The Ion-Dipole Effect is a Force Thesis by David Alan Stauffer In

300 Pages·2012·7 MB·English

The Ion-Dipole Effect is a Force
for Molecular Recognition and Biomimetic Catalysis
Thesis by
David Alan Stauffer
In Partial Fulfillment of the Requirements
for the Degree of
Doctor of Philosophy
California Institute of Technology
Pasadena, California
1989
(Submitted May 25, 1989)
ii
© 1989
David Alan Stauffer
All rights reserved
111
Two Moms
Too Dads
Tu Holmes
To those who Bum
iv
Acknowledgement
My experiences at Caltech have been enriched by many special
friends. I wish I had time and space to put into words my appreciation for
your support and affection. Here is a flavor of what I take with me. ...
I thank Dennis Dougherty for his encouragement, enthusiasm,
support, and advice about science and my career objectives. His patience
and tolerance during difficult times are most appreciated. His relentless,
often subtle, advocacy of scientific truth continues to grow with me. (There
is one word to describe Dennis that cannot be found in this thesis; those who
know him well know that this word is not unremarkable.)
I have been fortunate to stand upon the shoulders of two brilliant
scientists. Drs. Michael Petti and Timothy Shepodd laid the foundation and
put up most of the structural framework for the evolving work described in
this thesis. I am grateful for Tim's "Ah!" contagious enthusiasm for our
project in particular and for life in general; Mike's brainstorming ability
during "rhea sessions" and "work with similar compounds" are part of the
growing legend of The Babe. (l apologize for the exaggerated images I've
helped to create for these two gentleman; however, I am both confident and
fearful that future generations will make "Spud" filled with schmaltz.)
I am also grateful to Rich Barrans for his invaluable assistance with
data reduction. "Mr. Metabolism's" computational and programming
appetite can devour all the experimental results we feed him. I am happy
to "pass the torch" into the increasingly capable hands of Rich, Pat, Alison,
Laura, and Liz.
v
On the hardware side of things, I thank Dave Wheeler and Dom
McGrath for helpful discussions and consideration for my countless time
consuming nmr experiments.
I had 'lots of fun apart from the lab, too. Summer smog was much
easier to digest with the comical athleticism of the Chicken Boy Mutant
Killer Pig Potato Smeggies. Whether it was football, softball, or basketball,
I'm happy that Frank Coms was a late-afternoon co-conspirator. (I
sometimes wonder if Dennis ever went outside when we weren't
conspiring?) Thanks to Gary Snyder and his U nc1e Roy for teaching Brian
Masek and myself how to sail without a keel. Thanks to Josh The Boy and
Dave Mack for letting me hack with them Brookside. Also thanks to
Rakesh Jain, and expecially David Kaisaki, for helping me survive the Last
Road Trip of Our Lives (yeah, right!).
I warmly thank Ernie Harrison and Phil DeShong for spar~ng my
interest in chemistry a long time ago in a galaxy called Penn State.
I also thank the NSF for a Predoctoral Fellowship and BioDesign and
Caltech Housing for financial assistance.
Finally, I acknowledge the incredible love and support of my mother,
without whom I could not have come so far, and still have so far to go ....
vi
Random thoughts I remember:
A nanogram is a ton of iron
This is what happens when God gives you infinite computer time--you stop
thinking
This is an important point
It's kind of subtle
And it really doesn't matter
I have worked with similar compounds
Tuesday
Ah!!!
Speed bah
Please don't be a lazy boo-boo head
Never mind
This may be a stupid question, but. ..
12:13
Nothing ever lasts
I know anudder X word: Xcape
Get back to work!
8040-2
Oh, definitely!!
Myahm!
Where's the beef?!
Brunie and ChlOe ...
Didn't anyone ever tell you. .. ?
The permutational approach to dynamic stereochemistry
vii
Syncomposition
Well, how did I get here?
One step
And down the hall we fall ...
To catch my breath. ..
Said the woman give him
Courage and
Strength
In the long run. ..
One pebble snatched
The fortune hunt continues
I'll be back
ibidibidi
viii
"I think that enzymes are molecules that are complementary in
structure to the activated complexes of the reactions. they catalyse, that is, to
the molecular configuration that is intermdeiate between the reacting
substances and the products of reaction for these catalysed processes. The
attraction of the enzyme moleucle for the activated complex would thus lead
to a decrease in its energy, and hence to a decrease in the energy of
activation of the reaction, and to an increase in the rate of the reaction.
Although convincing evidence is not yet at hand, I believe that it will be
found that the highly specific powers of self-duplication shown by genes and
viruses are due to the same intermolecular forces, dependent upon atomic
contact, and the same processes of replica formation through
complementariness in structure as are operative in the formation of
antibodies under the influence of an antigen. I believe that it is molecular
size and shape, on the atomic scale, that are of primary importance in
these phenomena, rather than the ordinary chemical properties of the
substances, involving their power of entering into reactions in which
ordinary chemical bonds are broken and formed."
Linus Pauling, 1948
ix
Abstracts
Chapterl
In aqueous and organic media, electron-rich synthetic macro cycles
serve as hosts for positively-charged guests. Binding studies in different
solvents have quantified hydrophobic, donor/acceptor, and ion-dipole
interactions as forces for molecular recognition. We have found clear
evidence for substantial host-guest donor/acceptor x-stacking interactions
(ca. 1.5 kcallmol) in aqueous media only. The ion-dipole effect is an
appreciable driving force (worth up to 3.5 kcallmol) for molecular
recognition in both aqueous and organic media.
Cbapter2
Variable-t~mperature binding studies were performed to assess
enthalpic (dHO) and entropic (dSO) contributions to free energies (dGO) of
host-guest complexation. The van't Hoff plots (RlnKa vs T-l), which are
clearly non-linear, have revealed significant values for the heat capacities
(dCp) of complexation in both organic and aqueous media. The dCp values
reflect a phenomenon generally overlooked in molecular recognition
studies: both dHO and dSo are strongly temperature-dependent.
Hydrophobic, donor/acceptor, and ion-dipole interactions are
tentatively partitioned into dHO and dSo contributions at 298K. "Classic"
hydrophobic binding is characterized by a large, positive dSo and a near
zero dHO term. Strong donor/acceptor x-stacking interactions are typically
balanced between large, favorable enthalpic and unfavorable entropic
contributions. The ion-dipole effect is primarily an enthalpically-driven
binding force.
x
Chapter 3
Electron-rich synthetic macrocyclic host 1 accelerates a class of
alkylation reactions in aqueous media. Specifically, host 1 catalyzes the
reactions of pyridine-type nucleophiles with alkyl halides in an aqueous
pD-9 borate buffer. The rate constants of catalyzed versus uncatalyzed
reactions and the binding affinities for substrates and products demand
that host 1 binds transition states more tightly than ground states. This
extension of molecular recognition through ion-dipole interactions to
biomimetic catalysis provides compelling evidence for transition-state
stabilization via favorable dipole-dipole interactions in aqueous media.
Chapter 4
A new class of high-symmetry, water soluble, hydrophobic binding
sites is described that feature 1,5-substituents on a rigid ethenoanthracene
(DEA) framework. These new 1,5-hosts are compared to the analogous 2,6-
hosts described in the Ph.D. theses of Petti and Shepodd. Because of more
favorable solvation (by water) of amide linker groups that line the cavity, the
1,5-hosts exhibit significantly reduced affinities for all guests considered:
only positively-charged guests are bound to any appreciable extent.
While the binding sites designed herein are composed of
topographically well-defined, rigid units to give a chiral host (with a
"greater sense of twist"), the disposition of the 1,5-substituents allows the
collapse of hosts into a "bowl" conformation. We therefore suggest that the
more successful high-symmetry, hydrophobic binding sites are to be found
with 2,6-DEA-constructed hosts rather than with 1,5-DEA-constructed
hosts.