A self-organizing chemical assembly line

Article abstract of DOI:10.1021/ja412235e

Chemical syntheses generally involve a series of discrete transformations whereby a simple set of starting materials are progressively rendered more complex. In contrast, living systems accomplish their syntheses within complex chemical mixtures, wherein the self-organization of biomolecules allows them to form assembly lines that transform simple starting materials into more complex products. Here we demonstrate the functioning of an abiological chemical system whose simple parts self-organize into a complex system capable of directing the multistep transformation of the small molecules furan, dioxygen, and nitromethane into a more complex and information-rich product. The novel use of a self-assembling container molecule to catalytically transform a high-energy intermediate is central to the system's functioning.

Full text of DOI:10.1021/ja412235e

Communication
pubs.acs.org/JACS
A Self-Organizing Chemical Assembly Line
Airton G. Salles, Jr.,‡ Salvatore Zarra,‡ Richard M. Turner, and Jonathan R. Nitschke*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
S
* Supporting Information
situ from its “programmed” subcomponents without interfer-
ence from other components of the constitutionally dynamic
system.11
This process demonstrates not only how a high-energy
intermediate may be selectively transformed by a metal−
organic cage, but also how a self-organizing system based on
simple building blocks can be designed to transform and
functionalize a simple molecule within a complex mixture under
mild conditions using water as a solvent, dioxygen as a reagent,
and visible light as the energy source.
ABSTRACT: Chemical syntheses generally involve a
series of discrete transformations whereby a simple set of
starting materials are progressively rendered more
complex. In contrast, living systems accomplish their
syntheses within complex chemical mixtures, wherein the
self-organization of biomolecules allows them to form
“assembly lines” that transform simple starting materials
into more complex products. Here we demonstrate the
functioning of an abiological chemical system whose
simple parts self-organize into a complex system capable of
directing the multistep transformation of the small
molecules furan, dioxygen, and nitromethane into a more
complex and information-rich product. The novel use of a
self-assembling container molecule to catalytically trans-
form a high-energy intermediate is central to the system’s
functioning.
In its initial state, the aqueous reaction mixture contains the
subcomponents necessary to assemble the previously described
[FeII L6]4− cage 112 (i.e., 2-formylpyridine, iron(II) ions, and
4
4,4′-diaminobiphenyl-2,2′-disulfonic acid) together with furan,
nitromethane, L-proline, methylene blue, and dioxygen. Within
this chemical system, the hetero-Diels−Alder cycloaddition of
furan with singlet oxygen (1O2) generated by catalytic action of
the sensitizer methylene blue takes place (cycle A in Figure 1).
Concurrently, cage 1 assembles in situ and catalyzes the
subsequent transformation (cycle B), which yields fumaralde-
hydic acid b. Cycle A thus feeds into cycle B, which in turn
feeds into organocatalytic cycle C to afford the final product c
through the L-proline-catalyzed 1,4-addition of nitromethane to
intermediate b followed by cyclization. The absence of one of
the subcomponents of the cage was observed to lead to
nonselective pathways, whereby the high-energy intermediate
endoperoxide10 reacted to give different products. These did
not react further in cycle C to give product c.
iological systems have developed the ability to efficiently
B
shuttle high-energy chemical intermediates along specific
transformational pathways, thus avoiding side reactions and
interference between processes that operate in parallel,1 and
preventing these reactive intermediates from initiating damag-
ing events.2 Whereas eukaryotes rely upon membrane
compartmentalization to separate subsystems, prokaryotes are
able to direct the fates of reactive intermediates within a single
space bounded by the cell membrane. Prokaryotes’ biomo-
lecular machinery thus requires functional subsystems to self-
organize so as to avoid destructive interference between them.1
Chemists have recently begun to investigate the design of
systems that undergo complex self-organization3 or self-
sorting,4 due to the orthogonality of the interactions among
their various chemical components.5 The present work brings
together the concept of self-organization with the emerging
area of relay multicatalysis,6 whereby several catalysts work
together to effect sequential transformations.
The design of these one-pot relay transformations required
not only understanding of each individual step, but also analysis
of their combination in order to guarantee compatibility
between the different catalytic cycles,13 as discussed below.
It has long been established that the hetero-Diels−Alder
cycloaddition of singlet oxygen (1O2) with furan leads to the
formation of an unstable endoperoxide (Figure 1), which
undergoes ring opening to yield multiple products.10 Based
upon prior studies,14 we envisioned that the endoperoxide
would be a suitable guest for host 1, and that encapsulation
might lead to selective transformation into a single product.15
Here we describe a mixture of simple chemical precursors
that self-organize to generate a functional “assembly line” 7 of
molecular actors able to transform the simple substrate furan
(a, Figure 1) into the more structurally complex 5-hydroxy-3-
(nitromethyl)dihydrofuran-2(3H)-one (c). Key features of this
system are the in situ self-assembly8 of metal−organic cage9 1
(Figure 1) and the lack of interference between the different
catalytic cycles.
The photooxidation cycle (Figure 1A) generates a high-
energy intermediate endoperoxide10 (shown in Figure 1B) that
subsequently passes through cage 1 and is thus transformed
into a lower-energy intermediate b, which is able to participate
in the organocatalytic cycle (Figure 1C). Cage 1 assembles in
1
3
The reaction of O2, photogenerated from O2 by methylene
blue (3.5 mol%), with furan a in the presence of cage 1 (0.5
mol%) in D2O buffered to pD 4.0 at room temperature
provided b in 60% yield (reaction I, Figure 2). This reaction
performed in the absence of cage 1 gave hydroxybutenolide d
as the major product (35% yield) along with several other
oxidation products (reaction II, Figure 2). Interestingly,
product b could also be generated from d following addition
Received: December 2, 2013
Published: December 9, 2013
© 2013 American Chemical Society
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Communication
Figure 1. Relay multicatalytic system, in which all steps take place in water at room temperature at pH 4.0. In this one-pot sequential transformation,
reaction of furan a with singlet oxygen (photogenerated by methylene blue, cycle A) gave the corresponding endoperoxide. This high-energy
intermediate was transformed into fumaraldehydic acid b in the presence of a catalytic amount of cage 1 (cycle B) which assembled in situ without
interference from the other components within the mixture. The L-proline-catalyzed 1,4-addition of nitromethane to b (cycle C) afforded the final
product c in 30% overall yield. The derivatization of c allowed the determination of its ratio of enantiomers (er = 84:16).
photooxidation of furan under conditions similar to those
employed in reaction I (Figure 2), wherein the individual
subcomponents of the cage were used separately in place of the
whole cage, showed d as the major product along with other
oxidation products and no trace of product c (SI, section 1.6).
Other experiments confirmed that cage 1 clearly acted to
transform d into b over much shorter times (e.g., after 26 min,
25% of d was converted to b at pD 4 and room temperature,
see Figures S16 and S17). Under otherwise identical
conditions, a maximum conversion of d to b of only 5% after
1 week (see Figure S19) was obtained in the absence of cage 1
or in the presence of an incomplete subset of its
subcomponents.
The use of chiral amine catalysts to accomplish asymmetric
transformations has become a topic of intense development in
the field of enantioselective organocatalysis.16 Combining
concepts of organocatalysis with a photoredox catalytic cycle
has been shown to result in useful selective transformations.17
This development prompted us to explore the proline-catalyzed
1,4-addition of nitromethane to b, envisaging its combination
with the previously described cycles A and B (Figure 1).
1
Figure 2. Reaction of furan with O2 in the presence and absence of
Iminium-catalyzed reactions are usually performed in the
cage 1. Reaction I shows the conversion of furan a to fumaraldehydic
acid b in the presence of a catalytic amount of cage 1 (0.5 mol%) in
presence of acid co-catalyst.18 Cage 1 was observed to be
stable at pH >3.5; therefore, we performed our reaction at pH
4. After screening different molar ratios for the catalyst L-
proline it was found that 25 mol% was required at pH 4 in
order to convert b into c (71% yield) in 16 h (Figure 3). The
conversion of c into the lactone e through in situ reduction
D2O (pD 4). In the absence of cage 1 (reaction II), hydroxybutenolide
d was formed along with other oxidation products. In reaction III,
product b was generated from d upon addition of cage 1 to the
mixture of intermediate products. Only one of the six ligands is
represented for clarity in cage 1.
1
of cage 1 to the mixture of products from O2 and a (reaction
III, Figure 2). Although this same transformation of d might be
operative in reaction I, the absence of photooxidation
byproducts in this reaction lends weight to the inference that
cage 1 is acting on a high-energy intermediate, such as the
endoperoxide, thus transforming it selectively into b (Figure 1)
before competitive pathways leading to multiple byproducts can
become operative. This hypothesis is corroborated by the
observation of no d by 1H NMR spectroscopy whenever 1 was
present. Mechanistic hypotheses for the cage-mediated
production of b are presented in the Supporting Information
(SI), section 2.
Figure 3. Proline-catalyzed conversion of aldehyde b to (nitromethyl)-
hydroxyfuranone c, and further derivatization to the more stable
lactone e. The addition of nitromethane to b in the presence of L-
proline (25 mol%) was followed by cyclization, affording c in 71%
yield (after isolation) and diastereomeric ratio (dr) = 1:1 (as
1
determined by H NMR). Reduction in situ provided lactone e in
Control experiments confirmed that the presence of cage 1
was essential for the production of b. Conducting the
46% overall yield (after isolation) and 70:30 er (determined by chiral
GC using a CP-Chirasil-Dex CB column).
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Journal of the American Chemical Society
Communication
using NaBH4 was necessary to determine its enantiomeric ratio
(er = 70:30) by chiral gas chromatography (Figure 3).
transformation (Figure 4) was measured to be 84:16, showing
an enhancement in enantioselectivity compared to the
independently carried-out 1,4-addition to product b (Figure
3, er = 70:30). As cage 1 has no obvious influence on the
organocatalytic cycle, we ascribe the improvement in
enantioselectivity to the lower steady-state concentration of
aldehyde b during the combined reaction (see Figure S34B,C).
At a lower concentration, proportionally more of the aldehyde
will be bound to proline, leading to enantioselective reaction
pathways being favored.
The multicatalytic system described herein is easily scalable
(from 0.026 to 1.4 mmol of furan, a 54-fold increase), and there
is no need for column chromatography to isolate the final
product c. In the absence of 4,4′-diaminobiphenyl-2,2′-
disulfonic acid, which is one of the subcomponents of cage 1,
only the photooxidative catalytic cycle was active, giving d as
the major product (SI, section 1.13). This outcome confirms
that the self-assembly of subcomponents into cage 1 is of
paramount importance to obtain b through the sequential
transformations depicted in Figure 1. In more general terms,
the removal of any one of the components from the system, i.e.,
the deletion of one of the instructions from the system’s
“program”, derails its synthetic outcome.
Our investigation and understanding of each individual step,
described above, was crucial to the design of the one-pot
conversion of a into c. Components of each of the catalytic
cycles shown in Figure 1 were mixed with the subcomponents
required to form cage 1 in water buffered to pH 4 (t = 0 in
Figure 4). Following irradiation with a 20 W compact
fluorescent bulb at room temperature for 48 h under a
dioxygen atmosphere, product c was isolated in 30% overall
yield (t = 48 h in Figure 4). The enantioselectivity of the
proline-catalyzed step was determined by chiral GC after
derivatization to lactone e using NaBH4 as described above.
Surprisingly, the enantiomeric ratio obtained in the one-pot
Two levels of orthogonality can be identified within this one-
pot molecular assembly line. First, the orthogonal reactivities of
the catalytic cycles avoid interference between the different
catalysts and reagents brought together.13 Second, while the
reactions that result in the formation of cage 1 are not strictly
chemically orthogonal to the other reactions taking place in the
system, their reversibility leads to de facto orthogonality. For
example, cage 1 is able to self-assemble in the presence of
proline (Figure 4) despite the ability of proline to condense
with the aldehyde group of the cage subcomponent 2-
formylpyridine. The iminium linkage thus formed can
exchange, however, allowing an error-checking process to
proceed and for cage 1 to self-assemble cleanly.
Similarly, FeII is prone to oxidation to FeIII under a dioxygen
atmosphere; nevertheless, the mutual stabilization19 between
imine ligands and FeII plays an essential role preventing the
oxidation and allowing the formation of a stable assembly. The
interplay between the two levels of orthogonality along with the
compatible kinetics of the catalytic cycles was thus crucial for
function to be achieved.
The functioning of this self-organizing system is thus
underpinned by the robust self-assembly of cage 1 and its
novel ability to catalyze the production of b, which could be
joined to a subsequent organocatalytic step in order to allow for
further transformations to occur. This one-pot process avoids
intermediate purification procedures and changes in reaction
conditions and is scalable 50-fold. All starting materials are
commercially available, and mild experimental conditions were
employed. Further investigations may allow this approach to be
extended and refined, for example, to allow for the preparation
of a wider array of organic molecules of interest20 by taking
advantage of other cage-mediated transformations.21
ASSOCIATED CONTENT
■
Figure 4. Relay multicatalytic system incorporating the in situ assembly
of cage 1. Components of each one of the catalytic cycles were mixed
with the subcomponents required to form cage 1 in water (t = 0). The
flask was irradiated using a 20 W compact fluorescent bulb for 48 h
under an O2 atmosphere.
S
* Supporting Information
Experimental procedures; control experiments; one-pot multi-
catalytic procedure. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Journal of the American Chemical Society
Communication
(10) Gollnick, K.; Griesbeck, A. Tetrahedron 1985, 41, 2057.
AUTHOR INFORMATION
■
(11) Lehn, J.-M. Chem. Soc. Rev. 2007, 36, 151.
(12) Mal, P.; Schultz, D.; Beyeh, K.; Rissanen, K.; Nitschke, J. R.
Angew. Chem., Int. Ed. 2008, 47, 8297.
Corresponding Author
jrn34@cam.ac.uk
(13) Wang, Z. J.; Clary, K. N.; Bergman, R. G.; Raymond, K. N.;
Toste, F. D. Nat. Chem. 2013, 5, 100.
(14) Smulders, M. M. J.; Zarra, S.; Nitschke, J. R. J. Am. Chem. Soc.
2013, 135, 7039.
(15) Fiedler, D.; Bergman, R. G.; Raymond, K. N. Angew. Chem., Int.
Ed. 2004, 43, 6748.
Author Contributions
‡A.G.S. and S.Z. contributed equally.
Notes
The authors declare no competing financial interest.
(16) (a) Asymmetric Organocatalysis; List, B., Ed.; Springer: Berlin/
Heidelberg, 2009; Vol. 291. (b) Zhai, H.; Borzenko, A.; Lau, Y.-Y.;
Ahn, S.-H.; Schafer, L. L. Angew. Chem., Int. Ed. 2012, 51, 12219.
(17) (a) Nicewicz, D. A.; MacMillan, D. W. Science 2008, 322, 77.
(b) Yoon, H.-S.; Ho, X.-H.; Jang, J.; Lee, H.-J.; Kim, S.-J.; Jang, H.-Y.
Org. Lett. 2012, 14, 3272.
ACKNOWLEDGMENTS
■
This work was supported by the CAPES Foundation, Ministry
of Education of Brazil, Proc. BEX 3555/11-9. and the UK
Engineering and Physical Sciences Research Council (EPSRC).
The authors thank D. A. Vosburg and M. J. Gaunt for useful
comments on the manuscript.
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