Niklas
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Synthesis of Isatin
Isatin is a historically important chemical compound with it being the last chemical intermediate in the first total synthesis of indigo by
Adolf-von-Beyer [1].
Fig.1: Structure of isatin
Fig.2: First published total synthesis of indigo
Over the years there have been some great improvements regarding the synthesis of isatin, and in 1919 Sandmeyer published a rather nifty two-step
approach starting from aniline that may now be commonly referred to as Sandmeyer Isatin Synthesis. First an acid catalyzed condensation of the
corresponding aryl amine with chloral hydrate and hydroxylamine hydrochloride to make an isonitrosoacetanilide is performed, which then cyclizes in
concentrated sulfuric acid to form the desired isatin.
Fig.3: The Sandmeyer Isatin Synthesis
I found this reaction to be quite interesting, and with me having all the required precursors around and isatin being supposed to have a nice
orangey-red color, I decided to try out this synthesis myself by following an OrgSyn procedure [2].
All reagents used in the following preparation were purchased from reliable chemical suppliers such as WarChem and SordaLab. The aniline was stored
under argon and therefore wasn’t destilled before use.
Isonitrosoacetanilide:
A 250 ml round-bottom-flask containing two boiling stones was charged with 4,5 g of chloral hydrate (27,2 mmol) and 60 ml dest. water were added to
dissolve the crystals. Then, in sequence with intermediate stirring of the mixture, 65 g sodium sulfate decahydrate (201,75 mmol), a solution of 2,3 g
aniline (24,7 mmol) in a mixture of 2 ml fuming hydrochloric acid and 15 ml dest. water, and a solution of 5,5 g hydroxylamine hydrochloride (79,2
mmol) in 25 ml dest. water were added to the clear solution, resulting in a colorless slushy of undissolved sodium sulfate. The mixture was set in a
sand bad over a gas burner, rapidly heated to a vigorous reflux and kept boiling for around 10 minutes. During this time all the solids dissolved and
the mixture turned increasingly more yellow, suddenly turning cloudy as soon as the desired temperature was reached with some brown oil separating. It
was left to cool down to room temperature (currently 10-15°C) for two hours, during which time a good amount of white crystalline flakes precipitated
and the byproduct oil solidified. All solids were removed by vacuum filtration, the crude isonitrosoacetanilide washed with a little dest. water, and
dried on the pump for around a hour. The product was collected as slightly off-white flakes with some solid chunks of tar in between, and was used as
such in the following step.
Fig.4: Progress of the first step of the synthesis
Fig.5: Crude isonitrosoacetanilide
Isatin:
A 50 ml round-bottom-flask was charged with 30 g of 96% sulfuric acid and heated to 50°C with the help of a glycerol bath. All of the intermediate
product was then slowly added in portions over the course of around 15 minutes, so that the internal temperature is kept between 60 and 70°C. On
addition the mixture very quickly turned a dark red, almost black color and all the solids ended up dissolving within a couple of minutes of stirring.
The flask was capped with a septum and the solution was then kept at 80°C for ten minutes, during which time the color further intensified. After
cooling the reaction mixture was poured onto crushed ice, stirred for a couple of minutes, and the orangey-red precipitate of crude isatin removed by
vacuum filtration. The residue was washed with a little more dest. water, dried throughly on the pump for two hours, and then kept in the vacuum
desiccator over anhydrous calcium chloride over night.
For further purification the bright orange powder was recrystallized from 7,5 g of glacial acetic acid and residual solvent removed in the vacuum
desiccator over anhydrous potassium carbonate. The product was collected as garnet crystalline plates that appear dark orange under the microscope.
1,37 g, 37,7% ; 53,3% lit.
Fig.6: Progress of the second step of the synthesis
Fig.7: Recrystallized isatin
 
Fig.8: Recrystallized isatin under the microscope
Sources:
[1] Schmidt, H. (1997). Indigo - 100 Jahre industrielle Synthese. ChiuZ. 1997/3, 121-128
[2] Marvel, C. S., Hiers, G. S. (1925). Isatin. Org. Synth. 1925/5, 71
[Edited on 14-11-2024 by Niklas]
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Boffis
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@Niklas, Another really nice write up of a practical synthesis and very well timed since I am current preparing a write-up on my experiments into the
Pfitzinger reaction, that is the reaction of isatin with a ketone, or aldehyde with an alpha methylene moiety adjacent to the carbonyl, in the
presence of KOH.
I must admit I didn't prepare my own isatin, I purchased it from an Ebay seller many years ago.
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Niklas
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Thank you Boffis! Pfitzinger reaction, that’s quite an interesting one, definitely looking forward on seeing your writeup on that.
Personally planning on doing some follow-up experiments with my isatin as well, likely either making isatoic anhydride by oxidation with CrO3, or
3-hydroxyquinoline by a Pitzinger type reaction. Or both if I end up getting more chloral hydrate so I can scale up my procedure.
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Boffis
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Niklas, do you think that this reaction would work with aminophenols, specifically 2-aminophenol? With the latter compound the expected product would
be 7-hydroxy-isatin which could potentially be an interesting ligand when deprotonate at the imino N.
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Niklas
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I personally don’t see why it shouldn’t, it’s definitely worth a try at least. If I had more chloral hydrate around I could probably have the
synthesis done as soon as Wednesday, as it’s rather quick to perform, but unfortunately I only have like 1 g left so this will have to wait.
Trying out different substrates in general just seems fun honestly, even if there is no practical value, the products are beautiful and the synthesis
is easy so it’s something you can do on the side. Kinda like I’ve been making a lot of different beta-nitrostyrenes lately, as their nice yellow
to orange crystals offer a nice variety compared to the usual tars of my actual projects xD
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