Quantum chemical calculation of 19F NMR chemical shifts of trifluoromethyl diazirine photoproducts and precursors

Article abstract of DOI:10.1016/j.jfluchem.2014.06.027

Irradiation of aryl(trifluoromethyl)diazirines may result in a multitude of products, which are difficult to assign in the ¹⁹F NMR spectrum. In this article, it is demonstrated that an average accuracy of 2.9 ppm (standard deviation) can be achieved by quantum chemical calculations at the B3LYP 6-311G++(2d,2p) level of theory, followed by a Boltzmann weighting of the optimized conformers. A set of 30 compounds was investigated both experimentally and theoretically. ¹⁹F NMR chemical shifts of precursor Z-oximes and Z-tosyloximes ranged from δ_F-62.9 to -61.8 ppm, whereas their E counterparts showed shifts between δ_F-67.2 and -66.2 ppm. Stereochemical assignments were confirmed by two X-ray analyses. Quantum chemical calculation also allowed the assignment of the configuration of an (E,E) azine. Trifluoromethyl diazirines exhibited a δ_Fbetween -66.1 and -65.6, diaziridines between -76.2 and -75.9 ppm. The smallest δ_Fvalues were observed for α-oxygenated trifluoromethyl compounds (δ_F-78.9 to -77.4 ppm). The average deviation of the calculated from the experimental values corresponds to only about 1% of the standard ¹⁹F NMR chemical shift range.

Full text of DOI:10.1016/j.jfluchem.2014.06.027

Journal of Fluorine Chemistry 166 (2014) 8–14
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
19
Quantum chemical calculation of F NMR chemical shifts
of trifluoromethyl diazirine photoproducts and precursors
a
b
a,
Bj o¨ rn Raimer , Peter G. Jones , Thomas Lindel *
a
Institute of Organic Chemistry, TU Braunschweig, Hagenring 30, 38106 Braunschweig, Germany
b
Institute of Inorganic and Analytical Chemistry, TU Braunschweig, 38106 Braunschweig, Germany
A R T I C L E I N F O
A B S T R A C T
Article history:
Irradiation of aryl(trifluoromethyl)diazirines may result in a multitude of products, which are difficult to
Received 28 April 2014
Received in revised form 24 June 2014
Accepted 25 June 2014
Available online 3 July 2014
19
assign in the F NMR spectrum. In this article, it is demonstrated that an average accuracy of 2.9 ppm
(standard deviation) can be achieved by quantum chemical calculations at the B3LYP 6-311G++(2d,2p)
level of theory, followed by a Boltzmann weighting of the optimized conformers. A set of 30 compounds
1
9
was investigated both experimentally and theoretically. F NMR chemical shifts of precursor Z-oximes
and Z-tosyloximes ranged from
ꢀ62.9 to ꢀ61.8 ppm, whereas their E counterparts showed shifts
between
ꢀ67.2 and ꢀ66.2 ppm. Stereochemical assignments were confirmed by two X-ray analyses.
Quantum chemical calculation also allowed the assignment of the configuration of an (E,E) azine.
Trifluoromethyl diazirines exhibited a
d
F
Keywords:
d
F
1
9
F NMR spectroscopy
Diazirines
d
F
between ꢀ66.1 and ꢀ65.6, diaziridines between ꢀ76.2 and
values were observed for -oxygenated trifluoromethyl compounds (
78.9 to ꢀ77.4 ppm). The average deviation of the calculated from the experimental values corresponds
Trifluoromethyl groups
Quantum chemical calculation
ꢀ
ꢀ
75.9 ppm. The smallest
d
F
a
d
F
1
9
to only about 1% of the standard F NMR chemical shift range.
ß 2014 Elsevier B.V. All rights reserved.
1
. Introduction
compound causing the signal at ꢀ73.91 ppm. It would be of
advantage to be able to rapidly estimate on the components of such
a crude reaction mixture without the need to isolate each of them.
There are several reports on quantum mechanical calculations
19
F NMR spectra of organofluorine compounds cover a chemical
shift range of more than 300 ppm [1]. In principle, that large
dispersion should allow distinction of very similar fluorinated
compounds. There is considerable interest in predicting F NMR
shifts [2], because fluorine is very important for the development
of pharmaceuticals [3]. Recent work has analyzed the F NMR
chemical shifts of trifluoroacetylated molecules [4]. When
studying the chemistry of photoaffinity labeling [5] employing
trifluoromethylated diazirines, we became aware of the possible
complexity of mixtures of trifluoromethylated products. Fig. 1
1
9
of F NMR chemical shifts. Maximal accuracy of about 2 ppm was
achieved when electron correlation and perturbative corrections
were taken into account in high-level CCSD(T) calculations with
1
9
19
6
large basis sets [7]. Here, calculation times are proportional to N to
7
N
(where N is the number of basis functions), which, at least
currently, limits broad applicability of such approaches for larger
systems [8]. Other quantum chemical approaches are faster,
3
4
because they scale only as N to N . There are also semiempirical
MNDO approaches for larger systems employing NMR-specific
parameters [9].
1
9
shows a typical F NMR spectrum obtained in our laboratory by
irradiation of (p-methoxyphenyl)(trifluoromethyl)diazirine (1) in
the presence of phenol. Only after preparative isolation of the
compounds could the major signals at ꢀ66.21, ꢀ66.83, ꢀ77.37, and
Our synthetic work has provided us with several CF
containing compounds, together with their experimental
3
9
-
F
1
ꢀ
78.93 ppm be assigned to compounds 17, 18, 30 (Fig. 2), and 32
NMR chemical shifts [10]. We felt it would be interesting to
analyze which combination of functional and basis set would give
the best quantum chemical prediction of NMR chemical shifts of
(
Fig. 4), respectively [6]. We were not able to identify the
CF
3
groups, which cover the rather small area between ꢀ60 and
ꢀ
90 ppm, corresponding to about 10% of the total chemical shift
*
Corresponding author. Tel.: +49 5313917300.
1
9
E-mail address: th.lindel@tu-bs.de (T. Lindel).
range in F NMR spectroscopy.
http://dx.doi.org/10.1016/j.jfluchem.2014.06.027
022-1139/ß 2014 Elsevier B.V. All rights reserved.
0

B. Raimer et al. / Journal of Fluorine Chemistry 166 (2014) 8–14
9
19
3 3 F
Fig. 1. F NMR spectrum (376 MHz, CDCl , referenced to CFCl , d = 0.0 ppm) after irradiation (350 nm) of diazirine 1 in the presence of phenol (2).
1
9
Fig. 2. Investigated molecules, grouped by decreasing experimental F NMR chemical shifts (CDCl
3
, referenced to CFCl
3
,
dref 0 ppm, PMP = p-methoxyphenyl). Values in
brackets were calculated by GIAO NMR calculations on the B3LYP PCM (CHCl ) 6-311G++(2d,2p) level of theory and are referenced to hexafluorobenzene (
3
d
ref ꢀ164.9 ppm).

1
0
B. Raimer et al. / Journal of Fluorine Chemistry 166 (2014) 8–14
2
. Results and discussion
19
2
.1. Experimental F NMR data
Fig. 2 shows the 30 molecules that we analyzed, all of which
share a 2,2,2-trifluoroethylbenzene core unit. References are given
in the footnotes of Table 1. The only hitherto undescribed
compounds in the list are ketones 6 and 7. Ketone 6 was
synthesized from 4-bromo-3,5-dimethylanisole (4) by bromine/
lithium exchange (nBuLi) and quenching with CF
Scheme 1). Use of N-trifluoroacetylpiperidine as electrophile led to
replacement of the CF group of product 6 by piperidide via
3 2
CO Et (79%,
3
haloform reaction (27%) [11,12]. Sterically hindered ketone 7 was
obtained in rather low yield (36%) from 2-bromo-1,3,5-triethyl-
benzene (5) after treatment with tBuLi and quenching with N-
trifluoroacetylpiperidine.
1
9
F NMR spectra were taken in CDCl
= 0.0 ppm). A rather narrow range of chemical shifts between
78.9 and ꢀ61.8 ppm was observed, with the shift interval
between
3 3
, referenced to CFCl
(
ꢀ
d
F
d
F
d
F
ꢀ65.5 and ꢀ67.5 ppm being particularly crowded. Still,
19
shifts can in part be sorted according to functional groups. F NMR
chemical shifts of Z-oximes (Z-11, Z-10) and Z-tosyloximes (Z-8, Z-
9
(
) range from
E-11, E-8, E-9, E-10) show shifts between
Diazirines (1, 13, 14) show a
d
F
ꢀ62.9 to ꢀ61.8 ppm, whereas their E counterparts
d
F
ꢀ67.2 and ꢀ66.2 ppm.
d
F
between ꢀ66.1 and ꢀ65.6,
19
19
Fig. 3. Experimental F NMR chemical shift ranges observed for the investigated
diaziridines (25, 26, 27) between ꢀ76.2 and ꢀ75.9 ppm. F NMR
structural types.
chemical shifts of disubstituted trifluoroacetyl benzenes 21, 22, 23
and 31 (
d
F
ꢀ71.8 to ꢀ71.4) differ from those of tetrasubstituted 6
ꢀ76.9 to ꢀ76.8). The smallest values were observed
ꢀ78.9 to
values
between ꢀ66.8 and ꢀ66.1 ppm. Fig. 3 gives a helpful overview over
and 24 (
d
F
d
F
for
a
-oxysubstituted compounds 28, 29, and 30 (
d
F
arbitrarily chosen molecules (6, E-11, Z-11, 32, 33, Fig. 4) was
optimized on the B97D 6-31G(d) level of theory and the obtained
structures were submitted to GIAO NMR calculations [13]
employing the B3LYP [14] and the B97D [15] functionals. The
B97D functional includes dispersion contributions, which are
important for the description of sterically demanding compounds.
Both functionals were used with and without modeling the
effects of chloroform employing the PCM model [16]. As LCAO basis
we used three different basis sets of increasing flexibility (6-
31G(d), 6-311G++(2d,2p) and 6-311G+(3df,3dp)) as implemented
ꢀ
77.4 ppm). Aryl adducts 15, 16, 17, and 18 showed
d
F
19
the F NMR chemical shifts to be expected for the groups of the
CF - containing compounds discussed herein.
An interesting case is represented by azine 19, for which only
3
1
9
one signal was observed in the F NMR spectrum (
d
F
ꢀ67.6). This
could be caused by an overwhelming predominance of one of the
symmetrical diastereomers (E,E or Z,Z) or by accidental isochrony
in case of the non-symmetrical diastereomer (E,Z) or mixtures. The
stereochemical assignment was unclear and, thus, azine 19
represented a suitable test case for
calculation.
1
9
in Gaussian09 [17]. The
F NMR chemical shift of a given
as
(calculated
ref ꢀ164.9 ppm). Fig. 5 gives the
19
F NMR chemical shift
compound was calculated from the isotropic shielding s
d
s
=
s
ref
ꢀ
s
+
d
ref
,
using
C
d
6
F
6
as
reference
ref = 333.6 ppm, tabulated
2.2. Quantum chemical calculations
average deviations of GIAO NMR calculation results obtained for
molecules E-11, Z-11, 32, 33, and 6 employing twelve combina-
tions of four functionals and three basis sets (chloroform, PCM).
The combination of the B3LYP (PCM) functional and the
At the beginning, a suitable combination of functional and basis
set had to be chosen. Therefore, the geometry of a set of five
Table 1
19
3
Calculated and experimental F NMR chemical shifts (CDCl ) of the 30 compounds shown in Figure 2.
Compound
d
calc
d
exp
d
calc
ꢀ
d
exp
Compound
d
calc
d
exp
d
calc
ꢀ
d
exp
E-11 [21]
Z-11 [21]
E-10 [6]
Z-10 [6]
E-8 [21]
Z-8 [21]
E-9 [6]
ꢀ63.4
ꢀ58.8
ꢀ63.4
ꢀ58.4
ꢀ63.2
ꢀ58.0
ꢀ63.4
ꢀ57.1
ꢀ63.2
ꢀ76.6
ꢀ76.5
ꢀ63.2
ꢀ63.4
ꢀ76.4
ꢀ68.6
ꢀ67.1
ꢀ62.9
ꢀ66.6
ꢀ62.8
ꢀ67.2
ꢀ61.8
ꢀ66.2
ꢀ61.9
ꢀ65.6
ꢀ76.0
ꢀ76.2
ꢀ65.7
ꢀ66.1
ꢀ75.9
ꢀ71.7
3.7
4.1
3.2
4.4
4.0
3.8
2.8
4.8
2.4
22 [22]
24 [23]
7
ꢀ68.8
ꢀ73.1
ꢀ73.8
ꢀ68.8
ꢀ69.4
ꢀ69.7
ꢀ81.0
ꢀ68.4
ꢀ83.4
ꢀ66.4
ꢀ69.3
ꢀ78.1
ꢀ68.6
ꢀ63.6
ꢀ68.7
ꢀ71.7
ꢀ76.9
ꢀ76.8
ꢀ71.8
ꢀ66.2
ꢀ66.8
ꢀ77.4
ꢀ66.1
ꢀ78.9
ꢀ64.1
ꢀ69.4
ꢀ77.4
ꢀ66.1
ꢀ67.6
ꢀ71.4
2.9
3.8
3.0
3.0
23 [10]
17 [6]
18 [6]
28 [6]
15 [6]
30 [6]
12 [6]
20 [6]
29 [6]
16 [6]
19 [25]
31 [6]
ꢀ3.2
ꢀ2.9
ꢀ3.6
ꢀ2.3
ꢀ4.5
ꢀ2.3
0.1
Z-9 [6]
1
2
2
1
1
2
2
3 [10]
6 [21]
7 [6]
ꢀ0.6
0.3
4 [21]
[6]
2.5
ꢀ0.7
ꢀ2.5
4.0
2.7
5 [10]
1 [24]
ꢀ0.5
ꢀ3.1
2.7

B. Raimer et al. / Journal of Fluorine Chemistry 166 (2014) 8–14
11
Higher absolute deviations between 4.0 and 4.8 ppm were
obtained for oxime derivatives Z-11, Z-10, Z-9, E-8, and for benzylic
alcohol 30. Fortunately, we were able to obtain X-ray analyses of
oxime E-11 and the O-tosylated analog E-8 (Fig. 7) [20]. Thus,
1
9
unambiguous assignment of the experimental F NMR chemical
shifts of both pairs of oximes became possible.
For all oxime diastereomers, the chemical shift deviation
between calculation and experiment
(
Dd
F
=
d
calc
ꢀ
exp
d ) was
positive (+2.8 to +4.1 ppm), which cannot currently be explained.
Choosing a more advanced basis set appears to help. After re-
optimization of E-9 employing a higher basis set [6-311G (2d,2p)]
than used previously for geometry optimization [6-31G*] we
observed a decrease of the shift deviation from 2.8 to 0.9 ppm.
Scheme 1. Synthesis of ketones 6 and 7.
6
-311G++(2d,2p) basis set proved to be the most accurate, with an
average absolute error of 1.9 ppm. We observed an advantage of
the B3LYP over the B97D functional.
1
9
However, the F NMR chemical shift difference of Z- and E-oximes
is already predicted accurately (5 ppm) by the employed standard
calculation procedure.
For the larger set of 30 compounds (structures shown in Fig. 2),
conformers with the lowest energy were determined employing
the MMFF force field [18]. Each conformer was optimized at the
B97D 6-31G(d) level of theory, followed by GIAO NMR calculations
What remained to be assigned was the configuration of azine
1
9
19. Quantum chemical calculation predicts F NMR chemical
shifts of the three possible diastereomers of ꢀ63.6 ppm (E,E),
ꢀ64.3/ ꢀ 59.8 (E,Z), and ꢀ57.7 ppm (Z,Z) if calculated as described
3
at the B3LYP PCM (CHCl ) 6-311G++(2d,2p) level of theory. The
conformer distribution was calculated using standard Monte Carlo
methods, as implemented in Spartan 08, leading to global
minimum geometries for the subsequent quantum chemical
19
by modeling CHCl
3
(PCM). Thus, accidental isochrony of the
F
NMR chemical shifts of the two diastereotopic CF
(E,Z) isomer can be excluded. In the experiment, we observed only
one signal at
ꢀ67.6 ppm, which clearly indicates the presence of
the (E,E) diastereomer, which is also the thermodynamically most
3
groups of an
19
optimizations [19]. The calculated F NMR chemical shifts of
the energetically different, optimized conformers were Boltz-
mann-weighted (298 K).
d
F
19
Deviations of the calculated values (
d
calc
ꢀ
d
exp, B3LYP (PCM) 6-
stable. The difference of calculated and experimental F NMR
chemical shifts (Dd = 4.0 ppm) is of the same sign and magnitude
3
11G++(2d,2p)) vary between ꢀ4.5 and +4.8 ppm (Table 1).
F
Calculated and experimental values are plotted against each other
in Fig. 6. The standard deviation was 2.9 ppm and did not increase
greatly when considering only the energetically most favored
conformer of each compound (3.2 ppm). Small absolute deviations
of less than 1 ppm were observed for the diaziridines 25–27, and
for N-trifluoroacetylpiperidine (20). For the regioisomeric photo-
as in the case of the structurally related oxime derivatives (Fig. 7)
3. Conclusion
In summary, we could show that GIAO NMR calculations,
combined with geometry optimization with the B97D functional
and a 6-31G* basis set followed by Boltzmann weighting of the
NMR shifts, constitute an interesting and useful tool to support
adducts 16 and 29 of
L-N,N-dimethyl tyrosine methyl ester we
obtained Dd values of 0.7 (29) and 2.5 ppm (16).
F
Fig. 4. Optimized geometries of compounds E-11, Z-11, 32, 33, and 6 on the B97D 6-31G(d) level of theory.

1
2
B. Raimer et al. / Journal of Fluorine Chemistry 166 (2014) 8–14
Fig. 5. Average absolute deviations of GIAO NMR calculation results obtained for
molecules E-11, Z-11, 32, 33, and 6 employing the 12 combinations of 4 functionals
and 3 basis sets (chloroform, PCM). Average Dd
F F
was calculated via the sum of Dd of
the chosen molecules for each combination divided by the number of molecules.
users by providing structural information about CF
3
-containing
molecules. We were able to identify a suitable combination of basis
19
set and density functional for the calculation of CF
chemical shifts [B3LYP/6-311G++(2d,2p), PCM = CHCl
3
F NMR
]. The cal-
3
culations took between 2 h and 2 days on a DELL Power Edge T110
PC with 8x Intel(R)Xeon(R) CPU X3470@2.93 GHz and 8192 MB
memory, and can be conducted on an everyday basis in a standard
laboratory. We were pleased by the accuracy of prediction.
Frequent problems such as the assignment of E/Z configuration
to trifluoromethylated oximes can be solved. Our results should
Fig. 7. X-ray analyses of E-8 (left) and E-11 (right). Hydrogen atoms have been
omitted for clarity.
1
3
1
75.5 MHz for C), Bruker DRX-400 (400.1 MHz for H, 100.6 MHz
1
3
19
encourage researchers dealing with mixtures of CF
3
- containing
for C, 376.3 MHz for F) and a Bruker AV III-400 (400.1 MHz for
H, 100.6 MHz for C), H and C NMR signals were referenced to
1
13
1
13
compounds to use quantum mechanical calculation for analysis.
This will be interesting for analyzing photoaffinity labeling with
aryl(trifluoromethyl)diazirines with chemical accuracy.
1
9
the solvent signal or TMS. Experimental F NMR signals were
referenced to CFCl
ref ꢀ0 ppm, virtual internal referencing).
NMR shifts were referenced to
ref ꢀ164.9 ppm). All measurements were
3
(d
1
19
Quantum chemical calculations of H NMR chemical shifts [26]
Calculated
F
6 6
C F
provided an average deviation of 0.12 ppm (GIAO/B3LYP/aug-cc-
(
sref = 333.6 ppm, d
19
pVDZ) [27], corresponding to an error of about 1%. The F NMR
chemical shift calculations presented in this article delivered an
average absolute deviation of only 2.9 ppm, also corresponding to
performed at 300 K. Mass spectra were obtained with a Thermo-
Finnigan MAT (MAT95XL) spectrometer and a ThermoFisher
Scientific (LTQ-Orbitrap Velos) spectrometer. IR spectra were
recorded with a Bruker Tensor 27 spectrometer. UV/Vis spectra
were measured with a Varian Cary 100 Bio UV/Vis-spectrometer.
Melting points were measured with a B u¨ chi 530 melting point
apparatus. Chemicals were purchased from commercial suppliers
19
about 1% of the standard chemical shift range of
spectroscopy of 300 ppm.
F NMR
4
. Experimental
.1. General methods
NMR spectra were taken with a Bruker DPX-200 (200.1 MHz for
and used without further purification. Silica gel 60 (40–63
mm,
4
Merck) was used for column chromatography. Petroleum ether had
a boiling range from 40 to 60 8C.
1
19
1
H, 188.3 MHz for F), Bruker AV II-300 (300.1 MHz for H,
4.1.1. (E)-2,2,2-trifluoro-1-phenylethanonoxime (E-11)
The synthesis of 11 was described earlier [21]. We observed the
isomerization of the originally E/Z mixture to pure E in the solid
state within 3 years at rt. X-ray analysis confirmed the configura-
tion of the oxime double bond. TLC: R
f
= 0.6 [PE/EtOAc (5/1)]; m.p.
1
8
8 8C. H NMR (400 MHz, CDCl
.52 (m, 2H, oCH), 7.49–7.46 (m, 3H, mCH, pCH).
3
): d = 9.52 (s, br), 1H, O-H), 7.55–
13
7
C NMR
= 147.1 (q, JCF = 32.4 Hz, CN), 130.8 (1C, pCH),
28.7 (2C, mCH), 128.6 (2C, oCH), 125.9 (1C, ipsoC), 120.7 (q,
2
(
3
100 MHz, CDCl ): d
1
1
19
J
CF = 274.8 Hz, 1C, CF
3
1
). F NMR (376 MHz, CDCl
3
):
d
= ꢀ67.1. IR
(
(
ATR): n
˜ ¼ 3265 cmꢀ (m, br), 3072 (w), 2911 (w), 1722 (w), 1460
m), 1439 (m), 1335 (m), 1280 (w), 1205 (s), 1183 (s), 1130 (s),
1
(
7
039 (m), 1013 (s), 959 (s), 925 (m), 772 (m), 745 (m), 707 (s), 691
s), 611 (m). UV–vis (CHCl ): max (log ) = 240 (3.82) nm. MS (EI,
0 eV): m/z (%) = 189.0 (71), 173.0 (17), 104.0 (77), 103.0 (73), 77.0
3
l
e
(
100).
4.1.2. (E)-2,2,2-trifluoro-1-phenylethanon-O-tosyloxime (E-8)
The synthesis of 8 was described earlier [21]. The E isomer was
isolated via column chromatography (silica, PE/EA = 30/1). X-ray
19
Fig. 6. Experimental F NMR chemical shifts of 30 trifluoromethyl compounds
structures see Fig. 2) plotted against the calculated values (standard deviation
.9 ppm).
(
analysis confirmed the configuration of the double bond. TLC:
2
1
R
f
= 0.2 [PE/EA (30/1)]; m.p. 86–88 8C. H NMR (400 MHz, CDCl
3
):

B. Raimer et al. / Journal of Fluorine Chemistry 166 (2014) 8–14
13
d
= 7.90–7.87 (m, 2H, oCHtosyl), 7.55–7.45 (m, 3H, oCH, pCH), 7.39–
CDCl
(1C, pC), 125.1 (2C, mC), 47.4 (1C, NCH
pCCH ), 26.4 (1C, NCH CH ), 25.9 (2C, oCCH
24.6 (1C, NCH CH CH ), 15.5 (1C, pCCH CH
IR (ATR):
3
):
d
= 169.7 (1C, CO), 144.3 (1C. ipsoC), 139.5 (2C, oC), 133.0
), 41.9 (1C, NCH ), 28.8 (1C,
), 25.7 (1C, NCH
), 15.1 (2C, oCCH
13
7
CDCl
1
(
.37 (m, 4H, mCH, mCHtosyl), 2.48 (s, 3H, CH
3
). C NMR (100 MHz,
CF = 33.4 Hz, 1C, CN), 146.2 (1C, pCHtosyl),
31.7 (1C, pCH), 131.3 (1C, ipsoCHtosyl), 129.9 (2C, mCHtosyl), 129.3
2C, oCHtosyl), 128.8 (2C, oCH), 128.4 (2C, mCH), 124.7 (1C, ipsoCH),
2
2
2
3
):
d
= 154.1 (q,
J
2
2
2
2
2
CH
CH
2
),
).
2
2
2
2
3
2
3
ꢀ
1
n
˜ ¼ 3233 cm (w), 2964 (m), 2934 (m), 2857 (m), 1628
1
19
1
19.6 (q,
J
CF = 277.6 Hz, 1C, C-1), 21.8 (1C, CH
3
ꢀ
).
F NMR
˜ ¼ 3061 cm (w), 2924
w), 2853 (w), 1596 (m), 1492 (w), 1450 (w), 1386 (s), 1344 (m),
305 (w), 1215 (m), 1193 (s), 1141 (s), 1090 (m), 1036 (w), 1004
m), 891 (s), 805 (s), 767 (s), 752 (s), 703 (s), 676 (s), 649 (s), 545 (s).
UV–vis (CHCl ): max (log ) = 242 (4.01) nm. MS (EI, 70 eV): m/z
%) = 343.1 (2), 249.1 (2), 173.0 (16), 155.0 (100), 104.0 (75), 91.0
86), 77.0 (39).
(s), 1427 (s), 1371 (m), 1278 (s), 1238 (m), 1182 (m), 1098 (m),
1028 (m), 999 (m), 955 (m), 899 (w), 873 (m), 853 (m), 781 (m),
1
3
(376 MHz, CDCl ): d = S67.2. IR (ATR): n
(
1
(
749 (m), 702 (m), 591 (w), 535 (m). UV–vis (CHCl
) = 231 (2.74), 240 (3.24) nm. GCMS (EI, 70 eV): m/z (%) = 273.2
(20), 244.2 (12), 189.1 (100), 105.1 (16). HRGCMS (EI): m/z calc. for
14 17 3
C H F O 273.20926; found 273.20827 (3.6 ppm).
3
): lmax (log
e
3
l
e
(
(
4.2.1. 2,2,2-Trifluoro-1-(4-methoxy-2,6-dimethylphenyl)ethanone
6)
(
4
.1.3. 2,2,2-Trifluoro-1-(2,4,6-triethylphenyl)ethanone (7)
Under N
atmosphere at ꢀ78 8C, 2-bromo-1,3,5-triethylben-
zene (5, 0.78 mL, 4.2 mmol, 1.0 equiv.) was dissolved in dry THF
in pentane, 4.6 mL, 8.7 mmol,
.1 equiv.) was added dropwise and the mixture was stirred for
Under N
4.6 mmol, 1.0 equiv.) was dissolved in dry THF (10 mL) and cooled
to ꢀ78 8C. nBuLi (1.6 in hexane, 3.5 mL, 5.6 mmol, 1.2 equiv.) was
added and the solution was stirred for 30 min. Afterwards
CCOOEt (796 mg, 5.6 mmol, 1.2 equiv.) was added and the
solution was stirred for 4 h. The reaction was stopped by addition
of saturated aqueous NH Cl (10 mL). The layers were separated
and the aqueous layer was extracted with TBME (10 mL). The
combined organic layers were dried over MgSO and the solvent
2
atmosphere, 4-bromo-3,5-dimethylanisole (7, 1.0 g,
2
M
(
11 mL). At ꢀ78 8C, tBuLi (1.9
M
2
3
2
F
3
0 min. 1-Trifluoroacetylpiperidine (20, 1.80 g, 10.0 mmol,
.4 equiv.) was added and the solution was stirred for 30 min at
4
ꢀ78 8C. The reaction was stopped by addition of saturated aqueous
NH
Cl (5 mL) at ꢀ78 8C and warmed to rt. The layers were
separated and the organic phase was dried over MgSO . Subse-
4
4
4
was removed under reduced pressure. The crude product was
quent removal of the solvent under reduced pressure gave the
crude product, which was purified over silica (pentane). Ketone 7
purified over silica [PE/EA = 40/1!20/1!4/1] and ketone 6 was
f
obtained as a colorless oil (845 mg, 2.6 mmol, 79%). TLC: R = 0.8
1
(
R
389 mg, 1.5 mmol, 36%) was obtained as a colorless oil. TLC:
[PE/EA (4/1)]. H NMR (600 MHz, CDCl
3
13
):
d
= 6.61 (s, 2H, mCH), 3.81
), 2.24 (s, 6H, CH3). C NMR (150 MHz, CDCl ):
d = 191.0 (q, JCF = 36.1 Hz, 1C, CO), 161.0 (1C, pC), 137.4 (2C, oC),
1
f
= 0.7 [Hex/EA (2/1)]. H NMR (400 MHz, CDCl
3
3
):
d
= 6.98 (s, 2H,
(s, 3H, OCH
3
3
3
2
mCH), 2.65 (q, JHH = 7.5 Hz, 2H, pCCH
oCCH
2
), 2.49 (q, JHH = 7.5 Hz, 4H,
3
3
1
2
), 1.25 (t, JHH = 7.6 Hz, 3H, pCCH
2
CH
NMR (100 MHz, CDCl
CF = 36.5 Hz, 1C, CO), 147.3 (1C, pC), 141.3 (2C, oC), 130.6 (1C,
3
), 1.19 (t, JHH = .5 Hz,
115.7 (q, JCF = 291.8 Hz, 1C, CF
3
), 112.8 (2C, mCH), 55.2 (1C, OCH
3
),
˜ ¼
13
19
6
2
H, oCCH
2
CH
3
).
C
3
): = 191.9 (q,
d
19.7 (2C, CH
3
). F NMR (376 MHz, CDCl ): = 77.0. IR (ATR):
3
d
n
ꢀ1
J
2967 cm (w), 2944 (w), 2843 (w), 1735 (m), 1603 (m), 1467 (m),
1324 (m), 1189 (s), 1138 (s), 1065 (w), 1034 (w), 1001 (w), 949 (m),
906 (s), 859 (m), 841 (m), 776 (w), 741 (m), 637 (m), 607 (m), 575
1
ipsoC), 125.8 (2C, mCH), 115.6 (q, JCF = 293.0 Hz, 1C, CF
pCCH ), 26.5 (2C, oCCH ), 15.5 (2C, oCCH CH ), 15.2 (1C,
pCCH ). F NMR (376 MHz, CDCl ): = S76.8. IR (ATR):
˜ ¼
972 cm (m), 2939 (w), 2880 (w), 1739 (m), 1607 (m), 1571 (w),
460 (m), 1379 (w), 1305 (w), 1253 (w), 1194 (s), 1150 (s), 1077
):
) = 274 (3.22), 234 (3.06), 231 (3.06) nm. MS (EI, 70 eV):
3
), 28.8 (1C,
2
2
2
3
19
2
CH
3
ꢀ
3
d
n
(m), 534 (w). UV–vis (CHCl
nm. MS (EI, 70 eV): m/z (%) = 232.1 (18), 163.1 (100), 135.1 (25),
3
): lmax (log e) = 295 (3.37), 239 (3.42)
1
2
1
(
17 3
103.1 (8), 91.1 (18). HRGCMS (EI): m/z calc. for C14H F O
w), 935 (s), 874 (m), 737 (m), 654 (w), 619 (w). UV–vis (CHCl
3
232.07111; found 232.07131 (0.9 ppm).
l
max (log e
m/z (%) = 258.1 (22), 189.1 (100), 161.1 (8), 133.1 (14), 115.1 (14),
4.2.2. (4-Methoxy-2,6-dimethylphenyl)(piperidin-1-yl)methanone
1
2
05.1 (26), 91.1 (16). HRGCMS (EI): m/z calc. for C14
58.12315; found 258.12341 (1.0 ppm).
H
17
F
3
O
(35)
Under N
.2 mmol, 1.0 equiv.) was dissolved in dry THF (40 mL) and cooled
to ꢀ78 8C. Subsequently nBuLi (1.6 m, 6.39 mL, 10.2 mmol,
.1 equiv.) was added and the solution was stirred for 2 h. At
2
atmosphere, 4-bromo-3,5-dimethylanisole (7, 2.0 g,
9
4.2. (Piperidin-1-yl)(2,4,6-triethylphenyl)methanone (34)
1
Under N
.22 mmol, 1.0 equiv.) was dissolved in dry THF (10 mL). At ꢀ78 8C,
in hexane, 4.3 mL, 6.84 mmol, 1.1 equiv.) was added
dropwise and the solution was stirred for 30 min. At ꢀ78 8C, 1-
trifluoroacetylpiperidine (20, 0.97 mL, 6.53 mmol, 1.05 equiv.) was
added and the mixture was stirred for 30 min at ꢀ78 8C. The
cooling bath was removed and the solution was warmed to rt, then
stirred for a further 30 min. The solution was cooled to 0 8C and the
2
atmosphere, 1-bromo-2,4,6-triethylbenzene (1.50 g,
ꢀ78 8C 2,2,2-trifluoro-1-(piperidin-1-yl)ethanone (20, 1.83 g,
10.1 mmol, 1.1 equiv.) was added and the solution was stirred
for a further 1.5 h at ꢀ78 8C. Afterwards the reaction was stopped
6
nBuLi (1.6
M
by the addition of saturated aqueous NH
4
Cl (30 mL). The phases
Cl (aq.,
were separated and the organic layer was washed with NH
4
3 ꢁ 15 mL). The combined aqueous layers were extracted with
TBME (3 ꢁ 15 mL). The combined organic layers were dried over
4
MgSO and the solvent was removed under reduced pressure. The
reaction was quenched with saturated aqueous NH
4
Cl (2 mL). The
crude product was purified over silica [PE/EA: 20/1!10/1!4/1]
solvent was removed under reduced pressure and the resulting
emulsion was suspended in EtOAc (10 mL). The layers were
separated and the aqueous layer was extracted with EtOAc
and the amide 35 was obtained as a yellowish oil (571 mg,
1
2.3 mmol, 27%). TLC: R
CDCl ):
3.13 (m, 2H, NCH
NCH CH CH ), 1.49–1.43 (m, 2H, NCH
CDCl ): = 169.5 (1C, CO), 159.2 (1C, pC), 135.3 (2C, oC), 129.4 (1C,
ipsoC), 112.9 (2C, mC), 55.1 (1C, OCH ), 47.1 (1C, NCH ), 42.1 (1C,
NCH ), 26.7 (1C, NCH CH ), 25.8 (1C, NCH CH ), 24.6 (1C,
NCH CH CH ), 19.4 (2C, CH ). IR (ATR):
˜ ¼ 2991 cm
2935 (w, br), 2854 (w), 1626 (s), 1605 (s), 1439 (m), 1316 (m),
1217 (m). 1146 (s), 852 (m). UV–vis (CHCl ): max (log ) = 232
(3.19), 240 (3.64), 276 (3.08), 283 (3.01) nm. MS (EI, 70 eV): m/z
f
= 0.4 (PE/EA 2/1). H NMR (600 MHz,
3
d
= 6.56 (s, 2H, mCH), 3.80–3.76 (m, 5H, NCH
2 3
, OCH ), 3.16–
(
3 ꢁ 15 mL). The combined organic layers were dried over MgSO
4
2
), 2.23 (s, 6H, CH ), 1.67–1.64 (1.67–1.64, 4H,
3
1
3
and the solvent was removed under reduced pressure. The crude
2
2
2
2 2
CH ). C NMR (150 MHz,
product was purified over silica [PE/10/1!5/1!EA] affording
3
d
amide 34 (624 mg, 2.28 mmol, 37%) and ketone 7 (226 mg,
3
2
1
8
80
NMR (400 MHz, CDCl
NCH ), 3.14–3.11 (m, 2H, NCH
.68–1.64 (m, 4H, NCH CH CH
.22 (t, JHH = .6 Hz, 9H, oCCH CH
m
mol, 14%) as yellowish oils. TLC: R
f
= 0.2 [PE/EA (4/1)].
H
2
2
2
2
2
ꢀ
1
3
):
d
= 6.92 (s, 2H, mCH), 3.78–3.76 (m, 2H,
2
2
2
3
n
(w),
2
2
), 2.64–2.48 (m, 6H, oCCH
), 1.46–1.45 (m, 2H, NCH
2
, pCCH
CH CH
2
2
),
),
1
1
2
2
2
2
2
3
l
e
3
13
2
3
, pCCH
2
CH
3
). C NMR (100 MHz,

1
4
B. Raimer et al. / Journal of Fluorine Chemistry 166 (2014) 8–14
(
(
c) C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37 (1988) 785–789;
d) S.H. Vosko, L. Wilk, M. Nusair, Can. J. Phys. 58 (1980) 1200–1211.
(
(
2
%) = 247.2 (22), 232.2 (15), 163.1 (100), 135.1 (14), 103.1 (6), 91.1
11). HRGCMS (EI): m/z calc. for C14 O 247.15723; found
47.15592 (5.3 ppm).
17 3
H F
[
15] S.J. Grimme, Comput. Chem. 27 (2006) 1787–1799.
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H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M.
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H. Nakai, T. Vreven, J.A. Montgomery Jr., J.E. Peralta, F. Ogliaro, M. Bearpark, J.J.
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Acknowledgements
We thank Prof. Dr. J o¨ rg Grunenberg for very helpful discussions
and for carefully reading this manuscript. We also thank the
Deutsche Forschungsgemeinschaft (Li 597/6-2) for financial support.
Ochterski, R.L. Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador,
J.J. Dannenberg, S. Dapprich, A.D. Daniels, O¨ . Farkas, J.B. Foresman, J.V. Ortiz, J.
Cioslowski, D.J. Fox, Gaussian 09, Revision A.1, Gaussian, Inc., Wallingford, CT,
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Appendix A. Supplementary data
[
[
19] Y. Shao, L.F. Molnar, Y. Jung, J. Kussmann, C. Ochsenfeld, S.T. Brown, A.T.B. Gilbert,
L.V. Slipchenko, S.V. Levchenko, D.P. O’Neill, R.A. DiStasio Jr., R.C. Lochan, T. Wang,
G.J.O. Beran, N.A. Besley, J.M. Herbert, C.Y. Lin, T. Van Voorhis, S.H. Chien, A. Sodt,
R.P. Steele, V.A. Rassolov, P.E. Maslen, P.P. Korambath, R.D. Adamson, B. Austin, J.
Baker, E.F.C. Byrd, H. Dachsel, R.J. Doerksen, A. Dreuw, B.D. Dunietz, A.D. Dutoi,
T.R. Furlani, S.R. Gwaltney, A. Heyden, S. Hirata, C.-P. Hsu, G. Kedziora, R.Z.
Khalliulin, P. Klunzinger, A.M. Lee, M.S. Lee, W.Z. Liang, I. Lotan, N. Nair, B. Peters,
E.I. Proynov, P.A. Pieniazek, Y.M. Rhee, J. Ritchie, E. Rosta, C.D. Sherrill, A.C.
Simmonett, J.E. Subotnik, H.L. Woodcock III, W. Zhang, A.T. Bell, A.K. Chakraborty,
D.M. Chipman, F.J. Keil, A. Warshel, W.J. Hehre, H.F. Schaefer, J. Kong, A.I. Krylov,
P.M.W. Gill, M. Head-Gordon, Phys. Chem. Chem. Phys 8 (2006) 3172.
20] CCDC-997871 and -997872 contain the supplementary crystallographic data for
compounds 8 and 11 respectively, which can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam. ac.uk/data_request/
cif (12, Union Road, Cambridge CB21EZ, UK; fax: +44 1223 336 033; or depos-
it@ccdc.cam.ac.uk.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.jfluchem.
2
014.06.027.
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