Posted by: Mark Foreman | March 7, 2012

The pepper spray cop’s neurotoxin

Dear Reader,

It has come to my attention that Lieutenant John Pike did something to make the neurotoxin in chilli peppers become something of public interest.

About the chilli peppers, now I am sure that some of you will be interested to know how pepper spray is made. I see two routes to making pepper spray. Either super strong chilli peppers could be grown and then processed to make the active ingredient for the sprays, or the active ingredient could be made by means of an organic synthesis.

If we look at the structure of the neurotoxin in chilli peppers (capsaicin) we will see that it has some functional groups in it. What you should do is to look at the final product and think of what bond you could break to form two smaller fragments (synthons). The two smaller synthons should be things which you can easily get reagents for.

Disconnecting the pepper spray toxin

If we break a bond in the retrosynthesis arrow A then we form two synthons, these synthons correspond to an electrophilic carboxylic acid derivative and an amine. What you should look for always are synthons with charges which correspond to reagents which you can buy or make at low prices.

The synthon on the left and the reagents on the right for what I think is the best disconnection

If on the other hand we break a bond in C then we will get a disconnection back to something much more irksome. Much worse than the pepper spray. The only synthon which I can think of for the left hand side bit would be an isocyanate, for those of you who are a bit younger than me one of the most horrible industrial accidents which occurred in my lifetime was the Bhopal chemical gas leak.

Here is the isocyanate, it would need a protecting group for the phenol group at the top of the molecule. Something like a benzyl group would do nicely. If you failed to add the benzyl group the compound would self condense to form a polyurethane.

The nasty isocyanate required for the not so sensible route to the neurotoxin

A large amount of methyl isocyanate leaked out of an insecticide factory in India and gassed out a whole town. The results in terms of human illness / death were far worse than Chernobyl. The thing to remember is that as a class the isocyanates tend to be nasty irritants of eyes and lungs, some of the isocyanates are also super toxic. Sadly the people living near the plant never knew that they could protect themselves by staying indoors and sealing any gaps in the house with wet towels. Maybe you should try to work out why a wet towel is a good protective device against methyl isocyanate by drawing curved arrows at home, but back to the chemistry problem.

What you would have to do would be to make an isocyanate (not a nice prospect) and the phenol group in the molecule would need to be protected against the super strong Grignard nucelophile. The use of a protecting group will normally add two stages to the synthesis. Firstly you need to put the protecting group on and secondly you need a step to take it off again. We will later find out why the extra steps tend to be bad.

The worst disconnection I have drawn is B, to be brutally honest with you I would say that this disconnection is a total no brainer. Normally if someone suggests such a disconnection to you which is so remote from the functional groups then try to resist the urge to say something hurtful just bite your lip and wait for the person to go away !

The reason it is such a no brainer is that it is hard to make synthons with no functional groups near the bond which needs to be made, while there are some methods which can get you out of such a jam they tend to be tiresome when compared with the easy synthons in A. So try to avoid a disconnection like B.

Now we can get closer to a cheap starting material for the amine half of the toxin. What we need to use is a functional group interconversion to make a cheap starting material into the amine. My best suggestion is to use a combination of an ammonium salt and a reducing agent. The best one to use may be sodium cyanoborohydride which is a weak reducing agent which is perfect for converting aldehydes into amines.

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