I had good results with chloroform-methanol-ammonia mixtures for purifying amines and other polar tailing stuff on silica. Some people claim that anhydrous ammonia in methanol instead of aqueous conc. ammonia works even better – but I personally found no difference. Few good ratios of CHCl3-MeOH-conc.NH4OH are here: (ordered by increasing polarity)
100:10:1
80:10:1
80:15:1.5
80:25:2.5
80:35:4 (this is quite polar already – useful for strong bases and free aminoacids)
Apart from basic compounds, these solvent systems are also good for purifying free carboxylic acids and phospholipids. The acids are eluted as ammonium salts from the column – so one has to liberate the purified acids from their ammonium salt if the next step is amide coupling.
These mixtures were originally developed for TLCs and they work for columns also; it is important to slurry-pack the column in the same solvent mixture in this case. Gradient elution is usaly unnecessary because an ammonia gradient naturaly forms on the column during the course of elution.
One has to make sure that the used chloroform is not acidic – to avoid ammonium chloride and urea in the product. Replacing the chloroform in these mixtures with dichloromethane does not work very well here.
Ammonia sticks to silica quite strongly. When one is using ninhydrin detection with this system on TLC, it is important to bake the TLCs or use heat gun until ammonia smell is no longer perceptible. (The ammonia on silica surprisingly does not interfere with the Dragendorff stain so heating the TLC before detection is unnecessary)
Org Prep Daily 
Has triethylamine in methanol worked for you or anyone else? When I was in grad school, I was mono-Boc protecting a diamine (1,6-hexanediamine) and did the columns in methanol/ammonium hydroxide; I never got satisfactory results with it (it took forever both to chromatograph and to rotovap and used lots of silica and solvent – yes, part of the failure was my lack of skill, but…). I don’t know if we had anhydrous ammonia around, and so I wonder if triethylamine/methanol would have been a better solvent system.
Comment by Hap — October 5, 2006 @ 7:47 pm
I did not like the triethylamine-containing mixtures too much – they tend to form a second front and even split some zones in two. But I have been using triethylamine-desactivated silica with good result for very acid- sensitive compounds (like 1-ethoxyethyl-protected alcohols) which have tendency to fall apart on normal silica. The procedure was to use the same solvent mix as on TLC but before packing the slurry one one would add triethylamine dropwise to the silica suspension – about 1 mL of NEt3 for 100g of silica with stirring.
Comment by milkshake — October 5, 2006 @ 7:57 pm
Hi,
did you use 1ml of NEt3 for 100 m og Silica???
Please help me to answer the question.
Thanks
Comment by nguyen hong — January 5, 2011 @ 1:20 am
I have purified polar phosphoramidite oligonucleotide monomers on silica, using chloroform/acetone mixtures with 1% NEt3 v/v (most recently 4:1 chcl3/acetone). it works great. The compounds are quite acid sensitive but they come through intact.
Comment by N.U. chemist — April 3, 2012 @ 12:58 am
I have passed anh. ammonia through silica gel for use in the chromatography of amines and amino pyridines. However for making the column, i mix equal portions of ammonia-treated-silica gel and regular silica gel as excess ammonia gets adsorbed on to silica gel (comment already made by milkshake). To run a TLC, i have submerged the unspotted TLC in this ammonia-treated-silica gel to neutralize the acidity. I did not get any streaking after developing it.
Comment by sks — October 5, 2006 @ 11:43 pm
I have found that bubbling ammonia gas through MeOH gives me much better separations. Of course, I have not looked at that rigorously, it is just a casual observation after running these types of columns for 5 years.
I also never use chloroform in these systems, too much acid… I have found DCM to be not only cheaper, but less acidic.
As you all have said, pretreating the silica is essential for a good separation. I use a 1% (MeOH/NH3) in DCM solution to make the silica slurry. This really cuts down on the ammonia “solvent front” effect.
Interestingly, I have run as high as 40% (MeOH/NH3)/DCM for poly pyridines and saw no dissolution of the silica. Running 40% MeOH/DCM will dissolve some silica, especially the fine flash grade.
Another favorite solvent system, this time for acids, it 5% (HOAc/MeOH)/DCM. Works well and make the lab smell like a big salad.
Comment by Milo — October 6, 2006 @ 1:13 pm
So pleased that a Google search brought me here. 🙂
Comment by Chemjobber — July 11, 2013 @ 5:01 pm
I’ve had a lot of success chromatographing highly polar compounds using the following systems (which came out of the Stoltz group @ Caltech)
***************************
Here are the “recipes” for the chromatography solvents useful for silica gel chromatography of polar materials.
EtOAc : MeCN : MeOH : water (relative volumes, not percentages)
60 : 20 : 20 : 20
60 : 15 : 15 : 15
60 : 10 : 10 : 10
70 : 10 : 5 : 5
70 : 5 : 2.5 : 2.5
70 : 2.5 : 1.25 : 1.25
If streaking occurs, or if you are trying to purify an acid with limited solubility in these systems, it sometimes helps to add 0.5% triethylamine.
For flash chromatography, it’s important to wash the silica gel well with the solvent (2-4 column volumes) and throw out the washings.
I don’t know whether these solvent systems will work for your compounds, but they’ve worked wonderfully for some of the stuff
I’ve made, including heterocyclic carboxylic acids, and water-soluble compounds with as many as 2 carboxy and 3 hydroxy
groups. Also they work well for chromatographing (unprotected) guanadines on silica gel! I have not had any problem with dissolution of silica gel during chromatography.
Comment by Stiv — July 12, 2013 @ 10:30 am
I’m a chemistry newbie… how does one liberate the ammonium salt from the carboxylic acid?
Comment by Julie — May 15, 2014 @ 3:06 pm
acidifying the ammonium salt with diluted HCl, followed by extraction with a solvent like ethyl acetate or ether usually does it…
Comment by milkshake — May 15, 2014 @ 3:41 pm
Thanks so much! I have been doing that, so I guess something else is wrong with my amide coupling reaction
Comment by Julie — May 19, 2014 @ 4:07 pm