Sciencemadness Discussion Board - Synthesis of 4-hydroxybenzaldehyde from phenol?

Synthesis of 4-hydroxybenzaldehyde from phenol?

Klute - 21-6-2008 at 18:46

I've been looking for a way of preparing 4-hydroxybenzaldehyde since a long time.
Apart from a modified Riemer-Tiemann using tertiary amines to favor p-formylation, there isn't much options.

I've considered making it out of phenol in 4 steps, most of which should be high yielding and using availabe materials:

bromomethylation of phenol isn't possible, as it produced phenol-formol polymers, so a protected phenol must be used. I've though of using a tosylate (or mesylate), as it is easily cleaved but refluxing in dilute alkali. This treatment would also hydrolyse the benzyl bromide to the benzylic alcohol if I'm correct, thus combing two recations in one step. 4-hydroxybenzyl alcohol, which is a valuable compound itself, can then be oxidized with TCCA in presence of TEMPO derivatives (

) to the aldehyde.

Granted, it's a bit long, but if the modified RT formylation is low yielding or very messy, it could be worth a try.

Tosylation is a very easy, direct recation (in presence of triethylamine), bromomehtylation seems to work pretty well with similarily activated compounds (thanks to Painkilla for the tip), and the basic hydrolysis should work out pretty well.

Hopefully the oxidation should be high yielding in presence of TEMPO derivatives (merging projects!

).

Any comments,a dvise? or other suggestions?

LSD25 pointed out to me that tyrosine could make a good precursor, but i just can't figure how to get to the benzaldehyde pretty directly. I know it could be converted to the phenylacetonitrile or the phenethylamine pretty easily, but from there on?

I was also considering electrolysis, the reduction of the corresponding benzoic acid (which is pretty cheap) seems to be pretty easy and used industrially, but is still obscure ground for me.

[Edited on 22-6-2008 by Klute]

Ritter - 21-6-2008 at 19:57

Quote:

Originally posted by Klute
I've been looking for a way of preparing 4-hydroxybenzaldehyde since a long time.
Apart from a modified Riemer-Tiemann using tertiary amines to favor p-formylation, there isn't much options.

The R-T reaction starting from phenol is your best bet here. The co-prodct salicylaldehyde (2-hydroxybenzaldehyde) is volatile with steam & is easily removed via steam distillation. This is the way it is done industrially.

Your multi-step hypothetical path is very problematical & likely unworkable.

[Edited on 21-6-2008 by Ritter]

[Edited on 21-6-2008 by Ritter]

S.C. Wack - 21-6-2008 at 19:59

Oxidation of anethole and demethylation of the anisaldehyde can't be worse than R-T, unless you have some specific reference better than what I've seen with the original R-T or using tertiary amines in the R-T - I'm not so sure that their use favors p-cpds.

not_important - 21-6-2008 at 20:32

How about hydroxymethylation of phenol, using cold, dilute base?

Attachment: 185-Hydroxymethylation of Guaiacol with Aqueous Solutions.pdf (90kB)
This file has been downloaded 1885 times

Klute - 22-6-2008 at 05:17

I was planning on trying the modified RT in the first place, but the only references I ahve are extrtacts from Japonese abstracts claiming good yields... pretty weak.. here

Hydroxymethylation could be worth a try, but Im' surprised they state no polymerisation apart from diaryl compound occured, while bromomethylation of phenol even at RT seems to give only polymers. Maybe the o-methoxy group reduces polymerisation considerably?

I could indeed try demethylation anisaldehyde directly, I'm sure I could find some uses to anisaldehyde (see how the corresponding 2-butanone smells like

), and it could yield the benzylic alcohol with a simple NaBH4 reduction.

LSD25 kindly supplied we with a article discussing selective m-demethylation of veratraldehyde and it's acetophenone, toisovanillin, leaving the p-methoxy alone, using conc. H2SO4. Maybe this procedure would work for anisaldehyde, having only one methoxy to cleave. Otherwise, it's AlCl3 or AlBr3... That I know of. I don't think the aldehyde would survive a aniline.HCl melt or similar, and I don't want to mess with BBr3.

not_important - 22-6-2008 at 06:38

I've seen mention of industrial fine chemical hydroxymethylation of phenol, the trick seems to be cold and dilute, followed by careful workup to avoid further reaction. There is some further condensation, but it's easy to separate and the raw materials are cheap.

And I was surprised when I ran across the description, too, as the text books all seem to talk about the condensation to resins.

To me it would seem that the additional methoxy group should make the aromatic ring even more reactive. It blocks one ortho location, but the other is wide open.

Ritter - 22-6-2008 at 07:55

Dow Chemical made salicylaldehyde (OHB) & 4-hydroxybenzaldehyde (PHB) via the R-T rxn for years. Their problem was that while there was a growing market for OHB in the gasoline additives area while there was little demand for the PHB. I know this story from direct, personal experience.

The review article of the R-T rxn in Organic Reactions vol. 28, p. 19 gives over 10 references & gives the yield of OHB as 20% and of PHB as 8-10%. The textbook where this synthesis is given is A. Vogel, Textbook of Practical Organic Chemistry, 1978, pp. 757 & 761. These yields are not a problem as the reactants are all inexpensive.

The hydroxymethylation of phenol will give you several problems: one, a mixture of o- & p-isomers; two, the need to separate these isomers; three, the need to oxidize the p-isomer to the aldehyde; four, avoiding making phenol-formaldehyde resins.

[Edited on 22-6-2008 by Ritter]

Klute - 22-6-2008 at 08:14

I personally prefer performing several steps then wasting my phenol with 20% yields, to predominantly obtain salicaldehyde that I can prepare in 84% yeild with the Mg(OCH3)2/(H2CO)n formylation.

I can easily oxidize benzylic alcohols with TCCA/ TEMPO derivatives in great yields, and the isomers could be seperated by steam distn after oxidation, just like in the RT process, or by bisulfite extraction (salicylaldehyde forms an adduct only very slowly and sluggishly, while 4-hydroxybenzaldheyde does so very quickly and quantitatively). The tertiary amine modification might be worth a try, but I generally feel uneasy with the RT process, very prone to tar formation.

Hydroxymethylation is very easy to perform, and eqaully worth a try. I will try it on asmall scale, if it results in tar, too bad. If it doesn't, i'll stick to that.

Ritter - 22-6-2008 at 09:13

FWIW, the Dow patent on their R-T process (US3365500) states a real-world yield of 57.4% OHB/26.5% PHB. That's a total yield of hydroxyaldehydes of nearly 84%.

Klute - 22-6-2008 at 09:23

Thank you, but i will still rather try a reaction that predominantly produces the p-isomer. The o-isomer can be obtained totally free of p- via other formylations, so no need on seperating them.
If methods of seperation such as fractionnal cristn, bisulfite extraction, or column chromatography are used, alone or one after the other, the o-isomer % should be kept as low as possible.

One advantage of going via anisaldehdye, is that the methoxy could be cleaved after aldol condensation and reduction, avoiding the lengthy reaction time for th ealdol with phenolic aldehydes. Hopefully the 2-butanone will not self-condense excessively.

Any suggestions for the demethylation? Org Syn doesn't seem to have much on the subject...

Ritter - 22-6-2008 at 09:32

Quote:

Originally posted by Klute
Any suggestions for the demethylation? Org Syn doesn't seem to have much on the subject...

I believe the usual method involves 48% HBr.

Ritter - 22-6-2008 at 13:28

Quote:

Originally posted by Klute
I've been looking for a way of preparing 4-hydroxybenzaldehyde since a long time.
-----------------------------------------
bromomethylation of phenol isn't possible, as it produced phenol-formol polymers, so a protected phenol must be used.

Halomethylation chemistry in general produces carcinogenic bis(halomethyl) ethers as volatile by-products. The few chemical companies that do this kind of reaction have to have workers in full pressure suits working inside sealed production units in order to safely control this. FWIW, bis(halomethyl) ethers are known to cause cancer by dross-linking DNA chains so cells can't divide.

Klute - 22-6-2008 at 14:22

Theses are intermediates, and only produced at the beggining of the reaction. After a few hours, there ar ehardly present anymore,a nd a aqueous workup destroyes them immeidatly. The bromo derivatives is much less volatil than the chloro- (bp ~100°C IIRC)

quote from: "Health Concern - Observation of Bromomethyl Ethers during the Bromomethylation of Aromatic Compounds"

Quote:

Thus, the earlier report that hazardous intermediates are not generated in the bromomethylation of aromatic compounds under these conditions is potentially misleading. It is true that, at least with highly reactive aromatics such as mesitylene and mesitol, bromomethyl ether intermediates do not persist through extended reaction periods or aqueous workup and are not detected in reaction products. Indeed, this method remains a highly efficient route to halomethylated aromatics which may be preferable to alternative routes involving chloromethyl ethers or high in situ concentrations of bromomethyl ethers.

However, these highly toxic materials are formed in the reaction mass during the early stages of the reaction. Further, the levels of these intermediates can be very high if the reaction is conducted in such a way that paraformaldehyde and HBr are combined in the absence or molar deficit of an aromatic compound, and likely also when relatively unreactive aromatic substrates are used.

So with minimal stoechiometric amounts of paraformaldehdye and HBr, and such a activated substartes, this reaction wouldn't be any more hazardous than others (less so than MeI alkylations for example).

Have you got any ref's for the HBr demethylation? Would be interested in reading them.

Ritter - 22-6-2008 at 17:36

Quote:

Originally posted by Klute
Theses are intermediates, and only produced at the beggining of the reaction. After a few hours, there ar ehardly present anymore,a nd a aqueous workup destroyes them immeidatly. The bromo derivatives is much less volatil than the chloro- (bp ~100°C IIRC)

Well, bon chance with that. I think you're over-thinking a very simple synthesis by ignoring the literature precedents. Phenol is cheap & PHB is easy to make via the R-T rxn. Your stated plan calls for an overly elaborate & problematical scheme that carries with it very toxic byproducts.

BTW, have you done a lit search on this synthesis?

Quote:

Have you got any ref's for the HBr demethylation? Would be interested in reading them.

No, I'm not in the lit search business unless I'm getting paid for it. This is organic chemistry 101, not alchemy. If you can find Google & the patent URLs I posted in the choral hydrate thread, you will learn a lot by finding the references by yourself.

[Edited on 22-6-2008 by Ritter]

PainKilla - 22-6-2008 at 18:08

Ritter, I think you are ignoring literature precedents yourself. The paper that describes the toxic intermediates of bromomethylation (did you read it?) clearly states that such intermediates do not persist through the reaction. On top of that, haloethers hydrolyze very rapidly upon a slight rise in pH, so the workup will very quickly eliminate any sort of dangerous intermediates.

By the way, do you really consider reactions that involve carbene intermediates safe?

On top of that, the point is not to synthesize 4-hydroxybenzaldehyde using literature precedents but to discuss potential methods of its synthesis. It would be even cheaper to buy 4-hydroxybenzaldehyde, but I see no one has suggested that (yet).

As far as the bromomethylation is concerned... I don't think bromomethylation is quite selective enough to yield only para-substituted product.... Although, the tosyl group may be big enough to promote mostly para product. I think this is one of those things that only experiment can say for sure.

I found a nice paper that seems to indicate that benzyl bromides may be convered into their aldehydes by refluxing in ethanol-H2O2-KBr (attached).

------
http://www.google.com/patents?id=5nZwAAAAEBAJ&printsec=a...

I'll see if I can find any references to phenol (or its relatives) halomethylation.

----(no access)----
Haloalkylation of aromatic compounds. III. Chloro- and bromomethylation of phenolic ethers.
Tourinho, Ana M.; Da Rocha, Nilmar V. P.
Anais da Associacao Brasileira de Quimica (1967) 26(3-4):19-22.
Journal written in Portuguese.

Abstract:
The chloromethyl derivs. of PhOR (where R = Me, Et, Pr, Bu, or C5H11) were prepd. in 48-70% yields by their reaction at room temp. with HCHO and HCl in AcOH, H2SO4 being slowly added. The bromomethyl derivs. were obtained by corresponding methods in 52.5-60% yields.

--------
Chloromethylation of alkoxybenzenes and the preparation of the corresponding benzaldehydes. Very Relevant!
Journal fuer Praktische Chemie (Leipzig) (1956) 3:274-7.

Abstract
The following p-alkoxybenzyl chlorides, p-ROC6H4CH2Cl (I), were prepd. at 15-20 by addn. of 1 mole ROPh in C6H6 to 48 g. paraformaldehyde in 200 ml. concd. HCl (R, % yield, and b.p./mm. given): Et, 71,120-4/12; Pr, 75, 134/12; iso-Pr, 63, 126-8/14; Bu, 65, 138-42/10; iso-Bu, 54, 98/0.8; Am, 59, 154-8/12; and iso-Am, 64, 146-8/12. Oxidation of I to the corresponding ROC6H4CO2H by refluxing with 50 g. HNO3 (35 B.acte.e.) 10 hrs. served for the identification of the a products. I with AcOH and hexamethylenetetramine (cf. Sommelet, C.A. 8, 660) produced the p-ROC6H4CHO: Et, 61, 119-22/10; Pr, 72, 129-30/10; iso-Pr, 69, 122-3/10; Bu, 70, 140-1/10; iso-Bu, 66, 152/16; Am, 61, 156-8/10; and iso-Am, 67, 147-8/10. Refluxing 0.5 mole I in 800 ml. Me2CO with 4.5 g. NaI and 33 g. NaCN gave the 4-ROC6H4CH2CN (II): Et, 84, 150-1/11; Pr, 79, 162/12; iso-Pr, 67, 154/14; Bu, 69, 174-8/15; iso-Bu, 64, 158-9/12; Am, 74, 176-8/10; iso-Am, 74, 194/22. Refluxing 0.2 mole II in 100 ml. EtOH, 32 ml. water, and 32 g. KOH gave the 4-ROC6H4CH2CO2H (R, % yield, and m.p.): Et, 78, 91.3; Pr, 63, 91; iso-Pr, 83, 87; Bu, 77, 88.5; iso-Bu, 82, 87; Am, 79, 86; and iso-Am, 88, 87.

(71% yield of the benzyl bromide from ethoxybenzene... probably means even better can be obtained with bromomethylation w/ R-OTs).

------

From what I saw, chloromethylation procedures carried out at room temperature, gave good yields of the para-product from variously substituted phenol ethers (methoxy, ethoxy etc). I think with -OTs, a carefully carried out bromomethylation will work quite well, given this information. Phenol itself is too reactive for the direct halomethylation (see patent).

Also, can someone please get the Chloromethylation of alkoxybenzenes and the preparation of the corresponding benzaldehydes reference? I would be very interested in seeing it, as I am sure would anyone else interested in this thread/halomethylation.

[Edited on 22-6-2008 by PainKilla]

Attachment: Efficient and convenient oxidation of organic halides to carbonyl compounds by H2O2 in ethanol.pdf (106kB)
This file has been downloaded 3955 times

PainKilla - 22-6-2008 at 18:38

Thanks for your help in finding references Ritter! :mad:

Attachment: An efficient procedure for the demethylation of aryl-methyl ethers in optically pure unusual amino acids.pdf (235kB)
This file has been downloaded 3351 times

PainKilla - 22-6-2008 at 18:47

Another:

Also (no access): Curphey, T. J.; Hoffman, E. J.; McDonald, C. Chem. Ind. 1967, 1138.

[Edited on 22-6-2008 by PainKilla]

Attachment: Tetrahydroiso quinolines - demethylation with HBr.pdf (219kB)
This file has been downloaded 950 times

Ritter - 22-6-2008 at 19:07

Quote:

Originally posted by PainKilla
Ritter, I think you are ignoring literature precedents yourself. The paper that describes the toxic intermediates of bromomethylation (did you read it?) clearly states that such intermediates do not persist through the reaction. On top of that, haloethers hydrolyze very rapidly upon a slight rise in pH, so the workup will very quickly eliminate any sort of dangerous intermediates.

By the way, do you really consider reactions that involve carbene intermediates safe?

On top of that, the point is not to synthesize 4-hydroxybenzaldehyde using literature precedents but to discuss potential methods of its synthesis. It would be even cheaper to buy 4-hydroxybenzaldehyde, but I see no one has suggested that (yet).

As far as the bromomethylation is concerned... I don't think bromomethylation is quite selective enough to yield only para-substituted product.... Although, the tosyl group may be big enough to promote mostly para product. I think this is one of those things that only experiment can say for sure.

I found a nice paper that seems to indicate that benzyl bromides may be convered into their aldehydes by refluxing in ethanol-H2O2-KBr (attached).

------
http://www.google.com/patents?id=5nZwAAAAEBAJ&printsec=a...

I'll see if I can find any references to phenol (or its relatives) halomethylation.

----(no access)----
Haloalkylation of aromatic compounds. III. Chloro- and bromomethylation of phenolic ethers.
Tourinho, Ana M.; Da Rocha, Nilmar V. P.
Anais da Associacao Brasileira de Quimica (1967) 26(3-4):19-22.
Journal written in Portuguese.

Abstract:
The chloromethyl derivs. of PhOR (where R = Me, Et, Pr, Bu, or C5H11) were prepd. in 48-70% yields by their reaction at room temp. with HCHO and HCl in AcOH, H2SO4 being slowly added. The bromomethyl derivs. were obtained by corresponding methods in 52.5-60% yields.

--------
Chloromethylation of alkoxybenzenes and the preparation of the corresponding benzaldehydes. Very Relevant!
Journal fuer Praktische Chemie (Leipzig) (1956) 3:274-7.

Abstract
The following p-alkoxybenzyl chlorides, p-ROC6H4CH2Cl (I), were prepd. at 15-20 by addn. of 1 mole ROPh in C6H6 to 48 g. paraformaldehyde in 200 ml. concd. HCl (R, % yield, and b.p./mm. given): Et, 71,120-4/12; Pr, 75, 134/12; iso-Pr, 63, 126-8/14; Bu, 65, 138-42/10; iso-Bu, 54, 98/0.8; Am, 59, 154-8/12; and iso-Am, 64, 146-8/12. Oxidation of I to the corresponding ROC6H4CO2H by refluxing with 50 g. HNO3 (35 B.acte.e.) 10 hrs. served for the identification of the a products. I with AcOH and hexamethylenetetramine (cf. Sommelet, C.A. 8, 660) produced the p-ROC6H4CHO: Et, 61, 119-22/10; Pr, 72, 129-30/10; iso-Pr, 69, 122-3/10; Bu, 70, 140-1/10; iso-Bu, 66, 152/16; Am, 61, 156-8/10; and iso-Am, 67, 147-8/10. Refluxing 0.5 mole I in 800 ml. Me2CO with 4.5 g. NaI and 33 g. NaCN gave the 4-ROC6H4CH2CN (II): Et, 84, 150-1/11; Pr, 79, 162/12; iso-Pr, 67, 154/14; Bu, 69, 174-8/15; iso-Bu, 64, 158-9/12; Am, 74, 176-8/10; iso-Am, 74, 194/22. Refluxing 0.2 mole II in 100 ml. EtOH, 32 ml. water, and 32 g. KOH gave the 4-ROC6H4CH2CO2H (R, % yield, and m.p.): Et, 78, 91.3; Pr, 63, 91; iso-Pr, 83, 87; Bu, 77, 88.5; iso-Bu, 82, 87; Am, 79, 86; and iso-Am, 88, 87.

(71% yield of the benzyl bromide from ethoxybenzene... probably means even better can be obtained with bromomethylation w/ R-OTs).

------

From what I saw, chloromethylation procedures carried out at room temperature, gave good yields of the para-product from variously substituted phenol ethers (methoxy, ethoxy etc). I think with -OTs, a carefully carried out bromomethylation will work quite well, given this information. Phenol itself is too reactive for the direct halomethylation (see patent).

Also, can someone please get the Chloromethylation of alkoxybenzenes and the preparation of the corresponding benzaldehydes reference? I would be very interested in seeing it, as I am sure would anyone else interested in this thread/halomethylation.

[Edited on 22-6-2008 by PainKilla]

The original poster stated that he (she?) was only concerned with making PHB, not exploring novel chemistry that amounts to reinventing methods to make this simple molecule. If you only want to make PHB, the literature is clear as to your options. And anyone seriously interested in doing halomethylation chemistry should reconsider that as being potential suicide.

PainKilla - 22-6-2008 at 19:10

"I've considered making it out of phenol in 4 steps, most of which should be high yielding and using availabe materials:"

Where is it mentioned that he only wants to use the literature methods? Bromomethylation is hardly a novel reaction by the way.

And I have done it multiple times and am still alive (and healthy).

[Edited on 22-6-2008 by PainKilla]

Ritter - 22-6-2008 at 19:55

Quote:

Originally posted by PainKilla
Thanks for your help in finding references Ritter! :mad:

My position is this: if you can't find the references yourself for the chemistry you intend to perform, you should take up another line of investigation instead. Expecting strangers on the Internet to spoonfeed you 'references' is just about the same deal as playing Russian Roulette. You either know what you're doing or you don't. Chemistry is very unforgiving & is not for those who cannot cut the mustard when it comes to basic lit research.

PainKilla - 22-6-2008 at 20:04

Quotes by Ritter:

Quote:

Since most of the other components in this chain have 2-letter codes, I'm wondering if anyone knows the code for 'diester'?

"My position is this: if you can't find the references yourself for the chemistry you intend to perform, you should take up another line of investigation instead. "

Quote:

I'd appreciate your sending some lit references. Pdfs would be appreciated. I could not locate a relevant UK patent to Friedrich Hoffmann in the EPO.

"My position is this: if you can't find the references yourself for the chemistry you intend to perform, you should take up another line of investigation instead."

Quote:

I would appreciate getting a copy of this article. Thanks in advance!

"My position is this: if you can't find the references yourself for the chemistry you intend to perform, you should take up another line of investigation instead."

Get the point?

-----

Has it ever occured to you that not everyone has access to references?

Has it ever occured to you that this is an AMATEUR chemistry forum?

This forum is about synthesizing materials in a non-academic settings. The literature is very academic.

Is it useful to us? Absolutely. Does it mean we are aware and can find every single reference regarding a topic. No!

This is why we socialize with other people with similar interests, SHARING information!

Do everyone a favor, and stop being so high and mighty. This is a forum for chemistry and friendly relationships.

Edit: If any mod feels this post is unjustified (I won't further drive this off topic after this post), please delete as you see fit.

[Edited on 22-6-2008 by PainKilla]

S.C. Wack - 23-6-2008 at 02:26

In this case demethylation with HBr would be in the usual solvent of GAA, or would require some PTC or something. There is an interesting microwave demethylation of anisole using methanesulfonic acid...on a very small scale...if you just happen to have some...2-hydroxy-3-methoxybenzaldehyde was made in 98% isolated yield from the dimethoxy cpd. with LiCl and DMF, if you have some.

Ritter - 23-6-2008 at 05:14

Quote:

Originally posted by PainKilla
Quotes by Ritter:

Quote:

Since most of the other components in this chain have 2-letter codes, I'm wondering if anyone knows the code for 'diester'?

"My position is this: if you can't find the references yourself for the chemistry you intend to perform, you should take up another line of investigation instead. "

Quote:

I'd appreciate your sending some lit references. Pdfs would be appreciated. I could not locate a relevant UK patent to Friedrich Hoffmann in the EPO.

"My position is this: if you can't find the references yourself for the chemistry you intend to perform, you should take up another line of investigation instead."

Quote:

I would appreciate getting a copy of this article. Thanks in advance!

"My position is this: if you can't find the references yourself for the chemistry you intend to perform, you should take up another line of investigation instead."

Get the point?

Not really. I have no intention of making these things. I'm just collecting journal articles that I otherwise would not have ready access to.
-----

Quote:

Has it ever occured to you that not everyone has access to references?

Has it ever occured to you that this is an AMATEUR chemistry forum?

This forum is about synthesizing materials in a non-academic settings. The literature is very academic.

Is it useful to us? Absolutely. Does it mean we are aware and can find every single reference regarding a topic. No!

This is why we socialize with other people with similar interests, SHARING information!

Do everyone a favor, and stop being so high and mighty. This is a forum for chemistry and friendly relationships.

Edit: If any mod feels this post is unjustified (I won't further drive this off topic after this post), please delete as you see fit.

Chemistry is chemistry, amateur or not. I've been doing it for over 40 years. It is very unforgiving if you are not prepared.

If I were to start supplying references, it would become my responsility as to their accuracy & completeness, and I choose not to take on that responsibility in cases where someone is actually considering doing synthesis work.

Starting a synthesis without having done the necessary lit work is equivalent to walking up to a craps table without ever having played the game or read about how it's played. You will likely lose, in the case of chemistry either your equipment, your raw materials, your house or your life.

[Edited on 22-6-2008 by PainKilla]

[Edited on 23-6-2008 by Ritter]

Klute - 23-6-2008 at 06:17

Yet another thread going off with a pissing test...

Ritter, if I asked you the HBr reference, it's because most of the time, when you propose a reaction, you give a little info to back it up. I wasn't particularily asking for a pdf or whatever, which, as Painkilla pointed out, was the first thing you did arriving on this forum, but even a reference to such an article/preparation.

Many people, beleive it or not, have not the funds to acces the litterature, or the means. I myself work in a lab where there is only one acces to scifiender, which is virtually occupied from 7h30am to 10pm, by people using it to do their work. I will not prevent anyone from doing their work so that I can do my hobby. Some every kind people here agree to spend a little time retreiving a paper for other people, so that the latter can go one with their hobby.

Yes, hobby. I have not much to add from Painkilla answer, that this is supposed to be a convivial place, where it costs nothing to exchange information in a friendly way. I would even try to venture this is one of the major aspects of this forum.

Again, you claim doing chemistry without extensive ref searching is dangerous, but you publicly post reactions schemes to making nerves gas. Much more dnagerous than bromomethyation dare I say, even if you don't plan on doing it, you are giving info to some kid who thinks he could. I would like to see the danger in supplying a reference to someone asking. That can never hurt.

The way I undersatnd your point, if someone cannot pay a several 100$ acces to publishers, he shouldn't even consider doing chemistry? What a sad world that would be... And yes, I have spent several hours searching the open litterature, patents, etc Patent's are a more than sketchy source of information. I have tried lots of reactions based mostly on patent's and only a very limited amount worked as described. So instead of simply looking elsewhere, I started changing the conditions myself, using what I have learned in the years of practicing chemistry, to try and optimize the reaction. In certain cases it worked very well, in others it didn't. I undersatnd someone in a pilot plant cannot change the conditions as he wishes just for the sake of explorating, but hopefully I do not have these pressures on me. It's actually a major source of joy to try things your way and make them work. Too bad for all the times where the reactions failed and I lost hours of work and reagents.

I love chemistry and learn about it everyday. Trying out new routes is one of the best ways to do so. It ables to make the difference between crappy journal and veridic reports. If I may, I would say than a day in the lab is worth a week in the library when you know where you're heading. That's why I ask for references that I can not acces, just like you did/do, to people that I mostly consider as friends. Where's the difference? You are seeking information of chemical warfare, me on precursor to aromas? This is getting caricatural.

I wasn't asking how to open as industrial plant, I wasn't asking for THE way of making p-hydroxybenzaldehyde (which IMHO the convential RT is not, at a lab scale, but again that only concerns me), but advice and suggestions. You gave yours, half of it was irrevelant, so be it. Please do not clutter the thread because people don't agree with you.

I sincerely appreciated your comments on the RT process, but do not undersatnd why you develop such bitterness. If it's something I have done, or said, please let's settle this by PM and discuss chemistry instead.

EDIT: (chemistry discussion)

According to Freudenberg et Gehrke , Chem. Ber, 84; 443-450 (1951),

4-hydroxybenzaldehyde can be obtained by demethylation of anisaldehdye with pyridine hydrobromide in 60% yield.
They prepare the compound by Rosemund reduction over Pd/BaSO4 of p-acetoxybenzoyl chloride, made by stepwise reaction of acetyl chloride and thionyl chloride on p-hydroxybenzoic acid

for a total yield of 56.5%...

They then discuss some interesting reaction (formation of the corresponding coumarins, etc)

Another few preparation mentionned in the litt:

-Diazotation of p-NH2-benzaldehyde Rec. Trav. Chim. Pays Bas 54, (1935) 97
(p-aminobenzaldehyde can surprisingly be easily made from p-nitrotoluene and sodium polysulfide, and must be kept in acidic conditions to avoid polymerisation, see US4273941)

-Condensation of phenol with formaldehyde in alkaline medium in presence of the sodium salt of 3-nitrobenzenesulfonic acid DE 580981

-Hydrogenation of p-hydroxybenzonitrile (easily made from the corresponding benzoic acid via urea/sulfamic acid) Helv. Chim. Acta. 19 (1936) 588

-Condensation of phenol with glyoxalic acid and subsequent hydrolysis of the intermediate DE 621567

-Condensation of phenol with trichloroacetic acid and subsequent alkaline hydrolysis J.Chem.Soc. (1933) 496

-Demethylation of anisaldehyde with pyridine.HCl at 200-220°C Ber. Chem. 74 (1971) 1219

Aparently HBr will not work with anisaldehdye, neither will BBr3, both producing excessive by products and low or no yield.
On the second hand, H2SO4 might work, or at least HBr could work on the 2-butanone (does so with the butanoic acid).

Quote:

from US4967013, quoting DE2904315
it is expressly pointed out that the treatment of p-methoxybenzaldehyde with HCl does not lead to p-hydroxybenzaldehyde, and treatment with HBr also makes possible only low yields. This is not surprising since aldehydes tend to undergo secondary reactions in the presence of mineral acids (column 2, lines 45-55).

I'm still unsure if I should start from anisaldehdye or 4-hydroxybenzoic acid, besides the phenol route. Anisaldehyde could be used for much more things, the benzoic acid less so.

An example of a modified RT reaction using b-cyclodextrin can be found at US4523037. Large amounts of b-cyclodextrin are used.

US4500721 teaches the use of copper salt treated raney nickel for the selective hydrogenation of subs. benzonitrile to the corresponding benzaldehydes in highyields. considering that up to 80% of copper can be used, maybe Cu/SiO2 can be as effective in this hydrogeantion..... A little Ni salt could added during the catalyst preparation. On the do-do's list

EDIT2:

Actually, I've just realized that, as I plan on using the 4-hydroxybenzaldehyde to for the raspberry ketone 4-hydroxyphenylbutan-2-one, the bromomethylation route would be even quicker:

Bromomethylate a ester-protected phenol (tosylate, mesylate, acetate), and react the benzyl bromide with the mono- sodium salt of acetoacetic ester. After saponification of the two ester functions, and decarboxylation, the 2-butanone would be obtained. No need for any reduction, vinyl ketone, etc, all that in 3 steps.

I still need to think this out...

[Edited on 24-6-2008 by Klute]

PainKilla - 25-6-2008 at 08:22

I have attached the paper on "Chloromethylation of alkoxybenzenes and the preparation of the corresponding benzaldehydes." As earlier stated, the authors chloromethylate ethoxybenzene in 71% yield, and then convert using the Sommelet reaction in 61% yield to yield 4-ethoxybenzaldehyde. They seem to do this, if my German is not terribly off, by refluxing in 50% acetic acid for 2 hours. I'm not sure if this will work for the phenyl tosylate, but if the reflux in ethanol works, as per the reference I posted earlier in the thread, then I think this is by far the easiest route to 4-hydroxybenzaldehyde!

Attachment: Chloromethylation of alkoxybenzenes and the preparation of the corresponding benzaldehydes.pdf (205kB)
This file has been downloaded 1117 times

Klute - 25-6-2008 at 14:15

thank you very much for that article Painkilla. It seems p-alkoxybenzenes are suffcirently activated to provided good yield in that reaction. Maybe I could use the benzyl protecting group, and remove it at the same time as I reduce the double bond by hydrogeantion. I will need to check if such deprotection can proceed at ATM pressures, IIRC high pressures are commonly used.

PainKilla - 25-6-2008 at 14:20

If I remember correctly, the lower end of reactivity required for good yields with bromomethylation is chlorobenzene. Chloromethylation does not yield well with chlorobenzene. Thus, I think just about any substrate with an aromatic ether/hydroxy group will work well for halomethylation.

What is perhaps more interesting than the bromomethylation, is the oxidation of the corresponding halide to the benzaldehyde using ethanol/h2o2 as posted earlier... That is just about the simplest procedure (and quite well yielding too) that I have seen for such a conversion.

Klute - 25-6-2008 at 16:35

Indeed, it seems very simple. But it needs practical backing up IMHO? thet fact that there is very little mention ofthis method isn't very reassuring. Maybe it works well only with specific substartes, or generally has lower yields than the sommelet?

I would expect some oxidation of the aldehyde by excess H2O2? Have you got experience with the sommelet? The only time I tried it was on a substrate I supposed to a benzyl chloride, but as it came out unchanged, I guess it was something else (cf. benzylic alcohols oxidation thread).

For my use I might better be off using the benzyl halide directly for alkylating sodium ethyl acetoacetate, but if this EtOH/H2O2 method works out well enough, it sure would be good news.

PainKilla - 25-6-2008 at 16:50

I've never used the Sommelet reaction, however I am sure it will work exactly as advertisted. German journals have always worked well for me and tend to be reliable and very reproducible. The ethanol-h2o2 oxidation is a bit sketchy, but it's so simple to try the procedure...

I'd do it myself, but I am currently away from home.

As far as further oxidation... it might occur, but it doesn't really matter as I imagine any such procedure would isolate with NaHSO3 anyway, so impurities are nicely avoided.

There are lots of ways from halides to benzaldehydes... I remember a few using DMSO, though I don't have the references nearby. The traditional halide --> alcohol --> aldehyde has long been used too, and I should think that the yields be no lower than 50% for total conversion.

[Edited on 25-6-2008 by PainKilla]

Klute - 15-7-2008 at 06:38

The problem to p-hydroxybenzaldehyde has been solved:

A bit more expensive that I would have liked, but I've been dying to make Rheosmin since some time now

Details on the condensation and reduction to Raspberry ketone to come in the dedicated thread.

[Edited on 15-7-2008 by Klute]

Ephoton - 22-11-2008 at 04:37

this is probably a little late but I have always had great success with the sommelet reaction.

though I advise not too use alcohol as the solvent but rather water.

I would say the problems you had were the benzyl halide you had.

all I do is add benzyl halide too hexamine with water and then reflux for a few hours.

once it is near finishing I setup for distillation and aldehyde comes over with water.

I add more water to distillation flask until no more aldehyde comes over.

a very very easy reaction if you have benzyl halide.

works for all three mono di and tri benzyl halides.

a bit off topic but still this was discussed above.

sorry.

Klute - 22-11-2008 at 06:38

Nice, great to hear some succes! Did you try dilute AcOH?

What benzyl halide was this?