Angewandte
Communications
Chemie
Encapsulated Reagents
Reagents with a Crystalline Coat
Alexander Schwenger, Wolfgang Frey, and Clemens Richert*
Abstract: Tetrakis(dimethoxyphenyl)adamantane (TDA)
readily forms crystalline inclusion complexes with reactive,
toxic, or malodorous reagents, such as benzoyl chloride, acetyl
chloride, cyclohexyl isocyanide, phosphorus trichloride, and
trimethylsilyl chloride. The crystals are stable and largely free
of the problematic properties of the free reagents. When
exposed to solvents such as DMSO or MeOH, the reagents
react, and a large portion of the TDA precipitates. The TDA-
coated reagents may lead to a safer way of storing, handling,
and delivering reagents, and ultimately to synthetic protocols
that do not require fume hoods.
encapsulate small molecules,[9] and so are metal–organic
sponges.[10] Crystals of porous organic cages that absorb gases
are also known,[11,12] and porous liquids are beginning to
emerge,[13] but what would constitute a good crystalline matrix
for formulating liquid reagents is unclear. While studying
organic cores for matrix-forming DNA hybrids,[14–17] we
observed that 1,3,5,7-tetrakis(2,4-dimethoxyphenyl)adaman-
tane (TDA) readily includes small organic molecules in the
unit cell of its crystal structures.[18] Even though a solvent-free
crystalline form is known, TDA crystallizes with many
different guest molecules. Herein, we show that TDA can
act as a protective crystalline coat for reagents, enabling the
formulation of reactive, malodorous, or toxic compounds,
including inorganic reagents such as PCl3. The crystalline
formulation can mask problematic properties while delivering
reactive compounds upon exposure to common organic
solvents.
T
aming reactive compounds until they are brought into
contact with the desired reaction partner is one of the
challenges of chemistry. The most common way of meeting
this challenge is to keep reagents in tightly sealed glass
containers. The container is only opened under a fume hood
or in a glove box, and the reactive compound is transferred
into the reaction vessel using appropriate procedures, which
often involve a protective gas.[1] This approach is expensive as
it requires a fully equipped laboratory. Furthermore, it is
hazardous. If a container breaks during transport, storage, or
handling, accidents can occur that have severe consequences
for operators and the environment.
First, we optimized the three-step synthesis of TDA.[18]
When one equivalent of toluenesulfonic acid was used in the
final step of the reaction of adamantane tetraol and 1,3-
dimethoxybenzene, and the temperature was lowered to
1208C, the yield of TDA increased from 38%[18] to 67%, as
detailed in the Supporting Information. We then screened
a range of different compounds that are liquid at room
temperature for their ability to form inclusion complexes with
TDA. Mixtures of the liquid and TDA were heated until
a solution formed, which was then allowed to cool to room
temperature. A part of the unit cell of TDA crystals
containing extremely malodorous 2,3,4-trimethylpyrazine as
the inclusion compound is shown in Figure 1. Table 1 lists
parameters of 15 representative X-ray crystal structures of
inclusion complexes.
Reagents may be tamed by embedding them in an inert
matrix. Examples of this approach include acetylene stored in
gas bottles with inorganic matrices, white phosphorus encap-
sulated in self-assembled molecular containers,[2] alkali metals
stored under mineral oil, and reactive hydrides in paraffin oil.
However, heterogeneous slurries make it difficult to dispense
reagents, and few homogenates of reagents[3] are available.
The challenge of measuring out portions of inhomogeneous
matrices can be overcome by embedding reactive compounds
in crystalline matrices that form inclusion complexes of
defined stoichiometry. For example, some inorganic reagents
form stable co-crystals with inert salts, as in the case of the
triple salt of persulfuric acid known as oxone.[4–6] However,
even for inorganic salts, stable co-crystals that provide
a reactive form of a reagent are the exception, not the rule.
For organic reagents, a generic crystalline matrix that acts
as a formulation is lacking. Hemicarcerands are classical
examples of molecules that can crystallize and form host–
guest complexes[7] with organic molecules.[8] Cryptophanes
are another class of compounds with designed cavities that
Figure 1. Structural details of the inclusion complex of TDA with 2,3,5-
trimethylpyrazine, as observed in the X-ray crystal structure. C gray,
N violet, O red. Hydrogen atoms omitted for clarity.
The tetraaryladamantane crystallized in three different
crystal systems. Aside from monoclinic and triclinic sys-
tems,[18] a hexagonal system was observed for the first time.
Stoichiometries between 2:1 and 4:7 were measured, and
partially disordered guest molecules were common. Com-
pounds such as pyridine, piperidine, morpholine, acetyl
chloride, and furfural were included in near-stoichiometric
[*] Dipl.-Chem. A. Schwenger, Dr. W. Frey, Prof. C. Richert
Institut fꢀr Organische Chemie
Universitꢁt Stuttgart
70569 Stuttgart (Germany)
E-mail: lehrstuhl-2@oc.uni-stuttgart.de
Supporting information for this article can be found under:
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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