Structures and conformational analysis of a 3 × 3 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides

Article abstract of DOI:10.1039/c0ce00326c

A 3 × 3 isomer grid of N-(fluorophenyl)pyridinecarboxamides is reported and integrating crystal structure analyses, ab initio optimisation calculations (gas phase and solvated forms in CH₂Cl₂, H₂O) and conformational analy

Full text of DOI:10.1039/c0ce00326c

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PAPER
Structures and conformational analysis of a 3 ꢀ 3 isomer grid of nine
N-(fluorophenyl)pyridinecarboxamides†
a
Pavle Mocilac, Alan J. Lough and John F. Gallagher
b
a
*
Received 22nd June 2010, Accepted 18th November 2010
DOI: 10.1039/c0ce00326c
A 3 ꢀ 3 isomer grid of N-(fluorophenyl)pyridinecarboxamides is reported and integrating crystal
structure analyses, ab initio optimisation calculations (gas phase and solvated forms in CH2Cl2, H2O)
and conformational analyses. The nine NxxF isomers (x ¼ 4-, 3- or 2-substitution on N and F) are
investigated and compared to determine and correlate factors underpinning (a) the roles of the F/N
atom substituents on molecular conformation and overall supramolecular aggregation, (b) competition
between intermolecular amide/amide (in NppF) or intra-/intermolecular amide/pyridine hydrogen
bond formation and (c) structural and physico-chemical properties. Crystal structure analyses of the
NxxF isomers reveal different primary aggregation processes as either N–H/N or N–H/O]C and
with NmpF forming an unusual cyclic N–H/N hydrogen bonded tetrameric assembly [as a R4 (24)
4
ring]. Compounds NpmF and NpoF are isomorphous and the latter is also disordered. Conformational
analysis of the NxxF molecular structures from DFT calculations differs from the crystal structure
results for several isomers and highlighting the co-operative effects of intra-/intermolecular interactions
in the solid state.
structure analyses.11,12 The relative energies of different molec-
ular conformations can be compared to aid us in a detailed
understanding of factors that facilitate the crystallisation and
isolation of particular conformations in the solid state; unex-
pected conformations from theory and the solid-state can
therefore be rationalised.5,9 This is particularly relevant for
compounds where rotational barriers in solution are low enough
to provide the possibility of a greater diversity of molecular
conformations and/or molecular disorder observed in the solid-
state. This information may also assist us in understanding why
some compounds readily crystallize as polymorphs and others
with some difficulty.5,8,9 Ultimately the roles that the substituent
atoms/groups play in supramolecular packing and organisation
in the solid state can be appraised and understood.8–12
1
Introduction
Cheminformatics has emerged in the past decade as a scientific
field that is proving to be of enormous benefit for our use as
scientists in analyzing a wide range of scientific problems.1,2 One
such challenge is the on-going demand to synthesise, analyse and
collate vast numbers of chemical compounds and data. This
information feeds directly into a global ‘drug-pharma’ enterprise
persistently searching for new and more effective molecules to
treat a variety of newly discovered and existing maladies.3,4
Comprehensive chemical and computational analyses of small
‘drug-like’ molecules together with structural systematic
approaches allow us to utilise an increasing data stream from
both crystallography and computational resources.5–8 Integra-
tion can yield essential information for analysing trends and
provides an insight into similar/different physical or chemical
properties, within or between molecular organic series.5,6,8–10
Isomer grids provide a basis for comprehensive studies
incorporating (a) synthesis and characterisation, (b) ab initio
computational and conformational analyses and (c) crystal
Our research focus is based on n ꢀ m isomer grids of benza-
mides (i.e. fluoro- and methyl-N-(pyridyl)benzamides) which
provide a semi-rigid, invariant scaffold to analyse the impact of
different substituent atom/group (e.g. CH3 or F) site variation
both on the molecular conformations and physico-chemical
properties.11,12 The influence of the aromatic group substitution
patterns can also be evaluated in terms of the preferred primary
hydrogen bonding (N–H/N or N–H/O]C) in the solid-state,
in tandem with the influence and effect of weaker interactions on
molecular aggregation.11,12
aSchool of Chemical Sciences, Dublin City University, Dublin 9, Ireland.
Web: http://doras.dcu.ie; E-mail: john.gallagher@dcu.ie; Fax: +353-1-
7005503; Tel: +353-1-7005114
bDepartment of Chemistry, University of Toronto, 80 St George Street,
Toronto, Ontario, Canada M5S 3H6
† Electronic supplementary information (ESI) available: The 1H, 13C and
19F NMR and spectroscopic data and the full listings of ab initio
calculations for all nine NxxF isomers. CCDC reference numbers
722730, 722731 and 781752 to 781758. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c0ce00326c
Related scientific studies5 have highlighted the importance of
fluorine and its role in weak interactions11,13,14 as well as the roles
of NxxF picolinamides in biological systems.15–17
Herein, the synthesis and characterisation of a 3 ꢀ 3 isomer
grid of nine N-(fluorophenyl)pyridinecarboxamides (NxxF)
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1
(with x ¼ para-/meta-/ortho-) (Scheme 1: C12H9FN2O) is repor-
ted with comprehensive crystal structure and conformational
analyses (calculations using CBS-QB3//B3LYP/6-311++G) on
gas-phase and solvated forms (PCM-SMD model). The confor-
mational features and differences between the solid-state and
model conformations, together with structural and property
trends, are discussed for the NxxF isomer grid. The amide group
is reversed between the aromatic rings in comparison with our
previous benzamide series11,12 derived from 4-aminopyridine (4-
AP, an experimental drug in multiple sclerosis, spinal cord injury
models18 and used as a Kv1 channel blocker19). A further desire is
to obtain more specific or less toxic drugs, structurally similar to
benzamide derivatives of 4-AP11,12 for exploitation as potential
K+ channel blockers.11,18–20
MHz for H, 100.62 MHz for 13C and 376.46 MHz for the 19F
1
resonances. For all nine NxxF derivatives the H spectra were
acquired in CDCl3 and DMSO-d6 with 13C and 19F spectra run in
DMSO-d6. The NMR chemical shift values (d) are expressed in
ppm and referenced to TMS (Cl3FC for 19F NMR) and coupling
constants (J) are quoted in Hz.
Ab initio molecular modeling and conformational analysis for
the gas phase was performed at the B3LYP/6-311++G level using
the Gaussian0325 package (version E.02) for the MS Windows
XP SP3 operating system running on a PC (Intel core i7-940 2.93
GHz, 8GB). The solvated form computations (PCM-SMD/
B3LYP/6-311++G), conformational analyses and high accuracy
energy (CBS-QB3) calculations were completed using Gaussian
0925 for Linux/Unix operating on a Bull Novascale R422-E2
system provided by the Irish Centre for High-End Computing.
NppF has previously been used as an intermediate in the
synthesis of 4-pyridinium cationic-dimer antimalarials.15 The
NmxF triad has been studied in an unusual synthesis of nicotin-
amides21 and recently NmoF has been cited as a promising
candidate for lead design as a selective inhibitor of LmSir2, a sir-
tuin protein from Leishmania, and therefore, a potential new drug
and/or scaffold for leishmaniasis drug design.16 In the NoxF series,
NopF has been incorporated as a deprotonated ligand into a CoIII
complex22 (NopF crystal structure reported recently23) and NomF
as an intermediate in the synthesis of thioamide analogues (mp
65–82 ꢁC24 vs. 77.2–78.0 ꢁC); NooF has been employed as a ligand
in a ruthenium complex developed as a potential cytotoxic
agent.17 Overall, modest spectroscopic data are available for
several of the NxxF isomers from these diverse reports.15–17,21–24
2.2 General description of the NxxF synthesis
Nucleophilic acyl substitution reactions between the fluoroani-
lines and pyridinoyl chlorides produced the nine N-(fluo-
rophenyl)pyridinecarboxamides (NxxF) (x ¼ para-/meta-/ortho-)
(Scheme 1) in modest to high yields (20–70%). Detailed synthetic,
purification procedures and all spectroscopic data are provided
in the ESI† (Sections 1–3).
Condensation reactions were performed with the fluoroani-
lines in CH2Cl2: the pyridinoyl chlorides were added directly to
the reaction in the presence of Et3N. Organic washing and work-
up was standard: the reaction mixture was washed with an
aqueous KHCO3 solution and the organic layer was dried with
anhydrous MgSO4. The solvent was evaporated and the NxxF
product left for crystallization. Yields were modest to good (30–
70%) in most cases with the exception of the NoxF isomers with
lower yields of 20–30%. The product purity was mostly high
(ꢄ99%), therefore crystallization and separation of the respective
products from impurities was successful for most cases.
2
Experimental section
2.1 Materials and equipment
All chemicals were purchased from Sigma Aldrich except for 2-
pyridinoyl chloride (Fluorochem): TLC alumina and silica plates
were purchased from Fluka. Melting points were performed
using a Stuart Scientific SMP40 automated melting point appa-
ratus. IR spectroscopy was performed on a Thermo Nicolet
Avatar 320 FTIR Spectrometer using the (a) thin-film method
with CHCl3 as solvent and (b) KBr disc method: bands are stated
in cmꢂ1. NMR spectroscopy was performed on a Bruker BioSpin
UltraShield NMR spectrometer at 293 ꢃ 1 K operating at 400
However, for the NoxF isomers, the accessible starting mate-
rial (2-pyridinoyl chloride) was of technical grade purity con-
taining 5-chloro-2-pyridinoyl chloride (a by-product of the
2-pyridinoyl chloride synthesis with SOCl2) and solubility of the
products in CHCl3 was greater: re-crystallization was performed
using isopropanol to give reasonably pure NoxF products. The
physical appearance and properties (solubility and melting
points) are broadly similar for all nine NxxF isomers and espe-
cially for the six NpxF and NmxF isomers. All NxxF are white,
odourless, crystalline solids, soluble in CHCl3, CH2Cl2, CH3CN,
DMSO, acetone and ethyl acetate, insoluble in water, though
sparingly soluble in cold methanol and isopropanol, but with
increased solubility when warmed. A substantial difference in
solubility in CHCl3 is evident with the NoxF isomers more
soluble in CHCl3 than the remaining six NxxF isomers.
2.3 Single crystal growth and X-ray diffraction methods
Single crystals of the NxxF compounds were grown from ethyl
acetate or CHCl3 by slow evaporation of the NxxF solutions at
room temperature (294 K). Single crystal X-ray data for all nine
NxxF isomers were collected on an Enraf-Nonius k-CCD
diffractometer atthe University of Toronto at 150(1)K (except for
Scheme 1 Structures and nomenclature of the NxxF isomers.
1900 | CrystEngComm, 2011, 13, 1899–1909
NppF
a
non-merohedral twinned crystal [89 : 11 twin
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a
Table 2 Relevant structural features (A, ꢁ) in the nine NxxF isomers
components] at 200(1) K), q range 2–27.5ꢁ with 100% data
coverage to 25ꢁ (on q). Data reduction procedures are standard
and SORTAV was used for the absorption corrections; compre-
hensive details have been published elsewhere.26,27 All structures
were solved using the SHELXS9728 direct methods program and
refined by full matrix least squares calculations on F2 with all non-
hydrogen atoms having anisotropic displacement parameters
(apart from disordered minor atom sites). Hydrogen atoms were
treated as riding atoms using the SHELXL97 defaults (at 150 K)
except for the amide N–H (isotropic refinement) using the
OSCAIL software29 with selected crystallographic and structural
information in Tables 1 and 2 and the ESI† (the amide as a five
atom plane). Molecular and hydrogen bonding diagrams (Fig. 1–
7) were generated using PLATON.30 All searches on the Cam-
bridge Structural Database (CSD) were performed with the
November 2009 release (version 5.31 + 3 updates).8,31
ꢀ
NxxF C6/C5N (ꢁ) C6/amide C5N/amide N/N/Ob Packingb
NppF* 56.74(5),
57.93(5)
29.24(7), 27.63(7),
33.16(6) 24.93(7)
NpmF 65.93(10) 39.16(10) 27.39(13)
NpoF 76.99(12) 51.39(12) 27.06(15)
3.203(2)*, 1D chains*
3.216(2)*
2.991(4)
2.930(4)
3.193(2), Tetrameric
2D sheets
1D chains
NmpF
5.42(9),
0.77(10),
5.39(9),
0.74(9)
3.38(9), 2.04(9),
1.99(9), 2.13(9),
3.21(9), 2.18(9),
1.82(9)
27.47(5) 24.00(7)
3.224(2),
3.171(2),
3.254(2)
assembly
1.56(9)
NmmF 50.16(5)
3.1146(18) 2D sheets
3.182(4)
2.679(3)
NmoF 22.67(14) 33.09(12) 10.75(13)
NopF 30.34(10) 27.74(11) 4.75(15)
1D chains
Intramolecular
2.675(4), Intramolecular
2.655(4)
2.630(3), Intramolecular
2.654(2)c
NomF
4.4(2),
4.6(2)
9.69(14)
5.5(2), 2.0(2),
6.4(2) 4.2(2)
8.67(14) 2.53(14)
NooF
a
b
Full structural details are available in the ESI†. The amideN–H/
c
Npyridine or N–H/O]C* interaction distances.
intramolecular distance.
The N/F
2.4 Computational methods
The nine NxxF isomers were analysed using the same methods
and techniques as described previously.12 The NxxF isomer
optimisation and conformational analysis was performed by ab
initio calculations (B3LYP/6-311++G) on isolated (gas-phase)
and solvated molecules (PCM-SMD32 solvation model with
CH2Cl2 or H2O) using Gaussian03/09.25 High accuracy energy
calculations (CBS-QB3)33 were performed to obtain the DG of
solvation and energy values are provided in the ESI† (Section 5).
Conformational analysis of the optimised NxxF isomers was
achieved by rotation of (a) the C26–C21–C1]O1 (a dihedral, N-
ring) and (b) the C1–N1–C11–C12 angles (b dihedral, F-ring)
both in the gas phase and solvated forms to analyse and predict
energetically favourable conformations.
3
Results and discussion
3.1 Comment on spectroscopic data
All spectroscopic data, including NMR and IR spectra, are
provided in the ESI† (Sections 2 and 3).
1
The H and 13C NMR data reveal a considerable degree of
similarity (as expected) and a high level of modularity (in the
pyridine and fluorophenyl rings) for all nine NxxF isomers.
Distinct trends and some salient features in the series will be
discussed further. The 19F NMR spectra in DMSO reveal distinct
differences (d values) with the NxpF series at ꢂ118 ppm and the
NxmF triad at ꢂ112 ppm. The NxoF triad has both NpoF and
NmoF at ꢂ121 ppm with NooF at ꢂ127.4 ppm highlighting the
additional intramolecular hydrogen bonding effect in the NxoF
series, but especially for NooF (Fig. 7).
Conformational analysis is necessary for verification of the
preliminary optimised conformations as real global minima.9
Comparisons of solid-state conformations with ab initio derived
results were an aim, as well as calculation of rotational energy
barriers for flipping the aromatic rings from one conformation to
another and rationalise conformational differences > 15ꢁ. As the
NxxF isomers have two aromatic rings connected via an amide
linkage a total of four conformations are possible for the aromatic
pyridine N and F site positions relative to the amide linkage. The
rings can have the syn (N-syn or F-syn) or the anti (N-anti, F-anti)
conformations (Scheme 2) and are relevant only for NxxF with the
N or F located in meta- or ortho-sites (x ¼ m or o).
1
The H NMR d values of the amide N–H proton lie in the
range 7.91–8.15 ppm (NpxF) and 8.23–8.75 ppm (NmxF) in
CDCl3 and from 10.38–10.68 ppm for the six NpxF/NmxF
isomers in DMSO-d6 showing the increased effect of the
hydrogen bonding influence (and deshielding effect) of the
DMSO S]O group on the N–H proton. The distinct location of
the amide proton d values for the three NoxF isomers at lower-
field values [10.04–10.36 ppm (CDCl3) and 10.37–10.86 ppm
(DMSO-d6)] and shifted from 8 / 10 ppm in CDCl3 (from
NpxF/NmxF / NoxF) is due to the position and effect of the
ortho-N atom in forming intramolecular amide N–H/Npyr and
intermolecular N–H/O]S interactions. However, for NooF the
intramolecular hydrogen bonding is at a maximum with the N–H
signal at 10.36 ppm (CDCl3) and 10.37 ppm (DMSO-d6) and
little influenced by the DMSO solvent. Overall, the spectroscopic
data for the NoxF triad show distinct differences amongst the
nine NxxF isomers and highlighting the NoxF amideN–H/
Table 1 Selected crystallographic data for the nine NxxF isomersa
3
ꢀ
Volume/A
NxxF
Space group
Z0
R-factors
ꢁ
P1
NppF
NpmF
NpoF
NmpF
NmmF
NmoF
NopF
NomF
NooF
2
1
1
4
1
1
1
2
1
963.94(6)
1032.22(10)
1027.33(8)
1995.47(9)
999.42(12)
989.44(9)
993.10(16)
1999.17(18)
986.32(14)
0.051, 0.142
0.042, 0.113
0.051, 0.135
0.050, 0.124
0.044, 0.118
0.049, 0.125
0.063, 0.166
0.074, 0.223
0.057, 0.154
Cc
Cc
ꢁ
P1
P21/n
P212121
P21/c
P21/n
P21/n
N
pyridine intramolecular interaction.
3.2 Crystallographic data and analysis
a
Complete crystallographic, refinement and structural details for all nine
NxxF isomers (C12H9FN2O) are listed in the ESI† (Section 4).
The principal intermolecular feature for eight of the NxxF crystal
structures is aggregation in the crystalline state via amideN–H/
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Npyridine interactions but mostly in different crystal systems and
space groups: NppF is the only isomer with standard N–H/
O]C hydrogen bonding. Only three isomers, NpmF, NmmF and
NmoF, crystallize with Z0 ¼ 1 and with no disorder: the
remaining six NxxF crystallize with (i) Z0 > 1 and/or (ii) C6H4F
ring disorder and/or (iii) have a minor Cl component of impurity
(derived from the original NoxF synthesis). Of special interest is
the NmpF structure which forms an unusual N–H/N hydrogen
bonded tetrameric assembly in the asymmetric unit, further
linked by C–H/F and C–H/O]C interactions in the crystal
structure.
3.2.1 NpxF series. The NxpF triad forms two
different primary interactions as N–H/O]C in NppF and
N–H/Npyridine in NpmF, NpoF.
Fig. 1 The N–H/O]C and C–H/O]C interactions in NppF with
symmetry codes # and * at positions 1 + x, y, z and ꢂ1 + x, y, z,
respectively.
0
ꢁ
The NppF isomer crystallizes in P1 (no. 2) with Z ¼ 2. Data
were collected at 200(1) K as a structure solution could not be
obtained at 150(1) K: the results at 200(1) K with the unit cell
halved revealed a non-merohedral twinned crystal with twin
components of 0.89 : 0.11. PLATON30 suggests a change to
monoclinic but this is not appropriate at 200(1) K (see ESI†
Section 4.1.1). Molecules A and B are non-planar (Table 2) and
differ by 4ꢁ as 29.24(7)ꢁ (A) and 33.16(6)ꢁ (B) (Fig. 1) in their C6/
amide linkageangle (as five atoms). Molecules aggregate along the
a-axis direction by amideN–H/O]C interactions [as C(4) 1D
ꢀ
chains] with long N/O distances of 3.203(2) and 3.216(2) A in the
[A/A/] and [B/B/] chains and in tandem with weak C16–
H16/O1 contacts (forming R1 (6) rings). Fluoro contacts as F/
2
ꢀ
F (2.86 A) also align in a zigzag chain along the a-axis direction.
The aggregation is principally 1D and the pyridine N24A/B atoms
do not participate in hydrogen bonding or even in weak contacts
which is quite unusual. Obviously formation of the more common
amideN–H/Npyridine interactions is not favoured in NppF and the
amide/amide hydrogen bonding forms with small additional
auxiliary support from weaker C–H/O/F interactions (Fig. 1).
The NpmF (Fig. 2) and NpoF (Fig. 3) crystal structures are
isomorphous in space group Cc (no. 9) though they differ with C6/
C5N interplanar angles of 65.93(10)ꢁ and 76.99(12)ꢁ, respectively.
Both NpmF and NpoF form short N1–H1/N24 interactions as
C(7) zigzag chains with N/N distances of 2.991(4) and 2.930(4)
Fig. 2 The NpmF interactions with molecules at symmetry equivalent
positions with label suffices as a ¼ ½ + x, ꢂ½ ꢂ y, ½ + z; b ¼ ꢂ½ + x, ꢂ½
ꢂ y, ꢂ½ + z; c ¼ x, y ꢂ 1, z; d ¼ ꢂ½ + x, ½ ꢂ y, ꢂ½ + z; e ¼ ½ + x, ½ ꢂ
y, ½ + z and f ¼ 1 + x, y, 1 + z.
ꢀ
A, respectively. Chains are linked by longer C–H/O]C inter-
ꢁ
molecular interactions into 2D sheets parallel to the (101) plane
resulting in the formation of R4 (26) rings (Fig. 2) via the C15–
4
H15/O1d interaction where symmetry code d ¼ ꢂ½ + x, ½ ꢂ y,
ꢂ½ + z (via C13 in NpoF): sheets are weakly linked into a 3D
structure by short C–H/p(arene) interactions. In NpmF the C–
ꢁ
ꢀ
H/p(arene) interaction with H/Cg ¼ 2.65 A, C–H/Cg ¼ 147
Fig. 3 The NpoF molecular structure with group disorder for F12 in the
F-anti conformation [91.7(9)%] and F16 as F-syn [8.3(9)%].
ꢀ
and C/Cg ¼ 3.484(3) A is not as short as that noted in the crystal
structure of Moo.12 Subtle differences between NpmF and NpoF
Scheme 2 Possible conformations of the NxxF isomers.
1902 | CrystEngComm, 2011, 13, 1899–1909
are noted and especially with regard to the secondary interactions
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ꢀ
groups is 3.40 A. Tetrameric units are further linked into a 3D
and F atom sites. The meta-F13 sites [with F-syn conformations]
are not disordered in NpmF, whereas the ortho-F12/F16 exhibit
0.917(9)/0.083(9) [F-anti/F-syn] conformational disorder in the
NpoF C6 ring involving a 180ꢁ rotation about the N1–C11 axis
with H/F atoms interchanged (Fig. 3). A key reason in performing
the conformational analyses is to attempt to ascertain factors
(energy) which may predispose why one isomorph NpmF is
ordered and why NpoF is disordered (see Section 4). Isomorphous
relationships in the related Fxx benzamides have been reported
previously,5,11,20 while disorder is a common phenomenon in flu-
orobenzamides given the isosteric relationships between H and F
atoms and small energy differences between the orientation of the
F-syn/F-anti conformations of the C6 aromatic rings, both in
solution and the crystalline state.5,20
structure by weaker C–H/F/O]C intermolecular interactions
ꢀ
with C/F distances from 3.266(2) to 3.281(2) A in either the a-
and b-axis directions in addition to the effect of p/p stacking
interactions. The C–H/O]C interactions link the tetramers
along the c-axis direction.
The four molecules (A) to (D) can be grouped into the A/C and
B/D molecular pairs within which are close similarities. The C6/
C5N interplanar angles are 5.42(9)ꢁ/5.39(9)ꢁ for the (A)/(C) and
0.77(10)ꢁ/0.74(9)ꢁ for the (B)/(D) pairs. There are, however,
significant differences within each pair and molecules (A) and (C)
have the closest fit. It is possible that a phase transition can occur
at a different temperature although the NmpF RT (294 K)
structure is similar. The unusual NmpF geometry (though
unexpected) and assembly can be attributed to the cis-orientation
and directional arrangement of both the N–H donor and pyri-
dine N acceptor groups. Cyclic hydrogen bonded dimers/cat-
emers almost certainly exist in solution but the presence of cyclic
tetramers probably drives the crystallization process in a pseudo-
macrocyclic chelation process and with the assembly held
together by four N–H/N and eight C–H/N interactions.
Comparable examples of hydrogen bonded tetrameric units
occur in both Ph3COH and Ph3GeOH where tetramers are linked
by a relay of [O–H/O–H/]2 interactions.34,35 The crystal
structure of 3-(CF3),5-(Ph)PzH36 [ESUJOR: CSD8] forms tub-
shaped tetramers via N–H/N interactions as hydrogen bonded
3.2.2 NmxF series. The three NmxF isomers aggregate
via amideN–H/Npyridine interactions, though they differ with
tetrameric assemblies in NmpF and as C(6) chains in the NmmF
and NmoF isomers.
The NmpF isomer crystallizes as a cyclic hydrogen bonded
0
ꢁ
tetrameric assembly in space group P1 (no. 2) with Z ¼ 4 and in
the overall shape of a ‘St Brigid’s’ cross (Fig. 4). In all four
molecules the Nm ring is in the N-syn conformation. This
tetrameric hydrogen bonded structure is unusual. The four
molecules (A) to (D), which have approximate mirror symmetry
(Cs) (with interplanar C6/C5N angles < 6ꢁ) differ slightly as
exemplified by the four long N–H/N intermolecular hydrogen
4
4
ꢁ
R (12) rings comparable to NmpF in space group P1 (no. 2) with
ꢀ
bonding distances of 3.171(2), 3.193(2), 3.224(2) and 3.254(2) A.
Z0 ¼ 4; tetramers though are the least common structural motifs
The cyclic tetrameric unit aggregates as an R4 (24) ring and is
found amongst the N-unsubstituted pyrazoles.36 The four N/N
4
ꢀ
augmented for each of the N–H/Npyridine interactions by two
flanking C–H/Npyridine interactions forming R1 (6) and R1 (7)
distances in ESUJOR36 are in the range from 2.844 to 2.866 A
and the tetramer is smaller than in NmpF. Another series of
tetrameric structures are the [AgXL]4 complexes {with X ¼
halide, L ¼ tertiary phosphine, e.g. P(4-MeC6H4)3} though the
structures of [AgXL]4 are very different to NmpF, with the cubic
vs. stella quadrangula [MX]4 cores recently discussed.37
2
2
rings with an overall size of R1 (9). The four flanking and longer
3
ꢀ
C16[A–D]/N23[A–D] interactions are from 3.364(2) to 3.387(2) A
with the four C22[A–D]/N23[A–D] distances in the range 3.366(2)
ꢀ
to 3.403(2) A. The closest stacking overlap between the aromatic
The NmmF and NmoF structures are regular and both
form amideN–H/Npyridine interactions as C(6) chains with N/N
ꢀ
ꢀ
distances of 3.1146(18) A and 3.182(4) A, respectively. In NmmF the
pyridyl N23 and fluoro F13 atoms are cisoid with respect to one
another and transoid to the N–H group [N-anti/F-anti conformation].
The combination of the primary N–H/N interaction, C–H/O]C
and two weaker interactions gives rise to a rumpled 2D sheet pꢁarallel
ꢁ
to the (101) plane. The C6/C5N interplanar angle is 50.16(5) with
C5N/amide and C6/amide intermediate at 24.00(7)ꢁ and 27.47(5)ꢁ
(Table 2). In NmoF this is reversed with an interplanar angle for C6/
C5N of 22.67(14)ꢁ, whereas the C5N/amide and C6/amide angles are
10.75(13)ꢁ and 33.09(12)ꢁ. The pyridyl N23 and fluoro F12 are cisoid
but are transoid to the C]O, in contrast to NmmF [NmoF has the N-
syn/F-syn conformation]. In NmoF, theN–H/N primary interaction
(with intramolecular C16–H16/O1, N1–H1/F12 contacts) is
assisted by an intermolecular C22–H22/N23* interaction forming
1
ꢀ
R 2(7) rings with C22/N23* ¼ 3.348(4) A (Fig. 5); C24–H24/F12
forms an unsymmetrical R22(8) ring. The N–H/N interaction
generates a zigzag 1D helical chain in the [100] direction as a stacked
herringbone column (along a 21 axis); longer C–H/N/O/F inter-
molecular interactions generate a 3D network. Aromatic p/p
stacking occurs with overlap of symmetry related [C11, ., C16] rings
i
ꢀ
along the [100] direction [C12/C15 ¼ 3.307(5) A (with i ¼ 1 + x, y,
z)]. For comparison the NmoF conformation when ‘docked’ in
Fig. 4 The N–H/N and flanking C–H/N intermolecular interactions
in the tetrameric assembly of molecules (A) to (D) in NmpF.
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Fig. 6 The asymmetric unit of NomF: the minor component of disorder
in molecule A (top) is at F15A.
Fig. 5 The N/C–H/N hydrogen bonding in NmoF generates zigzag
helical chains along the a-axis direction; molecules with labels # and * are
located at positions ½ + x, ꢂ½ + y, ꢂz and ½ + x, ½ + y, ꢂz, respectively.
along the b-axis direction. Weak C–H/F contacts link chains
into sheets completing the structure, with molecules forming
weak interactions along the b-axis direction parallel to the
Leishmania sirtuin (Fig. 5A in ref. 16) is similar to our NmoF but with
the amide plane twisted by ꢄ30ꢁ.
ꢁ
(102) plane. The related compound with CSD code,
GEPQIC,38 is the parent chloro derivative [NopCl] and is
isomorphous with WUVYIV39 (Br derivative as NopBr) but
not with NopF.23 The molecular overlay between the Cl/Br
3.2.3 NoxF series. The primary interaction in all three NoxF
isomers is the intramolecular N1–H1/N22 with N/N distances
ꢀ
of 2.679(3) A in NopF, 2.675(4)/2.655(4) A in NomF and 2.630(3)
ꢀ
ꢀ
analogues [GEPQIC/WUVYIV] is within 0.005 A and the C6/
ꢀ
A in NooF. The NopF molecule has a C6/C5N interplanar angle
C5N interplanar rings are also close to 0ꢁ.
of 30.34(10)ꢁ, while NomF and NooF are essentially planar
molecules with approximate mirror (Cs) symmetry [C6/C5N
angles of 4.4(2)ꢁ/4.6(2)ꢁ and 9.69(14)ꢁ], the planarity driven by
the intramolecular N–H/N interaction. Disorder is observed in
NomF and a minor Cl atom component is present as an impurity
with site occupancies of 4.2(3)% and 3.2(3)% at the meta-C25–
H25 site in NopF and NooF, respectively, and is a contaminant in
the original synthesis from the acyl chloride. The minor Cl atom
site component is not detected in the NomF structure, but there is
rotational disorder in one of the C6 rings with a minor F atom
site at C15A having 6.1(5)% site occupancy (Z0 ¼ 2): this group
disorder is similar to that described in NpoF. In the Mxx isomer
grid12 the Mxo triad (with an ortho-pyridine N atom) all aggre-
gates using intermolecular N–H/N interactions forming
In NomF two molecules (Z0 ¼ 2) are present in the asym-
metric unit with similar geometries and one of the molecules
exhibits group disorder with a major meta-F13A atom site
occupancy of 93.9(5)% (N-syn/F-anti conformation) and minor
site at F15A (N-syn/F-syn conformation, Fig. 6). The disorder
only involves 180ꢁ rotation about the N1–C11 bond and there
are no other unusual artefacts of disorder/impurities in the
structure. Geometric differences between the two molecules
are evident, e.g. the C1–N1–C11–C16 angle is 177.6(3)ꢁ in
molecule (A) and 172.0(3)ꢁ in (B). As in NopF, the NomF
structure is remarkable for the lack of strong interactions and
the strongest hydrogen bond is the intramolecular N1–H1/
ꢀ
ꢀ
N22pyridine ¼ 2.675(4) A in (A), 2.655(4) A in (B). Two
intramolecular C–H/O interactions involve C12A/B at
hydrogen bonded dimers by centrosymmetric R2 (8) rings.
2.845(4) A and 2.895(4) A. Otherwise, there are no other
ꢀ
ꢀ
2
However, for the NoxF triad the additional C atom between the
pyridyl-N and amide N–H (amide group is reversed) facilitates
the additional intramolecular N–H/Npyr interaction as S(5)
rings but mitigates against cyclic dimer formation (Fig. 6). This
intramolecular interaction forces the No ring in all NoxF
compounds to have the N-syn conformation.
direction specific interactions (Fig. 6) apart from a C–H/
ꢀ
O]C interaction (C/O ¼ 3.362(4) A) that links the (A) and
(B) molecules within the asymmetric unit.
In NooF the molecular structure (Fig. 7) is essentially planar
with only a small twist (<10ꢁ) of the three principal groups from
co-planarity (Table 2). A minor impurity of a chloro atom is
noted in a meta position on the pyridinyl ring. As in NmoF, there
is molecular bending in the amide group with respect to the two
In NopF the intramolecular N–H/Npyr is present with an
intramolecular C12–H12/O1 contact.
interaction further links the NopF molecules into 1D chains
A
C16–H16/O1
ꢀ
terminal aromatic rings in NooF, with C11 at 0.087(9) A and C21
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3
ꢀ
[241 A ] at 150(1) K {in contrast to Mpp (Fig. 1 in ref. 12) which
has the smallest with Mop the largest V/Z in the Mxx series12},
3
whereas NpmF [258 A ] and NpoF [257 A ] have the largest
3
ꢀ
ꢀ
molecular volumes in space group Cc. The range of volumes for
3
the remaining six NxxF molecules is narrow from 247 A for
ꢀ
3
NooF to 250 A for NmmF/NomF. The average molecular volume
ꢀ
3
3
ꢀ
ꢀ
is 250 A for all nine NxxF isomers as compared to 268 A for
Mxx,12 the difference being replacement of the F atom with CH3
in the latter.12
Melting points continue to be largely ignored in solid-state
chemistry40–42 apart from listing data values and ranges.
Within an isomer series with identical molecular weights and
numbers of each elemental component, some general trends
can be discerned and compared with literature data.40,41 This
will be of additional use in comparing expanding studies of
related isomer series.40,41 Melting point trends show the three
NoxF compounds have the lowest melting points compared to
the other six NpxF, NmxF and by ꢄ30 to 40 ꢁC: these six
NpxF, NmxF isomers have melting points within a 23 ꢁC
range (Table 3). The highest mp is for NpoF (139–140 ꢁC),
the lowest is NomF (77.2–78 ꢁC). The trends show as (a) the
NpxF triad (136 ꢁC average) > NmxF (124 ꢁC) > NoxF (93
ꢁC) and (b) within each of the NxxF triads there is a tendency
for the NxmF to have the lowest melting points. These
differences are not as dramatic as noted in the related Mxx
series where a range of 100 ꢁC is observed for the nine Mxx
isomers:12 therein, Mmo has the lowest melting point (78.8–
80.0 ꢁC) and similar to NomF (77.2–78.0 ꢁC). The Mxx and
NxxF series differ by a reversed amide bridge and substitution
of a CH3 group for an F atom on the C6 ring with Mxx
following the para-substitution > ortho- > meta-substitution
melting point trend in disubstituted benzenes.40–42 A ration-
alisation as why the melting point range is much greater in
the Mxx grid in comparison to the NxxF series may be due
to the weaker interactions. The methyl group in the Mxx
series forms weak but favourable and cumulative secondary
C–H/O/p(arene) interactions and reinforced especially in the
high melting point of Mpp (180.2–180.8 ꢁC).12 In NxxF the
effect of the F atom is smaller and weaker in supramolecular
aggregation (as weaker C–H/F interactions and contacts)
and does not justifiably preserve aggregation especially at the
melting point event. Only in NmpF and NmoF are the C–H/
Fig. 7 The N1–H1/N22/F12 intramolecular interactions in NooF (with
the minor Cl site depicted at C25).
ꢀ
at 0.033(11) A from the O1/C1/N1 amide group plane and with
C11 and C21 positioned on the same side. In NooF there are two
distinct intramolecular interactions from the amido group as (a)
ꢀ
N1–H1/F12 with the ortho-F12 [N1/F12 ¼ 2.655(3) A, N1–
H1/F12 ¼ 103ꢁ] and (b) N1–H1/N22 with the ortho-N22
ꢁ
ꢀ
[N1/N22 ¼ 2.630(3) A and N1–H1/N22 ¼ 115(2) ]: C16–
H16/O1 is an additional intramolecular contact (Fig. 7). These
interactions facilitate the N-syn/F-syn conformation in NooF.
Surprisingly, there are no intermolecular N1–H1/X interac-
tions (where X ¼ C/N/O/F) in NooF with the two closest N1/C
ꢀ
atoms at 3.539(3) A (C16 positioned at the symmetry equivalent
ꢀ
position 1 + x, y, z) and at 3.577(3) A for C23 (at x ꢂ 1, y, z). The
ꢀ
closest N1/H atom contact is H23 at 3.30 A (at ꢂx, ꢂy, ꢂz).
The lack of H bonding involving the amide N1–H1 is interesting
as it is the strongest donor group in NooF. The dominance of the
intramolecular N–H/F and N–H/N interactions with inter-
molecular steric packing effects prevents the close approach of
suitable acceptor atoms/groups; the effect is noted in the 1H
NMR in DMSO-d6. A stacking contact is present with C1/C23
ꢀ
(at x ꢂ 1, y, z) ¼ 3.335(4) A which manifests along the a-axis
direction. Furthermore NooF is of interest as it has potential as
a ligand for exploitation in coordination chemistry using a N2F
donor set.17
Analysis of the Cambridge Structural Database (CSD)8,31
(version 5.31 + 3 updates) reveals six compounds reported in the
literature with the same C12H9FN2O formula as the NxxF isomer
grid. Three structures (Fpp, Fmp, Fop)11 have the amide group
reversed when compared to NxxF, however, they differ consid-
erably in packing although the primary intermolecular interac-
ꢀ
F interaction distances considerably shorter (0.2 to 0.3 A)
than the contact radii. For comparisons of the Mxo and
NoxF series, the ortho-pyridine N atom facilitates dimer
formation as R2 (8) rings in Mxo, but only as intra-
2
tion is amideN–H/Npyr
.
11 Analysis of the three principal groups
molecular amideN–H/Npyridine interactions in NoxF and in
both series only weak additional aggregation interactions
are observed. These factors may explain why the NoxF triad
has the lowest mp data in the NxxF series, but the Mxo
triad as hydrogen bonded ‘dimers’ exhibits relatively higher
average melting points.
(2 ꢀ ring: amide) in (phenyl)benzamides on the CSD8,31 (153 hits
and 270 fragments, using ortho-ring H atoms and similar to
NxxF for x ¼ p-, m-) shows the three interplanar angles have
mean values from 24ꢁ to 34ꢁ and similar to the interplanar angles
observed in NmoF, though considerably greater than in the
almost planar NooF. Where sterically bulky groups are posi-
tioned in an ortho position on either ring the interplanar angles
increase dramatically towards orthogonality; this was observed
and commented on previously in the Mxo series.12
3.3 Ab initio calculations
3.3.1 Structure optimisation results. The main structural
aspects of the optimised NxxF structures are presented in Table
4. The three most important torsion angles are the C26–C21–
C1]O1 angle (a) between the C5N ring and amide group, the
3.2.4 Comments on molecular volumes and melting points. The
symmetrical NppF isomer has the smallest volume per molecule
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Table 3 Melting point data for the NxxF and Mxx12 derivatives
3.3.2 Conformational analysis. Conformational analyses in
the gas phase establish those conformations that are favourable;
Fig. 8 highlights the nine NxxF PES optimised in the gas phase
including both the N-ring (full line) and F-ring (dashed line). The
high modularity of all nine NxxF isomers is noted (as from the
NMR data). Each pyridine (N) or fluorophenyl (F) group has
a typical PES shape, and as each NxxF molecule is a combination
of a Nx and xF moiety, the expected arrangement is easy to
visualise with the amide link as a linker group separating both
aromatic rings. For the Np and pF rings all conformations at
their minima are energetically identical; for the Nm ring the N-
syn conformation is the most stable, although the N-anti
conformation is possible, but less likely. The No ring exists only
in the N-syn conformation, while for oF the F-syn conformation
is preferred. In NooF the intramolecular N1–H1/N22 interac-
tion is augmented by the weaker N1–H1/F12 hydrogen bond
(local maxima positions of both No and oF curves show that the
N–H/N interaction energy is ca. twice the strength of the N–
H/F). In comparison, the mF ring diagrams show that the
difference between the preferred F-syn and F-anti conformations
is small (0.58 kJ molꢂ1) and both conformations are possible.
This possibility is demonstrated in two cases (a) the NpmF
structure (Z0 ¼ 1) (Fig. 2) has the F-syn conformation and (b) the
NomF structure (Fig. 6) is disordered at F15A [occupancy
6.1(5)%]. When averaged over both molecules the mF rings have
ca. 3% as F-syn and 97% in the F-anti conformation.
NxxF
mp/ꢁC
Mxx12
mp/ꢁC
NppF
NpmF
NpoF
NmpF
NmmF
NmoF
NopF
NomF
NooF
135.0–136.5
131.2–133.6
139.0–140.0
131.5–133.8
121.2–122.6
116.7–118.2
92.0–96.0
Mpp
Mmp
Mop
Mpm
Mmm
Mom
Mpo
Mmo
Moo
180.2–180.8
106.7a
128.6–129.1
128.2–128.8
90.0–91.0
107.5–108.5
104.0–106.0
78.8–80.0
77.2–78.0
105.0–108.0
115.0–117.1
a
For Mmp the melt occurs at 106.7 ꢁC, a partial melt at 73.8–74.5 ꢁC.
C1–N1–C11–C12 angle (b) between the C6 and amide group and
the O1]C1–N1–C11 amide angle (d). In general, all of the NxxF
structures can be regarded as almost planar. The NoxF triad is
essentially planar with no discernible differences regarding the
medium (gas phase or solvation). The remaining six (NpxF,
NmxF) isomers have torsion angles deviating from planarity. In
the gas phase the a torsion angles of NpxF and NmxF rotate from
planarity by 24.55 ꢃ 1.67ꢁ, the d angle by an average of 3.51 ꢃ
0.24ꢁ and b by only 2.80 ꢃ 0.86ꢁ. In CH2Cl2, the six (NpxF,
NmxF) isomers have a torsion angles rotated by 29.18 ꢃ 1.34ꢁ
and b angles by an average of 3.58 ꢃ 0.76ꢁ; the d angle twists by
3.56 ꢃ 0.73ꢁ. For H2O, the NpxF and NmxF structures have
a torsion angles twisted by 28.26 ꢃ 1.07ꢁ and d angles by 3.06 ꢃ
0.64ꢁ. However, the b torsion angle is 11.99 ꢃ 0.14ꢁ for NppF and
NmpF but in NpmF, NpoF, NmmF and NmoF is smaller at 3.71 ꢃ
0.58ꢁ.
In summary, the optimised structures (gas phase) typically
have N-syn/F-syn conformations but the exceptions are NxmF
where the N-syn/F-anti conformation is the most stable. Differ-
ences between the N-syn/F-syn and N-syn/F-anti conformations
are small with both being plausible.
Overall, optimisation of the NxxF isomers predicts that the
three NoxF isomers are stabilised by the intramolecular amide
N1–H1/N22 interaction (from the crystallographic and spec-
troscopic evidence for the relatively planar NoxF series, Table 2,
Fig. 6 and 7). The other six NpxF and NmxF isomers distort from
co-planarity mainly through pyridine ring rotation from unfav-
ourable intramolecular H/H contacts. For the NpxF and NmxF
series the only notable differences between the structures opti-
mised in different media are the a angles (at ꢂ4.64 ꢃ 2.28ꢁ
optimised in CH2Cl2 and ꢂ3.71 ꢃ 1.67ꢁ in H2O); larger devia-
tions occur in the b angle for NppF and NmpF optimised in
water.
The conformational analysis results in the CH2Cl2 and H2O
solvents using the implicit PCM-SMD model are provided as
PES scans in the ESI†. Comparisons between the gas phase and
solvents reveal no conformation changes with all NxpF and
NxoF molecules (at the stationary point) having the N-syn/F-syn
conformation, while NxmF has the N-syn/F-anti conformations
regardless of the medium. Furthermore, the patterns of maxima
and minima are similar, but there are significant decreases in the
rotational energy necessary for flipping rings between confor-
mations. The implicit dielectric field in the PCM-SMD solvation
model predicts a decrease of the rotational barriers with
Table 4 Torsion angles (ꢁ) of optimised NxxF isomersa
Optimised in gas phase
Optimised in CH2Cl2
Optimised in H2O
a
b
d
a
b
d
a
b
d
NppF
NpmF
NpoF
NmpF
NmmF
NmoF
NopF
NomF
NooF
26.67
3.72
3.13
1.54
3.64
2.68
2.11
0.01
0.00
3.20
3.31
3.46
3.55
3.74
3.82
30.35
27.69
30.18
29.56
27.28
30.04
0.02
4.04
2.94
3.28
4.34
2.57
4.32
0.00
0.02
3.27
2.49
3.90
3.81
3.23
4.64
ꢂ0.02
ꢂ0.03
0.00
29.47
12.09
4.39
3.31
11.89
3.15
4.00
0.01
0.00
2.43
2.78
2.35
3.22
3.79
3.77
0.00
0.00
26.34
23.84
24.36
23.81
22.27
ꢂ0.02
0.00
27.53
27.58
29.76
27.29
27.94
0.01
0.00
ꢂ0.02
ꢂ0.01
0.01
0.01
0.06
0.01
0.00
ꢂ0.01
ꢂ0.01
ꢂ0.04
ꢂ0.01
a
The angle C26–C21–C1]O1 (N-ring) refers to the a; C1–N1–C11–C12 angle (F-ring) as b and O1]C1–N1–C11 angle (amide linkage) as d. All
geometries are based on B3LYP/6-311++G optimisation with PCM-SMD solvation model.
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Fig. 8 The PES conformational analysis for the nine NxxF isomers optimised in the gas phase: the equivalent solid state angle is depicted by (C), with,
if applicable, assigned identification letter and/or partial occurrence (%). High resolution figures and descriptions are provided in the ESI†.
potentially increasing conformational change. This model is
applicable only for solvents where the NxxF isomers are fairly
soluble. The high dielectric constant of water (3r ¼ 80) is
supposed to significantly reduce rotational barriers and disrupt
the NoxF intramolecular interactions. However, as is evident
from their insolubility in H2O and the calculated DGsolv (Section
5, ESI†), solvation in H2O is not favoured thermodynamically.
Spectroscopic data show that a solvent with a high dielectric
constant such as DMSO disrupts the intramolecular hydrogen
bonds in NoxF and supports ab initio predictions and results.
Differences in NxxF isomer conformations include (a) NpmF
having the F-syn conformation, (b) NmmF with an N-anti/F-anti
conformation, (c) the disordered molecule A in NomF where
a minor F site has the N-syn/F-syn conformation and surprisingly
(d) NpoF where the principal molecular conformation at
91.7(9)% occupancy has the F-ring in a metastable form in the F-
anti conformation.
In almost all cases the data values for the solid-state torsion
angles of the N-rings are on or near their calculated global minima
(Fig. 8)andoftenwithonlysmalldeviations. Theexceptionsinclude
the NmringsinNmpFand NmmF. ForNmpFwithZ0 ¼ 4 (Fig. 4) all
four independent molecules are planar in the hydrogen bonded
tetramer with the Nm ring torsion angles similar and located near
TSNmI which represents a relatively unstable position (gas phase).
However, the solid-state conformation allows the meta-pyridine N
atom to form intermolecular N1–H1/N23pyr hydrogen bonds
augmented by two flanking C–H/Npyr intermolecular interac-
tions. Ultimately the NmpF supramolecular structure represents
a hydrogen bonded tetramer aggregating from a series of weak but
cumulatively important N/C–H/Npyr interactions.
4
Comparison of the NxxF isomers
The nine NxxF isomers derived both from calculations and
crystal structures are compared by showing the differences in the
corresponding torsion angles (Dq) as (C) for each crystal
structure in each PES diagram (Fig. 8). For NppF, NmpF and
NomF with Z0 > 1, molecules are labelled as A, B, etc. and for
disordered systems (NomF, NpoF) the symbol (C) has an
assigned identification letter and partial occupancy (%).
In general, most solid state NxxF conformations correspond
with their gas phase or solvated structures without significant
torsion angle differences. Thermodynamically, formation of
intermolecular bonds and contacts in the NxxF crystallization
process brings stabilisation that is more than sufficient to over-
come destabilisation from torsion angle deviations.
For the NmmF structure the Nm ring torsion angle has the N-
I0
anti conformation in a metastable LMNm potential well. Despite
this unusual conformation, examination of the crystal packing
shows that the N-anti conformation facilitates the 1D chain of
N1–H1/N23 hydrogen bonding that is essential as the crystal
structure backbone.
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In contrast to the N-ring, the solid state F-ring torsion angles
usually do not overlap with the corresponding gas phase model
angle: the deviation Dq is almost ꢃ30 to 50ꢁ, excluding the
structures that are planar or close to planarity (NmpF, NomF,
NooF) and the NpoF structure. The NomF and NooF are the only
structures where the solid state structures correspond closely
with only a slight Dq deviation from the model structures.
Another phenomenon is noted in NpmF where the F-ring solid
state conformation is F-syn, although the F-anti conformation is
slightly thermodynamically favoured from calculations. The
main backbone of the NpmF crystal structure is the N1–H1/
N24b hydrogen bond (Fig. 2) forming C(7) 1D chains. As the F-
ring adopts the F-syn conformation, the H15 atom interacts with
analytical and spectroscopic methods. Ab initio calculations of
the nine NxxF isomers have been performed and the energy and
geometry of the optimised structures determined and analysed.
The molecular and crystal structures of all nine NxxF isomers
have been determined and compared with closely related struc-
tures on the CSD,8,31 as well as the global minima from calcu-
lations. Eight NxxF structures have the amideN–H/Npyridine
hydrogen bond as the primary interaction with the NppF isomer
with aggregation via N–H/O]C interactions. Furthermore,
analysis of the disordered structures has allowed an in-depth
consideration of the computational results with the crystal
packing. The unusual hydrogen bonded tetramer of NmpF is
reported with the tetrameric assembly rationalised in terms of the
directional and spatial arrangements of the N–H donor and N
acceptors.
ꢀ
O1 [C15/O1d ¼ 3.202(4) A] linking 1D chains into 2D sheets.
The F13 atom forms weak contacts (as H22, H23/F13f) with
neighbouring molecules, and augmenting the 2D sheets, which,
via C25–H25/p(arene) contacts link the 2D sheets into a 3D
structure. These contacts (Fig. 2) would not be possible if the F-
ring adopted the F-anti conformation. A steric and repulsive
clash of F13/O1d would result with the C15–H15/O1d inter-
action and F/H contacts negated (per molecule). Therefore, the
F-syn conformation, despite its meta-stability in gas phase, is
essential for the NpmF crystal structure assembly and stability.
The minor site with the N-syn/F-syn conformation in NomF (at 3%
occupancy) is interesting where analysis of the mF ring shows that the
F-syn conformation is similar to the F-anti conformation and
allowing F-syn to seem statistically probable. Analysis of the NomF
structure shows that the F atoms at their thermodynamically fav-
oured and major site (F13A/B, F-anti) are positioned to interact with
neighbouring molecules via weak C–H/F–C and C–F/F–C
The 3 ꢀ 3 isomer grid series is being expanded with key
modifications to the phenyl and pyridinyl rings with a view to
extending our ability to make extensive comparisons between
large numbers of closely related compounds in terms of spec-
troscopic analysis, crystal structure analyses and computational
calculations. Future research work will focus on polymorphs,
solvates and salts of these isomers.
Acknowledgements
The authors thank Dublin City University and the Irish
ꢂ
Government for postgraduate funding for Mr Pavle Mocilac
under the PRTLI-4 T3 funded initiative and especially the T3
Programme Manager Dr Neal Lemon in managing the PRTLI-4
T3 programme. The authors thank Dr A. M. Elena and Dr J.-C.
Desplat from the Irish Centre for High End Computing
(ICHEC) for advice and assistance.
ꢀ
interactions with F13A/C24A ¼ 3.339(4) A and F13A/F13A ¼
ꢀ
2.896(3) A. The F-syn conformation gives fewer possibilities for F/
H/F/C interactions compared to the present arrangement which
contributes to the overall crystal structure. Given that the difference
between F-syn and F-anti is 0.58 kJ molꢂ1, the minor F-syn confor-
mation is presumably statistical disorder, driven by kinetic factors.
The NpoF structure is atypical with 91.7(9)% of the NpoF
molecules in a thermodynamically unfavourable metastable local
minimum LMoFI with the ortho-F atom at F12. The NpoF isomer
is isomorphous with NpmF in space group Cc. A study of the
crystal packing of NpoF shows that with the minor F16 atom site
[at 8.3(9)%], positioned as F-syn, is directed near the N1–H1/
N24 primary intermolecular interaction [with F16/N24 ¼
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