Synthesis of perfluoro[2.2]paracyclophane

Article abstract of DOI:10.1021/jo7026849

(Chemical Equation Presented) A synthesis of perfluoro[2.2]paracyclophane has been sought ever since the partially fluorinated octafluoro[2.2]- paracyclophane (AF4) was prepared and its chemistry studied. This compound has now been prepared in 39% yield from the precursor, 1,4-bis(chlorodifluoromethyl) -2,3,5,6-tetrafluorobenzene by its reaction with Zn when heated in acetonitrile at 100°C. Two preparations of the precursor, first from 1,4-dicyano-2,3,5,6- tetrachlorobenzene and an improved method beginning from 1,2,4,5- tetrachlorobenzene, are also described as are key comparisons to our related synthesis of AF4.

Full text of DOI:10.1021/jo7026849

SCHEME 1. [2.2]Paracyclophanes and Their Conversion to
Parylene Polymers
Synthesis of Perfluoro[2.2]paracyclophane
William R. Dolbier, Jr.,* Puhui Xie, Lianhao Zhang,
Wei Xu, Ying Chang, and Khalil A. Abboud
Department of Chemistry, UniVersity of Florida,
P.O. Box 117200, GainesVille, Florida 32611-7200
quantities to be prepared.3-6 The best of our procedures, that
where 1,4-bis(chlorodifluoromethyl)benzene was allowed to
react with zinc in dimethylacetamide (DMA) under non-high-
dilution conditions, is shown in eq 1.4 This process is currently
used to manufacture AF4 for use in the Parylene industry.
wrd@chem.ufl.edu
ReceiVed December 17, 2007
Perfluoro[2.2]paracyclophane, herein referred to as F8, has
been the subject of much interest as a potential Parylene
precursor ever since the bridge-fluorinated AF4 was found to
be so useful. It was predicted that the polymer derived from F8
would retain the high thermal stability of the AF4-derived
polymer while having a lower dielectric constant, better
dielectric strength, a very low coefficient of friction, plus
transparency in regions of spectra (ir spectra, in particular) that
involve C-H bonds. Nevertheless, until this report no synthesis
of F8 had been reported.7,8
The approach to synthesis of F8 that ultimately proved
successful emulated the method shown above for AF4. However,
significant changes in key steps were required because of the
presence of the ring fluorines. For example, a completely
different synthesis of the logical [2.2]paracyclophane precursor
1,4-bis(chlorodifluoromethyl)-2,3,5,6-tetrafluorobenzene (1) proved
necessary because the ring fluorines effectively inhibited both
the chlorination and fluorination steps of our published proce-
dure for synthesis of the AF4 precursor.9
A synthesis of perfluoro[2.2]paracyclophane has been sought
ever since the partially fluorinated octafluoro[2.2]-
paracyclophane (AF4) was prepared and its chemistry
studied. This compound has now been prepared in 39% yield
from the precursor, 1,4-bis(chlorodifluoromethyl)-2,3,5,6-
tetrafluorobenzene by its reaction with Zn when heated in
acetonitrile at 100 °C. Two preparations of the precursor,
first from 1,4-dicyano-2,3,5,6-tetrachlorobenzene and an
improved method beginning from 1,2,4,5-tetrachlorobenzene,
are also described as are key comparisons to our related
synthesis of AF4.
[2.2]Paracyclophanes are useful chemical vapor deposition
(CVD) precursors of a family of thin film polymers known as
Parylenes.1 Parylene polymers are conformal coatings that are
ideally suited for a wide variety of applications within the
automotive, medical, electronics and semiconductor industries.
Parylene coatings are transparent, chemically inert, and they
have excellent barrier properties.
The process of conversion of a [2.2]paracyclophane into a
Parylene polymer is exemplified in Scheme 1 for the parent
hydrocarbon system. The hydrocarbon version of the polymer,
Parylene N, has good thermal stability, remaining useful (for
several hours) at temperatures up to 130 °C. However, for those
applications that require a coating of greater thermal stability,
the bridge-fluorinated Parylene-HT, which exhibits only 0.3%
weight loss per hour at 450 °C, is preferred. The precursor for
Parylene HT is 1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane,
commonly known as AF4, and which for the last 15 years has
been the subject of considerable synthetic interest. Since our
initial published preparation, in 1993,2 which allowed gram
quantities of AF4 to be prepared, four subsequent papers
provided procedures that would allow larger, even commercial
Instead, we utilized alternative synthetic schemes to prepare
precursor 1. Our initial approach utilized commercially available
2,3,5,6-tetrachloro-1,4-dicyanobenzene as the starting material
(Scheme 2). Tetrafluoro compound 2 was prepared in 89% yield
by facile Cl-F exchange using KF in DMF along with 2% phase
transfer agent tetrabutyl ammonium bromide.10 The cyano
groups were then reduced using DIBAL-H in toluene to form
(3) Amii, H.; Hatamoto, Y.; Seo, M.; Uneyama, K. J. Org. Chem. 2001,
66, 7216-7218.
(4) Dolbier, W. R., Jr.; Duan, J.-X.; Roche, A. J. Org. Lett. 2000, 2,
1867-1869.
(5) Dolbier, W. R., Jr.; Rong, X. X.; Xu, Y. L.; Beach, W. F. J. Org.
Chem. 1997, 62, 7500-7502.
(6) Zhu, S.-Z.; Mao, Y.-Y.; Jin, G.-F.; Qin, C.-Y.; Chu, Q.-L.; Hu, C.-
M. Tetrahedron Lett. 2002, 43, 669-671.
(7) F8 has been “mentioned” in a recent patent as a precursor of the
respective Parylene polymer.8 However, no preparation, properties or
characterization of F8 is described in this patent.
(8) Kaji, S. JP 2005-183729 (2005).
(1) Dolbier, W. R., Jr.; Beach, W. F. J. Fluorine Chem. 2003, 122, 97-
104.
(2) Dolbier, W. R., Jr.; Asghar, M. A.; Pan, H. Q.; Celewicz, L. J. Org.
Chem. 1993, 58, 1827-1830.
(9) Dolbier, W. R., Jr.; Duan, J.-X.; Rong, X. X. J. Fluorine Chem. 2007,
128, 1091-1093.
(10) Zhu, S.; Zhao, J.; Cai, X. J. Fluorine Chem. 2004, 125, 451-454.
10.1021/jo7026849 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/27/2008
J. Org. Chem. 2008, 73, 2469-2472
2469

SCHEME 2. First Synthesis of F8 Precursor 1
SCHEME 4. Chemical Characterization of Bis-Zn Reagent
6
SCHEME 3. Improved Synthesis of F8 Precursor 1
A fluorine NMR spectrum of the product mixture indicated that
1 had been converted cleanly to a single product that exhibited
two singlet signals, at -101.5 and -146.4 ppm, signals that
were not inconsistent with the product actually being the desired
perfluoro[2.2]paracyclophane. However, any attempt to work
the reaction up and isolate a product led to no isolable fluorine-
containing product. It finally was concluded that these new
signals were due to formation of the over-reduced bis-zinc
reagent 6. This conclusion was based upon two reactions of
the intermediate, both of which were consistent with it being
bis-zinc intermediate 6 (Scheme 4). Addition of Br2 to the
reaction mixture containing 6 led to formation of bis-bromodi-
fluoromethyl product 7, whereas addition of acetic acid led to
formation of the bis-difluoromethyl compound 4.13 Also the
observed fluorine chemical shift of 6 is consistent with its
structure.14,15
In view of these results, it was thought that using Zn in a
less polar solvent might inhibit the over-reduction that led to
the bis-Zn reagent 6. Indeed, when acetonitrile was used as the
reaction medium, a new product appeared in relatively low yield
(∼ 20%) which also had two signals in the fluorine NMR, this
time at δ - 102.8 and - 132.4 (eq 3). Upon isolation and
characterization, this product proved to be the desired perfluoro-
[2.2]paracyclophane, F8, as characterized by 13C, 19F NMR,
HRMS and elemental analysis. Upon optimization this yield
was able to be increased to an acceptable 39% of high purity
product.
dialdehyde 3 in 69% yield.10,11 Dialdehyde 3 could be efficiently
converted (87%) to the bis(difluoromethyl) compound, 4, via
reaction with SF4 in the presence of HF, with 4 then being
chlorinated to make the desired precursor 1 in 81% yield.
Although this procedure allowed the synthesis of the required
dichloride precursor 1, the required use of DIBAL-H and SF4
insured that this overall process would be expensive to utilize
for making larger quantities of F8. Thus an even more
convenient, but potentially much less expensive three-step
approach to the synthesis of 1 was developed, based upon the
preparation by Castaner and Riera of 1,4-bis(dichloromethyl)-
2,3,5,6-tetrachlorobenzene (5) by an AlCl3-catalyzed condensa-
tion of chloroform with 1,2,4,5-tetrachlorobenzene.12 Thus, as
shown in Scheme 3, 1,4-bis(difluoromethyl)-2,3,5,6-tetrafluo-
robenzene (4) could be prepared with an overall yield of 46%
from the inexpensive 1,2,4,5-tetrachlorobenzene. We anticipate
being able to further improve this synthesis though the use of
KF, instead of the relatively expensive CsF, in the chlorine-
fluorine exchange step.
Conversion of dichloride precursor 1 to the paracyclophane
F8 provided its own challenges, since the exact procedure used
to synthesize AF4 when applied to 1 gave no perfluoro[2.2]-
paracyclophane product. Indeed, when precursor 1 was allowed
to react with Zn in various polar aprotic solvents, a reaction
proceeded very smoothly to consume 1 (eq 2).
Thus, for the first time, the perfluoro[2.2]paracyclophane is
available for deposition experiments to determine the impact
(11) Yoon, N. M.; Young, S. G. J. Org. Chem. 1985, 50, 2443-2450.
(12) Castaner, J.; Riera, J. J. Org. Chem. 1991, 56, 5445-5448.
(13) Bailey, J.; Plevey, R. G.; Tatlow, J. C. J. Fluorine Chem. 1987, 37,
1-14.
(14) The fluorine chemical shift of HCF2ZnCl is -126 ppm.15 Generally,
changing a CF2H group to a CF2Ph group in various compounds leads to
deshielding to the extent of 22-25 ppm, which makes a chemical shift of
-101.5 for 6 quite reasonable.
(15) Burton, D. J.; Hartgraves, G. A. J. Fluorine Chem. 2007, 128, 1198-
1215.
2470 J. Org. Chem., Vol. 73, No. 6, 2008

due to atropisomers deriving from restricted rotation);17 13C NMR
δ 66.52, 137.29 (C1/C4 carbons not observed).
of perfluorination on properties of the respective Parylene
polymer. As for the paracyclophane itself, aspects of its unique
chemistry and electrochemistry will be reported in due course.
1,4-Bis(difluoromethyl)-2,3,5,6-tetrafluorobenzene (4) (Method
B). A mixture of 5 (23 g, 60 mmol), cesium fluoride (91.2 g, 600
mmol), and tetrabutylammonium bromide (1.2 g, 3.7 mmol) in
anhydrous DMSO (110 mL) was heated to 120 °C for 17 h. The
reaction mixture was then cooled to room temperature, poured into
ice-water (330 mL), and extracted with diethyl ether (2 × 250
mL). The combined organic layers were washed with water (500
mL), dried with magnesium sulfate, filtered, and concentrated to
remove solvent. The residue was distilled to give crude product
(8.4 g), which was recrystallized from hexanes (15 mL) to furnish
(4) (7.6 g, yield 50.6%, mp, 70-72 °C) as white crystals.
1,4-Bis(chlorodifluoromethyl)-2,3,5,6-tetrafluorobenzene (1).
Molecular Cl2 was introduced to a solution of 1,4-bis(difluorom-
ethyl)-2,3,4,5-tetrafluorobenzene (4) (18.7 g, 74.8 mmol) in CCl4
(250 mL) while irradiating with a sunlamp for 20 h. The reaction
mixture was slowly evaporated to remove CCl4 and the residue
distilled under reduced pressure (85-87 °C/20 mmHg) to give 1,4-
Experimental Section
1,4-Dicyano-2,3,5,6-tetrafluorobenzene (2).10 1,4-Dicyano-
2,3,5,6-tetrachlorobenzene (purity 95%) (40 g, 0.15 mol), KF (43.7
g, 5 equiv), and tetrabutylamonium bromide (TBAB) 0.99 g (2 mol
%) were added to a flask containing 250 mL of dry DMF, and the
mixture was stirred overnight at 120 °C under N2. Then the reaction
mixture was poured into a beaker with 2 L of ice-water, and the
resulting precipitate was filtered and washed with water. The crude
product was recrystallized from acetone to give the yellowish white
pure product 2 (25.5 g, 89%): mp 197-199 °C; 19F NMR, δ
-128.5 (s).10
2,3,5,6-Tetrafluorobenzene-1,4-dicarbaldehyde (3).10,11,16 To
a solution of 1,4-dicyano-2,3,5,6-tetrafluorobenzene (2) (20.0 g, 0.1
mol) and toluene (300 mL) at 0 °C was added 250 mL (0.25 mol)
of 1 M DIBAL-H (diisopropylaluminum hydride) toluene solution
dropwise under N2. The mixture was stirred at 0 °C for 1 h and
then was slowly warmed to room temperature and stirred overnight.
The reaction was quenched by addition of 300 mL of 2 N HCl
until pH <2, and then the mixture was stirred for 30 min. The
resulting precipitate was filtered and washed with CH2Cl2, and the
aqueous layer was extracted with CH2Cl2 (50 mL × 6). The organic
layer was washed with saturated sodium bicarbonate and brine, dried
over MgSO4, and evaporated, and the crude product (16.0 g, yield
78%) was further purified recrystallized from CH2Cl2 to give
product 3, 14.2 g (yield 69%): 1H NMR δ 10.33 (s);10 19F NMR
δ -144.2 (s);10 MS 207 (M + H+, 100).
bis(chlorodifluoromethyl)-2,3,4,5-tetrafluorobenzene (1) (19.4 g,
1
yield: 81.3%) as a colorless oil: 13C NMR δ 121.10 (t, JFC
)
1
295 Hz), 143.61 (d, JFC ) 268 Hz)(non-fluorine-substituted C-1/
C-4 not observed); 19F NMR δ -47.6 (m, 4F), -137.9 (m, 4F);
HRMS calcd for C8F8Cl2 317.9249, found 317.9239; GC-EI-MS
(C8F8Cl2, 319, C8F8Cl, 283, C8F8, 248).
1,4-Bis(bromodifluoromethyl)-2,3,5,6-tetrafluorobenzene (7).
A mixture of 1,4-bis(chlorodifluoromethyl)-2,3,5,6-tetrafluoroben-
zene (1) (1 g, 3.13 mmol) and zinc (0.82 g, 12.5 mmol) in 5 mL
of anhydrous DMSO was heated to 100 °C for 0.5 h. The reaction
mixture was then cooled to room temperature, and a 19F NMR
spectrum of the mixture revealed two equal intensity singlets at
-100.3 and -145.0 ppm. These two peaks were attributed to the
presence of bis-zinc intermediate 6: 19F NMR δ -100.3 and
-145.0 ppm (equal intensity).
Bromine (0.65 g, 8 mmol) was then added to the reaction, and
this mixture stirred at room temperature for 4 h, quenched with
ice-water (30 g), extracted with diethyl ether (2 × 10 mL), dried
over magnesium sulfate, and concentrated to give crude product,
which was purified by column chromatography (silica gel, hexanes)
to provide 1,4-bis(bromodifluoromethyl)-2,3,5,6-tetrafluorobenzene
(7) (0.11 g, yield: 8.6%) as a sticky colorless oil: 13C NMR δ
1,4-Bis(difluoromethyl)-2,3,5,6-tetrafluorobenzene (4) (Method
A).13 Tetrafluorophthalaldehyde (3) (27.3 g, 0.132 mol) and 50 mL
of CH2Cl2 were added into a 250 mL autoclave, which was then
evacuated with a dry ice-acetone bath. HF (8.0 g) and SF4
(135 g) were filled, and the reaction mixture was stirred at 180 °C
for 48 h. The reaction mixture was washed out with 200 mL of
CH2Cl2 and kept overnight to release HF and other gaseous
products. The reaction mixture was filtered, and the filtrate was
washed with saturated brine (60 mL × 3), dried (MgSO4),
evaporated to dryness, and recrystallized with CH2Cl2 to afford
product 4 (28.9 g, yield 87%): mp 68-70 °C (lit.13 mp
45-50 °C); 1H NMR δ 6.97 (t, 2JFH ) 53 Hz); 13C NMR δ 108.22
2
2
110.4 (t, JFC ) 308 Hz), 143.1 (d, JFC ) 284 Hz) (other carbon
not seen); 19F NMR -43.8 and -137.9 (both second order mult);
HRMS (all three isotopic combinations) calcd for C8F8[79]Br2
405.8239, found 405.8214; calcd for C8F8[79]Br[81]Br 407.8219,
found 407.8228; calcd for C8F8[81]Br2 409.8198, found
409.8234.
Perfluoro[2.2]paracyclophane (F8). A mixture of 1,4-bis-
(chlorodifluoromethyl)-2,3,5,6-tetrafluorobenzene 1 (10 g, 31.3
mmol) and zinc (8.2 g, 125.2 mmol) (99.7%, activated by 2% HCl)
in anhydrous acetonitrile (100 mL) was heated to 100 °C (oil bath
temperature) under N2 atmosphere. The reaction mixture was
refluxed gently for 38 h and then cooled to room temperature,
filtered, and washed with acetone (3 × 30 mL). The combined
filtrates were concentrated to dryness. The residue was purified by
column chromatography (silica gel, hexanes) to give crude product
(3.4 g) as a white powder. This crude product was recrystallized
from chloroform (40 mL) to furnish 2.7 g of pure product as white
needles. The mother liquor was concentrated to dryness and
recrystallized from chloroform (10 mL) to obtain a second crop of
pure product (0.3 g) as white needles. The yield is 38.6% based on
1
1
(t, JFC ) 242 Hz), 115.97 (br s), 144.79 (d, JFC ) 262 Hz); 19F
2
NMR δ -115.2 (d, JHF ) 52 Hz), -142.2 (s) (equal intensity).
Anal. Calcd for C8H2F8: C, 38.42; H, 0.81. Found: C, 38.07; H,
0.68.
1,4-Bis(dichloromethyl)-2,3,5,6-tetrachlorobenzene (5).12
A
mixture of 2,3,5,6-tetrachlorobenzene (22.6 g, 0.1 mol) and
aluminum chloride (30 g, 0.225 mol) in anhydrous chloroform
(300 mL) was refluxed for 22 h. The reaction mixture was cooled
to room temperature, diluted with chloroform (200 mL) and poured
into a mixture of hydrochloric acid (30 mL) and ice-water (300
mL). The organic layer was separated, dried over magnesium
sulfate, and concentrated to give crude product (45 g, wet), which
was recrystallized from hexanes (225 mL) to obtain 5 (31.6 g) as
a yellow solid. The mother liquor was concentrated to a volume of
45 mL, after which a second crop of product (4.1 g) was obtained.
The total yield was 91.1%: mp 134-136 °C (lit.12 mp
127-129 °C); 1H NMR, δ 7.59 (br s), 7.63 (br s) (equal intensity,
isolated pure F8 and X-ray crystal analysis: mp 195-196 °C; 19
F
NMR δ -102.8 (s), -132.4 (s) equal intensities; 13C NMR δ 118.0
(17) When octachloro compound 5 was heated to 70 °C in DMS-d6, the
two broad singlets collapsed to a sharp singlet at 7.90 ppm, this confirming
the fact that the pair of peaks at rt was due to the presence of atropisomers.
Note that the same phenomenon is not observed for the analogous octafluoro
compound 4.
(16) Krebs, F. C.; Jensen, T. J. Fluorine Chem. 2003, 120, 77-84.
J. Org. Chem, Vol. 73, No. 6, 2008 2471

(tt, J ) 283, 29 Hz), 147.4 (dd, J ) 267, 22 Hz), bridgehead carbon
not seen; HRMS calcd for C16F16 495.9739, found 495.9719. Anal.
Calcd for C16F16: C, 38.73; H, 0.00; N, 0.00. Found: C, 39.07; H,
0.00; N, 0.04.
Science Foundation and the University of Florida for funding
of the purchase of the X-ray equipment.
Supporting Information Available: General experimental
information, NMR spectra of compounds 1-7 and F8, and
crystallographic experimental and data (CIF) for F8. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Support of this research in part by
Specialty Coating Systems, Inc., Indianapolis, IN, is acknowl-
edged with thanks. K.A.A. wishes to acknowledge the National
JO7026849
2472 J. Org. Chem., Vol. 73, No. 6, 2008