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methylene_beam
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[*] posted on 9-1-2012 at 13:39
8-Iodocaffeine synthesis


I would first like to introduce myself to the community. I am a recent college graduate with my degree in chemistry. I have taken a real liking to organic chemistry and that is what I ultimately focused on in college. Now that school is over I have decided to continue on with my interest as a hobby until a start my grad program next fall.
I have decided to experiment with caffeine because it is a cheap bi-cyclic aromatic compound that has shown to have anti-caner properties in areas like the liver. Not only that it is a powerful stimuli of the cAMP messaging system (increased respiration). My procedure is as follows.
I have an excel attached to visually show what I am attempting to do.
Experimental
1.5g of anhydrous caffeine pure Caffeine (ebay vendor), 1.24 equiv KI(1.86g)(ebay vendor), and 30.0ml of MeOH(~99.8) were added to a 250ml RBF with magnetic stirring. Once added, flask contents were heated to 55c until all of the KI had gone into solution. Once into solution a solution of sodium hypochlorite (~6wt%) was added drop wise. There should be a noticed exotherm during the addition. Once addition is complete contents were stirred for 15mins then a small amount of sodium thiosulfate was added to neutralize the remaining iodide. Contents were then added to a sep funnel and extracted 3 times(10,10,5ml) with methylene chloride(product should be much more soluble in ch2cl2). Solvent was pulled off with vac and recrystalized by some method. (Typical work up procedure including drying).
Possible purification: doping a silica column with base then achieving separation knowing the more polar caffeine will interact with the column longer.
Thoughts: The drop wise addition of the hypochlorite will generate the I+ species which can substitute the highly activated proton on caffeine’s Imidazole center. I have read other papers concerning the iodination of Xanthine aromatic systems using I2 at 160c with low yields due to the degradation of the Xanthine ring system.
From what I understand this reaction could be done in hot water because caffeine is significally more soluble in hot water along with KI. Then a quick work up extracting the cooled solution in ch2cl2?
Also my crude amounts and equivalents came from the procedure at the bottom of this page following a similar system for active ring iodination. Remember I haven’t actually run this experiment but still preparing.
Sources
http://www.sciencemadness.org/talk/viewthread.php?action=pri...
bottom^



[Edited on 9-1-2012 by methylene_beam]

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[*] posted on 9-1-2012 at 14:58


Some remarks about the writeup: "1.5g of anhydrous caffeine pure Caffeine" - In mol? "Solvent was pulled off with vac and recrystalized by some method." Do you have a recrystallization solvent or not? If not, this step should not be described. "There should be a noticed exotherm during the addition." Then -- was there?

You have described a synthesis of the title compound, but no proof of it actually working. Synthesis involves purification and characterization of the product too. The literature on this iodination is scarce, but the synthesis is described:

"Gomberg [44] had reported the failure to iodinate caffeine (4a) with diiodine in chloroform; later
on, 8-iodocaffeine (4c) was obtained in ca 40% yield by heating caffeine (4a) with diiodine in a sealed
tube at 150°C [45]."

in a review article in Molecules 2001, 6, 927-958. The failure of iodination in CHCl3 makes me feel quite skeptical that you have actually iodinated caffeine. Do you get crystals out of the extraction? If so, make a mixture of pure caffeine and the product. Unchanged melting point would mean that you have just recovered unreacted caffeine.

Bromination of purines, such as the preparation of 8-bromocaffeine is a tad easier one.

[Edited on 9-1-2012 by kavu]

Whoops -- I should have read the last words of you post! Sorry about that :)

[Edited on 9-1-2012 by kavu]
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methylene_beam
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[*] posted on 9-1-2012 at 16:19


Like I said at the bottom of my first post "I haven't actually run this yet" This is more a crude thought process.

I saw the paper on bromo Caffeine but would rather iodinate for a possible suzziki coupling or a hartwig amination.(Pd inserts easier)

This procedure should work employing the hypo chlorate as the oxidant to generate the I+ species.

still in the process of devising a recrystallizing route

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[*] posted on 2-2-2012 at 18:39


Quote: Originally posted by methylene_beam  
Like I said at the bottom of my first post "I haven't actually run this yet" This is more a crude thought process.

I saw the paper on bromo Caffeine but would rather iodinate for a possible suzziki coupling or a hartwig amination.(Pd inserts easier)

This procedure should work employing the hypo chlorate as the oxidant to generate the I+ species.

still in the process of devising a recrystallizing route




Mind posting this paper on bromination of caffeine? I have been looking for a good way to 8-halogenocaffeine without producing dry chlorine gas.
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[*] posted on 3-2-2012 at 13:12


Decided to run a few experiments on caffeine in route to 8-bromocaffeine.

1st Experiment:

Mixed 10mmol caffeine, 11mmol hydrobromic acid, and 5ml water together then heated mixture to 50C with heavy stirring. Added enough water to dissolve caffeine completely. Over the course of 10 minutes I added 11mmol H2O2 keeping temperature at 50C. Kept mixture at 50C with stirring overnight then cooled to room temperature.

Quenched excess bromine then filtered the precipitate (hopefully 8-bromocaffeine), washed with water and is now drying. Cooled solution for 1 hour, filtered precipitate, washed with water and now drying.

Currently waiting for everything to dry before TLC.


2nd Experiment:

Dissolved 10mmol caffeine in minimal amount of 50C glacial acetic acid with heavy stirring. Added 11mmol N-bromosuccinimide in portions with stirring, maintaining solution at 50C. Maintained stirring and heating overnight.

Quenched excess bromine and cooled to room temperature, no precipitate. Placed solution in refrigerator for 2 hours, no precipitate. Started basifying with a 10% sodium carbonate solution and solution turned purple.

Switched to a 20% NaOH solution and stopped basifying once precipitate stopped forming. Placed in refrigerator for 1 hour and filtered the precipitate, washed with water, and placed in desiccator.

Will run TLC once dry.


It seems that the purple coloration is very similar to the murexide test, not sure how it happened. Any ideas?

I will report back with TLC results once done.


I think the first experiment is going to come back as mostly unreacted caffeine and side products. All the literature I have seen has mentioned that chlorination of caffeine in aqueous systems has ended in tons of side reactions. Not sure if this holds true with bromination though.

Anyone have any papers on the bromination or chlorination (no Cl2 gas please) of caffeine? I will probably try TCCA at some point but a literature example would be nice to have before the experiment. The only papers I have found detailing the synthesis of 8-chlorocaffeine have used the same method, pass dry Cl2 into a solution of caffeine and chloroform or DCM until the initial precipitate goes back into solution followed by rotavap.

The only bromination papers I have found contain no experimental procedures, just: "8-bromocaffeine was prepared via HBr in the presence of H2O2" or "8-bromocaffeine can be prepared via N-bromosuccinimide or bromine water"

Any help would be greatly appreciated.
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[*] posted on 3-2-2012 at 13:16


Whats wrong with Cl<sub>2</sub>?



BOLD

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[*] posted on 3-2-2012 at 13:27


One more thing, halogenation of caffeine would be an electrophilic substitution rather than free radical halogenation correct? I didn't notice any papers or patents mentioning a light source.

EDIT: Definitely an electrophilic substitution.

For the last two hours I have been looking through papers and patents looking for purine halogenations instead of caffeine halogenations and I still haven't found any detailed procedures.

Anyone happen to have any solubility data for 8-bromo or 8-chlorocaffeine? I assume they are less soluble in water than non halogenated caffeine.

[Edited on 3-2-2012 by johnames]

[Edited on 3-2-2012 by johnames]
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[*] posted on 4-2-2012 at 02:57


Yes, it is an electrophilic substitution with the peculiarity that the irreversible substitution at position 8 is inhibited by the kinetically favoured reversible N-halogenation (this is typical for electrophilic substitutions on azoles and azines, e.g. see the unreactivity of pyridine toward EAS at position 3). The N-halogenated intermediate should be susceptible to nucleophilic attack at position of 8 resulting in oxidation. I would thus avoid all nucleophilic and protic solvents for the halogenation, so rather stick to dichloromethane.
And yes, the halogenated caffeines should be less soluble in water so that the proper recrystallization solvent for removing any unreacted starting material is likely water/ethanol rather than some too non-polar solvent.

By UTFSE you can find other references for halogenation of caffeine:
https://www.sciencemadness.org/whisper/viewthread.php?tid=12...
https://www.sciencemadness.org/whisper/viewthread.php?tid=17...




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[*] posted on 4-2-2012 at 07:48


Quote: Originally posted by Nicodem  
Yes, it is an electrophilic substitution with the peculiarity that the irreversible substitution at position 8 is inhibited by the kinetically favoured reversible N-halogenation (this is typical for electrophilic substitutions on azoles and azines, e.g. see the unreactivity of pyridine toward EAS at position 3). The N-halogenated intermediate should be susceptible to nucleophilic attack at position of 8 resulting in oxidation. I would thus avoid all nucleophilic and protic solvents for the halogenation, so rather stick to dichloromethane.
And yes, the halogenated caffeines should be less soluble in water so that the proper recrystallization solvent for removing any unreacted starting material is likely water/ethanol rather than some too non-polar solvent.

By UTFSE you can find other references for halogenation of caffeine:
https://www.sciencemadness.org/whisper/viewthread.php?tid=12...
https://www.sciencemadness.org/whisper/viewthread.php?tid=17...


Thank you for that information. I searched for a long time before ever posting. The only relevant information in the first thread you posted are two international journal references which I have never been able to find, even if I could I wouldn't be able to read them. The second thread mentions the chlorination of caffeine with dry Cl2, which is what I am avoiding, see above.

Wouldn't conducting the halogenation in glacial acetic acid protect caffeine from N-halogenation due to it being in salt form (acetate) or is acetate too weak?

[Edited on 4-2-2012 by johnames]
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[*] posted on 4-2-2012 at 09:02


Found this paper with an interesting process for theobromine. Too bad they use Br2, I'd sooner use Cl2.

Synthesis of Some 8-Substituted Bis(β-chloroethyl)amino Derivatives of Naturally Occurring N-Methylated Purines

J. Org. Chem., 1962, 27 (6), pp 2173–2177
DOI: 10.1021/jo01053a067
Publication Date: June 1962

"To a stirred and refluxing suspension of 100g theobromine in 300g of carbon tetrachloride and 700g of nitrobenzene was added dropwise 140g of bromine dissolved in 90g of nitrobenzene. After addition was completed, the reaction mixture was refluxed and stirred for an additional 4 hours. The hot suspension was then poured, with stirring, into 2l of acetone. The resulting white precipitate was filtered, washed with acetone and ether, and dried in vacuo to give 120g of 8-bromotheobromine."


TLC Plate Results:

Developed the TLC plate in 95% ethyl acetate and 5% acetic acid. Starting material, anhydrous caffeine, showed one spot as expected Rf = 0.1

First reaction showed two spots. One small spot Rf = 0.1 (unreacted caffeine) and one larger spot Rf = 0.66

Second reaction also showed two spots. One small spot Rf = 0.1 (unreacted caffeine) and one larger spot Rf = 0.66

I will now attempt to recrystallize and run another TLC plate. While not conclusive, I'd say both reactions were a success. After recrystallization I will also conduct melting point tests and report back.


Recrystallization:

5ml of water was heated to boiling and then added to .5g of crude product from experiment 1 and 2 with heavy stirring. Caffeine would have dissolved easily, the crude product did not. I then added more and more boiling water until a total of 5ml of water had been added.

At this point barely any of the product had dissolved so I decided to start adding methanol. I added hot methanol drop by drop, after adding a total of 10ml of methanol most of the crude product still had not dissolved. I decided that enough solvent had been wasted and any unreacted caffeine would surely be dissolved.

Solution is currently sitting out to cool to room temperature and will then be filtered, washed with water and dried.

If this is 8-bromocaffeine it is extremely non soluble in even boiling water as opposed to caffeine which is extremely soluble in boiling water. It is also insoluble in a hot 50:50 methanol/water mixture.

If the paper I posted above regarding 8-bromotheophylline stands true for 8-bromocaffeine as well, 8-bromocaffeine should also be extremely insoluble in acetone. I will try this once product has been dried.

[Edited on 4-2-2012 by johnames]
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[*] posted on 7-2-2012 at 20:04


Quote: Originally posted by Nicodem  
Yes, it is an electrophilic substitution with the peculiarity that the irreversible substitution at position 8 is inhibited by the kinetically favoured reversible N-halogenation (this is typical for electrophilic substitutions on azoles and azines, e.g. see the unreactivity of pyridine toward EAS at position 3). The N-halogenated intermediate should be susceptible to nucleophilic attack at position of 8 resulting in oxidation. I would thus avoid all nucleophilic and protic solvents for the halogenation, so rather stick to dichloromethane.
And yes, the halogenated caffeines should be less soluble in water so that the proper recrystallization solvent for removing any unreacted starting material is likely water/ethanol rather than some too non-polar solvent.


Nicodem, are you saying that with the presented system i have now that the reaction will not goto completion? If i use an aprotic solvent (you suggested DCM) will the the N-iodo intermediate allow for formation of the of the 8-iodo desired product because of the nucleophilic nature of the intermediate carbon?

would quenching with HCl be enough to push any intermediate to final product?

should I then use a I2/KI system still using bleach as the oxidizer?
If i use DCM as a solvent how will the hyopchlorate react with the substrate when the 2 solvents aren't miscible.


I have also found a paper of iodonation of azoles and imidazoles employing silver acetate and I2.
http://doc.rero.ch/lm.php?url=1000,43,2,20100923105825-VL/al...

let me know what you guys think
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[*] posted on 8-2-2012 at 14:15


Quote: Originally posted by methylene_beam  
Nicodem, are you saying that with the presented system i have now that the reaction will not goto completion? If i use an aprotic solvent (you suggested DCM) will the the N-iodo intermediate allow for formation of the of the 8-iodo desired product because of the nucleophilic nature of the intermediate carbon?

would quenching with HCl be enough to push any intermediate to final product?

I don't think you fully understood what I meant. I only suggested you stick to inert non-nucleophilic solvents. Also, use Cl2 or Br2, rather than haloimides or other reagents for the halogenation, unless you follow a literature example. Solutions of Br2 in dichloromethane are very easy to prepare by oxidation of sodium, potassium or ammonium bromides followed by extraction, so use that if you don't have bromine.

Also, keep in mind that on imidazoles there are two possible mechanisms for the halogenation of imidazole positions 2 (see scheme). The N-halogenation, which is obviously kinetically favoured leads to the addition reaction which followed by the elimination gives the corresponding substituted products. The electrophilic attack followed by deprotonation (the most common mechanism for the electrophilic aromatic substitution) is thus not the only possible pathway. This has certain practical consequences, one of which is what I advised you in regard to nucleophilic solvents, the other is in regard to the use of elemental halogens. Both mechanisms can be operative in which case the halogenation is feasible under other conditions as well. Given that imidazole can be tribrominated in acetic acid, I would say that normal EAS mechanism is operative and possibly the main pathway. Yet, some authors consider the addition-elimination mechanism as likely (see the quote from Imidazole and benzimidazole synthesis by Grimmett; I did not yet check the cited document reference [1]).
It is hard to generalize to caffeine, because caffeine is not just some normal imidazole. But in any case, I would stick to a full proof methodology and the use of Cl2 or Br2 in inert solvents is the only one that satisfies both mechanisms. Of course, if you would have determined the identity of your products, all this preventive measures would be obsolete.

xcaffeine.gif - 44kB

[Edited on 8/2/2012 by Nicodem]




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[*] posted on 12-2-2012 at 15:22


The following procedure was done
Quote:

Caffeine 1.5g (7.72 mmol) was added to 30.ml of DCM. To this there was added 1.92g (11.5 mmol) KI. The KI had poor soubability in the DCM so 30 ml of water was added. Once both were into solution the dropwise addition of 6wt% NaOCl 25.0ml was added over the course of 15 mins. Upon addition solution would go from intesly red to fading to an amber completion. Addition was judged to be complete once addition of NaOCl stoped forming the noticeable color change. Contests were added to a sep funnel and the organic layer was saved. The solvent was striped leaving behind a tan colored crude crystals. A small amt of the crude crystal mass was added to a beaker and 10ml of hot water was added. The crystals went into solution ( un reacted caffeine) leaving behind a small amount of a yellow looking crystal that was only soluble in DCM.



Judging from the fact that the product was soluble in hot water leads me to believe that it is un-reacted caffeine. I would also image that the yellow precipitate left behind was I2 or polymerized product.
I had no NaS2O4 to work up the generated I2.

Anyone have any ideas on what happened?
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[*] posted on 15-2-2012 at 22:16


Quote: Originally posted by methylene_beam  
The following procedure was done
Quote:

Caffeine 1.5g (7.72 mmol) was added to 30.ml of DCM. To this there was added 1.92g (11.5 mmol) KI. The KI had poor soubability in the DCM so 30 ml of water was added. Once both were into solution the dropwise addition of 6wt% NaOCl 25.0ml was added over the course of 15 mins. Upon addition solution would go from intesly red to fading to an amber completion. Addition was judged to be complete once addition of NaOCl stoped forming the noticeable color change. Contests were added to a sep funnel and the organic layer was saved. The solvent was striped leaving behind a tan colored crude crystals. A small amt of the crude crystal mass was added to a beaker and 10ml of hot water was added. The crystals went into solution ( un reacted caffeine) leaving behind a small amount of a yellow looking crystal that was only soluble in DCM.



Judging from the fact that the product was soluble in hot water leads me to believe that it is un-reacted caffeine. I would also image that the yellow precipitate left behind was I2 or polymerized product.
I had no NaS2O4 to work up the generated I2.

Anyone have any ideas on what happened?



I'm not really surprised that a small portion (how much exactly?) of your final product dissolved in 10ml of hot water. You should have washed your final product with room temperature water, followed by drying and TLC.

Did you vigorously stir the mixture throughout the whole reaction? DCM and water are not miscible so you would have had an upper layer consisting of KI and water and a bottom layer consisting of DCM and caffeine. You probably would have needed to stir vigorously enough to cause an emulsion throughout the reaction.

Since you added the bleach slowly it is very possible that the evolved iodine simply dissolved in the aqueous KI layer and you didn't add enough bleach so KI was still remaining at the end of the reaction. Was your upper aqueous layer clear at the end of the reaction? Iodine is slightly soluble in water but very soluble in aqueous iodide solutions.

Iodinating caffeine is more difficult than chlorination or bromination. Is there a specific reason you need 8-iodocaffeine instead of 8-chloro or 8-bromocaffeine?

[Edited on 16-2-2012 by johnames]
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[*] posted on 7-3-2012 at 14:41


johnames what were you results using NBS. did you ever get product to form?

I ended up following the paper I linked a few back. I had to sub silver acetate for silver lactate. I was unable to provide the inert amt that was called for.

I refluxed at 50c for a few hours but kept getting gas evolution. i stoped the rxn. I am going to try with the acetate.

[Edited on 7-3-2012 by methylene_beam]
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