Dethreading of Tetraalkylsuccinamide-Based [2]Rotaxanes for Preparing Benzylic Amide Macrocycles

Article abstract of DOI:10.1021/acs.joc.5b01651

The dethreading of a series of succinamide-based [2]rotaxanes bearing benzylic amide macrocycles is reported herein. These transformations proceeded quantitatively either under flash vacuum pyrolysis, conventional heating, or microwave irradiation. Studying the size complementarity of the stoppers at the ends of the thread and the cavity of the macrocycle allowed us to set up the best substituents for implementing the extrusion of the thread from the interlocked precursors. A variety of ¹H NMR kinetic experiments were carried out in order to evaluate the rate constants of the dethreading process, the half-life times of the rotaxanes, and the influence of temperature and solvents on these processes. The use of dibutylamino groups as stoppers yielded the rotaxane precursor in a reasonable yield and allowed the quantitative deslipping of the rotaxane. The overall process, including the rotaxane formation and its further dethreading, has been exploited for preparing benzylic amide macrocycles enhancing, in most cases, the results of the classical (2 + 2) condensation and other reported stepwise syntheses. The kinetics of the dethreading process is fairly sensitive to the electronic effects of the substituents on the isophthalamide unit or to the electronic nature of the pyridine rings through a conformational equilibrium expanding or contracting the cavity of the interlocked precursor.

Full text of DOI:10.1021/acs.joc.5b01651

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Article
Dethreading of Tetraalkylsuccinamide-Based
[2]Rotaxanes for Preparing Benzylic Amide Macrocycles
Alberto Martinez-Cuezva, Leticia V. Rodrigues, Cristian Navarro, Fernando Carro-Guillen,
Lilian Buriol, Clarissa P. Frizzo, Marcos A. P. Martins, Mateo Alajarín, and José Berná
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01651 • Publication Date (Web): 25 Sep 2015
Downloaded from http://pubs.acs.org on September 27, 2015
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The Journal of Organic Chemistry
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Dethreading of Tetraalkylsuccinamide-Based [2]Rotaxanes for
Preparing Benzylic Amide Macrocycles
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Alberto Martinez-Cuezva,† Leticia V. Rodrigues,§ Cristian Navarro,† Fernando Carro-Guillen,† Lilian
Buriol,§ Clarissa P. Frizzo,§ Marcos A. P. Martins,*,§ Mateo Alajarin,† Jose Berna*,†
† Departamento de Química Orgánica, Facultad de Química, Regional Campus of International Excellence "Campus Mare
Nostrum", Universidad de Murcia, E-30100 Murcia (Spain)
§ Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria,
97105-900 Santa Maria-RS (Brazil)
ABSTRACT: The dethreading of a series of succinamide-based [2]rotaxanes bearing benzylic amide
macrocycles is reported herein. These transformations proceeded quantitatively either under flash
vacuum pyrolysis, conventional heating or microwave irradiation. By studying the size complementarity
of the stoppers at the ends of the thread and the cavity of the macrocycle allowed us to set up the best
substituents for implementing the extrusion of the thread from the interlocked precursors. A variety of
1H NMR kinetic experiments were carried out in order to evaluate the rate constants of the dethreading
process, the half-life times of the rotaxanes and the influence of temperature and solvents on these
processes. The use of dibutylamino groups as stoppers yielded the rotaxane precursor in a reasonable
yield and allowed the quantitative deslipping of the rotaxane. The overall process, including the
rotaxane formation and its further dethreading, has been exploited for preparing benzylic amide
macrocycles enhancing, in most cases, the results of the classical (2 + 2) condensation and other
reported stepwise syntheses. The kinetics of the dethreading process is fairly sensitive to the electronic
effects of the substituents on the isophthalamide unit or to the electronic nature of the pyridine rings
through a conformational equilibrium expanding or contracting the cavity of the interlocked precursor.
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1. INTRODUCTION
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Functional interlocked systems programmed to perform controllable mechanical motions are ideally
suited for the design of a broad range of molecular devices.1-3 In this arena, the ability to achieve the
spatial ordering of such switchable compounds at the solid state and the exportation of their properties
to the macroscopic world are important for the nanofabrication of molecular devices.4-6 Among the
different types of interlocked molecules integrated at the condensed phase, [2]rotaxanes are clearly
considered as one of the most widespread scaffolds for the construction of functional materials.4 Besides
of the dumbbell-shape component, these building blocks contain threaded macrocycles having diverse
architectures such as calixarenes, cyclodextrins, crown ethers, cucurbiturils, cyclophanes, pillarenes or
amide-based rings.6
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Non-interlocked benzylic amide macrocycles have been extensively employed as model compounds
when investigating the macroscopic effects of the mechanical bond in materials elaborated with
hydrogen-bonded interlocked compounds.1-6 In much less extension, these tetraamido macrocycles have
been used for sensing carbon dioxide7 and, more recently, glucose.8,9 Tetralactam rings of this kind are
usually obtained in 19-25% yield by means of a (2 + 2) condensation of p-xylylenediamine and an aroyl
dichloride.10,11 In fact, the corresponding [2]catenane is also a main product of this approach in which
the assembly of this interlocked octaamide is driven by hydrogen-bonded interactions.10 Moreover,
several oligomers are also obtained making even more difficult the isolation of the individual
macrocycles which are barely soluble in non-polar solvents. In order to circumvent this matter, Leigh et
al. were pioneers in describing the disassembly of hydrogen-bonded [2]rotaxanes through the
transesterification of the stoppers of the thread for affording this type of rings.7
Although alternative methods12 for the preparation of benzylic amide macrocycles have been described
in the literature, these procedures usually require multiple synthetic steps,8,9,13 the previous preparation
of templates,7,14,15 or the use of organo-clay derivatives.16 Herein we propose an amenable approach
based on the dethreading reaction17,18 of tetralkylsuccinamide-based [2]rotaxanes for the synthesis of a
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broad range of substituted benzylic amide macrocycles in which a dumbbell-shaped template can be
recovered and indefinitely reused. Different reaction conditions (conventional heating in solution,
microwaves and flash vacuum pyrolysis) were assayed in the deslipping step to efficiently afford the
macrocyclic compounds. This study also includes an exploration of the size complementarity between
the Leigh-type tetralactam rings and a series of succinamide-based threads having stoppers of diverse
spatial demand. The kinetics of the disassembling process is also reported giving a concise idea of the
stability of the mechanical bond of these interlocked compounds at different temperatures in polar and
non-polar solvents such as dimethylsulfoxide and tetrachloroethane. Overall this research sets the
experimental framework required for the synthesis of benzylic amide macrocycles including one or two
different isophthalamide units as well as for building up a practical use of the metastability of hydrogen-
bonded [2]rotaxanes.
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2. RESULTS AND DISCUSSION
2.1 Synthesis of tetraalkylsubstituted succinamide-based [2]rotaxanes. Early studies on the
deslipping of Hunter-Vögtle rotaxanes having a tetraanilide-based macrocycle revealed that a proper
size complementarity of the macrocyclic cavity and the stoppers is required for guaranteeing their
structural integrity and avoiding the dethreading of the axis from the molecule.19,20 In addition, Schalley
et al. also deepened into similar interlocked systems showing that small structural changes in the thread
(including variations on its length, flexibility or connectivity of their stoppers) have a significant impact
on the deslippage process.21-23 Although the macrocyclic hollow of the benzylic amide ring of the
Leigh-type rotaxanes is notably lesser than the aforementioned a study of the size complementarity has
been never accomplished with these compounds.
In order to establish the influence of the steric size24-26 of the stoppers of succinamide-based
rotaxanes27-29 on the stability of their mechanical bond30 we first prepared a series of surrogates keeping
constant the structure of the benzylic amide macrocycle and varying the alkyl substituents at the
nitrogen atoms of the succinamide-based template. For this purpose, we assayed the five-component
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clipping reaction by using the tetraalkyl succinamides 3a-g, easily prepared from the corresponding
secondary amines 1a-g and succinyl chloride (2), as templates and p-xylylenediamine and isophthaloyl
chloride as precursors of the benzylic amide macrocycle (Table 1).
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Table 1. Synthesis of the tetraalkylsubstituted succinamide-based [2]rotaxanes 4.a
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Entry Thread Yield [%]b
R
Me
Rotaxane Yield [%]c
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CH2Cye
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aReagent and conditions: (i) amine 1, succinyl chloride (2), CH2Cl2, rt; (ii) succinamide 3, isophthaloyl
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chloride, p-xylylenediamine, Et3N, CHCl3, rt. Yield of the thread preparation. Yield of the rotaxane
formation. dNo traces were observed by ESI-MS. eCy = cyclohexyl. fSee references 26 and 27.
Our attempts for obtaining the threaded species with tetramethyl- or tetraethylsuccinamide templates
were unsuccessful (entries 1 and 2) pointing out that the steric demand of the stoppers on the succinyl-
based binding site must be larger than that of the diethylamino substituent in order to kinetically
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stabilize the mechanical bond between the interlocked components. In addition, although the formation
of these (pseudo)rotaxanes30-32 could be achieved, their thermodynamic equilibria between each one and
the corresponding thread and ring must be largely shifted toward the formation of the unthreaded
species, most probably due to the high insolubility of the benzylic amide macrocycle (<1 mg/L in
chloroform)7 under the employed reaction conditions.
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On the other hand, the yields of the isolated rotaxanes containing linear alkylsubstituents, such as
propyl and butyl, 4c and 4e were 38 and 39% respectively. These values are clearly acceptable
considering that these rotaxanes are the resulting products of five-component clipping reactions.29,33
However the yield of this protocol drops off by half if the alkyl substituents on the nitrogen atoms of the
succinamide are branched as is the case of 4d (17%), 4f (19%) and 4g (23%) respectively bearing
isopropyl, isobutyl and cyclohexylmethyl substituents. The structure determination of the rotaxanes 4c-g
was accomplished by means of their analytical and spectral data (see Experimental Section).
It is known that the incorporation of 2,6-pyridinedicarbonyl unit acid diamide into the ring reduces the
void of the respective tetraanilide macrocycles due to the incidence of intracyclic hydrogen bonding
and, consequently, it affects the deslipping of the corresponding interlocked precursors.21 Aimed to
study how this effect alters the thermal stability of our rotaxanes, we first tested the hydrogen bond
directed assembly of rotaxanes 5a-d using succinamides containing linear alkyl substituents as
templates (Table 2). Although the yields of rotaxanes 5 are notably lower (<10%) than those obtained
for rotaxanes 4, the incorporation of two endotopic pyridine rings into the macrocycle tolerates the
preparation of 5b bearing two diethylamino groups as stoppers (entry 2, Table 2), that was proved
unfeasible in the attempted preparation of rotaxane 4b (entry 2, Table 1).
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Table 2. Preparation of the succinamide-based [2]rotaxanes 5.a
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Entry Rotaxane
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aReaction conditions: (i) succinamide 3a-c or 3e, 2,6-pyridinedicarboxylic acid chloride, p-
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xylylenediamine, Et3N, CHCl3, rt. Yield of isolated product based on 3. No traces of the [2]rotaxane
were observed by ESI-MS.
2.2 Reaction conditions for the dethreading of the benzylic amide [2]rotaxanes 4c and 4e. First,
we explored the thermally promoted dethreading of tetraalkylsuccinamides 3c and 3e from the benzyl
amide macrocycles of rotaxanes 4c and 4e. For this purpose, thermogravimetric (TG) experiments with
these rotaxanes were carried out (Figure 1). Pleasantly, the resulting thermograms of rotaxanes 4c and
4e show a weight loss near 300 ºC corresponding to the dethreading of succinamides 3c and 3e.
Differential scanning calorimetry (DSC) (see Supporting Information) revealed that the deslippage
processes occur after the melting of the rotaxane. In both cases, a second weight loss at 435 ºC, ascribed
to the sublimation of the macrocycle, was also observed.
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Figure 1. Thermogravimetric analysis of rotaxane 4c (5 ºC/min; N2 stream).
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On the basis of these TG-DSC analyses we assayed the heating of a neat sample of rotaxane 4c at 300
ºC but we recovered the starting material without any disassembly evidence. Then we explored the same
reaction in a flash vacuum pyrolysis (FVP)34,35 apparatus by placing a solid sample of rotaxane 4c in a
preheated furnace at 150 ºC and heating up to 375 ºC during 10 min keeping a moderate vacuum of 0.01
torr. The corresponding succinamide 3c was quantitatively recovered from the cooled U-tube and the
resulting dethreaded macrocycle remained in the initial vial, thus indicating that the complete deslippage
had taken place (Scheme 1, Method A) without any evidence of decomposition.36 An identical
efficiency was found in the dethreading of rotaxane 4e. With the aim of obtaining thermodynamic and
kinetic parameters of this deslippage process we considered the viability of carrying out this reaction in
solution. A solution of the rotaxane 4c or 4e heated in dimethylsulfoxide at 120 ºC in an oil bath for 12
h (Scheme 1, Method B) quantitatively yielded the corresponding axis 3c or 3e and the macrocycle 6a
which were easily separated by precipitation of the latter by adding water into the final reaction mixture.
Although other solvents such as methanol or tetrachloroethane were assayed for the deslipping of 4e, the
integrity of the mechanical bond persisted unaltered even after a prolonged heating treatment (3 days).
Remarkably, in the cases of rotaxanes 4c and 4e the use of microwave irradiation shortened the
deslipping time to 30 min when dimethylsulfoxide is used as solvent (Scheme 1, Method C).
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Scheme 1. Synthetic approaches for the deslipping of the benzylic amide rotaxanes 4c and 4e.
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The recovery of the thread by any of the above dethreading methods is quite straightforward. But
whereas method A only requires the addition of dichloromethane to the U-tube of the FVP apparatus
and solvent evaporation to recover quantitatively the resulting thread, methods B and C need a further
liquid-liquid extraction with chloroform and several washings with water and brine for completely
removing the DMSO. In these cases, after a drying treatment with magnesium sulfate as desiccant,
filtration and solvent evaporation more than 95% of the thread was recovered.
The overall yield for the preparation of the macrocycle 6a, including the clipping reaction (39%) and
the dethreading step (100%), compares favorably with other previously described methods7,11 proving
the suitability of the present protocol. Note that a further amount of the cyclic compound 6a (18%) is
also obtained during the rotaxane formation of 4e.
2.3 Thermodynamic and kinetic parameters of the dethreading processes. The deslipping
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reactions of hydrogen-bonded rotaxanes19-23 can be easily monitored by H NMR spectroscopy for
affording the kinetic parameters of the process. Thus, following the variation of the relative intensity of
the signals of the rotaxane and the tetralactam ring we were able to estimate the rate constant k and the
half-life time t1/2 of this first-order reaction. This study was first carried out with the rotaxane 4e by
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monitoring its H NMR spectra at different times while the temperature was kept at 373 K (Figure 2).
The signals of all the aromatic protons and the NH group of the macrocycle 6a can be clearly
distinguished from those of its interlocked precursor 4e [ (HA) = +0.11; (HB) = +0.21; (HC) =
+0.64;
(HF) = -0.13;
(HD) = -0.68 ppm]. The presence of the ring has a clear influence on the
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chemical shifts of the nuclei of the succinamide subcomponent due to the anisotropy originated by the
aromatic rings of the tetralactam macrocycle and so the lack of the latter restores the chemical shift of
the pristine 3e [ (Ha) = -1.4 ppm].
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Figure 2. Kinetic experiment with rotaxane 4e in DMSO-d6 at 373 K. Stack plot of partial H NMR spectra of 4e over time.
Capital letters A-F correspond to the hydrogen atoms of the macrocycle (see Scheme 1 for numbering) and lowercase letters
a-e correspond to the hydrogen atoms of the thread: [C(Ha)2CONC(Hb)2C(Hc)2C(Hd)2C(He)3]2. Prime symbols are used to
ascribe the signals of the non-interlocked compounds 3e and 6a. Signals marked with an asterisk are residual solvent peaks.
The decrease of the relative ratio of rotaxane 4e as a function of time allows to calculate a rate constant
of (7.56 ± 0.19) x 10-5 s-1 and a half live of 2.6 hours at 373 K by an exponential fitting of the deslipping
percentage against time (see Supporting Information). The progress of this reaction also allowed to
known the required time to reach the maximum conversion (approx. 8 h in the case of the dethreading of
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4e). To obtain further information about this transformation we performed similar kinetic H NMR
experiments at different temperatures (358, 368, 373 and 398 K). Thus the corresponding rate constants
at each temperature were determined by plotting ln(c/co) against time (Figure 3). The use of these values
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in an Eyring plot of ln(k/T) vs 1/T let to calculate the activation parameters of the process, H‡ = 40
kJ·mol-1 and S‡ = - 218 J·K-1·mol-1 (see Figure 4). Like in other related deslipping processes of amide-
based rotaxanes,21-23 a negative value for the activation entropy of the deslipping of 4e was expected.
The high flexibility of this rotaxane, containing four butyl substituents and a non-rigid template, is
vastly reduced, and therefore also their freedom degrees, in the transition state of the dethreading
process.
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Figure 3. Deslipping of the rotaxane 4e in DMSO-d6 at different temperatures. Plot of ln(c/c0) versus time for the
determination of the half-life times and the rate constants: T (K), k x 105 (s-1) = 358, 4.40 ± 0.51; 368, 7.08 ± 0.19; 373, 7.56
± 0.19; 398, 19.30 ± 1.40.
Figure 4. Eyring plot of ln(k/T) vs 1/T for the evaluation of the activation enthalpy, H‡ , and the activation entropy S‡ , for
the deslipping of the rotaxane 4e. A good correlation coefficient was obtained for this linear regression (R2 = 0.992).
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It should be noted that the featuring parameters of the dethreading process dramatically depend on the
hydrogen bond (HB) acceptor ability of the solvent. In fact, the process does not seem to proceed in
very weak HB acceptor solvents, such as tetrachloroethane, but in dimethylsulfoxide, an excellent HB
acceptor, the damage of the intercomponent HB interactions facilitates the egression of the thread
through a unimolecular, first order decomposition.
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Previous studies on the dethreading of tetraanilide-based rotaxanes19-23,26 revealed a noticeable
sensitivity of these processes even toward minor modifications in the structure of the interlocked
compounds. Thus, variations on the progress of the thermal treatment of the benzylic amide rotaxanes
4c-g having different alkyl substituents at the N atom of the succinamide should be expected. Aiming to
evaluate the magnitude of these variations for best choosing the ideal template in the tetralactam
macrocycles synthesis we performed 1H NMR kinetic experiments with rotaxanes 4c-g (see Supporting
Information) in order to determine the corresponding rate constants and half-life times at 398 K (Figure
5). In those conditions, the deslipping of 4c having a dipropylamino group as stopper is so fast that we
were unable to obtain suitable data (entry 1, Table 3). As we expected, the dethreading of rotaxane 4d,
with diisopropyl groups as stoppers, occurs notably slower than that of rotaxane 4c, t1/2 (~ 30 h) (entry
2, Table 3). This value is larger than that of 4e t1/2 (1 h) bearing a less sterically demanding
dibutylamino group (entry 3, Table 3). By further increasing the size of the stopper, as in the case of
rotaxane 4f which possesses diisobutyl groups, the reaction proceeds extremely slow and t1/2 rises up to
more than two weeks (entry 4, Table 3). When di(cyclohexylmethyl)amino groups are used as stoppers
the extrusion of the corresponding succinamide from the rotaxane 4g did not come about at the selected
reaction conditions. Taking into account our purpose of synthesizing tetralactam rings by the deslipping
of succinamide-based rotaxanes (see next section), the results summarized in Table 3 seem to point out
the convenience of using N,N,N',N'-tetrabutylsuccinamide (3e) as a suitable template by considering the
intermediate thermal stability of the resulting rotaxane and the yield in which is obtained.
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Figure 5. Deslipping of the rotaxanes 4d-f having different substituents on the succinamide thread in DMSO-d6 at 398 K.
Plot of ln(c/c0) versus time for the determination of the rate constants and half-life times.
Table 3. Rate constants and half-life times for the deslipping of the rotaxanes 4c-g in DMSO-d6 at 398 K.
Entry Rotaxane
R
t1/2 (h)
k x 106 (s-1)
G‡ (kJ mol-1)a
-b
1
2
3
4
5
n-Pr
i-Pr
-
-
4c
4d
4e
4f
29.7
6.48 ± 1.01
138.0
126.7
146.4
-
n-Bu
i-Bu
1.0 193.23 ± 13.98
375.3
0.50 ± 0.03
-
c
CH2Cy
-
4g
aGibbs free energies of activation were calculated at 398 K. bDeslipping of 4c occurs too much rapid to
1
c
be monitored by H NMR. No deslipping of 4g was observed under these conditions. Microwave
irradiation of this rotaxane did not promote the extrusion of the thread.
In order to get further information about the thread ejection from 4c we modified the reaction
conditions by using deuterated tetrachloroethane as a non-disrupting hydrogen bond solvent at 373 K for
decreasing the deslipping rate and enabling the calculation of the kinetic parameters of this particular
process. These modifications allowed to follow the progress of the dethreading by 1H NMR, featured by
a rate constant of (4.6 ± 0.7) x 10-5 s-1 and a half-live time of 4.2 h ( G‡ = 123.1 kJ mol-1). We also
monitored the reaction at 373 K using a mixture of dimethylsulfoxide : tetrachloroethane 1:1 (v/v) as
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solvent to obtain a rate constant of (6.3 ± 0.6) x 10-3 s-1 and a half-live time of 2 min ( G‡ = 107.8 kJ
mol-1) (see Supporting Information). The increase of the constant rate in two orders of magnitude and
the noticeable decrease of the t1/2 value highlight the remarkable effect of the hydrogen bond acceptor
strength of the solvent on this kind of process.
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2.4 Synthesis of benzylic amide macrocycles by dethreading of succinamide-based rotaxanes. We
extended the scope of the synthesis of benzylic amide macrocycles by examining the deslipping of
succinamide-based rotaxanes containing different substituents on the macrocycle, such as alkyl,
hydroxyl, alkoxy, alkoxycarbonyl or nitro groups, or incorporating pyridine rings. The syntheses of the
interlocked compounds 7a-f (Table 4) employed for this study were carried out by using the known
clipping methodology with N,N,N',N'-tetrabutylsuccinamide (3e) as the HB acceptor template,37 p-
xylylenediamine and the corresponding acid dichloride (see Experimental Section). The deslipping of
the rotaxanes 7a-f was carried out in dimethylsulfoxide at 373 K to afford the succinamide 3e and the
respective macrocycles 8a-f. Considering that subtle structural variations in the starting interlocked
compound can alter the kinetics of the deslipping process we extended the reaction time until 24 h for
ensuring a 100% conversion (Method B, Table 4). This conversion level is also reached by using
microwave irradiation for 1 h (Method C, Table 4). Table 4 includes the yields of the isolated
compounds by employing the same direct work-up used in the preparation of 6a. It is worth noting the
deslipping of 7b having a non-symmetrical ring with only one TBDMSO group which is converted into
a hydroxyl function during the thermal treatment.38 This deprotection is accelerated by adding water to
the reaction medium for affording the appealing macrocycle 8b (entry 2, Table 4) ready to be further
connected to other compounds or attached to materials through its available OH group. In stark contrast
with the dethreading of the rotaxanes 7a-f (entries 1-6, Table 4), which proceeds in a quantitative
manner by using any of the proposed protocols, we only could detect traces of 8g from the deslipping of
5d, irrespective of using the heating method B or C (entry 7, Table 4).
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Table 4. Synthesis of benzylic amide macrocycles by deslipping of succinamide-based rotaxanesa,b,c
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5
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7
8
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Entry Rotaxaned Yield [%]e
X
C-C(CH3)3
CH and C-OHg
C-O(CH2)4CH=CH2
C-COOCH3
C-NO2
Y
Macrocycle
Yield [%]f
77a
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2
3
4
5
6
7
25
37
38
17
32
27
3
CH
CH
CH
CH
CH
CH
N
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
84a
87a
99b
99a
N
95b
CH
tracesa,b
5d
8g
aMethod B: conventional heating in oil bath, 24 h. bMethod C: microwave irradiation, 1h. A complete
conversion was obtained in all cases except for the deslipping of 5d. dFor the syntheses of the rotaxanes,
p-xylylenediamine was used as the diamine component except for the preparation of 7b (entry 2), in
which N1,N3-bis(4-(aminomethyl)benzyl)isophthalamide was employed. eYield of the rotaxane
c
f
g
formation. Yield of the dethreading step. The rotaxane precursor 7b contains a TBDMSO substituent
which is converted into a hydroxy group during the thermal treatment. This deprotection was
accelerated by adding water to the reaction mixture.
Although the conversion of the dethreading of rotaxanes 7a-f was complete, slight fluctuations in the
yield of the macrocycles were observed because of their different solubilities in dimethylsulfoxide:water
mixtures.
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The templating effect of the thread 3a in the preparation of macrocycle 8a was evaluated. In the
presence of the template 3a using 2 equivalents of p-xylylenediamine and 2 equivalents of 5-tert-
butylisophthaloyl dichloride, 8a was obtained, after several chromatography purifications, in a 14%
yield together with a 22% of the rotaxane 7a. If the reaction is performed without 3a, the ring 8a can
also be hardly isolated in a 17% yield. These values prove the important role of the template7 allowing
the isolation in a 36% of yield after the complete deslipping step of the rotaxane, almost more than 20%
of the amount obtained by direct condensation.11 Overall, except for the pyridine-containing tetralactam
ring 8g (see Table 2), the approach herein described for the preparation of benzylic amide macrocycles
compares favorably, in terms of yield and amenability, with other reported methodologies.
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In order to explore the kinetics of the dethreading of some selected rotaxanes 7 we monitored over
1
time the heating of their solutions in deuterated dimethylsulfoxide at 373 K by H NMR spectroscopy.
The data registered at these conditions were compiled to plot the ln(c/c0) versus time (Figure 6). For
comparison, the graph corresponding to the deslipping of the rotaxane 4e has been also included in this
representation. The thermally activated expulsion of 3e from 4e has a Gibbs free energy of activation of
121.5 kJ mol-1 (k = 7. 6 x 10-5 s-1; t1/2 = 2.6 h). This energy value decrease, and also the half-life time
(entries 2-4, Table 5), if the benzylic amide macrocycle of the rotaxane precursor has two ester or nitro
functional groups as in 8d or 8e respectively, or incorporates two pyridine rings as in 8f. But if the ring
of the rotaxane contains alkoxy substituents, as 8c (entry 1, Table 5), the deslipping take places more
slowly than that of the rotaxane 4e lacking of substituents.
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Figure 6. Deslipping of the rotaxanes 4e and 7c-f having different substituents at the benzylic amide macrocycle in DMSO-
d6 at 373 K. Plot of ln(c/co) versus time for the determination of the rate constants and half-life times.
1
2
3
4
5
Table 5. Rate constants and half-life times for the deslipping of the rotaxanes 7c-f in DMSO-d6 at 373 K.
6
7
8
G‡ (kJ mol-1)a
Entry
Rotaxane
X
t1/2 (h)
k x 106 (s-1)
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1
2
3
4
C-O(CH2)4CH=CH2
3.8
1.3
0.4
0.3
50.86 ± 1.60
146.37 ± 9.48
549.73 ± 19.81
665.95 ± 48.04
122.7
119.4
115.3
114.7
7c
7d
7e
7f
C-COOCH3
C-NO2
N
aGibbs free energies of activation were calculated at 373 K.
In non-disrupting hydrogen bond solvents, the incorporation of electron withdrawing groups in the
isophthalamide-based macrocycles enhances the donating ability of their amide groups and, therefore,
bind more strongly the carbonyl groups of the threaded component.29,39 However, the dethreading of the
rotaxanes 7c-f in DMSO seems to follow an inverse trend. In such competitive solvent, the
intercomponent interactions should be less important than the intermolecular ones with the DMSO
molecules. In this scenario, these later interactions with the cyclic component would promote
conformational changes of the tetralactam ring such as the outward turning of the amide groups.40-42
These changes, modulated by the electronic effects of the substituents at the isophthalamide units or the
electronic nature of the pyridine units, modify the cross dimensions of the size of the cavity43 leading to
a faster deslipping of the rotaxanes with electron-poor macrocycles and a slower deslipping of those
with electron-rich macrocycles in comparison with that of the rotaxane 4e (Figure 6, Table 5).
Molecular mechanics calculations (see Supporting Information) pointed out that electron withdrawing
groups at 5 position of the isophthalamide moiety stabilize the conformation (B) represented in Figure 7,
in which one of the carbonyl groups of the macrocycle adopt an inner disposition. This conformation of
the macrocycle, further stabilized by the competitive formation of hydrogen bonds of this NH amide
group with DMSO (Solv in Figure 7), expands its cavity, when compared with conformation (A), thus
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facilitates its dethreading. Remarkably, electron donor substituents such as an alkoxy group stabilize the
conformation (A) of Figure 7 in which the carbonyl groups of the macrocycle adopt an outer disposition
favoring the intercomponent interactions and keeping a contracted shape of the ring that difficult its
dethreading.
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Figure 7. Conformational equilibrium of the partially represented rotaxanes via rotation of the amide group of the macrocy-
cle promoted by the competitive binding with an excellent HB acceptor solvent (Solv).
Finally, we were still intrigued by the synthesis of macrocycle 8g, unviable by the deslipping of
rotaxane 5d (entry 7, Table 4) having a dibutylamino group at the ends of the stoppers. Hence we
explored the thermal treatment of the dipyridine rotaxanes 5b,c with the less sterically demanding
stoppers diethylamino and dipropylamino groups, respectively. Likewise to the case of 5d, the heating
of a DMSO solution of 5c at 373 K was still unable to promote the desired dethreading. Note that
macrocycles with endotopic pyridine rings stabilize the tight conformation (A) shown in Figure 7 by the
formation of a strong network of intracyclic hydrogen bonds capable to survive even in hot
dimethylsulfoxide.11 This fact would explain the strong resistance of these rotaxanes to the dethreading
process. Satisfyingly, the macrocycle 8g was quantitatively obtained by the thermal deslipping of the
rotaxane 5b in DMSO at 373 K for 1.5 h or in tetrachloroethane at 353 K for 3 h. Interestingly, we also
found that this particular process occurred at room temperature using a mixture of dimethylsulfoxide :
tetrachloroethane 1:1 (v/v) after 14 h.
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3. CONCLUSIONS
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2
3
4
5
6
7
8
9
In summary, we have described the synthesis of a complete series of tetraalkylsuccinamide-based
[2]rotaxanes bearing a benzylic amide macrocycle. Three different protocols have been established for
the dethreading of these interlocked species in a quantitative fashion by either flash vacuum pyrolysis,
conventional heating or microwave irradiation. Varying the steric demand of the dialkylamino stoppers
on the succinamide template of the interlocked species allowed the examination of the size
complementarity with the benzylic amide macrocycle void to establish the most appropriate substituent
for implementing a practical preparation of tetralactam macrocycles by extrusion of the thread of the
rotaxanes. The kinetic and thermodynamic parameters of this process were thoroughly evaluated
including temperature and solvent effects. Decreasing size of the stoppers reduces the Gibbs free energy
of activation of the dethreading which is also favored in good hydrogen bond acceptor solvents. These
studies determined that the incorporation of dibutylamino groups as stoppers in the succinamide
template allowed the preparation of the interlocked precursor in a reasonable yield and the quantitative
deslipping by any of the protocols established in this work. Moreover, a deep exploration of the effect of
the substituents at the ring of the interlocked precursor on its deslipping in solution revealed that
electron withdrawing groups speed up the egression of the thread. The formation of intracyclic
hydrogen bonds due to the incorporation of two endotopic pyridine rings into the macrocycle requires a
noticeable decreasing of the steric demand of the lids on the succinamide to efficiently undergo
deslippage to afford the cyclic target.
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60
EXPERIMENTAL SECTION
General Methods. Unless stated otherwise, all reagents were purchased from commercial suppliers
and used without further purification. HPLC grade solvents were dried in a solvent purification system
by passing it through an activated alumina column before use.. Column chromatography was carried out
using silica gel (60 Å, 70-200 μm) as stationary phase, and TLC was performed on precoated silica gel
on aluminium cards (0.25 mm thick, with fluorescent indicator 254 nm) and observed under UV light.
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All melting points were determined on a Kofler hot-plate melting point apparatus and are uncorrected.
In the case of the main part of the rotaxanes decomposition was observed above 275 ºC due to the
1
2
3
4
5
6
1
deslipping pathway. H- and 13C-NMR spectra were recorded at 298 K on 200, 300 and 400 MHz
spectrometers. 1H NMR chemical shifts are reported relative to Me4Si and were referenced via residual
proton resonances of the corresponding deuterated solvent whereas 13C NMR spectra are reported
relative to Me4Si using the carbon signals of the deuterated solvent. Abbreviations of coupling patterns
are as follows: br, broad; s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet. Coupling constants
(J) are expressed in Hz. High resolution mass spectra (HRMS) were obtained using a time-of-flight
(TOF) instrument equipped with electrospray ionization (ESI). The experiments using microwave
irradiations were performed in a Discover CEM MW with simultaneous cooling. The power of the
equipment was established at 200 W. A microwave vessel (10 mL) equipped with a standard cap (vessel
commercially furnished by Discover CEM) and a level of internal pressure maximum of 250 psi.
Materials. Threads 3a,44 3b,45 3g28 and rotaxane 4g29 were prepared as previously reported.
General procedure for the synthesis of the succinamide-based threads 3b-g. To a solution of the
corresponding amine 1b-g (16 mmol) in CH2Cl2 (50 mL), succinyl dichloride 2 (4 mmol) in CH2Cl2 (10
mL) was added droppwise at 0 ºC. The reaction mixture was stirred for 20 h at room temperature under
N2 atmosphere. After this time the solution was washed with NaOH 1M (2 x 30 mL), HCl 1M (2 x 30
mL) and brine (2 x 30 mL). The organic phase was dried over anhydrous MgSO4 and concentrated
under reduced pressure. The reaction residue was subjected to column chromatography on silica gel
using a CHCl3/MeOH (99/1) mixture as eluent to give the corresponding thread.
7
8
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Thread 3a44 was prepared from a solution of dimethylamine 1a (40% in water, 2.58 mL, 16 mmol) and
succinyl chloride 2 (616 mg, 4 mmol). Colorless oil (466 mg, 81%). This compound was synthesized as
described in reference 44 and showed identical spectroscopic data as those reported therein.
Thread 3b45 was prepared from diethylamine 1b (1.17 g, 16 mmol) and succinyl chloride 2 (616 mg, 4
mmol). Colorless oil (684 mg, 75%). This compound was synthesized as described in reference 45 and
showed identical spectroscopic data as those reported therein.
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Thread 3c was prepared from dipropylamine 1c (1.62 g, 16 mmol) and succinyl chloride (2, 616 mg, 4
1
2
3
1
mmol). Yellow oil (900 mg, 79%); H NMR (400 MHz, CDCl3) 3.20–3.26 (m, 8H), 2.64 (s, 4H),
4
5
6
7
8
9
1.65–1.45 (m, 8H), 0.87 (t, J = 7.4 Hz, 6H), 0.82 (t, J = 7.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3)
171.8 (C), 49.7 (CH2), 47.9 (CH2), 28.5 (CH2), 22.2 (CH2), 21.05 (CH2), 11.4 (CH3), 11.3 (CH3);
HRMS (ESI+) m/z for C16H33N2O2 [M + H]+ 285.2537, found 285.2542.
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60
Thread 3d was prepared from di(isopropyl)amine 1d (1.62 g, 16 mmol) and succinyl chloride 2 (616
1
mg, 4 mmol). Colorless oil (741 mg, 65%); H NMR (200 MHz, CDCl3) 4.20–4.00 (m, 2H), 3.51–
13
3.34 (m, 2H), 2.64 (s, 4H), 1.34 (d, J = 6.8 Hz, 12H), 1.14 (d, J = 6.7 Hz, 12H); C{1H} NMR (50
MHz, CDCl3) 171.1 (C), 48.3 (CH), 45.7 (CH), 30.3 (CH2), 20.84 (CH3), 20.77 (CH3); HRMS (ESI+)
m/z for C16H33N2O2 [M + H]+ 285.2537, found 285.2533.
Thread 3e was prepared from dibutylamine 1e (2.06 g, 16 mmol) and succinyl chloride 2 (616 mg, 4
mmol). Yellow oil (1.21 g, 89%); 1H NMR (400 MHz, CDCl3) 3.28–3.20 (m, 8H), 2.63 (s, 4H), 1.57–
1.40 (m, 8H), 1.33–1.19 (m, 8H), 0.90 (t, J = 7.3 Hz, 6H), 0.86 (t, J = 7.4 Hz, 6H); 13C{1H} NMR (100
MHz, CDCl3) 171.7 (C), 47.8 (CH2), 46.02 (CH2), 31.1 (CH2), 30.0 (CH2), 28.4 (CH2), 20.3 (CH2),
20.2 (CH2), 13.9 (CH3), 13.88 (CH3); HRMS (ESI+) m/z calcd for C20H41N2O2 [M + H]+ 341.3163,
found 341.3172.
Thread 3f was prepared from di(isobutyl)amine 1f (2.06 g, 16 mmol) and succinyl chloride 2 (616 mg,
1
4 mmol). Yellow oil (763 mg, 56%); H NMR (400 MHz, CDCl3) 3.20–3.13 (m, 8H), 2.70 (s, 4H),
13
2.03–1.90 (m, 4H), 0.91 (d, J = 6.7 Hz, 12H), 0.84 (d, J = 6.7 Hz, 12H); C{1H} NMR (100 MHz,
CDCl3) 172.5 (C), 55.4 (CH2), 53.4 (CH2), 28.9 (CH2), 27.8 (CH), 26.5 (CH), 20.1 (CH3), 20.0 (CH3);
HRMS (ESI+) m/z calcd for C20H41N2O2 [M + H]+ 341.3163, found 341.3171.
Thread 3g28 was prepared from di(cyclohexylmethyl)ethylamine 1g (3.34 g, 16 mmol) and succinyl
chloride 2 (616 mg, 4 mmol). White solid (1.40 g, 70%). The title compound showed identical
1
spectroscopic data as those reported in reference 28 (see Supporting Information for a H NMR
spectrum).
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General procedure for the synthesis of the succinamide-based [2]rotaxanes 4, 5 and 7. The thread
(1 equiv.) and Et3N (24 equiv.) in anhydrous CHCl3 (300 mL) were stirred vigorously whilst solutions of
p-xylylenediamine (8 equiv.) in anhydrous CHCl3 (20 mL) and the corresponding acid dichloride (8
equiv.) in anhydrous CHCl3 (20 mL) were simultaneously added over a period of 5 h using motor-driven
syringe pumps. After a further 4 h the resulting suspension was filtered through a Celite pad, washed
with water (2 x 50 mL), a solution of HCl 1M (2 x 50 mL), a saturated solution of NaHCO3 (2 x 50 mL)
and brine (2 x 50 mL). The organic phase is then dried over MgSO4 and the solvent removed under
reduced pressure. The resulting solid was subjected to column chromatography (silica gel) to yield
unconsumed thread, [2]rotaxane and [2]catenane.
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Rotaxane 4c was obtained using the described method from thread 3c (500 mg, 1.75 mmol). The
resulting residue was subjected to column chromatography (silica gel) using a mixture CHCl3/MeOH
(98/2). The solvent was removed under reduced pressure to give the title product as a white solid (544
1
mg, 38%); mp > 250 ºC (decomp.); H NMR (400 MHz, CDCl3) 8.80 (s, 2H), 8.35 (d, J = 7.7 Hz,
4H), 7.71 (t, J = 5.4 Hz, 4H), 7.65 (t, J = 7.7 Hz, 2H), 7.09 (s, 8H), 5.34 (br s, 4H), 3.77 (br s, 4H),
3.25–3.14 (m, 4H), 2.72–2.60 (m, 4H), 1.60–1.50 (m, 4H), 1.26–1.16 (m, 8H), 1.04 (s, 4H), 0.90 (t, J =
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7.4 Hz, 6H), 0.21 (t, J = 7.3 Hz, 6H); C{1H} NMR (100 MHz, CDCl3) 173.1 (C), 165.5 (C), 139.0
(C), 133.6 (CH), 132.5 (C), 129.7 (CH), 129.1 (CH), 122.5 (CH), 50.3 (CH2), 48.9 (CH2), 43.4 (CH2),
28.3 (CH2), 21.9 (CH2), 21.5 (CH2), 11.7 (CH3), 10.6 (CH3); HRMS (ESI+) m/z calcd for C48H61N6O6
[M + H]+ 817.4647, found 817.4649.
Rotaxane 4d was obtained using the described method from thread 3d (500 mg, 1.75 mmol). The
resulting residue was subjected to column chromatography (silica gel) using a mixture CHCl3/MeOH
(98/2). The solvent was removed under reduced pressure to give the title product as a white solid (243
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mg, 17%); mp > 250 ºC (decomp.); H NMR (400 MHz, C2D2Cl4) 8.75 (s, 2H), 8.36 (d, J = 7.9 Hz,
4H), 7.73–7.62 (m, 6H), 7.10 (s, 8H), 5.35 (br s, 4H), 3.70 (br s, 4H), 3.32–3.24 (m, 2H), 3.00–2.90 (m,
2H), 1.38 (d, J = 6.7 Hz, 12H), 1.24 (s, 4H), 0.79 (d, J = 6.5 Hz, 12H); 13C{1H} NMR (100 MHz,
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C2D2Cl4) 171.9 (C), 164.8 (C), 138.8 (C), 132.9 (CH), 132.0 (C), 129.5 (CH), 128.5 (CH), 122.1
(CH), 48.6 (CH), 45.6 (CH), 43.0 (CH2), 29.8 (CH2), 20.6 (CH3), 19.8 (CH3); HRMS (ESI+) m/z calcd
for C48H61N6O6 [M + H]+ 817.4647, found 817.4661.
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Rotaxane 4e was obtained using the described method from thread 3e (500 mg, 1.46 mmol). The
resulting residue was subjected to column chromatography using a mixture CHCl3/MeOH (99/1) as
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eluent to give the title product as a white solid (497 mg, 39%); mp > 250 ºC (decomp.); H NMR (300
MHz, CDCl3) 8.82 (s, 2H), 8.35 (dd, J = 7.8, 1.5 Hz, 4H), 7.72 (t, J = 5.2 Hz, 4H), 7.65 (t, J = 7.8 Hz,
2H), 7.10 (s, 8H), 5.33 (br s, 4H), 3.75 (br s, 4H), 3.27–3.18 (m, 4H), 2.76–2.66 (m, 4H), 1.56–1.45 (m,
4H), 1.36–1.10 (m, 8H), 1.05 (s, 4H), 0.93 (t, J = 7.3 Hz, 6H), 0.65–0.45 (m, 10H); 13C{1H} NMR (75
MHz, CDCl3) 172.8 (C), 165.4 (C), 138.8 (C), 133.4 (CH), 132.4 (C), 129.6 (CH), 129.1 (CH), 122.6
(CH), 48.3 (CH2), 46.7 (CH2), 43.4 (CH2), 30.8 (CH2), 30.4 (CH2), 28.2 (CH2), 20.4 (CH2), 19.8 (CH2),
14.0 (CH3), 13.8 (CH3); HRMS (ESI+) m/z calcd for C52H68N6O6 [M + H]+ 873.5273, found 873.5291.
Rotaxane 4f was obtained using the described method from thread 3f (500 mg, 1.46 mmol). The
resulting residue was subjected to column chromatography using a mixture CHCl3/MeOH (99/1) as
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eluent to give the title product as a white solid (242 mg, 19%); mp > 300 ºC (decomp.); H NMR (400
MHz, CDCl3) 8.78 (s, 2H), 8.36 (d, J = 7.8 Hz, 4H), 7.67–7.59 (m, 6H), 7.11 (s, 8H), 5.19 (br s, 4H),
4.00 (br s, 4H), 3.11 (d, J = 7.2 Hz, 4H), 2.62 (d, J = 7.8 Hz, 4H), 1.99–1.88 (m, 2H), 1.62–1.52 (m,
2H), 1.12 (s, 4H), 0.94 (d, J = 6.7 Hz, 12H), 0.41 (d, J = 6.5 Hz, 12H); 13C{1H} NMR (100 MHz,
CDCl3) 174.2 (C), 165.4 (C), 138.9 (C), 133.6 (CH), 132.6 (C), 129.8 (CH), 129.1 (CH), 122.3 (CH),
57.2 (CH2), 56.0 (CH2), 43.2 (CH2), 28.8 (CH2), 28.0 (CH), 27.6 (CH), 21.0 (CH3), 19.8 (CH3); HRMS
(ESI+) m/z calcd for C52H68N6O6 [M + H]+ 873.5273, found 873.5288.
Rotaxane 4g29 was obtained using the described method from thread 3g (500 mg, 1 mmol). The
resulting residue was subjected to column chromatography using a mixture CHCl3/MeOH (95/5) as
eluent to give the title product as a white solid (237 mg, 23%). This compound was synthesized as
described in reference 29 and showed identical spectroscopic data as those reported therein.
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Rotaxane 5b was obtained using the described method from thread 3b (500 mg, 2.19 mmol). The
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resulting residue was purified by column chromatography on silica gel using a CHCl3/MeOH (97/3)
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mixture as eluent to give the title product as a white solid (150 mg, 9%); mp > 250 ºC (decomp.); H
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NMR (200 MHz, CDCl3) 9.46 (d, J = 9.2 Hz, 4H), 8.49 (d, J = 7.8 Hz, 4H), 8.10 (t, J = 7.8 Hz, 2H),
7.16 (d, J = 8.1 Hz, 4H), 6.88 (d, J = 7.9 Hz, 4H), 5.53 (dd, J = 14.1 Hz, 10.6 Hz, 4H), 3.60 (dd, J =
14.1 Hz, 2.0 Hz, 4H), 3.30 (q, J = 6.9 Hz, 4H), 2.62 (q, J = 7.0 Hz, 4H), 1.17 (t, J = 6.9 Hz, 6H), 0.69 (s,
4H), 0.43 (t, J = 7.0 Hz, 6H); 13C{1H} NMR (75 MHz, CDCl3) 172.5 (C), 163.8 (C), 149.3 (C), 139.2
(C), 138.9 (CH), 128.7 (CH), 128.2 (CH), 125.5 (CH), 42.7 (CH2), 41.9 (CH2), 40.7 (CH2), 28.1 (CH2),
13.7 (CH3), 13.2 (CH3); HRMS (ESI) m/z calcd for C42H51N8O6 [M + H]+ 763.3926, found 763.3964.
Rotaxane 5c was obtained using the described method from thread 3c (500 mg, 1.75 mmol). The
resulting residue was purified by column chromatography on silica gel using a CHCl3/MeOH (97/3)
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mixture as eluent to give the title product as a white solid (40 mg, 5%); mp > 250 ºC (decomp.); H
NMR (300 MHz, CDCl3) 9.54 (d, J = 8.5 Hz, 4H), 8.48 (d, J = 7.8 Hz, 4H), 8.07 (t, J = 7.8 Hz, 2H),
7.15 (dd, J = 8.0 Hz, 1.3 Hz, 4H), 6.88 (dd, J = 8 Hz, J = 1.5 Hz, 4H), 5.53 (dd, J = 14.3 Hz, 10.4 Hz,
4H), 3.60 (dd, J = 14.3 Hz, 2.2 Hz, 4H), 3.23–3.14 (m, 4H), 2.61–2.53 (m, 4H), 1.66–1.54 (m, 4H),
1.20–1.04 (m, 4H), 0.94 (t, J = 7.4 Hz, 6H), 0.72 (s, 4H), 0.01 (t, J = 7.4 Hz, 6H); 13C{1H} NMR (75
MHz, CDCl3) 172.9 (C), 163.8 (C), 149.4 (C), 139.0 (C), 138.9 (CH), 128.8 (CH), 128.4 (CH), 125.6
(CH), 50.0 (CH2), 48.8 (CH2), 42.7 (CH2), 28.3 (CH2), 21.8 (CH2), 21.5 (CH2), 11.8 (CH3), 10.3 (CH3);
HRMS (ESI+) m/z calcd for C46H59N8O6 [M + H]+ 819.4552, found 819.4520.
Rotaxane 5d was obtained using the described method from thread 3e (1.0 g, 2.92 mmol). The
resulting residue was purified by column chromatography on silica gel using a CHCl3/MeOH (98/2)
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mixture as eluent to give the title product as a white solid (80 mg, 3%); mp > 250 ºC (decomp.); H
NMR (400 MHz, CDCl3) 9.57 (d, J = 8.4 Hz, 4H), 8.48 (d, J = 7.8 Hz, 4H), 8.08 (t, J = 7.8 Hz, 2H),
7.15 (dd, J = 7.9 Hz, 1.5 Hz, 4H), 6.88 (dd, J = 7.9 Hz, 1.6 Hz, 4H), 5.53 (dd, J = 14.4 Hz, 10.3 Hz,
4H), 3.59 (dd, J = 14.4 Hz, 2.2 Hz, 4H), 3.25–3.19 (m, 4H), 2.65–2.59 (m, 4H), 1.60–1.50 (m, 4H), 1.34
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(dq, J = 14.6 Hz, 7.3 Hz, 4H), 1.15–1.05 (m, 4H), 0.95 (t, J = 7.3 Hz, 6H), 0.72 (s, 4H), 0.56 (t, J = 7.3
Hz, 6H), 0.35–0.24 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) 172.8 (C), 163.8 (C), 149.4 (C), 138.9
(C), 138.7 (CH), 128.9 (CH), 128.4 (CH), 125.6 (CH), 48.1 (CH2), 46.7 (CH2), 42.7 (CH2), 30.9 (CH2),
30.5 (CH2), 28.4 (CH2), 20.5 (CH2), 19.8 (CH2), 14.1 (2 x CH3); HRMS (ESI+) m/z calcd for
C50H67N8O6 [M + H]+ 875.5178, found 875.5201.
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Rotaxane 7a was obtained using the described method from thread 3e (500 mg, 1.46 mmol). The
resulting residue was purified by column chromatography on silica gel using CH2Cl2 as eluent to give
the title product as a white solid (340 mg, 25%); mp > 250 ºC (decomp.); 1H NMR (400 MHz, CDCl3)
8.66 (s, 2H), 8.40 (d, J = 1.2 Hz, 4H), 7.70 (t, J = 5.7 Hz, 4H), 7.09 (s, 8H), 5.38 (br s, 4H), 3.72 (br s,
4H), 3.28–3.16 (m, 4H), 2.74–2.64 (m, 4H), 1.55–1.45 (m, 4H), 1.41 (s, 18H), 1.35–1.10 (m, 8H), 1.05
(s, 4H), 0.92 (t, J = 7.3 Hz, 6H), 0.59 (t, J = 7.1 Hz, 6H), 0.55–0.40 (m, 4H); 13C{1H} NMR (100 MHz,
CDCl3) 172.8 (C), 165.8 (C), 153.2 (C), 138.9 (C), 133.2 (CH), 129.5 (C), 129.0 (CH), 120.1 (CH),
48.3 (CH2), 46.7 (CH2), 43.3 (CH2), 35.4 (C), 31.4 (CH3), 30.8 (CH2), 30.4 (CH2), 28.2 (CH2), 20.3
(CH2), 19.7 (CH2), 14.0 (CH3), 13.8 (CH3); HRMS (ESI+) m/z calcd for C60H85N6O6 [M + H]+
985.6525, found 985.6552.
Rotaxane 7c was obtained using the described method from thread 3e (339 mg, 1.19 mmol). The
resulting residue was purified by column chromatography on silica gel using a mixture CH2Cl2/AcOEt
(80/20) as eluent to give the title product as a white solid (376 mg, 38%); mp 203-206 ºC; 1H NMR (400
MHz, CDCl3) 8.39 (s, 2H), 7.86 (s, 4H), 7.68 (t, J = 5.7 Hz, 4H), 7.08 (s, 8H), 5.84 (ddt, J = 16.9 Hz,
10.2 Hz, 6.7 Hz, 2H), 5.35 (br s, 4H), 5.08–4.95 (m, 4H), 4.10 (t, J = 6.4 Hz, 4H), 3.72 (br s, 4H), 3.30–
3.15 (m, 4H), 2.75–2.65 (m, 4H), 2.15 (dd, J = 14.3 Hz, 7.2 Hz, 4H), 1.90–1.80 (m, 4H), 1.66–1.46 (m,
12H), 1.36–1.25 (m, 4H), 1.25–1.12 (m, 4H), 1.02 (s, 4H), 0.94 (t, J = 7.3 Hz, 6H), 0.66–0.52 (m, 10H);
13C{1H} NMR (100 MHz, CDCl3) 172.8 (C), 165.3 (C), 160.4 (C), 138.8 (C), 138.6 (CH), 135.0 (C),
129.0 (CH), 118.3 (CH), 115.0 (C), 114.8 (CH), 68.5 (CH2), 48.3 (CH2), 46.7 (CH2), 43.4 (CH2), 33.5
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(CH2), 30.9 (CH2), 30.4 (CH2), 28.7 (CH2), 28.2 (CH2), 25.4 (CH2), 20.4 (CH2), 19.9 (CH2), 14.0 (CH3),
13.9 (CH3); HRMS (ESI+) m/z calcd for C64H89N6O8 [M + H]+ 1069.6736, found 1069.6709.
Rotaxane 7d was obtained using the described method from thread 3e (500 mg, 1.46 mmol). The
resulting residue was purified by column chromatography on silica gel using a CHCl3/MeOH (98/2)
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NMR (400 MHz, CDCl3) 9.04–8.96 (m, 6H), 7.72 (t, J = 5.6 Hz, 4H), 7.11 (s, 8H), 5.31 (br s, 4H),
4.00 (s, 6H), 3.85 (br s, 4H), 3.26–3.18 (m, 4H), 2.76–2.68 (m, 4H), 1.55–1.45 (m, 4H), 1.35–1.15 (m,
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8H), 1.04 (s, 4H), 0.93 (t, J = 7.3 Hz, 6H), 0.62–0.50 (m, 10H); C{1H} NMR (100 MHz, CDCl3)
172.9 (C), 166.0 (C), 164.5 (C), 138.7 (C), 134.1 (C), 133.4 (C), 132.2 (CH), 129.1 (CH), 126.4 (CH),
52.7 (CH3), 48.4 (CH2), 46.8 (CH2), 43.5 (CH2), 30.8 (CH2), 30.4 (CH2), 28.2 (CH2), 20.4 (CH2), 20.0
(CH2), 14.0 (CH3), 13.8 (CH3); HRMS (ESI+) m/z calcd for C56H73N6O10 [M + H]+ 989.5388, found
989.5402.
Rotaxane 7e was obtained using the described method from thread 3e (500 mg, 1.46 mmol). The
resulting residue was washed with Et2O and filtered, giving the title product as a white solid (450 mg,
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32%); mp > 250 ºC (decomp.); H NMR (300 MHz, CDCl3) 9.16 (m, 6H), 7.75 (t, J = 5.2 Hz, 4H),
7.12 (s, 8H), 5.30 (br s, 4H), 3.86 (br s, 4H), 3.29–3.20 (m, 4H), 2.80–2.68 (m, 4H), 1.56–1.44 (m, 4H),
1.36–1.16 (m, 8H), 1.04 (s, 4H), 0.92 (t, J = 7.3 Hz, 6H), 0.64–0.56 (m, 10H); 13C{1H} NMR (100
MHz, CDCl3) 172.9 (C), 163.1 (C), 149.6 (C), 138.4 (C), 135.6 (C), 129.2 (CH), 127.6 (CH), 127.0
(CH), 48.4 (CH2), 46.9 (CH2), 43.7 (CH2), 30.7 (CH2), 30.3 (CH2), 28.2 (CH2), 20.3 (CH2), 20.0 (CH2),
14.0 (CH3), 13.7 (CH3); HRMS (ESI+) m/z calcd for C52H67N8O10 [M + H]+ 963.4975, found 963.4948.
Rotaxane 7f was obtained using the described method from thread 3e (500 mg, 1.46 mmol). The
resulting residue was purified by column chromatography on silica gel using a CHCl3/MeOH (98/2)
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mixture as eluent to give the title product as a white solid (349 mg, 27%); mp > 250 ºC (decomp.); H
NMR (300 MHz, CDCl3) 9.46 (d, J = 1.9 Hz, 4H), 9.14 (t, J = 1.9 Hz, 2H), 7.54 (t, J = 5.5 Hz, 4H),
7.10 (s, 8H), 4.52 (br s, 8H), 3.26–3.18 (m, 4H), 2.76–2.67 (m, 4H), 1.54–1.42 (m, 4H), 1.35–1.12 (m,
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8H), 1.04 (s, 4H), 0.91 (t, J = 7.3 Hz, 6H), 0.68–0.55 (m, 10H); C{1H} NMR (75 MHz, CDCl3)
172.7 (C), 163.9 (C), 153.3 (CH), 138.4 (C), 130.2 (C), 129.2 (CH), 127.8 (CH), 48.3 (CH2), 46.8
(CH2), 43.4 (CH2), 30.7 (CH2), 30.3 (CH2), 28.1 (CH2), 20.3 (CH2), 19.9 (CH2), 13.9 (CH3), 13.7 (CH3);
HRMS (ESI) m/z calcd for C50H67N8O6 [M + H]+ 875.5178, found 875.5156.
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Synthesis of rotaxane 7b. Thread 3e (200 mg, 0.60 mmol), Et3N (14.4 mmol) and N1,N3-bis(4-
(aminomethyl)benzyl)isophthalamide46 (1.46 g, 2.43 mmol) in anhydrous CHCl3 (300 mL) were stirred
vigorously whilst solution of 5-(tert-butyldimethylsiloxy)isophthaloyl dichloride47 (0.81 g, 2.42 mmol)
in anhydrous CHCl3 (20 mL) was added over a period of 5 h using motor-driven syringe pump. After a
further 4 h the resulting suspension was filtered through a Celite pad, washed with water (2 x 50 mL), a
saturated solution of NaHCO3 (2 x 50 mL) and brine (2 x 50 mL). The organic phase was then dried
over MgSO4 and the solvent removed under reduced pressure. The resulting residue was purified by
column chromatography on silica gel using CH2Cl2 as eluent to give the title product as a white solid
(7b, 220 mg, 37%); mp 235-236 ºC; 1H NMR (300 MHz, CDCl3) 8.82 (s, 1H), 8.41 (s, 1H), 8.35 (d, J
= 7.8 Hz, 2H), 7.79 (s, 2H), 7.76–7.70 (m, 5H), 7.09 (s, 8H), 5.35 (br s, 4H), 3.72 (br s, 4H), 3.26–3.19
(m, 4H), 2.76–2.68 (m, 4H), 1.55–1.45 (m, 4H), 1.35–1.15 (m, 8H), 1.04 (s, 4H), 1.02 (s, 9H), 0.93 (t, J
= 7.3 Hz, 6H), 0.66–0.50 (m, 10H); 13C{1H} NMR (75 MHz, CDCl3) 172.8 (C), 165.4 (C), 165.2 (C),
157.1(C), 138.84 (C), 138.76 (C), 135.0 (C), 133.4 (C), 132.4 (CH), 129.6 (CH), 129.1 (CH), 123.8
(CH), 122.6 (CH), 115.5 (CH), 48.3 (CH2), 46.7 (CH2), 43.3 (CH2), 30.8 (CH2), 30.4 (CH2), 29.8 (C),
28.2 (CH2), 25.8 (CH3), 20.4 (CH2), 19.9 (CH2), 14.0 (CH3), 13.8 (CH3), -4.3 (2 x CH3); HRMS (ESI+)
m/z calcd for C58H83N6O7Si [M + H]+ 1003.6087, found 1003.6084.
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Synthesis of 5-(hex-5-enyloxy)isophthalic acid. To a DMF solution (150 mL) of dimethyl 5-
hydroxyisophthalate (13.06 g, 62.18 mmol) was added 6-bromohexene (12.1 g, 74.61 mmol) and K2CO3
(9.88 g, 71.61 mmol), and the mixture was heated at 65 ºC for 14 h. The reaction mixture was
partitioned between H2O and Et2O. The aqueous layer was separated and washed with Et2O. Combined
organic layers were washed with 1 M aqueous NaOH and brine, dried (MgSO4), filtered and
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concentrated under vacuum. The resulting residue was subjected to column chromatography (silica gel)
using a mixture hexane/AcOEt (90/10) as eluent to yield dimethyl 5-(hex-5-enyloxy)isophthalate as a
yellow oil (16.84 g, 92%).48 This oil (5.89 g, 20 mmol) was dissolved in MeOH (50 mL) and NaOH
(1.60 g, 40 mmol) was added. The mixture was refluxed overnight and after this time the solvent was
removed under vacuum. The corresponding residue was filtered and washed with CHCl3 to yield the
title compound as a white solid (2.89 g, 53%); mp 192-194 ºC; 1H NMR (400 MHz, DMSO-d6) 12.93
(br s, 2H), 8.05 (t, J = 1.4 Hz, 1H), 7.61 (t, J = 1.4 Hz, 2H), 5.87–5.75 (m, 1H), 5.06–4.93 (m, 2H), 4.05
(t, J = 6.4 Hz, 2H), 2.07 (q, J = 7.2 Hz, 2H), 1.77–1.66 (m, 2H), 1.55–1.46 (m, 2H); 13C{1H} NMR (100
MHz, DMSO-d6) 166.6 (C), 158.9 (C), 138.6 (CH), 132.7 (C), 122.2 (CH), 119.1 (CH), 115.1 (CH2),
68.0 (CH2), 32.9 (CH2), 28.1 (CH2), 24.7 (CH2); HRMS (ESI-) m/z calcd for C14H15O5 [M - H]-
263.0925, found 263.0932.
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General for the preparation of benzylic amide macrocycles. Method A: The rotaxane (0.2 mmol)
was placed in a 1 mL vial under high vacuum (0.01 Torr) at 150 ºC (Ti). The system was heated at 375
ºC (Tf) for 10 minutes. The corresponding thread was trapped in a U-tube situated at the exit point of the
furnace and cooled with liquid N2. After this time, the corresponding macrocycle was obtained
quantitatively as a white solid. The addition of dichloromethane (10 mL) to the U-tube allows to recover
the pure thread after solvent evaporation. Method B: The corresponding rotaxane (0.2 mmol) was
dissolved in DMSO (1 mL) and stirred vigorously at 120 ºC during 24 h. After this time the reaction
mixture was cooled to room temperature and H2O (2 mL) was added. The resulting white solid was
filtered, washed with water (10 mL) and Et2O (10 mL) and dried under reduced pressure to give the
corresponding macrocycle. Then the ether was removed from the filtrate by rotatory evaporation and the
resulting solution was extracted with chloroform (3 x 12 mL). The combined organic fractions were
washed with water (2 x 30 mL) and brine (30 mL), dried over MgSO4 and, finally, concentrated under
reduced pressure to recover the corresponding thread as a yellow oil. Method C: The corresponding
rotaxane (0.2 mmol) was dissolved in DMSO (1 mL) in a 10 mL vessel and stirred vigorously at 120 ºC
during 30 min under microwave radiation (200 W). After this time the reaction mixture was cooled to
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room temperature and H2O (2 mL) was added. The resulting white solid was filtered, washed with water
(10 mL) and Et2O (10 mL) and dried under reduced pressure to give the corresponding macrocycle.
Then the ether was removed from the filtrate by rotatory evaporation and the resulting solution was
extracted with chloroform (3 x 12 mL). The combined organic fractions were washed with water (2 x 30
mL) and brine (30 mL), dried over MgSO4 and, finally, concentrated under reduced pressure to recover
the corresponding thread as a yellow oil.
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Macrocycle 6a7 was quantitatively obtained as a white solid using method A, B or C from rotaxane 4c
or 4e. The title compound showed identical spectroscopic data as those reported in reference 7 (see
Supporting Information for a 1H NMR spectrum).
Macrocycle 8a (104 mg, 77%) was obtained as a white solid using method B from rotaxane 7a (205
mg, 0.21 mmol); mp > 300 ºC; 1H NMR (400 MHz, DMSO-d6) 8.94 (t, J = 5.6 Hz, 4H), 7.96 (s, 4H),
7.90 (s, 2H), 7.24 (s, 8H), 4.40 (d, J = 5.6 Hz, 8H), 1.34 (s, 18H); 13C{1H} NMR (100 MHz, DMSO-d6)
166.2 (C), 151.1 (C), 138.2 (C), 134.6 (C), 127.8 (CH), 126.6 (CH), 123.2 (CH), 42.7 (CH2), 34.7 (C),
31.0 (CH3); HRMS (ESI+) m/z calcd for C40H45N4O4 [M + H]+ 645.3435, found 645.3411.
Macrocycle 8b (80 mg, 84%) was obtained from rotaxane 7b (173 mg, 0.17 mmol) as a white solid
1
using method B, heating at 120 ºC for 24 h in a mixture DMSO : H2O (9 : 1); mp > 300 ºC; H NMR
(200 MHz, DMSO-d6) 9.97 (s, 1H), 8.93 (t, J = 5.4 Hz, 2H), 8.93 (t, J = 5.3 Hz, 2H), 8.07 (s, 1H),
7.95 (d, J = 7.7 Hz, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.52 (s, 1H), 7.34 (s, 2H), 7.24 (s, 8H), 4.45–4.35 (m,
4H); 13C{1H} NMR (50 MHz, DMSO-d6) 166.0 (C), 165.9 (C), 157.4 (C), 138.2 (C), 138.1 (C), 136.2
(C), 134.8 (C), 129.9 (CH), 128.6 (CH), 127.9 (CH), 125.8 (CH), 116.8 (CH), 116.4 (CH), 42.7 (CH2);
HRMS (ESI+) m/z calcd for C32H29N4O5 [M + H]+ 549.2132, found 549.2151.
Macrocycle 8c (59 mg, 87%) was obtained as a white solid using method B from rotaxane 7c (100 mg,
0.0936 mmol); mp > 300 ºC; 1H NMR (400 MHz, DMSO-d6) 8.92 (s, 4H), 7.67 (s, 2H), 7.47 (s, 4H),
7.23 (s, 8H), 5.90–5.75 (m, 2H), 5.10–4.95 (m, 4H), 4.39 (d, J = 4.6 Hz, 8H), 4.07 (s, 4H), 2.15–2.05
(m, 4H), 1.82–1.70 (m, 4H), 1.58-1.50 (m, 4H); 13C{1H} NMR (100 MHz, DMSO-d6) 165.6 (C),
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The Journal of Organic Chemistry
158.5 (C), 138.5 (CH), 138.1 (C), 136.1 (C), 127.8 (CH), 118.1 (CH), 115.7 (CH), 115.0 (CH2), 67.7
(CH2), 42.7 (CH2), 32.8 (CH2), 28.1 (CH2), 24.7 (CH2); HRMS (ESI+) m/z calcd for C44H49N4O6 [M +
H]+ 729.3647, found 729.3657.
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Macrocycle 8d (140 mg, 99%) was obtained as a white solid using method C from rotaxane 7d (222
mg, 0.224 mmol); mp > 300 ºC; 1H NMR (400 MHz, DMSO-d6) 9.20 (t, J = 5.6 Hz, 4H), 8.50 (d, J =
1.5 Hz, 4H), 8.33 (s, 2H), 7.23 (s, 8H), 4.40 (d, J = 5.6 Hz, 8H), 3.91 (s, 6H); 13C{1H} NMR (100 MHz,
DMSO-d6) 165.4 (C), 164.9 (C), 138.1 (C), 135.4 (C), 130.5 (C), 130.3 (CH), 130.1 (CH), 128.0
(CH), 52.7 (CH3), 42.9 (CH2); HRMS (ESI+) m/z calcd for C36H33N4O8 [M + H]+ 649.2293, found
649.2282.
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Macrocycle 8e (64 mg, 99%) was obtained as a white solid using method B from rotaxane 7e (100 mg,
0.104 mmol); mp > 300 ºC; 1H NMR (300 MHz, DMSO-d6, 333K) 8.91 (t, J = 5.4 Hz, 4H), 8.71 (d, J
= 1.5 Hz, 4H), 8.51 (t, J = 1.5 Hz, 2H), 7.30 (s, 8H), 4.49 (d, J = 5.4 Hz, 8H); 13C{1H} NMR (75 MHz,
DMSO-d6, 333K) 163.4 (C), 147.7 (C), 137.3 (C), 136.2 (C), 130.9 (CH), 127.5 (CH), 123.4 (CH),
42.6 (CH2); HRMS (ESI+) m/z calcd for C32H27N6O8 [M + H]+ 623.1885, found 623.1860.
Macrocycle 8f13 (150 mg, 95%) was obtained as a white solid using method C from rotaxane 7f (258
mg, 0.295 mmol). The title compound showed identical spectroscopic data as those reported in
reference 13 (see Supporting Information for a 1H NMR spectrum).
Macrocycle 8g16 (149 mg, 99%) was obtained as a white solid using method B from rotaxane 5b (216
mg, 0.283 mmol). The title compound showed identical spectroscopic data as those reported in
reference 16 (see Supporting Information for a 1H NMR spectrum).
ASSOCIATED CONTENT
Supporting Information. Copies of the 1H and 13C NMR spectra of all the new compounds described,
TGA analyses and full kinetics data. This material is available free of charge via the Internet at
http://pubs.acs.org.This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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