There is a special fascination with organic matter that can take up and release molecules.
Perhaps this is because the phenomenon is intimately linked to life. Breathing is
a process that leads to the uptake of oxygen and the release of carbon dioxide from
the body. Likewise, the uptake of water and nutrients by organisms is linked to life
as we know it. Efficient storage for times of need, as in potatoes that accumulate
starch in the amyloplasts of their tubers during summer, is also important for the
survival of the plant and those who cultivate and consume it. Being able to emulate
nature's approaches to take up, store, and release for chemicals, perhaps as part
of sustainable processes, could provide a solution to energy problems but may also
lead to safer synthesis procedures because of proper formulation of reactive compounds.
There is active research on new ways to store molecules in solids. Different materials
are being proposed for achieving this task. Perhaps the best known solids that can
capture and release small molecules are zeolites,[1] that is, inorganic polymers with covalent bonds setting up a rigid structure that
reversibly binds water and small organic molecules (Figure [1]). But, other porous materials are rapidly gaining ground. Among them are metal-organic
frameworks (MOFs) and covalent organic frameworks (COFs) that are partially or entirely
based on stiff organic building blocks assembling with crystalline or partially crystalline
order.[2] Another exciting new class of compounds are organic cage compounds that posses a
cavity large enough to host other molecules.[3] As materials, the organic cages can be porous in amorphous or in crystalline states.
Like calixarenes they can engage in supramolecular host–guest interactions even when
they are found as individual molecules in solution.[4] A different class of organic compounds that can act as hosts for small molecules
are compounds that require crystallization to form the cavities that bind the guests.
When they are porous, such organic materials are said to exhibit ‘extrinsic’ porosity,
as opposed to an intrinsic porosity that is inherent in the molecular structure.[5]
Figure 1 Structural components of materials for the uptake and release of small molecules.
Besides a zeolite, substructures of a metal-organic framework (MOF), a covalent organic
framework (COF), a compound designed not to pack tightly (packing compromised), and
Dianin’s compound are shown.
The better known organic materials with extrinsic porosity posses hydrogen-bond donor
and acceptor functionalities and form their crystal lattice via strong hydrogen bonds.[6] Recent advances in computational structure prediction have led to impressive advances
in the design and experimental realization of highly porous organic crystals that
are held together by directional intermolecular interactions between molecules with
shapes that hinder close packing.[7] Some examples of such molecules ‘designed not to pack tightly’ form inclusion compounds
or solvates with guest molecules, even if they lack hydrogen-bond donor groups,[8] but no tightly packed, solvate-free forms have been reported.
Organic crystals with extrinsic porosity are a special case of the significant number
of compounds that include solvent upon crystallization when tight packing is geometrically
difficult or when hydrogen-bond acceptor/donor groups cannot be ‘satisfied’.[9] Perhaps the best known example of such inclusion-forming compounds that shows ‘zeolite-like’
behavior is ‘Dianin’s compound’ (Figure [1]). It is long known to take up (and release) a range of small molecular guests in
cavities lined by a hydrogen-bonding network.[10]
[11]
There are molecules, though, that readily form inclusion compounds even though solvate-free,
tightly packed crystalline forms are also accessible to them. So the conventional
wisdom that solvate formation is a consequence of remaining intermolecular cavities
that cannot be readily filled during crystallization does not seem to apply. Many
of us have recrystallized a new compound, hoping that we obtain a solvate-free form
that matches the theoretical values in the elemental analysis. A new solvent often
solved the problem. But there are also compounds for which guest molecules as different
as n-hexane, trimethylphosphate, and nitrobenzene are being incorporated efficiently.
The first such compound found in our laboratory is tetraaryladamantane octaether 1,3,5,7-tetrakis(2,4-dimethoxyphenyl)adamantane
(TDA). The second such compound is the related ethyl ether 1,3,5,7-tetrakis(2,4-diethoxyphenyl)adamantane
(TEO). For these compounds, we feel the term ‘encapsulating organic crystals’ (EnOCs)
is particularly fitting.
Figure 2 Structures and representative crystal forms of tetraaryladamantane EnOCs, as described
in the recent literature[12]
[14]
The tetraaryladamantanes shown in Figure [2] exhibit significant diversity in their crystal structures. This is probably because
the structural arrangements in their crystals are not fixed in place by strong, directional
interactions or covalent bonds. As shown in Figure [2], both TDA and TEO crystallize in solvate-free forms and in encapsulating forms with
similar density. For TDA, monoclinic, triclinic, and hexagonal crystal systems have
been published.[12]
[13] For TEO, both a monoclinic and a tetragonal tightly packed solvate-free form were
found. But, another monoclinic form was found to encapsulate more than three molar
equivalents of p-xylene as guest molecule, and many other inclusion compounds were of a triclinic
crystal system.
How are these EnOCs useful as tools in synthesis? After encapsulating and stabilizing
fairly reactive molecules, like acid chlorides, the octaether-based EnOCs can shed
their guest molecules, either upon dissolving in a solvent or upon warming. So, after
formulation by crystallization, captured guests can be released.[12]
The two EnOC-forming compounds shown in Figure [2] are accessible in a three-step synthesis from inexpensive starting materials.[13]
[14] They crystallize readily, often within minutes. Their loading capacity for small
molecules is up to 35% of the dry weight of the material. Overall, more than 100 crystal
structures with encapsulated small molecules have been solved for these two compounds
thus far in our laboratories. Most importantly, as mentioned above, the ability to
form inclusion compounds with liquids is not limited to solvents. Encapsulation upon
crystallization can be used to formulate toxic, malodorous, or highly reactive compounds.
In the encapsulated form, the undesirable properties of the guests are masked, so
that encapsulated acid chlorides or isocyanides are odorless. Some reagent formulations
of water-sensitive compounds are stable to air, or, as in the case of benzoyl chloride
encapsulated in TEO, stable to immersion in water.[14]
All encapsulated reagents studied thus far by us can be handled outside a fume hood
and are easy to dispense. The most common way to induce the release of the reagent
is to dissolve the material in the reaction solvent. Because the crystalline formulation
unleashes the reagent more slowly than addition in neat form, some transformations
are cleaner with the encapsulated reagent.[13] Slight increases in yield were also traced back to a smaller extent of hydrolysis,
probably because the encapsulated form is a solid that does not get in contact with
as much surface water as a liquid that is being dispensed with the help of glass pipettes.
In solvents such as DMSO or acetone, TDA that had acted as crystalline coat for an
acid chloride or an isocyanide was found to precipitate upon shedding its molecular
cargo, so that up to 99% could be recycled by filtration at the end of the synthetic
transformation (Figure [3]).[13]
Figure 3 Flow-chart for a synthetic procedure involving encapsulation of a reagent in TDA
Recently, the vacuum-dried form of TEO that had been crystallized as a high-loading
solvate was found to adsorb xylene vapors reversibly from the gas phase, with 15 uptake
and release cycles over the course of 17 days.[14] This suggests that the loading of liquid guest molecules can occur not only through
gentle thermal crystallization, as performed with reagents such as benzoyl chloride,
trimethylsilyl chloride, cyclohexyl isocyanide, or pyrrolidine, but may also be performed
by absorbing vapors. This, again, may be useful for synthetic procedures where problematic
compounds must be captured to avoid contamination or side reactions.
It is not clear to us how many substance classes other than tetraaryladamantane octaethers
show attractive features as crystalline coats for reagents. The ability to encapsulate
such a broad range of small molecules in crystals was found serendipitously. Structurally,
the EnOC-forming tetraaryladamantanes are made up of aliphatic and aromatic rings
and eight ether functionalities. Neither of these structural elements is unusual in
the context of crystal engineering.[15] So, to predict new EnOCs, there is a need for a better molecular understanding of
their properties, and a quantitative description of the kinetic and thermodynamic
processes that govern their crystallization. Even without such deeper theoretical
insights, TDA and TEO can be tested as coats for other problematic reagents, so that
safe formulations are found, with little remaining vapour pressure of the reagent
and the option to perform synthetic transformations without a fume hood. The use of
EnOCs thus complements Buchwald's method for glovebox-free syntheses involving single-use
capsules.[16]
In summary, while zeolites, MOFs, COFs, organic cages, and organic materials assembling
via hydrogen bonds or with compromised packing are well-established matrices for uptake
and release of gases, EnOCs appear to be particularly well suited for liquids. They
are distinct from the porous matrices in that they form cavities without covalent
bonds or hydrogen bonds between host molecules, and despite the accessibility of tightly-packed,
solvate-free crystal forms. Not one specific cavity is formed when EnOCs assemble,
as with Dianin’s compound, but many different structural arrangements lead to encapsulation,
many of them with high crystalline order. This opens up a broad structure space of
potential guest molecules, making EnOCs attractive for the formulation of labile compounds.
Experiments aimed at formulating even more reactive reagents than those studied thus
far[12]
[13]
[14] are currently under way in our laboratories.
Independent of what the final breadth of the method will be, EnOCs are interesting
for practical applications and academic exploration alike. Their capability to take
up and release small molecules as if they were ‘breathing’, sometimes without macroscopic
loss of crystallinity, provides a fascination to us as strong as if they were involved
in processes of life.
