1,4-Selective Diels - Alder reaction of 9,10-diethynylanthracene with 3,6-difluorobenzyne

Article abstract of DOI:10.1246/bcsj.20150017

Diels - Alder reaction of 9,10-bis(3-hydroxy-3-methyl-1-butynyl)anthracene with 3,6-difluorobenzyne yields the naphthobarrelene derivative via 1,4-addition of difluorobenzyne in a higher yield than the 9,10-adduct having a triptycene core. The DFT calculations revealed that the intermediate for the former reaction is stabilized more significantly by attractive interaction between a fluorine atom at the benzyne ring and a hydrogen atom at the anthracene ring.

Full text of DOI:10.1246/bcsj.20150017

Short Articles
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1,4-Selective Diels-Alder Reaction
of 9,10-Diethynylanthracene
with 3,6-Difluorobenzyne
+
10
R1
R2
anthracene
benzyne
R1 = -H, -C≡CC(CH3)2OH R2 = -H, -F
Yoshitaka Tsuchido,1 Tomohito Ide,2
Yuji Suzaki,1 and Kohtaro Osakada*1
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1Chemical Resources Laboratory, Tokyo Institute
of Technology, 4259 Nagatsuta, Midori-ku,
Yokohama, Kanagawa 226-8503
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2Corporate Research & Development Center, Toshiba
Corporation, 1 Komukai-Toshiba-cho, Saiwai-ku,
Kawasaki, Kanagawa 212-8582
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E-mail: kosakada@res.titech.ac.jp
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Received: January 13, 2015; Accepted: February 17, 2015;
Web Released: June 15, 2015
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9,10-adduct
(triptycene)
1,4-adduct
(naphthobarrelene)
Diels-Alder reaction of 9,10-bis(3-hydroxy-3-methyl-
1-butynyl)anthracene with 3,6-difluorobenzyne yields the
naphthobarrelene derivative via 1,4-addition of difluoro-
benzyne in a higher yield than the 9,10-adduct having a
triptycene core. The DFT calculations revealed that the inter-
mediate for the former reaction is stabilized more signifi-
cantly by attractive interaction between a fluorine atom at the
benzyne ring and a hydrogen atom at the anthracene ring.
Scheme 1. Diels-Alder reaction of anthracene derivative
with benzyne or 3,6-difluorobenzyne.
methoxybenzyne and attributed the selectivity to electronic
effects of the substituents.9 Formation of the 1,4-adduct as a
minor product was also reported.10,11 Herein we report the 1,4-
favorable Diels-Alder reaction using 3,6-difluorobenzyne as
the dienophile, which is enhanced by an attractive interaction
between a fluorine atom at the benzyne ring and a hydrogen
atom of the anthracene ring. Yamamoto and Heney also con-
ducted the reaction of 9-substituted anthracene with 1,2,3,4-
tetrafluorobenzyne and obtained the 1,4-adduct as a minor
product.12,13
Diels-Alder reaction, a fundamental cycloaddition, forms a
six-membered ring from a diene and a dienophile (i.e. alkene,
alkyne). It has been applied to synthesis of wide variety of
research fields including total synthesis of natural products,1
bio-related compounds,2 and supramolecular compounds.3
Since the transition state of the concerted reaction involves
interaction between the HOMO of the diene and the LUMO
of the dienophile,4 the Diels-Alder reaction of substrate with
different diene groups in the molecule produces isomeric
products and the regioselectivity is governed by the energy
level of the frontier orbitals.
Two different diene groups of anthracenes, the central (9,10-
position) and terminal (1,4-position) six-membered rings, are
able to undergo the reaction with dienophiles. Diels-Alder
reaction between the anthracene and a typical dienophile, such
as maleic anhydride and the diester of fumaric acid, provides
the 9,10-addition product, because the orbital coefficients of
the central diene is higher than that of terminal dienes.5 The
reports of the reactions that provide 1,4-addition products are
limited. Anthracenes with two phenyl or ferrocenyl substituents
or with two CN substituents at 9- and 10-positions prefer the
1,4-addition of maleic anhydride.6,7 The reaction within a
hollow coordination molecular cage allows the 1,4-addition to
9-(hydroxymethyl)anthracene.8 Recently, McKeown obtained
the 1,4-adduct as the major product from the reaction of
1,2,3,4,8,9,10,11-octahydropentacene derivative with 4,5-di-
Stirring a MeCN solution of anthracene or 9,10-bis(3-
hydroxy-3-methyl-1-butynyl)anthracene and 2-(trimethylsilyl)-
phenyltriflate or 3,6-difluoro-2-(trimethylsilyl)phenyltriflate, in
the presence of CsF yielded the cycloaddtiton products at 25 °C
(Scheme 1).14 Table 1 summarizes the ratio of two isomeric
products via 1,4-addition and 9,10-addition. Only the cyclo-
addition reaction between 9,10-bis(3-hydroxy-3-methyl-1-
butynyl)anthracene and 3,6-difluorobenzyne afforded the 1,4-
adducts (naphthobarrelene) as the major product (Table 1,
Run 4). Other reactions (Table 1, Runs 1, 2, and 3) produced
only 9,10-adducts (triptycene).
Figure 1 shows the 1H NMR spectrum of the 1,4-adduct
purified by silica gel column chromatography, which exhibited
five major signals (A, B, C, D, E) in the same integration ratio.
The signal at 6.69 ppm (A) is split by 1H-19F coupling (JH-F
=
1
5.8 Hz). H-1H COSY spectrum contains cross-peaks between
the signals at 6.11 ppm (B) and 7.17 ppm (C), and those at 7.52
ppm (D) and 8.16 ppm (E), which indicates those paired peaks
are assigned to the hydrogen atoms attached to the same ring. In
the 19F{1H} NMR spectrum appears a singlet peak at 129 ppm.
Although crystallography of the study was not feasible, X-ray
measurement of the derivative after removal of the acetone
Bull. Chem. Soc. Jpn. 2015, 88, 821–823 | doi:10.1246/bcsj.20150017
© 2015 The Chemical Society of Japan | 821

Table 1. Diels-Alder Reaction of Anthracenes with Arynesa)
Run
R1
R2
9,10-adduct
1,4-adduct
anthracenes
1
2
3
4
-H
-H
-H
-F
-F
15b)
34b)
51b)
7b)
:
:
:
:
>0.1b)
>0.1b)
>0.1b)
13b)
:
:
:
:
85b)
66b)
49b)
80b)
-C¸CC(CH3)2OH
-H
-C¸CC(CH3)2OH
a) Reaction condition; anthracene (1 equiv), benzyne precursor (1.5 equiv), CsF (1.5 equiv), MeCN, 25 °C,
1
24 h. b) Ratios were determined by H NMR peak area of the reaction mixture.
Table 2. Activation Parameters (¦G‡, ¦H‡) of the Diels-
Alder Reaction between Anthracene and Benzyne Deriv-
; 9,10-Adducts
A
; Anthracene
derivative
E
D
C
atives at 1,4- or 9,10-Positions by DFT Calculations
(BHHLYP/6-31G(d))
A
F
F
B
R2
2
R2
C
HO
B
R2
R2
R2
3
1
8
5
1
4
2
9
1
4
3
2
3
7
6
OH
+
9
D
4
9
or
10
10
8
10
8
E
R2
5
5
7
δ
7
8.0
7.0
6.0
6
6
R2 = -H, -F
Figure 1. 1H NMR spectrum of 1,4-adducts after purifica-
tion (500 MHz, CDCl3, r.t.).
¦G‡
/kcal mol
¦H‡
/kcal mol
Run
R2
H
Product
¹1
¹1
1
2
3
4
9,10-Adducts
1,4-Adducts
9,10-Adducts
1,4-Adducts
18.49
19.13
16.25
14.80
6.21
7.28
3.64
2.69
(a)
(b)
F
F2
117°
F1
H2
(a)
(b)
F1
H7
F2
‡
F2
‡
F1
Figure 2. Crystal structure of 1,4-adduct after deprotection.
10
F1
4
9
molecules indicated the naphthobarrelene skeleton (Figure 2).
The angle of two aromatic rings was 117°. The distance between
fluoride atom (F1) and closed hydrogen atoms (H7, H2) were
2.663 ¡ (F1-H7) and 2.545 ¡ (F1-H2), respectively.
1
d
= 2.58 Å
22
(Electrostatic interaction)
Figure 3. Calculated structures of the transition state of
Diels-Alder reaction of 9,10-diethynylanthracene with
3,6-difluorobenzyne at (a) 9,10- or (b) 1,4-positions
(BHHLYP/6-31G(d)).
We compared the reaction pathways of 9,10-diethynyl-
anthracene with benzyne as the model reaction. Table 2 sum-
marizes the activation energies of the Diels-Alder reaction
obtained from DFTcalculations at the BHHLYP/6-31G(d) level
of theory, which involves the smaller delocalization error
compared to the B3LYP density function.15 The activation
energy of the reaction at the 9,10-position was lower than that at
the 1,4-position in the reactions of 9,10-diethynylanthracene
with benzyne (Table 2, Runs 1 and 2). The reaction of 9,10-
diethynylanthracene with 3,6-difluorobenzyne (Table 2, Runs 3
and 4) shows lower activation energies at 1,4-position (¦G‡ =
14.80 kcal mol¹1) than that of 9,10-position (¦G‡ = 16.25
kcal mol¹1). These results are consistent with the selectivity of
the reactions.
The 1,4-favorable cycloaddition between 9,10-diethynyl-
anthracene and 3,6-difluorobenzyne is related to the structures
of the transition state.16 The transition states of 1,4-addition and
9,10-addition have a different structural relationship between
the molecules. Parallel orientation was obtained for transition
state of the 9,10-addition (Figure 3a). The transition state of
the 9,10-addition has a C¸C bond of the aryne and anthracene
plane at 22° (Figure 3b). The 1,4-addition of benzyne has a
transition state with parallel orientation. The activation energy
of the second reaction is lower than the others, and enhances
the 1,4-addition of 3,6-difluorobenzyne. On the basis of the
natural population analysis (NPA), the electric charges of
fluorine atom at the benzyne ring and hydrogen atom at the 1-
position of anthracene ring were simulated to be ¹0.35, +0.28,
respectively. This result implies the electrostatic interaction
between the fluorine and the hydrogen atoms induces decrease
in the activation energy of 1,4-addition.17
In summary, we found the Diels-Alder reaction of anthra-
cene with 1,4-selectivity in organic solvents. A fluorine atom of
3,6-difluorobenyne forms attractive H£F interaction with a CH
group of the 9,10-diethynylanthracene at the intermediates and
transition state, and renders the 1,4-addition smoother than the
9,10-addition.
822 | Bull. Chem. Soc. Jpn. 2015, 88, 821–823 | doi:10.1246/bcsj.20150017
© 2015 The Chemical Society of Japan

Schröder, R. Wacker, C. Niemeyer, K. Alexandrov, H. Waldmann,
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diffractometer with graphite monochromated Mo Kα radiation.
Single-crystal X-ray structure and supplementary crystallo-
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obtained free of charge from the Cambridge Crystallographic
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The computation of Diels-Alder
reactions between anthracenes and benzynes were performed
with Firefly 8.0.1.18 Minimum energy and transition state struc-
tures were optimized by BHHLYP functional in conjunction
with the 6-31G(d) basis set. Frequency scale factor suitable for
fundamental vibrations is set to be 0.9244.19 All optimized
structures were verified to be local minima or transition states
by Hessian calculations. The intrinsic reaction coordinates
(IRC) followed the transition states corresponding to Diels-
Alder reaction. The activation energy included thermal energy
corrections based on scaled vibrational frequencies. Natural
population analysis20 was performed by NBO 5.G program.21
251.
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This research was supported by the Global COE program
and KAKENHI from the Japan Society for the Promotion
of Science (JSPS). Y. T. is grateful for the JSPS Research
fellowship for Young Scientists. This work was supported by a
Grant-in-Aid for Scientific Research on Innovative Areas “The
Coordination Programming (No. 24108711).” We thank our
colleagues at the Center for Advanced Materials Analysis,
Technical Department, Tokyo Institute of Technology for NMR
and X-ray analysis as well as MS measurement.
Supporting Information
Detailed experimental procedures, NMR spectra, crystal
structure and DFT data for the molecules. This material is
available electronically on J-STAGE.
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Bull. Chem. Soc. Jpn. 2015, 88, 821–823 | doi:10.1246/bcsj.20150017
© 2015 The Chemical Society of Japan | 823