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Author: Subject: The Pfitzinger Reaction
Boffis
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[*] posted on 10-12-2024 at 12:00
The Pfitzinger Reaction


This project is "work in progress" and I will pick it up again after Christmas. Much characterisation of the products is required but I though I would post this preliminary report as I had promised Niklas I would do so.

The Pfitzinger Reaction and its use to prepare some interesting ligands

As part of a long-standing interest in ligands with the functional motif:
01-moiety.gif - 2kB
I investigating possible -N=C-C=N- type ligands of the bipyridyl type. One such ligand that caught my was 2,2’-bis-cinchoninic acid:
02-bis-cinchoninic acid.gif - 5kB

While looking for a synthesis for this compound, a search of the technical literature led me to the Pfitzinger reaction as the most likely route.

This reagent is prepared by the condensation of a biacetyl proxy with isatin in strong potassium hydroxide solution. I tried this reaction with biacetyl itself and it forms only tar. This is confirmed by the literature which indicate that 3-hydroxybutanone (acetoin)(1) or 3-chlorobutanone(2) are usually used as a proxy for diacetyl, biacetyl-monoxime may also work.

In its original form the Pfitzinger reaction comprises the condensation of isatin with an aldehyde or ketone, that contains a methyl or active methylene group adjacent to the carbonyl group, in potassium hydroxide solution to give 4-quinoline-carboxylic acid (cinchoninic acid) or a derivative of it. The reaction was originally described by Pfitzinger in 1886(3a) with isatin and acetone to give 2-methylcinchoninic acid (2-methylquinoline-4-carboxylic acid) and with more varied substrates in 1888(3b). Cinchoninic acid itself can’t be prepared from isatin and acetaldehyde, probably due to the instability of the latter in strongly alkaline solutions. Subsequently the reaction has been extended into a fairly general synthetic tool. When isatin dissolves in a strong alkali solution it initially gives a deep purple solution from the deprotonation of the isatin but this quickly fades to a pale straw colour of the potassium isatinoate:
09 isatinoate.gif - 5kB

For detail of the mechanism and many other examples of this reaction see the review by Shvekhgeimer, 2004(4)

My attempt to prepare the bis-cinchoninic acid from biacetyl failed for the reason mentioned above, the biacetyl appears to condense with itself rather faster than with the condensation with the isatinoate ion. However, I found an interesting patent(5) that described the preparation of another compound with the -N=C-C=N- moiety, the 2-pyridyl derivative from 2-acetylpyridine that also has the desired motif:
10 pyridyl-cinchoninic.gif - 3kB
As I didn’t have any 2-acetylpyridine, I decided to try the reaction on the much more readily available food flavouring compound acetylpyrazine and on 2,6-diacetylpyridine, of which I have a small amount. Both of these reactions were successful and are described in detail below. They yield respectively:
12 ligands.gif - 12kB

However, before launching into these syntheses without proven procedures I decided to try the reaction on some well establish substrates; namely butanone, acetone and diethyl oxaloacetate. The two simple ketones react easily giving the resulting substituted cinchoninic acids in good yield(3b).
With acetone the reaction is:
04 isatin-acetone.gif - 6kB

With diethyl oxaloacetate the reaction is:
05-isatin-oxaloacetate.gif - 8kB

Theoretically, butanone can give rise to two possible products, 2,3-dimethyl-cinchoninic acid and 2-ethyl-cinchoninic acid:
11 dimethyl-ethyl acid.gif - 5kB

However, the original literature(6) claims that only the 2,3-isomer is produced though later researchers refute this claim, stating that a small amount of the 2-ethyl isomer is also formed. All, however, agree that the 2,3 dimethyl derivative is the major product.

Diethyl oxaloacetate is a much more difficult substrate. Large amounts of brown tar and unreacted isatin are present in the reaction product if it is treated in a similar fashion as the simple ketones above and the final recovered yields of white crystalline quinoline-2,3,4-tricarboxylic acid was always low. The basic procedure I used was that described by Halberkann(7), I ran this procedure 5 time with subtle variations in an attempt to improve the yield but it remains a difficult reaction; some of my experiments are described below the remainder are just summarised.

I have several more substrates on which I am going to try the Pfitzinger reaction including acetaldoxime (target cinchoninic acid(8)), 3-isonitrosobutanone (to bis-cinchoninic acid in three steps, my own procedure), sodium pyruvate (to quinoline-2,4-dicarboxylic acid) and ethyl acetoacetate (2-methylquinoline-3,4-dicarboxylic acid).

An interesting variation of this reaction is the use of cyclic ketones such as cyclohexanone and phenols capable of tautomeric existence as ketones such and resorcinol and phloroglucinol. The latter compound reacts with isatin to yield 1,3-dihydroxyacridine-9-carboxylic acid.
08 acridine-dihydroxycarb acid.gif - 4kB
All of the reactions described here used unsubstituted isatin but this reaction works with most benzene-ring substituted isatins. These are easily prepared from substituted anilines, chloral hydrate and hydroxylamine salts in the same way as isatin itself is prepared(9).

1) Lesesne & Henze, J. Amer. C. Soc., v64, p1897, (1942).
2) A. Gershuns and A. Pavlyuk, Ukr. Khim. Zh., v30, p1086 (1964).
3a) W. Pfitzinger, J. Prakt. Chem., v33 [2], 100 (1886); 3b) v38 [2], 582, (1888).
4) S Shvekhgeimer, Chem. Heterc. Comp., p257-294, vol.40, [3], (2004).
5) Holmes, US 3799929, Cinchoninic acid derivatives.
6) W. Pfitzinger, J. Prakt. Chem., v56 [2], 283 (1897)
7) Halberkann, Berichte d. deut. Ges., v54 p3090, (1921).
8) W. Pfitzinger, J. Prak. Chem., v66, 263-264, (1902)
9) http://www.sciencemadness.org/talk/viewthread.php?tid=160684

Experimental procedures

2,3-Dimethyl-quinoline-4-carboxylic acid

13 dimethylcinchoninic.gif - 3kB
This procedure was based on that of Pfitzinger in his 1897 paper(6). The procedure was carried out twice, this description is based on the second, larger scale, experiment.

30.38g (approx. 0.2 moles) of isatin were dissolved in 450ml of water and 130ml of 50% sodium hydroxide solution and stirrer gently until the initial deep purple colour has change to a light straw brown. 60ml of butanone were then added all at once and the mixture gently refluxed for 8 hours.
01 refluxing reaction mix.jpg - 58kB
Start of the reflux, the brown colour develops quickly.

02 final reaction mixture.jpg - 33kB 04 neutralised solution.jpg - 33kB
The final reaction mixture, nothing much appears to have changed. The tar precipitating from the mixture on neutralisation

05 filtered solution.jpg - 34kB 07 acidification complete.jpg - 31kB
The solution after tar removal. The free acid ppt at pH circa 2-2.5

When the reflux was complete the reaction mixture was poured into a large bowl and boiled briefly until the smell of butanone had practically gone. While still fairly hot the solution was diluted to 850ml with cold water and partially neutralised to pH 7 with conc. hydrochloric acid; about 103ml were required. The solution was filtered to remove the small amount of tarry material that precipitated. While still warm the solution was rendered acid to Congo Red paper, about pH 2, with 18.5ml of conc. hydrochloric acid and then reheated to 90°. The precipitate of the free acid did not redissolve so the suspension was cooled to room temperature and then chilled in the fridge overnight. The pale solid was filtered off and washed by drawing a little water through the cake. The cake was oven dried at 100° to constant weight to yield 38.144g of crude off-white dimethyl-quinoline-4-carboxylic acid.
08 crude filter cake.jpg - 50kB
The raw dried filter cake

The solid was recrystallised from boiling water, 1200ml of were required, but the light brown solution remained cloudy and so was treated with 5ml each of decolourising charcoal and kieselguhr. The solution was filtered through a pre-heated Buchner funnel to give a clear, pale golden yellow solution. This was cooled and then chilled to 4°C for several hours. The almost pure white crystalline product was filtered off, washed with a little cold water and dried as before to give 31.376g of 2,3-dimethyl-quinoline-4-carboxylic acid or 75.5% of theory.

Evaporating down the filtrate to about 300ml gave a further 3.848g and evaporating the filtrate down further to circa 50ml gave a final 0.898g of less pure acid. These two crops were combined and recrystallised from 150ml of water to give a further 3.780g of 2,3-dimethyl-quinoline-4-carboxylic acid, giving a combined yield of 35.149g or 84% of theory.

Very little information seems to be available on this compound other than that given by Pfitzinger. It melts above 310°C at which point decomposition sets in, no mention is made by him regarding water of crystallisation so it is assumed to be anhydrous. I will test this and also run some TLC when time permits to check it for the 2-ethyl isomer.

2-Methyl-quinoline-4-carboxylic acid (Quinaldine-4-carboxylic acid)
14-quinaldinecarboxylic.gif - 3kB
This compound was prepared by an almost identical process to the previous compound but substituting acetone for butanone.

30.210g of isatin were dissolved in 500ml of cold water and 150ml of 40% sodium hydroxide solution. When the initial violet colour had faded to a straw brown 60ml of acetone were added all at once. The solution was refluxed gently for 8 hours during which time little appeared to change.

When the reflux period was over the solution was cooled to 50-60°C and partly neutralised to pH7.5-8 with conc. hydrochloric acid: About 105ml were required. After standing for about 15 minutes the small amount of brown flocculent precipitate that formed was filtered off. The clear brown solution was reheated to about 90°C and the pH lowered to about 2.5. The solution was allowed to cool to room temperature and then chilled to 4°C in the fridge for 24 hours. The straw-coloured crystals that formed were filtered off (9cm Buchner funnel), washed with a little cold water and sucked as dry as possible. The filter cake was dried at 40°C for 8 hours to give 32.869g of crude product.

By evaporating down the filtrate to <200ml allowed the recovery of about 4.8g of very impure brown product. This can be worked up by dissolving in boiling water (circa 20ml per gram), treating with charcoal and kieselguhr (circa 0.3-0.4ml per gram.) and filtering hot through a preheated Buchner funnel. On cooling almost white crystals form. Or it can be added to the main crop as on this occasion but this then requires charcoal treatment of the whole of the recrystallisation solution.

The roughly 37.7g of combined crops were recrystallised from 800ml of boiling water, treated with 5ml of charcoal and 5ml of Kieselguhr, after five minute it was filtered hot through a preheated Buchner funnel and poured into a large beaker to cool then chilled to 4°C for 24 hours. The pale yellow solution deposited practically colourless crystals, which were filtered off, washed with a little cold water and dried at 45°C to give 31.487g of apparently anhydrous 2-methylquinoline-4-carboxylic acid. The filtrate was evaporated down to 150ml and treated with 0.5ml of charcoal and 0.5ml of kieselguhr to give a further 2.901g of white scaly dried product. The total yield was 34.388g or about 89% of theory.
11 recrystallising 2-methylcinchoninic acid.jpg - 37kB
The clear filtered solution just starting to crystallise

Pfitzinger reports that the acid crystallises from water as a hydrate but this effloresces and loses it water readily on exposure to the air even at ambient temperature after drying at 100° it is anhydrous.


Quinoline-2,3,4-tricarboxylic acid
15-tricarboxylic.gif - 4kB
This synthesis is based on the procedure given by Halberkann(7). Due to the sensitivity of diethyl oxaloacetate to alkalis the procedure for this compound is slightly differently. The reaction is carried out at room temperature or just above and as a result the reaction time is long (more than 2 days). Attempt to reduce the time by increasing the temperature and adding the sodium diethyl-oxaloacetate in small portion over the reaction time failed to improve then yield, in fact the yields at elevated temperatures were always poorer and the product contaminated with increasing amounts of tar. A large excess of oxaloacetate is also required to compensate for the loss due to side reaction.

3.800g of isatin were dissolved in 24ml of 50% potassium hydroxide in a small conical flask by shaking vigorously. 13.452g of sodium diethyl-oxaloacetate were then added followed by a further 6ml of 50% potassium hydroxide diluted with 15ml of water. The mixture was swirled around to dissolve the solids and warmed gently (to a max of about 34-40°C) until most of the solid had dissolved. A small amount of fine solid remains undissolved. The flask was stoppered and the light brown solution was then set aside for 2 days.

After 2 days much solid had precipitated; the mixture was heated to boiling and then simmered for an hour. The suspension was then diluted until the solid dissolved in the hot liquid to give a clear brown solution. Whilst still hot the solution was acidified with conc. hydrochloric acid to pH 3, about 25ml were used. Initially the solution became lighter in colour until about 20ml had been added and then it darkened again with slight effervescence.

The solution, still fairly hot, was allowed to cool slowly and then chilled to 4°C for 12 hours in the fridge. The pale brown scaly crystalline precipitate that formed was filtered off, washed with a little cold water and dried to give 5.679g of crude quinoline-2,3,4-tricarboxylic acid.

The filtrate was acidified with a further 0.6ml of conc. hydrochloric acid and maintained at 4°C for 12 hours. A pale orange precipitate formed that was filtered off, washed with a little water and dried to give 1.204g. Under the microscope it could be seen to be composed of colourless plates and an amorphous, orange brown, tar-like material.

An experiment with 0.500g of the crude product was mixed with increasing amounts of boil water until complete solution occurred; 18ml were required or 36ml per gram. The remaining 5.179g of crude material were dissolved in 200ml of boiling water and mixed with the solution of the 0.5g test solution, treated with 0.5ml of decolourising charcoal, filtered and evaporated down to about 60ml. curiously no crystals formed until the orange solution was cooled.

On cooling a little isatin crystallised along with large colourless plates. Isatin has been found to dissolve slowly in warm whereas the tricarboxylic acid dissolves quickly. So when no further crystals appeared to be forming the solution was quickly reheated until the large colourless crystals had dissolved and the solution decanted from the residue of isatin and cooled. When no further colourless crystals appeared to be forming the liquid was decanted and chilled for 24 hours at 4°C to precipitate further isatin. The crystals of acid were collected in a small Hirsch funnel using a little water, drained and dried to give 2.614g of slightly pink crystals that under the microscope could be seen to contain minute red isatin inclusions.

The chilled decanted solution was filtered to remove the isatin and then evaporated down to about 12ml and cooled. The selective dissolution procedure described above was repeated and the new liquid chilled for 12 hours to yield a further 0.677g of slightly pink tricarboxylic acid. The final liquor was saved and worked up with the residues from later experiments. An experiment at this point on the partly purified acid revealed that only 5ml of water were required to recrystallise 1g of acid.

The combined 3.291g were recrystallised from 17ml of water to give 2.774g of still slightly pink crystals in spite of the fact that no isatin could now be seen under the microscope. The filtrate was saved and work up with later residues. The acid is anhydrous so the yield is about 41% of theory but the mechanical losses during the recovery and purification are considerable.

In later experiments it was found to be better to isolate the acid as the potassium salt which crystallises directly from the reaction mixture and the dilution used above is actually detrimental. Other methods of isolation and purification are also being tried such as sodium bicarbonate leach of the crude product and removing the potassium salt by filtration in stages and add further oxaloacetate after each filtration.

Even with a 2½ fold excess of sodium diethyl-oxaloacetate there is still residual isatin in the final reaction mixture and raising the reaction temperature makes this situation worse. The implication of this is that in this system lower temperatures favour the Pfitzinger reaction over the decomposition of oxaloacetate ion in an alkaline solution.

An attempt to prepare 2,2’-bis-cinchoninic acid from isatin and biacetyl was a complete failure, no quinoline derivative at all was recovered.


2-(2-pyrazinyl)-quinoline-4-carboxylic acid
16 pyrazinyl acid.gif - 4kB
The original target of this reaction was to have been the 2-pyridyl- derivative but 2-acetylpyridine is hard to get and expensive so the experiment was run using 2-acetylpyrazine which is now a readily available flavouring compound. A small-scale experimental run using 1.5g (c 0.01M) of isatin was carried out first and based on the observations the follow larger scale procedure was used:

8.263g of isatin were dissolved into 28ml of 50% potassium hydroxide and 18ml of water in a small conical flask and stirred until the isatin had dissolved and the initial purple solution faded to a straw brown colour. 6.119g of acetylpyrazine suspended in 25ml of isopropanol were added and the mixture refluxed gently with magnetic stirring for 2 hours. The solution was then cooled then finally chilled to 4°C and the brown solid filtered off using a glass filter and washed with about 50ml of isopropanol. The cake was transferred to a small beaker and dispersed into 20ml of isopropanol and the solid collected in a small Buchner funnel; the isopropanol washing removes most of the coloured impurities. The dried filter cake weighed 11.831g, this is the crude potassium salt of the pyrazinyl-cinchoninic acid. The filtrate was acidified with 80% acetic acid causing a dark brown precipitate to form. This was filtered off, washed with a little water and dried to give 1.872g of very impure dark brown material that awaits investigation.

The 11.831g of crude potassium salt was recrystallised by dissolving in a mixture of 35ml of methanol ad 5ml of water at boiling point, treated hot with 1ml of charcoal and 1ml of kieselguhr and filtered hot. When slowly cooled it deposited straw-coloured fibrous crystals, these were filtered off, washed with a little cold methanol and dried to give 8.988g of the potassium 2-pyrazinyl-cinchoninate as straw coloured crystals. Recrystalising these from 27ml of methanol and 3.5ml of water gave 6.128g of pale straw-coloured fibrous crystals. The hydration state of the potassium salt has not yet been determined.

The combined filtrates were evaporated to dryness and worked up with the residues from the previous experiment.

Free 2-(2-pyrazinyl)-cinchoninic acid is very sparingly soluble in all of the solvents tried and the potassium salt is very soluble in water with a rather flat solubility/temperature curve making recrystallisation from water difficult. An attempt to use the sodium salt for recrystallisation has yet to be made. The free acid is easily liberated from a strong solution of the potassium salt by adding excess 80% acetic acid. It retains the pale straw colour of the potassium salt. It is possible that this is the natural colour of the free acid, however, the potassium salt is almost certainly white when pure.

2,6-Pyridyl-bis(2-quinoline-4-carboxylic acid)
17 pyridyl-bis-acid.gif - 5kB

Although I didn’t have access to 2-acetylpyridine and had to substitute it with acetylpyrazine I did have some 2,6-diacetylpyridine and decided to give the double Pfitzinger reaction a go as it should yield an interesting tridentate ligand. In most Pfitzinger reactions I have used an excess of the ketone component in an attempt to minimise the amount of residual isatin in the product as it is often difficult to remove, however, in this case an excess of isatin was used to ensure maximum utilisation of the precious 2,6-diacetylpyridine.

6.644g of isatin were dissolved in 16ml of 50% potassium hydroxide solution and 6ml of water in a small conical flask equipped with a stir bar. The solution was stirred until the purple colour had faded to straw brown and then 3.262g (0.02 M) of diacetylpyridine dissolved in 20ml of isopropanol added in one go, the flask being rinsed with 5ml of isopropanol. The mixture was heated until it began to boil and then gently refluxed for 1 hour. The solution immediately started to turn reddish and after a short time a pale precipitate began to form.
02 reflux complete.jpg - 37kB
The reaction mixture after refluxing, note the ppt of the product K salt

After the reflux was complete the reaction mixture was poured into 100ml of cold water and chilled to 4°C. The red mixture almost solidified on cooling. It was stirred up and drained hard in a Buchner funnel and the cake washed with a little cold isopropanol. Air was drawn through the cake and then it was dried at 35°C to constant weight yielding 10.520g of slightly pinkish cake of the dipotassium salt, presumably as a hydrate.
03 crude potassium salt.jpg - 36kB
The filtered of and isopropanol washed K salt and the red filtrate

The Filtrate from the K salt was acidified with conc. hydrochloric acid, about 8.5ml were required, and the slimy orange precipitate filtered off. The precipitate was sucked as dry as possible but was too slimy to be washed on the filter. The cake was dispersed into 30ml of water and a 12% solution of sodium carbonate added to the suspension until most solid had dissolved and only a little orange red isatin remained; about 9ml were required. The solution was filtered to remove the isatin and then treated with 2.5ml of charcoal and 1ml of kieselguhr and heated almost to boiling, cooled and filtered warm. The resulting pale orange red solution was diluted to 80ml with water, heated almost to boiling and then carefully acidified with 18% hydrochloric acid, about 5ml were required, and cooled to obtain a more easily filterable suspension. The mustard yellow precipitate was filtered off washed with a little water and oven dried at 80-90°C to give 2.300g of crude acid.

The original 10.52 grams of potassium salt were dispersed into 20ml of cold water and heated until dissolved giving a pale pink solution. On cooling, the solution solidified into a mass of fine fibrous crystals, these were stirred up and filtered at the pump ad the cake washed with a little cold water but the product is very soluble. Isopropanol would have been better! The cake was oven dried at 100°C to give 4.277g of dipotassium 2,6-pyridyl-bis-2,2’-cinchoninate hydrate consisted of very pale pink, matted fibres.

The combined filtrate and washings were acidified to Congo Red paper with 18% hydrochloric acid, 6ml were required, to give a bright yellow gelatinous precipitate. This was heated to almost boiling and cooled to obtain a more readily filterable solid. The solid was filtered at the pump and drained hard and washed with water. The cake was oven dried at 90-100°C to give 3.731g of crude free acid.
04 liberated acid.jpg - 34kB
The acidified K salt solution, the bright yellow free acid precipitates.

An experiment with 0.2g of the free acid revealed that it is practically insoluble in boiling water. It does not appear to be much more soluble in other common solvents either. The compound was purified by recrystallising its sodium salt which has a steeper thermal solubility gradient than the potassium salt.

The combined batches of free acid (2.300 and 3.731g = 6.031g) were dispersed into 5ml of water and 3ml of 40% sodium hydroxide. The suspension was heated to boiling and more water added until complete solution occurred, another 7ml were required. On cooling the solution solidified into a mass of fibrous crystals but still discoloured. Another 5ml of water were added and the mixture heated to boiling, treated with 0.5ml each of charcoal and kieselguhr, filtered hot and cooled. The solution solidified as before but the fibrous prisms were coarser. The crystals were filtered off and drained at the pump using a medium sized Buchner funnel and washed with a little isopropanol. The crystals were air dried at about 30-35° to give 6.568g of the sodium salt. The amount of water of crystallisation is not known at present so the yield cannot be calculated from this figure.

The filtrate was acidified and the small amount of greyish yellow acid filtered off, washed with isopropanol and dried gave only a small amount of grey residue and was discarded.

The 4.085g of remaining potassium salt were then also converted to the sodium salt by dissolving in 100ml of hot water and acidifying with 18% hydrochloric acid to just acid to Congo red paper, about 5m were required. This causes a bright yellow, rather gelatinous, precipitate to form. This was filtered off at the pump using a 7cm Buchner funnel but a larger one would have been better, and sucked s ry as possible. The cake was difficult to wash on the filter so was dispersed into 150ml of hot water, cooled to room temperature and filtered again. The vacuum was maintained for 30 minutes healing any cracks as they formed with a spatula, to remove as much water as possible. The moist cake was placed in a beaker with 5ml of water and 3ml of 40% sodium hydroxide solution. The mixture was warmed gently until everything had dissolved, treated with 0.5ml each of decolourising charcoal and kieselguhr and filtered. The pale straw-coloured filtrate was maintained warm until it had evaporated to about 25ml and cooled slowly. The crystalline mass was chilled to 4°C and drained in a small Buchner funnel, washed with isopropanol and air dried at about 20°C for several days to give 4.457g of sodium pyridyl-2,6-bis(2-quinoline-4-carboxylate) of uncertain hydration state.

Work is continuing on the hydration state of the alkali salts and a solvent to recrystallise the obviously bright yellow free acid. I have yet to test its ability to act as a ligand.
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Niklas
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[*] posted on 13-12-2024 at 13:55


Great writeup Boffis, definitely put a lot of work into it. Nice colors as expected. Looking forward to the planned experiments mentioned, especially regarding the products’ application as ligands.
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[*] posted on 18-12-2024 at 13:36


Thank you Niklas. I have just run another reaction of the Pfitzinger type. This time with phloroglucinol to give 1,3-dihydroxyacridine-9-carboxylic acid. I didn't have any published data to go by so I winged it based on my prior experience and obtained a brownish orange product that is sparingly soluble in water and solvents but dissolves in even sodium bicarbonate giving a deep magenta solution. I was expecting the product to be white or yellow so I was initially disappointed but this afternoon I managed to find a published reference to this reaction and it appears that my product fits the description of this compound. I have yet to purify it by dissolving it in sodium bicarbonate solution and precipitating with acetic acid which removes unreacted isatin. The crude product is currently drying.

I have done some more research on the 7 substituted isatins and it appears that the hydroxy, amino and nitro compounds are not directly available via Sandmeyer's reaction though the 7-hydroxyisatin should be via the 2-nitroanisole or phenitole followed by de-alkylation. It appears that isatin can be 5,7-dinitrated and dichlorinated
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Illegal Parkinson
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[*] posted on 7-1-2025 at 00:31


Pfitzinger reaction of isatin used to prepare:
1. Quinacainol
2. Pavinetant
3. Oxycinchophen
4. Cinchophen
5. Tetrophan [83-93-2]
6. Cinchocaine (aka Dibucaine)
7. Talnetant
8. Pipequaline & PK 9084 [77472-99-2]
9. SB-218795
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Boffis
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[*] posted on 21-1-2025 at 22:37


Over Christmas I managed to find a bit of time to carry out further experiments on this reaction. I completed my work on the isatin phloroglucinol condensation and obtained a brick red powder of the free acid, a deep purple, almost black amorphous sodium salt and a deep maroon red free acid precipitated from hot alkaline solution by mineral acid. This latter form has the same chemical properties when dissolved in dilute alkali as the brick red form and I wonder if this is a lactonised form.

I repeated this reaction on a very small scale using using orcinol in the hope of obtaining a hydroxy-methyl-acridine-9-carboxylic acid but no reaction took place even after 8 hours of reflux. Virtually all of the isatin was recovered.

I had seen in the review article referenced above that nitromethane and isatin undergo a "Pfitzinger-like" condensation to 3-nitrocinchoninic acid when treated with 33% KOH solution. However, the reaction in my hands was very messy, giving mainly a dark brown gloopy tar and a small amount of crystalline solid that is a mixture of at least 3 different crystalline substances. I hind-sight it may have been better to have reacted each of the reactant with KOH solution separately so as to convert the nitromethane into the C2 derivative methazonic acid first since the Pfitzinger reaction requires at least 2 carbon atoms in the "keto" component.

I also tried the reaction described by Pfitzinger himself between isatin and ethyl acetoacetate to give quinaldine-3,4-dicarboxylic acid. The only difference is that I used the methyl ester but the reaction failed completely with no product at all in spite of the fact that I followed the original instruction to the letter and prorated the methyl ester accordingly. I can offer no explanation though Pfitzingers original description is a bit vague in one respect; it states that the reactant are mixed hot and stood for 2 days. It doesn't state whether this is 2 days hot or at room temperature. I tried room temperature for 2 days and when I got no crystals of the K salt I tried refluxing gently for 2 days. All I recovered was unreacted isatin and a little brown tar.
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[*] posted on 22-1-2025 at 10:36


If you throw all the reactants into the pot at once, most often the Pfitzinger reaction ends up as a mess. There is a modified procedure where the isatin is first reacted with alkali to open the ring, This results in the orange isatin color to be mostly reduced to pale yellow. The ketone or other component is then added and the reaction carried out as usual. I can attest that using acetone as the ketone under these conditions affords 2-methylquinoline-4-carboxylic acid in better than 60% yield. I do not have the reference at hand right now but I will check and post it when I can.

AvB

Whoops- I see that you have already pre-reacted the isatin with KOH in your earliest post. Apologies

AvB

[Edited on 22-1-2025 by AvBaeyer]
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[*] posted on 22-1-2025 at 22:49


@ AvBaeyer, Yes I always allow the initial intense purple deprotonate isatin solution to fade to pale straw colour before using it in the reaction. I think the problem with the nitromethane reaction is that I didn't give the nitromethanoate time to dimerise to a methazonate salt before adding it to the reaction mixture. I got rather concerned when I mixed the nitromethane with strong KOH solution that the temperature suddenly started to rise dramatically so I mixed it quickly with the pre-prepared potassium isatinoate solution before all of he nitromethane had dissolved in the alkali. Looking into the preparation of methazonates afterwards I can see that slow addition of the nitromethane and temperature control are required to get a reasonable yield of methazonate and it may also be better to use a slightly more dilute solution to stop any solid from precipitating. The optimum temperature seems to be about 50 C, below this temperature the conversion of the nitronate salt to methazonate is slow while much above this temperature the methazonate starts to rearrange to nitroacetate. I'll have another go at this when I get time. Unfortunately the original reference does not apper to be available digitally.

The failure of the acetoacetate condensation is baffling and I can only presume that I made a mistake somewhere. After the failure I tested the acetoacetate (ex Sigma Aldrich) with nitroprusside (nice orange reaction) and ferric chloride (purplish colour) and while this is not a guarantee of purity it does a least support the identity of the ester. A curious feature I did notice was that when I opened the bottle after standing for 48 hours there was still a smell of the ester, I was surprised as I expected the ester to have hydrolysed by this time. Its possible therefore that I didn't add enough KOH but I thought I had followed Pfitzinger's text religously. Again I'll have another go at this reaction in the future.

I also ran a few tests to investigate the reaction of the 2-pyazinylcinchoninic acid and the pyridyl-bis-cinchoninic acids with metal iron. Interestingly, niether gives a coloured reaction with ferrous ions under near neutral conditions and when made slightly alkaline only iron hydroxides ppt, which quickly turn brown so no stable complex here. Cupric ions do not give a coloured reaction unless a mild reducing agent is present then both give strong purple colours in a test tube, the selective reaction of ligands with this motife with cuprous ions is standard. On filter paper the pyrazinyl reagent rapidly gives a purple colour even with cupric ions, so I presume the filter paper is an adequate reducing agent here. Ni, Co, Fe3+, Zn, Pb, molybdate and tungstate ions give no coloured reation.
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