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Topic: para-formaldehyde reaction is unexpectedly sluggish  (Read 8486 times)

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Offline Babcock_Hall

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Re: para-formaldehyde reaction is unexpectedly sluggish
« Reply #15 on: October 08, 2014, 10:12:14 AM »
My student would like to make di-tert-butylhydroxymethylphosphonate, (t-butylO)2P(O)-CH2OH.  He found a procedure in the patent literature that suggested using microwaving for 20 minutes (90 °C) in the presence of 0.1 equivalents of triethylamine and an excess of para-formaldehyde.  Based on previous experience (mentioned upthread) I am a little bit worried about loss of the tert-butyl protecting groups, but I told him to go ahead on a small scale.  If it fails, we have previously used a route involving Michaelis-Becker chemistry.  It is unclear to me how the temperature is known in this procedure, inasmuch as it is done in a sealed vial.  Although others in our department do, we don't have any experience with microwave reactions, so any suggestions would be appreciated.

Reference
Synthesis of high relaxivity chelates for potential use as MRI contrast agents
Caravan, Peter D.; Jacques, Vincent; Dumas, Stephane; Sun, Wei-Chuan; Zhou, Kevin L.; Schmitt-Willich, Heribert
Assignee Epix Pharmaceuticals, Inc., USA
2008
« Last Edit: October 08, 2014, 01:14:32 PM by Babcock_Hall »

Offline Dan

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Re: para-formaldehyde reaction is unexpectedly sluggish
« Reply #16 on: October 08, 2014, 05:19:19 PM »
It is unclear to me how the temperature is known in this procedure, inasmuch as it is done in a sealed vial.

Our microwave detects the temperature and pressure in the vessel. You can set it to maintain either a certain pressure, temperature or wattage (these parameters are displayed graphically in real time as the reaction runs). Presumably there is a probe that goes through the septum - the mechanism is not accessible so I can't actually see what it does. I've only used it a couple of times, usually attempting to repeat literature reactions from India that used domestic microwave ovens (without success).

You can also just heat it normally, it will still work but may take longer.

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Offline Babcock_Hall

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Re: para-formaldehyde reaction is unexpectedly sluggish
« Reply #17 on: October 08, 2014, 07:52:31 PM »
We obtained a mixture of two closely related compounds plus quite a bit of starting material.  I think a small fraction of the starting H-phosphonate lost a tert-butyl group.  Some of the para-formaldehyde ended up on the side of vessel, by the look of it.

Offline Babcock_Hall

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Re: para-formaldehyde reaction is unexpectedly sluggish
« Reply #18 on: October 12, 2014, 12:39:06 PM »
You can also just heat it normally, it will still work but may take longer.
We tried this once with an impure sample of HP(O)(OtBu)2, but the starting material appeared to decompose.  Yesterday, we tried our standard method of making the phosphonate, using LiN(TMS)2, followed by TMS-Cl, followed by para-formaldehyde and finally removal of the TMS protecting group.  The reaction with PFA is very sluggish, as monitored by P-31 NMR.  We usually see a complete reaction in 2.5 hours at 45 °C, but in this case even after the reaction has run overnight, the starting material, (OtBu)2P(OTMS) is still the dominant peak.  It is hard to come up with a mechanism for why a reaction is proceeding more slowly than it usually does.

Offline Babcock_Hall

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Re: para-formaldehyde reaction is unexpectedly sluggish
« Reply #19 on: November 05, 2014, 09:01:59 AM »
We bought some new paraformaldehyde, and the formation of the P-C bond worked much more smoothly:  (tBuO)2POTMS + PFA  :rarrow: (TBuO)2P(O)CH2OTMS.  It is still unclear to me what is the matter with our older PFA samples, and what we can do to ensure a smooth reaction in the future.  In theory we could always buy a new bottle, but that gets expensive.

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