Common questions asked at job interviews for synthetic organic chemistry

Here is a list of questions that I have come across and some recommended answers to each.

• You have three compounds mixed together: compound A (amino acid), compound B (amine) and compound C (carboxylic acid). How would you separate them?

Most obvious answer: Liquid liquid extraction using water and an organic solvent (like ethyl acetate). The amine will enter the organic phase when the aqueous phase is made basic, the carboxylic acid will enter the organic phase when the aqueous phase is made acidic. The amino acid will be zwitterionic and will have a charge on it at any pH, meaning that it will remain in the aqueous phase under acidic or basic conditions.

• How might you make paracetamol (known in the USA as acetaminophen)?

Most obvious answer: Nitration of Phenol. Place phenol into dilute sulphuric acid and add sodium nitrate (NaNO3). This will give a mixture of ortho-nitrophenol (BP 215 °C) and para-nitrophenol (BP 279 °C), two compounds which can be separated by distillation. Take the para-nitrophenol, reduce the nitro group to an amine by any number of methods. Para-aminophenol can then be acylated, most easily using acetic anhydride (which will give acetic acid as a by-product) or any number of other acylating reagents, for example acetyl chloride, which will give HCl as its by-product.

Preparation of paracetamol

In a job interview you should stop right there. But I hear the more curious chemist ask: How is N acylation carried out without any O acylation? Acylations are highly pH dependent. An acid medium would prevent reaction at the OH but it would also protonate the NH2 to give NH3+ and prevent acylation at the N. The acylation step is therefore done in a water/sodium acetate solution. This keeps the hydroxyl from becoming deprotonated, but does not protonate the NH2. At this pH the acetic anhydride reacts so slowly with the water as to be negligible compared with the rate of reaction with the amino group. A slight molar excess of acetic anhydride is used and the reaction is shaken and occurs at room temperature. Excess acetic anhydride is quenched slowly by water on workup and the reaction is seen to occur in high yield (>90%).

• Name and describe a carbon-carbon bond forming reaction.

Most obvious answer: It depends on what else is bonded to the two carbons you want bonded together. Wikipedia has a list of over 100 carbon-carbon bond forming reactions. Choose any, but perhaps choose one of the most obvious and widely known. My top five picks are: Grignard reaction, Diels-Alder reaction, Aldol reaction, Michael reaction and Friedel-Crafts reaction.

• Are you familiar with the Diels-Alder reaction? What is the catalyst?

Most obvious answer: The Diels-Alder reaction is a concerted cycloaddition where a 1,3-butadiene (a diene) reacts with an alkene (a dienophile) to give a cyclohexene. It can be widely used with many different functional groups in place of hydrogen. As it proceeds by a concerted mechanism, it does not have a catalyst, but it can be placed under either thermal or photochemical control to achieve stereospecificity.

General Diels-Alder reaction

• Is it possible to form a C-C bond to an aryl carbon?

Most obvious answer: Yes. You can alkylate or acylate using the Friedel-Crafts reaction which uses an alkyl or acyl chloride and is catalyzed by AlCl3 under reflux and with anhydrous conditions.

Not a chemistry question, but I was once asked:

• When we call your referees, what bad things might they say about you?
  

I think the best answer to this is: "I don't know. You'll just have to ask them and find out".

Another non-chemistry question I was asked recently:

• When do you see yourself in five year?
  

I answered "Here", which apparently was the right answer, but I still wasn't offered the job.