Elemental F2 with transannular dienes: Regioselectivities and mechanisms

Article abstract of DOI:10.1002/chem.201402640

Three reaction paths, namely, molecule-induced homolytic, free radical, and electrophilic, were modeled computationally at the MP2 level of ab initio theory and studied experimentally for the reaction of F₂ with the terminal dienes of bicyclo[3

Full text of DOI:10.1002/chem.201402640

DOI: 10.1002/chem.201402640
Full Paper
&
Reaction Mechanisms
Elemental F2 with Transannular Dienes: Regioselectivities and
Mechanisms
Maxim V. Ponomarenko,*[a, b] Yuriy A. Serguchev,[a] Markus E. Hirschberg,[c] Gerd-
Volker Rçschenthaler,[b] and Andrey A. Fokin*[d]
Abstract: Three reaction paths, namely, molecule-induced
homolytic, free radical, and electrophilic, were modeled
computationally at the MP2 level of ab initio theory and
studied experimentally for the reaction of F2 with the termi-
nal dienes of bicyclo[3.3.1]nonane series. The addition of flu-
orine is accompanied by transannular cyclization to the ada-
mantane derivatives in which strong evidence for the elec-
trophilic mechanism both in nucleophilic (acetonitrile) and
non-nucleophilic (CFCl3, CHCl3) solvents were found. The
presence of KF in CFCl3 and CHCl3 facilitates the addition
and substantially reduces the formation of tar products.
Introduction
The preparations of fluorine-containing organic compounds for
medicinal,[1] polymer,[2] and material[3] applications usually uti-
lize a large variety of fluorinating agents[4] rather than direct
fluorinations with elementary F2.[5] Exponentially growing at-
tention to direct fluorinations of unsaturated systems is associ-
ated with the development of the new electronic materials
based on fullerenes,[6] nanotubes,[7] and in particular, graph-
enes.[8] However, the addition of fluorine mechanistically is not
well understood: The simplest prototypical F2 +H2C=CH2 reac-
tion still puzzles theoreticians due to substantial discrepancies
between the computed and experimental (5.5ꢀ0.5 kcal
molꢁ1 [9]
barriers. Already, earlier studies have ruled out both
)
concerted[10] and nonconcerted[11] addition mechanisms due to
the high computed barriers of 51 and 23 kcalmolꢁ1, respective-
ly. The more realistic Cs symmetric (close to C2v) transition
structure (TS1, Figure 1) for the F2 attack on the C=C bond was
located at many levels. However, all DFT and high-level ab
Figure 1. The MP2/aug-cc-pVTZ-optimized transition structures for the
attack of molecular fluorine on ethylene (TS1) and 1,3-butadiene (TS2) as
well as molecular-induced homolytic 1,2- [Eq. (1)] and transannular [Eq. (2)]
additions of elemental fluorine to the unsaturated systems.
[a] Dr. M. V. Ponomarenko, Prof. Dr. Y. A. Serguchev
Organic Reactions Mechanism Department
Institute of Organic Chemistry, NAS of Ukraine
5 Murmanskaya Str., 02094 Kiev (Ukraine)
initio methods are not able to reproduce the experimental bar-
rier (from +1.8 kcalmolꢁ1 at B3LYP to +6.3 kcalmolꢁ1 at BHH
with aug-cc-pVTZ basis set),[12] and overestimate it by 1.6 and
2.5 kcalmolꢁ1 at CASPT2[9] and CCSD(T),[13] respectively. The
problem may arise from the fact that due to low dissociation
energy of fluorine (37 kcalmolꢁ1) the F2 +H2C=CH2 reaction
proceeds through the molecule-induced homolysis, that is,
[b] Dr. M. V. Ponomarenko, Prof. Dr. G.-V. Rçschenthaler
School of Engineering and Science
Jacobs University Bremen gGmbH
Campus Ring 1, 28759 Bremen (Germany)
E-mail: m.ponomarenko@jacobs-university.de
[c] Dr. M. E. Hirschberg
with the formation[14] of two radical species (F and CH2ꢁCH2F)
at the first reaction step (see below). This mechanism, which
was confirmed[9] for the gas phase by crossed beam experi-
ments, is difficult to validate computationally. Although, it was
demonstrated that single-reference computational approaches
such as CCSD, CCSD(T), and MP2 are trustworthy,[9,13] the open-
shell states may develop on route to the F2 attack and cause
C
C
Inorganic Chemistry, Bergische Universitꢀt Wuppertal
Gaußstrasse 20, 42097 Wuppertal (Germany)
[d] Prof. Dr. A. A. Fokin
Department of Organic Chemistry
Kiev Polytechnic Institute, pr. Pobedy 37, 03056 Kiev (Ukraine)
E-mail: aaf@xtf.kpi.ua
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402640.
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discrepancies between the experimental and theoretical data.
Whereas the attack of F2 on H2C=CH2 occurs on the singlet sur-
face cleanly (our TS1 reoptimized[15] as the open-shell singlet is
identical geometrically and energetically to the closed-shell
singlet structure), the situation with other olefins is clearly dif-
ferent. For instance, already for 1,3-butadiene the closed-shell
singlet transition structure (TS2, Figure 1) is distinctly different
from the one reoptimized as the open-shell singlet (TS2oss,
Figure 1) due to much higher spin separations.
The experimental mechanistic studies of the homolytic reac-
tion paths are also complicated because the F radical, which is
released from the diradical intermediate, may cause parallel
free-radical processes, resulting in the same CH2FꢁCH2F prod-
uct as expected from the molecular homolysis-rebound mech-
anism. Alkyl substituents increase the reactivity of the C=C
double bond and create additional reaction channels associat-
ed with HF elimination.[16] As a consequence, the primary reac-
tion channel is hard to determine experimentally for propyl-
ene, cyclohexene, and butadiene as they react spontaneously
with F2 even at 15 K.[17,18] Again, high-level ab initio computa-
tions overestimate the experimental reaction barriers
systematically.[9]
Scheme 1. Products expected form the addition of the reagent XY to 3,7-
dimethylenebicyclo[3.3.1]nonane (1).
In the condensed state the fluorination occurs under the
strong influence of solvent in which the electrophilic addition
of fluorine was postulated.[19] At low temperatures a very dilut-
ed stream of fluorine promotes this mechanism in polar sol-
vents (C2H5OH and AcOH) resulting in syn-addition of F2 to the
double bonds. However, such stereochemistry also may be at-
tributed to the homolytic mechanism due to difficulties in the
diffusion of F atom.[11, 12] Such contradictions make the stereo-
chemical results insufficient for the mechanistic studies.
Results and Discussion
Molecule-induced homolytic reaction of diene 1+F2
We first computed the reaction of 3,7-dimethylenebicyclo-
[3.3.1]nonane (1) with elemental fluorine at the MP2/6-31+G*
level of theory. We have chosen this method because of the
size of the systems and the fact that the MP2 results parallel
the most trusted CCSD(T) computations for the F2 +H2C=CH2
reaction.[11] The DFT functionals were not considered because
the discrepancies with the experiment for this reaction are too
high.[12,22] At MP2/6-31+G* the reaction starts with the exo-
thermic (18.7 kcalmolꢁ1) formation of the entrance complex
MIN1 (Figure 2). Further reaction may proceed either as 1,2-ad-
dition through TS3, or as a synchronous transannular cycliza-
tion though TS4. Despite the first reaction, which gives the
1,2-adduct MIN2, is highly exothermic (ꢁ103.9 kcalmolꢁ1) it is
characterized by relatively high barrier of 14.2 kcalmolꢁ1 and
Generally, for 1,2-addition it is rather difficult to identify the
molecule-induced homolytic channel, because the biradical
states, even if formed, are very tightly bound and may recom-
bine rapidly ([Eq. (1)], Figure 1). One can expect that the situa-
tion with the transannular addition is distinctly different as the
cyclization, which follows the fluorine attack, separates the rad-
ical centers spatially and may hamper the rebound ([Eq. (2)],
Figure 1). The most pronounced effects may be expected for
relatively rigid transannulated systems like unsaturated 3,7-de-
rivatives of bicyclo[3.3.1]nonane.[20] With electron-deficient re-
agents, the bicyclo[3.3.1]nonane dienes usually undergo trans-
annular cyclizations to adamantane or noradamantane deriva-
tives depending on the reagent employed.[21] Herein, we pres-
ent a combined experimental and computational study on the
reaction of F2 with dienes of bicyclo[3.3.1]nonane series that
allows one to distinguish between the free radical, molecule-
induced homolytic, and electrophilic addition modes already
on the structures of products (Scheme 1). Distinctly different
results are expected for the molecular-induced homolytic
([Eq. (3)], Scheme 1) and electrophilic ([Eq. (4)], Scheme 1) addi-
tions that give differently substituted adamantane derivatives.
For the free-radical additions, the formation of noradamantane
derivatives is characteristic ([Eq. (5)], Scheme 1).
¼
the cyclization through TS4 (DH298 =10.5 kcalmolꢁ1) is about
4 kcalmolꢁ1 more favorable than the 1,2-addition. This reaction
path is accompanied by substantial spin/charge delocalizations
within a number of carbon atoms of the cage and resulted in
the formation of two radicals (MIN3). The fact that substantial
spin separation occurs on route the cyclization, arises from the
reoptimization of TS4 as open-shell singlet that led, in contrast
to TS1 (see above), to the entirely different structure TS4oss.
This structure features the molecule-induced homolytic path as
the FꢁF bond is almost broken (2.549 ꢁ). This open-shell sin-
glet state is very close energetically and structurally to the trip-
let TS4T, indicating the possibility of almost complete spin sep-
aration already at the early stages of the cyclization to the ada-
mantane structure. Although the open-shell states are about
5 kcalmolꢁ1 higher in energy than the close shell TS4, the ho-
molytic path may be followed in the condensed state, in
which charge separations are favored: We found a substantial
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Figure 2. The MP2/6-31+G* stationary points for reaction of 3,7-dimethylenebicyclo[3.3.1]nonane (1) with F2 (critical bond lengths [ꢁ] and relative DH298 [kcal
molꢁ1]).
negative charge (0.55e) accumulated on the “outer” fluorine in
TS4.
that if the F radical would participate in the side free-radical re-
actions with 1, the formation of noradamantane derivatives is
expected.
Computations clearly show that the transannular cyclization
is more favorable than the 1,2-addition of F2 to 1 and may
occur as a molecule-induced homolysis, in which, due to large
spatial spin separations, the F radical may eliminate, causing
side free-radical processes. Thus, we modeled the possible out-
come of the reaction between 1 and the F radical.
In contrast, the formation of adamantane derivatives would
provide strong evidence against the participation of the F radi-
cal in the fluorinations with F2.
Electrophilic addition of F2 to 1
In accordance to the experimental data, the attack of the elec-
trophilic reagent X+ on 1 is always directed on the terminal
carbon atoms resulting in the X-methyladamantyl derivatives
(Scheme 1, [Eq. (4)]). The main driving force of this reaction is
the formation of stable tertiary adamantyl cations. We comput-
ed the electrophilic transannular cyclization of 1 with the com-
plex F+···H2O to model the transfer of hypothetical “F+” from
the solvent to the double bond of 1. The reaction is highly
exothermic and the transition structure for the “F+” transfer
(TS7) is located 86.3 kcalmolꢁ1 below the reactants. The attack
of fluorine is accompanied by the participation of both double
bonds of 1 that is viewed from the changes in the C=C and
non-valent sp2C–sp2C distances in TS7 versus those in diene
1 (Figure 4). The transannular cyclization downhill from TS7
Homolytic reaction of 1 and the F radical
Fortunately, compound 1 allows us distinguish between the
radical and non-radical addition modes because the reaction
of 1 with radicals gives noradamantane derivatives predomi-
nantly,[20c,21b] in contrast to the reactions with electrophiles that
lead to substituted adamantanes.[21a,23] We found that this is
indeed true for treatment of 1 with the F radical (Figure 3).
The F-radical attack on 1 is exothermic by 46.6 kcalmolꢁ1 and
gives the intermediate radical MIN4. Further exothermic cycli-
zations of this radical may give either substituted adamantyl
(MIN5) or noradamantyl (MIN6) radicals through TS5 and TS6,
respectively. The cyclization to noradamantane MIN6 is charac-
terized by substantially lower barrier (9.8 kcalmolꢁ1) implying
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Experimental fluorinations of the dienes of bicyclo-
[3.3.1]nonane series
The reaction of 1 with elemental fluorine highly diluted with
nitrogen was studied at ꢁ788C in the solution of CFCl3 or its
1:1 mixture with CHCl3. The fluorination in pure CFCl3 gave di-
fluoro- (2) and monofluoro (3) adamantane derivatives in low
yields and was accompanied by the formation of tar products
complicating the mechanistic findings. When CHCl3 is present
in the reaction mixture, the difluoride 2 and the monofluoride
3 were isolated in high preparative yield (Scheme 1), which is
attributed to the fluorination with HF formed from the reaction
of CHCl3 with F2.[24] The formation of difluoride 2 may be in
accord with electrophilic reaction path (Scheme 1, [Eq. (4)], X=
Y=F), in which the intermediate 1-fluoromethyl-adamant-3-yl
cation is trapped with HF. As the side nucleophiles may trap
the cationic intermediates (if formed) more efficiently, we have
first tested the influence of KF on the fluorination in the CFCl3/
CHCl3 system and indeed found that the relative amount of
the difluoride 2 increases (Scheme 2). Even higher selectivities
were observed for the fluorination in nucleophilic acetonitrile
in which the formation of acetamides 4–6 was observed
(Scheme 2). The formation of 4 as main reaction product is at-
tributed to electrophilic attack of solvated fluorine followed by
the transannular cyclization to fluoromethyl-adamantyl cation
of type MIN7 (Figure 4) and its trapping with acetonitrile; fur-
ther side CH3 fluorinations of 4 gave fluorides 5 and 6.
The participation of the F radical, which may be formed
through homolysis, can be excluded because the noradaman-
tane derivatives that result from the F-radical attack on 1 (see
Figure 3) were not detected in the reaction mixture. The set of
the products formed allows us to postulate the electrophilic
addition Scheme for the fluorination of 1 in the condensed
phase.
Figure 3. The MP2/6-31+G* stationary points for reaction of 3,7-
dimethylenebicyclo[3.3.1]nonane (1) with the F radical (critical bond lengths
[ꢁ] and relative DH298 [kcalmolꢁ1]).
Additional information about the fluorination mechanism
was obtained utilizing methyl (1a) and phenyl (1b) bicyclo-
[3.3.1]nonane derivatives (Scheme 3). Fluorination in a CFCl3/
CHCl3 mixture gave two types of difluoro derivatives (2a,b and
2a’,b’) resulting from the attack of F2 on both unsubstituted
and substituted double bonds of 1a,b. The difluorides 2a,a’
and 2b,b’ were formed in trace amounts and their ratio was
determined from the NMR spectra of the reaction mixtures.
The main products (3a and 3b) resulted from the reaction
with HF formed due to a F2 +CHCl3 side reaction. This is typical
for the reaction of dienes of bicyclo[3.3.1]nonane series with
proton acids in which only the unsubstituted double bond is
attacked.[25] Electrophilic halogenations are always less
selective.[21a,26]
leads to the fluoromethyl-adamantyl cation MIN7 complex
with water additionally releasing about 95 kcalmolꢁ1 of energy.
Based on the high overall 181.4 kcalmolꢁ1 exothermicity for
the electrophilic addition to 1, one should expect the forma-
tion of adamantane derivatives exclusively. Questioning the
positional selectivities, we modeled this reaction for unsym-
metrical diene 1a (Figure 4) and found that the differences be-
tween the attack of fluorine onto the methylene (path A) and
ethylidene fragments (path B) are negligible. This is in sharp
contrast to the transannular cyclization of 1a with uncharged
electrophile
{1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-
Transannular cyclization of 1a,b with F2 in acetonitrile is ef-
fective due to trapping of the intermediates with the nucleo-
philic solvent. We were able to isolate and characterize two
types of 3-fluoromethyladamantyl derivatives 4a,b and 4a’,b’,
as well as products of their consecutive fluorination (5a,b,
5a’,b’, and 6b,b’). The product 4a was synthesized by treat-
ment of 1a with F-TEDA-BF4 in CH3CN with addition of 3 equiv
of water. The same reaction of 1a in dry acetonitrile following
with addition of water leads to the formation of a byproduct
[2.2.2]octane bis(tetrafluoroborate)} (F-TEDA-BF4), in which the
attack on the substituted double bond of 1a is favored ener-
getically and agrees nicely with the experimentally observed
selectivity.[20a] Thus, any pronounced regioselectivities for the
fluorinations of 1a through the electrophilic Scheme are not
expected.
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Figure 4. The MP2/6-31+G* stationary points (critical bond lengths [ꢁ] and relative DH298 [kcalmolꢁ1]) for reaction of 3,7-dimethylenebicyclo[3.3.1]nonane (1)
+
with the F···OH2 complex (TS7 and MIN7) and relative energies (in italics) of the transition structures (TS8 and TS9) for the electrophilic fluorination of un-
symmetrical 3-methylene-7-ethylidenebicyclo[3.3.1]nonane (1a).
2a in 14% yield. Such a set of products unequivocally eviden-
ces for the electrophilic addition mechanism as differently sub-
stituted double bonds are not discriminated. Such selectivities
are in sharp contrast with those observed for the reactions of
1a and 1b with perfluoroalkyl radicals[20c] or neutral electro-
philes[20a] and are in accord with computed model reaction of
1a with the F+···H2O complex (Figure 4).
efficiently by nucleophiles. We have found strong evidence for
the electrophilic addition of elementary fluorine both in nucle-
ophilic (acetonitrile) and non-nucleophilic (CFCl3/CHCl3) sol-
vents. In the latter case, the presence of KF facilitates the elec-
trophilic addition and substantially reduces the formation of
tar products.
Conclusion
Experimental Section
The unsaturated derivatives of bicyclo[3.3.1]nonane undergo
selective transannular cyclization with elemental fluorine and
serve as suitable mechanistic probes for the olefin fluorinations
in solution. The molecular-induced homolytic mechanism,
which is characteristic for the gas phase, in which the interac-
tion of two closed-shell molecules (F2 and olefin) leads to for-
mation of the biradical states with further dissociation into
two radical species, may be ruled out in solution (CFCl3) even
for transannulated dienes. There is also no evidence for the
participation of the F radical in the reaction because the nora-
damantane derivatives were not found even in trace amounts.
The main driving force of the reaction is the formation of
stable tert-adamantyl cationic intermediates that are trapped
CHCl3 and CH3CN were dried, and trace amounts of water (<5–
6 ppm) were controlled by a Karl Fischer titration. Reactions were
carried out in traps made from FEP tubes (i.d.=25 mm). Fluorine
gas (Solvay) was passed through a layer of KF to absorb traces of
HF and its flow was adjusted to 2 mLminꢁ1 by means of a mass
flow controller (MKS type 1479 A). Parallel flow of nitrogen was ad-
justed to 98 mLminꢁ1 by a second mass flow controller (MKS type
1179 A) and both gases were mixed in stainless steel tube (i.d.=
4 mm). The gas mixture was forced through a FEP tube (i.d.=
0.7 mm) and finally bubbled through the reaction mixtures while
stirring with
a
magnetic stirring bar. 1H- (399.78 MHz), 13C-
(100.53 MHz), and 19F (376.17) NMR spectra were recorded using
TMS or CCl3F as internal standard. Column chromatography was
performed on Kieselgel Merck 60 (230–400 mesh).
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Scheme 2. Preparative yields for the transannular cyclization of 3,7-
dimethylenebicyclo[3.3.1]nonane (1) with F2 in different solvents.
General fluorination procedure CHCl3/CFCl3
F2 gas (0.116 g, 3.04 mmol, 2% in N2) was bubbled through a mix-
Scheme 3. Transannular cyclizations of 3-methylen-7-ethylinedenebicyclo-
[3.3.1]nonane (1a) and 1-methylen-7-benzylidenebicyclo[3.3.1]nonane (1b)
with F2 in different media.
ture of
1 (0.30 g, 2.03 mmol) and spray-dried KF (0.14 g,
2.41 mmol) in a CHCl3/CFCl3-mixture (60 mL, 1:1) at ꢁ788C. Then,
N2 gas was passed through the reaction mixture for 30 min, and
the solvents were removed under reduced pressure. The residue
was dissolved with CH2Cl2 (30 mL), and the mixture was washed
with NaHCO3 (aq., 2ꢂ5 mL), water (2ꢂ5 mL), dried over anhydrous
Na2SO4 and concentrated in vacuo. The crude reaction mixture was
separated by column chromatography on SiO2 (n-hexane). The
spectral data of products 2 (211 mg, 56%), 2a,b (a: 33 mg, 9%; b:
17 mg, 5%), and 2a’,b’ (a’: 15 mg, 4%; b’: 6 mg, 2%) are identical
to described previously.[20a,27]
1-Fluoro-3-(fluoromethyl)-2-methyladamantane (2a’):[20a] Pale-
yellow oil (14 mg, 4%); 1H NMR (400 MHz, CDCl3): d=4.13 (ABX,
2
2
2
2JAB =9.0 Hz, JAF =48.0 Hz, 1H, CH2F), 4.02 (ABX, JBA =9.1 Hz, JBF
=
4
48.0 Hz, JBH =1.6 Hz, 1H, CH2F), 2.26 (m, 2H), 2.10–1.38 (m, 11H),
0.98 ppm (d, J=6.9 Hz, 3H, CH3); 19F NMR (376 MHz, CDCl3): d=
ꢁ140.7 (s, 1F, F-1), ꢁ232.4 ppm (t, J=47.7 Hz, 1F, CH2F); elemental
analysis calcd (%) for C12H18F2: C 71.97; H 9.06; found: C 71.70; H
10.43.
1-Fluoro-3-methyladamantane (3): Colorless oil (81 mg, 24%).
1H NMR (400 MHz, CDCl3): d=2.24 (m, 2H), 1.88–1.72 (m, 4H), 1.59
(d, J=6.0 Hz, 2H), 1.54–1.46 (m, 2H), 1.37 (m, 4H), 0.88 ppm (s,
CH3); 13C NMR (101 MHz, CDCl3): d=93.3 (d, J=183.0 Hz, C-1), 49.4
(d, J=16.3 Hz), 43.1 (d, J=2.0 Hz), 42.1 (d, J=17.2 Hz), 35.2 (d, J=
2.2 Hz), 34.7 (d, J=9.6 Hz, C-3), 31.6 (d, J=9.7 Hz, C-5, C-7),
30.1 ppm (d, J=1.3 Hz, CH3); 19F NMR (376 MHz, CDCl3): d=
ꢁ131.0 ppm (s); elemental analysis calcd (%) for C11H17F: C 78.52; H
10.18; found: C 78.43; H 10.14.
1-Fluoro-3-methyl-2-phenyladamantane (3b): Colorless oil
(114 mg, 35%). 1H NMR (400 MHz, CDCl3): d=7.39 (d, J=7.6 Hz,
2H), 7.34–7.19 (m, 3H), 2.91 (s, 1H, H-2), 2.43 (m, 2H), 2.32 (m, 1H),
2.19 (d, J=13.7 Hz, 1H), 2.11–1.95 (m, 2H), 1.76–1.60 (m, 4H), 1.52
(m, 1H), 1.31 (d, J=13.8 Hz, 1H), 0.66 ppm (s, 3H, CH3); 13C NMR
(101 MHz, CDCl3): d=139.4 (d, J=2.5 Hz), 130.8, 128.0, 126.6, 94.1
(d, J=187.8 Hz, C-1), 62.4 (d, J=16.4 Hz, C-2), 47.3 (d, J=1.8 Hz),
45.6 (d, J=17.9 Hz), 38.1 (d, J=1.5 Hz), 38.0 (d, J=5.9 Hz, C-3), 36.5
(d, J=15.0 Hz), 36.4 (d, J=1.1 Hz, C-6), 36.48 (d, J=15.0 Hz), 36.38
(d, J=1.1 Hz), 31.7 (d, J=10.0 Hz, C-5 or C-7), 31.0 (d, J=9.7 Hz, C-
5 or C-7), 27.9 ppm (d, J=2.3 Hz, CH3); 19F NMR (376 MHz, CDCl3):
d=ꢁ136.4 ppm (s); elemental analysis calcd (%) for C17H21F: C
83.56; H 8.66; found: C 83.51; H 8.64.
1-Fluoro-2,3-dimethyladamantane (3a): Colorless oil (71 mg,
21%). 1H NMR (400 MHz, CDCl3): d=2.22–2.11 (m, 2H), 2.02–1.94
(m, 1H), 1.92–1.37 (m, 9H), 1.14–1.06 (m, 1H), 0.93 (d, J=6.9 Hz,
3H, 2-CH3), 0.80 ppm (s, 3H, 3-CH3); 13C NMR (101 MHz, CDCl3): d=
94.8 (d, J=185.9 Hz, C-1), 48.4 (d, J=15.7 Hz, C-2), 45.7 (d, J=
2.0 Hz), 44.1 (d, J=17.9 Hz), 36.6 (d, J=1.6 Hz), 36.4 (d, J=6.8 Hz,
C-3), 36.1 (d, J=2.0 Hz), 35.8 (d, J=17.7 Hz), 31.4 (d, J=10.4 Hz, C-
5 or C-7), 31.0 (d, J=10.1 Hz, C-5 or C-7), 27.3 (d, J=2.4 Hz, CH3),
8.6 ppm (d, J=4.4 Hz, CH3); 19F NMR (376 MHz, CDCl3): d=
ꢁ139.0 ppm (s); elemental analysis calcd (%) for C12H19F: C 79.07; H
10.51; found: C 78.85; H 10.47.
1-Fluoro-3-(fluoromethyl)-2-phenyladamantane (2b’):[20a] Pale-
1
yellow oil (6 mg, 2%); H NMR (400 MHz, CDCl3): d=7.64–7.06 (m,
5H), 3.85 (ABX, 2JAB =9.0 Hz, 2JAF =47.1 Hz, 1H, CH2F), 3.81 (ABX,
2
4
2JBA =9.0 Hz, JBF =47.1 Hz, JBH =1.6 Hz, 1H, CH2F), 3.17 (s, 1H, H-2),
2.63–1.40 ppm (m, 12H); 19F NMR (376 MHz, CDCl3): d=ꢁ138.1 (s,
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1
1F, F-1), ꢁ231.9 ppm (d, J=46.8 Hz, 1F, CH2F); elemental analysis
(5a’): Pale-yellow oil (62 mg, 13%). H NMR (400 MHz, CDCl3): d=
2
calcd (%) for C17H20F2: C 77.83; H 7.68; found: C 77.53; H 7.65.
5.96 (brs, 1H, NH, 5a), 5.82 (brs, 1H, NH, 5a’), 4.65 (d, JHF =
47.7 Hz, 2H, C(O)CH2F, 5a’), 4.64 (d, 2JHF =47.6 Hz, 2H, C(O)CH2F,
5a), 4.19 (dq, 2JHF =47.1 Hz,3JHH =6.4 Hz, 1H, CHF, 5a), 4.11 (ABX,
2JAB =9.1 Hz, 2JAF =47.8 Hz, 1H, CH2F, 5a’), 4.02 (ABX, 2JBA =9.1 Hz,
General fluorination procedure in CH3CN
2JBF =47.8 Hz, 1H, CH2F, 5a’), 2.58 (qm, JHH =7.0 Hz, 1H, H-2, 5a’),
3
F2 gas (0.116 g, 3.04 mmol, 2% in N2) was bubbled through a mix-
2.56–2.51 (m, 1H, 5a’), 2.20 (m, 2H, 5a), 2.14 (m, 2H, 5a’), 2.03–
1.40 (m, 12H 5a, 10H 5a’), 1.22 (dd, 3JHF =25.2, 3JHH =6.4 Hz, 3H,
CH3, 5a), 0.88 ppm (d, 3JHH =7.0 Hz, 3H, CH3, 5a’); 13C NMR
(101 MHz, CDCl3): d=166.6 (d, J=15.5 Hz, C=O), 166.3 (d, J=
15.4 Hz, C=O), 96.6 (d, J=170.5 Hz, CHF, 5a), 90.2 (d, J=172.3 Hz,
AdCH2F, 5a’), 80.3 (d, J=187.6 Hz, C(O)CH2F), 80.2 (d, J=187.5 Hz,
C(O)CH2F), 55.3 (d, J=1.0 Hz, C-1, 5a’), 52.6 (d, J=0.9 Hz, C-1, 5a),
42.0, 41.5 (d, J=4.5 Hz), 41.2, 40.3 (d, J=3.5 Hz, C-2, 5a’), 39.5 (d,
J=3.9 Hz), 38.8 (d, J=18.9 Hz), 38.1 (d, J=17.1 Hz), 36.5, 36.3, 36.3
(d, J=4.3 Hz), 36.1 (d, J=4.2 Hz), 35.8, 30.9, 30.9, 29.1, 28.8, 28.7,
14.5 (d, J=24.0 Hz, CH3, 5a), 9.2 ppm (CH3, 5a’); 19F NMR (376 MHz,
CDCl3): d=ꢁ185.1 (dq, 2JFH =47.4 Hz, 3JFH =25.2 Hz, 1F, CHF, 5a),
ꢁ219.8 (td, 2JFH =47.7 Hz, JFH =4.3 Hz, 1F, C(O)CH2F, 5a’), ꢁ220.1
ture of
1 (0.30 g, 2.03 mmol) and spray-dried KF (0.14 g,
2.41 mmol) in acetonitrile (60 mL) at ꢁ408C. The reaction mixture
was warmed up to room temperature while passing N2 gas
through the reaction mixture for 30 min. The solvent was removed
under reduced pressure. The residue was dissolved with CH2Cl2
(30 mL), and the mixture was washed with NaHCO3 (aq., 2ꢂ5 mL),
water (3ꢂ5 mL), dried over anhydrous Na2SO4, and concentrated in
vacuo. The crude reaction mixture was separated by column chro-
matography on SiO2 (CH2Cl2/ether).
N-[3-(fluoromethyl)-1-adamantyl]acetamide (4): White crystals.
M.p. 97–988C (242 mg, 53%); 1H NMR (400 MHz, CDCl3): d=5.19
(brs, 1H, NH), 3.99 (d, 2JHF =48.0 Hz, 2H), 2.17 (m, 2H), 1.94 (m,
2
4H), 1.89 (s, 3H, CH3), 1.81 (s, 2H), 1.66 (m, JAB =12.7 Hz, 1H), 1.58
2
2
(m, 2JAB =12.5 Hz, 1H), 1.50 ppm (m, 4H); 13C NMR (101 MHz,
CDCl3): d=169.5, 91.9 (d, J=172.1 Hz), 52.1 (d, J=1.3 Hz), 42.0 (d,
J=4.4 Hz), 41.1, 37.2 (d, J=4.2 Hz), 36.4 (d, J=17.7 Hz), 35.8, 29.0
(d, J=0.9 Hz), 24.7 ppm; 19F NMR (376 MHz, CDCl3): d=ꢁ230.1 (t,
J=48.0 Hz); HRMS: m/z calcd for C13H20FNNaO: 248.1427 [M+];
found: 248.1426.
(td, JFH =47.6, JFH =4.2 Hz, 1F, C(O)CH2F, 5a), ꢁ231.5 ppm (t, JFH
=
47.8 Hz, 1F, 5a’); elemental analysis calcd (%) for C14H21F2NO: C
65.35; H 8.23; N 5.44; found (for the mixture of 5a and 5a’): C
65.27; H 8.23; N 5.43.
N-{3-[Fluoro(phenyl)methyl]-1-adamantyl}acetamide
(4b)
(109 mg, 27%): Colorless crystals. M.p. 128–1308C; 1H NMR
(400 MHz, CDCl3): d=7.39–7.27 (m, 3H), 7.20 (dm, J=7.9 Hz, 2H),
2-Fluoro-N-[3-(fluoromethyl)-1-adamantyl]acetamide (5): Color-
less oil (83 mg, 17%). H NMR (400 MHz, CDCl3): d=5.96 (brs, 1H,
NH), 4.64 (d, 2JHF =47.6 Hz, 2H, C(O)CH2F), 4.01 (d, 2JHF =47.9 Hz,
2
1
5.23 (brs, 1H, NH), 4.97 (d, JHF =45.3 Hz, 1H, CH2F), 2.14 (m, 2H),
2.00–1.79 (m, 5H), 1.88 (s, 3H, CH3), 1.72 (dm, J=11.8 Hz, 1H),
1.65–1.54 (m, J=12.5 Hz, 3H), 1.50 (dm, J=12.5 Hz, 2H), 1.43 ppm
(dm, J=12.1 Hz, 1H); 13C NMR (101 MHz, CDCl3): d=169.5 (C=O),
136.6 (d, J=21.8 Hz), 128.1, 127.7, 127.1 (d, J=8.2 Hz), 100.8 (d, J=
176.6 Hz), 52.4, 41.6 (d, J=3.9 Hz), 41.0 (d, J=3.7 Hz), 39.5 (d, J=
21.8 Hz), 36.4 (d, J=10.9 Hz), 35.7, 29.1, 24.7 ppm (CH3); 19F NMR
(376 MHz, CDCl3): d=ꢁ190.5 ppm (d, J=45.3 Hz); elemental analy-
sis calcd (%) for C19H24FNO: C 75.71; H 8.03; N 4.65; found: C
75.65; H 8.02; N 4.64.
2
2H, AdCH2F), 2.18 (m, 2H), 1.99 (m, 4H), 1.86 (s, 2H), 1.68 (m, JAB
=
12.7 Hz, 1H), 1.61 (m, 2JAB =12.5 Hz, 1H), 1.52 ppm (m, 4H);
13C NMR (101 MHz, CDCl3): d=166.6 (d, J=15.5 Hz), 91.7 (d, J=
172.5 Hz), 80.2 (d, J=187.9 Hz), 52.4 (d, J=1.4 Hz), 42.0 (d, J=
4.5 Hz), 41.1, 37.1 (d, J=4.3 Hz), 36.5 (d, J=17.7 Hz), 35.7, 29.0 ppm
(d, J=0.9 Hz); 19F NMR (376 MHz, CDCl3): d=ꢁ220.1 (td, J=47.6,
4.2 Hz, 1F, C(O)CH2F), ꢁ230.16 ppm (t, J=47.9 Hz, 1F, AdCH2F);
HRMS: m/z calcd for C13H19F2NNaO: 266.1332 [M+]; found:
266.1329.
N-[3-(Fluoromethyl)-2-phenyl-1-adamantyl]acetamide (4b’): col-
orless crystals (97 mg, 24%). M.p. 118–1208C; 1H NMR (400 MHz,
2,2-Difluoro-N-[3-(fluoromethyl)-1-adamantyl]acetamide (6): Col-
orless oil (48 mg, 9%). H NMR (400 MHz, CDCl3): d=5.94 (brs, 1H,
NH), 5.75 (t, 2JHF =54.5 Hz, 1H, CF2H), 4.01 (d, 2JHF =47.9 Hz, 2H),
2.22 (m, 2H), 1.99 (m, 4H), 1.86 (s, 2H), 1.69 (m, JAB =12.7 Hz, 1H),
1.62 (m, JAB =12.5 Hz, 1H), 1.53 ppm (m, 4H); 13C NMR (101 MHz,
1
CDCl3): d=7.59 (d, J=7.5 Hz, 1H), 7.44–7.08 (m, 4H), 4.76 (brs, 1H,
2
NH), 3.75 (ABX, 2JAB =8.9 Hz, 2JAF =47.5 Hz, 1H), 3.69 (ABX, JBA
=
2
2
2
8.9 Hz, JAF =47.5 Hz, 1H), 3.58 (s, 1H), 2.72 (dm, J=12.3 Hz, 1H),
2
2
2.34 (m, 1H), 2.24 (m, 1H), 2.19 (dm, J=12.6, 1H), 2.09 (m, 2H),
1.98–1.85 (m, 2H), 1.77 (dm, 2J=12.4 Hz, 1H), 1.69 (dm, 2J=
12.4 Hz, 2H), 1.56 (s, 3H, CH3), 1.45 ppm (dm, 2J=13.1 Hz, 1H);
13C NMR (101 MHz, CDCl3): d=169.6 (C=O), 139.1, 133.6, 128.6,
128.0, 127.5, 127.1, 90.2 (d, J=171.9 Hz), 55.1 (d, J=0.9 Hz, CAd-
NH), 54.1 (d, J=3.4 Hz, CH-Ph), 42.8, 40.9 (d, J=3.6 Hz), 39.5 (d, J=
17.2 Hz), 37.0, 36.9, 31.9 (d, J=4.9 Hz), 29.1, 28.7 (d, J=1.3 Hz),
24.31 ppm (CH3); 19F NMR (376 MHz, CDCl3): d=ꢁ231.8 ppm (t, J=
47.7 Hz); elemental analysis calcd (%) for C19H24FNO: C 75.71; H
8.03; N 4.65; found: C 75.62; H 8.01; N 4.64.
CDCl3): d=161.6 (t, J=23.4 Hz, C=O), 108.6 (t, J=254.0 Hz, CF2H),
91.6 (d, J=172.5 Hz, CH2F), 52.9, 41.7 (d, J=4.8 Hz), 40.7, 37.0 (d,
J=3.8 Hz), 36.5 (d, J=17.3 Hz), 35.6, 29.0 ppm; 19F NMR (376 MHz,
CDCl3): d=ꢁ125.1 (dd, J=54.7, 2.1 Hz, 2F), ꢁ230.2 ppm (t, J=
47.9 Hz, 1F); HRMS: m/z calcd for C13H18F3NNaO: 284.1238 [M+];
found: 284.1240.
N-[3-(Fluoromethyl)-2-methyl-1-adamantyl]acetamide (4a’, from
a mixture of 4a and 4a’): Colorless crystals. M.p.=46–518C,
(256 mg, 58%). 1H NMR (400 MHz, CDCl3): d=5.02 (brs, 1H, NH),
2
4.09 (ABX, 2JAB =9.0 Hz, 2JAF =47.8 Hz, 1H, CH2F), 4.02 (ABX, JBA
=
2-Fluoro-N-{3-[fluoro(phenyl)methyl]-1-adamantyl}acetamide
(5b): Colorless crystals (55 mg, 13%). M.p. 54–558C; 1H NMR
(400 MHz, CDCl3): d=7.38–7.29 (m, 3H), 7.21 (dm, J=7.9 Hz, 2H),
5.93 (brs, 1H, NH), 5.00 (d, 2JHF =45.2 Hz, 1H, CHFPh), 4.64 (d,
2JHF =47.6 Hz, 2H, CH2F), 2.18 (m, 2H), 1.95 (m, 5H), 1.78 (dt, J=
11.6, 2.0 Hz, 1H), 1.67–1.57 (m, 3H), 1.53 (dm, J=12.7 Hz, 2H),
1.46 ppm (d, J=12.7 Hz, 1H); 13C NMR (101 MHz, CDCl3): d=166.6
(d, J=15.4 Hz, C=O), 136.5 (d, J=21.7 Hz), 128.2 (d, J=1.4 Hz),
127.8, 127.1 (d, J=8.0 Hz), 100.7 (d, J=177.0 Hz, CHF), 80.3 (d, J=
187.7 Hz, CH2F), 52.6 (d, J=1.0 Hz, C-1), 41.6 (d, J=4.2 Hz), 41.0 (d,
J=1.3 Hz), 39.6 (d, J=21.9 Hz, C-3), 36.3 (dd, J=16.9, 4.0 Hz, C-2),
35.5, 29.03 ppm (C-5,7); 19F NMR (376 MHz, CDCl3): d=ꢁ190.5 ppm
2
9.0 Hz, JBF =47.8 Hz, 1H, CH2F), 2.61 (m, 2H), 2.10 (m, 2H), 1.91 (s,
3
3H, C(O)CH3), 1.86 (m, 1H), 1.80–1.46 (m, 8H), 0.86 ppm (d, JHH
=
7.0 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3): d=169.2 (C=O), 90.4
(d, J=171.9 Hz, CH2F), 55.0 (C-1), 41.8, 39.8 (d, J=3.6 Hz, C-2), 39.5
(d, J=4.0 Hz), 38.0 (d, J=17.1 Hz, C-3), 36.7, 36.6, 31.1, 31.0, 28.7,
24.5 (C(O)CH3), 9.21 ppm (2-Ad-CH3); 19F NMR (376 MHz, CDCl3): d=
ꢁ231.2 ppm (t, J=47.9 Hz); elemental analysis calcd (%) for
C14H22FNO: C 70.26; H 9.27; N 5.85; found (for the mixture of 4a
and 4a’): C 70.01; H 9.25; N 5.84.
2-Fluoro-N-[3-(1-fluoroethyl)-1-adamantyl]acetamide (5a) and 2-
fluoro-N-[3-(fluoro-methyl)-2-methyl-1-adamantyl]acetamide
Chem. Eur. J. 2014, 20, 10383 – 10391
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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(d, J=45.3 Hz, 1F, CFH), ꢁ220.1 ppm (td, J=47.7, 4.1 Hz, 1F, CH2F);
elemental analysis calcd (%) for C19H23F2NO: C 71.45; H 7.26; N
4.39; found: C 71.34; H 7.24; N 4.38.
Acknowledgements
This research was supported by the Ministry of Science and
Education of Ukraine and by the Ukrainian Basic Research
Foundation. A.A.F. is grateful to the University of Giessen (Ger-
many) and the Institute of Applied System Analysis (Kiev, Uk-
raine) for computing facilities. M.V.P. gratefully acknowledges
Dr. N. V. Ignat’ev (Merck KGaA) and Prof. H. Willner (Bergische
Universitꢃt Wuppertal) for their helpful discussions and work-
ing facilities.
2-Fluoro-N-[3-(fluoromethyl)-2-phenyl-1-adamantyl]acetamide
(5b’): Colorless pale-yellow oil (38 mg, 9%). 1H NMR (400 MHz,
CDCl3): d=7.60 (d, J=7.7 Hz, 1H), 7.42–7.15 (m, 5H), 5.65 (brs, 1H,
2
2
NH), 4.41 (ABX, 2JAB =14.0 Hz, JAF =47.7 Hz, 1H), 4.28 (ABX, JBA
=
=
2
2
2
14.0 Hz, JBF =47.7 Hz, 1H, C(O)CH2F), 3.77 (ABX, JAB =9.0 Hz, JAF
47.5 Hz, 1H, AdCH2F), 3.71 (ABX, 2JBA =9.0 Hz, 2JBF =47.5 Hz, 1H,
AdCH2F), 3.56 (s, 1H, CHPh), 2.63 (dm, J=7.4 Hz, 1H), 2.38 (m, 1H),
2.33–2.25 (m, 2H), 2.21 (dm, J=12.2 Hz, 1H), 2.10 (dm, J=13.5 Hz,
1H), 1.99 (m, Hz, 2H), 1.80 (dm, J=12.4 Hz, 1H), 1.71 (dm, J=
12.5 Hz, 2H), 1.46 ppm (d, J=13.2 Hz, 1H); 13C NMR (101 MHz,
CDCl3): d=166.6 (d, J=15.6 Hz, C=O), 138.5, 133.4, 128.7, 128.2,
127.6, 127.4, 90.0 (d, J=172.0 Hz, AdCH2F), 80.0 (d, J=187.7 Hz,
C(O)CH2F), 55.2 (d, J=0.9 Hz, C-1), 54.6 (d, J=3.7 Hz, C-2), 43.0,
40.9 (d, J=3.5 Hz), 39.6 (d, J=17.3 Hz, C-3), 36.9, 36.6, 31.7 (d, J=
5.2 Hz), 29.2, 28.6 ppm (d, J=1.4 Hz); 19F NMR (376 MHz, CDCl3):
d=ꢁ220.48 (td, J=47.6, 4.2 Hz), ꢁ232.03 ppm (t, J=47.6 Hz); ele-
mental analysis calcd (%) for C19H23F2NO: C 71.45; H 7.26; N 4.39;
found: C 71.40; H 7.25; N 4.38.
Keywords: density functional theory · dienes · electrophilic
addition · fluorine · reaction mechanisms
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2,2-Difluoro-N-{3-[fluoro(phenyl)methyl]-1-adamantyl}acetamide
(6b) and 2,2-difluoro-N-[3-(fluoromethyl)-2-phenyl-1-adamanty-
l]acetamide (6b’): Pale-yellow oil (9 mg, 2%). 1H NMR (400 MHz,
CDCl3): d=7.60 (d, J=7.8 Hz, 1H, 6b’), 7.43–7.11 (m, 5H 6b, 4H
6b’), 5.90 (brs, 1H, NH, 6b), 5.74 (t, 2JHF =54.7 Hz, 1H, CF2H, 6b),
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2
5.64 (brs, 1H, NH, 6b’), 5.46 (t, JHF =54.6 Hz, 1H, CF2H, 6b’), 4.99
2
(d, 2JHF =45.4 Hz, 1H, CHFPh, 6b), 3.77 (ABX, 2JAB =9.0 Hz, JAF
=
47.7 Hz, 1H, CH2F, 6b’), 3.72 (ABX, 2JBA =9.0 Hz, 2JBF =47.7 Hz, 1H,
CH2F, 6b’), 3.51 (s, 1H, CHPh, 6b’), 2.58 (dm, J=12.2 Hz, 1H, 6b’),
2.40 (m, 1H, 6b’), 2.35–1.40 ppm (m, 14H 6b, 10H 6b’); 19F NMR
(376 MHz, CDCl3): d=ꢁ125.1 (dd, J=54.7, 2.0 Hz, 2F, CF2H, 6b),
ꢁ125.8 (dt, J=54.7, 2.5 Hz, 2F, CF2H, 6b’), ꢁ190.6 (d, J=45.2 Hz, 1F,
CH2F, 6b), ꢁ232.1 ppm (t, J=47.5 Hz, CH2F, 6b’); elemental analysis
calcd (%) for C19H22F3NO: C 67.64; H 6.57; N 4.15; found (for the
mixture of 6b and 6b’): C 67.45; H 6.55; N 5.42.
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Preparation of N-[3-(1-fluoroethyl)-1-adamantyl]acetamide
(4a) using F-TEDA-BF4
A solution of 1a (0.693 g, 4.28 mmol) in acetonitrile (2 mL) was
added to a mixture of F-TEDA-BF4 (1.82 g, 5.14 mmol, 1.2 equiv)
and water (0.23 mL, 3 equiv) in acetonitrile (8 mL). The reaction
mixture was stirred for 2 h at ambient conditions. The solvent was
removed under reduced pressure. The residue was dissolved with
CH2Cl2 (50 mL), and the organic layer was washed with water (5ꢂ
5 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
The solvent was evaporated to obtain the crude product that was
purified by crystallization from n-hexane giving 0.85 g (83% yields)
of N-[3-(1-fluoroethyl)-1-adamantyl]acetamide (4a) as colorless
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1
crystals. M.p. 93–948C; H NMR (400 MHz, CDCl3): d=5.18 (brs, 1H,
2
3
NH), 4.18 (dq, JHF =47.3 Hz, JHH =6.4 Hz, 1H, CHF), 2.16 (s, 2H, H-
5, H-7), 1.93 (m, 4H), 1.89 (s, 3H, C(O)CH3), 1.87 (m, 1H), 1.72 (dm,
J=11.7 Hz, 1H), 1.65 (m, 1H), 1.61–1.51 (m, 3H), 1.37–1.49 (m, 2H),
3
1.21 ppm (dd, 3JHF =25.2, JHH 6.4 Hz, 3H, CFCH3); 13C NMR
´
ˇ
3433–3438; j) F. Karlicky, K. K. R. Datta, M. Otyepka, R. Zboril, ACS Nano
2013, 7, 6434–6464.
(101 MHz, CDCl3): d=169.5 (C=O), 96.8 (d, J=170.1 Hz, CHF), 52.3
(C-1), 41.4 (d, J=4.4 Hz), 41.2 (d, J=2.8 Hz), 38.7 (d, J=18.9 Hz, C-
3), 36.3 (d, J=4.2 Hz), 35.9, 29.1 (C-5, C-7), 24.7 (CH3), 14.5 ppm (d,
J=24.0 Hz, CH3); 19F NMR (376 MHz, CDCl3): d=ꢁ185.0 ppm (dq,
2JFH =47.8 Hz, 3JFH =25.4 Hz); HRMS: m/z calcd for C14H23FNO:
284.1757 [M+]; found: 240.1758.
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Published online on July 7, 2014
Chem. Eur. J. 2014, 20, 10383 – 10391
www.chemeurj.org
10391
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim