May you need slightly high pH than that of Sat NaHCO3, try washing with Na2CO3 solution to see!

good luck!

@Guobing Xiang I have not tried this yet but would there not be a risk of hydrolysing the ester due to the high pH?

I think your problem could be that TsO- is pretty happy as a phase-transfer counterion to bring H3N+-AA-OPEG into CH2Cl2 solution, and this fairly greasy anion is unenthusiastic about dissolving in saturated (i.e. high ionic strength) aqueous bicarbonate. TsOH is a strong acid, meaning that the strength of base is not an issue for deprotonation, therefore you presumably have TsONa in your organic phase. I would reduce the amount of NaHCO3 to ~ 3-4 equiv, or 1.5 - 2 equiv Na2CO3, and do a water wash before before the brine.

[Quick question: before you add methylene chloride, are you doing the reaction as a PEG melt or are you using a solvent? If there is no solvent, what I suggest will require you to dilute with water or another polar solvent. After reaction, dilution with alcohols at room temperature or below will give conditions which should not produce alkyl esters, particularly if the AA is fully consumed, but this will be apparent in the NMR if it does occur. ]

Instead of aqueous extractions, you could try passing your reaction mixture through a bed of strong anion exchange resin : BioRad AG1, Dowex 1, Amberlyst A26, etc.) The resin will need to be in either hydroxide form or bicarbonate form and some heat (and CO2 bubbles) will be generated at first due to acid-base neutralization. Am guessing that your H2N-AA-O-PEG is soluble in water, which will be a slight nuisance to remove. (Lyophilization works - don't start too concentrated.) Also, don't use a large excess of hydroxide form ion exchanger or if you are worried about saponifying the PEG ester, use bicarbonate form of the resin.

Please try the following steps:

1. Wash the dichloromethane (DCM) solution of your crude product with equal volume portions of saturated sodium bicarbonate solution to neutrality (test pH of the aqueous extract with pH paper)

2. Wash the organic layer with equal volume portions of de-mineralised (DM) water, check pH and ensure neutrality of the aqueous layer.

3. Wash with brine solution (saturated NaCl solution).

4. Dry the organic layer with anhydrous MgSO4

This is most likely to work.

If not, you may repeat the same procedure taking diethyl ether as solvent, in place of DCM.

James Kilgore the PEG is star type with MW of 3000 kDA. I did the reaction in toluene. I had to use quite a bit (1,2 eq) of the pTsOH because using smaller amounts did not give good conversion. Your explanation seems quite reasonable to me and maybe this is why the NMR peaks persist despite all the washing. Does it make sense to use a DM water wash when the product has quite some water solubility?

I will try your suggestions out and see if it gives good results. Thank you.

Ashis Ranjan Bandyopadhyay I did do exactly the same steps as you mentioned except for the DM water wash in between. Thank you for your suggestion and I will try doing the water wash in addition to the other steps

It's important to know if you are using excess amino acid (presumably you don't want incomplete acylation of the poly-ol). I am not surprised that you needed greater than 1 eq of TsOH, in fact I would predict that if you use 0.95 eq, you will get no esterification. The first 1.0 eq (vs AA) is serving as a phase transfer agent to get the AA into toluene/PEG mixture as TsO- H3N+AA-OH, and only an fractional equivalent more is needed as esterification catalyst. Also, since your product has multiple ester groups per molecule, you should avoid stronger base than CO3= because there is no simple way to separate partially de-esterified impurities.

I still suggest using SAX anion exchangers (HCO3- form) to remove tosic acid as TsO-. My recommendation is that once reaction is complete, you first rotary evaporate the mixture to remove toluene (it will get sticky and probably will bump a lot), then take up the paste that is left behind in ethanol or 2-propanol. Pass that solution through the resin bed (A little water may improve solubility.) Alcohol solvent can mediate H+ transfers and then it will help removing water at the end. The SAX should also remove excess amino acid, so make sure there are enough meq capacity to deprotonate both. Also, this produces free amino esters which are only prevented from self-reaction by the physical separation on the star-PEG backbone. Use as little bath heat for the rotovap as you can to remove the alcohol and once you have convincing characterization of this intermediate, run the next reaction as soon as possible.