Sciencemadness Discussion Board

preparation of thymolphthalein

Magpie - 26-4-2016 at 17:58



Introduction & Background
Thymolphthalein is an acid-base indicator that changes from clear to blue in the pH range 9.3 to 10.5. Use of this indicator is occasionally specified in some of the old procedures such as those found in Organic Synthesis.

Thymolphthalein can be made via a Friedel-Crafts alkylation of phthalic anhydride with thymol:

0. thymolphthalein reaction equation.jpg - 93kB
0. rx eqn

Thymol is the active ingredient in thyme, a common kitchen herb. To add some OTC to this synthesis I had originally planned to separate the thymol from the oil extract of thyme, commonly available at health food stores. Then I read that ajowan oil was an Indian spice especially rich in thymol. So I purchased 50ml planning to isolate the thymol by distillation. However, this was a failure as my ajowan oil did not contain any significant amount of thymol based on the boiling points I obtained. I had purchased my ajowan oil from Dr Adorable. Perhaps this should have been my first clue.

Next time around, not taking any chances, I purchased 25g of pure thymol. I have since found a supplier of thyme extract in Hungary claiming a very high thymol percentage, but I did not buy this.

At first I could only find one very succinct and old procedure for making thymolphthalein (ref 1). It specified anhydrous ZnCl2 as the Lewis acid catalyst. I tried this procedure using 10g of my thymol. It was a failure, resulting in a tarry mess.

I then decided to check my local university library where I can access all ACS journals. Here I found one article with a more detailed procedure (ref 2). Anhydrous SnCl4 was specified as the Lewis acid catalyst.

Experimental

A. Reaction
The procedure used was that provided in reference 2 at ½ scale. 15g of thymol (0.1 mole), 7.4g (0.05 mole) of phthalic anhydride, and 12.5g of SnCl4 were heated in an oil bath at 95°C while stirring. The SnCl4 was added over a period of 30 minutes. For this I used a 3-neck 100mL RBF as shown in the picture below.

1. thymophthalein reaction set-up.jpg - 82kB
1. reaction set-up

The CaCl2 guard tube and the p-e funnel were not specified in the procedure but seemed appropriate to me. The temperature of the reaction was monitored and controlled with a K type thermocouple and PID controller.

After the addition of the SnCl4 the flask was to be heated for an additional 30 minutes at 96°-103°C.

The temperature did get away from me rising to as high as 123°C.

B. Workup
The product was a very dark purple, hard, solid lump as shown below.

2. thymolphthalein dark lump.jpg - 75kB
2. dark purple solid lump

To this was added to 100mL of 0.1M HCl and the stiff solid broken up with a spatula. It was somewhat difficult to break into pieces small enough to be removed from the RBF.

The product was separated into the dark solids and a pink, flakey slurry. The dark pieces were ground to a sticky powder in a mortar. The pink slurry of unknown identity was discarded; the dark powder was kept as the putative thymolphthalein. The picture below shows the two products.

[ 3. thymolphthalein reaction products.jpg - 88kB
3. rx products

After the mortar had been rinsed clean I placed it in my sink. I had made up a strong NaOH solution for testing. When I added this to the mortar it turned an intensely dark blue color as shown below.

4. thymolphthalein mortar with NaOH soln.jpg - 81kB
4. mortar with thymolphthalein residue and NaOH

The dark powder was washed several times with water using a 7cm Buchner funnel. This washing turned the powder a dull, light yellow as shown below.

5. thymolphthalein black powder washed.jpg - 88kB
5. powder washed with water

This powder was then dissolved in 350mL of acetic acid whereupon it turned an orange-red color as shown below.

6. yellow thymophthalein powder dissolved in acetic acid.jpg - 76kB
6. thymolphthalein dissolved in acetic acid

The 350mL of thymolphthalein in acetic acid solution was then filtered, removing ~ 1/2g of white solids. The solids were thymophthalein (1st crop).

The filtrate was then distilled removing 225mL of acetic acid distillate per procedure. The 100mL of pot residue was now a deep carmine with no solids present. This distillation is shown in the picture below.

7. distillation of thymophthalein in acetic acid.jpg - 100kB
7. Distillation of thymolphthalein dissolved in acetic acid

I attempted to get the thymolphthalein to precipitate by cooling the remaining 100mL of solution in an ice bath. But with the mp of acetic acid at 17°C this quickly froze. However, upon melting and setting overnight significant solid thymophthalein did precipitate (2nd crop). This was removed by filtration. The filtrate is shown in the picture below.

8. thymolphthalein in acetic acid - last 100mL.jpg - 100kB
8. 100mL of filtrate

The filtrate was then set up for a 2nd distillation. This time another 65mL of acetic acid was recovered. I expected to see significant precipitation in the 35mL of pot residue after cooling but there was none. Again this compound showed it was capable of significant supersaturation. Scratching the flask bottom with a glass stirring rod and adding thymolphthalein crystals did not cause precipitation. The flask was then left again overnight. The next day revealed precipitated white solids on the bottom of the flask (3rd crop).

The 3 crops were allowed to dry at ~70°C. The 1st crop was ground to a fine powder in a mortar. The 2nd & 3rd crops were combined and ground to a fine powder. Pictures of these products are shown below.

9. thymolphthalein 1st, 2nd, & 3rd crops.jpg - 121kB
9. 3 crops of thymolphthalein precipitate

10. thymolphthalein 1st, 2nd-3rd combined crops.jpg - 122kB
10. the ground product
Results

The mp of the 1st crop powder was 250°C. That for the combined 2nd & 3rd crops was 245°C. The wiki value is 248°- 252°C.

The yield was 0.50g of 1st crop, and 2.48g of the combined 2nd & 3rd crops, for a total of 2.98g. This gives a %yield of 13.8%.

A few mg of the product was dissolved in a ml of 95%ethanol. To this was added a few grains of solid NaOH. The solution turned an intense blue as shown in the picture below.

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11. thymophthalein in alcohol at high pH

Discussion
I have been working on this preparation for some time. My faux pas with the ajowan oil and poor first procedure (ref 1) were mostly responsible for this.

The Hubacher procedure (ref 2) provides good detail for the reaction conditions. However, details for the workup were very limited. My choice of 3 distillations in retrospect seems excessive. But I really didn’t know what I was dealing with for sure as to how it was going to precipitate, etc, so proceeded cautiously. This made for a tedious workup.

The yield was low but I did get the intended product. In picture 3 above the pinkish product in the beaker was discarded. It may have contained significant product that I was not aware of. At any rate 3g will be a lifetime supply as it doesn’t take much to get a color change from clear to blue.

It is interesting to note that Ex-Lax, once a popular laxative, was formerly made of phenolphthalein. Reference 2 is Hubacher’s evaluation of carvacrolphthalein as a laxative. The declarative phrase “Smooth move Ex-Lax” can still be heard occasionally around my house when someone makes a mistake.

References
1. “Practical Druggist and Pharmaceutical Review of Reviews,” Vol. 33 (1915).
2. “Carvacrolphthalein,” JACS, Vol. 64, Issue 11, pp. 2538-2539, [Contribution from the Laboratory of Ex-Lax, Inc], by Max H. Hubacher (Nov 1942) http://pubs.acs.org/doi/abs/10.1021/ja01263a003?journalCode=...

Questions, comments, and suggestions are welcomed.






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JJay - 26-4-2016 at 20:53

Cool. I wish I had some. I would think it would be pretty easy to purify with chromatography.

Pumukli - 26-4-2016 at 23:01

Nice work, Magpie!

It seems we share a quite wide field of interest regarding organic synthesis because what you do usually picks my interest too and/or something I always wanted to do and maybe show to the public. :-) E.g. during the last few months I tried extracting carvacrol from a plant oil (but bought the bad oil) to use in a synthesis instead of thymol. Then I came across a bottle of cymol (good precursor to carvacrol), but had no money with me to buy it. :-) Maybe next time. :-)

Anyway, congratulations.

I felt a bit "premature" to discard that pinkish fluffy precipitate at the beginning of the workup and would surely postpone of the emptying of its flask until I tried some sort of extraction on it. But you are right, 3 g pH indicator lasts a lifetime in an amateur laboratory.

CuReUS - 27-4-2016 at 04:36

I remember reading somewhere that phenolphthalein could be prepared by condensing pthalic anhydride with phenol in the presence of conc H2SO4 itself ? maybe the same could by done for thymol
anyways I found a paper claiming a 90% yield using methane sulfonic acid
http://www.sciencedirect.com/science/article/pii/S0040403909...

j_sum1 - 27-4-2016 at 05:20

Magpie. That's a great write-up and a nice little synthesis. I'm inspired.

I don't know how useful another indicator is, but it's a purty colour.

Magpie - 27-4-2016 at 08:44

Thank you JJay, Pumukli, and j_sum1.
Quote: Originally posted by CuReUS  
I remember reading somewhere that phenolphthalein could be prepared by condensing pthalic anhydride with phenol in the presence of conc H2SO4 itself ? maybe the same could by done for thymol


Yes, I've seen this synthesis equation expressed with H2SO4 as catalyst, Wiki, IIRC.

I believe there is a synthesis of phenolphthalein in Brewster, also one for methyl orange indicator using phthalic anhydride.

I should mention that with this thymmolphthalein preparation as I was just adding the SnCl4 to the p-e funnel the thymol and phthalic anhydride were being heated and the thymol had melted. At that time I saw the white/yellow reactants start to turn a very dark purple or black. At first I thought "oh no! here comes the tar." But it was the first appearance of thymophthalein. I had not yet added any SnCl4. So, my point is: maybe the Lewis acid is not all that necessary?

[Edited on 27-4-2016 by Magpie]

CharlieA - 27-4-2016 at 09:57

Great write-up, and great perseverance!:)

DraconicAcid - 27-4-2016 at 10:15

Very nice.

Out of my field, but I would guess that similar reactions with phenol or cresol would give phenolphthalein and cresolphthalein (ETA: and naptholphthalein]. I wonder how many other "..olphthaleins" one could make.

Hmmm...."The Carbon Compounds" (Porter, 1931) mentions this reaction on its chapter on dyes. Resorcinol reacts with phthalic anhydride to give fluorescein, which can be brominated to give eosine. m-dimethylaminophenol will give rhodamine B.

[Edited on 27-4-2016 by DraconicAcid]

Dr.Bob - 27-4-2016 at 10:19

Nice writeup again. I like the photos and details. I wish JOC and J Med Chem required those... Very colorful work.

I can vouch that the preparation of phenolphthalein from phthalic anhydride with phenol in the presence of conc H2SO4 works, that was one of my first experiments as a teenager. I did not test it as a laxative, however. I also made Bakelite, was was a giant mess, as it hardens into a glob that was impossible to remove from anything it got on.

Fluoroscein is one of my favorite dyes to make and play with, a little goes a long way. I might still have some phthalic anhydride if anyone ever needs some. Also, 3-nitrophthalic anhydride and hydrazine will make luminol, which is a great experiment to make and oxidize it to make light. That and the dioxylates are some of my favorites chemoluminescent experiments as well.

Magpie - 27-4-2016 at 11:58

Quote: Originally posted by Dr.Bob  

Fluoroscein is one of my favorite dyes to make and play with, a little goes a long way.


Yes, I too have made a little fluorescein, which was fun because of its striking color. But making the resorcinol precursor was the real challenge. Its precursor is the sodium salt of m-disulfonic acid which is made with a caustic fusion. Some time ago I had a metalworker make a copper crucible especially for making this but I haven't used it yet. Someday I'll get back to it.

aga - 27-4-2016 at 12:18

Superb work Magpie.

Very good write-up and inspiring photos.

Did you make the SnCl4 ?

Magpie - 27-4-2016 at 13:26

Thank you aga. Yes, I made the SnCl4 a short time ago: http://www.sciencemadness.org/talk/viewthread.php?tid=28879

clearly_not_atara - 27-4-2016 at 16:50

Why tin? At first I thought it was the easy synthesis, but you just used chlorine anyway.

Boffis - 27-4-2016 at 17:06

Nice work magpie, good to see someone still does real chemistry that is drug related.

A couple of questions though. In the original paper (reference 2 above) they recrystallised the crude material from acetic acid after leaching with dilute HCl. The later presumably removes the tin salts. Why did you not follow this protocol? Why did you do an alkali extraction? I have found that most phthaleins tend to oxidize in alkaline solutions so I would expect the alkali extraction to promote a certain amount of oxidation too.

My understanding of your procedure is that after the acid wash you decanted the flocculant precipitate and discarded it (mostly thymolphthalein?), extracted the residue with alkali (in which thymolphthalein is pretty soluble and gives a solution that is prone to oxidation), is this correct? Did you acidify the blue alkali extract to precipitate the thymolphthalein that went into solution?

Magpie - 27-4-2016 at 18:25

Quote: Originally posted by clearly_not_atara  
Why tin? At first I thought it was the easy synthesis, but you just used chlorine anyway.


I used SnCl4 since that was what the procedure called for. Toggle the link in reference 2 and you can read the Hubacher procedure.
Quote: Originally posted by Boffis  
Nice work magpie, good to see someone still does real chemistry that is drug related.


Do you mean "not drug related"?
Quote: Originally posted by Boffis  

Why did you do an alkali extraction?


I never did an alkali extraction. I just washed it with water. The procedure said to wash it.

Edit: Maybe my use of the word "residue" in the mortar is confusing. What I meant was the traces of the dark purple gummy powder left in the mortar. The ground up powder was taken up in acetic acid per procedure. I would clarify this in the OP but it is too late.
Quote: Originally posted by Magpie  

After the mortar had been rinsed clean I placed it in my sink. I had made up a strong NaOH solution for testing. When I added this to the mortar it turned an intensely dark blue color as shown below.


I do agree that I should probably have filtered/washed all of the products instead of just the dark purple gummy mass.

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UC235 - 27-4-2016 at 22:33

Here is a GC(MS?) for genuine ajowan essential oil with peak IDs. As you can see, the real deal is about 40% thymol. In general, trust no "essential oils" for sale on ebay or amazon. Fraud is rife and even reputable suppliers are sometimes taken for a ride (though by more sophisticated and harder to detect methods). If it seems too cheap, there's a good reason for that (with few exceptions. some oils are just astoundingly cheap).

https://www.newdirectionsaromatics.com/msds/GCMS_AjowanEssen...

I am somewhat surprised that the ajowan you purchased was not authentic, however. It is an exceedingly cheap oil. The company that the GC is from sells 100ml for $4.38 (They have a $100 order minimum, however).

Given the extremely low cost, perhaps ajowan essential oil is used to produce thymol that qualifies as a "natural flavor" (which commands a significant premium over the synthetic material) and you were sold the forerun waste product. It looks like a fractionating the oil would leave a stillpot residue of almost pure thymol after p-cymene passes over at 177C.

[Edited on 28-4-2016 by UC235]

Magpie - 28-4-2016 at 10:14

Thanks for your research UC235.

Here's some excerpts from the notes I took during my distillation of Dr Adorable's ajowan oil:

"The ajowan oil from Dr Adorable is to be distilled by fractional distillation to attempt to obtain pure thymol. Other terpenes, etc, are expected to be in the ajowan oil. 50% thymol would meet expectations. The bp of thymol is 232°C. A 100mL pot will be used. Ajowan oil charge of ~50mL of a dark liquid.

Due to severe flooding shutdown and added magnetic stirring. First drop of condensate at 96°C. Quite a bit of condensate coming over at 170°C. Shutdown - will do simple vacuum distillation tomorrow.

A lot of bumping - installed ebulliator. Went to packed column but too much flooding. Replaced packed column with Vigreux column in an effort to eliminate flooding. Still too much flooding & foaming. Tried adding simethicone and DOT 5 silicone oil to eliminate foaming. Gave up due to excessive foaming & flooding. There was only about 20mL in the pot. It didn't smell like thymol."

DraconicAcid - 28-4-2016 at 10:18

Quote: Originally posted by Magpie  
Thanks for your research UC235.

Here's some excerpts from the notes I took during my distillation of Dr Adorable's ajowan oil:

"The ajowan oil from Dr Adorable is to be distilled by fractional distillation to attempt to obtain pure thymol. Other terpenes, etc, are expected to be in the ajowan oil. 50% thymol would meet expectations. The bp of thymol is 232°C. A 100mL pot will be used. Ajowan oil charge of ~50mL of a dark liquid.



Thymol is also a phenol, and terpenes are not. Why not extract with strong base?

UC235 - 28-4-2016 at 12:11

Quote: Originally posted by DraconicAcid  
Quote: Originally posted by Magpie  
Thanks for your research UC235.

Here's some excerpts from the notes I took during my distillation of Dr Adorable's ajowan oil:

"The ajowan oil from Dr Adorable is to be distilled by fractional distillation to attempt to obtain pure thymol. Other terpenes, etc, are expected to be in the ajowan oil. 50% thymol would meet expectations. The bp of thymol is 232°C. A 100mL pot will be used. Ajowan oil charge of ~50mL of a dark liquid.



Thymol is also a phenol, and terpenes are not. Why not extract with strong base?


Because that's too easy!

Incidentally, this is a good way to purify eugenol from clove oil as well.

Magpie - 28-4-2016 at 12:41

It seems that DraconicAcid is a better organic chemist than he purports. ;)

aga - 28-4-2016 at 12:46

'Easy' sounds like a good plan to me ...

DraconicAcid - 28-4-2016 at 12:46

Quote: Originally posted by Magpie  
It seems that DraconicAcid is a better organic chemist than he purports.


Let's just say that I'm well-versed in first-year organic chem. Anything past that is a crap shoot.

Paddywhacker - 19-5-2016 at 23:36

Magpie, does the procedure for making Fluorescein not work for thymolphthalein: melting thymol and phthalic anhydride together with a drop of H2SO4 and holding the mixture molten for some time. I would have thought that the same procedure would work for phthalic anhydride and any phenol.

Magpie - 20-5-2016 at 08:10

I suspect you are right. Brewster (forum library) has a procedure. The big challenge is just making the resorcinol.

gsd - 20-5-2016 at 08:27

As I understand it, Paddywhacker is suggesting that why not use the method used for making Fluoroscein to make Thymolphthalein. In making Fluoroscein, 98% H2SO4 (or Anhydrous ZnCl2) is used as dehydrating agent. Why not use C. H2SO4 as dehydrating agent for Thymolphthalein also?

gsd

On second thoughts I suspect H2SO4 will react with Thymol. Anhydrous ZnCl2 will not pose that problem it will act as dehydrating agent only.
BTW I have made Fluoroscein using both these reagents. They work like a charm.

gsd

Magpie - 20-5-2016 at 09:52

Thank you gsd, I did misread the question. According to Wiki using just H2SO4 will work:

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

Paddywhacker - 22-5-2016 at 15:57

Quote: Originally posted by gsd  
As I understand it, Paddywhacker is suggesting that why not use the method used for making Fluoroscein to make Thymolphthalein. In making Fluoroscein, 98% H2SO4 (or Anhydrous ZnCl2) is used as dehydrating agent. Why not use C. H2SO4 as dehydrating agent for Thymolphthalein also?

gsd

On second thoughts I suspect H2SO4 will react with Thymol. Anhydrous ZnCl2 will not pose that problem it will act as dehydrating agent only.
BTW I have made Fluoroscein using both these reagents. They work like a charm.

gsd


Yes. Magpie's work-up procedure is very valuable, but the SnCl4 for the FC reaction is a bit exotic. Hence my suggestion of using catalytic H2SO4. All of these *phthalein reactions are between two molecules of a phenol and one molecule of phthalic anhydride, so they all might take place is similar conditions, although admittedly, the resorcinol in the fluorescein synthesis is a highly activated molecule.