ortho-Fluorobenzanilides and ortho-fluorothiobenzanilides: Molecular conformations and crystal packing

Article abstract of DOI:10.1016/j.jfluchem.2016.07.004

Series of 2-fluoro and 2,6-difluorobenzanilides and their thiobenzanilide analogs have been synthesized to investigate the influence of the fluorine atom on their crystal structures and self-assembly in the crystal lattice. The X-ray analysis of the singl

Full text of DOI:10.1016/j.jfluchem.2016.07.004

Accepted Manuscript
Title: ortho-Fluorobenzanilides and
ortho-fluorothiobenzanilides: molecular conformations and
crystal packing
Author: Teresa Olszewska Jarosław Chojnacki Barbara
Wicher Maria J. Milewska
PII:
S0022-1139(16)30187-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.07.004
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Received date:
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28-4-2016
13-7-2016
15-7-2016
Please cite this article as: Teresa Olszewska, Jarosław Chojnacki, Barbara
Wicher, Maria J.Milewska, ortho-Fluorobenzanilides and ortho-fluorothiobenzanilides:
molecular conformations and crystal packing, Journal of Fluorine Chemistry
http://dx.doi.org/10.1016/j.jfluchem.2016.07.004
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ortho-Fluorobenzanilides and ortho-fluorothiobenzanilides: molecular
conformations and crystal packing
Teresa Olszewska,a* Jarosław Chojnacki,b Barbara Wicher,c Maria J. Milewskaa
aDepartment of Organic Chemistry, Gdańsk University of Technology, 80-233 Gdańsk,
Poland
bDepartment of Inorganic Chemistry, Gdańsk University of Technology, 80-233 Gdańsk,
Poland
cDepartment of Chemical Technology of Drugs, Poznań University of Medical Sciences,
60-780 Poznań, Poland
*Fax: +48 58 3472694; Tel: +48 58 3471425; E-mail address: terolsze@pg.gda.pl
Graphical abstract
X = H or F
X
X
O
N
S
N
LR
toluene
F H
F H
R
R
Highlights
.
•
•
•
Role of ortho fluorine substituent in the crystal structures of o-fluorobenzanilides.
Synthesis of two new 2,6-difluoro(N-phenyl)thiobenzanilides was performed.
Weak CArFHCAr or CArFFCAr interactions are observed in the molecular self-
assembly in the crystals lattices.

ABSTRACT
Series of 2-fluoro and 2,6-difluoro(N-phenyl)benzanilides and their thiobenzanilide analogs
have been synthesized to investigate the influence of the fluorine atom on their crystal
structures and self-assembly in the crystal lattice. The X-ray analysis of the single crystal
revealed that the synthesized molecules adopt a geometry being deflected from planarity.
The deflection was investigated by analysis of dihedral angles between mean planes of
benzoyl, amide and aniline residues. Molecular conformation depends mainly on strong N–
H···O bonds, although operation of N–H···F hydrogen bonding was observed in one case.
Crystal packing is controlled mainly by interactions of the C–H···O type, also by –
stacking and in one difluorosubstituted case by operation of weak CAr–F...F–CAr halogen
bonding.
Fluorine substitution in ortho position in benzoyl subunit of benzanilides and thiobenzanilides is not
without significance of their molecular conformations and crystal packing.
Keywords: o‐fluorobenzanilides, o‐fluorothiobenzanilides, fluorinated benzanilides, crystal
structures, self‐assembly.

1. Introduction
Secondary amide linkage [1] RC(O)HNR1, as a key element of polypeptide chains, is the
fundamental structural unit in living organisms and one of the most important functional
group in contemporary organic chemistry [2] present in many natural products, polymers, and
pharmaceuticals [3]. Due to the ability to form highly directional hydrogen bonds, the amide
group is also an extremely useful building block in supramolecular chemistry and crystal
engineering [4].
The detailed structural parameters of the secondary amide linkage RC(O)HNR1 such as CO
and CN bonds length and orders, or planarity of the amide unit are determined by the size and
electron-releasing or electron-withdrawing character of the substituents R and R1. Restricted
rotation about C–N bond in amide group results in the existence of the cis-trans
configurational isomers. The trans isomer is generally more stable over the cis one [5] and
demonstrates preferences to form intermolecular hydrogen bonding patterns (chain or
polymeric structures), whereas the other one tends to create dimers.
Benzanilides with two aromatic substituents constitute a special group of amides, which due
to the wide range of biological activities have been extensively studied both theoretically and
experimentally [6]. In particular, their fluorinated derivatives have gained much attention as
drugs intermediates, potential drug candidates [7a-e], herbicides [7f], and useful model for
observation of intra- and intermolecular interactions associated with the presence of fluorine
atom and strong hydrogen bonds in crystal lattices [8].
It is known that the molecule of benzanilide having two unsubstituted phenyl rings R=R1=Ph,
in crystal lattice assumes the conformation in which the central C–C(O)–N(H)–C fragment of
benzanilide molecule is essentially planar, with the phenyl rings twisted about 30 degrees
from this plane in opposite directions [9]. Additionally, the results of DFT calculations

indicate that the non-planar trans conformer is the most stable structure for benzanilide
molecule [10].
Introduction of an ortho substituent at either C–phenyl or N–phenyl ring in benzanilide, in
close proximity to the amide bonding, should strongly affect molecular conformation of the
molecule. Moreover, through interaction with the amide unit they could also affect ability of
the molecule to form hydrogen bonds.
2. Results and discussion
An analysis of the Cambridge Structural Database for molecular geometry of benzanilides
having ortho substituent on either of the C–phenyl or N–phenyl ring resulted in 316 hits. The
search was restricted to the compounds neither involved in metal complexes structures nor in
cyclic di- or triantranilides. Examination of the selected structures brings out a few general
conformational features. First of all, amide bond C–C(O)–N(H)–C linking the two phenyl
rings is essentially planar, with CO–NH torsion angle of 180 deg. apart from the cyclic
molecules the torsion is close to zero (see ESI Fig. 1S).
In order to examine intramolecular hydrogen bond interactions we defined three planes: R1,
R2 and R3. R1 is the mean least squares plane defined by the six carbon atoms of the benzoyl
ring, R2 is the mean plane of amide residue, defined by C–N(CO)–C atoms and R3 is defined
by the six atoms of the anilide ring. Since strong hydrogen bonding requires coplanarity of
residues bearing donor NH and acceptor group, dihedral angles between R2 and R1 or R3 can
be used to indicate the strengths of intramolecular hydrogen bond. Low values of ANG1=
(R1, R2) or ANG2 = (R2, R3) (see ESI Fig. 2S) can be interpreted as result of strong
bonding to an acceptor attached to the benzoyl or anilide ring, respectively.
Furthermore, the studied molecules tend to have their phenyl rings coplanar when both of the
ortho substituents are halogens (not able to participate in hydrogen bond formation). In such

cases chains of intermolecular N–H···O interactions define the crystal packing and molecular
conformation. The presence of substituent (-NH2, -COOH, -OH) capable to form
intermolecular hydrogen bond with amide group lead to the conformation in which the amide
bond and the C–phenyl or N–phenyl ring bearing the ortho substituent are coplanar and the
remaining phenyl ring is out of this plane.
To the best of our knowledge, no systematic studies were carried out to evaluate the influence
of substituents in ortho position on the central amide moiety in benzanilide molecule and
subsequently the changes in its molecular conformation and crystal packing. In this context
we have focused our attention on 2-fluoro-N-phenylbenzamide (I) with defined crystal
structure and have decided to investigate the influence of the ortho substituent on molecular
conformation
of
ortho-fluoro(N-phenyl)benzamides
1-2
and
ortho-fluoro(N-
phenyl)thiobenzamides 3 analogs, including 2,6-difluoro substitution in benzamide rings.
Fluorine atom present in ortho position in our base structure of 2-fluoro-N-phenylbenzamide
(I) is similar in size to hydrogen, however it has a different chemical nature [11]. Due to the
high electronegativity and low polarizability [11a] its presence in close proximity to amide
unit alters molecular conformation and crystal packing of molecule (I) comparing to
benzanilide. As reported by Chopra and Row, the structure of 2-fluoro-N-phenylbenzamide
(I) lacking additional functional groups, assumed in crystal a non-planar conformation
stabilized by strong N–H···F hydrogen bond (NH···F distance: 2.16 Å) and C–H···O=C
hydrogen bonds [12]. It is worth noting that the N–H···F hydrogen bonds are not common
interactions in crystal lattice, as organic fluorine is a weak hydrogen bond acceptor in contrast
to fluorine ion which is a very strong proton acceptor [13]. The molecules of compound (I)
are held together by an intermolecular N–H···O hydrogen bonds and weak C–H···F and C–
H··· intermolecular interactions generating a ‘‘molecular staircase”.

Thus, introduction of the second fluorine atom at ortho position in benzoyl ring in molecules
2a-3b should lead to considerable changes in their conformations, particularly in terms of the
arrangement of amide group relative to the phenyl rings.
To assure crystallinity of designed molecules as well as the formation of highly favorable
intramolecular bonding, the -NO2 or -COOCH3 group was incorporated into (I). Both of them
being in close proximity of amide unit should prevent formation of intermolecular hydrogen
bonding through blocking access to -NH- of the amide group and thus facilitating the
observation of conformational effects associated with presence of organic fluorine atom(s) in
molecules 1a-3b.
The sequence of reactions leading to the formation of aromatic amides 1a-2b and
thionoamides 3a,b is outlined in Scheme 1. Commercially available 2-nitroaniline 4a and
methyl 2-aminobenzoate 4b were used as substrates that were treated with acid chloride 5a or
5b in dichloromethane in the presence of triethylamine to give amides 1a,b or 2a,b,
respectively. Resulting compounds 2a,b were converted to thionoamide 3a,b with the
Lawesson’s reagents [14] in boiling toluene. Crystals of compounds suitable for X-ray
analysis were grown from toluene/hexane mixture by slow evaporation.
We expected that introduction of electronegative substituent to the basic structure (I), which
is better hydrogen acceptor comparing to the covalently bound fluorine atom, should lead to
formation of intramolecular hydrogen bonds between an oxygen atom from the substituted
group and the amide NH group.
1
The H NMR spectra of compounds 1a-3b taken in CDCl3 confirmed the existence of
intramolecular H-bonding in solution. Its presence is manifested by the chemical shift of the
amide proton that appears in the range of 11.83 (1b) to 10.89 (2a) ppm and is significantly
shifted downfield in comparison to the amide proton of N-phenylbenzamide, that cannot form
intramolecular H-bonding and shows up between 7.91-7.88 ppm [15]. The signal of the amide

proton NH in molecules 1a-3b is also downfield shifted in respect to 2-fluoro-N-
phenylbenzamide (NH at 8.56-8.31 ppm) in structure of which only weak intramolecular
CArFHN(CO) bonding was reported [16]. Moreover, the signals are in a good agreement
with the amide proton shift of N-(2-nitrophenyl)benzanilide 11.37 ppm [17] or methyl-2-
(benzamido)benzoate 12.07 ppm [15], in which structures strong intramolecular H-bonding
are observed.
Table 1 lists the relevant crystallographic data for all synthesized compounds 1a-3b.
In the crystal structures of all ortho-fluorosubstituted compounds 1a-3b, formation of a strong
six-membered intramolecular hydrogen bond, between the amide NH group and the nitro
group N−H···O2N in molecules 1a-3a or the COOCH3 group N−H···OCCOCH3 in molecules
1b-3b is observed. All they show the same graph set motif S(6). Additionally, the bifurcated
hydrogen bonding pattern involving fluorine atom as the additional acceptor is present in 1a.
Geometrical parameters of selected intra- and intermolecular interactions for all investigated
compounds are listed in Table 2 and Table 3. In each of the compounds 1a-3a, hydrogen
bonds motifs are the main factors responsible for stabilization of molecule conformation as
well as for inhibition of the intermolecular hydrogen bonding formation in the crystal lattices.
It affects also the trans amide group. Owing to the steric effect of the ortho substitution, the
nitro groups attached to C2 of aniline subunits are not co-planar with the benzene ring. The
dihedral angles (O2−N2−C2−C1 in 1a, 2a or O1−N2−C2−C1 in 3a) are equal to -22.04° in
compound 2a, -29.05° in 3a and -21.17° in 1a, respectively. Similar behavior is observed for
COOCH3 groups, attached to C2, in molecules 1b-3b. However, the dihedral angles between
the substituent’s mean plane and the aromatic ring plane are much smaller:

(O2−C14−C2−C1) equals 4.41° in compound 1b, (O2−C14−C2−C1) -7.78° in 2b, and
(O1−C14−C2−C1) -7.44° in 3b.
Compound 1a crystallizes in the monoclinic system in the space group P21/n with four
molecules in the unit cell. The crystal structure revealed a well-defined coplanar orientation of
both phenyl rings of the molecule (Table 3) with the amide unit twisted by dihedral angle of
ca 15°. An additional intramolecular N1−H1···F1 hydrogen bond, with H···F separation of
2.04 (2) Å can be observed. The packing motif in the crystal structure comprises of an infinite
stack of alternating molecules (Fig. 1.) which are related by the inversion centers.
In the stack, adjacent phenyl rings, fluoro- and nitro- substituted, contact face-to-face with the
centroids separation of 3.624 and 3.706 Å. The electrostatic attraction of the aromatic rings is
enhanced vertically by amide groups interactions which are oriented in the opposite direction
in the alternating molecules in columns with the contact distances (N1H1···O1=C7) of 3.49
and 4.02Å alternately. The packing motif is similar to that found in some arene-
perfluoroarene complexes showing a stacked structure with the alternate sequence of
molecules and can be attributed to CAr−H···O2N−CAr and CAr−H···O=C (C10−H10···O2−N2
and C5−H5···O1=C7) interactions between neighboring rings in layer. Due to the numerous
weak interactions between molecules in neighboring columns, they are assembled into regular
slipped stacks.
Compound 1b (Fig. 2.), bearing the methoxycarbonyl functionality at ortho position of anilide
aromatic subunit which is, similarly to NO2, an electron withdrawing group, crystallizes in the
P1space group. In contrast to compound 1a, structure of which is almost planar (with the
dihedral angle of 2.41º) two aromatic subunits in molecule 1b are twisted by 49.47° (dihedral
angle between mean planes of aromatic rings), see Table 3. Stacking interactions between
fluorinated phenyl rings (centroid···centroid distance 3.767 Å), supported with C–H···O

hydrogen bonds formed between phenyl rings and carbonyl O atoms of COOCH3 groups, join
molecules into centrosymmetric dimmers. In the crystal structure those dimmers are arranged
into stacks along a axis, but fluorinated phenyl rings within columns do not overlap, only
theirs F atoms are located directly above (or below) of the center of the adjacent dimmers
(centroid···F distance 3.368 Å).
Both of the structures 1a,b are similar to those of 2-(2-fluorobenzylamino)benzoic acid in
which the NH donor group, located in a sterically hindered position, does not participate in
any intermolecular hydrogen-bonding interactions [18].
Introduction of the second fluorine atom in the ortho position in compounds 2a,b does not
considerably enlarge the molecular volume (see Table 1) due to the similarity in van der
Waals radii between H and F. On the other hand, this kind of modification changes
significantly the charge distribution in the molecules as well as the attractive and repulsive
forces between adjacent aromatic subunits. It is noteworthy that due to the presence of a
second fluorine atom in ortho position of benzoyl subunits in 2a,b the coplanar assemble of
amide group and benzoyl ring is hampered (Table 3, second column). Negative charge on the
fluorine atom disfavors the approach of the carbonyl oxygen atom to the plane formed by 2,6-
difluoro substituted benzoyl ring. Dihedral angles between mean planes defined by aromatic
subunits in molecules 2a,b are 31.63° and 82. 06°, respectively (Table 3).
The molecules of 2a (Fig. 3.) crystallize in the orthorhombic non-centrosymmetric space
group Pca21 with Z = 4, having an intramolecular N1−H1···O2 hydrogen bond which causes
coplanar orientation of nitrosubstitued ring and N–H amide group. As in 1a, in 2a columns

formed through stacking interactions of both benzanilide phenyl rings are observed. However,
in 1a the nitro-substituted rings interact with fluoro-substituted rings, while in 2a nitro-
substituted rings interact with nitro-substituted rings and difluoro substituted rings with other
fluorinated rings. Molecules in those columns are related by translation along b axis (centroid
···centroid distance 3.72 Å). Neighboring 1D motifs are connected via weak C–H···O
hydrogen bonds (Table 2).
P1
The inspection of the crystal structure of compound 2b (triclinic, space group
) reveals
again stacks of fluorinated phenyl rings, along the b axis, in antiparallel positions, separated
by local symmetry centers. Moreover, short contacts C5−H5···O1 form links between the
molecules from the stacks held by − interactions (Fig. 4.). Such chains are further
supported by weak C9−F1···F2 interactions between neighboring aromatic subunits. In
addition, homo-halogen F1···F2 directional contacts (letter L arrangement of atoms or Type II,
according to geometrical classification of halogen···halogen interactions) enhanced the
stability of packing.The double bond in thiocarbonyl group is longer than that in the carbonyl
group due to the larger size of sulfur atom, its higher polarizability and lower
electronegativity. So that it was expected that introduction of sulfur atom in lieu of oxygen in
thiobenzanilides 3a,b that is localized between two ortho fluorine atoms in space will enhance
weak interactions related with the presence of fluorine atoms in their crystal lattices.
Thiobenzanilides 3a,b have been synthesized for the first time.Both 3a and 3b crystallized in
the monoclinic system in space-group type No. 14. Structure 3a was solved and refined in
P21/c space group while symmetry of 3b was analyzed using different setting, i.e. P21/n.
Packing in both structures are dominated by − stacking interactions. In 3a difluorinated
rings C8−C13 stack run in direction parallel to the c axis Fig. 5, with separation between
centroids of 3.857(2) Å, while nitro-substituted rings C1−C6 have their centroids separated

by 3.916(2) Å. Either of the interacting rings in 3a are related by glide planes c. Interestingly,
2,6-difluorobenzene rings are not antiparallel, but are rotated ca 120º to one another. Also the
positions of nitro substituents in interacting rings form an angle smaller than 180 degree. On
the other hand, the dihedral angle between the mean planes of the two rings, defined by
carbon atoms, is small (12.39º) indicating they are almost parallel.
Packing in structure 3b is mainly dictated by - stacking interactions of 2,6-difluorinated
rings related by the symmetry center with distance of centroids of 3.7169(15) Å (naturally
strictly parallel) Fig. 6. Other rings have their centroids distant more than 5.2 Å, so those
interactions can be neglected. Such antiparallel position ensures the resultant electric dipole
moments of both rings are in the energetically preferred configuration. Since stacking of the
other rings is not operating the two kinds of rings are almost mutually perpendicular – the
dihedral angle between mean planes is equal to 80.99º.
It is observed that thioamide bonds C(S)−NH have a partial double bond character in both
structures 3a and 3b. Moreover, the geometric parameters such as bond lengths and bond
angles determined for the central thioamide group in ortho-fluoro(N-phenyl)thiobenzamides
3a,b remain in a good agreement with the values reported by Saeed et al. [19] for fluoro-
substituted thiourea derivatives containing the thioamide moiety.
To sum up, crystallographic investigation of benzanilides 1a-3b revealed that
intramolecular hydrogen bonding between amide hydrogen NH and oxygen of -NO2 or
carbonyl oxygen of -COOCH3 group in ortho position of anilide subunits are the main factors
responsible for molecular conformation of investigated structures. They exist in both solid
state as well as in the solution that was confirmed by the 1H NMR spectroscopy.
Apart from compound 1a in which three centered, bifurcated hydrogen bonding pattern
CArFHN(CO)O2N rigidified the structure, molecules 1b-3a,b adopt geometry being

more or less disturbed from planarity which is related with the presence of fluorine atom(s) in
ortho position of benzoyl ring. Theirs close proximity to amide/thioamide group results in
deflection out of the benzoyl ring plane the amide/thioamide group due to the weak
interaction CArFHN(CO) or/and mutual repulsive forces between the CArF and carbonyl
oxygen C=O (or C=S) dipoles. The small deviation of the amide group from the benzoyl ring
plane was found in crystal structure of compound 1b whereas two fluorine atoms in ortho
position of benzanilide/thiobenzanilide framework in molecules 2-3a,b enhanced the
deviation of the amide/thioamide group effect.
Intermolecular − stacking together with weak hydrogen bonds are mainly responsible for
the molecular self-assembly in the crystal structure; NO2···H−CAr, CAr−H···O=C in the
compounds 1a-3a, CO2CH3(C=O)···H−C, CAr−H···O=C(CO2CH3) in 1b and
CAr−H···O=C(CONH) in 2b. They are generating corrugated layers or infinite molecular
chains which are main building blocks in the discussed crystals. Stability of crystal packing in
compounds 2a,b is enhanced through weak CArFHCAr or CArFFCAr interactions,
respectively. In compound 3b − stacking and weak CArFHCAr interactions dominate in
the molecular self-assembly in the crystal.
3. Conclusion
In conclusion, strong hydrogen bondings related to the presence of -NO2 or -COOCH3 groups
play the major role in the adopted molecular conformations of the studied ortho substituted
fluorobenzanilides and their thiobenzanilide analogs as well as their self-assembly. However,
week interactions CAr–F...F–CAr, CArFHCAr or NHFCAr involving fluorine atom(s)
are still noticeable in stabilizing their conformations and formation of supramolecular
structures. Due to the electronic effects of the orto-substituted phenyl rings and the nature of
the amide or thioamide central linkage the synthesized molecules adopt a geometry being

deflected from planarity. The presence of sulfur atom in the central thioamide linkage of
ortho-fluoro(N-phenyl)thiobenzamides decreases their ability of formation intermolecular
hydrogen bonds and therefore lead to crystal packing controlled mainly by week – stacking
type interactions.
4. Experimental
All solvents and reagents were used as obtained from commercial source. 1H NMR,13C NMR
and 19F NMR spectra were obtained at 500, 125 and 470 MHz (Varian Unity Plus),
respectively, and the deuterated solvents were used as internal lock. Melting points were
determined on a melting point apparatus equipped with thermometer and were uncorrected.
Column chromatography was carried out in silica gel 0.040-0.063 mm. The mass spectra
analyses were carried out using the Aqilent Technologies 6540 UHD Accurate – Mass Q-TOF
LC/MS mass spectrometer.
4.1 Fluorobenzanilide (1, 2) – general procedure
To a solution of o-substituted aniline (2.7 mmol) in dichloromethane (10 mL), fluorobenzoyl
chloride (2.5 mmol) and triethylamine (0.37 mL, 2.7 mmol) were added and the mixture was
kept at room temperature overnight. The reaction mixture was washed with water, dilute
hydrochloric acid, and saturated aqueous NaHCO3. The organic layer was dried over MgSO4
and then evaporated at reduced pressure. The resulting solid was recrystallized to obtain the
product.
4.1.1 2-Fluoro-N-(2-nitrophenyl)benzamide (1a)
1
Compound 1a was obtained as ecru crystals 600 mg (92 %); mp 117-118 ºC (EtOH); H
NMR (DMSO-d6) : 10.89 (s, 1H, NH); 8.18 (dd, J=1.1 and 8.2 Hz, 1H); 7.93 (d, J=7.9 Hz,

1H); 7.79 (dt, J=1.4 and 7.7 Hz, 1H); 7.70 (dt, J=1.4 and 7.7 Hz, 1H); 7.50 (m, 3H); 13C NMR
(DMSO-d6) : 163.1; 160.1 (d, J=251.0 Hz); 142.5; 135.1; 134.5 (d, J=8.9 Hz); 132.0; 131.2;
126.2; 125.9; 125.8; 125.6; 123.3 (d, J=13.0 Hz); 117.2 (d, J=22.0 Hz); 19F NMR (DMSO-d6)
: -113.84; MS (ESI) calcd m/z for C13H9FN2O3 260.0597; found m/z 261.0601 [M+1].
4.1.2 Methyl 2-(2-Fluorobenzamido)benzoate (1b)
Crude product 1b was purified by chromatography on silica gel with chloroform as an eluent
and recrystallized from toluene–hexane. Compound 1b was obtained as white crystals 510 mg
(75%); mp 83-84ºC; 1H NMR (DMSO-d6) : 11.49 (d, J=5.5 Hz, 1H, NH); 8.56 (d, J= 8.4 Hz,
1H); 7.96 (d, J=7.5 Hz, 1H); 7.90 (dt, J=1.5 and 7.7 Hz, 1H); 7.65 (m, 2H); 7.39 (m, 2H);
13
7.23 (t, J=7.5 Hz, 1H); 3.85 (s, 3H, CH3O); C NMR (DMSO-d6) : 168.2; 162.4; 160.0 (d,
J=249.0 Hz); 140.4; 134.9; 134.7 (d, J=9.0 Hz); 131.5; 131.4; 125.8 (d, J=4.0 Hz); 124.3;
19
123.3 (d, J=12.0 Hz); 121.8; 117.8; 117.2 (d, J=23.0 Hz); 53.2; F NMR (DMSO-d6) : -
113.34; MS (ESI) calcd m/z for C15H12FNO3 273.0801; found m/z 272.0805 [M+1].
4.1.3 2,6-Difluoro-N-(2-nitrophenyl)benzamide (2a)
1
Compound 2a was obtained as white crystals 675 mg (97%); mp 146-147ºC (EtOH); H
NMR (DMSO-d6) : 11.15 (s, 1H, NH); 8.00 (dd, J=1.1 and 8.2 Hz, 1H); 7.75 (t, J=7.4 Hz,
1H); 7.61 (m, 2H); 7.46 (dt, J=1.1 and 7.7 Hz, 1H); 7.25 (t, J=8.1 Hz, 2H); 13C NMR
(DMSO-d6) : 159.4; 159.7 (dd, J=7.0 and 250.0 Hz); 144.0; 134.7; 133.4 (t, J=10.0 Hz);
19
130.4; 127.1; 126.6; 125.7; 114.9; 112.9 (dd, J=4.5 and 25.0 Hz); F NMR (DMSO-d6) : -
113.61 (t, J=7.3 Hz); MS (ESI) calcd m/z for C13H8F2N2O3 278.0503; found m/z 279.0501
[M+1].
4.1.4 Methyl 2-(2,6-difluorobenzamido)benzoate (2b)

1
Compound 2b was obtained as white crystals 640 mg (88%); mp 129-130ºC (toluene); H
NMR (DMSO-d6) : 11.20 (s, 1H, NH); 8.18 (d, J=8.2 Hz, 1H); 7.91 (d, J=7.7 Hz, 1H); 7.62
13
(t, J=7.8 Hz, 1H); 7.62 (m, 1H); 7.28 (m, 3H); 3.80 (s, 3H, CH3O); C NMR (DMSO-d6) :
168.1; 159.6 (dd, J=7.0 and 250.0 Hz); 158.9; 138.6; 134.5; 133.5 (t, J=10.0 Hz); 131.3;
19
125.3; 122.6; 120.5; 115.3; 113.0 (dd, J=4.0 and 20.0 Hz); 53.1; F NMR (DMSO-d6) : -
113.84 (t, J=7.2 Hz); MS (ESI) calcd m/z for C15H11F2NO3 291.0707; found m/z 292.0705
[M+1].
4.2 Fluorothiobenzanilide (3) – general procedure
To the solution of benzamide 2 (1.8 mmol) in toluene (10 ml) was added the Lawesson’s
reagents (0.9 mmol) and the reaction mixture was heated to maintain a gentle reflux for 40 h.
Then the reaction mixture was allowed to cooled to room temperature and the solvent was
evaporated in vacuo. The residue was treated with methanol (10 ml) and immediately a solid
precipitated which was filtered off. The residue was concentrated and purified by
chromatography on a silica gel column eluted with 1:9 (v/v) ethyl acetate in petroleum ether
to give the product 3.
4.2.1 2,6-Difluoro-N-(2-nitrophenyl)thiobenzamide (3a)
Compound 3a was obtained as yellow orange solid 320 mg (60 %); mp 101-105ºC; 1H NMR
(DMSO-d6) : 12.58 (s, 1H, NH); 8.10 (dd, J=1.0 and 8.3 Hz, 1H); 7.85 (t, J=7.8 Hz, 1H);
13
7.64 (m, 2H); 7.46 (m, 1H); 7.22 (t, J=7.8 Hz, 2H); C NMR (DMSO-d6) : 188.8; 159.1;
157.1 (d, J=6.0 Hz); 145.9; 135.2; 132.1; 131.8 (t, J=10.0 Hz); 129.8 (d, J=2.0 Hz); 125.9;
112.7 (d, J=24.5 Hz); 19F NMR (DMSO-d6) : -115.03 (t, J=6.6 Hz); MS (ESI) calcd m/z for
C13H8F2N2O2S 294.0275; found m/z 295.02698 [M+1].

4.2.2 Methyl 2-(2,6-difluorothiobenzamido)benzoate (3b)
1
Compound 3b was obtained as yellow solid 126 mg (12 %); mp 117-120ºC; H NMR
(DMSO-d6) : 12.37 (s, 1H, NH); 7.92 (dd, J=1.0 and 8.0 Hz, 1H); 7.70 (m, 2H); 7.49 (m,
2H); 7.21 (t, J=7.4 Hz, 2H); 3.78 (s, 3H, CH3O); 13C NMR (DMSO-d6) : 187.5; 166.6; 159.0
(d, J=6.2 Hz); 157.0 (d, J=6.5 Hz); 138.3; 133.7; 131.4 (t, J=10.0 Hz); 128.4; 128.1; 127.5;
112.7 (dd, J=4.0 and 20.0 Hz); 53.1; 19F NMR (DMSO-d6) : -115.48 (t, J=7.0 Hz); MS (ESI)
calcd m/z for C15H11F2NO2S 307.0479; found m/z 308.04705 [M+1].
4.3 X-ray crystal structure analyses
Reflection intensities were determined with: Oxford Diffraction SuperNova (1, 2a), Oxford
Diffraction Xcalibur E (2b) or Oxford Diffraction KM4CCD (3) diffractometers.
Measurements for all but two crystals were performed at room temperature. Experiments for
1a and 2a were conducted at 130 K. Data were processed with the CrysAlis PRO [20]
software, the structures were solved by direct methods using SIR2004 [21] (1, 2) or SHELXS
[22] (3) and refined by full matrix least-squares based on F2 (SHELXL-2014) [22]. C-bound
hydrogen atoms were placed at idealized positions and refined as riding on their carriers with
Uiso(H)=1.2eq (CH) and Uiso(H)=1.2eq (CH3). Amide H atoms were located in difference
electron-density maps and, expect this from 2a, were freely refined. Because of significant
contraction of N–H bond in 2a (0.75 (5) Å) AFIX43 was used during refining. Uiso parameters
for all amide H were refined.
Crystal data for 1a (C13H9FN2O3, M =260.22 g/mol): monoclinic, space group P21/n
(no. 14), a = 7.1448(2) Å, b = 7.43040(10) Å, c = 20.9781(5) Å, β = 90.060(2)°, V =
1113.70(4) Å3, Z = 4, T = 130(2) K, μ(CuKα) = 1.053 mm-1, Dcalc = 1.552 g/cm3, 6479
reflections were measured up to θmax = 68.24° (Rint = 0.0124, Rsigma = 0.0112). The final R

indices for 1894 reflections with I > 2σ(I) and 176 refined parameters are R1= 0.0310, wR2 =
0.0852 (R1= 0.0327, wR2 = 0.0869 for all 2028 data). (CCDC no. 1474679)
Crystal data for 1b (C15H12FNO3, M =273.26 g/mol): triclinic, space group P-1 (no.
2), a = 7.8406(8) Å, b = 8.4026(6) Å, c = 10.8252(12) Å, α = 74.041(8)°, β = 73.372(10)°, γ =
76.291(8)°, V = 647.25(12) Å3, Z = 2, T = 295(2) K, μ(CuKα) = 0.908 mm-1, Dcalc =
1.402 g/cm3, 6837 reflections were measured up to θmax = 68.24° (Rint = 0.0131, Rsigma
=
0.0118). The final R indices for 2131 reflections with I > 2σ(I) and 186 refined parameters are
R1= 0.0382, wR2 = 0.1050 (R1= 0.0413, wR2 = 0.1092 for all 2368 data). (CCDC no. 1474680)
Crystal data for 2a (C13H8F2N2O3, M =278.21 g/mol): orthorhombic, space group
Pca21 (no. 29), a = 22.7758(5) Å, b = 3.7202(7) Å, c = 13.4022(3) Å, V = 1135.6(2) Å3, Z =
4, T = 130(2) K, μ(CuKα) = 1.207 mm-1, Dcalc = 1.627 g/cm3, 2333 reflections were
measured up to θmax = 68.24° (Rint = 0.0122, Rsigma = 0.0143). The final R indices for 1519
reflections with I > 2σ(I) and 182 refined parameters are R1= 0.0444, wR2 = 0.1070 (R1=
0.0446, wR2 = 0.1075 for all 1534 data). (CCDC no. 1474681)
Crystal data for 2b (C15H11F2NO3, M =291.25 g/mol): triclinic, space group P-1 (no.
2), a = 7.1277(8) Å, b = 8.0841(10) Å, c = 12.2305(14) Å, α = 88.375(9)°, β = 82.483(9)°, γ =
79.298(10)°, V = 686.52(14) Å3, Z = 2, T = 295(2) K, μ(MoKα) = 0.116 mm-1, Dcalc =
1.409 g/cm3, 8040 reflections were measured up to θmax = 25.35° (Rint = 0.0206, Rsigma
=
0.0222). The final R indices for 1833 reflections with I > 2σ(I) and 182 refined parameters are
R1= 0.0502, wR2 = 0.1309 (R1= 0.0683, wR2 = 0.1457 for all 2514 data). (CCDC no. 1474682)
Crystal data for 3a (C13H8F2N2O2S, M =294.27 g/mol): monoclinic, space group
P21/c (no. 14), a = 19.1987(10) Å, b = 8.5469(5) Å, c = 7.7029(6) Å, β = 91.885(5) , V =
1263.28(14) Å3, Z = 4, T = 293(2) K, μ(MoKα) = 0.283 mm-1, Dcalc = 1.547 g/cm3, 7570
reflections were measured up to θmax = 25.49° (Rint = 0.0297, Rsigma = 0.0263). The final R

indices for 1991 reflections with I > 2σ(I) and 185 refined parameters are R1= 0.0521, wR2 =
0.1284 (R1= 0.0605, wR2 = 0.1344 for all 2353 data). (CCDC no. 1474683)
Crystal data for 3b (C15H11F2NO2S, M =307.31 g/mol): monoclinic, space group
P21/n (no. 14), a = 7.3218(8) Å, b = 23.3328(16) Å, c = 8.4995(6) Å, β = 98.986(8)°, V =
1434.2(2) Å3, Z = 4, T = 293(2) K, μ(MoKα) = 0.251 mm-1, Dcalc = 1.423 g/cm3, 5117
reflections were measured up to θmax = 25.99° (Rint = 0.0234, Rsigma = 0.0353). The final R
indices for 1976 reflections with I > 2σ(I) and 194 refined parameters are R1= 0.0524, wR2 =
0.1248 (R1= 0.0775, wR2 = 0.1453 for all 2823 data). (CCDC no. 1474684)
Crystallographic data (excluding structure factors) for the structures in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication
numbers CCDC 1474679-1474684. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk)
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a)
b)
Fig. 1. (a) Atom labeling in the asymmetric unit, bifurcated hydrogen bonding depicted by
dotted line (b) molecular stacking in the structure of 1a.
a)
b)
Fig. 2. (a) Atom numbering scheme and intramolecular interaction depicted by dotted line (b)
crystal packing, view along the b-axis in the structure of 1b.

a)
b)
Fig. 3. (a) Atom labeling in the asymmetric unit, intramolecular interaction depicted by dotted
line (b) crystal packing, view along the c-axis in the crystal structures of 2a.
a)
b)
Fig. 4. (a) Atom labeling in the asymmetric unit with intramolecular interaction depicted by a
dotted line (b) crystal packing viewed along the b-axis showing C5−H5···O1 hydrogen bonds
and C9−F1···F2 interactions in 2b.

a)
b)
c)
Fig. 5. (a) Atom labeling in the asymmetric unit, intramolecular interaction depicted by dotted
line (b) crystal packing, viewed along the b-axis c) C4−H4···O2 and C10−H10···S1 hydrogen
bonding in structure of 3a.

a)
b)
Fig. 6. (a) Atom labeling in the asymmetric unit, intramolecular interaction depicted by a
dotted line (b) crystal packing in 3b.

O
N
O
N
F
H
F
H
R
(I)
1a R = NO2
1b R = COOCH3
F
S
F
F
O
N
N
F
H
H
R
R
2a R = NO2
3a R = NO2
2b R = COOCH3
3b R = COOCH3
Scheme 1: . Chemical structures of ortho-fluorobenzanilides 1-2 and ortho-
fluorothiobenzanilides 3.
R1
F
R1
F
R
R1
F
(C2H5)3N,
CH2Cl2
S
N
O
N
O
LR, toluene
NH2
0 C to r.temp.
°
Cl

reflux
H
H
R
R
4a R = NO2
4b R = COOCH3
5a R1 = H
5b R1 = F
1a R = NO2, R1 = H
1b R = COOCH3, R1 = H
2a R = NO2, R1 = F
3a R = NO2, R1 = F
3b R = COOCH3, R1 = F
2b R = COOCH3, R1 = F
CH3O-pC6H4
S
S
S
S
P
P
LR =
pC6H4-OCH3
Scheme 2. Synthesis of ortho‐fluorobenzanilides 1‐2 and ortho‐fluorothiobenzanilides 3.

Table 1 Crystallographic data and structure parameters for compounds 1a-3b.
Compound
Formula
MW
1a
1b
2a
2b
3a
3b
C13H9FN2O3 C15H12FNO3 C13H8F2N2O3 C15H11F2NO3 C13H8F2N2O2S C15H11F2NO2S
260.22
273.26
278.21
291.25
294.28
307.31
Crystal
system
Space group
a/Å
monoclinic
Triclinic
orthorhombic
triclinic
monoclinic
monoclinic
P
P
P21/n
7.1448(2)
7.43040(10)
20.9781(5)
90.00
Pca21
22.7758(5)
3.7202(7)
13.4022(3)
90.00
P21/c
19.1987(10)
8.5469(5)
7.7029(6)
90
P21/n
7.3218(8)
23.3328(16)
8.4995(6)
90
7.8399(3)
8.4111(4)
10.8184(5)
73.991(4)
73.336(4)
76.244(4)
647.094
2
7.1277(8)
8.0841(10)
12.2305(14)
88.375(9)
82.483(9)
79.298(10)
686.519
2
b/Å
c/Å
α/°
β/°
90.060(2)
90.00
90.00
91.885(5)
90
98.986(8)
90
γ/°
90.00
V/Å3
1113.7
1135.58
4
1263.28
4
1434.22
4
Z
4
Table 2 Geometrical parameters of intra- and intermolecular interactions for compounds 1a-
3b.
Compound
D—H···A
N1—H1N···O2
N1—H1N···F1
C3—H3···O3i
C5—H5···O1ii
D—H (Å)
0.85 (2)
0.85 (2)
0.95
D···A (Å)
2.660 (1)
2.716 (1)
3.233 (1)
3.415 (1)
H···A(Å) D—H···A (deg)
1a
1.98 (2)
2.04 (2)
2.60
135.4 (1)
135.5 (1)
124
0.95
2.53
156

C10—H10···O2iii
0.95
3.480 (1)
2.60
155
Symmetry codes: (i) −x+3/2, y+1/2, −z+1/2; (ii) −x+2, −y+2, −z+1; (iii) −x+1, −y, −z+1.
2a
N1—H1N···O2
N1—H1N···F1
C12—H12···O2i
C11—H11···O3i
C3—H3···O1ii
0.88
0.88
0.95
0.95
0.95
2.647 (3)
2.787 (3)
3.316 (3)
3.440 (3)
3.146 (3)
1.96
2.35
2.65
2.63
2.46
134
111
127
143
129
Symmetry codes: (i) −x+3/2, y, z−1/2; (ii) −x+1, −y+2, z+1/2.
0.83(3)
0.93
2.14(3)
2.79
3a
1b
N1−H1···O1
C6−H6···S1
2.713(3)
3.211(3)
126(3)
108
N1—H1N···O2
N1—H1N···F1
C12—H12···O2ii
0.89 (2)
0.89 (2)
0.93
2.690 (1)
2.821 (1)
3.548 (2)
1.96 (2)
2.38 (2)
2.68
139.1 (1)
110.6 (1)
156
Symmetry codes: (i) x, y, z+1; (ii) −x+1, −y+2, −z.
0.92 (3)
0.93
1.89 (3)
2.44
2b
N1—H1N···O2
C5—H5···O1i
C9−F1···F2ii
2.656 (2)
3.311 (3)
2.897(3)
140 (2)
157
Symmetry codes: (i) 1-x, 1-y, -z; (ii) -1+x, y, z.
0.86(2)
0.93
1.94(2)
2.36
3b
N1−H1N···O1
C3−H3···O2
2.672(2)
2.706(3)
141(2)
102

0.93
0.93
2.58
2.51
C6−H6···S1
3.247(3)
3.348(3)
129
149
C10−H10···F2i
Symmetry code: (i) -1+x, y, z.
Table 3 Selected dihedral angles (°) in structures 1a-3b.
Compound
 (R1, R2)
 (R1, R3)
 (R2, R3)
1a
2a
3a
1b
2b
3b
16.62 (5)
11.16 (13)
42.8(15)
8.54 (7)
15.51 (5)
42.73 (8)
54.71(15)
41.26 (4)
68.10 (10)
66.72(12)
2.41 (4)
31.63 (7)
12.39(14)
49.47 (4)
82.06 (9)
80.89(12)
14.02 (9)
17.42(13)
R1 = mean plane of amide group (C1, N1, C7, C8, O1 (S1)), R2 = mean plane of
C1-C6 (aniline) ring, R3 = mean plane of C8-C13 (benzoyl) ring.