Control of planar chirality: The construction of a copper-ion-controlled chiral molecular hinge

Article abstract of DOI:10.1002/anie.200800062

(Figure Presented) An open-and-closed case: When a chiral clamp is attached to a molecular hinge the open-close motion induced by coordination to a metal ion becomes unidirectional (see scheme). The large change in amplitude caused by the unidirectional rotation and the relatively simple preparation of the hinge open up the possibility of using this concept for even more-complex molecular machines.

Full text of DOI:10.1002/anie.200800062

Angewandte
Chemie
DOI: 10.1002/anie.200800062
Molecular Machines
Control of Planar Chirality: The Construction of a Copper-Ion-
Controlled Chiral Molecular Hinge**
Gebhard Haberhauer*
The control of the mechanical motion of single molecules by
external stimuli is a rapidly growing scientific area of great
contemporary interest.[1] Until now, a variety of molecular
devices, such as motors, rotors, shuttles, ratchets, and tweez-
ers, have been developed.[1,2] A crucial point is the construc-
tion of synthetic molecular machines that utilize—in analogy
to their macroscopic pendants—the directional and synchron-
ized movements of smaller parts. In these systems an external
stimulus triggers the controlled, large-amplitude or direc-
tional mechanical motion of one component relative to
another which results in a task being performed.[2a] Especially
useful for this purpose are molecular devices in which
unidirectional rotations are controlled by changes of config-
uration or conformation. Examples of such systems are
unidirectional rotors rotating around single or double
bonds,[3] catenanes showing unidirectional rotary motion,[4]
and molecular scissors.[5] In the latter, irradiation triggers the
opening and closing of the blades with an alteration of the
angle between the blades from approximately 98 to 588.
A unidirectional open–close
tional open–close motion we chose the 2,2’-biypridine unit
ꢀ
(Scheme 1). Here the pivot is the C C bond between the two
pyridine units. In the uncomplexed state, 2,2’-bipyridine
exhibits an N-C-C-N dihedral angle of 1808. This value
changes to 08 when the bipyridine unit forms a complex with,
for example, a copper(II) ion. The substituents para to the
nitrogen atoms undergo a relative amplitude motion of 1808.
The driving force for the closing process is the formation of
the copper(II) bipyridine complex, whereas the driving force
for the opening is the repulsive interaction between the
hydrogens in positions 3 and 3’ of the bipyridine in the
absence of copper(II) ions. The removal of the copper(II) ions
can be achieved chemically by the addition of an even
stronger CuII-complexing agent such as cyclam. To prevent an
overrotation of the flexible pyridine unit, a medium-sized
bridge is introduced, thus making the entire molecule planar
chiral when it is not complexed. Consequently, the differ-
entiation between the desired and the undesired open–close
motion can be reduced to the selective formation of only one
mechanism with even higher rel-
ative amplitudes (around 1808) is
possible with a hinge. The two
flexible wings of the hinge (blue
elements in Scheme 1) can be
opened and closed by motion
about the rotation axis (red ele-
ment) in only one direction (area
framed in green in Scheme 1);
opening in the opposite direction
is not possible (area framed in
red). Closing at the hinge also
occurs only in one direction; a
flipping “inside out” (overrota-
tion), a closing motion extending
from a dihedral angle of 1808 to
an angle of 3608, is prevented by a
fixing bracket (black element).
Scheme 1. Schematic representation of the chiral molecular hinge 1 and its unidirectional open–close
motion.
As a basis for the design of a
molecular hinge with a unidirec-
of two enantiomers ((M)-1 and (P)-1 in Scheme 1), in other
words, the control of the planar chirality. The conformers
[*] Prof. Dr. G. Haberhauer
Institut für Organische Chemie, Fachbereich Chemie
Universität Duisburg-Essen
Universitätsstrasse 5, 45117 Essen (Germany)
Fax: (+49)201-183-4252
(M)-1 and (P)-1 are diasteromers when a bridge with
additional chiral units is used. Accordingly, the control of
the direction of the open–close motion is essentially based on
the choice of suitable diastereomers of type 1 in which the
conformers (M)-1 and (P)-1 are so different in energy that
only one of the two conformations is adopted.
E-mail: gebhard.haberhauer@uni-due.de
[**] This work was generously supported by the Deutsche Forschungs-
gemeinschaft (DFG). I thank Dr. Andreea Schuster for helpful
discussions.
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As we had already used cyclic peptides having imidazole
and oxazole units in the backbone for the control of axial
chirality[6] and for chirality transfer in C3-symmetric com-
pounds,[7] we decided to use this type of chiral clamp also for
the design of a molecular hinge with unidirectional open–
close motion. The synthesis of 1 is shown in Scheme 2. The
chiral clamp 2[6] can be alkylated with 3-methoxybenzyl
bromide using Cs2CO3 as base. Removal of the methoxy
groups with BBr3 and subsequent nucleophilic aromatic
substitution with the corresponding dihalogenobipyridines 4
led to the desired hinges (M)-1.
Figure 1. Molecular structures of (M)-1a and (M)-1b calculated using
B3LYP/6-31G*. All hydrogen atoms have been omitted for clarity.
Scheme 2. Preparation of the chiral molecular hinges (M)-1. Reaction
conditions: a) 3-methoxybenzyl bromide, Cs2CO3, CH3CN, D, 66%;
b) BBr3, CH2Cl2, ꢀ788C!RT, 95%; c) Cs2CO3, DMF, 1108C, 20% for
(M)-1a and 25% for (M)-1b.
are virtually perpendicular to each other. As a result the C7–
C7’ distance in the P isomers is greater than that in the M
isomers: For (P)-1a the distance was calculated to be 9.80 Š,
whereas in (M)-1a it amounts to only 8.98 Š (see Table 1).
The greater C7–C7’ distance causes tension in the rigid
peptidic scaffold, thus explaining the high energetic discrim-
ination between the conformers.
The large energy difference between the isomers leads to
the conclusion that in solution bipyridines 1 also adopt
exclusively the M conformation at room temperature. To
confirm this assumption we performed NMR experiments in
CDCl3/CD3OD as solvent. Since for 1a all peaks in the
aromatic area are separated, we were able to determine H–H
distances from 2D NOESY experiments allowing conclusions
about the three-dimensional structure. The most important
values are compiled in Table 1. The deduced spatial structure
corresponds unambiguously to the M conformation. The most
important difference between the conformers is the distance
between the protons H11 and H5 and the distance between
the protons H11 and H3. For (M)-1a a very large H11–H5
distance is calculated (5.02Š), whereas for ( P)-1a it is
distinctly smaller (2.97 Š). In the NMR experiment the H11–
The essential feature of the hinge is the significant
energetic discrimination of the M and P isomers so that the
opening occurs selectively in only one direction. To determine
the energy value by which the M isomer is stabilized relative
to the P isomer as a result of the chiral clamp, DFT
calculations were carried out.[8] The structures of (M)-1 and
(P)-1 were determined by geometry optimizations using
B3LYP and the 6-31G* basis set (see Figure 1). The calculated
energy difference between the M and P isomers amounts to
42.2 kJmolꢀ1 for 1a and 33.4 kJmolꢀ1 for 1b. The calculated
dihedral angle N1-C2-C2’-N1’ is 1788 in (M)-1a, whereas in
(M)-1b it is 1638 and thus somewhat lower (for the numbering
of the atoms in 1 see Scheme 2). The reason for the large
energy gap between the isomers becomes clear when one
looks at the position of the bipyridine units relative to the
chiral peptidic scaffold: In the P isomers the axes C2–C2’ and
N13–N13’ are almost parallel, whereas in the M isomers they
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Table 1: Distances [Š] for 1a obtained from NMR experiments and
calculated distances [Š] for the conformers (M)-1a and (P)-1a using
B3LYP/6-31G*.
(M)-1a (calcd)
1a (NMR)
(P)-1a (calcd)
O6–O6’
C7–C7’
8.24
8.98
1.75
2.35
2.49
3.52
3.72
5.02
2.96
2.72
8.12
9.80
1.74
2.98
2.45
4.98
2.47
2.97
3.57
4.93
H10a–H10b
H10a–H9
H11–H10a
H11–H9
H11–H8
H11–H5
H11–H4
H11–H3
1.75[a]
2.18
2.41
3.02
3.00
–
2.49
2.36
[b]
[a] The distance between the diastereotopic protons H10a and H10b was
used as a reference for calibration. [b] In the 2D NOESY spectrum no
cross-peaks between H11 and H5 were observed.
H5 distance could not be determined because corresponding
cross peaks are not observed in the 2D NOESY spectra. This
indicates that this distance is greater than 4 Š. The situation is
reversed for the H11–H3 distance: Here the B3LYP calcu-
lations attribute a value of 2.72 Š to (M)-1a and 4.93 Š to
(P)-1a. The distance determined experimentally with the
NOESY technique amounts to 2.36 Š; this is not a mean
value for the two individual diastereomers. In solution, too,
only the M conformer is present.
The closing at the hinge by complexation with CuII ions
was examined by high-resolution mass spectrometry as well as
by CD and UV spectroscopy. When Cu(OTf)2 was added to a
solution of 1a (or 1b) in dichloromethane, the formation of
the corresponding Cu bipyridine complexes was observed. In
the case of 1a the newly formed copper–bipyridine band
appears at 335 nm, whereas in 1b owing to the two phenyl
rings it shows a bathochromic shift to 340 nm. After addition
of 2.5 equiv CuII ions bipyridines 1 were completely trans-
formed into the corresponding 1·Cu2+ complexes, and thus a
further addition of CuII ions (for example, 3.0 equiv in total)
led to no change in the spectra. High-resolution mass spectra
of 1a and 1b show unambiguously that under these con-
ditions, the mononuclear 1·Cu compounds are formed. In
contrast, with 3b (R = Me), which is the chiral clamp without
bipyridine units, no complexation of CuII ion was observed
under equivalent conditions. This means that in 1 the
complexation of copper(II) ions takes place at the bipyridine
units.
Figure 2. a) CD spectra of 1a (blue) with 2.5 (red) and 3.0 (yellow)
equiv Cu(OTf)2 and with 3.0 equiv Cu(OTf)2 plus 6.0 equiv cyclam
(green) ([1a]=1.0”10ꢀ5 m in dichloromethane). b) CD spectra of 1b
(blue) with 2.5 (red) and 3.0 (yellow) equiv Cu(OTf)2 and with
3.0 equiv Cu(OTf)2 plus 6.0 equiv cyclam (green) ([1b]=1.0”10ꢀ5 m in
dichloromethane). c) CD spectra of 1a (red), 1b (blue), and 3b
(R=Me; green) each with 3.0 equiv Cu(OTf)2 (c=1.0”10ꢀ5 m in
dichloromethane).
The formation of the copper–bipyridine complex, which is
complete after the addition of 2.5 equiv CuII ions, can also be
observed in the CD spectra of 1a and 1b (Figure 2). Addi-
tionally, the CD spectra reveal the changes of conformation
caused by the complexation with copper(II) ions. The CD
spectrum of (M)-1a shows negative Cotton effects at 293 nm
and 256 nm and positive Cotton effects at 272 nm and 242 nm
(Figure 2a). The complex formation effected by the addition
of CuII ions causes a drastic change in the CD spectrum. The
broad negative band at 293 nm disappears completely and the
spectrum shows even slightly positive values in this area.
Furthermore, the positive band at 272 nm disappears and only
two bands—the negative Cotton effect at 266 nm and the
positive Cotton effect at 236 nm—remain. This result is
consistent with the expected behavior of the hinge: In the
open state 1a exhibits planar chirality[9] and as a result of the
chiral peptidic scaffold only the M conformation is adopted.
The negative band at 293 nm and the positive band at 272 nm
reflect the presence of planar chirality. Closing at the hinge
leads to a loss of the planar-chiral elements and the 1a·Cu2+
complex shows merely the chiral elements of the clamp.
Indeed, the shape of the CD spectrum of the 1a·Cu2+ complex
strongly resembles the spectrum of 3b (R = Me), which is the
chiral clamp without bipyridine units, under analogues
conditions (Figure 2c).
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Also in case of (M)-1b closing at the molecular hinge by
[1] a) Topics in Current Chemistry, Vol. 262 (Ed.: T. R. Kelly),
Springer, Berlin, 2005; b) V. Balzani, M. Venturi, A. Credi,
Molecular Devices and Machines, Wiley-VCH, Weinheim, 2003.
[2] See following reviews and literature cited therein: a) E. R. Kay,
D. A. Leigh, F. Zerbetto, Angew. Chem. 2007, 119, 72 ;Angew.
Chem. Int. Ed. 2007, 46, 72; b) Y. Shirai, J.-F. Morin, T. Sasaki,
J. M. Guerrero, J. M. Tour, Chem. Soc. Rev. 2006, 35, 1043;
c) D. A. Leigh, E. M. Parez, Top. Curr. Chem. 2006, 265, 185;
d) K. Kinbara, T. Aida, Chem. Rev. 2005, 105, 1377; e) G. S.
Kottas, L. I. Clarke, D. Horinek, J. Michl, Chem. Rev. 2005, 105,
1281.
[3] a) D. Pijper, R. A. van Delden, A. Meetsma, B. L. Feringa, J.
Am. Chem. Soc. 2005, 127, 17612; b) S. P. Fletcher, F. Dumur,
M. M. Pollard, B. L. Feringa, Science 2005, 310, 80; c) N.
Koumura, R. W. J. Zijlstra, R. A. van Delden, N. Harada, B. L.
Feringa, Nature 1999, 401, 152.
copper complexation can be observed as a drastic change in
the CD spectrum. As a result of the better chromophore in
(M)-1a, all CD bands effected by the planar-chiral element
are more pronounced than in (M)-1a (Figure 2b). In this case,
too, the closing motion at the molecular hinge 1b by copper
complexation leads to a spectrum resembling the spectrum of
3b (R = Me) under analogues conditions (Figure 2c).
The opening at the hinge can be achieved chemically by
addition of an excess of cyclam, which binds copper(II) ions
much better than the bipyridine units of 1. After addition of
cyclam, the CD spectra of 1a and 1b return to their original
shape (green curves in Figure 2a,b). Consequently, the
molecular hinge can be opened and closed reversibly and
unidirectionally. The stimulus for closing by copper(II) ions
and subsequent opening can be repeated over a number of
cycles.[10]
[4] a) J. V. Hernꢀndez, E. R. Kay, D. A. Leigh, Science 2004, 306,
1532; b) D. A. Leigh, J. K. Y. Wong, F. Dehez, F. Zerbetto,
Nature 2003, 424, 174.
In conclusion, we have succeeded in the design of a
molecular hinge showing a unidirectional open–close motion
by using a chiral peptidic clamp. The high change of
amplitude caused by the unidirectional rotation and the
relatively simple preparation of the hinge open up the
possibility for using this concept for even more-complex
molecular machines.
[5] a) T. Muraoka, K. Kinbara, T. Aida, Nature 2006, 440, 512; b) T.
Muraoka, K. Kinbara, Y. Kobayashi, T. Aida, J. Am. Chem. Soc.
2003, 125, 5612.
[6] G. Haberhauer, Angew. Chem. 2007, 119, 4476; Angew. Chem.
Int. Ed. 2007, 46, 4397.
[7] a) ꢁ. Pintꢂr, G. Haberhauer, I. Hyla-Kryspin, S. Grimme, Chem.
Commun. 2007, 3711; b) G. Haberhauer, T. Oeser, F. Rominger,
Chem. Commun. 2005, 2799.
[8] All calculations were carried out with the program Gaussian 03.
[9] S. Grimme, J. Harren, A. Sobanski, F. Vꢃgtle, Eur. J. Org. Chem.
1998, 1491.
Received: January 7, 2008
[10] The number of reversible cycles is not limited by the system but
by the measurement technique: With increasing overall concen-
tration of all components the absorption of the entire system is
too high to obtain meaningful CD signals in the desired part of
the spectra.
Keywords: CD spectroscopy · molecular machines ·
molecular switches · planar chirality · stereocontrol
.
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