Subject: Reactive sites... .a summary

From: "Michael D. Bartberger" <[email-masked]>
Date: Wed, 14 Jun 1995 20:07:17 -0400 (EDT)

Hello again....

A (rather long, I'm embarrassed to admit) while back, I posted a question 
regarding the idea of correlation of a molecules regioselectivity with 
some calculable quantity, thinking in terms of the suitability of, say, 
the FMO model.  I was met with a number of interesting responses.  

Apologies for the delay, but the original post and the summary of 
responses follows.

Thanks to all who responded.

Regards,

Michael

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-ORIGINAL POST-

>
>Dear Netters:
>
>I would very much appreciate references concerning any methods used to
>correlate a given molecule's regioselectivity in a given reaction with a
>property calculable with ab initio methods.
>
>For example, using a simple FMO approach, we are taught that "attack" by
>a nucleophile on a given substrate are predicted / rationalized by looking
>at the AO coefficients at the LUMO of the substrate and envisioning
>maximum overlap in the transition state, etc etc.  The same goes for
>electrophilic reactions using the HOMO of the substrate; that (in this
>case) the electron density and overlap in a TS is greatest at the site
>with the greatest coefficient.
>
>Now, AO coefficients are easily generated in semiempirical programs,
>where they are generated from a minimal basis, and seem to mimic what one
>would generate from a valence-only, Huckel-type approximation (for example,
>look at the AM1 coefficients for ethylene, allyl radical, etc.)  With ab
>initio methods and extended basis sets, "reading" the coefficients in
>such a manner doesn't seem as plausible, as one obtains coefficients for
>each of the sets of functions used in the basis.
>
>I had asked a question similar to this some time ago; asking whether it is
>possible to obtain a "total" coefficient of a given AO at a certain MO, or
>whether one of the coefficients generated in this way should be "plucked
>out" and used as "the" coefficient.  The question was met with mixed
>sentiments without really ever getting any concrete answer.
>
>(By the way, I'm still very much open for suggestions here.)    :-)
>
>This brings me to the main question.  What is the "best" (if any) method for
>correlating the types of reactivities I've discussed above, whether
>in polar (like discussed above) or in radical reactions, with either
>calculated coefficients, or some other property caclulable by ab initio
>methods.  Of course, total TSs can be calculated and the energetics
>compared, but it would be nice to have some sort of qualitative or
>semi-quantitative rationale for what governs these reactivities.
>
>I will certainly summarize if there is sufficient interest.  I hope what
>I have written makes some sense.    :-)
>
>Thanks very much!
>
>Regards,
>
>Michael

** AND NOW, THE RESPONSES.... **

From: Jack Smith <[email-masked]>
To: "Michael D. Bartberger" <[email-masked]>
Subject: Re: CCL:Prediction of reactive sites

Michael:

  I would suggest you look into the concepts of chemical potential, global
(absolute) hardness/softness, and local softness (Fukui functions) as
defined by Yang and Parr in "Density Functional Theory for Atoms and
Molecules" (Oxford, 1989) and references therein.  Their definitions are
applicable to MO schemes as well, if one "equates" K-S orbitals with HF
MOs.  One can then perform the equivalent of a Mulliken analysis on the
Fukui functions (or local softness) to get "atomic" contributions (similar
to partial charges) - or even "bond" contributions.  I'd also look into how
this relates to Pearson's HSAB (Hard-Soft Acid-Base) Principle. 
Nalewajski's work is also worth following.  Fukui's book "The Theory of
Orientation and Stereoselection" (Springer-Verlag, 1975) is also a must
read.

- Jack 

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From: Jan Jensen <[email-masked]>
To: "Michael D. Bartberger" <[email-masked]>
Subject: Re: CCL:Prediction of reactive sites

Dear Michael Bartberger:

	We have had some luck using molecular electrostatic potential
maps to predict and explain regioselectivity of Diels-Alder reactions.  The
references are:

George A. Kraus, Jun Li, Mark S. Gordon, and Jan H. Jensen, ÒRegiocontrol
by Remote Substituents.  An Enantioselective Total Synthesis of Frenolicin B 
via a Highly Regioselective Diels-Alder ReactionÓ, Journal of the American 
Chemical Society, 1993, volume 115, pages 5859-5860.

George A. Kraus, Jun Li, Mark S. Gordon, and Jan H. Jensen, ÒRegiocontrol 
by Remote Substituents.  A Direct Total Synthesis of Racemic HongconinÓ, 
Journal of Organic Chemistry, 1994, volume 59, pages 2219-2222.

George A. Kraus, Jun Li, Mark S. Gordon, and Jan H. Jensen, ÒDirect Total
Syntheses of Frenolicin B and Kalafungin via Highly Regioselective
Diels-Alder ReactionsÓ, Journal of Organic Chemistry, in press.

These papers also contain references to similar work by Warren Hehre.

		Best regards,
				Jan Jensen
				Dept. of Chemistry
				Iowa State University

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From: [email-masked]
To: "Michael D. Bartberger" <[email-masked]>
Subject: Re: CCL:Prediction of reactive sites

Michael,
        I've had pretty fair success in predicting the regioselectivity of
nucleophilic additions to quinones by using LUMO coefficients calculated at
the 3-21G* level.  Since this is, of course, a split valence basis set, I
use the square root of the sum of the squares of the coefficients at a given
carbon.  In most cases, this is simply two 2p coefficients.
        I'' be very interested to see your summary - if anyone else responds.
        Regards,
                Ray

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From: "Robert K. Szilagyi" <[email-masked]>
To: "Michael D. Bartberger" <[email-masked]>
Subject: Re: CCL:Prediction of reactive sites

Dear Michael D. Bartberger,

	I know my answer is a little bit far from your original posting but we
have some remarkable results on description of regioselective olefin metathesis
and polymerisation. The main difference is the method used.
	Basicaly, we are using the molecular mechanical method (METMOD1) force
field. The ab-initio calculations performed only when no experimental data were
available. Please find the full publication list in our WWW server, under
research activity.

		I hope this can help you,

						Rob

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From: [email-masked]
To: [email-masked]

          Michael,
          You may want to look at the book "Experiments in Computational
          Organic Chemistry" by W.J. Hehre et al.  It is intended to be used
          with the Spartan program but can be used with others.  I believe
          you can get it from Wavefunction, Inc.
  
          Anthony D. DeBellis
          Ciba Corp.
          [email-masked]

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From: John Liebeschuetz <[email-masked]>
To: [email-masked]
Subject: Regioselectivity

   Your question is one that exercised me greatly some years ago when
I was looking at regioselectivity of addition at C=C bomds. Basically,
I concluded there is there is no `best' method. You can and often have
to calculate different types of properties to explain different sets of 
experimental data. I assume the reactions you are dealing with are
kinetically controlled.  For many `hard' reagents it is appropriate to 
determine  the molecular electrostatic potential field and use that to
rationalise rgioselectivity. For `soft' reagents some sort of FMO 
approach often works. We got a lot of mileage out of looking at what might
be termed a `perturbed functional group' approach. The molecular orbitals
involved in a given reaction to a functional group are often easily
identifiable. Although concentrated around the functional group, these will
in general have large contributions from adjacent filled localised sigma/pi
orbitals and the extension of the MO over these orbitals  
can often be qualitatively used to explain the stereoselectivity of reaction,
sometimes in suprising ways. For instance we were able to convincingly establish
how the interaction of a beta C-O or C-C bond influenced stereo and regioselectivity
of addition to a double bond.

   The tool that worked in our case was to do semi empirical/ ab initio calculations,
view the results graphically, and then interpret them qualitatively in a manner
intuitive to an organic chemist. This approach is one championed by such as
Warren Hehre and Leo Paquette and they have both published a number of
elegant studies.

                     Regards

                             John Liebeschuetz     Proteus Molecular Design Ltd

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From: Steve Bowlus <[email-masked]>
To: "[email-masked]"@SNDZEH.dnet.sandoz.com
Cc: [email-masked]
Subject: reactivity

I would be interested to see a summary of your responses.

My $.02:  In addition to HOMO/LUMO coefficients (broken down at whatever 
level) is the ESP a (good?) index of reactivity?  This seems to be quite 
generally computable, and certainly there are examples of this being used 
in some cases.  I don't know whether the use is general or, if not, it 
would be applicable to your problems.

sb

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From: "A.V.Sokolov" <[email-masked]>
To: [email-masked]
Subject: CCL:TS compared with PMO; Prediction of reactive sites.

Hullo, chemists!

I have some comments on the topic.

To study validity of PMO calculations (pi-aproximation) I compared
its results with directly calculated activation energies,
NOT WITH EXPERIMENTAL DATA.
Using MNDO I got the following radical reactions TS (and so activation
energies):

CH2=CXY + HOO, CH3, CH3O, CCl3, CF3 and some substituted peroxy and
                                                         alkyl radicals,
where X is H, CH3, Cl, -COOCH3, -O-COCH3 or C6H5.

Having compared these act. energies with "charge transfer" energies of
PMO methods I dare state now that Frontier MO approximation is good
for nothing (in my case it fails completely).

So, FIRST: using PMO use full summing over set of MOs (or subset,
in pi-approximation).
Then, if you don't want to deal with a great deal of MOs, either:

1. project occupied shell on AOs of your reactive center and brood
   upon the coefficients and H{_i_i} of localized MO (when center
   is non-conjugated projection will give MO nearly 99% localized on it)
or
2. I can propose an additive scheme of PMO sums evaluation.
  (you need to calculate some sums beforehand to parametrizate your
  compounds. Each reagent gets 2 parameters, you can use them instead
  of FMO coefficients). I've tested it on my set of reactions.

BUT: all said doesn't mean that you will correctly predict results of
     direct calculations (in my case there were also strong influence
     of steric effect).

________________________________

Bye for now. Respectfully yours,
A. Sokolov,
Dept. of Phys.Chem., Yaroslavl Polytech. Inst.,  Russia
"""""""""""""""""""""""""""""""""""""""""""""""""""""""

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