Selective alternate derivatization of the hexaphenylbenzene framework through a thermodynamically controlled halogen dance

Article abstract of DOI:10.1021/ol500041j

We report a practical synthetic protocol and mechanistic details for the selective alternate derivatization of the hexaphenylbenzene (HPB) framework through a thermodynamically controlled halogen dance. The stability of the alternately trilithiated specie

Full text of DOI:10.1021/ol500041j

Letter
pubs.acs.org/OrgLett
Selective Alternate Derivatization of the Hexaphenylbenzene
Framework through a Thermodynamically Controlled Halogen
Dance
Tatsuo Kojima* and Shuichi Hiraoka*
Department of Integrated Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku,
Tokyo 153-8902, Japan
S
* Supporting Information
ABSTRACT: We report a practical synthetic protocol and
mechanistic details for the selective alternate derivatization of
the hexaphenylbenzene (HPB) framework through a thermody-
namically controlled halogen dance. The stability of the
alternately trilithiated species of HPB is interpreted by the
through-space interaction at the ipso-carbons of the phenyl groups
of the HPB framework. By using this approach, C3-symmetric and
lower-symmetric HPB derivatives possessing two or three kinds of
substituents on the periphery have become easily and practically
available.
Scheme 1. Synthetic Approaches to Alternately Substituted
HPB Derivatives
exaphenylbenzene (HPB) is a versatile precursor of
hexabenzocoronene (HBC) and its extended analogues,
H
i.e. partial fragments of graphene, which play an important role
in a wide range of emerging fields.1 The very strong aggregation
ability of HBC has been often employed to construct well-
defined nanostructures.2,3 HPB itself has also been exploited as
a rigid molecular scaffold in liquid crystal,4 organic electronic
materials,5 chromophores,6 ligands,7 amphiphiles,8 and molec-
ular receptors.9 To regulate the electronic and physical
properties of HPB and HBC derivatives, the introduction of
proper substituents in an appropriate symmetry is vitally
required. Especially, HPB and HBC derivatives with C3-
symmetry, which possess two kinds of substituents arranged
in an alternate pattern on the periphery, are established as an
invaluable class.3,7a,8,10
Despite their importance, almost all C3-symmetric HPB
derivatives have been prepared so far by an inefficient synthetic
protocol based on trimerization of unsymmetrical diarylalkynes
with two different substituents (Scheme 1).11 In principle, this
protocol inevitably affords a greater amount of the undesired
“1,2,4-type” isomer than the desired “1,3,5-type” isomer
because the former one is statistically preferred. Furthermore,
the isolation of the desired isomer is quite difficult because
these isomers have similar chemical properties. Accordingly, a
conceptually different approach has long been demanded. For
example, if the selective replacement of three of the chemically
equivalent six peripheral substituents of the C6-symmetric HPB
framework in an alternate manner is realized (Scheme 1), the
synthesis of C3-symmetric HPB derivatives should be greatly
improved. Herein, we report a late-stage desymmetrization
approach for the selective synthesis of alternately functionalized
HPB derivatives utilizing a thermodynamically controlled ArBr/
ArLi exchange reaction, a halogen dance. It is also found that
this approach enables us to achieve the synthesis of HPB
derivatives with a substitution pattern that is completely
unavailable by any conventional approaches.
To our surprise, from thoroughly surveying the literature, we
found one example reported by Rathore et al.12 a decade ago
which included an alternately substituted HPB derivative that
was accidentally produced in high yield through lithiation of C6-
symmetric hexakis(p-bromophenyl)benzene (1) by using 7.2
equiv of t-BuLi followed by electrophilic trapping with
benzophenone. Although this reaction seems promising for
the synthesis of C3-symmetric HPB derivatives, its mechanistic
details and versatility have remained unexplored. Thus,
Received: January 7, 2014
© XXXX American Chemical Society
A
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Letter
modifying Rathore’s conditions, we added 6.0 equiv of t-BuLi
into the suspension of 1 in THF at −98 °C, warmed it to rt to
obtain a clear solution, and then quenched it with trimethylsilyl
chloride (TMSCl) at −98 °C. HPB derivative 2 was selectively
generated (1H NMR yield: 84%) and isolated in 67% yield after
recrystallization (Scheme 2). This reproducible result indicates
the selective generation of the C3-symmetric alternately
trilithiated species 3 before quenching.
all (Figure 1d). This result indicates that alternately trilithiated
species 3 is not a kinetic product but is produced from 1 and
“overlithiated” species 5 during the warming process.
The reversibility of the ArBr/ArLi exchange reaction in THF
was demonstrated,13 and the process leading to a thermody-
namic equilibration is known as a halogen dance reaction.14
The formation of 3 can be interpreted on the basis of the
halogen dance (Scheme 3). At the initial stage of the warming
Scheme 3. Mechanism of Selective Alternate Trilithiation of
Compound 1
Scheme 2. Selective Alternate Trilithiation of Compound 1
process, hexalithiated species 5 is selectively generated. The
selective formation of 5 without any other partially lithiated
species was attributed to the slower dissolution rate of
precipitated 1 than the rate of Br/Li exchange on the dissolved
partially lithiated species with t-BuLi.15,16 Then the halogen
dance between 1, 5, and the various partially lithiated species
takes place to afford an equilibrium mixture which contains 3 as
a major component. It should be noted that the highly site-
selective derivatization based on the halogen dance has been
limited to the monocyclic aromatics and quinoline, and there is
no example of such high site selectivity to be attained for larger
molecular frameworks such as HPB. As far as we know, this is
the first report demonstrating that the halogen dance is
applicable for the selective derivatization of polyaromatic
hydrocarbons.
Considering the statistical unfavorability of the alternate
substitution pattern, the alternately trilithiated species 3 should
be thermodynamically much more stable than the other
trilithiated species. To reveal the origin of the thermodynamic
stability of 3 and the versatility of this reaction for other HPB
derivatives that can lead to a novel substitution pattern, we
subjected brominated HPB derivatives 6−10 possessing one
substituent (CF3, Cl, H, Me, or OMe) and five Br atoms to the
conditions of trilithiation for compound 1 (Scheme 4). The
To clarify the reaction mechanism, we monitored the
composition of the reaction mixture by electrophilic trapping
of lithiated intermediates with TMSCl at −98 °C. The H
NMR spectra of the resulting crude mixture at various times are
shown in Figure 1. The product obtained 2.5 min after removal
1
Scheme 4. Attempted Selective Alternate Trilithiation of
HPB Derivatives 6−10
1
Figure 1. Partial H NMR spectra (500 MHz, CDCl3) of the crude
mixture obtained by quenching with TMSCl at various times: (a) 2.5
min, (b) 5 min, (c) 7.5 min, (d) 30 min after removal of the cooling
bath.
high alternate selectivity was observed only for 6 and 7, which
contain an electron-withdrawing group (R = CF3, Cl), to give
the products bearing three TMS groups arranged in an
alternate manner in 57% and 45% isolated yield, respectively.
It should be emphasized that we first realized the synthesis of
the low symmetric HPB derivatives with this type of
substitution pattern by utilizing the halogen dance. On the
other hand, the trilithiation of 8, 9, and 10 bearing a hydrogen
or an electron-donating group (R = Me, OMe) gave a complex
of the cooling bath was a 1:1 mixture of starting material 1 and
compound 4 derived from hexalithiated species 5 (Figure 1a).
During the warming process, the ratio of 5 progressively
decreased, and via a rather complex mixture (Figure 1b and c),
finally the alternately trilithiated species 3 became the main
component of the reaction mixture, which did not contain 5 at
B
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Letter
mixture.17 These results indicate that the substituents of 6−10
strongly affect the alternate selectivity of trilithiation of the
HPB framework.
qualitatively deduced from the stability of p-substituted
aryllithiums, in which σ/π polarization is the predominant
stabilization, and the order is as follows: Br ≈ CF3 > Cl ≫ H >
Me ≈ OMe.20 Accordingly, it is electron-withdrawing groups,
Br, CF3 and Cl, that stabilize the adjacent lithiated phenyl
group preferentially.
How do the substituents affect the arrangement of Li even
though they were distributed onto the different phenyl groups?
The direct π-conjugation through the central benzene unit
should not be operative owing to the large dihedral angles
between the benzene units of the HPB framework. On the
other hand, the through-space interaction between the adjacent
phenyl groups in the HPB framework has been well recognized
on the basis of the effective overlap of the p-orbitals of the ipso-
carbons of the six phenyl groups (Figure 2a).18 Therefore it is
On the basis of the above order, we qualitatively interpreted
the thermodynamic stability of the alternately trilithiated
species. In the case of the “1,3,5-type” alternately trilithiated
species obtained from compound 1, each lithiated moiety can
be stabilized by the two Br substituents on the adjacent phenyl
groups (Figure 2b). In the case of the “1,2,4-type” trilithiated
species, on the other hand, the number of the through-space
stabilizing interactions decreases. In addition, the destabiliza-
tion arising from the electronic repulsion between the two
adjacent lithiated phenyl groups might be expected. As a result,
the “1,3,5-type” alternately trilithiated species becomes the
major component in the equilibrium mixture in spite of its
statistical disadvantage. In the same manner, the alternately
trilithiated species acquires high stability in the case of the
compounds bearing an electron-withdrawing substituent, 6 and
7 (Figure 2c).
This selective late-stage desymmetrization of readily available
polybrominated HPBs, 1,21 6, and 7, through the halogen
dance is quite practicable to obtain alternately functionalized
HPB derivatives. For instance, selective alternate introduction
of three TMS groups was accomplished in 75% yield after
recrystallization at the 10-g scale (Scheme 5). Large-scale
Scheme 5. Application of Selective Alternate Trilithiation of
Compound 1
Figure 2. (a) Schematic representation of the through-space
interaction at the ipso-carbons of the six phenyl groups on the HPB
framework. (b) Qualitative comparison of the thermodynamic stability
of the two trilithiated regioisomers from compound 1. (c) Qualitative
comparison of the thermodynamic stability of alternately trilithiated
species from compounds 6−10. Bold arrows represent the stabilizing
interaction of the peripheral substituent via the through-space
interaction at ipso-carbons.
sequential trilithiation also succeeded in producing HPB
derivative 13 with Me and TMS groups arranged in an
alternate pattern, which was difficult to obtain through the
conventional trimerization approach because of the tedious
separation of the two possible isomers. The synthetic versatility
of organolithiums and bromoarenes can effectually expand the
availability of HPB derivatives.
In conclusion, we have developed the selective late-stage
desymmetrization approach for the alternate derivatization of
the HPB framework utilizing a thermodynamically controlled
halogen dance. The key for success was the combination of the
geometrical characteristics of the HPB framework and the
advantageous feature of the halogen dance reaction. This
success demonstrates that in some cases a late-stage
desymmetrization approach can be more effective than that
with prederivatized precursors for the preparation of low-
symmetric π-conjugated frameworks. The elucidation of the
detail of the stability of the alternately trilithiated species and
research toward developing novel HPB derivatives based on
this protocol are now underway in our laboratory.
reasonable that the peripheral substituents effectively affect the
stability of the lithiated moieties via a through-space interaction
at the ipso-carbons. Although the effectiveness of this through-
space interaction has been demonstrated experimentally, it has
never been applied in the derivatization of the HPB framework.
The substituent effects on the thermodynamic stability of
aryllithium were recently pursued by Schlosser et al.19 They
proposed that the proximal σ-polarization and the distal σ/π
polarization are the key operative factors to determine the
stability of aryllithiums. In the latter, the increased electron
density in the σ-framework of the lithiated carbon is reduced by
the polarization of the π-cloud. Likewise, in the case of the HPB
framework, the extraction of the excessive electron density on
the lithiated phenyl groups to the adjacent phenyl groups
should be the prominent contribution to the stabilization of the
lithiated moieties. Therefore, the substituent effects on the
stabilization of the adjacent lithiated phenyl group can be
C
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Letter
Moorefield, C. N.; Wesdemiotis, C.; Cheng, S. Z. D.; Newkome, G. R.
J. Am. Chem. Soc. 2011, 133, 11450−11453.
(8) (a) Hiraoka, S.; Harano, K.; Shiro, M.; Shionoya, M. J. Am. Chem.
Soc. 2008, 130, 14368−14369. (b) Hiraoka, S.; Harano, K.; Nakamura,
T.; Shiro, M.; Shionoya, M. Angew. Chem., Int. Ed. 2009, 48, 7006−
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ASSOCIATED CONTENT
* Supporting Information
Experimental details for the synthesis, spectral character-
izations, and additional data. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
(9) (a) Shukla, R.; Lindeman, S. V.; Rathore, R. J. Am. Chem. Soc.
2006, 128, 5328−5329. (b) Shukla, R.; Lindeman, S. V.; Rathore, R.
Chem. Commun. 2007, 3717−3719. (c) Bhalla, V.; Vij, V.; Kumar, M.;
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chiraoka@mail.ecc.u-tokyo.ac.jp.
*E-mail: ckojima@mail.ecc.u-tokyo.ac.jp.
Notes
(10) (a) Lambert, C.; Noll, G. Chem.Eur. J. 2002, 8, 3467−3477.
The authors declare no competing financial interest.
̈
(b) Traber, B.; Wolff, J. J.; Rominger, F.; Oeser, T.; Gleiter, R.;
Goebel, M.; Wortmann, R. Chem.Eur. J. 2004, 10, 1227−1238.
ACKNOWLEDGMENTS
■
(c) Xiao, W.; Feng, X.; Ruffieux, P.; Groning, O.; Mullen, K.; Fasel, R.
̈
̈
This work was supported by JSPS Grants-in-Aid for Scientific
Research on Innovative Areas “Dynamical Ordering of
Biomolecular Systems for Creation of Integrated Functions”
(25102005), Yamada Science Foundation, and Tokuyama
Science Foundation. M. Terasaki (Nihon Waters K.K.) is
acknowledged for HRMS measurements.
J. Am. Chem. Soc. 2008, 130, 8910−8912. (d) Zeng, Z.; Guan, Z.; Xu,
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