Deep cavitands featuring functional acetal-based walls

Article abstract of DOI:10.1039/c2cc36517k

The synthesis of deep cavitands with functionalized acetals as a fourth-wall is described. Recognition properties and stabilities of the complexes of two representative cavitands with aliphatic, aromatic, carbocyclic and adamantane guests were evaluated b

Full text of DOI:10.1039/c2cc36517k

View Online / Journal Homepage
ChemComm
Accepted Manuscript
This is an Accepted Manuscript, which has been through the RSC Publishing peer
review process and has been accepted for publication.
Accepted Manuscripts are published online shortly after acceptance, which is prior
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
Chemical Communications
www.rsc.org/chemcomm
Volume 46
| Number 32 | 28 August 2010 | Pages 5813–5976
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
ISSN 1359-7345
COMMUNICATION
FEATURE ARTICLE
J. Fraser Stoddart et al.
Directed self-assembly of
ring-in-ring complex
Wenbin Lin et al.
a
Hybrid nanomaterials for biomedical
applications
1359-7345(2010)46:32;1-H
www.rsc.org/chemcomm
Registered Charity Number 207890

ChemComm
Page 1 ofJ3ournal Name
►
View Online
ARTICLE TYPE
Deep Cavitands Featuring Functional Acetal-Based Walls
‡ Melissa Degardin, ‡ Eric Busseron, Dang-A Kim, Dariush Ajami, and Julius Rebek, Jr.*
‡ These authors contributed equally.
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000
of suitable benzaldehyde derivatives with boron tribromide in
The synthesis of deep cavitands with functionalized acetals as
fourth-wall is described. Recognition properties and
stabilities of the complexes of two representative cavitands
with aliphatic, aromatic, carbocyclic and adamantane guests
35 dichloromethane, whereas 8 was synthesized from m-toluic acid
a
through a radical bromination.7

he,-dibromotoluene 9 and benzal bromide derivatives 6-8
were installed on the hexaamide diol cavitand 1 featuring C11 feet
by treatment for 3 days at 60°C in N,N-dimethylacetamide in the
40 presence of DBU as an homogeneous base.5b Hexaamide acetal
cavitand 2, heptaamide acetal cavitand 3 and halogenated
cavitands 4 and 5 were obtained in 86 %, 83 %, 90 % and 73 %
yields, respectively, after purification (Scheme 1).
10 were evaluated by NMR methods.
Self-folding cavitands are resorcinarene-based synthetic receptors
providing a deep vase-like shape that can be stabilized by a seam
of intramolecular hydrogen bonds.1 Their cavities show
molecular recognition properties and act as hydrophobic nano
15 environments that can promote molecular interactions.2 Reduced
symmetry hosts formed by six amide groups and a functionalized
panel were used for the isolation and characterization of elusive
reaction intermediates and to accelerate, even catalyze, organic
reactions within their cavities.3 The hexaamide diol cavitand 14
20 (Scheme 1) is the module for the introduction of new functions.2b,
Although two diastereoisomers (inward and outward
45 orientation of the benzal hydrogen) might have been formed
1
during the reaction, TLC and crude H NMR spectra showed the
exclusive formation of only one isomer, the one with the
inwardly-directed hydrogen. The chemical shifts of the benzal
hydrogens of cavitands 2-5 ( = 5.38 ppm, 5.32 ppm, 5.30 ppm
50 and 5.30 ppm, respectively, in chloroform-d1) are in accordance
with the literature in a similar solvent ( = 5.38 ppm in
dichloromethane-d2) confirming their inward orientations.6, 8
We used halogenated acetal cavitands 4 and 5 as substrates for
Suzuki-Miyaura couplings (Scheme 2). Treatment of 4 with
55 PdCl2(PPh3)2 in aqueous sodium carbonate (1M) and THF for 24
hours at 70°C led to the ortho-formylated cavitand 10 in 46 %
yield after purification. The same conditions were applied to the
iodo derivative cavitand 5 and improved the isolated yield to 74
%. The meta-formylated derivative 11 was obtained in the same
60 way by coupling 3-formylphenylboronic acid with 5 in 73 %
yield. Formylated cavitands 10 and 11 were also derivatized by
3b
However, the formation of deep cavitands via the
stereoselective bridging of resorcinarenes with four benzal
bromides was introduced by Gibb, and resulted in a new
generation of container molecules.5 We recently used an acetal to
25 functionalize hexaamide diol 1 with a pyridyl group as a fourth
wall.6 Here we report the versatility of this approach to access a
range of monofunctionalized cavitands with unique recognition
properties.
The hexaamide diol cavitand 1 was outfitted with various phenyl
30 acetal walls: unsubstituted, meta-methylamide, para-bromo and
para-iodo, providing respectively cavitands 2-5 (Scheme 1). The
requisite (noncommercial) benzal bromide derivatives 6 and 7
were prepared according to literature precedents,5a, 5b by treatment
65
Scheme 1 Installation of various acetal walls on the hexaamide diol cavitand 1 providing acetal cavitands 2 - 5. Reagents and conditions:
(i) 1 (1 equiv), benzal bromide derivative 6-9 (4-4.6 equiv), DBU (4-4.8 equiv), DMA, 60°C, 3 days.
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

ChemComm
Page 2 of 3
View Online
Scheme 2 Functionalization of acetal cavitands by Suzuki-Miyaura couplings on halogenated precursor cavitands 4-5 and derivatization
to oximes 12-13. Reagents and conditions: (i) PdCl2(PPh)3, aq Na2CO3 1M/THF 30/70 (v/v), 70°C, 24 h ; (ii) NH2OH • HCl, aq NaOH
1M/THF 50/50 (v/v), RT, 24 h.
5
condensation of hydroxylamine hydrochloride in THF at room
temperature in presence of aqueous 1M NaOH. Oxime cavitands
12 and 13 were obtained in 86 % and 95 % yields, respectively.
Accordingly, cavitand 5 represents a versatile platform for the
10 introduction of numerous functionalities, thanks to the impressive
number of boronic acid derivatives available commercially or
through synthesis. All new compounds were fully characterized
1
by H, 13C NMR spectroscopy and MALDI-TOF or ESI mass
spectroscopy.
15
Acetal cavitands 2-5 differ from the other well-known deep
resorcinarene-based hexaamide cavitands. The inwardly-oriented
benzal hydrogen modifies the inner space at the bottom of the
cavity, by decreasing its symmetry,7 and the free rotation of the
20 phenyl group can decrease the shielding effect experienced by
complexed guests. First, binding studies were conducted to
compare the recognition properties and to ascertain these
influences between host 2 and the reference octaamide.7
50 Fig. 1 Guests screened with cavitands 2 and 3 in this study.
Table 1 Thermodynamic parameters Ka for host 2 and 3 (2 mM)
with guests G4 – G6 determined by 1H NMR in mesitylene-d12 at
300 K and 270 K.
Ka (M-1) a
Ka (M-1) a
Hexaamide 2
Heptaamide 3
A series of ten guests (Fig. 1) were screened with cavitand 2 at
25 300 K and 270 K in mesitylene-d12, a non-competitive solvent.
To build a binding profile of the cavity shape, we chose a list of
guests composed of aliphatic chains, aromatic, alicyclic
derivatives and the bulky 2,2’-paracyclophane.
300 K
270 K
300 K
270 K
-
-
170
50
435
broad
40
broad
440
200
740
G4
G5
G6
broad
a
The symbol “-“ denotes that no binding was observed; Errors
No kinetically stable inclusion complex with host 2 could be
30 detected at either 300 K or 270 K with toluene derivatives G1,
G2 or 2,2’-paracyclophane G3 which is one of the largest guests
known for resorcinarene-based cavitands.9 Adamantane
derivatives are particularly good complements for the cavity of
the octaamide cavitands.1a, 10 Guests 2-adamantanone G4 and 1-
35 adamantane carbonitrile G5 both bound 2 at 270 K with
respective Ka values of 170 M-1 and 50 M-1 (Table 1). The most
upfield signals of bound G4 and G5 show chemical shifts
respectively of  = -0.6 ppm and  = -1 ppm while G5 gave a
value of  = -2 ppm with reference octaamide cavitand.11 The
40 chemical shifts of the guest signals are directly related to their
positions inside the cavity; in particular, the deeper a nucleus
resides, the more it is magnetically shielded. It appears that the
adamantane anchors of both guests G4 and G5 float higher in the
cavity of host 2 than in the octaamide cavitand; the benzal
45 hydrogen at the bottom of the cavity apparently prevents deeper
sinking of the adamantane into the cavity. Also, the divergent
orientation of the phenyl acetal wall likely reduces the magnetic
shielding.
are within 10 % from an average of at least three experiments.
55
With n-butyl-1-carboxamide adamantane G6, two broad bound
guest signals are observed at 300 K ( = -0.74, -1.09 ppm). At
270 K, a Ka value of 435 M-1 was determined and the bound
signals ( = -0.82 and  = -1.15 ppm) were sharper than for the
60 two previous adamantane guests G4 and G5 showing a higher
kinetic stability of the host-guest complex, as previously
observed with octaamide cavitand.12 The ability of G6 to form
hydrogen bonds with the amides at the host’s rim improves its
binding to 2 at 300 K. However, toluyl derivative (toluene
65 methylamide G2), branched alkyl chain (leucine methylamide
G7) and alicyclic derivatives (adamantane methylamine G8 and
cyclohexylmethylamine G9) – all able to form such hydrogen
bonds – showed no kinetically stable complexes with 2 on the
NMR timescale at 300 K. Only a broad signal was observed with
70 G7 and G8 indicating little kinetic stability at the lowest
temperature (270 K). With G9, a complex pattern displaying
broad bound guest signals is observed in the upfield region at 270
K, this might be due to the chiral environment experienced by the
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 2

Page 3 of 3
ChemComm
View Online
complexed guest.12
Reduction Agency Joint Science and Technology Office, and the
Skaggs Institute. M.D. and E.B. are Skaggs Post-Doctoral
Fellows.
A fast-exchange complex (on the NMR timescale) was
observed between 2 and G10. The use of 0.5 equivalent of guest
allowed the observation of a set of three guest signals at 300 K
which shift upfield when the temperature decreases.7 With a
higher amount of guest (1 equiv), no guest signal could be
observed in the upfield area, showing a reduced stability. Free
amine may interact with the seam of hydrogen bonds formed by
the six amides of the rim of the cavitand and thereby destabilize
55 Notes and references
5
The Skaggs Institute for Chemical Biology and Department of Chemistry,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla,
California 92037, USA. E-mail: jrebek@scripps.edu
† Electronic Supplementary Information (ESI) available: Synthetic
60 procedures and characterization data for compounds 2-5, 7, 10-13, NMR
spectra of the studied host-guest systems, VT-NMR and NOESY
experiments. See DOI: 10.1039/b000000x/
10 the complexed state between the amine and 2.
A hepta-amide acetal cavitand 3 was obtained by introducing
an amide group at the meta position on the phenyl wall. The
effect of the additional hydrogen-bonding site was apparent by
15 comparing 2 and 3 in variable temperature NMR experiments7 in
chloroform-d1 but the effect was modest.13 These VT-NMR
observations were supported by modelling studies.7 The acetal
amide can act as a hydrogen bond acceptor with good geometry
(NH…O angle = 170°; length = 1.86 Å) or as an hydrogen bond
20 donor (NH…O angle = 165°; length = 1.85 Å).
The thermodynamic parameters for complexation of well-
behaved guests G4-G6 with hosts 2 and 3 are compared in Table
1. Compounds G4 and G5 bind host 3 at 270 K with respective
association constant values Ka of 440 M-1 and 200 M-1, being
25 higher than 170 M-1 and 50 M-1 for the same guests with 2,
indicating stabilization of the inclusion complexes with host 3
compared to 2. With G6, a broad signal was observed at 300 K
while, at 270 K, sharper signals were observed, showing a
kinetically stable complex with a Ka of 740 M-1. In addition, the
30 bound signals patterns with 2 and 3 denote slightly different
positions and orientations of the guests inside their cavities (Fig.
2).
1. (a) D. M. Rudkevich, G. Hilmersson and J. Rebek, J. Am. Chem.
65
70
75
80
85
90
Soc., 1998, 120, 12216; (b) D. M. Rudkevich and J. Rebek, Eur. J.
Org. Chem., 1999, 1991; (c) A. Shivanyuk, K. Rissanen, S. K.
Korner, D. M. Rudkevich and J. Rebek, Helv. Chim. Acta, 2000, 83,
1778.
2. (a) B. W. Purse, A. Gissot and J. Rebek, J. Am. Chem. Soc., 2005,
127, 11222; (b) S. M. Butterfield and J. Rebek, Chem. Commun.,
2007, 1605.
3. (a) B. W. Purse and J. Rebek, PNAS, 2005, 102, 10777; (b) R. J.
Hooley and J. Rebek, Chem. Biol., 2009, 16, 255.
4. P. Amrhein, A. Shivanyuk, D. W. Johnson and J. Rebek, J. Am.
Chem. Soc., 2002, 124, 10349.
5. (a) H. P. Xi, C. L. D. Gibb, E. D. Stevens and B. C. Gibb, Chem.
Commun., 1998, 1743; (b) H. P. Xi, C. L. D. Gibb and B. C. Gibb, J.
Org. Chem., 1999, 64, 9286; (c) R. Kulasekharan, R. Choudhury, R.
Prabhakar and V. Ramamurthy, Chem. Commun., 2011, 47, 2841; (d)
S. Liu, H. Gan, A. T. Hermann, S. W. Rick and B. C. Gibb, Nat.
Chem., 2010, 2, 847.
6. E. Menozzi and J. Rebek, Chem. Commun., 2005, 5530.
7. See ESI.
8. (a) As a result of a shielding effect from the aromatic panels defining
the cavity, Dutasta et al. (ref 8b) and Dalcanale et al. (ref 8c)
observed on their examples a large upfield shift (more than one ppm)
of the benzal hydrogen signal between an outward and inward
orientation; (b) B. Dubessy, S. Harthong, C. Aronica, D. Bouchu, M.
Busi, E. Dalcanale and J. P. Dutasta, J. Org. Chem., 2009, 74, 3923;
(c) E. Menozzi, M. Busi, R. Ramingo, M. Campagnolo, S. Geremia
and E. Dalcanale, Chem.-Eur. J., 2005, 11, 3136; (d) The occurring
mechanism for stereoselectivity is not yet fully understood even
though steric hindrance plays likely an important role in this
stereoselectivity.
35 Fig. 2 Partial 1H NMR spectra (600 MHz, mesitylene-d12, 270 K)
of guest G6 with cavitands (a) 2 and (b) 3. Hydrogen assignments
were determined with 2D NOESY experiments.
95 9. S. X. Xiao, D. Ajami and J. Rebek, Org. Lett., 2009, 11, 3163.
10. A. R. Renslo, F. C. Tucci, D. M. Rudkevich and J. Rebek, J. Am.
Chem. Soc., 2000, 122, 4573.
In summary, acetal-bound walls were installed on a hexaamide
40 diol cavitand to allow further functionalization through Suzuki-
Miyaura coupling. A wide range of introverted functionalities
could be introduced with this strategy. Host-guest complexes
were observed with adamantane guests with binding constants
ranging from 40 to 740 M-1. The introduction of an additional
45 hydrogen bonding site resulted in modest increases in the stability
of the complexes. Applications of this new family of synthetic
receptors bearing introverted functionalities will be reported in
due course.
11. R. J. Hooley, S. R. Shenoy and J. Rebek, Org. Lett., 2008, 10, 5397.
12. S. H. Ma, D. M. Rudkevich and J. Rebek, Angew. Chem. Int. Ed.
100
Engl., 1999, 38, 2600.
13. (a) A. Lledo and J. Rebek, Chem. Commun., 2010, 46, 1637; (b) D.
M. Rudkevich, G. Hilmersson and J. Rebek, J. Am. Chem. Soc., 1997,
119, 9911.
50 Acknowledgements
We are grateful for financial support from Defense Threat