GreenD
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Check my reaction
I need to synthesize this compound.
SOMEHOW I found a reference the other day for this. However, now I have retraced all my steps and seems to have disappeared completely (I know -
should have saved).
I just want to make sure I didn't miss something from the lit.
Why chlorobenzene, btw? Is this REALLY necessary? I've never seen this used as a solvent.
For the first step I would add to the chlorobenzene the methoxybenzoic acid, followed by SOCl2. 1:1, allow for the reaction to occur, and add the
sulfamide.
I would need to purify at this step, and then further chlorinate the acid in a subsequent step?
The chlorobenzene would need to be anhydrous?
Quite rusty in O-chem, will definitely need to do some practice.
[Edited on 8-11-2012 by GreenD]
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kristofvagyok
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No, you could also use dichlorobenzene (ODCB), or I think nitrobenzene could also work.
Chlorobenzene is a good solvent, used in classical organic synthesis, because it has a relative high bp, a large heatcapacity, is is soluble in a lot
things and cheap. The chemical industry also uses it, or the dichlorinated version, the ODCB, what is also a perfect solvent.
So if you can, use it, if you can't, then substituate it with a simmilar high bp. non reactive solvent.
And yes, the ClPh should be anhydrous.
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GreenD
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Thank you, I will get anhydrous.
I've never done a SOCl2 reaction, and my vogel book is in the mail. I went on to organic synthesis and they don't they don't use drying agents as one
would for a grignard and don't dry the glassware prior to use.
Am I safe to assume that SOCl2 isn't as reactive with water, and being absolutely dry isn't paramount?
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kavu
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After a quick search I found this patent on the subject: EP1491527
SOCl2 will hydrolyze in contact with water, but in small scale this is not usually a problem (apart from having to compensate for the hydrolyzed
thionyl chloride). You don't need rigorous drying, but it won't hurt.
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GreenD
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Quote: Originally posted by kavu  | After a quick search I found this patent on the subject: EP1491527
SOCl2 will hydrolyze in contact with water, but in small scale this is not usually a problem (apart from having to compensate for the hydrolyzed
thionyl chloride). You don't need rigorous drying, but it won't hurt. |
Thanks, I'm aware of the patent literature - terrible to read. I know for a fact there is a journal paper out there - unless I dreamt this reaction up
myself (highly unlikely!).
But, if my only option is the patent lit... so be it 
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GreenD
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Work up of acyl chloride??
How would one purify the product of the first reaction, the acid chloride?
The solvent - chlorobenzene is very high boiling, but I could vacuum distill off the solvent.
But separating starting materials from the end product?
I would have ALMOST just washed with basic water, but oop! Its an acid chloride... I searched here with nothing, and will look into the literature
soon. Its apparent not many people get to work with SOCl2
Edit: looks like most lit just distills off the product at the respective B.P.
[Edited on 11-11-2012 by GreenD]
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kristofvagyok
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Basic organic chemical knowledge is always a big help when you are performing a synthesis.
Your starting materials are carboxylic acids and your end product is an amide.
What does an acid know? It is acidic. Woah!
Dissolve your product in an organic solvent e.g. EtAc or dichloroethane and wash it with cc K2CO3 sol. it will get out the impuries.
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GreenD
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Wouldn't this interfere with the acyl chloride? Unless I am able to do this one-pot, I was going to purify the acid-chloride after the first step.
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kristofvagyok
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| Quote: Originally posted by GreenD |
Wouldn't this interfere with the acyl chloride? Unless I am able to do this one-pot, I was going to purify the acid-chloride after the first step.
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Thought you want to clean the final product... The isolation and the purification of these like acid chlorides usually goes by chromatography or by
repeated crystallization after distilling the excess chlorobenzene and sulfuryl chloride.
Or wash it out with a solvent what won't dissolve the starting carboxylic acids.
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GreenD
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This could probably be done in a one-pot, no?
I won't attempt a one-pot my first attempt, but I think it could be possible... Low yields, but the isolation of the final product from the starting
materials would be pretty simple.
I will just do a distillation, probably under reduced pressure. I am very rusty, haven't done O-chem for 2, 3 years!
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GreenD
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Ok guys so i attempted the above 1st reaction and need some help;
Sulfamoyl benzoic acid does not seem to be soluble at all in chloro-benzene, which is not what the patent implied, however I attempted the reaction
anyway.
I had 1.1 molar eq methoxybenzoic acid to 1 molar eq. of sulfamoyl benzoic acid.
This was heated, and SOCl2 dripped in (1.9 molar eq to TOTAL acids) over some time. It was heated to 100-115° as per the patent literature (below BP
of chlorobenzene - the "preferred" solvent)
The reaction did not do much - it contained a white ppt the entire time, little change.
Having never done anything with SOCl2 I'm unfamiliar with what is happening on my TLC plates (SOCl2 reacts with silica?!)
In 20:80 EtOAc:Hexanes I get no movement of roughly 3 spots on my product filtrate - 1 fluorescent at the solvent start, 1 non-fluorescent at the
solvent start, and one that moves up slightly, for an Rf of ~.1
The major product, however - a large amount of PPT is the starting material.
In 100% acetone I get one large fairly fluorescent spot at the the solvent start, conserved in both tests - could this be the silica-chloride reaction
of SOCl2? Or perhaps the SOCl2 reaction with acetone - but these wouldn't be fluorescent?
I would do a distillation but I have to wait on a short-path to come... any advice until then would be helpful.
I will upload the patent soon if you cannot find it.
[Edited on 10-12-2012 by GreenD]
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smaerd
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I don't think I'd trust a patent for a synthesis. They likely left out many of the conditions if it even works.
Was the reaction stirred? If it's homogenous and theres no reflux that's a good idea.
Maybe try DMF as a solvent instead or something your reactants are soluble in. Was HCl gas evolved durring the reaction, did you use a base scrubber?
Was your solvent completely dry?
I've never worked with the stuff but I always thought that generally first the acid chloride was created then it is added the amine. In your case I
guess it could be one pot? I don't know but personally I'd try making the acid chloride first, adding it to the amine, doing some workup then try and
make the final acid chloride? The reason why I'd not do it one pot would be, why wouldn't the sulfamoyl benzoyl chloride react with another molecule
of itself?
Also I never thought about running a TLC with SOCL2 still in the solution figure there is a way to quench that or extract the products from it first.
If you knew the rfs of your products and reactants or had access to better analysis it would sure help you out a whole bunch. edit - also try
adjusting your eluent for better resolution.
[s]also you were doing this on a mole scale? That doesn't sound like a good idea for a first try.[/s] nvm one molar equivalent.
[Edited on 10-12-2012 by smaerd]
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GreenD
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Was stirred, well stirred. I don't know if HCl was evolved and have never heard of a base scrubber.
Solvent was fresh from Sigma, anhydrous, or so it was labelled, didn't bother to re-distill or anything.
I thought about doing the methoxy-benzoic acid chloride first, too. I will do that next time I try this. The patent lit. made the statement that with
"1.1 molar equivalent of [methoxy benzoic acid] dimers are avoided in this way"...
I also did not have the reaction to full temperature before adding SOCl2 - it was around 80°C before addition began, but finished at ~115°C. I don't
think this would have that much of an effect on making dimers versus the intended product though.
I was working on a 1-2 gram scale. I HATE working with DMF, I've never been able to separate/work up well with it... always ends up in my NMR
analysis, but then again I've never distilled to get a product either, so maybe that will help with this.
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GreenD
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here is the paper
attached is patent lit, if anyone is interested.
Attachment: Cyprosulfamide Patent Synth.pdf (1.1MB)
This file has been downloaded 431 times
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smaerd
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Well HCl and SO2 are released from the reaction so I wasn't sure if you were letting the fume-hood take the full brunt of the gasseous products or
not. By a base scrubber I simply meant an inverted funnel in say NaOH soln. Solvent doesn't need to be super dry just so long as the majority of your
reagent(SOCl2) isn't completely spent on it. I'd try playing with the TLC a bit more and seeing if you can get a better resolution. Sorry I can't be
of more help hoping to hear what wiser chemists have to say.
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GreenD
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Apparently adding formic acid to a solution containing SOCl2 produces CO + SO2 + HCl, which may or may not help this...
I'll keep thinking. I will try another solvent system with something additional to acetone, maybe something like 20:80 acetone:EtOAc... will test that
now.
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smaerd
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Not sure what you are talking about with formic acid, but what I meant was this:
SO2 and HCl are products of the reaction. It probably makes carbon monoxide because formyl chloride is very unstable.
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GreenD
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No I understood what you meant, formic acid is used to remove SOCl2 from a solution, sometimes, if it won't react with anything else and adding water
isn't an option.
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GreenD
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This is odd, something I've never seen before and can't seem to wrap my head around;
I did the Acetone:EtOAc 20:80 solvent system, had some better resolution, not perfect, though, but within my product spot I'm seeing concentric
circles - one of which is highly fluorescent while the others are not.
It may just be one very large non-fluorescent spot, and a ring, literally a ring, of fluorescent inside.
Here is a drawing, if it helps (lol)
[Edited on 11-12-2012 by GreenD]
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Eddygp
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How... how... uhh... awkward.
there may be bugs in gfind
[ˌɛdidʒiˈpiː] IPA pronunciation for my Username |
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GreenD
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Hey guys would the dimer / product be fluorescent? I know its probably not easy to tell, but is the N-S(O2) bond in conjugation, or would that break
conjugation between the rings?
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zed
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I was going to caution you about the use of SOCl2, but since you are still alive, I guess you know what you are doing.
My concern about your reaction is, that it seems to me...it probably cannot proceed in high yield to the desired product.
It would appear that your initial reaction would simultaneously produce two different Acid Chlorides, each of which would be free to form an amide.
Two different products. In fact, even a polymer might be formed.
To my way of thinking, you should first convert the Salicylic Acid Analog to a carboxylic acid chloride. Then react that to form your initial
sulfamide. Thereafter, you can convert the remaining Carboxyl group to a carboxylic acid chloride, and proceed.
Two rounds with SOCl2, not one.
[Edited on 13-12-2012 by zed]
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GreenD
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Zed I will be doing that next. The Patent literature had made a bogus claim that the molar ratios somehow determined that the desired product would be
the major product and "Dimers would be avoided" - this was a joke.
Next question;
Solvent for the first 2 acyl-chloride reactions: DMF, Pyridine, or DCM (with catalytic amount of DMF)?
DMF and Pyridine seem to form a salt with SOCl2 which catalyze the acyl-chloride formation.
However, my solvent needs to be anhydrous and both Pyridine and DMF are hygroscopic.
My options; buy some sieves for either solvent.
Or just use DCM with a catalytic amount of DMF.
Note: Chlorobenzene did not dissolve the sulfamoyl reagent!
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zed
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Well, it is just a thought, but if you have lots of Thionyl Chloride, someone has probably figured out how to use it as a drying agent.
Can the reaction be run in dry Diethylether? It isn't my favorite solvent, but sometimes we are estranged from our favorite things. Good things
about Ether.....It's inexpensive, it dissolves a lot of things, and it is easy to get rid of when your reaction is complete. Just distill it away.
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GreenD
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This is my next reaction after forming the acyl chloride;
Question is - will the sulfamide be nucleophilic enough to carry this out without a base?
Adding a base would also pose a problem, though - in that it would deprotonate the acid moiety on the sulfamide compound, possibly forming an
anhydride? Which would cause many problems, and forming a mixture of products.
So if a sulfonamide is not nucleophilic enough to carry this out, I will have to resort to doing a totally different reaction using DMAP and EDC
(don't know what EDC is yet!)
Edit:
This paper uses Bismuth compounds as catalysts...
http://www.tandfonline.com/doi/abs/10.1080/00397910903318732
Ok it seems a catalyst is necessary.
I am wondering, though, whether or not these catalysts would also interfere with the carboxylic acid moiety...
I think esterification would solve this problem, though, too...
It seems like this reaction is a lot more steps than I first though...
ugh.
[Edited on 11-1-2013 by GreenD]
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