Continuous flow synthesis of a carbon-based molecular cage macrocycle via a three-fold homocoupling reaction

Article abstract of DOI:10.1039/c5cc05181a

The facile synthesis of the cage molecule (C₁₁₀H₅₆Br₂) via a remarkable three-fold homo-coupling macrocyclization reaction using continuous flow methodology is reported. Synthesis via continuous flow chemistry improves the residence time, safety, and environmental profile of this synthetically challenging reaction. Further, the new cage possesses halogen atoms at its apex that serve to expand the potential reaction space of these intrinsically porous, all carbon-carbon bonded molecular cage molecules.

Full text of DOI:10.1039/c5cc05181a

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Konstas, M. L. Czyz, P. Valente, C. J. Sumby, M. R. Hill, A. Polyzos and C. J. Doonan, Chem. Commun.,
2015, DOI: 10.1039/C5CC05181A.
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DOI: 10.1039/C5CC05181A
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Continuous Flow Synthesis of a Carbon-Based Molecular Cage
Macrocycle via a Three-Fold Homocoupling Reaction
Melanie Kitchin,a,c Kristina Konstas,a Christopher J. Sumby,c Milena Czyz,a Peter Valente,c Matthew
R. Hill,*a,c Anastasios Polyzos,*a,b and Christian J. Doonan.*a,c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The facile synthesis of the cage molecule (C110H56Br2) via a remarkable halides is well documented in the literature.15,16,17 In particular,
three-fold homo-coupling macrocyclization reaction using continuous flow we note the potential for transition metal-catalyzed processes
methodology is reported. Synthesis via continuous flow chemistry such as the Sonogashira-,18,19 Suzuki-,20,21 Stille-,22,23 Heck-24,25
improves the residence time, safety, and environmental profile of this and Ullmann-26,27 type coupling reactions. Accordingly,
synthetically challenging reaction. Further, the new cage possesses replacement of the terminal methoxy group with a halogen
halogen atoms at its apex that serve to expand the potential reaction would allow access to reactive halides, thereby increasing the
space of these, intrinsically porous, all carbon-carbon bonded molecular potential utility of Cage C1 as a molecular building block. We
cage molecules.
were therefore encouraged to pursue the synthesis of Cage C2
(Br), a bromo-terminated analogue of Cage C1, via a three-fold
oxidative homocoupling macrocyclization.28
Shape-persistent cage molecules are of broad interest due to
their unique photophysical properties,1,2 host-guest
chemistry3,4 and remarkable permanent porosity.5,6 Such
porous molecular solids have recently emerged as attractive
materials for application to gas adsorption and separation
science,7 as whilst they possess comparable porosity8 to
extended framework materials such as metal-organic
frameworks and covalent-organic frameworks, they are also
soluble. This solubility facilitates processing and incorporation
into extended molecular architectures9 such as mixed-media
technologies10 and porous polymers.11,12 Importantly though,
to fully realise the potential of these materials in emerging
applications13 efficient synthetic protocols must be developed.
We have previously reported the synthesis and
characterisation of a novel cage, Cage C1 (R = OMe)14 (Scheme
1), with a molecular architecture constructed entirely from
carbon-carbon bonds. Furthermore, we demonstrated that
Cage C1 can be controllably processed into a solid of high
surface area. To promote the use of molecular species like
Cage C1 as building blocks for novel materials, however,
synthetically versatile functional groups need to be
incorporated into their structures to enable further
elaboration. In this respect, the extensive reactivity of aryl
The exploration of chemically robust cage materials is
usually limited by low-yielding transformations,29 and in
connection with Cages C1 and C2, this synthetic challenge is
due to the irreversible nature of C-C covalent bond formation
that favours kinetically driven reaction products. Thus, in cases
where the desired 3-dimensional macrocycle is ultimately
formed by a multifold cross- or homocoupling step, the
reactions are performed under high dilution conditions to
minimize the production of oligomers and polymeric species.30
As such, in addition to decorating the cage with functional
groups,
a general synthetic methodology that affords
significant quantities of the cage product in a facile manner,
and in a workable reaction volume, is highly desirable.
Scheme 1. General scheme for the preparation of molecular cage macrocycles.
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Continuous flow chemistry was recently demonstrated
to be an effective strategy for substantially improving the
yield of the final Glaser-Hay coupling step in the formation
conditions, the coupling reaction was unsuccessful. Rather, the
Breslow modification36 to the Glaser-Eglinton conditions were
the only conditions found to lead to any product. The
rotational flexibility of the tetraphenylmethane backbone of
the half cage (Scheme 1, Half Cage HC2) allows for oligomer
formation and therefore, in order to promote the formation of
the cage, the reactants must be present at very low
concentrations. Additionally, in batch conditions, a large
excess of copper(II)/(I) reagents are required to facilitate the
coupling reaction thereby maximising the probability of cage
formation with respect to oligomers (Fig. 2, Table S1). As a
32
of carbon-based macrocycles.31,
Similar benefits were
realised for a macrocyclization utilising an azide-acetylene
cycloaddition reaction at high temperature, which did not
proceed under batch conditions 33
To our knowledge,
.
however, there have been no reports to date regarding the
use of continuous flow chemistry in two- or three-fold
homocoupling macrocyclizations. On the basis of the
precise control of reagent concentration, mixing via static
mixing devices and efficient heat and mass transfer
achievable in flow microreactors, we contend that
continuous flow methodology provides optimal conditions
result, performing these reactions on large scales in
a
laboratory setting represents a significant operational
challenge. The rapid and efficient heat and mass transfer
offered by the laminar flow of reagents under continuous flow
conditions allows for shorter reaction times that, in this
reaction, should favour the desired kinetic product.37 With
respect to the above dimerization, the continuous flow of
reactants would also enable the synthesis of large quantities of
product whilst maintaining the high dilution factor of half cage
and a large excess of copper species.
for conventionally slow macrocyclization reactions 15,7
.
Here we demonstrate the development of a three-fold
oxidative homocoupling macrocyclization under both batch
and continuous flow conditions for the preparation of a new
molecular cage derivative, Cage C2. We assert that continuous
flow synthesis can be successfully employed as a strategy to
dramatically increase the efficiency of multifold carbon-carbon
bond coupling reactions and, as a result, greatly expand the
field of porous molecular solids.
Flow synthesis conditions were chosen based on the
reaction time and concentration of half cage required for the
batch synthesis. However, the molar ratio of copper reagents
was significantly reduced, to 32% of Cu(OAc)2, and 71% of CuCl
used in the traditional batch synthesis to ensure solubility. Two
separate reagent streams were used, that were combined at a
T-mixing piece before entering the first of two 10 mL, 1.0 mm
inner
diameter
(ID)
perfluoroalkoxypolymer
(PFA)
microreactor coils. The first flow stream contained a pre-mixed
solution of anhydrous Cu(OAc)2 (21 eq.) and CuCl (32 eq.) in
dry pyridine. The second flow stream contained a 1 mmol
solution of Half Cage HC2 in dry pyridine. The solutions were
continuously pumped through two reaction coils, which were
heated to 70 °C. The most successful flow rate was found to be
0.6 mL min-1, equating to a residence time of 33.3 min, and
which produced Cage C2 in a yield comparable to batch
chemistry (20% batch chemistry vs. 21% flow chemistry). This
represents a significant decrease (92.5%) in reaction times
when compared with the corresponding batch synthesis. (Fig
2, Table S1). The observed decrease in residence time gave rise
to an appreciable increase in the space-time yield (STY) of Cage
Figure 1. A schematic representation of the synthesis of Cage C2 through a three-fold
Eglinton homocoupling.
As a control, Cage C2 was synthesised under traditional
batch synthesis conditions via the homocoupling of Half-Cage
HC2. High dilution conditions and a large excess of copper
coupling reagents were required in order to minimise oligomer
formation, with the reaction proceeding in a 20% yield. The
C2
and process chemistry, and gives a measure of the mass of
product per m3 of reaction mixture per day.38, 39 For Cage C2
. STY is a concept gaining increasing traction in industrial
1
formation of Cage C2 was confirmed by H NMR and 13C NMR
,
the STY achieved under flow conditions amounted to 104.6 g
m-3 day-1 . A limitation of the flow method relative to batch
howver, relates to the increased dilution of Half Cage HC2 and
copper reagents (c.a. 4-fold solvent increase for Half Cage HC2
and 2-fold for copper.
spectroscopy, the latter showing aromatic resonances
consistent with the cage molecule appearing in the range 7.15-
7.76 ppm, with the alkyne peak of the brominated half cage
notably absent at 3.09 ppm. Electrospray ionization mass
spectrometry (ESI-MS) revealed a peak for the parent ion at
m/z 1537, and a peak isotope pattern that corresponds to an
ionized dibromo cage. Promisingly, in terms of further
modifications, Cage C2 was found to be soluble in common
organic solvents, such as dichloromethane and chloroform.
The limiting step for the synthesis of Cage C2 is the final
homocoupling reaction of the rigid, alkyne-terminated
precursors. Under traditional Glaser34 and Eglinton35
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-1
Flow Chemistry (2 mL min )
Batch Chemistry
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Reaction
Time
CuCl
Figure 3. a) Space-filling depiction of Cage C2, carbon and bromine atoms are pale grey
and yellow, respectively. b) A view of the crystal packing of Cage C2, a single cage
molecule is highlighted in a space-filling representation. In a) and b) hydrogen atoms
have been omitted for clarity.
Conversion
Cu(OAc)
2
Figure 2. A comparison of the reaction conditions required for the synthesis of Cage C2
via Flow Chemistry (0.6 mL min-1) vs. Traditional Batch Chemistry. The conditions for
traditional batch chemistry have been normalised for clarity.
In summary, we have developed a new process to access
The increase in solvent-to-reagent ratio was necessary to
ensure complete solubilisation of the reagents in pyridine,
thereby avoiding potential blocking of the flow apparatus. It is
clear however, that the increase in dilution is compensated by
the higher throughput and reduced reaction times of the flow
method relative to batch. Finally, it should be noted that any
unwanted oligomerization products, were removed during the
the novel porous organic cage compound, Cage C2, through
continuous flow technology via
a three-fold oxidative
homocoupling macrocyclization. A benefit of our approach
derives from the inherent scalability of continuous flow
synthesis, in which the macrocyclization can be readily scaled
in the laboratory without the impracticality associated with
scaling macrocyclization reactions via traditional batch
techniques. Furthermore, although we have demonstrated a
reduction in the use of Cu(OAc)2 and CuCl reagents relative to
batch synthesis, we believe that this will be further reduced to
sub-stoichiometric amounts through the use of immobilised
copper species. This approach is currently being investigated.
As such, we have shown that continuous flow methods offer a
realistic, feasible and economic route to the scaling-up of
shape-persistent organic cage synthesis. This work
demonstrates the potential for using flow chemistry methods
to readily and rapidly generate multi-gram quantities of
complex molecules that are of interest in contemporary
technologies such as polymer chemistry, and microelectronics
where materials synthesised via multifold carbon coupling
reactions are common. Furthermore, the Br-substituted cage is
now a synthetic starting point of efforts to understand the role
capping substituents play in the packing of these carbon-
bonded cage molecules.
1
purification process and analysis of the crude HNMR did not
reveal the presence of de-halogenated cage products.
Crystals of Cage C2 suitable for X-ray diffraction were
grown from diffusion of petroleum spirits into a benzene
solution of the cage. Single crystals grown under these
conditions, and
a variety of others, were very weakly
diffracting; even for the best quality crystals obtained, using
synchrotron X-ray sources, diffraction data was only obtained
to 2θ = 37.32°. As such only basic structural parameters will be
described. Nonetheless, the formation of the bromo-
functionalised cage could be readily confirmed. Cage C2
crystallises in the tetragonal space group I41/acd with half a
cage molecule in the asymmetric unit. As it possesses an
identical carbon-bonded backbone, the cage adopts a very
similar structure (Fig. 3a) to that encountered for the
previously reported, methoxy-derivatised cage C1,14 with
similar bond lengths, angles and internal dimensions to the
previously reported entity. Viewed down the axis of the cage
the phenyl rings of the tetraphenylmethane head groups are
eclipsed with subtle twists of the alkyne arms; interestingly
two are twisted in one direction and the third in the opposite
direction which attests to the flexibility of the
tetraphenylmethane moiety. Cage C2 packs to form an open,
Notes and references
§ ACKNOWLEDGMENT
C.J.D. and C.J.S. would like to acknowledge the Australian
Research Council for funding (DP120103909 (C.J.D.),
potentially porous structure that is filled with disordered FT100100400 (C.J.D.), and FT0991910 (C.J.S.)). A.P would like to
acknowledge CSIRO OCE Julius Award for funding. Parts of this
work were funded by the Science Industry and Endowment
Fund. Aspects of this research were undertaken on the MX1
beamline at the Australian Synchrotron, Victoria, Australia. Dr
Campbell Coghlan is thanked for collecting and solving X-ray
solvent. Due to the lack of functional groups, packing
interactions are dominated by numerous weak C-H···π and π-
stacking interactions. Despite the presence of a halogen, no
halogen bonding interactions are observed in the crystal
packing and the bromine moiety extends into the void of an crystallographic data on Cage C2
.
adjacent cage entity.
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