Sciencemadness Discussion Board - Reduce cinnamaldehyde to hydrocinnamaldehyde

I know that NaBH4 will prefer reduction of the a,b-unsaturated conjugated double bond since it is a softer nucleophile

NaBH₄ will actually reduce the aldehyde rather than the double bond ( cinnamaldehyde to cinnamyl alcohol ) ,instead of the other way round but LiAlH₄ will reduce both the double bond and the aldehyde.
I think the best thing to do would be to reduce it completely to hydrocinnamyl alcohol and then bleach it back to aldehdye,like laserlisa suggested
literally every selective method uses some or the other crazy catalyst or H₂ gas-
http://pubs.rsc.org/en/content/articlelanding/1984/c3/c39840...
http://www.sciencedirect.com/science/article/pii/S0022328X09...
https://www.thieme-connect.com/products/ejournals/abstract/1...
http://pubs.rsc.org/en/content/articlelanding/2009/gc/b81556...

[Edited on 1-12-2017 by CuReUS]

Loptr - 1-12-2017 at 07:10

Quote: Originally posted by CuReUS

I know that NaBH4 will prefer reduction of the a,b-unsaturated conjugated double bond since it is a softer nucleophile

I have read that you will actually end up with a mixture of the two... it just depends on which is attacked first, since both are likely. I have read conflicting information in chemistry books, where one states it would tend towards one being reduced before the other, and vice-versa. At this point, I think it's left to experimentation to determine. If I have some time, I will try and find what I am talking about to back up my statements.

There is also the potential of altering the NaBH4 to cause it to attack the carbonyl more slowly, such as using acetic acid, but I am not sure what effect that has on its ability to reduce that double bond. I have a paper that states it took 40 hours for NaBH(OAc)3 to reduce an aldehyde in 60% yield. However, I think it's too mild of a reducing agent for this purpose.

I haven't had a chance to read through your links yet.

I was also thinking it might end up being a couple steps to the end product, but wanted to see if there were a more selective reduction method. I am seriously considering the catalytic hydrogenation route, and seeing if a less expensive catalyst could work. I don't have a lot of time to spend experimenting, so I like to make heads or tails of what would most likely work before trying anything... a lot of naval gazing, and then experimentation. I know that I can get to hydrocinnamyl alcohol, and then oxidize it back to the aldehyde, but a single reduction is what I am looking for.

[Edited on 1-12-2017 by Loptr]

Loptr - 1-12-2017 at 14:29

Well, this is certainly interesting. Hydroxylamine hydrochloride and ethyl acetate used for the preparation of diimide. I have read about diimide reductions before, but thought they required harder to obtain reagents, such as potassium azodicarboxylate.

This might be a viable option. Trying to find an overview of the mechanism now to see if it would have any affect on that aldehyde.

Attachment: gangadhar1984.pdf (343kB)
This file has been downloaded 527 times

Loptr - 1-12-2017 at 14:38

According to this, there might be some issues with reducing double bonds in a,b-unsaturated carbonyl compounds.

diimide_a,b-unsaturated_double_bond_reduction.png - 195kB

Attachment: miller1965.pdf (4.5MB)
This file has been downloaded 880 times

The easiest method really does seem to be Pd/C and formate. I might be purchasing some in the future. What is the cheapest source?

[Edited on 1-12-2017 by Loptr]

clearly_not_atara - 1-12-2017 at 16:10

I continue to recommend dithionite/PTC. The objection of kmno4 is not relevant and the literature attached explains why.

Quote:

Then Na2S2O4, but recently I have read that cinnamic acid (or rather its sodium salt) is inert to dithionite. Some article from Tet.Lett. gives ~100 % reduction of cinnamate esters for Mg/MeOH system....

This is not too surprising, because dithionite is only reported effective for ketones and aldehydes, not acids. However, it will perform a regioselective reduction of dienoic acids to allylic acids, that is, it reduces alpha,beta,gamma,delta-unsaturated acids to beta,gamma-unsaturated acids. See Camps et al 1986 and Camps et al 1982.

Attachment: camps1986.pdf (449kB)
This file has been downloaded 460 times

Attachment: camps1982.pdf (5.3MB)
This file has been downloaded 605 times

Loptr - 1-12-2017 at 16:46

I continue to recommend dithionite/PTC. The objection of kmno4 is not relevant and the literature attached explains why.

Quote:

Thanks for the info. I will prioritize the dithionite/PTC reduction.

Corrosive Joeseph - 30-12-2017 at 23:55

There is also this

Reduction to the saturated aldehyde by passing over alumina........ Attached

/CJ

Attachment: Reductions with Alcohols of Cinnamaldehyde to Beta-Phenylpropionaldehyde (1929).pdf (72kB)
This file has been downloaded 498 times

Magpie - 31-12-2017 at 10:35

Could sodium metabisulfite be use to protect the aldehyde?

JJay - 31-12-2017 at 15:47

According to Hilgetag and Martini's Preparative Organic Chemistry page 6 (in the SM library), sodium and alcohol can reduce the double bond of cinnamic acid. In the case of cinnamaldehyde, I think the bisulfite adduct would be decomposed by the strongly basic conditions, but that might work with a different reducing agent.

Interestingly, they cite this paper on poison ivy to back up their claim: http://pubs.acs.org/doi/abs/10.1021/ja01587a025

wxyz - 31-12-2017 at 18:29

Catalytic hydrogenation with Pd/C will reduce double bonds, usually without affecting aldehydes. One exception is that aldehydes alpha to an aromatic ring can be reduced by catalytic hydrogenation ... which isn't the case with cinnamaldehyde. And even in that case the double bonds would be reduced first. But, note that the double bond in this case puts the aldehyde carbon in conjugation with the benzene ring so it may be reducible with catalytic hydrogenation. So it would be wise to not overdo it. Still, all signs point to the double bond being reduced much more easily by catalytic hydrogenation.

Chemi Pharma - 2-1-2018 at 04:38

Hy @Loptr.

Isn't easier oxidate phenyl propyl alcohol to hidrocinnamaldehyde?

phenyl propyl alcohol is easily find at perfumary stores as an essence and it's very cheap.

You can oxidize it by swern oxidation, PCC or with nickel peroxide in organic media, withouth break the aliphatic chain, to hidrocinnamaldehyde.

Loptr - 2-1-2018 at 19:42

That's a good idea, but my interest wasn't in obtaining hydrocinnamaldehyde. It was more about the regiospecific reduction.

Thanks for the info, though.

I hopefully will have some time to experiment coming up.

Chemi Pharma - 1-8-2018 at 08:23

According what I have studied, It's not possible to reduce the double bond of cinnamaldehyde without reduce the carbonyl group either.

The opposite is possible, just to reduce the carbonyl group and not the double bond, but to reduce the carbon double bond you necessarily have to reduce the carbonyl group first.

Then, you can reduce cinnamaldehyde to cinamyl alcohol or go further and reduce it to hidrocinamyl alcool, but it's not possible to reduce only the double bond to obtain hydrocinnamaldehyde from cinnamaldehyde.

You can do that with borohydride complexes or with LiAlH4. The last has an interesting action upon cinnamaldehyde. "add LAH to cinnamaldehyde and you get just reduction of the carbonyl group; invert the order of addition and you additionally get reduction of the double bond", the researcher claims:

http://www.ch.imperial.ac.uk/rzepa/blog/?p=13688

(extracted from my post in: http://www.sciencemadness.org/talk/viewthread.php?tid=6380&a...

See also:

F.A. Hochstein, and W.G. Brown, "Addition of Lithium Aluminum Hydride to Double Bonds", J. Am. Chem. Soc., vol. 70, pp. 3484-3486, 1948. http://dx.doi.org/10.1021/ja01190a082

Unfortunately It's impossible for me to give you the answer you're expecting, cause apparently the regioselectivity favours the reduction of the carbonyl group first, before the double bond reduction, with all modern reagents I researched.

May be exists a way to do what you are asking for, but I humbly admit I don't know how.

Reconsider the phenylpropyl alcohol mild oxidation like I said before if you really want to get hydrocinammaldehyde. If you are only interested in the regioselectivity, I apologize, but unfortunately I can't help you with this, despite my efforts.

Loptr - 1-8-2018 at 08:39

According what I have studied, It's not possible to reduce the double bond of cinnamaldehyde without reduce the carbonyl group either.

The opposite is possible, just to reduce the carbonyl group and not the double bond, but to reduce the carbon double bond you necessarily have to reduce the carbonyl group first.

Then, you can reduce cinnamaldehyde to cinamyl alcohol or go further and reduce it to hidrocinamyl alcool, but it's not possible to reduce only the double bond to obtain hydrocinnamaldehyde from cinnamaldehyde.

You can do that with borohydride complexes or with LiAlH4. The last has an interesting action upon cinnamaldehyde. "add LAH to cinnamaldehyde and you get just reduction of the carbonyl group; invert the order of addition and you additionally get reduction of the double bond", the researcher claims:

http://www.ch.imperial.ac.uk/rzepa/blog/?p=13688

(extracted from my post in: http://www.sciencemadness.org/talk/viewthread.php?tid=6380&a...

See also:

F.A. Hochstein, and W.G. Brown, "Addition of Lithium Aluminum Hydride to Double Bonds", J. Am. Chem. Soc., vol. 70, pp. 3484-3486, 1948. http://dx.doi.org/10.1021/ja01190a082

Unfortunately It's impossible for me to give you the answer you're expecting, cause apparently the regioselectivity favours the reduction of the carbonyl group first, before the double bond reduction, with all modern reagents I researched.

May be exists a way to do what you are asking for, but I humbly admit I don't know how.

Reconsider the phenylpropyl alcohol mild oxidation like I said before if you really want to get hydrocinammaldehyde. If you are only interested in the regioselectivity, I apologize, but unfortunately I can't help you with this, despite my efforts.

Thank you for the feedback, Chemi Pharma. I appreciate your efforts.

I have made a bit of headway in my research since this thread. I think I have some references that refer to solvent effects on the reduction of cinnamaldehyde with NaBH4 to favor 1,4-reduction instead of 1,2-reduction. There is also the possibility of altering the activity of NaBH4 so that it attacks the carbonyl group more slowly, such as is the case with Na(CH3COO)3BH, where it can take days for completion.

I also have a parallel effort where I am researching a catalytic transfer hydrogenation with a nickel metal catalyst supported on activated charcoal. I posted pictures in the hydrogenation thread currently in Today's Posts. I am not interested in a full-on hydrogenation, but am rather interested in an activated nickel catalyst with another hydride donor, such as ammonium formate, formic acid, etc. I am aiming for atmospheric pressure reaction conditions. Pyridine can be added to a nickel catalyst to keep it from reducing the aldehyde.

[Edited on 1-8-2018 by Loptr]

Chemi Pharma - 1-8-2018 at 08:49

@ Loptr, may be you achieve what you are looking for following this way. If so, you deserve an article at chemical periodic bulletins, cause to reduce the double bond of insatured carbonyl compounds without affect the carbonyl group deserve a honor medal. It would solve a lot of pharmacological synthesis problems.

Post your results here. Of course all SM comunity is anxiously waiting for your good results.

[Edited on 1-8-2018 by Chemi Pharma]

clearly_not_atara - 1-8-2018 at 09:19

Loptr: any word on dithionite?

According to this paper:

https://onlinelibrary.wiley.com/doi/abs/10.1002/(SICI)1097-4660(199807)72:3%3C264::AID-JCTB897%3E3.0.CO;2-2

acetal formation occurs spontaneously during the hydrogenation of cinnamaldehyde in alcohols. Taking this as a guide, it seems like a good idea to try the hydrogenation in ethylene glycol.

Quote:

According what I have studied, It's not possible to reduce the double bond of cinnamaldehyde without reduce the carbonyl group either.

Of course this is very silly, anyone who is familiar with the literature on these compounds knows that catalytic hydrogenation tends to attack the C=C double bond whereas hydride reagents attack the carbonyl. It's not surprising that someone who only pays attention to hydrides would be misled.

However, even rudimentary searches turn up many systems with good selectivity for the conversion of cinnamaldehyde to hydrocinnamaldehyde; the difficulty is that many involve rare metal catalysts on exotic supports, although you occasionally see methods using eg nickel phosphide for this transformation.

https://www.sciencedirect.com/science/article/pii/S0926860X0...
https://www.sciencedirect.com/science/article/pii/S138111690...
https://www.sciencedirect.com/science/article/pii/S0926860X9...
https://www.sciencedirect.com/science/article/pii/S016943320...
https://link.springer.com/article/10.1007/s10562-008-9472-y

Impossible, indeed...

[Edited on 1-8-2018 by clearly_not_atara]

Chemi Pharma - 1-8-2018 at 09:53

oh, clearly_not_atara, you are so smart!

If I were not a man I will fall in love with you! argh!

Yes, I'm involved with borohydrides complex in my recent researchs. Any problem with this? Any problem if I don't know about anything despite you PROFESSOR?

The problem here is you man! You claims I don't look about the real necessity of SM members, but you, in all your posts you preach the use of exothic reagents, hyper complexes techniques and think all of this is normal an acessible for the amateur chemistry.

You complain about me wanting to favour a healthy competition with other SM suppliers to put down the chemical prices in bennefit of all SM members, but YOU, is the first that post about reactions that use exothic and inacessible reagents to the home user. Tell me what are you really intend to do here? joke with our faces? Or prove that you are more inteligent than the others?

Stop to criticize other members and try to be more polite here. I'm fed up your rudeness. Your ironies are deserving a moderator action!

I have no problems with @Loptr anymore after we talked at U2U. The only one I still having problems here is YOU! Come on man, call me at U2U and tell me what's your real problem with me. Until there, don't piss me off, ok?

Loptr - 1-8-2018 at 11:22

Loptr: any word on dithionite?

No, this is that time I spoke of that I would be able to start experimenting. I have a couple reactions planned, and the dithionite/PTC is one of them.

Planned is a strong word. I am gathering the info to produce a planned reaction.

Any ideas on tests and work up would be great. Solvents, tests, etc.

[Edited on 1-8-2018 by Loptr]

Loptr - 1-8-2018 at 11:56

According to this paper:

https://onlinelibrary.wiley.com/doi/abs/10.1002/(SICI)1097-4660(199807)72:3%3C264::AID-JCTB897%3E3.0.CO;2-2

acetal formation occurs spontaneously during the hydrogenation of cinnamaldehyde in alcohols. Taking this as a guide, it seems like a good idea to try the hydrogenation in ethylene glycol.

I had thought about the use of acetalation in an attempt to protect the carbonyl from reduction, but thought the double bond was then isolated as is the case with styrene derivatives. They can be reduced, but under more strenuous conditions. The article mentions something like ~150 PSI of hydrogen.

What do you think about this under CTH conditions, or 1 atm.?

I was planning on purchasing some ethylene glycol soon for protection of ketones.

[Edited on 1-8-2018 by Loptr]

clearly_not_atara - 1-8-2018 at 13:19

Chemi Pharma: I replied specifically to your statement that the reduction is "not possible" and would constitute a breakthrough in organic chemistry if it were to be achieved. These claims are baseless, and I provided examples from the literature to demonstrate this. I never suggested the reactions in those links were practical for amateurs, because that's not what I was talking about.

In fact those links are just the first five Google Scholar results for the query "cinnamaldehyde hydrocinnamaldehyde". A review states:

https://www.tandfonline.com/doi/abs/10.1080/0161494980800710...

"The hydrogenation of alpha,beta-unsaturated carbonyls into saturated carbonyls is comparatively easy to achieve because thermodynamics favor the hydrogenation of the C=C bonds."

Loptr: Transfer hydrogenations are rare here. Metal-free reductions based on the Hantzsch ester look interesting. One version uses Hantzsch ester with dibenzylamine:

https://onlinelibrary.wiley.com/doi/full/10.1002/anie.200461...

Others exist as well:

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.2004624...

There are some others using isopropanol and complex catalysts, but I'm guessing that standard Pd/C/formate will give okaaayyyyyy regioselectivity with the major source of difficulty being the separation of hydrocinnamaldehyde from the unreacted starting material. One advantage of transfer hydrogenation is the ability to control the quantity of reductant, which may prevent over-reduction.

For transfer hydrogenation of an unactivated double bond with Pd/C and ammonium formate, see:

https://www.sciencedirect.com/science/article/pii/S004040390...

I am slightly concerned that the use of ammonium formate with cinnamaldehyde may result in reductive amination or Mannich reactions. Perhaps a tertiary ammonium formate (eg triethylammonium) would be better.

[Edited on 1-8-2018 by clearly_not_atara]

Loptr - 1-8-2018 at 14:46

I just have a hard time spending so much for so little Pd/C. Maybe I will just buy a Pd bar, and then dissolve that in aqua regia. I have seen papers on preparing the Pd/C catalysts, but can't recall how easy it is. It was something I perused when reading up on supported catalysis.

$316.61 - 10g Pd
https://www.apmex.com/product/96681/10-gram-palladium-bar-pa...

clearly_not_atara - 1-8-2018 at 15:51

You know the Hantzsch ester/dibenzylamine method is metal-free, right? I don't know what Hantzsch ester costs but I'm betting that ethyl acetoacetate, formaldehyde and ammonia are all pretty cheap. Dibenzylammonium trifluoroacetate might be a little more expensive... but not at 5% catalyst loading. I'm not sure how to make dibenzylamine, but I don't imagine it being very hard. At the least, a mixture of mono/di/tribenzylamines will be easy to separate by distillation.

Corrosive Joeseph - 1-8-2018 at 17:04

Reference 42 (equation 28) looks very possible, simple and OTC........
http://reag.paperplane.io/00003049.htm

There is also a REAXYS upload in Reaxys thread of all possible routes to hydrocinnamaldehyde.
I'm sure there are a few more reactions using cinnamaldehyde as a substrate.
And a few more that haven't even been tried yet.

/CJ

[Edited on 2-8-2018 by Corrosive Joeseph]

Attachment: Chapter 18 - Reduction of a,b Unsaturated Carbonyl Compounds.pdf (4.4MB)
This file has been downloaded 788 times

[Edited on 2-8-2018 by Corrosive Joeseph]

Attachment: Partial Reduction of Enones, Styrenes and Related Systems.pdf (7.8MB)
This file has been downloaded 732 times

Loptr - 1-8-2018 at 19:53

Loptr: any word on dithionite?

Any ideas on tests and work up would be great. Solvents, tests, etc.

[Edited on 1-8-2018 by Loptr]

I found an article that reduces chalcones under dithionite/PTC conditions in CH2Cl2 with TBAHS.

Attachment: 12_chapter 5.pdf (1.1MB)
This file has been downloaded 513 times

Corrosive Joeseph - 1-8-2018 at 22:14

The paper known as 'camps1986' AKA ' Regiospecific Reduction of Unsaturated Conjugated Ketones with Sodium Dithionite under PTC',
kindly uploaded by clearly_not is by far the most attractive looking dithionite method IMO.

If I was to attempt it I would try a two-phase toluene/water reaction with 'biocide' PTC.........

https://www.bonnymans.co.uk/products/product.php?categoryID=...

/CJ

Chemi Pharma - 2-8-2018 at 06:00

Although you guys are bravely looking for a decent way to reduce cinnamaldehyde to hydrocynnamaldehyde, I'm no convinced yet about this possibility and really want that who can do it in practice, post the results here.

Just a note for the one who understands: I never said it's not possible to reduce the double bond without reduce the carbonyl group, I just have said I humbly admit I don't know how to do it, despite my researchs, cause nobody knows everything, isn't right?

Every paper posted here, until now, tells about the reducion of cinnamaldehyde to hydrocinnamyl alcohol. I want to see a kind of hydrogenation of double bond that doesn't reduce the carbonyl group to an alcohol or alkane either.

Sorry, but dithionite wouldn't make this job, according with all that I have read here and the papers submited. The aldehyde will be reduced to an alcohol either, according this papers.

@C/J brought an interesting paper dealing with zinc/cooper reduction of double bond, but the case he brought is about an amide, not an aldehyde, extremely reactive.

Come on guys, bring something really effective to do that and prove it's effectiveness. It will be a great feat, I guess!

Loptr - 2-8-2018 at 06:11

Although you guys are bravely looking for a decent way to reduce cinnamaldehyde to hydrocynnamaldehyde, I'm no convinced yet about this possibility and really want that who can do it in practice, post the results here.

Just a note for the one who understands: I never said it's not possible to reduce the double bond without reduce the carbonyl group, I just have said I humbly admit I don't know how to do it, despite my researchs, cause nobody knows everything, isn't right?

Every paper posted here, until now, tells about the reducion of cinnamaldehyde to hydrocinnamyl alcohol. I want to see a kind of hydrogenation of double bond that doesn't reduce the carbonyl group to an alcohol or alkane either.

Sorry, but dithionite wouldn't make this job, according with all that I have read here and the papers submited. The aldehyde will be reduced to an alcohol either, according this papers.

@C/J brought an interesting paper dealing with zinc/cooper reduction of double bond, but the case he brought is about an amide, not an aldehyde, extremely reactive.

Come on guys, bring something really effective to do that and prove it's effectiveness. It will be a great feat, I guess!

I will have some time this weekend for a first experiment. I will post my results and get feedback. I will test for double bonds and alcohols after the reaction. I plan to precipitate any remaining aldehyde from the solution using the bisulfite adduct, back extract, and then test for alcohols.

Corrosive Joeseph - 2-8-2018 at 06:55

@C/J brought an interesting paper dealing with zinc/cooper reduction of double bond, but the case he brought is about an amide, not an aldehyde, extremely reactive.

It takes out double bonds conjugated with carbonyls..........
"Alkenes with powerful electron-withdrawing groups like esters, ketones, or nitriles are reduced with zinc-copper couple in refluxing methanol"
(eq 28) [Ref. 42]

More later.

/CJ

[Edited on 2-8-2018 by Corrosive Joeseph]

Chemi Pharma - 2-8-2018 at 07:11

@/CJ, the paper you brought, deal about esters, ketones and nitriles. And the example given, was about an amide. I doubt high reactive aldehyde group woudn't be reduced to an alcohool as well.

Prove me I'm wrong, ok?

zinc-cooper double bond reductions.jpg - 44kB

Corrosive Joeseph - 2-8-2018 at 07:42

@ Chemi Pharma - You might be interested to know the nitro group is also a polar EWG.......

Back on topic.......... This deserves to be here............ Many, many ways...... But not really

/CJ

Attachment: 3-Phenylpropanal.pdf (3.3MB)
This file has been downloaded 1021 times

[Edited on 3-8-2018 by Corrosive Joeseph]

Loptr - 2-8-2018 at 07:51

So how should I test for the presence of that double bond if the aldehyde is in fact not touched? Should I oxidize the aldehyde to the carboxylic acid using sodium chlorite, and then use KMnO4 to test for the double bond?

clearly_not_atara - 2-8-2018 at 08:29

Quote:

According to this:

https://pubchem.ncbi.nlm.nih.gov/compound/3-Phenylpropanal#s...

3-phenylpropanal melts at 47 C, while cinnamaldehyde melts at -5 C:

https://en.wikipedia.org/wiki/Cinnamaldehyde

To be honest I find this a bit suspicious because cinnamaldehyde seems like it should be more polar and have a higher mp, but anyway, those are the numbers, so that should serve to differentiate the compounds.

You should do OK with dithionite as long as you control the stoichiometry. Dithionite does reduce carbonyl groups, but it will generally reduce alkenes first.

Loptr - 2-8-2018 at 08:45

Quote:

Ahh, so I could also attempt to separate them via distillation under vacuum. Maybe first try and see if I can separate them with partial crystallization.

3-phenylpropanal, BP 217.7*C
cinnamaldehyde, BP 248*C

[Edited on 2-8-2018 by Loptr]

DraconicAcid - 2-8-2018 at 09:05

That surprises me, because 3-phenylpropanoic acid has a melting point of 47 oC.

Loptr - 2-8-2018 at 10:40