Reactivity and regiochemical behavior of the 2,2-difluorocyclopropylcarbinyl cation: A new and improved mechanistic probe to distinguish radical and carbocation intermediates

Article abstract of DOI:10.1021/ol990527k

(equation presented) Acetolysis of 2,2-difluorocyclopropylcarbinyl tosylate (5) yields products derived from both S_N1 and S_N2 processes. Product identification and kinetic data indicated, as had been predicted computationally, that t

Full text of DOI:10.1021/ol990527k

ORGANIC
LETTERS
1
999
Vol. 1, No. 2
93-195
Reactivity and Regiochemical Behavior
of the 2,2-Difluorocyclopropylcarbinyl
Cation: A New and Improved
1
Mechanistic Probe To Distinguish
Radical and Carbocation Intermediates
Feng Tian, Merle A. Battiste, and William R. Dolbier, Jr.*
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611-2011
wrd@chem.ufl.edu
Received March 17, 1999
ABSTRACT
N N
Acetolysis of 2,2-difluorocyclopropylcarbinyl tosylate (5) yields products derived from both S 1 and S 2 processes. Product identification and
kinetic data indicated, as had been predicted computationally, that the cyclopropylcarbinyl−allylcarbinyl cationic rearrangement of 5 occurs
simultaneously with its ionization and with regiospecific proximal bond cleavage to give products that formally derive from the 1,1-difluoro-
4
3
-butenyl cation with a rate constant that is 8.3 × 10 smaller than that of the parent cyclopropylcarbinyl tosylate and 1.8 times larger than
isobutyl tosylate at 96.6 °C.
The 2,2-difluorocyclopropylcarbinyl radical, 1, undergoes an
extraordinarily fast, regiospecific unimolecular ring opening
distal to the geminal fluorine substituents to form the 2,2-
it can, by virtue of differences in regiochemistry, distinguish
between a radical and a carbocation intermediate.
Because â-fluorine substituents destabilize carbocations,
whereas R-fluorines are stabilizing, it appeared likely to us
that reactions involving the 2,2-difluorocyclopropylcarbinyl
cation, 3, would undergo rearrangement via regiospecific
cleavage of the proximal bond to form the1,1-difluorobut-
1
difluoro-3-butenyl radical, 2 (Scheme 1). Its calculated
Scheme 1
4-6
3
-enyl cation, 4. This intuitive prediction received support
from our recent DFT calculations that indicated a regio-
specific conversion of 3 to a homoallylic, stabilized version
of 4 with virtually no activation barrier (Scheme 2). At this
time, we report experimental corroboration of these predic-
tions.
activation barrier of 1.9 kcal/mol and estimated rate constant
1
1
-1
of 1.5 × 10
s
at 25 °C qualifies this system as a
“
hypersensitive” probe of reactions involving radicals as
2
intermediates. As demonstrated by the extensive work of
Scheme 2
3
Newcomb, a radical probe is made much more valuable if
(
1) Tian, F.; Bartberger, M. D.; Dolbier, W. R., Jr. J. Org. Chem. 1999,
4, 540-546.
2) Rate constant calculated using conventional transition-state theory,
6
(
using computed values of 1.6 kcal/mol and -2 cal/mol K for activation
1
enthalpy and entropy, respectively.
1
0.1021/ol990527k CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/11/1999

Scheme 3
-5
The solvolysis of 2,2-difluorocyclopropylcarbinyl tosylate,
, in glacial acetic acid at 96.6 °C led to the formation of
(1.8 ( 0.1) and (3.6 ( 0.4) × 10 s-1 for 0.200 and 0.400
-
5
M [ OAc], respectively, clearly demonstrate the dependence
-
both ring-opened (6 and 7) and non-ring-opened products
on [ OAc], hence the S
N
2 nature of the process that leads
to non-ring-opened product 8. On the other hand, the values
of k for the three reactions increase only slightly, consistent
7
(
8), with 6 and 7 reflecting exclusively the regiochemistry
1
of ring opening that had been predicted computationally
∆
(
Scheme 3).
with the influence of a small salt effect on the ionization
process.
Assuming that the ring-opened and ring-closed products
derived from competing S
the partial rate factors for the two processes could be
calculated. Thus, the S 1 process, in which tosylate 5
N
1 and S
N
2 processes, respectively,
These results do not completely rule out the possibility
that some of 8 might be formed via the S 1 process.
N
However, when the solvolysis was carried out in trifluoro-
acetic acid, a solvent of high ionizing power but poor
nucleophilicity, only ring-opened products were formed
(Scheme 4), under conditions where the potential ring-closed
N
undergoes heterolytic cleavage to (presumably) form ring-
opened cation 4, which then is trapped by either HOAc or
-
TsO to give products 6 and 7, was assigned a first-order
-
6 -1
rate constant (k
∆
) of (4.4 ( 0.1) × 10 s , and the process
involving solvent participation, which led to ring-closed
product 8, was assigned a pseudo-first-order rate constant
Scheme 4
-
6
-1
(k
S
) of (5.8 ( 0.1) × 10 s .
To confirm that competitive unimolecular and bimolecular
reactions were involved and that all three products do not
derive from the common intermediate carbocation 3, ad-
ditional acetolysis experiments were carried out in 0.200 and
0.400 M NaOAc/HOAc solutions. The results are given in
Table 1.
product, 2,2-difluorocyclopropylcarbinyl trifluoroacetate, was
demonstrated to be stable to the solvolytic conditions.
The above solvolytic results are completely consistent with
the ionization of 5 proceeding directly and regiospecifically
to the homoallylic carbocation 4, as had been predicted
Table 1. Kinetic Results for Solvolyses of
2
,2-Difluorocyclopropylcarbinyl Tosylate in NaOAc/HOAc
Solutions at 96.6 °C
1
computationally. Our results would appear to be at odds
with an earlier report by Schlosser, indicating that solvolysis
kobs
10-5
mass
balance
(%)
kS
k∆
(10-6 (10-6
(
ratio
s-1
8/(6 + 7) s-1
s-1
of 2,2-difluoro-3,3-dimethylcyclopropylcarbinyl tosylate, 10,
conditions
)
)
)
6
proceeds with regiospecific distal ring opening (Scheme 5).
pure HOAc
1.0 ( 0.1
2.87 ( 0.07
92
92
90
57:43
84:16
90:10
5.8
24
42
4.4
4.6
4.7
0
0
.200 M NaOAc
.400 RM NaOAc 4.7 ( 0.3
Scheme 5
Correcting k
which is the k
first-order rate constants k
S
by subtracting the background k
S
(HOAc)
(
S
in pure HOAc), one can obtain the pseudo-
-
S
( OAc) that reflect the rates of
-
nucleophilic attack by acetate ion. The values for k
S
( OAc),
(
3) (a) Newcomb, M.; Chestney, D. L. J. Am. Chem. Soc. 1994, 116,
9
753-9754. (b) Toy, P. H.; Newcomb, M.; Hollenberg, P. F. J. Am. Chem.
Soc. 1998, 120, 7719-7729 and references therein.
(4) Previous reports of solvolytic studies of 2,2-difluorocyclopropyl-
5
,6
carbinyl systems led to varying regiochemical results.
However, further calculations (HF/6-31G*) indicate that even
a single methyl group on the cyclopropane ring is apparently
sufficient to alter the regiochemistry in favor of distal ring
opening. This simply indicates, of course, that the stabiliza-
(
5) Proximal cleavage: Boger, D. L.; Jenkins, T. J. J. Am. Chem. Soc.
996, 118, 8860-8870.
6) Distal cleavage: (a) Bessard, Y.; Kuhlmann, L.; Schlosser, M.
1
(
Tetrahedron 1990, 46, 5230-5236. (b) Kobayashi, Y.; Morikawa, T.;
Taguchi, T. Chem. Pharm. Bull. 1983, 31, 2616.
194
Org. Lett., Vol. 1, No. 2, 1999

tion provided by a methyl group is sufficiently greater than
that provided by the two fluorine substituents to overcome
the destabilization of the â-fluorines.
to make such enhancements greater. Therefore, experimental
results obtained from use of most of the present cyclopro-
pylcarbinyl probes need to be interpreted with care in those
cases where a carbocation intermediate is detected.
With the 2,2-difluorocyclopropylcarbinyl radical and cation
both undergoing requisite, ultrafast ring opening, but with
opposite regiochemistries, the system certainly qualifies as
a hypersensitive probe capable of distinguishing between the
two types of mechanisms. In evaluating the potential efficacy
of such a new probe, it should be remembered that in addition
to its ability to differentiate between the intermediacy of a
radical and a carbocation, it should ideally play simply the
role of an “observer” of the reaction. That is, it should not
exert a significant mechanistic influence upon the reaction
system it is testing. If the diagnostic probe itself has a steric
or electronic bias so as to favor or disfavor one of the
possible mechanistic pathways, then the interpretation of the
results from use of such a probe may be ambiguous. This is
certainly one of the potential flaws of any cyclopropylcar-
binyl system that purports to distinguish carbocation from
radical intermediate, because although the cyclopropyl group
should exert little if any kinetic influence upon a radical-
forming process, it is well-recognized to greatly enhance
Considering the acetolysis of 5 in this context, its rate
constant (k ) is only 1.8 times greater than that of isobutyl
∆
tosylate at 96.6 °C, which means that the two fluorine
substituents of 5 have a substantial inductive destabilizing
influence on its ionization transition state. The net result of
such destabilization is to essentially eliminate the rate-
enhancing effect of the cyclopropylcarbinyl moiety relative
to a typical primary substrate, such as isobutyl tosylate.
Therefore, as a result, the 2,2-difluorocyclopropylcarbinyl
system exhibits no kinetic bias toward either the radical or
the carbocation mechanism.
Steric or stereoelectronic influences should also not pose
a problem for the 2,2-difluorocyclopropylcarbinyl system.
Therefore, we conclude, on the basis of our kinetic and
computational examination of the 2,2-difluorocyclopropyl-
carbinyl radical and cation systems, that, being sterically and
electronically benign, but exhibiting high rearrangement
reactivity and regiospecificity, this system should be capable
of acting as an ideal, hypersensitive probe of radical and/or
carbocation mechanisms.
8
formation of carbocations. Cyclopropylcarbinyl tosylate, for
example, undergoes acetolysis with a rate constant more than
1
00 000 times that of model primary system, isobutyl
9,10
tosylate.
Carbocation-stabilizing substituents on the cy-
Acknowledgment. Support of this research in part by the
clopropane ring, such as phenyl or alkoxy, will only serve
National Science Foundation is acknowledged with thanks.
(
7) Cyclopropylcarbinyl acetate product 8 was found to be stable to the
reaction conditions.
8) (a) Wiberg, K. B.; Hess, B. A., Jr.; Ashe, A. J., III. In Carbonium
Supporting Information Available: Full details regard-
ing the synthesis and characterization of all starting materials
and products, procedures for kinetic experiments, and tables
of kinetic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(
Ions; Olah, G. A., Schleyer, P. V. R., Eds.; Wiley: New York, 1972; Vol.
III, p 1295. (b) Wiberg, K. B.; Shobe, D.; Nelson, G. L. J. Am. Chem. Soc.
1
993, 115, 10645-10652.
(
9) Wiberg, K. B.; Ashe, A. J., III. J. Am. Chem. Soc. 1984, 90, 63-74.
(10) Reich, I. L.; Diaz, A.; Winstein, S. J. Am. Chem. Soc. 1969, 91,
5
635-5637.
OL990527K
Org. Lett., Vol. 1, No. 2, 1999
195