[Reddart]

I seem to be running into difficulties recovering product from reacting 2 eq of acetic anhydride with o-phenylene diamine in pyridine. I'm wondering if the second amine becomes more difficult to acylate? This usually works really good for mono anilines.

[Dan]

What do you see is you simply remove all the volatiles under vacuum and analyse the crude? i.e. is the problem with the reaction or the isolation?

[pgk]

I have prepared various bis-enamines of o-phenylene diamine in quantitave yields, without serious problems (except in the case of bulky and highly hindered ketones).
But you have to prolong the reaction time because the monoderivatization decreases the nucleophilicity of the second amine and therefore, its reaction rate constant is also decreased and thus the reaction rate is decreased, too.
You can also try triethylamine catalysis but you have to add Et3N/Ac2O at 1/1 molar ratio and eliminate the so formed triethylammonium acetate by extractions, after the end of the reaction.

[Reddart]

It seems to have gone well, but the product has high water solubility, so extraction is tedious. I'm thinking of trying propanoic anhydride to get better organic solubility, which will be better for some of the next steps.

[Dan]

It seems to have gone well, but the product has high water solubility, so extraction is tedious.

I'd try just removing the pyridine, Ac₂O and AcOH on a rotavap followed by recrystallisation (or column). All your byproducts and excess reagents are volatile, so aqueous workup can be avoided.

[pgk]

1). You do earn a lot, by forming the bis-propionamide. You need at least the butyric anhydride, in order to obtain an adequate lipophilicity.
2). Dan is right. Try to remove the raw materials in excess by the rotary evaporator. But there is a problem. All these components are difficult to remove, not only due to their high boiling points but also due to their high latent heats of vaporization (evaporation is slow). Besides, pyridinium acetate that is formed in situ, forms a highly negative complicated azeotrope with all above, at the end of evaporation. Thus, what can be done is:
Add water and adjust the pH ≈ 7.5 with NaOH solution (DO NOT use carbonates) and thus, only pyridine will pass into the organic phase and evaporate as being. Pyridine forms azeotrope with water at 93oC. You may add additional amounts of water (pH ≈ 7.5) until almost all pyridine is removed and then add toluene to remove water by azetropy at 84oC (pyridine /toluene azeotrope bp = 110oC). Then add water and adjust the pH ≈ 6.5 with HCl solution. Thus, there is only AcOH in the organic phase. However, AcOH does not form azeotrope with water. So, you add toluene and evaporate as being. AcOH, toluene and water form a ternary azeotrope at 103oC and ACOH, toluene form a binary azeotrope at 105oC and HCl/water a binary azeotrope at 110oC. After the end of evaparations, you add any desired organic solvent (EtOH or i-PrOH in preference, in order to pick up the remaining traces of HCl) , filter the formed NaCl and then,  purify by recrystallization or by column chromatography.
Of course, the azetrope boiling points are different at reduced pressure but the volume ratios of constituents are about the same.
By ending, all above may seem complicated but the whole evaporation procedure is rather fast.

[Reddart]

Tried it with isobutyric anhtdride, and it worked beautifully (crystals crashed out in water; filtered, rinsed, and dried).

[Dan]

^Update appreciated, thank you.

[pgk]

Good. Very good!

[Reddart]

pgk,

would this type of procedure work with removing triethylamine? I'm using triethylamine in a procedure with a compound that contains a caboxylic acid, and I want to be careful acid washing since it also contains a Boc protected amine on the molecule.

1). You do earn a lot, by forming the bis-propionamide. You need at least the butyric anhydride, in order to obtain an adequate lipophilicity.
2). Dan is right. Try to remove the raw materials in excess by the rotary evaporator. But there is a problem. All these components are difficult to remove, not only due to their high boiling points but also due to their high latent heats of vaporization (evaporation is slow). Besides, pyridinium acetate that is formed in situ, forms a highly negative complicated azeotrope with all above, at the end of evaporation. Thus, what can be done is:
Add water and adjust the pH ≈ 7.5 with NaOH solution (DO NOT use carbonates) and thus, only pyridine will pass into the organic phase and evaporate as being. Pyridine forms azeotrope with water at 93oC. You may add additional amounts of water (pH ≈ 7.5) until almost all pyridine is removed and then add toluene to remove water by azetropy at 84oC (pyridine /toluene azeotrope bp = 110oC). Then add water and adjust the pH ≈ 6.5 with HCl solution. Thus, there is only AcOH in the organic phase. However, AcOH does not form azeotrope with water. So, you add toluene and evaporate as being. AcOH, toluene and water form a ternary azeotrope at 103oC and ACOH, toluene form a binary azeotrope at 105oC and HCl/water a binary azeotrope at 110oC. After the end of evaparations, you add any desired organic solvent (EtOH or i-PrOH in preference, in order to pick up the remaining traces of HCl) , filter the formed NaCl and then,  purify by recrystallization or by column chromatography.
Of course, the azetrope boiling points are different at reduced pressure but the volume ratios of constituents are about the same.
By ending, all above may seem complicated but the whole evaporation procedure is rather fast.

[pgk]

Triethylamine has a low latent heat of vaporization and therefore, it can easily be removed by distillation at 90oC and thus you don’t need water azeotropy, like pyridine. Just evaporate trimethylamine, as being. However, the triethylammonium carboxylate salt might also form a highly negative complicated azeotrope with all above, at the end of evaporation. Therefore, pH adjustments might be necessary. If the organic acid must also be removed, try toluene azeotropy (if the corresponding azeotrope is formed) and not water one that forms negative azeotopes and therefore, it increases the boiling point. But this finally depends on the chemical nature of the organic acid.

[Reddart]

The caboxylic acid is on the desired compound. By weight analysys, It looks like there is some TEA still in the product, but, this shouldn't effect the next step (DIC esterification), so I'll probably just go on with it still there (pending NMR analysys...it's like the dark ages being in a startup with no NMR on site )

[pgk]

I wish you the best. Furthermore, let me remind a few basic principles that everybody knows (obviously, you included) but everybody forgets after graduation (indeed, me included):
Triethylammomium carboxylate is not fully ionized and thus, there is equilibrium of the ionized and non-ionized form.
RCO2H + Et3N ← →  RCO2(-) + Et3NH(+)
With anequilibrium constant:
Keq = [RCO2(-)][Et3NH(+)] / [RCO2H][Et3N]
In practice, all above mean that the excess of triethylamine will firstly evaporate from a mixture of triethylammomium carboxylate and triethylamine and then the non-ionized form will start to evaporate, too. Evaporation of the triethylamine from the salt will continue by pushing the above equilibrium to the left (Le Chatelier) principle) but at the end, Ionized concentration will be very low and therefore, evaporation will be very slow due to the kinetics of equilibrium reaction.
u = - K(rate)[RCO2(-)][Et3NH(+)]
As a consequence, traces of triethylamine will always remain, even after highly prolonged evaporation. Thus, complete evaporation of trimethylamine occurs after alkalization, only.
2). According good laboratory practice, a compound must be fully purified before been introduced in the next synthetic step, otherwise surprises (good or bad) might arrive. In other words, nobody knows whether triethylamine is competitive or synergistic with DIC during esterification.

[Reddart]

NMR showed TEA ~ 90mol% to acid (Yeah, me thinks my vacuum sucks, or is it doesn't suck?). I got thrown off at first since the shifts didn't match TEA...because it is the ammonium, not the amine     A small vial scale DIC coupling reaction looked good on tlc. I saw a few DCC esterification preps in the literature that included TEA, so I wasn't too worried. I also figured via the mechanism (with DMAP), it should be inert, other than it may slow it down a bit by interfering with the DMAP. I also used a little DPTS, the secret sauce for DCC/DIC esterifications 

[pgk]

Probably, your vacuum may works perfectly but it cannot overcome the laws of Physical Chemistry.
Do not further push the vacuum because your pump risks being plenty of triethylamine.