Cadiot-Chodkiewicz active template synthesis of rotaxanes and switchable molecular shuttles with weak intercomponent interactions

Article abstract of DOI:10.1002/anie.200800891

(Chemical Equation Presented) Shuttling fast and loose: Weak interaction, switchable, rotaxane-based molecular shuttles, in which the positional fidelity of the macrocycle is conferred by a single hydrogen bond in each state, are constructed through the high-yielding and selective active template heterocoupling of different functionalized alkynes using the Cadiot-Chodkiewicz reaction.

Full text of DOI:10.1002/anie.200800891

Communications
DOI: 10.1002/anie.200800891
Rotaxanes
Cadiot–Chodkiewicz Active Template Synthesis of Rotaxanes and
Switchable Molecular Shuttles with Weak Intercomponent
Interactions**
JosØ Bernµ, Stephen M. Goldup, Ai-Lan Lee, David A. Leigh,* Mark D. Symes,
Gilberto Teobaldi, and Francesco Zerbetto*
The noncovalent binding motifs used to template the syn-
thesis of mechanically interlocked architectures are generally
retained in the final products.[1] This feature has been widely
exploited to make molecular shuttles,[2] rotaxanes with two or
more discrete binding sites or “stations” on the thread
between which the macrocycle incessantly shuttles through
Brownian motion. However, the noncovalent interactions
used to maximize the rotaxane yield and localize the position
of the ring on the thread also provide the major contribution
to the activation energy to shuttling.[3] To achieve faster
moving rotaxane-based molecular machines, it will be neces-
sary to make molecular shuttles with much weaker intercom-
ponent interactions than are typically introduced with clas-
sical template methods.[4] Here we report on a new rotaxane-
forming reaction that can produce rotaxanes with unsym-
metrical threads (as required for switchable molecular
shuttles) but does not leave strong intercomponent binding
motifs in the rotaxane product. Instead the active template[5]
Cadiot–Chodkiewicz[6] reaction is compatible with building
blocks that can provide relatively modest macrocycle–thread
binding motifs in the rotaxane, but which are still strong
enough to afford good positional integrity of the ring. The
methodology is exemplified through the synthesis of a “weak
interaction” molecular shuttle in which a single hydrogen
bond between the components determines the predominant
position of the macrocycle in each of two well-defined states
which can be switched between by reversible complexation
with Li+ or protonation.
Active template syntheses differ from classical “passive-
template” reactions in that a single species acts as both the
template for the product architecture and the catalyst for the
formation of the covalent bond(s) that captures it.[5] Although
combining these two roles has several potential advantages,[5a]
controlling the positions of the metal-ligated building blocks
during the reaction to template the product puts additional
demands (which can provide insight into the reaction
pathway)[5d] on the mechanism of catalysis. Accordingly,
successful combinations of ligands and metal-catalyzed reac-
tions for active template syntheses are still rare and the
development of new systems challenging.[5e]
The active metal template homodimerization of acety-
lenes to form rotaxanes[5b,c] introduces a relatively rigid linear
connector which inhibits folding—potentially desirable for
fully exploiting the spatial separation of the ring between
different states[7]—but can only be used to make [2]rotaxanes
with symmetrical axles. The coupling of two different building
blocks is necessary to produce bistable molecular shuttles in
which the macrocycle can be switched between two different
positions on the thread. The CuI-mediated Cadiot–Chodkie-
wicz[6] heterocoupling of a terminal alkyne with an alkyne
halide appeared a suitable candidate reaction for such studies
(Table 1).
Promisingly, [2]rotaxane was produced (Table 1) using
appropriately “stoppered” alkyne halide (1a or 1b) and aryl
alkyne (2) derivatives and a bidentate macrocycle (3) under
typical conditions[6] used for the Cadiot–Chodkiewicz reac-
tion in nonaqueous solvents. However, in these initial studies
poor selectivity for the heterocoupled rotaxane (4) versus the
homocoupled rotaxanes (5 and 6) was observed together with
low overall conversion of the alkyne starting materials to bis-
acetylene products. In an attempt to improve both the
reaction yield and the selectivity for the heterocoupled
rotaxane, we investigated changing the traditional Cadiot–
Chodkiewicz procedure of mixing the alkyne and alkyne
halide components with neutral amine bases, to preforming
the copper acetylide by treatment of terminal alkyne 2 with
nBuLi, followed by transmetalation with CuI (Table 2).[8]
Following this protocol, we were delighted to find that
subsequent addition of bipyridine macrocycle 3 and bromoa-
cetylene 1b led to the desired [2]rotaxane 4 in high yield
(84%) and with excellent selectivity (> 98%) for the hetero-
coupled product (Table 2, entry 1).[9] Although the procedure
did not prove compatible with reversing the reactive bromine/
hydrogen functionalities of the alkyl and aryl acetylene
building blocks (7 with 8, Table 2, entry 2),[10] when coupling
[*] Dr. J. Bernµ, Dr. S. M. Goldup, Dr. A.-L. Lee, Prof. D. A. Leigh,
M. D. Symes
School of Chemistry, The University of Edinburgh
The King’s Buildings, West Mains Road, Edinburgh EH9 3JJ (UK)
Fax: (+44)131-650-6453
E-mail: David.Leigh@ed.ac.uk
Homepage: http://www.catenane.net
Dr. G. Teobaldi, Prof. F. Zerbetto
Dipartimento di Chimica “G. Ciamician”, Università di Bologna
via F. Selmi 2, 40126 Bologna (Italy)
Fax: (+39)051-209-9456
E-mail: Francesco.Zerbetto@unibo.it
Homepage: http://www.ciam.unibo.it/sitcon/
[**] This work was supported by the European Union project STAG and
the EPSRC. D.A.L. is an EPSRC Senior Research Fellow and holds a
Royal Society-Wolfson Research Merit Award.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
homocoupling of alkynes,[11] and the proposed pathway for
the active-metal template rotaxane assembly of 4 is shown in
Scheme 1. The preformed copper(I)–acetylide I is seques-
Table 1: Preliminary solvent screen for the bis-acetylene rotaxane form-
ing active template Cadiot–Chodkiewicz reaction.[6]
Entry
Alkyne
halide
Solvent
Rotaxane yield
1+2+3!4+5+6
Selectivity
4:5:6
1
2
3
4
5
1a
1a
1a
1a
1b
(iPr)2NH
NEt3
pyrrolidine
benzene[b]
(iPr)2NH
40%
20%
<2%
35%
<5%
10:9:1
2:15:1
no rotaxane
1.7:1:1
2:5:1
[a] Asolution of 1, 2, 3, and CuI (all 1 equiv) was allowed to stir at 298 K
under an atmosphere of N2 for 18 h. [b] Plus 2 equiv of (iPr)2NH.
Scheme 1. Proposed mechanism for the Cadiot–Chodkiewicz active
metal template formation of [2]rotaxane 4.[11]
Table 2: Substrate scope of the Cadiot–Chodkiewicz active metal
template synthesis of heterocoupled [2]rotaxanes.
tered by bipyridine macrocycle 3.[12] Oxidative addition across
ꢀ
the C Br bond of the bromoacetylene occurs from the
opposite face of the macrocycle to produce CuIII intermediate
II and subsequent reductive elimination furnishes the hetero-
coupled [2]rotaxane.
To demonstrate the utility of this new active template
reaction, we synthesized a stimuli-switchable molecular
shuttle 12 which has modest strength intercomponent inter-
actions of a type that would be difficult or impossible to access
by traditional template methods. The single contact H-bond
that molecular modeling (see the Supporting Information)
indicates (Figure 2) exists between the aniline unit of the
thread and bipyridine group of the macrocycle in 12 is too
weak to template rotaxane formation through “stoppering”
or “clipping” strategies[1] and no passive metal templates
which utilize a 1+2 donor ligand set have been reported to
date. However, the modified Cadiot–Chodkiewicz active
metal template method readily produced molecular shuttle
12 in good yield (61%) from functionalized building blocks 13
and 14 with no homocoupled rotaxane products being
detected (Scheme 2).
Entry Terminal
acetylene[a]
Bromo-
acetylene
Rotaxane Selectivity
yield [%]
1
84
>98%[b]
2
3
4
32
85
74
1.7:8:1 (4:5:6)
>98%[b]
>98%[b]
[a] R=(tBuC6H4)3CC6H4. [b] No homocoupled rotaxanes observed.
two different alkyl alkynes (7 with 9 or 11 with 1b to give 10)
either could be used successfully as the bromoacetylene
partner whilst maintaining high yields and apparent exclusive
selectivity for the heterocoupled rotaxane (Table 2, entries 3
and 4).
1H NMR Spectroscopy clearly shows the macrocycle to be
predominantly held over the axle aniline unit in neutral
molecular shuttle 12 at 300 K in CD2Cl2. The 1H NMR
spectrum of the rotaxane (Figure 1b) displays significant
upfield shifts (Hd 0.2 ppm, He 0.4 ppm, Hg 0.6 ppm) of signals
associated with the aniline station relative to those in the free
thread (Figure 1a). Calculations on the macrocycle-station
The Cadiot–Chodkiewicz reaction is thought to proceed
via a different mechanism to the (also Cu-catalyzed) Glaser
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4393

Communications
shuttle 12, returning the macrocycle to its original
position on the thread.
A similar change in co-conformation could be
generated by shaking a solution of rotaxane 12 in
CD2Cl2 with excess LiI (Scheme 2, MX = LiI). The
1H NMR spectrum of the shuttle after treatment with
LiI (Figure 1 f) displays significant upfield shifts and
broadening of the resonances of the DMAP station (Hj
and Hk) compared with the corresponding protons in the
non-interlocked thread in the presence of excess LiI
(Figure 1e).[17] As was seen with protonation, the signals
of the rotaxane aniline station Hd, He, and Hg return to
the positions they occupy in the non-interlocked thread.
These changes are consistent with the mechanically
interlocked components of rotaxane 12 coordinating
Li+ through the bipyridine moiety of the macrocycle and
the DMAP station of the axle. A simple aqueous wash
removes the metal salt and regenerates rotaxane 12 in its
original form.
The utility of the Cadiot–Chodkiewicz active tem-
plate strategy has been exemplified through the con-
struction and operation of a switchable molecular shuttle
which features a single hydrogen bond between the
Scheme 2. Active template synthesis and stimuli-induced [by protonation
(MX=HOTs) or complexation with Li+ (MX=LiI)] translocation of the
macrocycle in molecular shuttle 12.
fragments for 12 in CH2Cl2 at B3LYP/3-21G* level[13] (see the
Supporting Information) show that the minimum structure
intercomponent binding energy, DGbind, of ꢀ3.9 kcalmolꢀ1 is
largely attributable to a single contact H-bond of 2.1 Š
between the (N)H of the aniline and one nitrogen atom of the
macrocycle bipyridine unit (Figure 2a). A review of the
Cambridge Structural Database (CSD) reveals a range of 2.1–
2.4 Š for similar aniline-to-pyridine contacts in the solid
state.[14]
Addition of 1 equivalent of TsOH to a solution of
rotaxane 12 in CD2Cl2 causes significant shifts in several of
the axle signals in the 1H NMR spectrum (Figure 1c).[15]
Protons Hd, He, and Hg associated with the aniline unit
return to the position they occupy in the non-interlocked
thread in the presence of TsOH (Figure 1d), while those of
the DMAP station shift to higher field (Hj and Hl each
0.5 ppm, Hk 0.2 ppm). This is consistent with protonation of
the DMAP nitrogen and translocation of the macrocycle
along the thread so that the pyridinium NH hydrogen bonds
strongly with the bipyridine moiety of the macrocycle
(Scheme 2, MX = HOTs). B3LYP/3-21G* level calculations
(see the Supporting Information) indicate that the protonat-
ed-DMAP-bound co-conformation is now favored by ca.
0.9 kcalmolꢀ1 (Figure 2b). A search of the CSD finds that the
calculated H-bond contact distance of 1.8 Š is in the 1.4–1.9 Š
range found for pyridinium-to-pyridine H-bonds in the solid
state.[16] Treating a solution of rotaxane 12·H+ with solid
Na2CO3 quantitatively regenerates the neutral molecular
Figure 1. 1H NMR spectra (400 MHz, CD2Cl2, 300 K) of a) non-inter-
locked thread, b) rotaxane 12, c) rotaxane 12 + 1 equiv TsOH, d) non-
interlocked thread + 1 equiv TsOH, e) non-interlocked thread in the
presence of excess LiI, f) rotaxane 12 in the presence of excess LiI.
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Keywords: Cadiot–Chodkiewicz reaction · heterocoupling ·
.
molecular shuttles · rotaxanes · template synthesis
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Figure 2. B3LYP/3-21G* level quantum chemical calculated minimum-
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estimated by increasing the solvent cavity radius by 0.5 ꢀ.
mechanically interlocked components in each state, much less
than half the intercomponent binding energy found in typical
molecular shuttles yet still strong enough to ensure a high
degree of positional integrity of the macrocycle in both forms.
The methodology paves the way for faster moving, faster
responding, mechanically interlocked molecular machines
which can be designed to feature only the weakest non-
covalent interactions necessary for their function.
Experimental Section
Procedure for the Cadiot–Chodkiewicz active template synthesis of
rotaxane 4: A solution of acetylene 2 (20 mg, 0.032 mmol) in THF
(0.4 mL) was cooled to ꢀ788C. To this solution was added nBuLi
(0.32 mL, 0.1m in THF) at ꢀ788C. The resulting solution was allowed
to warm to 08C over 15 min. CuI (6.2 mg, 0.032 mmol) was added at
08C and the resulting yellow solution allowed to warm to room
temperature over 15 min. The reaction mixture was recooled to
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[9] Employing an iodoacetylene in place of the bromoacetylene led
to poor selectivity (8:2:5 of 4:5:6) and reduced (78%) con-
version.
[10] As well as producing only 32% rotaxane (the majority arising
from homodimerization of the bromoacetylene; Table 2,
entry 2), 8 is prone to decomposition. To ensure high yields
and selectivity of the heterocoupled rotaxane, it appears that
aryl acetylenes should only be employed as the terminal
acetylene coupling partner in such reactions.
ꢀ788C and bipyridine macrocycle
3 (18 mg, 0.032 mmol) and
bromoacetylene 1b (22 mg, 0.032 mmol) were added as a solution
in THF (0.6 mL). The resulting orange solution was allowed to stir at
room temperature for 20 h before the reaction was quenched by
addition of an aqueous solution of 17.5% NH3 saturated with
ethylenediaminetetraacetic acid (EDTA). The layers were allowed to
stir in air for 40 min during which time the aqueous layer turned blue.
The aqueous layer was extracted with CH2Cl2 (” 3) and the combined
organic layers were washed with brine and dried over anhydrous
MgSO4. Chromatography (silica gel, 7:2.5:0.5 hexane:CH2Cl2:MeCN
as eluent) yielded [2]rotaxane 4 as a colorless film (47 mg, 84%).
Full details of the experimental procedures, compound character-
ization and molecular modelling are given in the Supporting
Information.
Received: February 25, 2008
Published online: April 29, 2008
[11] The mechanism of the Cadiot–Chodkiewicz coupling is generally
held to proceed in an analogous fashion to the Castro–Stephens
Angew. Chem. Int. Ed. 2008, 47, 4392 –4396ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4395

Communications
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mechanism of the Glaser Cu-catalyzed homocoupling of alkynes
in that 1) the key intermediate is monometallic and 2) the
oxidation state of copper formally changes from CuI to CuIII
during the key step of the Cadiot–Chodkiewicz and Castro–
Stephens reactions, whereas in the Glaser homocoupling it
switches between CuI and CuII.
[12] The heterocoupling does not proceed in the absence of the
bipyridine macrocycle ligand 3 under these conditions. A control
reaction repeating this procedure in the absence of 3 resulted in
no heterocoupled thread (by 1H NMR analysis). The high yields
of the active template rotaxane forming reaction without the
need for excess reactants can be attributed to the absence of
background reactivity.
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J. E. Zachara-Horeglad, J. Chem. Inf. Model. 2007, 47, 875 – 886).
Solvent phase (CH2Cl2) calculations were performed with the
self-consistent reaction field method (SCRF) (M. W. Wong,
K. B. Wiberg, M. J. Frisch, J. Am. Chem. Soc. 1992, 114, 1645 –
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