[shrent]

Hi friends ! 

I'm trying silyl protection of l-Alanine with Hexamethyldisilazane (HMDS).

i.e. making H2NCH(CH3)COOH  to  H2NCH(CH3)COOSi(CH3)3.

How can I do this task ? Just mixing & reflux in acetonitrile or something else ? Adding base (TEA) is necessary ? 

[Organishe]

You do not need a base (at least in most cases, I would imagine).  I would recommend, however, to use a small ammount of acid catalyst, either TMS-Cl or a pinch of HCl.  Otherwise the reaction will be painfully slow (my experience, at least). I don't know about the selectivity of the protection to the carboxylic acid versus the amine, but considering the amine is likely to be protonated, I'd give it a shot. Acetonitrile should work, I think. I've seen hexane suggested as well (doubt that will work in your case).

Some wonderful information on silicon protecting groups can be found here:
http://www.gelest.com/company/InfoRequest.asp

And select the option to download the "silicon based blocking reagent" one.
(for those not in the know, Gelest is a maker of lots of silicon compounds, as well as tin, germanium, and some others)

for the last 2 years of research I have lived and breathed this catalogue (my reserach dealt with the study of pentavalent silicate intermediates in alkyl migration reactions)

[shrent]

Thanks Organishe !

However, I was suggested to also check this reference : "Silylation of organic compounds", by A.E.Pierce, published by Pierce chemical company, Rockford, Ill, especially chapter 8 thereof. But unfortunately I could not find it in our university library..

Can anyone help me get this reference, pls .? 



shrent

[Organishe]

Oh, I did forget to mention in my post earlier that as you said, you want to heat it to around 40-50 C to reflux, depending on how things look.  An easy (and kind of fun) way to check reaction progress is check the outlet nitrogen stream's pH with a small bit of pH paper. If it is basic, you are still releasing ammonia and its still going!   

As for the reference you are after, my best suggestion is try to see if your library has an Interlibrary Loan program. If so, put in a request and you can get absolutely anything.  Can take a while, but you will eventually get it. 

Unfortunately I'm not working in the same lab anymore and don't have access to my old notebooks and collection of articles. I have probably 20 articles on the subject you'd love to have, just no way for me to get at them any longer. 


Also I've thought more on the selectivity issue, and I think with HMDS you should have excellent selectivity to the carboxylic acid.  If you were to protect the amine, it could easily be protonated again and deprotected, so assuming your reaction goes to thermodynamic equilibrium, you will get the acid protected in high ratio to the amine. (Correct me if I am thinking incorrectly here, please)

[hurfblurf]

There's a JOC paper on using saccharin as a silyl transfer reagent with HMDS.  A labmate of mine used it to silylate a carboxylic acid with good results.  I'm not sure about selectvitity, I would assume you're OK thermodynamically, pretty sure the O-Si bond is stronger than N-Si bond.

[shrent]

Pls sugest me that exact JOC paper (vol./issue/year) or pls send me the pdf copy if you have that.




thanks !
shrent 

[movies]

Please don't solicit copywritten material on the forums.

Feel free to post links to the journal web page that contains the article, but please refrain from distributing the articles themselves through this site.

[hurfblurf]

JOC 1982 47 3966

http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/jo00141a031

[shrent]

Thanks dear ! 

[lavoisier]

A few catalysts I've used for HMDS silylations are H2SO4, I2 and TMSI. The last two were really good, but I had to use a large excess of HMDS (like 3 eq).

There's also a method widely used in the industry which is meant to accelerate the reaction (with HMDS only it may be sluggish sometimes) and to avoid release of ammonia.
You use both (TMS)2NH and TMSCl, and you get NH4Cl as the byproduct:

(TMS)2NH + TMSCl + 3 RCOOH --> 3 RCOOTMS + NH4Cl (solvent=DCM, MeCN...)

Concerning the N/O chemoselectivity, according to Greene's P.G. you can safely assume that N won't be affected at all (in fact, HMDS is silylated ammonia and it does transfer its TMS to the carboxylic oxygen).
With a large excess of silylating agent you could get N,O-bis-silylation (this is done on some cephalosporine zwitterionic nuclei to solubilise them in DCM), but your N will remain reactive.

Hope it helps.

[shrent]

I also adviced from a friend that I may use TMSCl in this silylation with HMDS & it is used in catalytic amount to speed-up the silylation process.

But here, the HMDS & Amino acid would be in same molar proportions or anyone in axcess ? Temp. ambient ?

[lavoisier]

I tell you my impression, even though I have no data for your specific case.
The amino acid will probably be present as a zwitterion (COO- and NH3+), so the COO- will react with the silylating agent, but the NH3+ group will not react.
This means you can use any excess of reagents you wish without problems. You normally use a slight excess (say 1.1 Eq) to remove possible traces of water in your system, so that the conversion of your substrate is complete.

I'd say, just try it and see if it works - chemistry is not a theoretical science!

[shrent]

Hey friends !

I got a very nice process for this. I just mixed TMCS (1.1 eq.) with L-Alanine in DMF at room temperature & after 10-15 minutes stirring, all alanine got dissolved.

But the problem here I face is the HCl liberated during the reaction. For this, I added TEA (1 eq. against TMCS) in the reaction but besides making the TEAHCl, it also affects the TMS ester generating insoluble particles.

Can you pls suggest me how to overcome this HCl & making the reaction media neutral without using TEA ?

By the way, here I assume that the TMS-L-Alanine is liquid ??  Do you have exact idea about that if it is liquid or solid ? (Sorry, I tried first time for this material & could not get any information about its nature from net..)

[lavoisier]

How do you know that the 'insoluble particles' contain your ester? Did you analyse them? And how?
Is TEA.HCl completely soluble in DMF at any concentration?

If the particles don't contain your product, but you really don't want to see them, you may try a more lipophylic amine (Bu3N, iPr2EtN...) or one of those very strong amines like N,N,N',N'-tetramethylguanidine, DBU...

If, on the contrary, the particles do contain your product, then it probably means that it's (partially)precipitating as the HCl salt, and in this case you really need a stronger base as the ones cited above, or a different solvent.