How can we convert phenylacetic acid to 3-phenylpropionitrile?

Question

I understand that phenylacetic acid reacts with KSCN can form phenylacetonitrile plus the side product (CO2 and KSH).This is Letts nitrile synthesis

However the problem is to convert phenylacetic acidi to 3-phenylpropionitrile

Is that possible? What reagents do we need?

Answer 1

Your first clue is that the carbon chain is extended by one carbon -- phenylacetic acid has one -CH2- then the CO2H. In the product, there are two carbons (-CH2-CH2-) between the phenyl ring and the -CN. If you didn't need to add a carbon, you would be changing the -CO2H into -CN.

But since you need to add a carbon, I think the most straightforward way is by a SN2 reaction. CN- is an excellent nucleophile. So all you need to do is change Ph-CH2-CO2H into Ph-CH2-CH2-LG (where LG is any good leaving group).

The first sensible step is reduction of the acid. This can be done with LiAlH4 (lithium aluminum hydride) followed by a workup step (either H3O+ or H2O, depending on how your instructor has presented it). That will change Ph-CH2-CO2H into Ph-CH2-CH2-OH.

Then, just change the -OH into a good SN2 leaving group. This can be done several ways, and the preferred way will depend on how it has been presented in your class. I think PBr3 is the simplest -- changes -OH into -Br. You could use SOCl2, which makes -Cl. Or TsCl (tosyl chloride), usually accompanied by pyridine, which makes a tosylate (-OTs) which is an excellent leaving group.

It does not matter which one of these options you use (although the -Cl is the worst SN2 leaving group of the bunch), as all of them should react well with CN- in an SN2 reaction. But after the SN2 with cyanide, voila! 3-Phenylpropionitrile!

I hope this answer and explanation make sense! Knowing the reactions you have been taught is critical in order to string them together to accomplish a synthesis. But once you know your reactions, you can start to get the hang of it!