Sciencemadness Discussion Board - Path to 4-Anisaldehyde

The path starting from toluene will probably work well up to 4-methoxytoluene; all the reactions involved are well known. I don't know about the last step though. I've never heard of MgO2 being used as an oxidant, and it might over-oxidize the 4-methoxytoluene to the carboxylic acid.

There’s a whole chapter dedicated to oxidation by MgO₂ in the book Organic Syntheses by Oxidation with Metal Compounds. But here, my reference is the wikipedia page on 4-anisaldehyde, from which I quote: 'Anisaldehyde is prepared commercially by oxidation of 4-methoxytoluene (p-cresyl methyl ether) using manganese dioxide to convert a methyl group to the aldehyde group.' Now, the word 'commercially' is important here.

There is simpler way to go from toluene to p-cresol: sulfonation of toluene to p-toluenesulfonic acid (this sulfonation should exclusively form the para product) and then reaction with molten NaOH. The result is Na2SO3 and sodium p-cresolate.

Ah, interesting. Thanks for suggesting this! I’m always a bit wary of nitrations.
Of course, this sort of reaction has to be carried out in a stainless steel vessel, I suppose.

As for the path starting from phenol, there's of risk of over-iodination of the phenol in the first step, If over-iodination occurs, you would need to install a protecting group, for example by converting the phenol into its acetate ester.

According to Vogel, mono-bromination (so I suppose, mono-iodination) of phenol is possible under cold conditions (~ 0°C) using a non-polar solvant, and produces almost only p-iodophenol. In the related experiment, Vogel uses CS₂, which I don’t have in stock and seems touchy. I could use chloroform or diethyl ether, though.

I never heard of the reaction in the second step, so I wouldn't be able to comment on it.

Thinking about it, that was just idiotic from me. You can’t use a Grignard style addition with iodophenol, since the Grignard reagent could react with both the iodo- and the hydroxy- side.

So that leaves us definitely with the first path.

Hydroquinone probably wouldn't work as a starting material. However, p-aminophenol (from hydrolysis of paracetamol) might work by methylation to p-methoxyaniline, diazotization, replacement with cyanide, and reduction with tin(II) chloride and hydrochloric acid (Stephen Aldehyde Synthesis). There's the obvious issue of requiring cyanide, but if you are willing to work with cyanide, you can choose this route as it skips the often problematic oxidation step.

Why not? I don’t have cyanide at that point, but I've precisely dehydrated a hundred grams of potassium hexaferrocyanate to get cyanide as shown in Chemplayer's video (hot reduction by sodium metal). I intended to carry that out next time, so this route is definitely something I could consider.

Thanks for all the valuable suggestions.

UranylPeroxysulfate - 27-4-2021 at 05:03

There’s a whole chapter dedicated to oxidation by MgO₂ in the book Organic Syntheses by Oxidation with Metal Compounds. But here, my reference is the wikipedia page on 4-anisaldehyde, from which I quote: 'Anisaldehyde is prepared commercially by oxidation of 4-methoxytoluene (p-cresyl methyl ether) using manganese dioxide to convert a methyl group to the aldehyde group.' Now, the word 'commercially' is important here.

Manganese dioxide is MnO2, not MgO2. MgO2 is magnesium peroxide, which, while oxidizing, is very different from MnO2. It's also worth noting that "chemical" manganese dioxide is required to carry out the oxidation. Battery MnO2 and MnO2 from most other sources won't work. If you want to know whether your MnO2 will work, look at its color: if it's brown, then it's good; if it's black, then it won't work. "Chemical" manganese dioxide can be prepared by mixing KMnO4 and MnSO4, and the oxidation should be carried out in a chlorinated solvent.

However, even with high-quality MnO2, I can't guarantee the reaction will proceed as expected because MnO2 might simply not have enough oxidizing power. I know it can easily oxidize aromatic alcohols to aldehydes (such as benzyl alcohol to benzaldehyde), but I don't know about its reaction with aromatic side chains. Commercial methods might employ special conditions and/or catalysts to effect this reaction. For a better chance of success, I recommend using chromyl chloride in dichloromethane (or chloroform) as the oxidant.

Interesting. Thanks for letting me know about that.

Keep in mind that cyanide is extremely toxic. For sodium cyanide, the form of cyanide that is most likely to be used in this reaction, a mere 0.2 grams dose is enough to kill an adult. Go with this route only if you know all the proper safety precautions for handling cyanide.

Boffis - 27-4-2021 at 06:51

There are many methods of introducing an aldehyde group into an activated aromatics so why not start with anisole and use one of these? Some tend to give predominately o-isomers but if you check through them some I am sure will give the desired p-anisaldehyde. If you don't have anisole but do have phenol then maybe do the aldehyde introduction first and then methylate. I seem to recall there is a thread already that discusses the preparation of p-hydroxyphenol from phenol rather than the more common o-isomer (salicylaldehyde).

Also take a look at this thread for ideas;
http://www.sciencemadness.org/talk/viewthread.php?tid=14323#...

Also this reference might help;
Attachment: Aromatic aldehyde syntheses Chem Rev L N Ferguson 1946.pdf (1.8MB)
This file has been downloaded 295 times

Texium - 27-4-2021 at 07:35

For a better chance of success, I recommend using chromyl chloride in dichloromethane (or chloroform) as the oxidant.

Keep in mind that cyanide is extremely toxic. For sodium cyanide, the form of cyanide that is most likely to be used in this reaction, a mere 0.2 grams dose is enough to kill an adult. Go with this route only if you know all the proper safety precautions for handling cyanide.

So you warn about the hazards of sodium cyanide, an acutely toxic, but easily handled solid, while “recommending” the use of chromyl chloride, a volatile, corrosive, carcinogenic liquid? Have you made chromyl chloride before?

Also for what it’s worth, that 0.2 grams is very much on the low end of the LD50. Going by other reported data, it could be as high as a gram, and that’s still LD50, so it’s only a 50% chance that it actually kills you. And do you realize how hard it would be to accidentally ingest even 0.2 grams of something?

njl - 27-4-2021 at 07:48

Mass harder to visualize for me than volume, so for reference (with a density of 1.6 g/cc) .2 grams of NaCN is one-eighth of a cc or a half centimeter cube.

clearly_not_atara - 27-4-2021 at 08:01

Start with the substrate. 4-methoxytoluene is electron-rich and therefore easily oxidized. As such, it is a good candidate for MnO2 oxidation. Some excellent work on the MnO2 reaction is in this old thread from 2004:
http://www.sciencemadness.org/talk/viewthread.php?tid=2223

For the prep of p-TsOH from toluene, it is not necessary to obtain concentrated sulfuric acid; read over Nicodem's comments here:
http://www.sciencemadness.org/talk/viewthread.php?tid=17783#...

You might also want to consider using dimethyl oxalate instead of methyl iodide, since the latter reagent is quite carcinogenic. While not as immediate of a risk as cyanide shutting down cellular respiration or chromyl chloride burning out your alveoli, cancer is not to be trifled with: it happened to me, it can happen to you.

S.C. Wack - 27-4-2021 at 08:02

Well, the entire discussion is silly and pointless, as the oxidation of anethole by just about anything in one step is WELL documented. Surely all the video people have their own videos...(no we do not need youtube links here or anywhere else as this site is not a youtube discussion forum and those incapable of searching youtube will be generally incapable)

NaCN is about as dangerous as bicarbonate unless you're working with lots of it, but one of our members did kill himself with it, doubt it was over a gram...

clearly_not_atara - 27-4-2021 at 08:33

Cyanide is an especially weird poison because it is far more dangerous to some people than others. If you have the cyanide-smelling gene, you're not at too much risk. But if you don't have the cyanide-smelling gene, they're extremely dangerous. Once you recognize the symptoms, it may be too late; you may be unable to evacuate and self-administer an antidote. It is good practice to have a bottle of nitrite esters handy, but it's no guarantee.

But it absolutely should not be necessary here. If you really want to go from paracetamol, CuCN can be made directly from ferrocyanide by reaction with cuprous salts. There's a thread about it somewhere.

Keras - 27-4-2021 at 10:56

Quote: Originally posted by Boffis

There are many methods of introducing an aldehyde group into an activated aromatics so why not start with anisole and use one of these?

In fact, I had that in mind when I made my recent batch of MeI. But I was then somewhat deterred by the very low yield of the Williamson ether synthesis (~50%). Someone suggested that, instead of carrying out the ether synthesis in methanol, it could be done in DMSO in order to improve the yield. Does that seem even remotely likely?

For a better chance of success, I recommend using chromyl chloride in dichloromethane (or chloroform) as the oxidant.

First I apologise for Mg instead of Mn. As usual with typos, even when you peruse your sentences three times and you never catch them. Anyway, I have a few millilitres of chromyl chloride I made by the wet method more than a year ago. It might still be usable, though last time I checked part of it had reverted to Cr (III), giving a nice two layers system, green over red.

So you warn about the hazards of sodium cyanide, an acutely toxic, but easily handled solid, while “recommending” the use of chromyl chloride, a volatile, corrosive, carcinogenic liquid?

Don’t forget the profuse fuming!

Quote: Originally posted by clearly_not_atara

You might also want to consider using dimethyl oxalate instead of methyl iodide, since the latter reagent is quite carcinogenic. While not as immediate of a risk as cyanide shutting down cellular respiration or chromyl chloride burning out your alveoli, cancer is not to be trifled with: it happened to me, it can happen to you.

I very much appreciate your concern ♡. It’s okay, I always work outside, preferably when a little wind blows, and I plan to refrigerate MeI before using it, so as to minimise the vapour pressure.

Also thanks a bunch for all the pointers on the various other relevant threads!

UranylPeroxysulfate - 27-4-2021 at 16:18

I do realize how hard it would be to accidentally ingest 0.2 grams of NaCN. However, considering diazotization mixtures are highly acidic, there's a significant risk of generating HCN, which is far more dangerous. So, I think it is still a good idea to give a warning to those who want to handle cyanide.

I haven't handled chromyl chloride before, but I do know about its dangers; thank you for reminding me about them. I should have warned about the hazards of chromyl chloride as well.

UranylPeroxysulfate - 27-4-2021 at 16:25

Quote: Originally posted by clearly_not_atara

Start with the substrate. 4-methoxytoluene is electron-rich and therefore easily oxidized. As such, it is a good candidate for MnO2 oxidation. Some excellent work on the MnO2 reaction is in this old thread from 2004:
http://www.sciencemadness.org/talk/viewthread.php?tid=2223

For the prep of p-TsOH from toluene, it is not necessary to obtain concentrated sulfuric acid; read over Nicodem's comments here:
http://www.sciencemadness.org/talk/viewthread.php?tid=17783#...

You might also want to consider using dimethyl oxalate instead of methyl iodide, since the latter reagent is quite carcinogenic. While not as immediate of a risk as cyanide shutting down cellular respiration or chromyl chloride burning out your alveoli, cancer is not to be trifled with: it happened to me, it can happen to you.

Well, the entire discussion is silly and pointless, as the oxidation of anethole by just about anything in one step is WELL documented.

Good points. I think MnO2 oxidation is definitely worth a try. As for the oxidation of anethole, it might be easier said than done. As far as I know, there's only two (common and efficient) ways to go from alkene to aldehyde: ozonolysis followed by reductive workup and periodate with OsO4 as a catalyst. Both are inaccessible to most amateurs. However, dihydroxylation with alkaline KMnO4 followed by oxidation with sodium periodate (from bubbling chlorine into alkaline NaI) might work.

S.C. Wack - 27-4-2021 at 17:27

Not sure what's so efficient about OsO4...increasing the budget of the chemistry program and the safety office maybe. Sure, add curly arrows, computer programs, and dirt at 1000 atm and you've defined the chemistry of the past 50 years...fortunately, those who went to school before this left directions how to actually get shit done...with those specific examples that students are told don't exist or are irrelevant.

clearly_not_atara - 27-4-2021 at 17:45

Uniquely for an alkene, anethole can be cleaved to anisaldehyde by chromic acid:

http://www.sciencemadness.org/talk/viewthread.php?tid=12784

UranylPeroxysulfate - 27-4-2021 at 18:13

Quote: Originally posted by clearly_not_atara

Uniquely for an alkene, anethole can be cleaved to anisaldehyde by chromic acid:

http://www.sciencemadness.org/talk/viewthread.php?tid=12784

Interesting. The only issue is that chromic acid is carcinogenic. Still, much better than chromyl chloride or cyanide.

Texium - 27-4-2021 at 20:30

Sure, add curly arrows, computer programs, and dirt at 1000 atm and you've defined the chemistry of the past 50 years...fortunately, those who went to school before this left directions how to actually get shit done...with those specific examples that students are told don't exist or are irrelevant.

Wow! What did the past 50 years of chemistry ever do to you? You talk about it as if a cross-coupling killed your dog.

S.C. Wack - 27-4-2021 at 22:06

The extremely expensive reagents and/or engineering used in modern chemistry are of little comparative benefit except for making profits (except e.g. some Pt chemotherapy types that could probably be a lot cheaper if they didn't have to fulfill some patent requirement)...do you have any idea how much money has been flushed down the toilet by sick Americans in this time frame. It would have been better spent in some other way.

Keras - 28-4-2021 at 02:36

As for the oxidation of anethole, it might be easier said than done. As far as I know, there's only two (common and efficient) ways to go from alkene to aldehyde: ozonolysis followed by reductive workup and periodate with OsO4 as a catalyst. Both are inaccessible to most amateurs. However, dihydroxylation with alkaline KMnO4 followed by oxidation with sodium periodate (from bubbling chlorine into alkaline NaI) might work.

Making ozone needn't be such a hassle. I see ozone generators are sold for less than 70 bucks. 26 g O₃ per hour. Can probably be tweaked to produce more if needed. There are smaller models capping up at 400 mg/hour (10 mol/hour) and they can be directly bubbled into solution.

zed - 28-4-2021 at 05:08

Ummm. Anethole usta be as common as dirt.

Anise, which grows wild in these parts, is saturated with it.

It can be cleaved to the Aldehyde via Ozone.

But, it might be possible to form an epoxide or a diol, via Sodium Perborate in acetic acid. And, thereafter cleave that.

Touchy thing, oxidations. Hard to stop them at the Aldehyde stage.

Methylation of P-Methoxy Toluene, followed by Chlorination might yield P-Methoxy-Benzalchloride. Which on hydrolysis would yield the aldehyde.

P-Amino Benzoic acid, might be a decent starting point, were the intended product rare and valuable. It might be possible, to convert the diazotized PABA directly to the methyl ether. Thereafter, the acid could be treated with Thionyl Chloride and the Acid Chloride, could be reduced by the Rosemund Method.

Well, never-mind. I checked. Benzene Diazonium Salts can be converted directly to Methyl Ethers, but yields are generally crappola.

https://scholarworks.uni.edu/cgi/viewcontent.cgi?article=100...

Awful lot of work, for something simple, that you can probably just buy. But, I'll check on that.

https://www.ebay.com/itm/203117624709?_trkparms=ispr%3D1&...

[Edited on 28-4-2021 by zed]

[Edited on 28-4-2021 by zed]

[Edited on 28-4-2021 by zed]

[Edited on 28-4-2021 by zed]

Texium - 28-4-2021 at 07:08

The extremely expensive reagents and/or engineering used in modern chemistry are of little comparative benefit except for making profits (except e.g. some Pt chemotherapy types that could probably be a lot cheaper if they didn't have to fulfill some patent requirement)...do you have any idea how much money has been flushed down the toilet by sick Americans in this time frame. It would have been better spent in some other way.

I’m well aware of that, and it’s tragic, but it sure as hell isn’t due to expensive reagents! Reagent cost is a minuscule factor in the expense of modern pharmaceuticals. Pharma companies jack up the price of life saving treatments because they know they can. They claim it’s all in the name of R&D costs which is utter BS as most of the money they spend goes into marketing their drugs, and they’re still raking in billions in profits. Blaming this problem on modern chemistry techniques may be the most inane argument I’ve ever heard.

Recently, my grandfather told me about a new medication he was prescribed. The price per DAILY dose (20 mg), without insurance or financial assistance, is $350. I decided to look into the synthesis, and see how much it would cost me to make it. I came across an easy synthesis: just 2 steps from commercially available starting materials, and 62% overall yield. I researched the best prices for the starting materials. The most expensive one was about $10 per gram. Pretty expensive stuff compared to things we typically work with in the home lab. But when you consider that the dose is only 20 mg, the cost of all the necessary chemicals comes out to a mere $0.23 per dose, accounting for the 62% yield. Sure, there’s labor involved too, but this is something that one person could make on a large scale in a single day. The cost of their labor divided between thousands of doses produced would probably amount to a few cents per dose at most.

So, the reagent cost of that drug is less than 0.1% of what they sell it for. Oh, and it’s worth noting that this drug doesn’t even come close to the top ten most expensive drugs in the US, many of which would be just as simple and inexpensive to make.

Keras - 28-4-2021 at 09:03

Quote: Originally posted by zed

Ummm. Anethole usta be as common as dirt.

Awful lot of work, for something simple, that you can probably just buy. But, I'll check on that.

I know, but that’s just cheating.

AvBaeyer - 28-4-2021 at 14:43

It seems to me that a bit of thinking about the OP's problem suggests the following solution:

1. CH3OH + KI +H3PO4 -> CH3I (well documented on the forum)

2. 4-HO-C6H4-NHAc (acetaminophen) + CH3I+ K2CO3 -> 4-CH3OC6H4NHAc

3. 4-CH3OC6H4NHAc + HCl (aq) -> 4-CH3OC6H4-NH2

4. 4-CH3OC6H4-NH2 +NaNO2/HCl -> [4-CH3OC6H4-N2+] not isolated

5. [4-CH3OC6H4-N2+] +HC=NOH -> 4-CH3OC6H4-CHO

For steps 4 and 5 see reference below

Alternatively:

1. [4-CH3OC6H4-N2+] +KI -> 4-CH3OC6H4-I

2. 4-CH3OC6H4-I +Mg -> [4-CH3OC6H4-Mg-I] + (CH3)2NCHO -> 4-CH3OC6H4-CHO

Aldehydes from Gignard reagents and DMF is well documented and easy to find.

Comments?

AvB

Attachment: Aromatic Aldehydes and Ketones from Diazonium Salts beech1954.pdf (634kB)
This file has been downloaded 327 times

[Edited on 28-4-2021 by AvBaeyer]

clearly_not_atara - 28-4-2021 at 14:56

I have read recently a paper suggesting that methanolic deacetylation is quite effective. The solubility in methanol will be higher, and the product methyl acetate is more volatile than methanol (bp 57 vs 64). The anilines were electron-deficient, but I don't think this will be too much of an obstacle:

https://dc.etsu.edu/cgi/viewcontent.cgi?article=3937&con...

EDIT: Also, I would have expected a dialkylhydrazone rather than formaldoxime. Isn't it a bit unstable? Maybe the O-methyl? I think the more conventional approach here would be CuCN[1] followed by SnCl2/HCl.

But I thought we were starting with toluene. Or anethole. Or phenol. Maybe paracetamol. There are quite a lot of ways to make anisaldehyde!

1: http://www.sciencemadness.org/talk/viewthread.php?tid=156276

[Edited on 28-4-2021 by clearly_not_atara]

S.C. Wack - 28-4-2021 at 15:05

Yeah that's all way more sensible and attractive than 1 step from anethole costing nearly nothing when frozen out of oils, using oxidizer that costs less.

(there could of course be problems elsewhere sourcing oxidizers that are trivial here)

I see ozone generators are sold for less than 70 bucks. 26 g O₃ per hour.

Dubious (used maybe...for 26 *actual* g)...surprised to find that the use of Os to make this cpd. is almost 100 years old, but, I'll still pass on Os.

[Edited on 29-4-2021 by S.C. Wack]

Texium - 28-4-2021 at 15:25

Quote: Originally posted by zed

Ummm. Anethole usta be as common as dirt.

Awful lot of work, for something simple, that you can probably just buy. But, I'll check on that.

I know, but that’s just cheating.

If you want it to feel less like it’s cheating, why not extract it yourself? In the organic lab that I taught this year, my students did steam distillation of anise. The NMR spectrum showed that the essential oil obtained appeared to be a ~9:1 mixture of anethole and p-anisaldehyde (no doubt there were also numerous other minor components present in concentrations too low to register on the NMR). You could take the crude essential oil, subject it to oxidation conditions to convert all the anethole to anisaldehyde, and then purify the aldehyde by conversion to bisulfite adduct.

Keras - 29-4-2021 at 21:45

Quote: Originally posted by zed

Ummm. Anethole usta be as common as dirt.

Awful lot of work, for something simple, that you can probably just buy. But, I'll check on that.

I know, but that’s just cheating.

That’s another interesting experiment, alright. I have a soxhlet extractor that I never used so far, that could be a worthy maiden experiment for it. TBH I also planned to extract menthol from the tons of mint stalks that grow in my garden.

What solvent did you use?

Texium - 29-4-2021 at 22:08

As I mentioned, it was a steam distillation, so... water. I'm afraid you won't want to bring out the Soxhlet for this one. Steam distillation by simply mixing the anise with water and distilling will yield plenty of oil, and more can be extracted from the hydrosol with ether, DCM, or chloroform. If you do a Soxhlet extraction instead, you'll end up with a much less pure extract, since a lot of non-volatile stuff that doesn't come over in the steam distillation will be extracted too.

Keras - 29-4-2021 at 23:26

As I mentioned, it was a steam distillation, so... water.

Oh, great. Sorry, I apologise for not twigging this. It was early in the morning, I was just still half sleepy. Okay, never mind then. I’ll use my soxhlet for menthol extraction.

Besides I just bought a round bottom flask perfectly fit for steam distillation (see below). I suppose you crush the seed before beginning the extraction, right?

Thanks a lot!

[Edited on 30-4-2021 by Keras]

Texium - 3-5-2021 at 13:15

Yeah, it's best to grind up the aniseed into a fine powder before doing the steam distillation. That type of flask isn't even necessary, assuming you're wanting to put the anise powder in that flask and pass steam from another flask through it. Honestly, simply putting the anise powder into the boiling flask with water and running a simple distillation, often referred to as a "wet" steam distillation, as opposed to the more complicated "dry" steam distillation that you're probably wanting to do, works very well.

I actually just used some p-anisaldehyde yesterday, to make a TLC stain, and to be honest, I didn't think that it smelled all that great. Similar to benzaldehyde, except with a sharp medicinal odor that kind of overpowered the more pleasant undertones. I think anethole itself smells a lot better! Nonetheless, it's well worth making to use as a stain, if not for the odor, as it stains different compounds a wide variety of colors, making it easier to see impurities and verify if you've isolated the compound that you want. See this plate I ran yesterday:

Orange, pink, red, yellow, blue, and white, all from reaction with anisaldehyde!

Edit: the TLC plate pictured is of the crude product from a Suzuki coupling to make a biaryl aldehyde. The desired biaryl aldehyde is the dark blue spot. Baseline pale orange one is probably triphenylphosphine oxide. No idea about the others!

[Edited on 5-3-2021 by Texium]

S.C. Wack - 3-5-2021 at 18:25

Acetic and sulfuric acids are often added. Good/bad?

Keras - 4-5-2021 at 04:15

Quote: Originally posted by Texium

I actually just used some p-anisaldehyde yesterday, to make a TLC stain, and to be honest, I didn't think that it smelled all that great. Similar to benzaldehyde, except with a sharp medicinal odor that kind of overpowered the more pleasant undertones. I think anethole itself smells a lot better! Nonetheless, it's well worth making to use as a stain, if not for the odor, as it stains different compounds a wide variety of colors, making it easier to see impurities and verify if you've isolated the compound that you want. See this plate I ran yesterday […]

Nice TLC! That reminds me I need to do one to assess the purity of the butyl acetate batch I recently made. Now that is a compound that really smells good

Texium - 4-5-2021 at 07:18