Rational Design of a Metallocatalytic Cavitand for Regioselective Hydration of Specific Alkynes

Article abstract of DOI:10.1002/ejoc.201701613

The synthesis of a functionalized supramolecular cavitand with inwardly oriented Au^I and P=O moieties was explored, including its catalytic proclivity in the selective hydration of internal alkynes. The cavitand works as a supramolecular flask device: Au^I coordinates to the triple bond, the P=O moiety connects with a H₂O molecule, and the cavity favors folding of a single alkynyl side chain. Several tests of different substrate patterns indicated that the cavity was substrate specific, similar to enzymatic catalysis.

Full text of DOI:10.1002/ejoc.201701613

A Journal of
Accepted Article
Title: Rational Design of a Metallo-catalytic Cavitand for Regio-
selective Hydration of Specific Alkynes
Authors: Tetsuo Iwasawa, Naoki Endo, and Mami Inoue
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701613
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701613
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201701613
COMMUNICATION
Rational Design of a Metallo-catalytic Cavitand for Regio-
selective Hydration of Specific Alkynes
[
a]
[a]
[a]
Naoki Endo, Mami Inoue, and Tetsuo Iwasawa*
Abstract:
A
new synthesis of functionalized supramolecular
hidden talent in the 1•AuCl, we have made an investigation into
its performance with adopting hydration reaction of internal
alkynes as a probe reaction.
cavitand with inwardly oriented Au(I) and P=O is described, including
a description of its catalytic proclivity in selective hydration of internal
alkynes. The cavitand works as a supramolecular flask device: the
Au(I) coordinates to the triple bond, and the P=O connects with a
2
H O, and the cavity favored to fold a single alkynyl side-chain.
Several tests of different substrate patterns indicated that the cavity
has substrate specificity like as enzymatic catalysis.
Enzymes are attractive, appealing, and inviting compounds to
synthetic chemists, because they catalyze highly selective
1
transformations under rather mild conditions. Two quintessence
provide chemists a continuing challenge to mimic. One is to
orient metal centers inwardly towards somewhat isolated space:
for example, multiple metals activate otherwise inert molecules
Figure 1. Mono-Au complex cavitand 1•AuCl functionalized with PNMe
O=PNMe in which the two P-N bonds point outside toward the cavity space. A
part of the quinoxaline moiety is colored with gray for ease of viewing.
2
and
2
inside the enclosed cavities. The other is to prepare two or
2
more active sites onto the concave surface of hosts, which
synergistically works to make substrate guest more reactive and
3
selective. Overcoming these formidable challenges perhaps will
allow synthetic chemists to make more significant inroads into
new modes of chemical catalysis and transformations that
4
, 5
enzymes achieve from the viewpoint of green chemistry.
Recently we reported a synthesis of introverted bis-Au
cavitand that is flanked by two quinoxaline walls and based on a
resorcin[4]arene, and found that it catalyzed cross-dimerization
6
of terminal alkynes. The cavitand set the two Au atoms
symmetrically, but each Au trapped a different alkyne; which
brought two alkynes together to result in a cross-dimerization
event. Presumably the enforced cavity would confine fitting
guests in a limited space and properly position them to actively
stabilize the reactive species in transition state. Such a positive
effect drove us to develop a new mono-Au complex 1•AuCl
Scheme 1. Synthesis of 1•AuCl derived from cavitand 1 prepared by mCPBA
oxidation.
(
Figure 1) that is endowed with phosphoramidite (PNMe
phosphoramidate (O=PNMe ); the PNMe works as a supporting
ligand for Au metal, and the O=PNMe would act as an electron-
2
) and
2
2
2
7
donating point for activation of substrates. The question we
continue to pursue is “can the new organometallic-cavitand
framework enable potent chemical transformations?”
We thus synthesized 1 in 24% yield, the result of an
oxidation of parent bis-phosphoramidite cavitand that was
previously reported by our group with elucidation of
8
,6a
crystallographical analysis (Scheme 1).
The double oxidation
of both two phosphorus atoms accompanied in 21% yield, and
the unreacted parent bis-phosphoramidite cavitand remained in
2
5%. Upon reaction of 1 with AuCl•S(CH
3 2
) , the corresponding
9
complex 1•AuCl was prepared in 93% yield. To bring out the
+
Figure 2. Three strategies of 1•Au in mind on selective hydrations of internal
alkynes (the two quinoxaline walls are omitted for ease of viewing); (1)
+
[a]
N. Endo, M. Inoue and Prof. Dr. T, Iwasawa
Department of Materials Chemistry, Ryukoku University
Seta, Otsu, Shiga, 520-2194, Japan
coordination of Au toward the triple bond; (2) hydrogen bonding between P=O
and
substituents.
2
H O; (3) the inner space favorably includes a one side of alkyne
E-mail: iwasawa@rins.ryukoku.ac.jp
http://www.chem.ryukoku.ac.jp/iwasawa/index.html
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
The alkyne hydration reaction to construct the carbonyl
motif with use of water and alkynes is fundamentally important in
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European Journal of Organic Chemistry
10.1002/ejoc.201701613
COMMUNICATION
modern organic synthesis, because it is typically atom-economic
1
0
+
and environmentally benign. Historically, the strong acids of
We wondered whether 1•Au gives us an approach to
1
1
H
2
SO
4
and Hg(II) salts catalyzed the hydration; on the other
solve the simple but profound challenge, and anticipated that
+
hand, recently, (IPr)Au(I)-catalyzed acid-free alkyne hydration
1•Au plays triple roles for the hydration (Figure 2). One, its
1
2, 13
+
was reported by Nolan’s group.
The method is a highly
Lewis acidic Au coordinates the carbon-carbon triple bond. Two,
efficient and useful system for a wide range of alkynes; however,
its fatal drawback is production of terribly regio-isomeric
mixtures when the method is applicable to unsymmetrical
internal alkynes. For example, (IPr)Au(I)-catalyzed hydration of
its Lewis basic O=P would work as a hydrogen bonding acceptor
with a water molecule. Three, the pi-clouded cavity may show
molecular recognition to favorably fold a single side-chain of
alkynes, which could bring highly regio-selective addition of the
2
-octyne yielded mixtures including 51% of 2-octanone and 23%
H
2
O to the unsymmetrical triple bonds.
of 3-octanone. Thus, it is too difficult to discriminate between two
carbon atoms of the triple bond in 2-octyne. Here, a major
challenge remains.
We started to evaluate the catalytic proclivity of 1•AuCl on
hydration of commercially available 1-phenyl-1-butyne (3a): the
reactions with 2 mol% of 1•AuCl and 2.4 mol% of AgOTf were
1
4
carried out in toluene including 5 equiv of distilled water. These
results were summarized in Table 1, noting the results of
Table 1. Evaluation of reactivity of 1•AuCl in selective hydration of 1-phenyl-1-
15
[
a]
(IPr)AuCl and 2 (Figure 3). For entry 1, 1•AuCl consumed all of
butyne 3a as compared to several Au catalysts.
3
a in 1 h at the mild 50 ºC, predominantly producing 98% yield
of 5a. The raise to 80 ºC resulted in the loss of the selectivity,
which gave a 4a:5a ratio of 3:86 (entry 2). For entries 3-6, the
reactivity of mono-AuCl 2 that was flanked by tri-quinoxaline-
spanned resorcin[4]arene was evaluated: 2 lacks the P=O
moiety in 1 and its sealing property is increased. For entries 3
and 4, surprisingly, the hydration hardly occurred: 3a remained
unreacted in more than 78%, and the ketones were scarcely
produced. Although the temperature was raised to 80 ºC (entries
[
b]
temp.
time
/h
%Yield
4a
<2
3
Entry
cat.
Additive
/
ºC
[c]
3
a
5a
98
86
1
5
and 6), the reaction efficiency was not improved. From the
1
2
3
4
5
6
7
8
9
1•AuCl
1•AuCl
2
-
-
-
50
80
50
50
80
80
50
80
50
50
50
50
50
50
1
0.5
1
0
viewpoint of structure-activity relationship, the P=O moiety of 1
0
proved to be important for its catalysis, which indicates the
+
proximity effect in 1•Au between alkyne and water would
82
78
70
72
9
3
accelerate the hydration. For entries 7-10, reactions were
2
O=PPh
3
3
1
3
1
3
carried out with (IPr)AuCl. The aid of O=PPh in entry 9
achieved 68% yield; however, the prolonged reaction time to 4 h
gave a terrible mixture of 16% of 4a and 68% of 5a with
unreacted 3a of 7%. The representative Au precursors of
2
-
0.5
0.5
4
11
10
18
12
16
0
4
2
O=PPh
5
(IPr)AuCl
(IPr)AuCl
(IPr)AuCl
(IPr)AuCl
-
56
44
68
0
-
0.5
4
20
7
O=PPh
O=PPh
-
3
3
1
1
1
1
1
1
2
3
4
5
4
72
78
94
72
92
AuCl•PPh
AuCl•PPh
3
4
1
1
3
O=PPh
-
3
3
4
<1
0
<1
0
AuCl•PPh
3 2
(entries 11 and 12) and AuCl•SMe (entries 13 and
1
4) were not effective.
AuCl•SMe
AuCl•SMe
2
2
4
Figure 3. (IPr)AuCl, and Mono-AuCl 2 tethered to a tri-quinoxaline-spanned
resorcin[4]arene. A part of the quinoxaline moiety was colored with gray for
ease of viewing.
O=PPh
4
0
0
[
a] Conditions: 3a (0.07 mL, 0.5 mmol), H
2
O (0.05 mL, 2.5 mmol), 2 (18 mg,
0
.01 mmol), additive (0.01 mmol), toluene (1 mL). For entries 1, 2, 7-9, the
1
yields were averages of two runs. [b] Determined by H NMR analyses on the
basis of samples that were purified by short-plugged silica-gel column
chromatography (eluent: toluene only). H NMR spectra of 4a and 5a were
Next, we studied the influence of alkyl groups joined to 1-
1
phenyl-1-ethynyl moieties for catalyst capability of 1•AuCl (Table
identical to those of commercially available 1-phenyl-2-butanone and 1-
phenyl-1-butanone, respectively. 3a is volatile owing to hydrocarbons of low
boiling point, and so the samples were carefully dried up for obtaining yields.
2
). Yields and selectivities at 50 ºC for 1 h have been evaluated
for aliphatic substituents of methyl, ethyl, n-propyl, n-butyl, and
+
[
c] Unreacted 3a. [d] Without AgOTf. [e] Only use of AgOTf.
n-heptyl. Although 1•Au could not coordinate to the terminal
triple bond of 3b (entries 1 and 7) owing to the electron-
deficiency, 1•AuCl hydrated 3c (entry 2) and 3a (entry 3) with
near perfect selectivities of products, yielding 5c and 5a in each
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European Journal of Organic Chemistry
10.1002/ejoc.201701613
COMMUNICATION
9
8%. The elongated substrates 3d and 3e caused loss of their
1
0
n-C
n-C
3
4
H
H
7
9
3d
3e
3f
88
61
94
5
11
3
7
28
3
conversion ratios, and finally 3f remained intact. On the other
hand, for entries 8-12 in the use of (IPr)AuCl, neither reaction
progress nor product distributions were good in this mild
condition. These results explain that 1•AuCl is specific for its
reactivity and selectivity in the hydration of 3c and 3a, which
would suggest the methyl and ethyl groups fit well inside the
11
1
2
n-C
7
H
15
[
a] Conditions: alkyne (0.5 mmol), H
for 1•AuCl, and 6 mg for (IPr)AuCl, and 3 mg for O=PPh
2
O (0.05 mL, 2.5 mmol), catalyst (18 mg
, 0.02 mmol), toluene
3
+
1
cavity of 1•Au . Indeed, as illustrated in Scheme 2, the 1•AuCl-
(1 mL). [b] Determined by H NMR analyses on the basis of samples that
were purified by short-plugged silica-gel column chromatography (eluent:
catalyzed hydration of 1-methyl-4-(phenylethynyl)benzene under
the same condition was not observed at all. Thus, the phenyl
moiety in 3a-3f would be difficult to reside in the inner space.
In the same vein, we assessed the shape of octynes that
include unsymmetrical 3-, 2-, 1-octynes, and symmetrical 4-
1
toluene-d
8
only). H NMR spectra of 4c, 5d, 4e, and 5e were identical to those
of commercially available propiophenone, valerophenone, haxanophenone,
and benzyl butyl ketone, respectively. The spectra of 5c and 4d were inferred
from ChemDraw-estimated charts. [c] Unreacted 3a.
2
2
octyne (Table 3). For entries 1 and 2, 3g (R = C
2 5
H ) and 3h (R
=
CH ) were totally converted to the corresponding ketones with
3
predominant formation of 5g (91%) and 5 h (82%). In contrast,
for entry 3 in the use of terminal alkyne 3i, no reaction was
observed. On the other hand, for entries 5-7 utilizing (IPr)AuCl,
the reactions didn’t complete, giving horrible mixtures of 4g/5g
(
13%/23%) and 4h/5h (21%/39%). For entries 4 and 8 in use of
-octyne, 1•AuCl achieved high-yielding transformation of 96%
4
in contrast to (IPr)AuCl that resulted in less 75% yield. These
strongly suggest that different distribution of products 4/5 by
1
•AuCl would be attributed to different strength of host-guest
Scheme 2. Reactivity of 1-methyl-4-(phenylethynyl)benzene at 50 ºC in the
1•AuCl.
interactions between the alkyl moiety and cavity space.
Particularly, methyl and ethyl moieties immediately adjacent to
the triple bond seem to have strong affinity with the space, which
would fix the geometry of the nucleophilic attack of the water
molecule to cause relatively high regio-selectivity of ketone
products. The outstanding product distributions in 3a, 3c, 3g and
Table 3. Influence of isomeric octynes on catalytic hydrations with 1•AuCl and
[a]
(
IPr)AuCl.
3
h mean the cavity has substrate specificity for alkynyl methyl
and ethyl groups.
Table 2. Influence of aliphatic substituents joined to 1-phenyl-1-ethynyl moiety
[
a]
on Au-catalyzed selective hydration.
[
b]
%
Yield
4
1
2
octyne
Entry
cat.
R
R
3
[c]
3
5
1
2
3
4
5
6
7
8
n-C
4
H
9
C
2
H
5
3
3g
3h
3i
0
9
91
82
0
[
b]
%
Yield
alkyne
Entry
cat.
R
n-C
n-C
5
H
H
11
13
CH
0
18
0
3
[c]
3
4
5
1•AuCl
6
H
100
4
1
2
3
4
5
6
7
8
9
H
3b
3c
3a
3d
3e
3f
100
0
0
2
0
n-C
n-C
3
4
H
H
7
9
n-C
3
2
H
7
5
3
3j
96
13
21
26
75
-
CH
3
98
98
33
3
C
H
3g
3h
3i
64
40
74
25
23
39
0
C
2
H
5
0
2
1
•AuCl
(IPr)AuCl
and
n-C
n-C
5
H
H
11
13
CH
n-C
n-C
3
4
H
H
7
9
51
87
100
100
98
70
16
10
0
O=PPh
3
6
H
n-C
3
H
7
n-C
3
H
7
3j
-
n-C
7
H
15
0
[
a] Conditions: octyne (55 mg, 0.5 mmol), H
2
O (0.05 mL, 2.5 mmol), catalyst
, 0.02 mmol),
H
3b
3c
3a
0
0
(
18 mg for 1•AuCl, and 6 mg for (IPr)AuCl, and 3 mg for O=PPh
toluene (1 mL). [b] Determined by H NMR analyses on the basis of samples
3
(
IPr)AuCl
and
1
CH
3
2
2
that were purified by short-plugged silica-gel column chromatography (eluent:
toluene-d
1
O=PPh
3
8
only). H NMR spectra of 4g (= 4j), 5g (= 4h), 5h (= 4i) were
C
2
H
5
4
17
identical to those of commercially available 4-, 3-, 2-octanone, respectively. [c]
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European Journal of Organic Chemistry
10.1002/ejoc.201701613
COMMUNICATION
1
8
Unreacted 3a.
simultaneously orienting its paired-moiety outwardly. These
results would emphasize the relevance of the quinoxaline-
spanned resorcin[4]arene structure to design highly effective
cavitand catalysts and to achieve new and potent chemical
1
9,20
transformations not achievable heretofore.
Further
Additionally, as depicted in Scheme 3, we verified the
quality of this specificity on the hydration of 2-pentyne (3k), 4-
methyl-2-pentyne (3l), and 3-decyne (3m). For 3k, the chemical
development of new selective transformations is ongoing and
will be reported in due course.
1
6
yields of 4k and 5k were 59% and 41%, respectively. Thus,
there is not much difference in affinity to the cavity between the
methyl and ethyl groups. For 3l, the product distribution was
reasonably good to yield 5l in 86%, which means methyl group
fits much better than the iso-propyl. For 3m, the high selectivity
Experimental Section
Synthesis of 1: Under an argon atmosphere, to the two-neck flask
charged with
a solution of the starting parent bis-phosphoramidite
of 12/88 was given as we expected, because the longer n-C
6
H
13
molecule in Scheme 1 (600 mg, 0.4 mmol) in dry toluene (16 mL) was
added a solution of mCPBA (92 mg, 0.4 mmol) in toluene (8 mL)
dropwise over 10 min at 0 ºC. After 30 min at 0 ºC, the reaction was
group in 5m than the C was not suitable guest for the cavity.
2
H
5
These results will allow us to illustrate the hydration
mechanism as shown in Figure 2. The narrow space welcomes
quenched by addition of satd. aq. NaHCO
organic layer was washed with water (20 mL x 3), brine (20 mL), and
dried over Na SO , and concentrated in vacuo to give a crude of 585 mg
as white solid material. Purification by silica-gel column
3
(8 mL) over 10 min. The
3 3 2
the small groups like alkynyl-CH or -CH CH , even in mild
1
7
2
4
condition; however, the entrance of larger substituents such as
n-butyl, iso-propyl and phenyl moieties was unfavorable. This
molecular recognition leads to the formation of significant host-
guest complex, which precisely approaches a hydrogen-bonded
water toward one side of two carbons in the carbon-carbon triple
bond.
a
chromatography (toluene/EtOAc = 9/1 ~ 4/1) afforded 1 of 147 mg as
yellowish white solid materials (24%). Further reprecipitation from
CH
2 2 3
Cl /CH OH (1/8) whitened 1 in 134 mg (22%). For data of 1: Rf value
1
0.16 (eluent, toluene/EtOAc = 9/1); H NMR (400 MHz, CDCl
3
) 7.83-7.78
m, 4H), 7.51-7.50 (m, 4H), 7.41 (s, 2H), 7.33 (s, 2H), 7.22 (s, 2H), 7.14
(
(
3
s, 2H), 5.72 (t, J = 8.1 Hz, 2H), 4.60-4.56 (m, 2H), 2.91 (d,
J
PH = 10.9
3
Hz, 6H), 2.84 (d,
JPH = 10.5 Hz, 6H), 2.28-2.22 (m, 8H), 1.45-1.28 (m,
1
3
7
1
2H), 0.90-0.87 (m, 12H) ppm; C NMR (100 MHz, CDCl
3
) 153.2, 153.1,
52.6 (d, JCP = 1.4 Hz), 152.4, 150.3 (d, JCP = 4.8 Hz), 146.6 (d, JCP = 8.3
Hz), 140.1 (two peaks are overlapped), 137.3 (d, JCP = 2.2 Hz), 136.7 (d,
CP = 2.1 Hz), 134.4 (d, JCP = 3.6 Hz), 134.1, 129.7, 129.6, 128.5, 128.2,
J
1
3
3
23.2, 122.5, 117.7, 117.3 (d, JCP = 4.1 Hz), 37.2 (d, JCP = 3.1 Hz), 36.2,
6.0, 35.4 (d, JCP = 18.6 Hz), 34.3, 32.3 (many peaks are overlapped),
2.0, 31.9, 31.4, 30.1 (many peaks are overlapped), 29.8 (many peaks
are overlapped), 28.4, 28.3, 23.1 (many peaks are overlapped), 14.5
3
1
(
3
many peaks are overlapped) ppm; P NMR (162 MHz, CDCl ) 140.6, -
-
1
1
.5 ppm; IR (neat): 2922, 2851, 1482, 1271, 1119, 1068, 868 cm .
+
HRMS (MALDI-TOF) calcd for C92
H
125
N
6
O
9
P
2
: 1519.8983 [MH] , Found:
1
519.9099; Anal. Calcd for C92
H
124
N
6
O
9
P
2
: C, 72.70; H, 8.22; N, 5.53.
Found: C, 72.66; H, 8.20; N, 5.44.
Acknowledgements
Scheme 3. Catalytic capability of 1•AuCl on selective hydrations of 2-pentyne
The authors thank Dr. Toshiyuki Iwai and Dr. Takatoshi Ito at
ORIST for gentle assistance with HRMS.
3
k, and 4-methyl-2-pentyne 3l, and 3-decyne 3m (Yields were determined by
1
H NMR analyses on the basis of samples that were purified by short-plugged
1
silica-gel column chromatography eluted with toluene-d
4
8
. H NMR spectra of
1
k, 5k, 4l, and 5l were inferred from ChemDraw-estimated charts. H NMR
Keywords: Catalytic cavitand •Regio-selective reaction
spectra of 4m and 5m were identical to those of commercially available 4-,
and 3-decanone, respectively.)
•Supramolecular catalysis •Au catalysis • Hydration reactions
[
[
1]
2]
A. Fersht, Enzyme Structure and Mechanism, Freeman, New York,
984, p. 47–97.
1
In conclusion, the inward arrangement of P-Au and P=O in
the 1•AuCl provides a new functional architecture for selective
hydration of simple internal-alkynes. The supramolecular
catalyst presented a cutting-edge solution in which the host-
guest interaction enables to distinguish between two side-chains
a) F. A. Tezcan, J. T. Kaiser, D. Mustafi, M. Y. Walton, J. B. Haward, D.
C. Rees, Science 2005, 309, 1377-1380; b) T. Spatzal, M. Aksoyoglu, L.
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Ettenhuber, Y. Hu, M. W. Ribbe, F. Neese, U. Bergmann, S. DeBeer,
Science 2011, 974-977.
of internal alkynes. Comparison with model catalysts of 2 and
+
(
IPr)AuCl strongly indicates that 1•Au activated the triple bond
[3]
a) G. Varani, Annu. Rev. Biophys. Biomol. Struct. 1995, 24, 379-404; b)
M. V. Rodnina, W. Wintermeyer, Curr. Opin. Struct. Biol. 2003, 13, 334-
by the cationic Au with trapping a molecular water by its O=P
+
3
40; c) K. Shen, A. C. Hines, D. Schwarzer, K. A. Pickin, P. A. Cole,
moiety, selectively folding one of two alkynyl side-chains. 1•Au
Biochim. Biophys. Acta Proteins Proteomics 2005, 1754, 65-78.
specifically welcomes methyl and ethyl groups inside the cavity,
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European Journal of Organic Chemistry
10.1002/ejoc.201701613
COMMUNICATION
[
4]
a) P. Molenveld, J. F. J. Engbersen, D. N. Reinhoudt, Chem. Soc. Rev.
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187-2209; c) M. Terada, T. Komuro, Y. Toda, T. Korenaga, J. Am.
2
[14] In use of 1 mol% of 1•AuCl, the unreacted 3a remained in ~10%.
[15] M. P. Schramm, M. Kanaura, K. Ito, M. Ide, T. Iwasawa, Eur. J. Org.
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[
[
5]
6]
T. Iwasawa, Tetrahedron Lett. 2017, 58, 4217-4226 and references
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European Journal of Organic Chemistry
10.1002/ejoc.201701613
COMMUNICATION
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COMMUNICATION
Development of supramolecular flask
device with inwardly oriented Au(I)
and P=O is described, including a
description of its catalytic proclivity in
regio-selective hydration of specific
alkynes. The bi-functional cavity
favored to selectively fold a single
side-chain of the unsymmetrical
alkynes through host-guest
Naoki Endo, Mami Inoue, Tetsuo
Iwasawa*
Page No. – Page No.
Rational Design of a Metallo-catalytic
Cavitand for Regio-selective
Hydration of Specific Alkynes
interaction, which skillfully led the
water molecule to the one carbon of
the triple bond.
This article is protected by copyright. All rights reserved.