Subject: Re: CCL:Chiral Selectivity -Reply

From: </G=Matthew/S=Harbowy/OU=LIPTONUS-EC02/O=TMUS.TJL/@LANGATE.gb.sprint.com>
Date: Fri, 12 Jan 1996 13:32:00 -0500

>One of the problems to be aware of is that in real life there will not 
>be 100 % enantioselectivity. Hence there are probably two pathways to 
>product, one going through a higher energy pathway than the other,
>which corresponds to the chiral selectivity observed. This real energy 
>difference only has to be small to give large enantiomeric excesses. 
>Unfortunately,  I feel the accuracy of the calculations involved can be 
>less than the accuracy required. The good minimisers available today 
>would prefer to seek out this global minimum - corresponding to the 
                               ^^^^^^^^^^^^^^
>product in excess, and hide the pathway that gives the other
>enantiomer - hence hiding valuable information.
     
     The vast majority of minimization algorithms *do not* see global 
     minima, but the *nearest* minimum. While small differences in energy 
     do represent large differences in enantioselectivity, this says 
     nothing about the potential energy surface and two 'minima' can have 
     drastically different geometies and can be separated by fairly large 
     energy barriers, allowing good discernment between minima. In 
     addition, it should be noted that enantioselective catalysts may 
     result in different geometries/energies for the transition state of 
     one isomer or the other, so doing an 'optimization' of a 'minimum' is 
     not always the desired calculation. 
     
     True differences in product distributions should only be measurable by 
     dynamic modeling of an ensemble of conformations. One should be able 
     to minimize to both enantiomers (which should be exactly the same 
     energy in vacuo/in the absence of other molecules). One should be able 
     to minimize a catalyst. But the tacking of substrate onto catalyst 
     requires good intermolecular paramaters, and a simple 'minimization' 
     will probably see hunderds of local minima, depending on orientation. 
     It is less that you hide the unfafored enantiomer, but that you have 
     no idea whether you're at the 'true' preferred conformers for either 
     favored *or* unfavored.
     
     In short, such modelling is clearly beyond the limited capabilities of 
     Hyperchem at the present time.
     
>My advice is therefore to try and explain things in terms of steric 
>hindrance to explain the observed chiral selectivity, and apply a little 
>chemical  intuition before trusting the numbers generated. Try to think of 
>how the enantiodifferentiation could occur, and place the reactant in a 
>relavant orientation wrt to the chiral adduct and then perform a 
>minimisation. Do this for both enantiomers. Not an ideal situation I know 
>but it may help.

At that point, you have to ask, why are you doing computer modeling? If you 
are using a massively qualitative model, why go through the expense of 
extended computation if you can make good 'guesses' with chemical 
intuition? At some point, it seems that one is using 'modeling' to generate 
good 'visualizations' and not much 'data'. That seems like a fine use of 
hyperchem, to easily generate 3-d models for visualization, but it would 
seem that any computation one does will be heavily biased by the model. All 
assumptions should be designed to be falsifiable: that is, you can say the 
opposite, and prove it is untrue.

Additionally, what parameters do you use? Molecular Mechanics? At some 
point, you'll need to create a new parameter specific to your model, one 
which you can 'fudge' but have a good justification for doing so. Then 
minimizations can occur; but with 'standard' parameters, I'm not sure how 
well intermolecular and electronic effects are reproduced.

matt