Formation of a hydrogen-bonded barbiturate [2]-rotaxane

Article abstract of DOI:10.1021/ol500099u

Interlocked structures containing the classic Hamilton barbiturate binding motif comprising two 2,6-diamidopyridine units are reported for the first time. Stable [2]-rotaxanes can be accessed either through hydrogen-bonded preorganization by a barbiturate

Full text of DOI:10.1021/ol500099u

Letter
pubs.acs.org/OrgLett
Formation of a Hydrogen-Bonded Barbiturate [2]-Rotaxane
Arnaud Tron,† Peter J. Thornton,‡ Mathias Rocher,‡ Henri-Pierre Jacquot de Rouville,†
Jean-Pierre Desvergne,† Brice Kauffmann,§ Thierry Buffeteau,† Dominique Cavagnat,†
James H. R. Tucker,*,‡ and Nathan D. McClenaghan*,†
†Institut des Sciences Molec
‡School of Chemistry, University of Birmingham, Edgbaston, B15 2TT Birmingham, United Kingdom
§Institut Europee
n de Chimie et Biologie, CNRS UMS 3033, Univ. Bordeaux, 33607 Pessac, France
́
ulaires, CNRS UMR 5255, Univ. Bordeaux, 33405 Talence, France
́
S
* Supporting Information
ABSTRACT: Interlocked structures containing the classic Hamilton barbiturate binding motif
comprising two 2,6-diamidopyridine units are reported for the first time. Stable [2]-rotaxanes can
be accessed either through hydrogen-bonded preorganization by a barbiturate thread followed by
a Cu+-catalyzed “click” stoppering reaction or by a Cu2+-mediated Glaser homocoupling reaction.
nterlocked structure synthesis generally relies on preorgani-
implementing this well-known H-bonding motif in various
Ization or templating using self-assembly, for example functional interlocked systems.
Bead component 2 was designed with the characteristic
harnessing noncovalent interactions between a guest and a
macrocyclic host, before covalent capture of the dynamic
ensemble.1 While a wealth of interlocked catenane and rotaxane
structures have been reported, their synthesis often relies on the
use of one of a limited number of popular motifs. Examples of
directed synthesis of interlocked structures, where the necessary
templates relies on hydrogen bonds, which afford intermo-
lecular interactions between neutral molecules, have been
reported.2,3 Hydrogen bonds can offer both directionality and
selectivity when multiple interactions are employed and have
the advantage of being optically transparent and electrochemi-
cally stable. One of the most successful receptors for
complexation of neutral molecules using hydrogen bonds is
based on the highly selective barbiturate receptor developed by
Hamilton and co-workers.4 The complementarity between a
bis-2,6-diamidopyridine group and the two imide sites on
barbiturates results in the formation of six hydrogen bonds with
a high association constant in noncompetitive solvents.5
Various supramolecular systems harnessing this motif,6 in the
context of catalysis,6a sensing,6b,c photochromism,6d photo-
induced charge separation,6e and the generation of self-
assembled superstructures,6f have been reported. However,
despite the success of this receptor−guest motif in generating
supramolecular functionality, its use in the formation of
interlocked structures has not been reported to date. Here we
report the synthesis of such interlocked structures via two
distinct strategies (Scheme 1) including 5, which comprises an
optimized macrocyclic variant of the Hamilton receptor bead
and a barbiturate thread motif. Both bead and thread
components of this rotaxane are accessible in two steps from
commercial products, which demonstrates the potential for
DADDAD H-bonding pattern suitable for binding a barbiturate
guest, where D represents an H-bond donor group and A
represents an H-bond acceptor group. Synthesis of 2 started
with preparation of the central H-bonding unit through
condensation of 3-tert-butylisophthalolyl chloride with 2,6-
diaminopyridine.7 Subsequent formation of a macrocycle of
optimized size was achieved through condensation with the
appropriate α,ω-diacyl chloride, giving 2 in 19% yield (see
Supporting Information (SI) for synthetic details and character-
ization). Barbiturate thread synthon 1 offered the comple-
mentary ADAADA H-bonding pattern, while incorporation of
only short alkyl chains was found to allow quantitative
threading. Azide-terminated barbiturate 1 was synthesized in
two steps (Scheme S1, SI).8 Following dialkylation of diethyl
malonate, condensation with urea in DMSO in the presence of
NaH gave 1 in 35% yield. Formation of a 1:1 complex, fully
satisfying the H-bonding motif, implies an interpenetrating
pseudorotaxane structure, where the central barbiturate sp3-
carbon assures an orthogonality of the two chains in the
barbiturate 5-position with respect to the plane of the receptor
ring. Incorporation of reactive end groups on the thread, such
as azides, would then allow further synthetic modification
including stoppering.
Structural predisposition of this host/guest motif toward
formation of complexes conducive with interlocked structure
formation is supported by X-ray diffraction analysis of crystals
of the molecular complex formed between 2 and barbital (5,5-
Received: January 11, 2014
Published: February 26, 2014
© 2014 American Chemical Society
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Letter
Scheme 1. Synthesis of [2]-Rotaxane 5, Thread 4, and Glaser
Coupling Product 6
Figure 1. X-ray crystal diffraction structure of barbital ⊂ 2 (see SI for
details). Dashed lines represent short contact distances of length (from
left to right) 3.2, 2.0, 2.4, 2.2, 2.3, 2.1, and 1.9 Å.
of the receptor (Δδ = 1.5 and 1.6 ppm) compared to
uncomplexed barbiturate 1 (Figure 2a) and receptor 2 (Figure
2c). A through-space correlation between amide protons of 1
and 2 (Figure S4) was observed by 2D NMR (NOESY) and
confirmed their close proximity in the complex. Similarly,
resonances corresponding to protons Ha, Hb, and Hc of the two
alkyl arms of 1 correlated with the methylene protons (most
clearly visible with HA) of the alkyl chain of 2. These
observations are consistent with a symmetric interpenetrating
pseudorotaxane structure. IR spectra of the 1:1 complex 1 ⊂ 2
(Figure S12, 10 mM) show intermolecular hydrogen bonding
via a shift of characteristic N−H and CO peaks, compared to
uncomplexed 1 and 2. In deuterated chloroform, free 2 shows
an amide N−H stretching band at 3423 cm−1, while guest 1
presents an N−H stretching band at 3378 cm−1 (see Figure
S12). On mixing 1 and 2, these bands shift to 3328 cm−1 for
the N−H of 2 which is hydrogen bonded to the CO of 1 and
to 3100−2700 cm−1 (broad band) for the N−H of 1. These
results show complexation invoking all CO and N−H groups
consistent with formation of six hydrogen bonds.
Having the pseudorotaxane in hand, covalent capture of
interlocked [2]-rotaxane 5 could be performed. Indeed,
incorporation of the azide functions on 1 renders the
pseudorotaxane 1 ⊂ 2 amenable to a mild stoppering reaction
utilizing an efficient copper(I)-catalyzed alkyne−azide 1,3-
cycloaddition (CuAAC) click reaction between an azide and an
alkyne-containing stopper group,9 which is an effective strategy
for rotaxane and catenane formation.10 The click reaction was
performed between 1 ⊂ 2 (54 mM of each component in
CHCl3) and alkyne-terminated stopper 3 (Scheme 1), in the
presence of a catalytic amount of Cu(MeCN)4PF6 and tris[(1-
benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA)11 which
resulted in the formation of [2]-rotaxane 5, as well as free
stoppered thread 4. [2]-Rotaxane 5 and thread 4 were isolated
by column chromatography (SiO2: cyclohexane/ethyl acetate,
diethylbarbituric acid); see Figure 1 and SI. Crystals were
obtained via slow diffusion of pentane into a solution of the
inclusion complex in dichloromethane, with a unit cell
comprising two independent 1:1 complexes of similar geometry
(see SI). The barbiturate guest is bound by six complementary
H-bonds from the bisamidopyridine motif along with a central
short contact [C−H---OC] interaction and a length [N−H---
OC] of 1.9 to 3.2 Å with angles of 164° to 170°. In the
complex, the medium annular plane of barbital formed an
average tilt angle of ca. 26° with the medium plane of receptor
2 (see SI). Importantly, the two alkyl arms of the guest bonded
to the sp3 carbon protrude from both sides of the macrocycle
cavity, a prerequisite for a stable threaded product.
Formation of complex 1 ⊂ 2 in chloroform could be followed
by NMR, IR, and UV−vis spectroscopy. Indeed, analysis of the
complexation-induced red-shifting of the pyridine absorption
band of 2 at 315 nm allowed determination of an elevated
binding constant (Kass = 23 500 M−1; see Figure S2). A 1:1
stoichiometry of the supramolecular inclusion complex 1 ⊂ 2
was confirmed via a Job plot (Figure S3), with the maximum
absorbance change being obtained when the molar fraction
ratio reached 0.5.
Binding in solution leading to complex 1 ⊂ 2 was also
evidenced by 1H NMR spectroscopy (Figure 2b). Addition of 1
equiv of guest to the macrocycle (10 mM, CDCl3) resulted in
strong downfield shifts of the N−H resonances of the
barbiturate (Δδ = 3.8 ppm) and those of the amide protons
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Letter
5 compared with pseudorotaxane 1 ⊂ 2 is shown through
further downfield shifting and narrowing of the barbiturate
amide HNH resonance (Δδ = 0.6 ppm; Figure 2d vs Figure 2b).
NOESY experiments on pure 5 (Figure S44) show similar
through-space barbiturate−receptor interactions as the pseu-
dorotaxane 1 ⊂ 2 (see description above). IR spectroscopy was
used to monitor the progression of the stoppering reaction
between complex 1 ⊂ 2 and 3 (Figure S13). A decreasing
intensity of alkyne (3308 cm−1) and azide bands (2101 cm−1),
concomitant with the increase of the 1,2,3-triazole product
absorption (3100−3150 cm−1), was observed. Tracking
absorbance changes with time (Figure S14) showed that the
concentration of the two reactants diminished at a similar rate,
typical of the click reaction, which corresponds to formation of
thread 4 within the rotaxane. There was also evidence for the
emergence of some free receptor with respect to the initial
mixture of 1 and 2, represented by an increase in a band
associated with uncomplexed N−H (3423 cm−1). This implies
some dethreading on adding the first stopper group. A lower
binding constant would contribute to, and explain, the
formation of free 4 in addition to [2]-rotaxane 5.
Further evidence for the formation of the [2]-rotaxane comes
from comparison of 1H NMR data of 5 with the non-
interpenetrating perched complex 4·2, formed by mixing the
two preformed components in CDCl3 (Figure S7, 10 mM).
Compared to the signals for [2]-rotaxane 5 under the same
conditions, these give small upfield shifts in the two signals of
the amide protons of 2 (Δδ = 0.1 ppm), and a strong upfield
shift in the barbiturate amide proton resonances (Δδ = 4.2
ppm). The 4·2 perched complex binding constant of 4000 M−1
in CHCl3 (measured by fitting spectrophotometric data, Figure
S8) is significantly weaker than that for the 1 ⊂ 2 complex,
presumably for steric reasons. In addition, while the NMR
spectrum for the 4·2 system in DMSO indicates a
predominantly dissociated complex (Figure S6), the signals
for 5 in DMSO (Figure S5) are remarkably similar to those in
CDCl3, denoting that the H-bonding motif remains intact in
this competitive solvent. The kinetically-inert nature of
interlocked compound 5 was verified via slippage experiments
(Figure S5). No evidence for dethreading was obtained, as
1
Figure 2. Partial H NMR spectra (600 MHz) of barbiturate 1 (a),
pseudorotaxane 1 ⊂ 2 (1:1, 10 mM) (b), macrocyclic receptor 2 (c),
[2]-rotaxane 5 (d), and corresponding thread 4 (e) recorded at room
temperature in CDCl3.
7:3, v/v) in 22% and 35% yields, respectively, under conditions
where the initial proportion of bound pseudorotaxane was
>97%. Thread 4 could also be obtained in a much higher yield
(80%) by performing the reaction between 1 and stopper 3 in
the absence of 2. It is noteworthy that macrocylic receptors
containing a pyridine chelator have previously been shown to
participate in rotaxane formation through complexed metal-
mediated coupling reactions with different transition metals,
including copper.12 However, in the current case no evidence of
alkyne−alkyne coupling was evidenced under reaction con-
ditions used in the presence of barbiturate 1. Optimized
conditions for the Glaser homocoupling reaction in the absence
of barbiturate 1 (bottom, Scheme 1), which is catalyzed by
copper(II) rather than copper(I), showed only a modest yield
of rotaxane 6 (9%). This result allows us to conclude that the
click reaction is both compatible and orthogonal with H-
bonded barbiturate templating.
Rotaxane 5 was fully characterized by 1D- and 2D-NMR,
mass spectrometry, and IR measurements (Figures S1, S21,
S27, S32, S37, S42, and S44). The H NMR spectrum of 5
(Figure 2d) shows downfield shifts of several signals with
respect to noninterlocked 2 and 4 (Figure 2c and 2e,
respectively). In particular, downfield shifts of the amide
proton signals of the macrocycle (Δδ = 1.7 ppm and 1.9 ppm)
and those of the barbiturate protons in the thread (Δδ = 4.8
ppm) indicate H-bonding interactions. Stronger H-bonding in
1
judged by H NMR spectroscopy, even upon heating 5 (10
mM) for several days at 120 °C in DMSO. Similarly, heating
equimolar quantities of 4 and 2 together for several days under
similar conditions showed no evidence of threading (Figure
S6).
In summary, unprecedented barbiturate-templated rotaxane
formation is shown, thus adding to the relatively small library of
motifs responsible for formation of mechanically interlocked
structures. Rotaxane capture was achieved by an orthogonal
stoppering reaction using a 1,3-cycloaddition click reaction on a
readily accessible hydrogen-bonded pseudorotaxane. This
versatile information-rich H-bonding templating motif holds
promise for the development of multistation molecular
machines and devices and is compatible with photoactive and
electroactive variants.
1
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, synthesis and characterization data of
1−7 (1H, 13C, COSY, HMBC, HSQC, NOESY NMR, HRMS,
IR), single crystal X-ray data, and FTIR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Letter
5609. (e) Jacquot de Rouville, H.-P.; Iehl, J.; Bruns, C. J.; McGrier, P.
L.; Frasconi, M.; Sarjeant, A. A.; Stoddart, J. F. Org. Lett. 2012, 14,
5188. (f) Joosten, A.; Trolez, Y.; Collin, J.-P.; Heitz, V.; Sauvage, J.-P. J.
Am. Chem. Soc. 2012, 134, 1802. (g) Busseron, E.; Coutrot, F. J. Org.
Chem. 2013, 78, 4099.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: j.tucker@bham.ac.uk (J.T.).
*E-mail: nathan.mcclenaghan@u-bordeaux.fr (N.McC.).
Notes
(11) Chan, T. R.; Hilgraf, R.; Sharpless, B.; Fokin, V. V. Org. Lett.
2004, 6, 2853.
The authors declare no competing financial interest.
(12) (a) Crowley, J. D.; Goldup, S. M.; Lee, A.-L.; Leigh, D. A.;
McBurney, R. T. Chem. Soc. Rev. 2009, 38, 1530. (b) Crowley, J. D.;
Goldup, S. M.; Gowans, N. D.; Leigh, D. A.; Ronaldson, V. E.; Slawin,
A. M. Z. J. Am. Chem. Soc. 2010, 132, 6243. (c) Chalifoux, W. A.;
Tykwinski, R. R. Nat. Chem. 2010, 2, 967. (d) Movsisyan, L. D.;
Kondratuk, D. V.; Franz, M.; Thompson, A. L.; Tykwinski, R. R.;
Anderson, H. Org. Lett. 2012, 14, 3424.
ACKNOWLEDGMENTS
■
Financial support from the School of Chemistry at the
University of Birmingham (Ph.D. studentships to M.R. and
P.J.T.); Advantage West Midlands for equipment; the EPSRC
for the award of a Leadership Fellowship (EP/G007578/1);
Reg
Minister
́
ion Aquitaine; University of Bordeaux; CNRS; and
e de la Recherche et de l’Enseignement Superieur
̀
́
(A.T.) is gratefully acknowledged.
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