A rotaxane-based switchable organocatalyst

Article abstract of DOI:10.1002/anie.201201364

Switch it on! The activity of an organocatalytic group incorporated within a rotaxane architecture can be controlled by switching the position of the macrocycle. The system was used to mediate the progress of the Michael addition of an aliphatic thiol to trans-cinnamaldehyde. Copyright

Full text of DOI:10.1002/anie.201201364

Angewandte
Chemie
DOI: 10.1002/anie.201201364
Switchable Catalysts
A Rotaxane-Based Switchable Organocatalyst**
Victor Blanco, Armando Carlone, Kevin D. Hꢀnni, David A. Leigh,* and Bartosz Lewandowski
The activity of enzymes is often modulated by cofactors,
phosphorylation, allosteric binding, or other trigger-induced
effects.[1] Achieving similar control over synthetic catalysts[2]
could be useful for influencing both the rate and outcome of
chemical transformations, the latter perhaps by switching
“on” and “off” different catalysts that promote alternative
reactions in the same pot. Rotaxane-based molecular shuttles
have previously been used for information storage,[3] mechan-
ical work,[4] gel formation,[5] fluorescence[6] and chiroptical[7]
switching, to control binding events[8] and in various con-
trolled-release[9] systems.[10] Herein we show that the well-
defined positional changes of the components in a switchable
rotaxane can be exploited to conceal and reveal an organo-
catalytic site.[11]
The design of the system is based on a switchable rotaxane
motif[12] developed by Coutrot.[12a–c] The rotaxane (1) consists
of a dibenzo[24]crown-8 macrocycle and an axle containing
both triazolium rings and
a dibenzylamine/ammonium
moiety[13] (Scheme 1). In principle, a secondary amine/
ammonium group is able to carry out iminium catalysis[14]
over a wide pH range (that is, irrespective of whether the
catalyst is initially in the amine or ammonium ion form).
However, when the rotaxane is protonated (1-H·3PF6), the
ammonium group is a better binding site for the macrocycle
than the triazolium rings and so the macrocycle encapsulates
the central region of the axle blocking access of reactants to
the catalytic center. When the secondary amine of the
rotaxane is not protonated (1·2PF6), the triazolium groups
are the preferred binding sites for the macrocycle and the
dibenzylamine group on the axle is exposed and available to
perform catalysis.
Scheme 1. Acid–base switching of the position of the macrocycle in
rotaxane 1-H·3PF6/1·2PF6.
alkyne–ammonium axle (see the Supporting Information).[13]
1
Rotaxane 1 was prepared using the CuAAC click
reaction[15] of an azide-functionalized bulky 3,5-di-tert-butyl-
phenyl derivative as the key step to covalently capture
a threaded complex of dibenzo[24]crown-8 with a suitable
Comparison of the H NMR spectra of the protonated and
unprotonated thread and rotaxane confirms the different
position of the macrocycle on the thread in the two switchable
states of the rotaxane in various solvents (CD3CN (see
Figure 1), CDCl3, and CD2Cl2). In the 1H NMR spectrum of 1-
H·3PF6 (Figure 1b), there is an upfield shift of the benzyl-
amine aromatic proton signals compared to those in the non-
interlocked thread 2-H·3PF6 (Figure 1a) owing to shielding
by the macrocycle (DdHi = À0.32 ppm and DdHj =
À0.14 ppm). The downfield shift and broadening of the
benzylic CH2 groups (DdHk = 0.45 ppm) is a result of strong
hydrogen bonding between the ammonium group and the
crown ether. In contrast, the chemical shifts of the triazolium
protons (Hg and Hm) are similar in both the protonated
rotaxane (1-H·3PF6) and the thread (2-H·3PF6).
When rotaxane 1-H·3PF6 was deprotonated with aqueous
NaOH or 2-tert-butylimino-2-diethylamino-1,3-dimethylper-
hydro-1,3,2-diazaphosphorine (BEMP) phosphazene resin to
give 1·2PF6,[16] significant changes were observed in the
1H NMR spectrum. At room temperature in CD3CN, two
sets of resonances are present for the triazolium groups and
[*] Dr. V. Blanco, Dr. A. Carlone, Dr. K. D. Hꢀnni, Prof. D. A. Leigh,
Dr. B. Lewandowski
School of Chemistry, University of Edinburgh, The King’s Buildings
West Mains Road, Edinburgh, EH9 3JJ (UK)
Prof. D. A. Leigh
School of Chemistry, University of Manchester
Oxford Road, Manchester M13 9PL (UK)
E-mail: david.leigh@manchester.ac.uk
Homepage: http://www.catenane.net
[**] We thank the EPSRC National Mass Spectrometry Centre (Swansea
(UK)) for high resolution mass spectrometry. This research was
funded by the EPSRC. V.B. and A.C. are Marie Curie Fellows (IEF)
within the 7th European Framework Program. We also thank
Fundacja na Rzecz Nauki Polskiej (FNP) for a postdoctoral fellow-
ship to B.L.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201364.
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Table 1: Investigation of the catalytic properties of threads 2·2PF6 and
2-H·3PF6 and rotaxanes 1·2PF6 and 1-H·3PF6 on the Michael addition of
thiol 4 to trans-cinnamaldehyde (3).[a]
Entry
Catalyst
Yield[b]
1
2
3
4
5
6
7
8
no catalyst
dibenzylamine
2·2PF6
2-H·3PF6
1·2PF6
1-H·3PF6
no reaction
69%
30%
49%
83%
no reaction
1·2PF6/1-H·3PF6 +10 min NaOH(aq) wash
no catalyst+10 min NaOH(aq) wash
66%[c]
traces[d]
[a] Reactions were run with 5 mol% catalyst loading at 0.1m concen-
tration of thiol 4 with 1.5 equiv of aldehyde 3. [b] Yield of 5 isolated after
column chromatography. [c] Yield after 10 min washing with 1m
NaOH(aq) and subsequent 1 h stirring at room temperature. [d] Traces of
5 were detected after the NaOH(aq) wash but, in the absence of an amine,
the amount of 5 present did not increase over 5 d of subsequent stirring.
Figure 1. 1H NMR spectra (400 MHz, CD3CN, 298 K) of a) thread
2-H·3PF6; b) rotaxane 1-H·3PF6; c) rotaxane 1·2PF6 (338 K); d) solution
from (c) after addition of 1 equivalent of CF3CO2H. The lettering and
color coding of the signals corresponds to that shown in Scheme 1.
The most convenient way of switching the rotaxane
catalyst “on” (1·2PF6) from its protonated “off” state
(1-H·3PF6) is to simply wash a solution of the rotaxane in
dichloromethane with 1m aqueous NaOH.[16] Interestingly,
when a mixture initially containing 3, 4, and 1-H·3PF6 (or
1·2PF6) was washed with 1m aqueous NaOH, the reaction
reached complete conversion to 5 within 1 h (Table 1,
entry 7), instead of a reaction time of 5 days when starting
with pristine 1·2PF6 (that is, with no NaOH wash; Table 1,
entry 5). We presume that the rate enhancement is due to
deprotonation of thiol 4 by NaOH, making it more nucleo-
philic. However, treatment with NaOH is not sufficient in
itself to allow the reaction to occur efficiently in the absence
of an amine catalyst (Table 1, entry 8).
neighboring protons (He, Hf, Hg, Hh, Hm) in 1·2PF6, indicating
that shuttling of the macrocycle between the two triazolium
stations is slow on the NMR timescale. At 338 K, the two sets
of resonances coalesce and the remaining peaks sharpen
(Figure 1c).[17] Most significantly, the benzylic protons are
shifted upfield (DdHk = À0.88 ppm) and the triazole protons
downfield (DdHg ꢀ 0.37 ppm), confirming that the macro-
cycle resides over the triazolium groups in 1·2PF6 (Figure 1c).
Upon reprotonation of the secondary amine group with
1
CF3CO2H (Scheme 1), the H NMR shifts indicate that the
macrocycle returns to its original position over the ammo-
nium site (Figure 1d).
Having demonstrated acid–base control over the position
of the ring on the axle in 1, and confirmed the positional
integrity of the components in the two different states, we
investigated the efficacy of the rotaxane as a switchable
organocatalyst. The Michael addition of an aliphatic thiol,
such as 4,[18] to trans-cinnamaldehyde (3) is typical[19] of a class
of reactions accelerated by iminium organocatalysis[14]
(Table 1). We first confirmed that the reaction between 3
and 4 does not proceed to a perceptible extent in the absence
of a secondary amine catalyst (Table 1, entry 1) and then
carried out a series of experiments involving different
potential reaction-promoting species (Table 1).
Dibenzylamine and the thread (in both protonated and
deprotonated forms, 2-H·3PF6 and 2·2PF6, respectively)
catalyzed the Michael addition of 4 to 3 over 5 days at room
temperature in CH2Cl2 (Table 1, entries 2–4). The deproton-
ated form of the rotaxane (1·2PF6) catalyzed the reaction
equally effectively (Table 1, entry 5). However, use of the
protonated form of the rotaxane, 1-H·3PF6, resulted in the
starting materials being recovered unchanged after 5 days
(Table 1, entry 6).
Finally, it proved possible to control the progress of the
Michael addition by in situ switching of the rotaxane organo-
catalyst (Figure 2; see the Supporting Information for exper-
imental details). After 48 h of stirring 3 and 4 in the presence
of 5 mol% rotaxane in its inactive, protonated, state
(1-H·3PF6), no conversion to product 5 was observed (Fig-
ure 2c). Upon brief washing with 1m aqueous NaOH, the
rotaxane catalyst was switched “on”, resulting in virtually
complete conversion of 4 to 5 within 1 h at room temperature
(Figure 2d).
In conclusion, we have developed a switchable organo-
catalyst based on a rotaxane architecture. The catalyst can be
switched “on” or “off” by addition of acid or base, which acts
to move the rotaxane ring to either conceal or reveal the
catalytic site. The system can effectively control the rate of
Michael addition of an aliphatic thiol to trans-cinnamalde-
hyde, either by adding the catalyst in its active form or by
in situ switching. Organocatalysts are often considered to be
the small-molecule counterparts of enzymes.[14] The ability to
regulate their activity through external stimuli brings the
analogy closer still.
2
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Received: February 18, 2012
Published online: && &&, &&&&
Keywords: Michael addition · molecular machines ·
.
molecular switches · organocatalysis · rotaxanes
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4
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Chemie
Communications
Switchable Catalysts
V. Blanco, A. Carlone, K. D. Hꢁnni,
D. A. Leigh,*
B. Lewandowski
&&&& — &&&&
A Rotaxane-Based Switchable
Organocatalyst
Switch it on! The activity of an organo-
catalytic group incorporated within
cycle. The system was used to mediate
the progress of the Michael addition of an
a rotaxane architecture can be controlled
by switching the position of the macro-
aliphatic thiol to trans-cinnamaldehyde.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!