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Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Babcock_Hall on May 10, 2021, 10:11:00 AM

Title: silylation and desilylation reviews or information
Post by: Babcock_Hall on May 10, 2021, 10:11:00 AM
https://pubs.acs.org/doi/pdf/10.1021/i360042a003. 1972 "Silylation of organic chemicals" by Charles Roth
https://www.intechopen.com/books/gas-chromatography-derivatization-sample-preparation-application/derivatization-methods-in-gc-and-gc-ms. 2017

One of our synthetic targets this summer requires us to use silylation of a derivative of glucose, and we will initially use the tert-butyldimethylsilyl group, as per wildfyr's suggestion.  We will need to deprotect in the presence of a vinyl sulfone.   In the past I used to use cesium fluoride to deprotect a primary alcohol that was trimethylsilylated; in this case I was planning to use TBAF.  I have done a little bit of reading in Greene and Wuts's book on protecting groups, and that raised a few questions.  I have turned up one or two old papers, and one open access chapter, the second link above.  Perhaps some additional background reading would help us.  Would anyone care to recommend a good review article or book chapter?
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on May 10, 2021, 04:20:27 PM
If your compound is sensitive, you should be ware that the reaction mixture becomes very alkaline when you desilylate with the reagents you suggest, if you want to avoid this you can use pyridine-HF or similar acidic fluoride source.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on May 11, 2021, 10:39:19 AM
That's a good point. When I worked with CsF, it was dissolved in methanol, and our product was a primary alcohol.  If methanol became deprotonated (presumably an equilibrium mixture of alcohols and alkoxide ions was present), it would produce a decent nucleophile.  That might cause problems.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on May 11, 2021, 09:09:21 PM
I have not previously encountered pyridine•HF, but I just looked it up and saw it referred to as the Olah reagent.  I trust that there is not a problem with toxicity.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on May 11, 2021, 10:52:29 PM
Its really bad to get on skin, painfull burns, pain can remain for long time. I think there is also triethylamine trihydrofluoride that can be used, this is probably less nasty I would guess.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on May 12, 2021, 04:51:31 PM
Halmos T et al., "STUDIES OF THE SELECTIVE SILYLATION OF METHYL α-D-AND β-D- ALDOHEXOPYROSIDES: STABILITY OF THE PARTIALLY PROTECTED DERIVATIVES IN POLAR SOLVENTS". Carbohydrate Research 170 1987 57-69.

We would like to add four TBDMS groups to an aromatic glucoside.  We have an aldehyde group on the aromatic ring.  The paper above was mainly concerned with partially silylated derivatives of four methyl glycosides, two glucose, two galactose, and one mannose derivative.  Under their condition A (2 mole of imidazole per mole of TBDMSCl in DMF; 24 hours at room temperature), they varied the ratio of TBDMSCl from 2.2 to 3.2 to 4.3 equivalents.  When they used 4.3 equivalents, they saw a variable amount of tetrasilylated product, from undetected (apparently both anomers of methyl galactoside) to 5% (the alpha forms of methyl glucopyranoside and methyl mannopyranoside) to 38% (methyl-β-D-glucopyranoside).

This leads to some questions.  The first is whether our change from methyl to an aromatic group at C-1 (the anomeric position) will cause the reaction to speed up or slow down (my prediction is that it will not make much difference either way).  The second is how to increase the yield of the tetrasilylated product.  There are only a few non-patent references I have found so far on the use of TBDMSCl to react with glucosides, but I may have narrowed my search too much.  IIRC I focused on TBDMSCl/imidazole-utilizing reactions, because these are the reagents that we purchased.

Two more things.  I found a paper (see below) which turned glycosides into trimethylsilyl derivatives, using bis(trimethylsilyl)trifluoroacetamide with 1% TMSCl in pyridine at 60 °C for 30 minutes.  It is fair point that the conditions are different, but could it be that the greater bulk of the tert-butyldimethylsilyl group makes it difficult to obtain fully silylated material?

Finally, is  N-methyl-N-(tert-butyldimethylsilyl)-trifluoroacetamide a stronger donor of tert-butyldimethylsilyl groups than the silyl chloride?  I will do a search for recipes in the next few days.

Isidorov, VA Journal of Chromatography A, 1521 (2017) 161–166.  http://dx.doi.org/10.1016/j.chroma.2017.09.033 
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on May 13, 2021, 11:29:14 AM
In the 1987 paper that I cited, their Method B used catalytic DMAP (8% by mole), along with 2 equivalents of TBDMSCl, and triethylamine was the base.  Their method A used a variable number of equivalents of TBDMSCl.  I have not yet compared Methods A and B at the same mole ratio of TBDMSCl to methylglycopyranoside.

I also wanted to draw attention to the failure to observe any tetra-silylation with methyl galactopyranosides as substrates.  The three substituents on C3 (-OH), C4(-OH), and C5(-CH2OH) are all on the same side of the ring, in contrast to glucopyranosides, where the substituent at C4 is on the opposite side of the ring.  This is consistent with a steric problem, although I would hesitate to call it strong evidence.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on May 13, 2021, 02:38:42 PM
You can use TBDSOTf its more powerfull. When you want to protect this many groups in close proximity it does not seem ideal to chose such a large PG because if steric bulk. Have you thought of other PG-s? I think SEM can be similar deprotected with fluoride and has similar stability but much less bulk.
M https://pubchem.ncbi.nlm.nih.gov/compound/2-_Trimethylsilyl_ethoxymethyl-chloride
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on May 13, 2021, 06:55:56 PM
One possibility is to add DMAP into the standard conditions (TBDMSCl/imidazole).  However, I only found one published example, and the results were not impressive.  I did another search, and I found several examples where TBDMS-trifluoromethanesulfonate was used in similar reactions.
EDT
Another possibility is to take our chances with trimethylsilyl as the protecting group.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on May 14, 2021, 02:52:27 AM
If you want to do stuff like chromatography or wet workup the TMS will not be stable.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on May 14, 2021, 09:41:26 AM
Zelenka, Karel et al., Chemistry - A European Journal, 17(49), 13743-13753, S13743/1-S13743/45; 2011.  https://doi.org/10.1002/chem.201101163

Good point about chromatography.  Concerning DMAP/TBDMSCl/imidazole/DMF, there is one paper which used these conditions at 50 °C for 5 days.  The substrate was a steroid derivative of glucose, and the yield was 10%.  I could live with 38%, which is what the 1987 paper obtained with slightly different conditions.
EDT
Kaburagi Y, Kishi Y, "Operationally Simple and Efficient Workup Procedure for TBAF-Mediated Desilylation: Application to Halichondrin Synthesis" https://pubs.acs.org/doi/pdf/10.1021/ol063113h
I found a paper on deprotection using Dowex-50 and calcium carbonate that might be useful.  "For the cases where deprotected products have a high water solubility, the protocol of aqueous-phase extraction is not ideal. Despite this concern, very limited TBAF workup methods are known to avoid an aqueous-phase extraction. Thus, a TBAF workup with no use of aqueous-phase extraction is potentially useful."
This paper adds TBDMS groups to methyl-α-glucopyranoside using TBDMSCl, pyridine, and AgNO3.  It also works for methyl-β-galactopyranoside.  Silver nitrate is not exactly inexpensive, but this method has yields greater than 70%.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on May 14, 2021, 10:17:22 AM
I strongly suggest you change PG-strategy, the SEM can be introduced with mild conditions, TEA/DCM I believe. If you can see so much problem  at this early stage its really not good.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on May 14, 2021, 10:29:45 AM
I strongly suggest you change PG-strategy, the SEM can be introduced with mild conditions, TEA/DCM I believe. If you can see so much problem  at this early stage its really not good.
I will look at SEM, but I wonder whether or not we cross-posted.  The silver nitrate protocol from the Kishi lab looks attractive, unless silver nitrate is incompatible with the presence of an aromatic aldehyde.  Based on Tollens chemistry, I suspect that silver ion would oxidize the aldehyde, unfortunately.  However, the desilylation methodology in this paper may still be applicable to our project.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on May 14, 2021, 02:13:47 PM
TBDMSOTf is probably more efficient then TBDSCl and silver nitrate. For workup I suggest you filter through a short column with RP-18 silica, maybe eluting with MeOH/H2O say 2:1. The Q-salts from TBAF will stick hard to the gel. If you use pyridine-HF you can perhaps just evaporate and apply som vacuum. The compound you are making is so polar  that it is likely you need RP-silica for purification, this requires some training. You can also run RP-TLC for monitoring, again this is so different from straight-phase silica so it will be extra work. If you use prep-HPLC for purification its easier.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on May 15, 2021, 12:21:15 PM
One source of general information that I found useful is the fourth edition of Greene and Wuts' book on protecting groups.  They have three useful tables near p. 190 giving the lability of various silyl groups to acidic and basic conditions, and to the presence of TBAF in THF.  TBDMS is much less labile to base than TMS is, although both are quite labile to 1% HCl.  There is some discussion of how to reduce the water content of TBAF.  I think that there might be an error in one entry of the second.  There is a long-chain alcohol protected with TBDMS, and its half life in the presence of Bu4NF is given as 140 hours.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on May 16, 2021, 02:25:53 AM
That sounds very strange, in my experience even TBDS-groups are completely deprotected by TBAF in a few minutes. TMS-ethers are unstable even to moist air.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on May 16, 2021, 11:14:50 AM
In the first table (p. 197), the substrate is C12H25OTBDMS.  In a different table on page 198, they give 20 minutes for TBAF in THF, to deprotect the TBDMS group.  At a couple of places in the text, they mention the use of acetic acid or ammonium fluoride to buffer the basicity of TBAF.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on May 16, 2021, 11:21:53 AM
Its possible that they did not monitor the reaction untill 20minutes had passed. Acetic acid seems very good, mayby TBAF can also be used in combination with HF-Pyridine as buffer?
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on May 17, 2021, 08:29:07 AM
Our budget is quite limited; preparative HPLC is not something we can consider just yet.  Even ordering more reagents is tricky, especially as we near the end of the fiscal year.  If we could push our yield to 50% with TBDSCl, that might be enough; that is why was thinking about adding DMAP.  AgNO3 is something I will keep in mind when I have a compatible substrate, but I don't believe that our present one is.  I am continuing to look into TBDMSOTf protocols and will try to order some, if possible.  Right now the calcium carbonate/Dowex-50 protocol looks like a contender in the Desilylation derby.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on May 17, 2021, 08:45:37 PM
https://doi.org/10.1016/j.carres.2005.05.016

I just read a number of references such as the one above that concern adding TBDMS groups to glycosides.  It seems as if TBDMSOTf/ludidine is much more likely to succeed than TBDMSCl/imidazole is, and I am in the process of ordering some.  Although I have not looked at every protocol in detail, only one used copper sulfate as one of the wash steps.  This was probably to help in the removal of the lutidine.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on May 18, 2021, 11:48:54 AM
That seems very good. Also you can heat, maybe reflux in DCE or DMF if it is really sluggish to get all the PG on. If you have a good pump and heat to 50°C you will remove lutidine I think.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on May 18, 2021, 05:53:16 PM
When imidazole is used as base and catalyst, the reacting species will be the silyl-imidazolide regardless what silylating reagent is used, that means that imidazole is no good with the triflate, the triflate itself is more reactive then the imidazolide so lutidine is better.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on May 19, 2021, 10:32:59 AM
Good point about imidazole.  I wanted to discuss the choice of deprotection/clean-up method.  Along with an aromatic ring our product will have four free hydroxyl groups (being an aromatic glucoside), making it fairly polar.  The technique in the 2007 Organic Letters paper (10.1021/ol063113h) does not use an aqueous work-up.  Four of the entries in their table are glycosides based upon monosaccharides.  I don't have a strong opinion on whether or not this is a better approach versus versus the ones we have already mentioned.

"General workup procedure for removal of TBAF residue (Table 1, entry 1): A 10 mL flask containing a stirring bar was charged with substrate
(110 mg, 0.169 mmol). TBAF (1.0 M in THF, 1.35 mL, 1.35 mmol) was added via syringe. After the solution was stirred at room temperature for 4
h (no SM nor partially deprotected intermediate detected by TLC), CaCO3 (280 mg), DOWEX 50WX8-400. (840 mg, used as supplied), and MeOH
(2.0 mL) were added. The suspension was stirred at room temperature for 1 h. All insoluble materials were removed by filtration through a pad of Celite, and the filter cake was washed with MeOH thoroughly. The combined filtrates were evaporated to dryness under reduced pressure to give the crude product (36.3 mg, 111%) as a white solid. 1H NMR spectra of the crude product showed that 99.3% of tetrabutylammonium salt was removed by these operations."
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on May 19, 2021, 11:52:28 AM
The workup seems very good, clever.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on May 24, 2021, 05:43:33 PM
In the 1987 paper that I cited, their Method B used catalytic DMAP (8% by mole), along with 2 equivalents of TBDMSCl, and triethylamine was the base.  Their method A used a variable number of equivalents of TBDMSCl.  I have not yet compared Methods A and B at the same mole ratio of TBDMSCl to methylglycopyranoside.

I also wanted to draw attention to the failure to observe any tetra-silylation with methyl galactopyranosides as substrates.  The three substituents on C3 (-OH), C4(-OH), and C5(-CH2OH) are all on the same side of the ring, in contrast to glucopyranosides, where the substituent at C4 is on the opposite side of the ring.  This is consistent with a steric problem, although I would hesitate to call it strong evidence.
https://doi.org/10.1002/ejoc.201200277
Last week I found a reference from 2010 which also obtained 0% tetrasilylation for a galactoside derivative, when using TBDMSCl/imidazole.  Galactose is epimeric with respect to glucose at carbon-4, and they obtained disilylation and some trisilylation.  This gives me more confidence in the results from the 1987 paper, although I was already pretty convinced.  The second group switched to TBDMSOTf.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on June 22, 2021, 08:25:45 PM
https://pubs.acs.org/doi/10.1021/ol063113h
We tried the work-up from the paper I mentioned above, which appeared in Organic Letters 2007.  After one removes the TBDMS groups with TBAF, one has the problem of how to get rid of excess TBAF.  Sometimes an aqueous work-up is not possible, owing to high water solubility of the product.  Basically the method is to use Dowex-50 and CaCO3.  The Dowex-50 provides protons and binds the tetrabutylammonium ions, and the calcium forms a precipitate with fluoride.  We removed a little over 99% of the tetrabutylammonium groups.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on June 25, 2021, 10:12:37 AM
The question remains of the best way to remove the remaining tetrabutylammonium fluoride from the desired product (an aromatic glycoside that does not have charged groups. Whether or not the counter-ion is still fluoride is open to question, but the presence of the methyl group from the TBA cation is clear.  We have roughly 30 mg.

I have been thinking about various reverse-phase methods.  As an alternative, one idea that just occurred to me is mixed-bed ion exchange resin, such as Dowex 501.  I would think in terms of swirling a solution with the ion-exchange beads, filtering, and rinsing to recover as much sample as possible.  It is possible to follow the deionization of urea using a conductivity meeter, although our volume is probably too small for a standard meter.  Does anyone have any thoughts or suggestions?
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on June 26, 2021, 09:41:32 AM
I think if you have say 1% TBAF left you have very little ions left considering the high mw of TBAF?
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on June 26, 2021, 09:57:22 AM
Yet the original TBAF was in eightfold molar excess over the glycoside (2-fold per -OH group in the final product).  Therefore, 99% removal still means 0.08 mole TBAF per glycoside.  The questions are whether or not the remaining TBAF would interfere with the intended purpose and whether or not the material in its present form would be considered pure enough for publication.  On the former question, I can make a plausible case for interference.

I may try Dowex-501 on the NMR sample, which I still have.  Centrifuging the ion-exchange beads is another alternative.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on June 26, 2021, 11:44:55 AM
Using the NMR sample, I tried some old Dowex 501, which I first rinsed with a small portion of D2O.  The good news is that the triplet assigned to the methyl group in the tetrabutylammonium ion is about 40% of the area it used to be.  The bad news is that there is now a sharp singlet in the H-1 spectrum, at 2.16 ppm.  This is not far from acetone in water.  I had just been cleaning NMR tubes prior to performing this experiment, and it is possible that I used a tube that was not dry.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on June 27, 2021, 03:24:35 AM
I understand that you can have mixed feelings about using a unfamiliar technique such as RP-silica chromatography but if you submit this paper reviewers will probably question why you have not tested this to purify your material especially if it is intended for testing in some kind of biological assay.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on June 28, 2021, 08:39:12 AM
The Dowex-501 that I used was old, and it has occurred to me that this might have hurt its effectiveness.  I think we should scale up the synthesis and optimize the yield in the first step (we had to rerun one column, owing to a suboptimal choice of solvent).  Although I have not entirely given up on the mixed-bed idea, I will look forward to trying the RP-silica.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on June 28, 2021, 03:58:52 PM
Yes, I had also had problem with degraded ion-exchange resin. I think you dont need more than 1.2 fold excess TBAF. Have you considered other reagent like HF-pyridine?
Title: Re: silylation and desilylation reviews or information
Post by: wildfyr on June 30, 2021, 08:43:49 PM
Why not just take an anion exchange resin, stir in KF or NaF in methanol, wash the heck out of it again with clean methanol, dry it, then stir your compound for several hours over this resin. Filter off resin and rinse, rotovap down and voila pure product. Make sure to use a notable excess of resin eqs (like 2) since it will be slower than liquid phase. No need to mess around with TBAF.

I saw you were doing something with resin, but I didn't really follow and it seemed painful.

OR! Do it biphasic. KF in water, product in organic phase, then stir the christ out of it. Use saturated KF because the high salt concentration should force the organic products to stay in the organic phase since I saw your substrate is rather hydrophilic. I know MeCN and sat KFHF in water are not miscible, that's how I made sulfonyl fluorides out of sulfonyl chlorides. If that solution can keep MeCN out of the water phase, then I bet it will force your product to stay in the organic phase, MeCN is freely miscible with pure water.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on July 01, 2021, 09:35:02 PM
wildfyr,

Are you suggesting in effect putting the anion-exchange resin into the fluoride form?  That is a very creative idea.  IIUC either there will be some methoxide and it and the methanol will be in the equilibrium with the product, ROH, and RO-.  If RO- is formed, it will be the counter-ion to the anion exchange resin.

Rolnor,

I need to look into pyridine•HF more closely; I have been a slacker.
Title: Re: silylation and desilylation reviews or information
Post by: wildfyr on July 03, 2021, 12:04:36 PM
Yep that is my suggestion. Then don’t use methanol, use thf Or acetone?  You can find a good solvent. I know you can dissolve a salt in methanol and use a resin and the resin will be the desired anion.

But fluoride is a crappy base, I don’t think there would be much Methoxide present. The autoionization of methanol is very small. KF in methanol plus anion exchange resin will give you 99.9% fluoride in the active sites. Then you can rinse it once with clean methanol follow up by an aprotic solvent to flush all the methanol out.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on July 04, 2021, 02:33:57 AM
Its clever wildfyr, is it maybe possible to have a resin with amino-residues (Sephadex) and make a hydrofluoride-salt of this? It feels as if this will give more free fluoride ions than a quaternary ammonium fluoride resin. It could also be possible  to have the amino-resin loaded with excess hydrogen fluoride like in HF-pyridine.
Title: Re: silylation and desilylation reviews or information
Post by: wildfyr on July 12, 2021, 03:50:23 PM
I think the amount of "free" fluoride is based more on the number of active sites than the nature of the cation. This is a bit more of just choosing a resin and less the moiety within.

I don't feel like going back through the post, but perhaps if the substrate is highly sensitive then plain fluoride is preferable to a "HF" source, not to mention a bit safer to handle, since I bet ammonium HF will give off some HF gas in the presence of ambient water.

I think also its worth trying the biphasic method with saturated fluoride salt and MeCN. I used to to convert sulfonyl chlorides to sulfonyl fluorides with KFHF and it worked beautifully. The trick is just to stir like crazy. As with the resin method, workup is incredibly trivial.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on July 12, 2021, 04:04:05 PM
With four hydroxyl groups, I think that our product will prefer to remain in the water layer.

The Kaburagi/Kishi method worked pretty much as advertised, and if we are able to remove the ~0.1 equivalent of tetrabutylammonium ion, the compound will be nearly pure.  However, my students won't be able to pursue this for a while.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on November 12, 2021, 10:35:13 AM
We tried the Kaburagi/Kishi work-up method again last week on an aromatic glycoside.  This is the method of using Dowex-50 and calcium carbonate to remove tetrabutylammonium fluoride after removing TBDMS groups from an oxygen.  There are four TBDMS groups in our glycoside intermediate, and the ratio of TBAF to TBDMS group was 2:1.

We increased the amount of Dowex-50 by 50% over our previous attempted clean-up.  By H-1 NMR (using the signal from the methyl groups from the tetrabutylammonium ion) we see about 99.7% removal of the tetrabutylammonium groups.  We saw about 99.2% removal last time. 
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on November 12, 2021, 04:29:35 PM
Great! A good end of the week.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on February 01, 2022, 08:27:28 AM
We tried using TBAF on the para-isomer of our first compound (which had an ortho-relationship between the two functional groups on the aromatic ring).  For some reason, the reaction failed completely.  We stored the TBAF solution in the refrigerator.  When we remove aliquots, we remove using a syringe.  Any thoughts as to how to proceed?
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on February 01, 2022, 08:52:11 AM
How do you know it didnt work, NMR? If you have a hydroxy ortho to a carbonyl, deprotection may not show on TLC because you get internal hydrogen bond so Rf does not change
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on February 01, 2022, 09:25:46 AM
Both C-13 and H-1 NMR showed the presence of the tertiary-butyldimethylsilyl group.  The product was not soluble in D2O.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on February 01, 2022, 11:55:15 AM
Fluorine is so small so steric factors are small, its hard to say. Have you tried to add more reagent? As you know, its almost a fool-proof reaction.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on February 01, 2022, 07:28:30 PM
Fluorine is so small so steric factors are small, its hard to say. Have you tried to add more reagent? As you know, its almost a fool-proof reaction.
We worked the reaction up using Dowex and calcium carbonate.  We could try stirring with a fresh portion of TBAF, but the stoichiometry may be off a bit.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on February 02, 2022, 12:31:27 AM
You can do this in very small scale, just enough for a TLC.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on February 07, 2022, 09:04:22 AM
I recently learned that TBAF can come out of a solution in THF at low enough temperature.  I also was advised that this reagent can go bad over time, even in sealed vessels.  I will replace the bottle and be on the lookout for a solid mass in the bottle in the future.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on February 07, 2022, 11:02:43 AM
OK, thats typical, you are carefull and put it in refrigerator but it crystalizes…
You will still have fluoride in the solution or? I have used same bottle for long time but offcourse, good to have fresh bottles.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on February 07, 2022, 11:41:12 AM
I warmed it to room temperature with gentle stirring this morning, and everything came back into solution.  However, the age of the solution (now about 11 months) is starting to concern me.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on February 07, 2022, 11:59:46 PM
11month does not sound as a problem but you can realy dig deep into this, run one reaction with your old bottle and one with a fresh bottle, then you would be an expert on TBAF-aging.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on February 08, 2022, 08:57:39 AM
It occurs to me that the old THF/TBAF and the reaction mixture could be mixed and the reaction tried again.  I imagine that we will have to perform the whole synthesis over again, anyway, but it would be nice to have some product, even if it were less pure than is ideal.  We are obtaining new TBAF/THF.
EDT
The old bottle is probably slightly more concentrated than it was before, but given all other uncertainties, the difference may not matter very much.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on February 09, 2022, 02:45:21 PM
You can perform many small scale reactions and just run TLC, it should be clear if the silyl group cleaves from TLC.
Title: Re: silylation and desilylation reviews or information
Post by: Babcock_Hall on February 09, 2022, 05:21:48 PM
One thing that concerns me is that there are five silylation states (4, 3, 2, 1, or 0 TBDMS groups).  I think we can be certain that a reaction too place by TLC but maybe not how complete it is.
Title: Re: silylation and desilylation reviews or information
Post by: rolnor on February 10, 2022, 01:27:25 AM
You need a sample of your desired produkt as reference. Yes, you will have a large number of intermediates before you get the completely deprotected you want. You will offcourse need a very polar system to get you polyhydroxy product to move on straightphase TLC, perhaps you need RP-plates.
Title: Re: silylation and desilylation reviews or information
Post by: MOTOBALL on February 11, 2022, 08:48:23 AM
Have you seen this review article?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531329/

Org Biomol Chem. 2019 May 28; 17(20): 4934–4950.
Published online 2019 May 2. doi: 10.1039/c9ob00573k
PMCID: PMC6531329
NIHMSID: NIHMS1027860
PMID: 31044205

Synthesis of carbohydrate building blocks via regioselective uniform protection/deprotection strategies
Tinghua Wang and Alexei V. Demchenko*

Figure 14 may be of relevance/use to your synthesis.

Regards,
Motoball