Selective Activation of Aromatic Aldehydes Promoted by Dispersion Interactions: Steric and Electronic Factors of a π-Pocket within Cage-Shaped Borates for Molecular Recognition

Article abstract of DOI:10.1002/chem.202003594

Selective bond formations are one of the most important reactions in organic synthesis. In the Lewis acid mediated electrophile reactions of carbonyls, the selective formation of a carbonyl–acid complex plays a critical role in determining selectivity, wh

Full text of DOI:10.1002/chem.202003594

Accepted Article
Accepted Article
Title: Selective Activation of Aromatic Aldehydes Promoted by
Dispersion Interactions: Steric and Electronic Factors of a π-
Pocket within Cage-Shaped Borates for Molecular Recognition
Authors: Daiki Tanaka, Yuya Tsutsui, Akihito Konishi, Koichi Nakaoka,
Hideto Nakajima, Akio Baba, Kouji Chiba, and Makoto
Yasuda
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.202003594
Link to VoR: https://doi.org/10.1002/chem.202003594
01/2020

10.1002/chem.202003594
Chemistry - A European Journal
RESEARCH ARTICLE
Selective Activation of Aromatic Aldehydes Promoted by
Dispersion Interactions: Steric and Electronic Factors of a -
Pocket within Cage-Shaped Borates for Molecular Recognition
Daiki Tanaka,[a] Yuya Tsutsui,[a] Akihito Konishi,*[a,b] Koichi Nakaoka,[a] Hideto Nakajima,[a] Akio Baba,[a]
Kouji Chiba,[c] and Makoto Yasuda*[a]
[a]
D. Tanaka, Y. Tsutsui, Dr. A. Konishi, K. Nakaoka, Dr. H. Nakajima, Prof. Dr. A. Baba, Prof. Dr. M. Yasuda
Department of Applied Chemistry
Graduate School of Engineering
Osaka University
2-1 Yamadaoka, Suita, Osaka 565-0871, (Japan)
E-mail: yasuda@chem.eng.osaka-u.ac.jp
a-koni@chem.eng.osaka-u.ac.jp
[b]
[c]
Dr. A. Konishi
Center for Atomic and Molecular Technologies
Graduate School of Engineering
Osaka University
2-1 Yamadaoka, Suita, Osaka 565-0871, (Japan)
Dr. K. Chiba
Material Science Division
MOLSIS Inc.
1-28-38 Shinkawa, Chuo-ku, Tokyo 104-0033, (Japan)
Supporting information for this article is given via a link at the end of the document.
–
Abstract: Selective bond formations are one of the most important
reactions in organic synthesis. In the Lewis acid–mediated
electrophile reactions of carbonyls, the selective formation of a
carbonyl–acid complex has played a critical role in determining
selectivity, which is based on the difference in the coordinative
interaction between the carbonyl and Lewis acid center. Although
this strategy has attained progress in selective bond formations, the
discrimination between similarly sized aromatic and aliphatic
carbonyls that have no functional anchors to strongly interact with
the metal center still remains a challenging issue. In this manuscript,
we alternatively focus on the molecular recognition driven by
dispersion interactions within some aromatic moieties. We designed
a Lewis acid catalyst with a -space cavity, which was referred to as
a -pocket, as the recognition site for aromatic carbonyls. The cage-
shaped borates 1B with various -pockets demonstrated significant
chemoselectivity for aromatic aldehydes 3b–f over the aliphatic 3a in
the competitive hetero Diels-Alder reactions. The effectiveness of
our catalysts was also evidenced by intramolecular recognition of the
aromatic carbonyl within a dicarbonyl substrate. The mechanistic
and theoretical studies demonstrated that the selective activation of
aromatic substrates is driven by the preorganized step with a larger
dispersion interaction rather than the rate-determining step of the C–
C bond formation, and this likely contributes to the preferred
activation of aromatic substrates over aliphatic ones.
bonding,[4–6] –  and ion/lone pair– interactions[12–16] is one
of the promising approaches for selective transformation of
organic molecules.[17],[18] In biological systems, enzymes utilize
hydrogen bonding as one of the major catalytic factors that
selectively recognize substrates and facilitate chemical
transformations. Notably, mimicking geometric and electronic
structures of enzymes has provided many small organic
molecules that possess potent catalytic activities,[19–22] which
realizes the regio-, chemo-, and stereoselective transformations
of fine chemicals.[23–25]
Introduction
The development of selective bond-forming reactions has
been an important subject in organic synthesis. Use of non-
covalent interactions, such as hydrogen bonding,[1–3] halogen
1
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10.1002/chem.202003594
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RESEARCH ARTICLE
(A) Our concept of a catalyst having a -pocket as a molecular recogniꢀon site
" -pocket"
" -pocket"
B
O
M
O
L
O
L
Aldehyde
o
+
L
M
L
m
L
L
M
p
Cage-shaped
metal complex
H
1b
B
blocked
Clathrate substructure
Cage-shaped metal complex
bearing -pocket
B
O
O
o
O
m
Cage-shaped borate
p
H
1a
B
(B) Our previous work: Aromaꢀc selecꢀvity catalyzed 1bB (ref.52)
O
O
1a
1b
catalyst
yield / %
B·thf
B·thf
H
3a
O
O
OMe
4a
+
(1 mmol)
73
71
catalyst (10 mol%)
CH2Cl2, rt, 4 h
+
+
4a 4b
+
O
(
)
O
Me3SiO
4a 4b 52:48 30:70
/
H
2
(1 mmol)
4b
3b
(1 mmol)
(C) This study: Electronic and steric effects of a -pocket on the aromaꢀc selecꢀvity
(I) Changing the number of the ortho-phenyl groups
B
B
H
B
H
B
O
O
O
O
O
O
O
O
O
O
O
O
o
m
p
H
H
1a
1b
1c
1d
B
B
B
B
(II) -Pocket built by various aryl groups
Ar
Ar
Ar
Ar
CH3
CN
tBu
CF3
=
B
O
O
O
o
1e
1h
1f
1i
1g
m
p
SiMe3
H
1e j
B
1j
(III) without -Pocket but with three alkyl groups
Synthesis
Lewis acid catalyst
Kineꢀc study
B
O
O
O
o
m
p
DFT calculaꢀons
H
1k
B
Figure 1. (A) Our concept of the design for the cage-shaped borate with a -pocket. (B) Our previous result for the aromatic selective hetero Diels-Alder reaction
of 2 with 3 catalyzed by 1aB or 1bBꞏthf. (C) Molecular structures of 1B described in the manuscript to investigate the electronic and/or geometric effect of a -
pocket on molecular recognitions.
Lewis acid–mediated electrophilic reactions of carbonyls
are the most fundamental and important reactions for carbon–
carbon bond formations that construct many useful molecules.[26]
The coordination of carbonyl groups to Lewis acids exerts a
dramatic effect on the rates and selectivities of the reactions at
the carbonyl center.[27] The Lewis acidity of the metal center and
heteroatom as well as coordinative interactions can work as the
principal interaction for molecular recognition.[28] This selective
formation of
a carbonyl–acid complex has realized the
chemoselective functionalization of carbonyl compounds.[29–32]
Several accomplishments of the chemoselective transformation
of carbonyls have become available, based on the size of
reagents,[33–39] the difference in the Lewis basicity of
carbonyls,[38,40,41] and the use of the supramolecular donor-
the geometric features of ligands play
a critical role in
determining selectivities. Binding between the metal and
2
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10.1002/chem.202003594
Chemistry - A European Journal
RESEARCH ARTICLE
acceptor interactions.[42] However, the discrimination between
similarly sized aromatic and aliphatic aldehydes that have no
functional anchors to strongly interact with the metal center still
remains a challenging issue[41,43,44] due to the lack of suitable
methodologies including the developments of acceptable
catalytic systems.
on the step of substrates approaching the metal center, which
leads to the preferred selectivity of aromatic aldehydes.
Results and Discussion
Synthesis
For extrication from this problem, we have focused on
clathrate structures, which can embed the Lewis acid center into
the -space cavity (Figure 1A). The -space surrounding the
metal center of the Lewis acid is referred to as a -pocket.
Aromatic components with a -pocket can behave as a host unit
and should mainly distinguish aromatic over aliphatic aldehydes
as guest molecules through multipoint aromatic–aromatic non-
covalent interactions involving – stacking, CH– interactions
and CH–CH interactions, which are typified by London
dispersion.[44–51] The molecular recognition ahead of the usual
carbonyl-acid interaction capturing certain aldehydes leads to
the chemoselective transformation of aromatic aldehydes over
aliphatic ones. On the basis of the design concept, a cage-
shaped borate 1aB has been identified as a key framework
(Figure 1A).[52],[53] Our previous study demonstrated that the
ortho-phenyl substituted cage-shaped borate 1bB catalyzed the
chemoselective hetero Diels-Alder reaction of Danishefsky's
diene 2 with a mixture of aldehydes 3a/3b (Figure 1B).[54] The
borate 1bBꞏthf selectively activated benzaldehyde 3b over
butanal 3a in a competitive reaction to give the corresponding
adducts (4a/4b) in a ratio of 30:70. The chemoselectivity did not
appear when loading the borate 1aBꞏthf, which has no -pocket.
This selectivity was the first example where an aromatic
aldehyde was recognized over an aliphatic one in a catalytic
manner. Within 1bB, the three phenyl groups built a -pocket
around the B atom of the Lewis acid center, which may function
as the site for molecular recognition. The preferential recognition
of aromatic aldehydes over aliphatic ones might be driven by
aromatic–aromatic interactions among -pocket components
and aldehydes; however, further insights into the mechanistic
details remain elusive. Scoping the generality of the
chemoselectivity and evaluating its origin should allow for the
discovery of novel catalytic design based on the concept of the
-pocket.
The cage-shaped borates having either no -pocket
(1aBꞏL; L = ligand: THF or pyridine) or a -pocket (1bBꞏL) were
synthesized according to our previous studies.[52],[55] In Scheme
1A, the synthetic route of the partially phenyl substituted cage-
shaped borates 1cBꞏL and 1dBꞏL are represented. Ortho-
lithiation of anisole derivatives followed by treatment with N,N-
dimethylcarbamoyl chloride gave the benzophenone derivative
5.[60] The introduction of the third aromatic group was conducted
by treating 5 with anisyllithium salts to afford the triarylmethanol
derivative 6. The treatment of 6 with chlorodimethylsilane in the
[61]
presence of a catalytic amount of InCl3
gave the reduced
compound 7. The triphenol derivatives 1c/dH3 were obtained
after treatment of 7 with BBr3. The reaction of 1c/dH3 with
BH3·thf generated cage-shaped borates 1c/dB·thf as a THF
complex.
The feasible scrutiny of the modulated -pocket on
chemoselectivity required the late-stage diversification of the
tripodal ligand for the cage-shaped borates bearing various
aromatic group at the ortho-positions. The presence of three
ortho-bromo groups in precursor 9 of the tripodal ligand is
suitable for the introduction of various aromatic or aliphatic
substituents through transition metal–catalyzed coupling
reactions. The synthetic route for the cage-shaped borates 1e–
jH3 with various ortho-aryl groups is shown in Scheme 1B. After
methylation of the hydroxyl group of 2,6-dibromophenol, the
monolithiation of 1,3-dibromo-2-methoxybenzene followed by
treatment with ethyl chloroformate gave ortho-brominated
triarylmethanol 8. The use of less than a stoichiometric amount
of nBuLi suppressed the undesirable dilithiation. The treatment
of 8 with chlorodimethylsilane in the presence of a catalytic
[61]
amount of InCl3
gave the reduced compound 9. The
The high accessibility of the tripodal ligand has ensured
that the chemical modifications of cage-shaped Lewis acids,
which lead to fine control of the Lewis acidity,[55],[56] enables a
variety of catalytic activities.[57–59] The feasibility of the chemical
modifications of the complex 1bB prompted us to investigate the
electronic and/or geometric effect of a -pocket on molecular
recognition. For assessment of these factors, we designed the
three types of cage-shaped borates by changing the ortho-
substituents. The first derivatives (1aB, 1bB, 1cB, and 1dB)
have varying numbers of ortho-phenyl groups from zero to three,
making a non-, partially, and fully constructed -pocket (Figure
1C-I). The second derivatives (1bB and 1e–jB) have the -
pocket built by various aryl groups with electron-
donating/withdrawing or bulky substituents, creating an
electronically and sterically perturbed -pocket (Figure 1C-II).
The third derivative (1kB) has no -pocket but a space built by
three alkyl groups (Figure 1C-III). The synthesis and
characterization of these derivatives of cage-shaped borates,
including competitive reactions, kinetic studies, and quantum
chemical calculations, demonstrate that the geometric and
electronic environments of a -pocket have a significant impact
introduction of aromatic groups into 9 was carried out under
Suzuki-Miyaura coupling conditions. The palladium-catalyzed
coupling of 9 with various arylboronic acids having electron-
donating/withdrawing and bulky substituents proceeded to give
the ortho-arylated triarylmethane derivative 10. Changing the
arylboronic acids into tributylborane under the palladium-
catalyzed
coupling
conditions[62]
furnished
tributylated
triarylmethane 11. The triphenol derivatives 1e–kH3 were
obtained after treatment of 10/11 with BBr3 or 1-
dodecanethiol.[63] The reaction of 1e–kH3, with BH3·thf,
generated the cage-shaped borates 1e–kB·thf (Scheme 1B). All
1
cage-shaped borates were fully characterized by H, 13C, and
11B NMR spectroscopies.
3
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RESEARCH ARTICLE
(A) Synthesis of the cage-shaped borates 1cB·L and 1dB·L
OMe
Li
R2
R2
R2
HSiClMe2
cat. InCl3
i) nBuLi
TMEDA
OMe
OMe O
OMe
OMe
OMe
OMe
OMe
(R2 = Ph or H)
R1
R1
R1
R1
R1
O
ii)
H
OH
5
MeO
MeO
Cl
NMe2
1
R1
=
Ph
H
R
=
R1
6
R1
7
c
d
:
:
57%
76%
Ph
H
R1
=
c
d
c
d
:R1 = Ph, R2 = H 36%
:R1 = Ph, R2 = H 79%
:R1 = H, R2 =Ph 56%
:R1 = H, R2 =Ph 75%
R2
THF
1R1
R
B
R2
OH
OH
O
O
BBr3
BH3·thf
O
R1
H2
H
HO
CH2Cl2
R1
H
1c
B·thf
1c d
-
H3
quant.
quant.
(R1 = Ph, R2 = H)
:R1 = Ph, R2 = H 56%
:R1 = H, R2 =Ph 72%
c
d
1d
B·thf
(R1 = H, R2 = Ph)
(B) Synthesis of the cage-shaped borates 1e–kB·L
Br
Br
HSiClMe2
cat. InCl3
MeI
K2CO3
OH
OMe
OMe
OMe
OMe
OMe
i) nBuLi
Br
Br
Br
Br
Br
Br
O
ii)
H
MeO
9
OH
Cl OEt
MeO
8
99%
Br
Br
47%
83%
Ar
Ar
THF
Ar-B(OH)3
BBr3
or
CH3(CH2)11SH
Pd(OAc)2
SPhos
B
Ar
O
CH3
CN
OMe
OMe
OH
OH
Ar
Ar
Ar =
O
BH3·thf
O
e
g
f
Ar
Ar
H2
CH2Cl2
Na2CO3
toluene/EtOH/H2O
H
H
CF3
SiMe3
MeO
HO
h
H
Ar
Ar
1e j
- H3
10
1e j
- B·thf
tBu
up to 98%
up to quant.
quant.
i
j
nBu
nBu
BnBu3
Pd(OAc)2
SPhos
THF
Py
nBu
nBu
nBu
O
B
B
nBu
nBu
nBu
O
OMe
OMe
nBu
OH
OH
nBu
O
O
BH3·thf
BBr3
i) pyridine (Py)
ii) evaporation
O
O
nBu
nBu
K3PO4
toluene/H2O
H2
CH2Cl2
H
H
MeO
HO
H
H
1k
H3
90%
11
97%
1k
B·thf
quant.
1k
B·py
quant.
Scheme 1. Synthetic routes for cage-shaped borates of (A) 1cB∙L and 1dB∙L and (B) 1e–kB∙L.
Figure 2. Ortep drawings of cage-shaped borates 1bB∙thf, 1dB∙thf, 1eB∙thf, 1jB∙thf, and 1kB∙py with 50% probability ellipsoids. Some hydrogen atoms are omitted
for clarity. (A) Side view and (B) top view.
4
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RESEARCH ARTICLE
Molecular geometries and Lewis acidity of
cage-shaped borates having a -pocket
contributed to the gradual shift of the energy level of the LUMOs,
providing precise control of the Lewis acidity of the cage-shaped
borates having a -pocket (Figure S7).
First, we examined the molecular geometries and the
fundamental catalytic activity of cage-shaped borates with a -
pocket. Cage-shaped borates 1bB∙thf, 1dB∙thf, 1eB∙thf, 1jB∙thf,
and 1kB∙py gave crystals of sufficient quality to be analyzed as
single-crystal structures. The ORTEP drawings of the cage-
shaped borates are shown in Figure 2 and the selected
geometrical parameters and tetrahedral character (THC)[64] of
the boron atom are summarized in Table 1.
Table 2. Estimation of Lewis acidity and LUMO level.
borate 1
ortho-group
within 1B
(C=O)[a]
LUMO[b]
/ eV
/ cm–1
1aB·thf
1bB·thf
1eB·thf
1fB·thf
1gB·thf
1hB·thf
1iB·thf
1jB·thf
1kB·thf
non
C6H5
13.7
13.9
14.5
17.4
15.7
14.0
14.0
16.2
13.7
–0.79
–1.16
–1.05
–2.20
–1.76
Table 1. Summary of selected bond lengths, angles, and tetrahedral character
(THC) of the boron atom for 1bB∙thf, 1eB∙thf, 1jB∙thf, and 1kB∙py.
1bB∙thf
2.946
1dB∙thf
2.968
1eB∙thf
1jB∙thf
2.916
1kB∙py
3.003[a]
p-CH3C6H4
p-CNC6H4
p-CF3C6H4
p-SiMe3C6H4
p-tBuC6H4
p-PhC6H4
nBu
B–C1 / Å
2.950[a]
B–OTHF
(NPy) / Å
1.594(2)
1.592(2)
1.592(2)[a]
1.597(2)
1.544(2)[a]
114.3(1)
54.1
[c]
-
O–B–O
114.9(1)
48.2
114.9(1)
48.5
114.8(2)
49.6
114.8(1)
50.0
/ °[a]
[c]
-
THC / %
–1.40
–0.63
[a] Mean values.
[a] The stretching frequency of the carbonyl of free 12 appears at 1670.1 cm–1
[b] The calculations were conducted at the B3PW91/6-31+G**//B3PW91/6-
31G** level. The coordinated THF was omitted for the calculations. [c] The
structural optimizations failed due to the high cost of the calculations.
.
No significant structural differences were observed in the
molecular geometries of 1bB∙thf, 1dB∙thf, 1eB∙thf, 1jB∙thf, and
1kB∙py, as shown in Table 1. This observation indicates that the
steric and/or electronic effects of the ortho-substituents on
molecular geometry is quite small. The ligand on the B atom
slightly influenced the THC values; the pyridine complex of
1kB∙py exhibited a somewhat larger THC (54.1%) than those of
the THF complexes (~49%).
To test the catalytic activity of the borates with -pockets,
we used the borates as catalysts in the hetero Diels-Alder
reaction with 1,3-butadiene 13 and 4-methoxybenzaldehyde 3c
(Table 3 and S1). The conventional Lewis acids, such as
B(OPh)3 and BF3ꞏEt2O, did not catalyze the reaction (Table S2).
The Lewis acidity of these conventional Lewis acids would be
too weak to activate the substrates or too strong to dissociate
from the products. Both situations are unfavorable to
establishing the catalytic reaction system. The borate 1aB·thf
without a -pocket also exhibited no catalytic activity (entry 1). In
contrast, the borates with a -pocket demonstrated catalytic
activities (entries 2–6). The yield of the adduct 14 approximately
correlates with the order of the Lewis acidity, which is estimated
by IR measurements of the applied borate catalyst (1aB < 1bB <
1iB < 1eB < 1gB < 1jB). Notably, the borates with a -pocket
around the B atom furnished sufficient yields, which implies that
the distinctive cage-shaped structure plays an important role in
enhancing the catalytic activity. The borates of 1gB·thf and
1jB·thf demonstrated high catalytic activities despite the low
reactivity of the electron-rich aldehyde 3c. The modifications of
the -pocket at distant positions from the B atom center can
impact the catalytic activity of cage-shaped borates.
In contrast to the structural similarity of these cage-shaped
borates, the Lewis acidity of the cage-shaped borates 1bB and
1e–kB, which are the analogues bearing three aromatic
substituents at the ortho-positions, gradually shifted depending
on the introduced substituents. The Lewis acidity was evaluated
via the infrared (IR) stretching frequency of 2,6-dimethyl--
pyrone 12 ligated to the complex, as shown in Table 2. The
stretching frequency of the carbonyl (C=O) in 12 clearly shows
the degree of Lewis acidity. The larger (C=O) values mean
higher Lewis acidities. The electron-donating groups (1eB: p-
CH3; 1hB: p-SiMe3; 1iB: p-tBu) on the -pocket exhibited a small
shift of  values compared to that of 1bB. In contrast, the
introduction of electron-withdrawing groups (1fB: p-CN; 1gB: p–
CF3) and the extension of -conjugation (1jB: p-Ph) on the -
pocket effectively increased the Lewis acidity of borates. The
highest Lewis acidity of 1fB should be derived from both the
electron-withdrawing and -extension features of CN-groups.
The effect of alkyl groups on the shift of the (C=O)value was
minimal; the borate 1kB with three butyl groups exhibited the
same value as that of 1aB. According to our previous studies,
Table 3. Catalytic activity of borates with various -pockets in the hetero Diels-
Alder reaction with 13 and 3c
[52][55][57]
we calculated the LUMO energy levels of the cage-
shaped borates. The calculated LUMO levels at the B3PW91/6-
31+G**//B3PW91/6-31G** level correlated with the experimental
observations. An effective conjugation between the B atom and
the aryl groups of the -pocket was estimated in the LUMO. The
electronic communications between the
surrounding aryl groups including the para-substituents
B atom and the
entry
borate 1
ortho-group
yield of 14[a]
(C=O)
5
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Chemistry - A European Journal
RESEARCH ARTICLE
within 1B
/ %
5
/ cm–1
13.7
13.9
14.5
15.7
14.0
16.2
indicating that two aldehydes 3a and 3b exhibited the same
affinities with the B center (Figure 3A). Next, fully or partially
ortho-phenyl substituted cage-shaped borates 1bB·thf, 1cB·thf,
and 1dB·thf were examined (Figures 3B–D). Although the
catalytic activity was irreverent to the whether there were one or
two or three (the total yields [4a+4b] were similar among all
entries in Figure 3), the selective ratio of 4a/4b was highly
dependent on the structural integrity of the -pocket. The
significant selectivity of 3b over 3a appeared only in the catalytic
system of the borate 1bB having the fully constructed-pocket
(4a/4b = 30:70). The others, having the partially constructed -
pockets exhibited no selectivity, which is comparable to that of
1aB (4a/4b = 52:48) having no -pocket (51:49 (1cB); 54:46
(1dB)).
1
2
3
4
5
6
1aB·thf
1bB·thf
1eB·thf
1gB·thf
1iB·thf
1jB·thf
non
C6H5
43
49
96
38
73
p-CH3C6H4
p-CF3C6H4
p-tBuC6H4
p-PhC6H4
[a] Yields were determined by 1H NMR measurement using 1,1,2,2-
tetrachloroethane as an internal standard.
Effect of the number of phenyl groups for the
-pocket on aromatic selectivity
Effect of the electronically and sterically
perturbed -pocket on the selectivity for
aromatic compounds
Figure 3. Competitive hetero Diels-Alder reaction between 3a and 3b
catalyzed by cage-shaped borates 1aB, 1bB, 1cB, and 1dB. Yields were
determined by 1H NMR measurement using 1,1,2,2-tetrachloroethane as an
internal standard.
Secondly, we investigated the importance of -pocket
structure around the B center by using a series of borate
catalysts 1aB, 1bB, 1cB, and 1dB. To test chemoselectivity, we
used these borates as catalysts in a competitive hetero Diels-
Alder reaction of Danishefsky’s diene 2 with a mixture of 3a and
3b. This competitive cycloaddition had already served as a
model reaction previously (Figure 1B).[54] Because butanal 3a
and benzaldehyde 3b have similar steric demands,[65] the
competitive reaction between these aldehydes with
Danishefsky’s diene 2 would be a suitable combination of
substrates to investigate chemoselectivity.
The yields with a ratio of 4a/4b in the competitive hetero
Diels-Alder reaction are summarized in Figure 3. As previously
reported, the cage-shaped borate 1aB·thf having no -pocket
gave the products in a 73% yield with the ratio of 52:48,
6
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10.1002/chem.202003594
Chemistry - A European Journal
RESEARCH ARTICLE
Figure 4. Observed chemoselectivity in competitive hetero Diels-Alder
reaction between 3a and various benzaldehyde derivatives 3b–f.
trends were observed in the reactions catalyzed by the borates
1eB and 1jB with the methylated and phenylated -pocket,
respectively (Figures 4C and H). These observations imply that
an electron-rich -pocket assists with some electrostatic
interactions,[7],[66] such as donor-acceptor or dipolar interaction,
with aromatic aldehydes, realizing high chemoselectivity.
Next, we examined the effect of the electronically or
sterically perturbed -pocket on the selectivity of aromatic
aldehydes. The borates 1bB and 1e–jB were used as catalysts
in the competitive hetero Diels-Alder reactions between 3a and
various benzaldehyde derivatives 3b–3f with Danishefsky’s
diene 2. These results should provide valuable information on
the interaction between the aromatic groups for the applied -
pockets and aldehydes. A total of 45 reactions was investigated.
The summary for the yields of the adducts (4a+4b–f) is shown in
Table S3. All reactions were sufficiently catalyzed by the borates
to give the adducts in acceptable yields, thus, we herein
concentrated on the chemoselectivity of 3b–3f over 3a.
The observed chemoselectivity between aliphatic (3a) and
aromatic (3b–f) aldehydes is depicted in Figure 4. The borate
1aB without a -pocket exhibited no selectivity for aromatic
aldehydes 3b–e, which tends to be a low preference of aliphatic
aldehyde 3a (Figure 4A). For 4-cyanobenzaldehyde 3f,
moderate chemoselectivity for the aromatic aldehyde appeared,
which might be caused by the high reactivity of 3f induced by the
low LUMO energy level. In contrast to the results of 1aB·thf, the
cage-shaped borates with various -pockets 1bB·thf and 1e–
jB·thf demonstrated the significant chemoselectivity of aromatic
aldehydes 3b–f over 3a (Figures 4B–H). The following
noteworthy aspects are represented.
(i) The Lewis acidity of borates is indirectly correlated with
the observed selectivity of the aromatic aldehydes. While the
borate 1fB with the highest Lewis acidity gave moderate
selectivity for all aldehydes (Figure 4D), the borate 1eB with
moderate Lewis acidity among them showed high selectivity for
a wide range of aromatic aldehydes (Figure 4C). The highest
selectivity for 3f (4a/4f = 4:96) yielded by 1eB was comparable
to the one previously reported.[54] These results suggest that the
observed selectivity is determined by the approaching steps of
the substrates to the B center rather than the generation steps of
carbonyl–acid complexes.
However, the borate with
a
-pocket with electron-
donating/withdrawing groups does not always exhibit preferential
activation of the aromatic aldehyde with electron-
withdrawing/donating groups. For the borate 1eB with the
methylated -pocket, a better selectivity for the electron-rich
aldehyde, 4-methoxybenzaldehyde 3c, was observed compared
with those catalyzed by the other borates (Figure 4C). The
catalytic systems of 1fB with the cyanated -pocket and 1gB
with the trifluoromethylated -pocket showed low selectivity for
the electron-rich aldehydes 3c and 3d (Figures 4D and E).
These results suggest that other non-covalent interactions, such
as CH– and – stacking interactions, play a more important
role in selectivity.
(iv) The three aromatic panels are essential for
determining the chemoselectivity of aromatic aldehydes over
butanal 3a. The borate 1kB that has three butyl groups instead
of aromatic groups for the -pocket showed no chemoselectivity
towards aromatic aldehydes 3b–d over 3a (Figure 4i). Even
when the aldehydes 3e and 3f with electron-withdrawing groups,
which are apt to show the selectivity of aromatic aldehydes,
were employed, the preferences of these aldehydes over 3a
were constrained compared with the reactions catalyzed by
other borates with -pocket moieties. These results strongly
indicate that merely introducing some substituents into the ortho-
positions of the borate is not necessary nor sufficient for the
selectivity of aromatic aldehydes. The presence of the three
aromatic panels around the B center is an essential factor to
give the observed chemoselectivity of aromatic substrates.
Table 4. Kinetic studies for hetero Diels-Alder reaction.
(ii) Steric hindrance on a -pocket has a small impact on
selectivity. The borates 1hB and 1iB, which have the large
substituents on the -pockets, showed comparable selectivity to
that of 1bB (Figures 4F and G). The uptake of substrates into
the -pocket is not inhibited by these large substituents.
(iii) The electrostatic interaction between the -pocket and
substrates might be effective for selectivity but the selectivity
depends on the combination of borates and aldehydes. We
previously reported that high selectivity was attained when
applying the electron-poor aromatic aldehydes, such as 3e and
3f, to the reactions catalyzed by 1bB (Figure 4B). The same
entry
borate
1
aldehyde
H‡
S‡
G‡(298 K)
/ kcalꞏmol–1
3
/ kcalꞏmol–1
/ calꞏ(Kꞏmol)–1
1
2
3
4
3a
3b
3a
3b
3.15
3.95
7.02
7.51
–54.1
–55.6
–41.2
–40.6
19.3
20.5
19.3
19.6
1aB·thf
1bB·thf
7
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RESEARCH ARTICLE
Figure 5. The energy profiles of the hetero Diels-Alder reaction of 2 with 3a or 3b catalyzed by (A) 1aB or (B) 1bB. DFT calculation was performed using
B97XD/def2svp. Solvation effect was introduced using the IEFPCM model, and dichloromethane was used as a solvent.
To gain further insights into the chemoselectivity of 3b over 3a,
kinetic studies of the hetero Diels-Alder reactions of 2 with 3a/b
catalyzed by borates 1a/bB·thf were conducted using in situ
React IR spectroscopy. Kinetic parameters were assumed by
monitoring the decay of the ν(C=O) of aldehyde 3 around 1700
cm–1 in the reaction mixture in CH2Cl2 (Figure S6). The detailed
reaction profiles are summarized in the Supporting Information.
All reactions obey the first order for 2, aldehyde 3, and the
borate 1B·thf (rate = kobs[2]1[3]1[1B·thf]1); the reaction order was
irrelevant of the types of aldehydes and borates. The estimated
activation parameters are summarized in Table 4. No significant
difference in these parameters was observed between the
reactions of 3a and 3b with each borate catalyst (entries 1 vs. 2
or 3 vs. 4). The negative values for the activation entropy (S‡)
suggested that the rate-determining steps of the reactions
include the associative step for the C–C bond formations
between 2 and 3. When comparing the catalysts 1aB and 1bB,
the activation enthalpies (H‡) of 1bB were twice as large as
those of 1aB. These results imply that the initial state driven by
1bB should be energetically more stable than that driven by 1aB.
Considering the small differences in the activation free energy
(G‡), the initial reaction step, which includes the approach of
the substrates to the B center, rather than the rate-determining
stage, would be essential for the observed chemoselectivity of
3b catalyzed by 1bB over 3a catalyzed by 1bB.
8
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Theoretical studies on chemoselectivity
The small difference of the activation free energy (G‡)
between 3a and 3b raises the question regarding the factor that
determines chemoselectivity. To reveal the reaction
mechanisms for the hetero Diels-Alder reactions of 2 with 3a/b
catalyzed by the borate 1a/bB·thf, quantum chemical
calculations at the ωB97XD/def2svp level (including solvent
effect by the IEFPCM model for CH2Cl2) were performed. Figure
5 shows the computational results for the reaction mechanism.
In all reactions, the estimated mechanism consists of three
steps. Initially, the borate 1B activates the aldehyde 3 to give the
carbonyl–acid complex 1B·3 at the IM1 state; subsequently, the
diene 2 approaches the complex 1B·3 to form an inclusion
complex 1B·3⸧2 at the preorganized state IM2 (Step 1). The
addition of diene 2 to the carbonyl of 3 occurs from 1B·3⸧2.
Although a concerted addition is predicted in the non-catalyzed
reaction (Figure S8), the catalyst 1B shifts the mechanism to a
step-wise formation of the two C–C bonds. The first C–C bond
formation passes through a transition state with a small energy
barrier (TS1) to exergonically give the IM3 state (Step 2). The
second C–C bond formation proceeds through a transition state
(TS2), giving rise to the adduct 16 as an adduct–borate complex
1Bꞏ16 (Step 3). The highest activation energy observed at TS2
indicates that Step 3 is the rate-determining step. For reactions
catalyzed by 1aB without a -pocket, the activation energy for
butanal 3a (11.1 kcal/mol at 298 K) is comparable to that of
benzaldehyde 3b (10.3 kcal/mol). In the case of 1bB with a -
pocket, the more both activation energies are lowered, the
slightly larger value of 3b (8.1 kcal/mol) is estimated compared
to that of 3a (5.4 kcal/mol). These low and similar activation
energies between 3a and 3b in the reactions catalyzed by 1bB
illustrate that Step 3 hardly participates in the chemoselectivity
given by the -pocket catalyst 1bB, which agrees with the results
of the kinetic studies (Table 4).
Alternatively, the preorganization from the initial reactants
to the inclusion complex 1B·3⸧2 (Step 1) gives an evocative
difference in the stabilization energy (ES). For the reactions
catalyzed by 1aB without a -pocket, the stabilization energy for
1aB·3a⸧2 (–9.7 kcal/mol) is comparable to that of 1aB·3b⸧2 (–
11.0 kcal/mol). In contrast, the borate 1bB with a -pocket
shows the widening gap of ES between 1bB·3a⸧2 and
1bB·3b⸧2. For the 1bB·3b⸧2, the IM2 state is 5.5 kcal/mol
more stabilized relative to that of 1bB·3a⸧2, which should lead
to the observed chemoselectivity of 3b over 3a (4a/4b = 30:70).
Figure 6. The top views of the inclusion complexes of 1aB·3⸧2 and 1bB·3⸧2
at the IM2 states. The geometries are optimized by B97XD/def2svp with a
IEFPCM model of CH2Cl2. The selected atoms are drawn by a space-filling
model and the others are drawn by a capped sticks model. In the gray boxes,
the inclusion complexes are drawn by a wireframe and a ball and stick model.
The molecular geometries of 1aB·3⸧2 and 1bB·3⸧2 drawn
by a space-filling model are shown in Figure 6. Three aromatic
panels of the -pocket within 1bB nicely encapsulate the
aldehyde 3 and diene 2 (Figures 6C and D). The figure also
suggests that the inclusion complex 1bB·3b⸧2 exhibits a tighter
capsulated structure than that of 1bB·3a⸧2. To obtain further
insights, the non-covalent interactions (NCI) among the -pocket
and the substrates were evaluated by NCIPLOT analysis[67],[68] of
the inclusion complexes 1bB·3⸧2 (Figures 7 and S9–11). For
both inclusion complexes 1bB·3⸧2, two of the three aromatic
panels of the -pocket nicely interact with the diene 2 via –
/CH– contacts and with aldehyde 3 via CH– contacts, which
creates a moderately attractive isosurface (green to blue) area
within the -pocket. The interactions between the diene 2 and
aldehyde 3, which resemble – stacking interactions, is also
shown as a moderately attractive isosurface in both inclusion
complexes. The significant difference in the attractive isosurface
within the -pocket between 1bB·3a⸧2 and 1bB·3b⸧2 was
observed in the interaction between the remaining one aromatic
panel and the aldehyde 3 (magnifications in Figure 7). In
9
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10.1002/chem.202003594
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RESEARCH ARTICLE
1bB·3b⸧2, a moderate CH– interaction between the remaining
one aromatic panel and 3b widely extended the attractive
isosurface area. Conversely, in 1bB·3a⸧2, the attractive contact
between the remaining one aromatic panel and 3a was
insignificant, which led to the looser capsulated structure than
that of 1bB·3b⸧2.
dispersion energy should be effectively gained by multipoint
CH–, –, and CH–CHcontacts,[51,70–75] which stabilize the
preorganized structure and realizes the unique chemoselectivity
of aromatic aldehydes over aliphatic ones. The generation of the
inclusion complex might seemingly be an unfavorable process;
within the complex, the degree of molecular freedom is severely
restricted and the sizable Pauli repulsions among the
components destabilize the structure. Considering the
importance of the integrity of the -pocket in the selectivity of
aromatic aldehyde (Figure 3), the rigid -cavity built by three
aromatic panels is absolutely essential for selectivity. The large
dispersion energies driven by the densely arranged structure at
the IM2 state would compensate for these unfavorable factors,
which assist in molecular recognition and facilitate the
chemoselective reaction.
The appearance of selectivity should require some rapid
exchanges between 3a and 3b on the B atom during the
preorganized period. However, our DFT calculations do not
support the exchange process because the small energy
barriers at the TS1 and TS2 states proved unable to give the -
pocket catalyst enough time to select one aldehyde. The
approaching step of each substrate to the B atom might
accompany some energy barriers for the molecular recognition.
Figure 7. Non-covalent interaction (NCI) plots for (A) 1bB·3a⸧2 and (B)
1bB·3b⸧2. (reduced density gradient [RDG] surfaces = 0.65 a.u. and the color
range blue (attractive)–green–red (repulsive) for –0.018 < ρ < +0.030 a.u.).
Intramolecular recognition of aromatic moiety
The similar non-covalent interactions were also estimated
in the carbonyl–acid complexes 1bB·3 at the IM1 states.
Although no significant attractive contact was observed within
the -pocket of the complex 1bB·3a, the complex 1bB·3b
formed a more attractive isosurface area among the aromatic
panels of the -pocket and 3b (Figures S12–14). During
preorganization (Step 1), the NCI with the -pocket helped the
catalyst 1bB selectively recognize 3b over 3a and import the
diene 2 into the -pocket space. More precise fitting of 3b
compared to 3a into the -pocket of 1bB should lead to a more
stabilized inclusion complex 1bB·3b⸧2 compared to 1bB·3a⸧2.
These experimental and theoretical insights into the
chemoselectivity driven by a -pocket raise the hope of
intramolecular recognition of aromatic moieties. To test the
intramolecular selectivity, the hetero Diels-Alder reactions of 2
with a dialdehyde 17[42] that has both aromatic and aliphatic
carbonyls were investigated. We selected the borates 1bB, 1eB,
and 1jB as catalysts because these borates with -pockets
exhibited high selectivity toward various aromatic aldehydes
(Figure 4). The obtained results are summarized in Table 6. For
all entries, the generation of 18c, the product of the two-fold
cycloadditions of 2 with both carbonyl moieties, was not perfectly
suppressed presumably due to the high reactivity of 17 with 2.
The borate 1aB with no -pocket afforded a mixture of 18a, 18b,
and 18c in a total yield of 61% (entry 1). Importantly, the ratio of
the product 18a/18b was 51:15, illustrating the preference of the
aliphatic carbonyl over the aromatic one. In sharp contrast to the
result, borates with a -pocket moiety showed significant
selectivity toward the aromatic carbonyl (entries 2–4). It should
be noted that the yields of 18b dramatically increased for these
catalytic systems. 1bB showed the double production ratio of
18b to 18a (entry 2). For the catalyst 1eB and 1jB (entries 3 and
Table 5. Summary for the stabilization energy (ES) in the reactions catalyzed
1bB.
entry
inclusion complex
ES
dispersion energy[a]
/ kcal·mol–1
/ kcal·mol–1
1
2
3
4
1aB·3a⸧2
1aB·3b⸧2
1bB·3a⸧2
1bB·3b⸧2
–9.7
–11.0
–24.8
–30.3
–116.6
–127.6
–188.9
–198.4
4), which have
a
methylated or phenylated -pocket,
respectively, an improved selectivity of the aromatic carbonyl
over the aliphatic one (18a/18b) was observed (1eB: 15:66; 1jB:
2:57). The highest selectivity was attained when using a flow
system (entry 5; the details are described in the Supporting
information.). Whilst the total yield was moderate, the generation
of 18c was suppressed and the ratio of 18a/18b dramatically
increased (7:78). The high mixing efficiency in the flow system
even at short reaction time might effectively inhibit undesired
overreactions, giving the high selectivity of 18b over 18a.
[a] Grimme’s D3 dispersion correction with Becke–Johnson (BJ) damping
calculated by the B3LYP/6-31G**//B97XD/def2svp level.
The dispersion energy estimated by the DFT-D3(BJ)
method of Grimme[69] supported these interactions; 1bB·3⸧2
showed a larger dispersion energy than that of 1aB·3⸧2 (Table
5), which should be driven by the close contacts among the -
pocket and substrates. In the capsulated structure, a larger
Table 6. Intramolecular recognition of aromatic carbonyl of 17.
10
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10.1002/chem.202003594
Chemistry - A European Journal
RESEARCH ARTICLE
This work was supported by JSPS KAKENHI (Grant Numbers
JP18H01977 and 20K05464). We acknowledge Prof. I. Ryu and
Prof. T. Fukuyama (Osaka Prefecture University) for valuable
advice regarding flow system synthesis. We also thank Dr. N.
Kanehisa (Osaka University) for valuable advice regarding X-ray
crystallography. Thanks are also due to the Analytical
Instrumentation Facility, Graduate School of Engineering, Osaka
University.
Keywords: cage-shaped borates • Lewis acid catalysts •
molecular recognitions • non-covalent interactions • dispersion
interactions
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Chemistry - A European Journal
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10.1002/chem.202003594
Chemistry - A European Journal
RESEARCH ARTICLE
Entry for the Table of Contents
The cage-shaped borates 1B with various -pockets demonstrated significant chemoselectivity for aromatic aldehydes 3b–f over the
aliphatic 3a in the competitive hetero Diels-Alder reactions. The selective activation of aromatic substrates is driven by the
preorganized step rather than the rate-determining step of the C–C bond formation, in which large dispersion interactions assist the
selective recognitions of aromatic carbonyls over aliphatic one.
13
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