Azoles as reactive nucleophiles with cyclic perfluoroalkenes

Article abstract of DOI:10.1002/chem.200901508

Di- and multiazole-substituted fluorocyclic products (2-13) were readily synthesized in good to high yields. These were synthesized by nucleophilic substitution reactions of perfluorocycloalkenes with azoles (i.e., imidazole, triazole) involving simple re

Full text of DOI:10.1002/chem.200901508

DOI: 10.1002/chem.200901508
Azoles as Reactive Nucleophiles with Cyclic Perfluoroalkenes
Sonali Garg, Brendan Twamley, Zhuo Zeng, and Jean’ne M. Shreeve*[a]
Abstract: Di- and multiazole-substitut-
the allylic fluorine atoms. This resulted
in the substitution of up to six azoles
on the fluorinated rings. Stoichiometry
plays a key role in determining the
degree of substitution. For comparison,
the analogous reactions of N-substitut-
ed fluorocyclic products (2–13) were
readily synthesized in good to high
yields. These were synthesized by nu-
cleophilic substitution reactions of per-
fluorocycloalkenes with azoles (i.e.,
imidazole, triazole) involving simple re-
action procedures. Interestingly, these
azoles were later found to be reactive
not only with the vinylic, but also with
ed 1-(trimethylsilyl)-imidazole and 1-
(trimethylsilyl)-1,2,4-triazole were also
investigated. All of the new compounds
were fully characterized by elemental,
spectral (19F, 1H, 13C NMR), and ther-
mal differential scanning calorimetry
(DSC) analyses.
Keywords: alkenes · azoles · het-
erocycles · nucleophilic substitution ·
perfluorinated compounds
Introduction
ces, and so forth. A large number of perfluorinated ethers,
which were otherwise difficult to synthesize by electrochem-
ical fluorination methods have been realized by using this
simple methodology.[2–5,11a,b] Use of organosilicon compounds
as nucleophiles in the presence of anionic catalysts enhances
the syntheses of these ethers.[3] Recently, substitutions of
perfluorocyclopentene have been used successfully in fabri-
cating photochromic dithiazolylethene-based derivatives,
which find application in many optoelectronic devices.[17]
Perfluorinated olefins are a good source for generating reac-
tive carbanions, which can be used to make stable isolable
salts.[18] They also form stable coordination complexes with
metal ions.[19] Typically, mono- or disubstituted products[2–10]
are formed in which either one or both of the vinylic fluo-
rine atoms is substituted depending upon the nucleophilicity
of the reagent. However, in the case of some bifunctional
nucleophiles,[5,20] it was observed that occasionally not only
vinylic but also allylic fluorine atoms may be substituted to
yield trisubstituted compounds.
Over the last half century, acyclic or cyclic fluorinated ole-
finic compounds have been of considerable interest[1] be-
cause of the presence of the reactive vinylic fluorine atoms,
which provides an easy route for the introduction of a wide
variety of functional groups ranging from alkoxides,[2,3]
phenoxides,[4,5] primary or secondary amines,[6] sulfanyls,[7]
lithium salts,[8] and carbon[9] to phosphorus-bonded
groups.[10] Various synthetic methods including free radical
addition,[11] electrophilic,[12] and nucleophilic[2–10] substitution
have been employed for the introduction of these groups.
Among these methods, nucleophilic substitution of fluoroal-
kenes, which involves addition followed by b-elimination in
the presence of a base, is a well-established strategy. Substi-
tutions of fluoroaromatic,[13] fluoroheterocyclic,[14] fluoroal-
kene,[2–10,12] and, more recently, fluorinated fullerenes[15] are
being used to carefully design compounds with desired phys-
ical and chemical properties. This enables their use in di-
verse applications,[4,16] such as blood substitutes, agrochemi-
cals, electric insulators, liquid-crystalline materials, conduct-
ing polymers, the construction of super hydrophobic surfa-
Synthesis and characterization of fluorinated heterocyclic
compounds is one of the areas of continuing interest to our
group.[21] Aromatic five-membered heterocyclic compounds
that contain more than one nitrogen atom, such as imid-
AHCTUNGTREGaNNUN zole, triazole, and tetrazole, are versatile and widely used
[a] S. Garg, Dr. B. Twamley, Dr. Z. Zeng, Prof. Dr. J. M. Shreeve
Department of Chemistry, University of Idaho
Moscow, D 83844-2343 (USA)
systems. However, these heterocycles are not only important
as energetic materials,[2] they also play an important role in,
amongst other things, the synthesis of natural products, anti-
fungal chemicals, drugs, biologically active substances, and
optical devices.[23] Using azoles as nucleophiles enables the
synthesis of a new series of cyclic fluorinated compounds,
Fax : (+1)208-885-9146
E-mail: jshreeve@uidaho.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901508.
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FULL PAPER
which have excellent properties. Interestingly, we have
found them to be sufficiently reactive to introduce six sub-
stituents into cyclic perfluoroalkenes. Also, employing the
N-silylated derivatives of azoles allowed the ready introduc-
tion of these heterocyclic rings into fluorinated molecules.
The formation of volatile trimethylsilyl fluoride as a product
provides an excellent driving force for this reaction. Herein,
we report the synthesis and characterization of a new family
of compounds, in which di- and multisubstituted fluorocyclic
products were obtained in good to excellent yields. This
work involves reactions of azoles with a variety of halogen-
ated compounds by the use of straightforward reaction pro-
cedures. For comparison, the reactivity of N-substituted sily-
lated analogues, 1-(trimethylsilyl)imidazole and 1-(trimeth-
at m/z 260, which corresponded to compounds containing
two triazole rings attached to the perfluorinated four-mem-
bered ring. By carrying out flash column chromatography
with hexane/ethyl acetate (1:5) as the eluent, the first frac-
tion was separated as the major product (89:11) from the re-
action mixture. In the 19F NMR spectrum, a singlet was ob-
served at ꢀ113.83 ppm, supporting the presence of a highly
symmetric product, 5a. However, the second fraction was
found to have an AA’BB’ pattern in the 19F NMR spectrum
(see Supporting Information) indicating that the four fluo-
rine atoms attached to the ring in 5b were non-equivalent,
suggesting that the two triazole rings were bonded to the
fluorinated ring through non-equivalent nitrogen atoms in
the azole rings. This behavior of 1,2,4-triazole could be ex-
plained by considering the reactivity of the two nitrogen
atoms present at different positions in the heterocyclic ring
(i.e., N1 and N4). Previously, it had been shown that alkyla-
tion of 1,2,4-triazole proceeded mainly with the formation
of the N1-substituted species with smaller amounts of the
N4-alkylated triazole depending upon the alkylating
agent.[24] The presence of a nitrogen atom, which has a non-
bonded pair of electrons, adjacent to the N1 position in tri-
ACHTUNGTRENNUNG
Results and Discussion
The synthetic routes that were utilized to obtain a variety of
azole-substituted fluorinated compounds are summarized in
Schemes 1–3. Reactions of imidazole with hexafluorocyclo-
AHCTUNGTRENNUNG
azole enhances the nucleophilicity.[25] However, higher ring
strain in the case of i and j increases the reactivity of the flu-
orine atom attached to the double bond; thus the carbocat-
ion formed in the reaction can readily bond to both the N1
and N4 positions of the triazole ring. Subsequently, an X-ray
structure of 5b confirmed that the two triazole rings were
bonded at N5 (N1 tautomer) and N10 nitrogen atoms (N4
tautomer) across the double bond of the four-membered
perfluorocyclobutene ring (i; Figure 1). The structure of 5b
Scheme 1. Addition of azoles to fluorinated olefins in a 2:1 ratio.
butene (i), octafluorocyclopentene (j), and decafluorocyclo-
hexene (k) proceeded smoothly when carried out in a 2:1
ratio in the presence of triethylamine (Scheme 1). The cor-
responding imidazolyl-disubstituted products (2–4) were
formed in moderate yields (55, 64, and 60%, respectively).
The formation of monosubstituted products was not ob-
served, even when equimolar amounts of reactants were uti-
lized. Not unexpectedly, reagents that were more nucleo-
philic displaced both of the fluorine atoms at the double
bond. When trimethylsilylimidazole was used as a nucleo-
phile under neat conditions, similar reaction products (2–4)
were obtained in comparable yields.
Following similar procedures, when triazole was reacted
with i and j, two products were obtained in each case
(Scheme 1). With i, 5a, and 5b were observed in the GC–
MS spectrum. In spite of the fact that the compounds exhib-
ited different retention times, 11.72 and 13.21 min, respec-
tively, their parent ions were found to have identical masses
Figure 1. Molecular structure of 5b (displacement ellipsoids shown at
30% probability). Hydrogen atoms are omitted for clarity.
shows the triazolyl-substituted perfluorinated cyclobutene
ꢀ
with C6 C9=1.347(2) ꢁ and internal cyclic angles ranging
between 85.8–94.28. Each triazole has bonded to the cyclo-
butene ring differently, resulting in a 1,2,4- and 1,3,4-triazol-
yl substitution pattern. These triazole rings are essentially
coplanar to the central carbon ring with dihedral angles of
approximately 68 and 38, implying a degree of delocalization
across the ring systems. Distances and angles in the cyclobu-
tene ring are similar to those in 3,3,4,4-tetrafluoro-N-
methyl-2-(cis,s-trans-methyl-N,N,O-azoxy)-s-cis-1-cyclobu-
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J. M. Shreeve et al.
tene-1-amine,[26] and 3-dimethylamino-4-[(pentacarbonyl-
chromium)(dimethylamino)carbenyl]-6,6,7,7-tetrafluoro-2,4-
diazabicycloACHTUNGTRENNUNG
[3.2.0]hepta-1(5),2-diene.[27] Analogous isomeric
compounds were obtained with perfluorocyclopentene (j);
one with two similarly attached triazole rings 6a and the
other having two triazole rings bonded through different ni-
trogen atoms 6b in a ratio of 86:14, respectively. Separation
was successful by column chromatography with hexane/ethyl
acetate (1:5) as the eluent.
Scheme 2. Addition of azoles to decafluorohexene in a 2:1 ratio.
By using DFT calculations, the N1-H 1,2,4- triazole has
been shown to be 28.22 kJmolꢀ1 more stable than the N4
tautomer.[28] The formation of the unsymmetrically substitut-
ed products can be rationalized as being kinetically con-
trolled, because such species are not thermodynamically fa-
vored. The minor product, 5b, was found to have lower sta-
bility as demonstrated by the fact that it was converted to
5a in the presence of a slight excess of triazole or with an
increase in reaction temperature. Also, when the unsymmet-
ric moiety was heated, or when the initial reaction was car-
ried out at 608C, a similar result was observed, that is, no
5b was seen. In comparison with the triazole, the metatheti-
cal reactions of 1-(trimethylsilyl)-1H-1,2,4-triaozle with fluo-
rinated olefins i and j gave two isomers in each case; howev-
er, the ratios of the products, 5a/5b and 6a/6b, were re-
versed (10:90 and 15:85, respectively). The shift of electrons
within the triazole ring of the N-silylated triazole enhances
the proclivity of both the N1- and N4-positions of the ring to
nucleophilic attack.[29]
Figure 3. Molecular structure of 7 (displacement ellipsoids shown at 30%
probability). Hydrogen atoms are omitted and only the ipso atom of the
triazole is labeled for clarity. A single conformation of the disordered tri-
azole rings is shown.
one carbon disubstituted by triazoles. Three perfluorinated
carbon atoms remain on the ring. In 7, unlike 5b, all of the
triazole rings are bonded in the 1,2,4-arrangement. Howev-
er, given the disorder in 7, there are two conformations in
which this is possible and both are seen in approximately
50% occupancy (see Supporting Information). When N-silyl
triazole was reacted with k, an inseparable mixture of many
products, for example, isomeric di-, tri-, and tetrasubstituted
moieties were observed in the GC–MS spectrum. This result
suggested that the nucleophilicity of the N-containing het-
erocycles was higher than expected. Further experiments
were carried out to determine the facile character of these
nucleophiles. Investigations revealed that with a large excess
of nucleophile (i.e., triazole, imidazole), multisubstituted
cyclic fluorinated compounds could easily be obtained. In-
terestingly, these azoles were found to be reactive not only
with the vinylic, but also with the allylic fluorine atoms
(Scheme 3). This resulted in the substitution of up to six
azole moieties on the fluorinated rings.
The presence of the bulky silyl group on the N1 position
of the triazole ring causes the N3 position to be more reac-
tive toward substitution (Figure 2). A similar rearrangement
Figure 2. Electronic rearrangement of 1-(trimethylsilyl)-1H-1,2,4-triaozle
and of 1-(trimethylsilyl)-1H-1,2,4-imidazole.
of electrons can also be observed within imidazole and N-
substituted silyl imidazole. However, the equivalence of the
N1- and N4-positions of the imidazole ring accounts for the
formation of a single symmetrically disubstituted imidazolyl
product.
Unexpectedly, the tetrasubstituted hexafluorocyclohexene,
7, was the only product from the reaction of triazole with k,
even though the reaction was carried out in a 2:1 ratio
(Scheme 2). Compared to imidazole, the increase in the ring
size not only gave a thermodynamically stable product, but
also aided in the more ready substitution of additional fluo-
rine atoms. The structure of 7 was determined by single-
crystal X-ray diffraction (Figure 3).
Substitution occurred at the 1-, 2-, and 3-positions on the
fluorinated perfluorocyclohexene ring. The substitution pat-
tern of this ring shows that the triazoles are all on the
double bond (C1=C2=1.342(2) ꢁ) side of the ring with only
Scheme 3. Addition of azoles (12–20 molar excess) to perfluorinated
cyclic olefins.
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Azoles as Nucleophiles with Cyclic Perfluoroalkenes
FULL PAPER
A 12-fold excess of triazole at room temperature resulted
in substitution of all of the fluorine atoms on i, but this be-
havior was not duplicated with j and k (Scheme 3). No fluo-
rine atoms remained in the hexasubstituted butane, 11,
whereas 12 and 13 contain two and four fluorine atoms, re-
spectively. When imidazole was used as a nucleophile, un-
usual results were obtained. Although imidazole (pKa =
14.52) is more basic than triazole (pKa =10.04),[30] only the
products resulting from substitution by four imidazole moi-
eties, 8–10, were observed. This may arise from the fact that
the electron-withdrawing capacity of triazole is much higher
than that of imidazole.[31] Upon reaction of triazole with the
perfluorinated ring compounds, a more electron-deficient
center (when compared to imidazole) is formed on the ring,
which results in a higher number of nucleophilic substitu-
tions. Different reaction conditions were employed in order
to determine the optimum conditions for this multiple sub-
stitution behavior. The data obtained are summarized in
Table 1. Extending the reaction time from 12 to 48 h did not
Figure 4. Molecular structure of 12 (displacement ellipsoids shown at
30% probability). Hydrogen atoms are omitted and only the ipso atom
of the triazole is labeled for clarity.
obtained from a large excess of silylated azoles with fluori-
nated rings were a mixture of symmetrically and unsymmet-
rically tetra- and hexasubstituted products. The presence of
fluoride ion, when added to enhance the nucleophilicity of
the silylated azoles, had little or no effect on the products
formed. This suggests that steric hindrance due to the pres-
ence of the bulky trimethylsilyl group is the limiting factor
for higher substitution. An increase in temperature does not
have an impact on the products obtained, with the exception
that the symmetrically disubstituted products were favored
relative to the unsymmetric analogues.
Table 1. Reaction products obtained by using different amounts of reac-
tants and varying the reaction conditions.
Product(s)
Alkene/Nucleophile
Reaction conditions
8
i/imidazole (1:12)
i/imidazole (1:6)
i/imidazole (1:20)
i/imidazole (1:20)
j/imidazole (1:16)
j/imidazole (1:32)
j/imidazole (1:32)
k/imidazole (1:20)
i/triazole (1:12)
Et3N, CH3CN, RT and 708C
Et3N, CH3CN, RT and 708C
Et3N, CH3CN, RT
Et3N, CH3CN, 708C
Et3N, CH3CN, RT and 708C
CH3CN, RT
2, 8
2, 8
8
9
3, 9
9
10
11
12
13, 7
13
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
The physical properties of compounds 2–13 are summar-
ized in Table 2. The yields of the products obtained from
both azoles and silylated azoles were found to be essentially
ACHTUNGTRENNUNG(major)
CH3CN, 708C
Et3N, CH3CN, RT and 708C
Et3N, CH3CN, RT and 708C
Et3N, CH3CN, RT and 708C
Et3N, CH3CN, RT and 708C
Et3N, CH3CN, RT and 708C
Table 2. Physical properties of azole-substituted perfluorinated olefins 2–
13.
j/triazole (1:12)
k/triazole (1:10)
k/triazole (1:20)
[a]
G
Yield
(azoles as
Yield
Tm
1[b]
[gcmꢀ3
]
(silylatedazoles as [8C]
U
nucleophiles) [%] nucleophiles) [%]
2
3
4
5a
5b 22
6a 52
6b 17
7
8
55
64
60
63
50
59
62
14
59
15
70
–
–
–
–
–
60
79
1.634
1.724
1.762
1.768
1.782
1.818
1.892
1.739
1.472
1.521
affect the results. Also, increasing the reaction temperature
from 25 to 65–708C did not have an impact on the degree of
substitution. The results show that stoichiometry plays a key
role in determining the degree of substitution, for example,
when the amount of imidazole used was the same as re-
quired to substitute all the fluorine atoms in fluorinated
ring, i, (1:6), a mixture of di- and tetrasubstituted products
was obtained (Table 1). To obtain the tetrasubstituted prod-
uct only, a higher ratio of azole to olefin was required. The
crystal structure of 12 (Figure 4) confirms the maximum
limit of substitution when all allylic or vinylic fluorine atoms
are displaced. Only one carbon atom is perfluorinated, C1,
directly opposite the double bond (C3=C4=1.341(2) ꢁ).
The triazole substitution pattern is once again the 1,2,4-ar-
rangement. The triazoles on C2 and C5 are eclipsed. How-
ever, the triazole on C3 is essentially coplanar and the tria-
zole on C4 has a dihedral angle of approximately 648 with
the cyclopentene ring.
125
126
175
116
151
197
105
116
191
224
245
268
67
68
65
60
62
69
58
9
10
11
12
13
ACHTUNGTRENNUNG
1.529
1.581
1.637
–
–
[a] DSC under nitrogen gas, 108Cminꢀ1. [b] Gas pycnometer (258C).
comparable. The densities of these compounds range from
1.472–1.892 gcmꢀ3. The presence of a larger number of fluo-
rine atoms in the disubstituted compounds enhances the
density of these materials relative to the multisubstituted
ring compounds.
Surprisingly, trimethylsilyltriazole and trimethylsilylimid-
A
The mechanistic interpretation for the formation of the
disubstituted halogenated rings is based on a two-step nucle-
ophilic substitution; initially the addition of the incoming
kenes relative to triazole and imidazole when the last two
were in the presence of triethylamine. The reaction products
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J. M. Shreeve et al.
Conclusions
In conclusion, we have synthe-
sized and characterized a series
of new azole-substituted cyclic
fluorinated compounds by
a
straightforward approach. The
N-containing heterocyclic nu-
cleophiles (i.e., triazole, imid-
AHCTUNGTERGaNNUN zole) resulted not only in dis-
ubstituted products, but also
gave polysubstituted rings with
up to six substituents; a struc-
ture that had not been ob-
served previously. Triazole was
found to be more nucleophilic
than imidazole. Silylated deriv-
atives of both imidazole and
Scheme 4. Possible reaction pathway for the polysubstitution of perfluorocycloalkene (i: n=0, j: n=1, k: n=
2).
nucleophile across the double bond with concomitant hydro-
gen halide loss occurs.[2–10] However, the formation of poly-
substituted products cannot be rationalized by using this
single reaction mechanism and therefore a combination of
reaction mechanisms (addition–elimination, SN2, [1,3]-sig-
matropic shift) must be employed. The best possible path-
ways to form the perfluorinated polysubstituted rings are
detailed in Scheme 4. Also, for polysubstituted compounds,
the initial addition–elimination leads to the displacement of
both the vinylic fluorine atoms at C1 and C2 of the fluorinat-
ed ring to yield a disubstituted product II (Scheme 4). In ad-
dition to simple addition–elimination, 1,3-allylic substitution
(SN2’) is also proposed to occur in these compounds. Be-
cause of the rather high nucleophilicity of the reactants, that
is, triazole and imidazole, this mechanism apparently be-
comes operative in the case of polysubstituted products. In
this substitution, the fluorine atom at the allylic position
(i.e., C3) becomes the leaving group (Scheme 4, III). The
susceptibility of the allylic fluorine towards substitution is
explained on the basis of the lone pair of electrons on the
fluorine at the g-position. The mesomeric shift of this pair
of electrons towards the p bond enhances the electrophilici-
ty of the allylic position. Because of this allylic substitution,
another reactive fluoride ion becomes available at C3 for an
addition–elimination reaction and leads to a tetrasubstituted
product, IV (Scheme 4). Steric hindrance at C2, arising from
the presence of three adjacent bulky azoles, may necessitate
a [1,3]-sigmatropic rearrangement of the fluorine atom from
C4 to C2 rather than allylic substitution (Scheme 4, V). This
movement of the fluorine atom allows additional 1,3-allylic
substitution to take place at C4 (Scheme 4, VI). Again, steric
hindrance at C2 possibly leads to another [1,3]-sigmatropic
rearrangement to give VII (Scheme 4) followed by allylic
substitution at C4 giving a hexasubstituted perfluorinated
olefin, VIII (Scheme 4). The absence of any vinylic and al-
lylic fluorine atoms remaining in this six substituted product
may explain the lack of further substitutions even with in-
crease in time, temperature, and change of reaction stoichi-
ometry.
triazole resulted mainly in the substitution of the vinylic flu-
orine atoms in perfluorocyclic olefins to form disubstituted
products. Most of these compounds exhibit high densities
(>1.50 gcmꢀ3) and have good thermal stabilities. Formation
of the disubstituted perfluorinated compounds involves
simple addition–elimination steps, whereas a highly complex
mechanism is suggested for the formation of the higher sub-
stituted ring compounds.
Experimental Section
Hexafluorocyclobutene and octafluorocyclopentene were gratefully re-
ceived from Professor Gary L. Gard, Portland State University. Decaf-
luorocyclohexene was purchased from Matrix Scientific. 1-(Trimethyl-
silyl)-1H-1,2,4-triazole[32] and 1-(trimethylsilyl)-1H-imidazole[33] were ob-
tained by following literature preparations. Acetonitrile was distilled
from calcium hydride and tetrahydrofuran (THF) from sodium/benzo-
phenone. All other chemicals were obtained from Acros or Aldrich and
were used as received.
A conventional Pyrex glass vacuum system
equipped with a Heise-Bourdon tube gauge was used to handle gaseous
and volatile compounds. Quantities of volatile materials were determined
by PVT measurements assuming ideal gas behavior. A Bruker 300 MHz
AMX nuclear magnetic resonance spectrometer was used to record 1H,
13C, and 19F NMR spectra at 300.1, 282.4, and 75.5 MHz, respectively,
with chemical shifts reported in ppm relative to appropriate standards
[(CH3)4Si for 1H and 13C nuclei, and CFCl3 for 19F nuclei]. Mass spectra
(MS) were obtained by using either GC–MS or by direct injection with a
solid probe (CI) on a Shimadzu GC–MS QP5050. DSC measurements
were recorded on TA Instrument Q10 in the range of 40 to 4008C at
108Cminꢀ1. TLC analysis was performed on Al-backed plates precoated
with silica gel and were examined under a UV lamp (l=254 nm). Silica
gel (60–200 mm, 60 ꢁ) was used to conduct flash column chromatography.
Elemental analyses (EA) data was obtained on an Exeter CE440 elemen-
tal analyzer.
X-ray crystallography: Crystals of compounds 5b, 7, and 12 were re-
moved from the flask, a suitable crystal was selected, attached to a glass
fiber, and data were collected at 90(2) K by means of a Bruker/Siemens
SMART APEX instrument (MoKa radiation, l=0.71073 ꢁ) equipped
with a Cryocool NeverIce low-temperature device. Data were measured
by using omega scans 0.38 per frame for 5 s, and a full sphere of data was
collected. A total of 2400 frames were collected with a final resolution of
0.77 ꢁ. Cell parameters were retrieved with SMART[34] software and re-
fined by using SAINTPlus[35] on all observed reflections. Data reduction
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Azoles as Nucleophiles with Cyclic Perfluoroalkenes
FULL PAPER
and correction for Lp and decay were performed by using the SAINT-
Plus software.[35] Absorption corrections were applied using SADABS.[36]
The structure was solved by direct methods and refined by least squares
method on F2 by means of the SHELXTL program package.[37] Structures
General procedure for the preparation of polysubstituted perfluorocy-
cloalkenes by treatment with silylated nucleophiles: All the reactions
were carried out at 0.5–1.0 mmol scale in vacuum. Silylated azoles were
carefully added to a Pyrex tube in the required stoichiometric amount
under a nitrogen atmosphere. The desired amount of perfluoroalkene
was transferred into the reactor at ꢀ1968C under vacuum. The reactor
was closed with a Teflon stopcock, slowly warmed to room temperature,
and allowed to stir overnight. The residue was washed repeatedly with di-
chloromethane to remove any unreacted trimethylsilyl azole. Nearly all
the compounds were obtained by flash chromatography with hexane/
ethyl acetate (1:10) or methanol/dichloromethane (1:10) as eluent. The
products formed were identical with those obtained from the azoles but
in different yields.
¯
were solved by analysis of systematic absences, P21 (# 4) for 5b, P1 (# 2)
for 7, and P21/n (# 14) for 12. In the all-light-atom structure of 5b, the
value of the Flack parameter did not allow the direction of the polar axis
to be determined and Friedel reflections were then merged for the final
refinement. In 7, the triazole groups were disordered in two positions
with approximately 50% occupancy each. These atoms were held iso-
tropic and mild restraints were applied between each triazole and the flu-
orinated ring. In all structures all other non-hydrogen atoms were refined
anisotropically. Hydrogen atoms were placed geometrically (riding
model). No decomposition was observed during data collection. Details
of the data collection and refinement are given in Table 3. Further details
are provided in the Supporting Information.
Preparation of 1,2-di(1,2,4-triazolyl)tetrafluorocyclobutene (5a) and 1-
(1,2,4-triazolyl)-2-(1,3,4-trizolyl)tetrafluorocyclobutene (5b): Hexafluoro-
cyclobutene (i; 1 mmol), triazole (0.14 g, 2 mmol) and triethylamine
(0.21 g, 2 mmol) were dissolved in dry acetonitrile (2–5 mL). As observed
from the GC–MS spectral chromatogram, two products were formed
during the reaction, which were later separated by column chromatogra-
phy on silica gel with hexane/ethyl acetate (1:5) as eluent and were iden-
tified as 5a: Colorless solid; yield: 63% (14% for silylated nucleophile);
m.p. 1268C; 19F NMR (CDCl3): d=ꢀ113.83 ppm (s, 2CF2); 1H NMR
(CDCl3): d=8.30 (s, 1H; C-H), 9.21 ppm (s, 1H; C-H); 13C NMR
Table 3. Crystal data[38] and structure refinement parameters for com-
pounds 5b, 7, and 12.
5b
7
12
formula
Mr
C8H4F4N6
260.17
C14H8F6N12
458.32
C17H12F2N18
506.45
crystal size [mm]
crystal system
space group
a [ꢀ]
b [ꢀ]
c [ꢀ]
0.56ꢂ0.43ꢂ0.13 0.40ꢂ0.30ꢂ0.10 0.40ꢂ0.36ꢂ0.16
(C,F)=277.4 Hz, 2J
(CDCl3): d=116.02 (tt, JAHCTUNGRTENGUNN ACHTUNGRTEN(GUNN C,F)=23.6 Hz, 2CF2),
monoclinic
P21
triclinic
P1
monoclinic
P21/n
120.55–121.62 (m, 2C-N), 146.43 (s, 2C-H), 155.30 ppm (s, 2C-H); GC–
MS (EI): m/z (%): 260 (100) [M]+; elemental analysis calcd (%) for
C8H4N6F4 (260.15): C 36.93, H 1.55, N 32.30; found: C 36.91, H 1.58, N,
31.72. 5b: Colorless, crystalline solid; yield: 22% (59% for silylated nu-
cleophile); m.p. 1758C; 19F NMR (CDCl3): d=ꢀ113.32–ꢀ113.93 ppm
(AA’BB’, 2CF2); 1H NMR (CDCl3): d=8.39 (s, 1H; C-H), 8.61 (s, 1H;
C-H), 9.14 ppm (s, 2H; C-H); 13C NMR (CDCl3): d=115.34–116.21 (m,
2CF2), 121.43–121.67 (m, C-N), 125.37 (m, C-N), 141.62 (s, C-H), 144.89
(s, C-H), 156.10 ppm (s, 2C-H); GC–MS: (EI): m/z (%): 260 (100) [M]+;
elemental analysis calcd (%) for C8H4N6F4 (260.15): C 36.93, H 1.55, N
32.30; found: C 36.69, H 1.45, N 32.36.
¯
6.5424(6)
6.9547(7)
10.5824(10)
–
90.4280
–
7.6395(4)
8.1796(5)
15.1307(8)
97.5560(8)
94.0739(8)
109.9267(7)
874.33(8)
2
7.8213(9)
19.206(2)
14.4816(16)
–
102.733(2)
–
a [ꢁ]
b [ꢁ]
g [ꢁ]
V [ꢁ3]
481.49(8)
2
2121.9
4
Z
1calcd [gcmꢀ3
]
1.795
1.741
1.585
m [mmꢀ1
T [K]
]
0.174
0.162
0.124
Preparation of 1,2-di(1,2,4-triazolyl)hexafluorocyclopentene (6a) and 1-
(1,2,4-triazolyl)-2- (1,3,4-trizolyl)hexafluorocyclopentene (6b): The com-
pounds were synthesized by using the same procedure as for 5a and 5b
except that octafluorocyclopentene (1 mmol) was used. 6a: Colorless
solid; yield: 52% (15% for silylated nucleophile); m.p. 1168C; 19F NMR
90(2)
90(2)
90(2)
lMoKa [ꢁ]
reflections collected 7060
0.71073
0.71073
12934
3996/4/273
0.71073
31348
4863/0/334
data/restraints/pa-
rameters
1315/1/163
(CDCl3): d=ꢀ110.40 (t, 3J
ACHTUNGTRENNUNG
GOF on F2
1.072
0.0273
0.0726
0.0280
1.054
0.0379
0.0953
0.0443
1.062
0.0383
0.0960
0.0465
AHCTUNGTRENNUNG
(F,F)=2.8 Hz; CF2); 1H NMR (CDCl3): d=8.19 (s, 2H;C-H), 8.69 ppm
R1 [I> 2s(I)][a]
wR2 [I> 2s(I)][b]
R (all data)
(s, 2H; C-H); 13C NMR (CDCl3): d=110.23 (tt, J
(C,F)=274.0 Hz; 2J-
ACHTUNGTRENNUNG
AHCTUNGTRENGUN(N C,F)=24.16 Hz; 2CF2), 114.02–117.54 (m, CF2), 124.89 (m, 2C-N),
146.62 (s, 2C-H),154.87 ppm (s, 2C-H); GC–MS (EI): m/z (%): 310 (100)
[M]+; elemental analysis calcd (%) for C9H4N6F6 (310.15): C 34.85, H
1.30, N 27.10; found: C 34.86, H 1.24, N 26.11. 6b: Colorless crystalline
solid; yield: 17% (70% for silylated nucleophile); m.p. 1518C; 19F NMR
wR (all data)
0.0732
0.334/ꢀ0.172
0.1006
0.485/ꢀ0.374
0.1017
0.441/ꢀ0.243
D1min/max [eꢁꢀ3
]
[a] R1 =SjjFo jꢀjFc jj/SjFo j ; [b] wR2 ={S[w(F2oꢀFc2)2]/S[w(Fo2)2]}1/2
.
(CDCl3): d=ꢀ109.90–ꢀ110.01 (m, CF2), ꢀ110.10 (t,3J
ACHTUNGTREN(NUNG F,F)=3.5 Hz;
CF2)), ꢀ129.13–ꢀ129.19 ppm (m; CF2); 1H NMR (CDCl3): d=8.20 (s,
1H; C-H), 8.48 (s, 2H; C-H), 8.70 ppm (t, J=2.75 Hz, 1H; C-H);
13C NMR (CDCl3): d=108.97 (tq, J(C,F)=277.8 Hz, 2J
ACTHNUTRGENNUG ACHUTTGNREN(NUGN C,F)=28.7 Hz,
General procedure for the preparation of polysubstituted perfluorocy-
cloalkenes with azoles in the presence of triethylamine: All reactions
were carried out on a 0.5–1.0 mmol scale in vacuum. Equivalent amounts
of aromatic heterocycle (triazole/imidazole) and triethylamine were dis-
CF2), 112.68–113.09 (m, CF2), 119.09 (m, C-N), 126.82–127.47 (m, C-N),
141.40 (s, 1C-H), 144.70 (t, J=2.75 Hz, 1C-H), 154.86 ppm (s, 2C-H);
GC–MS (EI): m/z (%): 310 (100) [M]+; elemental analysis calcd (%) for
C9H4N6F6 (310.15): C 34.85, H 1.30, N 27.10; found: C 34.89, H 1.19, N
26.52.
solved in dry acetonitrile (2–5 mL) in
a 50 mL Pyrex tube reactor
equipped with a Teflon stopcock and magnetic stirring bar. By using
vacuum line techniques desired amounts of perfluorocycloalkene were
measured and transferred into the reactor by condensing at ꢀ1968C. The
reaction was allowed to warm to 258C with stirring being continued for
10–12 h. After ensuring the completion of the reaction, the solvent and
excess of triethylamine were first removed on a rotary evaporator and
then vacuum pump. Ethyl acetate (40–50 mL) was added to the residue.
After repeated washings (3ꢂ5 mL) with water, the organic solution was
dried over sodium sulfate, and the solvent was evaporated to leave the
desired product. In some cases, the residue was a viscous liquid, which
was purified by column chromatography with hexane/ethyl acetate (1:5)
or methanol/dichloromethane (1:10) as eluent.
Preparation of 1,2,3,3-tetra(1,2,4-triazolyl)hexafluorocyclohexene (7):The
procedure is the same as above except that decafluorocyclohexene was
used. A single product was obtained with slight impurities, which were
removed on a silica gel column with hexane/ethyl acetate (1:5) as eluent
to give a colorless crystalline solid. Yield: 67%. m.p. 1978C; 19F NMR
(DMSO): d=ꢀ110.91 (brs, CF2), ꢀ123.07 (brs, CF2), ꢀ130.83 ppm (brs,
1
CF2); H NMR (DMSO): d=7.75 (s, 1H; CH), 8.05 (s, 1H; C-H), 8.10 (s,
2H; C-H), 8.19 (s, 1H; C-H), 8.39 (s, 1H; C-H), 8.76 ppm (s, 2H; C-H);
13C NMR (DMSO): d=113.74–103.94 (m, 3CF2), 128.10–129.62 (m, 3C-
N), 145.20 (s, 2C-H), 146.43 (s, C-H), 146.91 (s, C-H), 151.95 (s, 2C-H),
153.48 (s, C-H), 153.92 ppm (s, C-H); GC–MS (EI): m/z (%): 458 (3)
Chem. Eur. J. 2009, 15, 10554 – 10562
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10559

J. M. Shreeve et al.
[M]+; elemental analysis calcd (%) for C14H8N12F6 (458.28): C 36.69, H
1.76, N 36.68; found: C 36.42, H 1.60, N 36.53.
m.p. 1058C; 19F NMR (CDCl3): d=ꢀ107.13 ppm (s, CF2); 1H NMR
(CDCl3): d=8.06 (s, 1H; C-H), 8.07 (s, 1H; C-H), 8.38 s, 1H; C-H) 8.39
(s, 1H; C-H), 8.61 (s, 1H; C-H), 8.93 (s, 1H; C-H), 9.13 ppm (s, 2H; C-
H); 13C NMR (CDCl3): d=110.02–111.02 (m, CF2), 114.05–115.25 (m,
3C-N), 116.54 (s, C-H), 116.87 s, C-H), 117.94 (s, C-H), 131.76 (s, 2C-H),
132.75 (s, 2C-H), 133.16 (s, 2C-H), 135.66 (s, C-H), 135.74 (s, C-H),
135.78 ppm (s, C-H); GC–MS (EI): m/z (%): 287 (100) [Mꢀ67]+; ele-
mental analysis calcd (%) for C16H12N8F2 (354.31): C 52.61, H 3.79, N
30.10; found: C 52.40, H 3.89, N 29.97.
Preparation of 1,2,3,3,4,4-hexa(1,2,4-triazolyl)cyclobutene (11): For
1 mmol of perfluorocyclobutene, a 12 mmol excess of both triazole and
triethylamine was used to carry out the reaction. White solid; yield:
1
62%, m.p. 2248C; H NMR (DMSO): d=8.06 (s, 2H; C-H), 8.21 (s, 2H;
C-H), 8.25 (s, 2H; C-H), 8.67 (s, 2H; C-H), 8.75 (s, 2H; C-H), 9.16 ppm
(s, 2H; C-H); 13C NMR (DMSO): d=117.44 (s, 2C-N), 127.85 (s, 2C-N),
146.81 (s, 2C-H), 147.52 (s, 2C-H), 147.83 (s, 2C-H), 153.43 (s, 2C-H),
154.00 (s, 2C-H), 154.54 ppm (s, 2C-H); MS (solid probe) (EI): m/z (%):
456 (1.7) [M]+; elemental analysis calcd (%) for C16H12N18 (456.28): C
41.11, H 2.65, N 55.24; found: C 41.27, H 2.53, N 54.41.
Preparation of 1,2,3,3-tetra(1,3-imidazolyl)tetrafluorocyclopentene (9):
The procedure was the same as for 8, but carried out with octafluorocy-
clopentene and a 16-fold excess of both triazole and triethylamine. White
solid; yield: 65%; m.p. 1168C; 19F NMR (CDCl3): d=ꢀ110.08 (t, 3J-
Preparation
of
1,2,3,3,4,4-hexa(1,2,4-triazolyl)difluorocyclopentene
A
(F,F)=4.73 Hz; CF2); 1H NMR
ACHTUNGTRENNUNG
(12):The procedure was the same as for 11, except that octafluorocyclo-
pentene was used. Colorless crystalline solid; yield: 69%, m.p. 2458C;
19F NMR (DMSO): d=ꢀ106.97 ppm (s, CF2); 1H NMR (DMSO): d=
8.28 (s, 2H; C-H), 8.29 (s, 4H; C-H), 9.08 (s, 2H; C-H), 9.31 ppm (s,4H;
(CDCl3): d=6.61 (s, 1H; C-H), 7.05 (s, 3H; C-H) 7.19 (s, 2H; C-H), 7.21
(s, H; C-H), 7.32 (s, 2H; C-H), 7.74 (s, H; C-H),7.79 ppm (s, 2H; C-H);
13C NMR (CDCl3): d=78.43–78.92 (m, 2CF2), 110.01–111.32 (m, CF2),
113.81–115.23 (m, 2C-N), 118.32 (s, C-H), 118.42 (s, C-H), 119.63 (s, C-
H), 130.64 (s, 2C-H), 131.25 (s, 2C-H), 131.49 (s, 2C-H), 136.36 (s, C-H),
136.82 (s, C-H), 137.27 ppm (s, C-H); GC–MS (EI): m/z (%): 337 (100)
[Mꢀ67]+; elemental analysis calcd (%) for C17H12 N8 F4 (404.32): C
48.85, H 3.34, N 26.53; found: C 48.73, H 3.01, N, 26.11.
C-H); 13C NMR (DMSO): d=82.94 (t, 2J
N
2
(t, J
N
2C-H), 153.25 (s, 4C-H), 153.86 ppm (s, 4C-H); MS (solid probe) (EI):
m/z (%): 506 (26.7) [M]+; elemental analysis calcd (%) for C17H12 N18 F2
(506.39): C 40.32; H 2.39; N 49.79; found: C 40.23, H 2.21, N 49.98.
Preparation of 1,2,3,3-tetra(1,3 -imidazolyl)hexafluorocyclohexene (10):
The procedure is the same as for 8, but carried out with decafluorocyclo-
hexene and a 20-fold excess of triazole and triethylamine. White solid;
yield: 60%; m.p. 1918C (decomp); 19F NMR (CDCl3): d=ꢀ111.01 (brs,
Preparation of 1,2,3,3,4,4-hexa(1,2,4-triazolyl)tetrafluorocyclohexene
(13): The procedure was the same as for 11, except that decafluorocyclo-
hexene was used. White solid; yield: 58%, m.p. 2658C; 19F NMR
(DMSO): d=ꢀ118.34 ppm (brs, 2CF2); 1H NMR (DMSO): d=8.09 (s,
2H; C-H), 8.39 (s, 4H; C-H), 8.62 (s, 2H; C-H), 9.33 ppm (s, 4H; C-H);
1
CF2), ꢀ122.65 (brs, CF2), ꢀ130.88 ppm (brs, CF2); H NMR (CDCl3): d=
13C NMR (DMSO): d=78.58 (t, 2J
(C,F)=272.3 Hz; 2J
(C,F)=26.34 Hz; 2CF2), 130.81 (s, 2C-N), 148.20 (s,
ACHTUNGTRNE(NUNG C,F)=92.1 Hz; 2C-N), 110.95 (tt, J-
6.64 (s, 1H; C-H); 6.79 (s, 1H; C-H), 7.07 (s, 1H; C-H), 7.11 (s, 1H; C-
H), 7.15 (s, 2H; C-H), 7.27 (s, 1H; C-H), 7.33 (s, 2H; C-H), 7.66 (s, 1H;
C-H), 7.85 ppm (s, 2H; C-H); 13C NMR (CDCl3): d=108.64–117.74 (m,
3CF2), 119.85–121.75 (m, 3C-N), 122.63 (s, C-H), 125.01 (s, C-H), 126.16
(s, C-H), 129.67 (s, 2C-H), 130.22 (s, 2C-H), 131.56 s, 2C-H), 135.63 (s,
C-H), 136.28 (s, C-H), 136.98 ppm (s, C-H); MS (solid probe) (EI): m/z
(%): 387 (28.6) [Mꢀ67]+; elemental analysis calcd (%) for C18H12N8F6
(454.10): C 45.77, H 2.99, N, 22.72; found: C 45.45, H 2.96, N 22.39.
A
ACHTUNGTRENNUNG
2C-H), 148.35 (s, 2C-H), 153.11 (s, 4C-H); 153.64 ppm (s, 4C-H); MS
(solid probe) (EI): m/z (%): 556 (6.3) [M]+; elemental analysis calcd (%)
for C18H12 N18F4 (556.40): C 38.76, H 2.17, N 45.31; found: C 38.43, H
1.98, N 45.16.
Preparation of 1,2-di(1,3-imidazolyl)tetrafluorocyclobutene (2): The reac-
tion was carried out by treatment of imidazole (0.14 g, 2 mmol) and tri-
ethylamine (0.21 g, 2 mmol) with hexafluorocyclobutene (1 mmol) in ace-
tonitrile (5 mL). The product was purified by silica gel column with
hexane/ethyl acetate (1:5) as eluent. Colorless crystalline solid; yield:
55% (50% for silylated nucleophile); m.p. 608C; 19F NMR (CDCl3): d=
ꢀ114.20 ppm (s, 2CF2); 1H NMR (CDCl3): d=7.24 (s, 2H; C-H), 7.25 (s,
2H; C-H), 7.90 ppm (s, 2H; C-H); 13C NMR (CDCl3): d=116.71 (tt, J-
Acknowledgements
ACHTUNGTRENNUNG ACHTUNGTRENNUNG(C,F)=25.5 Hz, 2CF2), 123.47 (m, 2C-N), 133.17 (s,
(C,F)=312.0 Hz, 2J
The authors gratefully acknowledge the support of the Defense Threat
Reduction Agency (HDTRA1-07-1-0024), the National Science Founda-
tion (CHE-0315275), and the Office of Naval Research (N00014-06-1-
1032).The Bruker (Siemens) SMART APEX diffraction facility was es-
tablished at the University of Idaho with the assistance of the NSF-
EPSCoR program and the M. J. Murdock Charitable Trust, Vancouver,
WA.
4C-H), 136.87 (s, 2C-H) ppm; GC–MS (EI): m/z (%): 258 (100) [M]+; el-
emental analysis calcd (%) for C10H6N4F4 (258.17): C 46.52, H 2.34, N
21.70; found: C 46.23, H 2.20, N 21.39.
Preparation of 1,2-di(1,3-imidazolyl)hexafluorocyclopentene (3): The
procedure was the same as for 2, except that decafluorocyclopentene was
used. Pale yellow crystalline solid; yield: 64% (59% for silylated nucleo-
phile); m.p. 798C; 19F NMR (CDCl3): d=ꢀ110.88 (t, 3J
ACHTUNGTREN(NUNG F,F)=2.82 Hz;
2CF2), ꢀ129.36–ꢀ129.41 ppm (m, CF2); 1H NMR (CDCl3): d=6.88 (s,
2H; C-H), 7.30 (s, 2H; C-H), 7.67 ppm (s, 2H; C-H); 13C NMR (CDCl3):
d=79.10–79.42 (m, CF2), 116.36–116.87 (m, 2CF2), 126.64–127.32 (m,
2C-N), 118.38 (s, 2C-H), 133.38 (s, 2C-H),137.05 ppm (s, 2C-H); GC–MS
(EI): m/z (%): 308 (100) [M]+; elemental analysis calcd (%) for
C11H6N4F6 (308.18): C 42.87, H 1.96, N 18.18; found: C 42.65, H 1.80, N
17.77.
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Preparation of 1,2-di(1,3-imidazolyl)octafluorocyclohexene (4): The pro-
cedure was the same as 2, except that decafluorocyclohexene was used.
Pale yellow solid; yield: 60% (62% for silylated nucleophile); m.p.
1258C; 19F NMR (CD3CN): d=ꢀ113.13 (brs, 2CF2), ꢀ134.09 ppm (brs,
1
2CF2); H NMR (CD3CN): d=7.11 (s, 4H; C-H), 7.52 ppm (s, 2H; C-H);
13C NMR (CD3CN): d=105.38–114.32 (m, 4CF2), 120.08–121.23 (m, 2C-
N), 131.72 (s, 4C-H),138.21 ppm (s, 2C-H); GC–MS (EI): m/z (%): 358
(100) [M]+; elemental analysis calcd (%) for C12H6N4F8 (358.19): C 40.24,
H 1.69, N 15.64; found: C 40.44, H 1.73, N 16.15.
Preparation of 1,2,3,3-tetra(1,3-imidazolyl)difluorocyclobutene (8). With
perfluorocyclobutene (1 mmol), a 12-fold excess of both triazole and trie-
thylamine was used to carry out the reaction. White solid; yield: 68%;
10560
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10554 – 10562

Azoles as Nucleophiles with Cyclic Perfluoroalkenes
FULL PAPER
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Received: June 4, 2009
Published online: September 10, 2009
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