Synthesis and Analysis of Substituted Bullvalenes

Article abstract of DOI:10.1002/anie.201712157

Herein we detail a practical synthesis of bullvalene and a variety of mono- and disubstituted analogues through cobalt-catalysed [6+2] cycloaddition of cyclooctatetraene to alkynes, followed by photochemical di-π-methane rearrangement. The application of isomer-network analysis, coupled with quantum-chemical calculations, provides a powerful automated tool for predicting the properties of bullvalene isomer networks.

Full text of DOI:10.1002/anie.201712157

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Accepted Article
Title: Synthesis and Analysis of Substituted Bullvalenes
Authors: Oussama Yahiaoui, Lukáš F Pašteka, Bernadette Judeel, and
Thomas Fallon
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10.1002/anie.201712157
Angewandte Chemie International Edition
COMMUNICATION
Synthesis and Analysis of Substituted Bullvalenes
Oussama Yahiaoui,[a] Lukáš F. Pašteka,*[b] Bernadette Judeel,[a] and Thomas Fallon*[a]
Abstract: In this communication we detail a new, practical synthesis
(a) fluctional isomerism of bullvalene
of bullvalene and variety of mono- and di-substituted analogues.
This has been accomplished through cobalt-catalyzed [6+2]
ensemble of 1 209 600
degenerate isomers
cycloaddition of cyclooctatetraene to alkynes, followed by
strain accelerated
photochemical di-π-methane rearrangement. The application of
isomer network analysis, coupled with quantum chemical
calculations, provides a powerful and automated tool for predicting
the properties of bullvalene isomer networks.
Cope rearrangement
1
(b) Schr
ö
der's 1963 synthesis of bullvalene
100 °C, neat
thermal
hν
retro [2+2]
dimerisation
Bullvalene (1) is the archetypal fluctional molecule. By virtue of
rapid Cope rearrangements it exists within an ensemble of >1.2
million degenerate isomers (Scheme 1a). With the exception of
the barbaralyl cations,[1] this property of total degeneracy is
unique. Substituents bound to this core structure will explore all
possible structural isomers. This geometrically rich fluctional
behaviour gives substituted bullvalenes a potentially significant
place within the rapidly developing context of dynamic covalent
chemistry.[2]
2
3
1
5.6% over 2 steps
(c) this work
R1
R2
R1
R1
R2
[Co] catalyst
hν
[6+2]
cycloaddition
di-π-methane
rearrangement
R2
2
5
4
Scheme 1. (a) Fluctional isomerism of bullvalene, (b) Schröder’s original
synthesis of bullvalene, (c) this work.
Doering and Roth first predicted Bullvalene in 1963.[3] Later
that year, Schröder serendipitously encountered the structure
while studying the photochemistry of cyclooctatetraene (COT)
dimers (Scheme 1b).[4] Despite the low overall yield (5.6%), this
first synthesis has remained the best, and the basis of
Schröder’s extensive studies into bullvalene chemistry, and the
preparation of many substituted examples.[5] Rational synthetic
strategies to bullvalene have also been devised by Doering[6]
Cobalt(I)-catalysed formal cycloaddition reactions have
recently emerged as
a
powerful method in organic
synthesis.[14,15] In 2006, Buono reported that cyclooctatetraene
undergoes [6+2] cycloadditions with alkynes to give substituted
BDTs, using
a
CoI2(dppe)/ZnI2/Zn catalyst system.[16] This
reaction has recently been re-evaluated, revealing that a variety
of Co(II) salts are viable precatalysts.[17]
and
Serratosa,[7]
both
employing
a
transannular
With access to substituted BDTs, we foresaw a rapid two-
step synthetic path to mono- and di-substituted bullvalenes. A
range of BDTs were prepared by adaptation of the reported
protocols (Scheme 2). Interestingly, acetylene gas also
participates in this reaction to give the parent hydrocarbon (84%
yield, 12 g scale).[18]
cyclopropanation as a key step. Recently, Echavarren has
introduced a new approach achieved through gold-catalatysed
synthesis of barbaralones.[8]
Bode and co-workers have developed a syntheses of tetra-
substituted bullvalenes and demonstrated supramolecular
opportunities including adaptive binding and sensing.[9] This
exciting new work is, however, limited by the lengthy synthetic
access to these heavily substituted bullvalenes.
CoBr2(dppe) (10 mol%)
R1
ZnI2 (20 mol%)
R1
R2
The photochemical di-π-methane rearrangement[10] of
Zn dust (30 mol%)
+
DCE
bicyclo[4.2.2]deca-2,4,7,9-tetraene (BDT) systems is
class of transformation. The parent hydrocarbon 4a was first
prepared by Jones and Scott via low-yielding
a rare
R2
2
4a-i
4f: R1, R2 = SiMe3, H, quant.
a
4a: R1, R2 = H, H, 84%
photoisomerisation of bullvalene.[11] It was found however, that
4a slowly but cleanly photoisomerises back to bullvalene when
irradiated with a medium pressure mercury lamp behind a Pyrex
filter. This type of di-π-methane rearrangement was instrumental
in Paquette’s classic synthesis of substituted aza-bullvalenes,[12]
as well as an attempted synthesis of diaza-bullvalene.[13]
4b: R1, R2 = Me, H, 70%
4c: R1, R2 = n-hex, H, 90%
4d: R1, R2 = CH2OH, H, 86%
4e: R1, R2 = Bn, H, 91%
4g: R1, R2 = CH2OH, CH2OH, 80%
4h: R1, R2 = Me, n-pent, 87%
4i: R1, R2 = Ph, H, 63%
Scheme 2. Cobalt catalysed synthesis of bicyclo[4.2.2]deca-2,4,7,9-tetraenes.
With BDT precursors in hand, photoisomerisation to the
corresponding bullvalenes was investigated. Irradiation of
solutions of 4a-h in acetone (150 W medium pressure mercury
lamp, Pyrex glassware) led to the corresponding bullvalenes in
fair to very good yield (Scheme 3). In some cases long reaction
times were needed. The synthesis of bullvalene itself proceeds
in 71% yield (8 g isolated, 60% yield from COT). This procedure
avoids the low yielding thermal dimerization of COT, and
provides practical access to the parent hydrocarbon. A variety of
mono-substituted bullvalenes were prepared (5b-f), as well as
[a]
[b]
O. Yahiaoui, B. Judeel, Dr. T. Fallon
Institute of Natural and Mathematical Sciences, Massey University
1/5 University Ave, Albany, Auckland 0632, (New Zealand)
E-mail: t.fallon@massey.ac.nz
Dr. L. F. Pašteka
Centre for Theoretical Chemistry and Physics, NZIAS, Massey
University, Oaklands Rd, Albany, Auckland 0632, New Zealand
Dept. of Physical and Theoretical Chemistry, Faculty of Natural
Sciences, Comenius University, Ilkovičova 6, Bratislava, Slovakia
E-mail: lukas.f.pasteka@gmail.com
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201712157
Angewandte Chemie International Edition
COMMUNICATION
the bis(methylenehydroxy) bullvallene 5g and methyl(n-
pentyl)bullvalene 5h.
network with corresponding codes for all isomers and
interconnecting transition states. Further, enantiomeric pairs are
identified and starting geometries for all nondegenerate species
are produced. These are subsequently optimized in two steps
with an increasing level of theory via the interface to the program
package ORCA 4.0.[23] In the first step, large-scale screening of
rotamers is performed and the lowest energy rotamer is chosen
for each isomer employing the combination of inexpensive
semiempirical and density functional theory (DFT) methods. In
the second step, geometries of all isomers are fully optimized
using DFT. Finally, for the optimized structures, single point
energies are calculated using the highest level of theory with or
without a solvation model. Detailed account of the computational
methods used to obtain the presented results can be found in SI.
R1
R1
hν
medium pressure Hg lamp,
pyrex fliter
R2
R2
4a-h
5a-h
acetone, RT
CH3
n-Hex
OH
5a (1), 71%
5b, 40%
5c, 81%
5d, 63%
(12g
4
a
scale)
CH3
OH
SiMe3
Ph
n-Pent
OH
Experimental isomer ratios were determined using low
temperature NMR measurements. For mono-substituted
bullvalenes 5b-f the analysis is routine (Figure 2). In all cases,
the computationally predicted ratios are consistent with the
experiment.[24]
5e, 42%
5f, 70%
5g, 40%
5h, 35%
Scheme 3. Photochemical synthesis of bullvalenes.
Interestingly, when phenyl-substituted BDT 4i was irradiated
under the standard conditions, phenyl “lumibullvalene” 6 was
isolated in 62% yield (Scheme 4). None of the expected
phenylbullvalene could be detected in the reaction mixture.
Presumably, the di-π-methane rearrangement proceeds, but
through an alternate path to give phenyl substituted
R
R
R
R
000 000 000 1
000 000 001 0
000 000 010 0
000 000 100 0
calc: 1 : 69 : 28 : 2
exp: 0 : 58 : 42 : 0
calc: 0 :
76 : 21 : 4
exp: 0 : 68 : 25 : 7
calc: 1 : 54 : 43 : 3
exp: 0 :
calc: 0 : 75 : 24 : 1
exp: 0 :76 : 24 : 0
calc: 0 : 95 : 5 : 1
exp: 0 :93 : 7 : 0
“isolumibullvalene” 7, which would rapidly undergo
a
R = Me, 5b
isomer coding system
9
9
cyclopropane accelerated Cope rearrangement to give phenyl
lumibullvalene.[19] This switch in reactivity is not yet understood,
and may preclude the use of our strategy for the synthesis of
aryl-substituted bullvalenes. However, access to substituted
lumibullvalene frameworks may prove useful.
8
1
8
R = n-Hex, 5c
0
0
7
7
6
6
5
5
4
4
3
3
R = CH2OH, 5d
R = Bn, 5e
57 : 25 : 18
1
2
2
123 456 7890
transition state
structure
123 456 789 0
ground state
structure
(0 = "apex position")
R = SiMe3, 5f
Ph
Ph
Figure 1. Monosubstituted bullvalene network analysis and populated isomers.
hν
medium pressure Hg lamp,
pyrex fliter
6
4i
acetone, RT, 63%
For disubstituted bullvalenes 5g and 5h, the complexity of the
mixtures and signal overlap necessitated the careful
interpretation of 2D NMR experiments. The bis(methylene-
hydroxy)bullvalene 5g proved to be the most challenging
analysis, which revealed a dynamic ensemble of six populated
isomers (Figure 2a).[25] For this system, the isomer distribution is
remarkably flat.[5f] In fact, all possible isomers that do not have a
vicinal arrangement of substituents, or a substituent at the apex
position, are found to be populated.
di-π-methane
rearrangement
Ph
[3,3]
7
Scheme 4. Synthesis of phenyl-lumibullvalene 6.
As dynamic ensembles of exchanging isomers, bullvalenes
represent a conceptually intriguing, and challenging analytical
problem. Mono-substituted bullvalenes have four possible
isomers, di-substituted networks have either 15 isomers
(identical substituents) or 30 isomers (unique substituents). With
further substitution the level of complexity rapidly escalates.[20]
Substituted bullvalenes represent closed reaction graphs.[21]
Bode introduced a convenient isomer coding system (Figure 1)
and algorithm that enumerates the interconnections of any
bullvalene substitution pattern.[22] Building on this method, we‘ve
developed a program that evaluates any possible substituted
bullvalene network and performs quantum chemical energy
calculations on all objects within the reaction graph.
Using the required substituent geometries as input, our
newly developed algorithm generates the full rearrangement
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(a) populated isomers of bis(methylenehydroxy)bullvalene 5g
In the case of methyl(n-pentyl)bullvalene 5h, the four
possible isomers which retain the substituents connected to
alkenes were found to be populated (Figure 2b). These
experimental ratios are all consistent with a computational
survey of isomer stability.
OH
OH
OH
HO
HO
OH
HO
HO
HO
HO
HO
OH
Our computational toolbox also allows for the generation of
reaction graph diagrams. This is a convenient method to
visualise the interconnectivity, and energy profile, of any given
bullvalene network. An example is shown for bullvalene 5h
showing the 30 possible isomers (Figure 2c). Nodes represent
isomers and edges transition structures. A vertical plane of
symmetry bisects the diagram and relates enantiomers. This
technique aids in highlighting the non-populated but low-lying
isomers, as well as giving an overview of the kinetic parameters
of rearrangement. In future, these features will become valuable
in the analysis of bullvalene ensembles in response to external
stimuli.
000 001 001 0 000 001 010 0 000 000 101 0 000 001 100 0 000 010 100 0 000 010 010 0
experimental: 44 : 23 : 14 : 9 : 6 : 5
calculated:
:
:
:
:
:
0
91
7
0
2
0
6 other unique isomers
(b) populated isomers of methyl(n-pentyl)bullvalene 5h
Me
Me
Me
Me
26 other
isomers
n-Pent
n-Pent
n-Pent
000 020 010 0
n-Pent
000 001 002 0
000 002 010 0
000 001 020 0
experimental: 42 : 30 : 17 :11
calculated:
:
:
:
6 3
79 11
(c) Reaction graph of methyl(n-pentyl)bullvalene 5h
000 000 200 1 (16.5)
To conclude, this work provides a two-step synthesis of
bullvalene itself, and substituted derivatives. This represents the
shortest synthesis of any substituted bullvalenes, and the most
practical preparation of the parent structure. Our network
analysis algorithm allows for rapid assessment of the energy
landscape and interconnections of any bullvalene isomer
ensemble. DFT calculations predict the ratios of populated
isomers in good agreement with experiment.
000 002 100 0 (9.7)
000 100 002 0 (9.7)
Me
000 000 100 2 (21.6)
000 200 001 0 (9.2)
000 001 200 0 (9.2)
000 002 010 0 (3.5)
n-Pent
000 010 002 0 (3.5)
Me
000 001 020 0 (4.6)
Acknowledgements
000 020 001 0 (4.6)
n-Pent
Me
We gratefully acknowledge the New Zealand Royal Society
(Marsden Fund No. 15-MAU-154). We gratefully thank Mr. Chris
Blake and Ms. Eliza Tarcoveanu (Australian National University,
Canberra) for assistance with NMR measurements. We
acknowledge support from the project NESI00302 of NeSI high-
performance computing facilities (NZ eScience Infrastructure)
funded jointly by NeSI's collaborator institutions and the Ministry
of Business, Innovation & Employment's Research Infrastructure
programme.
000 020 010 0 (6.1)
000 010 020 0 (6.1)
000 000 020 1 (12.9)
000 020 100 0 (11.7)
000 100 020 0 (11.7)
n-Pent
Me
000 000 102 0 (9.8)
000 010 200 0 (10.3)
000 200 010 0 (10.3)
000 000 201 0 (9.2)
n-Pent
Keywords: Valence isomerization • Sigmatropic rearrangement
• Photochemistry • Cycloaddition • Density functional
calculations
000 000 010 2 (17.1)
000 000 001 2 (27.3)
000 001 002 0 (0)
000 002 001 0 (0)
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000 000 210 0 (24.8)
000 000 012 0 (15.9)
000 100 200 0 (26.7)
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000 200 100 0 (26.7)
000 000 021 0 (16.6)
000 000 120 0 (24.9)
relative isomer energy
(nodes, kJ/mol)
0
28
82
[3]
[4]
56
transition structure
energy (edges, kJ/mol)
000 000 002 1 (24.8)
Figure 2. (a) experimental and computationally predicted populated isomers of
bis(methylenehydroxy)bullvalene 5g. (b) experimental and computationally
predicted populated isomers of methyl(n-pentyl)bullvalene 5h. (c) Reaction
graph of 5h. The nodes shaded blue comprises the populated isomers. A
mirror plane of symmetry bisects the graph vertically, and relates the
enantiomer pairs.
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[20] In fact, for 2 or more unique substituents, ꢀ!"#, the total numbers of
isomers, ꢀ!"# , and interconnecting transition states, ꢀ!" , follow the
relations:
!
!"!
! (!"!!!"#)!
[21] J. Brocas, J. Math. Chem. 1994, 15, 389–395.
!
!"!
.
! (!"!!!"#)!
ꢀ!"#
=
,
ꢀ!"
=
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[23] F. Neese, WIREs Comput. Mol. Sci. 2012, 2, 73
[24] For the disubstituted bullvalenes 5g and 5h our ratio of isomers was
determined by a comparison of like 13C signals and should be regarded
as indicative rather than quantitative.
[25] This analysis included
a range of high-resolution heteronuclear
correlation experiments including HSQC-TOCSY, H2BC and HMBC, as
well as a very high-resolution HSQC spectrum from which high-quality
carbon-resolved 1D proton spectra of each isomer could be extracted
and reconstructed. See the Supporting Information for details.
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Oussama Yahiaoui, Dr. Lukáš F.
Pašteka,* Bernadette Judeel and Dr.
Thomas Fallon*
Page No. – Page No.
Synthesis and Analysis of
Substituted Bullvalenes
Shape-Shifters. A rapid two-step synthesis of substituted bullvalenes is reported.
The method involves cobalt-catalysed [6+2] cycloaddition of alkynes to
cyclooctatetraene, followed by photochemical rearrangement. The fluxional nature
of these shape-shifting molecules is supported by DFT calculations and network
analysis.
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