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Author: Subject: Solid phase synthesis
frogfot
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[*] posted on 1-4-2007 at 12:59
Solid phase synthesis


Ok, long time I've been here.

I beleave we have some chem gurus in here that may help with this.. Sorry if this topic may seem like I want people to solve my homework... but hopefully, after couple of replies, we all will learn something and get some good tips.. mm :)

Well, recently I decided to run some synth on solid phase, mainly due to ease of purification of the intermediate products. The plan is to attach an amino acid (AA) with the N-functional group to solid support (SS), then do 3-4 reactions (or modifications) on the carboxylic acid group, and after, cleave and isolate the compound from SS.

So, the question is, what is the method of choise to attach an AA to SS? I'll need a clean rxn (with retention of abs configuration of AA), and easy cleavage from SS (acidic cleavage). The idea is to prepare 1-10 g of compound.

I probably should search more in litterature, but theres always people who will promote some favourite method that's foolproof :) Seen only some examples where AA is attached by the COOH group..

Also, how do people prefer to follow these types of reactions?
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matei
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[*] posted on 2-4-2007 at 09:20


I've done some solid phase synth recently. The simplest way for reaction monitoring is to use IR spectroscopy (KBr pellets or much better diamond ATR). I've also tried gel-phase 13C-NMR, which works well but you need quite a large quantity of resin (0.5 g or so) and also sufficient spectrometer time (my samples were left overnight in the machine). Of course, the best way to monitor the reaction is by MAS-NMR, which gives 13C and also 1H-spectra.
As for the attachment of AA to the resin, I'll post the links for two books in the references subforum.
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frogfot
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[*] posted on 7-4-2007 at 11:24


Sorry I'm late, something has died in my comp and I had to dig up my old one and connect to internet..

Thats some useful info. The most useful method for me would be quantitative, so IR is out of order. I'll also treat the solid supported compound with excesses of reagent, so it wouldnt be possible to follow decay of the reagent in rxn solution.

What is gel-phase NMR? Do you use somekind of thick substance to hold the SS particles in place or do you fill whole NMR tube with swollen SS particles?

I'm not an NMR-expert, but MAS-NMR sounds like something new.. is it about changing of couple of parameters for the spectra aquisition? or is it more complicated than that?

..found some article on google on MAS-NMR, dunno if that's the ultimate way to learn about this technique..
Applied Spectroscopy, Volume 58, Number 6, June 2004, pp. 698-704(7)

I couldn't understand much from the abstract but I hope that the rest of the article will make more sence..

Btw, that reference forum is password protected :(
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The_Davster
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[*] posted on 7-4-2007 at 11:50


Frogfot, if you have acess to the IR output data that is not simply the graph, but the output tables of wavenumber and intensity, and can obtain these tables for both the reactants, the pure products, and your reaction mixture, I can provide you with an excell file that will determine the percentages of everything present in your reaction mixture. Quantitative IR:P. It's been a while since I used it, and I remember having a rather hard time doing it(I don't get along with excell) but most instructions are in the file.

I have U2Ued you the password for references.




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matei
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[*] posted on 7-4-2007 at 16:52


Gel-phase NMR is simply recording the spectra of resin beads swollen in deuterated solvent. The bad thing about gel-phase is that you can only get 13C spectra. I'll send you some references if you're interested.
HRMAS-NMR is a solid phase technique which requires a special probehead for the spectrometer.
If you want quantitative results, probably elemental (combustion) analysis is also a good choice.
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[*] posted on 7-4-2007 at 22:37


Davster, thanks for the pass. I didn't know we had such forum section until now :)

Our software for FT-IR is kinda user-friendly so only thing I get out is a graph. Although theres probably a possibility to get numeric ouput in that soft too (this is where I have to read up on the instrumentation manuals :))
One thing I didn't understand is how to put SS particles several times into IR machine so that each time the IR-beam passage is of same length (to get comparable intensity outputs)..

Now I've read a bit in the books from matei (Thanks alot for these!!!!) and they actually mention both IR and (MAS-) NMR techniques, giving some useful references.

So far the gel-phase NMR seems to be the most comfortable technique in my case. Since my molecules are not that big, the C spectras should be pretty simple. What I'll basically do is, run rxn for some time, wash off all solubles, dry, soak in d-solvent, and see if starting material C signals dissapear! If not, I'll simply react it for longer times. Since workup of rxn is so simple, I wouldn't loose any time, yay, almost too good to be true.

The reagents a quite mild and gives clean reactions without SS. So I wouldn't expect any byproducts when going to SS. I think I've even seen similar transformations on SS by several people..
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matei
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[*] posted on 8-4-2007 at 04:24


@frogfot,

The parameters for recording 13C gel-phase spectra are in these articles:
1) J. Org. Chem. 1998, 63, 8719
2) Tetrahedron 1984, 40, 4141
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[*] posted on 13-4-2007 at 23:37


Thanks again!

They say, SS beads are swollen and made homogeneous by mechanical and ultrasonic stirring.
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matei
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[*] posted on 14-4-2007 at 05:26


The trick is to add the dryed beads to the NMR tube (aprox. 1 cm or so) and than add the solvent in portions, let the beads swell and sonicate. I found it impossible to fill the tube with pre-swollen resin because the beads tend to stick toghether and adhere to the tube walls.

When I recorded IR spectra I used a diamond ATR accesory and powdered the resin beads. If you want quantitative results I think the only way to go is to use the relative heights of the bands (i.e. you take one of the bands of the polymer backbone as a kind of internal reference).

[Edited on 14-4-2007 by matei]
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