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Topic: Alkylsilyl derivatives  (Read 4697 times)

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Offline Clinho

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Alkylsilyl derivatives
« on: March 09, 2018, 03:33:53 AM »
Is anyone familiar with alkylsilyl derivatives and alkylsilyl reagents for protection/derivatization which are both hydrolytically stable? I have to perform a protection on one compound, and the reaction must be done in aqueous solution.

I was recommended to check t-Butyldiphenylsilyl reagents. Is TBDPSCl stable in water? Is any source for introduction of TBDPS stable in water?

Offline wildfyr

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Re: Alkylsilyl derivatives
« Reply #1 on: March 09, 2018, 08:42:59 AM »
I don't think any silyl chlorides are going to be stable in water. Anything tertbutyldimethylsilyl ether or bulkier will be fairly stable in neutral water.

Why must it be done aqueous?

Offline Babcock_Hall

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Re: Alkylsilyl derivatives
« Reply #2 on: March 09, 2018, 11:07:42 AM »
Do you mean that the protection must be done in aqueous solution, or do you mean that subsequent reaction?  What functional group are you protecting, an alcohol?

Offline wildfyr

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Re: Alkylsilyl derivatives
« Reply #3 on: March 09, 2018, 01:07:17 PM »
Anything tertbutyldimethylsilyl ether or bulkier will be fairly stable in neutral water.

I should clarify, any TBDMS ether (or DMPS ether, or whatever bulky alkyl groups you use) products will be fairly water stable. However they probably won't be water soluble.

Offline Clinho

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Re: Alkylsilyl derivatives
« Reply #4 on: March 12, 2018, 04:44:05 AM »
Do you mean that the protection must be done in aqueous solution, or do you mean that subsequent reaction?  What functional group are you protecting, an alcohol?

The protection step must be done in aqueous solution. Nope, trying to protect a thiol.

Found a couple of reagents which can be used for thiol protection, e.g. TMSA, TMSI and ETSA, but none of them is water-stable, as far as I know...


I should clarify, any TBDMS ether (or DMPS ether, or whatever bulky alkyl groups you use) products will be fairly water stable. However they probably won't be water soluble.

I understood. The point is that I need a silylation reagent which itself is stable in water.

Offline DrCMS

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Re: Alkylsilyl derivatives
« Reply #5 on: March 12, 2018, 05:32:19 AM »
The point is that I need a silylation reagent which itself is stable in water.

To the best of my knowledge this is an impossibility.  Anything that will react with an SH or OH group on an organic molecule will also react with water.

Offline rolnor

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Re: Alkylsilyl derivatives
« Reply #6 on: March 12, 2018, 10:42:37 AM »
I think you can alkylate SH groups with alkylating agents like methyl iodide or benzyl bromide in water solution. Maby there is some usefull protective group you can use, check in Greenes book on protective groups.

Offline wildfyr

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Re: Alkylsilyl derivatives
« Reply #7 on: March 12, 2018, 01:00:16 PM »
Could you give us some more details of the problem at hand? It sounds interesting but to suggest even a work around we need data.

Offline wildfyr

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Re: Alkylsilyl derivatives
« Reply #8 on: March 12, 2018, 01:06:13 PM »
You could acylate it. Thioesters can be cleaved with some selectivity based on pH I believe.

Offline rolnor

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Re: Alkylsilyl derivatives
« Reply #9 on: March 12, 2018, 02:37:55 PM »
Is not acylation impossible in water? There are many examples in Greenes book about protection of thiols but to chose the best group we need more details.

Offline wildfyr

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Re: Alkylsilyl derivatives
« Reply #10 on: March 12, 2018, 03:05:11 PM »
Use bicarb to produce the thiolate, it should be more reactive with an acid chloride than water is. I sure don't like it, but if you use a ton of acid chloride you might get it to go. I've seen some oddly stable reactivity from acid chlorides in water (like how benzoyl peroxide is made, with benzoyl chloride in NaOH and hydrogen peroxide water solution at 0C)

I wonder if OP can do a neat reaction as opposed to an aqueous one at least. There may be essentially neat silylation procedures possible. Or even heterogeneous!

Offline Babcock_Hall

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Re: Alkylsilyl derivatives
« Reply #11 on: March 12, 2018, 03:48:17 PM »
This is a shot in the dark.  Assuming that it is possible to make a compound with an iodine where the thiol group is desired, the iodine could be substituted with thioacetate.  In a subsequent step, the thioester could be hydrolyzed in base.  I believe that I have seen this previously, but I don't recall the details.

Offline wildfyr

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Re: Alkylsilyl derivatives
« Reply #12 on: March 12, 2018, 06:13:15 PM »
Babcock I think any halide but fluorine would work with this. Thioacetate is a pretty good nucleophile.

Offline Clinho

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Re: Alkylsilyl derivatives
« Reply #13 on: March 13, 2018, 07:22:12 PM »
To the best of my knowledge this is an impossibility.  Anything that will react with an SH or OH group on an organic molecule will also react with water.

In other words, there are no existing silylation reagents which are water stable, even the  tris(trimethylsilyl)silane "super-silyl" reagents? It does not necessarily have to be a silyl halide...

I wonder if OP can do a neat reaction as opposed to an aqueous one at least. There may be essentially neat silylation procedures possible. Or even heterogeneous!

Unfortunately no, it has to be done in aqueous solution...

Could you give us some more details of the problem at hand? It sounds interesting but to suggest even a work around we need data.

In essence it's not a synthetic issue, but I wanted to ask the question here since derivatization could be viewed as "protection" in some cases, and some experience I gained during my MSc studies tells me that organic chemists might have a good advice.

I'm trying to develop a GC method for quantification of a couple of drug metabolites which are found in urine. They contain only alkyl chains, a thiol group and a keto group (γ to the thiol). I might always dissolve the pure standard in an organic solvent and derivatize the thiol group for calibration purposes. However, I need a reagent for protection of these thiols within the urine sample (that's why aqueous solution) while avoiding any sample prep steps like LLE, SPE etc.

Selectivity should not be an issue here. The derivatizing/protecting reagent can bind to other components of urine, but these should later be separated and the target compounds identified easily by GC-MS/MS.

Offline wildfyr

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Re: Alkylsilyl derivatives
« Reply #14 on: March 13, 2018, 07:49:58 PM »
Have you googled "aqueous silylation"?

I got a couple promising hits right at the top

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