Binding orientation and reactivity of alkyl α,ω-dibromides in water-soluble cavitands

Article abstract of DOI:10.1039/c9ob01018a

Host-guest complexation of long chain α,ω-dibromides was evaluated in deep water-soluble cavitands 1 and 2. The bound dibromides (C₇-C₁₂) tumble rapidly on the NMR timescale and averaged signals were observed. The complexation allows mono hydrolysis of dibromides in aqueous solution. The arrangement of the products in the host-guest complex was fixed in an unsymmetrical manner that protects the guest from further reaction. Up to 93% yields of the mono-alcohols were obtained. The α,ω-dibromides formed a capsule with cavitand 2 and remained unreactive to hydrolysis.

Full text of DOI:10.1039/c9ob01018a

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Binding orientation and reactivity of alkyl
α,ω-dibromides in water-soluble cavitands†
Cite this: DOI: 10.1039/c9ob01018a
a
a
a
Venkatachalam Angamuthu, Manuel Petroselli,
Faiz-Ur Rahman,
a
a,b
Yang Yu * and Julius Rebek, Jr.*
Host–guest complexation of long chain α,ω-dibromides was evaluated in deep water-soluble cavitands
and 2. The bound dibromides (C –C12) tumble rapidly on the NMR timescale and averaged signals were
1
7
Received 3rd May 2019,
Accepted 8th May 2019
observed. The complexation allows mono hydrolysis of dibromides in aqueous solution. The arrangement
of the products in the host–guest complex was fixed in an unsymmetrical manner that protects the guest
from further reaction. Up to 93% yields of the mono-alcohols were obtained. The α,ω-dibromides formed
a capsule with cavitand 2 and remained unreactive to hydrolysis.
DOI: 10.1039/c9ob01018a
rsc.li/obc
2
5–29
Mono functionalization is generally hard to achieve for sym- formation of stable host–guest complexes.
Application of
metrical compounds in bulk solution. The common problem molecular containers in aqueous media has shown much
3
0–33
is the formation of product mixtures due to identical func- promise development in organic transformations.
tional groups on the substrate. In a long chain substrate, term- Previously, we have applied deep, water-soluble cavitands to
2
5
inal sites are truly remote and act independently, leading to the mono hydrolysis of long-chain diesters, the synthesis of
3
4
29
mono-, di- and unfunctionalized products. Molecules in con- macrocyclic ureas and the Staudinger reactions of diazides.
fined spaces behave differently with respect to those in bulk The successes arise from the unusual orientations of linear
2
7,35,36
solution and confinement can create special circumstances. In and cyclic alkyl halides reported
in cavitands 1 and 2
this regard, a number of container molecules have been devel- (Fig. 1). Here we report the binding and reactivity of
oped to exploit these differences, and the use of these contain- α,ω-dibromides in these cavitands that promote mono
ers for the promotion of reactions in small spaces has hydrolysis.
1
–17
expanded.
Cavitands are open-ended containers used as hosts for reported by our group.
complementary organic and biological guests. They are readily lity in water (>2 mM) and are stable over a wide range of pH in
The synthesis of cavitands 1 and 2 has been recently
2
6,37
These cavitands have good solubi-
1
8
30,37
accessible through chemical synthesis and generally display water.
a dynamic equilibrium between two different structural con- methine protons appear at 5.6 ppm in the H NMR spectrum,
formations – the vase and kite – depending on experimental while in the kite form the signal is observed near 4 ppm.
conditions.
In the vase form of 1 and 2 the characteristic
1
3
8–40
1
9,20
Suitable guests are always required to stabilize The presence of N-Me groups on the upper rim of 1 prevents
2
1,22
the vase form of the cavitand.
The driving-force for the for- the formation of a hydrogen bonded capsule, but either cavi-
mation of the host–guest complex in water is principally due tand is a dimeric velcrand form in solution when suitable
to the hydrophobic effect, which drives the guest molecule guests are not present. Guests in the vase forms experience
2
3
into the confined space of the cavitand.
Many organic reactions do not proceed in aqueous medium
upfield shifts in their NMR spectra and the approximate
2
4
due to low solubility of reagents or catalysts. Water-soluble
cavitands can help the dissolution of insoluble guests by the
a
Center for Supramolecular Chemistry and Catalysis and Department of Chemistry,
Shanghai University, 99 Shang-Da Road, Shanghai 200444, P. R. China.
E-mail: yangyu2017@shu.edu.cn, jrebek@scripps.edu
b
The Skaggs Institute for Chemical Biology and Department of Chemistry,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla,
California 92037, USA
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 Chemical structures and schematic cartoons of the deep, water-
soluble cavitands 1 and 2.
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1
2
Fig. 2 (a) Partial H NMR (600 MHz, D O, 298 K) spectra of the com-
plexes formed between host 1 (1.4 mM) and α,ω-dibromides (3a–f). Red
circles indicate α,ω methylenes, green triangles indicate β,ψ methylenes
and blue squares indicate middle methylenes; stars indicates free guest.
1
Fig. 3 Top (a): Partial H NMR (600 MHz, D
α,ω-dibromide (C10) 3d in 1 recorded after sequential additions of
DMSO-d (4 µL). (a) After 6 h of sonication at 25 °C without DMSO-d
b) 4 µL, 24 h, 50 °C; (c) 8 µL, 56 h, 50 °C; (d) 12 µL, 112 h, 50 °C; (e)
2
O, 298 K) spectra of
6
6
;
(
b) Model of the rapid tumbling inside the cavitand that leads to sim-
(
plified signal patterns.
1
36 h, 50 °C; (f) 172 h, 50 °C; (g) authentic 10-bromodecan-1-ol in cavi-
tand 1. Bottom (b): Cartoons of reaction in the complex of (C10) dibro-
mide 3d with assignments of the product methylene signals.
upfield shifts (−Δδ) of guest nuclei are given in the ESI
(Fig. S1†).
The binding and reactivity of alkyl α,ω-dibromides (C –C )
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12
were investigated in 1. Compounds 3a–f were sonicated with and β positions from the Br in the monobromides are shifted
cavitand 1 in D O (1.4 mM) and formed (1 : 1) host–guest com- furthest upfield. This is apparently because the Br group
plexes. The H NMR signals of the guest shifted to the upfield allows a nearby sharp bend in its attached chain.
region (Fig. 2a). Guests 3a–f show proton signals clustered The fixed conformation of the complex in Fig. 3, with the
2
1
from 1.6 to −1.5 ppm (i.e., −Δδ of about 1.7 to 2.3 ppm). The bromide end buried in the cavity, prevents further hydrolysis
spectra are consistent with the rapid tumbling of the guests reactions. Addition of another 10 equivalents of DMSO to the
3
5
1
inside the cavity. The upfield shifts (−Δδ) for bound guests reaction mixture after 2 days did not change the H NMR
varied with different lengths of the carbon chain: in longer spectra and confirmed that the Br group is protected by cavi-
α,ω-dibromides, portions of the guest spend more time tand and inaccessible. Even after one month no changes in
outside the vase and the averaged signals move downfield and the spectra were observed. Only compounds with longer lipo-
are closer to those of the free guest. The assignments of the philic chains such as compounds 3e and 3f showed small
signals were made by 2D COSY experiments (Fig. S3–5†).
amounts (10%) of dihydroxy products in this reaction
The reactivity of bound guests was studied using DMSO as (Fig. S16†). The NMR yields of products were calculated using
4
1,42
a co-solvent because of its promotion of S
N
2 type reactions.
dimethyl sulfone as an internal standard and were 69, 93, 69,
Other co-solvents such as DMF, 1,4-dioxane, acetone, aceto- and 76% for 4c, 4d, 4e and 4f, respectively (Fig. S17 to S20†).
nitrile or acetic acid were also investigated (Fig. S7†). As shown
in Fig. 3a, the signals of the complexed α,ω-dibromide (C10
Stringent control experiments are difficult to perform
without the cavitand because most of the long chain dibro-
)
(
3d) decrease in intensity as a new set of peaks appear in the mides are practically insoluble in water. Instead, control
upfield region after several hours of stirring at 50 °C. These are experiments were performed using a mixture of acetone-d in
signals of mono hydroxyl bromide in the cavitand and range O (25% v/v) and with DMSO-d (3.6%) as co-solvent. In these
6
D
2
6
from +1.34 to −2.45 ppm. The signal pattern is consistent with experiments, the hydrolysis reactions were slower and gave
a fixed arrangement in the cavitand with the OH exposed and mixtures of products (Fig. S21†). After prolonged times or
the remaining Br buried. Parallel results were obtained with increased DMSO-d
6 2 6 6
concentrations (D O/acetone-d /DMSO-d
other dibromides (Fig. S8–11†). (5 : 2 : 1), the dibromides were converted quantitatively into the
The assignments of mono hydroxyl product signals are dihydroxyl products without any mono hydroxyl products
summarized in Fig. 3b, with −Δδ values calculated from the detected. This result highlights the striking ability of the cavi-
2
D COSY experiments (Fig. S12†). Methylene protons in the α tand to suppress the second hydrolysis step.
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Acknowledgements
We thank the National Science Foundation (CHE 1506266),
Chinese NSF (No. 21801164) and Shanghai University (N.13-
G210-19-230) for financial support. Dr. Yang Yu thanks the
Program for Professor of Special Appointment (Dongfang
Scholarship) of the Shanghai Education Committee.
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In summary, we reported the binding orientations of
α,ω-dibromides in water-soluble cavitands 1 and 2. These
dibromides show exchange of the two ends in 1 but the details
of the rapid motion are unknown. Mono hydroxyl bromides
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