Letter to Chemistry World

Dear Reader,

I wrote a letter some time ago to Chemistry World to try to get them to change their ways. What they did was to publish an article about Fracking in gas wells, where they wrote about chemicals but they failed to name the chemicals.

I was shocked today when I discovered that they printed the letter.

Whose afraid of the big bad number ?

Dear Reader,

It has come to my attention that many people are getting nervous becuase of numbers with lots of Os in them. Some thing like 1000000 grams looks a lot more than 1 ton. But if you do the maths then you will soon find that 1000000 grams is equal to one metric ton.

Also some units are smaller than others, my advice is to be careful of units. For example the grain is a very small unit of mass (circa 50 mg) so if someone tells you that they have a object which has a mass of 4 grains than it is only about 0.2 grams.

Testilying and the environmental movement

Dear Reader,

Twenty years ago or so the late Dennis Evans told me a story about some cops who thought that they would tell a “white lie” to protect society (I have no idea where this vile story occurred or if Dennis had made it up or not). What happened was these boys in blue raided a drug dealer’s hotel room. They find some packets of cocaine. Then to make sure that the man went away for longer they plant some extra packets of cocaine. I imagine that they wanted to make sure that the judge sent the vile coke dealer away for decades rather than just sending him to HMP holidaycamp for a few years.

The core thesis of the prosecution was that the man was a cocaine dealer who was mixing cocaine with sugar to turn a larger profit and that all the packets had come from a common source. The fact that different packets had different sugar levels made it look like the dealer was mixing purer cocaine with sugar to make a less pure grade.

The police’s expert issued a report on on cocaine content of each packet where he/she lumped all the adulterants together. It is a common habit for people in the illegal drug trade to mix illegal drugs with other materials to increase their profit. So it should not be a total shock for the police to have observed some evidence of such behaviour.

Dennis was contracted as an expert witness for the defence, he retested the cocaine and made a point of measuring the different sugars (glucose, fructose, sucrose etc) in the cocaine batches. He found a purer packet which the police claimed was the parent of the less pure cocaine contained a sugar which did not appear in the less pure packets.

Armed with this information the defence was able to prove that the story that the police were telling was false. They showed that someone (the police) had planted at least one packet in the room. They then suggested to the jury that all the cocaine had been planted in the room. The man then was acquitted on all charges and walked away from the court, I imagine without a stain on his vile character.

While some people might think “I have nothing to do with drugs” and “I am not a policeman” so this story has nothing to do with me. I would say that these people are being very foolish, this is a cautionary tale about telling a “white lie” to get the job done. This is an example of testilying and the vile perils it brings.

It is better to tell the truth about something even if you think by exaggerating that you will be more likely to get the outcome that you want.

Before we go any further I would like to make something clear to those of you who are not regulars here on my blog, I have to agree with the greens, antinuclear lobby or whatever you want to call them or be called yourself (if you are a member of the antinuclear lobby) that the Chernobyl and Fukushima events are horrible. These are events which need to be avoided where possible, and if total avoidance is not possible then these types of events need to be mitigated to eliminate the threat to the general public.

My (or your) revulsion at serious nuclear accidents is not however a license to exaggerate or attempt to use these events to score cheap political points. Frankly those who use these events for selfish ends disgust me just as much as the 19^th century mill owners who thought it was quite reasonable to force young children to work in dangerous factories, clean chimneys or go down the coal mine.

My loathing of serious nuclear accidents is one of the reasons why I devote time and energy doing research on trying to prevent a nuclear accident causing harm to the general public. In order to protect ourselves against reactor accidents we need to understand them, part of the quest to understand them involves a quest for truth and an insight. During this quest I am doing my best to share whatever grains of truth I uncover with others, and also to point out silly ideas when I find them. One of the things which irks me is when people exaggerate the consequences of an event, the fact that an event is horrible is not a license to lie. To me the exaggeration of the event is as wrong as a person falsely claiming that it is less bad than it really is.

It has been claimed that the cesium from the Chernobyl accident causes heart disease in adults and children, the core of the idea is that cesium goes into the heart and that the radioactive cesium then damages the heart. Next the person falls down dead from heart disease or at least becomes in invalid.

We need to ask ourselves if the radioactive cesium is able to damage the heart, some time ago (2008) a Yann Gueguen et. al. published a paper (Cardiovascular Toxicology, 2008, 8(1), 33-40) in which they exposed rats to cesium in their drinking water. The amount of cesium was 150 Bq per day for three months. Now the rats weighed 560 grams, which means that they were drinking 267.85 Bq per kilo. Now if we scale this up to a 75 kilo man then he would have drinking 20 kBq per day. As each year has 365.25 days then this 75 kilo ratman will be drinking 7.338 MBq of cesium each year.

We are making the assumption that the cesium behaviour in rats and humans is the same and that the same dose / activity coefficient should be used for both species.

Based on my ALI as a classified radiation worker which is 1.5 MBq of cesium-137 (oral), the rat man will be drinking 4.9 times the ALI which is based on a 20 mSv dose. So the 75 kilo ratman will get a 97.84 mSv dose from the cesium. So this amount of cesium is a very large amount of cesium.

I hold the view that if a member of the general public is getting a 98 mSv dose from an nuclear accident which happened decades ago that something is deeply wrong. This is a dose which is far in excess of what I am allowed to be exposed to at work. So while this study might be an interesting one it is set at a level of cesium which I think is too high.

I suspect that some differences between rats and humans exist, I have checked and the biological half life of cesium in rats is shorter (11 days) than it is in humans (B. Le Gall et. al., Biochimie, 2006, 88(11), 1837-1841). So rats are able to get rid of cesium from their bodies faster than humans can. The estimates for the biological half life of cesium in humans range from about 1 month to 4 months. If we take the UN’s estimate that biological half life to be 100 days then we can compare rats and humans.

I have done some calculations for rats and humans and based on the difference in the biological half life I think that cesium should be 9.1 times less toxic to a rat than it is to a human. So we should revise down out doses for the “rat man”. If we take this correction factor then the rat man used in this experiment if it had been a human would have had a 10.78 mSv dose (0.8 MBq intake)

Now I think a key part of the reasoning behind “chernobyl heart” is the idea that the cesium goes into the heart, I was looking in the literature at animal studies where the experimental animals were fed cesium-137. I found a second paper (Jean-Marc Bertho et. al., Radiation and Environmental Biophysics, 2010, 49(2), 239-248) where mice were contaminated with cesium-137 (20 kBq per litre) in their drinking water.

This paper stated that human exposure to cesium-137 in contaminated areas is in the range 20 to 2100 Bq per day, which works out as giving a worst case amount of 767 kBq per year. While I think that this amount of cesium is a large amount in the general public’s diet it is well below my ALI (Annual Limit of Intake) and far below the level which I worked out by scaling the rat up to the 75 kilo “rat man”.

The mice were feed the cesium in their diet from the age of four weeks onwards, I looked at the intake of the these mice and the females drank 465 Bq per week and the males drank 507 Bq per week. As the female mice (at 20 weeks) had a weight mass of 23 grams and the male mice had a weight mass of 30 grams we can make a first guess of what human level of exposure we are considering.

The 75 kilo “mouseman” would be getting 1.27 MBq per week while a 65 kilo “mousewoman” would be getting 1.31 MBq of cesium per week. This will work out as 66 MBq per year for the mouseman and 68 MBq per year for the mousewoman. This is a lot of radioactivity.

We are assuming here that the biological half life of cesium in mice is the same as it is in humans and that all other cesium biochemistry and biophysics is the same in both species. Again if we work out the biological half life of cesium in mice it works out being shorter than it is in humans. Using the data from J.M. Llobet et. al., Journal of Environmental Contamination and Toxicology, 1998,61, 289-296 it appears that the biological half life in mice is about 7 days. Thus based on the different biological half-lives the cesium will be 14 times less harmful to mice than men.

So micemen will now be getting an intake of 4.7 MBq per year. This is still a lot of cesium-137 to get in your diet.

Now back to the paper of Bertho, the important thing in this paper is that no clear signs of damage to the mice were seen. Also if you read the paper the radioactive cesium content of the heart (in Bq per gram) is less than the kidneys and the normal muscles of the mice. This paper makes me think that we need to take great care when we consider the possible link between chernboyl cesium and heart disease. This is because the cesium does not seem to be localizing inside the heart in the same way as iodine localizes inside the thyroid.

The next thing to be careful of is the fact that cesium-137 (together with its daughter barium-137m) emits three different forms of radiation. The average beta decay energy of cesium-137 is 188 keV, this is quite a low average beta energy when compared with yttrium-90 (933 keV) and phosphorus-32 (695 keV) but it is about the same as Sr-90 (196 keV). But it is a bit higher than carbon-14 (49 keV). So we can safely assume that some of the beta energy of the cesium which is in the heart will be deposited in the heart.

But 662 keV of the decay energy of the cesium will be in the form of gamma rays, even if the cesium is in the heart then much of this energy will escape from the heart. On average 363 keV of energy will fly away in the form of neutrinos. These are particles which are unlikely to interact with a slab of lead as think as the earth. So I think we are safe to assume that only part of the decay energy of the cesium which is in the heart will be delivered to the heart tissue.

Also bear in mind that the beta and gamma radiation are both low LET (Linear Energy Transfer) radiations. This means that ionization tracks formed by these radiations are long and diffuse, as a result these radiations are less able to damage living tissues. The issue of self repair needs to be considered, the background of radioactivity in a normal human body together with cosmic rays causes all tissue to be subject to ionizing events. The damage from most of these are repaired by the cells.

I think it would be a good idea if those who are making statements supporting the idea that cesium-137 causes cardiac damage to people should address the issues of how much cesium is in the heart and how much of the radioactive decay energy of the cesium is delivered to the heart.

Also they should consider the natural radioactivity (carbon-14 and potassium-40) which is in a normal clean and uncontaminated human body.

Well that is all for now, I will return with more of my thoughts later.

Mike Adams

Dear Reader,

It has come to my attention that a Mike Adams has published a claim that the spent fuel ponds at Fukushima are a dire threat which is likely to exterminate mankind. He claims that the release of “radiation would turn North America into a “dead zone” for humans… mutated (and failed) crops, radioactive groundwater, skyrocketing infant mortality, an explosion in cancer and infertility”

Now before I go any further I will address some of these bold claims. I think that on many things Mike is very wrong.

1. A radiation release from the spent fuel pond is very different to a release of radioactivity. I sincerely wish people would learn the difference ! The best way to think of it for the layman is to consider my dog, he sometimes barks and you could imagine the waves of sound coming from his mouth to be like radiation. His bark travels through the air obeying an inverse square law and with some distance from him the bark soon becomes less irksome. The dog is the object which emits the barks, you should think of the dog as being like the radioactivity. The barks from my dog might escape from the house when I open a window but the thing which emits the bark can not escape with the same ease.
2. As cesium (the most mobile of the medium to long term irksome radioisotopes) sticks like glue to clay, almost all ground water and wells will remain radiologically safe to drink from no matter what happens.

So with these two important mistakes, omissions, distortions or whatever you want to call them lets take a look at the rest of his article using the our intellect !

Mike wrote that the cesium release will snuff out all life in mainland USA; I very much doubt that this would be possible.

He assumes that all the cesium will be released, and that 85 times as much ¹³⁷Cs is in the ponds as was released at Chernobyl. I want to use the Chernobyl cesium in Scotland as a model for his proposed doomsday event.

I looked up the average level of ¹³⁷Cs in soil in the UK, in Scotland the level of this radioisotope as a result of Chernobyl is 1580 give or take 310 Bq m^-2 on moorland while it is 2510 give or take 510 Bq m^-2.[1] This might seem like a lot of radioactivity, but for a beta/gamma isotope this is not much. If we take the standard data[2] on ¹³⁷Cs we will find that the dose rate one meter above the surface of ground which is uniformly contaminated with 1 Bq m^-2 is 1.6 pSv hr^-1. So the dose rate due to the Chernobyl cesium in Scotland is 4.016 nSv hr^-1. Which works out as 35 microSv per year. This is not much !

If we assume that the Chernobyl release had been 85 times larger, then the yearly dose would be now 3 mSv per year. This dose will not exterminate humans ! The chances of getting cancer as a result of living 60 years in such a place will be small. Only 1 in 111 people will get cancer as a result of this exposure even if we ignore the radioactive decay of the cesium. Sadly about 1 in 4 people die of cancer from other causes such as bad diet, smoking and simple bad luck. As a result I would not expect to see any noticeable change in the population.

So we have caught him in another error, not too good !

I would also like to point out that Mike has not fully explained the mechanism by which he proposes that the cesium will be released from the pond.

The great problem with his idea is that the heat production in the fuel in the pond has gone down greatly, the fuel will hardly be emitting any heat by now. This makes it much harder for the cesium to be released from the pond. I would be very interested to see how he proposes the pond will belch forth the cesium.

To give you some idea of what Mike is like here is what he thinks of the UN, he thinks it is “a criminal globalist organization engaged in widespread sex slave trafficking, child abuse and mass murder”. The last time I looked the UN appeared to be much more benign than that. I recall that recently part of the UN (the IAEA) got a noble peace prize (they spent the money part of the prize on cancer care for people in the third world).

Some years ago the United Nations High Commissioner for Refugees (UNHCR), United Nations International Children’s Emergency Fund (UNICEF) and United Nations Peace-Keeping Forces have all been given Noble Peace Prizes.

I thought that the people in Norway who issue Noble peace prizes are careful not to issue them to bloodthirsty cut-throats and brigands.

This scorching condemnation of the UN does suggest to me that there is either something terribly wrong with either my understanding or Mike’s understanding of the UN. I think I will leave it up to my reader to judge the UN.

Before I do go, I would like to point out something. Fukushima was (and is) a horrible accident, but the horrible nature of the accident is not a license to exaggerate or lie. I fear that members of the Green movement who exaggerate or lie will do the environment a great harm, what will happen is that they will discredit the genuine concerns of those who want to protect the environment.

---

[1] A.S. Likuku, D. Branford, D. Fowler and K.J. Weston, Journal of Environmental Radioactivity, 2006, 90(1), 37-47.

[2] http://www-pub.iaea.org/MTCD/publications/PDF/Pub815_web.pdf

The synthesis of taxifolin

Dear Reader,

Well back to the synthesis of taxifolin, the last time I blogged I showed how we could disconnect the taxifolin back to an epoxide. Now this time I will show you how we can make the epoxide.

As is common with α,β-unsaturated carbonyl compounds we can treat a chalcone with alkaline hydrogen peroxide to form our epoxide. This is a funny reaction where the hydrogen peroxide is deprotonated to form a nucleophilic anion. The anion then attacks the alkene part of the α,β-unsaturated carbonyl compound to form a carbon oxygen bond and an enolate. The enolate then turns around and forms the second carbon oxygen bond and then kicks out a hydroxide anion as the leaving group.

Formation of an epoxide from hydrogen peroxide and chalcone

The only problem with such chemistry is that alkaline water would react with the phenol groups which are all over the benzene rings. Our solution is to use a protecting group, the idea of a protecting group is to mask off the reactivity of part of a molecule while we get to work on another part of the molecule. It may be best to think of it as a molecular sized dustsheet which we use while painting our house to avoid getting paint on the floor and the furniture.

In this case the methoxymethyl group has been chosen as a protecting group, this is a smart choice. The group is stable against bases but it is taken off with ease by acids. In the step after the epoxide formation we need to use acid to deprotect the phenol groups and make one of them react with the epoxide to form a six membered ring. So we can combine the deprotection step with one of the steps which we need to do anyway to get the molecule made.

As with many things the mechanism helps us understand what is going on, my advice to you is when in doubt is to just experiment with curved arrows to see where they get you. We can protonate the oxygen next to the benzene ring.

Protonation of MOM ether

Then get the cation to spit out a molecule of formaldehyde and form an oxygen ylide (thing with a cation (+) on the heteroatom next to a anionic (-) centre) using the top magenta arrows.

Two fragmentation reactions for the protonated MOM ether

Frankly I think that this would be a very high energy product so we should keep looking for a lower energy, an easy alternative I see is to form a methyl(methylene)oxonium ion and a molecule of the phenol. The methyl(methylene)oxonium is a very stable carbocation where the positive charge is delocalised from the carbocation onto the near by oxygen. This is a good example of neighbouring group participation (NGP) which lowers the energy of the cation. This lowering of the cation’s energy makes it more easy to remove the protecting group.

Now after the MOM groups are gone we are free to use one of the phenols to attack the protonated epoxide to form the ring. Now some of you might ask why does the methanol solvent not attack the epoxide instead, my answer is that while the methanol might attack the protonated epoxide the intramolecular (within the molecule) reaction of the phenol group is faster as the nucelophile (phenol group) is held close to the epoxide (electrophile). Thus the reaction goes faster.

Some of you might also wonder what happens to the methyl(methylene)oxonium, I think that it will react with methanol to form dimethoxymethane.

I think that the smartest of you will either ask how do we get the chalcone or you will be thinking about aldol chemistry. I think that the name “aldol” is a very good name, while many chemists want to give a reaction a name (based on their surname) the aldol reaction is based on the products of the reaction. It is possible to react an aldehyde with another aldehyde in the aldol reaction to form an aldehyde alcohol. We have a choice we could use a MOM protected dihydroxybenzaldehyde (cheap) with a MOM protected 2,4,6-trihydroxyacetophenone (cheap) to form the chalcone in an aldol reaction or we could use wittig chemistry.

Here is the first step of the aldol reaction between acetopheone and benzaldehyde which forms the carbon carbon bond.

The first step of the aldol reaction synthesis of a chalcone

The next step is a dehydration reaction, this will be favoured by the fact that the new double bond will be conjugated to a benzene ring. The first step is a deprotonation which will form an enolate anion which will then eject a hydroxyl group. While a hydroxyl group is not a good leaving group it is better than nothing and it will work.

Second step in the formation of chalcone by an aldol reaction

If we were to obtain 2-bromo-1-(2,4,6-trihydroxyphenyl)ethanone and react this with triphenyl phosphine we could make a phosphonium salt (expensive). If treated with a suitable base this would make a phosphorus ylide which can be reacted with the MOM protected dihydroxybenzaldehyde to form the same chalcone. This would be a more expensive reaction, the product would also be mixed with lots of triphenyl phosphine oxide which would force us to do a more difficult separation to obtain the product than the separation required in the aldol synthesis of the chalcone.

While the wittig reaction does have the problem of the triphenyl phosphine oxide I found an easy solution when I was working in Aberdeen for John Plater. I used to run large scale wittig reactions as a means of making polypyridines with alkyl spacers between the pyridine rings. I then used hydrogenation to convert the alkenes into saturated alkyl spacers. For example I needed 3-(pyridin-4-yl)-acrylaldehyde as an intermediate in one synthesis. I recall the day that I started with half a bottle of aqeuous chloroacetaldehyde this was mixed with a large volume of chloroform and subject to fractional distillation using a very long fractionation column to remove the water from this mixture. After what seemed like all day distilling out water, I added an excess of of triphenyl phosphine and gave the mixture a boil.

After boiling the mixture for a while I cooled it and isolated the phosphonium salt. After the treatment with base I then had the phosphorus ylide. I then heated the 2-(triphenylphosphoranylidene)acetaldehyde with isonicotinaldehyde and I boiled in under nitrogen in benzene. After cooling I had a mixture of 3-(pyridin-4-yl)-acrylaldehyde, isonicotinaldehyde, triphenyl phosphine oxide, benzene and goodness knows what else. This was a horrid mixture but I had a very easy solution, I made a solution of hydrochloric acid in some water and then I shaked the horrid mixture with the hydrochloric acid. This extracted the pyridines into the aqueous layer while leaving the triphenyl phosphine oxide in the benzene layer. In one simple shaking I had separated the carcinogenic benzene and the irksome triphenyl phosphine oxide from the product. I then made the aqueous solution alkaline with sodium hydroxide and then I extracted the product into ethyl acetate. I was then able to evaporate down the ethyl acetate to give a mixture of 3-(pyridin-4-yl)-acrylaldehyde, isonicotinaldehyde and tar which I was able to vacuum distill to give me the product I wanted.

Sadly in many cases (including the synthesis of the MOM protected chalcone) it is not possible to use a acid/base separation of the triphenyl phosphine oxide from the product.

Binding to receptors, new drugs and where should drugs come from ?

Well a brother blogger (An alternative medicine doctor) and me have raised some interesting points between us.

In the 1980s and early 1990s the drug companies seemed to think that computational chemistry would be a magic bullet which would give us the next generation of drugs. Sadly it did not work out so well as the drug companies hoped, the thing about computational chemistry is that it is all too easy to favour an answer by your choice of starting instructions (initial coordinates of the atoms). Also the mere binding strength of a drug to a receptor does not give the whole story.

Sadly I have never seen any databases in the public domain for binding strengths of drugs to receptors, but in some papers the binding strengths are listed. I suspect that some drug companies have their own private database of binding constants for some key receptors. One problem I see is that some drugs bind to receptors without turning them on, for example naloxone binds very tightly to the opiate receptors in the human brain but this drug does not turn on these receptors.

I suspect that Christopher will share my view that medicine and the production of medicine should not exist in a vacuum isolated from the rest of society. We need for example to consider the environmental impact of the production of drugs, a good example an early synthesis of ibuprofen produced lots of chemical waste. It used a Friedel-Crafts acylation using aluminium chloride, acetic anhydride and 2-methylpropylbenzene in the first step which will generate lots of aluminium containing waste. The later steps using other reagents also increase the amount of waste produced per kilo of the final drug product. Here is a chemical synthesis scheme for an early ibuprofen synthesis from some of my teaching materials.

An early synthesis of ibuprofen which generates lots of waste, all waste chemicals marked in red.

A later synthesis of the same drug was devised which produces much less waste per kilo of the drug product. This synthesis starts with the same starting materials but instead of using aluminium chloride it uses hydrogen fluoride. While I admit that the HF is a nasty so and so of a chemical (flesh eating horror acid) it is better in industry than the aluminium chloride as the product does not deactivate the catalyst. The key to the synthesis are the two catalytic steps (hydrogenation) and carbonylation using carbon monoxide where no atoms of waste are formed by the reagents when they do their work. This synthesis for the drug is likely to have a smaller impact on the environment.

New synthesis which makes less waste, all waste chemicals marked in blue.

I would like to point out that sometimes a man made pure drug is sometimes better than an poorly defined product from a plant and sometimes the less pure product from the plant is better. Now I will tell you a story about lung cancer and male smoking medical doctors. Some years ago when I was in Aberdeen I went to a lecture given by a man from the Rowett Institute of Nutrition and Health (Now part of Aberdeen University) where he told us some of the latest about vitamins and health. This lecture made me give up vitamin pills and but take up eating more fruit and veg.

We were told about a study where vitamin pills had increased the risk of lung cancer in smokers, ex-smokers and asbestos workers one example of this is G.S. Omenn et. al., New England Journal of Medicine, 1996, 334, 1150-1155 where the experiment was stopped early. This was the CARET study. In this study men were given either 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day or a placebo pill. The men on the vitamin pills were suffering more cases of lung cancer than the people taking the dummy pills.

Now I know that you all think that vitamins are good for your health, but this study suggested the total reverse. The man from the Rowette suggested that the reason might be that humans need a series of different isomers of the beta carotene and that by flooding the body with large amounts of one isomer will cause a shortage of the other isomers by overloading the transport process for the beta carotenes with one single compound.

In the end it has been shown that high doses of beta carotene do make smoking more dangerous by a different mechanism but it was an interesting hypothesis (I am not sure if it has been fully tested yet) which made me stop trying to fix a bad diet with vitamin pills. I then tried to eat a better diet with more fresh fruit and veg.

OK the score is now pills 0, plants 1. But after I have irked some of the pill pushers I am about to do likewise with the plant pushers in my next post.

Taxifolin

Dear Reader,

As I wrote earlier today, I will address the question of how to make taxifolin which the paper Yang, et. al. in Journal of Medicinal Chemistry,  2009 ,  volume 52,  issue 23, pages 7732 to 7752 does address. Now before you ask taxifolin is needed for the production of a series of herbal drugs. While for small amounts it might be perfectly OK to collect drugs from some rare plants for the production of drugs for mass treatment of humans it is often a good idea to make the drug in a factory by means of organic synthesis. This will drive down the price (with some luck) and make the drug supply independent of the plant or tree.

Before we get any further here is our synthesis target.

Taxifolin

I would be a good idea before we go any further to ask ourselves why it is unlikely that the taxifolin will not rearrange via an enol form to give the following species.

Other isomer of taxifolin

I think that the reason why the molecule is found in the first form is that the ketone group is conjugated to benzene ring on the left, but if we move the ketone to the alternative location it is not conjugated any more. But back to the synthesis, now the best thing to do when planning a synthesis is to use the retrosynthetic method. This is to break the molecule up in your mind to work out a way to make the molecule.

Retrosynthesis

After we have chosen a good disconnection we now need to work out a reagent which will represent the odd looking thing with the negative and positive charge. Now the negative charge on the oxygen can be provided by the lone pair of a phenol oxygen, while the positive charge can be provided by an epoxide (three membered cyclic ether) if we protonate the epoxide. Now it is important to note that when an epoxide is opened under acidic conditions that the regioselectivity (which way around the epoxide reacts) is dictated by the stability of the hypothetical carbocations formed when the protonated epoxide ring opens. Below is a diagram which will make it more clear.

Ring opening of the epoxide

I will discuss the chemistry required to form the epoxide compound at a later date.

Milk thistle

Dear Reader,

When I was reading a recent copy of a magazine from Aldrich (The Reporter) which in some ways is a series of adverts by Aldrich telling me about the latest analytical gadgets, gizmos, GC columns and other things I saw something interesting. It was on page 6 of the April edition of volume 50.

It was all about C-18 HPLC columns, now in common with many articles in the Reporter the writers show a application. In their case they choose the complex mixture of secondary metabolites from a plant called milk thistle. These include the the silybins and isosilybins. The herb is thought to be good for the liver and has some other medical applications.

When I looked at them I noticed something about the silybins and isosilybins. Here for your information is isosilybin A. I have highlighted in red the part which stood out to me.

Isosilybin A

I have put in red the part of the molecule which looks like it is very similar to eugenol, I looked in the chemical literature and I found that a biomimetic synthesis of a mixture of isosilybins and the silybins. L. Merlini, A. Zanarotti, A. Pelter, M.P. Rochefort and R. Hänsel, Perkin Transactions I, 1980, pages 775-778.

This is a synthesis which used taxifolin and coniferyl alcohol. The synthesis is an oxidation of a mixture of the two compounds in a mixture of benzene and acetone with silver(I) oxide. The first step is the production of some resonance stablised free radicals, these will be much less reactive and more stable than a typical alkyl free radical. As right now I can not be bothered to draw out the whole of the molecule and to make it more clear for you and to keep with the best traditions of organic chemistry I have represented the taxifolin part of the molecule with a simple 1,2-dihydroxybenzene.

The formation of the radicals by the one electron oxidations

Now the next step is the radical-radical coupling which forms the first C-O bond.

Radical radical coupling step

The next step is a nucleophilic attack by the phenol oxygen on the conjugated system in the right hand part of the molecule. This gives us the final product.

The final step of the reaction

I will discuss the synthesis of taxifolin in another post, I saw a paper by Yang, et. al. in Journal of Medicinal Chemistry,  2009 ,  volume 52,  issue 23, pages 7732 to 7752. This is a synthesis of this compound from small molecules. It was done using a combination of aldol and epoxide chemistry. I will write about it soon.