The consistent hexameric paddle-wheel crystallisation motif of a family of 2,4-bis(n-alkylamino)nitrobenzenes: Alkyl = pentyl, hexyl, heptyl and octyl

Article abstract of DOI:10.3184/174751917X14902201357356

Three examples of 2,4-bis(n-alkylamino)nitrobenzenes have been crystallised (alkyl = pentyl, hexyl and heptyl) and the single crystal structures were determined. The three structures are similar and adopt a cyclic hydrogen bonded hexameric motif. n-Octyl alkyl chains prevented a crystal structure determination owing to disorder.

Full text of DOI:10.3184/174751917X14902201357356

JOURNAL OF CHEMICAL RESEARCH 2017
VOL. 41 APRIL, 235–238
RESEARCH PAPER 235
The consistent hexameric paddle-wheel crystallisation motif of a family of
2,4-bis(n-alkylamino)nitrobenzenes: alkyl = pentyl, hexyl, heptyl and octyl
M. John Plater*, William T.A. Harrison, Laura M. Machado de los Toyos and Lewis Hendry
Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, UK
Three examples of 2,4-bis(n-alkylamino)nitrobenzenes have been crystallised (alkyl = pentyl, hexyl and heptyl) and the single crystal
structures were determined. The three structures are similar and adopt a cyclic hydrogen bonded hexameric motif. n-Octyl alkyl chains
prevented a crystal structure determination owing to disorder.
Keywords: hexameric, hydrogen bond, supramolecular, crystallisation, porous, 2,4-bis(alkylamino)nitrobenzenes
DNA is known for its ability to store and transfer genetic
information.1 However, the discovery of the guanine-quadruplex
structure has highlighted a new function for DNA in biology.2
Guanine-quadruplexes are four-stranded nucleic acid secondary
structures formed by DNA molecules (Fig. 1). The planar,
stacked, guanine-quadruplexes are formed by Hoogsteen
hydrogen bonding of guanine bases rather than by Watson–
They can form readily in solution under
Crick base pairing.3
physiological conditions. Their stabilisation is dependent on
the presence of the monovalent cations sodium and potassium.4
Potassium ions are more physiologically relevant than sodium
ions owing to their high intracellular concentration. The
stabilisation of the quadruplex is due to the coordination of the
cations by the guanine oxygen atoms in the channel formed by
the stacked guanine-tetrads.5
H
R
N
N
N
R
N
N
H
Recently we reported the crystal structures of non-biological
cyclic hexameric motifs formed from six 2,4-bis(butylamino)
nitrobenzene molecules or six 2,4-bis(phenylamino)
nitrobenzene molecules in which adjacent molecules are
linked by N–HO hydrogen bonds (Fig. 2).6 The hexamers
formed from 2,4-bis(butylamino)nitrobenzene have a staggered
stacking arrangement so that channels do not occur in the
crystal but the hexamers formed from 2,4-bis(phenylamino)
nitrobenzene are stacked on top of each other so that large
channels arise. This work might be related to solution
studies by Whitesides and Reinhoudt on melamine–cyanuric/
barbituric acid hexamers, although the building blocks here
are different and there are fewer hydrogen bonds to support
N
N
H
H
N
O
O
N
M+
H
N
H
H
N
N
H
H
O
N
O
H
N
N
H
N
N
N
R
N
N
H
R
Fig. 1 A guanine-quadruplex formed from Hoogsteen hydrogen bonds
and a templating monovalent cation.
NO2
H
NO2
H
N
N
HN
HN
1
2
Fig. 2 Hexameric hydrogen-bonded motifs: 2,4-bis(butylamino)nitrobenzene (1) and 2,4-bis(phenylamino)nitrobenzene (2).
* Correspondent. E-mail: m.j.plater@abdn.ac.uk

236 JOURNAL OF CHEMICAL RESEARCH 2017
NO2
NO2
F
R-NH2
NHR
4
5
R = n-pentyl
R = n-hexyl
EtOH/150 oC/15
h
6
7
R = n-heptyl
R = n-octyl
F
NHR
3
Scheme 1 Synthesis of the alkyl-substituted building units.
the self-assembly of the hexamer.7–10 Derivatives of melamine
and dibutylbarbituric acid can aggregate into different motifs,
but the use of a more crowded melamine derivative favours
the formation of single hexamers known as rosettes.11–13 In the
light of these interesting studies we sought further examples to
explore the structural requirements of the building block 1 that
lead it to crystallise in the hexamer motif. However, it should
be noted that not all derivatives crystallise as hexamers.6
Fig. 3Themolecularstructureofcompound4, showing50%displacement
ellipsoids. The intramolecular N–HO hydrogen bond is indicated by a
double-dashed line. The alkyl chain disorder is not shown.
Discussion
Compounds 4–7 were prepared in yields ranging from 44–70%
by reacting 2,4-difluoronitrobenzene (3) with the appropriate
long-chain amine (Scheme 1). Both of the fluorine atoms
in 3 are activated by the nitro group and can be displaced
by nucleophilic substitution (SNAr). Our previous studies
showed that the fluorine atoms can be distinguished with
good selectivity and that the ortho fluorine atom is completely
displaced first.6 The para fluorine atom is slower to displace but
this does occur with an excess of amine present.
Crystal structures
Compound 4 is essentially isostructural with the same space
group and packing6 as compound 1 (compare to Fig. 2), with one
molecule in the asymmetric unit in the trigonal space group. The
pentyl chains adopt extended conformations, with the terminal
methyl group of the para-chain statistically disordered over two
adjacent sites and an intramolecular N–HO hydrogen bond
from the ortho-NH group to one of the nitro group oxygen atoms,
which closes an S(6) ring (Fig. 3). The nitro group is almost
coplanar with its attached ring [dihedral angle = 2.34(2)°]. In the
crystal, the molecules are linked by N–HO [HO = 1.96(2)
Å; N–HO = 132(2)°] hydrogen bonds (from the para-NH
group) to generate hexamers (Fig. 4), which have point symmetry
about their centroids. Each intermolecular N–HO [HO
= 2.23(3) Å; N–HO = 165(2)°] hydrogen bond is reinforced
by an adjacent short C–HO [HO = 2.35 Å; C–HO =
168°] interaction from the 5-position of the benzene ring, as seen
previously.6 No other short directional intermolecular interactions
could be identified. The rhombohedral crystal symmetry for 4
means that the stacking pattern for the hexamers in the c direction
is staggered and therefore no channels are apparent as they are
in compound 2.6 However, a PLATON14 analysis indicated a
significant void of volume ∼240 Å3, centred at the origin, the
centroid of the hexamer and symmetry equivalent locations
presumably corresponding to regions of highly disordered solvent
molecules.
Fig. 4 Partial packing diagram for compound 4 showing the N–HO
plus C–HO hydrogen-bonded hexameric motifs and the ‘nestled’
alkyl chains. The C-bound H atoms not involved in hydrogen bonds are
omitted for clarity. The alkyl chain disorder is not shown.
Compound 5 crystallises in the triclinic space group with
six molecules in the asymmetric unit (Fig. 5). Four of the
six molecules feature disorder of the terminal atoms of the
para-alkyl chains and an intramolecular N–HO hydrogen
bond occurs within each molecule. Despite the lower crystal
symmetry, the packing for compound 5 is essentially the same as
for compound 4 and a hexamer arises, with N–HO hydrogen
bonds and reinforcing C–HO links between molecules. One
reason for the symmetry lowering may be that some of the para-
hexyl chains adopt non-extended conformations (i.e. gauche
Fig. 5Themolecularstructureofcompound5, showing50%displacement
ellipsoids. The hydrogen bonds are indicated by double-dashed lines.
Note that some of the terminal methyl groups are orientated out of the
plane of the hexamer. The alkyl chain disorder is not shown.

JOURNAL OF CHEMICAL RESEARCH 2017 237
void of volume ∼240 Å3 centred at the origin, the centroid of the hexamer
and symmetry equivalent locations, presumably corresponding to
regions of highly disordered solvent molecules. The application of
PLATON/SQUEEZE17 indicated a very low electron density of about 14
e per cavity, although a small reduction in R-factors was achieved. The
final R-factors for compound 6 and especially compound 7 are extremely
high (see below), but chemically plausible structures have resulted and
their gross features can at least be discerned.
4: C16H27N3O2, Mr = 293.40, yellow block, 0.06 × 0.05 ×
0.03 mm, trigonal, space group (No. 148), Z = 18, a = 29.6593(7) Å,
c = 10.4920(6) Å, V = 7993.0(6) Å3 at 100 K. Number of measured and
unique reflections = 35044 and 4071 respectively (–38 ≤ h ≤ 32, –38
≤ k ≤ 38, –13 ≤ l ≤ 13; 2θmax = 54.9°; Rint = 0.069). Final R(F) = 0.067,
wR(F2) = 0.163 for 199 parameters and 2641 reflections with I > 2σ(I)
(corresponding R-values based on all 4071 reflections = 0.108 and
0.185 respectively), CCDC reference number 1518390. The presumed
disordered solvent is not included in the calculations of Mr etc.
5: C18H31N3O2, Mr = 321.46, orange rod, 0.31 × 0.06 × 0.06 mm,
triclinic, space group (No. 2), Z = 12, a = 18.3214(3) Å, b = 18.6127(4)
Å, c = 20.0953(4) Å, α = 104.147(2)°, β = 105.226(2)°, γ = 111.987(2)°,
V = 5663.6(2) Å3 at 100 K. Number of measured and unique reflections
= 89863 and 25863 respectively (–23 ≤ h ≤ 23, –24 ≤ k ≤ 24, –26 ≤ l ≤
26; 2θmax = 55.0°; Rint = 0.048). Final R(F) = 0.063, wR(F2) = 0.143 for
1240 parameters and 16177 reflections with I > 2σ(I) (corresponding
R-values based on all 25863 reflections = 0.111 and 0.165 respectively),
CCDC reference number 1518391.
6: C20H35N3O2, Mr = 349.51, orange block, 0.30 × 0.10 × 0.07 mm,
triclinic, space group (No. 2), Z = 18, a = 11.2731(3) Å, b = 30.5744(7)
Å, c = 31.0881(8) Å, α = 62.603(2)°, β = 85.518(2)°, γ = 87.659(2)°,
V = 9484.0(4) Å3 at 100 K. Number of measured and unique reflections
= 109635 and 35305 respectively (–13 ≤ h ≤ 13, –37 ≤ k ≤ 37, –37 ≤ l ≤
37; 2θmax = 51.0°; Rint = 0.055). Final R(F) = 0.094, wR(F2) = 0.234 for
2015 parameters and 20746 reflections with I > 2σ(I) (corresponding
R-values based on all 35305 reflections = 0.156 and 0.267 respectively),
CCDC reference number 1518392.
C–C–C–CH3 torsion angles), with the terminal methyl groups
displaced either above or below the plane of the hexamer. In
terms of stacking, the hexamers are staggered and no channels
are apparent in the extended structure.
Compound 6 crystallises in the triclinic space group with nine
molecules in the asymmetric unit (see ESI, Figs 6 and 7), but
again hexamers arise in the crystal. One of these is comprised
of six independent molecules and the other is centrosymmetric
(i.e. has point symmetry about its centroid) and comprises three
unique molecules and their inversion-generated clones. In both
cases, cooperative N–HO and C–HO bonds link adjacent
molecules within their hexamers, as seen for compounds 4 and
5. No channels are evident in the extended structure.
In terms of compound 7, the refinement is extremely poor
and the terminal portions of some of the octyl chains are badly
disordered or indistinct (see ESI, Figs 8 and 9). However, it
may be discerned that compound 7 (triclinic, space group )
crystallises with no fewer than 12 molecules in the asymmetric
unit. Here, there are two independent hexamers, each comprised
of six unique molecules, with the same complementary
N–HO and C–HO links between the molecules as seen
in compounds 4–6.
Conclusion
The syntheses and crystal structures of the family of
2,4-bis(alkylamino)nitrobenzenes (alkyl = nC5–C8) have been
described. Although the crystal symmetries are different, which
possibly correlates with different orientations of the terminal
parts of the alkyl chains, a robust supramolecular hexameric
N–HO hydrogen-bonded motif is present in each structure.
Experimental
The IR spectra were recorded on an ATI Mattson FTIR spectrometer
using KBr discs. The UV spectra were recorded using a PerkinElmer
Lambda 25 UV-Vis spectrometer with CH2Cl2 as the solvent. 1H
and 13C NMR spectra were recorded at 400 MHz and 100.5 MHz
respectively using a Varian 400 spectrometer. Chemical shifts (δ) are
given in ppm and measured by comparison with the residual solvent.
Coupling constants (J) are given in Hz. Low resolution and high
resolution mass spectra were obtained at the University of Wales,
Swansea using electron impact ionisation and chemical ionisation.
Melting points were determined on a Kofler hot-stage microscope.
7: C22H39N3O2, Mr = 377.56, orange rod, 0.32 × 0.09 × 0.08 mm,
triclinic, space group (No. 2), Z = 24, a = 21.8346(12) Å, b = 24.4599(11)
Å, c = 25.5751(12) Å, α = 97.386(4)°, β = 92.123(4)°, γ = 90.780(4)°,
V = 13534.0(12) Å3 at 100 K. Number of measured and unique
reflections = 112684 and 52845 respectively (–26 ≤ h ≤ 26, –30 ≤ k
≤ 29, –30 ≤ l ≤ 31; 2θmax = 52.0°; Rint = 0.099). Final R(F) = 0.204,
wR(F2) = 0.404 for 2463 parameters and 18381 reflections with I > 2σ(I)
(corresponding R-values based on all 52845 reflections = 0.359 and
0.461 respectively), CCDC reference number 1518393.
Single crystal growth
Synthesis of 2,4-bis(n-pentylamino)nitrobenzene (4) and general
For all samples, the starting material was dissolved in
dichloromethane/petroleum ether (40–60 °C) and the solution was left
to evaporate slowly at room temperature.
procedure
2,4-Difluoronitrobenzene (1.0 g, 6.28 mmol) and n-pentylamine
(3.0 mL, 25.1 mmol) in EtOH (8 mL) were sealed in a teflon-lined Parr
bomb and heated at 150 °C for 15 h. On cooling, the mixture was mixed
with CH2Cl2 (50 mL), extracted with aqueous HBr (8% 60 mL), dried
over MgSO4, filtered, concentrated under reduced pressure and then
purified by chromatography on silica gel. Elution with ether/petroleum
ether (40–60 °C) (25:75) gave compound 4: Yield 0.63 g (70%); yellow
solid; m.p. 123–124 °C [from CH2Cl2/petroleum ether (40–60 °C)];
Crystallography
The intensity data for compounds 4–7 were collected on a Rigaku
Mercury CCD diffractometer (Mo Kα radiation, λ = 0.71073 Å,
T = 100 K). The structures of compounds 4 and 5 were routinely solved
by direct methods with SHELXS-97,15 but uninterpretable E-maps
emerged for compounds 6 and 7 with SHELXS-97. However, the ‘dual-
space’ algorithm in SHELXT16 gave recognisable structures in space
group P1 for compounds 6 and 7, which were both transformed to the
centrosymmetric space group prior to refinement. All of the structural
models were completed and refined against |F|2 with SHELXL-2014.
Some of the terminal groups of the alkyl chains are disordered over
two orientations. The N-bound H atoms were located in difference
maps and refined freely for compound 4 or placed in idealised locations
(N–H = 0.88 Å) for compounds 5, 6 and 7 and refined as riding atoms.
The C-bound H atoms were placed in idealised locations (C–H =
0.97–0.99 Å) in all cases and refined as riding atoms. The constraint
Uiso(H) = 1.2Ueq(carrier) or 1.5Ueq(methyl C) was applied in all cases. For
compound 7, the benzene rings were modelled as rigid hexagons (C–C =
1.39 Å). For compound 4, a PLATON17 analysis indicated a significant
λ
(EtOH)/nm 415 (log ε 4.8), 405 (4.83), 402 (4.83) and 398 (4.82);
νmmaaxx(KBr)/cm–1 3317s, 2955m, 2929m, 2857m, 1614vs, 1579vs, 1543vs,
1459m, 1400s, 1328m, 1310vs, 1260vs, 1248vs, 1189vs, 1165vs, 1131vs,
1030vs, 817vs, 793w, 767w, 751s, 734s, 671s, 652m, 605m, 591vs and
555vs; δH (400 MHz; CDCl3) 0.91–0.96 (6H, m), 3.42–4.0 (8H, m),
3.72–3.76 (4H, m) and 3.20–3.28 (4H, m), 5.80 (1H, s), 5.91 (1H, dd,
J = 9, 2) and 8.0 (1H, d, J = 9) (2 × NH peaks missing); δC (100.1 MHz;
CDCl3) 13.4, 13.4, 22.4, 22.4, 28.5, 28.5, 29.1, 29.3, 43.0, 44.0, 90.0,
105.3, 123.5, 129.1, 148.6 and 154.2; m/z (orbitrap ASAP): 294.2175
[M+ H]+ 100%, C16H28N3O2;requires: 294.2176
Synthesis of 2,4-bis(n-hexylamino)nitrobenzene (5)
Following the procedure for 4, but using n-hexylamine (3.0 mL)
in place of n-pentylamine gave compound 5: Yield 603 mg (59%);

238 JOURNAL OF CHEMICAL RESEARCH 2017
yellow solid; m.p. 85–86 °C [from ether/petroleum ether (40–60 °C)];
λ
the EPSRC National Crystallography Service (University of
Southampton) for the X-ray intensity data collections.
max (EtOH)/nm 403 (log ε 4.8) and 252 (log ε 4.82); νmax (KBr)/cm–1
3320m, 3071w, 2929m, 2856m, 2952m, 1614vs, 1579s, 1543s, 1462m,
1401s, 1313s, 1259vs, 1191vs, 1167s, 1129s, 819vs, 752m, 593s and
564s; δH (400 MHz; CDCl3) 0.89–0.95 (6H, m), 1.30–1.49 (12H, m),
1.65–1.79 (4H, m), 3.18–3.28 (4H, m), 5.86 (1H, s), 6.03 (1H, dd, J = 9,
2 Hz) and 8.05 (1H, d, J = 9) (2 × NH peaks missing); δC (100.1 MHz;
CDCl3) 13.9, 14.1, 22.6, 26.7, 28.7, 31.5, 42.9, 44.0, 91.2, 105.1, 124.1,
129.2, 148.4, 153.5 (4 peaks are overlapping); m/z (orbitrap ASAP):
322.2497 [M+ H]+ 100%, C18H32N3O2; requires: 322.2497
Electronic Supplementary Information
The ESI [molecular structures of compound 6 (Figs 6 and 7)
and compound 7 (Figs 8 and 9)] is available through
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
CCDC1518390.
CCDC1518391,
CCDC1518392
and
CCDC1518393 contain the crystallographic supplementary data
for this paper. The data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via https://summary.
ccdc.cam.ac.uk/structure-summary-form
Synthesis of 2,4-bis(n-heptylamino)nitrobenzene (6)
Following the procedure for 4, but using n-heptylamine (3.0 mL)
in place of n-pentylamine gave compound 6: Yield 777 mg (70%);
yellow solid; m.p. 79–80 °C [from ether/petroleum ether (40–60 °C)];
λ
max (EtOH)/nm 406 (log ε 4.8) and 251 (log ε 4.83); νmax (KBr disc)/
Received 1 December 2016; accepted 7 March 2017
Paper 1604460
https://doi.org/10.3184/174751917X14902201357356
Published online: 28 March 2017
cm–1 3319m, 2626m, 2853m, 1614vs, 1578s, 1542s, 1514m, 1466m,
1403s, 1382m, 1313s, 1258vs, 1226s, 1188vs, 1167vs, 1130s, 1087s,
819vs, 752m, 593s and 564s; δH (400 MHz; CDCl3) 0.88–0.93 (6H, m),
1.31–1.46 (16H, m), 1.64–1.79 (4H, m), 3.18–3.27 (4H, m), 5.79 (1H,
s), 6.00 (1H, dd, J = 9, 2 Hz) and 8.04 (1H, d, J = 9) (2 × NH peaks
missing); δC (100.1 MHz; CDCl3) 14.0, 22.5, 26.9, 27.1, 28.8, 28.9, 28.9,
30.8, 31.7, 42.9, 43.7, 90.83, 105.0, 123.9, 129.2, 148.4, 153.8 (3 peaks
are overlapping); m/z (orbitrap ASAP): 350.2810 [M + H]+ 100%,
C20H36N3O2; requires: 350.2810.
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3323m, 2926m, 2853m, 1614vs, 1577s, 1540s, 1514m, 1465m, 1401s,
1379m, 1329m, 1312s, 1259vs, 1219s, 1188vs, 1166s, 1129s, 1090s,
1055m, 820vs, 752m, 594s and 570s; δH (400 MHz; CDCl3) 0.88–0.92
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C22H40N3O2; requires: 378.3126.
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We thank the EPSRC National Mass Spectrometry Service
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