Subject: Summary of Steric Effect Calculation

From: "Robert K. Szilagyi" <[email-masked]>
Date: Tue, 20 Sep 1994 13:24:31 -0600

Dear Comp.-Chem.-List,

	a couple of weeks ago I posted a message about calculation and/or
QUANTITATIVE prediction of steric effect. I received many valuable comments
and hints concerning this topic. Thanks for everyone, who made any
contribution.
	Here comes the summary:

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[email-masked] | Robert Topper
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You may be interested in a series of articles by D.F. DeTar
in recent issues of the Journal of Organic Chemistry.

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>From [email-masked] | Kent Stewart
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For information regarding steric effects within organic compounds, here
are two refereces:
1. "Substituent Constants for Correlation Analysis in Chemistry and Biology"
   Hansch, C. and Leo, A., book published by John Wiley,  See chapter 2.

2. White, D. et al., J. Compu. Chem. 14, 1042-1049 (1993)

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>From [email-masked] | Jack
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   The most common measure of bulkiness I've seen is the Tolman Cone Angle,
primarily used for symmetric phosphines, but quite adaptable to other
(including non-symmetric) ligands.

   I've observed an interesting correlation, however, between the cone
angle (as well as other measures of size) and the ratio of volume to
surface area (V/SA) as determined from isodensity surfaces (roughly the vDW
surface).  For a sphere this would just be related to the radius, but for
conical shapes it varies with both cone angle and extent.  What I like
about V/SA is that it's independent of a reference point and removes the
arbitrariness about contact points (no need to "fold" everything back into
a cone shape).  It's also relatively insensitive to torsional degrees of
freedom.  It's not clear, though, whether "extent" is relevant as cone
angle. Perhaps some normalization scheme (based on principle axes/moments,
e.g.) could be used to remove (or deemphasize) the "extendedness".

[By the way, if you run across anything published along these lines, I'd
appreciate the reference.  In any case, if you (or anyone else reading
this) find V/SA to be a useful measure of steric size/bulk, I'd appreciate
a note.]

  Ted Brown (at Northwestern, I believe) does a MM-based substrate docking
"experiment" to quantify the steric effects (repulsive force) of ligands
(bound to a metal carbonyl complex, if I recall correctly).

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[email-masked] | Wayne E. Steinmetz
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May I suggest CoMFA (Comparative Molecular Field Analysis) as a vehicle
to correlate reactivity with steric effects.  The technique is described in
detail in H. Kubinyi, Ed., 3D QSAR in Drug Design, ESCOM, Leiden, 1993.
CoMFA was originally developed by medicinal chemists but can also be applied
to problems from organic and inorganic chemistry.  In applying the technique,
one completes the following steps:
1) calculate structures and partial charges via MOPAC or AMPAC of the
   molecules in the dataset
2) superimpose the molecules in the dataset,
3) imbed the superimposed molecules in a lattice with a lattice spacing of
   1 to 2 Angstrom,
4) calculate at each lattice position the interaction energy of a probe
   molecule with each molecule in the dataset,
5) correlate the chemical property with the interaction energies using
   the method of partial least squares.

	The method was developed by Richard Cramer of Tripos Associates and
is part of the Sybyl software package.
	I recently submitted an article to Inorganic Chemistry in which I
showed that CoMFA can handle the steric effects of ligands in a range of
inorganic reactions.

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[email-masked] | George
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A good starting point would probably be Taft's steric parameters (Es).
These are derived directly from experimental rate data (acid and base
hydrolysis of carboxylate esters) and do not therefore depend on rather
poorly defined notions of van der Waals radii, surfaces, volues, etc.
You can find compilations of Es parameters in virtually any book on
physical organic chemistry. For a particularly complete compilation see
for example: "A critical compilation of substituent constants" by
Otto Exner in: "Correlation Analysis in Chemistry", N.B. Chapman and J.
Shorter, Plenum, Press, 1978, pp. 439-540.

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[email-masked] |
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Look up Marvin Charton's work.  Some old references I have:
(1)	Charton, M. "The Upsilon Steric Parameter -- Definition and
	Determination," In Topics in Current Chemistry; (Vol.114 of ;
	M. Charton and I. Motoc, Ed.; Springer-Verlag: Berlin, 1983; pp 57-91.
(2)	Charton, M. "Volume and Bulk Parameters," In Topics in Current
	Chemistry; (Vol.114 of Topics in Current Chemistry) ;
	M. Charton and I. Motoc, Ed.; (F. L. Bosche, Series Ed.)
	Springer-Verlag: Berlin, 1983; pp 107-118.
(3)	Charton, M.; Motoc, I., Ed.; Steric Effects in Drug Design;
	Springer-Verlag: Berlin, 1983; Vol. 114.

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[email-masked] | Dave
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There are two recent reviews in this area:
White, D and Coville, N.J. Advances in Organometallic Chemistry, 36 (1994) 95
Brown, T.L. and Lee, K.J. Coord. Chem. Rev. 128 (1993) 89.

Basically there are three different methodologies to choose from:
cone angles (Tolman, chem. rev. 77 (1977) 313), solid angles
(White et al., J. Comput. Chem. 14 (1993) 1042) and ligand repulsive
energies (Brown, Inorg. Chem. 31 (1992) 1286).  There are some
other measures used in Organic chemistry and they are tabulated and
referenced in the Advances in Organomet. Chem review.  Ted Brown
and myself are going to be generating ligand repulsive energy values
for alkyl and other organic based groups in the near future.  If
you have specific values which you require please send them to me
and I shall include them in the lsit of values to be generated.

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[email-masked] |
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I'm studing the steric effects of ammine ligands and will be very interested
in responses you get.
There were few studies involving the quantification of steric ligand factors.
Earlier Tolman [1] introduced CONE ANGLE values calculated with the use of
simple CPK models for the comparison of the steric properties of monodentate
tertiary phosphine ligands.
Recently, Brown [2] utilised LIGAND REPULSIVE ENERGY as the measure of
ligand steric features based on molecular mechanics calculations.

1. C.A. Tolman, Chemical Reviews, 77 (1977) 313.
2. T.L.Brown, Inorg. Chem., 31 (1992) 1286.

************************* END OF THE SUMMARY ****************************

	If I receive further responses I will update the previous
summary, of course.

		Cheers,

				Rob

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Robert K. Szilagyi                     University of Veszprem   METMOD FF
research fellow                        Dept. Org. Chem.            L1
Email: [email-masked]          Veszprem, H-8201         L2 |   R1
       [email-masked]      Egyetem u. 10              >W=C<
Phone: +36-(88)-422022/156             P.O.Box 158              L3 |   R2
FAX:   +36-(88)-426016                 HUNGARY                     L4
 
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