Sciencemadness Discussion Board

Thymol synthesis

Keras - 26-12-2024 at 02:54

Amongst the (numerous) projects that I'd like to carry out one day is synthesis of thymol.

Now, as I see it, the first step would be to synthesise m-cresol, which in turn, I think, can be made by nitrating benzaldehyde, reducing m-nitrobenzaldehyde to m-aminobenzaldehyde, diazoting and hydrolysing, which leads to m-salicylaldehyde. A Wolff-Kishner reduction of m-salicylaldehyde with hydrazine should afford m-cresol.

The industrial reaction proceeds from m-cresol with propylene but requires both heat and above all high pressures, so is impractical.

I was thinking about completing the synthesis with a Friedel-Craft alkylation using 2-chloropropane (made from isopropanol) – but I’m not sure it would work. Positions 2 (what I need), 4 and 6 are opened. I think (6) is unfavourable because of steric hindrance, but 2 and 4 are likely. I’ll probably obtain a mix of isomers.

Any thoughts?

Boffis - 4-1-2025 at 04:58

Hi Keras, Have you checked out the book "The chemical synthesis of vital products" by R Meldola circa 1904. This book can be downloaded from Archive.org. Its a very interesting book.

Keras - 4-1-2025 at 06:04

No thanks for the pointer.
I always give the Internet Archive a few bucks every year because they do a remarkable job of culture and science preservation

Aqua-regia - 5-1-2025 at 01:17

use Friedel-Crafts alkylating reaction: solvent: carbon-disulfide with anh. AlCl3, dripping the meta-cresol int it and finally add isoproplychloride. very common procedure and the yield around 70% tymol.

meta-cresol: i would prepare it from 3-toluidine diazotating and decopmposing to get pure precursor. (3-toluidine from from acetyl-p-toluidine)

Keras - 5-1-2025 at 11:56

Quote: Originally posted by Aqua-regia  
use Friedel-Crafts alkylating reaction: solvent: carbon-disulfide with anh. AlCl3, dripping the meta-cresol int it and finally add isoproplychloride. very common procedure and the yield around 70% tymol.

meta-cresol: i would prepare it from 3-toluidine diazotating and decopmposing to get pure precursor. (3-toluidine from from acetyl-p-toluidine)


Of course F-C was my first bet, but I have no CS₂ and I’m a bit wary of over-alkylation, though steric hindrance should play a role. If you have an idea for an alternative solvent. I might save nitrobenzene for that (see below). If you have an another idea, be my guest :)

I’ll do metacresol from benzene → nitrobenzene → m-dinitrobenzene → m-phenylenediamine → diazotisation, yes.

Aqua-regia - 5-1-2025 at 12:48

what i recommended, works fine, dont worry about steric hidrance. You can instead CS2 using 1,2-dichloroethylene or tetrachlor ethane, both solvent tested. Nitrobenzene can works too, i have no experience with this as an inert solvent. If you want, can sending you the precise experimental description for thymol process.

3-cresol: your idea is 4 steps from benzene, but m-phenylenediamine as a precursor of 3 cresol. not fits. Missing the methyl group in the benzene ring during all the steps.

To get pure 3 cresol is a long way, can only be produced in a roundabout way. My recommendation: toluene----nitrotoluenes--------4 -toluidine-----
-acetyl-p-toluidine----3-Nitro-4-acetamino-toluene----3-nitro-4-aminotoluene-- ---------3-toluidine---------3-cresol. All steps well documented,easy to find. If you have shorter stepsline let me know
I am looking forward to it.

The funny thing is that you can make 3 cresols in one step from thymol by heating it with phosphorus pentoxide. The resulting phosphoric acid ester is decomposed with NaOH and obtained it in a 30-35% yield.


[Edited on 5-1-2025 by Aqua-regia]

Keras - 5-1-2025 at 13:08

Yeah you’re right, I’m mixing up two projects. The resorcinol is for making fluoresceine. :)

m-cresol I was considering benzaldehyde → m-nitrobenzaldehyde → m-hydroxybenzaldehyde (diazotisation and hydrolysis) → m-cresol, by a Wolff-Kishner reduction.

[EDIT: Typo.]

[Edited on 5-1-2025 by Keras]

Boffis - 5-1-2025 at 13:53

@ Keras. May I ask why you want to prepare thymol? Is it just out of curiosity or as a viable source of the phenol? It is easily available as a disinfectant for such things as beehives, whereas 3-cresol is expesive or a tough nut to crack given the number of steps required. Could it be prepared by nitrating or halogenating cymene (4-isopropyl-toluene)? If so the easily available citral from lemon oil is a potential starting material, again check out Meldola's book. There may be other routes since I recently prepared the isomer, carvacrol, from carvone; again from essential oils.

Keras - 5-1-2025 at 22:28

Quote: Originally posted by Boffis  
@ Keras. May I ask why you want to prepare thymol? Is it just out of curiosity or as a viable source of the phenol?


It’s more like a personal challenge, yes. Build a semi-complex molecule from simpler compounds. I have thyme in my garden and a Soxhlet extractor, so it would be easy to get at least a few grams if I needed it.

The ultimate goal is bromothymol blue.

Aqua-regia - 6-1-2025 at 06:26



The cymene is best precursor for 3-cresol, cause easy to prepare from toluene and IPA, and the secont step the halogenated or nitrated + reduced amine transforming to OH.

[Edited on 6-1-2025 by Aqua-regia]

Keras - 6-1-2025 at 23:34

I suppose you can prepare p-cymene by F-C alkylation of toluene under large excess with 2-chloropropane, which is easily made by SN2 from isopropanol.

Aqua-regia - 7-1-2025 at 08:36

No need to complicate it, the process is much simpler than what you thought:

preparation of p-cymene by F-C alkylation:

256 g toluene + 76 g isopropanol + 1600 ml 80% sulfuric acid, stir at 60-65 C for 4.5 hours. The organic phase is toluene and p-cymene, from which cymene can be extracted by simple atmospheric fractional distillation. (not azeotropic with toluene) The yield is 80%, the process can be repeated several times by returning the reactants. easy peasy

Aqua-regia - 7-1-2025 at 08:40

Just a little note to understand the ratios: In Friedel-Crafts alkylation, we need to know that no single product is formed. If the resulting alkylaromatic is more basic than the original aromatic, it will be further alkylated. If we need a monoalkyl product, then in order to obtain a good yield, the aromatic must be used in large excess, otherwise the proportion of dialkyl substrates will increase.

Keras - 8-1-2025 at 01:51

Quote: Originally posted by Aqua-regia  
No need to complicate it, the process is much simpler than what you thought:

preparation of p-cymene by F-C alkylation:

256 g toluene + 76 g isopropanol + 1600 ml 80% sulfuric acid, stir at 60-65 C for 4.5 hours. The organic phase is toluene and p-cymene, from which cymene can be extracted by simple atmospheric fractional distillation. (not azeotropic with toluene) The yield is 80%, the process can be repeated several times by returning the reactants. easy peasy


Ah, thanks, so no need for AlCl₃, I suppose the sulphuric acid is there to produce the carbocation by dehydroxydation of IPA.

Also, good news!.

With that carbon disulfide, it’s also easy to get carbon tetrachloride and sulphur dichloride, which can be used to make anhydrides :)

Lionel Spanner - 8-1-2025 at 15:19

Quote: Originally posted by Keras  
It’s more like a personal challenge, yes. Build a semi-complex molecule from simpler compounds. I have thyme in my garden and a Soxhlet extractor, so it would be easy to get at least a few grams if I needed it.

The ultimate goal is bromothymol blue.

And if that doesn't work, you can always use it to make Listerine-style antiseptic mouthwash.