Tetrakis(dimethoxyphenyl)adamantane (TDA) and its inclusion complexes in the crystalline state: A versatile carrier for small molecules

Article abstract of DOI:10.1002/chem.201406568

Molecular storage solutions for incorporating small molecules in crystalline matrices are of interest in the context of structure elucidation, decontamination, and slow release of active ingredients. Here we report the syntheses of 1,3,5,7-tetrakis(2,4-dimethoxyphenyl)adamantane, 1,3,5,7-tetrakis(4-methoxyphenyl)adamantane, 1,3,5,7-tetrakis(4-methoxy-2-methylphenyl)adamantane, and 1,3,5,7-tetrakis(4-methoxy-2-ethylphenyl)adamantane, together with their X-ray crystal structures. All four compounds crystallize readily. Only the octaether shows an unusual level of (pseudo)polymorphism in its crystalline state, combined with the ability to include a number of different small molecules in its crystal lattices. A total of 20 different inclusion complexes with guest molecules as different as ethanol or trifluorobenzene were found. For nitromethane and benzene, schemes for uptake and release are presented.

Full text of DOI:10.1002/chem.201406568

DOI: 10.1002/chem.201406568
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Inclusion Complexes
Tetrakis(dimethoxyphenyl)adamantane (TDA) and Its Inclusion
Complexes in the Crystalline State: A Versatile Carrier for Small
Molecules
Alexander Schwenger, Wolfgang Frey, and Clemens Richert*[a]
Dedicated to Prof. Dr. Alwin E. Goetz on the occasion of his 60th birthday
Abstract: Molecular storage solutions for incorporating
small molecules in crystalline matrices are of interest in the
context of structure elucidation, decontamination, and slow
release of active ingredients. Here we report the syntheses
of 1,3,5,7-tetrakis(2,4-dimethoxyphenyl)adamantane, 1,3,5,7-
tetrakis(4-methoxyphenyl)adamantane, 1,3,5,7-tetrakis(4-me-
thoxy-2-methylphenyl)adamantane, and 1,3,5,7-tetrakis(4-
methoxy-2-ethylphenyl)adamantane, together with their
X-ray crystal structures. All four compounds crystallize readi-
ly. Only the octaether shows an unusual level of (pseudo)po-
lymorphism in its crystalline state, combined with the ability
to include a number of different small molecules in its crys-
tal lattices. A total of 20 different inclusion complexes with
guest molecules as different as ethanol or trifluorobenzene
were found. For nitromethane and benzene, schemes for
uptake and release are presented.
Introduction
We have become interested in using tetrasubstituted ada-
mantanes as structuring elements in networks of oligonucleo-
tide hybrids. In these hybrids, the adamantanes act as branch-
ing elements that preorganize short DNA arms, so that they
can form three-dimensional networks via Watson–Crick base
pairing.[16–18] So far, we have studied hybrids with tetrakis(hy-
droxybiphenyl)adamantane[19,20] or tetrakis(triazolylphenyl)ada-
mantane[21] as core. Upon hybridization of short “CG zipper”
DNA arms, the hybrids form nanoporous materials from aque-
ous solution when treated with divalent cations. The materials
thus formed take up salts and intercalators, suggesting that
they are nanoporous.[21–24] Crystals of the cores themselves
have provided valuable insights.[21] This encouraged us to
pursue the synthesis of a wider range of symmetrical mole-
cules and to study their properties in the solid state. We fo-
cused on tetrasubstituted adamantanes because rigidity
should be favourable for crystallization into porous materials.
Here we report the synthesis of four methoxy-substituted
tetraphenyladamantanes, including derivatives with methyl or
ethyl side chains on the phenyl rings. Among them, 1,3,5,7-tet-
rakis(2,4-dimethoxyphenyl)adamantane (TDA) showed an inter-
esting propensity to act as host for guest molecules, incorpo-
rating a wide range of different small molecules in crystal
structures of three different space groups. Neither of the other
adamantanes showed the same behavior. The ability to crystal-
lize in different forms and to capture and release different host
molecules makes the octaether interesting for molecular stor-
age applications.
Developing molecular materials that form from organic mole-
cules and that have the ability to act as host for small mole-
cules is an interesting challenge.[1] The storage of guest mole-
cules is usually made possible by the formation of networks of
host molecules.[2,3] The assembly of host molecules into period-
ic lattices may be accompanied by chemical reactions, leading
to covalent organic frameworks (COFs).[4,5] Examples of crystal-
line or amorphous organic materials that have the potential to
incorporate guests include organic cages,[6a] porous aromatic
frameworks (PAF),[6b] porous polymer networks (PPN),[6c] and
porous organic frameworks (POF).[6d] Gases are frequently stud-
ied as guests, and the host structures are often rigid, being
composed of aromatic and/or aliphatic rings.[7] The adaman-
tane scaffold combines rigidity with the ability to induce for-
mation of diamondoid structures.[8] Branched adamantane de-
rivatives are known to form assemblies with the ability to act
as hosts for small molecules.[9,10] As a consequence, tetrasubsti-
tuted adamantanes are valuable building blocks. But, their syn-
thesis can be challenging, due to steric and electronic peculiar-
ities.[11–13] Still, tetrasubstituted adamantanes find applications
in medicine and materials sciences.[14,15]
[a] A. Schwenger, Dr. W. Frey, Prof. C. Richert
Institut fꢀr Organische Chemie, Universitꢁt Stuttgart
70569 Stuttgart (Germany)
Fax: (+49)711-608-64321
E-mail: lehrstuhl-2@oc.uni-stuttgart.de
Supporting information for this article is available on the WWW under
1
http://dx.doi.org/10.1002/chem.201406568: H and 13C NMR spectra of new
compounds and details of the crystal structures of compounds 3, 4, 5, and
6.
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Results
Table 1. Results of substitution reactions involving 2 and different arenes.
Entry Aromatic
reactant
Catalyst Reaction Reaction
time [h] temperature
[8C]
Product Yield
[%]
Syntheses
The synthesis of the tetraaryladamantes started from 1,3,5,7-
tetrabromoadamantane (1, Scheme 1), accessible by four-fold
bromination of adamantane under Stetter conditions.[25] The
tetrabromide was hydrolyzed to tetraol 2. Exhaustive Soxhlet
extraction improved the yield to 98% over the 84% reported
in the literature.[26] We selected phenyl rings as substituents for
the desired tetraaryladamantanes, assuming that they will offer
sites for molecular interactions with guest molecules in the
final crystalline assemblies. Anisoles with an additional me-
thoxy group (1,3-dimethoxybenzene) or alkyl group (3-methyl-
anisole or 3-ethylanisole) were chosen as arenes, complement-
ing the parent compound to be prepared with anisole itself.
This led to tetrasubstituted adamantanes 3–6 as target mole-
cules (Scheme 1).
1
1,3-dimethoxy-
benzene
TsOH
48
140
3
21
2
3
TsOH
TMS-
OTf
TfOH
TsOH
TMS-
OTf
TfOH
TfOH
[BMIM]
[OTf][a]
TsOH
TMS-
OTf
96
20
140
120
3
3
38
<1
4
5
6
20
72
72
120
140
120
3
4
4
<1
7
11
anisole
7
8
20
48
120
85
4
4
39
10
9
10
3-methylanisole
3-ethylanisole
72
72
130
130
5
5
41
11
11
12
TsOH
TsOH
24
48
120
120
6
6
20
30
[a] Ionic liquid 1-butyl-3-methylimidazolium trifluoromethanesulfonate
[BMIM][OTf] as solvent.
action times that favor thermodynamic control gave a more
narrow product distribution than short reaction times, most
probably because ortho/para isomers were slowly interconvert-
ing under these conditions.
For 5, Lewis acid TMS-OTf gave a lower yield than the
Brønsted acid tested (tosylic acid). For the reaction with anisole
that produced tetrakis(methoxyphenyl)adamantane (4), a yield
of just 4% was obtained with pTsOH, compared to 10% for
the reaction catalyzed by TMS-OTf, and over 39% for that cata-
lyzed by triflic acid. The different optima found for different
arenes might be a consequence of the equilibria leading to
the active electrophile and the different propensities of the
arene substrates to undergo side reactions, such as ether
cleavage.
Scheme 1. Synthesis of tetrasubstituted adamantanes 3–6.
Introducing the phenyl substituents to the adamatane re-
quired alkylation of the anisoles. Friedel–Crafts alkylations
often lead to overalkylation. Further, a high ortho-/para-selec-
tivity can be difficult to achieve, making even single substitu-
tions of adamantane substrates (be they alcohols or halides)
a synthetic challenge.[27] The challenge is greater still, if tetra-
substitution is to be achieved, as in our case. It is therefore not
surprising that there are a limited number of examples of suc-
cessful four-fold substitutions via alkylation, starting from a tet-
rafunctionalized adamantane.[8,13] Stetter and coworkers had
shown that anisole as an electron-rich arene can be introduced
with a Brønsted acid as catalyst.[28]
Crystal Structures
Anisole-containing parent compound 4 crystallized from n-
hexane/dichloromethane. The X-ray crystal structure (Figure 1
and Table 2) showed no peculiarities, with four molecules per
unit cell and an absence of solvent inclusions. Likewise, ada-
mantanes 5 and 6 with their methyl or ethyl groups did not in-
clude solvent molecules in their crystal lattices. Both crystal-
lized in a different space group.
Unlike 4–6, adamantane 3 with its four dimethoxyphenyl
substituents showed an unusual propensity to include guest
molecules in its crystals. A total of 20 different inclusion com-
plexes were found for this compound, along with two crystal
structures that do not show any guest molecules, which were
obtained when 3 was crystallized from acetic acid or aniline
(Figure 2 and entries 4 and 22 in Table 2).
We tested the catalysts and reaction conditions listed in
Table 1 to obtain acceptable yields of either of the symmetri-
cally tetrasubstituted adamantanes 3–6. The best result was
achieved for 5, which was isolated in 41% yield after reacting
2 with 3-methylanisole in the presence of tosylic acid as cata-
lyst for 72 h at 1208C. For this and other alkylanisoles, long re-
The inclusion complexes of 3 were obtained by crystallizing
the octaether in the presence of different solvents. Figures 3
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Figure 2. X-ray crystal structures of 3 without inclusion of a guest molecule,
as obtained by crystallizing a) from glacial acetic acid, and b) from aniline.
Non-equivalent molecules are shown in different colors. See Table 2, entry 4
and 22 for details.
including the structures lacking small molecules as guests. The
monoclinic structures showed inclusion of molecules as differ-
ent in size and polarity as dichloromethane, cyclohexane, nitro-
benzene, acetonitrile, and acetone. In many instances, the
guest molecules were well ordered (entries 5–7, 10–11, 13–20
and 23 in Table 2), whereas disordered guests were found in
the crystals obtained from crystallization in solvents such as
CH2Cl2 or CHCl3 with EtOH, 2-propanol, or propanol as co-sol-
vents (entries 8–9 and 12 in Table 2 and Supporting Informa-
tion).
Figure 1. X-ray crystal structures of tetraaryladamanates 4 (a), 5 (b), and 6
(c). Color code: Carbon, grey; oxygen, red. Hydrogens were omitted for clari-
ty. See entries 1–3 in Table 2 for details.
and 4 show details of the inclusion complexes as found in the
crystals. Interestingly, fifteen of the structures of 3 were mono-
clinic (Figure 3), whereas eight were triclinic (Figure 2 and 4),
Figure 3. Molecular recognition of small molecule guests in inclusion complex of 3 with a) dichloromethane; b) n-hexane; c) cyclohexane; d) ethanol;
e) chloroform; f) nitrobenzene; g) rac-2-methyl-2-butanol, h) 2-butanol, and i) n-propanol as guests. Hydrogen atoms were omitted for clarity. For further de-
tails, see entries 5, 6, 7, 10, 12, 13, 14, 15 and 18 of Table 2, respectively. Color code: Carbon, grey; oxygen, red; nitrogen, purple; chlorine, green.
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Table 2. Structural parameters for crystals of tetraaryladamantanes with our without guest molecules.
Entry Compound Crystal
system
Space
group
Volume
of u.c.
[ꢁ3]
Z[a] Density
Solvent(s)
Inclusion
guest
Calculated
stoichiometry
R1[b]/wR2
[MgmÀ3
]
(host/guest)
–
1
2
3
4
5
4
5
6
3
3
monoclinic
tetragonal
triclinic
P21/n
I41/a
3009
3414
1866
3538
15932
4
4
2
4
1.238
1,200
1.198
1.278
CH2Cl2/C6H12
CH2Cl2/C6H12
CH2Cl2/C6H12
acetic acid
CH2Cl2
–
0.0377/
0.0890
0.0561/
0.1480
0.0551/
0.0998
0.0424/
0.1056
–
–
¯
P1
–
–
¯
P1
triclinic
–
–
monoclinic
C2/c
16 1.312
CH2Cl2
4:5
0.0841/
0.2151
6
7
3
3
monoclinic
monoclinic
P21/n
C2/c
7415
16380
8
1.258
CH2Cl2/C6H14
CH2Cl2/C6H12
C6H14
C6H12
4:1
1:1
0.0453/0.1131
0.0358/
0.0902
16 1.241
8
9
3
3
monoclinic
monoclinic
P21/n
P21/n
P21/n
7484
7542
8
8
1.267
1.258
CH2Cl2/EtOH
CH2Cl2/EtOH
4:1:1
8:1:3
0.0546/
0.1346
0.0580/
0.1075
0.0461/0.1150
0.0669/
0.1719
CH2Cl2/2-propanol
CH2Cl2/2-propanol
10
11
3
3
monoclinic
triclinic
7497
7764
8
8
1.247
1.308
EtOH
CHCl3/n-propanol
EtOH
CHCl3/n-propanol
2:1
4:1:1
¯
P1
12
13
3
3
monoclinic
monoclinic
P21/n
P21/c
7513
7445
8
8
1.276
1.325
CHCl3/EtOH
nitrobenzene
CHCl3/EtOH
nitrobenzene
n.d.
2:1
0.0611/0.1575
0.0461/
0.0918
14
15
16
17
18
19
20
21
22
23
24
25
3
3
3
3
3
3
3
3
3
3
3
3
monoclinic
monoclinic
triclinic
P21/n
P21/n
7650
7572
2066
7511
8
8
2
8
8
1.259
1.259
1.306
1.279
1.246
2-methyl-2-buta-
nol
2-butanol
2-methyl-2-buta-
nol
2-butanol
2:1
2:1
1:1
0.0548/
0.1310
0.0400/
0.0967
0.0416/
0.0771
0.0683/
0.1816
0.0861/
0.1964
0.0641/
0.1566
0.0739/
0.1783
0.0927/
0.2135
0.0461/
0.0883
0.0442/
0.1080
0.0731/
0.1801
0.0656/
0.1559
¯
P1
trifluorobenzene
trifluorobenzene
CH2Cl2
monoclinic
monoclinic
monoclinic
monoclinic
monoclinic
triclinic
P21/n
P21/n
P21/n
C2/c
CH2Cl2/n-propanol
2:1
2:1
2:3
8:11
1:1.25
–
7577
15704
15798
15800
1746
2015
4087
1985
MeNO2/n-propanol n-propanol
16 1.304
16 1.279
16 1.230
nitromethane
acetone
nitromethane
acetone
C2/c
acetonitrile
aniline
acetonitrile
–
¯
P1
2
2
4
2
1.295
1.250
1.324
1.288
¯
P1
triclinic
EtOH/C6H6
+CHCl3
benzene
benzene/CHCl3
CHCl3
1:1
¯
P1
triclinic
8:3:7
4:3
¯
P1
triclinic
+CHCl3
[a] Number of molecules in a unit cell, asymmetric unit. [b] Final R indices [I>2 s(I)]. For binary solvent systems (Table 2, entries 8, 9, 11 and 12), an overlap
model of both solvent components was used for better fitting the strongly disordered parts of the solvent electron densities. The unit cell dimensions are
reported in the Supporting Information (Table S1).
Cyclohexane was incorporated in crystals of 3 at a molar
ratio of 1:1 (Figure 3c and entry 7 of Table 2). Here, a large
volume of the unit cell and a large asymmetric unit was found.
Crystallization with n-hexane (Figure 3b and entry 6 in Table 2)
showed inclusion of the acyclic alkane at a ratio of 4:1 (3: n-
hexane), and the crystal structure contained unit cells with less
than half the volume, showing the degree of variability in the
crystal packing of 3, and how differently the molecular recog-
nition of small molecules is achieved.
The observations listed above suggested that 3 avidly takes
up organic molecules, and that it does so by forming a rather
promiscuous set of inclusion pockets. When a mixture of di-
chloromethane or chloroform with ethanol or propanol was
used, crystals were found to contain a mixture of two solvents
(Figures S17–20 and S23–26, Supporting Information). Crystalli-
zation attempts from toluene gave crystals of poor order, so
that only the adamantane core could be observed in the X-ray
diffraction patters, possibly because the phenyl arms and any
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3. Nitromethane is also known for its role in the pro-
duction of rocket propellants, explosive materials,[34]
and as additive for high-performance fuel of com-
bustion engines. We therefore studied uptake of ni-
tromethane into TDA crystals and possible avenues
for its controlled release. Scheme 2 shows the pro-
posed regimen. First, the uptake of nitromethane by
crystallization of 3 was studied. Figure 5 shows de-
tails of the X-ray crystal structure obtained when
TDA was crystallized from nitromethane. It can be
discerned that the tetraaryladamantane takes up the
aliphatic nitro compound, and that the nitromethane
guests are partially disordered in the crystal.
Figure 4. Structural details from inclusion complexes of 3 in triclinic crystal systems with
a) chloroform (only one of the guest molecules is shown), b) 1,3,5-trifluorobenzene, and
c) benzene as guests. Hydrogens were omitted for clarity. Color code: Carbon, grey;
oxygen, red; chlorine, green; fluorine, light green. See Table 2, entries 11, 16, and 23 for
further details.
In order to identify conditions that allow for the
recovery of 3 after serving as storage material for
included solvent showed too high a mobility. When crystalliz-
ing 3 from dichloromethane alone, crystals were obtained that
appeared to lose solvent when exposed to air, leading to brit-
tle and eventually unstable crystals. This suggested that for
certain guests, a release of small molecules can be induced
quite readily.
Uptake and Release
The detection[29,30] and removal[31] of combustible compounds
Figure 5. Crystal structure of 3 containing nitromethane. When a warm solu-
tion of TDA in nitromethane was allowed to cool, crystals of 0.1 cm length
formed readily in less than 4 h. The graphic shows a portion of the X-ray
crystal structure obtained from such crystals, containing the nitroalkane at
a molar ratio of 2:3 (TDA:MeNO2). Two well-ordered guest molecules and
two inclusion sites with disordered nitromethane are shown, leading to a dis-
torted appearance of the nitromethane molecules. Color code: Carbon,
grey; oxygen, red; nitrogen, purple. See entry 19 of Table 2 for further de-
tails.
and explosives are important challenges that require molecular
solutions. Some unstable compounds, such as acetylene, have
to be stored in porous materials to render them safe for trans-
port and use. We were therefore encouraged to detect that
the range of small molecules incorporated in the crystal latti-
ces of 3 also included aromatic compounds with electron-with-
drawing substituents, namely trifluorobenzene and nitroben-
zene. Nitroarenes are a class of compounds, several members
of which are explosives, and so are small aliphatic nitro com-
pounds, such as nitromethane.[32]
a small molecule compound, we then screened for a solvent
that would have the potential to act as a release agent for ni-
tromethane. For this, mixtures of nitromethane and various sol-
vents (1:1, v/v) were screened for their ability to induce the
crystallization of 3. This included solvents such as methanol,
ethanol, toluene, and 1,2-dichloroethane. After adding TDA,
heating to obtain a clear solution, and cooling, the individual
samples were examined for crystals. Toluene and 1,2-dichloro-
ethane showed no crystals at the dilution chosen. In contrast,
both methanol and ethanol induced the crystallization of TDA.
When both the mother liquors and the crystals were examined
by NMR, and the peak integrals were compared with those of
the starting mixture of solvents, methanol showed itself as
a promising release solvent for nitromethane (Figure 6). Where-
as ethanol led to the incorporation of both nitromethane and
the alcohol itself at a ratio of approximately 2:1, methanol in-
duced the crystallization of 3 in largely guest-free form. Now,
just 14 mol% of nitromethane was found in the crystals
(Figure 6). Methanol was not detected in the NMR spectrum of
the crystalline material dissolved in CDCl3 (Figure 6b), and
a modest loss of nitromethane detected in the mother liquor
over the starting mixture confirmed the ability of methanol to
Nitromethane is occasionally used as solvent,[33] making it
a reasonable choice for studies on uptake by crystallization of
Scheme 2. Uptake of a hazardous or unstable small molecule into a crystal-
line phase of TDA and subsequent recovery of the TDA carrier material by
addition of a volatile solvent in the form of recrystallization that leaves the
small molecule in the solution with the solvent.
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structure of the material obtained from the mixture of ethanol
and benzene is listed as entry 23 in Table 2. The X-ray crystal
structure obtained with a mixture of MeOH/C6H6 was almost
identical (data not shown). The fact that, upon crystallization,
benzene is taken up selectively from a mixture suggests that
alcoholic solutions of TDA may become useful for decontami-
nating samples polluted with benzene.
An additional release mechanism was discovered for crystals
containing benzene (Figure 7). It involved displacing benzene
with chloroform at room temperature without loss of crystallin-
ity. A sample of crystals obtained from a mixture of ethanol
and benzene (1:1, v/v) that had given the crystal structure
shown in Figure 7a was harvested, washed with water and cy-
clohexane, and immersed in chloroform. After one day, a crystal
was collected, and the crystal structure shown in Figure 7b
was obtained, which shows what appears to be an intermedi-
ate in the process of displacement. A combination of well-or-
dered benzene and chloroform molecules, as well as sites par-
tially occupied by either of the two guests, are found in the
unit cell. After one more day of exposure to chloroform, the
crystal structure shown in Figure 7c was obtained from the
same sample, which now shows two strongly disordered
chloroform molecules only.
Figure 6. 1H NMR spectra from crystallization studies with TDA (3) and a mix-
ture of MeOH and nitromethane, recorded in CDCl3 at 300 MHz. a) Spectrum
the mother liquor of the crystallization of TDA from the 1:1 (v/v) mixture of
the two solvents, and b) crystals obtained from the mixture after brief wash-
ing with water and cyclohexane, followed by dissolving in CDCl3. Note that
little nitromethane is found in the crystals of 3 formed under these condi-
tions, making methanol suitable for release of the guest and recovery of the
host material.
retain a large fraction of the explosive and to induce the crys-
tallization of 3.
Exploratory experiments were then performed with 1:1 mix-
tures of other solvents. A mixture of acetic acid and toluene
gave crystals containing approx. 0.8 equivalents of toluene and
traces of AcOH, again confirming that TDA does not readily in-
clude the carboxylic acid. A mixture of acetic acid and cyclo-
hexane showed predominant inclusion of C6H12, whereas mix-
tures of both ethanol/benzene and methanol/benzene gave
benzene as the only detectable guest molecule. At least one
equivalent of benzene was taken up in either case. The crystal
¯
All three crystal structures were triclinic, space group P1, but
the volume of the unit cells was 2015, 4087, and 1985 ꢁ3, re-
spectively. As mentioned above, the displacement of the ben-
zene molecules occurred without macroscopically visible loss
of crystallinity. Perhaps, a combination of porosity of the lattice
and conformational flexibility in the TDA molecules allowed for
the level of structural diversity found in the unit cells. The
Figure 7. Release of benzene through displacement with chloroform at room temperature: a) X-ray structure of crystal obtained from a mixture of ethanol
and benzene (1:1, v/v) with four benzene in the unit cell (lower part), b) Structure of crystal after exposure to CHCl3 for 1 d, showing a mixture of both sol-
vents in the unit cell, and c) X-ray structure of a crystal from the same sample after exposure to chloroform for two days, showing disordered CHCl3 molecules
as the only detectable guests. Color code: Carbon, grey; oxygen, red; chlorine, green. See entries 23–25 of Table 2 for further details.
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chloroform molecules may have displaced the benzene guests
without entirely breaking down crystalline order. The fact that
the chloroform guests were less well ordered in the final struc-
ture than in the crystal structures obtained from chloroform as
a crystallization solvents (e.g., Figure 3e) supports this hypoth-
esis. Perhaps, the two chloroform molecules are filling voids
left behind by the more spacious benzene rings. That what ap-
pears to be an intermediate was caught by X-ray crystallogra-
phy also supports this view. Independent of the mechanism of
release, the fact that benzene can be released from inclusion
complexes of 3 at room temperature makes it likely that TDA
will become useful as carrier for the capture and release of
toxic aromatic compounds.
Further, the eight methoxy groups of 3 are able to rotate.
Thus, they are able to present a more polar (oxygen) or less
polar face (methyl groups). This allows 3 to present oxygen
lone pairs as interactions surface for hydrogen bond donors or
dipoles in guest molecules, as in the structure with CH2Cl2 as
guest. When rotating about their bonds to the phenyl rings,
the methoxy groups can also present their lipophilic surfaces
in order to bind lipophilic guests via van der Waals interac-
tions, as in the inclusion complexes with n-hexane and cyclo-
hexane. This Janus-like property may account for the ability to
include such as broad range of different small molecules.
Figure 9 shows an overlay of different conformations of 3, as
found in its crystal structures. The structure of seven different
conformations of TDA found in triclinic crystal systems, nine
conformations found in space group C2/c, and 19 different
Discussion
The results presented above are noteworthy on dif-
ferent levels. One level is that of molecular recogni-
tion. Earlier X-ray crystal structures of other di- and
other tetrarayladamantanes had shown inclusion
complexes and a modest level of structural flexibili-
ty.[35–38] Unlike known inclusion complexes, though, in
our case there is an absence of hydrogen bonds be-
tween the tetraaryladmantanes as host and small
molecule guests. Further, the degree to which the
guest molecules modulate the structure of the crys-
tals formed by octaether 3 is unusual and so is the
loading achieved for some guests, such as nitrome-
thane.
Figure 9. Overlay of the alignments of different conformations of TDA (3), as found in
a) the triclinic crystal systems; b) the monoclinic crystal systems with the space group C
2/c; and c) the monoclinic crystal system with the space group P21/n. Each conformer is
shown in a different color. In the triclinic crystal system, 19% of all neighboring methoxy
groups on individual phenyl rings were found in a tweezer-like, cisoid orientation, and
81% were found in a transoid conformation. In monoclinic structures of space group C
2/c, the ratio was 39% cisoid and 61% transoid. Finally, in the structures of monoclinic
system P 21/n, the ratio of the arrangements of the methoxy groups was 3% cisoid and
97% transoid.
It is difficult to predict crystal structures of organic
molecules,[39] so any explanation for the unusual be-
havior of 3 in the crystalline state will necessarily be
speculative. There are structural peculiarities that
come to mind, though. One is that, compared to tet-
raether 4, the inner sphere of aryl substituents (adja-
cent to the admantane) is more densely packed for 3, due to
the presence of the additional methoxy groups. As a conse-
quence, a cogwheel-like arrangement of neighboring phenyl-
adamantanes (Figure 8a) may be difficult to achieve. The more
shallow indentations may be responsible for a flatter energy
landscape, with more alternative packing arrangements and
crystals structures, including structures with guest molecules
(Figure 8b/c). Compared to unsubstituted tetraphenyladaman-
tane, octaether 3 presents a more spherical shape, closer to
that of truly spherical molecules, like fullerenes, which are
known for their orientational disorder in the solid state.[40]
conformations found in space group P21/n were aligned. The
overlays show that the phenyl rings rotate considerably when
accommodating guest molecules, and so do the methoxy
groups, particularly those at the para-position.
On the level of possible applications, it is noteworthy how
easily the uptake properties of 3 can be tuned by adding an al-
cohol as solvent and inducing recrystallization (Scheme 2 and
Figure 6) or by adding a halogenated solvent and inducing dis-
placement (Figure 7). This makes it reasonable to propose that
TDA can be used to absorb and later release toxic or unstable
small molecules. Thus, 3 may become useful as a material to
safely ship and later release toxic or explosive compounds,
such as nitromethane. Guest may be released by displacement
at room temperature (Figure 7), by dissolving the material in
a suitable solvent like methanol and recovering the TDA carrier
compound upon cooling (Scheme 2), or possibly by thermal re-
lease through melting of crystals containing guests.
Conclusions
Figure 8. Simplified, two-dimensional model of packing for a less spherical
(a) and a more spherical (b and c) four-fold substituted molecule. Guest mol-
ecules included in the packing are shown as dark objects.
In conclusion, we report that tetrakis(2,4-dimethoxyphenyl)ada-
mantane (3) shows a high degree of structural variation in its
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was dissolved in CH2Cl2 (40 mL) and was successively washed with
a saturated aqueous solution of NaHCO3 (50 mL), HCl (50 mL, 2m)
and H2O (50 mL), dried over Na2SO4, filtered, and the solvent was
evaporated in vacuo. The resulting dark brown crude product was
taken up in CH2Cl2 and filtered through a short silica gel pad, by
eluting first with petroleum ether (200 mL) and then with petrole-
um ether/CH2Cl2 (3:1, v/v, 300 mL). The second fraction was con-
centrated under reduced pressure. Purification via column chroma-
tography (silica gel, petroleum ether/CH2Cl2 1:4, v/v) yielded 3 as
a white solid (26 mg, 0.04 mmol, 38%). Rf =0.22 (petroleum ether/
CH2Cl2, 1:3, v/v); 1H NMR (300 MHz, CDCl3): d=7.28 (d, J=8.4 Hz,
4H), 6.48–6.44 (m, 8H), 3.78 (s, 12H), 3.77 (s, 12H), 2.41 ppm (s,
12H); 13C NMR (75.5 MHz, CDCl3): d=159.8, 158.8, 131.1, 127.2,
103.3, 99.7, 55.2, 55.0, 42.8, 39.0 ppm; MS (70 eV, EI): m/z: 680/681/
682/683 [M+]; HRMS m/z calcd for C42H48O8 680.335, found
680.334.
crystalline state and forms inclusion complexes with a wide
range of different guest molecules. The mode of interaction
differs between guests and so does the mode in which the
binding pocket is formed. Probably, the near-spherical shape
of this eight-fold substituted tetraaryladamantane, combined
with the tweezer-like positioning of the methoxy substituents
favors inclusion complexes. The crystals thus formed are fasci-
nating organic materials. Octaether 3 may be developed into
molecular storage materials for small molecules that form by
crystallizing readily (sometimes within minutes) and dissolve
when heated with the proper release solvent. This compound
may thus become useful for the absorption, safe transport,
and controlled release of toxic, explosive or otherwise func-
tional small molecules as well as for scientific studies that re-
quire the capture of a small molecule in a crystalline matrix.
1,3,5,7-Tetrakis(4-methoxyphenyl)adamantane (4): A mixture of 2
(50 mg, 0.25 mmol, 1 equiv), TfOH (11 mL, 0.12 mmol, 0.5 equiv),
and anisole (1 mL) was heated to 1208C for 20 h in a Dean–Stark
apparatus. After aqueous work up as described for compound 3,
purification via column chromatography (silica gel, petroleum
ether/CH2Cl2 1:1, v/v) yielded 4 as a colorless solid (54 mg,
0.096 mmol, 39%). Rf =0.28 (petroleum ether/CH2Cl2 1:1, v/v);
1H NMR (300 MHz, CDCl3): d=7.38 (d, J=8.7 Hz, 8H), 6.88 (d, J=
9 Hz, 8H), 3.84 (s, 12H), 2.80 ppm (s, 12H); 13C NMR (75.5 MHz,
CDCl3): d=157.7, 141.8, 126.0, 113.6, 55.2, 47.7, 38.6 ppm; MS (FAB,
3-NBA): m/z: 560, 561, 562 [M+]; HRMS m/z calcd for C38H40O4
560.293, found 560.293.
Experimental Section
General: NMR spectra were recorded on a Bruker AVANCE 300
spectrometer. Chemical shifts (d values) are in parts per million
(ppm) relative to tetramethylsilane (TMS, 0 ppm) as internal stan-
dard or residual solvent peaks; coupling constants (J) are given in
Hertz (Hz). Mass spectra were obtained on a Varian MS MAT 311 A
spectrometer in EI mode. The following starting materials were
synthesized according to literature procedures: 1,3,5,7-Tetrabro-
moadamantane (1) and 1,3,5,7-tetrahydroxyadamantane (2).[25,26] In-
tensity data were collected at low temperature (100 or 110 K) on
a Bruker KAPPA APEXII DUO diffractometer using MoKa (l=
0.71073 ꢁ) and, for small crystals, by a microsource CuKa (l=
1.54178 ꢁ). Cell refinements and data reductions were performed
by using the program package SAINT.[41] An absorption correction
was performed by using the program SADABS.[41] Structures were
solved by direct methods using SHELXS97 software.[42] Isotropic re-
finement of the structures by least-squares methods were also car-
ried out by using SHELXL97,[42] followed by anisotropic refinements
on F2 of all non-hydrogen atoms. The H-atom positions were calcu-
lated geometrically using the relevant riding models. For binary
solvent systems (Table 2, entries 8, 9, 11 and 12), an overlap model
of both solvent components was used for better fitting of the
strongly disordered parts in the solvent electron density.
1,3,5,7-Tetrakis(4-methoxy-2-methylphenyl)adamantane (5):
A
mixture of 2 (75 mg, 0.37 mmol, 1 equiv), p-toluenesulfonic acid
(35.6 mg, 0.18 mmol, 0.5 equiv) and 3-methylanisole (3 mL) was
heated to 1308C for 72 h in a Dean–Stark apparatus. After aqueous
work up as described for compound 3, the resulting dark brown
crude product was treated with MeOH (10 mL) in an ultrasonic
bath, and the slurry was centrifuged. This procedure was repeated
two times, and the title compound 5 was isolated as an off-white/
gray solid (94.7 mg, 0.165 mmol, 41%). Rf =0.41 (petroleum ether/
CH2Cl2, 2:1, v/v); 1H NMR (300 MHz, CDCl3): d=7.27 (d, J=7.9 Hz,
4H), 6.76–6.70 (m, 8H), 3.77 (s, 12H), 2.45 (s, 12H), 2.32 ppm (s,
12H); 13C NMR (75.5 MHz, CDCl3): d=158.7, 136.6, 135.5, 126.7,
120.8, 112.5, 54.9, 42.4, 39.2, 21.1 ppm; MS (70 eV, EI): m/z: 616/
617/618/619 [M+]; HRMS m/z calcd for C42H48O4 616.355, found
616.356.
CCDC-1040344 (4), 1040345 (5), 1040349 (6), 1040350 (3), 1040351
(3, entry 5, Table2), 1040354 (3, entry 6, Table2), 1040355 (3, entry
7, Table2), 1040356 (3, entry 8, Table2), 1040357 (3, entry 9,
Table2), 1040358 (3, entry 10, Table2), 1040359 (3, entry 11,
Table2), 1040360 (3, entry 12, Table2), 1040361 (3, entry 13,
Table2), 1040362 (3, entry 14, Table2), 1040363 (3, entry 15,
Table2), 1040364 (3, entry 16, Table2), 1040365 (3, entry 17,
Table2), 1040366 (3, entry 18, Table2), 1040367 (3, entry 19,
Table2), 1049318 (3, entry 20, Table2), 1049319 (3, entry 21,
Table2), 1049320 (3, entry 22, Table2), 1049321 (3, entry 23,
Table2), 1049322 (3, entry 24, Table2) and 1049323 (3, entry 25,
Table2) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif
1,3,5,7-Tetrakis(4-methoxy-2-ethylphenyl)adamantane (6): A mix-
ture of 2 (35 mg, 0.17 mmol, 1 equiv), p-toluenesulfonic acid
(16.6 mg, 0.09 mmol, 0.5 equiv), and 3-ethylanisole (0.61 mL) was
heated to 1208C for 48 h in a Dean–Stark apparatus. After aqueous
work up as described for compound 3, MeOH (5 mL) was added to
the resulting solid, and the slurry was treated in an ultrasonic bath.
After centrifugation, the supernatant was removed and discarded.
This washing procedure was repeated for two times. The title com-
pound 6 was isolated a colorless solid (34 mg, 0.05 mmol, 30%).
Rf =0.51 (petroleum ether/CH2Cl2, 2:1, v/v); 1H NMR (300 MHz,
1,3,5,7-Tetrakis(2,4-dimethoxyphenyl)adamantane (3): A mixture CDCl3) d=7.30 (d, J=7.8 Hz, 4H), 6.79–6.72 (m, 8H), 3.79 (s, 12H),
of 2 (20 mg, 0.1 mmol, 1 equiv), p-toluenesulfonic acid (9.5 mg, 2.63 (q, J=7.6 Hz, 8H,), 2.470 (s, 12H), 1.24 ppm (t, J=7.5 Hz,
0.05 mmol, 0.5 equiv), and 1,3-dimethoxybenzene (1.5 mL), was 12H); 13C NMR (75 MHz, CDCl3): d=158.8, 142.9, 135.7, 126.7, 119.4,
heated to 1408C for 96 h in a Dean–Stark apparatus. Then, the sol- 111.4, 54.9, 42.4, 39.3, 28.5, 15.3 ppm; MS (70 eV, EI): m/z: 672/673/
vent was evaporated in vacuo and the crude product was coeva- 674/675 [M+]; HRMS m/z calcd for C46H56O4 672.418, found
porated four times with methanol (3–5 mL). The resulting residue 672.418.
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[20] O. Plietzsch, C. I. Schilling, M. Tolev, M. Nieger, C. Richert, T. Muller, S.
Brꢂse, Org. Biomol. Chem. 2009, 7, 4734–4743.
Acknowledgements
[21] A. Singh, M. Tolev, M. Meng, K. Klenin, O. Plietzsch, C. I. Schilling, T.
Muller, M. Nieger, S. Brꢂse, W. Wenzel, C. Richert, Angew. Chem. Int. Ed.
2011, 50, 3227–3231; Angew. Chem. 2011, 123, 3285–3289.
[22] A. Singh, M. Tolev, C. I. Schilling, S. Brꢂse, H. Griesser, C. Richert, J. Org.
Chem. 2012, 77, 2718–2728.
The authors wish to thank H. Griesser for a review of the
manuscript, and Deutsche Forschungsgemeinschaft for finan-
cial support (grant No. RI 1063/13-1 to C.R.).
[23] H. Griesser, M. Tolev, A. Singh, T. Sabirov, C. Gerlach, C. Richert, J. Org.
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[24] A. Schwenger, C. Gerlach, H. Griesser, C. Richert, J. Org. Chem. 2014, 79,
11558–11566.
Keywords: adamantane
complexes · molecular storage · X-ray crystal structure
·
controlled release
·
inclusion
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Published online on && &&, 0000
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FULL PAPER
&
Inclusion Complexes
A. Schwenger, W. Frey, C. Richert*
&& – &&
Tetrakis(dimethoxyphenyl)adaman-
tane (TDA) and Its Inclusion
Complexes in the Crystalline State: A
Versatile Carrier for Small Molecules
Selective inclusion: A tetraaryladaman-
tane octaether was shown to form 20
different inclusion complexes, absorbing
toxic compounds such as benzene se-
lectively, and releasing guests such as
nitromethane upon recrystallizing from
alcohols.
Organic crystals as molecular storage materials…
…are described in the Full Paper by C. Richert et al. on
page &&. Tetrakis(dimethoxyphenyl)adamantane
(TDA) forms a dazzling array of crystalline inclusion
complexes, with guest molecules ranging from nitro-
methane to trifluorobenzene. Molecules thus stored
can be released by recrystallizing from an alcohol or by
solvate displacement. Hazardous materials and explo-
sives may be captured, and mixtures may be separated.
The picture illustrates the process of adding toxic solu-
tions to TDA, which then crystallizes.
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!