Reversible aromatic substitution reactions

If we take naphthalene then we can react it with electrophiles. For example if we treat it with nitric acid under mild conditions.

Now the nitration reaction does not appear possible to reverse, but the two nitronapthelenes are different in terms of thermodynamics. In the case of the 1-nitronaphthalene there is a steric repulsion between the hydrogen on the 8 position and the nitro group. In the case of the 2-nitronaphthalene there is no strong steric repulsion between the hydrogens on the 1 and 3 positions and the nitrogroup.

There is a reason why the less thermodynamically favored product will form, this is a kinetic reason. If we react naphthalene with an electrophile at the 1 position we go via a cationic intermediate. Two of the five lower energy resonance forms keep one of the two rings aromatic. This will lower their energy.

By now you should be learning that the more low energy resonance forms you can draw the lower the energy the ion has, also if you can draw resonance forms which are extra stable then the energy of the combination of the resonance forms will be lower. Lower energy means more stable. If we repeat the intellectual process for the reaction at the two position on naphthalene then we get a less stable cationic intermediate.

So what happens when naphthalene reacts is that the kinetic product (product which is formed more quickly) is higher in energy than the product whose formation is slower. If the formation of the product where the naphthalene has reacted at the one position (alpha isomer) can be reversed then if we stew the reaction mixture for a long time then we will get the beta isomer as our product.

While nitration is very irreversible the reactions of sulfuric acid and things like tert-butyl cations are reversible. Since 1870 (Merz, Chem. Ber., 1870, 3, 196) it has been known that naphthalene-1-sulfonic acid when heated at 130 oC in sulfuric acid will transform into naphthalene-2-sulfonic acid.

Another example is the reaction of tert-butyl chloride with benzene using aluminium chloride as the cataylst. If we do the reaction then we will have a Friedal-Crafts alkylation reaction. The first stage will be the reaction to form tert-butyl benzene.

Then a second molecule of tert-butyl chloride reacts to form 1,4-di-tert-butyl benzene.

Then things get a bit complex, one of the tert-butyl groups will come off the benzene ring and then we can react the tert-butyl cation at the meta site to form the 1,3-di tert-butyl benzene.

This can then react with more of the tert-butyl chloride to form the final product, I suspect that only one product will form. The reason is that the steric effects of the tert-butyl groups will oppose the loss of the protons from the cationic intermidates.

The steric energy of 1,2,3-tri-tert-butylbenzene is 75.3531 kcal per mole, 1,2,4–tri-tert-butylbenzene is 38.2984 kcal per mole and 1,3,5–tri-tert-butylbenzene is 14.3038 kcal per mole. On the other hand the steric energy for 1,3-di-tert-butylbenzene is 9.5103 kcal per mole. The steric energy of the tert-butyl cation is only 3.6054 kcal per mole. I think that a steric argument explains why the 1,3,5-product is a major product from the reaction of benzene with tert-butyl chloride.

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Phenol and chlorobenzene with electrophiles

Due to the very electron rich nature of phenol it is possible to nitrate phenol using gentle conditions. One method is to use a solution of nitric acid (6 % w/w) with a solution of the phenol in ethylene dichloride with some tributyl ammonium bromide. Now I do not like the sound of this system, I would suggest instead using aliquat 336 in aromatic kerosene with dilute nitric acid. My dislike of the method presented in Organic Process Research & Development 2003, 7, 95−97 by Ashutosh V. Joshi, Mubeen Baidoosi, Sudip Mukhopadhyay, and Yoel Sasson is that the solvent they choose to use is carcinogenic. I would advocate using a solution of the phenol in aromatic kerosene (How about Solvesso 150ND) do the reaction with the nitric acid and then extract the nitrated phenols with sodium hydroxide before making the sodium hydroxide solution acidic to allow the nitrophenols to be recovered.

You should be able to understand the mechanism of the nitration of the phenol using what you know already about the reactions of the 2-tert-butylanisole and toluene. Now we have to move onto something else.

What happens if we have an arene bearing a group which withdraws electron density by the inductive pull effect but donates by the resonance effect ? This might sound like a rather strange group but we already have some which do this.

We have anisole which has a slight electron withdrawing effect by means of its inductive pull and a strong electron donation effect by means of resonance. But a more clear case is chlorobenzene. The chlorine atom has a strong inductive pull and it donates by resonance. Here is a diagram showing the resonance and inductive effects.

Now many years ago there was a wonder chemical, a non toxic insecticide which is about as toxic to humans (acute effect) as aspirin. It was regarded as a safe alternative to things like lead, arsenic, thallium and nicotine for use on food crops. It offered humans a means of expunging insects from farmland and the extermination of disease carrying insects such as body lice and malaria mosquitos. Sounds great but we later found that there were some horrible problems.

  1. Many of the insect pests became immune to its effects
  2. The agent killed off lots of useful insects such as honey bees
  3. The agent breaks down into a long lived substance which is toxic to some mammals (such as bats)
  4. The agent breaks down to something which is a xenoestrogen, the agent itself might also be active as a xenoestrogen.

In the USA there have been problems at Lake Apopka (Florida) as a result of xenoestrogens entering the lake, these have harmed birds and alligators (Cynthia V. Rider et. al. Environ Toxicol Chem. 2010 September ; 29(9): 2064–2071. doi:10.1002/etc.233).

The compound in question is DDT, DDT was made by the electrophilic aromatic substitution reaction of chlorobenzene with choral using an acid catalyst. In the first stage a molecule of chlorobenzene reacts with choral (trichloroacetaldehyde) to form the first of the new C-C bonds.

Then a second molecule of chlorobenzene will react with the 2,2,2-trichloro-1-(4-chlorophenyl)ethan-1-ol. This will protonate to form a resonance stabilized cation.

We finish off the DDT synthesis with a second reaction of a chlorobenzene molecule on the new cationic intermediate.

Now we have formed a molecule of DDT, here is the crystal structure of DDT in case you are interested to know what it looks like.

It is important to keep in mind that the synthesis of DDT is not able to make a perfectly pure product, commercial DDT used to contain some of the ortho,para and the ortho,ortho isomers. Here is the molecular structure of the ortho, para isomer of DDT.

Now we have been going through the synthesis of a molecule which has been banned. It might never have been banned if some sectors of society had used DDT in a more responsible manner. If we ignore the harmful effects on wildlife (the man reaoson for the ban) and concentrate on the problem of DDT resistance in insects then it is likely that if DDT had never been used for agriculture but had been only used for controlling insects which transmit disease to humans (eg Malaria control) then DDT might still be in use. I reason that the widespread outdoor use of DDT created a legion of DDT resistant insects while causing the various problems.

In case you think that the chemistry required for the formation of DDT from chloral and chlorobenzene has gone away, it has not. The synthesis of bisphenol A from acetone and phenol is using close to identical chemistry. Bisphenol A is made by the reaction of phenol and acetone using an acid catalyst

When you are ready for the final part of the lesson on aromatic substitutions please click here.

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There are a series of about four main natural compounds found in humans and other animals which are the estrogens. These are female sex hormones which are steroids. These are E1 (Estrone), E2 (Estradiol), E3 (Estriol) and E4 (Estetrol).

Xenoestrogen means an artificial estrogen, some artificial estrogens such as EE2 which is commonly used in oral contraceptives is not particularly bad. The xenoestrogens all are molecules which can fit the estrogen receptor, some are steroidal like the natural estrogens while others are not steroids. Here is a picture of EE2. The reason why EE2 is used instead of estrogen in oral contraceptives is that many of the natural sex hormones are not very active when swallowed. They tend to be converted into other things by the body before they can get into the main part of the blood system. Here is a picture of EE2.

I have seen many people making the argument that urine from women who are taking “the pill” will turn male fish into female fish. But when I look at the evidence it is interesting that the pregnant woman releases estrogens which have a far higher estrogenic effect on the environment than a woman who is “on the pill”. Here is a bar chart showing the amount of the three most important estrogens released per person per day.

You can see here now a woman who is menstruating does emit more estrogens in their urine than a man. A woman who has gone through the menopause emits less estrogen than before she stopped, but a little more than a man. When pregnant women emit a lot of estrogens in their urine. The three compounds I have data for are not equal in strength as estrogens. The relative strength of the estrogens will depend on the receptor which they are binding to. But in the paper I was reading you can give a score of 2.8 micrograms worth of E2 to a man, the menopausal woman has a score of 3.5 micrograms worth of E2, the menstruating woman has a score of 6.0 micrograms of E2 and the pregnant woman 589 micrograms worth of E2 per day.

The typical dose in the oral contraceptive is about 30 to 35 micrograms per day, as women will fully metabolize between 20 and 50 % of the EE2 which they swallow. Then the dose to the environment of EE2 from a woman on the pill is between 15 and 28 micrograms for the days that they are taking it. As EE2 is twice as potent an estrogen as E2 (the standard one), I can reason that the woman on oral contraceptives is somewhere in the range of 20 to 40 micrograms worth of E2 per day.

I have seen data that in 2001 that indicated that 43 % of Dutch women of reproductive age took oral contraceptives while in the USA it was 28 % of women of reproductive age. So if we use these values it can be estimated that on average women of reproductive age are releasing between 12 and 24 microgram worth of E2 per day.

Compared with the 6 micrograms worth of E2 per day this is not a vast increase. What is interesting is the question of how stable is EE2 compared with the other estrogens in a sewage plant. The paper I was reading indicates that many sewage plants are able to remove more than 80 % of both E2 and EE2. Thus the sewage plant will mitigate any effect of EE2 use on the fish in the river.

The truly scary worst of the worst xenoestrogen is DES, the jury is out regarding the question of “does it cause breast cancer when an adult woman is exposed to it ?”.


But it is very clear that in utereo exposure to DES does increase a woman’s chance of getting an unusual gynological cancer at a young age (teens or 20s). The cancer is such that DES is close to a perfect storm, the cancer is one which is not normally seen in women before the menopause. Also a normal gynological examination is likely to fail to spot signs of this cancer. A word of warning if you are easily shocked or horrified then do not go googling “DES daughter cancer”, the topic is a nasty horror show.

Other xenoestrogens include bisphenol A, in rats this is a very weak estrogen. But there are some related compounds which are much stronger as estrogens in rats.

Another one which is interesting is DDE which is a breakdown product of DDT. This is an interesting xenoestrogen as it does not have a hydroxyl group. Here is a picture of DDE.

Thankfully in Sweden the birds of prey whose numbers declined due to the use of some chlorine containing pesticides have started to increase again.

Another xenoestrogen of note relates to the surfactant triton X-100, this surfactant is not an estrogen but it breaks down in nature into a surfactant. The reason it is a problem is that the branched alkyl chain is only very slowly digested by bacteria. But when the corresponding compound with a C9 linear chain (Nonoxynol9) is released into rivers it is degraded much faster.

I have drawn all the xenoestrogens to try to suggest a similar structure to estrogens like E1. I may come back and write some more later on this topic.


Reaction of bromine / toluene and methyl benzoate and the nitration mixture

When we react bromine and toluene using the iron(III) chloride we have to have a step to form the true electrophile. We need a catalyst to make the reaction go. Here is a short film in which I had a solution of bromine in toluene. I added some steel staples and then I lifted them out with a magnet.

What you should notice is that when the steel was in the mixture the mixture generated bubbles of hydrogen bromide gas, when the steel was taken out the gas production stops. The surface of the steel reacts with a little of the bromine to form some ferric bromide. This ferric bromide is the catalyst for the reaction.

The first step is normally considered to be the reaction of the bromine molecule with the Lewis acid. Commonly this is thought (and taught) to be the reaction of bromine and the Lewis acid to form a pair of separated ions.

This will then be followed by the reaction with the aromatic ring. Now when the reaction occurs we have a choice of reacting in three different locations. We can react at the ortho, meta and para sites.

The rate of reaction at these three sites will not be equal. If we consider for a moment what the mechanism for each of the three possible reactions will be. If we use what we have found out from the nitration of benzene and the reaction of the anisole with the P4S10 then we should be able to make a set of three mechanisms like these.

We have to decide which ones of these will be faster, now to get to the cationic intermediate we have to pass through a transition state. Here is a graph of energy against the progress of the reaction for one molecule which I drew today.

Now as the transition state is similar to the cationic intermediate in energy we can reason that the lower the energy of the intermediate the lower the energy of the transition state will be. We have to overcome the energy barrier of TS1. Here is the diagram with the activation energy barrier marked on it.

Now if we have a second path to a different product, shown in red. Then I hope that you can understand that if the reaction is operating under kinetic control then we will not form the red product. The reason is that as the activation barrier of TS1(red) is larger the rate at which the intermediate for the red reaction is entered is smaller than the rate at which the black one is entered. Thus more of the black will be formed than the red one.

Now the key thing for us to understand is that the energy of the cationic intermediate is not dictated by only one resonance form. All the resonance forms have an effect upon the energy of the cation. If we imagine for a moment that all the resonance forms were stable cations then we can imagine how those which are formally drawn as secondary carbocations have higher energies than those which are formally drawn as tertiary carbocations.

But it is the combination of the resonance forms which determines the energy of the cation. If we ignore crazy high energy resonance forms like this one

and limit ourselves to the three lower energy forms which are commonly drawn then we can make some easy progress. If we assume for arguments sake that the three lower energy forms all contribute equally to the overall energy. Then if form A has an energy of 100, form B 70 and form C 100 then the average of these will be 90. So when one of the forms is more stable then we can understand how we lower the energy of the cation.

If we make more of the resonance forms lower in energy then the overall energy of the cation will be even lower. If we consider for a moment the reaction of bromine and 1,3,5-trimethyl benzene (mesitylene). Then we can see how all three of the resonance forms are more stable than the resonance forms which would exist if benzene was reacted.

So as a result if I was to react mesitylene with bromine then it should react faster than toluene under the same conditions. What I am going to do when I get the chance is to react some bromine with a mixture of mesitylene, chlorobenzene, toluene, tert-butyl benzene and some other aromatic compounds. If I get a GCMS trace of the mixture before and after adding the bromine we should be able to see the relative reactivity of the different compounds.

Now there is something which is an important difference between the reaction of the bromine and the P4S10. This is the size of the electrophilic reagent. In the case of bromine it is small while for P4S10 it is large. For large electrophiles we tend to see less reaction at the ortho sites as the electrophile is less able to reach the site. I think that the steric effect on the ortho / para ratio is a rather advanced idea which at Chalmers is not normally something we would expect a first year to recall / understand. But it is still an interesting thing.

The final stage of the bromination reaction is for the cation to lose the proton, the proton then reacts with the anionic iron bromo complex to reform the Lewis acid and form a molecule of HBr.

In the same way as a group attached to the ring can increase the stability of the cation, there are groups which lower the stability of the cation. If we consider a group which is able to withdraw electron density by both the inductive pull effect and the resonance effect for a moment. One such group would be a carboxylic acid or one of its derivatives. If we consider methyl benzoate for a moment. I have drawn some resonance forms which make it clear how the carbonyl group can pull electron density towards itself by means of the resonance effect.

There are at least two ways of thinking about it, one way is that if you are trying to increase the stability of the cationic intermediate by moving a positive charge onto a carbon which already is being used by another group in the same way. Then we will have contest for which group gets to put its positive charge onto the carbon. Here is an organic chemistry joke.

Q: What did the carbonyl group say to the Wheland intermediate (Arenium ion) ?

A: Clear off ! You are not putting your positive charge there ! I was here first !

Now we can consider it in a more serious way, if we take a more simple molecule (formaldehyde). we should understand that the oxygen is the most electronegative of the elements in the molecule. According to my quantum mechanical calculations we have charges on the different atoms.

Now if we repeat the calculation for acrylaldehyde (Acrolein, also known as propenal) we get a more electron rich oxygen. This indicates that the quantum mechanical calculation is indicating that the carbonyl group is withdrawing electron density from the alkene. This time I have put the partial charges on the non hydrogen atoms only.

Now we do this for fumaraldehyde, this is a trans alkene where there are two aldehyde groups which are playing “tug of war” with the electron density in the pi system.

What we should look at is the fact that when we have two aldehydes playing “tug o’ war” with the electron density that they get less electron density from the alkene. We can apply the same ideas to the cationic intermediate.

As the carbonyl group is trying to withdraw electron density from both the benzene ring and the cationic intermediate it will lower the amount of electron density in the benzene ring and it will also lower the stability of the cationic intermediate.

Now in organic chemistry a lot of things are dictated by kinetics, while a thermodynamic driving force might favor the formation of all three isomers of methyl nitrobenzoate the rates of formation of these things will be different.

There are some cases where the electrophilic substitution of aromatic things are reversible. But generally we run most of these reactions under conditions where the reverse reaction is very slow. As a result they do not reach equilibrium.

In our case we can regard the nitration to be irreversible, so which ever isomer is formed quickly will be the isomer which will be the major product. The ester group has two effects there is the inductive pull on the electron density in the ring. This occurs through the sigma bonds. There is also the resonance effect through which the ester group withdraws electron density.

While the reaction at all three sites is slowed down by the inductive removal of electron density by the ester group. The resonance effect only has an effect on the reaction at the ortho and para positions. So as a result the main product of the reaction is the meta isomer. The reaction at the meta site will be slower than the reaction of benzene, so if we were to make a 1:1 mixture of methyl benzoate and benzene and combine it with one equivalent of an electrophile then the majority of the electrophile would be consumed by the reaction with the benzene. You should recall how the young Mark Foreman reacted a mixture of xylene and ferrocene with an electrophile, when he did this the ferrocene reacted rather than the xylene.

When you are ready to consider the next aromatic reaction please click here, this will be phenol with nitric acid.


Aromatics I

Benzene is a very important molecule, it is also a very challenging molecule which has helped greatly the development of organic chemistry both “in thought and deed“. The reason I mention thoughts and deeds is that aromatic chemistry is very important in the lab and in industry (deeds) and also benzene (and other aromatic chemistry) has enabled (or maybe provoked) organic chemists to think about molecules in a different way.

Aromatic molecules include neurotransmitters, hormones, pesticides, building blocks for polymers, drugs and more things. Here is a selection of four randomly chosen aromatic molecules.

Now I am sure that many of you will have heard of prozac, I recall the era of wild excitement about prozac and reading the late Elizabeth Wurtzel’s memior on the long train ride to a job interview in Aberdeen (I got the job).

The late Elizabeth Wurtzel (1967-2020), photo by Lynne Winters.

Elizabeth Wurtzel (1967-2020) at the end of her book painted a glorious picture of fluoxetine. My view as a chemist of fluoxetine is that it is an important drug which changed society and science’s view of depression but it is not a panacea.

Q1: a key part of fluoxetine can be regarded as a benzene ring which has two groups attached. the structure of benzene was a great challenge to chemists. Consider how many dimethyl benzene isomers could be formed if benzene had one of these alternative structures. For the purpose of the teaching event the benzene isomer on the top left should be regarded as having fixed single and double bonds. The one on the bottom right with the circle means that the single and double bonds are not fixed, instead the bond order between the carbons is 1.5.

Some alternative (and wrong) structures for benzene along with the correct one.

Now before we go any further I know that there is a thing which makes some organic chemists rage, emit steam or blow a gasket. That is the representation of a benzene ring with a circle in the middle rather than alternating single and double bonds. We will get back to this later.

With benzene rings it is important to understand that the bond order of the bonds between the carbon bonds is 1.5. Benzene rings have a special stability. It is important for you to understand that the double bonds are not fixed in a benzene ring. In the following diagram the interconversion of the two benzene resonance forms is occurring.

It is important to accept that all the resonance forms exist at the same time, they all make a contribution to the overall reality but these contributions are not always equal. The higher the energy an individual resonance form would have if it was a isolatable species the lower its contribution is to the overall reality. We can draw out more resonance forms for benzene.

There are some rules,

  1. The locations of atoms cannot change from one resonance form to another.
  2. The hybridization of atoms cannot change from one resonance form to another.
  3. Only pi bonds and lone pairs are involved in the resonance, the sigma bonds normally stay out of the resonance.
  4. The more charges we have in a resonance form normally the higher the energy will be.

Here are some resonance forms of benzene, I have included the two low energy resonance forms which are commonly seen along with five higher energy forms which are not commonly drawn.

There is a convention in organic chemistry, when you draw resonance you use a two ended straight arrow. When it is resonance to a form which makes a minor contribution (due to a high energy) it is common to use a smaller arrow. For example.

Please also do not “wrap around” curved arrows from one side of the paper to the other. Some years ago myself and Björn were grading exam papers and we saw that a student had drawn something like this.

Please do not do this, also do not use a curved arrow to move an atom. Next time we might not be quite so sympathetic. Please look at this simple reaction mechanism below. It is the deprotonation of a phenol by a methoxide anion. I have shown the correct and the wrong use of the curved arrows.

OK curved arrow lesson over we can now move onto some reactions of benzene and other aromatics. Lets go for a gentle one first. Please draw out the mechanism of the reaction of benzene with a mixture of nitric and sulfuric acids to form nitrobenzene.

When you have drawn out the mechanism please click here to move to the next page.

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Resonance forms

OK welcome back, I hope by now that you have drawn plenty of resonance forms of naphthalene and azulene. The usual resonance forms of naphthalene which are drawn and thought about are.

It is important to note that unlike benzene there is one resonance form which has the lowest energy of all of them, as a result the bond order in naphthalene between some carbons is higher than it is between some others. Here is a diagram of octafluoronaphthalene taken from the literature onto which I have added the carbon carbon bond lengths.

The shortest carbon carbon bonds (1.357 Å) and the longer carbon carbon bonds on the perimeter of the aromatic system indicate that the central bond (1.432 Å) is closer to being a double bond. The longer bonds on the perimeter (1.416 and 1.396 Å) are best thought of as carbon carbon bonds which are close to single bonds.

There are lots and lots of resonance forms of naphthalene, I think that we would be here until next Christmas if we were to draw them all out. Well maybe that is an exaggeration but it would take a long time to draw out all of them if we were to include the high energy ones with lots of charges. Here are some of them along with the three normal ones.

When you are finished thinking about the naphthalene we can move onto the blue coloured azulene. There are four resonance forms which should be obvious and have low energies. It is important to accept that aromatic rings do not always have six atoms in them. There are aromatic rings with other numbers of atoms. Also there are aromatic rings with different numbers of pi electrons to six. In fact an aromatic ring can have 4n+2 pi electrons. The number n can vary from zero to a very high integer.


A pep talk

Long long ago when I was an undergraduate in the 1990s at Imperial College we had rather different music and different tastes (or distastes) in clothing to today’s undergraduate. But there are somethings which are likely to remain constants. The late Neville Parsonage who was my tutor told me that before Christmas in the first years that the maths was the big source of trouble and distress to most of the undergraduates but after Christmas it was the organic chemistry. But there is hope, now I will tell you about two ways to view organic chemistry.

You can try to memorize every single reaction which crosses your path, this is a method which might seem to give you results. But you will need a bigger and bigger crib sheet either in your mind or on a sheet of paper.

The better way is to understand organic chemistry, there are very few reactions in organic chemistry. I estimate that there are only about five which a first year at Chalmers has to know. But this requires you to have an intimate understanding of the reactions. You will need to be able to recognize the key aspects and adopt the correct mental stance even under stress.

What I want to do with you as a class is to get as many of you to the point at which you can deal with the organic chemistry. When some organic molecule comes at a student I want you to be able to stop panicking about what the big bad molecule is going to do with you. When the big bad molecule comes at you in the exam I want you to have the mental tools needed to send it packing.

Rather than “Oh goodness, this can not be happening, oh please do not hurt me !” I want you to be able to think “Sit ! Now be a good little molecule !

Now this will not come in one day, by learning more and more chemistry and taking more courses I hope that you will become more and more like a Barbara Woodhouse for molecules. For those of you who do not know Barbara Woodhouse was an animal trainer from Ireland who was a horse and dog trainer. She was famous for dealing with “problem dogs“, she maintained that there was no such thing as a “bad dog” but there were “inadequate owners” who failed to assert their position in the dogs pecking order. She has strongly influenced other dog trainers like Victoria Stilwell.

Equally I would say that there are no “bad molecules“, but there are humans who are either unable or unwilling to deal with molecules correctly or in the right way. Hopefully soon you will be saying “Sit !” and “Walkies” at the molecules in a commanding tone, you will transform them from intellectual monsters into cute creatures who want to sit at your feet.



Now pyridine is an important molecule, I happen to rather like pyridine and its derivatives. At several points in my life as a chemist I have used pyridine derivatives to do things.

While in John Plater’s lab in Aberdeen one of my favorite reagents for restricting the cross linking in a coordination polymer was to use 2,2′-bipyridine while when working in the group of the late Mike Hudson I used 2,2′-bipyridine as the core of the BTBP solvent extraction reagents. The synthesis for the BTBPs starts with 2,2′-bipyridine.

Now pyridine can be regarded as azabenzene, it is a benzene molecule in which one of the CH units has been replaced with a nitrogen atom.

The nitrogen lone pair points out into space at 120 degrees away from the two carbon nitrogen bonds in pyridine, it is on the same plane as all the atoms in the pyridine molecule are.

Pyridine is aromatic as it has 4n+2 pi electrons in a planar (flat) ring. As nitrogen is more electronegative than carbon the pi system of pyridine is more electron poor than that of benzene. The effect of the pyridine nitrogen is about the same as a nitro group attached to a benzene ring.

Much of the chemistry of pyridine is dominated by the lone pair on the nitrogen, this enables the pyridine to act as a base and to bind to metals. I am sure however with the d-block metals that pyridine is able to act as a pi-acid which will increase its ability to bind to metals. Some of the oligopyridines such as 2,2′-bipyridine are able to chelate to metals, it is interesting that Constable has made very large oligopyridines and done some interesting chemistry with them.

With iron(II) the chelating oligopyridines are able to form very dark red complexes, I have heard horror stories from people in nuclear reprocessing research community about the use of BTP in machines made from stainless steel. We will get onto that in a moment. First it is interesting that if a person holds a gun in their hand then they can deposit iron onto the skin of their hands. Depending on good your skin is at adsorbing iron from a gun, how long you hold the gun and a range of other things it can be possible to see shape of the steel parts of the gun which was held in the hand if the hand is treated with 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine. While funny shapes caused by holding iron does not mean beyond all reasonable doubt that a person has held a gun recently, it may help the investigation of crimes which involve guns.

Many of the BTPs have such a strong ability to form iron(II) complexes that their solutions can strip iron from stainless steels such as SS316L. In case you do not know what BTP is here is a diagram of it.

Here is a picture of the iron(II) complex of the parent BTP (R = H), you can see how the iron is binding to six nitrogen atoms.

BTP is an example of a molecule which has both azabenzene (pyridine) and triazabenzene (1,2,4-triazine) rings. The BTPs are able to extract americium(III) from nitric acid. The americium is extracted as a tris-BTP complex with nitrate anions as counterions which enables it to enter a solvent such as octanol. The steric demands of the BTP when it binds to the americium are smaller than those of a terpyridine also the BTP is a weaker Bronsted base. This reduction in Bronsted base strength enables the BTP to extract from rather strong nitric acid solutions. The parent terpyridine is a far weaker extraction agent which requires a carboxylic acid such as 2-bromodecanoic acid to be added and this system only will function at very low nitric acid concentrations. Here is 2,2′:6′,2”-terpyridne.

An example of its use as a base is in the synthesis of O-phenyl phenylphosphonochloridothioate. When I was working in Josef Novosad’s lab in the Czech Republic I wanted to make a phosphorus compound which was chiral at the a phosphorus atom. While I had originally had the idea of reacting phenylphosphonothioic dichloride with an excess of methyl magnesium iodide to form 1,2-dimethyl-1,2-diphenyldiphosphane 1,2-disulfide which could be cleaved with bromine to form methyl(phenyl)phosphinothioic bromide we found it was more convenient to react a mixture of phenol and pyridine with phenylphosphonothioic dichloride in diethyl ether. The pyridine reacted with the hydrogen chloride formed by the reaction of the phenol with the phenylphosphonothioic dichloride.

By the way pyridine has a horrible smell and there are wild stories about the effects of pyridine on male sexual health. I think that the stories about pyridine are a bunch of “urban myths“. But when I was an undergraduate I heard jokes about the subject. When I first used it there was a strange smell in the lab, I asked the PhD student (It was a lady) who was supervising us in the second year inorganic lab course what the smell was. She replied with “It will do more to you than it will do to me, and then stated it was pyridine”.

All very funny, but it is purely a myth. I have seen a review of the data from an experiment in which rats were fed pyridine in their drinking water. In rats pyridine does not have a harmful effect on the sexual health of the rats. There is a slight effect in female rats but it appears to be an artifact.

Pyridine will not make men go sterile. However if you contaminate yourself with pyridine it is likely to impede the process of someone else falling in love with you. I think that the stench of pyridine would discourage most people. If your clothing is contaminated with pyridine, I suggest you remove it and wash any contaminated parts of your body.


Mechanistic eyes

Many things in the world which might at first appear to be unrelated can suddenly become related when you consider them in a mechanistic manner. For example alpha decay can be regarded as a helium nuclei escaping from an atomic nucleus by quantum tunneling. It is possible to observe other clusters of nucleons being emitted from some radioactive nuclei. This is known as “cluster emission”, I would argue that all cluster emission could be the same reaction in mechanistic terms.

If we consider the following two nuclear reactions, if we can imagine the carbon-12 nuclei knocking around inside the barium-112 nuclei trying to escape in the same way as alpha particles are thought to form inside the nuclei of alpha emitters before knocking around for a while. They either escape by quantum tunneling or the fall apart and the quarks rejoin the mass of quarks in the alpha active nuclei.

112Ba → 12C + 100Sn

224Ra → 4He + 220Rn

Equally often in organic chemistry we get the same mechanism dressed up differently, consider for a moment the reaction of benzyne, Lawesson’s reagent and maleic anhydride with a 1,3-diene. In all these cases this can be explained as a Diels-Alder reaction.


Gas chromatography III

OK you have either had a good laugh at the idea of doing the waltz in a day glow rave suit or you were not up for such an idea. But now we have to come back to earth. We need to consider the question of what alters K in gas chromatography.

While do some molecules travel more quickly than others along the column. In general the bigger a molecule the slower it travels in the column, this is due to the fact that it has more surface area for the London forces to bind it weakly to the column coating.

There are other things to consider,

If we choose a column coating such as ZB-5MS column from Zebron, this has a 95 % dimethylpolysiloxane coating where the remaining 5 % of the polymer is aromatic groups.

This is a short section of a dimethylpolysiloxane chain.

One option for a 5 type column which has 5 % aromatic groups is to include some diphenylsiloxane units in the polymer chain. A pure polydiphenylsiloxane would look like this.

While a ZB-1 column has a pure dimethylpolysiloxane coating. This difference will greatly alter the behavior of aromatic compounds in the column. The difference is that the aromatics like benzene and the larger hydrocarbons such as naphthalene and anthracene interact with the benzene rings in the coating. Through attractive pi-pi interactions they bind more strongly than a molecule made of CH2 units (such as an alkane) would.

There are other column coatings such as the 35 % -Phenyl- 65 %-Dimethylpolysiloxane used in the ZB-35 columns.

There are more polar columns such as the ZB-23 which has a coating which is 50 % cyanopropyl methyl, 50 % dimethyl polysiloxane. This one is designed to bind to polar molecules. One of the most polar column coatings which is in regular use is the wax (Carbowax) formed by the polymerization of ethylene oxide. This is a long polyether, here is a short part of the polymer chain.

There is a general rule, “like dissolves like”. A polar solvent is more able to dissolve polar compounds than non polar compounds. So if we use a carbowax column then will give longer retention times for the polar compounds. It will also be better for this. For example there is a method for the measurement of ethyl acetate, methanol, propanol and isobutanol in alcoholic drinks. In this method a filtered sample of drink is injected into a GC fitted with a flame detector.

The boiling point of methanol is 65 oC while the boiling point of ethyl acetate is 77 oC. While in general we expect the more volatile things to come out first in with the carbowax column the ethyl acetate comes out before the methanol. This is clear evidence that the polar group in the methanol (hydroxyl group) is attracted to the polar carbowax. It is also worth noting that the boiling point of ethanol is 78 oC, the retention time of the ethanol in that column is about 3.8 minutes while the ethyl acetate has a retention time of about 3.1 minutes. The retention time of the methanol in that column was 3.2 minutes. So it is clear that the polar compounds are being retained.