A one-pot synthesis of constitutionally unsymmetrical rotaxanes using sequential Cui-catalyzed azide-alkyne cycloadditions

Article abstract of DOI:10.1002/chem.200800067

A one-pot sequential Cu^I-catalyzed azide-alkyne cycloaddition (CuAAC) strategy is presented for the synthesis of constitutionally unsymmetrical cyclobis(paraquat-p-phenylene)-based rotaxanes in good yields from simple starting materials. The methodology consists of performing multiple CuAAC reactions to stopper a pseudorotaxane in a stepwise manner, the order of which is controlled through silyl-protection and Ag^I-catalyzed deprotection of a terminal alkyne. The methodology is highlighted by the synthesis of an amphiphilic branched [4]rotaxane. The methodology increases the ability to access ever more complicated mechanically interlocked compounds to serve in devices as sophisticated and functional molecular machinery.

Full text of DOI:10.1002/chem.200800067

DOI: 10.1002/chem.200800067
A One-Pot Synthesis of Constitutionally Unsymmetrical Rotaxanes Using
Sequential CuI-Catalyzed Azide–Alkyne Cycloadditions
Jason M. Spruell,[a, b] William R. Dichtel,[a, c] James R. Heath,*[c] and J. Fraser Stoddart*[b]
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Chem. Eur. J. 2008, 14, 4168 – 4177

FULL PAPER
Abstract: A one-pot sequential CuI-
catalyzed azide–alkyne cycloaddition
(CuAAC) strategy is presented for the
synthesis of constitutionally unsymmet-
rical cyclobis(paraquat-p-phenylene)-
based rotaxanes in good yields from
simple starting materials. The method-
ology consists of performing multiple
CuAAC reactions to stopper a pseudo-
C
protection of a terminal alkyne. The
methodology is highlighted by the syn-
thesis of an amphiphilic branched
[4]rotaxane. The methodology increas-
es the ability to access ever more com-
plicated mechanically interlocked com-
pounds to serve in devices as sophisti-
cated and functional molecular machi-
nery.
Introduction
complexity and are thus even more challenging synthetic
targets. Herein, we report 1) the extension of a general,
one-pot method[10] that uses sequential CuAAC reactions to
address this challenge, and 2) demonstrate its application to
the highly convergent synthesis of an amphiphilic [4]ro-
taxane.
Highly efficient and convergent strategies for the synthesis
of mechanically interlocked compounds are essential in
order to facilitate the development of sophisticated and
functional artificial molecular machinery.[1] In this context,
we recently developed[2] a simple and high-yielding method
for the synthesis of donor–acceptor rotaxanes[3,4] based on a
threading-followed-by-stopper-
A sequence of two or more CuAAC reactions may be
controlled (Figure 1) through I) performing the reaction of
ing approach[5] that utilizes the
CuI-catalyzed azide–alkyne cy-
cloaddition (CuAAC).[6] Al-
though we have employed[2–4]
this method to prepare previ-
ously unavailable mechanically
interlocked compounds, it is
best suited for the template-di-
rected synthesis[7] of [n]ro-
taxanes stoppered by identical
bulky groups. Rotaxanes that
Figure 1. Graphical representation of the sequential CuAAC strategy applied to the synthesis of mechanically
interlocked molecular compounds. A constitutionally unsymmetrical monoprotected pseudorotaxane may be
stoppered in the initial step (I), the protecting group removed in the second step (II), and then functionalized
with a different type of stopper in the third step (III) to form a constitutionally unsymmetrical [2]rotaxane.
The use of a multifunctional stopper allows higher order rotaxanes (e.g., the branched [4]rotaxane described
in this article) to be assembled sequentially in one pot.
incorporate two different stop-
pers, such as the amphiphilic bi-
stable [2]rotaxanes[8] used as
the storage elements in crossbar
memory circuits,[1f,9] represent a
significant increase in structural
the desired azide and alkyne partners in the presence of an-
other masked reactive functionality, II) removing the mask-
ing group to present another reaction partner, and III) re-
[a] J. M. Spruell, Dr. W. R. Dichtel
The California NanoSystems Institute and Department of Chemistry
and Biochemistry
University of California, Los Angeles
peating the CuAAC reaction of the unmasked functionality.
These sequences would prove most efficient if they could be
performed in one-pot, a goal that adds the requirements
that each of the three (or more) steps must proceed to
nearly quantitative conversion and that the reagents used in
the beginning of the sequence must not interfere with those
employed in subsequent steps. Such a sequence was de-
vised[10] for the covalent attachment of peptide building
blocks to a central unit directed by a silyl protecting group.
The extension of such a method to mechanical bond forma-
tion adds several challenges, most prominently, the need for
all components of sensitive donor–acceptor mechanically
405 Hilgard Avenue, Los Angeles, CA 90095 (USA)
[b] J. M. Spruell, Prof. Dr. J. F. Stoddart
Department of Chemistry, Northwestern University
2145 Sheridan Road, Evanston, IL 60208 (USA)
Fax : (+1)847-491-1009
E-mail: stoddart@northwestern.edu
[c] Dr. W. R. Dichtel, Prof. Dr. J. R. Heath
Division of Chemistry and Chemical Engineering
California Institute of Technology
1200 East California Boulevard, Pasadena, CA 91125 (USA)
E-mail: heath@caltech.edu
1
Supporting information for this article (2D and VT H NMR spectra
AHCTREUNG
of the [4]rotaxane 11·12PF6 and the dumbbell compound 12) is avail-
able on the WWW under http://www.chemeurj.org/ or from the
author.
AHCTREUNG
AHCTREUNG
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J. F. Stoddart, J. R. Heath et al.
pounds, namely cyclobis(paraquat-p-phenylene) (CBPQT4+),
ACHTREUNG
Table 2. Reaction condition development: one-pot TMS deprotection of
1 followed by CuAAC reaction of the generated alkyne.
is sensitive to most bases, nucleophiles, and reducing agents,
severely limiting the range and scope of reagents and condi-
tions available to carry out the deprotection(s). The preva-
lent use of silyl groups for the protection of alkynes, and the
availability of relatively mild methods for the deprotection
Entry Deprotection
conditions
Conv.
[%][a]
CuAAC re-
agents[b]
CuAAC Conv.
time
[h]
[%][c]
(additive)
(additive)
of trimethylsilyl
(TMS)-protected alkynes[11] in particular, led
G
1
258C, 48 h
98[d] CuSO4·5H2O
90
45
us to investigate this protecting group with the intention of
developing a one-pot sequential CuAAC method compati-
ble with the CBPQT4+ ring and its donor–acceptor com-
plexes.
ascorbic Acid
2
3
4
258C, 48 h
408C, 18 h
408C, 18 h
98[d] Cu nanopowder 90
>98
93
>98
>98[e] [Cu
>98[e] Cu nanopowder
[Cu(MeCN)4]PF6
90[e] Cu nanopowder
[Cu(MeCN)4]PF6
(CBPQT·4PF6)
A
1
5
AHCTREUNG
5
408C, 54 h,
(CBPQT·4PF6)
>98
ACHTREUNG
Results and Discussion
[a] With respect to 1, monitored by integration of 1H NMR spectra. [b] 3
(1.1 equiv) was used. [c] With respect to propargyl alcohol intermediate.
[d] 0.05 equiv of AgPF6 was used. [e] 0.10 equiv of AgPF6 was used.
As a preliminary appraisal of the ability of the TMS group
to prevent a contiguous alkyne functionality from participat-
ing in the desired CuAAC reaction, 3-trimethylsilyl-2-
propyn-1-ol (1) and 1-azidohexane (3) were treated
(Table 1, entry 1) with the CuSO4·5H2O/ascorbic acid cata-
18 h when the reaction mixture was heated to 408C. AgPF6
was introduced into the reaction mixture in order to prevent
counterion exchange and subsequent precipitation of AgI or
CBPQT4+-containing salts. Interestingly, the desilylation
proceeded noticeably more slowly when the reaction was
Table 1. Chemoselectivity between 1 and 2 in CuAAC reaction with 3 to
form either 4 or 5.
performed (Table 2, entry 5) in the presence of CBPQT4+
.
No decomposition of the CBPQT4+, however, was observed.
Next, we developed conditions to effect the second CuAAC
reaction in the presence of silver salts remaining from the
deprotection. The CuSO4·5H2O/ascorbic acid catalytic
system (5/10 mol%, respectively) formed (Table 2, entry 1)
the CuAAC product, albeit somewhat slowly. Upon addition
of the CuSO4·5H2O and ascorbic acid, a silver mirror
formed on the walls of the reaction vessel, most likely as a
result of the reduction of AgI to Ag0 by CuI and/or ascorbic
acid, both processes that would impact negatively upon the
availability of CuI required to catalyze the cycloaddition. Al-
though the CuAAC reaction proceeds to higher conversions
when an excess of ascorbic acid (1.3 equiv per alkyne;
Entry
1 : 2 : 3
Time [h]
4 : 5
Conversion[a] [%]
1
2
1 : 0 : 1
1 : 1 : 1
24
16
1 : 0
1 : 99
54
96
1
[a] With respect to 3, monitored by integration of H NMR spectra.
lyst system in DMF.[12] Somewhat surprisingly, under these
reaction conditions, significant amounts of the 1,2,3-triazole
product 4 (54% conversion) were formed over the course of
24 h, presumably as a result of the slow hydrolysis of the
TMS group. The protecting group did, however, slow down
the CuAAC reaction substantially, and a competition experi-
ment (Table 1, entry 2) between 1 and 1-octyne (2) in a
CuAAC reaction with 3 resulted in excellent chemoselectivi-
ty for the formation of 1,4-dihexyl-1,2,3-triazole (5), despite
the observation of partial hydrolysis of 1 to propargyl alco-
hol (8%) at the conclusion of the experiment. This test-bed
work demonstrates that the TMS protecting group is suffi-
ciently kinetically stable under the conditions of the
CuAAC reaction, so much so that the cycloaddition occurs
almost exclusively with the unprotected alkyne.
6.3 equiv per
A
) is used, the intensities of the
A
1
broadened CBPQT4+ resonances in the H NMR spectrum
of the reaction mixture were attenuated to 17% of their ini-
tial values. The excess of ascorbic acid (E8=0.3 V)[13] pre-
sumably reduces the CBPQT4+ (E8=À0.29 and À0.71 V),[14]
and while the reversibility of this process was not deter-
mined, reduced CBPQT4+ derivatives do not bind electron
rich guests. As an alternative to adding ascorbic acid at all,
Cu0 was used (Table 2, entry 2) as a copper source, which
presumably generates the catalytically active CuI following
oxidation by AgI. Indeed, this procedure did ultimately pro-
duce the desired CuAAC reaction, although we subsequent-
Next, appropriate conditions for the sequential desilyla-
tion and CuAAC reactions required for the desired one-pot
procedure (Table 2) were investigated. The AgI-catalyzed
hydrolysis of TMS protected alkynes[11] was assumed to be
ly found that a small amount of additional [Cu
helped to speed up the reaction (Table 2, entry 4) further,
despite the fact that the addition of [Cu(MeCN)4]PF6 alone
A
AHCTREUNG
sufficiently mild to ensure the survival of the CBPQT4+
.
catalyzed the CuAAC reaction only slowly (Table 2,
entry 3). Finally, it was confirmed that, when the above se-
quence is carried out in the presence of CBPQT4+, the se-
quential deprotection/CuAAC reactions proceed (Table 2,
Indeed, 10 mol% AgPF6 in the presence of H2O (1 equiv
per alkyne) catalyzed the hydrolysis of the TMS group, re-
sulting (Table 2, entry 3) in nearly quantitative conversion in
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Constitutionally Unsymmetrical Rotaxanes
FULL PAPER
entry 5) to high conversion with no decrease in the intensi-
ties of the CBPQT4+ 1H NMR resonances.
With the three-step sequential CuAAC methodology op-
erating well in our hands, we envisioned that the sequential
CuAAC reactions could be used to attach different stoppers
to each end of a pseudorotaxane. Furthermore, in order to
test this method for the synthesis of compounds with partic-
ularly complicated structures, a branched [4]rotaxane was
chosen so that each CuAAC reaction and deprotection step
would have to occur, not just once, but three times within
each molecule. The threefold symmetry, previously incorpo-
rated into acid/base-switched molecular elevators[15,16] and
present in the non-trivial amphiphilic [4]rotaxane 11·12PF6
was accessed (Scheme 1) in one-pot by sequentially stopper-
ing the constitutionally unsymmetrical dioxynaphthalene
(DNP) derivative 7, first with the trifunctional azide 6 and
then subsequently with the monofunctional azide 10. The
DNP derivative 7 was synthesized (Scheme 2) bearing one
TMS-protected alkyne and one terminal alkyne such that
the constitutional asymmetry endowed by the TMS group
would be expressed in the amphiphilic character of the final
branched [4]rotaxane. The triazide 6 and monoazide 10
were each obtained (Scheme 3) through azide displacement
of their benzyl chloride precursors.
Scheme 2. The synthesis of the constitutionally unsymmetrical DNP de-
rivative 7.
manner in the absence of CBPQT·4PF6, first with the tri-
azide 6 and then subsequently with the monoazide 10—fol-
lowing silyl deprotection of the protected alkyne—we antici-
pated obtaining compound 12 in high yield. This three-step
reaction sequence was carried out in an NMR tube in
[D7]DMF such that each step of the reaction could be moni-
tored (Figure 2) closely by 1H NMR spectroscopy. Upon
mixing the triazide 6 with the monoalkyne 7 in a 1:3 molar
ratio, the first CuAAC reaction proceeded to form the tris-
TMS-protected compound 8, the outcome of which was con-
firmed by the transformation of the terminal alkyne proton
resonance (d=3.39 ppm in Figure 2a) of the DNP derivative
7 to the triazole proton resonance (d=8.25 ppm in Fig-
ure 2b) of the tris-DNP intermediate 8. The chemical shifts
of the methylene group resonances neighboring the terminal
alkyne and azide (d=4.22 and 4.61 ppm, respectively, in Fig-
Before attempting the template-directed synthesis of the
[4]rotaxane, we first of all pursued (Scheme 1) the same re-
action sequences—which we had in mind to prepare
11·12PF6—to form the dumbbell compound 12. The relative
1
simplicity of the H NMR spectrum of 12 compared to that
(vide infra) of the [4]rotaxane was the motivation for us
making the dumbbell compound first. By stoppering the
monofunctional DNP derivative 7 in a controlled, sequential
1
Scheme 1. Sequential CuAAC synthesis[a] of the [4]rotaxane 11·12PF6 and the dumbbell compound 12. [a] Labels for H NMR spectroscopic monitoring
of the reactions identified by boxed letters.
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J. F. Stoddart, J. R. Heath et al.
in high conversion (>98%). Completion of the desilylation
was confirmed by the migration and transformation of the
methylene group singlet resonance (d=4.23 ppm in Fig-
ure 2b) neighboring the silyl protected alkyne of 8 to a dou-
blet (d=4.20 ppm with J4 ꢀ3 Hz in Figure 2c) for the meth-
ylene group neighboring the terminal alkyne in 9. This diag-
nostic splitting pattern is a result of long-range coupling be-
tween the liberated terminal alkyne proton and the neigh-
boring methylene protons in 9. Upon addition of 3.3
equivalents of the azide-containing hydrophilic precursor 10
(Figure 2f), the methylene peak (d=4.45 ppm) neighboring
the added azide was evident along with the terminal alkyne
proton peak (d=3.38 ppm) for the tris-alkyne 9. Both of
these peaks reappeared as another set of signals—for the
methylene group next to a triazole (d=5.62 ppm) and
for the second triazole proton (d=8.33 ppm) in Fig-
Scheme 3. The synthesis of the triazide 6 and the monoazide 10.
ure 2g—after the second (Cu-nanopowder/[Cu(MeCN)4]PF6-
A
promoted) CuAAC reaction was carried out to form the
final dumbbell compound 12 with >98% conversion with
respect to tris-alkyne intermediate 9.
ure 2a) are transformed into the methylene group resonan-
ces (d=4.62 and 5.76 ppm in Figure 2b) neighboring the
newly formed triazole. In keeping with the model experi-
ments, some partial hydrolysis (17%) of the TMS protecting
groups also occurred during the first CuAAC reaction of 6
with 7. Even so, as indicated by the model experiments, the
TMS group protects the alkynes to the extent that the
CuAAC reaction occurs, forming 8 with a high conversion
(>98% with respect to 6). The AgI-catalyzed desilylation
was then performed, affording the tris-alkyne 9, once again
With an intimate knowledge of the spectroscopic charac-
teristics accompanying the sequential CuAAC reaction in
the formation of the dumbbell compound 12, the synthesis
of the [4]rotaxane 11·12PF6 was attempted in a similar
manner with periodic monitoring (Figure 3) by 1H NMR
spectroscopy. The steps leading to the formation of the tris-
alkyne intermediate 9 were exactly the same as those fol-
lowed in the synthesis of 12. The addition of 3.3 equivalents
of CBPQT·4PF6 at À58C to the intermediate 9 resulted
Figure 2. 1H NMR (600 MHz, [D7]DMF, 258C) spectroscopic monitoring of the synthesis of the dumbbell compound 12. Several diagnostic resonances
are numbered and the changes monitored throughout the reaction steps indicated by letters a, b, c, f, g in Scheme 1. See the text for further discussion.
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Constitutionally Unsymmetrical Rotaxanes
FULL PAPER
Figure 3. 1H NMR (600 MHz, [D7]DMF, 258C) spectroscopic monitoring of the synthesis of the [4]rotaxane 11·12PF6. Several diagnostic resonances are
numbered and the changes monitored throughout the reaction steps indicated by letters a, b, c, d, e in Scheme 1. See the text for further discussion.
in
[9ꢁ3CBPQT]·12PF6 which was stoppered with the mono-
azide 10 using the Cu-nanopowder/[Cu(MeCN)4]PF6-pro-
the
formation
of
the
[4]pseudorotaxane
arative thin-layer chromatography was required in order to
isolate the highly polar amphiphilic branched [4]rotaxane as
a pure compound. In addition, a small quantity of a minor
[2]rotaxane by-product, comprised of a CBPQT4+-encircled
thread 7, stoppered by two hydrophilic stoppers 10, was iso-
lated. The formation of this compound can be attributed to
the use of a very slight excess of 7 over 6 at the start of the
three-step reaction sequence. Importantly, no evidence of
constitutional defects—for example, missing rings, missing
DNP threads, or crosslinking—was observed during the tem-
plate-directed synthesis of 11·12PF6. The successful silver-
catalyzed silyl deprotection, performed in the second and in-
termediate step of the sequence, although not forming a
bond itself, enabled the direction of the useful bond-forming
CuAAC reaction in the third step of the sequence. More-
over, this reaction is another example that can be added to
the small list of chemical reactions that may be performed
G
ACHTREUNG
moted CuAAC reaction to yield the amphiphilic branched
[4]rotaxane 11·12PF6. The addition of CBPQT·4PF6 caused
broadening of all the peaks (Figure 3d) as a consequence of
the many dynamic equilibria associated with the formation
of pseudorotaxanes. The terminal alkyne proton resonance,
however, was resolved clearly (d=3.17ppm) from the other
signals and so it was used as a diagnostic resonance with
which to monitor the progress of the final CuAAC reaction.
The disappearance of the terminal alkyne proton resonance
(Figure 3d) in the [4]pseudorotaxane [9ꢁ3CBPQT]·12PF6
and the appearance of a second triazole peak (d=8.10 ppm
in Figure 3e) for the [4]rotaxane 11·12PF6 heralded the com-
pletion of the second CuAAC reaction. Although we had
never performed the second CuAAC reaction at low tem-
peratures in the test-bed investigations (Table 2, entry 5),
the tris-alkyne 9 was consumed completely during the final
CuAAC reaction performed at À58C. All three of the
second CuAAC reactions occurred with considerable effi-
ciency, forming the three-fold symmetric amphiphilic [4]ro-
taxane in 44% yield from a one-pot synthesis. Although, the
isolated yield of 11·12PF6 at first glance may seem low in
comparison with the near-quantitative conversions observed
in the presence of CBPQT4+
.
Conclusion
The protocol presented demonstrates the general and highly
convergent nature of the sequential CuAAC strategy for the
template-directed synthesis of a tripodal [4]rotaxane. Em-
ploying this one-pot methodology, constitutionally unsym-
metrical rotaxanes may be prepared quickly and efficiently,
aiding and abetting their continued use as components of
molecular machinery and electronics. This methodology sets
1
by H NMR spectroscopy, it represents the overall yield for
a sum of nine “consecutive” reactions,[17] including the for-
mation of three mechanical bonds, starting from no less
than 10 building blocks. Also, extensive purification by prep-
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J. F. Stoddart, J. R. Heath et al.
forth a new synthetic paradigm for CBPQT4+-containing
compounds in which the formation of the mechanical bond
need not occur in the final step of the synthesis. These ad-
vances have been driven by the discovery and use of reac-
tions amenable to the sensitive nature of CBPQT4+. We
intend to continue to develop new synthetic strategies per-
formed under thermodynamic[18] as well as kinetic[2–4] control
so that mechanical bonds may be precisely and predictably
introduced into a wide range of complex functional mole-
cules.
sion, to this solution was added 1-azidohexane (3) (0.0080 g, 0.060 mmol)
and stock solutions of CuSO4·5H2O in [D7]DMF (18 mL, 0.072m,
0.05 equiv per azide) and ascorbic acid in [D7]DMF (18 mL, 0.144m,
0.10 equiv per azide) and the reaction was left at room temperature. Con-
version of the CuAAC reaction was monitored by comparing the inte-
grated area of the disappearing -CH2N3 resonance at d=3.50 ppm with
that of the appearing -CH2N
(triazole) at d=4.57ppm in the 1H NMR
G
spectrum of the reaction mixture.
Methodology experiment for Table 2, entry 2: The above procedure was
followed by using 3-trimethylsilyl-2-propyn-1-ol (1) (0.0070 g,
0.055 mmol), [D7]DMF (0.546 mL), stock solution of AgPF6 in [D7]DMF
(30 mL, 0.10m, 0.05 equiv per alkyne), H2O (3 mL, 0.164 mmol), 1-azido-
hexane (3) (0.0080 g, 0.060 mmol), and copper nanopowder (0.0010 g,
0.016 mmol). The reaction mixture was heterogeneous, as the copper
nanopowder remained at the bottom of the NMR tube.
Experimental Section
Methodology experiment for Table 2, entry 3: The above procedure was
followed using 3-trimethylsilyl-2-propyn-1-ol (1) (0.0080 g, 0.055 mmol),
[D7]DMF (0.530 mL), stock solution of AgPF6 in [D7]DMF (23.5 mL,
0.235m, 0.1 equiv per alkyne), H2O (3 mL, 0.16 mmol), 1-azidohexane (3)
General methods: All reagents were purchased from commercial suppli-
ers (Aldrich or Fisher) and used without purification. Dry solvents were
obtained from a commercial DriSolv solvent delivery system (EMD
Chemicals). The molarity of nBuLi solutions was determined immediate-
ly before use by titration using salicyaldehyde phenylhydrazone[19] as an
indicator. Cyclobis(paraquat-p-phenylene),[20] 1,5-bis[2-(2-{2-(2-propy-
ne)ethoxy}ethoxy)ethoxy]naphthalene,[4b] and 3,4,5-tris-[{2-(2-methoxy)-
(0.0080 g, 0.060 mmol), and [Cu(MeCN)4]PF6 (0.002 g, 0.005 mmol,
G
0.1 equiv per alkyne). After the addition of the AgPF6 solution, the mix-
ture was warmed to 408C. The subsequent CuAAC reaction was per-
formed at room temperature.
Methodology experiment for Table 2, entry 4: The above procedure was
followed by using 3-trimethylsilyl-2-propyn-1-ol (1) (0.0070 g,
0.055 mmol), [D7]DMF (0.546 mL), stock solution of AgPF6 in [D7]DMF
(23.5 mL, 0.235m, 0.1 equiv per alkyne), H2O (3.0 mL, 0.16 mmol), 1-azi-
dohexane (3) (0.0080 g, 0.060 mmol), copper nanopowder (0.0010 g,
ethoxy}ethoxybenzyloxy]benzyl chloride[9i] were prepared by using previ-
ously published procedures. Copper nanopowder was used as received
from Aldrich and is described as metallic copper (99.8%) particles
<100 nm in size. Thin layer chromatography (TLC) was performed on
silica gel 60 F254 (E. Merck). Preparative thin layer chromatography
(Prep TLC) was performed on glass plates with a 1 mm thick layer of
silica gel 60 F254 (E. Merck). Column chromatography was performed on
silica gel 60F (Merck 9385, 0.040–0.063 mm). Nuclear magnetic resonance
(NMR) spectra were recorded on a Bruker Avance 600 (1H: 600 MHz;
13C: 150 MHz) or 500 (1H: 500 MHz; 13C: 126 MHz) spectrometer. Chem-
ical shifts are reported as parts per million (ppm) downfield from the
0.016 mmol), and [Cu(MeCN)4]PF6 (0.002 g, 0.005 mmol, 0.1 equiv per
E
alkyne). After the addition of the AgPF6 solution, the mixture was
warmed to 408C. The subsequent CuAAC reaction was performed at
room temperature.
Methodology experiment for Table 2, entry 5: The above procedure was
followed by using 3-trimethylsilyl-2-propyn-1-ol (1) (0.0070 g,
0.055 mmol), [D7]DMF (0.546 mL), stock solution of AgPF6 in [D7]DMF
(23.5 mL, 0.235m, 0.1 equiv per alkyne), H2O (3.0 mL, 0.16 mmol), 1-azi-
dohexane (3) (0.0080 g, 0.060 mmol), copper nanopowder (0.0010 g,
1
Me4Si resonance as the internal standard for both H and 13C NMR spec-
troscopies. Electrospray ionization (ESI) mass spectra were measured on
a Finnigan LCQ ion-trap mass spectrometer using 1:1 MeCN/H2O as the
mobile phase. High-resolution fast atom bombardment (HR-FAB) mass
spectra were obtained on a JEOL JMS-600H high-resolution mass spec-
trometer equipped with a FAB probe. Electrospray ionization (EI) mass
spectra were obtained on a Finnigan LCQ ion trap mass spectrometer.
0.016 mmol), [Cu(MeCN)4]PF6 (0.002 g, 0.005 mmol, 0.1 equiv per
E
alkyne), and CBPQT·4PF6 (0.0115 g, 0.0110 mmol, 0.2 equiv per alkyne).
CBPQT·4PF6 was dissolved initially with 1 and remained as a spectator
throughout the sequence. After the addition of the AgPF6 solution, the
mixture was warmed to 408C. The subsequent CuAAC reaction was per-
formed at room temperature.
Method development
General procedure for single-step methodology experiments and Table 1,
entry 1: 3-Trimethylsilyl-2-propyn-1-ol (1) (0.010 g, 0.078 mmol) and 1-
azidohexane (3) (0.010 g, 0.078 mmol) were dissolved in [D7]DMF
(0.780 mL) in an NMR tube. Stock solutions of CuSO4·5H2O in
[D7]DMF (18 mL, 0.072m, 0.05 equiv per azide) and ascorbic acid in
[D7]DMF (18 mL, 0.144m, 0.10 equiv per azide) were added and the mix-
ture was left at room temperature. The reaction progress was monitored
by comparing the integrated area of the disappearing -CH2N3 resonance
Synthesis and characterization
1-[2-(2-{2-(3-Trimethylsilyl-2-propyne)ethoxy}ethoxy)ethoxy]-5-[2-(2-{2-
(2-propyne)ethoxy}ethoxy)ethoxy]naphthalene (7): nBuLi (0.52m in hex-
anes, 665 mL, 0.343 mmol) was added dropwise to
a solution of
1,5-bis[2-(2-{2-(2-propyne)ethoxy}ethoxy)ethoxy]naphthalene,[4b] (0.156 g,
0.311 mmol) dissolved in dry THF (15.7mL) at À788C under an Ar at-
mosphere. After stirring for 15 min at À788C Me3SiCl (48.0 mL,
0.374 mmol) was added dropwise and the reaction mixture was stirred at
room temperature for 12 h. The crude reaction mixture was quenched
with saturated aq. NH4Cl (15 mL) and extracted with CH2Cl2 (4”20 mL).
The combined organic extracts were washed with brine (20 mL), dried
(MgSO4), and evaporated. The crude product was subjected to chroma-
at d=3.50 ppm with that of the appearing -CH2N(triazole) at d=
G
4.57ppm in the 1H NMR spectrum of the reaction mixture.
Methodology experiment for Table 1, entry 2: The above procedure was
followed by using 3-trimethylsilyl-2-propyn-1-ol (1) (0.010 g,
0.078 mmol), 1-octyne (2) (0.0090 g, 0.078 mmol), and 1-azidohexane (3)
(0.010 g, 0.078 mmol) dissolved in [D7]DMF (0.780 mL) and stock solu-
tions of CuSO4·5H2O in [D7]DMF (18 mL, 0.072m, 0.05 equiv per azide)
and ascorbic acid in [D7]DMF (18 mL, 0.144m, 0.10 equiv per azide).
tography (SiO2, 93:7to 90:10 CH Cl2/Et2O eluent) to give 7 (47mg, 26%
2
yield) as a pale yellow oil. 7: 1H NMR (600 MHz, CDCl3, 258C, TMS):
d=7.86 (d, 3J
8 Hz, 2H, DNP aryl -H m-O), 6.84 (d, J
o-O), 4.30 (t, 3J
A
ACHTREUNG
3
ACHTREUNG
General procedure for two-step methodology experiments and Table 2,
entry 1: 3-Trimethylsilyl-2-propyn-1-ol (1) (0.0070 g, 0.055 mmol) was dis-
solved in [D7]DMF (0.546 mL) in an NMR tube. A stock solution of
AgPF6 in [D7]DMF (30 mL, 0.1m, 0.05 equiv per alkyne) and H2O (3 mL,
0.164 mmol) were added and the mixture was left at room temperature.
The reaction progress was monitored by comparing the integrated area
of the disappearing -CH2CCSi singlet resonance at d=4.19 ppm with that
of the appearing -CH2CCH doublet resonance at d=4.16 ppm in the
1H NMR spectrum of the reaction mixture. Following sufficient conver-
AHCTREUNG
AHCTREUNG
A
ACHTREUNG
(151 MHz, CDCl3, 258C, TMS): d=154.5, 126.9, 125.2, 114.8, 105.8,
101.6, 91.5, 79.8, 74.6, 71.1, 70.9, 70.9, 70.6, 70.6, 70.0, 69.3, 69.2, 68.1,
59.3, 58.5, 0.0 ppm; HRMS (FAB): calcd for C31H44O8Si: m/z 572.2805;
found: m/z 572.2823.
4174
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4168 – 4177

Constitutionally Unsymmetrical Rotaxanes
FULL PAPER
Tris-1,3,5-(4’-azidomethyl)benzene (6): NaN3 (1.079 g, 16.61 mmol) was
purple solid (78 mg, 44% yield). 11·12PF6: 1H NMR (600 MHz,
CD3COCD3, 528C, TMS) (assignments verified by COSY and HMQC):
added to
a solution of tris-1,3,5-(4’-chloromethyl)benzene, (0.500 g,
1.11 mmol) dissolved in dry DMF (75 mL) and the solution was stirred at
608C for 24 h. The crude reaction mixture was quenched with H2O
(75 mL) and extracted with CH2Cl2 (2”50 mL). The combined organic
extracts were dried (MgSO4), and evaporated. The crude product was
d=9.08 (brs, 24H, a-CBPQT4+), 8.19 (brs, 24H, phenylene-CBPQT4+),
3
7.92 (s, 3H, central benzene aryl -H), 7.90 (d, J
A
aryl -H m-methylene triazole), 7.83 (s, 3H, triazole -H), 7.74 (s, 3H, tria-
3
zole -H), 7.56 (brs, 24H, b-CBPQT4+), 7.46 (d, J
ACHTREUNG
tral aryl -H o-methylene triazole), 7.32 (d, 3J
AHCTREUNG
subjected to chromatography (SiO2, 7:3 hexane/CH2Cl2) to give
5
(450 mg, 86% yield) as a white solid. 5: 1H NMR (400 MHz, CDCl3,
3
aryl -H m-O), 7.28 (d, J
ACHTREUNG
3
3J
(H,H)=8 Hz, 12H, stopper aryl -H o-O), 6.83 (d, 3J
ACHTREUNG
258C, TMS): d=7.78 (s, 3H, central aryl-H), 7.73 (d, J
A
aryl -H m-CH2N3), 7.45 (d, 3J
(H,H)=8 Hz, 6H, aryl -H o-CH2N3),
A
4.42 ppm (s, 6H, CH2N3); 13C NMR (151 MHz, CDCl3, 258C, TMS): d=
141.8, 140.9, 134.8, 128.7, 127.7, 125.2, 54.5 ppm; HRMS (EI): calcd for
C27H21N9: m/z 471.1920; found: m/z 471.1939.
A
ACHTREUNG
AHCTREUNG
AHCTREUNG
CBPQT4+ benzyl -H), 5.56 (s, 6H, central CH2-triazole), 5.39 (s, 6H,
stopper CH2-triazole), 4.96 (s, 12H, stopper phenyl-OCH2), 4.88 (s, 6H,
stopper phenyl-OCH2), 4.45–4.39 (m, 12H, DNP-OCH2), 4.37(s, 6H,
OCH2-triazole), 4.34 (s, 6H, OCH2-triazole), 4.25–4.17(m, 12H), 4.13 (t,
3,4,5-Tris[{2-(2-methoxy)ethoxy}ethoxybenzyloxy]benzyl
azide
(10):
NaN3 (0.379 g, 3.53 mmol) was added to a solution of 3,4,5-tris-[(2-(2-me-
thoxy)ethoxy)ethoxybenzyloxy]benzyl chloride,[9i] (0.282 g, 0.353 mmol)
dissolved in DMF (3.7mL) and the solution was stirred at 60 8C for 24 h.
The crude reaction mixture was quenched with H2O (50 mL) and extract-
ed with CH2Cl2 (2”25 mL). The combined organic extracts were washed
with H2O (2”20 mL), brine (20 mL), dried (MgSO4), and evaporated.
The crude product was subjected to chromatography (SiO2, EtOAc
eluent) to give 10 (221 mg, 77% yield) as a pale yellow amorphous solid.
3J(H,H)=5 Hz, 12H, stopper aryl-OCH2), 4.10 (t, 3J (H,H)=5 Hz, 6H,
A
stopper aryl-OCH2), 4.06–3.97(m, 12H), 3.95–3.85 (m, 12H), 3.83–3.74
(m, 30H), 3.67–3.60 (m, 18H), 3.53–3.48 (m, 18H), 3.31–3.27 (m, 27H,
stopper-OCH3), 2.72 (d, 3J
ACHTREUNG
2.68 ppm (d, 3J
AHCTREUNG
10: 1H NMR (600 MHz, CDCl3, 258C, TMS): d=7.32 (d, 3J
(H,H)=9 Hz,
(151 MHz, CD3COCD3, 28C, TMS): d=159.6, 153.6, 151.9, 145.9, 145.6,
145.2, 141.1, 138.1, 137.7, 136.8, 132.2, 132.0, 131.9, 131.1, 130.8, 130.4,
129.7, 129.6, 128.9, 128.6, 126.8, 126.6, 125.2, 125.1, 125.0, 115.0, 114.7,
109.0, 107.9, 104.9, 104.7, 75.1, 72.4, 72.4, 71.7, 71.3, 71.2, 71.0, 70.9, 70.7,
70.1, 69.7, 68.8, 68.1, 65.8, 65.7, 64.3, 64.2, 58.7, 54.1, 53.5 ppm; MS (ESI;
3
3
4H, aryl -H m-O), 7.27 (d, J
ACHTREUNG
A
ACHTREUNG
O), 6.57(s, 2H, aryl -H o-CH2N3), 5.01 (s, 4H, benzylic CH2O), 4.94 (s,
2H, benzylic CH2O), 4.21 (s, 2H, -CH2N3), 4.16 (t, 3J
A
MeOH/H2O 1:1, 0.1% AcOH): m/z: 1777.4 [MÀ4PF6]4+
, 1392.7
3
4.12 (t, J
A
[MÀ5PF6]5+, 1136.5 [MÀ6PF6]6+, 953.4 [MÀ7PF6]7+, 816.2 [MÀ8PF6]8+
.
3.57(m, 6H), 3.40 (s, 6H, OCH 3), 3.39 ppm (s, 3H, OCH3); 13C NMR
(151 MHz, CDCl3, 258C, TMS): d=158.7, 158.6, 153.2, 138.5, 130.9,
130.3, 130.2, 129.3, 129.2, 114.7, 114.3, 108.2, 74.7, 72.1, 71.2, 70.9, 70.8,
69.9, 67.6, 67.5, 59.2, 55.1 ppm; HRMS (FAB): calcd for
C43H55O12N3(Na): m/z 828.3649; found: m/z 828.3684; elemental analysis:
calcd: C 64.08, H 6.88, N 5.21; found: C 64.33, H 6.81, N 5.19.
Dumbbell Compound (12): Tris-1,3,5-(4’-azidomethyl)benzene (6)
(0.0103 g, 0.0219 mmol) and DNP derivative 7 (0.0378 g, 0.0659 mmol,
1.0 equiv per azide) were dissolved in [D7]DMF (0.45 mL) in an NMR
tube. Stock solutions of CuSO4·5H2O in [D7]DMF (43 mL, 0.072m,
0.05 equiv per azide) and ascorbic acid in [D7]DMF (43 mL, 0.144m,
0.10 equiv per azide) were added and the reaction mixture was held at
room temperature for 20 h (until the -CH2N3 resonance at d=4.61 ppm
[4]Rotaxane (11·12PF6): Tris-1,3,5-(4’-azidomethyl)benzene (6) (0.0107g,
0.0227mmol) and DNP derivative 7 (0.0390 g, 0.0682 mmol, 1.0 equiv per
azide) were dissolved in [D7]DMF (0.45 mL) in an NMR tube. Stock so-
was replaced by the -CH2N(triazole) resonance at d=5.76 ppm in the
G
1H NMR spectrum of the reaction mixture). A stock solution of AgPF6 in
[D7]DMF (50 mL, 0.235m, 0.17equiv per TMS) and H 2O (3.7 mL,
0.208 mmol, 9 equiv per TMS) were added and the mixture was heated
to 408C for 36 h (until the -CH2CCSi singlet resonance at d=4.36 was re-
placed by the -CH2CCH doublet resonance at d=4.23 ppm and the
A
N
azide) and ascorbic acid in [D7]DMF (45 mL, 0.144m, 0.10 equiv per
azide) were added and the mixture left at room temperature for 20 h
(until the -CH2N3 resonance at 4.61 ppm was replaced by the -CH2N-
1
A
-CCSi
A
G
mixture).
A stock solution of AgPF6 in [D7]DMF (50 mL, 0.235m,
1
resonances at d=0.08 and 0.05 ppm in the H NMR spectrum of the reac-
tion mixture). 3,4,5-Tris-[{2-(2-methoxy)ethoxy}ethoxybenzyloxy]benzyl
azide (10) (0.0584 g, 0.0725 mmol, 1.1 equiv per alkyne), Cu nanopowder
0.17equiv per TMS) and H 2O (3.7 mL, 0.2081 mmol, 9 equiv per TMS)
were added and the mixture left at 408C for 36 h (until the -CH2CCSi
singlet resonance at d=4.36 was replaced by the -CH2CCH doublet reso-
(Aldrich, 0.002 g, 0.0315 mmol), and [Cu(MeCN)4]PF6 (0.002 g,
0.0054 mmol) were then added and the reaction mixture was allowed to
rest at room temperature for 24 h (until the -CCH resonance at d=
A
nance at d=4.23 ppm and the -CCSi
was replaced by the -Si(CH3)3 resonances at d=0.08 and 0.05 ppm in the
1H NMR spectrum of the reaction mixture). 3,4,5-Tris[{2-(2-methoxy)-
ethoxy}ethoxybenzyloxy]benzyl azide (10) (0.0584 g, 0.0725 mmol,
(CH3)3 resonance at d=0.16 ppm
ACHTREUNG
3.38 ppm was replaced by the -CH(triazole) at d=8.31 ppm in the
G
ACHTREUNG
1H NMR spectrum of the reaction mixture), after which time a Ag
mirror had formed on the walls of the NMR tube. The reaction mixture
was filtered through a fritted funnel to remove the residual solids and the
solvent evaporated. The resulting brown oil was subjected to chromatog-
raphy (SiO2, 10:90 Me2CO/CH2Cl2 followed by 10:90 MeOH/CH2Cl2
eluent) to give 12 (63.2 mg, 65% yield) as a colorless oil. 12: 1H NMR
1.1 equiv per alkyne), CBPQT·4PF6 (0.0840 g, 0.0763 mmol, 1.1 equiv per
DNP), Cu nanopowder (Aldrich, 0.002 g, 0.0315 mmol), and [Cu-
A
purple reaction mixture was cooled to À58C for 40 h (until the -CCH res-
onance at d=3.17ppm was no longer observed in the 1H NMR), after
which time a Ag mirror had formed on the walls of the NMR tube. The
reaction mixture was filtered through a fritted funnel to remove residual
solids and the solvent evaporated. The resulting purple oil was redis-
solved in Me2CO and the [4]rotaxane was purified by preparative TLC
using 50% MeOH/CH2Cl2 followed by 3% w/v NH4PF6 in Me2CO fol-
lowed by a 12:7:1 1 m NH4Cl/MeOH/MeNO2 mobile phases consecutively
on one preparative TLC plate. The rotaxane product was recovered from
the silica gel by washing with excess water, then Me2CO, and finally a
4% w/v NH4PF6 solution in Me2CO. The recovered material was then re-
subjected to preparative TLC using a 12:7:1 1 m NH4Cl/MeOH/MeNO2
mobile phase. The rotaxane product was again recovered from the silica
gel as before. The Me2CO was concentrated to a minimum volume, and
the product was precipitated from this solution through the addition of
an excess of cold water. The [4]rotaxane 11·12PF6 was isolated as a
(600 MHz, CDCl3, 258C, TMS) (assignments verified by COSY and
3
HMQC): d=7.84 (d, J
A
3
central benzene aryl -H), 7.64 (d, J
methylene triazole), 7.53 (s, 3H, triazole -H), 7.43 (s, 3H, triazole -H),
7.34 (d, 3J
(H,H)=8 Hz, 6H, central aryl -H o-methylene triazole), 7.35–
7.26 (m, 24H), 6.91 (d, 3J
(H,H)=8 Hz, 12H, stopper aryl -H o-O), 6.81–
AHCTREUNG
6.79 (m, 12H, stopper aryl -H o-O and DNP aryl -H o-O), 6.53 (s, 6H,
stopper aryl -H o-methylene triazole), 5.51 (s, 6H, tris-phenyl benzene-
CH2N), 5.33 (s, 6H, stopper phenyl-CH2N), 4.96 (s, 12H, stopper O-CH2-
phenyl), 4.92 (s, 6H, stopper O-CH2-phenyl), 4.67(s, 6H, triazole-
CH2O), 4.67(s, 6H, triazole-CH 2O), 4.26–4.23 (m, 12H, DNP-OCH2),
4.15 (t, 3J
5 Hz, 6H, stopper phenyl-OCH2), 3.97–3.94 (m, 12H), 3.89–3.85 (m,
A
N
Chem. Eur. J. 2008, 14, 4168 – 4177
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4175

J. F. Stoddart, J. R. Heath et al.
18H), 3.79–3.76 (m, 12H), 3.74–3.72 (m, 18H), 3.70–3.66 (m, 36H), 3.60–
3.58 (m, 18H), 3.40 ppm (s, 27H, stopper -OCH3); 13C NMR (151 MHz,
CDCl3, 258C, TMS): d=158.6, 158.6, 154.3, 153.2, 145.7, 145.9, 141.7,
141.2, 138.7, 134.2, 130.2, 130.0, 129.9, 129.2, 129.0, 128.7, 127.9, 126.7,
125.3, 125.1, 122.6, 122.6, 114.6, 114.3, 108.0, 105.7, 74.7, 71.9, 71.1, 70.9,
70.7, 70.7, 70.6, 70.6, 69.8, 69.8, 67.9, 67.4, 67.4, 64.7, 64.7, 59.1, 54.2,
53.7ppm; MS (ESI; MeOH/H 2O 1:1, 0.1% AcOH): m/z: 1464.4
[M+3H]3+, 1098.5 [M+4H]4+, 879.2 [M+5H]5+; HRMS (ESI; MeOH/
H2O 1:1, 0.1% AcOH): m/z: calcd for [C240H298N18O60]4+: 1098.5220
[M+4H]4+; found: 1098.5203.
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The research was supported by the Microelectronics Advanced Research
Corporation (MARCO) and its Focus Center of Functional Engineered
NanoArchitectonics (FENA) and Materials, Structures, and Devices
(MSD). J.M.S. gratefully acknowledges the award of a Graduate Re-
search Fellowship from the National Science Foundation (NSF).
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Received: January 14, 2008
Published online: April 2, 2008
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