Can C–H?F–C hydrogen bonds alter crystal packing features in the presence of N–H?O[dbnd]C hydrogen bond?

Article abstract of DOI:10.1016/j.molstruc.2017.08.083

Intermolecular interactions involving organic fluorine have been the contemporary field of research in the area of organic solid state chemistry. While a group of researchers had refuted the importance of “organic fluorine” in guiding crystal structures, others have provided evidences for in favor of fluorine mediated interactions in the solid state. Many systematic studies have indicated that the “organic fluorine” is capable of offering weak hydrogen bonds through various supramolecular synthons, mostly in the absence of other stronger hydrogen bonds. Analysis of fluorine mediated interaction in the presence of strong hydrogen bonds has not been highlighted in detail. Hence a thorough structural investigation is needed to understand the role of “organic fluorine” in crystal engineering of small organic fluorinated molecules having the possibility of strong hydrogen bond formation in the solution and in the solid state. To fulfil this aim, we have synthesized a series of fluorinated amides using 3-methoxyphenylacetic acid and fluorinated anilines and studied their structural properties through single crystal and powder X-ray diffraction methods. Our results indicated that the “organic fluorine” plays a significant role in altering the packing characteristics of the molecule in building specific crystal lattices even in the presence of strong hydrogen bond.

Full text of DOI:10.1016/j.molstruc.2017.08.083

Accepted Manuscript
Can C-H⋯F-C hydrogen bonds alter crystal packing features in the presence of N-
H⋯O=C hydrogen bond?
Hare Ram Yadav, Angshuman Roy Choudhury
PII:
S0022-2860(17)31150-X
10.1016/j.molstruc.2017.08.083
MOLSTR 24221
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 18 April 2017
Revised Date: 18 August 2017
Accepted Date: 23 August 2017
Please cite this article as: H.R. Yadav, A.R. Choudhury, Can C-H⋯F-C hydrogen bonds alter crystal
packing features in the presence of N-H⋯O=C hydrogen bond?, Journal of Molecular Structure (2017),
doi: 10.1016/j.molstruc.2017.08.083.
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ACCEPTED MANUSCRIPT
Can C–H···F–C hydrogen bonds alter crystal packing features in the
presence of N–H···O=C hydrogen bond?
Hare Ram Yadav and Angshuman Roy Choudhury*
Department of Chemical Sciences, Indian Institute of Science Education and Research
(IISER) Mohali, S. A. S. Nagar Sector 81 Knowledge City, Mohali, Punjab. 140306. India
Abstract
Intermolecular interactions involving organic fluorine have been the contemporary field
of research in the area of organic solid state chemistry. While a group of researchers had
refuted the importance of “organic fluorine” in guiding crystal structures, others have
provided evidences for in favor of fluorine mediated interactions in the solid state. Many
systematic studies have indicated that the “organic fluorine” is capable of offering weak
hydrogen bonds through various supramolecular synthons, mostly in the absence of other
stronger hydrogen bonds. Analysis of fluorine mediated interaction in the presence of
strong hydrogen bonds has not been highlighted in detail. Hence a thorough structural
investigation is needed to understand the role of “organic fluorine” in crystal engineering
of small organic fluorinated molecules having the possibility of strong hydrogen bond
formation in the solution and in the solid state. To fulfil this aim, we have synthesized a
series of fluorinated amides using 3-methoxyphenylacetic acid and fluorinated anilines
and studied their structural properties through single crystal and powder X-ray diffraction
methods. Our results indicated that the “organic fluorine” plays a significant role in
altering the packing characteristics of the molecule in building specific crystal lattices
even in the presence of strong hydrogen bond.
Key words: “Organic fluorine”, weak interactions, structural diversity

ACCEPTED MANUSCRIPT
Introduction
Various supramolecular assemblies in gaseous [1], liquid [2] and solid [3] states of
mater are always governed by the non-covalent interactions between the atoms and
molecules. Molecular recognition through strong and weak forces in the solid state lay
the path for supramolecular chemistry and crystal engineering [4]. A careful control on
strong and weak intermolecular interactions allows us to form different molecular
assemblies in the solid state. Among the well-studied intermolecular forces, conventional
hydrogen bonding (X–H···Y, X,Y= F, O, N etc.) offers stabilization by 15-40 kcal/mole
and hence is considered to be the most important intermolecular force in building and
controlling the crystal structures of various covalent molecules [3, 5]. Other hydrogen
bonds (X–H···Y–C where X = O, N and Y = O, N, S) are also considered as significant in
crystal engineering as the stabilization energy associated with such intermolecular forces
falls in the range of 4-15 kcal/mole [3]. Weaker intermolecular forces having energy less
than 4 kcal/mole include C–H···X (X = O, N, S), X–H···π, (X = C, N, O, S) and π···π
interactions [3]. Intermolecular interactions involving halogens have also been recognized
to provide directional preferences in building organic supramolecular synthons in the
crystal lattice with the stabilization energy <5 kcal/mole [6].
Among the halogens, fluorinated organic molecules find wide applications in the
syntheses of drugs, pharmaceutical products, agrochemicals etc due to its unique
properties [7]. The structural chemistry aspects of fluorinated organic molecules have
been the theme of contemporary research. Since the C–F bond is stronger than a C–H
bond, majority of the fluorinated compounds are more resistant to metabolic degradation
and external affects (temperature) than its non-fluorinated analogue [8]. Our recent efforts
and reports from other groups indicate that the intermolecular interactions involving one
or more C–F groups in a small molecule offers significant stabilization to crystal packing
[9]. Although, the intermolecular interactions involving C–F bond in organic compounds
were historically described in the literature as ‘very weak’, ‘van der Waals’ or ‘not so
significantly short’ and hence were not categorized among the crystal engineering tools
for a long time [10], our results contradicts such belief. In late 90s and later, groups of
authors have demonstrated the importance of C–F bond in the solid state chemistry of
small organic molecules [11]. It was demonstrated that interactions involving a C–F

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group do occur frequently then was predicted earlier [11]. During the last decade it has
been demonstrated that fluorine generates different types of packing patterns via
C
−
H···F, C
bond donors (N
possible types of C
−
F···F, and C
H, O H etc) and acceptors (C=O) [12]. Thalladi et al. identified four
···F hydrogen bonded synthons (Figure 1) in 1998 [11a].
−F···π interactions especially in the absence of strong hydrogen
−
−
−H
F
H
H
F
H
H
F
F
I
II
F
H
H
F
III
F
H
H
F
H
F
H
F
IV
Figure 1: Types of known C−H···F hydrogen bonded synthons. Synthon I, Synthon II,
Synthon III and Synthon IV.
Most of the previously reported studies on such C–H···F–C hydrogen bonds have been
limited to a selection of compounds where potential strong hydrogen bond donors and
acceptors were absent [9a-d]. The role of C
bonding has been noted before [12] but the area needs better understanding and insights.
Chopra et al., [12a] and Nayak et al., [12b, c] reported crystal structures of a series of
benzanilides having halogen substitution at various positions (Figure 2).
−F group in the presence of strong hydrogen
,
,
Figure 2: System of benzanilide studied by Chopra et al. [12a], and Nayak et al. [12b, c]
Their structural analyses with the halogenated benzanilides indicated that although all
the crystal structures were highly stabilized by a strong N H···O=C hydrogen bond
−
(forming molecular chain), the packing characteristics were significantly different based
on the identity (F, Cl and Br) and position (ortho-, meta-, para-) of the halogen
substitution on the either rings. They have shown that with the change in the nature and
position of halogen substitution, several different structural features were generated
among the compounds studied by them. Due to the near planarity of all the molecules, the
scope for fluorine mediated interactions in the crystal structures were somewhat limited.

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Therefore, we wanted to induce better flexibility in the molecule and study the effects of
fluorine mediated interactions in a different series of molecules. In the current
manuscript, we intend to analyze the crystal structures of eighteen new phenylacetanilides
(Figure 3) containing a methoxy group in the phenyl ring originating from the
phenylacetic acid and one or two fluorine atoms in the phenyl ring originating from
aniline. This molecular framework allows for the torsional flexibility of the molecules due
to the incorporation of an additional –CH2– group in the system, thereby increasing the
possibility of occurrence of different fluorine mediated interactions.
X = mono-F or di-F
Figure 3: System of phenyl acetanilide studied
In these structures, the strong N
−
H···O=C hydrogen bond is expected to be the key
H···F, C H···O, and C H···π are
feature and the weaker intermolecular forces such as C
−
−
−
expected to play a significant role in altering the molecular conformation and thereby
resulting into structural diversity.
Experimental:
All the starting materials were purchased from Sigma-Aldrich and were used without
further purification. All the compounds (Scheme 1) were synthesized from their corresponding
aniline and 3-methoxyphenylacetic acid initially following the procedure reported by Nagarajan
et al. [13], and later, on experiencing poor yield of some of our target molecules we followed a
different synthetic procedure for better yield with the use of less hazardous chemicals [14]. 3-
methoxy-phenyl-acetic acid 1a (1.0 eqv), fluorine substituted aniline 1b (1.10 eqv), N-(3-
Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl) (1.10 eqv) and
hydroxybenzotriazole (HOBt) (0.50 eqv) were mixed in a round bottom flask and N-
methylpyrrolidin-2-one (NMP) solvent was added at room temperature (25 ˚C) under N2
environment. The reaction mixture was stirred at room temperature for 18 hours. After the
reaction was over, water and ethyl acetate were added and the mixture was stirred for 15 mins.

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The mixture was then allowed to settle in a separating funnel, and the lower aqueous phase was
removed and discarded. The organic phase was washed a few times with water and brine solution
to remove the unreacted water-soluble compounds and to achieve better separation of organic
and aqueous layers. Then the organic phase was collected over excess anhydrous sodium sulfate
to remove traces of moisture in the organic phase. Then the organic solvent was removed under
reduced pressure on a rotary evaporator to extract the solid target compound. The crude product
was purified by column chromatography using ethyl acetate/hexane mixture as the mobile phase.
All the pure compounds were characterized by 1H, 13C and 19F NMR (400 MHz, Bruker Biospin
Avance-III NMR spectrometer), FTIR (Perkin Elmer Spectrum 2) and the melting point of all the
compounds were determined by differential scanning calorimetry (DSC) (Perkin Elmer Diamond
8000 DSC). All the characterization details (NMR, IR, DSC and PXRD) are provided as
electronic supporting information (ESI).
Scheme 1
Powder X-ray Diffraction (PXRD) Analysis
PXRD patterns of all the pure compounds were recorded on a Rigaku Ultima IV
diffractometer using parallel beam geometry equipped with a Cu – Kα radiation, 2.5° Primary
and secondary solar slits, 0.5° divergence slit with 10 mm height limit slit, sample rotation stage
(120 rpm) attachment and DTex Ultra detector. The tube voltage and current applied were 40 kV
and 40 mA. The data were collected over an angle range 5 to 50° with a scanning speed of 2°
per minute with 0.02° step. The observed PXRD patterns have been compared (using
WINPLOTR [15]) with the simulated PXRD patterns generated from the crystal coordinates
using Mercury.

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Crystal Growth, Single Crystal Data Collection, Structure Solution and Refinement
Single crystals of desired size and quality were grown by slow evaporation by dissolving
the compound in different solvents like acetone, methanol, ethanol, ethyl acetate,
dichloromethane, acetonitrile, toluene or a mixture of solvents such as DCM/hexane,
chloroform/hexane, ethyl acetate/hexane, methanol/hexane and acetone/hexane etc.
Single crystal X-ray diffraction data (Table 1-2) were collected using a Rigaku
XtaLABmini X-ray diffractometer equipped with Mercury CCD detector with graphite
monochromatic Mo-Kα radiation (λ = 0.71073 Å) at 100.0(2) K using ω scans. The data were
reduced using Crystal Clear suite 2.0 [16] and the space group determination was done using
Olex2 [17]. The crystal structures were solved by using ShelXL [18] and were refined using
ShelXT [19] through Olex2 suite. All the hydrogen atoms were geometrically fixed and refined
using the riding model. Absorption correction was done by multi-scan method. Data collection,
crystal structure solution and refinement details for all the compounds are listed in the Table
1(a)-(b). All the packing and interaction diagrams have been generated using Mercury 3.5 [20].
Geometric calculations have been done using PARST [21] and PLATON [22].
Computational analysis
The structures of all the molecules were stabilized mostly by strong N−H O=C and
weak C−H F−C hydrogen bonds. Intermolecular C−H O hydrogen bonds generally involved
the proton connected to sp3 C atom of the methoxy group. As these C−H O hydrogen bonds are
considered very weak, their contribution in stabilizing the crystal structure is insignificant. The
stabilization energy offered by the N−H O=C and C−H F−C hydrogen bonds are calculated
using Gaussian 09 [23] package, MP2 [24] level of theory and 6-31++(d,p) basis set similar to an
earlier report [9d, e]. The single point energy of the dimer (without optimization) and the
monomer (without optimization) molecule were calculated using Gaussian09 and the
stabilization energy (SEg09) was computed as SEg09 = Edimer – 2 × Emonomer starting from the
experimentally observed geometry of the dimer and the monomer respectively in their respective
crystal structures. The Basis set superposition error (BSSE) was corrected by the counterpoise
method [25]. GaussView [26] was used to visualize the molecules during the energy
calculations.

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Table 1: Single crystal X-ray diffraction data of compounds 1c-1 to 1c-5
Identification code
CCDC Number
Formula
1c-1
1540707
1c-2
1c-3
1540710
1c-4
1c-5
1540712
C15H13F2NO2
277.26
1540709
1540711
C15H13F2NO2
277.26
C15H13F2NO2
277.26
C15H13F2NO2
277.26
C15H13F2NO2
277.26
Formula weight
Crystal system
Space group
a (Å)
Monoclinic
P21/c
Monoclinic
P21/c
Monoclinic
P21/c
Monoclinic
C2/c
Monoclinic
P21/c
11.6788(17)
4.8674(7)
27.251(4)
124.699(9)
10.9903(6)
4.6917(2)
28.1963(13)
118.451(3)
11.0509(16)
12.231(3)
9.4633(17)
96.740(7)
22.3996(16)
4.7464(4)
25.2796(16)
103.356(4)
5.8400(12)
26.820(5)
10.960(2)
131.45(3)
b (Å)
c (Å)
β (o)
V (Å3)
1273.6(3)
1278.30(11)
1270.2(4)
2615.0(3)
1286.7(5)
4
4
4
8
4
Z
ρcalc (g cm-3)
Temperature (K)
µ/ mm-1
1.446
1.441
1.450
1.409
1.431
100.0
0.116
100.0
0.115
100.0
0.116
100.0
0.113
100.0
0.114
2θmin,max (o)
3.636 to 50.04
576.0
3.92 to 58.26
576.0
6.316 to 54.976
3.312 to 56.564
3.038 to 49.8
F(000)
576.0
-14, 14; -13, 15;
-12 ,12
1152.0
-26, 29; -6, 6;
-30, 33
576.0
-6, 4; -31, 31;
-12, 12
-13 ,13; -5,4; -31, -15, 14; -5, 6; -38
hmin,max; k min,max; l
32
,38
;
min,max
8518
12235
8207
6649
5567
No. of observed
reflections
Rint
0.0201
2242
0.0539
3454
0.0319
2892
0.0272
3235
0.0486
2189
No. of unique
reflections
0.0366
0.1037
0.0484
0.1242
0.0424
0.1203
0.0447
0.1122
0.0491
0.1181
R1 [I > 2σ(I)]
wR2 (all data)
GooF
1.043
1.023
1.035
1.016
1.036
∆ρmax,min/eÅ-3
0.61, -0.28
0.27, -0.25
0.28, -0.26
0.31, -0.36
0.22, -0.29

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Table 2: Single crystal X-ray diffraction data of compounds 1c-6 to 1c-10*
Identification code
CCDC Number
Formula
1c-6
1540713
C15H13F2NO2
277.26
1c-7
1540714
C15H14FNO2
259.27
1c-9
1c-10
1540708
C15H15NO2
241.28
1540715
C15H14FNO2
259.27
Formula weight
Crystal system
Space group
a (Å)
Monoclinic
P21/c
Monoclinic
P21/c
Monoclinic
P21/c
Monoclinic
P21/c
10.989(2)
12.176(3)
9.5202(19)
97.740(12)
4.729(3)
11.406(5)
23.474(12)
93.85(2)
5.0169(14)
12.106(4)
20.553(9)
95.217(16)
9.5059(16)
10.8524(17)
24.154(4)
96.267(7)
b (Å)
c (Å)
β (o)
V (Å3)
1262.3(5)
1263.4(11)
1243.1(8)
2476.9(7)
4
4
4
8
Z
ρcalc (g cm-3)
Temperature (K)
µ/ mm-1
1.459
1.363
1.385
1.294
100.0
0.117
100.0
0.100
100.0
0.102
100.0
0.086
2θmin,max (o)
6.284 to 55.02
6.324 to 55.056
6.732 to 55.226
6.096 to 50.052
F(000)
576.0
-14, 14; -15, 15;
-12, 12
544.0
-4, 6; -14, 14;
-30, 30
544.0
-6, 6; -15, 15;
-26, 26
1024.0
-11, 10; -12, 12;
-28, 28
hmin,max; k min,max; l
;
min,max
13420
11536
8716
17289
No. of observed
reflections
Rint
0.0532
2905
0.0636
2889
0.0658
2833
0.0700
4332
No. of unique
reflections
0.0478
0.1239
0.0560
0.1537
0.0475
0.1213
0.0594
0.1505
R1 [I > 2σ(I)]
wR2 (all data)
GooF
1.091
1.056
0.986
1.110
∆ρmax,min/eÅ-3
0.30, -0.21
0.27, -0.23
0.30, -0.31
0.21, -0.25
*Crystals of 1c-8 could not be grown and hence structure determination was not possible.

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Results and discussions
All the compounds reported in this manuscript contains an amide group (‒CONH‒)
therefore all the crystal structures discussed in this manuscript exhibit the strong N–H···O=C
hydrogen-bonded chain as a common feature. All the compounds preferred to crystallize in
P21/c space group except one (1c-4) having different unit cell parameters and there were no
indication of isostructurality in terms of unit cell parameters among these compounds.
Structure of the compound 2-(3-methoxyphenyl)-N-(2,3-difluorophenyl)acetamide (1c-1):
In the structure of the compound 1c-1 (Table 1a and Figure 4a), the strong N–H···O=C
hydrogen bond is responsible for the formation of one-dimensional catameric chain along the
crystallographic b direction (Figure 4b, Table 3) with all the molecules aligned in parallel
(↑↑↑↑) orientation (Figure 4b). Although there are two fluorine atoms i.e. F1 and F2
corresponding to ortho- and para- positions but none of these fluorine atoms participated in the
C–H···F hydrogen bond with any of the available aromatic protons and hence there is no
significant contribution of fluorine in crystal packing. Two parallel molecular chains of strong
N–H···O=C hydrogen bonds are itself connected by C4–H4···O2 hydrogen bond (Figure 4c).
Carbonyl oxygen is also participate in the formation of dimer synthon via inversion center
symmetry by utilization of C15–H15···O1 hydrogen bond. The shortest F···F distance
(3.002(2)) observed is also beyond the sum of the van der Waals’ radii of the interacting F
atoms.
(a)
(b)
Figure 4: (a) ORTEP of 1 drawn with 50% ellipsoidal probability, (b) N1–H1···O1
Hydrogen bond in one-dimensional catameric chain along b-axis.

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(c)
(d)
Figure 4: (c) Two parallel N1–H1···O1 Hydrogen bond chain interconnected by C4–H4···O2
hydrogen bond. (d) A dimer synthon via inversion center symmetry by utilization of C15–
H15···O1 hydrogen bond.
Table 3: Intermolecular interactions in 1c-1
D–H···A/o
164
SEg09 (kcal/mol)
D–H···A/(Å)
N1–H1···O1
C4–H4···O2
C15–H15···O1
(D···H)/Å
1.030
D(D···A)/Å
2.976(2)
d(H···A)/Å
1.97
SYMMETRY
x, y - 1, z
-14.3
-5.4
3
1.080
3.374(3)
2.38
153
1 - x, y - ½, /2 - z
1.080
3.380(2)
2.60
129
- x, 1- y, 1 - z
-7.1
Structure of 2-(3-methoxyphenyl)-N-(2,4-difluorophenyl)acetamide (1c-2)
In the structure of the compound 1c-2 (Figure 5a) strong hydrogen N1–H1···O1 bond
propagates along the b axis with all the molecules aligned in parallel (↑↑↑↑) orientation
(Figure 5b, Table 4) as was seen in 1c-1. Two parallel N1–H1···O1 Hydrogen bond chain
itself interconnected by C4–H4···O2 hydrogen bond. Fluorine atoms were not involved in any
C–H···F hydrogen bond.
Table 4: Intermolecular interactions in 1c-2
SEg09 (kcal/mol)
D–H···A/(Å)
N1–H1···O1
C4–H4···O2
(D···H)/Å
1.030
D(D···A)/Å
2.806(2)
d(H···A)/Å
1.85
SYMMETRY
x, y - 1, z
D–H···A/o
154
-13.8
-5.8
1.080
3.510(3)
2.62
139
1 - x, ½ - y, 3/2 - z

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(a)
(b)
(c)
Figure 5: (a) ORTEP of 1c-2 drawn with 50% ellipsoidal probability, (b) Strong N1–
H1···O1 Hydrogen bond and C2–H2A···π interaction in one-dimensional catameric chain
along b-axis and bond both are parallel. (c) Two parallel N1–H1···O1 Hydrogen bond chain
interconnected by C4–H4···O2 hydrogen bond.
Structure of N-(2,5-dichlorophenyl)-3-methoxyphenylacetamide (1c-3)
Compound 1c-3 (Figure 6a) mainly displays three types of interactions have been found, N–
H···O, C-H···O and C–H···F hydrogen bonds. Strong N–H···O hydrogen bond is responsible
for the formation of one-dimensional infinite catameric chain with molecules arranged in anti-
parallel (↑↓↑↓↑↓) orientation along the crystallographic c direction (Figure 6b, Table 5).
(a)
(b)
Figure 6: (a) ORTEP of 1c-3 drawn with 50% ellipsoidal probability, (b) Strong N1–
H1···O1 Hydrogen bond generating one-dimensional alternate antiperiplanar infinite
catameric chain along c-axis.

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Ortho-fluorine (F1) of amine ring is found to act as a bifurcated acceptor. The hydrogen bond
involving C13–H13···F1 and C7–H7···F2 leads to the formation 2-dimentional net-like
structure (Figure 6c). Further, through C12–H12···F1 hydrogen bond, centrosymmetric dimers
have been identified. These dimers are once again connected to each other by C7–H7···F2
hydrogen bond forming a ribbon-like structure (Figure 6d).
(c)
(d)
Figure 6: (c) a 2-dimentional sheet-like structure (d) head to head
8-membered
supramolecular synthon in which aromatic C–H···F interactions are involved (a dimer form).
Table 5: Intermolecular interactions in 1c-3
D–H···A/o
SEg09 (kcal/mol)
D–H···A/(Å)
N1–H1···O1
(D···H)/Å
D(D···A)/Å
d(H···A)/Å
SYMMETRY
1.030
2.876(1)
1.87
166
-12.1
x, ½ -y , ½ +z
1.080
3.236(2)
2.32
142
C2–H2A···O1
1.080
1.080
1.080
3.294(2)
3.380(2)
3.602(2)
2.56
2.46
2.53
124
143
170
x, y -1, z
-1.3
-2.7
-2.8
C7–H7···F2
1-x, 1-y, -z+2
1-x, y+ ½, 3/2-z
C12–H12···F1
C13–H13···F1
Structure of 2-(3-methoxyphenyl)-N-(2,6-difluorophenyl)acetamide (1c-4)
The molecules of the compound 1c-4 (Figure 7a) are found to form catameric chain along the
b direction involving N1–H1···O1 hydrogen bond (Figure 7b, Table 6) in parallel (↑↑↑↑)
orientation. Weak C2–H2···π interactions (2.88 Å), are also observed here in this molecular
chain (Figure 7b).

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(a)
(b)
(c)
(d)
Figure 7: (a) ORTEP of 1c-4 drawn with 50% ellipsoidal probability, (b) Strong N1–
H1···O1 Hydrogen bond and aromatic C–H···π interactions both parallel generating one-
dimensional infinite catameric chain along b-axis. (c) Two different type of homo synthon via
inversion center by utilization of C–H···O hydrogen bond and creating a tap like structure. (d)
C12–H12···F1 hydrogen bond that generate 8-member non-planar supramolecular synthon.
Both ortho- hydrogens of the methoxyphenyl ring are individually involved in two different
C–H···O hydrogen bonds via inversion center. The carbonyl oxygen is the acceptor in one
hydrogen bond while the oxygen of the methoxy group in another is acting as the acceptor
thereby generating a ribbon-like structure (Figure 7c). The m-hydrogen (H12) of the aniline
ring forms a dimer through a very weak C–H···F hydrogen bond ( C12–H12···F1 = 125o)
involving F1, and that second fluorine (F2) does not participate in any type of interactions
(Figure 7d).
Table 6: Intermolecular interactions in 1c-4
D–H···A/o
167
SEg09 (kcal/mol)
D–H···A/(Å)
N1–H1···O1
C2–H2B···π
C8–H8···O1
C4–H4···O2
C12–H12···F1
(D···H)/Å
1.030
D(D···A)/Å d(H···A)/Å
SYMMETRY
x, 1+y, z
2.767(2)
3.499
1.75
2.92
2.58
2.56
2.65
-13.8
1.080
118
x, y -1, z
1.080
3.417(2)
3.598(2)
3.384(2)
134
½ -x, ½ -y, 1+z
1-x, 1-y, 1-z
1-x, y, 3/2-z
-6.7
-3.1
-2.4
1.080
160
1.080
125

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Structure of 2-(3-methoxyphenyl)-N-(3,4-difluorophenyl)acetamide (1c-5)
This compound 1c-5 (Figure 8a), unlike other amides discussed above, the carbonyl oxygen is
found to act as a bifurcated acceptor (Figure 8b, Table 7). In addition to the bifurcated
hydrogen bonds (N1–H7···O1 and C8–H8···O1), weak C7–H7···F1 hydrogen bonds are also
identified in the same synthon (Figure 8b). Herein the molecules are arranged in the opposite
directions (↑↓↑↓↑↓). A zig-zag molecular chains are formed by C14–H14···O2 hydrogen
bond offered by methoxy oxygen via c-glide symmetry (Figure 8c).
(a)
(b)
(c)
Figure 8: (a) ORTEP of 1c-5 drawn with 50% ellipsoidal probability, (b) Strong N1–H1···O1
Hydrogen bond along with weak C7–H7···F1 and C8–H8···O1 hydrogen bonds in one
dimensional catameric chain type structure. (c) A zig-zag molecular chain offered by methoxy
oxygen via c-glide symmetry.

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Table 7: Intermolecular interactions in 1c-5
D–H···A/o
152
SEg09 (kcal/mol)
D–H···A/(Å)
N1–H1···O1
C8–H8···O1
C7–H7···F1
C14–H14···O2
(D···H)/Å
1.030
D(D···A)/Å
2.828(3)
3.531(3)
3.624(3)
3.307(3)
d(H···A)/Å
1.88
SYMMETRY
x-1, 1/2-y, z-1/2
x-2, -y+1/2, z-1/2
1.080
2.58
147
-13.3
-2.9
1.080
2.68
145
1.080
2.34
148
Structure of 2-(3-methoxyphenyl)-N-(3,5-difluorophenyl)acetamide (1c-6)
Compound 1c-6 (Figure 9a) also has molecular chains involving N1–H1···O1, C2–H2A···O1
and C8–H8···F1 hydrogen bonds just as was seen in 1c-5 (Figure 9b, Table 8) though the unit
cell parameters are different for 1c-5 and 1c-6. The molecules in this chain are arranged in the
opposite directions (↑↓↑↓↑↓) like 1c-3 and 1c-4. Like the compound 1c-3, this molecule also
forms a symmetrical 8-membered dimer by the utilization of C15–H15···F2 hydrogen bonds
(Figure 9c). The F1 group also involved in the formation of molecular chain by C7–H7···F1
hydrogen bonds via translational symmetry along b-axis (Figure 9d).
(a)
(b)
(c)
Figure 9: (a) ORTEP of 1c-6 drawn with 50% ellipsoidal probability, (b): Strong N–H···O
hydrogen bond and weak C8–H8···F1 hydrogen bond involved in formation of one-
dimensional band like structure in crystal packing. (c) Inversion center related 8-member head
to head supramolecular homo synthon.

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Table 8: Intermolecular interactions in 1c-6
D–H···A/o
161
SEg09 (kcal/mol)
D–H···A/(Å)
N1–H1···O1
C2–H2A···O1
C8–H8···F1
C7–H7···F1
C15–H15···F2
(D···H)/Å
1.030
D(D···A)/Å
2.879(2)
3.282(2)
3.455(2)
3.358(2)
3.448(2)
d(H···A)/Å
1.89
SYMMETRY
1.080
2.39
139
x, ½ -y, ½ +z
-13.7
1.080
2.52
145
1.080
2.61
125
x, y-1, z
-1.3
-2.9
1.080
2.40
163
1-x, 1-y, 2-z
Figure 9: (d) A molecular chain by C7–H7···F1 hydrogen bonds via translational symmetry
along b-axis.
Structure of 2-(3-methoxyphenyl)-N-(2,-fluorophenyl)acetamide (1c-7)
This mono-fluorinated acetamide (1c-7) (Figure 10a) also displays strong N–H···O
hydrogen bond along the a axis forming an infinite chain with molecules packed in parallel
(↑↑↑) orientation via translational symmetry only (Figure 10b, Table 9).
(a)
(b)
Figure 10: (a) ORTEP of 1c-7 drawn with 50% ellipsoidal probability, (b) A symmetrical one-
dimensional linear chain of strong N1–H1···O1 hydrogen bond along a-axis.
Simultaneously with the strong hydrogen bond, 4 molecules are connected by weak C–H···O
hydrogen bonds and generate a tetramer in which methoxy oxygen behave as a bifurcated

ACCEPTED MANUSCRIPT
acceptor and this tetrameric unit propagates in a direction perpendicular to the strong hydrogen
bond i.e. in the b direction (Figure 10c). In addition, the ortho- fluorine and meta- hydrogen
participates in the formation of a centrosymmetric 8 membered dimer through C12–H12···F1
hydrogen bond (Figure 10d).
(c)
(d)
Figure 10: (c) A tetramer synthon unit held by bifurcated C–H···O hydrogen bond, (d) Inversion
center related 8-member head to head supramolecular homo synthon via C12–H12···F1
hydrogen bond.
Table 9: Intermolecular interactions in 1c-7
SEg09 (kcal/mol)
D–H···A/(Å)
N1–H1···O1
C13–H13···O2
C7–H7···O2
C12–H12···F1
(D···H)/Å
1.030
D(D···A)/Å
2.856(3)
3.585(3)
3.609(3)
3.393(3)
d(H···A)/Å
1.86
SYMMETRY
1-x, y, z
D–H···A/o
164
-14.0
-2.2
-4.1
-1.8
1.080
2.62
149
x, ½ -y, ½ +z
2-x, ½ +y, ½ -z
1-x, -y, 1-z
1.080
2.53
174
1.080
2.50
140
Structure of 2-(3-methoxyphenyl)-N-(4,-fluorophenyl)acetamide (1c-9)
Compound 1c-9 (Figure 11a) packs via strong N–H···O hydrogen bond propagating along a-axis
(Figure 11b, Table 10). Two molecules are found to form a head-to-tail dimer through C8–
H8···F1 hydrogen bond (Figure 11c). Since the fluorine behaves as a bifurcated acceptor here, it
also forms a zig-zag chain by C4–H4···F1 hydrogen bond by c-glide (Figure 11d).
(a)
(b)

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(c)
(d)
Figure 11: (a) ORTEP of 1c-9 drawn with 50% ellipsoidal probability, (b) A symmetrical one-
dimensional linear chain of strong N1–H1···O1 hydrogen bond along a-axis. (c) Inversion center
related dimer synthon through the C8–H8···F1 hydrogen bond (d) C4–H4···F1 hydrogen bond in
zig-zag chain.
Table 10: Intermolecular interactions in 1c-9
D–H···A/o
154
SEg09 (kcal/mol)
D–H···A/(Å)
N1–H1···O1
C12–H12···O1
C14–H14···O2
C4–H4···F1
(D···H)/Å
1.030
D(D···A)/Å
2.897(2)
3.531(2)
3.631(2)
3.367(2)
3.380(2)
d(H···A)/Å
1.94
SYMMETRY
1+x, y, z
-13.6
-4.5
-1.3
-1.4
-5.9
1.080
2.60
144
1-x, 1-y, 1-z
3
1.080
2.60
152
1+x, /2-y, ½ -z
3
1.080
2.29
175
x, /2-y, ½ +z
1.080
2.38
154
2-x, 1-y, 1-z
C8–H8···F1
Structure of 2-(3-methoxyphenyl)-N-phenylacetamide (1c-10):
The non-fluorinated compound 1c-10 (Figure 12a) has two molecules (A and B) in the
asymmetric unit and they differ in their conformation. The torsion angle between the –CONH−
group and the –NPh ring are 54o and 33o respectively. These two crystallographically
independent molecules are connected by strong N–H···O hydrogen bond and weak aromatic C–
H···π interactions (Figure 12b, Table 11). Interestingly, the two molecules of the asymmetric
unit pack in the lattice by ···A···B···A···B···A···B··· fashion through strong N–H···O
hydrogen bonds (Figure 12c). This is a unique feature, which was not observed in any of the
fluorinated molecules discussed before.

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Table 11: Intermolecular interactions in 1c-10
D–H···A/o
173
SEg09 (kcal/mol)
-14.5
D–H···A/(Å)
N1–H1···O3
N2–H2···O1
C6–H6···O1
C7–H7···O2
C13–H13···O2
C28–H28···O4
C22–H22···O4
C27–H27···O3
(D···H)/Å
1.030
1.030
1.080
1.080
1.080
1.080
1.080
1.080
D(D···A)/Å
2.855(3)
2.861(3)
3.473(3)
3.573(3)
3.430(3)
3.472(3)
3.467(3)
3.520(3)
d(H···A)/Å
1.83
SYMMETRY
x, y, z
1.88
158
x-1, y, z
-14.1
2.49
150
2-x, ½ +y, ½ -z
-4.4
2.50
170
2.48
146
x, ½ -y, ½ +z
x, ½ -y, ½ +z
1-x, ½ +y, ½ -z
1-x, 1-y, 1-z
-2.0
-0.4
-4.0
-6.7
2.47
154
2.40
168
2.59
143
(a)
(b)
(c)
(d)
(e)
Figure 12: (a) ORTEP of 1c-10 drawn with 40% ellipsoidal probability with atom numbering
scheme, (b) two molecules of the asymmetric unit with different conformations are connected
by strong hydrogen bond and weak C–H···π interactions, (c) weak hydrogen bonded dimer
involving C–H···O hydrogen bond bonds through carbonyl and methoxy groups, (d) C–H···O

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hydrogen bond bonded chain involving methoxy group, (e) C–H···O hydrogen bond bonded
motif through carbonyl and methoxy groups.
All the structures reported above indicate that strong N−H···O=C hydrogen bond
generally governs the crystal structures of these amides in cooperation with weaker C−H···F−C
and C−H···O hydrogen bonds and C−H···π(Cg) interactions. It is well-known in the literature
that the amide linkage can result into two types of hydrogen bonded synthons, namely dimer and
chain (Scheme 2).
Amide Dimer
Amide Chain
Scheme 2
A recent search in the database (CSD, 2017) revels that among the structures reported in
the latest version of CSD that there are 3742 hits having the dimer synthon and 7712 hits having
the chain synthon. The dimers are mostly formed in cases where the amide is a part of a ring or
having −CONHR moiety with R = H, −CH3, −C2H5 groups. The formation of chain is preferred
for molecules having two bulky groups attached to either side of the −CONH− group as is also
observed in the structures reported herein. From the crystal data tables (Table 1 and Table 2), it
is evident that the non-fluorinated analogue (1c-10) has the lowest density (1.295 g/cm3)
compared to the corresponding fluorinated analogues. The density of the difluorinated molecules
are in the range between 1.459 g/cm3 (max) and 1.409 g/cm3 (min), while that for the two mono-
fluorinated compounds are 1.385 g/cm3 and 1.363 g/cm3. Although the structure of 1c-10 is
stabilized by strong N−H···O=C hydrogen bond in combination with many weak C−H···O
hydrogen bonds, the corresponding fluorinated molecules pack better in the lattice thereby
resulting into higher density of the compounds. The most striking feature of these hydrogen
bonded structures reported in this manuscript is that the weaker C−H···F−C hydrogen bonds are
forcing the molecules to pack differently [↑↑↑↑ directions of molecules compared to ↑↓↑↓↑↓
direction of the molecules] in the lattice. Because of such alteration, the unit cell parameters of
these compounds are different though the space groups of all the structures (except one) were

ACCEPTED MANUSCRIPT
same (P21/c). It is interesting to observe that these compounds did not display polymorphism
although there were possibilities of different molecular arrangements keeping the strong
hydrogen bond unaltered. The molecular conformation of the compounds reported here are
significantly different (Table 12). The orientations of the aromatic rings (C3-C8 and C10-C15)
are significantly different in these 9 molecules thereby allowing the fluorine atoms to get
involved in different C−H···F−C hydrogen bonds.
Table 12: Torsion angle in (o) of the crystal structures
Compounds
Torsion Angle
C4-C3-C2-C1
-70
Torsion Angle
C3-C2-C1-O1
1
Torsion Angle
O1-C1-N1-C10
5
Torsion Angle
C11-C10-N1-C1
137
1c-1
1c-2
1c-3
1c-4
1c-5
1c-6
1c-7
1c-9
1c-10
-97
-74
-86
104
-74
98
-3
32
2
6
140
-157
57
-13
-69
26
-1
0
-28
25
4
-20
14
2
-125
-31
33
-113
103
-2
3
-25
In addition to C−H···F−C hydrogen bonds, many C−H···O hydrogen bonds involving
both C=O and –OCH3 groups have been observed in these structures. The stabilization energy
offered by C−H···O=C hydrogen bonds are higher than those offered by C−H···OCH3 hydrogen
bonds, which are comparable to those offered by C−H···F−C hydrogen bonds in general.
Supramolecular synthons involving 8 members (Scheme 2) forming a dimer through a pair of
C−H···F−C hydrogen bonds have been a common feature in these structures. These dimers have
been found to be interconnected to each other by another C−H···F−C hydrogen bonds just like
the known cases with strong hydrogen bonds involving carboxylic acid dimers. Therefore, it is
evident that “organic fluorine” is also capable of acting as hydrogen bond acceptor and can
behave in the same manner like other good hydrogen bond acceptors. It is noteworthy that the
PXRD patterns, simulated from the single crystal X-ray diffraction data using Mercury, were
found to match with the experimental PXRD pattern of the compound concerned, indicating that
the bulk phase and the single crystals studied were same. The comparison of the experimental
and simulated PXRD patterns are provided in the supporting information.

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Conclusions
The structural analysis of this series of fluorinated 2-(3-methoxyphenyl)-N-
phenylacetamide derivatives invokes that although the structures of all these compounds are
generated by strong hydrogen bonds, several weaker hydrogen bonds together are responsible for
altering the molecular packing in the lattice. Different weak C−H···F−C hydrogen bonds
immensely influences the crystal structures of these molecules and C−H···π(Cg) interactions
together. While strong hydrogen bonds are responsible for the formation of one dimensional
molecular chains, the weaker hydrogen bonds involving “organic fluorine” are seen to form
chains, dimers, tetramers etc. in the crystal lattice. It is also noted that the presence of several
weaker interactions has resulted into different unit cell dimensions for these molecules though
the unit cell volume remains similar. Therefore, it may be concluded that the influence of many
weak hydrogen bonds involving “organic fluorine”, which was earlier neglected by Glusker
[10a], Dunitz [10c,d], and Howard [10b], is highly significant in altering the crystalline
architecture even in the presence of other strong and weak hydrogen bonds.
Acknowledgements
The authors thank IISER Mohali for funding, infrastructural facility, all the instrumental
facilities including NMR, FTIR, XtaLABmini X-ray diffractometer, DSC and computational
facility etc. HRY Thanks IISER Mohali for research fellowship.
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Highlights for the manuscript entitled “Can C–H···F–C hydrogen bonds alter crystal
packing features in the presence of N–H···O=C hydrogen bond?”
•
•
•
•
•
Importance of fluorine mediated interactions in presence of strong hydrogen bond
Synthesis and characterization of fluorinated amides
Structural analysis using model molecular system
Computational analysis of the strong and weak hydrogen bonds
Crystal engineering using “organic fluorine”