Product Distribution from Precursor Bite Angle Variation in Multitopic Alkyne Metathesis: Evidence for a Putative Kinetic Bottleneck

Article abstract of DOI:10.1021/jacs.8b02184

In the dynamic synthesis of covalent organic frameworks and molecular cages, the typical synthetic approach involves heuristic methods of discovery. While this approach has yielded many remarkable products, the ability to predict the structural outcome of

Full text of DOI:10.1021/jacs.8b02184

Subscriber access provided by UNIV OF SCIENCES PHILADELPHIA
Product Distribution from Precursor Bite Angle Variation in Multitopic
Alkyne Metathesis: Evidence for a Putative Kinetic Bottleneck
Timothy P. Moneypenny, Anna Yang, Nathan P. Walter, Toby
J. Woods, Danielle L. Gray, Yang Zhang, and Jeffrey S. Moore
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02184 • Publication Date (Web): 19 Apr 2018
Downloaded from http://pubs.acs.org on April 19, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Product Distribution from Precursor Bite Angle Variation in
Multitopic Alkyne Metathesis: Evidence for a Putative Kinetic
Bottleneck
1,2
1
2,3
4
Timothy P. Moneypenny, II, Anna Yang, Nathan P. Walter, Toby J. Woods, Danielle L.
4
2,3
,1,2
Gray, Yang Zhang, and Jeffrey S. Moore*
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Department of Chemistry, University of Illinois at Urbana—Champaign, Urbana, Illinois 61801, United
States
2
Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana−Champaign,
Urbana, Illinois 61801, United States
3
Department of Nuclear, Plasma, and Radiological Engineering, University of Illinois at Urbanaꢀ
Champaign, Urbana, Illinois 61801, United States
4
School of Chemical Sciences, University of Illinois at Urbana—Champaign, Urbana, Illinois 61801,
United States
ABSTRACT
In the dynamic synthesis of covalent organic frameworks and molecular cages, the typical
synthetic approach involves heuristic methods of discovery. While this approach has yielded
many remarkable products, the ability to predict the structural outcome of subjecting a multitopic
precursor to dynamic covalent chemistry (DCC) remains a challenge in the field. The synthesis
of covalent organic cages is a prime example of this phenomenon, where precursors designed
with the intention of affording a specific product may deviate dramatically when the DCC
synthesis is attempted. As such, rational design principles are needed to accelerate discovery in
cage synthesis using DCC. Herein, we test the hypothesis that precursor bite angle contributes
significantly to the energy landscape and product distribution in multitopic alkyne metathesis
(AM). By subjecting a series of precursors with varying bite angles to AM, we experimentally
demonstrate that the product distribution, and convergence towards product formation, is
strongly dependent on this geometric attribute. Surprisingly, we discovered that precursors with
the ideal bite angle (60º) do not afford the most efficient pathway to the product. The systematic
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 35
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
study reported here illustrates how seemingly minor adjustments in precursor geometry greatly
affect the outcome of DCC systems. This research illustrates the importance of fineꢀtuning
precursor geometric parameters in order to successfully realize desirable targets.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
INTRODUCTION
1
, 2
Dynamic covalent chemistry (DCC)
is a powerful synthetic method to construct shapeꢀ
3ꢀ5
6ꢀ12
persistent molecular architectures including macrocycles,
cages,
and covalent organic
1
3, 14
frameworks.
The ability of DCC reactions to proceed via thermodynamic control –
ultimately allowing for error correction and convergence towards thermodynamically stable
products – provides a means of synthesizing large, complex molecules in one step with high
1
yields on gram scales. Implicit in this thermodynamically controlled scenario is the fact that
DCC systems explore a multitude of structures and molecular arrangements before finally
reaching an energy minimum and corresponding product distribution. Furthermore, DCC
provides the ability to reꢀequilibrate the product distribution by simply adjusting the reaction
conditions (e.g., concentration, temperature, or solvent). It is no coincidence that DCC has
emerged as the most viable candidate to construct large, complex 2D and 3D molecular
architectures comprised solely of covalent bonds. One field in particular – the synthesis of
covalent molecular cages – has benefitted from wellꢀknown DCC reactions and continues to be a
heavilyꢀresearched area.
The typical approach in this field is to use a heuristic method to design precursors with
reasonable geometric attributes required for a targeted structure. With this approach, the topicity
(number of reactive functional groups), geometry, and directionality of precursors allow the
chemist to propose a reasonable thermodynamicallyꢀstable structural outcome. While such an
approach is tempting, it occasionally fails to produce the desired outcome or yields no
2
ACS Paragon Plus Environment

Page 3 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
discernible products at all. Although the field of metalꢀligand coordination complexes has found
1
5, 16
great success using heuristic methods,
the construction of cages via DCC has additional
kinetic considerations and difficulties that must be overcome to achieve reliable architecture
formation. In a practical sense, these difficulties arise from finite catalyst lifetimes, slower rates
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
of reactions, and potential kinetic bottlenecks in comparison to coordination complexes.
Whereas kinetically labile metalꢀligand coordination systems siphon through intermediates on
1
7, 18
6, 19ꢀ22
the order of seconds,
DCC systems may take up to several days.
Consequently, slow
reaction rates and kinetic bottlenecks may result in extended intermediate lifetimes, affording
unanticipated structures including intractable mixtures and complex precipitates that impede the
6
, 12, 23, 24
approach toward equilibrium or halt it completely.
In the context of multitopic (greater than two reactive sites) DCC systems where kinetic
factors may intervene, it is useful to frame the problem of reaching the desired product not in
terms of a single reaction pathway but rather in terms of a reaction energy landscape, where each
2
5
point on the landscape corresponds to a molecular entity with a specific internal free energy. As
such, the DCC reaction is more accurately described as a process which progresses through an
ensemble of various structural intermediates and reaction pathways en route toward the
thermodynamic product distribution. In this context, the systems that fail to reach a single
discrete product suggest that the energy landscape governing the reaction is in either one of two
2
5
categories: 1) the landscape is too flat—leading to an analogous “Levinthal’s paradox” where
there is insufficient time to reach the thermodynamic product, or 2) the landscape is too rough—
leading to premature kinetic bottlenecks at intermediate stages. It is because of these scenarios
that precursor design considerations must take into account not only the thermodynamics of
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 35
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
products but also that the reaction energy landscape provides pathways to these products on
reasonable time scales.
As it stands in the field of synthesizing covalent molecular cages via DCC, there is a need for
a deeper understanding of how the DCC energy landscape depends on geometric attributes of
precursors. Only when a dynamic system proceeds along a smooth energy landscape, or a
landscape which does not allow intermediates to irreversibly fall into deep energy minima, will
the thermodynamic product be achieved in appreciable yields. Accordingly, precursors must be
designed with geometric attributes that direct product distributions along smooth energy
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
6
lanscapes.
9
, 27
While several covalent organic cages have been prepared via DCC,
there are few reports on
unsuccessful attempts from which much could be learned. Additionally, while there are no clear
set of design principles to form molecular cages, the literature hints that subtle environmental
effects or changes in precursor geometric attributes result in the nonꢀintuitive formation of cage
products with unexpected architectures. For example, Warmuth and coworkers discovered a
solvent dependent cageꢀforming system using imine condensation, where one precursor
selectively formed an octahedron, a tetrahedron, or a square antiꢀprism depending on the solvent
2
8
used in the reaction. Cooper and coꢀworkers developed a strategy to determine oddꢀeven effects
in the synthesis of imine cages where the products from the reactions with an even α,ωꢀ
alkanediamine carbon chain length afforded tetrahedral [4+6] cages and the products from the
2
9
reactions with an odd chain length afforded [2+3] cage structures. Zhang and coꢀworkers
devised a study on altering the size of precursor units. They designed multiple tritopic precursors
with ca. 90º carbazole arms, varied the size of the central panel, and observed that the size of the
building blocks plays a significant role in determining the resulting structural outcome.
4
ACS Paragon Plus Environment

Page 5 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Precursors with smaller panels tended to form D h tetramers, while precursors with larger panels
2
3
0
tended to form dimers. Klotzbach and Beuerle discovered the shapeꢀselective formation of
bipyramidal, tetrahedral, or cubic organic cages when diboronic acids with bite angles of 60º,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
20º, and 180º are reacted, respectively, in the condensation with catecholꢀfunctionalized
12
tribenzotriquinacenes. These results collectively indicate that multitopic DCC energy
landscapes are complex and their product distributions are affected by various reaction
parameters that are not always intuitive.
To understand multitopic DCC landscapes more completely, we sought to perform systematic
studies that experimentally discern design principles for tetrahedral organic cages synthesized
2
6, 31
via dynamic alkyne metathesis (AM).
Since this example forms a tetrahedral cage product in
nearly quantitative yields, we supposed it would be a key system to investigate the effects of
minor adjustments in precursor geometry on the DCC energy landscape. Taking inspiration from
3
2ꢀ34
work by Fujita,
we hypothesized that precursor bite angle (or the angle between phenyleneꢀ
containing arms) significantly alters the dynamic energy landscape and resulting product
distribution in multitopic AM.
Herein, we test this bite angle hypothesis by synthesizing a series of analogous tritopic
precursors with different bite angles—one with a tight bite angle, one with a medium bite angle,
and one with a bite angle that matches (within the limits of our measurement technique) the ideal
2
5
angle of a tetrahedron (60º) —to deliberately alter the DCC energy landscape. Subjecting each
precursor to identical AM conditions and characterizing the resulting mixtures demonstrates that
precursors with ideal bite angles are not the most efficient at forming a tetrahedral molecular
cage. Monitoring reaction progress at various time points via gel permeation chromatography
(GPC) provides evidence that slight changes in bite angle induce restructuring of the dynamic
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 35
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
26
AM energy landscape. Our results demonstrate that even minor adjustments in precursor
geometry significantly bias the dynamic AM energy landscape. Cage formation via AM is thus
reminiscent of other reactive systems that venture through multiple intermediates, some of which
3
2,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
are on a pathway to the target, while others have strayed from a pathway directed to the target.
34
RESULTS AND DISCUSSION
Synthesis and Characterization of Precursors. A series of tritopic precursors with varying bite
angles were synthesized: PSulf, PCarb, and POxy (Figure 1b), with small, medium, and large bite
angles, respectively. The original precursor, PCarb, was synthesized according to a previously
2
6
reported procedure and represents the medium bite angle precursor. The small bite angle
precursor, PSulf, was synthesized in high yields from a fourꢀstep synthesis, with the key step
involving a threeꢀfold nucleophilic aromatic substitution of 1,3,5ꢀtribromoꢀ2,4,6ꢀtriethylbenzene
3
5
using sodium thiophenylate in 1,3ꢀdimethylꢀ2ꢀimidazolidinone at 140 ºC (Scheme 1). The large
bite angle precursor, POxy, was synthesized in good yields from an eightꢀstep synthesis (Scheme
1
). The key synthetic steps involve a threeꢀfold nucleophilic aromatic substitution of trihydroxy
intermediate, 6, with 4ꢀfluoroꢀ1ꢀnitrobenzene using cesium carbonate in dimethylformamide, and
iodineꢀpromoted transformation of the trisꢀ(1ꢀarylꢀ3,3ꢀdialkyltriazene) intermediate, 9, with
36
iodine in diiodomethane. The 4ꢀtertꢀbutylbenzyl moities in the P precursor were installed for
Oxy
the purposes of solubility.
In order to accurately compare the bite angles of each precursor, we utilized single crystal Xꢀ
ray diffraction (XRD) analysis (Figure 2). Single crystals of PSulf were grown from slow
evaporation of a 1:1 mixture of dichloromethane and methanol and crystallized in the monoclinic
space group P2 /n. The Xꢀray crystal structure exhibits an alternating upꢀdown orientation of the
1
6
ACS Paragon Plus Environment

Page 7 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
central hexasubstituted benzene ring, with upꢀoriented ethyl groups and downꢀoriented
3
7ꢀ39
phenylene arms.
The angle between benzylic edges and the central benzene moiety (using a
centroid) was found to be 103.4º on average (Figure S57). To determine the bite angle, three
vectors were computed from two atoms on each arm of the precursor (see Figure S59). The
angles between vectors were calculated and averaged to give the bite angle for PSulf of 31º.
Single crystals of PCarb were grown by slow diffusion of methanol into a solution of ethyl
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
acetate and crystallized in the monoclinic space group P2 /n. The crystal structure exhibits the
1
expected alternating upꢀdown orientation of hexasubstituted benzenes. The Xꢀray crystal
structure shows that the angle between the benzylic edges and the central benzene moiety was
118.6º on average (Figure S56). In the fashion described previously (see above), a bite angle of
5
1º was calculated.
Lastly, single crystals of POxy grew by slow diffusion of methanol into a solution of
dichloromethane and crystallized in the hexagonal space group Pꢀ3c1. This structure also
exhibits the expected alternating upꢀdown configuration about the center hexasubstituted
benzene. The angle between the benzylic edges and the central benzene moiety was found to be
1
23.2º on average (Figure S58). The calculated bite angle of 60º matches (within the limits of
our measurement technique) the ideal angle for a tetrahedron. While we acknowledge that
precursor bite angles may vary slightly in solution, and that crystal packing may bias the
measured angle, we believe the calculation from solid state structures provides a reasonable
approximation of the average bite angle for each precursor.
Single Precursor AM Experiments. To test the bite angle hypothesis, each precursor was
subjected to AM with identical conditions. Initial AM experiments were performed at 70 ºC with
10 mM precursor concentration in 1,2,4ꢀtrichlorobenzene (TCB) for 12 hours using a
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 35
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
molybdenum catalyst ([Mo], 5 mol %), triphenylsilanol ligand (30 mol %), and molecular sieves
4
0
(
5 Å, 800 mg/mmol of propynyl groups) to sequester the 2ꢀbutyne byproduct. The results of
these experiments are illustrated in Figure 3. Specifically, AM of PSulf affords a product
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
distribution exhibiting a mixture of illꢀdefined oligomers, as shown by the GPC trace (Figure
1
3
a). The H NMR spectrum of this mixture exhibits broad resonances, typical of oligomerization
(Figure S48). These observations indicate that within the reaction conditions, there is no
preferred discrete molecular entity that forms upon subjecting PSulf to AM for 12 hours at 70 ºC.
Subjecting PCarb to AM at 70 ºC for 12 hours affords a very narrow product distribution, and
2
6
forms exclusively the desired tetrahedral cage (Figure 3b). The GPC trace exhibits one sharp
1
peak with a narrow PDI of 1.02. The H NMR exhibits sharp peaks, indicative of a highly
symmetric, discrete product. Characterization by MALDIꢀMS and single crystal XRD analysis
2
6
confirms the formation of a tetrahedral cage in near quantitative yield. Repeating this
experiment at room temperature for 12 hours affords an identical product distribution with
similar yield.
Subjecting POxy to AM at 70 ºC affords a product distribution that exhibits signs of both
1
oligomers and a discrete structure as shown by the GPC trace in Figure 3c. The H NMR
spectrum of this mixture exhibits sharp peaks indicative of a highly symmetric molecule as well
as broad resonances at the baseline due to the presence of oligomers (Figure S49). Flash
chromatography of this mixture affords a new cage, TdOxy, in 23% yield (Figure 4a).
Characterization of the resulting product by NMR and MALDIꢀMS reveals a highly symmetric
compound with a mass corresponding to a tetramer (Figure 4), confirming the formation of
TdOxy
.
8
ACS Paragon Plus Environment

Page 9 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Although these initial experiments indicate that the product distribution of multitopic AM is
affected by precursor bite angle, they only provide data for a single set of reaction conditions. To
examine how each system behaves over time, the reaction progress was monitored by GPC. Each
precursor was subjected to AM using similar conditions described above except at room
temperature and in chloroform, and aliquots of the reactions were taken at various time points.
The aliquots were then quenched with hydrated chloroform and the product mixtures were
characterized via GPC. The results obtained from these experiments are shown in Figure 5.
Room temperature reaction conditions were chosen to better sample early reaction progress.
Chloroform was used as the solvent to allow direct injection into the GPC. In our hands, there
were negligible solvent effects on product distribution during AM of these precursors under
these reaction conditions (see Figure S12).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In the case of PSulf, the system progresses through a series of intermediates within the first
three minutes of the reaction as shown in Figure 5a. As the reaction proceeds, however, the
product distribution broadens and enters a regime where formed intermediates are unable to
locate a single thermodynamicallyꢀstable product. As such, the reaction results in a broad
product distribution of illꢀdefined oligomers within eight hours of reaction time. In the case of
PCarb (Figure 5b), initially this precursor forms smaller and larger oligomers, similar to PSulf. As
the reaction progresses, however, all of the oligomeric intermediates funnel toward TdCarb, until
the entirety of the dynamic mixture converges within 4 hours. The POxy system starts in a similar
fashion as the previous two cases, initially forming a mixture of oligomers (Figure 5c). Some
intermediates are able to form TdOxy and the concentration of cage increases steadily over time.
Other intermediates, however, enter a regime where they continuously grow larger and these
intermediates are unable to locate the cage product within eight hours.
9
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 35
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The results from these experiments provide evidence to validate the hypothesis that precursor
bite angle governs multitopic AM energy landscapes. As shown by PSulf, it was observed that
tightening the bite angle directs intermediates to offꢀtarget pathways. The result is a broad, illꢀ
defined product distribution with undetectable cage formation under the reaction conditions and
allotted reaction time. Precursor PSulf thus has a bite angle that is simultaneously too tight to
favor the exclusive formation of a tetrahedron and too wide to favor the exclusive formation of a
closed dimer under these conditions. Thus, the dynamic system drifts into an oligomeric regime
of the energy landscape.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The results from POxy are counterintuitive to heuristic design principles based on the
geometrically ideal bite angle. Although the bite angle measured for POxy was closest to the ideal
angle for a tetrahedron, the earlyꢀtime product distribution indicates that the system initially
ventures off the target pathway. Additionally, while some intermediates are able to form TdOxy
,
the majority of the dynamic system continues to progress along offꢀtarget pathways within eight
hours. Hence, precursor POxy provides an example where the bite angle still allows the system to
converge toward a discrete cage product, but the rate of convergence is decreased relative to
PCarb. If the reaction is allowed to proceed for 24 hours, the product distribution ultimately
funnels toward TdOxy in nearꢀquantitative yields (See Figure S11).
Finally, precursors with a slightly tighter bite angle than the mathematically ideal angle for a
3
3
tetrahedron provide the most direct convergence to the tetrahedral cage. While the bite angle of
PCarb is ca. 9º tighter than the optimum for a tetrahedron, the dynamic mixture achieves nearly
quantitative yields of the cage within four hours at room temperature. We deduce that the
dynamic energy landscape in this case has a "funneled" surface, allowing the intermediates to
10
ACS Paragon Plus Environment

Page 11 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
siphon toward the most thermodynamicallyꢀstable product while avoiding other offꢀtarget
2
5
pathways.
Precursor Mixing Experiments. Although PSulf was not able to form detectable quantities of
a tetrahedral cage during AM after 8 hours of reaction time, we hypothesized it is possible to
incorporate it into a cage structure using a mixture of the other precursors. To test this
hypothesis, we performed mixing experiments between the various precursors. Precursor mixing
experiments were performed by reacting PSulf and PCarb, PSulf and POxy, PCarb and POxy, and all
three in one pot. The experiments were performed with 10 mM concentration of precursors
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
total), using 5 mol % [Mo], 30 mol % Ph SiOH, and 5 Å MS in TCB for 12 hours at room
3
temperature. The GPC traces from the mixtures afforded by these experiments are shown in
Figure 6.
We first investigated the product distribution formed from mixing PCarb and POxy. Subjecting a
1:1 by mole mixture of PCarb and POxy to AM afforded a wellꢀbehaved product distribution
containing a molecular weight between that of TdCarb and TdOxy (Figure 6a). Characterization of
1
this mixture by H NMR indicated that a distribution of mixed cage products was obtained
(Figures S53 and S55). For simplicity, cage composition is denoted in molar ratios by
[PSulf:PCarb:POxy]. MALDIꢀMS analysis confirmed the formation of three mixed cage species
[0:3:1], [0:2:2], and [0:1:3] (Figure S14). A similar result was obtained when precursors POxy
and PSulf were mixed in a 1:1 molar ratio and subjected to AM (Figure 6b). Characterization by
MALDIꢀMS confirmed the formation of TdOxy ([0:0:4]) and the mixed [1:0:3], [2:0:2], and
[
3:0:1] cages (Figure S13). Additionally, precursors PCarb and PSulf were mixed in various molar
ratios (1:3, 2:2, and 3:1, respectively) and subjected to AM and the product distributions were
characterized (Figure 6c). Characterization of each mixture via MALDIꢀMS confirmed the
11
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 35
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
formation of TdCarb ([0:4:0]) and the [3:1:0], [2:2:0], and [1:3:0] mixed cages (Figures S15 and
S16). As a final experiment, all three precursors were mixed in equimolar concentrations and
subjected to AM. As shown by the GPC trace in Figure 6d, a broad product distribution was
obtained. Characterization by MALDIꢀMS confirmed the formation of various cages, including
the [2:1:1], [1:2:1], and [1:1:2] mixed cages (Figures S17 and S18). All combination of cages
were detected from mixing experiments using MALDIꢀMS except for the cage comprised solely
of PSulf precursors.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The obtained results allow us to deduce characteristics of dynamic AM. Although bite angle
deviations greatly affect the DCC energy landscape, they do not elicit selfꢀsorting of the various
multitopic components within the reaction parameters. Secondly, precursor PSulf is incorporated
into cage architectures provided the other precursors in the structure can accommodate the strain.
In each mixing experiment, PSulf was successfully incorporated into a molecular cage
architecture.
DFT Calculations. To further understand the process of cage formation, we performed DFT
calculations to determine the relative structural enthalpies (∆E) between the final open tetramer
(OT) intermediate (one edge open) and the tetrahedral cage (Td) for each precursor system. In
our calculations, the OT intermediate contained two methylꢀcapped acetylene moieties and the
Td cages were all minimized with one 2ꢀbutyne molecule as the side product. The DFT
calculations were performed in VASP using the PBE functional, with 2000 minimization steps.
The results from these calculations, as shown in Figure 7, allow rationalization of the
experimentally observed product distributions for each system. In the PSulf system, the
corresponding closed cage, TdSulf, is 32.5 kcal/mol higher in enthalpy than the open tetramer
(OTSulf). Thus, the final “cageꢀclosing” step in the PSulf system results in significant structural
12
ACS Paragon Plus Environment

Page 13 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
strain energy for TdSulf and is not enthalpically favored. To further illustrate this point, the
average bite angle in the calculated structure for TdSulf of 45.1º (Figure 7c) is ca. 14º larger than
the bite angle calculated from the crystal structure of PSulf, indicating that the precursor must
widen its bite angle significantly for successful Td cage formation. In the PCarb system, the
tetrahedral cage (TdCarb) is only 4.2 kcal/mol higher in enthalpy than the corresponding open
tetramer (OTCarb), indicating that the cageꢀclosing step results in minor cage strain. This strain
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
26
energy is evident in the crystal structure of TdCarb, where the acetylene moieties are slightly
bent inwards toward the center ca. 17º from a linear geometry. Lastly, in the POxy system, the
tetrahedral cage (TdOxy) is 0.6 kcal/mol lower in enthalpy than the corresponding open tetramer
(OTOxy). These results are not surprising, as this precursor was designed to have a bite angle that
closely resembled the ideal angle for a tetrahedral cage.
Our calculations support the argument that enthalpic considerations alone are insufficient to
describe the experimental observations from DCC reactions. Comparison between the PCarb
system and the POxy system demonstrates this point: although TdOxy is more enthalpically
favored to form than TdCarb (with respect to their corresponding OT intermediates), our
experimental results show that TdCarb forms via a more efficient pathway. We hypothesize that
this discrepancy is reconciled by kinetic considerations in that there are significant differences in
the relative energy barriers for formation of the last metallacyclobutadiene intermediate in the
final “cageꢀclosing” step. If correct, this final step becomes a kinetic bottleneck on the DCC
energy landscape and this putative bottleneck is governed by the precursor bite angle. Further
molecular modeling analysis will be performed in future studies to test this hypothesis.
CONCLUSION
13
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 14 of 35
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In conclusion, a systematic study investigating the effects of precursor bite angle on the DCC
energy landscape of multitopic AM was performed. Three precursors were synthesized with bite
angles ranging from 31º to 60º, and each was subjected to dynamic AM. It was observed that
tightening the bite angle, as illustrated by AM of PSulf, effectively biased the DCC energy
landscape and prevented the system from funneling exclusively toward a discrete architecture.
On the other hand, widening the bite angle to the ideal tetrahedron geometry, as evidenced by
POxy, surprisingly biased the DCC energy landscape so as to lengthen the required time for the
system to locate the desired cage product. It was also observed that precursors with angles
slightly tighter than the ideal bite angle for a tetrahedron (PCarb) afford the desired cage
architecture most efficiently. DFT calculations of relative structural enthalpies allowed us to
validate that there exists a discrepancy between our experimental observations and simple,
idealized geometric predictions. Given added complexities in DCC systems such as kinetic
bottlenecks, an intuitive approach toward designing DCC molecular cage precursors is thus not
always predictive. Detailed pathway analyses are likely to supply the missing insight to
overcome the design challenges in DCC.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Our results lend credence to the underlying systemic issues facing the synthesis of 3D
architectures via DCC, where variations in precursor geometry lead to significant deviation of
product distributions away from discrete products. Such behavior considerably challenges
rational design and limits synthesis of novel covalent organic cage targets. These experiments
demonstrate that precursor bite angle dominates energy landscapes and product distributions in
multitopic AM. Geometric control of dynamic energy landscapes provides insight toward
essential precursor design parameters for successful architecture formation. Our results suggest
that to synthesize novel covalent organic cages in high yields via multitopic AM, one must
14
ACS Paragon Plus Environment

Page 15 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
design and synthesize precursors with slightly smaller bite angles than that of the theoretically
optimum angle for the targeted structure. We envision the information learned from this study
will alleviate difficulties in novel architecture synthesis via other DCC chemistries and
contribute to rational precursor design rules that allow a priori targeting of structures with
specific architectural features. Future efforts will focus on quantifying the observations made
here with a pathway model that accounts for the sensitivity in product distribution to the kinetic
variations resulting from geometric attributes of the precursor. Such a model is poised to obviate
trialꢀandꢀerror practices for synthesizing novel molecular cages via multitopic DCC.
ASSOCIATED CONTENT
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The Supporting Information is available free of charge on the ACS Publications website at DOI: .
See the Supporting Information for experimental conditions and procedures, syntheses, and
1
13
compound characterizations including GPC, H NMR, C NMR, MALDIꢀMS, and single crystal
XRD analysis. Single crystal crystallographic data for this paper have been deposited at the
Cambridge Crystallographic Data Centre under deposition numbers CCDC 1590139 (PSulf),
CCDC 1590140 (PCarb), and CCDC 1590138 (POxy). These data can be obtained free of charge
from www.ccdc.cam.ac.uk/data_request/cif.
AUTHOR INFORMATION
Corresponding Author
*
jsmoore@illinois.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGEMENTS
15
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 16 of 35
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
This work was supported by the National Science Foundation CHE under Grant Number 16ꢀ
1
0328. T. P. M. II gratefully acknowledges the Arnold and Mabel Beckman Foundation for a
Beckman Institute Graduate Fellowship and the Drickamer family for a Harry G. Drickamer
Fellowship. T. P. M. II thanks Prof. Semin Lee for helpful discussions. The authors thank the
School of Chemical Sciences NMR Lab and Mass Spectrometry Lab and the George L. Clark Xꢀ
ray Facility.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
REFERENCES
1
.
S. J. Rowan, S. J. Cantrill, G. R. L. Cousins, J. K. M. Sanders and J. F. Stoddart, Angew. Chem. Int. Ed., 2002, 41, 898ꢀ
952.
2.
Y. Jin, C. Yu, R. J. Denman and W. Zhang, Chem. Soc. Rev., 2013, 42, 6634ꢀ6654.
W. Zhang and J. S. Moore, J. Am. Chem. Soc., 2005, 127, 11863ꢀ11870.
A. J. Gallant and M. J. MacLachlan, Angew. Chem. Int. Ed., 2003, 42, 5307ꢀ5310.
S. W. Sisco, B. M. Larson and J. S. Moore, Macromolecules, 2014, 47, 3829ꢀ3836.
M. Mastalerz, ChemComm., 2008, DOI: 10.1039/B808990F, 4756ꢀ4758.
D. Xu and R. Warmuth, J. Am. Chem. Soc., 2008, 130, 7520ꢀ7521.
3
4
5
6
7
.
.
.
.
.
8.
T. Tozawa, J. T. A. Jones, S. I. Swamy, S. Jiang, D. J. Adams, S. Shakespeare, R. Clowes, D. Bradshaw, T. Hasell, S.
Y. Chong, C. Tang, S. Thompson, J. Parker, A. Trewin, J. Bacsa, A. M. Z. Slawin, A. Steiner and A. I. Cooper, Nat.
Mater., 2009, 8, 973ꢀ978.
9
1
.
0.
M. Mastalerz, Angew. Chem. Int. Ed., 2010, 49, 5042ꢀ5053.
J. W. Colson, A. R. Woll, A. Mukherjee, M. P. Levendorf, E. L. Spitler, V. B. Shields, M. G. Spencer, J. Park and W.
R. Dichtel, Science, 2011, 332, 228ꢀ231.
1
1
13.
14.
1.
2.
C. Yu, Y. Jin and W. Zhang, Chem. Rec., 2015, 15, 97ꢀ106.
S. Klotzbach and F. Beuerle, Angew. Chem. Int. Ed., 2015, 54, 10356ꢀ10360.
A. P. Côté, A. I. Benin, N. W. Ockwig, M. O'Keeffe, A. J. Matzger and O. M. Yaghi, Science, 2005, 310, 1166ꢀ1170.
S.ꢀY. Ding and W. Wang, Chem. Soc. Rev., 2013, 42, 548ꢀ568.
1
1
1
5.
6.
7.
S. R. Seidel and P. J. Stang, Acc. Chem. Res, 2002, 35, 972ꢀ983.
T. R. Cook and P. J. Stang, Chem. Rev., 2015, 115, 7001ꢀ7045.
T.ꢀZ. Xie, K. J. Endres, Z. Guo, J. M. Ludlow, C. N. Moorefield, M. J. Saunders, C. Wesdemiotis and G. R. Newkome,
J. Am. Chem. Soc., 2016, 138, 12344ꢀ12347.
1
8.
X. Lu, X. Li, K. Guo, T.ꢀZ. Xie, C. N. Moorefield, C. Wesdemiotis and G. R. Newkome, J. Am. Chem. Soc., 2014, 136,
18149ꢀ18155.
19.
A. G. Slater, M. A. Little, PulidoA, S. Y. Chong, HoldenD, ChenL, MorganC, WuX, ChengG, ClowesR, M. E. Briggs,
HasellT, K. E. Jelfs, G. M. Day and A. I. Cooper, Nat. Chem., 2017, 9, 17ꢀ25.
A. R. Stefankiewicz and J. K. M. Sanders, ChemComm, 2013, 49, 5820ꢀ5822.
N. Ponnuswamy, F. B. L. Cougnon, J. M. Clough, G. D. Pantoꢁ and J. K. M. Sanders, Science, 2012, 338, 783ꢀ785.
F. B. L. Cougnon, N. Ponnuswamy, N. A. Jenkins, G. D. Pantoꢁ and J. K. M. Sanders, J. Am. Chem. Soc., 2012, 134,
2
2
2
0.
1.
2.
1
9129ꢀ19135.
23.
24.
M. W. Schneider, I. M. Oppel and M. Mastalerz, Chem. Eur. J, 2012, 18, 4156ꢀ4160.
J. Sun and R. Warmuth, ChemCommun, 2011, 47, 9351ꢀ9353.
2
2
2
2
2
5.
6.
7.
8.
9.
K. A. Dill and H. S. Chan, Nat. Struct. Mo.l Biol., 1997, 4, 10ꢀ19.
S. Lee, A. Yang, T. P. Moneypenny and J. S. Moore, J. Am. Chem. Soc., 2016, 138, 2182ꢀ2185.
T. Hasell and A. I. Cooper, Nat. Rev. Mater., 2016, 1, 16053.
X. Liu and R. Warmuth, J. Am. Chem. Soc., 2006, 128, 14120ꢀ14127.
K. E. Jelfs, E. G. B. Eden, J. L. Culshaw, S. Shakespeare, E. O. PyzerꢀKnapp, H. P. G. Thompson, J. Bacsa, G. M. Day,
D. J. Adams and A. I. Cooper, J. Am. Chem. Soc., 2013, 135, 9307ꢀ9310.
30.
Q. Wang, C. Yu, C. Zhang, H. Long, S. Azarnoush, Y. Jin and W. Zhang, Chem. Sci, 2016, 7, 3370ꢀ3376.
A. Fürstner, Angew. Chem. Int. Ed., 2013, 52, 2794ꢀ2819.
J. Bunzen, J. Iwasa, P. Bonakdarzadeh, E. Numata, K. Rissanen, S. Sato and M. Fujita, Angew. Chem. Int. Ed., 2012,
3
3
1.
2.
5
1, 3161ꢀ3163.
3
3.
M. Yoneya, S. Tsuzuki, T. Yamaguchi, S. Sato and M. Fujita, ACS Nano, 2014, 8, 1290ꢀ1296.
16
ACS Paragon Plus Environment

Page 17 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
34.
Q.ꢀF. Sun, J. Iwasa, D. Ogawa, Y. Ishido, S. Sato, T. Ozeki, Y. Sei, K. Yamaguchi and M. Fujita, Science, 2010, 328,
1144ꢀ1147.
J. H. R. Tucker, M. Gingras, H. Brand and J.ꢀM. Lehn, J. Chem. Soc., Perkin Trans. 2, 1997, DOI: 10.1039/A608455I,
3
5.
1
303ꢀ1308.
3
3
3
3
6.
7.
8.
9.
Z. Wu and J. S. Moore, Tetrahedron Lett., 1994, 35, 5539ꢀ5542.
S. Simaan, J. S. Siegel and S. E. Biali, J. Org. Chem., 2003, 68, 3699ꢀ3701.
J. Kim, Y. K. Kim, N. Park, J. H. Hahn and K. H. Ahn, J. Org. Chem., 2005, 70, 7087ꢀ7092.
T. Terada, T. Wakimoto, T. Nakamura, K. Hirabayashi, K. Tanaka, J. Li, T. Matsumoto and K. Tatsumi, Chem. Asian
J., 2012, 7, 920ꢀ929.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
40.
J. Heppekausen, R. Stade, R. Goddard and A. Fürstner, J. Am. Chem. Soc., 2010, 132, 11045ꢀ11057.
17
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 18 of 35
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
TOC Graphic
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
18
ACS Paragon Plus Environment

Page 19 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Main Text Figures:
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 1: (a) Synthesis of a tetrahedral organic cage via AM. TCB = 1,2,4ꢀtrichlorobenzene; MS
molecular sieves. (b) A series of analogous tritopic precursors synthesized in this study. The
=
bite angle is defined as the angle between phenyleneꢀcontaining arms and is determined via Xꢀ
ray crystallography. R = 4ꢀtertꢀbutylbenzene.
19
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 20 of 35
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 1: Synthesis of PSulf and POxy precursors.a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
aReagents and conditions: (a) bromine (5 equiv), Fe powder (0.3 equiv), 10 min, rt, 98 %; (b) sodium
thiophenolate (7 equiv), DMI, 140 ºC, 3 d, 72 %; (c) NBS (3.3 equiv), DCM/MeCN 2:1 (v/v), 0 ºC, 15
min then rt, 2 d, 74 %; (d) propynyl magnesium bromide (5 equiv), Pd(dppf)Cl (0.06 equiv), THF, 65 ºC,
2
2
d, 90 %; (e) paraformaldehyde (9 equiv), HBr in acetic acid (9.4 equiv), 85 ºC, 38 %; (f) 1ꢀbromoꢀ4ꢀ
tertꢀbutylbenzene (5 equiv), Mg (10 equiv), benzene, 100 ºC, 16 hr, 70 %; (g) BBr (4.3 equiv), DCM, 0
ºC → rt, 14 hr, 99 %; (h) 1ꢀfluoroꢀ4ꢀnitrobenzene (5 equiv), Cs CO (5 equiv), DMF, 90 ºC, 6 hr, 84 %;
3
2
3
(
i) Pd/C (0.10 mass equiv), hydrogen atmosphere, EtOAc, rt, 24 hr, 99 %; (j) HCl (12 equiv), NaNO (4.5
2
equiv), MeCN/H O 2:1 (v/v), 0 ºC, 30 mins; (k) K CO (15.6 equiv), pyrrolidine (7.5 equiv), MeCN/H O
2
2
3
2
1:1 (v/v), 0 ºC → rt, 1 hr, 93 % over two steps; (l) iodine (3.1 equiv), diiodomethane, 80 ºC, 4 hr, 90 %;
(m) propyne atmosphere, CuI (0.1 equiv), Pd(PPh ) Cl (0.08 equiv), Et N/THF 5:1 (v/v), rt, 12 hr, 77 %.
3
2
2
3
DMI = 1,3ꢀdimethylꢀ2ꢀimidazolidinone, NBS = Nꢀbromosuccinimide, BBr = boron tribromide.
3
20
ACS Paragon Plus Environment

Page 21 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2: Xꢀray crystal structures of (a) PSulf, (b) PCarb, and (c) POxy shown as ellipsoids at the
5
0% confidence level. Hydrogen atoms and the 4ꢀtertꢀbutylbenzyl moieties for POxy are removed
for clarity.
21
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 22 of 35
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3: GPC chromatograms of the product distributions afforded after AM of (a) PSulf, (b)
PCarb, and (c) POxy at 70 ºC for 12 hours.
22
ACS Paragon Plus Environment

Page 23 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 4: Purification of the product distribution afforded from subjecting POxy to AM at 70 ºC.
(a) Structure of TdOxy. (b) GPC traces before (blue) and after (black) purification. (c) MALDIꢀ
1
MS spectrum of purified product using a DCTB matrix. (d) H NMR (400 MHz, dꢀchloroform)
comparison of POxy (top) and TdOxy (bottom). The red dotted box corresponds to the propynyl
proton resonance.
23
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 24 of 35
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 5: GPC chromatograms taken after various time points of AM of (a) PSulf, (b) PCarb, and
(c) POxy at room temperature with 5 mol % [Mo] catalyst. Red arrows denote cage products.
24
ACS Paragon Plus Environment

Page 25 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 6: GPC chromatograms of the product distribution afforded from precursor mixing
experiments. (a) GPC traces of TdCarb (blue), TdOxy (red), and the 1:1 mixture of PCarb and POxy
(pink). (b) GPC traces of TdOxy (red), the product distribution from AM of PSulf (black), and the
1:1 mixture of POxy and PSulf (orange). (c) normalized (by area) GPC traces of TdCarb (black), the
1
:3 mixture (pink), the 1:1 mixture (blue), the 3:1 mixture (red) of PCarb and PSulf, respectively,
and the product distribution of PSulf (green). (d) GPC traces of TdCarb (blue), TdOxy (red), the
product distribution after AM of PSulf (black), and the 1:1:1 mixture of PSulf, PCarb, and POxy
(green).
25
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 26 of 35
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 7: Results from DFT calculations. (a) Representative “cage closing” metathesis reaction
starting from the open tetramer of PSulf (OTSulf) to form TdSulf. (b) Plot of calculated relative
structural energies, ∆E (relative to the open tetramer) vs. bite angle (calculated from DFT) of
each system. All values in kcal/mol. (c) Overlay of the energy minimized structures of TdSulf
(blue), TdCarb (orange), and TdOxy (green). Hydrogen atoms are removed for clarity. From these
structures, the bite angles (ϴ) were calculated as 45.1º, 52.8º, and 58.5º for TdSulf, TdCarb, and
TdOxy respectively. DFT, PBE functional, 2000 minimizations steps.
26
ACS Paragon Plus Environment

Page 27 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 1: (a) Synthesis of a tetrahedral organic cage via AM. TCB = 1,2,4-trichlorobenzene; MS = molecular
sieves. (b) A series of analogous tritopic precursors synthesized in this study. The bite angle is defined as
the angle between phenylene-containing arms and is determined via X-ray crystallography. R = 4-tert-
butylbenzene.
2
32x165mm (150 x 150 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 28 of 35
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 1: Synthesis of PSulf and POxy precursors.a aReagents and conditions: (a) bromine (5 equiv), Fe
powder (0.3 equiv), 10 min, rt, 98 %; (b) sodium thiophenolate (7 equiv), DMI, 140 ºC, 3 d, 72 %; (c) NBS
(3.3 equiv), DCM/MeCN 2:1 (v/v), 0 ºC, 15 min then rt, 2 d, 74 %; (d) propynyl magnesium bromide (5
equiv), Pd(dppf)Cl2 (0.06 equiv), THF, 65 ºC, 2 d, 90 %; (e) paraformaldehyde (9 equiv), HBr in acetic acid
(
9.4 equiv), 85 ºC, 38 %; (f) 1-bromo-4-tert¬-butylbenzene (5 equiv), Mg (10 equiv), benzene, 100 ºC, 16
hr, 70 %; (g) BBr3 (4.3 equiv), DCM, 0 ºC → rt, 14 hr, 99 %; (h) 1-fluoro-4-nitrobenzene (5 equiv),
Cs2CO3 (5 equiv), DMF, 90 ºC, 6 hr, 84 %; (i) Pd/C (0.10 mass equiv), hydrogen atmosphere, EtOAc, rt, 24
hr, 99 %; (j) HCl (12 equiv), NaNO2¬ (4.5 equiv), MeCN/H¬2O 2:1 (v/v), 0 ºC, 30 mins; (k) K2CO3 (15.6
equiv), pyrrolidine (7.5 equiv), MeCN/H2O 1:1 (v/v), 0 ºC → rt, 1 hr, 93 % over two steps; (l) iodine (3.1
equiv), diiodomethane, 80 ºC, 4 hr, 90 %; (m) propyne atmosphere, CuI (0.1 equiv), Pd(PPh¬3)2Cl2 (0.08
equiv), Et3N/THF 5:1 (v/v), rt, 12 hr, 77 %. DMI = 1,3-dimethyl-2-imidazolidinone, NBS = N-
bromosuccinimide, BBr3 = boron tribromide.
2
02x166mm (150 x 150 DPI)
ACS Paragon Plus Environment

Page 29 of 35
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3: GPC chromatograms of the product distributions afforded after AM of (a) PSulf, (b) PCarb, and (c)
POxy at 70 ºC for 12 hours.
1
20x96mm (220 x 220 DPI)
ACS Paragon Plus Environment