You don’t say (1) which size CD, (2) if it’s mono-tosylation, or (3) which position you want to tosylate, but here are a few leads:

Natural cyclodextrins and their derivatives for polymer synthesis. Przybyla, M. A.; Yilmaz, G.; Becer, C. R. Polymer Chemistry 2020, 11, 7582–7602 DOI: 10.1039/D0PY01464H

Methods for Selective Modifications of Cyclodextrins.Khan, A. R.; Forgo, P.; Stine, K. J.; D'Souza, V. T. Chemical Reviews 1998, 98(5), 1977–1996 DOI: 10.1021/cr970012b

Biomimetic Reactions Catalyzed by Cyclodextrins and Their Derivatives. Breslow, R.; Dong, S. D. Chemical Reviews 1998, 98(5), 1997–2011. DOI: 10.1021/cr970011j

6A-O-p-Toluenesulfonyl-β-Cyclodextrin [ β-Cyclodextrin, 6A-(4-methylbenzenesulfonate)]. Byun, H.-S.; Zhong, N.; Bittman, R. Organic Syntheses 2000, 77,225 DOI: 10.15227/orgsyn.077.0225

Efficient synthesis of pure monotosylated beta-cyclodextrin and its dimers. Tripodo, G.; Wischk, C.; Neffe, A. T.; Lendlein, A. Carbohydrate Research 2013, 381(15), 59–63 DOI: 10.1016/j.carres.2013.08.018

Rouvain Bension Hey thanks for the resources. I am working with beta cyclodex. So 7 sugars. Its mono-tosylation. I have been trying the aqueous method with NaOH, but it doesn't seem to be working

Which compound do you use as the tosyl-source?

p-toluensulofonic acid

p-toluenesulfonic chlorid

I have been using tosyl chloride. But j think it's getting hydrolysed by the base I am adding

The base should give a deprotonation to the CD. Tosylchlorid also hydrolyses in water, but this does not mean the reaction is not working in water.

An other question is, how old is the tosylchlorid? Is it still the chlorid or is it allready hydrolysed?

the reagents are new and purchased just a month ago. I am having difficulties in harvesting the end product. I believe the unreacted tosyl chloride is forming inclusion complexes which is why the NMR is getting skewed

Dear Debasmita Paul many thanks for sharing this very interesting technical question with the RG community. If you have problems with the synthetic method using tosyl chloride, you might want to try the following alternative two-step synthesis in which the readily accessible 1-(p-tosyl)-imidazole is used as tosylating agent. The protocol has been described in great detail and is easy to follow::

Synthesis of mono-6-tosyl-β-cyclodextrin, a key intermediate for the functional cyclodextrin derivatives

https://protocols.scienceexchange.com/protocols/synthesis-of-mono-6-tosyl-cyclodextrin-a-key-intermediate-for-the-functional-cyclodextrin-derivatives

Good luck with your experiments and best wishes, Frank Edelmann

Dear Debasmita,

You have to keep the reaction temperature reaction < 10oC during the TsLc solution addition and >15 oC during the additional stirring time (4h). The optimal dropping time of the TsCl/acetonitrile solution is 55-65 min. Then put the reaction mixture into a fridge overnight (or in a cold place, 0-5 oC).

The next day filter the product, wash it to neutral with water (pH 5.5-7, paper), and then suspend the crystals ~equal ml of the theoretical 100 % product MeOH (e.g., if 100% yield is 100 g, then 100 ml MeOH). If you are working on a 10 g scale, you can use 30-50 ml MeOH. Finally, wash it with some MeOH.

The TsCl is insoluble in water, so very vigorous stirring is necessary. Dissolution of the TsCl in ACN is endothermic, and the TsCl/ACN solution cools down to 0-5 oC. The foam forms during the TsCl addition contains TsCl and the product. Because the TsbCD is wetting better, the products slowly sediment in the reaction mixture.

Slower or longer addition results in lower yields.

Eventually, after the overnight crystallization, before the filtration, you can neutralize the reaction mixture with dry ice, but the yield will not increase dramatically.

The MeOH wash removes the excess of TsCl.

Dry it not higher than 40 oC in the presence of P2O5 and KOH, at reduced pressure.

For recrystallization, you can you 3:1 nPrOH-water (2-3-fold of solid). Dissolve the crude in boiling solvent mixture, then leave it to cool to 20-25 oC. Some periodical ultrasonication or mixing helps to get fine crystals. After the filtration, the MeOH wash of the crystals is also necessary because the nPrOH is hard to remove.

By this method (modified Petter&Salek), you cannot prepare monoTs alpha- and gamma-CD because the TsbCD->3,6-monoanhydro-a/gCD conversion is much faster than in the case of bCD (solubility reasons).

If you want to prepare monoTs a/gCD, then you can use pyridine. In those cases, the optimal reaction time is around 40-45 min (which means you cannot follow the reaction by TLC). Longer reaction results in not only multitosylated compounds but isomers, as well.

Good luck,

Laszlo

Laszlo Jicsinszky Thank you so much for the very detailed procedure. I would try to do it. Does your method talk about crystallisation twice? one with MeOH and another with nPrOH?

Thank you again

No. The crystallization is from 3:1 water-nPrOH, but after filtration, you should wash the crystals with MeOH, otherwise, the propanol remains (partially complexed) in the solid. You can sense its odor.

Will drying in rotovap instead of P2O5 and KOH cause any problems?

Yes, it is significantly less efficient. Alternatively, you can use a freeze dryer without heating. First dry in the open air, in the fume hood, until the MeOH evaporates, then use the freeze dryer.

TsCD may retain a few percent of water which may affect derivatization reactions. See my attached article for a diagram of the "kinetics" of drying. The graph in the article also shows that after removing all the water, a certain percentage of the water quickly adsorbs from the air. The adsorption is fast indeed, so if you need an absolute reaction condition, you need to weigh it very fast and eventually use an activated 3A molecular sieve Activation means drying the molecular sieve > 100 oC, using P2O5 and KOH. KOH alone is less effective, while P2O5 is a slightly sublimating powder - or at least the fine powder is flying easy during the manipulations - and KOH binds it.

Dear Debasmita,

In my first comment, the beginning sentence contains an error. Correctly:

You have to keep the reaction temperature reaction < 10oC during the TsCl solution addition and

hey, I tried using a para tosyl imidazole. It actually worked. I recrystallized with MeOH but not with the nPrOH but still got good NMR and mass. I will try the recrystallization. Also, I put my compound under high vaccum. But thanks a lot for all the help. I am trying to make guest host compounds with cyclodextrins. Thanks a lot.