found.

Background

First, a tiny bit of background; all the regulations under discussion only apply to EEA countries. In 2006, the Regulation (EC) No 1907/2006 concerning ‘Registration, Evaluation, Authorisation and
Restriction of Chemicals (REACH), establishing a European Chemicals Agency’ was passed by the European Parliament and the Council of the European Union. In the ‘Recitals’ section (as I’ve been told by someone knowledgeable it’s called, thank you!), entry 25 (page 10) indicates that it is the responsibility of manufacturers and importers of substances to assess the risks and hazards of those substances, and of those handling the substances to follow the prescribed ‘risk management measures’.

In 2018, the Italian Ministry of Health submitted a request (Annex V Proposal for a Restriction concerning DMF) to the European Chemicals Agency to amend the legislation concerning use of DMF, under the terms described in the Regulation (EC) No 1907/2006.

Scientific grounds

I think it would be interesting to cover the scientific method backing this request:

  • Setting DNEL (Derived No-Effect Level) values. Using reported toxicological studies and REACH guidelines, the maximum amount of DMF to which humans can be exposed on a long-term basis, either via inhalation or by dermal contact, is set. These levels indicate the maximum amount humans can be expected to tolerate without noticing adverse health effects.
  • Estimating the expected exposure for different scenarios: DMF manufacture, its use in petrochemical, polymers, and leather, fur, and textiles industry, formulation, fine chemicals synthesis, and finally, the only registered non-industrial, professional use, as a laboratory chemical using dedicated software. Exposure is only considered for occupational purposes as DMF is not found in consumer products and it is readily biodegradable (therefore no environmental exposure).
  • Risk characterisation ratios (RCRs) are calculated using the DNEL and predicted exposure values. RCRs provide a measure for the perceived risk: how much is a person likely to be exposed to, related to how much they should be exposed to. Values of RCR above 1 indicate a potential risk. From the analysed scenarios the following indicate an unaddressed risk to the operator: production of fine chemicals including pharmaceuticals (exposure via dermal contact, even with high protection level gloves), polymer and leather, fur, and textiles production (if processes are performed at elevated temperature, exposure mainly via dermal contact).
    Aside: for using DMF as laboratory chemical the following statement is made: ‘professional use of DMF as laboratory agent is not expected to bear a safety concern for workers’. The Annex to this document does however mention ‘users should ensure that a sufficient and effective gloves management system is in place’ (page 297).

For the practising organic chemist working in R&D, this tells us what we already know. DMF is toxic, but can be handled safely by a well-trained and responsible chemist in a laboratory with adequate control measures. The fairly low volatility of DMF at room temperature and the adequate ventilation and containment make the risk of respiratory exposure low. Dermal contact is more of a problem as disposable nitrile gloves are not resistant to DMF.

Restriction options

Going back to the legal part of the story, what measure did the Annex V Proposal suggest? Certainly not banning DMF. This procedure was well-researched and the involved bodies aware that DMF does in general not have adequate replacement available and ‘banning of the manufacturing and uses of DMF, which is the ultimate consequence of an authorisation process, is not an appropriate risk management option’ (page 26). The report clearly predicts that banning DMF would cause some business to either shut down or relocate. The other Risk Management Options (RMOs) include restriction or authorisation. The authorisation route was deemed unsuitable, as not only it would involve higher costs, but ‘based on the socio-economic [authorisation] route some (uncontrolled) risks may remain’ (page 47).

Conclusion

And this brings us to the current affairs. On 19th November 2021, the Commission Regulation (EU) 2021/2030 was issued, which comes into force on 12th December 2021, and states that from 12th December 2023, DMF can be manufactured, sold, and used only if the DNEL values for occupational exposure of 6 mg/m3 for exposure by inhalation and 1.1 mg/kg/day for dermal exposure (values increased from the original proposal of 3.2 and 0.79, respectively) are ensured by appropriate control measures.

DMF will not be banned in the EEA. The increased costs associated with implementing the additional safety controls might result, however, in the DMF Winchester price going up. So, for those of you who need to wash your MOFs, research at will!

Three Chemical Elements Not Getting the Recognition They Deserve in Organic Chemistry

A while back, I made the poster featured as the cover image to improve my vector graphics skills, to subdue feelings of shame acquired during my student years for never making a good enough poster, and to reminisce on my days as a synthetic organic chemist. After reviewing the periodic table and thinking of all the important uses for each element, I realised that some elements get a lot more use than predicted and a lot less credit for how important they are. Some organic chemists play the game of having a periodic table around and crossing off elements after having used them at least once. In the process, they don’t even bother with some of the common ones. Here is my top 3.

  1. Deuterium. Being an isotope of hydrogen, it technically doesn’t need referencing as an individual element. It is the same element, but due to hydrogen being tiny in the first place, deuterium gets a chance owing to its being significantly heavier. I had almost forgotten it off the list, before I remembered that in organic chemistry running an NMR is a must, and for that we needed deuterated solvents. I think the reason it doesn’t get the love it deserves is for being useful precisely as a ‘ghost’ element. With the exception of deuterium labelling studies, when people go searching for it, it gets blamed for being expensive, potentially hard to introduce where you want it, not occuring naturally in compounds due to its low abundance, and just not doing anything chemically its little (or big?) brother hydrogen cannot. A chemistry degree will teach you this is not quite true. But I have to make its case, just so that those lab chemists give it a spot next to the ‘firstborn’ sibling hydrogen.
  2. Manganese. Whether you’re into posh catalysis or not, give this one some love. You probably rely on it almost exclusively for doing the dirty work of staining your TLCs. Cross it off. And think of it before going to bed. I am giving it second place, even though I am more of a PMA person.
  3. Argon. A noble gas, it gets used almost exclusively to fill up flasks when air or nitrogen won’t cut it. Lots of chemists depend on it, invoke the ‘magic’ properties of blanketing it has, but ignore it after all. The chemists who actually use it for chemistry..I don’t know. Such a rare breed, I can’t say anything about them. So make sure you give argon a thumbs up and a cross off the table.

Why Chemistry is a Weird Career Choice

If you have not studied chemistry past the secondary school/high school level, or if you have, but have been unfortunate enough to follow a bad curriculum with a bad teacher, chances are you probably misunderstand what modern chemistry is like. No need to feel bad; I myself don’t really know what physicist do nowadays. We all are a bit ignorant.

Why is chemistry a particularly troublesome science to explain briefly? That is because of its very broad nature. Before interdisciplinarity was a thing, chemistry was riding that wave, because it had no other choice. The stereotype involving the chemist mixing solutions using test tubes or having some green solution bubble around a statement glassware setup (just as entertainment venues use statement lighting, chemists occasionally use such setups, fail, and then avoid them like the plague) is rooted somewhat in the long distant past involving alchemists trying to turn lead into gold, but mostly in the early development of chemistry as a true science, starting about 250 years ago. Great chemists discovered the elements and their combinations, invented the statement glassware, because they had to, and step by step laid the foundation of our current understanding of the world, and life in particular, as a chemical problem. But in order to do so, chemistry had to bridge the gap between physics and its concern with the particular and biology and its concern with the general. Put it differently, physics gave us the atom, biology gave us evolution theory, and chemistry had to figure out how atoms make up living creatures.

And this historical metaphor sets the precept of chemistry as fundamentally empirical: trapped between seeing and imagining, the chemist just had to try it out. And that is what chemistry is all about. Trying it out. If this is what attracts you to chemistry in the first place, before you understand much of what is going on, then you are a chemist at heart.

Why is pursuing a chemistry career in modern times a weird choice then? It has to do with money. It always does. And I don’t mean average pay, but the cost of research. Research is expensive. And the body paying for research, unlikely to be an individual, will want to see what they are getting for their money. Which means, that unless your ‘trying it out’ is contributing towards solving a commercially relevant problem, it will probably be scrapped for a different approach. Pretty much everything is ‘commercially relevant’ in one way or another. No need for us to get disgusted at the idea that money makes the world work. Thank Science! that scientific research is on the expenditure list. Humanity needs it! But the drawback is that the resulting pressure can be uncomfortable for the curious chemist who wants to do the mixing for a living.

And that is why chemistry is weird: pursuing it professionally often involves dropping attachment to its core values. The commercial issue is easy to see in the industrial setting. It is somewhat more tricky in the academic setting. The research in most such institutions is funded using public money. Again, thank Science! for the governments spending money on improving the human condition. But how is the created value assessed? I believe the answer has to do with publication. In chemistry, most of the current publication is carried out through peer-reviewed journals, which belong to a publishing house. The publisher holds the rights to the content, and sells it to anyone who needs that scientific information. And although contradictory (public money funding scientific journal publishers?), and certainly not free of flaws, this model accounts for how the economy turns over and everyone gets what they want: the scientist has created new knowledge, had it approved by his peers, and disseminated it widely; the publisher has new content to sell; the government will receive tax money in return; and only finally, sadly, chemistry, science, and humanity benefit themselves from the expanding body of knowledge.

Sounds kind of great? Let’s not forget who had to sacrifice their job satisfaction for this to work? The poor ol’ chemist, who couldn’t just ‘try it out’, but had to carry out a laborious analysis beforehand to assess the potential gain to loss ratio. And they might not be the only ones losing out: serendipitous discoveries are made less often this way, and perhaps more important, fewer chemists will want to pursue that career.

How can I help fight that? I think everyone has the right to an informed decision, and that is why I tried to create a balanced picture in this article. It is certainly not sufficient for anyone to make a decision. But I would encourage you to start thinking of all these things before you, if you happen to be in the position, find a scapegoat to vent your frustration.

And if you want to know more about what modern chemists use in the lab, it is a mixture of very simple (look up the round-bottom flask) and very complicated (look up NMR spectroscopy). We still use test tubes sometimes, we just don’t like washing them.

Am I going to keep writing? – Brown sauce, anyone?

The particulars concern myself. The argument might have some use to you.

In the past couple of months since leaving my chemist job, I have embarked on a series of overly ambitious, and probably destined to fail projects. Inspired by some big Youtuber chemists, I decided to start my own channel. I found so far that people do not want me to teach them chemistry, and only marginally better would they rather watch me try to improvise lab equipment. With the current growth rate, I will be eligible for monetisation only after my projected lifespan ends.

I have spent a lot of time making art, and also tried selling it. Initial disappointment aside, I can’t say I am surprised. I have seen much better art not selling. I want to keep developing my artistic side, but I think it is best to scrap the idea of making a living this way.

What I present as a backup plan, and ‘excuse’ for my ridiculous self-employment plans (I need one of course, people judge you more or less openly), is the idea that if it all fails, at least I have learnt new skills, improved my CV, and taken some much needed career reorientation time.

As of this week, I started a blog. I have previously dabbled with the idea of creative writing, and even started a Youtube channel around it. I would like to believe the idea might not have been fundamentally flawed. This is no longer online. Until now, I was a fan of the ‘scrubbing your mistakes and failures out’ approach. People call this ‘improvement’. Now, I take immature pride in leaving them there whenever I can.

The problem with all these attempts, beside having spread myself out too thinly, is that the amount of time required to succeed far exceeds the amount of time it takes me to get bored. And this brings me to question whether I will be able to stick with writing, even if only for a hobby?

Boredom does not make me give up. I have sure wasted a lot of my life working on things I had long given up caring about. In order to increase the rate of progress, as opposed to just making progress, I need to be motivated.

Chemistry offered me early on, from my school days, things I wanted and needed: occupation, the chance to be good at something, approval and appreciation, and positive (as judged by others) career prospects. Writing, literature, philosophy, and art offered me none of these things. They had a rigid school system, family, and society thwarting the efforts of even their able proponents. As for their incapable proponents..

All this made me early on decide to cover my eyes, shut my ears, and put a heavy pair of boots on to dig a channel to navigate my life. I occasionally remember moments when people tried to tell me that I don’t need a channel; the terrains are not so bad and there are other ways to sail than by boat. I also committed another error: covering my mouth. Mi-zaru, kika-zaru, iwa-zaru. I still like chemistry. I just don’t think working it as a job is sustainable for me.

Having studied science, the prospect of academic writing seemed sensible. Experience has turned this into a less than ideal option on my list. My skills were not good. But writing about something I didn’t find exciting and being criticised for my writing when I needed help with content are things that put me off so far. The problem with having something corrected without being given a chance to understand what it was you did wrong, is that it leaves you with the feeling that ‘this’ had to be written a certain way. The way they wanted it.

Unfortunately, I feel creative writing does not work for me either. I make connections, I play with words, but I don’t seem to have the ability or the desire to create worlds. I tried. I picture ideas, plots, the meaning behind a story. But I struggle to paint the picture in words. Maybe that’s what painting is for; ‘a picture is worth a thousand words’. Maybe I will try again.

What I seem to be enjoying is this kind of writing: a mix between analysis, reporting, and some literary ‘condiments’ (brown sauce, anyone?). That is probably what has long held me back: the lack of ‘structure’ that people crave.

Am I going to keep writing? Yes, as long as I keep getting ideas and feel like the words come out easily.