Multiple Electrophilic Substitution of 1,1,2,2,9,9,10,10-Octafluoro[2.2]paracyclophane

Article abstract of DOI:10.1021/jo000436x

Synthetic methods for introduction of two substituents into the rings of octafluoroparacyclophane are presented. Nitration gives three isomers with nitro substituents on different rings: pseudoortho, pseudo-meta, and pseudo-para, in equal amounts. These dinitro compounds are shown to be precursors of a variety of other disubstituted OFP derivatives. Methods of characterization of isomeric disubstituted OFPs are extensively discussed, and the ¹H and ¹⁹F NMR spectra of these derivatives are analyzed explicitly.

Full text of DOI:10.1021/jo000436x

5282
J . Org. Chem. 2000, 65, 5282-5290
Mu ltip le Electr op h ilic Su bstitu tion of
1,1,2,2,9,9,10,10-Octa flu or o[2.2]p a r a cyclop h a n e
Alex J . Roche and William R. Dolbier, J r.*
Department of Chemistry, University of Florida, Gainesville, Florida, 32611-7200
wrd@chem.ufl.edu.
Received March 23, 2000
Synthetic methods for introduction of two substituents into the rings of octafluoroparacyclophane
are presented. Nitration gives three isomers with nitro substituents on different rings: pseudo-
ortho, pseudo-meta, and pseudo-para, in equal amounts. These dinitro compounds are shown to be
precursors of a variety of other disubstituted OFP derivatives. Methods of characterization of
1
isomeric disubstituted OFPs are extensively discussed, and the H and 19F NMR spectra of these
derivatives are analyzed explicitly.
In tr od u ction
Here we wish to report the synthesis, characterization
and thermal isomerization of a variety of both homo- and
heteroannularly disubstituted OFP derivatives. Prior to
this paper, there were no reports of disubstituted OFP
derivatives in the literature.12
[2.2] Paracyclophane ([2.2] PCP) chemistry has grown
considerably since the isolation of the parent compound
in 1949.1 Besides finding commercial application as
monomers for parylene-type polymers,2 these attractive
molecules have spawned an unusual and unique chem-
istry.3 The close proximity of the face to face aromatic
rings, coupled with the rigid skeleton and high strain
energy4 translates into such effects as transannular
interactions, thermal racemization and isomerism, sur-
prising directing effects in multiple electrophilic substitu-
tion and unusual spectroscopic phenomena.3 The use of
ring-substituted [2.2] PCP skeletons as chiral backbones
is of considerable current interest.5 Highly fluorinated
cyclophanes on the other hand, have received much less
attention, even though these compounds have desirable
industrial properties6 and should at least display as
equally rich a chemistry as their hydrocarbon counter-
parts. This imbalance is slowly being redressed following
the improved syntheses of the bridge fluorinated cycle
1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane (OFP) 1
that have been reported over the last 7 years7-10 and our
initial report of the chemistry of this fluorinated cyclo-
phane.11
Syn th etic Resu lts a n d Discu ssion
Recently we reported that nitration of 1 gave a mono-
nitro product in high yield.11 However, when such nitra-
tion is carried out under the more forcing conditions of 5
equiv of NO2BF4 and a temperature of 80 °C, the products
generated were observed to be a mixture of three isomeric
dinitro derivatives in over 80% combined isolated yield.,
with the ratio of the isomers being 1:1:1 [Scheme 1].
One of the isomers could be separated from the other
two by column chromatography since it displayed a lower
Rf value than the other two, which coeluted. The quicker
running mixture of two isomers could be enriched in one
or the other isomer by fractional crystallization or
sublimation. The 19F NMR spectrum of each isomer
showed only two AB patterns. (Recall that the 19F NMR
spectra of OFP consists of a singlet, and that mononitro-
OFP appears as four AB patterns).11 The increase in the
symmetry of these new products relative to mononitro-
OFP indicated incorporation of at least two nitro groups.
Mass spectrometry confirmed not only that the prod-
ucts did indeed contain two nitro groups but also that
they were located on different rings. The relative orienta-
tion of the nitro groups in each of the three isomers was
established through 1H NMR and further confirmed by
thermal isomerizations and correlation of their physical
properties with those already established for heteroan-
(1) Brown, C. J .; Farthing, A. C. Nature 1949, 164, 915.
(2) Gorham, W. F. J . Polym. Sci. Part A-1 1966, 4, 3027.
(3) Reviews: (a) Vogtle, F. Cyclophane Chemistry; Wiley: New York,
1993. (b) Boekelheide, V. Top. Curr. Chem. 1983, 113, 87. (c) Hopf,
H.; Marquard, C. Strain and Its Implications In Organic Chemistry;
Kulwer: Dordrecht, 1989.
(4) Hope, H.; Bernstein, J .; Trueblood, K. N. Acta Crystallogr., Sect.
B 1972, 28, 1733.
(5) Selected examples from 1997: (a) Pye, P. J .; Rossen, K.; Reamer,
R. A.; Tsou, N. N.; Volante, R. P.; Reider, P. J . J . Am. Chem. Soc. 1997,
119, 6207. (b) Rossen, K.; Pye, P. J .; Maliakal, A.; Volante, R. P. J .
Org. Chem. 1997, 62, 6462. (c) Pelter, A.; Kidwell, H.; Crump, R. A.
N. C. J . Chem. Soc., Perkin Trans. 1 1997, 3137. (d) Cipiciani, A.;
Fringuelli, F.; Mancini, V.; Piermatti, O.; Pizzo, F.; Ruzziconi, R. J .
Org. Chem. 1997, 62, 3744. (e) Belokon, Y.; Moscalenko, M.; Ikonnikov,
N.; Yashkina, L.; Antonov, D.; Vorontsov, E.; Rozenberg, V. Tetrahe-
dron: Asymmetry 1997, 8, 3245. (f) Pamperin, D.; Hopf, H.; Syldatk,
C.; Pietzsch, M. Tetrahedron: Asymmetry 1997, 8, 319.
(6) (a) Beach, W. F.; Lee, C.; Basset, D. R.; Austin, T. M.; Olson, A.
R. Xylylene Polymers. In Wiley Encyclopaedia of Polymer Science and
Technology; Wiley: New York, 1989; Vol. 17, p 990. (b) Majid, N.;
Dabral, S.; McDonald, J . F. J . Electron. Mater. 1989, 18, 301. (c)
Williams, K. R. J . Thermal Anal. 1997, 49, 589.
(7) Dolbier, W. R., J r.; Asghar, M. A.; Pan, H.-Q.; Celewicz, L. J .
Org. Chem. 1993, 58, 1827.
(8) Dolbier, W. R., J r.; Rong, X. X.; Xu, Y. J . Org. Chem. 1997, 62,
7500.
(9) Dolbier, W. R., J r.; Duan, J .-X.; Roche, A. J . U.S. Patent 5,841,-
005, 1998.
(10) Dolbier, W. R., J r.; Duan, J .-X.; Roche, A. J . Org. Lett. 2000, 2,
1867-1869.
(11) Roche, A. J .; Dolbier, W. R., J r. J . Org. Chem. 1999, 64, 9137.
(12) Bromination of OFP was reported in these two patents. The
products were ill-characterized, and in our hands, the reaction was
unable to be reproduced. (a) Marvel, C. S. U.S. Patent 4,499,258, 1985
(b) Marvel, C. S. U.S. Patent 4,476,062, 1984.
10.1021/jo000436x CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/29/2000

Substitution Octafluoro[2.2]paracyclophane
J . Org. Chem., Vol. 65, No. 17, 2000 5283
Sch em e 1. Syn th eses of Din itr o-, Dibr om o-, a n d
Diiod o AF 4 Der iva tives
It is noteworthy that the reactions in Scheme 1 were
all performed on both single isomers and mixtures of the
three isomers. The pseudo-ortho isomer could always be
separated from the pseudo-meta/pseudo-para mixture by
column chromatography, regardless of the substituents.
The pseudo-meta/pseudo-para isomers were, in general,
unable to be separated by column chromatography.
Monosubstituted and unsubstituted OFP contaminants
arising from reduction processes could always be removed
from disubstituted products by column chromatography.
All reaction yields were essentially the same whether
performed on single or multiple isomers, and they are
comparable to the corresponding reactions used to make
the monosubstituted OFP analogues.11 The only differ-
ence in reactivity for the three disubstituted isomers in
the reactions in Scheme 1 was observed in their trifluo-
romethylation reactions, where the pseudo-ortho diiodo
isomer gave lower conversions and slower reactions. This
anomaly is addressed later in the text. No isomerism or
loss of integrity of the OFP skeleton was observed during
any of these reactions, although the deliberate high
temperature thermal isomerization of selected examples
of these compounds was studied.
The reduction of 2a -c using iron powder/concentrated
hydrochloric acid gave the corresponding diamino prod-
ucts 3a -c in good isolated yields (82-84%). Cyclophanes
containing electron donating substituents in one ring and
electron acceptors in the other ring are often reported to
be colored, and the corresponding interannular nitro/
amino systems for the hydrocarbon [2.2] PCP vary from
yellow to red, depending on the relative orientation of
the two substituents.3,15 In an attempt to generate 6 with
an amino group in one ring and a nitro in the other, the
milder reducing agent of cyclohexene and Pd on carbon
was used in conjunction with 2c. Besides the correspond-
ing diamino OFP 3c (38%), we were able to isolate the
nitro-amino derivative 6 (11%), and the hydroxylamino-
amino product 7 (15%).
nularly disubstituted [2.2] PCP derivatives. (More de-
tailed explanations of these characterizations are pro-
vided later). Thus the products were identified as pseudo-
m-, pseudo-p-, and pseudo-o-dinitrooctafluoropara-
cyclophanes 2a -c. No evidence of the pseudo-geminal
isomer was observed, although as little as 1% could have
been detected.
Obviously the introduction of a nitro functionality into
one ring deactivates that ring to further electrophilic
substitution and guides subsequent reaction to the other
unsubstituted ring. The lack of a pseudo-geminal isomer
is somewhat surprising since there are many examples
of complete (or predominant) pseudo-geminal electro-
philic aromatic substitutions promoted by substituents
bearing basic functionalities, through their participation
as intramolecular bases.3 However, nitrations are known
to be less susceptible to such kinetic effects, in compari-
son to brominations, for example.11 We propose that the
lack of such a dinitro isomer in this reaction is due to a
steric effect. (The nitration of the hydrocarbon [2.2] PCP
using nitric acid at 75 °C is reported14 to yield mononitro
[2.2] PCP (26%), and pseudo-meta (2%), pseudo-para
(2%), pseudo-ortho (1.4%) and pseudo-geminal (0.7%)
dinitro isomers).
Disappointingly, 6 was a white solid, in contrast to the
orange/yellow color of the corresponding [2.2] PCP com-
pound.15 This difference can be attributed to removal of
electron density from the interacting π systems by the
electron-withdrawing fluoroalkyl bridging units,16 thus
reducing charge transfer.
The diamino OFP isomers 3a -c proved versatile
starting materials for further transformations, with the
most straightforward being the formation of the respec-
tive N-acetyl- and -trifluoroacetyl-amides in high isolated
yield (84-97%). These compounds proved useful not only
for characterization purposes but also as protecting
We have previously demonstrated that nitro-OFP
provides a route to a variety of ring-substituted OFP
derivatives,11 and thus we were able to apply similar
synthetic methodology that allowed the generation of a
number of interannularly disubstituted OFP products.
(15) Allgeier, H.; Siegel, M. G.; Helgeson, R. C.; Schmidt, E.; Cram,
D. J . J . Am. Chem. Soc. 1975, 97, 3782.
(13) Reich, H. J .; Cram, D. J . J . Am. Chem. Soc. 1969, 91, 3505.
(14) Reich, H. J .; Cram, D. J . J . Am. Chem. Soc. 1969, 91, 3527.
(16) Chambers, R. D. Fluorine in Organic Chemistry; Wiley: New
York, 1973.

5284 J . Org. Chem., Vol. 65, No. 17, 2000
Roche and Dolbier
groups that moderated the reactivity of the diamino OFP
systems and thus made appropriate materials for the
high temperature thermal isomerization studies de-
scribed later.
simply being located either on the same or different sides
of the cyclophane. Although exchange of trifluoromethyl
for iodine should make the iodo-trifluoromethyl inter-
mediate compounds more reactive toward further sub-
stitution, clearly this is not the case for the pseudo-ortho
isomer. It is likely that the two reaction centers in the
pseudo-ortho isomers are so close4 that when one iodine
is replaced by a trifluoromethyl group, there is sufficient
steric and electronic shielding by the attached trifluo-
romethyl group to inhibit further substitution. Having
observed through space NMR interactions between syn
bridging fluorines and a trifluoromethyl substituent on
the ring,11 we believe that these syn bridge fluorines also
provide steric and electrostatic shielding to an attacking
nucleophile. The use of a relatively large transition metal
catalyst like Pd(II) may serve to reduce such steric
constraints on the incoming nucleophile by coordinating
the substrate and the nucleophile before joining them
through a reductive elimination,18 thus resulting in the
superior observed yields of trifluoromethylated products
in PdCl2 catalyzed reactions.
The double diazotization of these diamino-systems
proved as successful as diazotization of monoamino-
OFP,11 and thus the three isomeric dibromo- (5a -c) and
diiodo-OFP (4a -c) derivatives were prepared in good
isolated yield (60-78%) via Sandmeyer-type chemistry.
The heteroannular dibromides proved useful for com-
parison purposes when we later prepared a homoannular
dibromide (vide infra), and they also served as useful
intermediates for further transformations, although the
diiodides generally gave higher yields in such reactions
and were therefore the more desirable starting materials.
Trifluoromethylation17 of the pseudo-meta and pseudo-
para OFP diiodides 4a ,b gave moderate yields of corre-
sponding bis(trifluoromethylated) products 8a ,b (50%),
along with appreciable amounts monotrifluoromethylated
10 (30%). This is in keeping with our previous experience
regarding the trifluoromethylation of iodo-OFP,11 and
more importantly, it was again observed that the addition
of a catalytic amount of palladium dichloride gave vast
improvements in the yields of bis(trifluoromethylated)
products (80%), and a consequent decrease in chemically
reduced side products.
The pseudo-ortho diiodide 4c was also used to produce
the corresponding diphenyl derivative via reaction with
phenylmagnesium bromide and PdCl2, providing the
diphenyl derivative, 11, in 21% yield along with 20%
monophenyl-OFP, 12. Identical mono and diphenylated
products were also obtained via diazonium chemistry and
benzene.
Although the overall yields of the diiodides and dibro-
mides were acceptable for a three-step procedure (40-
53% isolated yield from OFP), a direct bromination
procedure to dibrominate OFP would be much more
desirable. To this end, OFP was subjected to several
literature bromination methods,9,19 but the only method
that was successful in generating more than a trace of
dibromo-OFP was a method recently reported from this
laboratory for bromination of deactivated aromatics.20
When a trifluoroacetic acid solution of OFP was
exposed to a combination of four equivalents of NBS and
sulfuric acid at 80 °C, a single major product was
produced. The presence of two AB patterns in the 19F
NMR of this compound led us to believe it was a
dibromide product. The isolated yield of this compound,
after column chromatography, was 55%, and somewhat
surprisingly, the NMR spectra of the product did not
match any of those of the three interannular dibromides
that had been prepared via the nitration/reduction/
diazonium chemistry described earlier. Mass spectrom-
etry revealed that the product was indeed a dibromide
isomer, but that the bromines were both on the same
ring. This information, coupled with the 1H and 19F NMR
patterns (see discussion later) indicated that this was
p-dibromo OFP 5d .
When a typical uncatalyzed trifluoromethylation was
performed on pseudo-ortho OFP diiodide 4c, the only two
products obtained besides starting material were identi-
fied as 10 (33%) and pseudo-ortho iodo-trifluoromethyl
OFP 9 (21%). However, addition of PdCl2 promoted a
superior reaction with the pseudo-ortho bis(trifluoro-
methyl) derivative, 8c, being isolated in 68% yield, along
with a 10% yield of iodo-trifluoromethyl derivative, 9,
which could itself be reduced by zinc in acetic acid to form
trifluoromethyl-OFP (91%).
A bromine substituent is normally viewed as a deac-
tivating and ortho/para directing substituent in electro-
philic aromatic substitution.21 Usually a deactivating
substituent would guide subsequent substitution into the
(18) Rozenberg, V. I.; Sergeeva, E. V.; Kharitonov, V. G.; Vorontsova,
N. V.; Vorontsov, E. V.; Mikul’shina, V. V. Russ. Chem. Bull. 1994,
43, 1018.
(19) (a) Kodaira, K.; Okuhara, K. Bull. Chem. Soc. J pn. 1988, 61,
1625. (b) Mongin, F.; Maggi, R.; Schlosser, M. Chimia 1996, 50, 650.
(c) Porwisiak, J .; Schlosser, M. Chem. Ber. 1996, 129, 233.
(20) Duan, J .-X.; Zhang, L.-H.; Dolbier, W. R., J r. Synlett. 1999,
1245.
(21) Carey, F. A.; Sundberg, R. J . Advanced Organic Chemistry, 3rd
ed., Part A; Plenum Press: New York, 1990; Chapter 10.
The difference in reactivity displayed by the isomeric
diiodides can be best understood in terms of the iodides
(17) Chen, Q.-Y.; Wu, S.-W. J . Chem. Soc., Chem. Commun. 1989,
705

Substitution Octafluoro[2.2]paracyclophane
J . Org. Chem., Vol. 65, No. 17, 2000 5285
other ring of a [2.2] PCP,13 but this was obviously not
the case for this reaction, although the second bromine
did enter para to the first. (When [2.2] PCP was dibro-
minated using Fe/Br2, the product ratio was para (5%),
pseudo-ortho (16%), pseudo-para (26%) and pseudo-meta
(6%).)13
higher temperatures to undergo such isomerizations. We
were therefore interested to determine whether OFP
derivatives would undergo such thermal isomerizations,
and if so, what temperatures would be required.
Initially the pseudo-ortho dibromo-, pseudo-ortho di-
amino- and dinitro-OFP derivatives were examined, but
these compounds proved to be perfectly stable and
unchanged when heated neat at 200 °C for 12 h. After 8
h at 300 °C, the diamino compound had fully decomposed,
while the dibromo and dinitro compounds showed no
isomerization. When the temperature was raised to 350
°C the dinitro compound was extensively charred but
showed traces of isomerization to its pseudo-para coun-
terpart, whereas the dibromide was also charred but
showed no isomerizations. In contrast, heating the pseudo-
ortho bis(trifluoroacetamido) OFP, 13c, led to no char-
ring, and the sample showed traces of isomerization to
its pseudo-para isomer, 13b. Therefore 13c was heated
to 381-390 °C for 2 h, and was shown by NMR analysis
to have been converted to a 5:1 ratio of pseudo-ortho and
pseudo-para isomers. Encouraged by this result, this
With p-dibromo OFP (5d ) in hand, it was then possible
to prepare the p-bis(trifluoromethyl) OFP derivative, 8d ,
albeit in lower yields than had been obtained for the
heteroannular diiodides. As expected, the NMR spectra
of 8d were also distinctively different from those of 8a ,
b, and c.
Syn th etic Con clu sion s. Two complementary meth-
ods for the introduction of two substituents into the rings
of octafluoroparacyclophane have been reported. Nitra-
tion gives three isomers with the nitro functionalities in
different rings, oriented pseudo-meta, pseudo-para and
pseudo-ortho. Bromination on the other hand gives a
dibromide where both halogens are in the same ring, para
to each other. All such products serve as versatile starting
materials for preparation of a variety of novel homo- and
heteroannular disubstituted OFP derivatives.
mixture was further heated at 350-360 °C for 24 h and
the ratio of isomers was found to have changed to 1:7 in
favor of the less sterically congested pseudo-para isomer.
The mass recovery was 75%, with the balance presum-
ably being insoluble polymeric material. Therefore the
bridging fluorine atoms in OFP appear to impart 150 °C
more kinetic thermal stability to a [2.2] PCP ring system.
This not only demonstrates the stabilizing effect of
exchanging fluorine for hydrogen, but has serious impli-
cations in the use of these fluorinated phanes as chiral
ligands, catalysts and auxiliaries, since they display far
superior resistance to thermal isomerization than the
hydrocarbon analogues, and could therefore be employed
at higher temperatures without losing their chirality
through thermal racemization. (The observed isomeriza-
tions were also useful as they helped to further confirm
the correctness of our isomer assignments).
Th er m a l Isom er iza tion s
The [2.2] PCP skeleton is rigid4 and under normal
conditions maintains its integrity, allowing, for example,
the application of [2.2] PCP derivatives as chiral ligands
and molecular scaffolds of known fixed geometry.5 This
holds true for temperatures below 150-200 °C. Above
these temperatures, ring substituted [2.2] PCP deriva-
tives exhibit a thermal isomerization that is unique to
this system. Typically, the deliberate isomerizations have
been performed without solvent at 200 °C for 24 h, and
Cram elegantly demonstrated that they proceeded though
a bibenzyl-type diradical intermediate.22
One might expect the longer C-C bridge length in OFP
(1.577 Å) relative to [2.2] PCP (1.569 Å)4 to allow the
racemization of OFP derivatives to occur at lower tem-
peratures since it is this bond that must break and
reform. Conversely, since replacement of hydrogen by
fluorine in saturated systems usually increases thermal
and chemical stability,16 coupled with the lower stability
of difluorobenzyl radicals relative to benzyl radicals,23
OFP derivatives might be predicted to require much
Ch a r a cter iza tion
The introduction of a second substituent onto a ring
in a [2.2] PCP system can give rise to seven possible
isomers, of which three are racemic and four are meso
(if the two substituents are equivalent). Therefore struc-
ture elucidation and perhaps more importantly, one’s
ability to distinguish isomeric products, is fundamental
to meaningful work in this field. For this reason, there
has been substantial work in this area,15,24,25 and numer-
ous strategies and techniques have evolved that allow
unambiguous isomer and structure determination in
1
hydrocarbon [2.2] PCP systems, with H NMR and mass
(22) Reich, H. J .; Cram, D. J . J . Am. Chem. Soc. 1969, 91, 3517.
(23) Dolbier, W. R., J r. Chem. Rev. 1996, 96, 1557.
(24) Reich, H. J .; Cram, D. J . J . Am. Chem. Soc. 1969, 91, 3534.
(25) Ernst, L. Liebigs Ann. 1995, 13.

5286 J . Org. Chem., Vol. 65, No. 17, 2000
Roche and Dolbier
Ta ble 1. Am in o OF P SCS Va lu esa
o
m
p
m′
p′
o′
gem
-1.21
0.36
-0.76
-0.20
0.01
-0.12
+0.69
a
Where o ) ortho, p ) para, m ) meta, m′ ) pseudo-meta, p′
) pseudo-para, o′ ) pseudo-ortho and gem ) pseudo-geminal.
Ta ble 2. P r ed icted 1H Ch em ica l Sh ifts Usin g Am in o
OF P SCS Va lu es
peak
type
SCS
effects
calcd
(ppm)
obsd
(ppm)
compound
pseudo-meta diNH2 3a
singlet
A
B
singlet
A
B
singlet
A
B
o + p′
6.10
7.63
6.42
5.89
6.82
7.23
6.78
6.95
6.34
6.08
7.57
6.44
6.00
6.87
7.04
6.89
7.00
6.36
m + gem
p + o′
pseudo-para diNH2 3b
pseudo-ortho diNH2 3c
o + m′
m + o′
p + gem
o + gem
m + p′
p + m′
spectrometry comprising the most powerful tools. Previ-
ously we reported that not only were these strategies and
techniques equally applicable to the characterization of
mono substituted OFP derivatives, but that the OFP
derivatives also offered the added bonus of 19F NMR to
distinguish between products.11 In the following section
1
we will demonstrate that the H Substituent Chemical
Shift (SCS) values previously derived for the amino-OFP
F igu r e 1. Assignment of bridge fluorine resonances in tri-
fluoromethyl-substituted OFPs 10 and 8a -d .
1
system11 allow accurate prediction of the H shifts of the
three new diamino-OFP products synthesized in this
paper and also that the 19F NMR shifts of the bis-
(trifluoromethylated) OFP compounds (both hetero- and
homoannular) can also be predicted via the use of the
19F SCS values derived from monotrifluoromethylated
OFP.
1
curately predict H NMR spectra of appropriately disub-
stituted OFP derivatives.
19F NMR. Monofunctionalized OFP derivatives exhibit
a characteristic four AB pattern in their 19F NMR
spectra,11 whereas interannular identically disubstituted
OFP derivatives contain only four different bridging
fluorine atoms, which manifest themselves as two AB
patterns. (This is also true for para and ortho oriented
intraannular substituted OFP derivatives). All of the
disubstituted OFP derivatives described herein display
only two AB patterns in their 19F NMR spectra. (Of
course, OFP derivatives bearing two different substitu-
ents have eight different bridge fluorines that appear as
four ABs, similar to a mono OFP product).
We believe that this is the first report of the calculation
of 19F SCS values, and the first demonstration that they
may be used to predict the shifts of the bridging fluorines
in multiply substituted OFP derivatives.
1H NMR. As a result of their symmetric nature,
heteroannularly identically disubstituted [2.2] PCPs
display a simple and characteristic 1H NMR pattern
consisting of one singlet and one AB pattern. All of the
disubstituted OFP products described herein also display
this feature. The pseudo-ortho disubstituted isomer is
generally the easiest to recognize since any “gem shift”
operates upon the resonance which is a singlet, forcing
it downfield, normally clear of the other resonances.
The problem previously described concerning the as-
signment of fluorine resonances to specific fluorine atoms
still exists for the derivatives described here except for
the four bis(trifluoromethyl)-OFP derivatives. The
“through space” coupling that occurs between a trifluo-
romethyl ring substituent and the proximate syn bridging
fluorines11 allowed the instant recognition of those bridge
fluorines since they appear as quartets. Their partners
in the respective AB patterns could be located by line
shape and coupling constants. Thus F1s/F1a, F2s/F2a for
trifluoromethyl-OFP could be assigned, although the
assignment of the remaining four fluorines was ambigu-
ous.
However, because of symmetry in the bis(trifluoro-
methyl)-OFP derivatives 8a -d , we can use this coupling
interaction to fully assign, for the first time, the bridge
fluorine resonances of these systems (and further confirm
the accuracy of our isomer assignments) (Figure 1). The
strategy was to first identify the resonances split into
the large and small quartets and then find their AB
partners. Easiest to identify was the pseudo-meta isomer,
since this is the only isomer to contain both quartet
Since it has been demonstrated that amino substituted
[2.2] PCPs are the most convenient for NMR investiga-
tion,15 we earlier derived the SCS values for the amino-
OFP system (Table 1). Prior work in hydrocarbon [2.2]
PCP systems has amply shown that these SCS values
are additive and therefore may be used to calculate
proton shifts for multiply substituted systems. We can
now compare the observed 1H shifts for our three di-
amino-OFP isomers, with those shifts calculated from our
SCS values (Table 2).
It is clear that there is good agreement between the
predicted and observed chemical shifts. This is taken as
further confirmation that not only were we accurate in
our previous assignment of the amino-OFP resonances,
but also our isomer assignments of the disubstituted
products were also correct. In future work we aim to
acquire SCS values for all of the monosubstituted OFP
derivatives, and also demonstrate their ability to ac-

Substitution Octafluoro[2.2]paracyclophane
J . Org. Chem., Vol. 65, No. 17, 2000 5287
Ta ble 3. 19F SCS Va lu es for 10 (p p m )
number of substituents on each ring.3,24 This has also
been demonstrated to be the case for monosubstituted
OFP derivatives,11 and all the new OFP compounds
described herein have mass spectra appropriate to the
general rules previously established for both the hydro-
carbon and fluorocarbon systems.
F1a
F1s
F2a
F2s
F3a
F3s
F4a
F4s
3.18
4.19
9.77
4.72
3.32
-0.19
2.55
0.38
Ta ble 4. Ca lcu la ted 19F Ch em ica l Sh ifts for 10, 8a -d
isomer
assignment
calculated
found
This technique provides the simplest way to discrimi-
nate between homo- and heteroannular disubstituted
isomers. For example, both the para and pseudo-para bis-
(trifluoromethyl)-OFP’s give the same molecular parent
ion of 488. The isomer with a trifluoromethyl group in
each ring fragments into two xylylene units of mass 244,
whereas the homoannular isomer fragments into unsub-
stituted and disubstituted xylylene fragments of mass
176 and 312.
P h ysica l P r op er ties. Cram derived many correla-
tions between physical properties and relative orientation
of disubstituted [2.2] PCP isomers.24 These general
relationships proved equally valid for the OFP systems
and indeed were fundamental to our early characteriza-
tion work. For example, during column chromatography
the disubstituted OFP derivatives always eluted in the
same order of pseudo-meta/pseudo-para, pseudo-ortho,
pseudo-gem. The pseudo-meta and pseudo-para isomers
could never be separated by column chromatography,
although they could be separated on a capillary GC (DB5)
column. The pseudo-para/pseudo-meta isomer mixture
could be enriched in one isomer or the other by fractional
crystallization or sublimation, with the pseudo-para
isomer being the least soluble and slowest to sublime.
In certain cases, analytical samples of pure pseudo-para
isomer could be obtained by fractional crystallization. The
pseudo-para isomer was also the isomer with the highest
melting point.
pseudo-para 8b
F2s
F2a
F1s
F1a
F1s
F1a
F2s
F2a
F2s
F2a
F1s
F1a
F2s
F2a
F1s
F1a
-110.73
-107.85
-110.49
-115.01
-110.10
-104.04
-115.64
-114.30
-112.90
-105.68
-114.00
-111.50
-109.96
-108.42
-111.26
-114.44
-112.90
-108.28
-111.77
-115.65
-112.03
-105.86
-118.29
-113.56
-112.23
-108.07
-114.75
-113.16
-112.85
-109.27
-114.83
-113.47
pseudo-meta 8a
pseudo-ortho 8c
para 8d
resonances within the same AB. (This also has the
unfortunate consequence that the other two fluorines for
this isomer cannot be assigned unambiguously). For the
other isomers, the resonances with the larger and smaller
quartets were assigned F2s and F1s respectively. Identi-
fication of their AB partners via line shape and coupling
constant gave F2a and F1a. Thus, for the first time, all
the fluorine atoms could be assigned to their fluorine
resonances.
This presented a situation where we had 19F chemical
shifts and assignments for four disubstituted OFP de-
rivatives and assignments for half of the shifts for the
corresponding monosubstituted derivative. Since we have
demonstrated that 1H SCS values are additive for the
OFP system, it was projected that the 19F SCS values
should be too, and therefore we should be able to work
backward and assign the remaining four fluorine shifts
for the mono derivative. Indeed, one set of assignments
for the remaining four fluorines gave much better agree-
ment than the others, as predicted from SCS values
taken from the disubstituted systems. These assignments
were therefore used in the calculation of the 19F SCS
values for the monotrifluoromethyl OFP system 10 (Table
3).
Ch a r a cter iza tion Su m m a r y. We have demonstrated
that both the previously established rules and strategies
for characterization of [2.2] PCP and mono OFP deriva-
tives are equally applicable to the identification of
disubstituted OFP derivatives and furthermore allow the
discrimination between disubstituted OFP isomers. The
use of previously derived 1H SCS values allowed the
1
prediction of H NMR spectra of disubstituted isomers,
and also derived 19F SCS values for trifluoromethyl OFP
can be used for the prediction of the 19F NMR shifts of
the bridge fluorines for bis(trifluoromethylated) OFP
isomers. Mass spectroscopy allows the easiest discrimi-
nation between homo- and heteroannular disubstituted
isomers.
When these values were used to calculate the shifts
for the four bis(trifluoromethyl) derivatives, reasonable
agreement was found (Table 4).
Hom oa n n u la r Su bstitu tion . When a second identi-
cal substituent is introduced into the same ring as the
first in an OFP, there are only three possible isomeric
products, of which two are meso and one is racemic. The
three isomers can in principle be differentiated simply
by inspection of the format of the 19F and 1H NMR
spectra. The para isomer will result in AB patterns in
both the 19F and the 1H spectra, whereas the ortho isomer
will produce 19F ABs but singlets in the 1H NMR
spectrum. The para meta isomer would also produce no
AB patterns in the 19F spectrum but would give an AB
Con clu sion s
We report for the first time the synthesis of 27 novel
octafluoroparacyclophanes with two substituents on the
aromatic rings. Both inter- and intraannular substitution
could be controlled by method of functionalization. The
characterization of these compounds using a combination
1
of mass spectrometry, 19F and H NMR allowed unam-
biguous determination of the relative locations of the
substituents, and these were further confirmed by the
general trends and characteristics of their physical
properties. Thermal isomerizations were studied, and it
was shown that temperatures around 350 °C were
required before isomerization through the breaking of
difluorobenzyl bonds would occur. This is almost 200 °C
higher than required for the analogous hydrocarbon [2.2]
PCPs.22
1
in the H spectrum. The only isomer to give rise to AB
patterns in both fluorine and proton NMR spectra would
be the para isomer. This is what was observed for
dibromo OFP, 5d , and bis(trifluoromethyl) OFP, 8b.
Ma ss Sp ectr om etr y. It has been well documented
that mass spectroscopic analysis of [2.2] PCP derivatives
provides an excellent method for determination of the

5288 J . Org. Chem., Vol. 65, No. 17, 2000
Roche and Dolbier
Anal. Calcd for C16H10F8N2: C, 50.26; H, 2.62; N, 7.33.
We believe this work provides the synthetic and
corresponding characterization foundations necessary for
a wide variety of future work in the previously barren
area of fluorinated cyclophanes.
Found: C, 49.98; H, 2.55; N, 7.07. MS m/z 382 (M+, 21%), 191
3
3
(100). 3a : 1H NMR δ 7.566 (d, J ) 8.40 Hz, 1H); 6.442 (d, J
) 8.40 Hz, 1H); 6.084 (s, 1H); 19F NMR δ -100.315 (m, 2F);
-112.440 (d, 2J ) 234.25 Hz, 1F); -116.601 (d, 2J ) 234.25
Hz, 1F). 3b: 1H NMR δ 7.038 (d, J ) 8.40 Hz, 1H); 6.874 (d,
3
Exp er im en ta l Section
3J ) 8.40 Hz, 1H); 6.003 (s, 1H); 19F NMR δ -103.339 (d, 2J )
239.33 Hz, 1F); -109.085 (d, 2J ) 239.33 Hz, 1F); -108.562
2
2
All NMR spectra were obtained at ambient temperatures
in deuterated acetone, using TMS and CFCl3 as references for
1H and 19F, respectively. All reagents, unless otherwise speci-
fied, were used as purchased from Aldrich or Fischer. Column
chromatography was performed using chromatographic silica
gel, 200-425 mesh, as purchased from Fischer. Melting points
are uncorrected. Mass spectroscopic analyses were performed
with an ionizing potential of 70 eV.
(d, J ) 234.25 Hz, 1F); -109.685 (d, J ) 234.25 Hz, 1F).
An ethanol (10 mL) solution containing pseudo-o-dinitro-
1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane 2c (380 mg,
0.86 mmol), cyclohexene (420 mg, 5.16 mmol) and 10% Pd on
carbon (0.2 g) was warmed to reflux, and after 15 min of
observable reflux, the reaction was evaporated under reduced
pressure to a solid residue which was subjected to chroma-
tography (chloroform/hexane 7/3, then chloroform) to give three
compounds: (Rf ) 0.46) p seu d o-o-n itr oa m in o-1,1,2,2,9,9,-
10,10-octa flu or o[2.2]p a r a cyclop h a n e 6 (40 mg, 11%): 1H
Din itr a tion of OF P 1. Under a counter current of dry
nitrogen, nitronium tetrafluoroborate (22.10 g, 166.17 mmol)
was added to octafluoroparacyclophane 1 (10.20 g, 28.98 mmol)
dissolved in sulfolane (100 mL), and the reaction was warmed
to 80 °C and stirred at this temperature overnight. The
reaction mixture was then allowed to cool to room temperature
and added to ice water (400 mL), and the white precipitate
was filtered and chromatographed (hexane/dichloromethane
7/3) to give (Rf ) 0.32) pseudo-m- and pseudo-p-dinitro-
1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophanes 2a ,b (6.92 g,
54% combined; 1:1 mixture): MS m/z 442 (M+, 6%), 125 (100).
Anal. Calcd for C16H6F8N2O4: C, 43.44; H, 1.36; N, 6.33.
Found: C, 43.70; H, 1.23; N, 6.21. 2a : 1H NMR δ 8.009 (s,
1H); 8.009 (m, 1H); 7.783 (d, 3J ) 8.10 Hz, 1H); 19F NMR δ
-108.806 (d, 2J ) 244.70 Hz, 1F); -111.989 (d, 2J ) 244.70
3
3
NMR δ 8.267 (s, 1H); 7.692 (d, J ) 8.40 Hz, 1H); 7.466 (d, J
) 8.40 Hz, 1H); 7.107 (d, 3J ) 8.40 Hz, 1H); 6.631 (d, 3J )
8.40 Hz, 1H); 6.453 (s, 1H); 5.818 (br s, 2H, NH2); 19F NMR δ
-105.172 (d, 2J ) 244.70 Hz, 1F); -112.620 (d, 2J ) 244.70
2
2
Hz, 1F); -106.128 (d, J ) 239.90 Hz, 1F); -110.660 (d, J )
239.90 Hz, 1F); -109.339 (d, 2J ) 244.70 Hz, 1F); -112.615
(d, 2J ) 244.70 Hz, 1F); -111.964 (d, 2J ) 234.82 Hz, 1F);
-116.298 (d, J ) 234.82 Hz, 1F); MS m/z 412 (M+, 25%), 191
2
(100); HRMS calcd for C16H8F8N2O2 412.0458, found 412.0481.
(Rf ) 0.20, chloroform) p seu d o-o-d ia m in o-1,1,2,2,9,9,10,10-
octa flu or o[2.2]p a r a cyclop h a n e 3c (126 mg, 38%), as above.
(Rf ) 0.11, chloroform) p seu d o-o-h yd r oxyla m in oa m in o-
1,1,2,2,9,9,10,10-octa flu or o[2.2]p a r a cyclop h a n e 7 (51 mg,
15%): 1H NMR δ 7.609 (s, 1H); 7.118 (d, 3J ) 8.40 Hz, 1H);
2
2
Hz, 1F); -115.321 (d, J ) 239.90 Hz, 1F); -117.317 (d, J )
239.90 Hz, 1F). 2b: 1H NMR δ 8.009 (s, 1H); 8.009 (m, 1H);
7.783 (d, 3J ) 8.10 Hz, 1H); 19F NMR δ -109.829 (d, 2J )
246.95 Hz, 1F); -113.986 (d, 2J ) 246.95 Hz, 1F); -114.352
3
6.958 (d, 3J ) 8.40 Hz, 1H); 6.627 (d, J ) 8.40 Hz, 1H); 6.373
(d, 3J ) 8.40 Hz, 1H); 6.691 (s, 1H); 8.249 (br s, 1H NH); 7.952
(br s, 1H, OH); 5.337 (br s 2H, NH2); 19F NMR δ -104.796 (d,
2J ) 242.16 Hz, 1F); -111.062 (d, 2J ) 242.16 Hz, 1F);
-106.012 (d, 2J ) 244.70 Hz, 1F); -111.220 (d, 2J ) 244.70
2
2
(d, J ) 237.36 Hz, 1F); -115.028 (d, J ) 237.36 Hz, 1F); (Rf
) 0.20). P seu d o-o-d in itr o-1,1,2,2,9,9,10,10-octa flu or o[2.2]-
p a r a cyclop h a n e 2c (3.46 g, 27%): mp 213-215 °C. 1H NMR
2
2
Hz, 1F); -106.120 (d, J ) 235.10 Hz, 1F); -113.514 (d, J )
235.10 Hz, 1F); -106.529 (d, 2J ) 232.28 Hz, 1F); -114.462
δ 8.075 (s, 1H); 7.827 (m, 2H); 19F NMR δ -111.023 (d, J )
2
244.70 Hz, 1F); -112.293 (d, 2J ) 244,70 Hz, 1F); -114.428
(d, 2J ) 242.44 Hz, 1F); -115.582 (d, 2J ) 242.44 Hz, 1F); MS
m/z 442 (M+, 10%), 125 (100). Anal. Calcd for C16H6F8N2O4:
C, 43.44; H, 1.36; N, 6.33. Found: C, 43.70; H, 1.29; N, 6.19.
The combined yield of the three dinitro isomers is 81%.
When only 4 equiv of nitronium tetrafluoroborate was used,
the product mixture was subjected to chromatography and
shown to contain the mononitrated cyclophane (36%), the
pseudo-m-2a (16%), pseudo-p-2b (16%) and pseudo-o-2c (16%)
dinitro-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophanes.
P se u d o-o-d ia m in o-1,1,2,2,9,9,10,10-oct a flu or o[2.2]-
p a r a cyclop h a n e 3c. A suspension of pseudo-o-dinitro-
1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane 2c (1.30 g, 2.94
mmol) in ethanol/water (1/1 v/v, 50 mL) was stirred for 1 h at
room temperature. Iron powder (2.00 g, 35.71 mmol) was
added, and the reaction mixture was heated to reflux. Con-
centrated hydrochloric acid (7 mL) was added dropwise to the
mixture, and reflux was continued for 4 h. After this time, the
reaction was cooled to room temperature and was added to
ice water (200 mL). The solids thus produced were filtered and
redissolved in chloroform. This chloroform solution was filtered
and evaporated, and the solid residue was chromatographed
(chloroform) to give (Rf ) 0.41) pseudo-o-diamino-1,1,2,2,9,9,-
10,10-octafluoro[2.2]paracyclophane 3c (0.91 g, 82%): mp 211
(d, J ) 232.28 Hz, 1F); MS m/z 398 (M+, 23%), 207 (5), 191
2
(100); HRMS calcd for C16H10F8ON2 398.0665, found 398.0656.
Typ ica l Dia zotiza tion P r oced u r e. A solution of pseudo-
o-diamino-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane 3c
(2.00 g, 5.24 mmol) in acetic acid (4 mL) was cooled to 0 °C in
an ice/brine bath; ice (1.5 mL) and concentrated 98% sulfuric
acid (1.5 mL) were carefully added with stirring; and ensuring
the temperature was still below 0 °C, sodium nitrite (2.00 g,
28.99 mmol) was added in one batch. The reaction was stirred
at this temperature for 2 h and then used for the following
transformations:
P se u d o-o-d ib r om o-1,1,2,2,9,9,10,10-oct a flu or o[2.2]-
p a r a cyclop h a n e 5c. An aqueous solution (10 mL) of copper-
(I) bromide (4.00 g, 27.87 mmol) and 47% hydrobromic acid
(10 mL) was warmed to 70 °C, and the diazotization solution
previously prepared was added in one batch with stirring. The
mixture was kept at 70 °C for 1 h and then left to cool
overnight. The precipitated product was filtered, and chro-
matographed (hexane/ether 9/1) to give (Rf ) 0.45) pseudo-o-
dibromo-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane 5c (1.60
1
g, 60%): mp 125-126 °C; H NMR δ 7.845 (s, 1H); 7.520 (d,
3J ) 8.10 Hz, 1H); 7.369 (d, 3J ) 8.10 Hz, 1H); 19F NMR δ
-109.460 (d, 2J ) 239.90 Hz, 1F); -113.529 (d, 2J ) 239.90
2
2
Hz, 1F); -110.473 (d, J ) 239.90 Hz, 1F); -110.620 (d, J )
239.90 Hz, 1F); MS m/z 510 (M+, 5%), 508 (2), 512 (2), 254
(100), 256 (94). Anal. Calcd for C16H6F8Br2: C, 37.65; H, 1.18.
Found: C, 37.69; H, 1.15.
3
°C (dec); 1H NMR δ 6.999 (d, J ) 8.40 Hz, 1H); 6.885 (s, 1H);
6.361 (d, 3J ) 8.40 Hz, 1H); 19F NMR δ -106.652 (dd, 2J )
3
2
232.56, J ) 9.60 Hz, 1F); -114.370 (d, J ) 232.56 Hz, 1F);
2
3
2
-106.873 (dd, J ) 242.44, J ) 9.60 Hz, 1F); -111.223 (d, J
) 242.44 Hz, 1F); MS m/z 382 (M+, 19%), 191 (100). Anal.
Calcd for C16H10F8N2: C, 50.26; H, 2.62; N, 7.33. Found: C,
50.17; H, 2.41; N, 7.21.
An identical reaction with a 1:1 mixture of pseudo-m- and
pseudo-p-diamino-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclo-
phanes 3a ,b gave the corresponding pseudo-m- and pseudo-
p-dibromo-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophanes 5a,b
in 65% yield: (hexane/chloroform 9/1, Rf ) 0.62). Anal. Calcd
for C16H6F8Br2: C, 37.65; H, 1.18. Found: C, 37.44; H, 1.13.
MS m/z 510 (M+, 4%), 508 (2), 512 (2), 254 (100), 256 (94). 5a :
1H NMR δ 7.428 (s, 1H); 7.799 (d, 3J ) 8.10 Hz, 1H); 7.486 (d,
An identical reaction with a 1:1 mixture of pseudo-m- and
pseudo-p-dinitro-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclo-
phanes 2a ,b gave the corresponding pseudo-meta- and
pseudo-para-diamino-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclo-
phanes 3a ,b in 84% yield. (hexane/chloroform 1/1, Rf ) 0.46):
2
3J ) 8.40 Hz, 1H); 19F NMR δ -103.640 (d, J ) 239.90 Hz,

Substitution Octafluoro[2.2]paracyclophane
J . Org. Chem., Vol. 65, No. 17, 2000 5289
2
6
1F); -113.529 (d, 2J ) 239.90 Hz, 1F); -110.473 (d, 2J ) 239.90
Hz, 1F); -110.620 (d, 2J ) 239.90 Hz, 1F). 5b: 1H NMR δ
-113.747 (dq, J ) 234.82, J ) 14.54 Hz, 1F); -114.623 (dd,
3 5 6
2J ) 234.82, J ) 7.20 Hz, 1F); -59.257 (dd, J ) 29.07, J )
14.54 Hz, 3F); MS m/z 546 (M+, 5%), 302 (100), 244 (10); HRMS
calcd for C17H6F11I 545.9339, found 545.9401. (Rf ) 0.17)
pseu do-o-bis(tr iflu or om eth yl)-1,1,2,2,9,9,10,10-octaflu or o-
3
3
7.165 (s, 1H); 7.895 (d, J ) 8.40 Hz, 1H); 7.411 (d, J ) 8.40
Hz, 1H); 19F NMR δ -108.141 (d, 2J ) 239.62 Hz, 1F);
2
-109.137 (d, J ) 239.62 Hz, 1F); -110.582 (m, 2F).
1
P s e u d o -o-d iio d o -1,1,2,2,9,9,10,10-o c t a flu o r o [2.2]-
p a r a cyclop h a n e 4c. An aqueous solution (10 mL) of potas-
sium iodide (5.11 g, 30.78 mmol) was warmed to 70 °C, and
the diazotization solution previously prepared was added in
one batch with stirring. The mixture was kept at 70 °C for 1
h and then left to cool overnight. The precipitated product was
filtered and chromatographed (hexane/ether 9/1) to give (Rf )
0.42) pseudo-o-diiodo-1,1,2,2,9,9,10,10-octafluoro[2.2]para-
cyclophane 4c (2.47 g, 78%): mp 132-133 °C; 1H NMR δ 8.157
(s, 1H); 7.457 (d, 3J ) 8.70 Hz, 1H); 7.403 (d, 3J ) 8.70 Hz,
[2.2]p a r a cyclop h a n e 8c (1.65 g, 68%): mp 154-155 °C; H
NMR δ 7.493 (s, 1H); 7.733 (m, 2H); 19F NMR δ -108.067 (dd,
2J ) 242.16, J ) 9.60 Hz, 1F); -112.234 (dq, J ) 242.16, J
3
2
5
) 29.07 Hz, 1F); -113.163 (dd, 2J ) 237.36, 3J ) 9.60 Hz, 1F);
2
6
-114.751 (dq, J ) 237.36, J ) 14.68 Hz, 1F); -59.160 (dd,
5J ) 29.07, 6J ) 14.68 Hz, 3F); MS m/z 488 (M+, 5%), 244 (100).
Anal. Calcd for C18H6F14: C, 44.26; H, 1.24. Found: C, 44.24;
H, 1.02.
An identical reaction with a 1:1 mixture of pseudo-m- and
pseudo-p-diiodo-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclo-
phanes 4a ,b gave the corresponding pseudo-m- and pseudo-
p-bis(t r iflu or om et h yl)-1,1,2,2,9,9,10,10-oct a flu or o[2.2]-
paracyclophanes 8a ,b in 80% yield: (hexane/ether 9/1, Rf )
0.67). Anal. Calcd for C18H6F14: C, 44.26; H, 1.24. Found: C,
44.32; H, 1.15. MS m/z 488 (M+, 4%), 244 (100).
2
1H); 19F NMR δ -107.330 (d, J ) 237.36 Hz, 1F); -112.570
(d, 2J ) 237.36 Hz, 1F); -109.323 (d, 2J ) 239.90 Hz, 1F);
2
-110.319 (d, J ) 239.90 Hz, 1F); MS m/z 604 (M+, 3%), 302
(100). Anal. Calcd for C16H6F8I2: C, 31.79; H, 0.99. Found: C,
31.96; H, 0.92.
An identical reaction with a 1:1 mixture of pseudo-m- and
pseudo-p-diamino-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclo-
phanes 3a ,b gave the corresponding pseudo-m- and pseudo-
p-diiodo-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophanes 4a ,b
in 78% yield: (hexane/ether 9/1, Rf ) 0.61). Anal. Calcd for
There was no evidence of any iodo-trifluoromethyl isomers
in this reaction. (It was possible to collect an analytic sample
of the more insoluble pseudo-p-bis(trifluoromethyl)-1,1,2,2,9,9,-
10,10-octafluoro[2.2]paracyclophane 8b by fractional crystal-
lization, which had mp 199-200 °C). 8a : 1H NMR δ 7.824 (s,
3
3
C
16H6F8I2: C, 31.79; H, 0.99. Found: C, 31.86; H, 0.86. MS
1H); 7.710 (d, J ) 8.40 Hz, 1H); 7.543 (d, J ) 8.40 Hz, 1H);
m/z 604 (M+, 3%), 302 (100). 4a : 1H NMR δ 7.820 (s, 1H); 7.758
19F NMR δ -105.860 (dq, 2J ) 242.16, 6J ) 14.68 Hz, 1F);
3
3
2
5
(d, J ) 8.10 Hz, 1H); 7.450 (d, J ) 8.10 Hz, 1H); 19F NMR δ
-112.029 (dq, J ) 242.16, J ) 29.07 Hz, 1F); -113.562 (d,
2J ) 247.24 Hz, 1F); -118.289 (d, 2J ) 247.24 Hz, 1F); -58.633
-102.046 (d, 2J ) 241.03 Hz, 1F); -105.807 (d, 2J ) 241.03
Hz, 1F); -115.704 (d, J ) 239.90 Hz, 1F); -116.452 (d, J )
239.90 Hz, 1F). 4b: 1H NMR δ 7.573 (s, 1H); 7.994 (d, 3J )
8.40 Hz, 1H); 7.482 (d, 3J ) 8.40 Hz, 1H); 19F NMR δ -107.109
(d, 2J ) 237.36 Hz, 1F); -109.445 (d, 2J ) 237.36 Hz, 1F);
-108.734 (d, 2J ) 237.36 Hz, 1F); -111.322 (d, 2J ) 237.36
Hz, 1F).
(dd, J ) 29.07, J ) 14.68 Hz, 3F). 8b: 1H NMR δ 7.850 (s,
2
2
5
6
3
3
1H); 7.693 (d, J ) 8.40 Hz, 1H); 7.574 (d, J ) 8.40 Hz, 1H);
19F NMR δ -107.280 (dd, 2J ) 242.16, 3J ) 7.06 Hz, 1F);
2
5
-112.902 (dq, J ) 242.16, J ) 31.61 Hz, 1F); -111.769 (dq,
2J ) 237.36, J ) 9.88 Hz, 1F); -115.648 (dd, J ) 237.36, J
6
2
3
5
6
) 7.06 Hz, 1F); -58.300 (dd, J ) 31.61, J ) 9.88 Hz, 3F).
4-Tr iflu or om e t h yl-1,1,2,2,9,9,10,10-oct a flu or o[2.2]-
p a r a cyclop h a n e 10. An acetic acid solution (30 mL) contain-
ing pseudo-o-iodo-trifluoromethyl-1,1,2,2,9,9,10,10-octafluoro-
[2.2]paracyclophane 9 (230 mg, 0.42 mmol) and zinc (110 mg,
1.70 mmol) was refluxed overnight. The mixture was cooled
to ambient temperatures and added to ice water (100 mL). The
precipitates were collected and subjected to column chroma-
tography (hexane/diethyl ether 8/2) producing (Rf ) 0.56)
4-trifluoromethyl-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclo-
phane 10 (160 mg, 91%), analytically identical to an authentic
sample.11
P se u d o-o-d ip h e n yl-1,1,2,2,9,9,10,10-oct a flu or o[2.2]-
p a r a cyclop h a n e 11. Benzene (10 mL) was added to the
chilled diazotization solution, and 1 min later an aqueous (3
mL) solution of sodium acetate (1.00 g, 12.20 mmol) was added.
The biphasic mixture was allowed to warm to room temper-
ature overnight with vigorous stirring. Ether was then added,
and the bright orange organic phase was separated, dried and
evaporated. The crude residue was chromatographed (hexane/
dichloromethane 9/1) to give (Rf ) 0.27) 4-phenyl-1,1,2,2,9,9,-
10,10-octafluoro[2.2]paracyclophane 1210 (0.72 g, 32%) and (Rf
) 0.20) pseudo-o-diphenyl-1,1,2,2,9,9,10,10-octafluoro[2.2]-
paracyclophane 11 (0.42 g, 16%): 1H NMR δ 7.437 (s, 1H);
P seu d o-o-d ia ceta m id o-1,1,2,2,9,9,10,10-octa flu or o[2.2]-
p a r a cyclop h a n e, 14c. A dichloromethane (5 mL) solution of
pseudo-o-diamino-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclo-
phane 3c (200 mg, 0.52 mmol) was warmed to reflux, acetyl
chloride (2 mL) was added dropwise, and the reaction was
refluxed overnight. Rotary evaporation afforded a pale brown
residue, which after chromatography (hexane/ether 1/9) gave
(Rf ) 0.60) pseudo-o-diacetamido-1,1,2,2,9,9,10,10-octafluoro-
[2.2]paracyclophane 14c (0.24 g, 97%): mp 199-201 °C; 1H
3
3
7.782 (d, J ) 8.10 Hz, 1H); 7.641-7.523 (m, 5H); 7.452 (d, J
) 8.10 Hz, 1H); 19F NMR δ -104.750 (d, J ) 239.62 Hz, 1F);
2
-113.413 (d, 2J ) 239.62 Hz, 1F); -112.688 (d, 2J ) 244.70
Hz, 1F); -117.061 (d, J ) 244.70 Hz, 1F); MS m/z 504 (M+,
2
8%), 251 (80), 232 (100); HRMS calcd for C28H16F8 504.1124,
found 504.1157.
P s e u d o -o-b i s (t r i flu o r o m e t h y l)-1,1,2,2,9,9,10,10-
oct a flu or o[2.2]p a r a cyclop h a n e 8c. A degassed DMF (40
mL) solution containing pseudo-o-diiodo-1,1,2,2,9,9,10,10-
octafluoro[2.2]paracyclophane 4c (3.00 g, 4.97 mmol), methyl
2-(fluorosulfonyl) difluoroacetate (9.53 g, 49.67 mmol) and
palladium dichloride (40 mg, 0.23 mmol) was warmed to 80
°C under a blanket of nitrogen. Copper(I) bromide (5.33 g,
37.25 mmol) was added in one portion, and the mixture was
maintained at that temperature overnight. Then the mixture
was cooled to ambient temperature before adding ice water.
The mixture was stirred for 30 min and then the precipitates
were removed by filtration and were subjected to column
3
3
NMR δ 7.818 (s, 1H); 7.392 (d, J ) 8.10 Hz, 1H); 7.074 (d, J
) 8.40 Hz, 1H); 8.854 (br s, 1H, NH); 2.243 (s, 3H, CH3); 19F
2
2
NMR δ -107.595 (d, J ) 244.70 Hz, 1F); -111.870 (d, J )
244.70 Hz, 1F); -111.439 (d, 2J ) 237.36 Hz, 1F); -114.882
(d, J ) 237.36 Hz, 1F); MS m/z 466 (M+, 27%), 446 (40), 233
2
(12), 191 (100). Anal. Calcd for C20H14F8N2O2: C, 51.50; H,
3.00; N, 6.01. Found: C, 51.32; H, 3.05; N, 5.91.
An identical reaction with a 1:1 mixture of pseudo-m- and
pseudo-p-diamino-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclo-
phanes 3a ,b gave the corresponding pseudo-m- and pseudo-
p-dia cet a m ido-1,1,2,2,9,9,10,10-oct a fluoro[2.2]pa ra cyclo-
phanes, 14a and b, in 84% yield: (hexane/ether 4/6, Rf ) 0.44).
Anal. Calcd for C20H14F8N2O2: C, 51.50; H, 3.00; N, 6.01.
Found: C, 51.38; H, 2.91; N, 5.91. MS m/z 466 (M+, 5%), 446
(42), 233 (22), 191 (100). Pseudo-meta isomer 14a : 1H NMR δ
chromatography (hexane/diethyl ether 9/1) affording (Rf
)
0.31) p seu d o-o-iod otr iflu or om eth yl-1,1,2,2,9,9,10,10-octa -
flu or o[2.2]p a r a cyclop h a n e 9 (0.27 g 10%): 1H NMR δ 7.309
3
3
(s, 1H); 6.726 (s, 1H); 6.892 (d, J ) 8.40 Hz, 1H); 6.757 (d, J
) 8.40 Hz, 1H); 6.705 (d, 3J ) 8.70 Hz, 1H); 6.652 (d, 3J )
8.70 Hz, 1H); 19F NMR δ -107.182 (dd, 2J ) 242.16, 3J ) 7.20
Hz, 1F); -112.966 (dq, 2J ) 242.16, 5J ) 29.06 Hz, 1F);
3
3
8.112 (s, 1H); 7.401 (d, J ) 8.40 Hz, 1H); 7.013 (d, J ) 8.40
Hz, 1H); 8.817 (br s, 1H, NH); 2.251 (s, 3H, CH3); 19F NMR δ
-103.130 (d, 2J ) 247.10 Hz, 1F); -104.959 (d, 2J ) 247.10
2
3
-107.635 (dd, J ) 239.90, J ) 12.10 Hz, 1F); -110.960 (dd,
2J ) 239.90, J ) 7.30 Hz, 1F); -108.138 (dd, J ) 236.23, J
Hz, 1F); -115.615 (d, J ) 237.36 Hz, 1F); -115.911 (d, J )
237.36 Hz, 1F). Pseudo-para isomer 14b: 1H NMR δ 7.808 (s,
3
2
3
2
2
) 12.10 Hz, 1F); -110.315 (dd, 2J ) 236.23, 3J ) 7.30 Hz, 1F);

5290 J . Org. Chem., Vol. 65, No. 17, 2000
Roche and Dolbier
3
3
1H); 7.401 (d, J ) 8.10 Hz, 1H); 7.082 (d, J ) 8.10 Hz, 1H);
8.942 (br s, 1H, NH); 2.251 (s, 3H, CH3); 19F NMR δ -107.616
(d, 2J ) 244.70 Hz, 1F); -111.836 (d, 2J ) 244.70 Hz, 1F);
-113.462 (d, 2J ) 237.36 Hz, 1F); -114.314 (d, 2J ) 237.36
Hz, 1F).
and TLC showed the presence of starting material, mono-
bromo OFP and several dibromide isomers, one of which
seemed predominant. The reaction was warmed to 80 °C and
left another 12 h. The mixture was cooled to ambient temper-
atures, and added to 100 mL of ice water. The pale yellow
precipitate was subjected to column chromatography (hexane/
chloroform 50/1) and gave (Rf ) 0.36) p-dibromo-1,1,2,2,9,9,-
10,10-octafluoro[2.2]paracyclophane 5d (0.65 g, 55%): mp
P se u d o-o-b is(t r iflu or oa ce t a m id o)-1,1,2,2,9,9,10,10-
octa flu or o[2.2]p a r a cyclop h a n e 13c. A solution of pseudo-
o-diamino-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane 3c
(270 mg, 0.71 mmol) in trifluoroacetic anhydride (4 mL) was
refluxed overnight. After this time, rotary evaporation yielded
a solid residue that after chromatography (chloroform) afforded
(Rf ) 0.64) pseudo-o-bis(trifluoroacetamido)-1,1,2,2,9,9,10,10-
octafluoro[2.2]paracyclophane 13c (0.39 g, 95%): mp 123-124
°C; 1H NMR δ 7.550 (s, 1H); 7.470 (d, 3J ) 8.40 Hz, 1H); 7.237
(d, 3J ) 8.40 Hz, 1H); 9.801 (br s, 1H, NH); 19F NMR δ
1
3
159-161 °C; H NMR δ 7.416 (s, 1H); 7.970 (d, J ) 8.40 Hz,
3
2
1H); 7.481 (d, J ) 8.40 Hz, 1H); 19F NMR δ -110.194 (d, J
) 237.36 Hz, 1F); -112.642 (d, 2J ) 237.36 Hz, 1F); -111.499
(m, 2F); MS m/z 508 (M+, 6%), 510 (13), 512 (6), 334 (5), 254
(53), 256 (49), 176 (100). Anal. Calcd for C16H6F8Br2: C, 37.65;
H, 1.18. Found: C, 37.81; H, 1.19. (Rf ) 0.20) A mixture of
monobromo-, dibromo- (2 isomers) and tribromo-(3 isomers)
-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophanes (0.172 g).
GLCMS indicted that the dibromo isomers in the second
fraction showed one isomer each of hetero- and homoannular
distribution, while the tribromides all contained two bromines
on one ring and one in the other. This second fraction was not
further analyzed.
2
2
-109.464 (d, J ) 247.24, Hz, 1F); -112.265 (d, J ) 247.24,
2
2
Hz, 1F); -113.333 (d, J ) 239.90 Hz, 1F); -114.249 (d, J )
239.90, Hz, 1F); -75.832 (s, 3F); MS m/z 574 (M+, 6%), 554
(32), 287 (22), 267 (100). Anal. Calcd for C20H8F14N2O2: C,
41.81; H, 1.39; N, 4.88. Found: C, 41.64; H, 1.29; N, 4.80.
An identical reaction with a 1:1 mixture of pseudo-m- and
pseudo-p-diamino-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclo-
phanes 3a ,b gave the corresponding pseudo-m- and pseudo-
p-bis(trifluoroacetamido)-1,1,2,2,9,9,10,10-octafluoro[2.2]-
paracyclophanes 13a and b in 97% yield: (hexane/ether 4/6,
Rf ) 0.44). Anal. Calcd for C20H8F14N2O2: C, 41.81; H, 1.39;
N, 4.88. Found: C, 41.77; H, 1.34; N, 4.81. MS m/z 574 (M+,
3%), 554 (32), 287 (82), 267 (100). Pseudo-meta isomer 13a :
1H NMR δ 7.641 (s, 1H); 7.533 (d, 3J ) 8.40 Hz, 1H); 7.252 (d,
3J ) 8.40 Hz, 1H); 10.117 (br s, 1H, NH); 19F NMR δ -107.988
(d, 2J ) 247.24 Hz, 1F); -108.255 (d, 2J ) 247.24 Hz, 1F);
-116.278 (d, 2J ) 239.90 Hz, 1F); -118.013 (d, 2J ) 239.90
Hz, 1F); -75.514 (s, 3F). Pseudo-para isomer 13b: 1H NMR δ
p-Bis(tr iflu or om eth yl)-1,1,2,2,9,9,10,10-octa flu or o[2.2]-
p a r a cyclop h a n e 8d . A degassed DMF (20 mL) solution
containing p-dibromo-1,1,2,2,9,9,10,10-octafluoro[2.2]para-
cyclophane 5d (0.53 g, 1.04 mmol) and methyl 2-(fluorosulfo-
nyl) difluoroacetate (0.80 g, 4.16 mmol) was warmed to 100
°C under a blanket of nitrogen. Copper(I) bromide (0.59 g, 4.16
mmol) was added in one portion, and the mixture was
maintained at that temperature overnight. Then the mixture
was cooled to ambient temperature before adding ice water.
The mixture was stirred for 30 min and then the precipitates
were removed by filtration and were subjected to column
chromatography (hexane/diethyl ether 9/1) affording (Rf
)
3
3
7.765 (s, 1H); 7.406 (d, J ) 8.40 Hz, 1H); 7.374 (d, J ) 8.40
0.72) p-bis(trifluoromethyl)-1,1,2,2,9,9,10,10-octafluoro[2.2]-
paracyclophane 8d (66 mg, 13%): mp 125-126 °C; 1H NMR δ
7.810 (s, 1H); 7.427 (m, 2H); 19F NMR δ -109.271 (dd, 2J )
244.67, 3J ) 9.88 Hz, 1F); -112.848 (dq, 2J ) 244.67, 5J )
Hz, 1H); 10.117 (br s, 1H, NH); 19F NMR δ -111.130 (d, J )
2
246.95 Hz, 1F); -111.292 (d, 2J ) 246.95 Hz, 1F); -113.375
(d, 2J ) 239.62 Hz, 1F); -115.955 (d, 2J ) 239.62 Hz, 1F);
-75.574 (s, 3F).
2
3
29.07 Hz, 1F); -113.468 (dd, J ) 232.54, J ) 9.88 Hz, 1F);
2
6
P se u d o-o-d ip h e n yl-1,1,2,2,9,9,10,10-oct a flu or o[2.2]-
p a r a cyclop h a n e 11. A degassed THF solution (5 mL) con-
taining pseudo-o-diiodo-1,1,2,2,9,9,10,10-octafluoro[2.2]para-
cyclophane 4c (300 mg, 0.50 mmol) and palladium dichloride
(21 mg, 0.12 mmol) was stirred and brought to reflux under a
nitrogen atmosphere. A 1 M THF solution of phenylmagnesium
bromide (3.0 mL, 3.00 mmol) was added via syringe, and the
black solution was refluxed overnight. Evaporation of the
solvent was followed by the addition of ice water, and the
precipitated solids were chromatographed (hexane/dichlo-
romethane 9/1) to give (Rf ) 0.44) 4-phenyl-1,1,2,2,9,9,10,10-
-114.830 (dq, J ) 232.54, J ) 16.93 Hz, 1F); -59.187 (dd,
5J ) 29.07, J ) 16.93 Hz, 3F); MS m/z 488 (M+, 3%), 312 (3),
6
176 (100). Anal. Calcd for C18H6F14: C, 44.26; H, 1.23. Found:
C, 44.47; H, 1.19. (Rf ) 0.40) 4-Trifluoromethyl-1,1,2,2,9,9,-
10,10-octafluoro[2.2]paracyclophane 10 (74 mg, 17%), whose
characterization was identical to an authentic sample.11
Th er m a l Isom er iza tion . A tube containing pseudo-o-bis-
(trifluoroacetamido)-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclo-
phane, 13c, (90 mg, mmol) was evacuated, sealed and im-
mersed in a Woods metal heating bath at 381-390 °C for 2 h.
After this time, the tube was cooled, opened and shown by 19
F
octafluoro[2.2]paracyclophane 1211 (43 mg, 20%) and (Rf
)
NMR to contain both pseudo-o- and pseudo-p-bis(trifluoroac-
etamido)-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophanes in a
5:1 ratio. This material was placed into another identical tube,
and again evacuated, sealed and immersed into the Woods
metal heating bath and heated at 350-363 °C for 24 h. The
resulting product mixture was shown by 19F NMR to now
contain a 1:7 ratio of pseudo-o- and pseudo-p-bis(trifluoroac-
etamido)-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophanes. In-
tegration versus an internal standard of trifluorotoluene
showed the mass balance of the two isomers was 75%.
0.37) pseudo-o-diphenyl-1,1,2,2,9,9,10,10-octafluoro[2.2]para-
cyclophane 11 (53 mg, 21%): 1H NMR δ 7.437 (s, 1H); 7.782
(d, 3J ) 8.10 Hz, 1H); 7.641-7.523 (m, 5H); 7.452 (d, 3J ) 8.10
Hz, 1H); 19F NMR δ -104.750 (d, 2J ) 239.62 Hz, 1F);
-113.413 (d, 2J ) 239.62 Hz, 1F); -112.688 (d, 2J ) 244.70
Hz, 1F); -117.061 (d, J ) 244.70 Hz, 1F); MS m/z 504 (M+,
2
8%), 251 (80), 232 (100); HRMS calcd for C28H16F8 504.1124,
found 504.1157.
p -D i b r o m o -1 , 1 , 2 , 2 , 9 , 9 , 1 0 , 1 0 -o c t a f l u o r o [ 2 . 2 ] -
p a r a cyclop h a n e 5d . A trifluoroacetic acid solution (3 mL)
containing 1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane 1
(1.00 g, 2.84 mmol) and N-bromosuccinimide (2.02 g, 11.35
mmol) was stirred magnetically in a flask protected by a silica
drying tube. After 5 min, 98% sulfuric acid (1 mL) was added,
and left to stir for 16 h. After this time analysis by 19F NMR
Ack n ow led gm en t. Support of this work in part by
AlphaMetals, Inc. is gratefully acknowledged, and the
authors thank Mr. J .-X. Duan for helpful discussions.
J O000436X