Solution and Solid State Study on the Recognition of Hydroxyaromatic Aldoximes by Nitrogen Containing Compounds

Article abstract of DOI:10.1021/acs.cgd.5b01375

Structural aspects and fluorescence behaviors of a series of cocrystals of hydroxyaromatic aldoximes, namely, 2(H₂NAP)·(4,4′-bipyridine), 2(H₂NAP)·(HMTA), H₂NAP·caffeine, and (H₃OHPA)·theophylline·2H₂

Full text of DOI:10.1021/acs.cgd.5b01375

Article
pubs.acs.org/crystal
Solution and Solid State Study on the Recognition of
Hydroxyaromatic Aldoximes by Nitrogen Containing Compounds
Arup Tarai and Jubaraj B. Baruah*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, Assam, India
S
* Supporting Information
ABSTRACT: Structural aspects and fluorescence behaviors of
a series of cocrystals of hydroxyaromatic aldoximes, namely,
2(H2NAP)·(4,4′-bipyridine), 2(H2NAP)·(HMTA), H2NAP·
caffeine, and (H3OHPA)·theophylline·2H2O, where H3OHPA
= 2,3-dihydroxyphenylaldoxime, H2NAP = 2-hydroxynaph-
thaldoxime, HMTA = hexamethylenetetramine, were studied.
A difference in fluorescence behavior of oxime molecules in
solution and solid states was observed. The H2NAP·caffeine
cocrystals are fluorescence active in the solid state but not in
solution. The combinations of H3OHPA and 4,4′-bipyridine, HMTA or caffeine in the solid state did not yield cocrystals;
however, these combinations in solution caused fluorescence quenching of H3OHPA. On the other hand, a hydrated cocrystal of
H3OHPA with theophylline, namely, (H3OHPA)·theophylline·2H2O, was isolated and characterized. It was found that this
combination causes fluorescence quenching of 2,3-dihydroxyphenylaldoxime (H3OHPA) in the solution state but not in the solid
state as a cocrystal. The fluorescence change of H3OHPA interacting with theophylline can be identified among several aldoximes
such as 2-hydroxynaphthaldoxime (H2NAP), 2-hydroxyphenylaldoxime (H2PA), and 2,4-dihydroxyphenylaldoxime (H3PHPA).
The synthons involved in each cocrystal are identified, and the fluorescence emission differences leading to molecular recognition
are determined. The differences in fluorescent behavior among aldoximes were exploited for their identification and separation.
shown by Anslyn and co-workers14−16 project them as an
INTRODUCTION
■
important class of molecules needing attention from solid state
The chromophoric molecule in the solid state can be stacked by
the formation of cocrystals in a systematic manner to rationally
studies. Aakeroy’s group17−20 has established various synthons
of oximes and their cocrystals. Moreover, available green
alter luminescence properties.1 Jones and co-workers2 had
synthetic methods for the preparation of oximes have added a
shown that the fluorescence properties of face-to-face stacked
arrangements guided by weak aromatic interactions of
chromophoric compounds can be tuned by coformers. On
the basis of extensive studies, it was also suggested that the
orientation and stacking patterns of chromphoric units in a
crystal structures influence the luminescence of organic
new flavor with future prospects.21,22 Recently, we have shown
various assemblies of oximes generated by fluoride ions.23 The
pioneering research of Desiraju on the concept of synthons24
made a big impact in crystal engineering,25−27 and having said
this aromatic aldoximes have a large scope to serve as one of
the basis to study varieties of hydrogen bonded assemblies.28
Because of the directional nature of hydrogen bonds, there is
a large scope for different orientations of hydroxyaromatical-
doximes or in their host−guest complexes in the solid state to
construct new synthons.29 Generally aldoximes form assemblies
materials.3−5 A frequently occurred problem in tuning
fluorescence emissions has been to obtain a suitable packing
pattern that dictates the emission process.6 Strongly self-
interacting systems, namely, pyrene and its derivatives in the
solid state, generally show low fluorescence efficiencies due to
such effects. However, these problems can be overcome by
cocrystal formation with coformers.6 There are also examples of
anthrylpyrazole derivatives which show anthracene arrange-
ment dependent emissions in the solid state.7 Further, the
aggregation due to stacking and related weak interactions can
influence the fluorescence emission in different com-
pounds.8−10 Because of the difference in the fluorescence
property of a component of molecule in a cocrystal, there is
ample scope to study such properties in solid or in solution to
bring out diversity in applications. The fluorescence properties
associated with hydroxyaromatic oximes to sense nerve gas as
shown by Rebek and co-workers11−13 and the utilities of such
compounds in the detection of chemical warfare reagents as
having R2 (8) homosynthon21,22 as shown in Figure 1a, but
2
introducing a hydroxy group to the aromaticaldoximes such as
in 2-hydroxyphenylaldoxime (H2PA) changes self-assemblies,
and in this particular case R4 (10) type heterosynthon as
4
illustrated in Figure 1b was observed.30 Thus, it would be of
interest to know about synthons present in polyaromaticaldox-
imes and polyhydroxyaromaticaldoximes, as such compounds
would differ in packing patterns due to the presence of the
polyaromatic rings or the additional hydroxy groups. Two such
Received: July 20, 2015
Revised: November 14, 2015
© XXXX American Chemical Society
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fluorescence studies in solution were carried out to see if such
selectivity in interactions can be obtained in the solution state
too. To understand if any change in the chemical shift of the
protons of the oxime molecules takes place it was essential to
record a 2D HOMOCOSY of the oxime molecules so as to
clearly assign the aromatic peaks through the correlation (cross
peaks). From the correlation shown in Supporting Figure 1S
(H2NAP) and 2S (H3OHPA), we arrived at the assignment of
each peak on the aromatic ring. The respective solution of the
Figure 1. (a) Homosynthon observed in aldoximes and (b)
heterosynthon observed in 2-hydroxyphenylaldoxime (H2PA).
1
cocrystal did not show any change in the HNMR chemical
shifts of the protons on the oxime (Supporting Figures 3S−6S).
Fluorescence emissions of the H2NAP and cocrystals in
solution and solid state are discussed under a separate heading
to explain structural relationships.
examples are 2-hydroxynaphthaldoxime (H2NAP) and 2,3-
dihydroxyphenylaldoxime (H3OHPA) for which different
possibilities of arranging hydroxy groups as shown in Figure
2a,b exist. In this study we have explored the structures of these
Attempts were made to prepare cocrystals of H3OHPA with
theophylline or caffeine under analogous conditions used for
obtaining cocrystals of H2NAP with caffeine. Only a cocrystal
between H3OHPA and theophylline was obtained, but no
cocrystal between H3OHPA and caffeine was observed. In
addition to these the slow evaporation of methanol solutions of
oximes such as H2PA and H3OHPA with the coformers,
namely, 4,4′-bipyridine or hexamethylenetetramine or caffeine
or theophylline, did not yield any cocrystals, but precipitation
of the respective parent compounds was observed in each case.
The fluorescence behaviors of the cocrystals in solid are
different from the solution of the similar combinations, which
are listed in Table 1. To understand these observations, a
systematic structural study and consequences of packing in
their optical properties was examined.
Structural Study. Analysis of the structure of the H3OHPA
has shown that it has R4 (10) O−Haldoxime···O−Hhydroxy
4
heterosynthons similar to the heterosynthons found in the
structure of the H2PA.30 The self-assembly of the compound
has an intramolecular hydrogen bond of O−H of the 2-hydroxy
group with the nitrogen atom of the oxime as illustrated in
Figure 3a. The dimeric self-assembly of the H3OHPA has two
O−H···O interactions to stabilize a 10-member ring. The
crystal structure of H2NAP was reported earlier;31 it forms a
dimeric self-assembly by two C−H···O interactions to construct
a eight-member ring as illustrated in Figure 3b. The self-
Figure 2. Orientations of active hydrogen atoms in (a) 2-
hydroxynaphthaldoxime and (b) 2,3-dihydroxyphenylaldoxime. (c)
Coformers 4,4′-bipyridine, hexamethylenetetramine (HMTA), theo-
phylline, and caffeine.
assembly of the H2NAP is comprised of R2 (8) type
2
homosynthons, which has C−H···O interactions. Such
synthons are common in aldoximes.17−20 In this case, an
intramolecular hydrogen bond between the hydroxy group and
the nitrogen atom of oxime was observed. From the stability
point of the synthons observed in the case of H3OHPA and
H2NAP, the former has higher stability for obvious reasons for
the hierarchy of the bond strength between the O−H···O
interaction over a C−H···O interaction.
two compounds and also their cocrystals with a series of
nitrogen containing heterocyclic molecules (Figure 2c) that are
of general interest in crystal growth. We also correlated the
fluorescence properties in solid and solution states for
molecular recognition in these combinations.
Slow evaporation of the respective solution (in methanol,
dimethyl sulfoxide, acetonitrile, ethanol, etc.) of H3OHPA with
4,4′-bipyridine or HMTA or caffeine or theophylline yielded
crystals from only one of these combinations, namely, from the
solution of H3OHPA with theophylline. This cocrystal was a
dihydrate of a 1:1 cocrystal between H3OHPA and theophyl-
line. Self-assembly of this cocrystal is formed through hydrogen
bonds with the water molecules to hold the oxime and
coformer molecules. While forming self-assemblies as shown in
the Figure 4a, the dimeric assemblies that were present in the
packing pattern of the parent structure of the H3OHPA were
disrupted. In the cocrystal each aldoxime molecule forms water
assisted assemblies with theophylline. One O−H bond of water
molecule hydrogen bonds with the carbonyl oxygen atom of
RESULTS AND DISCUSSION
■
The H2NAP was found to be a good coformer and accordingly
from different solutions of H2NAP and 4,4′-bipyridine or
hexamethylenetetramine (HMTA) or caffeine 2:1 molar ratios
were allowed to crystallize, and the respective cocrystal was
crystallized. H2NAP formed a 2:1 cocrystal with 4,4′-bipyridine
or HMTA. But the cocrystal formed with caffeine was in a 1:1
ratio of H2NAP and caffeine. The theophylline molecule has a
close structural similarity with caffeine. Theophylline has an
N−H bond to form hydrogen bond, but H2NAP failed to yield
a cocrystal with theophylline. In this case the parent
1
compounds were recovered upon slow evaporation. H NMR
spectra of parent compounds and cocrystals were recorded, and
B
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Table 1. Different Cocrystals of Oximes and Fluorescence Properties
a
b
c
In solution no change. No cocrystal was obtained, hence solid state fluorescence not measured. Nonfluorescent in solid.
Figure 3. Dimeric assemblies of the compounds (a) H3OHPA and (b) H2NAP.
Figure 4. (a) Self-assemblies of hydrated cocrystal of H3OHPA with theophylline. (b) π−π interactions between oxime and coformer.
theophylline and the oxygen atom of the same water molecule
connects to the oxime O−H bond of the H3OHPA. The
carbonyl group of theophylline is involved in a bifurcated
hydrogen bond by connecting the phenolic O−H group
present at the 2-position of the aromatic ring. These
interactions yield a R3 (7) motif, which holds the key to
3
form the cocrystal of three components. The orientation of the
active hydrogen atoms of oxime in this cocrystal is different
with respect to the orientations observed in the parent oxime
without a coformer. The parent oxime molecule adopts the
C
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Figure 5. Structures of cocrystals of H2NAP with (a) 4,4′-bipyridine, (b) HMTA, and (c) caffeine. (d−f) Different weak interactions present in the
packing patterns of the three cocrystals.
orientation IX of the Figure 2, but the orientation X shown in
the Figure 2 is observed in the cocrystal. An interesting feature
of this cocrystal is the stacking interactions between theophyl-
line and oxime molecules. The molecules show π-stacking
(Figure 4b) between the rings with a separation distance 3.471
Å, which is conducive to strong π−π interactions.6 This
interaction originates from the dipolar nature of the theophyl-
line molecule which has an electron deficient ring to interact
with the electron rich ring of H3OHPA.
After attempted crystallization of various solutions of H2NAP
and 4,4′-bipyridine or HMTA or caffeine or theophylline,
cocrystals were obtained from three out of four such
D
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Article
independent combinations. Accordingly cocrystals 2(H2NAP)·
(4,4′-bipyridine) or 2(H2NAP)·(HMTA) or H2NAP·caffeine
were isolated but attempts to get cocrystals from the solutions
of H2NAP with theophylline failed. The precipitate obtained
from the solution of H2NAP and theophylline was analyzed by
a conventional technique (powder X-ray diffraction, PXRD,)
and found that the precipitate was composed of just a physical
mixture of two components. This confirmed that there was no
cocrystal formation in this particular case. The interesting
feature is that the cocrystals of H2NAP with 4,4′-bipyridine or
HMTA had a 2:1 molar ratio of oxime to coformer, whereas
with caffeine it was a 1:1 cocrystal. It may be mentioned that
polymorphic forms and solvates of caffeine with anthrallinic
acid was reported in the literature;32 moreover same host
molecule can form cocrystals with caffeine and theophylline
differing in molar ratios.33 Water bridged assemblies in the
cocrystals of caffeine or theophylline were also reported.34
Hence in anticipation of hydrated cocrystals in the present
study the powder XRD patterns of the bulk samples of the
cocrystals were examined to ascertain their phase purity
(Figures 7S−8S). All the cocrystals of H2NAP reported in
this study are found to be anhydrous, and no solvated cocrystals
were observed from any of the solvents used for crystallization.
But the cocrystal of H3OHPA with theophylline is a dihydrate.
The structures of the cocrystals of H2NAP with 4,4′-bipyridine
or HMTA possesses similar O−H···N interactions as shown in
Figure 5a,c, but the packing patterns widely differ. Packing
patterns are guided by O−H···N, C−H···O, and C−H···π
interactions in the cocrystals with 4,4′-bipyridine, but in the
case of the HMTA cocrystal, the packing pattern is guided by
O−H···N, C−H···O, C−H···π, and π···π interactions. Here
π···π interactions play a crucial role in distinguishing the
packing patterns of these two cocrystals.
not participate in a strong hydrogen bond. The cocrystal
H2NAP·caffeine has a strong CO stretching at 1704 cm−1
from the carbonyl group of the caffeine part. A similar carbonyl
stretching absorption in the IR spectra of the cocrystal
H3OHPA·theophyilline·2H2O appears at 1706 cm−1.
Fluorescence Studies. To ascertain the suitable wave-
lengths for fluorescence excitation studies, UV-visible spectra of
solid samples of each cocrystal were recorded. They show
broad absorption in the region of 350−400 nm originating
from the host molecule. The broadening arises due to a
proximity broadening effect from self-interacting molecules in
the vicinity in solid samples. The absorbance peaks of individual
oxime molecules and the corresponding cocrystals are given in
the Supporting Figure 9S. On the basis of the observation on
the UV−visible absorption shown by the oximes and cocrystals,
the emission spectra in each case were investigated by exciting
at 368 nm (Figure 6). The oxime H2NAP exhibited a broad
Parent H2NAP has an orientation II shown in Figure 2,
whereas in the cocrystals the oxime part has structure of
orientation I of Figure 2. In general the structures of the three
cocrystals of H2NAP may be suggested to be composed of
H2NAP molecules held by weak interactions with respective
coformers in two different ways. The first two cocrystals,
namely, with H2NAP with 4,4′-bipyridine or HMTA, are based
on either a planar or a nonplanar bridging unit anchoring two
guest molecules through O−H...N hydrogen bonds, whereas the
third cocrystal that is H2NAP with caffeine has two stacked
guest molecules holding two H2NAP molecules (Figure 5c).
The prominent weak interactions of these cocrystals are shown
in Figure 5d−f, and the hydrogen bond parameters are given in
the Table 1S.
The IR spectrum of H2NAP has O−H stretching frequency
at 3331 cm−1. This peak shifts to a higher wavenumber in the
case of each cocrystal and appears in the region 3445−3460
cm−1. Such shifts are attributed to the formation of hydrogen
bonds in the cocrystals through the oxime OH and nitrogen
atom of the respective coformer. The O−H frequency of
H2NAP is shifted in cocrystals; it is 3445 cm−1 in the 4,4′-
bipyridine cocrystal and 3446 cm−1 in the HMTA cocrystal,
whereas it is at 3460 cm−1 in the cocrystal with caffeine. This
trend is reflected in the O−H···N bond parameters; the caffeine
cocrystal has the higher donor−acceptor distance with the
largest O−H···N angle among the three cocrystals. The H2NAP
has CN stretching at 1632 cm−1, and the cocrystals of
H2NAP show a characteristic CN bond stretching in the
region of 1628−1658 cm−1. This shows that the CN bond is
intact in the cocrystals, and the nitrogen atom of this unit does
Figure 6. Solid state fluorescence emission spectra of the (i) H2NAP,
(ii) 2(H2NAP)·(4,4′-bipyridine), (iii) 2(H2NAP)·(HMTA), and (iv)
H2NAP·caffeine (excitation in each case at 368 nm).
emission band around 475−530 nm. The cocrystal of H2NAP
with caffeine showed a relatively higher fluorescence emission
intensity with a shift toward a shorter wavelength, whereas the
cocrystals of the H2NAP with 4,4′-bipyridine or hexamethyle-
netetramine are weakly fluorescent. This suggests that upon
cocrystal formation with 4,4′-bipyridine or HMTA the
fluorescence of the H2NAP gets quenched by the respective
coformer. In these experiments uniformity in sample
preparation was ensured by carrying out experiments with
similar amounts, and the fluorescence was measured under
identical conditions.
It is a well-known fact that fluorescence of organic
compounds in the solid state depends on the architecture of
crystal packing,35 and π···π stacking interactions cause
fluorescence quenching.6 On the other hand it was also
suggested that C−H···π interactions can contribute to
fluorescence changes.6 Aggregation such as H-aggregate formed
by assembling of the same type of molecules on top of each
other results in shifting of fluorescence to shorter wavelength,
whereas a J-aggregate does it in an opposite manner.36 The
difference of fluorescence in the present cocrystals illustrated in
Table 2 can be attributed to the respective packing patterns.
Close analyses of the structures of the H2NAP and cocrystals
have shown that self-assemblies of the oxime molecules are
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crystal density than the HMTA cocrystal, and both have several
weak interactions, but the latter has additional π···π
interactions. Since the cocrystals H2NAP with 4,4′-bipyridine
and HMTA are in 1:2 molar ratio, this factor contributes to
cause a large difference between the packing patterns of these
two crystals with respect to the packing pattern of the cocrystal
of H2NAP with caffeine which has a 1:1 molar ratio of host and
coformer. The caffeine molecules in the caffeine cocrystal are
positioned on top of the oxime molecules, and the center core
distance is 3.718 Å. The carbonyl group of caffeine molecule
forms a hydrogen bond with oxime. The naphthalene unit of
caffeine cocrystal is involved in C−H···π interaction with the
neighboring naphthalene unit present in the lattice. To have
effective π···π stacking interactions between two planar
fluorophoric π-units, they should have a parallel arrangement,
and each of the interacting rings must be positioned on top of
each other, whereas to have a center-dot C−H···π interaction
Table 2. Characteristic Fluorescence Properties of H2NAP
and Cocrystals in the Solid State
λab
λex
λem
quantum yields
compound/cocrystals
H2NAP
(nm)
(nm)
(nm)
ΦF
390
395
397
368
368
368
510
468
470
0.052
0.095
0.015
H2NAP·caffeine
2(H2NAP)·(4,4′-
bipyridine)
2(H2NAP)·(HMTA)
395
368
470
0.014
guided by several weak interactions. The weak interactions like
O−H···N, C−H···O, and O−H···O in the H2NAP and
cocrystals are shown in Figure 7a−d. The packing pattern of
each cocrystal is different from the packing pattern observed in
the parent oxime. From the crystal densities among these
cocrystals (Table 3), the 4,4′-bipyridine cocrystal has a lower
Figure 7. Packing diagram of (a) H2NAP, (b) cocrystals 2(H2NAP)·(4,4′-bipyridine), (c) cocrystals 2(H2NAP)·(HMTA), (d) cocrystals H2NAP·
caffeine. The stacking of the fluorphoric H2NAP in the cocrystal (e) (H2NAP)2·4,4′-bipyridine [∠67.17°], (f) (H2NAP)2·HMTA [∠76.06°], and (g)
(H2NAP)·caffeine [∠86.12°]. In each case the angle between the planes of the H2NAP is shown in the third bracket.
F
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Table 3. Crystallographic Parameters of the Host and the Cocrystals
H2NAP
(redetermined)
(H2NAP)2·4,4′-
(H2NAP)2·
HMTA
H3OHPA-theophylline·
H3OHPA
bipy
(H2NAP)·caffeine
2H2O
formula
C11H9NO2
187.19
C7H7NO3
153.14
C32H26N4O4
530.57
C19H19N5O4
381.39
C14H15N3O2
257.29
C14H19N5O7
369.34
mol wt
space group
a (Å)
P21/c
P21/c
P21/c
P21/c
Aba2
P21/n
14.856(2)
4.0568(6)
16.585(2)
90.00
11.211(10)
4.662(4)
14.146(12)
90.00
11.8301(5)
14.4094(6)
23.9854(10)
90.00
8.9467(9)
25.487(3)
8.8264(9)
90.00
10.0199(5)
27.8962(17)
9.1641(6)
90.00
8.8538(8)
17.6944(15)
10.7717(10)
90.00
b (Å)
c (Å)
α (deg)
β (deg)
115.029(9)
90.00
111.793(17)
90.00
96.922(3)
90.00
114.334(6)
90.00
90.00
90.464(5)
90.00
γ (deg)
V (Å3)
density, g cm−3
abs coeff, mm−1
F(000)
90.00
905.6(2)
1.373
686.5(10)
1.482
4058.9(3)
1.302
1833.8(3)
1.381
2561.5(3)
1.334
1687.5(3)
1.454
0.096
0.118
0.088
0.100
0.092
0.118
392
320
1668
800
1088
776
total no. of reflections
reflections, I > 2σ(I)
max θ/°
1616
1173
7344
3335
2320
3040
1147
599
3858
2709
1948
2308
25.24
25.25
25.25
25.25
25.24
25.24
ranges (h, k, l)
−17 ≤ h ≤ 16
−4 ≤ k ≤ 4
−19 ≤ l ≤ 19
98.70
−12 ≤ h ≤ 11
−5 ≤ k ≤ 5
−12 ≤ l ≤ 16
93.70
−13 ≤ h ≤ 14
−17 ≤ k ≤ 16
−28 ≤ l ≤ 28
99.90
−10 ≤ h ≤ 10
−24 ≤ k ≤ 30
−10 ≤ l ≤ 10
100.00
−7 ≤ h ≤ 7
−8 ≤ k ≤ 8
−15 ≤ l ≤ 15
100.00
−10 ≤ h ≤ 10
−20 ≤ k ≤ 21
−12 ≤ l ≤ 12
99.60
complete to 2θ (%)
data/restraints/
parameters
GOF (F2)
1616/0/129
1173/0/103
7344/0/547
3335/0/258
2320/1/175
3040/4/256
1.059
1.045
1.003
1.058
1.072
1.025
R indices [I > 2σ(I)]
wR2 [I > 2σ(I)]
R indices (all data)
wR2 (all data)
0.0414
0.0661
0.0623
0.0718
0.0721
0.1577
0.1337
0.1948
0.0481
0.1046
0.1119
0.1317
0.0573
0.1794
0.0704
0.1957
0.0384
0.1020
0.0475
0.1094
0.0428
0.1338
0.0575
0.1468
the interacting C−H of one ring should appear at a position
which is perpendicular to the central point of the other ring.
Thus, we examined the arrangements of the fluorophoric π-
units, namely, H2NAP in the cocrystals, and compared with the
packing pattern of the H2NAP. The angles between such planes
are shown in Figure 7e−g. In the case of the caffeine cocrystal it
is ∠86.12°, which is very close to a perpendicular arrangement
and hence has the least π···π stacking interactions but has better
C−H···π interactions among the others. On the other hand, the
parent compound does not have similar C−H···π interactions,
but the packing has rings at a slightly translated parallel position
to each other, so that a highly effective π···π stacking interaction
is not feasible. Further analysis of the other two cocrystals
shows a less than 90° angle between the planes suggesting the
positions of the rings to be nonparallel. However, the deviations
from perpendicular positions are not enough to cut off the
effective C−H···π interactions. Such qualitative analysis is not
good enough to form an overall picture to explain the
fluorescence changes. It can easily explain fluorescence changes
in three cases leaving aside the 4,4′-bipyridine cocrystals as an
exception. Complete segregation of H2NAP molecules in the
cocrystal with caffeine leads to monomer type arrangements to
show emission with higher intensity with a slight blue shift.
This may be compared to J-aggregate (H2NAP) transformed to
an arrangement of discrete monomers (H2NAP in caffeine
cocrystal).36 The parent compound can be considered as a
partially quenched state, and the π-stacking induced by the
HMTA cocrystal causes quenching of the fluorescence in the
case of the cocrystal with HMTA. To provide even a qualitative
explanation of the solid state fluorescence property of the
cocrystal with 4,4′-bipyridine, an explanation has to account for
three symmetry independent host molecules, which is difficult;
nonetheless we can suggest with the data available from the
experiments that parallel stacking of the pyridine ring of
bipyridine units could be the major factor contributing to the
quenching of fluorescence in this particular case.
To ascertain interactions between the H2NAP with the
coformers in solution, the fluorescence emission spectra of
solution of H2NAP by adding coformers were recorded. No
changes in fluorescence emissions were observed by these
coformers. Hence these results suggest that dilute solution
interactions between the respective coformer and H2NAP are
too weak to detect. Similar results are reflected in the 1H NMR
titrations between selected coformers with H2NAP where no
change in peak positions was observed (Figures S14−S15).
These results clearly demonstrate that the optical properties of
the compound H2NAP is not affected by coformers in solution
but in solid coformers play a major role to either enhance or
reduce the intensities and positions.
The compound H3OHPA is nonfluorescent, and its cocrystal
with theophylline is also nonfluorescent in the solid state. But
H3OHPA shows fluorescence in solution, whereas the
respective solution of compounds H2NAP or H3OHPA in
dimethyl sulfoxide−water mixture has an emission peak at 395
and 387 nm upon excitation at 310 and 270 nm, respectively.
The fluorescence emission of the H3OHPA at 387 nm was
gradually decreased upon addition of theophylline as shown in
the Figure 8. Similar changes were also observed at pH = 3 and
pH = 10 (Figure 10S). A relatively higher quenching effect was
observed at pH = 3 as compared to pH = 10; hence it may be
suggested that it is the exchange of hydrogen between the
hydrogen bond donor and acceptor that holds the key to the
quenching of fluorescence. The differences observed in
fluorescence by theophylline have prompted us to take up
G
DOI: 10.1021/acs.cgd.5b01375
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Crystal Growth & Design
Article
CONCLUSIONS
■
Two different hydrogen bonded cyclic motifs of the H3OHPA
and H2NAP are modified by coformers. In solution 4,4′-
bipyridine, HMTA, and caffeine cause quenching of fluo-
rescence of H3OHPA, suggesting that interactions of these
compounds with H3OHPA involve the hydoxy group at the 3-
position, whereas in the theophylline cocrystal all the hydrogen
bonding sites are used, causing complete quenching of
fluorescence. On the other hand, the cocrystals of H2NAP
with 4,4′-bipyridine or HMTA or caffeine were formed easily.
π-Stacking plays the decisive role to increase or decrease
fluorescence in the solid state of H2NAP and cocrystals of
H2NAP. In solution no interactions of H2NAP with coformers
were observed. By virtue of such properties different oximes can
be distinguished by the fluorescence technique either in the
solid state or in solution. The differences in fluorescent
behavior among aldoximes could be exploited for their
identification and separation.
Figure 8. Changes in the fluorescence emission spectra of H3OHPA
(10−5 M solution in DMSO-H2O) on addition of theophylline (10−5
M in DMSO-H2O, 10 μL aliquot).
EXPERIMENTAL SECTION
■
Synthesis and Characterization of the Oximes and
Cocrystals. Oximes H2NAP and H3OHPA were prepared from
their respective hydroxyaromatic aldehyde by reacting them with
hydroxylamine hydrochloride in the presence of pyridine. A general
procedure for the synthesis of 2-hydroxynaphthaldoxime (H2NAP)
and 2,3 dihydroxypenylaldoxime (H3OHPA) is as follows: pyridine (1
mL) was added dropwise to a solution of hydroxylamine hydro-
chloride (0.138 g, 2 mmol) in ethanol (20 mL). The resulting solution
was stirred at room temperature for 15 min, and respective aldehyde
(2 mmol) was added. The solution was stirred at room temperature
for 1 h. A yellow precipitate of compound H2NAP or H3OHPA was
obtained. The entire reaction mixture was extracted with ethyl acetate
and washed with water. The ethyl acetate layer was taken separately,
and on removal of solvent by using a rotary evaporator yielded
compound H2NAP or H3OHPA.
screening of aldoximes by theophylline. For this purpose
fluorescence specta of H2NAP, H3OHPA, H3PHPA, and H2PA
(the latter two compounds were taken as screening
compounds) were monitored by adding a solution of
theophylline to the respective oxime solution. It was interesting
to note that addition of theophylline to a respective solution of
H2NAP or H2PA or H3PHPA (Supporting Figures 11S−13S)
did not cause fluorescence spectral changes. These oximes were
not recognized by theophylline to cause changes in their
respective emission spectra. We have also examined the effect
on fluorescence emission of H3OHPA by adding a solution of
caffeine or 4,4′-bipyridine or HMTA; in each case fluorescence
quenching was observed, but these compounds could not
change the fluorescence emissions of the H2NAP, H2PA, and
H3PHPA. Even though all four coformers resulted in
fluorescence quenching of H3OHPA in the solution state,
only one of them (theophylline) formed a cocrystal. Hence the
solution study clearly tells that careful choice of nitrogen
aromatic compounds can screen a series of oximes to identify a
particular oxime. Theophylline is the most important
metabolite of caffeine, and it is found in tea, coffee, cocoa
beans, and chocolate.37 Theophylline forms cocrystal with
phenols,38−41 carboxylic acids,42,43 and various other organic
molecules.44,45 On the other hand, caffeine has the ability to
form cocrystals with carboxylic acids46 and nicotinamides.47
Since the quenching process is very selective to H3OHPA by
coformers; it is attributed to the effect of the 3-hydroxy group
which is participating in proton transfer in this particular
example. Three other examples of oximes lack a hydroxy group
at the 3-position with respect to the oxime functional group of
the aromatic ring. It may be noted that among the oximes
H2NAP, H2PA, H3PHPA, and H3OHPA, H3OHPA has the
distinction of having a hydroxy group at the 3-position of the
ring with respect to the oxime functional group. This is hydroxy
group is not in conjugation with the oxime functional group
through the intervening π-electrons of the ring. This makes the
fluorescence behavior of this oxime different from the other
three oximes in the presence of coformers in solution.
2-Hydroxynaphthaldoxime (H2NAP). Melting point: 155−160
°C, isolated yield: 82%.1H NMR (400 MHz, DMSO-d6): 11.53 (s,
1H), 9.04 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 6.4 Hz, 1H),
7.84 (d, J = 6.4 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 6.8 Hz,
1H), 7.34 (d, 1H). IR (KBr, cm−1): 3331 (br, m), 3013 (w), 2924 (w),
2766 (w), 1947 (w), 1758 (w), 1632 (s), 1591 (s), 1526 (w), 1464
(w), 1463 (m), 1414 (m), 1369 (w), 1310 (m), 1268(s), 1239 (s),
1182 (s), 1163 (w), 1143 (w), 1079 (w), 1034 (w), 1014 (s), 938 (s),
878 (w), 854 (w), 814 (s), 776 (s), 744 (m), 718 (w), 649 (w), 541
(w), observed mass (ESI) m/z: 188.0698 (M + 1); (calculated exact
mass for (M + H) 188.0712 for C11H10NO2.
2,3-Dihydroxypenylaldoxime (H3OHPA). Melting point: 115−
1
120 °C, isolated yield: 83%. H NMR (400 MHz, DMSO-d6): 11.30
(s, 1H), 9.58 (s, 1H), 9.27 (s,1H), 8.31 (s, 1H), 6.91 (d, J = 7.2 Hz,
1H), 6.66 (d, J = 7.6 Hz, 1H), 6.59 (t, J = 8 Hz, 1H). IR (KBr, cm−1):
3454 (bm), 1620 (s), 1592 (w), 1478 (s), 1444 (m),1412 (w), 1347
(m), 1308 (m), 1285 (m), 1251 (m), 1165 (s), 1075 (m), 1030 (s),
967 (s), 850 (s), 782 (s), 744 (m), 727 (m), 626 (s), 566 (w).
Observed mass (ESI) m/z: 154.1049. (Calculated exact mass for M +
H 154.0504 for C7H8NO3).
Cocrystals were obtained by slow evaporation of a solution of the
respective aldoxime and the guest molecules with respective molar
ratio in methanol.
(H2NAP)2·4,4′-bipyridine. Isolated yield: 76%. 1H NMR (600
MHz, DMSO-d6): 11.52 (s, 1H), 11.14 (s, 1H), 9.03 (s, 1H), 8.72 (d, J
= 5.4 Hz, 3H), 8.47 (d, J = 8.4 Hz, 1H), 7.85 (m, 4H), 7.50 (t, J = 7.2
Hz, 1H), 7.35 (t, J = 6.8 Hz, 1H), 7.20 (d, J = 9, 1H). IR (KBr, cm−1):
3445 (bs), 1631 (s), 1596 (s), 1537 (w), 1467 (m), 1405 (m), 1369
(w), 1344 (w), 1307 (m), 1276 (s), 1239 (s), 1215 (s), 1183 (m),
1161 (w), 1145 (w), 1080 (w), 1062 (w), 1038 (s), 1023 (m), 999
(m), 940 (s), 880 (w), 825 (s), 799 (s), 776 (w), 744 (m), 671 (w),
645 (w), 620(s).
H
DOI: 10.1021/acs.cgd.5b01375
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
(H2NAP)2·HMTA. Isolated yield: 78%. 1H NMR (600 MHz,
DMSO-d6): 11.50 (s, 1H), 11.10 (s, 1H), 9.03 (s, 1H), 8.47 (d, J =
8.4 Hz, 1H), 8.00 (s, 1H), 7.85 (t, J = 8 Hz, 2H), 7.51 (t, J = 7.2 Hz,
1H), 7.37 (t, J = 6.8 Hz, 1H), 7.20 (d, J = 9 Hz, 1H), 4.55 (s, 12H). IR
(KBr, cm−1): 3446 (bs), 2959 (w), 2924 (w), 2875 (w), 1628 (m),
1591 (s), 1525 (w), 1464 (s), 1424 (w), 1370 (m), 1348 (w), 1312
(s), 1276 (s), 1238 (s), 1227 (s), 1180 (m), 1163 (w), 1144 (w), 1083
(w), 1007 (s), 947 (w), 933 (s), 870 (m), 825 (w), 813 (s), 800 (s),
738 (s), 723 (m), 693 (s), 673 (m), 665 (m), 644 (m).
Accession Codes
CCDC 1417714−1417718 contains the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(H2NAP)·caffeine. Isolated yield: 82%. 1H NMR (600 MHz,
DMSO-d6): 11.50 (s, 1H), 11.10 (s, 1H), 9.03 (s, 1H), 8.47 (d, J = 8.4
Hz, 1H), 8.00 (s, 1H), 7.85 (t, J = 8.4 Hz, 2H), 7.51 (t, J = 7.2 Hz,
1H), 7.37 (t, J = 6.8 Hz, 1H), 7.20 (d, J = 9 Hz, 1H), 3.87 (s, 3H),
3.41 (s, 3H), 3.21 (s, 3H). IR (KBr, cm−1): 3460 (bs), 3003 (w), 2922
(w), 1704 (s), 1658 (s), 1593 (w), 1553 (s), 1496 (s), 1468 (m), 1407
(w), 1362 (w), 1326 (m), 1282 (s), 1240 (s), 1211 (w), 1181 (s),
1140 (w), 1037 (m), 1022 (m), 978 (w), 938 (s), 878 (w), 829 (s),
780 (m), 757 (w), 744 (s), 669 (m), 645 (m), 607 (m).
AUTHOR INFORMATION
■
Corresponding Author
*Fax: +91-361-2690762; phone +91-361-2582311; e-mail:
juba@iitg.ernet.in; Web: http://www.iitg.ernet.in/juba.
Notes
The authors declare no competing financial interest.
(H3OHPA)·theophylline·2H2O. Isolated yield: 86%. 1H NMR
(600 MHz, DMSO-d6): 11.29 (s, 1H), 9.56 (s, 1H), 9.25 (s, 1H), 8.30
(s, 1H), 8.02 (s, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 8.4 Hz,
1H), 6.68 (t, J = 7.8 Hz, 1H), 3.44 (s, 3H), 3.23 (s, 3H). IR (KBr,
cm−1): 3479 (s), 3218 (bs), 1706 (s), 1650 (s), 1558 (s), 1505 (s),
1465 (w), 1440 (w), 1421 (w), 1385 (m), 1315 (m), 1259 (s), 1232
(s), 1190 (s), 1099 (w), 1058 (m), 994 (s), 959 (w), 933 (m), 849
(m), 780 (m), 764 (m), 741 (s), 711 (w), 654 (w), 620 (w), 505 (s).
Physical Measurements. Powder X-ray diffraction patterns were
recorded using Bruker powder X-ray diffractometer D2 phaser.
Infrared spectra of the solid samples were recorded on a PerkinElmer
Spectrum-One FT-IR spectrophotometer in the region 4000−400
cm−1 by making KBr pellets. Mass spectra were recorded on a micro
mass Q-TOF (waters) mass spectrometer by using an acetonitrile/
formic acid matrix. Solution state UV−visible spectra were recorded
using PerkinElmer Lamda-750 spectrometer. Solid state UV−visible
spectra were recorded by the same equipment using the diffuse
reflectance technique by taking the respective powdered sample in a
solid sample holder. Fluorescence emissions were measured in a
PerkinElmer LS-55 spectrofluorimeter by taking a definite amount of
solutions of samples and exciting them at required wavelengths. Solid
state fluorescence spectra were recorded using a PerkinElmer LS-55
spectrofluorimeter by taking constant amounts of finely powdered
samples. Solid fluorescence quantum yields (ΦF) were measured using
a Quanta-φ accessory. X-ray single crystal diffraction data for the
cocrystals and 2,3-dihydroxypenylaldoxime (H3OHPA) were collected
at 298 K with Mo Kα radiation (λ = 0.71073 Å) with the use of a
Bruker Nonius SMART APEX CCD diffractometer equipped with a
graphite monochromator and an Apex CCD camera, whereas for the
2-hydroxynapthaldoxime (H2NAP) data were collected on a Oxford
SuperNova diffractometer where the data refinement and cell
reductions were carried out by CrysAlisPro. Data reduction and cell
refinement were performed using SAINT and XPREP software.
Multiscan empirical absorption corrections were carried out with the
help of face-indexing. Structures were solved by direct methods using
SHELXS-97 and were refined by full-matrix least-squares on F2 using
SHELXL-97. All the non-hydrogen atoms were refined in anisotropic
approximation against F2 of all the reflections. The hydrogen atoms
were placed at their calculated positions and refined in the isotropic
approximation. In the case of H3OHPA-theophylline·2H2O the
hydrogen atoms on the water molecules were fixed. Crystallographic
data collection was done at room temperature, and data are tabulated
in Table 3.
ACKNOWLEDGMENTS
■
The authors thank Ministry of Human Resource and
Development for providing financial facilities to the Depart-
ment of Chemistry Indian Institute of Technology, Guwahati.
REFERENCES
■
(1) Wuest, J. D. Nat. Chem. 2012, 4, 74−75.
(2) Yan, D.; Delori, A.; Lloyd, G. O.; Friscic, T.; Day, G. M.; Jones,
W.; Lu, J.; Wei, M.; Evans, D. G.; Duan, X. Angew. Chem., Int. Ed.
2011, 50, 12483−12486.
(3) Mizobe, Y.; Tohnai, N.; Miyata, M.; Hasegawa, Y. Chem.
Commun. 2005, 14, 1839−1841.
(4) Zhang, G. Q.; Lu, J. W.; Sabat, M.; Fraser, C. L. J. Am. Chem. Soc.
2010, 132, 2160−2162.
(5) Zhou, T. L.; Jia, T.; Zhao, S. S.; Guo, J. H.; Zhang, H. Y.; Wang,
Y. Cryst. Growth Des. 2012, 12, 179−184.
(6) Feng, Q.; Wang, M.; Dong, B.; Xu, C.; Zhao, J.; Zhang, H.
CrystEngComm 2013, 15, 3623−3629.
(7) Zhang, Z.; Zhang, Y.; Yao, D.; Bi, H.; Javed, I.; Fan, Y.; Zhang,
H.; Wang, Y. Cryst. Growth Des. 2009, 9, 5069−5076.
(8) Wagner, B. D.; McManus, G. J.; Moulton, B.; Zaworotko, M. J.
Chem. Commun. 2002, 18, 2176−2177.
(9) Lee, E. Y.; Jang, S. Y.; Suh, M. P. J. Am. Chem. Soc. 2005, 127,
6374−6381.
(10) Kupcewicz, B.; Malecka, M. Cryst. Growth Des. 2015, 15, 3893−
3904.
(11) Dale, T. J.; Rebek, J., Jr. J. Am. Chem. Soc. 2006, 128, 4500−
4501.
(12) Dale, T. J.; Rebek, J., Jr. Angew. Chem., Int. Ed. 2009, 48, 7850−
7852.
(13) Kerkines, I. S. K.; Petsalakis, I. D.; Theodorakopoulos, G.;
Rebek, J., Jr. J. Phys. Chem. A 2011, 115, 834−840.
(14) Wallace, K. J.; Fagbemi, R. I.; Folmer-Andersen, F. J.; Morey, J.;
Lynth, V. M.; Anslyn, E. V. Chem. Commun. 2006, 37, 3886−3888.
(15) Wallace, K. J.; Morey, J.; Lynch, V. M.; Anslyn, E. V. New J.
Chem. 2005, 29, 1469−1474.
(16) Hewage, H. S.; Wallace, K. J.; Anslyn, E. V. Chem. Commun.
2007, 38, 3909−3911.
(17) Aakeroy, C. B.; Beatty, A. M.; Leinen, D. S. Cryst. Growth Des.
2001, 1, 47−52.
(18) Aakeroy, C. B.; Epa, K. N.; Forbes, S.; Desper, J. CrystEngComm
2013, 15, 5946−5949.
(19) Sinha, A. S.; Epa, K. N.; Chopade, P. D.; Smith, M. M.; Desper,
J.; Aakeroy, C. B. Cryst. Growth Des. 2013, 13, 2687−2695.
(20) Bruton, E. A.; Brammer, L.; Pigge, F. C.; Aakeroy, C. B.; Leinen,
D. S. New J. Chem. 2003, 27, 1084−1094.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.cgd.5b01375.
(21) Aakeroy, C. B.; Sinha, A. S.; Epa, K. N.; Spartz, C. L.; Desper, J.
Chem. Commun. 2012, 48, 11289−11291.
1
The HNMR and PXRD of the cocrystals and various
(22) Aakeroy, C. B.; Sinha, A. S. RSC Adv. 2013, 3, 8168−8171.
(23) Tarai, A.; Baruah, J. B. CrystEngComm 2015, 17, 2301−2309.
fluorescence titrations (PDF)
I
DOI: 10.1021/acs.cgd.5b01375
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
(24) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311−
2327.
(25) Dey, A.; Kirchner, M. T.; Vangala, V. R.; Desiraju, G. R.;
Mondal, R.; Howard, J. A. K. J. Am. Chem. Soc. 2005, 127, 10545−
10559.
(26) Sarma, J. A. R. P.; Desiraju, G. R. Cryst. Growth Des. 2002, 2,
93−100.
(27) Thakur, T. S.; Desiraju, G. R. Cryst. Growth Des. 2008, 8, 4031−
4044.
(28) Salmon, D. J.; Smith, M. M.; Desper, J.; Aakeroy, C. B. Cryst.
Growth Des. 2006, 6, 1033−1042.
(29) Etter, M. C. Acc. Chem. Res. 1990, 23, 120−126.
(30) Wood, P. A.; Forgan, P. A.; Henderson, D.; Parsons, S.; Pidcock,
E.; Tasker, P. A.; Warren, J. E. Acta Crystallogr., Sect. B: Struct. Sci.
2006, 62, 1099−1111.
(31) Guo, Z.; Li, L.; Liu, G.; Dong, J. Acta Crystallogr., Sect. E: Struct.
Rep. Online 2008, 64, o568−o569.
(32) Madusanka, N.; Eddleston, M. D.; Arhangelskis, M.; Jones, W.
Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater. 2014, 70, 72−80.
(33) Jacobs, A.; Noa, F. M. A. CrystEngComm 2015, 17, 98−106.
(34) Das, B.; Baruah, J. B. Cryst. Growth Des. 2011, 11, 278−286.
(35) Kupcewicz, B.; Malecka, M. Cryst. Growth Des. 2015, 15, 3893−
3904.
(36) Spano, F. C. Acc. Chem. Res. 2010, 43, 429−439.
(37) Jafari, M. T.; Rezaei, B.; Javaheri, M. Food Chem. 2011, 126,
1964−1970.
(38) Schultheiss, N.; Roe, M.; Boerrigter, S. X. M. CrystEngComm
2011, 13, 611−619.
(39) Wang, Z.-L.; Wei, L.-H. Acta Crystallogr., Sect. E: Struct. Rep.
Online 2007, 63, o1681−o1682.
(40) Chattoraj, S.; Shi, L.; Sun, C. C. CrystEngComm 2010, 12,
2466−2472.
(41) Sarma, B.; Saikia, B. CrystEngComm 2014, 16, 4753−4765.
(42) Das, B.; Baruah, J. B. Cryst. Growth Des. 2011, 11, 278−286.
(43) Abourahma, H.; Urban, J. M.; Morozowich, N.; Chan, B.
CrystEngComm 2012, 14, 6163−6169.
(44) Aitipamula, S.; Wong, A. B. H.; Chow, P. S.; Tan, R. B. H.
CrystEngComm 2014, 16, 5793−5801.
(45) Delori, A.; Galek, P. T. A.; Pidcock, E.; Patni, M.; Jones, W.
CrystEngComm 2013, 15, 2916−2928.
(46) Karki, S.; Friscic, T.; Jones, W.; Motherwell, W. D. S. Mol.
Pharmaceutics 2007, 4, 347−354.
(47) Lu, J.; Rohani, S. Org. Process Res. Dev. 2009, 13, 1269−1275.
J
DOI: 10.1021/acs.cgd.5b01375
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