A modular molecular tweezer designed using CAVEAT

Article abstract of DOI:10.1039/b605756j

A pair of water-soluble molecular tweezers designed using the computer program CAVEAT were prepared and their binding to an N-ethylquinolinium cation was demonstrated by ¹H NMR spectroscopy. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b605756j

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A modular molecular tweezer designed using CAVEAT{
Haidong Huang and Dale G. Drueckhammer*
Received (in Austin, TX, USA) 25th April 2006, Accepted 23rd May 2006
First published as an Advance Article on the web 7th June 2006
DOI: 10.1039/b605756j
structures of this type have been made water-soluble and have
A pair of water-soluble molecular tweezers designed using the
computer program CAVEAT were prepared and their binding
to an N-ethylquinolinium cation was demonstrated by 1H
NMR spectroscopy.
been extended to cation receptors for lysine and arginine.12 The
tweezer system that best represents the ideal of linked parallel
aromatic faces is that extensively developed by the Zimmerman
group and represented by 2 in Fig. 1.13–16 The original design has a
Receptors for aromatic groups are of interest for a variety of
reasons including biological and biomimetic applications, and as
components of chemosensors.1–5 Several types of macrocyclic
receptors that encapsulate aromatics and other guests have been
studied including the natural cyclodextrins6 and the designed
calixarenes7 and cyclophanes.8 Molecular tweezers and clips have
been developed that bear a pair of parallel or near-parallel
aromatic binding groups connected by a spacer or linker between
which an aromatic guest molecule can insert.9–16 These non-
macrocyclic receptors may be less limited in the size of the guest
molecule that can be bound and have the potential to be more
modular for convenient introduction of different aromatic binding
groups for complementarity to different guests. Ideally the distance
between binding groups should be about 7.0 s or slightly less, as
aromatic groups stack at an interplanar distance of ¡3.5 s. A
pioneering tweezer design by Whitlock and coworkers had a pair
of caffeine molecules connected by a very flexible linker.9 More
recent efforts have been directed at tweezers or clips having the
binding groups preorganized for guest binding. A recent design by
Lehn has a cavity that is preorganized by metal ion binding to the
linker.10 An example of a type of more rigidly organized structure
is the design from the group of Kla¨rner having norbornane-linked
aromatic groups, represented by 1 (Fig. 1).11 The receptor surfaces
in the Kla¨rner systems are substantially non-parallel, but these
receptor designs have given impressive binding results. The binding
groups and linker are not fully distinct and binding may occur to
the faces and edge of the guest molecule. In recent efforts,
pair of aromatic groups attached via single bonds to a
dibenzacridine spacer. Several aromatic binding groups have been
incorporated and numerous minor modifications of the linker have
been made, including the incorporation of hydrogen bonding
groups directed toward the central binding cavity. The linkage
points are at a distance of about 7.24 s, just above the
approximately 7.0 s ideal. As part of an ongoing project in the
use of the computer program CAVEAT in molecular design, we
undertook the application of CAVEAT to the design of a simple
tweezer structure that might have features complementary to those
of the Zimmerman system and related structures.17–20
The design approach is illustrated in Scheme 1. A pair of parallel
vectors at a distance of 7.0 s was used to define a CAVEAT
search of the TRISUB database of trisubstituted monocyclic
hydrocarbons.20 Fourteen unique potential linker structures were
identified from this search, including structure 3. In this structure
both the bonds to the hydrogens ortho and meta to the point of
attachment of the phenyl rings to the cyclopentene match the
defined vector pair. The vinyl group is present simply because the
database contains only trisubstituted structures and thus 3 is
representative of a group of structures having different ‘‘extra’’
substituents at different positions of the cyclopentene. Deletion of
the vinyl substituent and attachment of phenyl groups in place of
the meta hydrogens of 3 gives the minimal tweezer structure 4.
Computational modeling of this structure indicated a 7.2 s
distance between points of attachment of the phenyl rings, with a
dihedral angle about the phenyl–phenyl bonds of 62u needed for
the faces of the outer phenyl rings to be parallel.
Based on this linker structure, the tweezer 11 was initially
prepared as shown in Scheme 2. 11 incorporates naphthalene
rings as binding groups with a carboxylate on each naphthalene
to impart aqueous solubility. The racemic diol monoacetate 5
was prepared following literature methods by reaction of
Fig. 1 Molecular tweezers of Kla¨rner and Zimmerman.
Dept. of Chemistry, Stony Brook University, Stony Brook, New York,
USA. E-mail: dale.drueckhammer@sunysb.edu; Fax: 631 632 7960;
Tel: 631 632 7923
{ Electronic supplementary information (ESI) available: 1H NMR spectra
for binding experiments and experimental procedures. See DOI: 10.1039/
b605756j
Scheme 1 Design of a molecular tweezer using CAVEAT.
Chem. Commun., 2006, 2995–2997 | 2995
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Grignard that was reacted with isopropyl pinacolatoborate to
form 10, from which unreacted 14 was readily separated.28 Suzuki
coupling of 10 with the functionalized linker 8 followed by ester
hydrolysis formed 12 (Scheme 2).
The 1-ethyl-4-methylquinolinium cation 15 was chosen as a
convenient water-soluble guest. Complex formation was studied
by NMR titration in D2O. 1H NMR spectra were acquired upon
addition of increasing amounts of 11 to a solution of the iodide salt
of 15 (see ESI{ for spectra). An upfield shift of all the aromatic
protons of 15 was observed. The proton at C-2 and the protons of
the N-CH2 group of 15 gave distinct signals for which the change
in chemical shift was easily quantified. Changes of ¢1 ppm were
observed, while changes due to dilution were less than 0.1 ppm.
Data fitting gave an association constant of 950 M21. Binding of
15 to the chlorinated tweezer 12 was also studied by NMR
titration. Similar chemical shift changes were observed, but greater
line-broadening was observed such that peak positions could not
be accurately discerned beyond the first three injections. The line-
broadening may be attributed to reversible association on the
NMR time-scale. The association constant estimated from the first
Scheme 2 Synthesis of two molecular tweezers.
three injections was 330 M21
.
cyclopentadiene with singlet oxygen followed by reduction to the
diol and acetylation.21 Reaction of 5 with 3-bromophenyl
magnesium chloride 6, prepared by reaction of meta-bromoiodo-
benzene with isopropylmagnesium chloride, formed 7.22 These
conditions have been shown to give inversion as shown.23,24 The
chloride counterion was critical for good SN2 vs. SN29 selectivity.
Acetylation of the hydroxyl group of 7 followed by reaction again
with the Grignard reagent 6 formed 8. Attempts to form 8 in a
single step from the diacetate of cyclopentenediol gave a large
amount of SN29 substitution product. Suzuki coupling of 8 with
two equivalents of the boronic ester 9, derived by Miyaura reaction
of methyl 6-bromo-2-naphthoate, followed by ester hydrolysis
gave 11.25,26
The binding could be diminished by self-association of the
receptor and by the lack of complete preorganization of the
somewhat flexible tweezer. While individual resonances for 11 and
12 could not be discerned, the protons of the naphthalene rings are
also shifted significantly upfield upon binding of 15. This suggests
an absence of p-stacking in the receptor solution alone and thus
minimal self association. A conformational search of 11 (PM3)
gave a mixture of conformers due to rotation about the
cyclopentenyl–phenyl and phenyl–naphthyl single bonds. The
lowest energy conformer exhibits an edge to face interaction
between the two naphthyl groups, though these calculations do not
include solvent effects.
Also prepared was the corresponding tweezer 12 having chlorine
substituents on each naphthalene ring. The chlorines were
incorporated to influence the dihedral angle between the naphthyl
and phenyl rings as described below. Synthesis of the necessary
chlorinated boronic ester 10 began with chlorination of methyl
6-bromo-2-naphthoate 13, with the desired 5-chloro product 14
purified from the mixture of isomeric products (Scheme 3).
Attempts to directly convert 14 to the boronic ester 10 were
unsuccessful. The transformation to 10 was achieved by initial
reverse transhalogenation of the bromide to the iodide.27 This
reaction did not go to completion and separation of product from
unreacted starting material was not successful. Isopropylmagne-
sium chloride reacted only with the iodide to form the aryl
The binding constants for 11 and 12 are within the range
observed in binding of aromatic guests to other receptors,29–31
though some examples of about 10-fold stronger binding of
aromatic guests have been observed.12,32 Thus while the tweezers
11 and 12 do not exhibit as high affinity as the best related
receptors, they do exhibit fairly similar affinity within a much more
modular and open structure that should be amenable to binding of
a range of sizes and shapes of guests.
In our system as well as in the Zimmerman tweezers, the relative
position of the pair of aromatic surfaces of the tweezer is
influenced by the dihedral angle between the receptor face rings
and the aromatic rings of the linker. The barrier to rotation is
expected to be too small to observe atropisomers.33 In our system
the ideal dihedral angle for aligned parallel surfaces is about 62u,
while the Zimmerman tweezers are based on a 90u dihedral angle.
Deviation from the dihedral angle by rotating both aromatic
surfaces in the same direction from the ideal brings the faces closer
together and results in a horizontal displacement of one surface
relative to the other.16 A somewhat horizontally displaced
Scheme 3 Additional steps in the synthesis of the chlorinated tweezer.
2996 | Chem. Commun., 2006, 2995–2997
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Notes and references
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13 S. C. Zimmerman and C. M. VanZyl, J. Am. Chem. Soc., 1987, 109,
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Table 1 Dihedral angles for 1-substituted-2-phenylnaphthalenesa
Dihedral angle/u
X
C1–C2–C5–C4
C3–C2–C5–C6
Eopt 2 E62u /kJ mol21
H
Cl
a
45.2
68.8
45.2
65.8
21.89
21.21
Calculated at the HF/6-31G* level.
arrangement of p-stacking surfaces is preferred, and thus this
displacement of receptor surfaces may not be of great significance
if a fairly optimal displaced arrangement of the guest relative to
both receptor surfaces can be achieved. The current computing
power permits this issue to be addressed computationally at a
higher level than the molecular mechanics calculations reported for
the Zimmerman system. Table 1 shows the calculated dihedral
angles for 2-phenylnaphthalene and 1-chloro-2-phenylnaphthalene
as models for tweezers 11 and 12, respectively. Without the
chlorine, the dihedral angle is about 17u smaller than the ideal
while with the chlorine, it is about 5u greater than the ideal. This
indication that the chlorine substituent should provide a more
ideal dihedral angle provided the justification for its introduction.
The energetic cost of distorting the dihedral angle to the ideal is
moderately greater for the system without the chlorine, though the
difference in distortion energy is small relative to the difference in
angle of distortion. The cost of distorting both dihedral angles of
the receptor to the ideal would be double these values, and could
impede binding about three- and five-fold for 11 and 12,
respectively. While some distortion from the most stable dihedral
angle may occur, it seems unlikely that full distortion to the ideal
occurs but rather that binding occurs to a less ideal structure of the
tweezer. This seems likely to also be the case with the Zimmerman
tweezers. Our observation that the tweezer without chlorine binds
its guest about three-fold more strongly suggests that this issue is
not so important. The diminished binding of the chloro-substituted
tweezer may be attributed to the inductive effect of chlorine, which
results in weaker binding to an electron-deficient guest.
The molecular tweezer system described here is easily synthe-
sized and modular, such that various aromatic surfaces for guest
binding should be readily introduced. The comparison of the
receptors with and without chlorine suggest that precise tuning of
the dihedral angle between linker and binding groups is not
critical, which further simplifies the design and synthesis of
receptors based on this structure. The linker moiety may be
complementary to the conceptually similar Zimmerman system,
especially in regard to possible positions for introduction of other
functional groups to bind additional functionality of targeted guest
molecules. The general design may be widely applicable to
receptors for other aromatic compounds.
30 D. B. Smithrud, T. B. Wyman and F. Diederich, J. Am. Chem. Soc.,
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1992, 114, 10624; T. T. Goodnow, M. V. Reddington, J. F. Stoddart
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1988, 110, 1983.
Financial support from the National Science Foundation
(CHE0213457) is gratefully acknowledged. NMR facilities were
supported by a grant from the National Science Foundation
(CHE0131146).
33 F. Grein, J. Phys. Chem. A, 2002, 106, 3823.
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Chem. Commun., 2006, 2995–2997 | 2997