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CTH compilation, questions, future directions

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Catalytic Transfer Hydrogenation has recently gotten my attention as I think it should many other bees searching for a better way to help themselves and others get to the honey.  It is my intention here to compile what we know about CTH with all of its different possible variables (choice of metal catalyst, hydrogen donor, amine source, solvent mix, temp. etc.) because I believe that there are common threads between all of the possible catalysts.  This is not to say that the best hydrogen donor for one metal will be the same for another, but just that getting a better mental picture will make it possible for us to better understand what tweaking of conditions will likely bee the best direction to go.  Then one hits the lab and comes back with the results. 

So, please, post below your thoughts, knowledge, questions, and whatever else pertinent and helpful to the CTH reduction of imines and other stellar hydrogenations.  I'll go first. ;)

The elements: Ru, Rh, Pd, Pt, Ni, Zn (any others?)

Pd is known to do CTH in both its elemental and 4+ state (PdCl2). 

Ru is able to use IPA as a hydrogen source for CTH of imines.  IPA is oxidized to acetone. The best rate or rxn was found with a solvent mix of benzene or toluene to IPA being 1.7:1.  More polar solvents decreased the rate.  Less polar solvents with a ratio of 24 equivalents of IPA to imine was best.  The rate was further increased by a small amount of water (0.8%), so best rxn mix was found to be IPA:benzene or toluene:H2O = 1:1.7:0.02. Other optimized rxn conditions: a few hours @ 70 °C and 0.3-1 mol % of catalyst.  This gave 93-98% yields.  Ketimines were also found to react faster than aldimines.  (Chem. Eur. J. 2002, 8, No. 13, p.2955)

Formic acid has been used in many papers as the hydrogen source for Pd CTH rxns.  The hydrogens are donated from either the formyl or the carboxyl position on two molecules of formic acid.  Palladium diformate is considered a key intermediate. (Chem. Commun., 1998, p.1935)

Why then is it that so many have discussed Potassium formate and triethylamine formate for the hydrogen source, as well as ammonium formate who's obvious choice is for the imine formation with ammonia? 

In the case of ammonia as the amine source, might one want to adjust the pH to 4.5 with formic acid after adding the ammonium formate since this is supposedly the "magic pH" for imine formation with ammonia?

Although potassium formate and triethylamine formate (formic acid too?) have supposedly been shown to not require as high of Pd catalyst loading (Barium) for decent yields of amine as compared to ammonium formate, what would bee the explanation for this?

Methanol:H2O 9:1 has been shown to bee a good mix for Pd CTH.  Might we try IPA/H2O since it might act as both solvent and hydrogen donor?  Another thought, I believe that using the minimal amount of solvent in this rxn is the key to not needing such a high catalyst loading.  The proof is in the pudding or should I say honey.

More info and thoughts later......

This could beecome an interesting post, but please read Post 382254 (Barium: "A great CTH method", Novel Discourse) this might help us from just copy the old post.
And by the way, I'm much more interested in eksperimental work whitc good results than theoretikal ekplanation's why something might not  ;)

See also Post 531624 (indole_amine: "comprehensive catalytic hydrogenation overview", Methods Discourse)...  ;)

About NH3: "Due to the high reactivity of partially hydrogenated reaction intermediates, imines or Schiff bases, a conventional hydrogenation process leads to a mixture of primary, secondary, and tertiary amines. Promotion by bases of the reaction medium was found to decrease the formation of secondary and tertiary amines, though the primary amine yield was never complete. The promoting effect of NH3 can come from
* a thermodynamic influence on the reaction between primary imine and amine, leading to secondary imine and NH3
* a modification of the electronic properties of the hydrogenating metal; and
* a poisoning of the surface acid sites which would be mainly responsible for the coupling reaction between primary imine and primary amine to secondary amine."(Journal of Catalysis 167, 142-152 (1997)


So, at first it was thought that it would bee best to run a full series of rxns with different catalysts, but then she thought that, really, Pd/C is much cheaper and more common than Rh/Barium or Pt/C for the average chemist so that really isn't the way to go unless Pd/C simply can't do the job excellently, which I don't believe is the case.  Raney nickel was also an option but the experimentor was not familiar with the neccessary catalyst loading or safety issues and also she got the impression that it was inferior anywayz.  Maybe somebody might convince her that Ni would bee worth trying.  Those arguements are welcome...

So, 1st trial:

39 g or .219 moles 'tone
2 equivalents of MeNH4Cl
2 equivalents of triethylamine
4+ equivalents of formic
2 equivalents of NaOH
10 g 10% Pd/C
100 mL MeOH
250 mL IPA
40 mL H2O

She added the 'tone last after the temp had cooled down and let stir.  Then she left to get a drink with some friends and then thought "oh no!  Might the 'tone bee reduced to an alcohol b4 it gets a chance to form the imine?"  But a friend said (in a simplified sense) that Pd would much rather reduce an imine than a 'tone and so she needn't worry.  When she returned an hour or two later, she put the rxn flask and a beaker w/ 300 mL water in a regular microwave, set it on medium, and proceeded to microwave for 1 minute increments ten times.  She did this all because of her excitement after reading that microwave paper mentioned by I-forget-who.  Well, the microwave was definitely not beneficial.  Another ~36 hours until there was no more noticable bubbles (even very small ones) and after work-up, the product oil was a bit on the dark side.  Sunlight was absolutely right, heat is not good for this rxn, and microwaves are not a shorter route to product in this rxn.  Yield 55%.  Oh, and another thing realized is that triethylamine is a bitch to get rid of.  It was used instead of K+ ion because she felt it would help drive imine formation and thus require less methylamine.  Not worth it IMO.

2nd trial:

39 g 'tone
3.4 equivalents of MeNH2 (aq)
1.86 equivalents of MeNH3Cl
5 equivalents of KOH
formic acid until pH=6
325 mL MeOH
160 mL IPA
90 mL water (including aq. MeNH2)
10 g 10% Pd/C (used in the previous rxn, stored wet with water)

Notice both my higher ratio of water to solvent and the use of less overall solvent than Sunlight.  I believe the latter is crucial to using less catalyst.  This time the 'tone was added second, after the aq. MeNH2.  This will not bee done again because she felt it is prolly rough on the 'tone with all the base and acid adding and resultant heat.  The solution was cooled in a bath to a bit below r.t. and then the Pd/C was added and added slowly because the resultant release of CO2 was intense.  The rxn ran for the first 12 hours in a mostly closed hood about 8-10 inches from another reaction that was refluxing in a 150 °C oil bath- dummy.  The flask wasn't all that warm upon checking, but still, it is obvious that heat is not desirable.  Results will bee in soon. 

Improvements:  She thinks a more intelligent way would bee adding everything but 'tone and Pd/C, while cooling  to 0 °C in an ice bath, adding the 'tone, stir for an hour (paranoia), add Pd/C (still in ice bath) and let warm to r.t. over rxn period of ~36-48 hours, basically until absolutely no teeny tiny bubbles are noted.

Is storing Pd/C wet with dH2O the best way???

I, of course, give mad props to Sunlight, for any possible improvement would bee based on his/her work....


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