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Author: Subject: Tosylation of ethanolamine (??)
DrDevice
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[*] posted on 2-1-2017 at 05:23
Tosylation of ethanolamine (??)


I have been experimenting with tosylation of ethanolamine, expecting that both the alcohol and the amine components of the ethanolamine will react to give a "ditosylate".

I dissolved 38.65g (0.2mol) of tosyl chloride (TsCl) in 80ml tetrahydrofuran (THF), and added 30g (0.3mol) of triethylamine. This was then cooled using an ice bath to below 5C.

6.3g (slightly more than 0.1mol) of ethanolamine was added drop wise with magnetic stirring, ensuring the temperature did not rise above about 7C.

Once all the ethanolamine was added, the solution was stirred at room temperature overnight.

The insoluble white coloured triethylamine hydrochloride was filtered. Some pressing of the solids was required to extract as much liquid as possible. The solids and filter paper were washed again with more THF to remove as much product as possible.

The resulting liquid was heated to 80C under reduced pressure (0.1atm), to remove as much solvent as possible. On cooling, I was left with 38.1g of a viscous, pale yellow liquid. If it is what I think it is, structure is:

ditosylate.gif - 5kB


MW = 369.46, so 0.1mol. I'm sure there must be contaminants in there, but yield is pretty good.

Assuming of course that I'm not fooling myself... Comments or criticisms pls? Also, any suggestions on (accessible) quantitive or qualitative tests I can do to verify this result? Can I

Next, I want to substitute the "alcohol" end with iodine, leaving the "amine" end untouched. Suggestions? Will sodium iodide dissolved in acetone suffice?

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morsagh
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[*] posted on 2-1-2017 at 06:15


Most easy test is to try TLC and compare to ethanolamine and TsOH. Try colouring with iodine, every of these should be visible.
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DrDevice
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smile.gif posted on 2-1-2017 at 06:45


Can you (or anyone...) suggest an introductory text/website on TLC (or eg paper chromotography) with examples that I can use for checking my reaction?

Best to assume I know nothing about the subject :)
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morsagh
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[*] posted on 2-1-2017 at 06:55


You just take your TLC plate, on the bottom you make a line with pencil, there you will make one point with your product, next to it another points which are your reactants or possibly byproducts. Then just compare. https://en.wikipedia.org/wiki/Thin-layer_chromatography on wiki it is written very good. For your compounds i would use 1:1 mixture of petrolether to ethyl acetate. Then just adjust the ratio. One more tip, if you are getting a long line, then your solvent is just too polar.
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Tsjerk
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[*] posted on 2-1-2017 at 07:39


Just a brain fart; Can't you hydrolyse with a know quantity of NaOH and then titrate with acid to see how much base was consumed? Two mol NaOH per mol of compound would mean a ditosylation
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morsagh
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[*] posted on 2-1-2017 at 10:16


I think if there is any unreacted tosyl chloride present, it won´t be distilled so it will remain in his product so titration will always show "positive result". I am not sure...
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Dr.Bob
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[*] posted on 2-1-2017 at 19:41


Likely worked at least most of the way. I think the NaI in acetone should work, if not DMF instead, but acetone is better for solubility of the salt. You will likely need to reflux it a while.
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[*] posted on 3-1-2017 at 08:00


In my experience with 1,8-octaneditosylate, yellow oil meant "reaction did not go to completion." Beautiful white needles were the measure of success. Run the TLC and see how many products you have. You can always re-subject the yellow oil to the original reaction conditions (i.e., TsCl , NEt3, in THF) to improve your yield. Otherwise, starting with an excess of the TsCl here may be useful.

Depending on where you got your TsCl and its age, it may need to be cleaned up by a simple recrystallization. Two methods for doing so are as follows (I use the first, never tried the second):

Quote:
Tosyl chloride (CAS NO. 98-59-9) is purified by dissolving (10g) in the minimum volume of CHCl3 (ca 25mL) filtered, and diluted with five volumes (i.e. 125mL) of pet ether (b 30-60°C) to precipitate impurities. The soln is filtered, clarified with charcoal and concentrated to 40 mL by evaporation. Further evaporation to a very small volume gave 7g of white crystals which were analytically pure, m 67.5-68.5 °C. (The insoluble material was largely tosic acid and had m 101-104°C).

It is also crystd from toluene/pet ether in the cold, from pet ether (b 40-60 °C) or benzene. Its soln in diethyl ether has been washed with aqueous 10 % NaOH until colourless, then dried (Na2SO4) and crystd by cooling in powdered Dry-ice. Tosyl chloride has also been purified by dissolving in benzene, washing with aqueous 5% NaOH, then dried with K2CO3 or MgSO4, and distd under reduced pressure and can be sublimed at high vacuum.


From http://www.lookchem.com/Chempedia/Chemical-Technology/Labora...




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[*] posted on 3-1-2017 at 16:42


DrDevice:

Your reaction work up was incomplete. After filtration of the triethylamine hydrochloride and removal of THF, your CRUDE product needs to be taken up in a suitable solvent and subjected to an acid-base wash regimin. This is the minimum purification that you should do. As others have pointed out, you also need an analytical method to assess purity. The hydroxide hydrolysis/titration suggestion is going to tell you much if anything. Finally, your target compound is in all likelihood known. What do you know about it?

AvB
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DrDevice
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[*] posted on 4-1-2017 at 02:23


Thanks all for the feedback so far. I don't have TLC plates on hand, but attempted to use paper chromatography, with iodine as an indicator ie putting the paper into a beaker with a small amount of solid iodine to sublimate - thanks morsagh for chromatography suggestions.

The results were very dodgy, but there was a line in the "product" that was at the same displacement as the ethanolamine line, so I'm assuming an excess of ethanolamine.

I've re-dissolved the original product in THF and added more triethylamine and extra TsCl such that (compared to original amounts) would be 2.05 equivalents.

This is stirring now. I'm not seeing any white hydrochloride ppt however.

AvB, any suggestions on an acid-base wash workup?

And as for the final product, what do I know about it? I have had a look through the readily accessible literature for "tosylation of ethanolamine", but no obvious results.
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morsagh
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[*] posted on 4-1-2017 at 05:28


I don´t know how it is with solubility of Ts esters in water but amides should be insoluble. TsCl should hydrolyse and TsOH dissolve (violent reaction be careful, lot of HCl evolved, work in fumehood). Ethanolamine is soluble too.
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[*] posted on 4-1-2017 at 05:47


I recommend more like 3 - 4 equiv TsCl to 1 equiv ethanolamine. After the initial exotherm, try heating/refluxing for a bit. There really are no expected side reactions here, so you can force it to completion.



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[*] posted on 4-1-2017 at 08:57


DrDevice, I don't think you chose suitable conditions. Yes, triethylamine and TsCl can be used to tosylate alcohols, but preferably in dichloromethane. For some reason dichloromethane works best with either pyridine or triethylamine for the reaction of sulfonyl chlorides with alcohols, or poorly nucleophilic amines and anilines. Other solvents are either substantially inferior or do not work (with the exception of pyridine). Also, triethylamine is avoided in favor of pyridine when sulfonating primary alcohols because alkyltriethylammonium salts tend to form with excess triethylamine unless the reaction is properly monitored.

Since N,O-ditosylated ethanolamine is a crystalline solid, you should do two obvious things. First you should check the purity with TLC and then if still optimistic crystallize it from some solvent (e.g., methanol or ethanol/water). But without TLC plates... (I don't understand why you even started with organic reactions without first buying some TLC plates).

Why do you want to substitute the tosyloxy for the iodine? There are only very few reactions where this would be required. If you want to make N-tosylaziridine, then you just treat the product with NaOH. Also, if you want to alkylate something, you can also just use the O-tosylate. There is no need for iodine exchange.

Quote: Originally posted by DrDevice  
And as for the final product, what do I know about it? I have had a look through the readily accessible literature for "tosylation of ethanolamine", but no obvious results.


I don't know how hard have you looked, but there are several examples of this reaction in the literature. Since you say you don't have TLC plates, the least you should do is follow a verified procedure.

Quote: Originally posted by morsagh  
TsCl should hydrolyse and TsOH dissolve (violent reaction be careful, lot of HCl evolved, work in fumehood). Ethanolamine is soluble too.

The hydrolysis of TsCl is certainly not a violent reaction. It proceeds quite slowly actually and TsCl is not that easy to remove with just an extraction based work up.

[Edited on 4/1/2017 by Nicodem]




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[*] posted on 4-1-2017 at 12:19


I like using just 2.1 or so equiv of TsCl, too much will be a pain to remove. I do agree that DCM would be a better solvent, but it might go in THF. A small amount of pyridine, or better yet, DMAP, will help catalyze the reaction, DMAP does not smell so bad, and would partition into the acid wash if you take the crude reaction (in DCM) and wash with 1N HCl and then sat'd bicarb to remove excess SM and salts. While TEA might not be ideal, it should work OK, it is also easy to find, and will come out in the water wash. Certainly recrystallizing the product will help if it is not pure, but always better to drive the reaction to completion if at all possible. Pushing the crude material through a plug of silica gel in hexanes to ethyl acetate would also likely clean it up enough to crystallize.

I found the same article that Nicodem found, I think, it has an NMR of the product in the supplimentary material, might have other info in the paper itself, but I can't get to that right now. But their procedure is likely a good starting point. You should be able to get the article via a library or other sources.

http://www.tandfonline.com/doi/full/10.1080/10426507.2015.10...
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[*] posted on 4-1-2017 at 19:51


I agree with Nicodem that the solvent of choice for triethylamine tosylations is dichloromethane. Why this is so I cannot say.

DMAP often leads to side products with acid chlorides which involve addition of the acid chloride to the pyridine ring. This is documented but the reference is not currently at hand. DMAP catalysis with acid chorides is almost never any better than use of plain pyridine.

Here is the experimental data from the paper cited by Dr Bob:


N-[2-[(p-Tolylsulfonyl)oxy]ethyl]-p-tolylsulfonamide

Monoethanolamine (12.00 g, 0.197 mol) was dissolved in anhydrous pyridine (15 mL) and
cooled to 0 oC in a bath of ice and salt. Tosyl chloride (80.00 g, 0.419 mol), finely powdered,
was suspended in pyridine (50 mL) and cooled to -50 oC. The ethanolamine solution was added
while the temperature was maintained below 10 oC for 30 min. The mixture was kept at room
temperature for 6 h and then at 4 oC overnight. The mixture was poured, with stirring, on crushed
ice (500 g) and acidified with glacial acetic acid (20 mL), whereupon the oily material solidified.
The solid was crushed to a slurry in water, collected, and washed with water. The product was
dried in desiccator over P2O5 in vacuum. Recrystallization of the crude product (69 g) from hot
chloroform (50 mL) and addition of cold CCl4 (200 mL) gave 1 as a white powder (55.00 g, 76
%), mp 87-88oC, mp 86-87 oC.20 1H NMR (400.130 MHz, CDCl3): δ 2.41 (s, 3Н, Me), 2.44 (s,
3Н, Me), 3.18-3.22 (m, 2Н, CH2), 4.03 (t, J= 5.3 Hz, 2Н, CH2), 5.00 (br s, 1H, NH), 7.27 (d, J=
8.3 Hz, 2H, p-C6H4), 7.33 (d, J= 8.3 Hz, 2H, p-C6H4), 7.68 (d, J= 8.3 Hz, 2H, p-C6H4), 7.73 (d,
J= 8.3 Hz, 2H, p-C6H4) ppm; 13C NMR (100.613 MHz, CDCl3): δ 21.4, 21.6 (2Me), 42.0, 68.7(2CH2), 127.0, 127.9, 129.8, 130.0, 132.2, 136.6, 143.7, 145.2 (2C6H4) ppm


AvB
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brubei
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[*] posted on 4-1-2017 at 23:14


Quote: Originally posted by Nicodem  
But without TLC plates... (I don't understand why you even started with organic reactions without first buying some TLC plates).
so true ...

[Edited on 5-1-2017 by brubei]
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Dr.Bob
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[*] posted on 5-1-2017 at 06:40


Quote: Originally posted by AvBaeyer  
DMAP often leads to side products with acid chlorides which involve addition of the acid chloride to the pyridine ring. This is documented but the reference is not currently at hand. DMAP catalysis with acid chorides is almost never any better than use of plain pyridine. AvB


I will agree that there are some cases where DMAP is not as good as pyridine, maybe even more so for carboxlic acids, but I have made over 2000 discrete sulfonamides with DMAP, most using DCM (DCE also does quite well, better for some cases) as the solvent and TEA as the base, and most were >95% pure straight from the reaction, after a simple workup. If you use DMAP on resin (either catalytically or as the main base at 1.5 eq), that is even better, as it just filters away, and you can use a smaller amounts of TEA (catalytic, maybe as little as 0.1 to 0.5 eq), it acts as a proton shuttle in that case, and the DMAP on resin both activates the sulfonyl chloride and acts as a base. One of the best reactions I have ever used in parallel synthesis. Best way is react sulfonyl chloride with very well dried DMAP resin in dry DCM for an hour or so at RT, then add the amine or alcohol along with some TEA. Let them stir overnight and filter.

[Edited on 5-1-2017 by Dr.Bob]
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DrDevice
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[*] posted on 2-2-2017 at 05:22


Over the last few weeks I have been looking at this reaction again. I have purchased some TLC plates, and currently getting familiar with how to use this process. Encouraging results, but that's not the main reason for this post.

I have pursued two separate approaches to the tosylation, one based (very loosely) on the procedure provided by AvBaeyer, the other in DCM,, as others have commented. Basically:

Method 1 involved dissolving 30.54g (0.16mol) TsCl in 60ml DCM with 23.2g (0.23mol) triethylamine. This was chilled in an ice/salt mix, and 4.64g (0.076 mol) ethanolamine added drop wise ensuring temperature did not rise above 10C. This was left stirring overnight at room temperature. A yellow slurry formed. This was poured onto 200g of ice with 20ml acetic acid. Once the ice melted, the organic and aqueous layers were separated, and the solvent evaporated. The remaining solid was re-dissolved in boiling ethanol (it is not very soluble in EtOH), and re-crystalized to a white powder. Yield 7.5g. I did muck around a bit trying different solvents, so I probably lost a bit in the process.

Method 2 was closer to the one in the procedure provided by AvBaeyer. 21.91g (0.115mol) of TsCl, finely ground, was added in small portions to 60ml of rapidly stirring morpholine at -4C. A suspension is formed, and some dense white vapour is evident when the TsCl is added. 3.3g (0.054mol) of ethanolamine is dissolved in 20ml of morpholine, and added dropwise to the TsCl suspension, keeping the temperature below 10C. This was stirred for 0.5hr at 0C, then 24 hours at room temperature.

The slurry/solution was poured onto 200g of ice with 20ml acetic acid. The white precipitate was gathered by filtration and dried in air. The ppt was dissolved in warm chloroform. Some remaining water was evident so I dried with sodium sulfate, then filtered whilst hot. On cooling, the white precipitate re-formed in the CHCl3. I have taken some of this precipitate and dissolved in boiling IPA. The product recrystalized in beautiful long, fine needle-like crystals. Total yield approx. 16g (I am still drying the IPA crystalized product.

I used morpholine rather than pyridine as it is easier for me to obtain - and I had some. I reasoned that it was a relatively weak base like pyridine, so it might work.

So all this sounds good in that I am getting *something* consistent with either approach. HOWEVER, my product in each case has a melting point of 145C - 147C, vastly different from the 87C-88C quoted in the experimental results from the paper.

So any suggestions? I'm ending up with what looks like the same product from each approach, but doesn't agree with the quoted MP. Is it likely that I have ended up with something so completely different by a different solvent choice?
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[*] posted on 2-2-2017 at 06:10


Quote: Originally posted by DrDevice  

I used morpholine rather than pyridine as it is easier for me to obtain - and I had some. I reasoned that it was a relatively weak base like pyridine, so it might work.


Morpholine is some three orders of magnitude more basic than pyridine, and significantly more nucleophilic also. The other factor is that it is a secondary amine, and so reacts with the TsCl to form a stable sulfonamide, rather than the reactive N-p-toluenesulfonyl)pyridinium intermediate you get with pyridine which facilitates the desired reaction with the amine substrate.

All in all I'd say it was a poor substitution to make.

Edit: 4-tosylmorpholine is reported to have a mp of 142 to 144 *C, and the N-(2-hydroxyethyl)-p-toluenesulfonamide is reported to have mp 55 to 57 *C. Not sure where you got 87 to 88 *C from?

[Edited on 2-2-2017 by DJF90]
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[*] posted on 2-2-2017 at 15:41


My post of the experimental procedure explicitly stated the use of pyridine. I do not believe it is unreasonable for anyone running a tosylation experiment to know the difference between pyridine and morpholine with regard to chemical properties. That's pretty basic stuff. It's possible that N-methylmorpholine, a common acylation catalyst, could replace pyridine.

DFJ90: The 87-88*C mp is for the bis-tosylated compound. See my post above.

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