[sh20008]

Hi,
I have a general important question concerning H-NMR spectra.
Is a H-NMR spectrum that contains small rests of other solventes (EtOAc or THF for example) besides the solvent residue peak of the used deuterated solvent still acceptable for publication (I don't get it out)? Can anybody tell me the rules which most journals apply? If yes, how large can the peak be (for example compared to the smallest peak of the product or the H-integrals) ?
I would be very thankful for answers.
Chris

[Dude]

It depends on what you are trying to do.  If you are just referencing the peak locations, you don't need the NMR spectrum in the report and it will likely go unnoticed.  If you intend to put the NMR spectra in the publication as proof of structure or purity, it absolutely will be rejected if it is a highly respected journal (ie JACS, Macromolecules, etc).  Applied journals will be a bit more lenient (ie Journal of Applied Polymer Science, Industrial Engineering and Chemistry, etc) but one or more of the reviewers will still likely question and probably reject it. 

These are very loose guidelines and will depend primarily on which reviewers are looking at your paper.  As a rule of thumb, I would say if the impurity content is > 1 area % of the sample peak then it will need some explanation and rigorous documentation as to why it is there and confirmation that the peak locations check with previously published data.  A peak greater than 5 area % of the smallest peak will need to be rerun or any spectra with high baseline noise.

Is there a valid reason why the sample can't be "dried" and rerun?  Perhaps a valid reason for entrained solvent would be that the chemical you are dealing with rapidly degrades and can't be measured without residual solvent.  This would require a detailed explanation in the body of the report but would likely be accepted.  Any other reason (ie I didn't have NMR time, someone else needed the vacuum oven, the vacuum pump wasn't working properly, etc) would likely be intolerable.

[russellm72]

I can't see there being a problem if your sample contains less than 5% w/w.

I agree with "dude" if you are going to include the spectra (additional material) then yes you'd want to keep it low do you have to do this? A lot of people put it in as proof of synthesis but I can guarantee you a lot of people cheat and blow their NMR solvent down and re-dissolve thus removing traces of solvents. So, don't be too overwelmed if you see pristine spectra.

Again, I'd say it depends on why you are publishing your data. I work in the pharma industry and "in the real world" we don't have time to dry things to death as time is money so regularly I take things through with less than 5% solvent. Unless your making a final product or RSW/GMP don't waste your time.

R.

[sh20008]

Thank you for your answers. It's clear to me that a perfectly clean spectrum is the goal. I asked the question because I have a solid powder which I dried for 3 days using a vacuum pump and for two days using a Kugelrohr distillation apparatus (45 °C) under vacuum and no significant change in the EtOAc peak could be noticed.
Do you have an idea how to get the stuff out? On person said the "solvent is in the crystalls".
Chris

[movies]

You could try to recrystallize from a different solvent.  Also, you can remove EtOAc azeotropically with benzene, as I recall.  So dissolve your stuff up in PhH and strip it down.  Repeat a couple of times and you should be good to go, as long as benzene doesn't hang on your compound too.

[Dude]

I would also try what Movies recommended.  Ethyl acetate might adsorb strongly to the crystals, however, other recrystallization solvents might not have such an affinity.  The size of the crystal might also be partially responsible for the high level of solvent.  Another approach might be grinding up a portion of the crystals and washing with a solvent that does not dissolve your crystals but is miscible with ethyl acetate (pentane is what I would try initially, highly volatile - will not likely dissolve your material if it is polar - will be miscible with ethyl acetate). 

[russellm72]

Guys Guys Guys.....

Listen do you intend to have your crystals photo'd and placed in an art exhibition?

I am amazed at how much hassle some people will go to in order to produce a pristine spectrum. I agree that some EtOAc may be caught up in your crystals. If you are so desperate to remove this why not dissolve in say DCM and r/e a couple of times. This of course will remove the EtOAc but give u a solid adhering to the sides of your flask. Simply scrape it down and pump for a hour or so until constant vacuum has been reached (or constant weight if you have no piranhi guage).

I am sure your recrystallisation purified your product up nicely but thats what it was for. Yes its rewarding to see nice crystal forms but thats not the objective. The objective is to have a product that meets your specification for the next step whether it be taken on or whatever. Think about this, whats the hassle of going to all the trouble if your just going to dissolve it up and use either in another step or formulation.

I am amazed to hear of people pumping samples for days or washing things etc just to get a nice NMR.

R.

[movies]

Uhh...if you can't verify the purity of your product then you can't trust the yield that you calculate.

[russellm72]

Fair point yes but one can use NMR to calculate a solvent residue. I have been doing organic chemistry for over 10 years now and rarely have I had a product with trapped solvent in the crystal matrix. If so, it is dissolved in another solvent and spun down.

My only point was why waste days pumping something to death when your going to take it on. Ok if its EtOAc and your going to use a grignard next step clearly not a good idea. But if your going to do your grignard in THF then take your sample up in THF, spin down and re-dissolve i.e NO EtOAc...

Am I the only one who works commercially where time is money? All I am trying to do is inject some realism into the conversation.

R.

[Borek]

All I am trying to do is inject some realism into the conversation.

Have you read thread subject and OP question?

[Dude]

Russel,

You just gave two great reasons to rigorously purify the material.

1.  If the sample is a terminal product and it is a pharmaceutical, you would be promptly fired if you left 5 % ethyl acetate in a sample and sent it to pill formulation.  In the best case scenario, your concentration would be off and you would have contributed to air pollution.  A reputable company would likely discard the whole batch to avoid fraud charges.  In the worst case scenario, it would go unnoticed and ethyl acetate would have been consumed by the buyer.

2.  Even if is it isn't a terminal product, you can likely introduce problems in the next step of the synthetic scheme due to stoichiometry issues and potential side reactions. 

This is a classic case of a process engineers nightmare.  Some hotshot, half-assed organic chemist claims incredible yields or properties and upper management pushes the process.  The process engineers experience all kinds of problems when scaling up due to faulty data on yields and purity.  The knowledgeable engineers call these people "cheerleaders" (i.e. a person who only highlights the positive aspects of something).  Unfortunately, these cheerleaders frequently make it to upper management because of their gung-ho cheeriness.  That can be good.  At least they are out of the lab and not making fraudulent claims anymore.

[russellm72]

Hi thanks for the comments.

Totally agree with your analysis Dude.

I never said leaving 5% in a formulation would be Ok, the 5% issue was merely highlighting the point, in a previous post, if the chap wanted to publish it, it may be Ok. I do however agree with your analysis of half assed chemists who quote great yields but don't provide concrete proof. We all read the literature and have come across many of these individuals.

As for the non terminal product, it clearly depends on the next step in your synthesis e.g. if you just have to hydrolyse a nitrile, ester/ amide or do a simple displacement using excess reagents then I see no problem in carrying through a bit of solvent that won't interfere with the reaction. As I said in a previous post, i regularly spin compounds down from DCM/hexane to give a nice solid which shows hardly any solvent peaks if you run a NMR. I don't often run NMR's as I usually can tell if my product is the correct weight using specific activity calcualations (C-14). I only run NMR's for final compounds.

Anyway lets put this topic to bed as although it has been interesting to see how others work the topic was answered several messages ago.

I just wanted to highlight you do not have to go through rigorous tedious procedures in order to progress with your synthesis. When I heard of people pumping things for days well quite clearly that would get me fired, seeing as you brought up the employment issue . This was clearly Ok when I was a PhD student but in industry you won't find many bosses who find it Ok to spend days and days trying to remove solvents. There are always alternatives but as you point out a so called terminal product that is going to formulation must be of pristine quality.

R.