Sciencemadness Discussion Board - Modified Wolff-Kishner

Modified Wolff-Kishner

JnPS - 18-5-2018 at 09:37

TL;DR: Will the first transformation in the attached picture work to remove the C=O?

Last semester I did a project analyzing red wines for levels of resveratrol, quercetin, and polydatin via HPLC and we found a spike that we suspected was a form of catechin. Due to time restraints and deadlines we were unable to go back perform further tests to confirm our suspicions but I was allowed free reign with the leftover reagents and I'll have access to the university lab over the summer before I leave for MN. With that backstory out of the way here's my question:

Is it possible to perform the Wolff-Kishner reduction with a hydrazine derivative rather than just plain old hydrazine?

Another group had left over 2,4-Dinitrophenyldrazine that I wanted to try and use to reduce our excess quercetin's C=O in a transformation from quercetin to (+/-)-catechin. (I'm planning on reducing quercetin's C-C double bond with H2 and a Pt catalyst) I wasn't sure if this was possible since generally you're taught that the driving force behind the W-K is the removal of N2 gas. Based on that, and the mechanism, even if I got rid of the nitro groups to just phenylhydrazine I don't know if it might work.

I started going through the ACS's articles and an old 1949 paper [1] suggested that substituted hydrazines would actually form new C-C bonds upon W-K conditions, but a newer undergraduate lab to teach the W-K [2] uses a hydrazine derivative without fear of such side reactions.

Has anyone tried similar reactions before with any success or know more about the theory to give some suggestions? Thanks in advance!

It's been a while since I've been on SM, all the missed content will make for great reading on my flight

References:
1) J. Am. Chem. Soc., 1949, 71 (4), pp 1356–1358
DOI: 10.1021/ja01172a062
Publication Date: April 1949

2) J. Chem. Educ., 2016, 93 (5), pp 949–952
DOI: 10.1021/acs.jchemed.5b00954
Publication Date (Web): February 3, 2016

Metacelsus - 18-5-2018 at 11:13

See this mechanism: https://www.organic-chemistry.org/namedreactions/wolff-kishn...

As long as there's some water or other proton source around, I expect that the reduction will proceed normally.

[Edited on 5-18-2018 by Metacelsus]

Magpie - 18-5-2018 at 15:16

Why not make some hydrazine hydrate. I show how in another thread. FYI, here's my experience with the Wolff-Kishner, Huang-Minlon version: https://www.sciencemadness.org/whisper/viewthread.php?tid=68...

clearly_not_atara - 18-5-2018 at 15:57

tl;dr: no, but you're not screwed.

Step 2 in your attached picture says "H2/Pt" after using dinitrophenylhydrazine. I assume this is an important part of the reduction procedure. In particular, note that benzylic C-N and C-O bonds can usually be cleaved by hydrogenation whereas aliphatic ones are not. I think they just pop off the hydrazone with platinum. Note also the double bond is reduced.

In the Journal of Chemical Education paper, a hydrazinecarboxylate ester is used as a hydrazine substitute. Uniquely, this hydrazine derivative will decarboxylate to release free hydrazine under Wolff-Kishner reduction conditions. This is why this particular modified hydrazine is suitable for ketone reduction.

One interesting possibility might be to make the hydrazinecarboxylate ester yourself, which I suspect might be possible by performing a Hofmann degradation of urea in tert-butanol or another alcohol. This should generate intermediate isocyanatoamine H2NNCO which reacts with the alcohol to give the hydrazinecarboxylate ester.

[Edited on 18-5-2018 by clearly_not_atara]

unionised - 19-5-2018 at 06:30

DNPH and it's aldehyde/ ketone derivatives are unstable in alkaline environments.
Heaven knows what you would get from the proposed reaction.

JnPS - 19-5-2018 at 09:48

Thanks for the replies!

@Metacelsus - The third to last step in that mechanism though, where the di-imine (I think thats the nomenclature?) has a proton pulled off by hydroxide and the electrons fall back on the nitrogen which later kick out N2 from the carbon is the issue. In trying to use a hydrazine derivative I would have a phenyl ring there not a proton. I didn't think the base could just pull that off?

@Magpie - I was hoping I could limit the project to only using leftover reagents from my and the other groups over the semester, I'll check with the lab tech to see if they have any hydrazine hydrate or sulfate (from which I'll follow your prep to the hydrate) on hand.

@clearly_not_atara - Ah, so that specific hydrazine derivative is required, i.e. the carboxylate ester. I didn't even think of that decarboxylating, thanks for clearing that up. The hydrogen gas and platinum in the second step is solely to reduce the C-C double bond. The first step is what I'm trying to work out to remove the carbonyl on my way to catechin. I'll look into that Hofmann degradation route to the carboxylate ester.

@unionised - Damn, well it looks like I'll try to see what else they have on hand to reduce the carbonyl. Maybe a clemmensen reduction? I think they have some mercury metal in the storeroom. Or the hydrazine carboxylate ester route atara helped me understand.

Outer - 20-5-2018 at 05:20

DNPH fragment contains 2 nitro-groups which will be reduced at first by H2/Pt. Then C=N and N-N bonds (of the C=N-N fragment) can be reduced to obtain the corresponding amino-derivative (CH-NH2). And only at the last step it can be reduced to CH2.

Melgar - 21-5-2018 at 15:00

Quote: Originally posted by JnPS

@unionised - Damn, well it looks like I'll try to see what else they have on hand to reduce the carbonyl. Maybe a clemmensen reduction? I think they have some mercury metal in the storeroom. Or the hydrazine carboxylate ester route atara helped me understand.

I'm not sure if you'd have problems with that ether getting cleaved or not under clemmensen reduction conditions. However, if you're dead set on getting rid of that carbonyl oxygen, how about Monzingo reduction? As a bonus, the Raney nickel would (probably) hydrogenate the double bond.

[Edited on 5/21/18 by Melgar]

Outer - 22-5-2018 at 06:06

You can try reduction via tosylhydrazone formation and its NaBH4 reduction, see the next link:
http://orgsyn.org/demo.aspx?prep=CV6P0062