Chiral Non-Planar Oligophenylenes Bridged by Urea Linkage: Synthesis through Intramolecular Direct Arylation, Chiroptical Behavior, and Theoretical Investigation

Article abstract of DOI:10.1002/ejoc.201900191

The intramolecular direct arylation of N,N′-dihexyl-N-(2-bromophenyl)-N′-phenylurea using palladium catalyst gave BPU in 75 % yield. Longer terphenyl compound (TPbU) was likewise prepared. Other four conjugated oligomers (BPtU, BPU-1Np, BPU-2Np, and BPU-A

Full text of DOI:10.1002/ejoc.201900191

A Journal of
Accepted Article
Title: Chiral Non-Planar Oligophenylenes bridged by Urea Linkage:
Synthesis through Intramolecular Direct Arylation, Chiroptical
Behavior, and Theoretical Investigation
Authors: Koji Takagi, Yuto Hirano, Koichiro Mikami, Shoko Kikkawa,
and Isao Azumaya
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900191
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10.1002/ejoc.201900191
European Journal of Organic Chemistry
FULL PAPER
Chiral Non-Planar Oligophenylenes bridged by Urea Linkage:
Synthesis through Intramolecular Direct Arylation, Chiroptical
Behavior, and Theoretical Investigation
Koji Takagi,[a] * Yuto Hirano,[a] Koichiro Mikami,[b] * Shoko Kikkawa,[c] and Isao Azumaya[c]
Abstract: The intramolecular direct arylation of N,N'-dihexyl-N-(2-
bromophenyl)-N'-phenylurea using palladium catalyst gave BPU in
75% yield. Longer terphenyl compound (TPbU) was likewise
prepared. Other four conjugated oligomers (BPtU, BPU-1Np, BPU-
2Np, and BPU-Ant) were synthesized from BPU in short reaction
steps. From the X-ray crystallography, BPtU with the thiourea
with the helical conformation and one meso form were
observed.7 It was found that the chain elongation from biphenyl
to terphenyl results in the high rotation value and distinct circular
dichroism. Rathore and co-workers have reported a versatile
synthesis of a variety of bridged terphenyls from readily
available diacetylenic precursors via a simple three-step route.8
skeleton was suggested to have a quasi C=N double bond character. Although bulky substituents were installed onto the bridging
Each enantiomer was optically resolved on chiral HPLC to show
mirroring Cotton effects and monosignate CD patterns. The
enantiomeric excess (e.e.) values were evaluated by HPLC, from
which BPU and TPbU exhibited comparable racemization energy
position, the racemization energy barriers were still low to
racemize at room temperature. Recently, true banister oligomers
exclusively consisting of two enantiomers (without meso form)
were prepared by Mayor and co-workers by utilizing a length
mismatch strategy.9,10 They also investigated the influence of a
tether strap on the helix stability to figure out that the
introduction of larger and softer selenium atom reduces the
racemization energy barrier.11 As can be seen from these
examples, it is important to understand the origin of chirality and
the chiral structure-physical properties relationship, and bridged
biphenyl compounds are good candidates for predicting the
secondary structure of extended helical analogs. Mayor and co-
workers have carefully studied the rotation barriers of 4,4′-
disubstituted torsion-angle-restricted biphenyl cyclophanes with
the aid of density functional theory (DFT) calculation for the
transition state.12,13
barriers (DG‡
=
23.3 kcal·mol-1 and 23.4 kcal·mol-1). The
rac
racemization energy barrier of BPtU was considerably high (DG‡
=
rac
30.1 kcal·mol-1) likely due to the quasi C=N double bond character.
On the other hand, BPU-2Np and BPU-Ant having the p-conjugated
system exhibited DG‡
of 23.8 kcal·mol-1 and 24.0 kcal·mol-1,
rac
respectively. These experimental results were well explained by
theoretical analyses.
Introduction
Biphenyl compounds bearing an appropriate tether strap adopt
the forced non-planar conformation and have the rotation barrier
around the sp2 carbon-sp2 carbon bond of two phenyl rings.
Optically active compounds with the axial chirality can be
potentially separated by the chiral high performance liquid
chromatography (HPLC) and gas chromatography (GC) if the
rotation barrier is high enough. Chiral biphenyls have been
drawing much attention not only from a viewpoint of general
chemistry1 but also as functional materials including
organocatalysts2–4 and nonlinear optics.5 Longer oligo and
poly(para-phenylene) derivatives having the same axial chirality
are expected to have the persistent helical secondary structure.
In contrast to helicences and twistacenes, these so-called
Geländer or banister-type oligomers are relatively flexible and
exhibit the dynamic motion.6 Vögtle and co-workers have
propounded the concept of Geländer molecules and prepared
bridged terphenyl compounds, in which a pair of enantiomers
In order to widely investigate the chiral structure-physical
properties relationship, the development of new bridged biphenyl
compounds is highly desired. There are several methods to
prepare biphenyl derivatives with the three-atom bridge, namely,
seven-membered rings are fused on the side of biphenyl
skeleton.14–16 In relation to the framework of our molecules,
Kostyanovsky and co-worker have reported the synthesis and
HPLC analysis of chiral N,N'-dialkyl-2,2'-biphenylene-N,N'-
ureas.17 However, they did not evaluate the racemization energy
barriers. During the course of our study on functional conjugated
oligomers comprising of the aromatic cyclic triamide structure,18–
23
we have previously reported that an amide-bridged ladder
poly(para-phenylene) with the rigid and planar conformation
could be obtained by using the palladium-catalyzed
intramolecular direct arylation (Figure 1A).24 More recently, we
have systematically prepared lactam-fused p-extended
conjugated oligomers by the tandem direct arylation and
revealed their potential utility as a n-type field effect transistor
material25 as well as flexible optical waveguides/bending
mechanofluorochromic materials26 (Figure 1B). The direct
arylation is recognized as an alternative to the cross-coupling
reaction using organometallic reagents.27–31 Convenient and
atom-economic reactions are possible to form biaryl carbon–
carbon bond linkages without the need of time-consuming
preparation of organometallic reagents and the special care for
air/moisture sensitive intermediates. The key points of these
successful syntheses are based on the fact that N-alkylated
benzanilides preferentially adopt a cis conformation (E isomer)
with two benzene rings turned into the same direction both in
[a]
[b]
Graduate School of Engineering, Nagoya Institute of Technology
Gokiso, Showa, Nagoya, Aichi 466-8555, Japan
E-mail: takagi.koji@nitech.ac.jp
http://polysyn.web.nitech.ac.jp
Sagami Chemical Research Institute
Hayakawa 2743-1, Ayase, Kanagawa 252-1193, Japan
E-mail: koichiro.mikami@sagami.or.jp
http://sagami-
scri.jp/publics/index/117/&anchor_link=page117#page117
Faculty of Pharmaceutical Sciences, Toho University
Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan
[c]
Electronic Supplementary Information (ESI) available: Experimental,
NMR spectra, optical properties, theoretical calculations.
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10.1002/ejoc.201900191
European Journal of Organic Chemistry
FULL PAPER
Results and Discussion
Previous work
(B)
(A)
F
F
C6H13
O
Synthesis and chiroptical properties of main backbone
Biphenyl derivative bridged by the N,N'-dihexylurea skeleton
(BPU) was synthesized in three steps, namely, the reaction of 2-
bromoaniline with phenyl isocyanate, N-alkylation, and
intramolecular cyclization (Scheme 1). We have carried out the
palladium-catalyzed direct arylation of N,N'-dihexyl-N-(2-
bromophenyl)-N'-phenylurea (2) using Pd(OAc)2, PivOH, and
K2CO3 in DMAc, where the influence of phosphine ligand and
heating method were investigated (Table 1). We have previously
demonstrated that the microwave heating is effective for the
palladium-catalyzed direct arylation.24 When the ligand-free
reaction was performed at 145 °C under the microwave
irradiation, the high NMR yield was confirmed after 6 h (Entry 1).
The reaction at 120 °C decreased the NMR yield (Entry 2), while
the addition of PCy3·HBF4 gave an improved yield even at
100 °C for 6 h (Entry 4). In contrast, the lower NMR yield was
observed after 24 h under the similar condition with the oil bath
heating (Entry 6), although the detailed reason cannot be
discussed at the present moment. In a similar manner, terphenyl
derivative bridged by the N,N',N",N'"-tetrahexylbisurea skeleton
(TPbU) was synthesized albeit in relatively low yield (Scheme 2).
We have subsequently obtained biphenyl derivative bridged by
the N,N'-dihexylthiourea skeleton (BPtU) from BPU using
Lawesson's reagent in toluene at refluxing temperature for 3 h
(Scheme 3). In the 1H-NMR spectrum of BPU, the methylene
proton signals adjacent to the urea nitrogen atom were
separately detected at 3.4 ppm and 4.0 ppm (Figure S1-1),
which is most likely ascribed to the diastereotopic environment
of methylene protons due to the axial chirality of biphenyl
moiety.39 The corresponding proton signals of BPtU were
downfield-shifted to be detected at 3.6 ppm and 4.6 ppm. These
spectroscopic results are in good accordance with the reported
characteristic of urea and thiourea compounds, namely, the
small contribution of the thione form in the case of thiourea.40 In
the IR spectra, the C=O stretching vibration (urea I band) signal
of BPU at 1672 cm-1 was disappeared in BPtU.
O
C12H25
F
N
N
N
S
F
F
F
n
F
S
N
C6H13
N
N
O
F
C12H25
O
: 6-membered ring
This work
(C)
O
C6H13
C6H13
N
N
: 7-membered ring
Figure 1. (A) Amide-bridged ladder poly(para-phenylene) with the rigid and
planar conformation.24 (B) Lactam-fused p-extended conjugated oligomer.25,26
(C) Non-planar and urea-bridged conjugated oligomer. Red and blue lines
were formed by palladium-catalyzed intramolecular and intermolecular direct
arylation, respectively.
solution and solid states.32,33 On the other hand, fully N-alkylated
urea derivatives are also known to adopt similar conformation, in
which the aromatic rings are located in close proximity.34–37 With
these backgrounds in our mind, we came up with the
preparation of non-planar and urea-bridged conjugated
oligomers by the intramolecular direct arylation (Figure 1C). In
contrast to our previous papers, the present intramolecular direct
arylation furnishes the seven-membered ring that endows the
molecules with chirality. Herein, we report the optimized
synthesis of a set of conjugated oligomers with N-alkylated urea
and thiourea carrying various p-conjugated segments (Figure 2),
the analysis of single crystal X-ray structures, and the evaluation
of racemization energy barriers by the HPLC technique and
theoretical calculation. Because the C=S bond is longer than the
C=O bond and the C–N bond has a double-bond character
owing to the small contribution of the thione form,38 the C–N
rotation barrier of thiourea should be perturbated. Both the
bulkiness of p-conjugated segment appended on the biphenyl
framework and this resonance effect would influence the
racemization behavior, which are discussed in detail.
O
S
O
C6H13
C6H13
Table 1. Palladium-catalyzed direct arylation for preparing BPU.[a]
C6H13
C6H13
N
N
C6H13
C6H13
N
N
N
N
π-elongation
thionation
Entry
Ligand
—
Temperature/°C[b]
145 (MW)
120 (MW)
145 (MW)
100 (MW)
80 (MW)
Time/h
NMR yield/%[c]
N
O
N
BPU
BPtU
C6H13
C6H13
π-functionalization
TPbU
1
2
3
4
5
6
6
6
91
20
90
89
74
33
O
O
C6H13
C6H13
N
N
C6H13
C6H13
N
N
—
isomer
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
6
BPU-2Np
BPU-1Np
6
π-functionalization
O
6
C6H13
C6H13
N
N
100 (OB)
24
[a] Conditions; Pd(OAc)2 (5.6 mol%), PivOH (42 mol%), K2CO3 (3.5 equiv),
and PCy3·HBF4 (11.2 mol% in Entry 3–6). [b] MW; microwave. OB; oil bath.
[c] Calculated from the integral ratio in the 1H-NMR spectra.
BPU-Ant
Figure 2. Non-planar and urea-bridged conjugated oligomers.
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10.1002/ejoc.201900191
European Journal of Organic Chemistry
FULL PAPER
For the in-depth discussion about the molecular
conformation and packing structure of synthesized p-conjugated
oligomers, single crystallographic analyses were carried out.
Because the melting temperature of BPU with N-hexyl chains
was too low to obtain a single crystal, N-methyl derivative BPUMe
was prepared and a colorless crystal was grown by the slow
evaporation of the hexane solution. The C=O and CO–N bond
lengths are 1.22 Å and 1.38–1.39 Å, respectively (Figure 3). The
torsion angle between two phenyl rings (defined by the atoms in
cyclic urea) is 39.6°. The crystal packing structure indicates that
BPUMe is orthorhombic with a space group of Pbca. One unit cell
contains four pairs of two enantiomers (Z = 8) and the
enantiomers with the same chirality are aligned along the a axis
(Figure S7). A colorless crystal of TPbU was grown by the slow
evaporation of the ethanol solution. Although TPbU should
contain a pair of enantiomers with the helical conformation and
one meso form in solution, only meso form could be crystallized.
The C=O bond length (1.22 Å) and CO-N bond length (1.39 Å)
as well as the torsion angle between two phenyl rings (41.0°) are
almost identical to those of BPUMe. Conformation of TPbU in the
single crystal has a center of symmetry on the central benzene
ring. The crystal packing structure indicates that TPbU is
monoclinic with a space group of P21/c and Z = 2. Molecules are
aligned along the a axis and the one-dimensional chain
architecture along the c axis supported by the C=O···H–C
(benzene) hydrogen bonding interaction is observed. Like
Layers with the same chirality are formed along the a axis. In all
cases, no p-p stacking interactions were observed between
neighboring molecules. Although the C(=S)–N bond length of
BPtUMe is longer than bare S=C(NH2)2 (approximately 1.33 Å),41
BPtU would be expected to have a C=N double-bond character
in some degree (See theoretical calculation section).
Optically pure two enantiomers of BPU were isolated by
using a Daicel CHIRALFLASH IC column with n-hexane/i-PrOH
(95/5 in volume ratio) as the mobile phase (See Figure S8 for
analytical HPLC chromatogram). Because isolated enantiomers
gradually racemize at room temperature (vide infra), CD spectra
were collected immediately just after the separation. Figure 4
indicates CD spectra of the first eluent (blue line) and the
second eluent (red line) along with UV spectrum (black line), in
which each enantiomers exhibit mirroring Cotton effects and
monosignate CD patterns. As for the first eluent, the first
negative and second positive Cotton effect were observed at
295 nm and 262 nm, respectively, with the zero-crossing point at
281 nm. The CD anisotropy factor (De/e) at 295 nm was found to
be 103 gabs = 0.94. The time-dependent density functional
theory (TDDFT) calculation was carried out for the enantiomer
with a plus (P) configuration around the biphenyl moiety.
Although the experimental CD pattern could not be reproduced
completely, it was found that the CD sign corresponding to the p-
p* transition band at 291 nm is negative (Figure S17).
Accordingly, the first eluent likely has a chiral structure with two
benzene rings twisted in a clockwise fashion. On the other hand,
in the case of TPbU consisting of three optical isomers, only one
enantiomer could be optically resolved (n-hexane/i-PrOH=70/30
as the mobile phase) due to the overlap of HPLC peaks (See
Figure S9). The monosignate CD pattern having the peak
maximum at 305 nm was observed and the CD anisotropy factor
at this wavelength was 103 gabs = 3.0. In contrast to BPU,
TPbU with the longer p-conjugated backbone exhibited a weak
but detectable fluorescence emission at 398 nm (Figure S14, F
= 0.02). The low fluorescence quantum yield might be ascribed
to the relatively flexible backbone. In fact, the fluorescence
quantum yield was significantly increased (F = 0.20) when we
measured the emission spectrum in the solid state. Because p-p
stacking interaction is not observed between molecules in the
crystal state as we described above, the excimer formation can
be ignored resulting in the increased fluorescence quantum yield.
The optical resolution of racemic BPtU was likewise carried out
using n-hexane/i-PrOH (99/1 in volume ratio) as the mobile
phase (See Figure S10). In the UV spectrum of BPtU, a weak
absorption band was observed at around 350 nm. Although
BPtU has a biphenyl segment similar to BPU, the largest CD
anisotropy factor (103 gabs = 47) among three compounds was
observed at 350 nm. The TDDFT calculation indicated that the
p-p* absorption band at 296 nm can be ascribed to the electronic
transition not from the highest occupied molecular orbital
(HOMO) but from the next highest occupied molecular orbital
(HOMO-1). Anyhow, as for the enantiomer with a plus (P)
configuration around the biphenyl moiety, the CD sign
corresponding to the p-p* transition band is negative (Figure
S18).
BPUMe
, thiourea compound BPtUMe was prepared to be
subjected to the single crystallographic analysis. A colorless
crystal was grown by the vapor diffusion method using THF and
hexane. Conformation of TPbU in the single crystal has a two-
fold rotation axis. The C=S and C(=S)–N bond lengths are 1.66
Å and 1.38 Å, respectively. The torsion angle between two
phenyl rings (42.1°) is obviously larger than that of BPUMe. The
crystal packing structure indicates that BPtUMe is orthorhombic
with a space group of Fdd2. One unit cell contains four pairs of
two enantiomers (Z = 8) and the enantiomers with the same
chirality are aligned along the c axis.
BPUMe
TPbU
BPtUMe
Figure 3. ORTEP representation of BPUMe (CCDC 1883094), TPbU (CCDC
1883095), and BPtUMe (CCDC 1883096) with 50% thermal ellipsoid probability.
The purple, red, and orange atoms represent N, O, and S, respectively. Alkyl
chains are trimmed for clarity.
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10.1002/ejoc.201900191
European Journal of Organic Chemistry
FULL PAPER
We then became interested in the racemization behavior of
axially chiral biphenyl derivatives with (bulky) p-conjugated
system on the benzene ring. With BPU in our hand, the
bromination and Suzuki-Miyaura cross coupling reaction
afforded BPU-1Np, BPU-2Np, and BPU-Ant in good yields
3
2
BPU
TPbU
BPtU
20
10
1
0
0
270
300
330
360
390
260
280
300
320
340
-1
-2
-3
-10
-20
-30
4500
3000
1500
0
15000
10000
5000
0
1
(Schemes 4–6). In the H-NMR spectra of BPU-1Np and BPU-
260
280
300
320
340
2Np, the proton signals adjacent to the urea nitrogen atom were
observed at around 3.4 and 4.0 ppm, which are almost identical
to that of BPU. The corresponding signals of BPU-Ant were
shifted to the downfield region (3.7 and 4.3 ppm) probably
ascribed to the steric repulsion of anthracene rings and distorted
conformation of the urea moiety. Each enantiomer was isolated
on chiral HPLC by using a Daicel CHIRALFLASH IC column with
an appropriate solvent mixture as the mobile phase (See
Figures S11–13). Figure 6 indicates CD spectra of the first
eluent (blue line) and the second eluent (red line) along with UV
spectrum (black line), in which each enantiomer exhibits the
mirroring Cotton effect. Unfortunately, the perfect separation of
enantiomers of BPU-1Np was difficult and two CD spectra did
not show a complete mirror image. Basically, monosignate CD
patterns were observed. The CD anisotropy factors (De/e) of
BPU-2Np and BPU-Ant were 103 gabs = 1.09 at 307 nm and
103 gabs = 0.63 at 391 nm, respectively. BPU-Ant exhibited a
fluorescence emission at 408 nm with the vibronic fine structure
(Figure S15). The relative fluorescence quantum yield was 0.007,
which was very low probably because of the steric repulsion of
anthracene rings and the non-radiative decay from the excited
state in addition to the relatively flexible BPU backbone. The
racemization behavior of BPU-2Np and BPU-Ant were
subsequently investigated by monitoring HPLC chromatograms
at designated times after the optical resolution. Each solution
was kept at 25 °C and the enantiomeric excesses (e.e.) values
were determined by the integral ratio of two peaks. Figure 7
indicates the linear relationship between ln(e.e.) and time, and a
racemization rate constant was calculated from the slope.
270
300
330
360
390
Wavelength/nm
Wavelength/nm
Figure 4. CD and UV spectra of BPU (n-hexane/i-PrOH (95/5 in volume ratio)),
TPbU (n-hexane/i-PrOH (70/30 in volume ratio)), and BPtU (n-hexane/i-PrOH
(99/1 in volume ratio)). Blue line: first eluent, Red line: second eluent.
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
5
4
3
2
5
4
3
2
1
0
0.E+00 3.E+06 6.E+06
Time/sec
0
30000 60000
Time/sec
BPU
TPbU
BPtU
0
10 20 30 40 50
Time/d
0
5
10
Time/h
15
20
0
5
10
Time/h
15
20
25
Figure 5. Decrease of enantiomeric excess (e.e.) value as a function of time
for BPU, TPbU, and BPtU. The insets show the linear relationship between
ln(e.e.) and time.
Therefore, similar to BPU, the first eluent likely has a chiral
structure with two benzene rings twisted in a clockwise fashion.
The racemization behavior of BPU was subsequently
investigated by monitoring HPLC chromatograms at designated
times after the optical resolution (Figure S16). Figure 5 indicates
the decrease of enantiomeric excess (e.e.) value as a function of
time while keeping the n-hexane/i-PrOH solution (95/5 in volume
ratio) at 25 °C. The linear relationship was observed between
ln(e.e.) and time as depicted in the inset, and the slope gave a
racemization rate constant 105 krac
racemization energy barrier was calculated as DG‡
=
1.97. Therefore
a
= 23.4
rac
kcal·mol-1. TPbU demonstrated a similar racemization behavior
with 105 krac = 2.40 and DG‡rac = 23.3 kcal·mol-1 implying that the
elongation of p-conjugated backbone does not affect the rotation
barrier around two phenyl rings. Because the racemization of
thiourea compound BPtU was very slow at 25 °C, the
experiment was carried out at 74 °C. A racemization energy
BPU-1Np
BPU-2Np
BPU-Ant
barrier was thus calculated to exhibit 105 krac = 400 and DG‡
=
rac
30.1 kcal·mol-1, and +6.7 kcal/mol higher than that of BPU.
Závada and co-workers have investigated the synthesis and
racemization of axially chiral dilactams to claim that the inversion
barriers around phenyl rings are very similar to the parent
carbocyclic system and the quasi double bond character of the
amide group is the most probable reason.42 Because the C(=S)–
N bond in BPtU has a double bond character as deduced by the
X-ray crystallography (vide supra), the high rotation barrier
around the C(=S)–N bond likely results in the suppressed
racemization. This scenario was clearly supported by theoretical
investigation (See theoretical calculation section).
Figure 6. CD and UV spectra of BPU-1Np (n-hexane/CH2Cl2 (66/34 in volume
ratio)), BPU-2Np (n-hexane/THF (88/12 in volume ratio)), and BPU-Ant (n-
hexane/CH2Cl2 (27/73 in volume ratio)). Blue line: first eluent, Red line: second
eluent.
BPU-Ant
BPU-2Np
BPU
Synthesis and chiroptical properties of
derivatives
p
-functionalized
Figure 7. Linear relationship between ln(e.e.) and time for BPU-2Np, BPU-
Ant, and BPU.
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10.1002/ejoc.201900191
European Journal of Organic Chemistry
FULL PAPER
Table 2. Summary of racemization rate constants and racemization energy
barriers.[a]
105 krac/sec-1
1.97
DG‡rac/kcal·mol-1
Temperature/°C
BPU
TPbU
23.4
23.3
30.3
NA[b]
23.8
24.0
25
25
74
25
25
25
2.40
BPtU
0.03
E
E
H3C
CH3
NA[b]
H3C
CH3
N
N
BPU-1Np
BPU-2Np
BPU-Ant
N
N
1.00
0.80
Figure 8. Theoretical energy diagram of racemization of BPU and BPtU.
Inset; optimized structures of a), b), c) BPU and d), e), f) BPtU at ground and
transition states. The geometries were given by ball and stick type model
(atom color: blue = nitrogen, silver = carbon, yellow = S, red = oxygen). GS
and TS stand for ground state and transition state, respectively.
[a] Obtained by chiral HPLC analyses. [b] Not available due to imperfect peak
separation in HPLC.
Table
2
summarizes racemization rate constants and
racemization energy barriers of five non-planar and urea-bridged
conjugated oligomers. By introducing the p-conjugated system
on the benzene ring, the racemization energy barrier increased
as expected. BPU-2Np and BPU-Ant, however, exhibited a
small difference.
These decrements of WBI and stabilization energy at the
transition state of BPtU should be derived from the larger
deviation from the planarity of BPtU compared with that of BPU.
As provided in Figure S19, the dihedral angle (S=)C–N–C(Me) at
transition states of BPtU was –26.311˚, and the corresponding
value of BPU ((O=)C–N–C(Me)) was –13.171˚. The larger
deviation from the planarity in BPtU restricts the effective
delocalization of the pair of electron on the N atom to the p*
orbital of C=S bonding at BPtU, resulting in the decrement of the
value of WBI. Taking these theoretical and experimental
viewpoints into consideration, the higher racemization barrier in
BPtU than that of BPU should be attributed to two factors; 1) the
quasi double bond nature at the C(=S)–N bonding in BPtU
stabilizes the ground state geometry, and 2) the deviation from
the planarity prevents the stabilization of the transition state.
Finally, we theoretically evaluated the racemization energy
barrier of BPU-Ant at the same level as BPU (Figure S21). The
energy barrier was calculated as 23.8 kcal/mol exhibiting the
nearly same energy as BPU. This fact consists with the
experimental results, and implies that the substitution at the 4-
position does not affect the racemization energy barrier
significantly.
Theoretical analyses
The quasi double bond character in BPtU at the ground state
(GS1(BPtU) and GS2(BPtU)
)
was supported by theoretical
calculations (B3LYP/6-31G(d,p)) (Figure 8). The bond length of
C(=X)–N of BPtU (X = S) and BPU (X = O) were 1.385 Å and
1.399 Å, respectively, and the molecules were significantly
deviated from the planer structure nicely reproducing the
structures observed in the single-crystal X-ray analysis. The
Wiberg Bond Index (WBI) value of C(=S)–N of BPtU (1.123) was
higher than that of C(=O)–N of BPU (1.054) reflecting a quasi
C=N double bond character of BPtU. Second-order perturbation
theory analysis showed that the non-bonding pair of electron
localized at the N atom donated the stabilization energy to the
π* orbital of C=S bonding (+57.8 kcal/mol) and C=O bonding
(+47.1 kcal/mol), and the stronger secondary orbital interaction
would contribute to the quasi double bond character of BPtU.
On the contrary to the ground state structures, both of the
transition state structures adopted nearly planer conformation.
The energy barrier (ΔG‡) of BPU and BPtU were +23.1 kcal/mol
and +28.1 kcal/mol (Figure 8), respectively, indicating that the
value of BPtU was 5.0 kcal/mol higher than that of BPU. This
was qualitatively in good agreement of the experimental results
that the racemization of BPtU is much slower than that of BPU,
as described above. Notably, the WBI value of C(=S)–N of BPtU
at the transition state was decreased (1.119), although the value
of C(=O)–N of BPU was increased (1.069), compared with those
ground states. Second-order perturbation theory analysis of
BPtU and BPU at the transition states showed that the
stabilization energy donated by the non-bonding pair of electron
localized at the N atom to the p* orbital of C=S orbital was also
decreased (38.5 kcal/mol), whereas, in the cased of BPU, the
value was increased (54.3 kcal/mol).
Conclusions
Optically active biphenyl compounds occupy an important place
in the chiral technology and the structure-physical properties
relationship is a matter of discussion over the past several
decades. In this article, we have prepared non-planar and urea-
bridged conjugated oligomers by the palladium-catalyzed
intramolecular direct arylation and revealed their racemization
behaviors with the aid of theoretical calculation. The X-ray
crystallographic analyses revealed that the thiourea derivative
has a quasi C=N double bond character to result in the
increased racemization energy barrier. On the other hand, the
elongation of p-conjugation length and the substitution of
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10.1002/ejoc.201900191
European Journal of Organic Chemistry
FULL PAPER
chromophores at the 4-position did not affect the racemization
energy barrier significantly. These experimental results were
well explained by theoretical analyses. We believe that our
present findings can contribute to the design of chiral biphenyl
compounds and related longer conjugated oligomers for
developing functional chiral materials.
A mixture of 4 (1.2 g, 1.4 mmol), Pd(OAc)2 (37 mg, 0.16 mmol),
PCy3·HBF4 (0.12 g, 0.32 mmol), PivOH (0.13 g, 1.2 mmol), and
K2CO3 (1.4 g, 10 mmol) in DMAc (11 mL) was placed in a
microwave vial, which was heated at 100 °C for 6 h. After the
solvent was removed, CH2Cl2 was added and washed with brine,
and dried over MgSO4. After evaporating solvents, the crude
product was purified by SiO2 column chromatography using
hexane/ethyl acetate (4/1 in volume) (Rf = 0.43 and 0.36) as an
eluent to obtain colorless solid TPbU as
a mixture of
Experimental Section
diastereomers in 0.30 g (31% yield). Mp: 110.3–112.3 °C. 1H-
NMR (400 MHz, CDCl3) δ ppm 0.62–0.75 (m, 12H), 0.83–1.12
General information and synthetic procedure for the preparation
of precursors are described in the supporting information. The
important procedues for obtaining the target compounds and
synthetic scheme are provided below.
(
(
br, 24H), 1.19–1.53 (m, 8H), 3.38–3.56 (m, 4H), 3.94–4.12
m, 4H), 7.20–7.31 (m, 4H), 7.37–7.45 (m, 4H), 7.51 (dd, J =
7.70, 1.59 H
Z
, 2H). 13C-NMR (101 MHz,CDCl3) δ ppm 13.82,
13.87, 13.89, 13.92, 22.41, 22.43, 22.47, 25.90, 25.93, 26.06,
26.08, 27.28, 27.45, 27.49, 27.52, 31.02, 31.07, 31.15, 31.17,
47.41, 47.82, 120.60, 120.76, 121.64, 121.68, 125.02, 125.12,
128.17, 128.59, 133.60, 133.81, 134.09, 134.30, 140.46, 143.55,
Synthesis
Biphenylurea (BPU)
Br
H
N
H
N
Br
R
N
R
N
Br
H2N
NCO
+
O
O
1
143.67, 165.29, 165.36. H- and 13C-NMR signals are complex
1
2
due to the mixture of enantiomers and diastereomer. Anal Calcd
for C44H62N4O2: C, 77.83%; H, 9.20%; N, 8.25%; O, 4.71%.
Found: C, 77.61%; H, 9.43%; N, 8.21%. IR (ATR) 1658 cm-1
(C=O).
O
R
R
N
N
R=C6H13
BPU
Scheme 1.
Biphenylthiourea (BPtU)
A mixture of 2 (2.0 g, 4.4 mmol), Pd(OAc)2 (59 mg, 0.24 mmol),
PCy3·HBF4 (0.19 g, 0.49 mmol), PivOH (0.20 g, 1.8 mmol), and
K2CO3 (2.3 g, 15 mmol) in N,N-dimethylacetamide (DMAc, 20
mL) was placed in a microwave vial, which was heated at
100 °C for 6 h. After solvent was removed, CH2Cl2 was added
and washed with brine, and dried over MgSO4. After evaporating
solvents, the crude product was purified by SiO2 column
chromatography using hexane/ethyl acetate (4/1 in volume) (Rf
= 0.53) as an eluent to obtain pale yellow oil BPU in 1.2 g (75%
yield). 1H-NMR (400 MHz, CDCl3) δ ppm 0.64–0.72 (m, 6H),
0.89–1.07 (br, 12H), 1.27–1.42 (m, 4H), 3.43 (m, 2H), 4.01 (m,
2H), 7.17–7.25 (m, 4H), 7.34–7.40 (m, 2H), 7.48 (dd, J = 7.70,
1.59 Hz, 2H). 13C-NMR (101 MHz, CDCl3) δ ppm 13.81, 22.41,
25.99, 27.49, 31.10, 47.63, 121.43, 124.86, 128.17, 128.20,
134.37, 143.79, 165.54. Anal Calcd for C25H34N2O·0.25H2O: C,
78.39%; H, 9.08%; N, 7.31%. Found: C, 78.42%; H, 9.13%; N,
7.33%. IR (liquid film) 1672 cm-1 (C=O).
S
O
R
R
R
R
N
N
N
N
R=C6H13
BPtU
BPU
Scheme 3.
Lawesson's reagent (0.15 g, 0.38 mmol) was added to BPU
(0.24 g, 0.63 mmol) in toluene (4 mL), and the mixture was
heated to reflux for 3 h. After the precipitate was separated by
filtration, the solvent was removed. The crude product was
purified by SiO2 column chromatography using hexane/ethyl
acetate (4/1 in volume) (Rf = 0.61) as an eluent to obtain
colorless oil BPtU in 0.25 g (67% yield). 1H-NMR (400 MHz,
CDCl3) δ ppm 0.63–0.71 (m, 6H), 0.79–1.02 (br, 12H), 1.16–
1.41 (m, 2H), 1.34 (
dd, J = 8.07, 0.98 H
2H), 7.49 (dd, J = 7.58, 1.71 H
m
, 2H), 3.63 (
, 2H), 7.28–7.33 (m, 2H), 7.35–7.40 (m,
, 2H). 13C-NMR (101 MHz,
m, 2H), 4.57 (m, 2H), 7.20
(
Z
Z
CDCl3) δ ppm 13.87, 22.43, 25.82, 27.51, 31.12, 53.24, 122.30,
126.21, 127.75, 128.33, 135.56, 146.01, 199.52. Anal Calcd for
C25H34N2S: C, 76.09%; H, 8.68%; N, 7.10%; S, 8.12%. Found: C,
76.34%; H, 8.73%; N, 7.36%; S, 8.05%.
Terphenylbisurea (TPbU)
H
N
H
N
Br
Br
O
H2N
OCN
NCO
+
O
N
H
N
H
Br
Biphenylurea with 1-naphthyl group (BPU-1Np)
3
O
O
O
R
R
R
R
O
R
R
N
N
N
N
N
N
R
R
N
N
R
N
R
N
Br
O
Br
Br
O
BPU
N
N
5
N
N
R=C6H13
Br
R
R
R
R
4
R=C6H13
O
BPU-1Np
TPbU
Scheme 4.
Scheme 2.
A mixture of 5 (50 mg, 93 µmol), 1-naphthaleneboronic acid (39
mg, 0.22 mmol), Pd(PPh3)4 (11 mg, 9.3 µmol), K2CO3 (0.10 g,
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10.1002/ejoc.201900191
European Journal of Organic Chemistry
FULL PAPER
0.75 mmol) in toluene (11 mL), ethanol (1.4 mL), and water (1.4
mL) was heated at 90 °C for 17 h. After solvents were removed,
CH2Cl2 and water were added. An aqueous phase was extracted
with CH2Cl2, and combined organic phase was dried over
MgSO4. After evaporating solvents, the crude product was
purified by SiO2 column chromatography using hexane/ethyl
acetate (3/1 in volume) (Rf = 0.58) as an eluent to obtain
colorless solid BPU-1Np in 33 mg (56% yield). Mp: 158.1–
2H), 4.27 (m, 2H), 7.20–7.27 (m, 2H), 7.34 (m, 4H), 7.39–7.50
(m, 6H), 7.53 (d, J = 1.22 Hz, 2H), 7.61 (m, 4H), 7.92–8.05 (m,
4H) 8.44 (s, 2H). 13C-NMR (101 MHz, CDCl3) δ ppm 14.14,
22.61, 26.10, 27.61, 31.34, 47.90, 121.68, 125.10, 125.43,
125.64, 126.49, 126.59, 126.79, 128.34, 128.44, 130.27, 130.37,
130.79, 131.22, 131.27, 131.29, 134.20, 135.54, 135.93, 143.30,
165.57. Anal Calcd for C53H50N2O·2.3H2O: C, 82.41%; H, 7.13%;
N, 3.63%; O, 6.84%. Found: C, 82.47%; H, 6.75%; N, 3.50%. IR
158.7 °C. 1H-NMR (400 MHz, CDCl3) δ ppm 0.70–0.79 (m, 6H), (ATR) 1665 cm-1 (C=O).
1.04–1.18 (br, 12H), 1.42–1.55 (m, 4H), 3.58 ( , 2H), 4.16
, 2H), 7.33–7.54 ( , 12H), 7.64 ( , J = 1.96 H , 2H), 7.81–
7.94 (
, 6H). 13C-NMR (101 MHz, CDCl3) δ ppm 14.01, 22.61,
m
(
m
m
d
Z
m
Acknowledgements
26.15, 27.59, 31.22, 47.83, 121.39, 125.38, 125.80, 125.85,
126.17, 127.07, 127.84, 128.38, 129.75, 130.02, 131.61, 133.82,
134.13, 137.44, 139.30, 143.05, 165.48. Anal Calcd for
C45H46N2O·0.6H2O: C, 84.23%; H, 7.41%; N, 4.37%; O, 3.99%.
Found: C, 84.24%; H, 7.54%; N, 4.15%. IR (ATR) 1664 cm-1
(C=O).
This work was performed under the Cooperative Research
Program of “Network Joint Research Center for Materials and
Devices: Dynamic Alliance for Open Innovation Bridging Human,
Environment and Materials”. The computations were performed
using Research Center for Computational Science, Okazaki,
Japan.
Biphenylurea with 2-naphthyl group (BPU-2Np)
Keywords: urea • conjugated oligomers • direct arylation •
chiroptical properties • axial chirality
O
O
R
R
R
R
N
N
N
N
[1]
[2]
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1455.
Br
Br
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5632.
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R=C6H13
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BPU-2Np
Scheme 5.
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[8]
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,
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, 4H), 7.74–7.83 ( , 4H), 7.84–7.98 (
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, 6H), 1.05 (br, 12H), 1.44 (
, J = 8.56 H , 2H), 7.46–
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2H). 13C-NMR (101 MHz, CDCl3) δ ppm 13.87, 22.51, 26.15,
27.59, 31.16, 47.76, 122.03, 125.41, 125.73, 126.07, 126.46,
127.13, 127.34, 127.71, 128.20, 128.60, 132.67, 133.71,
134.76, 137.62, 137.86, 143.15, 165.33. Anal Calcd for
C45H46N2O·0.35H2O: C, 84.83%; H, 7.39%; N, 4.40%; O, 3.39%.
Found: C, 84.84%; H, 7.21%; N, 4.34%. IR (ATR) 1651 cm-1
(C=O).
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M. Mayor, Org. Biomol. Chem. 2011, 9, 86–91.
O
O
R
R
R
R
[13] J. Rotzler, H. Gsellinger, A. Bihlmeier, M. Gantenbein, D. Vonlanthen,
D. Häussinger, W. Klopper, M. Mayor, Org. Biomol. Chem. 2013, 11,
110–118.
N
N
N
N
Br
Br
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5
R=C6H13
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BPU-Ant
Scheme 6.
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1Np from 5 and 9-anthraceneboronic acid as colorless solid in
76% yield. Mp: 216.0–218.9°C. 1H-NMR (400 MHz, CDCl3) δ
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10.1002/ejoc.201900191
European Journal of Organic Chemistry
FULL PAPER
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FULL PAPER
Entry for the Table of Contents
FULL PAPER
Axial chirality: Six non-planar and
urea-bridged conjugated oligomers
were synthesized through palladium-
catalyzed intramolecular direct
Koji Takagi,* Yuto Hirano, Koichiro
Mikami,* Shoko Kikkawa, and Isao
Azumaya
O
O
C6H13
C6H13
C6H13
C6H13
Page No. – Page No.
arylation and their chiroptical
N
N
N
N
properties were investigated in detail.
Chiral Non-Planar Oligophenylenes
bridged by Urea Linkage: Synthesis
through Intramolecular Direct
Arylation, Chiroptical Behavior, and
Theoretical Investigation
S
S
25 ℃
C6H13
C6H13
C6H13
C6H13
N
N
N
N
Key Topic: Axial chirality
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