[molecularorbital]

Hello everyone,

i'm a newbie in a research lab and I want to perform a grignard reaction on a complex nitrile, to turn it into a ketone. I can't say what the nitrile is sorry, due to a non disclosure agreement. I've read a few posts on the forum about this so I have a little bit of an idea, but i'd like to clear a few things up.

I want to take the nitrile and methyl magnesium iodide grignard, reflux it in THF, dry conditions, N2 atmosphere etc. Then I need to do an acid workup to get the ketone. My questions are:

1) How much excess grignard reagent should I use? 2:1? 1.2:1?
2) Is THF the best solvent for this? Or should I use diethyl ether or something else? I have read that nitriles are much less reactive than other things in grignard reactions, maybe a higher boiling point solvent would give more yield as I could reflux at a higher temperature?
3) For the acid workup to generate the ketone, should I be using ammonium chloride or dilute HCl or something else? How do I know how much to add?
4) Any other suggestions you have

Thanks!!

Rebecca

[phth]

My aim to teach you about patent law; FYI this is a breach of your NDA.  Here is some supplemental information about the law, and why you shouldn't be disclosing any information http://www.aipla.org/about/iplaw/Pages/default.aspx.  I'm not saying that someone is going to go after your profesor's intelectual property because this is a community where people learn together.  Answering any question entitles the answerer a part of the property because its their idea.  Ask your professor.  It is probably more worrisome to them by not being asked questions.  Every chemist eventually encounters obstacles in synthesis. 
1) Is it freshly prepared? You should know how to determine purity to figure out how much to add.
2)  THF is easier to work with than Et₂O.
3)  You are doing a mole calculation before the experiment.  NH₄Cl is a milder acid.
4)  I would look into transition metal catalyzed grinard reactions e.g. gilman etc

[molecularorbital]

Thanks for the suggestions!

Actually I don't have a supervisor at the moment, I am at a Uni but at a privately funded research start up company. I could ask other professors but I feel a little awkward, especially being new. My actual boss is a mechanical engineer, and doesn't know hardly anything about chemistry (moles dig holes in the ground!).

1) Yes the grignard is freshly prepared. I'm not sure how to determine the purity of my grignard sorry. Could you steer me in the right direction?
3) So for the mole calculation on how much acid to use, do I assume that 100% of the nitrile changes into the intermediate imine? I'll definitely be adding an excess of acid that way, i'm not sure it's a good idea. Is there another way to check my acid workup is complete?
4) This suggestion was extremely helpful thank you!!!! I've found an article about copper(I) catalysts which greatly speed up the reaction, from 24 hours reflux 10% yield to 2 hours reflux 99% yield in some cases!

[phth]

Okay.  1) titrate a solution and measure the pH with an electrode.  what equation do you use?  2) Yes, the pKa of RR'=NMgBr is 33 NH₃ is 12.  Excess is fine unless there is a acid sensitive functional group, and use NH₄Cl(aq<in excess).  Can you think of a way of how to check? The answer lies within the intrinsic properties of the chemicals.  3) don't buy copper(I).  Prepare it. 

[rebecca88]

Sorry for making a new account, forgot my password to this site and have a new email.

I'm back on the task of adding my grignard to a nitrile, and it is working, but in incredibly low yield.

My nitrile has a CH2 group next to the CN, and I read on here and in a journal article that the grignard can can react to form RH, deprotonating alpha hydrogens from the nitrile, which leads to less formation of desired imine intermediate, and formation of trimers etc.

I've read that this reaction is often carried out at 0 deg C, what is the point of this if will be refluxed later anyway? Is there a reason?

Will refluxing make more of the trimer and less of the desired imine? Or it doesn't matter?

I'm using copper(I) iodide as catalyst. 1:1 grignard to nitrile. Should I be adding 2:1 grignard to nitrile?

Thanks!!

[phth]

Are you exposing the CuI to oxygen? do this reaction under inert aphmosphere, and also your CuI may be bad because of oxygen seeping into it; preparation from fresh Cu(II) is not that complicated of a procedure.  If you're refluxing, 0°C and dropwise at first to lessen the enthalpy change because grignard neutralizing will create alot of heat speeding up side reactions.  If it still not working just go with another reaction sequence.  For example, http://www.organic-chemistry.org/synthesis/N1H/reductionsnitriles.shtm or hydrate the thing to the COOH and then add oxalyl chloride(easy to distill) and DMF as a catalyst to convert to acid chloride etc.  Go the the uni and set up a scifinder account and research.  there are lots of ways to convert your starting material into what you want.  Better results than bumping your head into a wall trying the same procedure over and over