The observation of a large gauche preference when 2-fluoroethylamine and 2-fluoroethanol become protonated

Article abstract of DOI:10.1039/b312188g

The energies of the gauche and anti conformers of 2-fluoroethylamine, 2-fluoroethanol and their protonated analogues are calculated using density functional theory. Unlike the non protonated systems, the protonated systems show a strong gauche effect where the C-F and the C-⁺NH₃ or C-F and C-⁺OH₂ bonds are gauche rather than anti to each other. Single crystal X-ray diffraction studies of 2-fluoroethylammonium compounds identify the same conformational preference.

Full text of DOI:10.1039/b312188g

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The observation of a large gauche preference when
2-fluoroethylamine and 2-fluoroethanol become protonated
Caroline R. S. Briggs,a Mark J. Allen,b David O’Hagan,*a David J. Tozer,*b
Alexandra M. Z. Slawin,a Andrés E. Goetab and Judith A. K. Howardb
a School of Chemistry and Centre for Biomolecular Sciences, University of St. Andrews,
North Haugh, St Andrews, UK KY16 9ST. E-mail: do1@st-andrews.ac.uk
b University of Durham, Department of Chemistry, Science Laboratories, South Rd., Durham,
UK DH1 3LE
Received 3rd October 2003, Accepted 15th December 2003
First published as an Advance Article on the web 2nd February 2004
The energies of the gauche and anti conformers of 2-fluoroethylamine, 2-fluoroethanol and their protonated
analogues are calculated using density functional theory. Unlike the non protonated systems, the protonated systems
show a strong gauche effect where the C–F and the C–ϩNH3 or C–F and C–ϩOH2 bonds are gauche rather than anti
to each other. Single crystal X-ray diffraction studies of 2-fluoroethylammonium compounds identify the same
conformational preference.
ethanol has been the subject of several studies. Compared to
1,2-difluoroethane, 2-fluoroethanol has the additional capacity
to enter into intramolecular (O)H ؒ ؒ ؒ F hydrogen bonding via
1 Introduction
The preference for 1,2-difluoroethane 1 (Fig. 1) to adopt a
gauche over an anti conformation has been widely reported1–3
the hydroxyl group. Dixon and Smart calculated the energies of
and the observation has emerged as a classical example of the
different minimum conformations of 2-fluoroethanol 4.11 They
‘gauche effect’.4 Values for this conformational preference have
calculated the energies of structures 4a, 4b and 4e. A clear
been calculated in the range of 0.5–1.0 kcal molϪ1.5,6 The pref-
erence is contra-intuitive and appears to dominate over lone
pair repulsion between the fluorine atoms and their increased
steric influence relative to hydrogen.
preference for gauche structure 4a of about 2.0 kcal molϪ1
emerged, over gauche structure 4b which does not have an
intramolecular (O)H ؒ ؒ ؒ F. But notably 4b had a similar energy
to the anti-structure 4e, and the preference for 4a could be attri-
buted almost entirely (1.9 kcal molϪ1) to an intramolecular
(O)H ؒ ؒ ؒ F bond rather than a through-bond stereoelectronic
effect. The gauche effect, as measured by the relative energies of
4b and 4e, was only 0.1 kcal molϪ1.
Fig. 1 The gauche over anti conformational preference found in
1,2-difluoroethane is a classical example of the gauche effect.
Gauche effects are apparent in other organofluorine systems
when the second C–F bond is replaced with other polarised
In this study we have investigated the gauche effect in
bonds. For example, we have recently highlighted a fluorine-
2-fluoroethylamine 5 and its protonated form, 2-fluoroethyl-
amide gauche effect7,8 in which the C–F bond is vicinal to
ammonium 6. The latter system has bio-organic relevance
the C–N(CO) bond of an N-2-fluoroethylamide, such as 2.
as amines are protonated at physiological pH, and organo-
Similarly, a less pronounced but significant effect occurs in
fluorine compounds have found wide utility in bio-organic
O-2-fluoroethyl ester systems, where we have reported solid
studies.12
state and theoretical calculations describing a fluorine-ester
gauche effect,9 in which the C–F bond is vicinal to the C–O(CO)
bond in an O-2-fluoroethyl ester, such as 3. There is no evidence
that these effects benefit from an intramolecular F ؒ ؒ ؒ H bond
and their origins are attributed to a stereoelectronic gauche
preference.
Since the electronegativity of oxygen is second only to
fluorine,10 the potential influence of a gauche effect in 2-fluoro-
Calculations were also carried out on the oxygen analogues
2-fluoroethanol 4 and protonated 2-fluoroethanol 7. A number
of 2-fluoroethylammonium derivatives were prepared by
synthesis and their solid state structures determined by single
crystal X-ray analysis. These structures are reported and
their conformations discussed in the context of the gauche
effect.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 3 2 – 7 4 0
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
732

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Table 1 DFT derived absolute energies of conformational minima of structures 5 and 6 with F–C–C–N dihedral angles
Dihedral
angle (Њ)
Total energy
(Hartree)
Dihedral
angle (Њ)
Total energy
(Hartree)
gauche Ϫ anti
Structure
Structure
(kcal molϪ1
)
gauche-NH2
anti-NH2
5a
5b
5c
69.8
61.5
66.7
Ϫ234.338996
Ϫ234.342092
Ϫ234.342000
5d
5e
5f
178.3
180.6
181.7
Ϫ234.340450
Ϫ234.340615
Ϫ234.340450
ϩ0.9
Ϫ0.9
Ϫ1.0
NH3؉
6a
NH3؉
6b
52.7
Ϫ234.685112
181.0
Ϫ234.675825
Ϫ5.8
lower in energy than their corresponding anti structures 5e
and 5f. As with fluoroethanol, this clearly suggests stabilisation
via intramolecular F ؒ ؒ ؒ H bonding of between 1.0–2.0 kcal
2
Results and discussion
2.1 Computational details
molϪ1
.
All calculations were performed using Kohn–Sham density
functional theory (DFT) with the recently developed B97-2
hybrid exchange-correlation energy functional.13 To check the
validity of this method, we have also performed calculations
using the widely-used B3LYP hybrid functional and the MP2
correlated wavefunction method; all three methods yield quan-
titatively similar results. The TZ2P14 basis augmented with
an additional s and p diffuse function on non-H atoms (with
exponents determined using a simple geometric progression)
was used. For each molecule, fully optimised gauche and anti
conformations were determined using analytic first derivatives
(forces). Harmonic vibrational frequencies were determined
from finite differences of analytic first derivatives at perturbed
geometries. These frequencies were used to confirm that the
stationary points corresponded to minima on the potential
energy surface. They were also used to determine zero-point
vibrational energies. All relative energies quoted in this study
include zero-point vibrational corrections. All calculations were
performed using the CADPAC program.15
The study was then extended to the 2-fluoroethylammonium
system 6. A number of considerations emerge. An enhanced
stereoelectronic gauche effect can be expected in 6 as there is an
increased polarisation of the C–Nϩ bond due to the positive
charge on the nitrogen. Furthermore, the prospect also exists
for optimal intramolecular F ؒ ؒ ؒ H bonding due to proximity
and the increased acidic nature of the ammonium hydrogen
atoms. There is only one minimum gauche 6a and one minimum
anti structure 6b in this system. Both were evaluated by DFT
calculations (Table 1) and it emerged that the gauche structure
6a is more stable than the anti structure 6b by 5.8 kcal molϪ1
.
2.2 Theoretical studies on 2-fluoroethylamine 5 and 2-fluoro-
ethylammonium 6
This gauche preference clearly arises as a combination of
intramolecular (N)H ؒ ؒ ؒ F bonding and a stereoelectronic
gauche effect, however it is not straightforward to delineate the
magnitude of each of these contributions.
DFT calculations were carried out on 2-fluoroethylamine 5 to
establish the extent of a gauche preference in this neutral sys-
tem. Although fluoroethanol has been studied in some detail,11
we are unaware of any previous calculations on the conform-
ational preference of 2-fluoroethylamine 5. The energies of the
three optimised gauche conformers 5a–c (Fig. 2 and Table 1)
were calculated relative to their corresponding anti conformers
5d–f. The gauche conformer 5a is 0.9 kcal molϪ1 higher in energy
than the corresponding anti-conformer 5d.
2.3 Theoretical studies on 2-fluoroethanol 4 and protonated
2-fluoroethanol 7
With the data for the neutral and protonated fluoroethylamine
in hand (Table 1) the study was extended to a consideration of
the corresponding oxygen analogues. Initially 2-fluoroethanol 4
was examined, essentially as a control such that the current
study could be compared to the previous study,11 and in the
event very similar results emerged. A gauche preference of
∼2.0 kcal molϪ1 was observed for conformation 4a which
contains an intramolecular F ؒ ؒ ؒ H-bond, relative to the corre-
sponding anti structure 4d (Fig. 3). However the gauche struc-
tures 4b and 4c were only stabilised relative to their own anti
structures 4e and 4f respectively, by 0.1–0.2 kcal molϪ1. Clearly
4a is stabilised by intramolecular F ؒ ؒ ؒ H bonding, rather than
an inherent stereoelectronic gauche effect which is making only
a small energetic contribution.
For protonated 2-fluoroethanol 7, the appropriate structures
are shown in 7a–f (Fig. 4)and relative energies are given in
Table 2. The gauche structure 7a is more stable than the anti
structure 7d by 4.4 kcal molϪ1. This contrasts with the free
amine 5a/5d results, where lone pair repulsion reversed the
relative energies of the gauche and anti structures, whereas in
this case there is no such repulsion. This gauche preference does
not have its origin in an intramolecular F ؒ ؒ ؒ H bond and
appears to arise from a true stereoelectronic gauche effect. The
energy difference between gauche and anti structures increases
further when structures 7b/7e and 7c/7f are considered. The
Fig. 2 Calculated minimum conformations of 2-fluoroethylamine 5.
There is no apparent gauche effect in this compound, but
instead the electrostatic repulsion between F and the nitrogen
lone pair in 5a is overriding any gauche stabilisation. By con-
trast, the gauche structures 5b and 5c are 0.9 and 1.0 kcal molϪ1
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 3 2 – 7 4 0
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Table 2 DFT derived absolute energies and F–C–C–O dihedral angles of conformational minima for structures 4 and 7
Dihedral
angle (Њ)
Total energy
(Hartree)
Dihedral
angle (Њ)
Total energy
(Hartree)
gauche Ϫ anti
Structure
Structure
(kcal molϪ1
)
gauche-OH
anti-OH
4a
4b
4c
65.3
72.8
64.9
Ϫ254.225123
Ϫ254.222654
Ϫ254.222054
4d
4e
4f
178.5
180.5
181.5
Ϫ254.222006
Ϫ254.222198
Ϫ254.222006
Ϫ2.0
Ϫ0.3
0.0
؉
OH2
OH2؉
7a
7b
7c
63.5
48.2
50.5
Ϫ254.509319
Ϫ254.512994
Ϫ254.513888
7d
7e
7f
175.9
180.5
184.1
Ϫ254.502339
Ϫ254.501790
Ϫ254.502339
Ϫ4.4
Ϫ7.0
Ϫ7.2
Fig. 3 Calculated minimum conformations of 2-fluoroethanol 4.
Fig. 5 X-ray crystal structure of 2-fluoroethylammonium chloride 6
showing the gauche relationship between C–F and C–N bonds.
that the C–F and C–N bonds adopt a gauche conformational
preference in the solid state. The F–C–C–N dihedral angle is
67.83(1)Њ. The shortest intramolecular N–H ؒ ؒ ؒ F distance in
the structure of 2.73 Å is just beyond the van der Waals contact
distance (2.7 Å) and not indicative of an intramolecular
F ؒ ؒ ؒ H hydrogen bonding interaction.17,18
Fig. 6 shows a stack plot with layers formed by two anti-
parallel sheets of molecules of 6. Within each sheet, there are 2
(N)H ؒ ؒ ؒ Cl contacts, of around 2.3 Å, and between the sheets
there are further (N)H ؒ ؒ ؒ Cl contacts, also of around 2.3 Å,
holding the sheets together to form the ‘thick’ layer shown in
Fig. 6. The sheets and layers are perpendicular to the c-axis and
parallel to the ab plane. The shortest N(H). . .F contact is also
within each sheet. Clearly such crystal packing interactions may
account for the variance in the F–C–C–N dihedral angle with
that of the DFT calculation on 6a (52.7Њ, Table 1).
Fig. 4 Conformational minima of protonated 2-fluoroethanol 7.
gauche conformations are now lower in energy by 7.0 and 7.2
kcal molϪ1 respectively. Intramolecular F ؒ ؒ ؒ H bonding
clearly contributes more than 2.5 kcal molϪ1 additional stabilis-
ation energy in each case. A gauche/anti difference of greater
than 7.0 kcal molϪ1 is the largest calculated value for a fluorine
gauche preference, which is contributed both from intra-
molecular H ؒ ؒ ؒ F bonding (∼2.6–2.8 kcal molϪ1) and a
stereoelectronic gauche effect (∼4.4 kcal molϪ1).
2.4 Solid-state studies on protonated fluoroethylamine 6
The Cambridge Structural Database (CSD)16 is an excellent
resource in which to examine the conformational preferences
within set structural motifs, however a sub-structure search of
the CSD did not reveal any structures containing the F–CH2–
C–ϩNR3 motif. It appeared appropriate in the context of the
calculations described above to record the solid state structure
of the parent 2-fluoroethylammonium system 6 and to prepare
some specifically designed derivatives. In the first instance the
hydrochloride salt of 2-fluoroethylamine was examined. Inspec-
tion of the X-ray crystal structure of 6 (Fig. 5) clearly shows
Fig. 6 X-ray crystal structure of 2-fluoroethylammonium chloride
6.Cl.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 3 2 – 7 4 0
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Scheme 1 Reagents and conditions: (i) pyr, dibenzylamine, Ϫ78 ЊC to 25 ЊC, DCM, 36%; (ii) BH3 in THF (1.0 M), reflux, 6 h, 66%; (iii) HCl(g) in
THF (sat), 25 ЊC, 16 h, 97%.
2.5 Synthesis and X-ray structures of 2-fluoroethylammonium
compounds 8–11
The dibenzylamine hydrochloride 8 was prepared by treat-
ing dibenzylamine with fluoroacetyl chloride 12 (generated
from sodium fluoroacetate [TOXIC] via distillation in the
presence of phthalyl dichloride)19 in the presence of pyridine
to generate amide 13 (Scheme 1). Subsequent reduction of
amide 13 using a solution of borane in THF gave amine 14,
which was isolated as its hydrochloride salt 8 after treatment
with acidic THF. Crystallisation of 8 from methanol and di-
ethyl ether afforded crystals suitable for X-ray structure
analysis.
Inspection of the X-ray crystal structure of 8 (Fig. 7) clearly
shows that the C–F and C–N bonds align in a gauche arrange-
ment relative to each other with
a N(1)–C(15)–C(16)–
Fig. 8 The X-ray structure of morpholine derivative 9 showing the
gauche relationship between C–F and C–N bonds.
F(17) dihedral angle of Ϫ81.9(11)Њ across the 2-fluoroethyl-
ammonium moiety. So again the structure displays a clear
gauche preference. It is noteworthy in this case that there is no
intramolecular F ؒ ؒ ؒ H bonding as the C–F and N–H bonds
are remote from each other and this may account for the
relative widening of the dihedral angle.
to each other with a N(1)–C(7)–C(8)–F(8) dihedral angle of
Ϫ78.8(2)Њ. Again this is a relatively wide dihedral angle and
there is no intramolecular F ؒ ؒ ؒ H bonding apparent in the
structure.
In 9 the molecules in the crystal are linked together in chains
with N–H ؒ ؒ ؒ Cl hydrogen bonds (H ؒ ؒ ؒ Cl 2.062(6) Å,
N ؒ ؒ ؒ Cl 3.036(2) Å, N–H ؒ ؒ ؒ Cl angle 173(2)Њ) dominating
the intermolecular packing.
N-2-Fluoroethylamine hydrochloride (S)-10 was prepared
from the enantiomerically pure amine (S)-2-(diphenylmethyl)-
pyrrolidine20 following the general strategy described above.
A suitable crystal of (S)-10 was selected for X-ray structure
analysis.
Fig. 7 The X-ray structure of the tertiary 2-fluoroethylammonium ion
8 showing a gauche relationship between C–F and C–N bonds.
In the crystal the packing interactions between the molecules
are dominated by N–H ؒ ؒ ؒ Cl hydrogen bonds (H ؒ ؒ ؒ Cl
2.07(3) Å, N ؒ ؒ ؒ Cl 3.025(9) Å, N–H. . ..Cl angle 166(9)Њ)
which link the molecules together in chains.
4-(2-Fluoroethyl)morpholin-4-ium chloride 9 was prepared
in a similar manner to that described for 8 using morpholine as
the amine source.
Inspection of the X-ray crystal structure of (S)-10 (Fig. 9)
clearly shows the C–F and C–N bonds aligning in a gauche
arrangement relative to each other with a N(1)–C(6)–C(7)–F(7)
dihedral angle of 74.1(5)Њ in the 2-fluoroethylammonium
moiety. There are no significantly short intra- or inter-
molecular contacts between hydrogen and fluorine in the
structure.
The packing in (S)-10 is dominated by N–H ؒ ؒ ؒ Cl hydrogen
bonds (H ؒ ؒ ؒ Cl 2.03(1) Å, N ؒ ؒ ؒ Cl 3.00(1) Å, N–H–Cl angle
170(3)Њ).
Finally, the synthesis study was extended to the prepar-
ation of di(2-fluoroethyl)amine hydrochloride 11. It was
anticipated that such a system should accommodate two
gauche interactions between the C–F bonds and the C–N
bonds of this symmetric secondary amine hydrochloride.
The preparation of 11 followed Scheme 2 again using the
Inspection of the X-ray structure of 9 (Fig. 8) shows that the
C–F and C–N bonds also align in a gauche arrangement relative
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 3 2 – 7 4 0
735

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Scheme 2 Reagents and conditions: (i) Py, 12, Ϫ78 ЊC to 25 ЊC over 4 h in DCM, 67%; (ii) 1.5 M soln. borane in THF, reflux, 6 h, 74%; (iii) HCl(g) in
THF (sat), 25 ЊC, 16 h, 96%.
In 11 (Fig. 11) the molecules in the crystal are linked together
forming chains along the b axis via N–H ؒ ؒ ؒ ClϪ hydrogen
bonds (H(3a) ؒ ؒ ؒ Cl(1) = 2.134(8), N(3) ؒ ؒ ؒ Cl(1) = 3.107(4) Å,
N–H ؒ ؒ ؒ Cl = 172(4)Њ; H(3b) ؒ ؒ ؒ Cl(1a) 2.37(3), N(3) ؒ ؒ ؒ
Cl(1a) = 3.261(4) Å, N–H ؒ ؒ ؒ Cl 151(5)Њ).
Fig. 9 The X-ray structure of amine hydrochloride (S)-10 showing a
gauche relationship between C–F and C–N bonds.
condensation of fluoroacetyl chloride 12 with 2-fluoroethyl-
amine as the amine.
Inspection of the resultant X-ray crystal structure (Fig. 10)
clearly shows the two C–F bonds aligning syn with respect to
each other and gauche to both of the C–N bonds with F(1)–
C(1)–C(2)–N(3) and N(3)–C(4)–C(5)–F(5) dihedral angles of
75.9(6)Њ and 74.2(6)Њ respectively. The shortest (N)H ؒ ؒ ؒ F
contacts are 2.82(1) Å for (N)H ؒ ؒ ؒ F(1) and 2.65(1) Å for
(N)H ؒ ؒ ؒ F(5). A length of 2.7 Å for a F ؒ ؒ ؒ H contact sug-
gests a van der Waals contact and thus these interactions are at
the edge or beyond the length that suggests significant stabilis-
ation from intramolecular F ؒ ؒ ؒ H bonding. Nonetheless the
structure retains two clear gauche relationships in the solid
state.
Fig. 11 The chain like structure of 11 in the crystal.
2.6 Discussion
DFT calculations were performed on 2-fluoroethylamine 5 and
2-fluoroethanol 4. The data for 2-fluoroethanol 4 reinforced
earlier calculations suggesting a gauche preference of ∼2.0 kcal
molϪ1 with its origin only in intramolecular (O)H ؒ ؒ ؒ F bond-
ing. It is noteworthy that the gauche 4b/c and anti 4e/f pair of
structures of 2-fluoroethanol, where the hydrogen is orientated
away from an intramolecular contact, have similar energies and
there is evidence only of a weak (≤ 0.3 kcal molϪ1) stabilising
contribution from a stereoelectronic gauche effect. The situ-
ation is worse in 2-fluoroethylamine 5 where there is a clear anti
preference when there is no bridging hydrogen bond. This is
clear from the calculations, which indicate that structure 5a is
higher in energy by 0.9 kcal molϪ1 than structure 5d. However
for the other two gauche structures 5b and 5c, the fluorine nitro-
gen repulsion is more than compensated for by intramolecular
hydrogen bonding and these are more stable than the corre-
sponding anti structures 5e and 5f. An examination of the
conformational preference of N-2-fluoroethylammonium ion 6
has revealed a large gauche over anti preference of 5.8 kcal
molϪ1. It is difficult to delineate contributions in this sys-
tem from intramolecular F ؒ ؒ ؒ H bonding and an inherent
stereoelectronic gauche effect, as there is no structure where
intramolecular F ؒ ؒ ؒ H contacts are absent. Glusker21 has
calculated the stabilising interaction between fluoromethane
and the ammonium (NH4ϩ) ion in an intermolecular interaction
and measured the NϩH ؒ ؒ ؒ F stabilisation at 13.5 kcal molϪ1
.
This is a large value. The NϩH ؒ ؒ ؒ F bond length was extremely
short (1.65 Å) and the NϩHF angle almost 180Њ for this inter-
molecular interaction in the minimised structure, and such
geometries are unobtainable in the intramolecular system
studied here. Nonetheless, that study clearly indicates that a
F ؒ ؒ ؒ HNϩ electrostatic interaction can be significantly stabilis-
ing and may account in a large part for the magnitude of the
gauche preference in 6. However, it is also clear from the solid
Fig. 10 The X-ray structure of 11 showing the gauche relationship
between C–F and H–N bonds.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 3 2 – 7 4 0
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Fig. 12 3-Fluoropiperidine shows an axial preference for fluorine when protonated.
state structures that even in systems without intramolecular
F ؒ ؒ ؒ H contacts, the systems maintain a gauche preference. In
spite of this, it is not easy to delineate these two contributions
in 6. In the context of this study it is noteworthy that
3-fluoropiperidine 17 as a free base displays no conformational
preference in solution, whereas the corresponding 3-fluoro-
piperidinium system 18 has an absolute preference for the
conformation 18b with the fluorine in an axial configuration
(Fig. 12).22
3
Experimental
General
All chemicals were purchased from Acros Organics Ltd. Pyrid-
ine was dried and distilled prior to use using standard literature
procedures. The solvents used in reactions were dried, distilled
using standard literature procedures and stored under nitrogen
prior to use. Reactions were carried out under nitrogen atmos-
phere. FT-IR spectra were recorded using a Perkin-Elmer 2000
FT-IR as Nujol muls. NMR spectra were recorded on a Bruker
Advance 300 MHz (1H at 300.06 MHz, 13C at 74.45 MHz, 19F
282.34 MHz) spectrometer in CDCl3. Mass spectroscopy data
were recorded on a VG Autospec instrument. Elemental (C, H
and N) analyses were obtained using a CE Instrument EA 1110
CHNS analyser. Fluoroacetyl chloride 12 was prepared from
sodium fluoroacetate as previously described.19 [*CAUTION:
Sodium fluoroacetate and the product chloride 12 are extremely
toxic]
There is retrospective evidence that this fluorine/ammonium
gauche effect also remains prominent in some amino acids in
1
solution.23,24 A study in 1977 reported23 on the H-NMR con-
formational analysis of 2-fluoro-3-aminopropionic acid 19 in
water and revealed that the predominant conformer for the
ϩ
amino acids in solution had the C–F and C–NH3 bonds
gauche to each other. It was estimated that 77% of the rotamer
population in solution at neutral pH was one of the two pos-
sible gauche conformers. Also the preferred conformations of
cis-20 and trans-21 4-fluoroprolines in solution were reported
in 1973.24 The authors suggested that the fluorines had a pre-
disposition to occupy an axial orientation. This is entirely con-
sistent with the maintenance of a gauche relationship between
the C–F and C–NϩH2R bonds. Thus, the observations made in
this theoretical and solid state study for the 2-fluoroethyl-
ammonium system, are entirely consistent with observations in
other systems in solution.
Synthesis of N,N-dibenzyl-2-fluoroacetamide 13. A solution
of fluoroacetyl chloride19 (2.0 g, 21.0 mmol) in DCM (10 ml) at
Ϫ78 ЊC was added dropwise to a stirred solution of dibenzyl-
amine (3.99 ml, 21.0 mmol) and pyridine (1.70 ml, 21.0 mmol)
in DCM (10 ml) also at Ϫ78 ЊC. The resulting pale yellow solu-
tion was stirred and allowed to reach ambient temperature over
a period of 4 h. The reaction mixture was quenched with water
(10 ml) and extracted into DCM (3 × 25 ml), dried (MgSO4),
and concentrated under reduced pressure to yield a pale yellow
oil which was purified over silica (petrol and ethyl acetate (7 : 3))
to yield the title compound (1.94 g, 36%) as a pale yellow oil;
νmax (neat)/cmϪ1 3087, 3063, 3030, 2939, 1674 (C᎐O), 1453,
᎐
1363, 1227, 1076, 1029; δH (300 MHz, CDCl3) 4.25 and 4.50
(4H, s, Bn–CH2), 4.96 (2H, d, 2JH–F = 47.1 Hz, CH2F), 7.01–7.24
(10H, m, Ar–H ); δF (282 Hz, CDCl3) Ϫ225.0 (1F, t, 2JH–F = 47.1
4
Hz, CH2F); δC (75 Hz, CDCl3) 48.4 (d, JC–F = 35.9 Hz, Bn–
1
CH2), 53.0 (s, Bn–CH2), 79.7 (d, JC–F = 179.7 Hz, CH2F),
The study was extended to exploring a gauche effect in proto-
nated 2-fluoroethanol 7, a system that was evaluated for the first
time. A clear gauche preference was observed for 7, with a
greater gauche/anti differential than that calculated for 6, con-
sistent with the increased electronegativity of oxygen over
nitrogen. The energy difference (4.4 kcal molϪ1) calculated
between structures 7a and 7d is particularly striking as it is large
and there is no intramolecular OϩH ؒ ؒ ؒ F bond. The gauche/
anti differential increases further (7.0–7.2 kcal molϪ1) when
intramolecular OϩH ؒ ؒ ؒ F bonding is allowed to take place,
e.g. by comparison of 7b/7e and 7c/7f. In this system, unlike 6,
it is possible to delineate the contribution of the gauche pre-
ference from the gauche effect (∼4.4 kcal molϪ1) and from
intramolecular hydrogen bonding (2.6–2.8 kcal molϪ1). This is
the largest value of a gauche effect calculated so far in an
organo-fluorine system.
The X-ray structures of the hydrochlorides of the 2-fluoro-
ethylammonium compounds 6 and 8–11, all display a gauche
preference. The F–C–C–N dihedral angles are all larger (67.8Њ–
81.9Њ) than the one calculated for 6a (52.7Њ). This difference
must arise from weakened intramolecular (N)H ؒ ؒ ؒ F bonding
in the solid state and indeed, the dominating intermolecular
interactions in the solid state structures were (N)H ؒ ؒ ؒ Cl con-
tacts. Nonetheless all of the structures prepared showed a
gauche preference.
126.8, 128.0, 128.3 (s, Ar–C), 135.6 (s, Ar–C–CH2), 167.2
2
(d, JC–F = 18.2 Hz, –CO); m/z (CI): 258 (MHϩ, 100%),
(Found: MHϩ, 258.129827, C16H17FNO requires: 258.129418
(Ϫ1.6 ppm)).
Synthesis of N,N-dibenzyl-2-fluoroethylamine 14. A solution
of borane in THF (1 M, 9.73 ml, 64.0 mmol) was added drop-
wise to a cooled solution of N,N-dibenzyl-2-fluoroacetamide
(8.33 g, 32.0 mmol) in THF (10 ml). The reaction was heated
under reflux for a further 6 h and an aliquot of the reaction
mixture was removed for 19F NMR analysis to confirm the
absence of starting material. The reaction was quenched with
distilled water (10 ml) and the organic layer was separated. The
residual aqueous layer was washed with DCM (3 × 25 ml) and
the combined organic extracts were dried (MgSO4), and con-
centrated under reduced pressure. The product was purified
over silica (ethyl acetate and petrol (3 : 2)) to give the title
compound (5.18 g, 66%) as a clear oil; νmax (neat)/cmϪ1 3347,
3028, 2944, 2831, 1495, 1454, 1029, 748, 700; δH (300 MHz,
2
3
CDCl3) 2.71 (2H, dt, JH–H = 5.1 and JH–F = 26.0 Hz,
–CH2NBn2), 3.60 (4H, s, Bn–CH2), 4.42 (2H, dt, 2JH–H = 5.1 and
2JH–F = 47.6 Hz, –CH2F), 7.13–7.44 (10H, m, Ar–H ); δF (282
2
3
Hz, CDCl3) –219.3 (1F, tt, JH–F = 25.8 and JH–F = 47.4 Hz,
2
–CH2F); δC (75 Hz, CDCl3) 52.9 (d, JC–F = 20.5 Hz,
–CH2NBn2), 58.8 (s, Bn–CH2), 82.9 (d, JC–F = 167.5 Hz,
1
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 3 2 – 7 4 0
737

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–CH2F), 127.0, 128.3, 128.7 (s, Ar–C), 138.4 (s, Ar–C–CH2);
dropwise to a solution of 2-fluoro-1-morpholin-4-ylethanone
m/z (EI): 243 (Mϩ, 30%), 210 (Mϩ Ϫ CH2F, 100), 152 (Mϩ
Ϫ
(0.12 g, 0.88 mmol) in THF (5 ml) and stirred for 16 h at room
temperature. The solvent was removed under reduced pressure
to yield a viscous yellow oil which was re-crystallised from
methanol and ether to give the title compound (0.14 g, 95%) as
a white crystalline solid, mp 146–148 ЊC; (Found: C, 42.48; H,
7.72; N, 8.26. C6H13FOCl requires: C, 42.07; H, 7.93; N, 8.47%);
νmax (Nujol)/cmϪ12699, 1645, 1459, 1269, 1130, 1106, 1038, 931,
911, 875; δH (300 MHz, CD3OD) 4.14–4.86 (8H, m, 4 × –CH2),
4.93–5.01 (2H, m, –CH2), 5.73–5.93 (3H, m, –CH2F and
CH2Ph, 10), (Found: Mϩ, 243.142657. C16H18FN requires:
243.142328 (Ϫ1.4 ppm)).
Synthesis of N,N-dibenzyl-2-fluoroethylammonium hydro-
chloride 8. A saturated solution of HCl gas dissolved in THF
(10 ml) was added dropwise to a stirred solution of N,N-di-
benzyl-2-fluoroethylamine (0.98 g, 4.03 mmol) in THF (10 ml).
The reaction mixture was stirred for 16 h at ambient temper-
ature. The excess solvent was removed under reduced pressure
to give a viscous yellow oil which was re-crystallised from
methanol and ether to yield the title compound (1.13 g, 97%) as
a white crystalline solid, mp 182–184 ЊC (lit.,25 183–184 ЊC);
νmax (Nujol)/cmϪ1 3073 (ammonium ion), 2923 (CH), 1458
(ammonium ion), 1216 (C–F); δH (300 MHz, CDCl3) 3.17–3.50
(3H, m, –CH2N and NH ), 4.33 (4H, s, Bn–CH2), 4.64–4.86
(2H, m, –CH2F), 7.31–7.49 (10H, m, Ar–H ); δF (282 Hz,
CDCl3) –221.8 (1F, tt, 2JH–F = 27.2 and 3JH–F = 47.1 Hz, –CH2F);
δC (75 Hz, CDCl3) 53.2 (d, 2JC–F = 19.9 Hz, –CH2NBn2), 58.8 (s,
Bn–CH2), 66.7 (s, Bn–CH2), 79.1 (d, 1JC–F = 166.4 Hz, CH2F),
130.4, 131.2, 132.3 (s, Ar–C); m/z (CI): 244 (MHϩ Ϫ Cl, 100%),
210 (MHϩ Ϫ CH2F, 6).
2
–NH ); δF (282 Hz, CD3OD) Ϫ222.4 (1F, dt, JF–H = 47.4 and
3JF–H = 27.8 Hz, –CH2F); δC (75 Hz, CD3OD) 53.7 (s, CH2N),
2
58.4 (d, JC–F = 19.4 Hz, –NCH2), 65.0 (s, CH2N), 79.3 (d,
1JC–F = 169.1 Hz, –CH2F); m/z (CI): 170 (MHϩ, 100%).
Synthesis of (S )-2-benzhydryl-1-(fluoroacetyl)pyrrolidine. A
solution of fluoroacetyl chloride (0.48 g, 4.94 mmol) in DCM
(10 ml) at Ϫ78 ЊC was added dropwise to a stirred solution of
(S)-2-benzhydrylpyrrolidine (0.98 g, 4.12 mmol) and pyridine
(0.70 ml, 4.94 mmol) in DCM (10 ml) also at Ϫ78 ЊC. The
resulting pale yellow solution was stirred and allowed to reach
ambient temperature over a period of 4 h. The reaction mixture
was quenched with water (10 ml) and extracted into DCM
(3 × 25 ml), dried (MgSO4), and concentrated under reduced
pressure. The residue was re-crystallised from ethyl acetate and
petrol to give the title compound (0.95 g, 97%) as a clear crystal-
Synthesis of 2-fluoro-1-morpholin-4-ylethanone. A solution of
fluoroacetyl chloride (2.66 g, 28.0 mmol) in DCM (10 ml) at
Ϫ78 ЊC was added dropwise to a stirred solution of morpholine
(2.0 ml, 23.0 mmol) and triethylamine (3.9 ml, 28.0 mmol) in
DCM (10 ml) also at Ϫ78 ЊC. The resulting pale yellow solution
was stirred and allowed to reach ambient temperature over a
period of 4 h. The reaction mixture was quenched with water
(10 ml) and extracted into DCM (3 × 25 ml). The combined
organic extracts were washed with HCl (0.5 M, 1 × 25 ml), dried
(MgSO4), and concentrated under reduced pressure to yield a
pale yellow oil which was purified over silica (ethyl acetate and
petrol (6 : 4)) to give the title compound (2.56 g, 76%) as a
line solid, mp 165–167 ЊC; νmax (Nujol)/cmϪ1 2923, 1647 (C᎐O),
᎐
1491, 1459, 1354, 1207, 1074, 1031, 999, 755, 702; δH (300 MHz,
CDCl3) 1.48–1.57 (1H, m, –CH2), 1.75–2.02 (3H, m, –CH2),
3.38–3.55 (2H, m, –CH2), 4.22–4.24 (1H, m, –CHPh2), 4.33–
2
2
4.34 (1H, m, –CH ), 4.83 (2H, dd, JH–H = 5.6 and JH–F = 47.4
Hz, CH2F), 7.01–7.49 (10H, m, Ar–H ); δF (282 Hz, CDCl3)
225.2 (1F, t, 2JH–F = 47.1 Hz, –CH2F); δC (75 Hz, CDCl3) 24.2 (s,
C-4), 31.0 (s, C-3), 45.8 (s, CHPh2), 52.0 (s, C-5), 61.7 (s, –CH),
1
80.1 (d, JC–F = 180.8 Hz, –CH2F), 126.7, 127.5, 127.7, 142.2
1
(Ar–C), 175.0 (d, JC–F = 23.0 Hz, –CO); m/z (CI): 298 (MHϩ,
colourless oil. νmax (neat)/cmϪ1 3553, 2970, 2863, 1651 (C᎐O),
100%), (Found: MHϩ, 298.161593. C19H21FNO requires:
᎐
1438, 1367, 1276, 1243, 1114, 1071, 1027, 848, 787; δH (300
MHz, CDCl3) 3.46 (4H, m, 2 × –CH2-N), 3.62 (4H, m, 2 ×
–CH2–O), 4.92 (2H, d, 2JH–F = 47.1 Hz, –CH2F); δF (282 MHz,
298.160718 (Ϫ2.9 ppm)).
Synthesis of 2-benzhydryl-1-(2-fluoroethyl)pyrrolidine.
A
2
CDCl3) Ϫ225.7 (1F, t, JF–H = 45.4 Hz, –CH2F); δC (75 MHz,
solution of borane in THF (1.5 M, 5.85 ml, 3.9 mmol) was
added dropwise to a cooled solution of 2-benzhydryl-1-
(fluoroacetyl)pyrrolidine (0.4 g, 1.30 mmol) in THF (10 ml).
The mixture was heated under reflux for 6 h and then cooled in
ice. Water (10 ml) was added dropwise and the reaction mixture
was extracted into DCM (3 × 20 ml), dried (MgSO4) and con-
centrated under reduced pressure. The residue was purified over
silica (petrol and ethyl acetate (7 : 3)) to give the title compound
(0.31 g, 76%) as a clear oil; νmax (neat)/cmϪ1 3350, 3030, 2950,
2830, 1490, 1450, 1020, 750, 700; δH (300 MHz, CD3OD) 1.48–
1.70 (3H, m, –CH2), 1.79–2.0 (2H, m, –CH2), 2.26–2.28 (1H, m,
CHPh2), 2.70–2.94 (3H, m, –CH2), 3.29 (2H, dt, 2JH–H = 4.2 and
3JH–F = 28.1 Hz, –CH2CH2F), 3.88–3.92 (1H, m, –CH ), 4.19
CDCl3) 41.9 (s, –CH2–N), 44.9 (d, 4JC–F = 5.0 Hz, –NCH2), 66.4
(s, –OCH2), 79.7 (d, 1JC–F = 179.7 Hz, –CH2F), 165.2 (d, 2JC–F
=
17.7 Hz, –CO); m/z (CI) 148 (MHϩ, 100%), (Found: MHϩ,
148.077793. C6H11FNO2 requires: 148.077382 (Ϫ2.8 ppm)).
Synthesis of 4-(2-fluoroethyl)morpholine.
A solution of
borane in THF (1.5 M, 29.9 ml) was added dropwise to a
cooled solution of 2-fluoro-1-morpholin-4-ylethanone (2.20 g,
15.0 mmol) in THF (5 ml). The reaction mixture was stirred for
a further 3 h at room temperature and an aliquot of the reac-
tion mixture was removed for 19F NMR analysis to confirm the
absence of starting material. The reaction mixture was cooled
in an ice bath before being quenched with water (10 ml),
extracted into ether (3 × 25 ml), dried (MgSO4) and concen-
trated under reduced pressure. The crude material was purified
over silica (ethyl acetate and petrol (7 : 3)) to yield the title
compound (0.41 g, 21%) as a colourless oil. νmax (neat)/cmϪ1
2966, 2377, 1457, 1121, 1065, 880; δH (300 MHz, CDCl3) 2.40–
2.55 (4H, m, 2 × –CH2N), 3.15 (2H, dt, 2JH–H = 4.4 Hz and 3JH–F
= 28.8 Hz, –CH2CH2F), 3.56–3.72 (4H, m, 2 × –CH2O), 4.99
2
3
(2H, dt, JH–H = 5.5 and JH–F = 47.5 Hz, –CH2F), 7.11–
7.34 (10H, m, Ar–H ); δF (282 MHz, CD3OD) Ϫ219.9 (1F, dtt,
2JH–H = 4.1, 2JH–F = 47.4 and 3JH–F = 22.7 Hz, –CH2F); δC (75 Hz,
CD3OD) 23.0 (s, C-4), 29.2 (s, C-3), 54.7 (s, –CHPh2), 55.0 (d,
2JC–F = 19.9 Hz, –CH2F), 56.7 (d, 1JC–C = 2.8 Hz, -C-5), 67.3 (d,
1JC–C = 2.8 Hz, –CH), 82.6 (d, 1JC–F = 167.0 Hz, –CH2F), 125.1,
127.1, 127.8, 142.6 (Ar–C); m/z (CI): 284 (MHϩ, 100%),
(Found: MHϩ, 284.180974. C19H23FN requires: 284.181453
(1.7 ppm)).
2
2
(2H, dt, JH–H = 4.5 Hz and JH–F = 47.9 Hz, –CH2F); δF (282
MHz, CDCl3) Ϫ216.7 (1F, dt, 2JF–H = 47.4 Hz and 3JF–H = 28.9
Hz, –CH2F); δC (75 MHz, CDCl3) 58.6 (s, 2 × –NCH2), 61.6 (s,
Synthesis of 2-benzhydryl-1-(2-fluoroethyl)pyrrolidinium
hydrochloride 10. A saturated solution of HCl dissolved in THF
(10 ml) was added dropwise to a stirred solution of 2-benz-
hydryl-1-(2-fluoroethyl)pyrrolidine (0.20 g, 0.71 mmol) in THF
(5 ml). The reaction mixture was stirred for 16 h at ambient
temperature. The excess solvent was removed under reduced
pressure to yield a viscous yellow oil which was re-crystallised
2
2 × –OCH2), 64.3 (d, JC–F = 18.2 Hz, –CH2CH2F), 79.2 (d,
1JC–F =166.4Hz, –CO);m/z(CI)134(MHϩ, 65%), (Found:MHϩ,
134.098286. C6H13FNO requires: 134.098117 (Ϫ1.3 ppm)).
Synthesis of 4-(2-fluoroethyl)morpholin-4-ium hydrochloride
9. A saturated solution of HCl in THF (10 ml) was added
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 3 2 – 7 4 0
738

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from methanol and ether to give the title compound (0.19 g,
95%) as a white crystalline solid, mp 159–161 ЊC; νmax (Nujol)/
cmϪ1 2390, 2330, 1160, 1030, 700; δH (300 MHz, CD3OD) 1.66–
1.83 (2H, m, 4-CH2), 2.30–2.49 (2H, m, 3-CH2), 2.58–2.66 (1H,
m, 5-CH2), 2.93–3.01 (1H, m, 5-CH2), 3.26–3.37 (1H, m,
diethyl ether to yield the title compound (0.66 g, 96%) as a
white crystalline solid, mp 190–192 ЊC (lit.,26 190–193 ЊC);
(Found: C, 33.07; H, 6.93; N, 9.47. C4H10F2NCl requires: C,
33.00; H, 6.92; N, 9.62%); νmax (Nujol)/cmϪ1 3073 (ammonium
ion), 2926 (C–H), 1458 (ammonium ion), 1216; δH (300 MHz,
CD3OD) 3.38 (4H, dt, 2JH–H = 4.7 and 3JH–F = 26.8 Hz, –NCH2),
4.69 (4H, dt, 2JH–H = 4.7 and 2JH–F = 47.0 Hz, –CH2F), 4.81 (2H,
s (br), –NH2); δF (282 Hz, CD3OD) Ϫ226.7 (2F, tt, 2JF–H = 46.4
–CH2CH2F), 3.60–3.72 (1H, m, –CH2CH2F), 3.67–3.73 (1H, m,
2
–CH ), 4.55–4.56 (1H, m, –CHPh2), 4.68 (2H, dt, JH–H
=
4.2 and 3JH–F = 48.1 Hz, –CH2CH2F), 3.88–3.92 (1H, m, –CH ),
4.19 (2H, dt, 2JH–H = 5.5 and 3JH–F = 47.5 Hz, –CH2F), 6.77 (1H,
s (br), –NH ), 7.11–7.34 (10H, m, Ar–H ); δF (282 MHz,
3
and JH–F = 26.8 Hz, 2 × CH2F); δC (75 Hz, CD3OD) 48.8 (d,
1
2JC–F = 21.6 Hz, –NCH2), 79.4 (d, JC–F = 167.5 Hz, –CH2F);
2
2
3
CD3OD) Ϫ223.3 (1F, dtt, JH–H = 4.1, JH–F = 47.4 and JH–F
=
m/z (CI): 110 (MHϩ Ϫ Cl, 100%).
22.7 Hz, –CH2F); δC (75 Hz, CD3OD) 19.3 (s, C-4), 23.7 (s,
1
C-3), 45.0 (s, –CHPh2), 50.6 (dd, JC–C = 2.4 Hz, C-5), 51.4 (d,
Crystal data
2JC–F = 28.0 Hz, –CH2CH2F), 67.1 (d, JC–C = 2.80 Hz, –CH),
1
1
General. Data for 9, (S)-10 and 11 were corrected for
Lorentz, polarization and absorption effects, whilst 6 and 8
were not corrected for absorption. 8 was a curtailed data collec-
tion as a result of decomposition. The structures were solved by
direct methods and refined by full-matrix least squares on F 2
for all data using SHELXTL software. In all structures non-
hydrogen atoms were refined with anisotropic thermal param-
eters. In all structures except 6 the amine hydrogens were refined
isotropically subject to a distance constraint (N–H = 0.98 Å)
and all other hydrogen atoms were assigned riding isotropic
thermal parameters and constrained to idealised geometries. In
6 all hydrogen atoms were freely refined.
6: C2H7ClFN, M = 99.54, Orthorhombic, space group Pbca,
a = 7.621(1), b = 8.543(1), c = 14.830(2) Å, U = 965.4(2) Å3,
F(000) = 416, Z = 8, Dc = 1.370 Mg mϪ3, µ = 0.643 mmϪ1
(Mo-Kα, λ = 0.71073 Å). The data were collected at T = 150(2)
K, 10312 reflections (2.75 ≤ θ ≤ 30.29Њ) were measured on
a Bruker SMART-1K CCD diffractometer equipped with
an Oxford Cryostream low-temperature device27 (ω-scan,
0.3Њ/frame) yielding 1371 unique data (Rmerg = 0.0290). Con-
ventional R = 0.0265 for 1154 reflections with I ≥ 2σ, GOF =
1.078. Final wR2 = 0.0688 for all data (74 refined parameters).
The largest peak in the residual map is 0.454 e ÅϪ3. Crystallo-
graphic data have been deposited with the Cambridge Crystal-
lographic Data Centre.†
74.2 (d, JC–F = 167.0 Hz, –CH2F), 125.1, 127.1, 127.8, 142.6
(Ar–C); m/z (CI): 284 (MHϩ Ϫ HCl, 15%) (Found: MHϩ
Ϫ HCl, 284.180740. C19H24FN requires: 284.181453 (2.5 ppm)).
Synthesis of 2-fluoro-N-(2-fluoroethyl)acetamide 15. A solu-
tion of fluoroacetyl chloride (3.47 g, 36.0 mmol) in DCM
(15 ml) at Ϫ78 ЊC was added dropwise to a stirred solution of
2-fluoroethylamine hydrochloride (3.0 g, 30 mmol) and pyridine
(2.93 ml, 36.0 mmol) in DCM (15 ml) also at Ϫ78 ЊC. The
resulting pale yellow solution was stirred and allowed to
reach ambient temperature over a period of 4 h. The reaction
mixture was quenched with water (10 ml), extracted into DCM
(3 × 25 ml), dried (MgSO4), and concentrated under reduced
pressure to give a pale yellow oil which was purified over silica
(petrol : ethyl acetate (4 : 6)) to yield the title compound (2.49 g,
67%) as a colourless oil. (Found: C, 39.03; H, 5.73; N, 11.38.
C4H7F2O requires: C, 38.96; H, 5.72; N, 11.23%); νmax (neat)/
cmϪ1 3316, 3092, 2964, 1765 (C᎐O), 1653, 1540, 1443, 1396,
᎐
1361, 1294, 1107, 1050; δH (300 MHz, CDCl3) 3.59 (2H, dq,
2JH–H = 5.3 and 3JH–F = 27.8 Hz, –CH2NH2), 4.47 (2H, dt, 2JH–H
=
2
2
4.7 and JH–F = 47.2 Hz, CH2F), 4.77 (2H, d, JH–F = 47.2 Hz,
CH2F), 6.91 (1H, s (br), NH ); δF (282 Hz, CDCl3) –224.8 (1F, tt,
2JH–F = 47.4 and 3JH–F = 26.8 Hz, CH2F), –226.1 (1F, t, 2JH–F
=
2
47.4 Hz, –CH2F); δC (75 Hz, CDCl3) 39.1 (d, JC–F = 20.5 Hz,
1
1
–CH2NH), 79.9 (d, JC–F = 168.1 Hz, –CH2F), 82.2 (d, JC–F
=
¯
150.4 Hz, –CH2F), 168.1 (d, 2JC–F = 17.1 Hz, CO); m/z (EI): 123
(Mϩ, 50%); 103 (Mϩ Ϫ HF, 60); 90 (Mϩ Ϫ CH2F, 100).
8: C16H19ClFN, M = 279.77, Triclinic, space group P1,
a = 6.821(7), b = 10.177(9), c = 12.07(2) Å, U = 758.0(17) Å3,
F(000) = 296, Z = 2, Dc = 1.226 Mg mϪ3, µ = 0.249 mmϪ1
(Mo-Kα, λ = 0.71073 Å). The data were collected at T = 293(2)
K, 1605 reflections (1.81 ≤ θ ≤ 23.25Њ) were measured on a
Bruker SMART CCD diffractometer (ω-scan, 0.3Њ/frame)
yielding 1602 unique data (Rmerg = 0.2652). Conventional
R = 0.0887 for 801 reflections with I ≥ 2σ, GOF = 0.935. Final
wR2 = 0.2708 for all data (177 refined parameters). The largest
peak in the residual map is 0.221 e ÅϪ3. Crystallographic data
have been deposited with the Cambridge Crystallographic Data
Centre.†
Synthesis of bis(2-fluoroethyl)amine 16. A solution of borane
in THF (1.0 M, 6.0 ml, 60.0 mmol) was added to an ice
cool solution of 2-fluoro-N-(2-fluoroethyl)acetamide (2.49 g,
20.0 mmol) in THF (10 ml) and the reaction heated under reflux
for 6 h. An aliquot of the reaction mixture was removed for 19
F
NMR analysis to confirm the absence of starting material. The
reaction mixture was quenched by the dropwise addition of
water (10 ml) and the organic layer separated. The aqueous
layer was extracted into diethyl ether (3 × 25 ml) and the com-
bined organic extracts were dried (MgSO4) and concentrated
under reduced pressure. The product was purified over silica gel
(ethyl acetate and petrol (6 : 4)) to yield the title compound
(1.63 g, 74%) as a colourless oil. νmax (neat)/cmϪ1 3374 (NH),
2945, 2833, 2527, 2045, 1666, 1451, 1115, 1031; δH (300 MHz,
CD3OD) 3.26–2.79 (4H, m, 2 × –NCH2), 4.19 (1H, s (br), NH ),
3.26–2.79 (4H, m, 2 × –CH2F); δF (282 Hz, CD3OD) Ϫ225.9
9: C6H13ClFNO, M = 169.62, Monoclinic, space group P21/n,
a = 7.340(2), b = 9.302(3), c = 12.025(4) Å, U = 820.6(5)Å3,
F(000) = 360, Z = 4, Dc = 1.373 Mg mϪ3, µ = 0.419 mmϪ1
(Mo-Kα, λ = 0.71073 Å). The data were collected at T = 125(2)
K, 3185 reflections (3.20 ≤ θ ≤ 23.30Њ) were measured on a
Bruker SMART CCD diffractometer equipped with an Oxford
Cryostream low-temperature device25 (ω-scan, 0.3Њ/frame)
yielding 1131 unique data (Rmerg = 0.0428). Conventional
R = 0.0391 for 1029 reflections with I ≥ 2σ, GOF = 1.027. Final
wR2 = 0.1052 for all data (96 refined parameters). The largest
peak in the residual map is 0.461 e ÅϪ3. Crystallographic data
have been deposited with the Cambridge Crystallographic Data
Centre.†
2
3
(1F, tt, JF–H = 47.1 and JF–H = 23.7 Hz, –CH2F); δC (75 Hz,
2
1
CD3OD) 56.0 (d, JC–F = 19.4 Hz, –NCH2), 79.1 (d, JC–F
=
165.9 Hz, CH2F); m/z (CI): 110 (MHϩ, 100%), (Found: MHϩ,
110.077704. C4H10F2N requires: 110.078131 (3.9 ppm)).
Synthesis of 2-fluoro-N-(2-fluoroethyl)ethylammonium chlor-
ide 11. A saturated solution of HCl gas dissolved in THF
(10 ml) was added dropwise to a stirred solution of N,N-bis-
(2-fluoroethyl)amine (0.61 g, 5.5 mmol) in THF (10 ml). The
reaction mixture was stirred for 16 h at ambient temperature.
The excess THF was removed under reduced pressure to yield a
viscous yellow oil which was recrystallised from methanol and
(S )-10: C19H23ClFN, M = 319.83, Orthorhombic, space
group P212121, a = 9.21(3), b = 12.66(4), c = 14.89(5) Å,
† CCDC reference numbers 221927–221931. See http://www.rsc.org/
suppdata/ob/b3/b312188g/ for crystallographic data in.cif or other
electronic format.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 3 2 – 7 4 0
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U = 1735(10) Å3, F(000) = 680, Z = 4, Dc = 1.224 Mg mϪ3
,
6 P. Huber-Wälchli and Hs. H. Günthard, Spectrochim. Acta, Part A,
1981, 37, 285.
7 D. O’Hagan, C. Bilton, J. A. K. Howard, L. Knight and D. J. Tozer,
J. Chem. Soc., Perkin Trans. 2, 2000, 605–607.
8 C. R. S. Briggs, D. O’Hagan, J. A. K. Howard and D. S. Yufit,
J. Fluorine Chem., 2003, 119, 9–13.
9 R. J. Abraham and J. R. Monasterios, Org. Magn. Reson., 1973, 5,
305; C. R. S. Briggs, D. O’Hagan, H. S. Rzepa and A. M. Z. Slawin,
J. Fluorine Chem., 2004, 125, 19–25.
10 P. R. Wells, Prog. Phys. Org. Chem., 1968, 6, 111–145.
11 (a) D. A. Dixon and B. E. Smart, J. Phys. Chem., 1991, 95, 1609–
1612; (b) J. M. Bakke, L. H. Bjerkeseth, T. E. C. L. Ronnow and
K. Steinsvoll, J. Mol. Structure, 1994, 321, 205–214.
12 Biomedical Frontiers of Fluorine Chemistry, Eds I. Ojima,
J. R. McCarthy, J. T. Welch, ACS Symposium Series 639, 1996;
M. Schlosser and D. Michel, Tetrahedron, 2000, 56, 4253–4260.
13 P. J. Wilson, T. J. Bradley and D. J. Tozer, J. Chem. Phys., 2001, 115,
9233–9242.
14 T. H. Dunning, J. Chem. Phys., 1971, 55, 716–723.
15 R. D. Amos, I. L. Alberts, J. S. Andrews, S. M. Colwell, N. C. Handy,
D. Jayatilaka, P. J. Knowles, R. Kobayashi, G. J. Laming, A. M. Lee,
P. E. Maslen, C. W. Murray, P. Palmieri, J. E. Rice, E. D. Simandiras,
A. J. Stone, M.-D. Su and D. J. Tozer, CADPAC6.5, The Cambridge
Analytic Derivatives Package, Cambridge, UK, 1998.
16 P. Murray-Rust, W. C. Stallings, C. T. Monti, R. K. Preston and
J. P. Glusker, J. Am. Chem. Soc., 1983, 105, 3206–3214.
17 J. A. K. Howard, V. J. Hoy, D. O’Hagan and G. T. Smith,
Tetrahedron, 1996, 52, 12613–12622.
µ = 0.226 mmϪ1 (Mo-Kα, λ = 0.71073 Å). The data were
collected at T = 293(2) K, 7243 reflections (2.11 ≤ θ ≤ 23.37Њ)
were measured on a Bruker SMART CCD (ω-scan, 0.3Њ/frame)
yielding 2475 unique data (Rmerg = 0.0917). Conventional R =
0.0475 for 1386 reflections with I ≥ 2σ, GOF = 0.961. Final wR2
= 0.1007 for all data (204 refined parameters). The largest peak
in the residual map is 0.158 e ÅϪ3. Crystallographic data have
been deposited with the Cambridge Crystallographic Data
Centre.†
11: C4H10ClF2N, M = 145.58, Monoclinic, space group P21/n,
a = 7.335(2), b = 6.9524(19), c = 13.170(4) Å, U = 670.3(3) Å3,
F(000) = 304, Z = 4, Dc = 1.443 Mg mϪ3, µ = 0.509 mmϪ1
(Mo-Kα, λ = 0.71073 Å). The data were collected at T = 293(2)
K, 3017 reflections (3.10 ≤ θ ≤ 23.41Њ) were measured on a
Bruker SMART CCD diffractometer (ω-scan, 0.3Њ/frame)
yielding 914 unique data (Rmerg = 0.0605). Conventional R =
0.0645 for 594 reflections with I ≥ 2σ, GOF = 0.925. Final
wR2 = 0.1775 for all data (82 refined parameters). The largest
peak in the residual map is 0.892 e ÅϪ3. Crystallographic data
have been deposited with the Cambridge Crystallographic Data
Centre.†
Acknowledgements
18 J. Dunitz and R. Taylor, Chem. Eur. J., 1997, 3, 89–98.
19 M. R. Amin, D. B. Harper, J. M. Moloney, C. D. Murphy, J. A. K.
Howard and D. O’Hagan, Chem. Commun., 1997, 1471–1472.
20 D. O’Hagan and M. Tavasli, Tetrahedron: Asymmetry, 1999, 10,
1189–1192.
We thank the EPSRC for Studentships (CRSB and MJA) and
for a Senior Research Fellowship to JAKH.
21 L. Shimoni, J. P. Glusker and C. W. Bock, J. Phys. Chem., 1995, 99,
References
1194–1198.
1 N. C. Craig, A. Chen, K. H. Suh, S. Klee, G. C. Mellau, B. P.
Winniewisser and M. Winnewisser, J. Am. Chem. Soc., 1997, 119,
4789–4790.
2 R. D. Amos, N. C. Handy, P. G. Jones, A. J. Kirby, J. K. Parker,
J. M. Percy and M. D. Su, J. Chem. Soc., Perkin Trans. 2, 1992, 549–
558.
22 D. C. Lankin, N. S. Chandrakumar, S. N. Rao, D. P. Spangler and
J. P Snyder, J. Am. Chem. Soc., 1993, 115, 3356–3357.
23 R. J. Abraham, P. Loftus and W. A. Thomas, Tetrahedron, 1977, 33,
1227–1234.
24 J. T. Gerig and R. S. McLeod, J. Am. Chem. Soc., 1973, 95, 5725–
5729.
3 K. B. Wiberg, Acc. Chem. Res., 1996, 29, 229–234.
4 S. Wolfe, Acc. Chem. Res., 1972, 5, 102–111.
5 J. R. Durig, J. Liu, T. S. Little and V. F. Kalasinsky, J. Phys. Chem.,
1992, 96, 8224–8233.
25 J. Nosek, J. Kamis and F. Ruffer, Chem. Listy, 1952, 46, 672–674.
26 Z. B. Papanastassiou and R. J. Bruni, J. Org. Chem., 1964, 29,
2870.
27 J. Cosier and A. M. Glazer, J. Appl. Crystallogr., 1986, 19, 105–107.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 3 2 – 7 4 0
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