Manifestations of bridgehead-bridgehead interactions in the bicyclo[1.1.1]pentane ring system

Article abstract of DOI:10.1021/jo982124o

A series of 3-halo-substituted bicyclo[1.1.1]pentane-1-carboxylic acids 1 (Y = COOH; X = F, Cl, Br, I, and CF₃) as well as the parent compound 1 (Y = COOH, X = H) have been prepared, and a study of some of their properties have been made. It was found that their reactions with xenon difluoride cover a wide range of reactivities. On one hand, the fluoro acid 1 (Y = COOH, X = F) displayed no apparent reaction at all while, on the other, the bromo acid 1 (Y = COOH, X = Br) and parent compound 1 (Y = COOH, X = H) underwent ready reaction with complete disintegration of the ring system. A possible explanation is advanced based on polar kinetic and thermodynamic effects governing the lifetime of an intermediate acyloxy radical species. The relative ease of oxidation of the carboxylates 1 (Y = COO^-; X = H, F, Cl, Br, I, CF₃, and COOCH₃), as mirrored by their peak oxidation potential values (E_p) determined by cyclic voltammetry, also covers a wide range. These data coupled with the dissociation constants (pK_a) of some of the acids 1 (Y = COOH; X = H, F, Cl, and CF₃) reflect significantly on the modes of transmission of electronic effects acting through the bicyclo[1.1.1]pentane ring system.

Full text of DOI:10.1021/jo982124o

2618
J . Org. Chem. 1999, 64, 2618-2625
Articles
Ma n ifesta tion s of Br id geh ea d -Br id geh ea d In ter a ction s in th e
Bicyclo[1.1.1]p en ta n e Rin g System
William Adcock,*,† Andrei V. Blokhin,‡ Gordon M. Elsey,§ Nicholas H. Head,†
Alexander R. Krstic,† Michael D. Levin,‡ J osef Michl,*,‡ J amie Munton,† Evgueni Pinkhassik,‡
Marc Robert,| J ean-Michel Save´ant,*,| Alexander Shtarev,‡ and Ivan Stibor
Department of Chemistry, The Flinders University of South Australia, Adelaide, Australia, 5001,
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215,
Department of Chemical Sciences, Deakin University, Geelong, Victoria, Australia 3217, Laboratoire a’
Electrochimie Mole´culaire de L’Universite´ Denis Diderot (Paris 7), 2 place J ussieu, 75251 Paris Cedex 05,
France, and Institute of Chemical Technology, Prague, Czech Republic
Received October 22, 1998
A series of 3-halo-substituted bicyclo[1.1.1]pentane-1-carboxylic acids 1 (Y ) COOH; X ) F, Cl, Br,
I, and CF3) as well as the parent compound 1 (Y ) COOH, X ) H) have been prepared, and a study
of some of their properties have been made. It was found that their reactions with xenon difluoride
cover a wide range of reactivities. On one hand, the fluoro acid 1 (Y ) COOH, X ) F) displayed no
apparent reaction at all while, on the other, the bromo acid 1 (Y ) COOH, X ) Br) and parent
compound 1 (Y ) COOH, X ) H) underwent ready reaction with complete disintegration of the
ring system. A possible explanation is advanced based on polar kinetic and thermodynamic effects
governing the lifetime of an intermediate acyloxy radical species. The relative ease of oxidation of
the carboxylates 1 (Y ) COO-; X ) H, F, Cl, Br, I, CF3, and COOCH3), as mirrored by their peak
oxidation potential values (Ep) determined by cyclic voltammetry, also covers a wide range. These
data coupled with the dissociation constants (pKa) of some of the acids 1 (Y ) COOH; X ) H, F, Cl,
and CF3) reflect significantly on the modes of transmission of electronic effects acting through the
bicyclo[1.1.1]pentane ring system.
In tr od u ction
considerations have largely centered on through-space
interactions between the back- or rear-lobes of the
bridgehead bond molecular orbitals which depend sen-
sitively on the electronic characteristics of the substitu-
ents or reaction site located at the bridgehead positions.
Over the years the bridgehead positions of polycycloal-
kanes have been shown to have considerable utility as
probe sites for ascertaining structural and electronic
factors underlying various physical and chemical phe-
nomena. In the case of the bicyclo[1.1.1]pentane ring
system (1) these positions are uniquely disposed being
In this paper we report the surprising course of the
reactions between 3-halo and 3-trifluoromethyl-substi-
tuted (X) bicyclo[1.1.1]pentane-1-carboxylic acids 1 (X )
F, Cl, Br, and CF3; Y ) COOH) and xenon difluoride
(XeF2) which demonstrate further physical and chemical
consequences of cross-cage interactions in this small
bicyclic ring system. In addition, the dissociation con-
stants of the carboxylic acids 1 (X ) H, F, Cl, and CF3; Y
) COOH) have been determined and the electrochemical
(3) Barfield, M.; Della, E. W.; Pigou, P. E.; Walter, S. R. J . Am.
Chem. Soc. 1982, 104, 3549.
(4) (a) Kaszynski, P.; Michl, J . J . Org. Chem. 1988, 53, 4593. (b)
Wiberg, K. B.; Waddell, S. T. J . Am. Chem. Soc. 1990, 112, 2194.
(5) Adcock, W.; Krstic, A. R. Tetrahedron Lett. 1992, 33, 7397.
(6) Toops, D. S.; Barbachyn, M. R. J . Org. Chem. 1993, 58, 6505.
(7) (a) Maillard, B.; Walton, J . C. J . Chem. Soc., Chem. Commun.
1983, 900. (b) McKinley, A. J .; Ibrahim, P. N.; Balaji, V.; Michl, J . J .
Am. Chem. Soc. 1992, 114, 10631.
separated by only ca. 1.85 Å,1 and hence cross-cage
interactions are mandatory. Several striking manifesta-
tions of strong bridgehead-bridgehead interactions in
this system have now been recorded.1-12 Theoretical
(8) Della, E. W.; Grob, C. A.; Taylor, D. K. J . Am. Chem. Soc. 1994,
116, 6159.
(9) Wiberg, K. B.; McMurdie, N. J . Am. Chem. Soc. 1994, 116, 11990.
(10) Adcock, W.; Clark, C. I.; Houmann, A.; Krstic, A. R.; Pinson,
J .; Save´ant, J .-M.; Taylor, D. K.; Taylor, J . F. J . Am. Chem. Soc. 1994,
116, 4653.
† The Flinders University.
‡ University of Colorado.
§ Deakin University.
| L’Universite´ Denis Diderot.
Institute of Chemical Technology.
(1) Wiberg, K. B.; Hadad, C. M.; Sieber, S.; Schleyer, P.v. R. J . Am.
Chem. Soc. 1992, 114, 5820 and references therein.
(2) Wiberg, K. B.; Conner, D. S. J . Am. Chem. Soc. 1966, 88, 4437.
(11) Adcock, W.; Binmore, G. T.; Krstic, A. R.; Walton, J . C.; Wilkie,
J . J . Am. Chem. Soc. 1995, 117, 2758.
(12) Adcock, W.; Krstic, A. R. Magn. Reson. Chem. 1997, 35, 663.
10.1021/jo982124o CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/24/1999

Bridgehead-Bridgehead Interactions
J . Org. Chem., Vol. 64, No. 8, 1999 2619
Ta ble 1. P r od u ct Distr ibu tion of th e Rea ction betw een 3-Su bstitu ted (X) Bicyclo[1.1.1]p en ta n e-1-ca r boxylic Acid s 1 (Y )
COOH) a n d Xen on Diflu or id e
product distribution proportions, %a
entry no.
X
equiv of XeF2
solvent
1, Y ) F
1, Y ) Cl
1, Y ) D
dimer
1, Y ) COOHb
1
2
3
4
5
6
7
F
F
Cl
Cl
Br
2.5
1.2
3.0
4.0
1.5
2.5
4.0
CD2Cl2
CDCl3
CD2Cl2
CDCl3
CD2Cl2
CD2Cl2
CDCl3
0
0
0
0
23
20
0
0
0
11
27
0
0
0
3
4
0
5
4
100
100
63
49
0
tracec
0
0
4
CF3
CF3
19
10
7
36
65
50
tracec
a
b
Relative proportions determined by 1H NMR. Unreacted precursor acid. c Detected by 19F NMR.
oxidation of some carboxylates 1 (X ) H, F, Cl, Br, I, CF3,
and COOCH3; Y ) COO-) also investigated by means of
cyclic voltammetry. As we shall see below, the acidity
constants (pKa values) and peak potential data (Ep
values) from the latter work bear significantly on the
nature and transmission of substituent electronic effects
in the [1.1.1] system (1).
) F, Y ) COOH) and its parent 1 (X ) H, Y ) COOH) in
the ratio 71:29,11 respectively, with 1.5 equiv of XeF2 in
CD2Cl2 or CDCl3 did not lead to the formation of the
difluoride 1 (X ) Y ) F).16 It was found that on gradual
addition of XeF2 the parent acid was eventually con-
sumed, but surprisingly 1 (X ) F, Y ) COOH) appeared
to remain unchanged even after 4 days at room temper-
ature. The reaction of the former compound apparently
occurred via the kinetically labile parent cation 3 (X )
H)1,8,9 rather than the corresponding radical 2 (X ) H)1,7
since no obvious products were detected to suggest that
the integrity of the ring system was maintained.7-9 When
the reaction of the carboxylic acid mixture 1 (X ) F, Y )
COOH and X ) H, Y ) COOH) was carried out on a
preparative scale, it was found that 1 (X ) F, Y ) COOH)
could be recovered in a relatively pure state (>95% by
1H and13C NMR) from the reaction in good yield (ca. 80%)!
This remarkable resistance of the fluoro acid to oxidative
decarboxylation on treatment with XeF2 stands in stark
contrast to the result for the parent acid as well as the
previously investigated 3-carbomethoxy13c,14 and
3-phenyl13b,15 derivatives 1 (X ) COOCH3, Y ) COOH
and X ) C6H5, Y ) COOH, respectively). The latter two
compounds both gave good yields of reduction product 1
(X ) COOCH3, Y ) H and X ) C6H5, Y ) H(D),
respectively) as a result of solvent hydrogen (or deute-
rium) abstraction by the reactive radical intermediates
2 (X ) COOCH3 and C6H5) formed on ready decarboxy-
lation. The unexpected result for 1 (X ) F, Y ) COOH)
prompted us to examine the behavior of some other halo
acids 1 (X ) Cl, Br, and CF3; Y ) COOH) toward XeF2.
The product distribution of these reactions in CD2Cl2 and
CDCl3 are set out in Table 1 together with the results of
1 (X ) F, Y ) COOH).
Resu lts a n d Discu ssion
Xen on Diflu or id e Rea ction s. All the reactions were
carried out in 5 mm NMR tubes and their progress
1
monitored by H NMR. The latter measurements were
facilitated by the use of deuterated solvents (CD2Cl2 or
CDCl3). The product mixtures were finally characterized
by 13C NMR. Spectral assignments followed unequivo-
cally from the additivity of chemical shifts utilizing
appropriate data from well characterized compounds.
One of the reactions, namely, the attempted fluorode-
carboxylation of the fluoro acid 1 (X ) F, Y ) COOH)
was also performed on a preparative scale.
The original impetus behind this work was the desire
to synthesize 1,3-difluorobicyclo[1.1.1]-pentane 1 (X ) Y
) F) which was required in connection with a 19F
chemical shift study of an extensive series of 3-substi-
tuted (X) bicyclo[1.1.1]pent-1-yl fluorides 1 (Y ) F).5
Although previous attempts to introduce fluorine at the
bridgehead of the bicyclo[1.1.1]pentane system by treat-
ment of the appropriate carboxylic acid with XeF2 (fluo-
rodecarboxylation)13,14 were unsuccessful,13b,c,14,15 we were
encouraged to try the reaction by the knowledge that the
desired difluoride 1 (X ) Y ) F) has been detected among
the products from the photochemical reaction of the fluoro
bromide 1 (X ) F, Y ) Br) with triethylsilane.11 This
result was ascribed to disproportionation of two 3-fluoro-
bicyclo[1.1.1]pent-1-yl radicals 2 (X ) F). Unfortunately,
treatment of a mixture of the fluoro carboxylic acid 1 (X
Before scrutiny of the data (Table 1) in detail it is
instructive to take note of the generally accepted mech-
anism for fluorodecarboxylation at the bridgehead of
polycyclic systems (Scheme 1).13c,18
(13) (a) Patrick, T. B.; J ohri, K. K.; White, D. H. J . Org. Chem. 1983,
48, 4159. (b) Patrick, T. B.; J ohri, K. K.; White, D. H.; Bertrand, W.
S.; Mokhtar. R.; Kilbourn, M. R.; Welch, M. J . Can. J . Chem. 1986,
64, 138. (c) Patrick, T. B.; Khazaeli, S.; Nadji, S.; Hering-Smith, K.;
Reif, D. J . Org. Chem. 1993, 58, 705.
(14) Della, E. W.; Head, N. J . J . Org. Chem. 1992, 57, 2850.
(15) Kaszynski, P.; McMurdie, N. D.; Michl, J . J . Org. Chem. 1991,
56, 307.
(16) An attempt to obtain the desired difluoride 1 (X ) Y ) F) by
fluorodeiodination14 was also unsuccessful. Treatment of a mixture of
the fluoro iodide 1 (X ) F, Y ) I) and the parent iodide 1 (X ) H, Y )
I) in the ratio of 71:29, respectively, with a total of 3.0 equiv of XeF2
led to the consumption of both iodides, the latter much more rapidly
than the former. However, no bicyclo[1.1.1]pentyl products were
identified. Only noncharacterizable degradation products were ob-
served. Thus, the reaction outcome displays all the hallmarks of not
only the parent cation (3, X ) H) being a nondiscrete species8,9 but
also the 3-fluoro cation 3 (X ) F) as well. It is noteworthy that the
latter species has been calculated (MP2/6-31G*) to be a transition
state.9 Treatment of the diiodide 1 (X ) Y ) I) with XeF2 in CF2ClCClF2
also failed to yield 1 (X ) Y ) F).
It can be seen that the first step is the formation of a
thermally labile fluoroxenon ester (eq 1). This intermedi-
ate has been directly observed and studied in the case of
trifluoacetic acid.19 It subsequently decomposes to give
the radical as an intermediate (eqs 2-4). The exact mode
of fragmentation of the xenon ester is unknown but there
(17) (a) Della, E. W.; Pigou, P. E.; Schiesser, C. H.; Taylor, D. K.; J .
Org. Chem. 1991, 56, 4659. (b) Banks, J . T.; Ingold, K. U.; Della, E.
W.; Walton, J . C. Tetrahedron Lett. 1996, 37, 8059.
(18) Tius, M. A. Tetrahedron 1995, 51, 6605.
(19) Eisenberg, M.; Des Marteau, D. D. Inorg. Nucl. Chem. Lett.
1970, 6, 29.

2620 J . Org. Chem., Vol. 64, No. 8, 1999
Adcock et al.
Sch em e 1
radical is then governed by a competition between
hydrogen (or deuterium) atom abstraction from the
solvent versus fragmentation. The former reaction simply
regenerates the precursor carboxylic acid. It is important
to note that there is precedence in the literature for the
electrostatic field influence of electron-withdrawing di-
polar substituents being an important factor in signifi-
cantly reducing decarboxylation rates of alkyl acyloxy
radicals.23 The strong deactivation by F, Cl and CF3
suggests charge transfer in the transition state as shown
in structure 4.
is some evidence20,21 that it is initiated by simple ho-
molytic bond scission (eq 2 or 3) rather than simultaneous
multibond fission to give the radical and carbon dioxide
directly (RCOOXeF f R• + CO2 + •XeF). The radical is
then believed to either yield the fluoride directly (eq 5)
or indirectly via a carbocation (eqs 6 and 7). It is
important to note that there is no evidence to exclude
the possibility that a carbocation may be formed directly
from the fluoroxenon ester by heterolytic fission (RCOOX-
eF f R+ + CO2 + Xe + F-) rather than being formed
from the radical by electron transfer (eq 6). Some
attempts to observe the expected intermediate ester 1
(X ) F, Y ) COOXeF) by 19F and 129Xe NMR were
unsuccessful although the signals of XeF2 were clearly
identifiable (see Experimental Section). These experi-
ments suggest two possibilities. Either XeF2 fails to react
with 1 (X ) F, Y ) COOH), although 1 (X ) CF3, Y )
COOH) and 1 (X ) Cl, Y ) COOH) do (see later), or XeF2
reacts with 1 (X ) F, Y ) COOH) but the product rapidly
decomposes to 1 (X ) F, Y ) COO•) which abstracts
deuterium from the solvent (CD3CN) to yield 1 (X ) F, Y
) COOD). The latter appears the more likely. In light of
the aforementioned result for the parent acid 1 (X ) H)
from this study and the known radical nature of the
reaction for the 3-carbomethoxy13c,14 and 3-phenyl13b,15
acid derivatives 1 (X ) COOCH3, Y ) COOH and X )
C6H5, Y ) COOH, respectively), the competition between
the two mechanistic pathways (radical versus ionic) is
obviously finely tuned in this system. Thus, even the
presence of a relatively weak electron-withdrawing polar
group such as 3-C6H5 is sufficient to ensure that a radical
course is maintained.
With these mechanistic details in mind the complex
pattern of reactivity indicated by the results listed in
Table 1 brings to light several noteworthy features. First,
it can be seen that except for 1 (X ) Br, Y ) COOH),
which will be discussed separately below, there is a
general reluctance of the acids 1 (X ) F, Cl, and CF3, Y
) COOH) to be consumed by reaction with XeF2. This
result is in marked contrast to the ready decarboxylation
of the other 3-substituted acids 1 (X ) C6H5 and COOCH3,
Y ) COOH) noted above. If the common view is accepted
that the reaction involves the formation of an acyloxy
radical species (eq 2 or 3), the apparent lack of reactivity
of the acids listed in Table 1 can be explained by the rate
of the usually very rapid fragmentation step (eq 4)22 being
significantly retarded. Thus, the fate of the acyloxy
However, because the strong electrostatic field effects
(σF) of F, Cl, and CF3 are virtually identical (see below),
the completely unreactive fluoro-acid suggests an ad-
ditional factor is involved besides a kinetic polar effect.
In an attempt to shed light on the matter we have
calculated energies (Table 2) for the reactants and
products of the isodesmic reaction shown (eq 8).
X-[1.1.1]-COO• + H-[1.1.1]• f
H-[1.1.1]-COO• + X-[1.1.1]• (8)
The effect of the substituents on the energy (kcal/mol)
of the reaction determined at the same level of theory
(UHF/6-31G* and UMP2/6-31G*//UHF/6-31G*) are as
follows: 2.70 (F), 0.28 (Cl), -0.77 (CF3) and 3.29(F), 0.23
(Cl), -1.19 (CF3), respectively. The energy for F was 2.86
kcal/mol when estimated from energies obtained with
geometries fully optimized at the UMP2/6-31G* level of
theory. Clearly decarboxylation of the fluoro acyloxy
radical of 1 (X ) F, Y ) COO•) is thermodynamically less
favorable than the other radicals of 1 (X ) H, Cl, or CF3,
Y ) COO•). Thus, both kinetic and thermodynamic
factors appear responsible for the remarkable behavior
of the fluoro acid. Defining the predominant origin of the
latter factor requires consideration of the relative im-
portance of stabilizing through-space interactions (σcx*
- σ•; homohyperconjugation) in the product radical10
versus polar ground-state stabilization/destabilization
energies.24 There are two components to the latter
phenomenon: (i) an electronegativity effect which im-
pinges significantly on the degree of nonbonded repulsion
between the bridgehead positions as evidenced by the
change in length of the bridgehead to bridgehead distance
(C1 to C3) on bridgehead substitution.9,11,25 This will be
stabilizing for σ-electron-withdrawing groups (F > Cl >
CF3; see later). It should be noted that this effect is
expected to be much more pronounced for the closed shell
structures at the bridgehead (precursor acyloxy radical)
than for the open shell species (product bridgehead
radicals). (ii) a Coulombic effect due to electrostatic
destabilization of the starting or parent structure (1,Y
) CO2•) due to unfavorable dipole-dipole through-space
interactions between Cδ+-Xδ- and Cδ+OOδ-. The mag-
(20) Bardin, V. V.; Yagupolskii, Yu. L. Xenon Difluoride. In New
Fluorinating Agents in Organic Synthesis; German, L., Zemskov, S.,
Eds.; Springer-Verlag: Berlin, New York, 1989; Chapter 1.
(21) Gregorcic, A.; Zupan, M. J . Org. Chem. 1979, 44, 4120.
(22) Hilborn, J . W.; Pincock, J . A. J . Am. Chem. Soc. 1991, 113, 2683
and references therein.
(23) Traylor, T. G.; Sieber, A.; Kiefer, H.; Clinton, N. Intra-Sci.
Chem. Rep. 1969, 3, 289.
(24) Nau, W. M. J . Org. Chem. 1996, 61, 8312 and references
therein.
(25) Wiberg, K. B. Tetrahedron Lett. 1985, 26, 599.

Bridgehead-Bridgehead Interactions
J . Org. Chem., Vol. 64, No. 8, 1999 2621
Ta ble 2. Ca lcu la ted En er giesa ,b
moleculec
UHF/6-31G*
UMP2/6-31G*
UMP2/6-31G*//UHF/6-31G*
ZPVE
H-[1.1.1]-COO•
F-[1.1.1]-COO•
Cl-[1.1.1]-COO•
CF3-[1.1.1]-COO•
H-[1.1.1]•
-380.894675
-479.751611
-839.8012296
-716.521213
-193.264893
-292.117949
-652.171432
-528.891226
-381.972753
-480.997161
-381.972839
-480.997059
-841.011627
-718.230260
-193.892097
-292.911339
-652.930952
-530.150144
80.7
75.5
74.5
84.5
70.6
65.7
64.7
73.5
-193.894170
-292.914454
F-[1.1.1]•
Cl-[1.1.1]•
CF3-[1.1.1]•
a
b
Total energies in hartrees. Zero-point vibrational energy (ZPVE; kcal/mol) computed at the UHF/6-31G* level. c 1,3-
Disubstitutedbicyclo[1.1.1]pentanes ≡ X-[1.1.1]-Y.
nitude of this effect can be estimated by calculating the
isodesmic energy of reaction 9 which effectively segre-
gates the polar
of 1 (Y ) COOH) with XeF2 can be advanced based on
the idea that the rate-determining step of the reaction
involves simultaneous multibond scission (eqs 2 (or 3)
and 4 occur in one step) of the initially formed fluorox-
enon ester. If the transition state for such a mechanistic
scenario has significant charge separation as depicted in
structure 5 then similar polar kinetic and themodynamic
factors to those described above would prevail in deter-
X-[1.1.1]-[1.1.1]-X + 2H-[1.1.1]-COO• f
H-[1.1.1]-[1.1.1]-H + 2X-[1.1.1]-COO• (9)
field influence from radical stabilization energy in the
product24 and, as well, from the electronegativity effect
in the precursor. The similar energies (kcal/mol) of
reaction 9 (2.91(F), 3.58 (Cl), and 3.75 (CF3)) determined
at the RHF/6-31G* (X-[1.1.1]-[1.1.1]-X, calculated
energies (hartrees): -386.663319 (H), -584.38183 (F),
-1304.482133 (Cl), -1057.922376 (CF3)) and UHF/6-
31G* (see Table 2) level of theory are in accord with
various empirical scales of electrostatic field effects of
these substituents (see later).
mining reactivities. However, our inability to identify the
formation of a fluoroxenon ester in the case of 1 (X ) F,
Y ) COOH) makes this an unlikely possibility.
The energetics of reaction 9 for X ) F, coupled with
the fact that resonance stabilization of the product radical
by F is obviously small,10 leads us to conclude that the
unfavorable thermodynamic factor for this substituent
(from reaction 8) is governed by a large decrease in the
strain energy (>6 kcal/mol) of 1 (X ) F, Y ) COO•)
relative to the parent system 1(X ) H, Y ) COO•). This
is due to the very electronegative fluorine removing
electron density from the carbon bridgehead orbital and,
thus, significantly reducing 1,3 nonbonded repulsion9,25
(the calculated C1-C3 bond distance in 1 (Y ) COO•) is
1.865 and 1.823 Å for X ) H and F, respectively). This
decrease is less pronounced in the radical and translates
into a strengthening of the C-COO• bond in 1 (X ) F, Y
) COO•)(C1-COO• bond distances are 1.497 and 1.491
Å for X ) H and F, respectively). It is pertinent to note
that high-level ab initio calculated bond dissociation
energies of bicyclo[1.1.1]pentanes (1)11 indicate that the
C-H bond strength is increased by ca. 4 kcal/mol on
3-fluoro substitution of 1 (X ) F, Y ) H). Moreover, an
electrochemical study of 1-halo-and 1,3-dihalobicyclo-
[1.1.1]pentanes10 revealed a significant increase in the
strength of the bridgehead C-Br and C-I bonds when
H at the other bridgehead is replaced by fluorine. It
should be noted that the calculated energy of reaction 8
for Cl (0.23 kcal/mol) appears far too positive in the light
of the aforementioned electrochemical study10 which
suggests that a 3-chloro substituent strongly stabilizes
(ca. 5.0 kcal/mol) the bicyclo[1.1.1]pent-1-yl radical. Ad-
ditionally, the calculated energy of reaction 9 for Cl (3.58
kcal/mol) indicates a substantial destabilization of the
precursor 1 (X ) Cl, Y ) COO•) by a polar field effect
which augments the resonance stabilization of the prod-
uct radical contributing to the isodesmic energy of
reaction 8.
The idea that 1 (X ) F, Y ) COO•) is much more
resistant to decarboxylation than the parent (X ) H, Y
) COO•) prompted us to effect oxidative decarboxylation
2- 26
(Ag+/S2O8
)
on a mixture of the acids in a biphasic
system (H2O/cyclohexane)27 in an attempt to purify the
fluoro compound. We found after 15 min at 70 °C that
the parent acid is completely destroyed while the 3-fluoro
derivative (1; X ) F, Y ) COOH) can be recovered almost
quantitatively. If it is assumed that both acids are
oxidized, then the result suggests that decarboxylation
of 1 (X ) F, Y ) COO•) is too slow to compete with
hydrogen abstraction from c-C6H12 (1.4 × 106 M-1 s-1 in
CCl4 for C6H5COO• at 24 °C).28 Given that the rate of
decarboxylation of the cyclopropane carboxyl radical is
of the order of 109 s-1 at 80 °C29 (ca. 108 s-1 at 25 °C)29
and, therefore, the parent 1 (X ) H, Y ) COO•) is
probably fairly similar, this is a most dramatic substitu-
ent effect. However, a caveat to this interpretation is that
oxidation of the fluoro acid 1 (X ) F, Y ) COOH) relative
to the parent 1 (X ) H, Y ) COOH) by Ag+/S2O8 may
2-
be very slow (see electrochemical study below).
Second, as noted above the complete consumption of
the bromo acid 1 (X ) Br, Y ) COOH) is exceptional
among the halo acids listed in Table 1. Here the strong
deactivating kinetic polar effect is apparently over-
whelmed by the thermodynamic factor. It is known that
3-bromo substitution strongly stabilizes (>10 kcal/mol)10
the bicyclo[1.1.1]pent-1-yl radical and, therefore, is mani-
(26) Anderson, J . M.; Kochi, J . K. J . Am. Chem. Soc. 1970, 92, 1651.
(27) (a) Cyclohexane is a very effective hydrogen atom donor.27b (b)
Quiclet-Sire, B.; Zard, S. Z. J . Am. Chem. Soc. 1996, 118, 9190 and
references therein.
(28) Chateauneuf, J .; Lusztyk, J .; Ingold, K. U. J . Am. Chem. Soc.
1988, 110, 2886.
An alternative explanation for the strong deactivation
by X ) F, Cl, and CF3 relative to X ) H in the reaction
(29) Fujimori, K.; Hirose, Y.; Oae, S. J . Chem. Soc., Perkin Trans. 2
1996, 405.

2622 J . Org. Chem., Vol. 64, No. 8, 1999
Adcock et al.
Ta ble 3. Acid ities of 3-Su bstitu ted (X)
fested by a considerable weakening of the C-COO• bond
in 1 (X ) Br, Y ) COO•). Because the reaction leads to
the formation of only uncharacterizable degradation
products, fragmentation of the bicyclic ring system via a
kinetically labile bridgehead cation species is implied (see
above). This is explained by the known ready decomposi-
tion of the 3-bromobicyclo[1.1.1]pent-1-yl radical 2 (X )
Br) to give [1.1.1]propellane30 which subsequently reacts
with hydrogen fluoride.31
Bicyclo[1.1.1]p en ta n e-1-ca r boxylic Acid s 1 (Y ) COOH) in
50% (by w eigh t) Aqu eou s Eth a n ol a t 25 °C
a,c
b,c
X
pKa
pKa
H
F
Cl
CF3
5.63 ( 0.05 (0.00)
4.84 ( 0.04 (0.79)
4.69 ( 0.14 (0.94)d
4.75 ( 0.06 (0.88)
5.71 ( 0.06 (0.00)
4.90 ( 0.07 (0.81)
4.66 ( 0.08 (1.05)
4.82 ( 0.05 (0.89)
Determined by conductometry. b Determined by potentiometric
a
d
titration. c ∆pKa values in parentheses. Extrapolated to time
Third, the product distributions for the reactions of
3-chloro- and 3-trifluoromethyl acids 1 (X ) Cl and CF3,
Y ) COOH, respectively) are noteworthy for two reasons
(Table 1): (i) The reaction of alkyl radicals with CH2Cl2
(or CD2Cl2) and HCCl3 (or DCCl3) usually leads to
exclusive H-atom abstraction.32 This chemoselectivity is
governed primarily by the stability of the incipient
radical.32b However, it can be seen that the reactions of
the 3-chloro- and 3-trifluoromethylbicyclo[1.1.1]pent-1-
yl radicals 3 (X ) Cl and CF3, respectively) with the
respective solvents are not chemoselective. Note that Cl-
atom abstraction competes significantly against H-atom
abstraction in both solvents. In fact the former is the
dominant pathway in CD2Cl2. Since it is known that both
enthalpic and polar factors are important in determining
the rates of H-atom abstraction,33 we ascribe this unusual
result to the latter phenomenon. It should be noted that
we have already drawn attention to the importance of
kinetic polar effects in the chemical behavior of the
3-fluoro radical species 3 (X ) F).11 (ii) Given that
dimerization of highly reactive bicyclo[1.1.1]pent-1-yl
radicals7,17 is a most unlikely result, the formation of
significant amounts of dimer (X ) Cl, CF3, and COOCH3)
is perplexing. We can only speculate that this observation
implies the formation of a xenon ester ((X-[1.1.1]-
COO)2Xe) which undergoes multiple bond homolytic
fission with extrusion of CO2 and subsequent cage
dimerization of the bicyclopentyl radicals within the
coordination sphere of xenon. Interestingly, xenon bis-
(trifluoroacetate) decomposes on standing to give Xe, CO2,
and C2F6.19
zero.
Unfortunately, a value for the bromo acid could not be
obtained due to its rapid solvolysis. A similar but more
tractable problem was also encountered with the corre-
sponding chloro compound. Thus, the uncertainty associ-
ated with the measurement of this particular acid is
greater than that for the other compounds (Table 3). An
inspection of the results reveals that the acidity differ-
ences (∆pKa’s) clearly do not parallel the electronegativity
order of the substituents (F > Cl > CF3).34 The observed
order is more in accord with expectations based on their
polar field effects (σF values (CH3OH): F, 0.41; Cl, 0.43;
CF3, 0.42),35 namely, F ∼ Cl ∼ CF3. Other empirical scales
also suggest small differences in electrostatic field effects
for these groups.36 Thus, the substituent influence on the
acidities of 1 (X ) F, Cl, and CF3; Y ) COOH) can be
ascribed exclusively to the direct through-space interac-
tion of the substituent dipole with the negative charge
in the carboxylate ion. This situation corroborates an
earlier deduction of Applequist et al.37 that the acidities
of such acids could be described satisfactorily in terms
of an electrostatic field model, and agrees with conclu-
sions drawn recently from a study of hexafluorinated
bicyclo[1.1.1]pentane-1,3-dicarboxylic acids.38
It is of interest to note that the order of the calculated
(RHF/6-31+G*) effects of the substituents on the energy
(∆E(kcal/mol): F, -6.3; Cl, -8.3; CF3, -8.5) of the
isodesmic reaction (eq 10) in a vacuum is in reasonable
agreement with the aforementioned experimental order.
X-[1.1.1]-COOH + H-[1.1.1]-COO- f
H-[1.1.1]-COOH + X-[1.1.1]-COO- (10)
Finally, we wish to report that treatment of the half-
ester (1; X ) COOCH3) with XeF2 (3.5 equiv) in CD2Cl2
gave a product mixture which contained a significant
amount (27%) of the known fluoride 1 (X ) COOCH3, Y
) F) together with the deuterium derivative 1 (X )
COOCH3, Y ) D; 27%), the dimer (5%), and unreacted
precursor acid (41%). This contrasts with the results
Most pertinently, the calculated values parallel pre-
cisely the σF parameters in nonpolar solvents (c-C6H12
or CCl4: F, 0.39; Cl, 0.43; CF3, 0.44)35 which are more
likely to mirror the gas phase environment. Finally, it is
worth noting that the above picture is similar to one
finally painted for the acidities of 4-substituted (X)
bicyclo[2.2.2]octane-1-carboxylic acids.39 Data from this
latter system underpin the empirical parameters (σI ≡
σF) which characterize polar field effects of substituents.
Electr och em ica l Mea su r em en t. The discovery that
oxidative decarboxylation of bicyclo[1.1.1]pentane-1-car-
13c
14
obtained previously in CHCl3 and CH2Cl2 in which
only the reduction product 1 (X ) COOCH3, Y ) H) was
isolated. Note also that a significant amount of the
fluoride 1 (X ) CF3, Y ) F) was found in the product
mixture from treatment of the trifluoromethyl acid 1 (X
) CF3, Y ) COOH) with XeF2 in CD2Cl2 (Table 1).
p Ka Mea su r em en ts. The pKa values for some 3-sub-
stituted (X) bicyclo[1.1.1]pentane-1-carboxylic acids 1 (X
) H, F, Cl, and CF3; Y ) COOH) were determined and
are given in Table 3.
(34) Marriott, S.; Reynolds, W. F.; Taft, R. W.; Topsom, R. D. J . Org.
Chem. 1984, 49, 959.
(35) Adcock, W.; Abeywickrema, A. N. J . Org. Chem. 1982, 47, 2957.
(36) (a) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165
and references therein. (b) Reynolds, W. F.; Gomes, A.; Maron, A.;
McIntyre, D. W.; Tamin, A.; Hamer, G. K.; Peat, I. R. Can. J . Chem.
1983, 61, 2376.
(37) Applequist, D. E.; Renken, T. L.; Wheeler, J . W. J . Org. Chem.
1982, 47, 4985.
(38) Levin, M. D.; Hamrock, S. J .; Kaszynski, P.; Shtarev, A. B.;
Levina, G. A.; Noll, B. C.; Ashley, M, E.; Newmark, R.; Moore, G. G.
I.; Michl, J . J . Am. Chem. Soc. 1997, 119, 12750.
(39) Koppel, I. A.; Mishima, M.; Stock, L. M.; Taft, R. W.; Topsom,
R. D. J . Phys. Org. Chem. 1993, 6, 685.
(30) (a) Della, E. W.; Taylor, D. K. J . Org. Chem. 1994, 59, 2986.
(b) Taylor, D. K. Ph.D. Dissertation, The Flinders University of South
Australia, Adelaide, 1993.
(31) Adcock, J . L.; Gakh, A. A. J . Org. Chem. 1992, 57, 6206.
(32) (a) Free Radicals in Organic Chemistry; Fossey, J ., Lefort, D.,
Sorba, J ., Eds.; Wiley: New York, 1995; p 129. (b) Bernardi, F.; Bottoni,
A. J . Phys. Chem. A 1997, 101, 1912 and references therein.
(33) Dolbier, W. R., J r. Chem. Rev. 1996, 96, 1557 and references
therein.

Bridgehead-Bridgehead Interactions
J . Org. Chem., Vol. 64, No. 8, 1999 2623
Ta ble 4. P ea k P oten tia ls of 1 (Y ) COO-)
boxylic acids 1 (Y ) COOH) on treatment with XeF2 (see
above) varies markedly with the electronic character of
the 3-substituent (X) suggested that an electrochemical
study of the corresponding carboxylate anions (1, Y )
COO-) might be fruitful in providing insight into the
mechanism outlined in Scheme 1, in particular, on the
intermediacy of the RCOO• radical. The first stage of the
anodic oxidation of carboxylates (Kolbe reaction)40 in-
volves the transfer of one electron to the electrode from
RCOO- with subsequent formation of the radical (R•) and
CO2 (eq 11).
a,c
X
Ep
H
F
Cl
Br
I
1.15
1.47
1.38
0.90
0.39
1.37
1.22
CF3
COOCH3
a
b
Solvent, acetonitrile. At 0.2 V/s, in V vs SCE. c Accurate to
(5 mV.
the poor correlation between the Ep values and polar field
constants (σF)35 strongly indicates that other factors are
at play as well. In this respect, the impressive difference
(1.08 V) between the Ep values for the fluoro and iodo
carboxylates (Table 4; X ) F and I) is illuminating since
it is reminiscent of the large difference (0.72 V) between
the peak reduction potentials of 1-fluoro-3-iodobicyclo-
[1.1.1]pentane 1 (X ) F, Y ) I) and 1,3-diiodobicyclo-
[1.1.1]pentane 1 (X ) Y ) I).10 By means of dissociative
electron-transfer theory the latter result has been shown10
to be due to stabilizing through-space interactions (ho-
mohyperconjugation) largely in the product radical de-
rived from the diiodide and, as well, stabilization of the
starting fluoro iodide due to the very electronegative
fluorine reducing 1,3 nonbonded repulsion. Thus, if it is
assumed that the loss of CO2 occurs in the rate-
determining step of the anionic oxidation (concerted (eq
11) or stepwise (eq 13)) a qualitative appreciation of the
Ep trends (Table 4) can be achieved by consideration of
the aforementioned three factors (polar field effect,
homohyperconjugation (σ*C-X-σ•), and 1,3-nonbonded
repulsion). Finally, it is of interest to note that there is
a distinct parallelism between the oxidizability of the
carboxylates 1 (Y ) COO-) and the ease of oxidative
decarboxylation of the corresponding acids 1 (Y ) COOH)
with XeF2. Hence, it is not surprising that similar factors
appear to govern both processes.
RCOO- f R• + CO2 + e
(11)
The question of whether this process is concerted (eq
11) or stepwise (eq 12 and 13) is a subject of continuing
debate.41
RCOO- f RCOO• + e
RCOO• f R• + CO2
(12)
(13)
We reasoned that if as suggested above the 3-fluoro-
bicyclo[1.1.1]pentane-1-carboxyl radical 1 (X ) F, Y )
COO•) has a significant lifetime it might be possible to
observe it as an intermediate in the Kolbe reaction. Thus,
by using very fast scan rates in a cyclic voltammetry
experiment the usual irreversible anodic reaction of a
carboxylate might become reversible and, therefore,
provide quantitative information on the rate of fragmen-
tation of RCOO• (eq 13).22
The experiments were carried out in acetonitrile in the
presence of 0.1M n-Bu4NBF4 at a glassy carbon electrode.
The carboxylates were prepared in the electrochemical
cell by addition of a slightly less than stoichiometric
amount of n-Bu4NOH to the appropriate carboxylic acid
so as to avoid oxidation of OH-. All the cyclic voltammo-
grams of the carboxylates at a scan rate of 0.2 V/s gave
respectable single irreversible anodic waves which cor-
respond to a one-electron stoichiometry as previously
observed for some aryl acetates.42 Unfortunately, a dis-
crepancy between the peak-width and the variation of
the peak potential with the scan rate placed limitations
on the investigation. Thus, the assignment of the mech-
anism (concerted versus stepwise) is uncertain. No re-
versibility was observed on going to a very high scan rate
in the case of the fluoro carboxylate 1 (X ) F, Y ) COO-).
The peak potential data (Ep) for the carboxylates of 1
(X ) H, F, Cl, Br, I, CF3, and COOCH3; Y ) COO-) are
listed in Table 4.
Exp er im en ta l Section
Syn th esis of Com p ou n d s. Literature procedures were
followed in the preparation of 3-chlorobicyclo[1.1.1]pentane-
1-carboxylic acid 1 (X ) Cl, Y ) COOH),30 3-bromobicyclo[1.1.1]-
pentane-1-carboxylic acid 1 (X ) Br, Y ) COOH),30 3-iodobicyclo-
[1.1.1]pentane-1-carboxylic acid 1 (X ) I, Y ) COOH),30b
3-carbomethoxybicyclo[1.1.1]pentane-1-carboxylic acid 1 (X )
COOCH3, Y ) COOH),43 1-iodo-3-trifluoromethylbicyclo[1.1.1]-
pentane 1 (X ) CF3, Y ) I),31 and bicyclo[1.1.1]pentane-1-
carboxylic acid 1 (X ) H, Y ) COOH).43a The latter compound
was also synthesized from methyl 3-iodobicyclo[1.1.1]pentane-
1-carboxylate 1 (X ) COOCH3, Y ) I)14 following procedures
recently described for the preparation of bicyclo[2.2.1]heptane-
1-carboxylic acid from methyl 4-iodo-bicyclo[2.2.1]heptane-1-
carboxylate.44 A mixture of 3-fluorobicyclo[1.1.1]pentane-1-
carboxylic acid 1 (X ) F, Y ) COOH) and the parent acid 1 (X
) H, Y ) COOH) in the ratio 71/29 (respectively) was available
from another study.11 A further sample of this mixture was
obtained following the published procedure.11 The 3-fluoro- and
parent acid in the new sample were in the ratio 85/15,
respectively.
It can be seen that there is a striking variation in the
ease of oxidation of the compounds. The importance of
an electron-withdrawing electrostatic field influence is
highlighted by the deactivating effect of most of the
substituents (X ) F, Cl, CF3, and COOCH3). However,
(40) (a) Kolbe, H. Ann. Chem. 1849, 69, 257. (b) Wurtz, A. Ann.
Chim. Phys. 1855, 44, 291.
(41) (a) Eberson, L. Acta Chem. Scand. 1963, 17, 2004. (b) Eberson,
L. Electrochim. Acta 1967, 12, 1473. (c) Vijh, A. K.; Conway, B. E.
Chem. Rev. 1967, 67, 623 (d) Coleman, J . P.; Lines, R.; Utley, J . H. P.;
Weedon, B. C. L. J . Chem. Soc., Perkin Trans. 2 1974, 1064. (e)
Kraeutler, B.; Bard, A. J . J . Am. Chem. Soc. 1978, 100, 2239. (f)
Kraeutler, B.; Bard, A. J . J . Am. Chem. Soc. 1978, 100, 4903. (g)
Scha¨fer, H. J . Angew. Chem., Int. Ed. Engl. 1981, 20, 911. (h) Vassiliev,
Y. B.; Grinberg, V. A. J . Electroanal. Chem. 1990, 283, 359. (i)
Vassiliev, Y. B.; Grinberg, V. A. J . Electroanal. Chem. 1991, 308, 1.
(42) Andrieux, C. P.; Gonzalez, F.; Save´ant, J .-M. J . Am. Chem. Soc.
1997, 119, 4292.
3-(Tr iflu or om eth yl)bicyclo[1.1.1]p en ta n e-1-ca r boxyl-
ic Acid 1 (X ) CF 3, Y ) COOH). A solution of 1-iodo-3-
(trifluoromethyl)bicyclo[1.1.1]pentane 1 (X ) CF3, Y ) I;31 1.0
g, 3.82 mmol) in anhydrous ether (50 mL) was cooled to -80
(43) (a) Della, E. W.; Tsanaktsidis, J . Aust. J . Chem. 1986, 39, 2061.
(b) Kaszynski, P.; Michl, J . J . Org. Chem. 1988, 53, 4593.
(44) Adcock, W.; Clark, C. I. J . Org. Chem. 1995, 60, 723.

2624 J . Org. Chem., Vol. 64, No. 8, 1999
Adcock et al.
°C under nitrogen and treated with 4.94 mL of 1.7 M tert-
butyllithium (2.2 mol equiv) in pentane. After being main-
tained at this temperature for 30 min with stirring, the
reaction mixture was quenched quickly with excess dry CO2
gas. Sufficient water was then added to dissolve all solids, and
the crude reaction mixture was extracted (2 × 30 mL) to
remove organic impurities. The aqueous phase was carefully
acidified with dilute hydrochloric acid and after being satu-
rated with sodium chloride was subjected to continuous
extraction with diethyl ether. After the ether extract was dried
(MgSO4), the solvent was removed in vacuo to afford the crude
acid as a white solid. Sublimation (125 °C/0.1 mm) followed
by recrystallization from dichloromethane afforded the title
compound (540 mg, 84%) as white needles: mp 152-153 °C;
1H NMR (CDCl3) δ 9.89 (bs, 1H), 2.28 (s, 6H); 13C NMR (CDCl3,
(15 mL) containing silver nitrate (40 mg) maintained at 70
°C. The resulting mixture was allowed to stir at that temper-
ature for 15 min before the heating was stopped and the
mixture allowed to cool with stirring for 1 h. The cyclohexane
was separated, and the aqueous layer was thoroughly ex-
tracted (4 × 20 mL) with dichloromethane. The extracts were
combined and dried over magnesium sulfate, and the solvents
were evaporated in vacuo to afford the fluoro acid 1 (X ) F, Y
) COOH) as a white solid (170 mg) almost quantitatively. The
physical and chemical properties of this compound were
identical to the sample reported above.
Gen er a l P r oced u r e for Tr ea tm en t of 3-Su bstitu ted (X)
Bicyclo[1.1.1]p en ta n e-1-ca r boxylic Acid s 1 (Y ) COOH)
w ith XeF 2. To a solution of the carboxylic acid (15-20 mg) in
0.7 mL of CD2Cl2 or CDCl3 at 0 °C in a 5 mm NMR tube was
added granular XeF2 (45-75 mg). The tube was allowed to
warm to room temperature and left to stand overnight to
ensure complete reaction before being analyzed by 1H and 13C
NMR. The known spectral properties of the acids 1 (Y )
COOH; X ) F,11 Cl,30 Br,30 CF3,48 and COOCH343), the fluorides
1 (Y ) F; X ) Cl, CF3, and COOCH3)5, and several 1-substi-
tuted (X) bicyclo[1.1.1]pentanes 1 (Y ) H; X ) Cl,49 CF3,50 and
COOCH351) facilitated the assignments. The 13C chemical shifts
of the methylene carbons (C2) of the various products were
unambiguously assigned by additivity methodology utilizing
appropriate13C SCS data (Cl, 6.09 ppm; CF3, -2.26 ppm;
COOCH3, 0.56 ppm). The calculated values for the dimers were
determined from the 13C chemical shift data for the parent
[2]-staffane.52 The relevant NMR data for the reactions of the
various acids in CDCl3 and CD2Cl2 are listed in Table 5. See
Table 1 and text for product distributions.
Tr ea tm en t of a Mixtu r e of 3-F lu or obicyclo[1.1.1]-
p en ta n e-1-ca r boxylic Acid 1 (X ) F , Y ) COOH) a n d
Bicyclo[1.1.1]p en ta n e-1-ca r boxylic Acid 1 (X ) H, Y )
COOH) w ith XeF 2. Xenon difluoride (563 mg, 3.33 mmol)
crystals were added gradually to a well stirred solution of the
aforementioned mixture of acids (279 mg; 71/29, respectively;
ca. 2.2 mmol) in CD2Cl2 (3.0 mL) under N2. The mixture was
allowed to stir overnight at room temperature before the
solvent was evaporated in vacuo to afford a residue which was
subsequently sublimed. The spectroscopic properties of this
product (136 mg; >95% pure by 1H NMR) were identical to
those reported above for the pure fluoro acid 1 (X ) F, Y )
COOH). No parent acid 1 (X ) H, Y ) COOH) was detected.
P r oced u r e for th e Attem p ted Obser va tion of th e
F lu or oxen on Ester of 1 (X ) F , Y ) COOH). To a solution
of the fluoro acid 1 (X ) F, Y ) COOH; 9 mg, 0.069 mmol) in
CD3CN (0.7 mL) maintained at -20 °C under N2 was added
granular XeF2 (14 mg, 0.083 mmol), and the mixture was
stirred for 5 h at -20 °C. 19F NMR revealed a singlet and
doublet corresponding to XeF2 (δ(rel CFCl3): 131.7 ppm, J XeF
) 5644 Hz). Stirring the mixture for a further 1 day at -20
°C left the situation unchanged. The solution was then allowed
to warm to room temperature, but no new 19F and 129Xe NMR
resonances appear after 3 h at this temperature. 129Xe NMR
gave only the signal for XeF2.53 Further warming to 40 °C (1
h) and then to 60 °C (2 h) led to no new 129Xe signals. However,
at the latter temperature the XeF2 signals in 129Xe and 19F
NMR slowly decrease (the latter by reference to the singlet
resonance of 1 (X ) F, Y ) COOH)). No new 129Xe NMR peaks
appear, but new 19F NMR signals appear in a variety of places.
Similar experiments carried out in CD2Cl2 and CCl2FCF2-
Cl were unsuccessful. Solubility may have been a problem in
the former solvent.54
4
relative to Me4Si) δ 37.02 (C1, q, J C-F ) 2.0 Hz), 50.08 (C2,
q, 3J C-F ) 2.2 Hz), 37.18 (C3, q, 2J C-F ) 39.4 Hz), 122.30 (CF3,
q, 1J C-F ) 275.6 Hz), 174.90 (COOH); 19F NMR (CDCl3, relative
to FCCl3) δ -73.81; HRMS (EI) calcd for C7H7F3O2 180.0398,
found 179.0317 (M•+ - 1), calcd for (M•+ - 1) 179.0320, found
135.0405 (M•+ - 45), calcd for (M•+ - 45) 135.0542.
1-F lu or o-3-p h en ylbicyclo[1.1.1]p en ta n e 1 (X ) F , Y )
C6H5). A solution of butyllithium in hexane (22 mL, 1.6 M,
35.2 mmol) was added to a solution of crude 1-iodo-3-
phenylbicyclo[1.1.1]pentane45 1 (X ) F, Y ) C6H5; 4.5 g, 16.7
mmol) in dry THF (170 mL) at -70 °C over a period of 40 min.
The mixture was stirred at -60 to -70 °C for 1.5 h. Then it
was cooled to -90 °C, and a solution of N-fluorodibenzene-
sulfonamide (5.5 g, 17.5 mmol) in THF (40 mL) was added over
a period of 30 min. The mixture was stirred for 1 h at -90 °C
and then was allowed to warm to -10 °C over a period of 2 h.
Aqueous NH4Cl was added at -10 °C, the mixture was
extracted with ether (3 × 200 mL), the extract was washed
with water (2 × 100 mL), aqueous Na2S2O3, water, and finally
concd. NaCl, and it was then dried over MgSO4. The solvent
was distilled off through a short column. Column chromatog-
raphy on silica gel with pentane as the eluent yielded pure
1-fluoro-3-phenylbicyclo[1.1.1]pentane 1 (X ) C6H5, Y ) F; 0.35
3
g, 2.2 mmol, 13%). 1H NMR δ 2.33 (d, 6H, J H-F ) 2.4 Hz),
3
7.16-7.30 (m, 5H). 19F NMR δ -149.98 (septet, J H-F ) 2.4
Hz. 13C{1H} NMR (CD3CN) δ 31.72 (d, 3J H-F ) 46.5 Hz), 56.05
2
1
(d, J C-F ) 20.8 Hz, CH2), 76.34 (d, J C-F ) 323 Hz), 127.70,
5
127.85, 129.32, 137.70 (d, J C-F ) 27 Hz). Anal. Calcd for
11H11F: C, 81.48; H, 6.79. Found: C, 81.34; H, 6.86.
C
3-F lu or obicyclo[1.1.1]p en ta n e-1-ca r boxylic Acid 1 (X
) F , Y ) COOH). Meth od A. By use of the procedure of
Carben et al.,46 sodium periodate (5.13 g, 0.024 mol) and water
(10 mL) were added to a solution of 1-fluoro-3-phenylbicyclo-
[1.1.1]pentane 1 (X ) F, Y ) C6H5; 300 mg, 0.00185 mol) in
acetonitrile (17.5 mL) and dichloromethane (3.5 mL). Ruthe-
nium trichloride hydrate (15 mg) was then added to the
vigorously stirred reaction mixture. After stirring for 3 days
at room temperature, the reaction mixture was filtered and
the filter cake washed with dichloromethane (50 mL). After
the combined extracts were dried (MgSO4), the solvent was
removed in vacuo to afford the crude product which was
sublimed (80 °C/0.1 mm) twice to give a white solid (90 mg,
37%), mp 117-118 °C; HRMS (EI) calcd for C6H7FO2 130.0430,
found 129.0351 (M•+ - 1), calcd for (M•+ - 1) 129.0352. 1H,
13C, and 19F NMR spectra were identical to those previously
reported11 which were obtained from a mixture of the fluoro
acid 1 (X ) F, Y ) COOH) and the parent 1 (X ) H, Y )
COOH).
Meth od B. By use of a modified literature procedure,26,47
a
solution of ammonium persulfate (0.5 g, 0.0022 mol) in
deoxygenated water (10 mL) was added to a vigorously stirred
mixture (200 mg; see above) of 3-fluorobicyclo[1.1.1]pentane-
1-carboxylic acid (85%) and bicyclo[1.1.1]pentane-1-carboxylic
acid (15%) in cyclohexane (20 mL) and deoxygenated water
(48) This study.
(49) Della, E. W.; Taylor, D. K. Aust. J . Chem. 1991, 44, 881.
(50) Krstic, A. R. Ph.D. Dissertation, Flinders University of South
Australia, Adelaide, 1995.
(51) Della, E. W.; Taylor, D. K. Aust. J . Chem. 1990, 43, 945.
(52) Murthy, S. G.; Hassenru¨ck, K.; Lynch, V. M.; Michl, J . J . Am.
Chem. Soc. 1989, 111, 7262.
(53) Schrobilger, G. J .; Holloway, J . H.; Granger, P.; Brevard, C.
Inorg. Chem. 1978, 4, 980.
(54) Dukat, W. W.; Holloway, J . H.; Hope, E. G.; Townson, P. J .;
Powell, R. L. J . Fluorine Chem. 1993, 62, 293.
(45) Kaszynski, P.; Friedli, A. C.; Michl, J . J . Am. Chem. Soc. 1992,
114, 601.
(46) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.
(47) J acobsen, N.; Torssell, K. Liebigs Ann. Chem. 1972, 763, 135.

Bridgehead-Bridgehead Interactions
J . Org. Chem., Vol. 64, No. 8, 1999 2625
Ta ble 5. 1H, 13C, a n d 19F NMR Ch em ica l Sh ifts of CH2, CH2, a n d F , Resp ectively, of Rea cta n ts a n d P r od u cts of th e
Rea ction betw een 1 (Y ) COOH) a n d XeF 2
reactant 1 (Y ) COOH)
X ) Cl (17 mg)a
products 1
solvent
1H NMR (δ, ppm)
13C NMR (δ, ppm)
19F NMR (δ, ppm)
CDCl3
CDCl3
CDCl3
CDCl3
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
2.46 (6H)
2.47 (6H)
2.16 (6H)
2.03 (12H)
2.48 (6H)
2.50 (6H)
2.18 (6H)
2.06 (12H)
58.21
X ) Cl, Y ) Cl
62.49 (62.93)f
56.89
X ) Cl, Y ) D
X ) Cl, Y ) C5H6Cl
56.72 (55.84)f
57.80
X ) Cl (15.8 mg)b
X ) CF3 (14.0 mg)c
X ) CF3 (13.7 mg)d
X ) Cl, Y ) Cl
X ) Cl, Y ) D
X ) Cl, Y ) C5H6Cl
X ) Cl, Y ) F
62.08
56.47
56.30
-166.83
-74.51
-71.86
-75.15
-75.75
-69.20
-73.14
-70.49
-73.78
-73.35
-68.53
-152.04
2.30 (6H)
2.36 (6H)
2.00 (6H)
1.85 (12H)
50.17
X ) CF3, Y ) Cl
X ) CF3, Y ) D
X ) CF3, Y ) C5H6CF3
X ) CF3, Y ) F
55.43 (54.58)f
48.43
47.75 (47.89)f
2.32 (6H)
2.39 (6H)
2.03 (6H)
1.89 (6H)
2.44 (6H)
(2.55 Hz)
2.35 (6H)
2.08 (6H)
1.91 (12H)
2.37 (2.45 Hz)
49.71
55.02
47.27
46.62
52.24
(22.0 Hz)
52.48
X ) CF3, Y ) Cl
X ) CF3, Y ) D
X ) CF3, Y ) C5H6CF3
X ) CF3, Y ) F
X ) COOCH3 (16.1 mg)e
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
X ) COOCH3, Y ) D
X ) COOCH3, Y ) C5H6COOCH3
X ) COOCH3, Y ) F
50.99
50.10 (50.31)f
54.94 (21.8 Hz)
-149.53
a
b
d
XeF2 ) 74 mg (4 equiv). XeF2 ) 52.8 mg (3 equiv). c XeF2 ) 52.5 mg (4 equiv). XeF2 ) 44.9 mg (2.5 equiv). e XeF2 ) 53.9 mg (3.5
equiv). f Calculated value.
p Ka Mea su r em en ts. Conductivity water prepared by pass-
ing distilled water through Milli Quf apparatus was used for
both conductivity measurements and titrations. U.S.P. abso-
lute ethanol was refluxed with magnesium ethoxide under
nitrogen for 24 h and distilled. Titrations were monitored by
pH measurements with Orion 81-72 Sure-Flow electrode and
Orion 701A Ionalyzer. The titrations were performed at 25 °C
under a stream of nitrogen. Standard aqueous ethanol buffers
used for electrode calibration covered the pH range 2.8-7.7.55
Each titration was repeated three times at different concentra-
tions between 7 × 10-4 and 5 × 10-3 M. Conductance of
aqueous ethanol solutions (50 wt %) was measured at 25 °C
in a thermostated cell with platinum-coated electrodes and a
cell constant of 1. Fresh stock solutions of the acids, made by
weight, were sequentially diluted (8 × 10-3 to 9 × 10-5 M),
and conductance measurements were repeated three times for
each acid.56 Nonlinear regression analysis of titration curves
was performed with Axum software.57
proton abstraction (kcal/mol) for 1 (Y ) COOH; X ) H (354.6),
F (348.3), Cl (346.3), and CF3 (346.1) were calculated at the
HF level of theory using the 6-31+G* basis set for both neutral
and anionic forms.
Ack n ow led gm en t. One of us (W.A.) is grateful to
the Australian Research Council for partial financial
support of this work as well as to Professor Barry
Carpenter (Cornell University) for an insightful discus-
sion. Work at Boulder was supported by an NSF grant
CHE-9318469. Work in Prague was supported by the
Czech Republic-U.S. Program in Science and Technol-
ogy, no. 94037. We thank Dr. Neil A. Trout for some
experimental assistance and for some aspects of the
preparation of the manuscript.
J O982124O
Cyclic Volta m m etr y. The measurements were carried out
as previously described.10,42
(58) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith, T.; Peterson, G.
A.; Montgomery, J . A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski,
V. G.; Ortiz, J . V.; Foresman, J . B.; Cioslowski, J .; Stefanov, B. B.;
Nanayakkara, A.; Challocombe, M.; Peng, C. Y.; Ayala, P. Y.; Chen,
W.; Wong, M. W.; Andres, J . L.; Replogle, E. S. Gomperts, R.; Martin,
R. L.; Fox, D. J .; Binkley, J . S.; Defrees, D. J .; Baker, J .; Stewart, J . J .
P.; Head-Gordon, M.; Gonzalez, C. and Pople, J . A. Gaussian 94,
Revision D, Gaussian, Inc.: Pittsburgh, PA, 1995.
Com p u ta tion s. All calculations were carried out utilizing
the GAUSSIAN 94 program package.58 The enthalpies of
(55) Galster, H. pH Measurement: Fundamentals, Methods, Ap-
plications, Instrumentation; VCH: New York, 1991.
(56) Albert, A.; Serjeant, E. P. The Determination of Ionization
Constants; Chapman and Hall Ltd: New York, 1971.
(57) Axum 4.0 for Windows; 1995, TriMetrix, Inc.