Posted by: Mark Foreman | November 4, 2019

1,4 dicarbonyls

Dear Reader,

When I was a PhD student, now some of the PhD students of nuclear chemistry and even some of the seniors have noticed that this is a stock phrase but unless we learn from the past we are doomed to repeat the mistakes of the past without benefiting from the better bits.

Now I have already given my thoughts on 1,2 and 1,3 difunctional (not dysfunctional) compounds it is now time for 1,4. If we want to disconnect a 1,4 compound then I think we have two main choices. The top one requires a positive charged version of the enolate while the bottom one requires unpolung. Now unpolung is a funny sounding word which relates to the reversal of what is normal. In some ways both disconnections require it.

1 4 disconnection to synthons

Now if I had an aldehyde such as benzaldehyde then it can be regarded as a synthetic equivlent to a benzyl alcohol with a positive charge instead of one of the hydrogens on the benzylic carbon.

benzaldehyde normal synthetic equiv

What we need is a method of changing the benzaldehyde to make it act in a way which goes against its normal character. Thus we are reversing its polarity. There is a great wealth of reagents which will do this for us. The most simple one is to combine benzaldehyde with a little bit of sodium cyanide. This does the job for us in the following way.

PhCHO plus NaCN

The resonance stabalised carboanion on the right can react with a range of electrophiles including benzaldehyde and α,β-unsaturated compounds to form addition products. I would suggest that to increase the yield of the 1,4 compound that we should keep the concentration of the α,β-unsaturated compound nice and high and slowly add the aldehyde to the hot mxiture of sodium cyanide, water and alcohol. If we were to just make a strong solution of the aldehyde and add some cyanide to this we would increase the yield of 1,2-diphenyl-2-hydroxyethan-1-one which is formed by the action of the anion on a molecule of benzaldehyde.

Imagine in our case we use ethyl vinyl ketone as our α,β-unsaturated compound.

At the end of the reaction we recycle the cyanide by returning the negative charge to the oxygen which is attached to the carbon bearing the cyanide group. The carbon oxygen double bond reforms and the cyanide is lost from the molecule. Ready to continue its good work elsewhere.

end of the cyanide cat reaction

Another method is to react cyanide with an α,β-unsaturated compound to form an addition product. When then can convert the cyanide groups into carboxylic acid groups by boiling the living daylights out of the compound in concentrated hydrochloric acid. If you are going to do this be careful not to have a lot of residual sodium cyanide in the mixture when you add the acid. For example you can react cyanohexanone with ethyl cyanoacetate to form an α,β-unsaturated cyano ester which then reacts with sodium cyanide. Finally boil without mercy in hydrochloric acid and evaporate down to a mxiture of ammonium chloride and the diacid.

synthesis of a diacid from cyclohexanone which was reacted with ethyl cyanoacetate

Another method which is more expensive, but who cares about the cost of reagents when we are just thinking about chemistry, is to react the aldehyde with propane-1,3-dithiol and make a ring (1,3-dithiane). We can then deprotonate this with a strong base and then react it with a range of electrophiles. I am sure that this could be made to react with an unsaturated carbonyl compound. It is known that in HMPA that the separated ion pair form of the reagent will react in a 1,4 manner with cyclohex-2-en-1-one. But I suspect that like myself most chemists these days would rather not use HMPA. But it does not hurt to think about chemistry in HMPA.

A word of advice do not use HMPA if you have any choice, it is a nasty carcinogen which absorbs with ease through skin. To use it legally in Sweden you need a special license the last time I checked.

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