Skatole is a white crystalline solid that actually occurs naturally in feces.
Interestingly enough, in low concentrations, it can actually have a pleasant flowery smell.
But in higher concentrations, it's pretty gross.
It's also produced naturally by several different types of plants, and it can actually serve as an attractant to certain species of orchid bees.
The scent of indoles and skatole described as fecal-like and I find this is pretty accurate.
The scent of skatole to actual feces is like comparing the taste of orange candy to an actual orange.
In the case of an artificial orange candy, you can tell what it's supposed to taste like but it still definitely doesn't taste like a real orange.
Also, I apologize for comparing feces to oranges.
Anyway, the way that we'll be making it is by reaction known as the Fischer Indole Synthesis.
The process starts with a molecule called phenylhydrazine which is reacted with an aldehyde or a ketone
to form a molecule called the phenylhydrazone.
Using an acid catalyst the, phenylhydrazone will close in on itself and form a second ring.
This new two ring molecule is known as an indole.
By switching up what'd be put at different places on each of these molecules, we can make a variety of different indoles.
To make skatole, we use an unsubstituted phenylhydrazine and propionaldehyde.
In the first reaction we form the phenylhydrazone, and then we use an acid catalyst to close it.
Now, just as a final note, getting to skatole was a pretty long adventure.
My two main starting materials were sodium benzoate and 1-propanol
and it took me [quite] a long time to get to the final product of skatole.
If you're interested in seeing any of these steps, I actually have a video on each one! :)
So that was a long enough introduction, and we should get started with the synthesis.
For this synthesis, we'll use anhydrous ethanol, phenylhydrazine and propionaldehyde, all of which we made in previous videos.
As a catalyst, we'll use p-toluenesulfonic acid.
This acid is also known as p-TSA, and I bought it from the store. But in a future video, I might make it myself.
For the reaction I decided to use 0.5 grams of phenylhydrazine and 0.291 grams of propionaldehyde.
The amount of propionaldehyde that is used is a bit less than a 10% excess.
This makes sure that all of the phenylhydrazine is consumed and any excess propionaldehyde can be easily removed by evaporation.
So to start, to a small round bottom flask, I pipette in the phenylhydrazine,
To make sure that everything is transferred, the small vial and the pipette are washed several times with small amounts of ethanol.
After several washings with the ethanol, the pipette and the vial should be cleaned and we can move on to adding the propionaldehyde.
The propionaldehyde is pipetted in using the same pipette and this vial is also washed several times with a small amount of ethanol.
The propionaldehyde is first diluted with a little bit of ethanol.
Then, with strong stirring, we drop-wise add this dilute propionaldehyde solution to the phenylhydrazine.
The addition of the propionaldehyde is exothermic and for this reason, we want to use dilute conditions and do it slowly.
Then just like with the pheylhydrazine, I wash the little vial several times with the ethanol.
After all the washings, we use the total of the 10 milliliters of anhydrous ethanol that we started with.
Because this is a smaller scale, washing everything several times is quite important because even if a little bit is left behind, it will impact our yield.
After the propionaldehyde is added, we let it stir at room temperature for about 10 minutes.
Although it doesn't look like much has happened, a reaction between the phenylhydrazine and the propionaldehyde has taken place.
When the two are mixed, we quickly form the corresponding phenylhydrazone.
This is the important intermediate that when acid catalyzed, will form our desired indole.
After about 10 minutes, I added 0.761 grams of the monohydrate of p-toluenesulfonic acid.
You can see that immediately when it's added, the solution turns a deep red.
I let it stir for several minutes at room temperature to make sure that all the p-TSA has dissolved.
Then we set up a reflux with a water condenser on top and we bring it to a boil for a few hours.
Over the course of the reaction the color lightens a little bit, but there isn't any huge color change.
At this point we're hopefully carrying out our desired reaction and forming our indole.
The overall reaction that's occurring is shown above:
It might not be immediately obvious, but the molecule actually reacts with itself to form a new two ring system.
The core structure of this two ring system is known as an indole.
Every carbon that can have a substituent is given a number, and I've labeled it on the molecule.
The difference between the molecule that we formed here and just a plain old indole is we have something called a methyl group at the 3-position.
The common name for this molecule is skatole but because it has a methyl group at the 3-position
and the core structure is an indole, it can also be called 3-methylindole.
The mechanism is a little bit complicated but if you're interested in seeing it, I've provided a link below in the description.
After a few hours, it's taken off heat and allowed to cool.
You'll probably notice it's a little bit cloudy.
After cooling to room temperature, a lot of precipitate forms.
Ideally it would be taken off by vacuum, but since I didn't have one, we had to remove the ethanol by distillation.
So using distillation, we remove all of the solvent and we're left with a little crude residue on the bottom.
To remove the crude, we first add a little bit of water to dissolve as much as we can.
Up until now the stinkiness of the skatole really wasn't an issue,
but from this point on it's going to be a little bit of an annoyance.
A lot doesn't dissolve in this layer, which makes sense because indole isn't really soluble in water.
Anyway, the water is added to a separatory funnel, and then we continue washing out the crude residue.
I add a bit more water to dissolve it, but it really doesn't do much.
Even though it didn't do much, this water was also added to the separatory funnel.
So now we do a few washings with an organic solvent and in my case, I decide to use dichloromethane.
You can see that by adding just a few milliliters, it's already doing a much better job than the water.
This DCM washing is then also added to the separatory funnel.
So we continue washing the crude out with a little bit more dichloromethane.
After quite a bit of stirring, we can see it's getting a lot cleaner.
So this washing was again added to the separatory funnel and at this point the round bottom is pretty clean.
So now there's not much left in the round bottom but just for good measure, we wash it with a little bit more DCM.
Then as the final washing, we also add this to the separatory funnel.
To limit the contact that the stinky stuff comes into with other glassware, I directly drained the dichloromethane layer into another separatory funnel.
Then just for good measure, I wash the water layer a few times with DCM,
and you can see that it goes from a yellow color to a white.
This upper aqueous layer should contain most of the p-TSA.
You can actually see now that the lower DCM layer actually has the yellow color that the upper aqueous layer used to have.
So both these DCM washings are also drained directly into the separatory funnel.
So now we have our isolated dichloromethane extract and to further purify it of any p-TSA, we add some saturated bicarbonate solution.
I don't show it here, but in each washing step the separatory funnel was thoroughly shaken and vented.
The layers are allowed to settle and the bottom DCM layer is again drained directly into another separatory funnel.
For most people, this process of using so many separatory funnels isn't viable but I happen to have a lot.
Our dichloromethane layer is a little bit cloudy and wet with water, so we add some saturated sodium chloride solution to try and dry it.
Again, I don't show it here, but we do some capping shaking and venting, and then we let the layers separate.
You can see that once it's separated, the bottom layer is a lot clearer now.
Now we drain our bottom DCM layer, which should contain our indole products, into a beaker.
To further remove more water, we add some in anhydrous magnesium sulfate.
We let this sit for a little bit with occasional stirring.
It's important to be careful here when you stir because you don't want to splash any of the skatole mixture onto anything.
When I'm satisfied with how dry it is, the DCM was filtered off through a cotton plug.
I use a cotton plug here because the funnel is a lot easier to clean than any of my glass frits.
Just want to limit what the skatole mixture comes in contact with because cleaning off the stinkiness can be a little bit of a pain.
The magnesium salts at the bottom are washed a few times with some dry DCM.
The salts and the cotton plug are washed with DCM until it runs clear.
So now we're left with a pretty crystal clear solution of our crude skatole dissolved in dichloromethane.
The next thing to do is pretty simple and using a distillation setup, I remove the dichloromethane.
After the distillation. I'm left with a little bit of crude syrup on the bottom.
Using a pipette, I pull it out of the bottom of the flask and I transfer it to a small vial.
Skatole and indole are actually white solids, so this is obviously not pure. At this point, we have two options.
We can leave it as a crude mixture of skatole and its side products or we can try to purify it.
The important thing to know about its purification is that you're probably going to stink out whatever room you're in.
In general, my attempt to purify it pretty much has failed.
My first idea was to dissolve it in a little bit of ethanol and then crash out the insoluble skatole using water.
So when I try to do this and add the water to the ethanol skatole mixture, a precipitate does crash out.
And it kind of looks like we have a white precipitate and a yellowish liquid.
The precipitate was way too fine to even consider using a coffee filter, so I tried to use a densely packed cotton ball.
It seemed to work okay at first, but eventually the precipitate started to make it through.
This was unfortunate, but I figured now I'd try recrystallizing it from a water/ethanol mixture because you know, maybe that would work.
So after doing my whole recrystallization, I just again got a cloudy mixture .
I assumed that I just used way too much solvent, so I try to do it again using a smaller amount,
and again I just got a lot of fine precipitate that couldn't be filtered.
In the end, I evaporated everything off and then dissolved it in a little bit of ethanol.
Then like before, I added a little bit of water to crash out the skatole,
and I'm left with a suspension of skatole in a water/ethanol mixture and this is what I ended up keeping and storing.
In the end though, it doesn't really matter having pure skatole and I probably should have just stuck with the crude.
To me the only use of it is to be stinky and as a crude it serves that purpose very well.
Anyway, I was satisfied enough with what I had and I was kind of sick and tired of working with the smell.
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