Sciencemadness Discussion Board

Oxidation of styrene to phenylacetaldehyde

phendrol - 20-11-2012 at 02:32

I'm thinking about oxidizing styrene monomer to phenylacetaldehyde. I know styrene can be oxidized to the epoxide and then further to phenylacetaldehyde. Styrene oxide can be prepared from styrene via a chlorohydrin. Nicodem posted a nice, OTC recipe with TCCA:
http://www.sciencemadness.org/talk/viewthread.php?tid=15284#...
The method is simple and fast. The chlorohydrin can be surely prepared using sodium hypochlorite as well. But how can I rearrange the epoxide to the aldehyde? Is there any way to oxidize it further with TCCA or sodium hypochlorite? Can a one pot oxidation from styrene to the epoxide and then further to the aldehyde be done?

In this thread:
http://www.sciencemadness.org/talk/viewthread.php?tid=7641
Nicodem wrote that he was able to do a one pot oxidation of styrene all the way to phenylacetic acid, using H2O2, H2SO4 and formic acid in water. Now phenylacetic acid is not what I'm after, but if a reaction like that is possible, I'm sure it could be modified just a bit to stop at the aldehyde. I was trying to find some info on this and the closest thing I found is the oxidation of isosafrole with peracids.
https://www.erowid.org/archive/rhodium/chemistry/peracid.htm...
So if I'll use styrene instead of isosafrole what can I expect? Is it possible to get phenylacetaldehyde this way? Or maybe it would go even further with the oxidation and yield PAA?

Methyl.Magic - 20-11-2012 at 09:09

If you want to get the phenylacetaldehyde I dont know where is the problem of the peracid method. Styrene oxyde are not usually formed with peracid because they are very prone to be opened an acidic environement because of the stabilised benzylic carbocation. But to form the phenylacetaldeyde you MUST open the epoxide, so for me I don't see any problem here.

Another problem is the stability of the phenylacetaldehyde. it's not very stable. Moreover the commercial product is never sold as the pure form but always in solution. Maybe it's very prone to overoxydation to phenylacetic acid by oxygen the same way as benzaldehyde. If the case it's possible you cannot use strong oxydant such as peroxide especially with the presence of acid but check the stability of the compound first.

FSO3Me

phendrol - 21-11-2012 at 06:20

Well the peracid is advantaging because it can be a one pot synthesis and as soon as I'll get some formic acid I'll attempt it.

I want to follow one of the methods from rhodium archive (link in the first post) substituting styrene for isosafrole. It looks promising and the only thing I worry about is that phenylacetaldehyde may be further oxidized to phenylacetic acid.

SM2 - 21-11-2012 at 06:47

if you want phenylacetaldehyde in copious amounts, react D-LPhenylalanine to a well stirred solution of strong bleech, or HTH. The yellow oil with the sickly sweet smell is immediately apparent. Try to distill it out and separate ASAP, and make the bisulfite adduct, which IS stable.

Nicodem - 21-11-2012 at 07:52

But what exactly is wrong with the already published procedures for the styrene oxide to phenylacetaldehyde transformation?

I can understand the reluctance to consider some of the references for the rearrangement in the liquid phase which use non-trivial reagent or conditions, but what for example is wrong with the procedure described in DOI: 10.1080/00397919508011817? Or US4650908 and DE3708737? The setup is somewhat involved, but it is nothing that an average amateur could not do with some effort.

SM2 - 21-11-2012 at 17:29

Nicodem;

My intuition tells me such a reaction benefits greatly from experience working the procedure. I recently had a straight forward synthesis fail on me, and I did everything (or so I thought), strictly, according to the instructions. As to the beginning of your question "what is wrong...", I'd say the person in question would prefer an easier route, like, for instance, titration until a color change occurs. The Styrene oxide route>PhenylAcetaldehyde is far cheaper than starting from the pure amino acid as your feedstock.;)

kristofvagyok - 22-11-2012 at 14:11

I am reading an old (1995) Aldrichimica Acta and there is a reaction in it what fits to this topic.

It is about catalytic oxidative rearrangements made with Tl(III)-nitrate (TTL). There is 3 article mentioned here what are about to turn styrenes to phenylacetaldehyde-dimethyl acetals by some methanol and some TTL.

Check them out, they could be interesting:
J. Am. Chem. Soc. 1973, 95, 3635
Liebigs Ann. Chem. 1962, 656, 204
S. Can. J. Chem. 1973, 51, 2366

P.S.: TTL is quite toxic, but it is needed in catalytic amounts, could be reused, and it is a pretty awesome reagent.

tetrahedron - 22-11-2012 at 16:30

Quote: Originally posted by kristofvagyok  
pretty awesome reagent.

and especially OTC =)

check this out for more on that route:

McKillop, A., Hunt, J. D., Taylor, E. C., and Kienzle, F., "Thallium in Organic Synthesis: XX. Oxidative Rearrangement of Olefins with Thallium (III) Nitrate--A Simple One-Step Synthesis of Aldehydes and Ketones," Tetrahedron Letters, No. 60, 1970, pp. 5275-5280.

phendrol - 27-11-2012 at 10:31

The reaction is attractive because there is no problem with acquiring the reagents where I live. Furthermore the peracid oxidation looks like it can be run in a one pot reaction, which is very advantageous. Oxidation via the chlorohydrin uses OTC reagents and gives decent yields, but leads only to styrene oxide. I'm wondering if it's possible to oxidize it further with hypochlorouse acid? Maybe a ring opening with an acid and rearrangement?

Anyway I'm waiting for my order of chemicals and after I'll get them I'm planning to do as follows

I'll prepare some performic acid by mixing formic acid with hydrogen peroxide. Next I'll prepare a solution of styrene in DCM with a sodium carbonate/bicarbonate buffer. The performic acid will be then added dropwise to the solution with stirring left for 16 hours. Followed by extraction of the organic phase, and after some work up, dissolving it in methanol and lightly boiling with dilute sulfuric acid.

As an alternative I was thinking about preparing the epoxide via the chlorohydrin route, then forming styrene glycol as described here:

http://www.scribd.com/doc/55131328/furanoside-rhee

and boiling it in methanol with dilute h2so4 to form the aldehyde.

[Edited on 27-11-2012 by phendrol]

[Edited on 27-11-2012 by phendrol]

Nicodem - 28-11-2012 at 07:00

Quote: Originally posted by phendrol  
Followed by extraction of the organic phase, and after some work up, dissolving it in methanol and lightly boiling with dilute sulfuric acid.

It appears to me that you did not do the literature work properly. There is a reason why silica-gel is used as an acid in that Synth. Commun. article. Phenylacetaldehyde decomposes in such acidic environment as diluted sulfuric acid. Also, how is such an rearrangement supposed to be easier than the given literature example which claims nearly quantitative yields, easy to obtain solvent and catalyst, and a ridiculously simple isolation? You shouldn't be believing every nonsense that Fennel Ass Ih Tone manages to post - I bet he didn't even bothered reading the article before hitting the reply button!

phendrol - 30-11-2012 at 03:15

Nicodem you are right.

The extra work up is not a big problem. Most of my work will be consumed by building an aspirator vacuum satation. I'll need it in the first step (styrene --> chlorohydrin --> styrene oxide). Unless someone has an idea how to separate styrene oxide from unreacted styrene and side products without using any vacuum. Maybe forming an azeotrope?

[Edited on 1-12-2012 by phendrol]

phendrol - 13-12-2012 at 06:42

I've managed to prepare some styrene oxide and I'm getting ready to rearrange it in the gas phase. I need an advice thou. I'm not sure how the silica gel catalyst should be placed. Should it just be like a tube packed with silica dioxide powder or beads? Or should the catalyst be placed on something?

I just don't want the whole thing to explode because of high pressure.

US4650908

TheCatalyst - 12-1-2013 at 23:38

Phendrol,

Have you had any success ? By the way why don't you use the liquid phase isomerization of styrene oxide. Seems to me it would be much easier.

Lemini, C. , Ordo≁ez, M. , Pérez-Flores, J. and Cruz-Almanza, R.(1995) 'Synthesis of Aldehydes from
Oxiranes using Silica Gel as Reagent', Synthetic Communications, 25: 18, 2695 — 2702
To link to this Article: DOI: 10.1080/00397919508011817
URL: http://dx.doi.org/10.1080/00397919508011817

General Procedure for the conversion of oxiranes into aldehydes. In a threenecked
round bottom flask equipped with a magnetic stirrer a solution of 1 g of
oxirane in 20 ml of ethylacetate or acetone was placed and, 1 g of silica gel was
added. The reaction mixture was stirred vigorously at room temperature until the
oxirane disappeared (monitoring by TLC). Most of the reactitvis were finished
within 30 min. When the reaction was completed the silica gel was removed by
filtration, the filtrate dried on Na,SO, and the solvent evaporated under reduced
pressure.

phendrol - 30-1-2013 at 08:57

Well to be honest I couldn't do much because I haven't got a vacuum pump. An aspirator is no good because water pressure is to low at my place. Because of that I can't purify the epoxide via vacuum distillation. When I made a run with it, the silica gel was covering with tar pretty fast.

But this method sounds super easy. I definitely will try it and post results. Thanks!!!

Nicodem - 12-8-2013 at 08:33

An example of the acid catalyzed styrene oxide rearrangement to phenylacetaldehyde (applying H3PO4) and its concurrent acetalization with another styrene oxide equivalent is described at the Synthetic Pages:
Acid mediated cyclodimerization of styrene oxide to 2-benzyl-4-phenyl-1,3-dioxalane; ​​​​acetal formation (DOI: 10.1039/SP312)

Crowfjord - 1-2-2016 at 12:10

Tetrahedron Letters 55 (2014) 5047–5051 describes the reactions of several amino acids with sodium hypochlorite in phosphate buffer. The buffer, pH, dilute conditions, and slow addition are necessary to achieve good yields and avoid side reactions. From the supplementary materials:
Quote:

General Procedure for sodium hypochlorite oxidation. To a vigorously stirring solution of amino acid (1 mmol) in 250 mL of sodium phosphate buffer (10 mM, pH 7.0) was added a solution of NaOCl (1 equivalent as a 0.1 M aqueous solution) slowly over 10 minutes via syringe pump in a 37 °C warm room or water bath. The resulting solution was stirred vigorously at this temperature until the reaction was judged to be complete by HPLC (1-2 hours). In general, the reaction may be stopped after 2 hours if monitoring is inconvenient. The solution was then extracted into dichloromethane (4 x 40 mL), washed with brine (2 x 50 mL), dried over MgSO4, and the solvent removed under reduced pressure in an unheated water bath to afford the desired aldehyde.
Quote:
2-phenylacetaldehyde (2e). DL-Phenylalanine (0.165 g, 1 mmol) was dissolved in 250 mL of 10 mM pH 7 phosphate buffer and reacted by the above procedure for 2 hours to yield 72 mg of 2e (60 %) as a yellow oil. 1H-NMR, LRMS, and HPLC data matched an authentic commercial sample (Sigma-Aldrich).

clearly_not_atara - 1-2-2016 at 17:34

Step 1: styrene + HBr + H2O2 >> phenethyl bromide

Step 2: http://pubs.acs.org/doi/abs/10.1021/ja01524a080?journalCode=...

chemrox - 9-2-2016 at 13:18

would you please post the pdf? in refs? or here..

clearly_not_atara - 10-2-2016 at 13:08

Sure. The reaction is like this:

RHBr + AgOTs >> RHOTs + AgBr (s)
RHOTs + DMSO >> RO + HOTs + Me2S (g)

Silver tosylate is soluble in organic solvents but not water, so can be precipitated from a solution of AgNO3 and a tosylate. I do not know, but I strongly suspect, that other sulfonic acids work just as well (as long as they're inert).

Attachment: tosylatealdehyde.pdf (684kB)
This file has been downloaded 823 times

madcedar - 10-2-2016 at 18:50

Quote: Originally posted by clearly_not_atara  
Step 1: styrene + HBr + H2O2 >> phenethyl bromide

Step 2: http://pubs.acs.org/doi/abs/10.1021/ja01524a080?journalCode=...


Thank you for the reference. My problem is with your Step 1, I think it makes styrene dibromide and not phenethyl bromide.

DraconicAcid - 10-2-2016 at 18:55

Quote: Originally posted by madcedar  
My problem is with your Step 1, I think it makes styrene dibromide and not phenethyl bromide.


HBr will add across a double bond following Markovnikov's rule in the absence of peroxides, and add the other way in the presence of peroxides. The hydrogen peroxide isn't going to turn the HBr into bromine.

S.C. Wack - 10-2-2016 at 22:28

Does there exist actual preparations that used hydrogen peroxide in step 1, that got a phenylacetaldehyde in step 2?

clearly_not_atara - 11-2-2016 at 10:15

See http://en.wikipedia.org/wiki/Markovnikov's_rule#Anti-Markovnikov_reactions

The method with HBr/cat. H2O2 is a classic; you can find examples in most chemistry textbooks (you can usually find a cheap one at charity book-selling events and the like). Wiki does describe a synthesis of phenylacetaldehyde using a similar methodology with water and phenylacetylene. See also:

http://www.chemicalforums.com/index.php?topic=58919.0

madcedar - 11-2-2016 at 16:09

Thank you for the clarification DraconicAcid and clearly_not_atara, great stuff.

zed - 11-2-2016 at 16:50

And then, there are modifications of the Wacker.

Looks interesting, maybe Iĺl finish reading it tomorrow.

http://www.google.com/patents/US7582750

S.C. Wack - 11-2-2016 at 17:03

Quote: Originally posted by clearly_not_atara  
See http://en.wikipedia.org/wiki/Markovnikov's_rule#Anti-Markovnikov_reactions

The method with HBr/cat. H2O2 is a classic; you can find examples in most chemistry textbooks (you can usually find a cheap one at charity book-selling events and the like). Wiki does describe a synthesis of phenylacetaldehyde using a similar methodology with water and phenylacetylene. See also:

http://www.chemicalforums.com/index.php?topic=58919.0


In other words, no. OK.

PS: Has any chemistry book ever mentioned a HBr/H2O2 in any preparative context? BTW that's bromine and water, etc.

Really I want to know if these things are out there, but I'm also kind of hinting that if they're not...the directions that are out there to put the Br at that spot are specific and it looks like they have to be. But that's not all that important because no one will go to the aldehyde from there anyways.

[Edited on 12-2-2016 by S.C. Wack]

clearly_not_atara - 11-2-2016 at 20:45

Quote:
In other words, no. OK.


http://www.chem.ucalgary.ca/courses/350/Carey5th/Ch06/ch6-4-...
Quote:
PS: Has any chemistry book ever mentioned a HBr/H2O2 in any preparative context? BTW that's bromine and water, etc.


http://pubs.acs.org/doi/abs/10.1021/ja00176a075
http://pubs.acs.org/doi/abs/10.1021/jo00110a040

I guess it turns out other catalysts are better. Either hv or RCOCBrR'R"/O2 (hv sounds much easier).

[Edited on 12-2-2016 by clearly_not_atara]

S.C. Wack - 12-2-2016 at 04:10

Peroxide and hydrogen peroxide continue to be different things, in your links there is no hydrogen peroxide. Also, organic peroxide gives mainly the wrong isomer under these nonspecific conditions (solvent should be mentioned).

clearly_not_atara - 12-2-2016 at 10:05

One is a subset of the other. Regardless, your complaint is offtopic. The anti-Markovnikov addition of HBr to styrene is simple to achieve; H2O2 might not be the best catalyst, but who is going to publish a synthesis of something so trivial, especially if the method is suboptimal? The other papers provide much better ideas.

zed - 12-2-2016 at 14:47


http://www.google.com/patents/US7582750

Oh, the above paper? About a page or two in, they cut to the chase.
The tables of results, and conditions, are present, but they have been compressed.

When styrene (20) was treated with 1.03 equiv Cl2pyNO and 1.0 mol % 1 in refluxing CH2Cl2 for 5 h, a mixture of styrene oxide and phenylacetaldehyde (27) was obtained in 90% and 10% yield, respectively (Collman et al. J. Am. Chem. Soc. (1986), Vol. 108, page 2588; Burrows et al. J. Am. Chem. Soc. (1988), Vol. 110, page 6124; Minisci et al. J. Am. Chem. Soc. (1995), Vol. 117, page 226; Gross et al. Angew. Chem. Int. Ed. (2000), Vol. 39, page 4045; Gray et al. Angew. Chem. Int. Ed. (2001), Vol. 40, page 2132). To our surprise, adding more catalyst 1 and allowing the reaction to proceed for a longer time resulted in complete conversion of styrene oxide to aldehyde 27. For example, reaction of styrene with 1.03 equiv Cl2pyNO in the presence of 2.0 mol % 1 in CHCl3 at 60° C. for 12 h afforded 27 in 99% yield; no benzaldehyde was observed (Gray et al. Inorg. Chim. Acta (1998), Vol. 270, page 433). Other styrene derivatives 21-25 could also be converted to the corresponding arylacetaldehydes 28-32 in excellent yields (FIG. 6). However, for the non-aromatic alkene 26, only the epoxide product was obtained.

[Edited on 12-2-2016 by zed]

[Edited on 12-2-2016 by zed]

S.C. Wack - 12-2-2016 at 17:26

Quote: Originally posted by clearly_not_atara  
One is a subset of the other. Regardless, your complaint is offtopic. The anti-Markovnikov addition of HBr to styrene is simple to achieve; H2O2 might not be the best catalyst, but who is going to publish a synthesis of something so trivial, especially if the method is suboptimal? The other papers provide much better ideas.


You're telling me how easy it is, but I bet you haven't even read the original literature that started these textbook sentences. H2O2/HBr preparations are in fact out there and numerous, as expected the reactions are those of bromine and are obviously not radical additions. Feel free to cite a preparation with radical hydrobromination on any double bond that uses just H2O2 and HBr.

There is no such thing as a catalytic amount of hydrogen peroxide in HBr, or vice versa. There is no propagation, there is a reaction until one is gone and that's it. Bromine, water, and styrene is a recipe for styrene bromohydrin.

(EDIT: vice-versa was a step too far!!! Obviously HBr with H2O2 oxidant and the molecule being operated on gives bromine then HBr then back to bromine.)

It's true, responding to your post, I have nothing on topic to say. The reactions of styrene chlorohydrin in the vapor phase however is on topic regardless of a certain lack of convenience:

Attachment: jacs 67_518_1945.pdf (384kB)
This file has been downloaded 813 times

[Edited on 13-2-2016 by S.C. Wack]

clearly_not_atara - 14-2-2016 at 11:06

1. You're wrong, I have read it.

2. No. I'm obviously referencing a reaction that's common knowledge, if I were specifying conditions I'd give them. I've no reason to encourage your flamebaity nitpicking.

S.C. Wack - 14-2-2016 at 11:42

Quote: Originally posted by clearly_not_atara  
1. You're wrong, I have read it.

2. No. I'm obviously referencing a reaction that's common knowledge, if I were specifying conditions I'd give them. I've no reason to encourage your flamebaity nitpicking.


There is absolutely no common knowledge about using hydrogen peroxide in place of organic peroxide in this reaction, because it isn't possible. Hydrogen peroxide is not going to be regenerated from water full stop. If saying that your impossible reaction is impossible is nitpicking, maybe you're at the wrong site. If you wish for me to stop telling you that you're wrong, all you have to do is either prove you're right or stop making these claims.

[Edited on 14-2-2016 by S.C. Wack]

Nicodem - 15-2-2016 at 08:34

Before this end up with unnecessary misunderstanding and accusations...

Neither hydrogen peroxide or any other peroxide can be used as a catalyst for the radical addition of HBr on alkenes. In fact, I know no catalysts for this reaction (though they might exist). Radical additions of HX (where X is Br, I, SR, PR2, etc.) require some kind of radical initiation which can be chemical (with radical initiators like AIBN, diacyl peroxides, oxygen, etc.), photochemical (UV) or radiochemical (gamma or other ionization type). The reaction is rapid (it's a radical chain reaction) and for this reason it does not even need catalysis.

Hydrogen peroxide is rapidly reduced by HBr to yield H2O and Br2 and cannot be used neither as a catalyst or radical initiator. In fact, for this reason hydrogen peroxide is commonly used as an in situ oxidant for HBr in electrophilic aromatic brominations.

Radical addition of HBr on styrene is not some trivial reaction. A lot of conditions need to be fulfilled to slow down the otherwise much faster competing reactions like the electrophilic addition and polymerization. Anhydrous conditions and a highly non-polar solvent are used to prevent the electrophilic addition of HBr (already gassing the reaction mixture with dried HBr is not trivial). Traces of water will catalyze the electrophilic addition yielding 1-bromo-1-phenylethane. Low styrene concentrations (e.g., by slow addition of styrene) and higher HBr concentrations can slow down the polymerization.

Preparative examples of phenetyl bromide preparations from styrene using the radical HBr addition do exist, but as far as I could find, they are all but one written in Chinese (though admittedly, I did not spend much time searching). Yields can be excellent, except that achieving them is not simple. Here are a few Chinese references from a 5 minutes SF search:

Huaxue Shiji, 2006, 28, 326-328 (in CCl4, UV initiation, 96% yield)
Huaxue Gongye Yu Gongcheng (Tianjin, China), 23(5), 385-388 (in heptane, AIBN initiation, 92% yield)
Shandong Huagong, 2004, 33, 8-34 (in petroleum ether, unspecified initiator, 91%)
CN101255095 (in heptane, (BzO)2 initiation)
CN1429799 (in 1-bromohexane, AIBN initiation)
JP09040591 (O2 initiation)

clearly_not_atara - 15-2-2016 at 10:56

I posted a ref in English four posts up:

http://pubs.acs.org/doi/abs/10.1021/jo00110a040

It discusses the reaction in some detail. In any case, is it *really* too much for me to expect people to be familiar with the radical addition of HBr to alkenes (other HX suck for this reaction so they don't matter) and either know how to do it or know where to look it up? Yes, I got the conditions wrong. Congratulations. But I subsequently got the conditions right and yet here we are arguing about a line in a post from a week ago that doesn't even have any words in it.

[Edited on 15-2-2016 by clearly_not_atara]

S.C. Wack - 15-2-2016 at 21:21

We're using the term catalyst loosely, obviously. The particular examples I've had in mind are JACS 61, 2693 (1939) and the patent it mentions, GB438820.

madcedar - 16-2-2016 at 16:11

Quote: Originally posted by phendrol  
Well to be honest I couldn't do much because I haven't got a vacuum pump. An aspirator is no good because water pressure is to low at my place. Because of that I can't purify the epoxide via vacuum distillation. When I made a run with it, the silica gel was covering with tar pretty fast.

But this method sounds super easy. I definitely will try it and post results. Thanks!!!


You may not have used enough solvent and I think everything has to be anhydrous to get from stryene oxide to phenylacetaldehyde via silica gel, otherwise you'll end up with the diol.

Any comments on this will be very welcome.

Chemi Pharma - 8-5-2016 at 08:21

Everybody here in this discussion post are talking about styrene as starting material to sintesize some phenylacetaldehyde. Anybody thought about the use of phenethyl alcohol as starting material?

Phenethyl alcohool is sold at cheap prices by perfumery flagrancies stores as a litre bottle.

Just oxidate the alcohol with CA(OCL)2 - HTH pool and alumina in a microwave for 2 minutes or reflux the mixture for 4 hours and you get pure phenylacetaldehyde in >95% yeld.

See the papers below about alcohol oxidation to aldehydes by HTH pool and alumina:





Attachment: alcohol oxidation by CaOCL to aldehydes.pdf (161kB)
This file has been downloaded 745 times

Attachment: Microwave Assisted Selective Oxidation of Benzylic Alcohols with Calcium Hypochlorite under Solvent-Free Conditions.pdf (62kB)
This file has been downloaded 728 times

byko3y - 9-5-2016 at 08:00

None of those articles mentiones 2-phenylethylalcohol. And that's for reason, because the procedure does not work for this substrate, yielding a complex mixture of products.

Chemi Pharma - 9-5-2016 at 13:40

Do you have references about that? about only working with benzilic alcohools and not with phenyl alkyl alcohols with alifatic chains?

I trace a parallel with the oxidation of alcohols to acids with nickel peroxide (hipoclorite + nickel salt) that i read from an japanese article, that i bring to you all, below, as an attachment.

If you oxidate the phenyl alkyl alcohol at cold temperatures like 0º C, this afford phenyl alkyl acid with no chain split. See somewhere in the paper that they got this result with phenyl propyl alcohol with 70,5% yield of phenyl propionioc acid and a small amount of benzoic acid:

"...In the cases of alcohols possessing an active
methylene group in the molecule, the methylene
group was in part simultaneously oxidized at room
temperature to give compounds with less carbon
atoms. When the reaction temperature was low-
ered in such cases, however, the oxidation of a
carbinol group proceeded so predominantly that
the corresponding acid was obtained in good yield.
Thus the oxidation of y-phenylpropyl alcohol at
0" afforded 70.5% yield of y-phenylpropionic acid
together with a small amount of benzoic acid,
whereas at 30" it gave 56.7% yield of y-phenyl-
propionic acid and 17.6% yield of benzoic acid..."

Hey! Isn't a good way to produce tons of ever watched Phenyl Acetic Acid?:cool:

Attachment: Oxidations with nickel peroxide (NICL2 + NAOCL).pdf (567kB)
This file has been downloaded 802 times

[Edited on 9-5-2016 by Chemi Pharma]

clearly_not_atara - 9-5-2016 at 15:24

Just use an Oppenauer oxidation with benzoquinone, much simpler. You can use aluminum t-butoxide or just react your 2-phenylethanol with Al amalgam to get things started, IIRC.

https://www.researchgate.net/publication/244761206_On_Quinon...

This is usually the easiest alcohol oxidation.

Chemi Pharma - 9-5-2016 at 16:19

Thanks Clearly for the reference.

Ok I understood about the oppenauer, but didn't understand what you means about "just react your 2-phenylethanol with Al amalgam to get things started".

The latter thing you said it's about a reduction reaction, given probably phenylethane.

Could you make the things clear(ly) to me?:D

byko3y - 10-5-2016 at 00:40

Chemi Pharma, I have no references at hand, that's just my speculations, which happen to be true.
2-phenethyl alcohol is extreemely labile to oxidation at benzylic position, even more than 3-phenylpropanol. Of course, nickel peroxide might give as high as 50% yield for phenylethanol oxidation to phenylacetic acid.

Chemi Pharma - 10-5-2016 at 04:03

Ok byko3y, what do you think about a moffatt oxydation of 2-phenylethyl alcohol with DMSO and P2O5 and Et3N? By analogy to the Swern procedure, it seems the different mechanism of this type of alcohol oxidation doesn't affect the benzilic carbon.

Do you think i can achieve phenylacetaldehyde this way?

Attachment: DMSO - Phosphorus pentoxide - triethylamine (PDT) oxydation to aldehydes and ketones.pdf (278kB)
This file has been downloaded 656 times

[Edited on 10-5-2016 by Chemi Pharma]

clearly_not_atara - 11-5-2016 at 12:12

The reaction of an alcohol with aluminum amalgam or activated aluminum produces an aluminum alkoxide and hydrogen:

6ROH + 2Al >> 3H2 + 2Al(OR)3

The alkoxide is oxidized to the aldehyde by benzoquinone.

Chemi Pharma - 11-5-2016 at 12:24

Thanks for the explanation Clearly. I've got it.

Do you have any papers about aluminium alkoxides oxidation with benzoquinone?

And what do you think about a moffat oxidation of 2-phenethyl alcohol?

Could afford phenylacetaldehyde in reasonable yields?

CuReUS - 12-5-2016 at 00:09

atara,that's a smart idea,using the alcohol you want to oxidise to make its own alkoxide.Then you wouldn't have to use Al-tert butoxide separately. But isn't there a chance of condensation of the aldehyde formed due to the primary alkoxide(from phenyl ethanol ? ).Isn't that why they use a sterically hindered and bulky alkoxide like t-butoxide ?

if oppenauer oxidation is done,instead of using benzoquinone,cinnamaldehyde could be used,which would get reduced to cinnamyl alcohol.

other amateur friendly ways to oxidise alcohols to aldehydes would be NBS,lead tetracetate/pyridine, SeO2,DMP,Oxone to name a few.

[Edited on 12-5-2016 by CuReUS]

clearly_not_atara - 12-5-2016 at 12:53


Big problem with DMSO oxidations is the Me2S byproduct. This flammable toxic gas is not easy to scrub from efflux gas because it's very nonpolar. The safer modification is the Corey-Kim version, using a haloimide and catalytic amounts of a thioether.

It's not clear what the best thioether is -- methionine hydantoin comes to mind, but has solubility issues. Dodecyl methyl sulfide is popular. There are few OTC options; dibenzyl sulfide isn't too hard I guess.

CuReUS - 13-5-2016 at 09:48

Quote: Originally posted by clearly_not_atara  

Big problem with DMSO oxidations is the Me2S byproduct. This flammable toxic gas ...

not to mention the stench :D
Quote: Originally posted by CuReUS  

if oppenauer oxidation is done,instead of using benzoquinone,cinnamaldehyde could be used,which would get reduced to cinnamyl alcohol.

cinnamyl alcohol could be converted to propenylbenzene with this reaction
https://en.wikipedia.org/wiki/Barton%E2%80%93McCombie_deoxyg...

or this-http://www.organic-chemistry.org/abstracts/lit3/641.shtm

also I was thinking,How about using alcohol dehydrogenase enzyme to oxidise phenylethanol to phenylacetaldehyde ?

karlos³ - 13-5-2016 at 13:53

Pyridinium chlorochromate is also a very amateur friendly oxidant, especially for the conversion of alcohols to aldehydes. I like it very much, as it is easy to prepare and a convenient reagent.

gravityzero - 2-11-2016 at 15:39

After reading the thread in full, it is still unclear if anyone is able to get to Styrene Oxide simply using a peracid, such as performic acid or peracetic acid.
It is assumed it would work, but OrgSyn uses perbenzoic acid which I had never heard of until today. Not really a miracle or anything.

If anyone can confirm a success using a more convenient peracid or oxone that would be helpful.

Then it is stated using silica gel to isomerize the oxirane to the aldehyde.
Sorry for any spoonfeeding. Just want to make sure I'm understanding all this.

NitreRat - 2-11-2016 at 18:35

Quote: Originally posted by gravityzero  
After reading the thread in full, it is still unclear if anyone is able to get to Styrene Oxide simply using a peracid, such as performic acid or peracetic acid.


I have performed a few epoxidations of alkenes with peracids (including in-situ peracetic acid), albeit in a formal lab setting. Peracids are strong oxidising agents so the actually reaction occurs quite readily, the real difficulty is trying to isolate the epoxide before any nasty nucleophiles can attack the poor epoxide and break open its ring with their electrons...

Because of the inherent acid present with peracid epoxidations, any water, amines or alcohols present in the reaction mixture can react with the epoxide after it's formed - creating alcohols and vicinal diols. These alcohols and diols/glycols can then be oxidized and cleaved by the peracid forming aldehydes, ketones, hydroxy-ketones, diketones and carboxylic acids.

If you're using anhydrous peracetic, performic or (m-chloro)perbenzoic acid the hydrolysis can be avoided. If you're doing a one-pot in-situ peracid epoxidation with H2O2(aq) + acid + alkene, you will inevitably end up with the hydrolysis and oxidation products. With styrene, I would expect phenylacetic acid, phenylglyoxylic acid and benzoic acid to be the main products of this reacation.

[Edited on 11/3/2016 by NitreRat]

purplephanta - 5-1-2017 at 05:00

Hello Phendrol, or anyone else for that matter,

Have you had success using the method referenced by Nicodem and TheCatalyst?

DO.108/00397919508011817 (http://dx.doi.org/10.1080/00397919508011817)

If so, what were the pitfalls;

Is the reaction not scalable?
Is very pure, anhydrous styrene oxide required?
Can the ethyl acetate be recycled or is it consumed?

Thanks

styrene oxide to phenylacetaldehyde via the pinacol rearrangement?

madcedar - 17-6-2017 at 23:14

In theory, mixing styrene oxide and a non-halo acid (H2SO4) should give styrene glycol. A halo acid such as HCl will give a halohydrin instead.

styrene glycol.png - 3kB

On further mixing and heating phenylactaldehyde should be the product (see this Youtube video on the Pinacol Rearrangement).

phenylacetaldehyde.png - 3kB

I'm assuming roughly following this procedure in the attached pdf (Organic Syntheses, Coll. Vol. 1, p.462 (1941); Vol. 5, p.91 (1925)) and substituting an equal molar amount of styrene oxide for pinacol will give the desired results.

I don't have any glassware to try this out myself but any comments on the theory are welcome.

Attachment: Pinacol Rearrangement cv1p0462.pdf (298kB)
This file has been downloaded 681 times

[Edited on 18-6-2017 by madcedar]

JJay - 18-6-2017 at 00:02

I ran across this paper a while back. I can't read most of it, but according to the authors, it's possible to do the rearrangement from styrene oxide to phenylacetaldehyde using a catalyst consisting of nitric acid on activated carbon in ethyl acetate at 75 C:

Preparation of Phenylacetaldehyde and 1, 3-Dioxolanes from Styrene Oxide with Mineral Acid-Treated Activated Carbon Catalyst

Chemi Pharma - 22-6-2017 at 09:08

Better produce phenylacetaldehyde from the isomerization of styrene oxide with silica gel in acetone, at room time for an hour, like said in the paper i bring below.

I think the better route to phenylacetaldehyde is dissolving styrofoam in acetone, mix with MgSO4 as a cataliser and distill at 250-300ªC the styrene monomer with the acetone all onto the same flask.

The styrene in acetone obtained react with TCCA to form the chloridrine and further with KOH to form the epoxide.

Finally, proceed with the epoxide isomerization with silica gel as I said above.

Here's the papers:

Attachment: styrene oxide to phenyl acetaldehyde with silica gel.pdf (981kB)
This file has been downloaded 891 times

Attachment: styrene from polystyrene.pdf (1MB)
This file has been downloaded 636 times

Attachment: styrene to styrene oxide with TCCA and KOH.pdf (234kB)
This file has been downloaded 818 times

JJay - 14-7-2018 at 20:57

I've read a number of interesting papers about isomerization of styrene oxide with exotic catalysts, and there is a U.S. patent regarding the use of silica gel in the vapor phase, but doing it with silica gel in half an hour at room temperature... is that really possible?

Apparently, it is pretty easy to isomerize styrene oxide to phenylacetaldehyde in a bomb reactor with heat:

US3860614A - Thermolysis of Styrene Oxide

Attachment: Thermal Rearrangement of 1,2-Epoxyethylbenzene.pdf (252kB)
This file has been downloaded 502 times

I'm not terribly familiar with sealed tube reaction protocols, but I think the thermolysis could be performed using the ol' toaster oven with a long extension cord trick and some sandbags. I'm not seeing why you couldn't use an unlined iron pipe sealed with plumber's tape to contain the reaction, although I would advise extreme caution of course.

If you wanted to get really fancy, you could use an autoclave or a Parr reactor.

notoxicshit - 15-7-2018 at 10:17

Works in acetone over silica gel in high yield. Forgot the name of the paper though it should be easy to find.
However they dont mention how dry the acetone has to be. That may be the reason I failed once but I got too confident and didnt check before the follow-up reaction.
But it seemed legit.
Report back please.

JJay - 15-7-2018 at 11:18

Chemi Pharma posted the paper directly above. Silica gel 60 is pretty expensive... I'd be more inclined to try heat/pressure... the temperatures required are nothing ridiculous, and no fancy apparatus is required.

Nicodem mentioned an expired Dow Chemical patent on a continuous vapor phase process for isomerizing styrene oxide to phenylacetaldehyde. It uses silica gel and water. The process looks a little involved, but it might be useful if you want to produce more than a liter or so of phenylacetaldehyde.

Fyndium - 23-7-2020 at 11:47

I have been on this project since last weekend and I have some issues.

I prepared the styrene oxide by TCCA method, but I did not vacuum distill it, instead I just removed acetone, washed it with brine and dried on calcium sulfate.

Next I attempted the rearrangement by using 1:1 per weight of silica gel 60 (for chromatography) and the prepared oxide, but instead of the article I accidentally used only less than half of the acetone. I stirred the mixture for half an hour and then vacuum filtered the silica gel off. I then removed the acetone and tried to make bisulfite adduct for the aldehyde, but I have zero reaction.

Thing I did not check was pH after brine washing and drying. I wonder if residual NaOH from TCCA reaction could hinder the silica gel acidity?

[Edited on 23-7-2020 by Fyndium]

Fyndium - 25-7-2020 at 04:26

Second attempt. I vacuum distilled the styrene oxide succesfully and attempted a rearrangement. pH was in control, but zero reaction with bisulfite adduct was detected. Possible issues could be that acetone was not dry enough and it could have prior contaminated the silica gel as well, and second cause that could have actually destroyed the aldehyde was distilling off the acetone. I think I should give it another try and use carefully dried acetone and dry the silica gel prior, and instead of distilling acetone, crash the aldehyde out with water and reclaim the acetone later.

Edit: now when I fried silica gel in oven, my entire house smells of phenylacetaldehyde. So there sure is some of it, but maybe the reaction time was too short or something stopped the reaction, because according to the article the isomerization should take only 30 minutes.

[Edited on 25-7-2020 by Fyndium]

JJay - 25-7-2020 at 09:35

How do you know that you have successfully synthesized the epoxide? For that matter, how do you know that you synthesized the halohydrin? I have had my eye on this synthesis for a while, but I planned to use DCCA or bromine water instead of TCCA because I never seem to have much luck with it.

I probably wouldn't use acetone as the solvent. Chloroacetone is quite nasty, and bromoacetone has been used as a war gas. I don't think TCCA reacts very quickly with acetone at neutral or basic pH, but even small amounts of halogenated acetone are to be avoided. Also, the haloform reaction would be a side reaction that would decrease the pH and consume the halogen.

Fyndium - 25-7-2020 at 11:27

I have been under impression that the synthesis described in a link at the first post of this topic is valid. I have done it multiple times with results matching the description, and density and bp of styrene oxide seems to be where it should be. I just finished vacuum distilling this presumed epoxide and I came here to check what pressure my vac pump is able to generate and at 104C it seems to be 70mbar. All the leaking joints seem to be taking their toll.

Of course there is a possibility that the synthesis is bogus. It wouldn't be the first time. Also the silica gel step sounds fishy because it just seems too easy. I've got used that in chemistry to do a simple synthesis you will need five of the most watched reagents that are also contact poisons, will detonate upon their own crystal weight and are hypergolic, and probably sublime away if you don't use them immediately.

Anyways, I'll get back on the isomerization tomorrow. I will make sure all the reagents and equipment are dry, and I was planning on taking samples at ½h, 1h, 2h, 3h, 6h and 12h to see if anything happens. The way to test aldehyde is with bisulfite adduct. What I've read elsewhere, it should react readily upon mixing if pH is neutral. So far I haven't got any reaction whatsoever.

[Edited on 25-7-2020 by Fyndium]

Fyndium - 26-7-2020 at 02:21

So far nothing. 30 and 60min samples taken, filtered, washed with water to crash the aromatic out of acetone and applied to bisulfite solution.

EDIT: I made a control with acetone and also added ethanol. It seemed to be heating a little, but nothing formed. I read elsewhere that someone had an issue with potassium metabisulfite, which I've got.

EDIT2: Now I got it working. It needed some alcohol.

[Edited on 26-7-2020 by Fyndium]

JJay - 26-7-2020 at 19:05

Cool. This is actually second on my list of syntheses to try when I get a new lab space. I believe you are the first person on this forum to get it to work. It's worthy of a writeup in Prepublication.

Fyndium - 27-7-2020 at 10:42

I might give it a shot when I perfect the process, like ratios, timing, etc and see how the adduct is released and I also want to be totally sure the thing is real, because once I got it working it seems rather easy and fun part seems to be that a batch I made earlier and - luckily - left undisposed also precipitated white solids when adducted, so water content or purity of the oxirane does not seem to be a critical matter, although it could probably lower yields a lot. I had to basify it once during a batch because I used too much liquid and the adduct just went sort of suspension, so I decided to cut it because bicarb is a lot cheaper and abudant than sulfite and added a good amount of sat bicarb and oil accumulated to the top.

I left a test batch sit in a jar overnight and it had a bulk of crystals hanging from the organic layer which sunk down upon disturbing the jar a little. I suppose the adduct should be given time to form in this instance, or give it a good stir, like an overhead stirrer to agitate the whole solution. On the other hand, the crystals seem to be the larger the slower they form, hence easier to separate and purify. Dumping a fast adduction will form a suspension that just slips through filters, but it seem to settle eventually when left undisturbed and coagulates so that it can be decaned and filtered. When I made cyanides a long time ago I lost probably almost half because I did not give it enough time to coagulate so patience, or donothingness seems to be much more beneficial than pushing it. I think when finished the organic layer could be pipetted or suctioned off and then the liquid decanted and the adduct dumped and vacuum filtered and washed with ethanol and or ether. The adduct was pale yellowish when filtered, but turned pure white when rinsed with ethanol, and it was left to dry.

Downside is the smell. It's not bad, it's actually very nice - at first. But then it gets so strong and persistent it just annoys the hell out of you - and the best part is you can still sort of smell or sense it even when you have left the shop for hours. I can still smell it in my fingers and every time I touch my face it's just sweet flowers lol. Rinsing and cleaning all the ware and managing the waste liquid that has touched it will be a mess of it's own. Dump it down the drain? No, it will reek through the piping and interceptor and you and probably your neighbors can also enjoy the sweet smell.

But in the end, the smell of flowers was a smell of victory for me the moment I smelt it first.

[Edited on 27-7-2020 by Fyndium]

Fyndium - 29-8-2020 at 11:30

I wonder what went wrong.

I attempted an adduct purification of the aldehyde and prepared it according to the Benzaldehyde from toluene with UV catalyst prepublication.

- I first prepared a potassium metabisulfite solution, added the organic layer and added ethanol until no more precipitated. I made a control without organic layer and the sulfite did not precipitate. I vac filtered the white mass and washed it with more ethanol and dried it.
- I then prepared a sodium carbonate solution according to the same topic and I dissolved the adduct into it. It fizzled as it dissolved, and a very little oil precipitated, the solution remaining cloudy and yellow. I attempted to extract it with ether, but upon concentrating it I obtained some sharp smelling liquid that was nowhere the smell of aldehyde.

Now I wonder if I ever made phenylacetaldehyde in the first place? The smell is there, though. Is the adduct possibly made from something else? I can't figure out what else could react with the bisulfite, the ethanol I used is leftovers from my own production so even MEK is out of question and the amount of adduct formed is clearly much more than anything what could be the result of an impurity. I distilled and washed the organic layer with brine multiple times to extract any remaining water and acetone prior to adduction. Or is there something wrong with the breaking of adduct? I tried adding more carbonate and even hydroxide but nothing happened.

The breaking of adduct should be clear as a day, but nope, I guess. For the record, the adduct had strong odor of SO2 at least when it was still moist, similar to bisulfite solution.

I would really appreciate a help with this, I've putten some effort into it and made it this far.

clearly_not_atara - 29-8-2020 at 12:20

Does it smell burnt, stinging, smoky? Could be an aldol product, they often smell that way.

Unfortunately this is a particularly reactive aldehyde! One way to confirm and stabilize is to convert directly to the nitrile with hydroxylamine and tungsten-tin hydroxide (easily prepared; see ref att.)

Attachment: yamaguchi2007.pdf (108kB)
This file has been downloaded 372 times

Fyndium - 29-8-2020 at 13:05

Not at all burnt, just sulfur dioxide smell. You know it when it burns your throat and irritates your eyes, you cannot mistake it. Same smell as from solution of sulfite. Only other smell it carries is sweetish, aldehyde-like smell, a very faint one.

Would it be possible that the aldehyde suffers from boiling off acetone? I would prefer to skip the adduct phase if possible, it is arduous and costly, and if the isomerization step itself works above 92% yield, it should be pretty much useful as is, considering it will carry polymerization products as impurities due to reactivity anyways. Distilling is of no use though, since the major impurity would be styrene oxide anyways, which has the exact same boiling point and density. I have noted, by the way, that the aldehyde appears to be oxidising into what is probably phenylacetic acid, since it obtains a different, but still strong odor profile when it is exposed to atmosphere, eg. when droplets of solution is splashed on surfaces, etc.

If I just had hydroxylamine at hand. Are there any other methods to determine or purify the aldehyde from styrene oxide? Due to the isomer form, they are practically the same by their physical properties, only apparent difference is the reactivity towards adduct. The styrene oxide itself appears to be a volatile compound on it's own, it is stated that even trace amount of acid with water will turn it into phenethyl glycol, and if hydrolysis is not possible, it will isomerize into aldehyde. I presume, that trace amount of water will cause hydrolysis until it consumes all the water and after that only isomerization will occur?

Due to factors, I have vacuum distilled the oxide prior to isomerizing to neutralise it from the sodium hydroxide treatment and other trace impurities. I use calcium sulfate to dry acetone and the oxide, since magnesium sulfate is slightly acidic.

S.C. Wack - 29-8-2020 at 16:54

Quote: Originally posted by Fyndium  
I vac filtered the white mass and washed it with more ethanol and dried it.


In air? Try making the oxide or aldehyde a different way and compare?

JJay - 29-8-2020 at 20:49

I would probably suggest the bisulfite adduct-forming procedure written by Eleusis as the easiest and highest yielding, but I would suggest using methanol instead of ethanol since methanol is cheaper and less likely to contain problematic denaturants.

There was some discussion on here recently about quantitative determination of carbonyls, and a reagent which can be used for that purpose is 2,4-dinitrophenylhydrazine. It's not the easiest thing to find, but it's not unaccessible in the U.S.

[Edited on 30-8-2020 by JJay]

Fyndium - 30-8-2020 at 03:11

It seems that in every patent concerns the proneness to polymerization both the oxide and the aldehyde. Hence the aldehyde is prepared in solutions containing 0.1mol concentrations and the silica gel method also requires 20:1 ratio of acetone. Theis could indicate that aldehyde was formed, but proneness to polymerization and aldol could cause major part to turn into other stuff. Also catalyst deactivation by polymers could be a factor, I suppose it could be purified by soaking in pure acetone.

https://doi.org/10.1016/j.apcata.2010.06.005

I have tried both, the patent amount and more concentrated solution and both indicate by smell, but no separate tests were made though, they both reated with adduct.

Over-oxidation to acid could also be a factor.

It still bothers me though how such a large quantity of mass precipitated if it was not adduct, and basically nothing resulted when it was dissolved with Na2CO3?

The next test I will try:

- soak and wash the silica gel in acetone and dry it at 120C for 2 hours prior to use
- dry acetone with magnesium sulfate and calcium sulfate and redistill
- when finished and filtered off the acetone, I have two choices:

1) crash out the product by adding water until phase separates
2) distill off acetone

Which one should be better? I would actually opt for 1, because it can be done in room temp and it is basically instant, while distilling exposes the product to a very long duration of heat and it concentrates it as such up to a pure product. It would need to be washed anyways in order to remove rest of the acetone, unless it were to be extracted by vacuum.

1 liter of acetone would hold 50 grams of styrene oxide and 50 grams of silica gel. As such, I would need to measure the amount of water needed to crash out the product, but I've done it twice and it was successful.

I was also wondering if the reaction could be just carried out in a chromatography tube packed with silica, as the article originated from. The concentration of silica apparently is trivial, but the ratio of oxirane/aldehyde to solvent seems critical to prevent any side reactions. This way, even larger amounts of liquid could be handled with small amount of silica gel, and being protected from air and moisture as well. More testing, I presume..

[Edited on 30-8-2020 by Fyndium]

clearly_not_atara - 22-2-2024 at 15:08

Unfortunately this never worked out. The product is pretty unstable, and the reaction conditions for the pinacol rearrangement are roughly identical to the ones for the undesirable aldol condensation. In particular, the pinacol intermediate (the carbocation) is identical to the intermediate in acidic enolization.

Suppose that instead the pinacol rearrangement is carried out in ethylene glycol (itself resistant to the reaction) as solvent and hopefully most of the phenylacetaldehyde were trapped as the ethylene acetal in situ. Then you just need a mild acetal deprotection.

There's an Indian paper claiming deprotection by chloral hydrate in hexane, but it sounds a little too good to be true.