Synthesis of Water-Soluble Deep-Cavity Cavitands

Article abstract of DOI:10.1021/acs.orglett.6b01903

An efficient, four-step synthesis of a range of water-soluble, deep-cavity cavitands is presented. Key to this approach are octahalide derivatives (4, X = Cl or Br) that allow a range of water-solubilizing groups to be added to the outer surface of the co

Full text of DOI:10.1021/acs.orglett.6b01903

Letter
pubs.acs.org/OrgLett
Synthesis of Water-Soluble Deep-Cavity Cavitands
Matthew B. Hillyer, Corinne L. D. Gibb, Punidha Sokkalingam, Jacobs H. Jordan, Sarah E. Ioup,
and Bruce C. Gibb*
Department of Chemistry, Tulane University, New Orleans, Louisiana 70118, United States
*
S Supporting Information
ABSTRACT: An efficient, four-step synthesis of a range of
water-soluble, deep-cavity cavitands is presented. Key to this
approach are octahalide derivatives (4, X = Cl or Br) that allow
a range of water-solubilizing groups to be added to the outer
surface of the core host structure. In many cases, the
conversion of the starting dodecol (1) resorcinarene to the
different cavitands avoids any chromatographic procedures.
ecent work with water-soluble hosts such as cucurbitur-
ils and pillararenes have greatly expanded the realm of
general synthesis of a range of cavitands with cationic, anionic,
and uncharged coats in as few as four linear (chromatographic
free) steps from resorcinarene 2.
1
−4
5,6
R
aqueous supramolecular chemistry and our understanding of
noncovalent forces in water. Likewise, the deep-cavity cavitand,
octa-acid (OA) 1 (Scheme 1) has proven useful to a number of
research groups because of its ability to bind guests within its
hydrophobic pocket to form 1:1 complexes and for its propensity
Key to the synthesis of water-soluble deep-cavity cavitands is
octol 3, and we considered a range of approaches for introducing
eight electrophilic sites on the surface of this host (4, X =
various). Unfortunately, many proved unsuitable. For example,
tosylation in pyridine was complicated by the formation of
cavitand pyridinium salts, and even in the absence of this solvent,
a complex mixture of randomly tosylated and chlorinated
products was obtained with tosyl chloride. Mesyl anhydride
avoided this nucleofuge replacement issue, but this reaction
suffered other issues that limited the yield of 4 (X = OMs).
During this time, the partial characterization of octabromide 4 (X
7
to undergo self-assembly. For example, the orientation-specific
1
:1 complexes formed between 1 and amphiphiles have proven
useful to the predictive challenges of computational chemists
such as the statistical assessment of modeling of proteins and
8
ligands exercise. Additionally, small (partially hydrated) anions
are also observed to bind to 1, a fact that engenders the
Hofmeister effect within stronger host−guest complexes formed
9
−11
24
by this host.
OA 1 has also been shown to readily self-
= Br) was reported, and we found that modifications to the
assemble via the hydrophobic effect to form dimeric capsules
possessing dry, inner nanospaces. The resulting 2:n host−guest
Appel procedure used in its synthesis worked efficiently in our
hands. Initially, this synthesis of octabromide 4 (X = Br) was
optimized from pure octol 3. However, as the latter is insoluble in
most solvents and only available from crude 3 via acetylation
12
complexes have been used for physical separations and kinetic
1
3
14−16
resolutions, the control of redox-active guests,
and as
(
(
acetic anhydride), chromatographic separation, and hydrolysis
LiOH), we were interested in developing a chromatography-
yocto-liter reaction flasks for the precise control of a range of
25
1
7−20
photochemical reactions.
The Ramamurthy group con-
2
1,22
free procedure for the formation of pure 4 (both X = Br and Cl)
from crude 3. Ultimately, we identified conditions, and
octahalides 4 (X = Br and Cl) were efficiently synthesized on
the multigram scale in 56 and 62%, respectively (Supporting
Information). The conversion of octol 3 to octabromide 4 (X =
Br) was complete within 16 h, while the octachloride 4 (X = Cl)
required 3 days for complete reaction. The yields for these
reactions correspond to very reasonable conversions, taking into
account that crude octol 3 is typically only ∼75% pure and that
eight reactions occur in each conversion. Thus, in the case of the
octabromide 4 (X = Br), this equates to a 75% yield and a 96%
yield per reaction site for the octol 3 within the crude starting
material.
tinues to study this last line of investigation.
Two features of 1 likely contribute to this diverse application:
1) its ready accessibilityit is available in five linear steps from
(
resorcinarene 2, only one of which requires chromatographic
purification; (2) its well-behaved nature; thus under basic
conditions, the free host does not aggregate in the mM range
(
although this is buffer-dependent), while it readily forms
monodispersed dimeric capsules in the presence of suitable
guests. We attribute this excellent behavior to the pseudo, square
antiprism array of carboxylate groups that lead to the water-
solubilizing groups being spread evenly around its outer
2
3
surface. These points noted, the carboxylate coating on the
outer surface of the host limits studies of the host to basic
conditions. Consequently, we sought a short and efficient route
for the synthesis of a broad range of cavitands with different
water-solubilizing “coats”. To that end, we report here on a
Received: July 1, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01903
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Organic Letters
Letter
Scheme 1. Synthesis of Water-Soluble Cavitands from Resorcin[4]arene 2
a
b
Compound 4 (X = Br). Two-step syntheses.
Octabromide 4 (X = Br) was fully characterized and its
structure confirmed by single-crystal X-ray crystallography. The
crystals obtained from chloroform contained two cavitands in the
unit cell, one of which was slightly disordered around its rim
(Figure 1). The unit cell also contained multiple, disordered
chloroform molecules, with the cavity of both cavitands
containing one disordered chloroform. For these guests, the
chlorine atom located toward the base of the pocket was highly
ordered, emphasizing the attractive C−H···Cl−R hydrogen
26
bonds between host and guest.
Cavitand 4 (X = Br) proved to be an ideal intermediate for the
synthesis of the different cavitands by reacting quickly and
smoothly with a range of nucleophiles. Thus, the syntheses of
novel, positively charged cavitands 5 and 6 by treatment with
trimethyl amine and pyridine, respectively, were both uneventful.
Furthermore, in both cases, product isolation was a straightfor-
ward precipitation. Anion exchange converted the bromide salts
to the corresponding chlorides.
Figure 1. X-ray crystal structure unit cell of octabromide 4 (X = Br),
showing the two hosts each with a bound chloroform guest within its
cavity. Hydrogens and noncavity solvent molecules are omitted for
clarity.
That these hosts possess the expected properties was
demonstrated by positively charged cavitand 5, which readily
formed the expected host−guest complex with n-dodecane.
B
DOI: 10.1021/acs.orglett.6b01903
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Thus, the addition of an excess of n-dodecane (∼26 equiv) to a
ASSOCIATED CONTENT
Supporting Information
■
0
.8 mM solution of 5 in D O and vortexing the sample for 5 min
2
*
S
led to the quantitative formation of the corresponding 2:1 host−
guest complex with the characteristic upfield shifted guest signals
between 0 and −3.4 ppm (Figure S15).
In contrast, treatment of 4 (X = Br) with ammonia led to
significant amounts of polymer contaminating the desired
octaamine 7. Consequently, to form this cavitand, the
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01903.
1
Experimental procedures, characterization details, and H,
13
C, ESI/MALDI mass spectra, and X-ray crystallographic
data of new compounds (PDF)
Crystal structure of octahalide 4 (X = Br) (CIF)
octabromide 4 (X = Br) was first treated with NaN to give
3
the corresponding octaazide 7a (not shown) in near quantitative
yield. The subsequent Staudinger reduction gave the octaamine 7
in 65% yield. In both steps, the product was isolated by simple
precipitation.
Building on this range of amine/ammonium-coated cavitands,
the diethanolamine-coated cavitand 8 was targeted because the
AUTHOR INFORMATION
Corresponding Author
E-mail: bgibb@tulane.edu.
■
*
Notes
The authors declare no competing financial interest.
16 hydroxy groups were expected to augment the water solubility
provided by the ionizable ammonium groups. Moreover, the
hydroxyethyl groups were expected to attenuate the frequently
observed strong hydrogen bonding between free primary amines
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the National Science
Foundation (CHE-1507344) and the National Institutes of
Health (GM098141) for financial assistance. M.B.H. also
acknowledges the Louisiana Board of Regents for a fellowship
LEQSF(2012-17)-GF-SREB-03). Special thanks also to
Professor James P. Donahue for technical assistance.
(
8
such as 7) and their protonated conjugate acid forms. Cavitand
was isolated in 65% yield by treating 4 (X = Br) with
diethanolamine and precipitation.
(
Analogous to 8 but devoid of basic protonation sites,
hexadecaalcohol 9 was also synthesized to determine if the
dihydroxy propylthioether coating could bestow water solubility.
This cavitand was formed from 4 (X = Br) in 63% yield by
treatment with thioglycerol. Again, the pure product was isolated
via precipitation rather than chromatography.
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(
2
(
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27
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(
(
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C
DOI: 10.1021/acs.orglett.6b01903
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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(
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(
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D
DOI: 10.1021/acs.orglett.6b01903
Org. Lett. XXXX, XXX, XXX−XXX