[OrganicDan96]

I am synthesising a tosylate ester with tosyl chloride a, DMAP catalyst with triethylamine base in chloroform solvent. I did this reaction at room temperature without DMAP and the reaction goes a yellow-brown colour and takes about a week to complete. so I did this with 20mol% DMAP at room temp and it took about 3 days it went a very dark brown almost black colour. i tried it again at reflux with an excess of TsCl and it worked but did not go to completion as TsCl gets sensitive to water at high temperature so i repeated this whith dried and distilled chloroform and under nitrogen, the TsCl remained for longer. I did a mini work up to see if the reaction was done and the NMR clearly showed some starting material as well as product so i left it for another 24 hours and i worked it up but the NMR showed no product and only unidentifiable peaks in the aromatic region. there was no TsCl or DMAP after work up.

my substrate contains an ethyl ester and some ether groups. could DMAP be reacting with my molecule, I don't see how it could be possible but i have no other explanation at this point. I don't know what else i can do apart from going back to the bad literature method. attached is the structure of my substrate.

[wildfyr]

Tosyl chloride reacting with PEG-like molecules has always been a garbage reaction in my hands. I have a great idea for you though . Look at SuFEx! Sulfur(VI) Fluoride exchange. Its a new(ish) click chemistry reaction between a sulfonyl fluoride or fluorosulfonate and a silyl ether, in the presence of a base catalyst like DBU or TBD, or a certain fluoride sources to give the sulfonate or sulfate ester. Best done in MeCN but works in most polar aprotic solvents.

The literature to check out is Sharpless' work on the subject or, for you, I would check out this paper by Gembus (http://www.organic-chemistry.org/abstracts/lit2/132.shtm). Its pre-SuFEx, but it basically the same reaction.

You have to use tosyl fluoride, but its dead easy to make from tosyl chloride (KFHF in MeCN/H2O) or just buy it from sigma. Rock solid stable except in the presence of the right catalyst or pH>12. And TDBMS protecting your alcohols is very easy and quantitative. It easily handles aqueous workup, no column needed. Perhaps a gentle distillation if you want to get TBDMS dimer off. My preferred conditions are 1 eq alcohol 1.1 eq TBDMS-Cl, 2.2 eq imidazole in DCM or MeCN.

Feel free to ask any questions, my group was the first to follow up on Sharpless' work so short of finding someone who works directly for him I feel I'm a solid expert on the reaction. I've also made about a billion TBDMS alcohols and many sulfonyl fluorides as well.

[OrganicDan96]

thank you so much for the suggestion, i would love to try this, however I am on a very strict time limit now i have spent such a long time on this reaction. I might just end up having to go back to the literature procedure.

[wildfyr]

I think you could do this in 2-3 days if you have the raw materials (TsCl, KFHF, TBDMS-Cl, imidazole, and DBU). I have basically never had these reactions fail, even when I started off.

[rolnor]

You can have quaternization of DMAP as side-reaction. I would try a stericaly hindered base like 2,6-dimethylpyridine (2,6-lutidine) and heat, maby reflux in toluene.

[kriggy]

wildfyr: so do you need to use the silyl protected alcohols or can you jsut hit it with unprotected alcohol as well?

[OrganicDan96]

You can have quaternization of DMAP as side-reaction. I would try a stericaly hindered base like 2,6-dimethylpyridine (2,6-lutidine) and heat, maby reflux in toluene.

could you explain how quarternization may occur?

[kriggy]

TsCl reacts with the DMAP nitrogen forming tosylpyridinium chloride

[wildfyr]

Kriggy,
The SuFEx reaction is powered by fluorine's affinity for making a bond with silicon to the tune of 565 kJ/mol. An alcohol requires that you deprotonate it for it to be a good enough nucleophile to attack the sulfonyl center. The DBU or TBD is a catalyst in SuFEx, if you use a regular alcohol the conversion will be quite low. I guess you could use equimolar DBU or TBD, but OP is basically already doing that with a weaker base.

OP
And I'm thinking he means the sulfonyl is reacting with the ring nitrogen of the DMAP to make a chloride salt. It is a little nucleophilic, but I'm not a huge fan of this explanation since it should be water soluble and wash out. A little acid would disrupt this compound if you want to do a wash and see if your anonymous gunk disappears.

Long periods of time cooking those oligoPEG chains might becausing some chain scission.

[OrganicDan96]

TsCl reacts with the DMAP nitrogen forming tosylpyridinium chloride

yes i know but that is the intended reaction. this is how DMAP catalyses this esterification. its similar to how pyridine or triethylamine works in these reactions.

[OrganicDan96]

Long periods of time cooking those oligoPEG chains might becausing some chain scission.

that is an interesting thought, might explain why it did not take heat too well even in dry solvent and inert atmosphere. most of the reactions I have done so far have been under nitrogen.

Also i removed all the DMAP with 2 copper sulphate washes this was very successful.

[rolnor]

TsCl reacts with the DMAP nitrogen forming tosylpyridinium chloride

yes i know but that is the intended reaction. this is how DMAP catalyses this esterification. its similar to how pyridine or triethylamine works in these reactions.

I mean that the formed tosylate can react with DMAP, a good nucleophile forming a Q-salt.

[wildfyr]

I'll repeat that you should look at SuFEx. As a click type reaction its simplicity, ease of use, conversion, and reliability are considered top flight. Since I posted my reply you probably could have ordered the chemicals and tried a few variations. Also, its done at room temp, so no chain scission questions.

[OrganicDan96]

I'll repeat that you should look at SuFEx. As a click type reaction its simplicity, ease of use, conversion, and reliability are considered top flight. Since I posted my reply you probably could have ordered the chemicals and tried a few variations. Also, its done at room temp, so no chain scission questions.

I have been away from the lab for a few weeks, when I get back I will only have a week to finish this step before i have to move on to the next step due to time limitations.