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.

Arenes Chemistry Organic chemistry

Nitration of toluene

OK we are onto the final part of the lesson on aromatics, we need to consider the synthesis of TNT. It is interesting to note that non military and peaceful uses of explosives result in greater consumption / use. There are some explosives which are more suitable for military use rather than for mining. Years ago I visited a slate mine in England (Honister Pass) which was reopened by the late Mark Weir.

He was new to mining, and he attempted to mine a block of slate from the ine. He used plenty of black powder (gun powder) and he managed to break off a big lump of slate. The only problem was by using too much explosives he managed to reduce the slate block to small lumps which are close to worthless. At the mine he and his staff soon learnt that an Italian rock saw (nicknamed “the Italian job“) was a better method of freeing big blocks of slate.

I reason that TNT would be a dire explosive for slate mining, it is a rather fast explosive (detonation velocity 6900 ms-1) which has a high shattering ability (brisance). While TNT is not quite as shattering as RDX (8650 ms-1) would be it is far too shattering for slate mine use. For mining I think things like ANFO (4200 ms-1) or black powder would be more suitable when used in moderation. If I was a running a slate mine I would go for the black powder as the ANFO requires a rather strong boost charge to trigger it. If only a small amount of ANFO was to be used to loosen some rock then the boost charge will contribute a lot to the bang.

A word of advice do not play with explosives or experiment at home with them, the sentences for violations can include death or a serious injury resulting in permanent disability. These two harsh penalties can be dispensed by the energetic material, there is no appeal process. But after the energetic material has imposed its penalty then the criminal justice system may choose to impose a penalty.

This is no joke, some years ago some friends of mine at another university (University of Bleep) had a horrible event. A foolish student stole some chemicals from a teaching lab and illegally made a batch of an explosive. The student smuggled it out of the teaching lab and took it home. The student was later killed in an accidental explosion which destroyed the kitchen of the flat they were living in. Please do not bother asking me for more details as I will not answer that question.

The industrial synthesis of TNT is based on the reaction of a mixture of nitric and sulfuric acids with toluene. The reaction will occur in three stages, the first stage is the reaction of toluene with the nitration mixture to form the nitrotoluenes. From what we know already we should be able to understand how and why the main products of this reaction are 2-nitro-1-methyl benzene and 4-nitro-1-methyl benzene.

If we now consider the reaction of the 2-nitro-1-methyl benzene with the nitration mix. Before we start there are a couple of things to consider, there is something which is on my dirty washing list. Something which needs to slither back the swamp and crawl under a rock. Something which needs to never show its face again. I will let you look at it for a moment.

Bad bad bad, never let me see you drawing such a nitro group !

Now consider what is wrong, what is wrong is that we have a nitrogen to which we have five bonds. Now while things like sulfur and phosphorus (and more heavy p block atoms) can expand above and over the octet. Nitrogen can not do so, structure has a nitrogen which has five bonding pairs around it. This will not work well ! I know that the symmetry of this wrong nitro group might appeal to some people but it is still wrong.

Now we have seen it we should make it go away again, we should replace it with something far better. If we consider only the nitro group then this group of three resonance forms explains things better.

If we consider more of the resonance forms of nitrobenzene we can see that partial positive charges appear because of resonance on the carbons ortho and para to the nitro group.

Now lets look at the ortho-nitrotoluene. I calculated the partial charges on the carbons in the molecule, it is clear that those carbons which are ortho and para to the nitro group have partial positive charges while the carbons at the meta positions have slight partial negative charges.

This result suggests to me that the following resonance form makes a large contribution to the overall reality.

Now we should consider the reaction of the electrophile from the nitration mixture with 2-nitrotoluene. If we get it to react at the three position then we will go via the cation with the following resonance forms. The one on the left will have a very high energy, the nitro group will also be trying to remove electron density from the same carbons as were the positive charges in these three resonance forms are.

The formation of the other isomers of dinitrotoluene from 2-nitrotoluene will occur via the cations with the following resonance forms.

The last thing to do is to consider the order of reactivity. The reaction at the sites ortho and para to the nitro group will be slowed down by two things. These two things are the inductive pull of the nitro group on the electron density in the benzene ring and also the resonance withdrawal of electron density from both the benzene ring and the cationic intermediate by the nitro group.

The reaction at the positions meta to the nitro group will only be slowed by the inductive effect, so as the reaction. These positions are ortho and para to the methyl group. As a result the product of the second stage of the nitration of toluene will be a mixture of 2,4-dinitrotoluene and 2,6-dinitrotoluene.

Arenes Banned chemicals benzene Chemistry Insecticides Organic chemistry Uncategorized

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.

Chemistry drugs Insecticides Organic chemistry Uncategorized


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.

Arenes benzene Chemistry Organic chemistry

Aromatics I part 2

OK welcome back, I hope by now that you have worked out the mechanism of the nitration of benzene by the mixture of nitric and sulfuric acids.

Please spell sulfur and all related words using the f verion, when I was a PhD student the UK’s national chemistry organisation (Royal Society of Chemistry) instructed all chemists to stop using the ph version of sulfur and thus instead of writing sulphur we should write sulfur. As PhD students we found it fun to rebel by writing sulphur but please do not do this.

The first step in the reaction is to create the true electrophile for the reacton, in most cases benzene rings will not react with nitric acid. What is needed is sulfuric acid to protonate the nitric acid.

We can explain this reaction using curved arrows, keep in mind that just because there is no carbon atoms does not mean we can not use the curved arrow. Keep in mind that there are more than two ways to protonate nitric acid, just because we can draw a reasonable looking mechanism does not mean it is true. The other way to protonate nitric acid is to put the proton onto the oxygen atom which already bears the hydrogen.

Some Italian work from the 1980s suggests that in the gas phase that this second protonation is thermodynamically favored. It also indicates that in the gas phase the break up of the protonated nitric acid into a water molecule and a NO2 (Nitronium) cation is very easy. This will occur according to the following reaction. The concentrated sulfuric acid will help the reaction, water reacts with concentrated sulfuric acid thus the sulfuric acid acts as a dehydration reagent.

The tetrafluoroborate of this cation has been characterized by X-ray crystallography. If you want to see details of the work see I. Krossing, I Raabe and E Birtalan, Acta Crystallographica, Section E: Structure Reports Online, 2007, 63(2), i43-i44 or just look below.

What happens next is that the NO2 (Nitronium) cation will attack the benzene ring as an electrophile. The aromatic ring will stop being aromatic for a moment. The positive charge will be spread out over three carbon atoms, after forming the cationic intermediate a proton is lost and the ring returns to being aromatic. Thus we have formed nitrobenzene.

We can add lots of different things to benzene rings using different reagents which electrophiles. Using our imagination we can come up with lots of different useful transformations. Now in the same way as I gave out a lovely set of mathematical functions in my Magnum Opus on the MONIAC I am going to share with you a cheat sheet which may help get you out of some sticky problems.

SynthonTypical reagentProductComments
Cl+Cl2 / FeCl3PhClWorks for bromine but not well for fluorine or iodine
+SO3H H2SO4 or H2S2O7PhSO3Used to make anionic surfactants
+P(S)S2P(S)+P4S10Ph2P2S4 Works best on electron rich aromatics, used to make Lawesson’s reagent 
R+RCl / AlCl3 PhR The R group can change into an isomer
RCO+RCOCl / AlCl3PhCORNo rearrangement of R but the product poisons the Lewis acid catalyst
Ar-N=N+ArNH2 + HNO2PhN=NArOnly works well on electron rich arenes, this is used to make diazo dyes
RH++ RR’CO / H+ Ph2CRR’Used to make DDT and bisphenol A

Now before we go any further I will tell you a story, I hope that you are sitting comfortable and now I will begin. Oh, no lets give you a chance to nip off for a bowel of popcorn, a fizzy drink and an ice cream. OK now I start

A long time ago in the green and rainsoaked land of Loughborough there were those who worked in the lab of Derek Woollins. One of the these was a 21 year old man by the name of Mark Foreman, one afternoon he seized a round bottomed flask and put within it ferrocene (5.2 grams. 28 mmol), xylene (50 ml) and P4S10 (3 grams. 7 mmol). He boiled this mixture under reflux (30 minutes) before allowing it to cool. He collected the solid on a filter and washed it with toluene before drying it in vacuum. He was rewarded with 5.9 (78 %) of a orange solid. He showed it to Derek and he saw that it was good. Derek commanded Mark to crystallize it, Mark dissolved some of it in hot toluene and slowly cooled it thus making crystals. Mark gave the crystals to Alex Slawin. Alex performed a crystallography experiment upon it and saw that it was 2,4-diferrocenyl-l ,3,2,4-thiadiphosphetane 2,4-disulfide. The three looked upon it and it was good.

Here is a picture of the molecule, this was obtained using X-ray diffraction.

Now that was a nice and pleasant story, now before we go any further it is important to note that ferrocene is an electron rich aromatic compound while xylene is a less electron rich compound. The density of xylene is 860 grams per litre, so as the formula mass of xylene is 106 grams per mole then one litre of xylene is 8.11 moles per litre. Thus in 50 ml of xylene we have 406 mmol of xylene. This is almost 15 times as many xylene molecules as the number of molecules of ferrocene.

The fact that the dilute solution of ferrocene reacted faster than the xylene indicates to us that the nature of the aromatic molecule has a great effect on the rate of reaction with the electrophile. If the xylene and the ferrocene had similar abilities to react with the electrophile then Mark would have had a very small yield of his Fc2P2S4, he would have then needed another method of making the starting material for much of his PhD project.

Q3: Predict the major products from the following combinations of reagents. You use conditions where the aromatic is in excess to limit the reaction to monosubstitution. Please give the mechanisms for the reactions.

a. P4S10 and 2-tert-butyl-1-methoxybenzene

b. Bromine (with a Ferric bromide catalyst) with toluene (methyl benzene) in the dark

c. Methyl benzoate with a mixture of nitric and sulfuric acids

d. Phenol (hydroxybenzene) with nitric acid (this one does not need the sulfuric acid)

e. Chlorobenzene with chloral (Cl3CHO) and sulfuric acid

f. 2-Nitrotoluene and a mixture of nitric and sulfuric acids

Q4: The aromatics in Q3 state which ones would react faster than benzene and which would react more slowly than benzene under the same conditions.

When you have considered these problems then please click here to move to the next page.

Arenes benzene Chemistry Organic chemistry

Aromatics II

OK welcome back it is time to talk about aromatic mechanisms again. The first example in question three was one from Mark Foreman’s PhD days. Back in the days when he was in his early 20s working in Derek Woollins’s lab in a tranquil semi-rural location in a lab with a great view.

Much of the early part of Mark’s PhD project was reacting P4S10 and aromatic compounds. The thing to keep in mind is that sulfur is more electronegative than phosphorus so the phosphorus atoms in P4S10 have a partial positive charge on them. P4S10 has the following structure.

But when P4S10 is heated to 175 oC it is known to decompose into sulfur, P4S9, P2S5, P2S4, PS2 and PS. These things on cooling reform P4S10. While the boiling point of anisole is a bit lower (154 oC) than this temperature it is reasonable to imagine that some conversion of P4S10 into P2S5 occurs. The phosphorus sulfur side of the reaction looks like a “mechanistic mess” but the organic side of the mechanism is clear it is an electrophilic aromatic substitution reaction. We can summarize the organic mechanism with the following diagram.

We should note that the reaction occurs para to the methoxy group, this is due to the fact that the methoxy group has a far stronger activating ability than the tert-butyl group. The positive charge which is on the carbons in the ring which exists in the intermediate can be accommodated on the oxygen atom. The lone pair of the oxygen can be donated into the ring, this spreads the positive charge over more atoms. By lowering the charge density of the intermediate cation we lower its energy.

There are two bits of following chemistry which finish off the synthesis. Firstly the fragments from the phosphorus sulfide will lose hydrogen sulfide. One pair of equations which rationalize it are shown below.

While the organic side of the chemistry is finished off by the formation of a dimer of the product.

The dimer on cooling comes out of the reaction mixture as a crystalline solid. This has been characterized by crystallography along with almost every spectroscopic method I can think of.

When you are ready to move to the discussion of the answer to the second example (bromine as the electrophile with toluene) click here.


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.

Alkenes Arenes benzene Olefins orbitials Organic chemistry quantum mechanics

Resonance and pi systems

We are going to start with something within chemistry which has been deeply controversial. In the early Soviet Union there was a collision between political ideology (Dialectical materialism) and chemical thought.

Pauling’s “idealized resonance structures with no real independent existence” were deemed to be “antimaterialistic and hence anti-Soviet“. Now some might laugh at this but sadly this sort of nonsense continues to this day. It is important to note that this sort of nonsense continues to appear. It is important to note that there is no such thing as a socialist atom, nor are there capitalist molecules. Atoms and molecules lack morals and emotions. There was a case of some years ago which I got involved with, I was glad to drive a steak through the heart of the nonsense and thus help rid the world of it.

But on with the chemistry, now it is important to understand that the resonance forms do not exist independently of each other. If we have benzene we have two main resonance forms.

A bottle of benzene does not contain a mixture of the two, instead both resonance forms coexist in the same molecule at the same time. It is vital to understand that the benzene ring is special, it is not three isolated alkenes. There is a vast amount of evidence that the benzene ring is special. For example if we make a solution of bromine in benzene then this solution will be stable at room temperature with or without light. If we were to make a solution of bromine in an alkene it would react quickly in the dark to form a 1,2-dibromo compound.

Also the UV spectrum of benzene is very different to an alkene, the wavelength that benzene adsorbs at it much longer than that which a simple isolated alkene will adsorb at. This indicates that we have in benzene a much larger pi system than that found in an alkene such as ethylene.

Now I want to give you a short pep talk. To help us understand resonance we should consider this cation.

This cation exists as at least three different resonance forms. Here are the main ones.

Now this might just seem to some people like Mark Foreman and his mates in the organic chemistry world have come up with something to vex and trouble students which has nothing to do with real life. But this would be far from the truth.

Consider for a moment the following reaction, it is known as an allylic rearrangement. There is a reaction in a patent taken out by Bayer the German chemical compound (Bayer Aktiengesellschaft, US4515801, 1985, A). I have to confess this is the first one which I found in a search of the chemical literature.

In this reaction it looks like the “wrong” carbon in the bromo compound has attached to the oxygen attached to the benzene ring. We might ask how it has happened.

There is an older paper from the days of Teddy Boys and jive, C.A. Vernon, Journal of the Chemical Society, 1954, 423-428 in which the reaction rates for a series of chloro compounds with formic acid with a tiny trace of water was measured. Here is part of the data which was obtained at 100 oC.

Now here are the rate constants obtained by titrations with silver nitrate at different times in a bar chart, note that the y axis is a log scale.

What you should be able to see is that the alkene group on the left hand side of the molecule greatly increases the rate of the reaction. The allyl cation is able to spread the positive charge over two different carbons by means of resonance.

We can draw two resonance forms for the allyl cation.

What we can also see is that by adding chlorine atoms to the allyl cation we make a marginal increase in the stability (lower energy) of the cation.

There were further experiments in 1:1 water / ethanol. Using this new set of molecules we have more data.

Keep in mind that the y axis in the next chart is linear. It shows the effect of the location of the methyl group on the reaction rate.

Now these graphs tell us a lot. What they tell us is that there is a special stability of the following cation, also the location of the methyl groups matter. The methyl group in the cation from 2 is in the middle and it is not attached to a carbon where the positive charge is in one of the resonance forms.

Now I will give you a clue, the more alkyl groups attached to a carbon bearing a positive charge (a carbocation) the more stable the carbocation will be. If you imagine the two resonance forms as isolatable carbocations then the methyl group will not have a strong effect on making the carbo cation more stable.

Now if we move the methyl group to a different position then we can change the stability of the different resonant forms.

The form on the left hand side will have a greater stability than the one on the right. As the energy of the cation is affected by the energies of all the forms the energy of the cation is lowered further.

If we consider for a moment an alternative hypothesis that the rate limiting step is the attack of a second molecule on the carbon bearing the chlorine atom, then the methyl group in 3 should get in the way of the incoming second molecule and slow the reaction down. Also compound 4 should react at the same rate as compound 1 as the methyl group in 4 is remote from the reacting centre.

It is interesting if we look at the titration data for 3-methylallyl chloride being reacted in 99.5 : 0.5 and 90 : 10 mixtures of formic acid and water that when the water content is increased the rate constant for the reaction increases. We can see how the reaction went faster with the relative dielectric constant of the medium was higher. This is a change which will favor carbocations.

What is likely to have happened in the chemistry from the patent is that the allylic bromide formed a 1,1-dimethylallyl cation by the loss of a bromide anion. Then the charge was distributed by resonance between two carbons, the nucleophile mainly reacted at the less hindered end of the cation.

OK I have done enough for a while, time for you to do something. I want you to draw at least six of the resonance forms for two organic molecules with the formula C10H8. These are naphthalene (on the left )and azulene (on the right). By the way I will give you a clue about the second one, azulene has a permanent electric dipole moment while naphthalene does not.

When you are done click here to move onto the answers.

Arenes Chemistry orbitials Organic chemistry Uncategorized

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.