Could London Dispersion Force Control Regioselective (2 + 2) Cyclodimerizations of Benzynes? YES: Application to the Synthesis of Helical Biphenylenes

Article abstract of DOI:10.1021/jacs.1c05434

In recent years, London dispersion interactions, which are the attractive component of the van der Waals potential, have been found to play an important role in controlling the regio- and/or stereoselectivity of various reactions. Particularly, the dispersion interactions between substrates and catalysts (or ligands) are dominant in various selective catalyzes. In contrast, repulsive steric interactions, rather than the attractive dispersion interactions, between bulky substituents are predominant in most of the noncatalytic reactions. Herein, we demonstrate the first example of London dispersion-controlled noncatalytic (2 + 2) cyclodimerization of substituted benzynes to selectively afford proximal biphenylenes in high yields and regioselectivities, depending on the extent of dispersion interactions in the substituents. This method can be applied for the synthesis of novel helical biphenylenes, which would be fascinating for chemists as these compounds are potential skeletons for ligands, catalysts, and medicines.

Full text of DOI:10.1021/jacs.1c05434

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Could London Dispersion Force Control Regioselective (2 + 2)
Cyclodimerizations of Benzynes? YES: Application to the Synthesis
of Helical Biphenylenes
Takashi Ikawa,* Yuta Yamamoto,⊥ Akito Heguri,⊥ Yutaka Fukumoto, Tomonari Murakami,
Akira Takagi, Yuto Masuda, Kenzo Yahata, Hiroshi Aoyama, Yasuteru Shigeta, Hiroaki Tokiwa,*
and Shuji Akai*
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ABSTRACT: In recent years, London dispersion interactions, which are the attractive component of the van der Waals potential,
have been found to play an important role in controlling the regio- and/or stereoselectivity of various reactions. Particularly, the
dispersion interactions between substrates and catalysts (or ligands) are dominant in various selective catalyzes. In contrast, repulsive
steric interactions, rather than the attractive dispersion interactions, between bulky substituents are predominant in most of the
noncatalytic reactions. Herein, we demonstrate the first example of London dispersion-controlled noncatalytic (2 + 2)
cyclodimerization of substituted benzynes to selectively afford proximal biphenylenes in high yields and regioselectivities, depending
on the extent of dispersion interactions in the substituents. This method can be applied for the synthesis of novel helical
biphenylenes, which would be fascinating for chemists as these compounds are potential skeletons for ligands, catalysts, and
medicines.
groups,2b although the bulky TBDMSO- group on benzyne 3
ondon dispersion interactions are the attractive inter-
might enhance the regioselectivity.7,8
Lactions among instantaneous dipoles of molecular frag-
ments.1 Although they are considered to be weak interactions,
The (2 + 2) cyclodimerization of benzynes to biphenylenes
has been known for a long time.9−11 However, the reactions
they exist in all molecules, and the strength of the interaction
increases remarkably with increasing molecular size. London
dispersion forces have recently been gaining prominence in
Scheme 2. Proposed Hypothesis for London Dispersion-
Controlled (2 + 2) Cyclodimerizations of Benzynes 6
organic synthesis and have been vital in controlling substrate−
catalyst (or ligand) interactions in several catalytic processes.2,3
In contrast, reports on the involvement of London dispersion
interactions between the substrates in noncatalytic reactions
are sparse.4
Yamaguchi et al. reported an intriguing regioselective [4 + 2]
cycloaddition reaction between 3-adamantylbenzyne 3, gen-
erated from precursor 1, and 2-adamantylfuran 2 (Scheme
are generally low yielding and occur as side reactions. Recently,
1).5,6 A good yield of proximal-4, which contained two
Mullen et al. reported an elegant synthesis of graphenes using
̈
sterically hindered adamantyl groups on the same side, was
obtained as the major product. The authors in one of the key
reviews on London dispersion interactions opined that the
formation of proximal-4 might be favored because of the
attractive dispersion interaction between the two large alkyl
(2 + 2) cyclodimerization of benzynes.9f However, only three
symmetrically substituted benzynes were employed as
substrates in their study, and the biphenylenes were obtained
in 10%−17% isolated yields. Substituted biphenylenes are
potential skeletons of new ligands, catalysts, and medicines,
and therefore, the regiocontrol of the (2 + 2) cyclo-
dimerizations of unsymmetrically substituted benzynes, which
Scheme 1. Regioselective Cycloaddition between 3 and 2
Received: May 26, 2021
Published: July 1, 2021
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© 2021 American Chemical Society
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have never been reported so far,12,13 is urgent and in high
demand.
We hypothesized that the relatively strong London
dispersion interaction of the sterically hindered substituents
R on benzynes 6 at the 3-position should enable direct
regioselective (2 + 2) cyclodimerization reactions for accessing
proximal-7 in good yields (Scheme 2).
In the conversion of 5i, a significant amount (29%) of the
thia-Fries rearrangement side-product 8a was observed,14
which cannot be formed via benzyne 6i (Scheme 3). The 8a
Scheme 3. Inhibition of Thia-Fries Rearrangement
First, we generated a wide variety of 3-substituted benzynes
6 from 2-iodophenyl triflates 5 in the absence of arynophiles
using MeLi in THF at −78 °C (Table 1). Unsubstituted
Table 1. (2 + 2) Cyclodimerization Regioselectivities of 3-
a
Substituted Benzynes 6
formation indicated that the yield of proximal-7i could be
improved further by improving the benzyne generation from
precursor 5. After several trials, a new 3-adamantylbenzyne
precursor 5i′, bearing the p-toluenesulfonyloxy moiety, was
found as the leaving group and improved the yield of proximal-
7i to 74%, while maintaining complete proximal selectivity,
with the absence of the thia-Fries rearrangement product 8b
(Scheme 3). These varied results are likely due to the higher
bond strength of the O−S single bond of the p-
toluenesulfonyloxy group than that of the trifluoromethane-
sulfonyloxy group.
With these exciting results in hand, we hypothesized that
more attractive helical biphenylenes,15 such as proximal-10,
could be synthesized through the proximal-selective (2 + 2)
cyclodimerization of the fused tetracyclic benzyne 9. We
expected that the π−π interaction between two molecules of 9,
which is the key contributor of the dispersion force, would
work well as in the case of 6i (Scheme 4).16
b
ratio
yield
c
entry
R1
R2
5, 6
proximal:distal
7
(%)
d
1
2
3
4
5
6
7
8
9
H
H
H
5a, 6a
5b, 6b
5c, 6c
5d, 6d
5e, 6e
5f, 6f
5g, 6g
5h, 6h
5i, 6i
−
−
7a
7b
7c
7d
7e
7f
7g
7h
7i
20
0
e
OMe
Me
Me
Me
Me
Me
i-Pr
Me
Me
1.1:1
1.1:1
7.0:1
9.5:1
7.7:1
16:1
36
85
80
56
51
52
54
d
d
d
d
SiMe3
Si(t-Bu)Me2
Si(i-Pr)3
i-Pr
t-Bu
Ad
f
g
>20:1
a
Conditions: 1.0 equiv of 5, 1.5 equiv of MeLi in THF (0.10 M) at
b
−78 °C for 15 min. Ratio between proximal-7 and distal-7 was
c
determined by 1H NMR analysis of crude products. Combined
d
e
isolated yield of 7. Combined 1H NMR yield of 7. Complex mixture
f
g
was obtained. Ad = adamantyl. distal-7i could not be detected.
Scheme 4. Proximal-Selective (2 + 2) Cyclodimerization of
Benzo[c]phenanthryne 9 and Synthesis of Helical
Biphenylenes, proximal-10
benzyne 6a underwent (2 + 2) cyclodimerization to provide
biphenylene 7a in 20% yield (entry 1); however, 3-
methoxybenzyne 6b, which is known to give coupling products
in good yield with varieous arynophiles, did not afford
biphenylenes 7b (entry 2).12 The reaction of 3-methylbenzyne
6c gave proximal-7c and distal-7c in a 1.1:1 ratio in a combined
36% yield (entry 3). In contrast, a similar reaction with 3-
(trimethylsilyl)benzyne 6d produced the corresponding
biphenylene 7d in 85% yield, albeit with poor regioselectivity
(1.1:1) (entry 4). Eventually, we were delighted to see the
expected proximal selectivity (7.0:1) and good yield (80%)
when a tert-butyldimethylsilyl (TBDMS) group was adopted as
the directing group (entry 5). The reaction with the
triisopropylsilyl (TIPS) directing group exhibited in higher
regioselectivity (9.5:1) (entry 6).
Next, we surveyed the alkyl directing groups (entries 7−9).
The ratio of the proximal and distal biphenylenes 7g was 7.7:1
using 3-isopropylbenzyne 6g, and the combined yield of these
two products was 51% (entry 7). Notably, the proximal
selectivities improved according to the bulkiness of the R1 alkyl
substituent (entries 3, 7, and 8). Finally, the (2 + 2)
cyclodimerization of 3-adamantylbenzyne 6i provided prox-
imal-7i exclusively in 54% yield (entry 9). These results (Table
1) indicate that the London dispersion interaction between the
C3-directing groups successfully controls not only the
orientation of the reactions but also the product yields.
Before experimental verification of this hypothesis (Scheme
4), we conducted several theoretical studies (Figures 1 and 2).
The optimized structure of the desired product proximal-10a
(R1−R3 = H) and undesired distal-syn-10a and distal-anti-10a
were calculated at the B3LYP-D3(BJ)/PCM/def2-TZVP level,
where the Conductor-like Polarizable Continuum Model
(PCM) was adopted for including the solvent effects of
tetrahydrofuran (THF). The free energy difference among
them was evaluated at the DLPNO-CCSD(T)/def2-TZVP
level. Notably, the energy of the most sterically demanding
proximal-10a was the lowest and was 6.0 kcal/mol lower than
that of distal-anti-10a [Figure 1(a)]. While this large
stabilization of proximal-10a was unexpected, it would be
desirable for achieving regioselective (2 + 2) cyclodimeriza-
tions of fused benzynes 9. To rationalize the stability of
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structure of proximal-12a, which might be formed from the
tricyclic 1,2-phenanthlyne S2, is helical with minor overlapping
of the aromatic rings and has a narrow NCI area (green part in
Figure 2). On the other hand, the large attractive noncovalent
interaction area, probably derived from π−π attractive
interaction, is observed in the expected helical (2 + 2)
cyclodimerization product proximal-10a of the tetracyclicben-
zyne 9a. The stabilization of proximal-10a by intramolecular
interactions renders its energy the lowest among 10a isomers
[Figure 1(a)]. We have evaluated the energy difference
between B3LYP-D3(BJ) and B3LYP for evaluating the
dispersion correction of the proximal products (see Figure
S7 in the Supporting Information). With an increase in the
number of the benzene rings, the energy difference increases,
as the contact of the hydrophobic moieties increases. This
means that dispersion interaction can control the stability of
the proximal products at least at the equilibrium geometries.
Although the (2 + 2) cyclodimerization of 9 may not be
thermodynamically controlled, we expected that the dispersion
interaction would also stabilize the transition state structures in
the rate-determining step. Encouraged by the theoretical
studies presented in Figures 1 and 2, we turned our attention
to the experimental evaluation of the regioselective (2 + 2)
cyclodimerizations of the tetracyclic benzynes 9.
Figure 1. (a) Total molecular energy difference among proximal-10a,
distal-syn-10a, and distal-anti-10a (DLPNO-CCSD(T)/def2-TZVP//
B3LYP-D3(BJ)/PCM/def2-TZVP). (b) Energy decomposition anal-
ysis (EDA) (MP2/cc-pVDZ//B3LYP-D3(BJ)/PCM/def2-TZVP).
Ees: Electrostatic interaction energy. Eex+rep: Exchange-repulsion
energy. Epol: Polarization energy. Edisp: Dispersion interaction energy.
As expected, the helical molecules, proximal-10a−f were
selectively obtained by the (2 + 2) cyclodimerization of fused
tetracyclic benzynes, benzo[c]phenanthrynes 9, generated from
precursors 13, in 62−78% isolated yields (Table 2). The
Table 2. Scope of (2 + 2) Cyclodimerizations of
a
Benzo[c]phenanthrynes 9
Figure 2. Noncovalent interaction (NCI) plots (s = 0.6 au/−3.0 < ρ
< +3.0 au). Repulsion is color-coded red, and attractive interaction is
color-coded green. Geometry optimization: B3LYP-D3(BJ)/PCM/
def2-TZVP, solvent: THF.
proximal-10a, the energy decomposition analyses (EDA) of
proximal-10a, distal-syn-10a, and distal-anti-10a were per-
formed at the MP2/cc-pVDZ//B3LYP-D3(BJ)/PCM/def2-
TZVP level [Figure 1(b)].17,18 The EDA results indicated that
the large dispersion component of proximal-10a, which is the
main part of the π−π interaction, should be the most
important contributor to the stabilization of proximal-10a
despite its highest steric interaction.
a
Conditions: 1.0 equiv of 13, 1.5 equiv of MeLi in THF (0.10 M) at
b
c
1
−78 °C for 30 min. Determined by H NMR. 2.8 equiv of MeLi
was used.
unsubstituted model compound, proximal-10a, was isolated in
70% yield with perfect regioselectivity (87% H NMR yield,
entry 1). Variations in the aromatic ring substituents, such as
methyl and allyl groups, did not influence the high
regioselectivity and high yield; regioisomers such as distal-
10b−10f were not observed in the H NMR analysis of the
crude mixtures after the reactions in all cases.
It should be emphasized that the reaction of the bicyclic and
tricyclic benzynes or naphthalyne S1 and benzophenanthryne
The noncovalent interaction (NCI) plots19 of the optimized
biphenylene 7a and multifused biphenylenes, proximal-11a,
proximal-12a, and proximal-10a, were obtained by DFT
calculation (B3LYP-D3(BJ)/PCM/def2-TZVP, Figure 2).
Biphenylene 7a and proximal-11a, which are the (2 + 2)
cyclodimerization products of benzyne 6a and 1,2-naphthalyne
S1, respectively, have completely flat structures and show
almost no intramolecular interactions in their structure. The
1
1
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S2 did not produce any proximal-11a/12a or distal- 11a/12a
biphenylene derivatives under the same conditions. These
results suggest that the dispersion interactions from the
tetracyclic structure of benzynes 9 are important in the
formation of the biphenylene derivative proximal-10 in good
yields. Additionally, the (2 + 2) cyclodimerization of fused
benzyne 9d generated from 13d did not occur in toluene and
gave a complex mixture, despite only the [4 + 2] cycloaddition
of 9d with 2,3-dimethylfuran in toluene (Supporting
Information, Scheme S1).7 This variation in reactivity is likely
caused by the weakening of the intermolecular π−π
interactions among the fused benzyne molecules 9b in toluene.
The structures of proximal-10a, 10b, 10d, and 10e were
determined by single-crystal X-ray analysis. The two intra-
molecular head-to-tail aromatic π rings were clearly overlapped
in the X-ray structure of proximal-10a (Figure 3). The shortest
orbital interaction between the two 9A molecules (as shown in
14). The energy of the carbene intermediate INT-p[2s+1s]
,
formed through a two-to-one interaction, is much higher (52.6
kcal/mol) than that of the diradical INT-p[1s+1s] formed
through a one-to-one interaction (Figure S1). The reaction
path for the formation of INT-p[1s+1s] seems to be barrierless,
and the stabilization energy is quite low (≈0.1 kcal/mol, Figure
S2). Therefore, the first step likely involves an equilibrium
between the two diradicals 9A and INT-p[1s+1s]. Next, the aryl
ring of INT-p[1s+1s] would rotate around the newly formed σ-
bond, followed by complete rotation.20d The barrier for
rotation around the π−π-bond of INT-p[1s+1s] was 4.6 kcal/
mol, and the second step is likely the rate-determining step
(RDS) (Figures S3 and S4).
We believe that the attractive London dispersion inter-
actions between the extended π-systems of 9 would facilitate
the rotation, and the energy of the transition state TS-p[1s+1s]
might become lower than those of the other (2 + 2)
cycloadditions of less fused benzynes, such as naphthalyne S1
and phenanthlyne S2. Eventually, we could obtain proximal-10
from tetracyclic benzynes 9 in good yields with excellent
proximal selectivities (Table 2).
In conclusion, we developed London dispersion-controlled
(2 + 2) cyclodimerizations of substituted benzynes. Notably,
the proximal selectivities and yields of the products were
linearly related to the strength of the London dispersion
interactions between the substituents on the benzynes at the 3-
position. The adamantyl group on the benzyne completely
controlled the reaction and produced the proximal adduct
exclusively in a good yield. The developed reactions were
applied to the synthesis of helical molecules using fused
tetracyclic benzynes. The obtained novel helical biphenylenes
will serve as new chiral molecule platforms and will promote a
wide array of applications. The applications and mechanistic
studies using sophisticated theoretical calculations are
currently underway in our laboratory.
Figure 3. ORTEP structure of proximal-10a.
C−C length (3.24 Å) between these two π rings is shorter by
2-fold than that of the van der Waals’ radius of a carbon atom
(1.7 Å), which is in line with the results obtained from the NCI
plots of proximal-10a with a large attractive interaction
between them (Figure 2). The structures of proximal-7e, 7f,
7h, and 7i, and distal-7f (Table 1) were also determined by X-
ray analyses.
The mechanism of (2 + 2) cyclodimerizations of benzynes
has not been theoretically studied in the past (see the
Supporting Information).20,21 A plausible reaction mechanism
for the cyclodimerizations discussed above is shown in Scheme
5. The reaction mechanism likely comprises a stepwise
transformation involving singlet diradical intermediate 9A.
Preliminary theoretical calculations indicated that the (2 + 2)
cycloaddition reactions might commence from the one-to-one
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05434.
General procedures, synthesis of benzyne precursors,
analytical data, additional preliminary theoretical studies,
and X-ray crystallography data (PDF)
NMR spectra (PDF)
Scheme 5. Plausible Reaction Mechanism of (2 + 2)
Cyclodimerizations of Benzo[c]phenanthrynes 9
Accession Codes
CCDC 2019842, 2019846, 2019852−2019854, 2019859,
2019862, 2019865, and 2035060 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Takashi Ikawa − Laboratory of Organic Chemistry, Gifu
Pharmaceutical University, Gifu 501-1196, Japan;
orcid.org/0000-0002-1642-3273; Email: ikawa-ta@gifu-
pu.ac.jp
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Communication
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M.; Caldeweyher, E.; Hansen, A.; Neugebauer, H.; Ehlert, S.;
Grimme, S. Understanding and Quantifying London Dispersion
Effects in Organometallic Complexes. Acc. Chem. Res. 2019, 52, 258−
266. (f) Pollice, R.; Chen, P. A Universal Quantitative Descriptor of
the Dispersion Interaction Potential. Angew. Chem., Int. Ed. 2019, 58,
9758−9769.
Hiroaki Tokiwa − Department of Chemistry, Rikkyo
University, Toshima, Tokyo 171-8501, Japan; orcid.org/
0000-0002-3790-1799; Email: htokiwa@yahoo.co.jp
Shuji Akai − Graduate School of Pharmaceutical Sciences,
Osaka University, Suita, Osaka 565-0871, Japan;
orcid.org/0000-0001-9149-8745; Email: akai@
phs.osaka-u.ac.jp
Authors
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Yuta Yamamoto − Department of Chemistry, Rikkyo
University, Toshima, Tokyo 171-8501, Japan
Akito Heguri − Graduate School of Pharmaceutical Sciences,
Osaka University, Suita, Osaka 565-0871, Japan
Yutaka Fukumoto − Graduate School of Pharmaceutical
Sciences, Osaka University, Suita, Osaka 565-0871, Japan
Tomonari Murakami − Graduate School of Pharmaceutical
Sciences, Osaka University, Suita, Osaka 565-0871, Japan
Akira Takagi − Graduate School of Pharmaceutical Sciences,
Osaka University, Suita, Osaka 565-0871, Japan; Present
Address: Kobe Pharmaceutical University, Motoyamakita,
Higashinada, Kobe 658-8558, Japan; orcid.org/0000-
0002-5797-7440
Yuto Masuda − Graduate School of Pharmaceutical Sciences,
Osaka University, Suita, Osaka 565-0871, Japan
Kenzo Yahata − Graduate School of Pharmaceutical Sciences,
Osaka University, Suita, Osaka 565-0871, Japan;
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05434
Author Contributions
⊥Y.Y. and A.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI (grant
number 16K08164, 19K06996, and 18KK0154) and by the
Platform Project for Supporting Drug Discovery and Life
Science Research (Basis for Supporting Innovative Drug
Discovery and Life Science Research (BINDS)) from AMED
under Grant Number JP21am0101084, the Research Founda-
tion for Pharmaceutical Sciences, Hoanshya, Takeda Science
Foundation, and the Kobayashi International Scholarship
Foundation.
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