Selective Fluorination in Organic and Bioorganic Chemistry

215 Pages·1991·3.55 MB·English

by  John T. Welch (Eds.)

ACS SYMPOSIUM SERIES 456
Selective Fluorination in Organic
and Bioorganic Chemistry
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456.f John T. Welch, EDITOR
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91- State University of New York at Albany
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br Developed from a symposium sponsored
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n at the 199th National Meeting
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April 22-27, 1990
American Chemical Society, Washington, DC 1991
Library of Congress Cataloging-in-Publication Data
Selective fluorination in organic and bioorganic chemistry / John T.
Welch, editor.
p. cm.—(ACS symposium series; 456)
"Developed from a symposium sponsored by the Division of Fluorine
Chemistry at the 199th National Meeting of the American Chemical
Society, Boston, Massachusetts, April 22-27, 1990."
Includes bibliographical references and indexes.
1 ISBN 0-8412-1948-6
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56.f Co1n.g rFelsusoersi.n ation—Congresses. 2. Organofluorine compounds-
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1- I. Welch, John T. II. American Chemical Society. Division of
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9 Fluorine Chemistry. III. American Chemical Society. Meeting (199th:
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k- 1990: Boston, Mass.) IV. Series.
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2 QD281.F55S45 1991
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1 547'.02-dc20 90-26633
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19 The paper used in this publication meets the minimum requirements of American National
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bru Copyright © 1991
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Foreword
THE ACS SYMPOSIUM SERIES was founded in 1974 to provide
a medium for publishing symposia quickly in book form. The
format of the Series parallels that of the continuing ADVANCES
IN CHEMISTRY SERIES except that, in order to save time, the
papers are not typeset, but are reproduced as they are submit
01 ted by the authors in camera-ready form. Papers are reviewed
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5 Advisory Board and are selected to maintain the integrity of the
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1- symposia. Both reviews and reports of research are acceptable,
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9 because symposia may embrace both types of presentation.
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bk- However, verbatim reproductions of previously published
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Preface
INTEREST IN ORGANOFLUORINE CHEMISTRY IS GROWING at a rapid
pace. Fluorine as a substituent can significantly affect the properties of
molecular systems. Its high electronegativity and small atomic volume
have been used to probe reactivity—especially that of biologically impor­
tant molecules.
1
0 This book brings together works of authors who are active in theoreti­
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6.pr cal studies of organofluorine compounds, engaged in the development of
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4 new preparative methods and exploring the utility of specifically fluori-
0
91- nated compounds in biological systems. The volume is interdisciplinary in
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k-1 coverage and provides a forum for the exchange of information among
1/b theoreticians, synthetic chemists, biochemists, medicinal chemists, and
2
0 bioorganic chemists studying and using fluorine-containing compounds.
1
10. Readers with specialized interests will find new opportunities in their
oi: specific areas, as well as the latest progress in other areas.
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1 | In addition to reactivity and theoretical aspects, this volume provides
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19 significant coverage of biological applications. The contributions from
22, industry, academia, and government laboratories emphasize the fact that
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ar research on organofluorine compounds is far from an ivory tower
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br endeavor and, in fact, that selective fluorination does provide a useful
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e: alternative for the study of biological problems.
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on Acknowledgments
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ubli The preparation of this volume would not have been possible without the
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willing cooperation of both the contributors and the reviewers. I would
like to thank Professor H.-J. Hansen of the Organisch-Chemisches-
Institut of the Universitat Zurich for his hospitality and support during
the sabbatical leave where a large part of the editorial obligations associ­
ated with this volume were completed. It is also a pleasure to thank Pro­
fessor D. Seebach for the encouragement he gave me during my sabbati­
cal stay at the Laboratorium fur Organische Chemie of the ΕΤΗ Zurich.
The symposium from which this book was derived was organized during
vii
the time I spent there. Finally, it would not have been possible for the
symposium to have been held at all without the financial support of the
Division of Fluorine Chemistry of the American Chemical Society and the
Petroleum Research Fund of the American Chemical Society.
JOHN T. WELCH
State University of New York
Albany, NY 12222
November 5, 1990
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viii
Chapter 1
The Effects of Selective Fluorination
on Reactivity in Organic and Bioorganic
Chemistry
John T. Welch
Department of Chemistry, State University of New York,
Albany, NY 12222
1
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04 The influence of fluorine on the physical, chemical and biological
1- properties of molecules is described. A discussion of the effect
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19 of fluorination on bond lengths and bond strengths is presented
k- in the course of an analysis of the steric demand of fluorinated
b
1/ substituents. These steric effects as well as electronic
2
10 interactions are illustrated in a discussion of fluorinated vitamin
10. D and prostaglandin and thromboxane analogs.
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91 | d fluorinTahtee dc ucormrepnotu lnedvse li s oinfd iincateterdes bt yi tnh et hinec rperaespinagr antuiomnb eorf osfe pleucbtilivcealtyio ns
9
1 and presentations in this area (7). It has been known for some time that
22, fluorine can have profound and often unexpected effects on activity.
ary Selective fluorination has been an extremely effective synthetic tool for
u modifying and probing reactivity. Replacement of hydrogen or hydroxyl by
br
e fluorine in a biologically important molecule often yields an analog of that
F
e: substance with improved selectivity or a modified spectrum of activity (2-27).
at A number of very valuable monographs and other general reviews are
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n available for guiding chemists in the organic chemistry of fluorine (22-25).
o
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blic Historical Perspective
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Although hydrogen fluoridew as discovered by Scheele in 1771 (23),
molecular fluorine itself wasn't prepared until 1886 by Moissan (29).
Organofluorine chemistry really began to unfold with the work of S warts
(30) on the preparation of fluorinated materials by metal fluoride promoted
halogen-fluoride exchange reactions. The commercial utility of
organofluorine compounds as refrigerants, developed by Midgley and Henne
(31) , further accelerated the growth of the field by virtue of the economic
incentives involved. Wartime requirements stimulated research on thermally
stable and chemically resistant materials which led to an increased interest in
highly fluorinated and perfluorinated substances. Many of the exciting
developments of this period have been reviewed elsewhere (32-34). A
synopsis of the growth of organofluorine chemistry could not be complete
without recognition of the enormous impact of electrochemical fluorination
techniques. The electrolysis of organic compounds in anhydrous hydrogen
fluoride was discovered and developed by Simons (35-39).
0097-6156/91/0456-0001$06.00A)
© 1991 American Chemical Society
2 SELECTIVE FLUORINATION IN ORGANIC AND BIOORGANIC CHEMISTRY
It was the pioneering work of Fried on preparation of 9a-fluoro-
hydrocortisone acetate (1) (40) that led to the first significant successful
application of selective fluorination for the purpose of modifying biological
activity. This publication marked the beginning of a new era when medicinal
chemists and biochemists routinely introduced fluorine as a substituent to
modify biological activity.
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56. 9a-Fluoro-hyclrocortisone acetate
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1/ Structure and Bonding
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0. Fluorine is the most electronegative element with a Pauling
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oi: electronegativity of 4 as compared to 3.5 for oxygen, 3.0 for chlorine or 2.8
d for bromine. It is this property that is the apparent origin of many of the
1 | profound differences observed when fluorinated and non-fluorinated
9
19 molecules are compared. Fluorine forms the strongest bond to carbon of the
2, halogens, e.g., the carbon-fluorine bond energy is 456-486 kJ per mole and
2
y the carbon-chlorine bond 350 kJ per mole. For an additional comparison the
uar carbon-hydrogen bond energy varies from 356 to 435 kJ per mole.
br Important also is the observation that the carbon-fluorine bond is shorter,
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ate: F c1h.3lo1r inAe, bthoannd tahte 1 .o7t8h eÂr . caArgbaoinn- hfoarlo cgoemn pbaroinsodns,, tfhoer cianrsbtaonnc-eh,y dtrhoeg ecnar bboonnd-
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n is 1.09 A long and the carbon-oxygen bond measures 1.43 Â. However the
o bond lengths vary in an interesting manner in multipli-fluorinated methanes.
cati With increasing fluorination the bond lengths shorten and the bond strengths
bli increase. This phenomena is unique among the halogens (41).
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P Several alternative explanations of this phenomena have been put
forth. Most simply, the contraction has been suggested to be a result of the
donation of electron density from the non-bonded electron pair on fluorine
into an adjacent carbon-fluorine bond (22). Alternative explanations have
suggested that bonding with fluorine causes an increased likelihood that the ρ
electrons of carbon will be preferentially shared with fluorine and thus the
carbon fluorine bond will have more s-character and be shorter (44), in other
words, that bonding with fluorine has greater π character. Therefore the
carbon-fluorine bond in fluoromethane would be more p-rich and longer than
the bond in fluoroform (45). The number of alternative explanations that
have been put forward suggests how clouded understanding of these simple
experimental observations may be. As might be expected, fluorination also
has an effect on carbon-carbon bond strength. The carbon-carbon bond in
1,1,1-trifluoroethane or hexafluoroethane is considerably strengthened
relative to that of ethane, 59 or 42 kJ per mole, respectively (46,47).
WELCH Effects of Selective Fluorination on Reactivity
Table I. Carbon-Fluorine Bond Lengths and Bond Dissociation Energies in
Halomethanes (42-43)
CHX CHX CHX, ex.
3 2 2 4
F 1.385 Â 1.358 A 1.332 A 1.317 A
456 kJ moH 510 kJ mol"1 535kJmoH 543 kJ moH
Cl 1.782 A 1.772 A 1.767 A 1.766 A
350 kJ mol"1 339 kJ mol"1 325kJmoH 301 kJ mol"1
Br 1.939 A 1.934 A 1.930 A 1.942 A
289 kJ moH 267 kJ mol-1 259 kJ mol"1 235kJmoH
Source: Adapted from ref. 22.
1
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6.c Another general experimental phenomenon that is particularly pronounced
45 with organofluorine compounds is the gauche effect, the name given to the
0
1- tendency of 1,2-difluoroethane to exist in a synclinal conformation as
99 opposed to the antiperiplanar conformation, that would be expected on the
1
k- basis of dipolar repulsions. Although the gauche effect is a general
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1/ phenomenon that can occur with any vicinal electronegative substituents, it is
02 most pronounced with vicinally fluorinated molecules. It is has been
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0. rationalized by invoking molecular orbital interactions between the fluorines
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oi: (48,49).
d The electronegativity of fluorine can also have pronounced effects on
1 | the electron distribution within a molecule bearing other substituents and
9
9 affect the dipole moment of the molecule, the overall reactivity and stability of
1
2, the compound and acidity or basicity of the neighboring groups. Fluorine
2
y can also participate in hydrogen bonds (50,51 ) or function as a ligand for
ar alkali metals because of the available three non-bonded electron pairs (52).
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e: F Effects of Fluorine on Chemical Reactivity.
at
D Important differences in chemical reactivity of fluorinated compounds
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o are based upon the difference in electronegativity between fluorine and
cati hydrogen, on the higher carbon-fluorine bond strength versus the strength of
bli the carbon-hydrogen bond, and on the ability of fluorine to participate in
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P hydrogen bonding as an electron pair donor. The effects of fluorination have

been thoroughly summarized by Chambers (24), Smart (22) and others (53).
Fluorine has a pronounced electron withdrawing effect by relay of an
induced dipole along the chain of bonded atoms, a sigma withdrawing effect,
Ια, or this withdrawing may also result from a through space electrostatic
interaction also known as a field effect (54,55). These effects are apparent
when the acidity of trifluoroacetic acid (pKa 0.3) is compared with that of
acetic acid (pKa 2.24). However in the gas phase, although fluoroacetic acid
is more acidic than acetic acid, it is less acidic than chloroacetic acid,
presumably as a result of the lower polarizability of the carbon-fluorine bond,
0.53 A3, relative to that for the carbon-chlorine bond, 2.61 A3 (56). This
diminished charge induced dipole effect of the carbon-fluorine bond, relative
to the carbon-chlorine bond, is much closer to the polarizability of the carbon-
hydrogen bond. The electronic effect of fluorine directly attached to a π
system can be especially complex, as electrons from fluorine may be donated
4 SELECTIVE FLUORINATION IN ORGANIC AND BIOORGANIC CHEMISTRY
back to the π system in an Ι repulsive interaction. These repulsive
π
interactions are most important in the reactions of a-fluorinated anions and
radicals and in additions of nucleophiles to fluorinated alkenes.
In contrast Fluorine stabilizes α-cations by the interaction of the
vacant p-orbital of the carbocation with the filled orbitals of fluorine. Yet a-
trifluoromethyl groups are strongly destabilizing to cationic centers relative to
methyl groups. Trifluoromethyl groups have a very pronounced effect in
solvolytic studies and have featured prominently in some classic studies (57).
In recent work, it has been shown that fluorinated carbon-carbon bonds are
also capable of directing the stereochemistry of reactions. The more electron
deficient carbon-carbon bond (2a) has less electron density available to
donate to a developing vacant orbital; therefore the stereochemistry of the
process is controlled by the more electron richn on-fluorinated carbon-carbon
bond (2b) (55-67).
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oi: Fluorine bonded directly to a carbanionic center is generally
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1 | destabilizing by Ιπ repulsive interactions but when the carbanion ic atom is
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9 surrounded by trifluoromethyl groups, it is stabilized. In the case of
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2, pentakis-(trifluoromethyl)cyclopentadiene (3), stabilization of the carbanion
2
y accounts for a surprisingly high acidity (pKa<-2), comparable to nitric acid
uar (62).
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1
When speculating about the stability of α-fluorocarbanionic centers, the
opposing electron withdrawing effects and Ι repulsive effects must be
π
considered. The geometry of the system thus becomes very important in
evaluating the magnitude of each of these contributions. Pyramidal a-
fluorinated carbanions may be more stable than non-fluorinated pyramidal
carbanions; for example, trifluoromethane is significantly more acidic than
methane. If, however, fluorine resides on a planar carbanionic center, the ion
is less stable; difluoroacetates form enolates less easily than acetates,
presumably since the α-proton is less acidic (63).
Whereasf luorineb onded to a radical center may have a profound
effect on the geometry of that center, the effect of fluorination on the stability
of the radical is difficult to assess. However, the increased accessibility of