Switching between Anion-Binding Catalysis and Aminocatalysis with a Rotaxane Dual-Function Catalyst

Article abstract of DOI:10.1021/jacs.7b04955

The "off" state for aminocatalysis by a switchable [2]rotaxane is shown to correspond to an "on" state for anion-binding catalysis. Conversely, the aminocatalysis "on" state of the dual-function rotaxane is inactive in anion-binding catalysis. Switching b

Full text of DOI:10.1021/jacs.7b04955

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Article
Switching Between Anion-Binding Catalysis and Amino-
catalysis with a Rotaxane Dual-Function Catalyst
Katarzyna Eichstaedt, Javier Jaramillo-Garcia, David A. Leigh,
Vanesa Marcos, Simone Pisano, and Thomas A. Singleton
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 19 Jun 2017
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Switching Between Anion-Binding Catalysis and Aminocatal-
ysis with a Rotaxane Dual-Function Catalyst
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Katarzyna Eichstaedt, Javier Jaramillo-Garcia, David A. Leigh,* Vanesa Marcos, Simone Pisano,
Thomas A. Singleton
School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
KEYWORDS: Rotaxane, Molecular Machines, Switchable Catalyst, Anion-Binding Catalysis, Aminocatalysis, Tandem
Reactions
ABSTRACT: The ‘off’ state for aminocatalysis by a switchable [2]rotaxane is shown to correspond to an ‘on’ state for ani-
on-binding catalysis. Conversely, the aminocatalysis ‘on’ state of the dual-function rotaxane is inactive in anion-binding
catalysis. Switching between the different states is achieved through the stimuli-induced change of position of the macro-
cycle on the rotaxane thread. The anion-binding catalysis results from a pair of triazolium groups that act together to CH-
hydrogen bond to halide anions when the macrocycle is located on an alternative (ammonium) binding site, stabilizing
the in situ generation of benzhydryl cation and oxonium ion intermediates from activated alkyl halides. The aminocataly-
sis and anion-binding catalysis sites of the dual-function rotaxane catalyst can be sequentially concealed or revealed,
enabling catalysis of both steps of a tandem reaction process.
1. INTRODUCTION
Biology uses molecular machines in a broad range of
molecular construction processes, from the ribosome1 to
allosterically-regulated2 enzymes. The latter is inspiring
the development of ‘smart’ artificial catalysts3 in which a
stimulus is used to significantly alter the rate, or stereo-
or regioselective outcome, of a chemical reaction.4 How-
ever, systems that can switch between different catalytic
groups that promote different chemical transformations
remain scarce.5,6 We previously described7 a rotaxane-
based8 switchable aminocatalyst9 (1 ‘on’ state/1-H+ ‘off’
state) that modulates the rate of a range of organocata-
lyzed reactions via diverse activation pathways,7b includ-
ing iminium-ion, enamine and trienamine, and even tan-
dem iminium-enamine processes (Figure 1). Here we
show that the ‘off’ state of the aminocatalyst also corre-
sponds to an ‘on’ state for anion-binding catalysis,10 pro-
moted by the presence of two triazolium groups on the
rotaxane axle11 that work together to bind anions12,13 when
the rotaxane macrocycle is located on the central ammo-
Figure 1. Acid-base switching of the position of the macrocy-
cle in rotaxane 1 (‘on’ state)/1-H+ (‘off’ state) for controlling
nium group of the thread (Figure 2).
the rate of aminocatalysis via different activation pathways:
(i) iminium-ion (Im); (ii) enamine (En); (iii) tandem imini-
um-enamine (Im-En); and (iv) trienamine (Trien).7
In the last few years, hydrogen bonding catalysis has
emerged as a powerful tool for synthesis.14-16 The hydro-
gen bonding activation of neutral electrophiles, such as
carbonyl or imine moieties, is well established,15 and hy-
drogen bonding activation of electrophilic ionic sub-
strates by coordination to their counter anions is increas-
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ingly being exploited.15 Anion-binding catalysis generally
um halide salts (see Supporting Information). With rotax-
ane 1-H+, significant shifts in the resonances of the tria-
zolium protons upon addition of Bu4NCl or Bu4NBr was
observed by 1H NMR spectroscopy. Titration experiments
showed that rotaxane 1-H+ forms 1:1 complexes with both
bromide and chloride, with association constants (Ka) in
CD3CN of 200 M-1 in each case (see Supporting Infor-
mation).21 In contrast, 1H NMR spectroscopy showed little
or no interaction between halide salts and the triazolium
protons of rotaxane 1 (Supporting Information, Fig. S9
and S10).
1
2
3
4
5
6
7
8
utilizes catalysts based on strongly-polarized N−H bonds,
such as those in ureas, thioureas16 and thiophospho-
ramides.17 However, structures based on strong O−H
bonds,18 and even the cooperative action of less polarized
C−H19 or C−X20 bonds, have also proved effective. Accord-
ingly, we investigated whether the two triazolium groups
of rotaxane 1-H+ could act as an anion-binding catalyst for
the in-situ generation of ionic intermediates, such as
benzhydryl cations and oxonium ions via halide abstrac-
tion (Figure 2a). If so, the ‘off’ state of aminocatalyst (1-
H+) would also be an ‘on’ state for anion-binding catalysis,
and the ‘on’ state for aminocatalysis (1) would be an ‘off’
state for anion-binding catalysis. The two different cata-
lytic modes could, in principle, be activated in sequence,
allowing the rotaxane-based molecular switch to promote
tandem anion-binding/amino-catalyzed processes (Figure
2b).
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Having established the halide-binding properties of the
protonated rotaxane (1-H+) and confirmed that halide
binding is switched ‘off’ by changing the position of the
macrocycle (i.e. in 1), we investigated the efficacy of the
anion-binding state of the rotaxane as an anion-binding
catalyst.
The Ritter reaction of bromodiarylmethane compounds
and deuterated acetonitrile (CD3CN)20c–e was chosen for
the investigation of the in situ generation of benzhydryl
carbocation derivatives (Ar2CH+) formed through the
rotaxane 1-H+-promoted cleavage of a carbon-bromide
bond (Table 1). We first confirmed that the reaction of 5a
with CD3CN does not proceed in the absence of the cata-
lyst (Table 1, entry 1), and then carried out a series of ex-
periments involving different potential reaction-
promoting species (Table 1). Dibenzylamine (3), protonat-
ed dibenzylamine (3-H+) and pseudorotaxane 4-H+ (Table
1, entries 2–4) did not promote the Ritter reaction over 7
days at 40 °C. Under the same reaction conditions, the
threads in both protonated and deprotonated forms (2
and 2-H+, respectively) catalyzed the reaction equally
effectively after 5 days (Table 1, entries 5 and 6). The bis-
triazolium-based catalyst contained in the protonated
rotaxane, 1-H+, catalyzed the reaction as effectively as the
bis-triazolium-based unit of the threads (2 and 2-H+)
affording 6a with good conversion (Table 1, entry 7).
However, the deprotonated form of the rotaxane, 1, did
not afford any product (Table 1, entry 8). This demon-
strates that the inhibition of anion-binding catalysis by
the rotaxane is caused by the macrocycle position in 1,
which blocks the ability of the two triazolium groups to
bind halide ions.
The progress of the Ritter reaction could also be con-
trolled through in situ switching of the position of the
macrocycle in the rotaxane catalyst (Table 1, entries 9–12).
After 3 days of stirring 5a in the presence of 20 mol %
rotaxane in its inactive, deprotonated state (1), no conver-
sion of Ph2CHBr to the acetamide product 6a was ob-
served. Upon addition of CF3CO2H (20 mol %), the rotax-
ane catalyst was switched ‘on’, affording 6a in 60 % yield
within 5 days (Table 1, entry 9). The activity of protonated
rotaxane catalyst 1-H+ could also be switched ‘off’ in situ
by adding NaOMe (20 mol %) to the reaction mixture
(Table 1, entry 11). Control experiments, reactions carried
out with NaOMe (20 mol %) or CF3CO2H (20 mol %) in
the absence of the rotaxanes, also confirmed that product
formation requires the presence of the rotaxane organo-
catalyst (Table 1, entries 10 and 12).
Figure 2. Acid-base switching of the position of the macro-
cycle in rotaxane 1-H+/1: (a) for controlling the rate of anion-
binding-catalyzed reactions (X--Bo); (b) for promoting tan-
dem processes; an anion-binding-catalyzed reaction followed
by an enamine-catalyzed reaction.
2. RESULTS AND DISCUSSION
Switchable rotaxane catalyst 1-H+/1 consists of a diben-
zo-24-crown-8 macrocycle locked onto a thread bearing a
dibenzylamine/ammonium moiety and two triazolium
rings,11 and was prepared according to a previously estab-
lished synthetic route.7 The bromide and chloride anion
binding properties of rotaxanes 1-H+ and 1 in CD3CN were
1
investigated through H NMR spectroscopy and titration
experiments using the corresponding tetrabutylammoni-
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Under similar reaction conditions with other bromodi-
Table 2. Scope of the anion-binding-catalyzed Ritter
reaction of bromodiarylmethane derivatives (5b,c)
using rotaxanes 1-H+ and 1.a
1
2
3
4
5
6
7
arylmethane derivatives (5b,c), the use of protonated
rotaxane 1-H+ (anion-binding catalysis ‘on’) afforded the
corresponding acetamide products (6b,c) in comparable
conversions to that found for Ph2CHBr (Table 2, entries 1
and 3). In contrast, the use of deprotonated rotaxane 1
(anion-binding catalysis ‘off’) did not produce any prod-
ucts in these reactions (Table 2, entries 2 and 4).
8
9
Table 1. Investigation of the anion-binding-catalyzed
Ritter reaction of bromodiphenylmethane with vari-
ous potential catalysts and in situ switching of the
catalytic activity.a
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Entry
R
Catalyst
Conversion (%)b
1
OMe
OMe
Me
1-H+
52
<1
2
3
4
1
1-H+
1
48
<1
Me
a
Reaction conditions: 36 µmol of 5b–c, and 7.2 µmol of
catalyst (1 or 1-H+, 20 mol%) in 400 µL of CD3CN at 40 °C.
b
Conversion
Entry
Catalyst
Conversions determined after 5 days by 1H NMR.
(%)b
In order to further evaluate the effectiveness of the bis-
triazolium halide-binding groups in rotaxane 1-H+ in
catalysis, we investigated its performance for the in situ
generation of oxonium ions via carbon-chlorine bond
cleavage.22 The catalytic activity of both rotaxanes (1-H+
and 1), and other potential reaction-promoting species,
were studied in the reaction between 1-chloroisochroman
(7) and the silyl ketene acetal 8a (Table 3). Other than the
protonated rotaxane 1-H+, or the protonated or non-
protonated non-interlocked thread 2-H+ and 2, none of
the other potential reaction-promoting species (Table 3,
entries 2-4) catalyzed the formation of product 9a. In
contrast, both threads 2 and 2-H+ catalyzed the reaction
with excellent conversion (Table 3, entries 5 and 6). As
before, the reaction promoted with the protonated rotax-
ane 1-H+ (anion-binding catalysis ‘on’ state) is equally
effective. In contrast, no reaction was observed using
rotaxane 1 (anion-binding catalysis ‘off’ state).
1
2
–
<1
3
<1
3
3-H+
<1
4
5
4-H+
<1
2
2-H+
1-H+
54
55
6
7
69
8
9
10
11
12
1
<1
1+ CF3CO2H (20 mol%)
CF3CO2H (20 mol%)
1-H++ NaOMe (20 mol%)
NaOMe (20 mol%)
60c
<1c
<1d
<1d
a Reaction conditions: 36 µmol of 5a, and 7.2 µmol of catalyst
(20 mol%) in 400 µL of CD3CN at 40 °C. b Conversions de-
termined after 5 days by 1H NMR. c Addition of CF3CO2H (20
d
mol%) to the reaction mixture. Addition of NaOMe (20
mol%) to the reaction mixture.
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Table 3. Investigation of the anion-binding-catalyzed Table 4. Scope of the anion-binding-catalyzed reac-
1
2
reaction of 1-chloroisochroman (7) and the ketene
silyl acetal (8a) with various potential catalysts. a
tion between 1-chloroisochroman (7) and 8b–d with
rotaxanes 1-H+ and 1.a
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5
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9
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Entry
R1
R2
R3
Catalyst
Conv. (%)b
Entry
Catalyst
Conversion (%)b
1
–
3
<1
<1
<1
<1
81
72
76
<1
1
2
3
4
5
H
H
OMe
OMe
H
TBS
TBS
1-H+
84 (9b)
<1
2
3
4
5
6
7
8
1
1-H+
1
3-H+
4-H+
2
2-H+
1-H+
1
Me
Me
H
TMS
TMS
TMS
TMS
20 (9c)
<1
H
H
1-H+
70 (9d)
<1
6
H
H
1
a
Reaction conditions: 36.0 µmol of 7, 54.0 µmol of 8b–d
and 7.2 µmol of catalyst (1 and 1-H+, 20 mol %) in 750 µL of
THF at -50 °C. b After 12 hours, the reaction was quenched by
a
1
Reaction conditions: 36 µmol of 7, 54 µmol of 8a and 7.2
addition of NaOMe and the conversions determined by H
NMR.
µmol of catalyst (20 mol%) in 750 µL of THF at -50 °C. b After
12 hours, the reaction was quenched by addition of NaOMe
and the conversion determined by 1H NMR.
Finally, the ability of rotaxane 1-H+/1 to switch in situ
between the two catalytic states (anion-binding catalyst
and aminocatalyst), each promoting a different chemical
transformation, was exploited to bring about a tandem
reaction. The process consists first of an anion-binding-
catalyzed alkylation reaction between 7 and 8d, followed
by a nucleophilic addition of 10 via enamine activation of
the intermediate aldehyde 9d (Scheme 1). An equimolar
mixture of 7 and 8d (72 µmol) in the presence of 20 mol %
of protonated rotaxane 1-H+ (anion-binding catalyst ‘on’)
was stirred in THF at -50 °C, affording the alkylated prod-
uct 9d with 70 % conversion after 12 h. After this time,
NaOMe was added to quench the remaining excess of silyl
enol ether and to switch ‘on’ the aminocatalyst state of
the rotaxane (1) in situ. Subsequent addition of vinyl bis-
sulfone 10 afforded compound 11 (50 % conversion after
48 h at r.t.) through enamine activation of 9d (see Sup-
porting Information for experimental details). By control-
ling the order in which catalytic sites are revealed and
concealed, dual-function switchable rotaxane catalyst 1-
H+/1 is able to control the outcome of a tandem process,
creating two new C−C bonds, the first by anion-binding
catalysis and the second by aminocatalysis via enamine
activation.
The generality of rotaxane 1-H+/1 as a switchable anion-
binding catalyst was studied with diverse silyl ether nu-
cleophiles (8b,d; Table 4). Protonated rotaxane 1-H+ (‘on’
catalyst) promoted the reaction between 7 and
unsubstituted silyl ether nucleophiles (8b and 8d) with
high conversions (Table 4, entries 1 and 3). However,
α-
hindered
α-disubstituted silyl enol ether 8c (Table 4,
entry 5) afforded the corresponding aldehyde derivative
in a poor yield. The change of the position of the macro-
cycle on the rotaxane allows for total control over the rate
of the reactions, as the ‘off’ state of the system (1) does
not exhibit any observable catalytic activity at all (Table 4,
entries 2, 4 and 6).
3. CONCLUSIONS
A rotaxane that selectively masks or exposes a bis-
triazolium-based catalytic unit in response to acid/base
acts as an effective switchable anion-binding catalyst. The
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outcome of a tandem anion-binding-enamine catalytic
rotaxane can effectively control the rate of Ritter and
1
2
3
4
5
6
7
8
alkylation reactions by C–Br or C–Cl bond cleavage, re-
spectively, either by adding the catalyst in its active form
or by in situ switching. To the best of our knowledge the-
se are the first examples of anion-binding catalysis of
these reactions. The two catalytic functions of the system,
an anion-binding catalyst and an aminocatalyst, can be
selectively concealed or revealed and their activities
switched on or off, enabling control over the product
reaction sequence.
Controlling the order in which catalytic sites are re-
vealed and concealed by molecular machine multi-
function catalysts represents a ‘bio-like’ strategy for mo-
lecular construction.3e Turning ‘on’ and ‘off’ different cata-
lyst activities in response to a specific stimulus or analyte
may be useful for promoting alternative reactions and
product outcomes from mixtures of building blocks.5a
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Scheme 1. Controlling the product outcome of a tandem reaction using switchable dual-function rotaxane 1-
H+/1: Switching in situ between the two catalytic units, anion-binding catalyst 1-H+ and aminocatalyst 1.a
a See Supporting Information for experimental details.
(2) Traut, T. W. Allosteric Regulatory Enzymes, Springer, New
ASSOCIATED CONTENT
York, 2008.
(3) (a) Lüning, U. Angew. Chem., Int. Ed. 2012, 51, 8163. (b)
Leigh, D. A.; Marcos, V.; Wilson, M. R. ACS Catal. 2014, 4,
4490. (c) Neal, E. A.; Goldup, S. M. Chem. Commun. 2014, 50,
5128. (d) Erbas-Cakmak, S.; Leigh, D. A.; McTernan, C. T.;
Nussbaumer, A. L. Chem. Rev. 2015, 115, 10081. (e) Blanco, V.;
Leigh D. A.; Marcos, V. Chem. Soc. Rev. 2015, 44, 5341. (f) Pan
T.; Liu, J. ChemPhysChem 2016, 17, 1752. (g) Lewis, J. E. M.; Galli
M.; Goldup, S. M. Chem. Commun. 2017, 53, 298.
Supporting Information.
Experimental procedures, spectral data for new compounds
1
and H NMR data for catalytic experiments and binding
studies. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
(4) For representative examples of artificial catalysts that can
be switched ‘on’ and ‘off’ by a specific stimulus, see: (a)
Würthner, F.; Rebek Jr., J. Angew. Chem., Int. Ed. Engl. 1995, 34,
446. (b) Yoon, H. J.; Kuwabara, J.; Kim, J.-H.; Mirkin, C. A.
Science 2010, 330, 66. (c) Sohtome, Y.; Tanaka, S.; Takada, K.;
Yamaguchi, T.; Nagasawa, K. Angew. Chem., Int. Ed. 2010, 49,
9254. (d) Berryman, O. B.; Sather, A. C.; Lledó, A.; Rebek Jr., J.
Angew. Chem., Int. Ed. 2011, 50, 9400. (e) Wang, J.; Feringa, B.
L. Science 2011, 331, 1429. (f) Mortezaei, S.; Catarineu, N. R.;
Canary, J. W. J. Am. Chem. Soc. 2012, 134, 8054. (g) Neilson, B.
M.; Bielawski, C. W. J. Am. Chem. Soc. 2012, 134, 12693. (h)
Schmittel, M.; De, S.; Pramanik, S. Angew. Chem., Int. Ed. 2012,
51, 3832. (i) Schmittel, M.; Pramanik, S.; De, S. Chem. Commun.
2012, 48, 11730. (j) Wilson, D.; Branda, N. R. Angew. Chem., Int.
Ed. 2012, 51, 5431. (k) Viehmann, P.; Hecht, S. Beilstein J. Org.
Chem. 2012, 8, 1825. (l) Neilson, B. M.; Bielawski, C. W. Chem.
Commun. 2013, 49, 5453. (m) Neilson, B. M.; Bielawski, C. W.
Organometallics 2013, 32, 3121. (n) Osorio-Planes, L.;
Rodríguez-Escrich, C.; Pericás, M. A. Org. Lett. 2014, 16, 1704.
(o) McGuirk, C. M.; Stern, C. L.; Mirkin, C. A. J. Am. Chem. Soc.
2014, 136, 4689. (p) Blanco, V.; Leigh, D. A.; Marcos, V.; Mo-
rales-Serna, J. A.; Nussbaumer, A. L. J. Am. Chem. Soc. 2014,
Corresponding Author
david.leigh@manchester.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was funded by the European Research Coun-
cil (Advanced grant no. 339019) and the European Union’s
seventh Framework Program (FP7-PEOPLE-2013-ITN-
607602 ‘Hierarchical Self Assembly of Polymeric Soft Sys-
tems’ SASSYPOL). We thank the Royal Society for a New-
ton International Fellowship (to TS) and a Research Profes-
sorship (to DAL).
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