[kriggy]

Hi guys, im running catalytic hydrogenation of nitro group to amino and Im experiencing severe drop in yields. At first, I did run 1 mol in 30 ml of EtOAc with 98% but when I increased the amount of my starting material, yields started to drop. At first it was some 80% at 4 mmol scale and today I got about 30%.
The problem is, that my starting material is that greatly soluble in EtOAc (about 1 mmol in 30 ml) so I run the reaction in suspension. THe product is soluble and the removal of SM during reaction then allows for more of it to dissolve and react. From HPLC analysis I see that the reaction is always 100% complete with no SM left. Workup is simple just filter Pd/C and evaporate.
Does anyone have any idea what might be the cause of the yield drop? Could it be that my starting material is getting adsorbed onto Pd/C?

[TheUnassuming]

On scale up, are you seeing new side products or is it still spot-to-spot? Can you use a different solvent/solvent system?  How are you working up your samples before you shoot it on the LC?

I've had times when material sticks to the Pd, which usually means I have to wash it excessively with MeOH.  This usually happens when the compounds get very polar (MeOH/EtoAc silica column polar) and especially if they have amines which seem to like sticking to the Pd.

Random side thought is that the filter/wash step at the end usually doesn't get scaled up when people do the scale up, so make sure you are scaling up that step as well.

[kriggy]

1) Same products on scale up
2) I can and its something Im going to do. So far I did run the reaction  4 times and the worst yield was about 70% so I decided to keep it that way because the synthesis is just 3 steps and the chemicals are fairly cheap so I get lots of starting material. But yesterday I got 30 and that is just too bad.
Does it matter what solvent i use? I dont want to use MeOH because then ester could be formed and I dont want that. And I saw ppl running it mostly in EtOAc or MeOH but in theory I could use any solvent I want that dissolves the compounds?

3) That could be it, the structure is shown bellow so it could be sticking with two amino groups. I was thinking that the problem is in the filtration but somehow it didnt occur to me that I could wash it with another solvent and also I probably didnt scale up the washing step enough

Thanks for suggestions

[discodermolide]

We usually ran nitro to amine hydrogenations in the presence of ammonia to avoid the formation of secondary and higher amines. Also Raney nickel may be better.

[TheUnassuming]

Does it matter what solvent i use? I dont want to use MeOH because then ester could be formed and I dont want that. And I saw ppl running it mostly in EtOAc or MeOH but in theory I could use any solvent I want that dissolves the compounds?

Sort of, you also have to take into account the solubility of hydrogen in the solvent.  You might make the ester in a MeOH system, but it would be worth a try if your material is more soluble in MeOH. 

We usually ran nitro to amine hydrogenations in the presence of ammonia to avoid the formation of secondary and higher amines. Also Raney nickel may be better.

I've never used the NH4OH/MeOH/Raney nickel system for nitro reduction, but worked well for a nitrile reduction I've run.  In this case, adding ammonium hydroxide to the Pd system would also help with the concern about forming the ester. 

[discodermolide]

Here's a screen shot of one of our papers using ammonia/MeOH/Raney nickel for the nitro to amine reduction. It's an old PDF so I can't get the text directly. I can give you the reference if you need it.

[kriggy]

Thank you,
I did find similar procedure today (Im sick so couldnt do it today ) on exactly same compound as is mine with RaNi in DMF but DMF is not something I realy want to evaporate (and they get ester in the end because of recrystalization from MeOH). Im gonna try different solvents with Pd but I would realy appreciate if you could give me the reference for the Ra/Ni procedure

[phth]

There are TONS of ways to reduce nitro compounds besides Pd and Ni.  If the nitro group is ortho to a benzylic position then it is extremely easy.  Gultatione+365 nm light will do it.  If not it is a little bit harder.  Reduction to the hydroxylamine is simple.  If I were you, then I would focus on finding procedures to reduce hydroxylamines to amines.

[kriggy]

I know but hydrogenation is just the easiest way to do it.

[discodermolide]

Thank you,
I did find similar procedure today (Im sick so couldnt do it today ) on exactly same compound as is mine with RaNi in DMF but DMF is not something I realy want to evaporate (and they get ester in the end because of recrystalization from MeOH). Im gonna try different solvents with Pd but I would realy appreciate if you could give me the reference for the Ra/Ni procedure

It's J. Med. Chem. 1995, 38, 3313.
Or look in Houben-Wehyl

[rolnor]

If the product sticks to the Pd/C you could use palladium black instead perhaps? Its most likely the activated carbon it sticks to? You have a method that works and the worcup is very simple, I would use it instead of turning to another.