New indications for the potential involvement of C-F-bonds in hydrogen bonding

Article abstract of DOI:10.1016/j.molstruc.2005.10.033

Solid state structures of a selection of 2-fluoro-2-phenylcyclopropane derivatives were examined by X-ray crystallography in order to identify short intermolecular contacts of C-F groups to H-X moieties (X=C, N). Particularly, several cis-configured fluor

Full text of DOI:10.1016/j.molstruc.2005.10.033

Journal of Molecular Structure 787 (2006) 50–62
www.elsevier.com/locate/molstruc
New indications for the potential involvement
of C–F-bonds in hydrogen bonding
a
Roland Frohlich , Thomas C. Rosen , Oliver G.J. Meyer ,
a
a
¨
Kari Rissanen b, Gu¨nter Haufe a,
*
a
¨ ¨ ¨ ¨
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstr. 40, D-48149 Munster, Germany
b
¨ ¨ ¨
Department of Chemistry, NanoScience Center, University of Jyvaskyla, P.O. Box 35, FIN-40012 Jyvaskyla, Finland
¨
Received 4 August 2005; received in revised form 17 October 2005; accepted 26 October 2005
Available online 20 December 2005
Abstract
Solid state structures of a selection of 2-fluoro-2-phenylcyclopropane derivatives were examined by X-ray crystallography in order to identify
short intermolecular contacts of C–F groups to H–X moieties (XZC, N). Particularly, several cis-configured fluorinated phenylcyclopropane
˚
derivatives showed extremely close intermolecular contacts. The shortest of such C–H/F–C-distances (2.17 A, C–F–H angle 1628) was found in
˚
(1S,2R)-(2-fluoro-2-phenylcyclopropyl)methyl N-(4-bromophenyl)carbamate (8) and the closest N–H/F–C-interaction (2.01 A, C–F–H angle
1678) was found in (G)-cis-2-fluoro-2-phenylcyclopropyl carboxamide (4). Comparison of the structures of several of the fluorinated
cyclopropanes with those of the non-fluorinated counterparts revealed that close intermolecular contacts of fluorine substituents to hydrogen atoms
are not solely due to crystal packing effects, but are also caused by weak X–H/F–C hydrogen bridges.
q 2005 Elsevier B.V. All rights reserved.
Keywords: Carboxylic acid derivatives; Enantiomers; Fluorinated cyclopropanes; Hydrogen bonding; X-ray analysis
1. Introduction
The fluorine substituent in organic compounds is compar-
able in size to a hydrogen atom and in certain circumstances
also to a hydroxyl group [1–6,24–26]. The van der Waals radii
The introduction of fluorine atoms into organic molecules in
general causes drastic changes of the physico-chemical
properties, of the chemical reactivity and of the biological
activity of these compounds in comparison to their non-
fluorinated parent compounds [1–6]. Particularly, the opportu-
nity to tune the biological activity employing fluorine
substituents continues to attract much attention in bioorganic,
agricultural and medicinal chemistry [7–23]. The effect of
fluorine as a substituent in bioactive compounds is based on its
strong electron withdrawing (KI) effect, but, due to the low
energy lone pairs, also on an electron pair donating mesomeric
(CM) effect in conjugated systems [24–26]. Moreover,
intermolecular through-space interactions play an important
role as well [27–29]. Consequently, this substituent is able
to modify the physiological behavior of bioactive compounds
[7–23].
˚
˚
˚
are 1.20 A for H, 1.47 A for F, and 1.57 A for an OH group
[30]. Replacement of hydrogen by a single fluorine is often
regarded as an isosteric substitution [31]. Thus, a mono-
fluorinated analogue of an affector molecule is geometrically
very similar to its parent compound and hence meets the
steric requirements at enzyme receptor sites [7–23]. But, due to
its different electronic properties the original biological
response can be falsified [32–35]. Moreover, the similarity of
˚
typical C–F and C–O bond lengths (1.39 vs. 1.43 A) and the
comparable electronegativity suggest that replacement of a
hydroxyl group by fluorine can also be regarded as an isosteric
and isopolar substitution [24–26]. The ability of fluorinated
aromatics to function as substitutes for nucleobases [36]
supports this assumption [37,38]. The strong electronegativity
of the fluorine substituent enhances the acidity of neighboring
groups by its electron withdrawing ability and leads to a
different dipole moment compared to the parent compounds
[3,28,39,40]. Furthermore, it was discussed that a C–F bond
can function in certain cases as a weak hydrogen bond acceptor
(1–3 vs. 5–10 kcal/mol for oxygen as an acceptor) [41–45].
Though these interactions are much weaker than CaO/H–X
(XZO, N) interactions they do influence molecular packing in
*
Corresponding author. Tel.: C49 251 8333281; fax: C49 251 8339772.
E-mail addresses: kari.rissanen@jyu.fi (K. Rissanen), haufe@uni-muen-
ster.de (G. Haufe).
0022-2860/$ - see front matter q 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2005.10.033

¨
R. Frohlich et al. / Journal of Molecular Structure 787 (2006) 50–62
51
crystals [46–50]. In bioorganic and medicinal chemistry the
formation of intermolecular O–H/F–C and N–H/F–C
hydrogen bridges were assumed important in binding of
fluorinated compounds to enzyme active sites [51–60]. These
particular effects on the enzyme–ligand binding affinity and
selectivity together with the modulation of pharmacokinetic
properties by fluorine substitution resulted in a considerably
large number (ca. 150) of fluorinated drugs, which are in
clinical use [61,62]. Recently, in an analog of thrombin
inhibitors a close intermolecular contact of an aromatic C–F
bond to an H–C bond in a-position to a carbamide group as
C–C– and the C–H-bonds, which is reflected by the H–C–H
angle of 1158 [98]. Substitution of C–H bonds with C–F bonds
causes destabilization of the C–C bonding and increasing ring
strain [99]. These changes should also influence the acidity of
C–H bonds and hence its ability to act as hydrogen bond
donors. Remarkably new indications about the potential of
organic fluorine to act as a hydrogen bond acceptor were found
for different monofluorinated cyclopropanes. Recently, our
high-level quantum chemical calculations (MP2/QZVPP)
showed, that the fluorocyclopropane dimer has an intermole-
˚
cular C–H/F–C distance of 2.57 A and an interaction energy
˚
short as 2.41 A was found in the crystal packing environment
of 10 kJ/mol, about one half of that of a normal hydrogen bond
of a hydroxyl group to an oxygen acceptor [96]. Herein, we
report our results on a variety of monofluorinated cyclopropane
derivatives, which are expected to be essential for the
characterization of this biologically relevant class of com-
pounds [100–103].
[61,62]. Similar weak intermolecular interactions of a carbonyl
group to a-C–H bonds were suspected to contribute to the
stabilization of protein conformation [63].
Nevertheless, the role of C–F groups as hydrogen bond
acceptors is discussed controversially and it is questioned
whether they have any specific role [35,41–45,64–78].
Particularly for base pair surrogates of DNA it was suggested
that the nucleoside to be fitted into the growing helix is selected
by different shape rather than by hydrogen bonding capacities
[72–75]. In 1997 Dunitz and Taylor investigated about 6000 C–
F bonds in almost 1200 crystal structures (without compounds
containing metals or As, Se and Te, respectively) collected in
the Cambridge Crystallographic Data File, regarding possible
interactions to O–H or N–H bonds. These authors defined a
2. Experimental
Compounds 1a, 1c, 2a, 5, and 10 or 7 and 8, respectively,
were prepared as previously described in Refs. [104,105].
Synthesis of compounds 1b, 2b, 6a and 6b or 3, 4 and 9, is
published in Ref. [100–102].
2.1. (1R,2S)-(K)-2-Fluoro-2-phenylcyclopropanecarboxylic
acid ((1R,2S)-2a)
˚
distance of !2.3 A and a bonding angle O908 as the upper
limits for a hydrogen bond [70]. Among the 37 out of about
6000 examined C–F bonds which formally met these criteria,
only two compounds were qualified as truly hydrogen bonded.
Thus, it seems extremely rare that C–F moieties can act as
hydrogen bridge acceptors. At the same time, Howard et al.
identified 40 monofluorinated compounds having X–H/F–C
Analogous to a method described in the literature [106]
(1R,2S)-(K)-(2-fluoro-2-phenylcyclopropyl)methanol (87 mg,
0.524 mmol, O98% ee), prepared as previously described
[105], KMnO4 (414 mg, 2.62 mmol) and Bu4NBr (34 mg,
0.105 mmol) were dissolved in a suspension consisting of
benzene (1 mL) and H2O (4 mL) at 5 8C. After stirring the
reaction mixture vigorously for 17 h at 5 8C, sat. aqueous
NaHSO3 solution was added until the color disappeared. The
mixture was acidified with 10% H2SO4 and extracted with
CH2Cl2 (4!25 mL). The combined organic layers were dried
over MgSO4. After purification by flash chromatography
(SiO2, cyclohexane/ethyl acetate 1:1) (1R,2S)-2a (65 mg,
69%) was isolated as colorless oil. Different conditions and
solvent mixtures were applied to crystallize the oil. All
experiments did not give crystalline material. The spectro-
scopic data are in good agreement with those reported in
literature for the racemic compound [104].
˚
(XZO, N) contacts %2.35 A and classified them as weakly
hydrogen bonded [43]. Moreover, these authors identified more
˚
than 125 close C–H/F–C contacts %2.35 A, which were
classified as van der Waals complexes [43]. Recently, several
close X–H/F–C (XZO, N) contacts below these limits have
been described [79–83]. Other authors considered a distance of
˚
about the sum of the van der Waals radii (2.67 A) or even
longer for a good criteria for intermolecular hydrogen bridges
between C–F and H–X moieties [64–67,84,85]. Furthermore,
quite short intramolecular N–H/F–C distances have been
found in crystalline state and were classified as weak hydrogen
bridges stabilizing particular conformations [86–91]. Intra-
molecular hydrogen bonding was calculated for X–H/F–C
interactions in gauche conformations of 2-fluoroethanol and
2-fluoroethylamine as well as in their protonated forms [92,93].
In general, the poor polarizability of fluorine, which is due to
the energetically low-lying p-orbitals, leads to weak hydrogen
bonds [94,95]. X-ray data and quantum chemical calculations
reinforce the conclusion that C(sp3)–F groups are better
hydrogen bond acceptors than C(sp2)–F moieties [43,96].
In our studies, we focused on the examination of crystal
structures of monofluorinated cyclopropanes. Cyclopropane
itself is known to exhibit partial double bond character [97]. A
significant part of the p-character is used to form the strained
2.2. (1R,2S)-(K)-2-Fluoro-2-phenylcyclopropanecarboxamide
((R,S)-4)
(1R,2S)-(K)-2-Fluoro-2-phenylcyclopropanecarboxylic
acid ((1R,2S)-2a) (64 mg, 0.355 mmol, 98% ee) and SOCl2
(840 mg, 7 mmol) were refluxed in benzene (4 mL) for 5 h.
Benzene and excess SOCl2 were removed by distillation. The
crude product dissolved in 1,4-dioxane (4 mL) was treated with
ice-cold NH4OH (8 mL) and the resulting mixture was stirred
for 30 min at 0 8C and 1 h at room temperature. After
extraction with ethyl acetate (4!20 mL) the combined organic

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R. Frohlich et al. / Journal of Molecular Structure 787 (2006) 50–62
52
layer was washed with sat. NH4Cl (2!15 mL). The organic
layer was dried over MgSO4 and concentrated under vacuum.
After recrystallization from pentane/ethyl acetate (5:1) (1R,
2S)-(4) (49 mg, 77%, O98% ee, determined by chiral GC) was
mixture was refluxed for 5 h. Benzene and unconverted SOCl2
were removed by distillation. The crude product dissolved in
1,4-dioxane (3 mL) was treated with ice-cold NH4OH (6 mL)
and the resulting mixture was stirred for 30 min at 0 8C and 1 h
at room temperature. After extraction with CH2Cl2 (4!20 mL)
the combined organic layers were washed with sat. NH4Cl (2!
15 mL). The organic layer was dried over MgSO4 and
concentrated under vacuum. After recrystallization from
ethyl acetate at K20 8C (1S,2S)-3 (30 mg, 77%, O98% ee,
determined by chiral GC) was isolated as amorphous white
20
obtained as colorless solid. ½aꢀD K91.78 (c 1.0, CHCl3). The
spectroscopic data are in good agreement with those reported in
literature for the racemic compound [100].
2.3. (1S,2S)-(K)-2-Fluoro-2-phenylcyclopropanecarboxamide
((1S,2S)-3)
20
solid. ½aꢀD K218.6 (c 0.5, CHCl3). All experiments to obtain
suitable crystals for X-ray structural analysis resulted in the
formation of amorphous powders. The analytical data are in
good agreement with those reported in literature for the
racemic compound [100].
Enantiopure (1S,2S)-(K)-2-fluoro-2-phenylcyclopropane-
carboxylic acid ((1S,2S)-2a) (39 mg, 0.217 mmol, O98% ee),
prepared as previously described [101], and SOCl2 (521 mg,
4.34 mmol) were dissolved in benzene (4 mL). The reaction
Table 1
Crystal data and experimental details for compounds 1a–4a
Compound
(G)-1a
10H9FO2
(1S,2S)-1a
(G)-1b
(G)-1c
(G)-2a
(G)-2b
(G)-3
(G)-4
(1R,2S)-4a
Formula
F.W.
C
C10H9FO2
180.17
C10H8F2O2
198.16
C11H11FO2
194.20
C10H9FO2
180.17
C10H8F2O2
198.16
C10H10FNO
179.19
C10H10FNO
179.19
C10H10FNO
179.19
180.17
293(2)
0.71073
T (K)
223(2)
223(2)
223(2)
223(2)
223(2)
223(2)
198(2)
223(2)
Wavelength
˚
(A)
1.54178
1.54178
1.54178
1.54178
1.54178
1.54178
0.71073
1.54178
Crystal
Monoclinic
Monoclinic
Monoclinic
Monoclinic
Monoclinic
Monoclinic
Monoclinic
Triclinic
Trigonal
system
Space group
˚
A (A)
˚
B (A)
P21/c
P21
P21/n
5.853(1)
7.167(1)
21.175(3)
90
P21/n
C2/c
P21/c
P21/c
PK1
R3
5.4921(6)
7.5687(16)
20.451(2)
90
12.054(1)
5.609(1)
12.994(1)
90
8.0833(4)
5.6117(4)
21.5716(15)
90
24.124(3)
5.543(1)
40.282(6)
5331.4(14)
90
13.617(4)
5.591(2)
12.418(2)
90
17.620(3)
5.251(1)
9.720(1)
90
9.241(1)
9.859(2)
15.262(3)
78.06(1)
80.61(1)
78.47(1)
1322.1(4)
6
21.178(2)
21.178(2)
5.189(1)
90
˚
C (A)
a (8)
b (8)
g (8)
93.780(9)
90
94.56(1)
90
94.04(1)
90
91.013(5)
90
109.78(2)
90
93.68(1)
90
90
98.20(1)
90
120
3
˚
V (A )
848.3(2)
4
875.8(2)
4
886.1(2)
4
978.4(1)
4
889.6(4)
4
897.5(2)
4
2015.5(5)
9
Z
24
Dcalc (mg/
m3)
M (mmK1
1.411
1.367
1.486
1.318
1.347
1.480
1.326
1.350
1.329
)
0.112
0.918
1.132
0.859
0.905
1.128
0.838
0.102
0.840
F(000)
376
376
408
408
2256
408
376
564
846
Crystal size
(mm3)
0.40!
0.20!0.20
2.87–24.97
1654
0.35!
0.35!0.15
3.41–74.33
3932
0.25!
0.20!0.10
4.19–74.08
1849
0.30!
0.25!0.15
4.10–74.27
2038
0.50!
0.05!0.05
2.22–60.00
4032
0.50!
0.10!0.05
3.45–74.33
3585
0.70!
0.50!0.03
5.03–74.13
1944
0.35!
0.05!0.03
2.14–22.50
8389
0.70!
0.07!0.07
4.17–69.02
2184
q Range (8)
Reflections
collected
Independent
reflections
R(int)
1489
1969
1803
1986
3961
1795
1825
3429
1281
0.009
0.024
0.028
0.017
0.141
0.051
0.021
0.165
0.063
Data /restr./
param.
1489/0/120
1969/1/238
1803/0/129
1986/0/130
3961/0/355
1795/0/128
1825/2/124
3429/6/370
1281/3/126
Goodness-
of-fit on F2
1.054
1.090
1.033
1.062
1.097
0.930
1.004
1.055
1.057
R [IO2s(I)], 0.033/0.090
R1/wR2
0.038/0.101
0.040/0.104
0.08(17)
0.040/0.120
0.045/0.125
–
0.049/0.143
0.076/0.155
–
0.070/0.168
0.184/0.210
–
0.046/0.110
0.113/0.133
–
0.052/0.119
0.144/0.156
–
0.090/0.150
0.195/0.187
–
0.051/0.116
0.056/0.122
0.3(4)
R (all data),
R1/wR2
0.053/0.095
Abs. Struct.
parameter
Extinction
coefficient
–
0.026(4)
0.012(2)
0.011(1)
0.20/K0.24
245,910
0.008(2)
0.23/0.27
245,911
–
–
–
–
0.0027(3)
0.17/K0.18
245,908
Max. D peak/ 0.18/K0.21
0.24/K0.31
280,349
0.37/K0.34
245,917
0.17/K0.22
245,912
0.16/K0.18
280,350
0.24/K0.27
280,351
3
˚
hole (e/A )
CCDC
245,916
depos. No.

¨
R. Frohlich et al. / Journal of Molecular Structure 787 (2006) 50–62
53
Suitable single crystals for X-ray analysis of the other
compounds were obtained by slow evaporation of the
respective solvent or diffusion for solvent mixtures. The data
were collected with Nonius CAD4 or KappaCCD diffract-
ometers, the crystal data are presented in Tables 1 and 2. The
CCD data were processed with Denzo-SMN [107] and all
structures were solved by direct methods (SHELXS-97) [108]
and refined on F2 by full-matrix least-squares techniques
(SHELXL-97) [109]. The hydrogen atoms were calculated to
their idealized positions with isotropic temperature factors (1.2
or 1.5 times the carbon temperature factor) and the C–H, O–H
and N–H distances have been normalized to their neutron
diffraction distances during the refinements, viz. C–H to
CCDC 245908-245914, 245916-245918, and 280349-
280354 contain the supplementary crystallographic data
(excluding structure factors) for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/const/
retrieving.html (from the Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: C44-
1223-336033).
3. Results
In particular, X-ray structures of several 2-fluoro-2-
phenylcyclopropane derivatives (Scheme 1) synthesized from
corresponding a-fluorostyrenes by copper catalyzed cyclopro-
panation with ethyl diazoacetate (Scheme 2) and subsequent
further functionalization [104,105,111] were examined with
respect to short X–H/F–C contacts. C–H/p interactions
were not taken into account. The structures of the compounds
((G)-1b, (G)-1c, (G)-2b, (1R,2S)-4, (1S,2S)-6a, (1R,2R)-6b,
˚
˚
1.08 A, O–H and N–H to 1.00 A (done using the SHELXL
command AFIX in the final refinements). The figures have
been drawn using the SCHAKAL software [110].
Crystal data and experimental details for compounds 1a–4a
is given in Table 1 and for compounds 5–10 in Table 2.
Table 2
Crystal data and experimental details for compounds 5–10
Compound
(1S,2S)-5
16H13BrFNO
(1S,2S)-6a
(1R,2R)-6b
(1R,2R)-7
(1S,2R)-8
(G)-9
(G)-10
Formula
FW
C
C18H18FNO
283.33
223.0(1)
1.5478
Orthorhombic
P212121
9.762(1)
12.912(1)
24.489(1)
90
C21H24FNO
325.41
223(2)
1.54178
Monoclinic
P21
C17H15BrFNO2
364.21
198(2)
0.71073
Orthorhombic
P21212
8.840(1)
34.535(1)
5.054(1)
90
C17H15BrFNO2
364.21
198(2)
C10H13ClFN
201.66
C19H18F2N2O
328.35
223(2)
334.18
198(2)
T (K)
198(2)
˚
Wavelengths (A) 0.71073
0.71073
Monoclinic
P21
0.71073
Triclinic
P-1
1.54178
Orthorhombic
P212121
10.717(3)
14.361(2)
21.558(4)
90
Crystal system
Triclinic
P1
Space group
˚
a (A)
˚
b (A)
5.706(1)
7.890(1)
15.613(4)
90.55(1)
94.90(1)
91.84(2)
699.9(2)
2
9.788(1)
12.273(1)
15.842(1)
90
16.186(1)
5.348(1)
18.294(1)
90
9.598(1)
10.227(1)
21.637(2)
77.32(1)
84.67(1)
88.90(1)
2063.1(4)
8
˚
c (A)
a (8)
b (8)
g (8)
90
100.87(1)
90
90
93.91(1)
90
90
90
90
90
3
˚
V (A )
3086.8(4)
8
1868.9(3)
4
1542.9(4)
4
1579.9(3)
4
3317.9(12)
8
Z
D
calc (mg/m3)
1.586
1.219
1.157
1.568
1.531
1.299
1.315
M mmK1
2.942
0.675
0.616
2.681
2.618
0.338
0.812
F(000)
336
1200
696
736
736
848
1376
Crystal size
(mm3)
0.20!0.10!
0.05
0.70!0.10!
0.10
0.25!0.25!
0.05
0.50!0.10!
0.05
0.40!0.06!
0.03
0.40!0.10!
0.03
0.40!0.10!
0.10
q Range (8)
Reflections col-
lected
2.58–26.48
4298
3.61–65.61
4056
2.84–65.53
9730
1.18–27.87
8237
1.63–28.24
9847
1.94–24.76
9895
3.70–74.30
3788
Independent
reflections
R(int)
3298
4056
4078
3553
7096
6728
3788
0.041
–
0.061
0.051
0.043
0.096
–
Data /restr./
param.
3298/5/367
4056/2/384
4078/7/438
3553/1/202
7096/3/403
6728/0/473
3788/4/446
Goodness-of-fit
on F2
1.057
0.995
1.153
1.049
1.0567
1.096
1.028
R[IO2s(I)], R1/
wR2
0.051/0.132
0.059/0.139
K0.02(2)
–
0.071/0.192
0.112/0.220
K0.2(4)
0.064/0.178
0.125/0.218
K0.5(4)
0.047/0.086
0.082/0.098
K0.03(1)
–
0.062/0.091
0.126/0.111
0.00(1)
0.093/0.199
0.161/0.233
–
0.057/0.142
0.094/0.166
0.7(3)
R (all data), R1/
wR2
Abs. Struct. par-
ameter
Extinction coef-
ficient
0.0013(5)
0.54/K0.23
245,913
0.0035(7)
0.19/K0.17
245,914
–
–
0.0024(4)
0.30/K0.30
245,909
Max. D peak/
0.45/K0.43
245,918
0.37/K0.62
280,352
0.41/K0.60
280,353
0.54/K0.29
280,354
3
˚
hole (e/A )
CCDC deposit.
No.

¨
R. Frohlich et al. / Journal of Molecular Structure 787 (2006) 50–62
54
CO2H
F
F
CO2H
R
F1
X
X
H1
1a (X = R = H)
1b (X = F; R = H)
1c (X = H; R = CH3)
2a (X = H)
2b (X = F)
H6
F
CONH2
F
Fig. 1. Crystal structureof(G)-trans-2-fluoro-2-phenylcyclopropanecarboxylic
acid (1a).
CONH2
˚
1.65 A with a bond angle of 1718 were formed between the
4
3
carboxylic groups of two molecules. Additionally, there are two
C–H/F–C distances, which are close to the sum of the van der
Waals radii, namely 2.62 A (C1–H1/F1 with angle of 1358) to
the methine C–H in a-position to the carboxylic function and
F
F
CONHR
CONH(p-BrPh)
˚
˚
2.65 A to an ortho-hydrogen of the aryl ring (C6–H6/F1 with
angle of 1268) (Fig. 1). The heavy atom close contacts [the sum
X
˚
of van der Waals radii of fluorine and carbon is 3.17 A and
˚
fluorine and nitrogen it is 3.02 A] between the fluorine and the
5
6a (X = H; R = (S)-CH(CH3)Ph)
6b (X = C3H7;R = (S)-CH(CH3)Ph)
H-bond carbon/nitrogen and the O1208 angle C–F/C/N also
further support the weak C–F/H interaction between the
fluorine and the hydrogen atom, in 1a these values are
F
CH
2
OC(O)NHR
F
˚
˚
CH2OC(O)NHR
3.465(2) A (F1/C1), 3.403(2) A (F1/C6), 170.9(1)8 (C2–
F1/C1), and 130.5(1)8 (C2–F1/C6).
The analogous non-fluorinated (G)-trans-2-(4-tolyl)
cyclopropanecarboxylic acid, KEMPUN [112] (data retrieved
from Cambridge Crystallographic Data Base) crystallized in a
centrosymmetric orthorhombic space group Pbcn. Beside the
typical dimer formation with two strong hydrogen bonds no
other short intermolecular distances were found (Fig. 2).
The enantiomerically pure (C)-(1S,2S)-2-phenylcyclopro-
panecarboxylic acid (trans-configuration) (RIWKEN) [113]
crystallized in a non-centrosymmetric monoclinic space group
P21. In addition to the strong dimer H-bonding a weak inter-
8 (R = p-BrPh)
7 (R = p-BrPh)
H
H
+
-
F
CH2NH3 Cl
F
F
N
N
O
9
10
Scheme 1. Investigated compounds. Synthesis has been described in Refs.
[100–105,111].
˚
dimer hydrogen bond, C–H/O distance 2.54 A, C/O
˚
distance of 3.22 A, and the C–H/O angle of 1258 were
found (Fig. 3).
(G)-9 and (G)-10) are newly presented, the other compounds
((G)-1a, (1S,2S)-(1a), (G)-2a, (G)-3, (G)-4, (1S,2S)-5,
(1R,2R)-7 and (1S,2R)-8) are already published, but re-refined
for this study for better comparison.
The enantiopure fluorinated analogue (1S,2S)-1a crystallized
also as dimers in a monoclinic crystal type (P21), but compared
to the racemic compound 1a, revealed a shorter C–H/F contact
First some stereoisomeric 2-fluoro-2-arylcyclopropanecar-
boxylic acids 1 and 2 were investigated. As expected, these
compoundsformed dimersin the crystalline state. In the racemic
dimer of trans-2-fluoro-2-phenylcyclopropanecarboxylic acid
(1a) (monoclinic, P21/c) two strong hydrogen bridges as short as
˚
of 2.40 A (C1A–H1A/F1A with angle of 1548) to the methine
proton of the cyclopropane ring (Fig. 4). Due to the
conformation, induced by the crystal packing forces, also a
˚
short intramolecular C–H/F distance (2.45 A, 1408) to an
aromatic hydrogen was found. The F/C and C–F/C values in
CO2Et
F
F
F
N2CHCO2Et
CO2Et
+
Cu(acac)2,CH2Cl2
40 ˚C, 7h
88%
:
1
1
Scheme 2. Synthesis of diastereomeric ethyl 2-fluoro-2-phenyl-cyclopropylcarboxylates.

¨
R. Frohlich et al. / Journal of Molecular Structure 787 (2006) 50–62
55
H1
Fig. 2. Crystal structure of (G)-trans-2-(4-tolyl)cyclopropanecarboxylic acid
(KEMPUN) [112].
H11C
F1
Fig. 5. Crystal structure of (G)-2-fluoro-t-3-methyl-t-2-phenylcyclopropyl-r-
carboxylic acid (1c).
˚
bridges (1.64 A, 1768) led to the formation of dimers, but no
short contacts of a fluorine of the cyclopropane ring to any of
the C–H groups in the three-membered ring were found. In
contrast, this fluorine atom interacts with the ortho-hydrogen of
˚
the next molecule, 2.49 A, C1–H1/F2, with angle of 1488.
Moreover, the para-fluorine atom has a short distance of
Fig. 3. Crystal structure of (C)-(1S,2S)-2-phenylcyclopropanecarboxylic acid
(RIWKEN) [113].
˚
2.51 A, C6–H6/F1, with angle of 1208 to the methine C–H in
˚
(1S,2S)-1a are 3.401(3) A (F1A/C1A), 3.350(3) (F1B/
a-position to the carboxylic function (Fig. 6). The F/C and C–
C10A), 140.6(1)8 (C2A–F1A/C1A), and 128.9(1)8 (C2B–
F1B/C10A).
˚
˚
F/C values in 1b are 3.456(2) A (F2/C1), 3.189(2) A (F1/
C6), 146.1(1)8 (C2–F1/C6), and 125.5(1)8 (C8–F2/C1). The
para-fluorine might increase the acidity of the aromatic protons
and has also some effect on the cyclopropyl fluorine lowering
its electron density and hence its acceptor abilities for
hydrogen bridges.
An additional methyl group in the 3-position of the
cyclopropane ring trans-orientated relative to both the fluorine
and to the carboxylic function (compound 1c) did not disturb
the formation of dimers. The acid 1c crystallized in a
centrosymmetric monoclinic space group P21/n like racemic
1a and shows two quite short intermolecular contacts slightly
shorter than the sum of the van der Waals radii of the fluorine
Also the racemate of the cis-isomer 2a (a diastereomer of
1a) crystallized with three molecular dimers in the asymmetric
unit in a C-centered centrosymmetric monoclinic space group
C2/c and forms dimers via strong hydrogen bridging (1.64,
˚
atom to the a-methine proton, 2.55 A, C1–H1/F1, with angle
of 1428 and to the methyl group, 2.51 A, C11–H11C/F1 with
angle of 1228 (Fig. 5). The F/C and C–F/C values in 1c are
3.461(2) A (F1/C1), 3.216(3) A (F1/C11), 177.6(1)8 (C2–
F1/C1), and 132.8(1)8 (C2–F1/C11).
The introduction of an additional fluorine atom into the
para-position of the aromatic ring in the racemic compound 1b
led to a slightly different packing, nonetheless the space group
is the same: monoclinic P21/n. Again two very strong hydrogen
˚
˚
1.67, and 1.67 A with angles of 176, 173, and 1618,
respectively). Three different very short intermolecular C–
˚
˚
˚
H/F–C contacts of 2.41 A (C3C–H3CB/F1C) with angle of
˚
1718, 2.32 A (C3B–H3BB/F1B) with angle of 1548 and even
˚
2.28 A (C3A–H3AA/F1A) with angle of 1728 were formed to
the cyclopropane methylene group of the adjacent molecules
˚
(Fig. 7). The F/C and C–F/C values in 2a are 3.356(6) A
˚
˚
(F1A/C3A), 3.326(7) A (F1B/C3B), 3.482(7) A (F3C/
C3C), 151.9(3)8 (C2A–F1A/C3A), 142.6(3)8 (C2B–F1B/
C3B), and 147.1(3)8 (C2C–F1C/C3C).
H10A
F1B
F1A
H1A
F1
H6
H1
F2
Fig. 4. Crystal structure of (1S,2S)-(K)-2-fluoro-2-phenyl-cyclopropanecar-
boxylic acid ((1S,2S)-1a).
Fig. 6. Crystal structure of (G)-trans-2-fluoro-2-(p-fluorophenyl)cyclopro-
panecarboxylic acid (1b).

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R. Frohlich et al. / Journal of Molecular Structure 787 (2006) 50–62
56
H9
H3AA
F1C
H3B
F1
F1A
F2
H9
H3CB
H9
F2
Fig. 7. A-C-Dimer of the (G)-cis-2-fluoro-2-phenylcyclopropanecarboxylic
acid (2a).
Unfortunately, the (1S,2R)-enantiomer of the cis-configured
acid 2a, did not crystallize, but remained an oil. The
corresponding non-fluorinated racemic (G)-cis-2-phenylcy-
clopropanecarboxylic acid (RUWKOJ) [114] crystallized in a
centrosymmetric monoclinic space group P21/n. In addition to
the strong inter-dimer hydrogen bond, also a very weak inter-
Fig. 9. Crystal structure of (G)-cis-2-fluoro-2-(p-fluorophenyl)cyclopropane-
carboxylic acid (2b).
fluorine atom and a meta-hydrogen atom of the neighbored
molecule (cf. the above-mentioned influences of p-fluorine). In
˚
addition a longer intermolecular contact of 2.68 A (C9–
H9/F1) with angle of 1378 exists (Fig. 9). The F/C and
˚
dimer hydrogen bond with C–H/O distance 2.68 A, C/O
˚
˚
C–F/C values in 2b are 3.219(3) A (F2/C9), 3.470(4) A
˚
distance of 3.61 A, and the C–H/O angle of 1578 were found
(Fig. 8).
˚
(F1/C3), 3.551(3) A (F1/C9), 143.5(2)8 (C8–F2/C9),
151.9(2)8 (C2–F1/C3), and 150.3(2)8 (C2–F1/C9).
The attachment of a para-fluorine atom at the aromatic ring
(racemic compound 2b, monoclinic P21/c), in this case led to
two different short C–H/F–C-distances of the strongly
Thus, all investigated cyclopropanecarboxylic acids in the
crystalline state did form hydrogen bonded dimers. Addition-
ally, the fluorinated compounds exhibited close C–H/F–C-
contacts, which in general were shorter than the sum of the van
der Waals radii. The cis-configurated compounds 2 had the
shorter distances compared to the corresponding trans-
compounds 1a and 1b and do approach each other as close
˚
hydrogen bonded dimers (1.65 A, 1748). Between the
cyclopropyl fluorine and one hydrogen atom of the methylene
group of the next molecule’s three-membered ring a close
˚
contact of 2.39 A (C3–H3B/F1), 1788 was found, while
˚
2.45 A (C9–H9/F2), 1278 was observed between the para-
˚
˚
as 2.28 A (2a) or 2.39 A (2b). Crystal structures of fluorinated
compounds differed significantly from corresponding unfluori-
nated counterparts suggesting an attractive intermolecular
interaction of the fluorine substituent on the crystal structure.
Next the corresponding racemic primary carboxamides 3
and 4 were investigated. The trans-isomer 3 crystallized in a
centrosymmetric triclinic structure (PK1) as hydrogen bonded
˚
dimers and showed quite short N–H/OaC-contacts of 1.80 A
˚
(N1–H1A/O1) with angle of 1668 and 1.92 A (N1–
H1B/O1) and angle of 1748 (Fig. 10). However, the shortest
˚
C–H/F–C-distance was found to be 2.76 A, hence slightly
above the sum of the van der Waals radii.
In contrast, the racemic cis-isomer 4 crystallized with three
molecules in the asymmetric unit in a centrosymmetric
monoclinic space group P21/c and showed a complicated
structure. Since all attempts to get crystals of better quality
failed, the geometrical values with less accurancy should be
discussed here. There are several quite short intermolecular N–
˚
H/OaC-contacts of 1.88 A (N1A–H1AA/O1C) with angle
˚
of 1718, 1.89 A (N1B–H1BA/O1A) with angle of 1748, and
Fig. 8. Crystal structure of (G)-cis-2-phenylcyclopropanecarboxylic acid
(RUWKOJ) [114].
˚
1.93 A (N1C–H1CA/O1B) with angle of 1678. Most

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R. Frohlich et al. / Journal of Molecular Structure 787 (2006) 50–62
57
O1
O1
H1B
H1A
O1
H1B
H1A
N1
Fig. 10. Crystal structure of (G)-trans-2-fluoro-2-phenylcyclopropanecarbox-
amide (3).
O1
H3B
surprisingly, there are also three extremely short intermole-
˚
cular N–H/F–C distances of 2.09 A (N1B–H1BB/F1A)
F1
˚
with angle of 1588, 2.01 A (N1C–H1CB/F1B), angle of 1678,
˚
and 2.03 A (N1A–H1AB/F1C), angle of 1698. There also
˚
exists a longer C–H/F–C distance of 2.64 A (C9B–
H9B/F1C) with angle of 1298 (Fig. 11). The F/C/N
Fig. 12. Crystal structure of (1R,2S)-(K)-2-fluoro-2-phenylcyclopropanecar-
boxamide ((1R,2S)-4a).
˚
distances and C–F/C/N angles in 4 are 3.043(6) A (F1A/
˚
˚
N1B), 2.995(6) A (F1B/N1C), 3.022(7) A (F1C/N1A),
3.422(7) (F1C/C9B) and 167.3(4)8 (C2A–F1A/N1B),
169.6(4)8 (C2B–F1B/N1C), 155.8(4)8 (C2C–F1C/N1A),
and 125.0(4)8 (C2C–F1C/C9B), respectively. The extremely
short N–H/F distances in 4, to the best of our knowledge,
belong to the shortest intermolecular contacts ever observed for
monofluorinated compounds.
˚
compound, a quite short C–H/F–C-contact of 2.41 A with
angle of 1428 was identified (Fig. 12). The F/C and C–F/C
˚
values in (1R,2S)-4 are 3.326(6) A (F1/C3) and 124.6(2)8
(C2–F1/C3).
The (1S,2S)-2-fluoro-2-phenylcyclopropanecarbox-(4-
bromophenyl)amide (1S,1S)-(5) (trans-configuration of phenyl
group and carboxamide function) crystallized with two
molecules in the asymmetric unit in a non-centrosymmetric
triclinic space group P1. Two short N–H/OaC-distances of
These short distances forced us to synthesize also the
corresponding enantiopure compounds. Unfortunately, the (1S,
2S)-isomer of compound 3 could not be crystallized, but gave
an amorphous powder. Its diastereomer, (1R,2S)-4 crystallized
in a non-centrosymmetric trigonal space group R3, showing
˚
˚
1.86 A (N1B–H1BA/O1A), angle of 1518 and 1.89 A (N1A–
H1AA/OO1B), 1628 were identified. Additionally, also three
˚
quite short C–H/F–C-contacts of 2.39 A, (C3A–
H3AB/F1A) with angle of 1548, 2.47 A (C1B–H1B/F1A),
1288 and 2.35 A (C1A–H1A/F1B), 1578 were found
(Fig. 13). The F/C and C–F/C values in 5 are 3.392(9) A
(F1A/C3A), 3.253(8) A (F1A/C1B), 3.375(8) A (F1B/
C1A), 148.9(4)8 (C2A–F1A/C3A), 139.0(4)8 (C2A–F1A/
C1B), and 113.2(4)8 (C2B–F2B/C1A).
˚
normal N–H/OaC-contacts of 1.96 A with angle of 1688 and
˚
˚
2.19 A with angle of 1658. Surprisingly, no short N–H/F–C-
distances were found. But, in contrast to the racemic
˚
˚
˚
˚
C9B
O1B
Br1B
F1B
N1A
O1A
C1A
F1C
N1B
O1C
N1A
F1B
Br1A
F1A
N1A
F1B
N1B
O1B
N1C
F1A
N1B
O1A
C1B
O1A
H3AB
O1B
F1A
Fig. 11. Crystal structure of (G)-cis-2-fluoro-2-phenylcyclopropanecarbox-
amide (4).
Fig. 13. Crystal structure of (1S,2S)-2-fluoro-2-phenylcyclopropanecarbox-(4-
bromophenyl)amide ((1S,2S)-5).

¨
R. Frohlich et al. / Journal of Molecular Structure 787 (2006) 50–62
58
Moreover, (1S,2S)-(K)-2-fluoro-2-phenylcyclopropyl-N-
[(S)-1-phenylethyl)]carboxamide (6a) [101], crystallized in a
non-centrosymmetric orthorhombic space group P212121. The
structure shows six short intermolecular interactions of which
˚
two are N–H/OaC interactions of 1.96 A (N1B–H1BA/
˚
O1A) with angle of 1688 and 2.04 A (N1A–H1AA/O1B),
angle 1608. The four remaining interactions are C–H/F–C and
˚
N–H/F–C of 2.23 A (C10B–H10B/F1A) with angle of 1488,
˚
2.49 A (C1B–H1B/F1A), angle 1628, 2.57 (C8B–H8B/
F1A
O1A
˚
H1B
F1B), angle 1288, and 2.69 A (N1A–H1AA/F1B) with angle
1208 (Fig. 14). The F/C/N and C–F/C/N values in 6a are
3.531(5) A (F1A/C1b), 3.198(8) A (F1A/C10B),
3.345(10) A (F1B/C8B), 3.301(6) A (F1B/N1A), 131.3(3)8
(C2A–F1A/C1B), 162.0(4)8 (C2A–F1A/C10B), 142.2(4)8
(C2B–F1B/C8B), and 145.9(4)8 (C2B–F1B/N1A).
F1B
˚
˚
O1B
H1AA
˚
˚
H19A
N1B
H1BA
N1A
Furthermore, (1R,2R)-2-fluoro-2-(4-propylphenyl)cyclo-
propyl-N-[(S)-1-phenylethyl)]carboxamide (6b) [101] crystal-
lized with two molecules in the asymmetric unit in a non-
centrosymmetric monoclinic space group P21 showing normal
˚
N–H/OaC hydrogen bonding distances of 1.89 A (N1A–
˚
H1AA/O1B) with angle of 1588 and 1.83 A (N1B–H1BA/
Fig. 15. Crystal structure of (1R,2R)-2-fluoro-2-(4-propylphenyl)cyclopropyl-
N-[(S)-1-phenylethyl)]carboxamide (6b).
O1A) with angle of 1578. In addition there are three C–H/F–
C-contacts of 2.40 A (C1B–H1B/F1A) with angle of 1658,
˚
˚
˚
˚
2.54 A (C7B–H7B/F1A) with angle of 1598, and 2.61 A
(C17A–H17A/F1B) with angle of 1268, (Fig. 15). The F/C
(Fig. 16). The F/C and C–F/C values in 7 are 3.115(4) A
˚
(F1/C4), 3.517(5) A (F1/C17), 125.3(2)8 (C2–F1/C4) and
˚
and C–F/C values in 6 are 3.452(8) A (F1A/C1B),
90.1(2)8 (C2–F1/C17).
˚
143.1(4)8 (C2A–F1A/C1B), 3.575(10) A (F1A/C7B),
However, the cis-isomer (1S,2R)-(8) crystallized with two
molecules in the asymmetric unit in a non-centrosymmetric
monoclinic space group P21. The structure showed rather long
˚
88.0(4)8 (C2A–F1A/C7B), and 3.356(10) A (F1B/C17A),
151.0(5)8 (C2B–F1B/C17A).
˚
Two more diastereomeric enantiopure carbamates were
synthesized [105] and their crystal structures were analyzed.
The N-(4-bromophenyl)carbamate of the trans-configured
(1R,2R)-(2-fluoro-2-phenylcyclopropyl)methanol (1R,2R)-7
crystallized in a non-centrosymmetric orthorhombic space
N–H/OaC-distances of 2.23 A (N1A–H1AA/O2A) with
˚
angle of 1578 and 2.20 A (N1B–H1BA/O2B), angle of 1578.
Additionally, two very short intermolecular C–H/F–C-
contacts were identified. There is a very close distance of
˚
2.17 A (C3B–H3BA/F1B) with angle of 1628 of a fluorine
atom to a hydrogen atom of the cyclopropane ring and another
˚
group P21212. Besides the N–H/OaC-contact of 2.02 A (N1–
H1A/O2) with angle of 1718, the structure showed two
relatively short intermolecular C–H/F–C-distances of 2.48 A
˚
similar one in the second molecule of 2.19 A (C3A–
˚
H3AA/F1A) with angle of 1708 (Fig. 17). The F/C and
(C17–H17/F1) with angle of 1618 towards the ortho-
˚
C–F/C values in (1S,2R)-8 are 3.262(6) A (F1A/C3A),
˚
hydrogen of the phenyl ring and 2.55 A (C4–H4A/F1) with
a narrow angle of 1128 to the exocyclic methylene group
˚
3.215(6) A (F1B/C3B), 144.3(3)8 (C2A–F1A/C3A) and
141.0(3)8 (C2B–F1B/C3B). The increased acidity of cyclo-
propyl hydrogens and its ability to form intermolecular
N1B
H1BA
H1B
O1
H8B
F1B
H10B
O1A
F1A
F1
O2
N1A
Br
H8B
F1B
H1AA
O1B
H4A
H1A
C17
H17
C4
N1
F1
Fig. 14. Crystal structure of (1S,2S)-(K)-2-fluoro-2-phenylcyclopropyl-N-[(S)-
1-phenylethyl)]carboxamide (6a).
Fig. 16. Crystal structure of (1R,2R)-(2-fluoro-2-phenylcyclopropyl)methyl
N-(4-bromophenyl)carbamate (7).

¨
R. Frohlich et al. / Journal of Molecular Structure 787 (2006) 50–62
59
O
N
N
F1A
N1A
H1BA
F
Br1A
H3AA
O2A
C3A
Fig. 19. Crystal structure of N,N0-di(2-fluoro-2-phenylcyclopropyl)urea (10)
(only N–H/O contacts are shown, all other hydrogen atoms omitted for
clarity).
O1A
closest contacts to hydrogen atoms in the neighbourhood are
˚
˚
2.58 A (H6B) and 2.65 A (H3AB).
Finally, the di(fluorocyclopropyl)urea 10 [116], isolated as
a side product of the Curtius degradation of compound 1a,
crystallized in a non-centrosymmetric orthorhombic space
group P212121. The structure is extremely complex and
showed a multitude of short intermolecular interactions. Two
Fig. 17. Crystal structure of (1S,2R)-(2-fluoro-2-phenylcyclopropyl)methyl
N-(4-bromophenyl)carbamate (8) (molecule A).
hydrogen bridges to carbonyl groups in solid state has been
described already [115].
˚
Such very close intermolecular C–H/F–C contacts, to the
best of our knowledge, were not found in other non-aromatic
monofluorinated compounds to date.
short and two longer N–H/OaC-distances of 1.88 A (N1A–
˚
H1AA/O1C) with angle of 1678, 1.91 A (N1D–H1DA/
O1A), angle 1498, 2.33 A (N1B–H1BA/O1C), angle 1398
and 2.28 A (N1C–H1CA/O1A), angle 1378 were found
(Fig. 19). Also two weak C–H/OaC hydrogen bonds were
observed: 2.34 A (C7D–H7D/O1A) with angle of 1728 and
2.43 A (C9A–H9A/OO1C) with angle of 1338. Moreover,
in addition to the six short intermolecular C–H/F–C
contacts also one short N–H/F–C contacts were identified
(Table 3).
˚
˚
The racemic fluorinated aminomethylcyclopropane hydro-
chloride 9, with trans-configuration of the phenyl and the
aminomethyl groups, crystallized in a centrosymmetric
triclinic space group P-1 with four molecules in the
asymmetric unit. In this case the crystals were of poor quality
leading to less accurate data. Beside twelve N–H/Cl
˚
˚
˚
interactions (2.11–2.31 A, 147–1788) the structure shows
three different intermolecular C–H/F–C-contacts. A short
˚
contact of 2.39 A (C1A–H1A/F1D) with angle of 1438 was
˚
4. Discussion
found, while the two others of 2.51 A (C1D–H1D/F1A),
˚
angle of 1548 and 2.53 A (C1C–H1C/F1B), angle 1368 are
only slightly shorter than the sum of the van der Waals radii
The X-ray structures of the 2-fluoro-2-arylcyclopropane
derivatives demonstrate that an over-all correlation between
the short N/C–H/F–C-distances and angles and close to van
der Waals contact of the corresponding N/C/F–C-distances
and angles indeed exists. Controversy has been raised in
literature with the question, whether close X–H/F–C
distances (!sum of the van der Waals radii) and angles O
908, can be regarded as true but weak hydrogen bonds [35,41–
46,64–78]. The data presented here for particular 2-fluoro-2-
arylcyclopropane derivatives clearly show the ‘attractive’
hydrogen bonding type of interaction. However, the overall
3-D structure, conformation and other types of positive
interactions (e.g. ‘classical’ or weak hydrogen bonds) of the
compounds containing the F–C moieties will have a great
impact on the intermolecular ‘interaction’ distances. This can
be seen here as most of the trans-configured compounds reveal
longer C–H/F–C distances than the corresponding cis-
configured analogs. Moreover, the intermolecular C–H/F–C
contacts are shorter in enantiopure compounds as compared to
their racemates. If additional attractive forces are present, e.g.
˚
(Fig. 18). The F/C and C–F/C values in 9 were 3.512(7) A
˚
˚
(F1A/C1D), 3.388(7) A (F1B/C1C), 3.320(7) A (F1D/
C1A), 132.9(3)8 (C2A–F1A/C1D), 131.2(3)8 (C2B–F1B/
C1C), and 139.2(3)8 (C2D–F1D/C1A). Surprisingly, one of
the fluorines (F1C) is not involved in this type of bonding, the
N1A
Cl1A
H1D
H1A
F1A
H1C
F1D
F1C
F1D
F1B
Fig. 18. Crystal structure of (G)-trans-1-aminomethyl-2-fluoro-2-phenylcy-
clopropane hydrochloride (9).

¨
R. Frohlich et al. / Journal of Molecular Structure 787 (2006) 50–62
60
Table 3
Short intermolecular C–H/F–C, N–H/F–C, F/C and C–F/C contact distances and angles for compound 10
˚
˚
X
H
F
H/F (A)
X/F (A)
X–H/F (8)
CF/X (8)
N1C
C9D
C3B
C1C
C1B
C7A
C8B
H1CA
H9D
H3BB
H1C
F1A
F1A
F1A
F1B
F1C
F1D
F1D
2.56
2.57
2.58
2.39
2.62
2.46
2.62
3.416(5)
3.348(7)
3.447(6)
3.366(5)
3.605(6)
3.319(6)
3.663(6)
144
128
137
150
152
136
162
150.4(2)
116.4(3)
114.4(2)
117.2(2)
121.6(3)
130.8(3)
84.3(2)
H1B
H7A
H8B
N–H/OaC, this will further decrease the interaction
distances.
C
H
Y
H
X
C
F
H
C
C
F
This effect for C–H/F–C distances and angles is visible for
the enantiomers 7 and 8. The trans-configured compound 7
(asymmetric unit contains one molecule) shows a weak N–
H/OaC contact and has two intermolecular C–H/F–C
Y
Scheme 3. Structure fragments used, the minimum F/H search distance was
1.8 A and the maximum 2.3 A. Dotted line showing the H/F interaction, X
and Y being any atom.
˚
˚
˚
contacts. The Dd (2.48–2.67 and 2.55–2.67 A, respectively) are
˚
thus only K0.2 and K0.1 A shorter than the sum of the van der
˚
contact being 2.07 A with angle of 1668, but simultaneously
Waals radii. However, the corresponding cis-configured 8 (two
molecules in the asymmetric unit) has long N–H/OaC-
˚
distances too. The Dd values are K0.50 and K0.48 A (2.17–
˚
shows also an N–H/OaC contact of 2.03 A with angle of
1618, forming a carboxylic acid type of dimer structure. The
situation slightly changes with fluorine and hydrogen of an
amino group. Thus, the shortest C–F/H–N distance found in
catena-(bis(m2-thiourea-S,S-)-(2-fluorobenzoato-O,O)-lead(II)
2-fluorobenzoate monohydrate, NUMVIA [118], is only
˚
2.67 and 2.19–2.67 A, respectively), also the F/C and C–
F/C values in 8 manifest the stronger interaction by showing
much shorter values.
Extremely short N–H/F–C-interactions were found for
(G)-cis-2-fluoro-2-phenylcyclopropane carboxamide (4). The
crystal structure of 4 is very complex (three molecules in the
asymmetric unit). As 4 is a carboxamide, intermolecular N–
H/OaC-contacts represent the classical hydrogen bonding.
The above N–H/OaC interactions will further enhance the
weaker N–H/F–C interactions and the three extremely short
intermolecular N–H/F–C distances are, to the best of our
knowledge, among the shortest intermolecular contacts ever
observed for organic monofluorinated compounds. The
simultaneous N–H/OaC and N–H/F–C interactions corre-
late very well with the very short F/C/N and C–F/C/N, the
three of the being in the same order than the sum of van der
Waals radii of fluorine and carbon or fluorine and nitrogen,
˚
1.95 A with angle of 1418. However, this very short contact
is between an aromatic fluorine and amino hydrogen. This is
by far the shortest found organic fluorine to hydrogen
˚
˚
interaction distance, Dd (1.95–2.67 A) being K0.72 A,
manifesting a strong interaction between fluorine and
hydrogen.
Moreover, our high level calculations (MP2/QZVPP) on
the structure of cyclopropane–fluorocyclopropane adduct and
of the dimer of monofluorocyclopropane in the gas phase in
˚
the first case show a C–H/F–C distance of 2.60 A and an
interaction energy of K6 kJ/mol. In the latter case a distance
˚
of 2.57 A and about K10 kJ/mol a single C–H/F–C
interaction (about 40% electrostatic and 60% dispersion
forces) was calculated [96]. For ‘classical’ hydrogen bonds
of the O–H/O-type about K20 kJ/mol involving 60–80%
electrostatic forces are usual. Thus, in agreement with earlier
results [46], we find it justified to characterize the close
contacts found in the presented X-ray structures as weak
hydrogen bonds.
˚
(3.17 and 3.02 A, respectively). In contrast, enantiopure (1R,
2S)-4a crystallizing in a non-centrosymmetric trigonal space
group R3, showed normal N–H/OaC-contacts. Surprisingly,
no short N–H/F–C-distances were found, but, in contrast to
the racemic compound, a quite short C–H/F–C-distance.
Comparison of the structures of fluorinated cyclopropanes
with those of the non-fluorinated counterparts revealed that
close intermolecular contacts of fluorine substituents to
hydrogen atoms are not solely due to crystal packing effects,
but are also caused by weak X–H/F–C hydrogen bridges.
In order to compare our results with similar structures with
short C–F/H–C or C–F/H–N contacts a search from the
Cambridge Structural Data Base (CSD, ConQuest 1.5, July
2003 version, 278172 X-ray structures) was performed with the
following close non-covalently bonded contact distance
constraints presented in Scheme 3.
The ability to form weak hydrogen bonds sems to influence
the binding characteristics of monofluorinated cyclopropanes
to biological targets such as enzyme receptor sites. Results for
the interaction of fluorinated cyclopropylamines with mono-
amine oxidases indicated specific alterations of the inhibition
activity induced by the fluorine substituent [23].
Acknowledgements
This research project was supported by the Deutsche
Forschungsgemeinschaft (Graduiertenkolleg ‘Hochreaktive
Mehrfachbindungssysteme’ and Sonderforschungsbereich
The shortest C–F/H–C distance was found for CCDC
structure CEKJIL [117] (20-deoxy-20-fluoroadenosine), this

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R. Frohlich et al. / Journal of Molecular Structure 787 (2006) 50–62
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