Subject: Summary on Prediction of Chemical Reactions

From: Bill Laidig <[email-masked]>
Date: Thu, 06 Dec 2001 08:06:12 -0500

All,

I sent the following message to the list a few days ago:

: I have a colleague who needs software for predicting the probability
of a aqueous
: chemical reaction occurring between a variety of reactive chemicals at
around
: pH7.  Specificly,
:   1)nucleophilic substitiution of halogenated compounds
:   2) Schiff base formaiton
:   3) addition-elimination of acids, esters, amides
:   4) nucleophilic adition of aldehydes and ketones
:   5) Michael addition of alpha,beta unsaturated compounds
:   6) addition by ring cleavage of epoxides
:   7) electrophilic substitiution of diazonium salts
:I am not up on current synthetic prediction program and would
appreciate am
:pointers to current software, recommendations, etc.  I will summarize
responsews
:to the list

and have received a number of helpful responses.  First, I must
apologize for not being entirely clear in my question. I more or less
resent the message my non-computational chemist colleague wrote.  What
he is actually looking for is a fast method, probably expert-system
basedthat can estimate the likelyhood of whether any of reaction(s) of
the type above can occur.  The program need not be quantitative and he
is exploring using non-QM approaches (simple QM approaches have been
tried in the past).

To summarize the responses so far, they have fallen into a couple
categories:

1. Recommended expert system programs: Several responses suggested CAMEO
developed  by Prof. Jorgenson's group at Yale.  There is also a new
Windows version under development at CambrideSoft.  (Anyone know of
other programs that use a similar approach?)

2. Several responses pointed out the difficulty in accurately predicting
chemical reactions and their rates, etc. and stressed the need for
rigorous quantum modeling.  The fact that this is an active research
frontier and not a solved problem was stressed as well. (thanks for your
responses here - this may give my experimental collegue some perspective
into the dificulty of accurately doing what he proposes.)

Here are the specific responses:

***********************************************************************
Whoa!  Predicting reactivity is one hell of a problem especially if you
want
to cover such a wide range of systems.  There are many programs that can

help you to find reasonable structures for transition states, and more
or
less plausible activation energies.  But to quantitatively predict
relative
rates simply from the identities of reactant pairs is not trivial!  I
don't
think anyone can do it in a meaningful way.

We are working on a "simple" problem related to case 1 below -
nucleophilic
substitution of primary alkyl chlorides.  Believe me, it is consuming
large
amounts of high powered computer time, and we still haven't convinced
referees that we are right in our explanation of the relative
reactivities
(although I am sure that we are ;-) )!  You are not going to find this
sort
of thing "off the shelf".

Dr. Philip G. Hultin
Associate Department Head and
Associate Professor of Chemistry
University of Manitoba
Winnipeg, MB, Canada R3T 2N2
(vox) 204-474-9814
(fax) 204-474-7608
mailto:[email-masked]
http://www.umanitoba.ca/chemistry/

***********************************************************************
> From [email-masked]:

You may wish to check the current status of the "CAMEO" program system,
as
developed by the Jorgensen group at Yale.    Perhaps this might be
helpful
to you.

Best regards,
-Mike

***********************************************************************
I remember a program called Cameo (WL Jorgensen et al) that predicted
the
products of a reaction mixture.  I think it used rho-and-sigma-type
substituent effects for calculation of reaction rates and equilibria
rather
than any quantum calculations.  There is still a home page for Cameo at
http://zarbi.chem.yale.edu/products/cameo/ if you're interested.

I don't know what's been written since then (and probably I only know
about
Cameo because I used to know some of the people that worked on the
project).

--David Shobe
Süd-Chemie Inc.
phone (502) 634-7409
fax     (502) 634-7724
email  [email-masked]

Don't bother flaming me: I'm behind a firewall.

***********************************************************************
Also from David Shode:

Just by coincincidence I got this notice from CambridgeSoft today:

    ------------------------
3.  Cameo Comes to Windows
    ------------------------

One of the most useful applications of artificial intelligence to
organic
chemistry is to design syntheses of big and hairy molecules. Perhaps the

next most useful is to identify and rectify the weak steps in a proposed

scheme before any reagents are committed to flasks. To this end, the
CAMEO
program is used by a variety of chemical and pharmaceutical companies to

shed light on their syntheses. Given starting materials and reaction
conditions, CAMEO predicts the various reaction products, accompanied by

comments explaining factors affecting their yield. Hitherto it has been
available on VAX/VMS, Unix (Sun, SGI and AIX), and the Macintosh.
CambridgeSoft is now porting the application to Windows using Excel as
part
of the front (i.e. display) end.
Read more about this exciting product development at:
http://chemnews.cambridgesoft.com/art.cfm?S=160
or email [email-masked] for more information

***********************************************************************
Michael Bartberger and others have suggested CAMEO as a viable way of
predicting reactivity.

I have not seen CAMEO recently, and I certainly do not intend to "diss"
it
or its creators.  As I understand it, CAMEO is a sort of "expert system"

based on empirical rules.  This may well be the sort of prediction that
William Laidig was seeking, and there is nothing wrong with that.
Perhaps I
understood the question about "predicting reactivity" in a different
context
than was meant.

An "expert system" is only as good as its rules when it comes to
addressing
chemical systems outside the range of structures that went into its
parameterization.  Unfortunately, many of the "rules and
rationalizations"
that we learned as undergraduates and that are still widely used by
research
chemists are simply incorrect at a fundamental level, particularly as
they
apply to reactions in solution.  While they are in many cases
qualitatively
successful, the fundamental flaws in their logic mean that they will
fail
for some (unknown) set of situations.

If you don't agree with this assertion about "rules and
rationalizations",
you should consider the usual explanation organic chemists use for the
differing acidities of organic acids.  If it was true that acidities
could
be correctly understood in terms of delocalization of charge in the
conjugate base (by inductive withdrawal or by resonance), then a)
gas-phase
acidities and solution phase acidities would show parallel trends (they
do
not in general) and b)the trend would be reflected in the enthalpies of
ionization in solution (it is not, in general).  The data on this have
been
available for decades and can be found in standard (older) physical
organic
textbooks as well as compendia of physical data.

So, to return to my argument about reactivity, if we base our analysis
of an
unknown reaction on rationalizations that are based on questionable (or
false) premises, are we actually able to predict its behavior?  Or are
we
simply lucky?  Speaking as an experimental organic chemist who has
turned
recently to computational chemistry to find answers to nagging questions

that conventional wisdom (at least among organic chemists!) has not
adequately addressed, I still maintain that accurate prediction of
reactivity remains a highly challenging problem that is not really dealt

with by off-the-shelf solutions.

Dr. Philip G. Hultin
Associate Department Head and
Associate Professor of Chemistry
University of Manitoba
Winnipeg, MB, Canada R3T 2N2
(vox) 204-474-9814
(fax) 204-474-7608
mailto:[email-masked]
http://www.umanitoba.ca/chemistry/

***********************************************************************
Hi everyone:

It seems there are lots of people getting interested in predicting
chemical reactivity. However, half of my thesis work may challenge any
current program or method which declaims the ability to predict chemical

reactivity.

Maybe most of you are talking about different level of quality about
"prediction" from mine, but here are some of my comments about this
topic:

Vibrational excitation (for suitable mode coupling to the reaction
channel) will push a reaction from activated behavior(Arrhenius like:
an activation energy needed) to activationless behavior (no any barrier,

like H+H, O+H2, or many reactions between an ion and a molecule). And
the
enhancement of reactivity is really huge, thinking of the exponential
term!

Such an effect can be accomplished by continuous vibrational excitation:

the potential between reactants will switch from repulsive to totally
attractive (like K+ + Cl-  ---> form an ionic bond). How much excitation

is needed? Usually the energy of the system (vib-excited) higher
than the barrier (ground state reaction) is a crucial condition, but
it's
dependent on the vib-mode, and some steric effect.

Our research on H+H2O(OH local mode excited)--> H2+OH is the first
example, and results for more systems are going to come out soon...

This has seldomly been realized because it's really tough to get an
accurate potential energy surface(fit from ab initio results) for
4-atomic
reaction, and previous surfaces are not accurate enough to describe
vib-excited reactions. If there is more interest, check (1)Faraday
Discussion, 1999, 113,181 and (2)J. Chem. Phys. 2000, 113, 3150... To
keep
an eye on the progress of this direction, check my advisor(G. C.
Schatz)'s
publications in the future...

What all of these tell us? Previous theoretical results on
vib-excitation
reaction dynamics, or high temperature rate constants(contribution from
the channel of vib-excited state is very big) may need to be corrected.
And we need to work harder to get the "predicting the reactivity"...
It's very hard for H+H2O, then it's obviously harder for most reactions
you are interested in. One easy solution is to decrease the level of
"prediction", and be careful of vib-excited effect or results at high
temperature.

Hope my message may give you another kind of taste on this topic.

Any comments, please send to me one week later since my defence is
coming
very soon, otherwise I can not reply to you in time. Thanks.

Guosheng
---------------------------------------------
Guosheng Wu          [email-masked]
Ph: (847)491-7189    fax: (847)491-7713
Department of Chemistry, Northwestern Univ.
2145 Sheridan Road, Evanston, IL, 60208-3113
---------------------------------------------

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