A catalytic palladium active-metal template pathway to [2]rotaxanes

Article abstract of DOI:10.1002/anie.200701678

(Chemical Equation Presented) A multitasking template: [2]Rotaxanes have been synthesized with the help of a palladium active-metal template, which acts as both a template for threading and a catalyst for covalent-bond formation (see scheme). The synthesi

Full text of DOI:10.1002/anie.200701678

Angewandte
Chemie
DOI: 10.1002/anie.200701678
Rotaxanes
A Catalytic Palladium Active-Metal Template Pathway to
[2]Rotaxanes**
JosØ Bernµ, James D. Crowley, Stephen M. Goldup, Kevin D. Hänni, Ai-Lan Lee, and
David A. Leigh*
The preparation of rotaxanes and other mechanically inter-
locked molecules by the oriented assembly of ligands around
metal ions is a classic demonstration[1] of the utility and
effectiveness of template-directed synthesis.[2] However,
besides organizing the organic fragments through its prefer-
red coordination geometry,the metal template is usually
otherwise passive during such reactions. To exploit the
richness of the metalꢀs chemistry more fully in synthesis,we
recently started to explore a strategy for rotaxane formation
in which the metal plays a dual role,acting as both a template
for threading and catalyzing covalent-bond formation.[3]
Unlike “passive” template methodologies,in which the
rotaxane product is normally a better ligand for the metal
than the non-interlocked components,this type of “active”
template can,in principle,be made to work substoichiometri-
cally. The feasibility of such an approach was first demon-
strated[3] using tetrahedral CuI centers,which is both the most
well-established[1b,h,4] coordination geometry for metal tem-
plate rotaxane-forming reactions and an extremely structur-
ally tolerant catalyst[5] for the azide–alkyne 1,3-cycloaddition
(a so-called “click” reaction[6]). Herein we report an applica-
tion of the active-metal template concept to palladium
chemistry,which is rather more demanding in terms of
template geometry,but somewhat more significant in terms of
catalysis.
passive template strategies by utilizing steric control over the
required crossover point in the third dimension.[10]
Macrocycle 1a (Scheme 1)[9] was chosen as a suitable
candidate ligand for developing a palladium active-template
rotaxane synthesis. X-ray crystallography of a related palla-
dium(II) [2]catenate shows that the trans-coordinated chlo-
ride ligands protrude out of opposite sides of the macrocycle
The explosive growth in the number and variety of
palladium-catalyzed transformations over the latter part of
the 20th century has seen palladium become the workhorse of
modern synthetic chemistry.[7] Palladium-catalyzed processes
ꢀ
ꢀ
ꢀ
include the formation of C O,C N,C S,and,most notably,
ꢀ
C C bonds.[7] Although PdII has a square-planar coordination
geometry,it has proved possible to use its two-dimensional
motif to assemble rotaxanes[8] and catenanes[9] in classical
[*]Dr. J. Bernµ, Dr. J. D. Crowley, Dr. S. M. Goldup, K. D. Hänni,
Dr. A.-L. Lee, Prof. D. A. Leigh
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
[**]This work was supported by the European Union Future and
Emerging Technology program Hy3M, the Ramsay Memorial
Fellowships Trust, and the EPSRC. D.A.L. is an EPSRC Senior
Research Fellow and holds a Royal Society Wolfson Research Merit
Award. J.D.C. is a British Centenary Ramsay Fellow.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. PdII-mediated active-metal template synthesis of [2]rotaxane
4a. For yields and conditions see Table 1.
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Communications
cavity.[9b] We reasoned that if the chloride ligands of trans-
2a[9b] could be replaced by suitably functionalized stopper
groups it would generate a threaded complex (e.g. I,
Scheme 1). If the palladium center is able to retain the
stoppered ligands until it has mediated a covalent bond
forming reaction between them (II,Scheme 1),a [2]rotaxane
would be formed.
This idea was investigated using the palladium(II)-medi-
ated homocoupling of terminal alkynes (Scheme 1).[11–13]
Complex trans-2a was treated with 2.5 equivalents of an
appropriately derivatized alkyne (3) and CuI (5 mol% with
respect to 3) in diisopropylamine (DIPA; Table 1,entry 1). [14]
Table 1: Effect of reactant stoichiometry and experimental conditions on
the PdII-mediated active-metal template synthesis of [2]rotaxane 4a.[a]
Entry 1a
trans-2a
3
I2
t [h]Conversion
3!
Yield[d] of
4a [%]
Figure 1. 1H NMR spectra (400 MHz, CDCl3, 300 K) of a) macrocycle
1a, b) [2]rotaxane 4a, c) thread 5, d) half-thread 3. The assignments
correspond to the lettering shown in Scheme 1.
[equiv] [equiv]
[equiv] [equiv]
4+5 [%]
1[b]
2[b]
3[b]
4[c]
5[c]
6[c]
7[c]
–
–
1
1
2.5
10
–
–
12
12
12
12
24
72
72
>98
>98
37
57
83
43
61
<1
27
35
81
0.9
0.9
0.9
0.95
0.95
0.1
0.1
0.1
0.05
0.05
10
10
10
15
30
0.5
0.5
0.5
0.5
0.5
generates the Pd0–rotaxane complex II and decomplexation
of the weakly binding Pd0 liberates the free rotaxane 4a.
Having achieved an efficient stoichiometric version of the
active-metal template reaction,we turned our attention
towards developing a synthesis that was catalytic with respect
to palladium (Table 1,entries 3–7). This requires the metal to
turn over as both a template and a covalent bond forming
catalyst. The palladium-mediated alkyne homocoupling reac-
tion is particularly well-suited in this respect because diyne
formation is accompanied by reduction of the PdII to intrinsi-
cally weaker coordinating Pd0. A combination of iodine and
oxygen is typically used as the oxidant to render such
reactions catalytic.[7]
We initially tried conditions similar to those employed in
the stoichiometric rotaxane-forming reaction,but using
10 mol% of trans-2a in the presence of I2 (Table 1,entry 3).
However,no rotaxane was produced under these conditions
and the overall conversion of alkyne to diyne was only 37%.
Switching from DIPA to benzene as the solvent led to a
significant improvement in both the total yield of diyne
products and the formation of [2]rotaxane 4a (57% and 27%,
respectively,entry 4). Increasing the reaction time from 12 to
24 h gave further improvements (83% diyne products; 35%
[2]rotaxane,entry 5). Finally,increasing the equivalents of 3,
reducing the loading of 2a to 5 mol% with respect to 1a,and
further extending the reaction time to 72 h improved the yield
of rotaxane 4a to up to 90% (entries 6 and 7).[18,19]
We used the mono- (2b),bi- ( 2c),and tridentate ( 2d and
2e) macrocycles shown in Scheme 2 (their syntheses are
detailed in the Supporting Information) to explore the
influence of the nature of the macrocyclic ligand on the
active-metal template reaction.[20] Reaction of 2b or 2c under
the standard stoichiometric conditions resulted in the for-
mation of the corresponding [2]rotaxanes 4b and 4c[21] in
38% and 10% yields,respectively (Table 2,entries 1 and 4).
The low yield obtained with the bidentate complex 2c
presumably reflects the fact that the two chloride ligands
are necessarily cis for transmetalation. Even with the larger
94
49
90
[a]Reactions were carried out at 298 K [18] using anhydrous solvents and
protected from moisture (see the Experimental Section);[19] [b]10 m m
trans-2a, CuI (5 mol% with respect to 3), DIPA; [c]14 m m macrocycle
(1a+trans-2a) CuI (5 mol% with respect to 3), DIPA (5 equiv), benzene;
[d]with respect to 1a+trans-2a.
We were delighted to find that after 12 h at room temperature
the desired [2]rotaxane 4a was formed in 43% yield (based on
2a). The homocoupling reaction essentially proceeded to
completion (> 98% conversion into the diyne products,
rotaxane 4a,and non-interlocked thread 5).[15] Carrying out
the reaction using a fivefold excess of 3 increased the yield of
[2]rotaxane 4a to 61% (Table 1,entry 2).
The 1H NMR spectrum of 4a in CDCl3 (Figure 1b) shows
an upfield shift of several signals with respect to the non-
interlocked components (Figure 1a,c,d). The shielding,
which is typical of interlocked architectures in which the
aromatic rings of one component are positioned face-on to
another component,occurs for all the nonstopper resonances
of the axle (Hf–h),indicating that in the metal-free rotaxane
the macrocycle is able to access the full length of the thread.[16]
The proposed mechanism for rotaxane formation is shown
in Scheme 1. Standard Pd ligand-substitution chemistry[7,17]
means that under transmetalation the acetylide units should
directly replace the chloride ligands of trans-2a,initially
retaining their relative stereochemistry and thus leading to
the threaded trans palladium bis(alkyne) adduct I. Isomer-
ization of I to the cis geometry necessary for the reductive
elimination must occur without breaking either Pd–acetylide
bond,as models show that the unthreaded isomer of the
cis complex (which would generate noninterlocked macro-
cycle 1a and thread 5 rather than [2]rotaxane 4a) would be
preferred on steric grounds. Reductive elimination then
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Table 2: Effect of macrocycle structure on the PdII-mediated active-metal
template synthesis of [2]rotaxanes (Scheme 2).[a]
Entry Macrocycle–PdII
complex
3
t [h]Conversion 3! Yield[e] of
[equiv]
4+5 [%]
4b–e [%]
1[b]
2[b]
3[c]
4[b]
5[b]
6[c]
7[b]
8[b]
2b
2b
2b
2c
2c
2c
2d
2e
2.5
10
30
2.5
10
30
18 82
38
30
14
10
20
76
0[d]
0[d]
18 75
72 63
18 77
18 85
72 19
72 0[d]
72 0[d]
2.5
2.5
[a]Reactions were carried out at 298 K using anhydrous solvents and
protected from moisture (see the Supporting Information); [b]stoichio-
metric conditions (10 mm 2b–e): macrocycle–Pd complex 2b–e
(1 equiv), CuI (0.05 equiv), DIPA; [c]catalytic conditions (14 m m 1b+
2b or 1c+2c): macrocycle 1b or 1c (0.95 equiv), macrocycle–Pd
complex trans-2b or cis-2c (0.05 equiv), benzene, CuI (5 mol% with
respect to 3), I2 (0.5 equiv), DIPA (5 equiv); [d]no diyne product was
detected; [e]with respect to 2b–e (entries 1, 2, 4, 5, 7 and 8), 1b+2b
(entry 3), or 1c+2c (entry 6).
Table 2,entries 5 and 6) by changing from stoichiometric to
catalytic palladium conditions. In contrast,the yield of
rotaxane 4b decreased to 14% under similar catalytic
conditions,although the overall conversion into diyne prod-
ucts 4b + 5 is a respectable 63% (Table 2,entry 3). It is
possible that this disparity occurs because the benzylic oxygen
atoms in 2a can play a role in dynamic ligation to the
palladium center. In their absence the macrocycle is a poorer
ligand. Thus,when the amount of alkyne 3 present with
respect to 2b is increased (Table 2,entries 2 or 3),the excess
alkyne is able to compete with the pyridine macrocycle for the
palladium,thereby reducing the yield of rotaxane 4b.
It is interesting to note that the catalytic conditions with
2a and 2c provide much cleaner conversions and higher yields
of [2]rotaxanes than the stoichiometric conditions. The use of
stoichiometric amounts of PdII,especially with the solvent
concentrations of DIPA required for high conversions in the
stoichiometric reactions,probably gives rise to side-reactions
and other macrocycle–Pd species that do not afford [2]rotax-
ane.
The template-directed assembly of otherwise difficult-to-
access molecules and the catalysis of covalent-bond formation
are two of the most useful tasks that transition metals can
perform in organic chemistry. The present work demonstrates
that the currently rare combination of these apparently
disparate functions can produce high-yielding,mild,and
effective synthetic routes to complex molecular architectures
that require only substoichiometric amounts of metal. Studies
directed towards the design and development of other active
template systems are in progress.
Scheme 2. Screening of different macrocyclic ligands for the palladi-
um(II)-mediated active-metal template synthesis of [2]rotaxanes. For
yields and conditions see Table 2.
macrocycle cavity of 2c relative to 2a,the cis orientation
significantly decreases the chance of the two alkyne substi-
tutions occurring through opposite faces of the macrocycle.[22]
Carrying out the same reactions in the presence of 10 equiv-
alents of 3 increased the yield of [2]rotaxane 4c to 20%
(Table 2,entry 5) but,to our surprise,resulted in a decrease in
the yield of rotaxane 4b from 38% to 30% (Table 2,entry 2).
As expected,reaction of 3 with the tridentate palladium
complexes 2d and 2e failed to generate any reaction products
(Table 2,entries 7 and 8),as two labile coordination sites on
the metal are necessary for the alkyne homocoupling
mechanism (Scheme 1).
Experimental Section
General procedure for catalytic rotaxane synthesis: A 5-mL round-
bottomed flask,equipped with a drying CaCl 2 tube,was charged with
a solution of the terminal alkyne 3 (484 mg,0.84 mmol) in anhydrous
benzene (2 mL). Diisopropylamine (28 mg,0.28 mmol),copper
As found earlier for 4a (Table 1,entries 2 and 7),the yield
of rotaxane 4c was greatly improved (from 20% to 76%;
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Communications
iodide (8 mg,42.0 mmol),macrocycle 1a–c (26.6 mmol),and iodine
(4 mg,14.0 mmol) were added sequentially. solution of the
(Ed.: E.-i. Negishi),Wiley-VCH,Weinheim, 2002; d) J. Tsuji,
Palladium Reagents and Catalysts: New Perspectives for the 21st
A
corresponding palladium–macrocycle complex 2a–c (1.4 mmol) in
anhydrous benzene (1 mL) was slowly added over a period of 12 h
with a syringe pump. When addition was complete the reaction
mixture was allowed to stir for a further 72 h after which time the
crude product was taken into a partition of dichloromethane and a
saturated solution of sodium ethylenediaminetetraacetate
(Na4EDTA,15 mL) and stirred for 1 h. The layers were separated
and the aqueous layer extracted with dichloromethane (2 ” 5 mL).
The combined organic extracts were then washed with brine (15 mL),
dried over anhydrous magnesium sulfate,filtered,and concentrated
under reduced pressure. The resulting residue was purified by column
chromatography on silica gel to afford the corresponding [2]rotaxane
(4a 90%; 4b 14%; 4c 76%).
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Full details of the experimental procedures and compound
characterization are given in the Supporting Information.
Received: April 17,2007
Published online: June 26,2007
[10] Pseudorotaxanes,rotaxanes,and catenanes have also been made
featuring PdII incorporated into the framework of at least one of
the components,see: a) M. Fujita,F. Ibukuro,H. Hagihara,K.
Ogura, Nature 1994, 367,720 – 723; b) A. Hori,H. Kataoka,T.
Okano,S. Sakamoto,K. Yamaguchi,M. Fujita, Chem. Commun.
2003,182 – 183; c) C. Dietrich-Buchecker,B. Colasson,M.
Fujita,A. Hori,N. Geum,S. Sakamoto,K. Yamaguchi,J.-P.
Sauvage, J. Am. Chem. Soc. 2003, 125,5717 – 5725; d) A. Hori,
K. Yamashita,T. Kusukawa,A. Akasaka,K. Biradha,M. Fujita,
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ꢀ
Keywords: C C coupling · homogeneous catalysis · palladium ·
rotaxanes · template synthesis
.
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[13] For stoichiometric active-metal template CuI-mediated Ullman
and Glaser coupling rotaxane syntheses,in which the metal does
not turnover,see: S. Saito,E. Takahashi,K. Nakazono, Org. Lett.
2006, 8,5133 – 5136.
[14] Attempts to generate [2]rotaxanes from various metal acetylides
of 3 (Li,Cu,and Zn) with Pd complex trans-2a in nonbasic
solvents were unsuccessful.
[15] This reaction is ligand-accelerated: Repeating the reaction with
Pd(MeCN)2Cl2 in place of trans-2a resulted in only 20%
conversion into the homocoupled product 5 during the same
reaction time.
[19] Several control reactions were carried out to confirm the
necessity of both Pd and Cu. When the conditions used for
Table 1,entry 2 (i.e. stoichiometric) or Table 1,entry 6 (i.e.
catalytic) were repeated in the absence of Pd (i.e. with macro-
cycle 1a replacing the Pd complex 2a),no diyne products were
detected by 1H NMR spectroscopy. Thus,under these conditions
the CuI-mediated Glaser alkyne homocoupling[11] does not
operate to any significant extent (< 1%). Similarly,when the
same reactions were run in the absence of CuI instead of in the
absence of Pd,no diyne products were detected by 1H NMR
spectroscopy.
[16] All rotaxanes were fully characterized by 1H and 13C NMR
spectroscopy,as well as LRESI-MS and HRMS. 1H NMR stack
plots of [2]rotaxanes 4b and 4c with their non-interlocked
components are provided in the Supporting Information.
[17] For a similar example involving platinum,see: C. J. Adams,S. L.
James,P. R. Raithby, Chem. Commun. 1997,2155 – 2156.
[18] Attempts at increasing the reaction rate by heating to 508C,with
the other reaction conditions as for Table 1,entry 6,resulted in a
lower yield of rotaxane 4a (47%) and lower overall conversions
into diyne products (52%).
[20] The pyridine coordination site on the macrocycle is crucial for
rotaxane formation. When the conditions used for Table 1,
entry 1 were repeated with the non-pyridine version of macro-
cycle 1a (pyridine replaced by benzene),no rotaxane was
detected and non-interlocked thread 5 was formed in only 19%
yield after 3 days. See the Supporting Information for further
details.
[21] A further decomplexation reaction using KCN in MeOH/
CH2Cl2 was necessary before [2]rotaxane 4c could be isolated.
[22] For an X-ray crystal structure of 2c and the corresponding
crystallographic data,see the Supporting Information.
Angew. Chem. Int. Ed. 2007, 46, 5709 –5713
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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