Cavitands as Containers for α,ω-Dienes and Chaperones for Olefin Metathesis

Article abstract of DOI:10.1002/anie.201808265

Described herein is the behavior of α,ω-dienes sequestered within cavitands in aqueous (D₂O) solution. Hydrophobic forces drive the dienes into the cavitands in conformations that best fill the available space. Shorter dienes (C9 and C10) bind

Full text of DOI:10.1002/anie.201808265

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Accepted Article
Title: Cavitands as containers for α,ω-dienes and chaperones for olefin
metathesis
Authors: Julius Rebek, Jr., Nai-Wei Wu, and Yang Yu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808265
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10.1002/anie.201808265
Angewandte Chemie International Edition
COMMUNICATION
Cavitands as containers for α,ω-dienes and chaperones for olefin
metathesis
Nai-Wei Wu, Ioannis D. Petsalakis, Giannoula Theodorakopoulos, Yang Yu* and Julius Rebek, Jr.*
Abstract: We describe here the behavior of α,ω-dienes sequestered
in cavitands 1a and 1b in aqueous (D2O) solution. Hydrophobic
forces drive the dienes into the cavitands in conformations that best
fill the space on offer. Shorter dienes (C9 and C10) bind in
compressed conformations that tumble rapidly in the cavitands.
Longer dienes induce capsule formation in cavitands with self-
complementary hydrogen bonding sites, where the dienes exist in
extended conformations. In cavitands unable to form capsules,
longer dienes adopt folded structures. The wider open ends allow
the synthesis of medium sized cycloalkenes by ring closing
metathesis reactions with the Hoveyda−Grubbs-II catalyst. Yields of
cycloheptene and cyclooctene were enhanced by the chaperones in
water when compared with reactions of the free dienes in aqueous
media or chloroform, and even cyclononene could be prepared in
the cavitand.
1,8-nonadiene (2a), C10 1,9-decadiene (2b), C11 1,10-
undecadiene (2c), C12 1,11-dodecadiene (2d) and C13 1,13-
tetradecadiene (2f); the C14 1,12-tridecadiene (2e) was
O
O
O
O
X
X
N
N
X
X
N
N
X
N
N X
X
X
N
N
=
X
H
=
X
Me
O
O
O
O
O
O
O
O
R
R
R
R
1a
Me
1b
N
=
R
N
(CH2
)
3
Cl
n
n =
n =
n =
3a
3b
3c
1
2
3
n =
n =
n =
n =
n =
n =
2a
2b
2c
2d
2e
2f
1
2
3
4
5
6
n
Molecular container hosts have received much attention for
their ability to confine guest molecules and affect their reactivity.
The use of self-assembly has expanded the use of these
containers for the promotion of reactions in small spaces.[1] We
recently reported the synthesis and characterization of the deep
cavitand 1a[2] (Figure 1). The self-complementary pattern of
hydrogen bond donors and acceptors on the upper rim was
devised by de Mendoza,[3] who showed that dimerization to host
capsules occurs with suitable guests in organic solvents. We
found that pyridinium or methylimidazolium “feet” provided good
solubility in water, and the formation of capsules occurs even in
aqueous solutions when large hydrophobic guests are present.[4]
To prevent such dimerization, we exhaustively N-methylated the
benzimidazolones of the upper rim to form octamethyl urea 1b.
(See SI). Cavitand 1b showed good solubility in water (D2O),
where it exists as a velcrand[5] dimer in the absence of guests.
Here we report the complexation of symmetrical aliphatic α,ω-
dienes (C9–C14) with cavitands 1a and 1b, and their
applications for olefin metathesis in otherwise reluctant
cyclizations.
Figure 1. Chemical structures and cartoon abbreviations of cavitands 1a and
1b, the dienes 2a-2f and the cycloalkenes 3a-3c.
synthesized through reaction of 10-bromo-1-decene with
allylmagnesium bromide.[8] Brief sonication of these α,ω-dienes
(0.5 mM) with cavitand 1a (0.5 mM) in water (D2O) gave host-
guest complexes with guest 1H NMR signals characteristically
upfield-shifted by the shielding of the aromatic panels of the host
structure (Figure 2 and SI). The longer α,ω-dienes: 2c, 2d, 2e
and 2f show signals which are spread out between 1.5 and -2.0
ppm (Figure 2). The terminal vinyl hydrogen signals of C11
appear at +0.05 ppm (Δδ = -4.70 ppm, H11a) and -0.17 ppm (Δδ
= -4.84 ppm, H11b) (Figure S5 and Figure S6). These olefinic
protons experienced the maximum upfield shifts offered by the
deepest part of the cavity in 1a. This, and the wide spread of
other signals are characteristic of an extended conformation,
fixed in a symmetrical environment of the hydrogen-bonded
capsule: 1a·1a.
The spectra observed for encapsulated C12 and C13 also
followed this pattern, but their terminal C-H signals unexpectedly
moved downfield. Apparently, these longer dienes coil through
gauche conformations along the chains that pull their two
terminal olefinic hydrogens from the deepest parts of the
capsule. The large separation between H11a and H11b for C11
termini means that H11b is deeper than H11a. In contrast, similar
upfield shifts for C12 and C13 termini indicates their depths are
comparable (Figure S13). Yet for the longest guest C14, the
penultimate protons (H2 = H13) experience the furthest upfield
shift (-Δδ of 4.44 ppm): they are, on average, the deepest in the
Alkenes bound inside synthetic host structures are not often
reported,[6] because the NMR signals of the olefinic protons are
rarely observed because of overlap with the signals of the
cavitands.[7] We used the commercially available α,ω-dienes: C9
[a]
[b]
[c]
Dr. Nai-Wei Wu, Prof. Dr. Yang Yu, Prof. Dr. Julius Rebek, Jr.
Center for Supramolecular and Catalytic Chemistry and Department
of Chemistry, Shanghai University, 99 Shang-Da Road, Shanghai
200444, China;
E-mail: yangyu2017@shu.edu.cn
Prof. Dr. Julius Rebek, Jr.
The Skaggs Institute for Chemical Biology and Department of
Chemistry, The Scripps Research Institute, 10550 North Torrey
Pines Road, La Jolla, California 92037, United States.
E-mail: jrebek@scripps.edu;
Dr. Ioannis D. Petsalakis, Dr. Giannoula Theodorakopoulos,
Theoretical and Physical Chemistry Institute, National Hellenic
Research Foundation, 48 Vassileos Constantinou Ave., Athens 116
35, Greece.
cavitand. The terminal olefinic protons (H1a = H14a and H1b
=
H14b) show –Δδ’s of only 4.26 and 4.21 ppm, respectively. A
folded conformation of the diene at the tapered end of the cavity
is proposed in Figure 2 and Figure S14 that place H2 and H13 at
the deepest positions. This is in accord with observations of
longer n-alkanes (C14–C18) that are encapsulated in folded
conformations.[9] These subtleties are depicted in the cartoons of
Figure 2e, where the discontinuity occurs with the terminally
Supporting information (Additional information and figures) for this
article is given via a link at the end of the document.
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10.1002/anie.201808265
Angewandte Chemie International Edition
COMMUNICATION
folded C14. Complete COSY spectra and the assignments for
2c-2f inside capsule 1a·1a are available in Figures S5-S14.
R
e)
f)
R
d)
H1b
H2
H11
H1b
H1
a
H11
a
H10
H12
a
H2
H12b
H1a
H11b
c)
C11
C12
b)
R
R
H14b
H14
H14b
H13
H12
H14b
a
a)
H14
a
H14
a
H13
a
H13
H13b
H13
C13
C14
Figure 2. Left: partial 1H NMR (600 MHz, D2O, 298 K) spectra of the capsules formed between 1a·1a and (a) 1,10-undecadiene; (b) 1,11-dodecadiene; (c) 1,12-
tridecadiene; (d) 1,13-tetradecadiene. (The peaks labeled with red dots are from olefins, the peaks labeled with blue squares are from methylenes). Center: (e)
positions of the vinyl hydrogens vary with diene length. Right: (f) folding at one end of tetradecadiene is rapidly transmitted to the other end.
The shorter α,ω-dienes: C9 and C10 showed simplified spectra
in 1a with the methylene signals appearing between 0 and -1.5
ppm. The olefinic signals of these dienes appear at around 3.0
ppm, which overlap with the signals of the cavitand 1a.
Apparently, these short guests are not long enough to fill the
molecular capsule 1a·1a, and instead they occupy the monomer
1a. Their spectra are time-averaged by the exchange of
magnetic environments of the two ends of the dienes. A rapid
(on the NMR timescale) tumbling motion of a coiled guest is
consistent with the observed signals (Figure S15). This tumbling
is not an exclusive description: any rapid motion that exchanges
the magnetic environment of the guest’s ends would explain the
spectra. The proposed coiling of the guest leads to better C-H/π
contacts within the complex.[10]
and place them deepest in the cavity. Simply put, the chains are
folded inside cavitand 1b. Methylenes fixed at the bottom of
such cavitands experience the largest upfield shifts (-Δδ of 4.0 to
4.5 ppm) while those near the rim show the smallest upfield
shifts (-Δδ of 0 to 0.5 ppm). The NMR signals indicate folding of
the guests in 1b, and they are moving. We propose a rapid “yo-
yo” motion[12] between J-shaped conformations which leads to a
time-averaged environment for the signals; The binding energies
of J and folded conformations for 1,9-decadiene were calculated
using Gaussian 16[13] and only a 0.12 eV difference was found
between them, supporting the "yo-yo" motion (Figure 4 and
SI). Attempts to freeze out the motion of 2b at lowered
temperatures were unsuccessful (Figure S29). The longer
guests C12-C14 (2d, 2e and 2f) protrude further outside
cavitand 1b than the shorter ones (2a-2c).
The dimeric capsule 1a·1a is stabilized by hydrogen
bonding between two cavitand units and this makes for a
narrower, somewhat rigid space. The vase conformation of
cavitand 1a is also reinforced by hydrogen bonds between the
solvent D2O and the ureas of the rim.[11] The N-Me groups at the
upper rim of 1b widen the “mouth”, allow looser wall motions and
affect its guests’ conformations and mobilities. Sonication of 1b
with any of the α,ω-dienes also gave stoichiometric host-guest
complexes. Unlike the complexes of 1a, none of the olefinic
protons of the dienes appeared in the upfield region below 1.0
ppm; the termini do not spend much time at the bottom of the
cavitand. But there is reason to believe that the bottom of the
cavitand is always occupied, since an unsolvated cavitand
surface would create a vacuum. This leaves only methylenes to
occupy the bottom of the cavity, and their signals do appear in
the upfield region (Figure 3 and SI). For example, C9 (2a)
showed three methylene signals at 1.09, -2.02 and -2.12 ppm,
corresponding to upfield shifts (–Δδ) of 2.95, 3.23, 3.28 ppm
calculated from the spectrum of free diene in water (D2O). These
assignments were established by 2D COSY spectra (Figure
S17-S22). This NMR evidence indicates that the central CH2
groups of these guests (2a-2c) show the furthest upfield shifts,
f)
e)
d)
c)
b)
a)
Figure 3. Partial 1H NMR (600 MHz, D2O, 298 K) spectra of the complexes
formed between 1b and (a) C9; (b) C10; (c) C11; (d) C12; (e) C13 (f) C14.
(The signal assignments are in Figure S17-S28).
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10.1002/anie.201808265
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COMMUNICATION
C9
C2
C9
C2
C4
C4
Hoveyda-Grubbs-II
D2O
C4
C2
C9
f)
motion
"yoyo"
e)
d)
c)
b)
a)
Figure 4. Top: Cartoon of the proposed “yo-yo” motion between J-shaped
conformations of the complex of 1b with C10; Bottom: Calculated structures of
complexes of cavitand 1b with 1,9-decadiene.
Figure 5. Partial 1H NMR (600 MHz, D2O, 298K) spectra of the RCM reaction
of 2a catalyzed by Hoveyda-Grubbs-II with cavitand 1b. (a) 2a (2.0 mM) in the
cavitand 1b (2.0 mM); (b) after treatment with Hoveyda-Grubbs-II for 1.5 h; (c)
3.0 h; (d) 4.0 h; (e) 6.0 h; (f) authentic cycloheptene in cavitand 1b. The peaks
labeled with red arrows are from substrate 2a; the peaks labeled with blue
arrows are from product 3a.
The folded conformations of these α,ω-dienes in 1b bring
the ends closer together and expose them to reagents in the
bulk solution. These characteristics promote medium to large
ring cyclizations in amide forming reactions,[2,14] and their
application to ring-closing metathesis (RCM) reactions seemed
possible. Olefin metathesis is widely used for ring formation,[15]
but medium rings represent challenges,[16] as torsions and
transannular strains arising during the reaction result in relatively
inefficient cyclization.
We began by using 1b as a chaperone to synthesize a 7-
membered ring cycloheptene (3a) from C9 (2a). The complex
was formed by sonication of the diene and cavitand for one hour
in an NMR tube (2.0 mM). Then the commercially available
Hoveyda−Grubbs-II catalyst (3%), which shows high activity
under mild reaction conditions in water,[17] was added. As shown
in Figure 5, the signals of 2a disappeared while the product 3a
increased with time. The conversion of 3a is nearly quantitative
after a reaction time of 6 hrs. Reference spectra of authentic
cycloheptene in the cavitand 1b (top trace of Figure 5) indicated
nearly no byproduct formation. The signals of cycloheptene in
1b showed a –Δδ of 2.37 ppm for the olefin C-H’s and -Δδ of
3.24, 3.93, 4.07 ppm for the methylenes. The cartoon of the
product complex is consistent with these values, but doubtless
some spinning motion of the guest takes place in the cavitand
(Figure S30-S31). To the extent that the double bond is buried in
the cavitand, it would be protected from further reversible
reactions.
Closure of eight-membered rings is
a difficult RCM
process[18] and reactions that form Z-cyclooctene (3b) usually
require either appropriate vicinal ring substitution or fusion to
other ring systems[19]. For example, the case of Scheme S1
(compiled by Maier[20]) does not yield the 8-membered ring. The
complex of C10 (2b) in 1b, when treated as described above,
Hoveyda-Grubbs-II
and
D2O
g)
f)
e)
d)
c)
b)
a)
Figure 6. Partial 1H NMR (600 MHz, D2O, 298K) spectra of the RCM reaction
of 2b catalyzed by Hoveyda-Grubbs-II with cavitand 1b. (a) 2b (2.0 mM) in the
cavitand 1b (2.0 mM); (b) after treatment with Hoveyda-Grubbs-II catalyst for
0.5 h; (c) 2.0 h; (d) 4.0 h; (e) 6.0 h; (f) authentic cyclooctene in cavitand 1b; (g)
authentic cycloheptene in cavitand 1b. The peaks labeled with red arrows are
from substrate 2b, the peaks labeled with blue arrows are from product 3b and
green arrows are from 3a. (For more details see SI).
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10.1002/anie.201808265
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COMMUNICATION
gave rise to signals that matched the complex of authentic cyclo-
octene and cycloheptene bound by 1b (Figure 6). Diene
isomerization by metathesis catalysts or ruthenium–alkylidenes
is well established, and isomerization of terminal olefins is a
versatile tactic of organic synthesis.[21] The appearance of
cycloheptene likely derives from this process followed by
cyclization. When C11 (2c) in cavitand 1b at a more dilute
concentration (1.0 mM), was exposed to the same conditions, Z-
cyclononene (3c) was obtained, albeit in low yield. Oligomers
and polymers were also formed (Figure S41).
also plays a role as template for RCM reactions with a water
compatible catalyst.[23] The host/guest interactions bring the
reacting ends closer together in a precyclization conformation
that overcomes some internal strains. The yield of 7, 8 and 9-
membered cycloalkenes were significantly enhanced even
compared with the reaction in homogeneous chloroform phase.
The cavitand buries hydrophobic surfaces and the shape of the
space on offer pushes the reactions along congruent pathway,
even some that are not readily observed in bulk solution.
The conversions of these chaperoned reactions were
calculated by NMR integration using dimethyl sulfone as the
water-soluble internal standard. The conversion of cycloheptene
formed from 2a was 98% in cavitand 1b. The conversion of
cyclo-octene from 2b was 53%, along with 39% isomerization
product cycloheptene. Z-cyclononene was produced in 9% from
2c. No cycloalkene signals were found from the chaperoned
reactions of longer dienes 2d-2f. (SI) However, a recent report
shows successful RCM of large rings by removal of the products
through distillation as they are formed. [22] The isolated yield of
3a with cavitand on a preparative scale was 79%, obtained by
extraction followed by purification through chromatography.
Control reactions were performed in both an organic solvent
(CDCl3) and an aqueous medium (D2O/DMSO-d6) under the
same conditions without added cavitand 1b. Diene 2a in CDCl3
was found to produce 3a with 78% yield (NMR) as a completely
homogeneous phase in CDCl3. The yield of 3b formed from 2b
was only 13% in CDCl3. The isolated yield of 3a in CHCl3 was
64%. We found no Z-cyclononene under these reaction
conditions in CDCl3 (Figure S47-S50). In control experiments in
an aqueous phase (D2O/DMSO-d6 500µL/5µL), the α,ω-dienes
2a-c were treated with Hoveyda−Grubbs-II catalyst (3%). After
stirring for 6 hrs, excess cavitand 1b was added to completely
sequester any cycloalkene products. Neither cycloheptene nor
cyclooctene were observed from the reaction of 1,8-nonadiene
and 1,9-decadiene without cavitand 1b (Table 1 and Figure S51).
Stoichiometric amounts of cavitand were required for the olefin
Experimental Section
Experimental Details are provided in the Supporting Information.
Acknowledgements
We thank the National Science Foundation (CHE1213415 and
CHE 1506266), Shanghai University (N.13-0101-17-202), and
the Program for Professor of Special Appointment (Eastern
Scholar) at Shanghai Institutions of Higher Learning for financial
support. We also thank Prof. Amir Hoveyda for advice.
Keywords: water-soluble cavitands •α,ω-dienes • olefin
metathesis • cyclization • cycloalkenes
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pairwise
competition
experiments
show
cycloalkenes were better guests, but the cavitand could be
reused by simple extraction (Figure S52-S54).
Table 1. Yields of cycloalkenes with or without cavitand 1b.[a]
cycloalkene
Conv,[a]
%
Conv,%
without 1b
(CDCl3)
Conv,%
without 1b
(D2O/DMSO)
with 1b
3a
98
(79[b]
78
(64)
13
N[c]
[2]
[3]
[4]
[5]
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3b
3c
53
N
N
9
N
K.-D. Zhang, D. Ajami, J. Rebek, Jr., J. Am. Chem. Soc. 2013, 135,
18064-18066.
[a] Calculated based on 1H NMR integration. [b] Isolated yield. [c] N = too low
to be determined. The concentrations of the substrate 2a and 2b are 2.0 mM,
2c is 1.0 mM. The concentration of 1b is 4.0 mM.
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10.1002/anie.201808265
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
C9
C2
Nai-Wei Wu, Ioannis D. Petsalakis,
C9
C2
C4
C4
Hoveyda-Grubbs-II
H2O
Giannoula Theodorakopoulos, Yang Yu*
and Julius Rebek, Jr.*
C4
C2
C9
Cavitands as containers for α,ω-
dienes and chaperones for olefin
metathesis
Water-Soluble-Cavitand
Text for Table of Contents
This article is protected by copyright. All rights reserved.