Hello,
Im developing new organocatalyst for asymmetric reactions and in case my catalyst I observe:
a) Lowering cat. loading INCREASE ee of the product
b) Lowering temperature DECREASE ee of the product
Those two seem rather odd, because usually its the other way ie. low temp = better ee and loading seem to have small effect until some borderline loading is reached and after that the ee drops.
Can you suggest some kind of possible explanation or even lit. reference if you know about similar case?
Of coure there MIGHT be some kind of experimental error but I replicated the experiments few times and got from 30%ee at 20% loading to 50% ee at 1% loading.
Thank you
Hello Michal,
Your observations are interesting! I am not an expert in asymmetric catalysis and I suppose several hypotheses could be put forward.
One possibility I can think of would be the (reversible) formation of a dimer of the catalyst, where this dimer would still be catalytically active but less enantioselective:
- At lower loading, the formation of this dimer would be minimised, resulting in higher ee.
- At higher temperature, entropic factors would disfavour the formation of the dimer, also resulting in higher ee.
I do not know if this explanation is correct. There are probably quite many other possibilities. In the first place, is dimerisation of your catalyst plausible (by hydrogen bonding, for instance)?
Regards.
Hello Yvan,,
thank you for your answer.
After I asked here, I did some lit. reserach and found out the possibility of dimerization, however, my catalyst cannot really form hydrogen bonds with itself, since it has no hydrogen bond donors.
It might be dimerizing via some form of interaction with the substrate or reducing agent im using (the reaction is asymmetric reduction of imine). I think I need to figure out some experiments that would suggest what is going on.
Thank you
Michal,
Dimerization hypothesis is indeed one of the possible explanations for the phenomena that you observed. In fact, most of the similar non-linear effects in asymmetric catalysis are explained by association (oligomerization) of substrate, catalyst or both - and most importantly, by the changes in the transition state complex.
Another consideration to keep in mind is that the catalyst does not necessarily have to make a hydrogen bond in order to make a dimer. The transition state may be composed from several molecules of your substrate and catalyst.
My suggestion is to figure out the mechanism of catalysis and see what sort of species are formed at the transition state. Perhaps several possible pathways exist with different transition states, each providing different stereoselectivity. Changes in concentration, temperature and substrate/catalyst ratio may influence the transition state(s) composition and therefore lead to the difference in the end result.
T. H. Al-Noor thank you for the links, the other one (I think to another researchgate question?) is not working for me
Vladimir Khlebnikov Thank you for your insight. Those transition state analysis are mostly done by some DFT calculations?
Michal,
Unfortunately I am not an expert in quantum mechanical modelling and cannot give you really good advise about the calculation methodology; however, before doing any calculations, you need to have some reasonable hypothesis on the composition of your transition state, and this is probably the most difficult part.
Hi Michal,
It may happen that increasing the temperature increases the enantiomeric excess. This is another example for this phenomenon from organocatalysis, unfortunately also not providing an explanation:
Article Organocatalytic Knoevenagel Condensation by Chiral C2-Symmet...
Dimerization may be one possibility, but even if so, it will be very hard to find someone skilled to do quantum mechanical calculations on complicated transition states.
You should also keep some more general concepts in mind before thinking about new reaction pathways (transition states):
As it has been already said: “Changes in concentration, temperature and substrate/catalyst ratio may influence the transition state(s) composition and therefore lead to the difference in the end result.”
To be much more explicit on that:
Normally only one rate determining step (RDS) is considered assuming that all the other steps are fast and the intermediates are in thermodynamical equilibrium. Then, only the energy of the transition state of the RDS is necessary to determine the outcome of a reaction. So, basically everything but the RDS is only treated by thermodynamics. This is called the Curtin-Hammett-Paradigm and would end up predicting an increase of selectivity with decreasing temperature. So, when we- at first - do not want to look for new concurring pathways, something else must be wrong with the Curtin-Hammett-approximation:
You may already have a complicated reaction system with multiple steps that are all about as fast as the others. For example the formation of (or the equilibration between) some chiral intermediates may be only slightly faster than their reaction to the products. The formation step (or their equilibration) and the follow-up reaction of the intermediates may have different activation energies. If upon rising the temperature, one of the steps stops to be rate determining (is more strongly accelerated) it will also stop to determine stereochemistry. Instead another step of the mechanism may get important, that may have an opposite selectivity.
Also changing the catalyst concentration might just cause kinetic effects in your system as the proportions of free catalyst, reactants and intermediates will change.
This article describes the complexity of the situation for proline catalysis of the aldol reaction:
https://pubs.rsc.org/en/content/articlehtml/2016/sc/c6sc01328g
The following article describes a reaction network in which the enantioselectivity is reversed by addition of acid, thereby switching from kinetic to thermodynamic (Curtin-Hammett) reaction-control:
pubs.rsc.org/en/content/articlelanding/2012/SC/c2sc01082h#!divAbstract
So, you may also ask yourself: Can additives help my selectivity by altering kinetics? What happens if I change the ratios of my reactants? Can I thereby check different hypotheses which step is dictating my stereochemistry under each set of conditions?
Regards,
Paul
T affects strongly the ee, it is important to study this effect on the catalytic selectivity of each catalyst, T is a kinetic factor, more reaction is slow more ee is higher. We can generalize knowing that asymmetric catalysis is an adventure as said by scientist of this domain
Catalyst loading can also affect in case the inter-molecular interactions between two or more molecules of catalyst
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