I am leading a project in which I am attempting to synthesize 4-oxooctanoic acid in a (mostly) biological pathway. Currently, I have reached a dead-end. I have a way to create octanoic acid through bacterial growth, I could not seem to find a way to proceed to the 4-oxo step with enzymes so I turned to chemistry.

Although this seems to be impossible due to the structure of octanoic acid. There appears to be no way to specifically target the fourth carbon to obtain the 4-oxooctanoic acid.

My question is: Am I correct in assuming that converting octanoic acid to 4-oxooctanoic acid is impossible (at least via simple oxidation)? Or would there be a better way to go about doing this?

Thanks in advance

PS: Here are pubchem links to the two structures involved.



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    $\begingroup$ I would start from both functional groups and then attach the tail. That said, bacteria might well be more versatile in their business. What's a simple oxidation, come to think of it? Nothing is simple in biochemistry (at least, that's my impression of it). $\endgroup$ – Ivan Neretin Oct 17 '18 at 9:22
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    $\begingroup$ Very curious, it seems that your end product 4-oxo-octanoic acid can be easily made by direct hydrolysis of "gamma-Octalactone" (used in perfume and flavoring industry). The naturally occurring gamma-Octalactone compound is readily available, but it does seem very pricey. Would there be a way to 1) oxidize the octanoic acid non-specifically. 2) cyclic esterify to form reactant mixture plus gamma-Octalactone. 3) purify away unwanted reactants (distillation perhaps). 4) hydrolyze the purified gamma-Octalactone into the desired 4-oxo-octanoic acid product. leffingwell.com/glacton.htm $\endgroup$ – user22542 Oct 17 '18 at 14:17
  • $\begingroup$ It has been a while since I have thought about organic chemistry. I thought the "cyclic esterification step 2" might help with a purification process. The question piqued my interest. ncbi.nlm.nih.gov/pmc/articles/PMC5636794 $\endgroup$ – user22542 Oct 17 '18 at 14:26

If I was tasked with making 4-oxooctanoic acid I would not start from octanoic acid! There is no easy way of making 4-oxooctanoic acid directly from octanoic acid. It is however a relatively trivial exercise from other starting materials.

My suggestion is to react the commercially available ethyl succinyl chloride (ethyl 4-chloro-4-oxobutyrate) with n-butylmagnesium bromide (also commercially available) modified with manganese(II)chloride/lithium chloride as described in Tetrahedron Lett. 1992, 33 (31), 4439–4442. This will give the ethyl ester of the required 4-oxooctanoic acid. A simple base hydrolysis gives 4-oxooctanoic acid. You could probably use the widely available n-butyllithium in place of the Grignard.

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