Network Analysis of Substituted Bullvalenes

Article abstract of DOI:10.1021/acs.orglett.9b03737

Substituted bullvalenes are dynamic shape-shifting molecules that exist within complex reaction networks. Herein, we report the synthesis of di- and trisubstituted bullvalenes and investigate their dynamic properties. Trisubstituted bullvalenes share a co

Full text of DOI:10.1021/acs.orglett.9b03737

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Network Analysis of Substituted Bullvalenes
,§
Oussama Yahiaoui,†,‡ Lukas F. Pasteka,* Christopher J. Blake,∥ Christopher G. Newton,†
́
̌
̌
and Thomas Fallon*,†,‡
†Department of Chemistry, The University of Adelaide, Adelaide, SA 5005, Australia
‡Institute of Natural and Mathematical Sciences, Massey University, Auckland 0632, New Zealand
§Department of Physical and Theoretical Chemistry, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia
∥Research School of Chemistry, Australian National University, Canberra, ACT 0200, Australia
S
* Supporting Information
ABSTRACT: Substituted bullvalenes are dynamic shape-shifting molecules that exist
within complex reaction networks. Herein, we report the synthesis of di- and trisubstituted
bullvalenes and investigate their dynamic properties. Trisubstituted bullvalenes share a
common major isomer which shows kinetic metastability. A survey of the thermodynamic
and kinetic landscapes through computational analysis together with kinetic simulation
provides a map of the internal dynamics of these systems.
ore than half a century since its prediction and initial
rational design of applications built on fluxional molecules
remains underdeveloped.
M
preparation,1,2 bullvalene (1) remains a source of
continued intrigue. This archetypal fluxional molecule exists
as an ensemble of 1 209 600 degenerate isomers through rapid
Cope rearrangements (Scheme 1a). This property of total
Heavily substituted bullvalenes represent enormous reaction
networks with hundreds or even thousands of unique isomers.
However, the overall structure and dynamics of such systems
will ultimately be governed by a small subset of low-energy
isomers and isomerization pathways. A more detailed under-
standing of the internal dynamics of bullvalene networks will
help to advance these systems toward viable applications.
The activation energy of bullvalene isomerization was first
determined by Saunders at 49.4 0.4 kJ/mol using VT-NMR
measurements.6 Substituted bullvalenes present increasingly
complex kinetic landscapes. The only detailed kinetic study of
a substituted bullvalene was by Luz who experimentally
determined the kinetic parameters of all reactions within the
network of fluorobullvalene.7
Scheme 1. (a) Total Degeneracy of Bullvalene and (b) Our
Synthetic Route to Trisubstituted Bullvalenes
A picture of the internal energy landscapes of substituted
bullvalenes has generally come from measuring the distribu-
tions of populated isomers using low-temperature NMR
studies and assuming rapid equilibration at room temperature.
Occasionally metastable isomers have been observed and even
isolated by recrystallization8 or chromatography.5c Foremost of
these is a tetrasubstituted bullvalene encountered by Bode.
The stability of this structure was rationalized through a
computational analysis of the local network environment.5f
The synthesis of substituted bullvalenes has seen renewed
interest with important contributions from the Bode5 and
degeneracy is unique among stable organic structures.3
Substituted bullvalenes are particularly interesting, as degen-
eracy is lost and substituents will spontaneously explore all
possible structural arrangements.
Within the rapidly advancing context of dynamic covalent
chemistry,4 the unimolecular shape-shifting nature of bullva-
lene suggests a range of potential applications in medicinal
chemistry and molecular devices. In a series of reports, the
Bode group has explored these concepts,5 most notably in the
construction of a fluxional polyol sensing array.5e However, the
Received: October 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03737
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Letter
Echavarren9 groups. We recently reported an efficient two-step
synthetic protocol for the synthesis of mono- and di-
substituted bullvalenes.10 The method employs cobalt-
catalyzed [6 + 2] cycloaddition reactions of cyclooctate-
traene11 followed by photochemical di-π-methane rearrange-
ment.12 Alongside our synthetic work, we developed a
computational toolbox to automate the network analysis of
substituted bullvalenes and generate input structures for
quantum chemical calculations for all objects in any given
network. This provides a global picture of bullvalene energy
landscapes.
relatively simple networks.15 In all cases the major isomer is
observed, whereby both substituents flank the bridgehead
position (4a-e:A), together with a minor isomer 4a-e:B
(Figure 1a). Room-temperature NMR analysis of trisubstituted
bullvalenes 4f−i revealed a major isomer that is not in rapid
exchange with the ensemble, isomer 4f-i:A, together with
broad signals characteristic of dynamic bullvalene ensembles
(Figure 1b). Low-temperature NMR measurements revealed a
minor isomer 4f-i:B, along with several others. In all cases, 1H
In this paper, we extend our synthetic protocol to the
preparation of trisubstituted bullvalenes through the use of a
substituted cyclooctatetraene (Scheme 1b). This includes the
first synthesis of heterogeneously trisubstituted bullvalenes,
objects of considerable dynamic complexity, that surprisingly
all share a common metastable isomer. Computational analysis
coupled with kinetic simulations help rationalize this general
kinetic feature.
The synthesis employs a cobalt-catalyzed [6 + 2] cyclo-
addition of trimethylsilylcyclooctatetraene 213 and a range of
substituted alkynes (Scheme 2). The bicyclo[4.2.2]deca-
a
Scheme 2. Synthesis of Substituted Bullvalenes
a
Reagents and conditions: (a) NaH (3 equiv), TBSC1 (1 equiv),
THF, 0 °C, 16 h. (b) Photochemical reaction conditions as above. (c)
(COCl)2 (2.4 equiv), DMSO (5 equiv), Et3N (10 equiv), CH2Cl2
−78 °C, 1 h. (d) (COCl)2 (1.3 equiv), DMSO (2.6 equiv), Et3N (5
b
equiv), CH2Cl2 −78 °C, 1 h. Reaction run with 2,2,2-
trifluoroethanol as solvent at 55 °C.
2,4,7,9-tetraene (BDT) intermediates 3a−g were isolated as
inconsequential mixtures of constitutional isomers.14 A simple
TBS protection of 3f gave 3g, which structurally differentiates
the three substituents. Photochemical di-π-methane rearrange-
ment of the BDT intermediates proceeded smoothly to give
the corresponding bullvalenes in moderate yields. The alcohol
4g and diol 4f were oxidized under Swern conditions to give
the corresponding aldehydes.
With this collection of bullvalenes in hand, we began to
study their dynamic behavior. Population distributions of the
ensembles were determined using low-temperature NMR
experiments. Disubstituted bullvalenes 4a−e exist within
Figure 1. (a) Disubstituted isomer distributions. (b) Trisubstituted
isomer distributions. Experimental and computational analysis of
isomer distributions. (c) Meta-stability of trisubstituted bullvalenes.
(d) Predicted half-lives of trisubstituted bullvalenes. VT-NMR
experiments conducted-60 °C. Indicative experimental isomer ratios
are reported as a fraction of the sum of those identified. Single-point
DFT calculations at B3LYP-D3BJ/Def2-TZVPPD/CPCM solvent
(chloroform) performed in Orca.18 aPredicted population reported as
the sum of R1/R2 and R2/R1 isomers.
B
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Letter
Figure 2. (a) Network graph of 4d. (b) Simulation starting from 4d:A. (c) Simulation starting from 4d:E. (d) Network graph of 4f. (e) Simulation
starting from 4f:A. (f) Simulation starting from 4f:D.
and 13C NMR spectra indicated a range of other minor isomers
which could not be structurally elucidated.
a general trisubstituted bullvalene 5:A (Figure 1c). In order to
communicate with the rest of the network, any isomer of this
type must pass through two generations of relatively high-
energy isomers accompanied by high-energy barriers. This
combines to form a local kinetic well. Conjugating and/or
sterically demanding substituents will tend to provide
increased kinetic stability. This appears to be a general feature
across heavily substituted bullvalenes.16
Density functional theory calculations were run for all
ground states and transition structures for all the ensembles
studied (see SI for full details). The predicted population
distributions are presented in Figure 1a,b. In all cases, the
calculated population distributions are in fair agreement with
experiment.
The metastability of bullvalene isomers 4f-i:A can be
rationalized by considering the local network environment of
The local kinetic wells around bullvalenes 4f-i:A were
assessed by estimating the first- and second-generation rate
C
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constants using the Eyring equation and modeling the kinetics
using the KinTek Explorer software package.17 This predicts
room-temperature half-lives ranging from 0.57 s to 1.8 h
(Figure 1d).
Reaction network diagrams provide a powerful visual tool to
explore the connectivity and thermodynamic/kinetic land-
scapes of substituted bullvalenes. The network graphs of
disubstituted bullvalene 4d and trisubstituted bullvalene 4f are
shown in Figure 2. Nodes represent individual isomers and the
edges transition structures, each color coded according to
relative energy. Bullvalene 4d exists as an ensemble of 30
isomers connected by 46 transition states. The predicted
populated isomers 4d:A−E are shown (though only 4d:A and
4d:B have been identified experimentally). This visualization
reveals that the populated isomers reside within a local group
connected by a set of relatively low-energy isomerization
pathways. The “southern” region of the network will essentially
remain unpopulated.
A complete kinetic model of 4d was constructed by
estimating all 92 first-order rate constants. Stochastic Monte
Carlo simulations were run using the Kinetiscope software
package.19 Figure 2b shows a simulation from an initial
population of the major isomer 4d:A. The system rapidly
equilibrates within 0.1 s. Initiating the simulation from the
minor isomer 4d:E illustrates the path-dependent passage of
material through the system (Figure 2c).
The reaction graph of trisubstituted bullvalene 4f is
presented in Figure 2d showing all 120 isomers and 184
transition states. The major isomer 4f:A is relatively isolated
from the other populated isomers and resides within its
shallow local kinetic well. Several populated isomers
(calculated), 4f:B, ent-4f:B, and 4f:D, all reside within a
local group, mutually accessible via two-step isomerizations.
The lowest-energy pathway between these two regions of the
network is highlighted.
A kinetic simulation from an initial population of isomer
4f:A shows that the system reaches equilibrium within ∼1.5 s
(Figure 2e). A simulation from an initial population of the
minor populated isomer 4f:D is shown in Figure 2f. In this
scenario the system rapidly equilibrates toward a ∼1:1:1
mixture of 4f:D:4f:B:ent-4f:B within a period of ∼0.05 s. From
here the ensemble slowly generates the major isomer 4f:A over
a period of ∼2 s.
More heavily substituted bullvalenes represent a major jump
in complexity, as well as a considerable synthetic challenge.
However, the thermodynamic and kinetic properties of these
large systems may be anticipated. To demonstrate, we ran a
computational analysis of the (hypothetical) tetrasubstituted
bullvalene 6 (Figure 3). With this substitution pattern there are
1640 unique isomers (852 discounting enantiomers) and 2520
transition structures. A full DFT analysis of the ground-state
energies predicts only 16 isomers to be populated at room
temperature with a relative abundance of greater than 1%
(6:A-P, Figure 3). All these isomers (excepting 6:N) have 2−3
substituents adjacent to the bridgehead, analogous to the
dominant isomers of 4a−i. Intriguingly, the global minimum
isomer 6:A does not have an arrangement analogous to that of
4f-i:A and benefits from a specific intramolecular hydrogen
bond, as do isomers 6:D and 6:L.
Figure 3. Network analysis of (hypothetical) tetrasubstituted
bullvalene 6. The relative stability of the predicted populated isomers
6:A-P is shown based on single-point DFT calculations at the B3LYP-
D3BJ/Def2-TZVPPD/CPCM solvent (chloroform). The predicted
half-lives for isomers 6:B-E,L is shown based on the local first- and
second-generation transition structures calculated at B3LYP-D3BJ/
Def2-TZVPPD(chloroform).
The full computation analysis of all transition structures
represents an arduous and impractical exercise. However,
surveying the likely local kinetic wells would provide useful
insights. There are 28 possible isomers of 6 that maintain three
substituents adjacent to the bridgehead. Of these, only five
reside within the pool of 16 populated isomers shown in Figure
3, 6:B-E,L. For each of these, the first- and second-generation
D
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Authors
■
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(14) In principle these cycloadditions could proceed in any of eight
distinct modes, leading to eight regioisomers. In practice the
trimethylsilyl group is primarily directed to the bridging alkene. See
Supporting Information for full details.
(15) Disubstituted bullvalenes exist as ensembles of either 15
isomers (R1, R1) or 30 isomers (R1, R2), respectively. Trisubstituted
systems will exist as ensembles of 42 (R1, R1, R1), 120 (R1, R1, R2), or
240 isomers (R1, R2, R3), respectively.
(16) This feature was previously described by Bode, ref 5f.
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*E-mail: thomas.fallon@adelaide.edu.au.
*E-mail: lukas.f.pasteka@gmail.com.
ORCID
́
̌
̌
Lukas F. Pasteka: 0000-0002-0617-0524
Christopher G. Newton: 0000-0002-8962-5917
Thomas Fallon: 0000-0002-6495-5282
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the New Zealand Royal Society
(Marsden Fund No. 15-MAU-154). We gratefully thank Ms.
Eliza Tarcoveanu (Australian National University, Canberra)
for assistance with NMR measurements. Calculations were
performed using the supercomputing infrastructure of the
Computing Center of the Slovak Academy of Sciences
acquired in projects ITMS 26230120002 and 26210120002
supported by the Research & Development Operational
Programme funded by the ERDF. LFP is grateful for the
support from the Slovak Research and Development Agency
(grant no. APVV-15-0105) and the Scientific Grant Agency of
the Slovak Republic (grant no. 1/0777/19).
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DOI: 10.1021/acs.orglett.9b03737
Org. Lett. XXXX, XXX, XXX−XXX