Synthesis of a new 24-membered tetramide macrocycle and X-ray crystal structure determination

Article abstract of DOI:10.1016/j.tetlet.2019.03.066

The synthesis and characterization of a new 24-membered tetramide macrocycle (6) related to Leigh's macrocycles and catenanes is reported. The replacement of p-xylylenediamine (Leigh) by m-xylylenediamine (this work) strongly modifies the geometry and pro

Full text of DOI:10.1016/j.tetlet.2019.03.066

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a new 24-membered tetramide macrocycle and X-ray
crystal structure determination
a
b
b
c
Dolores Santa María a, , Rosa M. Claramunt , M. Carmen Torralba , M. Rosario Torres , José Elguero
⇑
a Dpto. de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, UNED, Paseo Senda del Rey, 9, E-28040 Madrid, Spain
b Dpto. de Química Inorgánica y CAI de Difracción de Rayos-X, Facultad de Ciencias Químicas, UCM, Ciudad Universitaria s/n, E-28040-Madrid, Spain
c Instituto de Química Médica, Centro de Química Orgánica ‘‘Lora-Tamayo”, Juan de la Cierva, 3, E-28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and characterization of a new 24-membered tetramide macrocycle (6) related to Leigh’s
macrocycles and catenanes is reported. The replacement of p-xylylenediamine (Leigh) by m-xylylenedi-
amine (this work) strongly modifies the geometry and properties of the new macrocycle. NMR spec-
troscopy (in DMSO d6 solution) and X-ray crystallography have been used to characterize compound 6.
The structural features in the crystal (conformational aspects and H-bonding) have been discussed com-
paratively to two similar macrocycles NEWHIJ and UJUNOC.
Received 21 February 2019
Revised 20 March 2019
Accepted 26 March 2019
Available online xxxx
Keywords:
Macrocycles
Amides
Ó 2019 Published by Elsevier Ltd.
Inclusion compounds
X-ray
In 1995 Leigh and co-workers discovered an original and unex-
pected synthesis of catenanes when attempting to prepare the 26-
membered tetramide macrocycle 1 (Scheme 1) [1,2].
in the presence of catalytic amounts of dimethylformamide. Then
two solutions, 1.4 mmol of (2) in 100 mL of dry dichloromethane
and 1.4 mmol of m-xylylenediamine (5) in 100 mL of dry dichloro-
methane, were simultaneously added dropwise to a well-stirred
solution of 4.54 mmol of trimethylamine in dry dichloromethane
(600 mL) under an inert atmosphere over a period of 3 h and the
reaction mixture stirred for an additional 24 h. After a difficult
purification process (see ESI) macrocycle 6 was obtained in 8% iso-
lated yield.
The characterization of 6 was achieved by high-resolution mass
spectrometry (HRMS, [M+H]+ at 645.3441) and by NMR spec-
troscopy. The most relevant resonances in 1H NMR spectra in
DMSO d6 are the presence of four NH groups appearing at
9.08 ppm (3J = 5.9, NH), two H1 at 7.23 ppm and two H10 at
8.16 ppm (4J = 1.6 Hz), four CH2 groups at 4.43 ppm and six CH3
groups at 1.31 ppm (Fig. 1). In the 13C NMR spectra the four car-
bonyl groups were detected at 165.5 ppm and the quaternary car-
bon of the t-butyl group at 34.7 ppm. In the 15N NMR spectra the
NHs were at ꢁ266.4 ppm. The remaining nuclei of the phenyl moi-
eties show signals in the normal ranges (see ESI).
In a subsequent paper, they showed that depending on the sub-
stituents, the main products are: i) the (2+2) macrocycle 1 and ii)
the catenane which were both obtained in about 20% yield;
together with iii) small amounts of the (4+4) macrocycle (ꢀ5%
yield) and iv) traces of a (3+3) macrocycle and the (4+4+2+2) cate-
nane [3]. Spectroscopically, the main difference between macrocy-
cles and catenanes is that catenanes show a dynamic behavior in
1H NMR spectroscopy with some signals coalescing at high tem-
peratures [3,4]. More recently, Leigh and co-workers [5] as well
as others [6] have developed considerably the use of this macrocy-
cle for the synthesis of rotaxanes.
In particular, the reaction of 5-tert-butylbenzene-1,3-dicar-
bonyl dichloride (2) with 1,4-phenylene-dimethamine (3) affords
a 26-membered tetramide macrocycle (4) that has shown interest-
ing supramolecular properties [3]. By analogy, we decided to inves-
tigate the possibility to synthesize the related macrocycle (6)
where para-diamine 3 is replaced by meta-diamine 5 (Scheme 1);
the parent compound (7) has been reported [7].
The signals are narrow indicating that the diastereotopic ben-
zylic protons of the non-planar 24-membered ring became iso-
chronous due to fast inversion of the ring.
The starting material, 5-tert-butylisophthaloyl dichloride (2),
was prepared in 82% yield according to the literature procedure
[8] by heating 5-tert-butylisophthalic acid with thionyl chloride
In the 1H NMR spectrum of the crude, in addition to the signals
of 6, there were the presence of signals of a similar compound
(same multiplicity, similar chemical shifts) that could not be
isolated pure but could be assigned as the (4+4) macrocycle. A
⇑
Corresponding author.
E-mail address: dsanta@ccia.uned.es (D. Santa María).
https://doi.org/10.1016/j.tetlet.2019.03.066
0040-4039/Ó 2019 Published by Elsevier Ltd.
Please cite this article as: D. Santa María, R. M. Claramunt, M. C. Torralba et al., Synthesis of a new 24-membered tetramide macrocycle and X-ray crystal
structure determination, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.03.066

2
D. Santa María et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Synthesis of macrocycles 4 and 6 (with the NMR atom numbering) and the parent structural compounds 1 and 7.
Fig. 1. 1H NMR of macrocycle 6 in DMSO d6.
catenane structure can be ruled out because this kind of compound
shows anisochrony of the benzylic protons and of selected aro-
matic protons [3]. In the HRMS spectrum of this minor compound
there appears a peak at 1289.6811 that corresponds to the mass of
a (4+4) macrocycle (C80H89N8O+8, 1289.6803). The most characteris-
tic signals of this compound are given in the ESI. Taking into
account that this compound has a mass twice that of 6, integration
of the signals at 1.31 (6) and 1.28 ppm (4+4) corresponds to an
80:20 mixture of the two compounds.
with half molecule per asymmetric unit; the entire molecule is
generated by one inversion center. This compound crystallizes
with two dimethylsulfoxide (DMSO) solvent molecules per molec-
ular unit. For a better understanding, Fig. 2 displays the ORTEP plot
with the labeling scheme of the corresponding asymmetric units
(a) along with the molecular unit with the solvent molecules
hosted (b).
As expected for this type of macrocycle, the molecules are not
planar in order to minimize the steric hindrance; the substituents
induced an almost perpendicular twist of the aromatic rings
located on the methylene carbon atoms. The dihedral angle
between them is 80.9(2)°. All of the amide moieties show a trans
Suitable crystals of macrocycle
6 were obtained from a
dimethylsulfoxide solution and studied by single crystal X-ray
diffraction [9]. It crystallizes in the monoclinic P21/c space group
Please cite this article as: D. Santa María, R. M. Claramunt, M. C. Torralba et al., Synthesis of a new 24-membered tetramide macrocycle and X-ray crystal
structure determination, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.03.066

D. Santa María et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Fig. 2. (a) ORTEP plot of 6 (20% probability for the ellipsoids) omitting the hydrogen disorder over C21 and C22 atoms for clarity. (b) View of the molecular unit and its
interaction with the solvent molecules.
disposition for the NH and CO groups, which deviate about 21°
from the aromatic ring plane. Additionally, all of the NH groups
point to the inner part of the macrocycle in a syn-conformation,
which favors the formation of hydrogen bonds with solvent mole-
cules. In fact, the O3 atom from each DMSO forms H-bonds with
N1H1 and N2H2 (Table 1) keeping the solvent molecules hosted
within the macrocycle structure. The macrocycle conformation
generates two equivalent voids [10] above and below the ring with
an accessible volume of about 90 Å3, able to host small molecules,
such as the DMSO in this compound (volume of about 95 Å3),
which can be stabilized by hydrogen bond formation with the
NH amido groups (Fig. 3).
Additionally, different macrocycles are interconnected through
weak contacts between the O2 atoms, pointing to the outer part
Fig. 3. View of the voids formed in macrocycle 6.
of the molecule, and the xylyl groups of neighboring moieties (dis-
tance O2ꢂ ꢂ ꢂH50C50 of about 2.47 Å) spreading the interactions in
two dimensions, as shown in the ESI (Fig. S6).
N–N diagonal distance between opposite amido groups in this
compound (9.9 Å) than in the previous examples (6.7 Å in 6,
8.5 Å in NEWHIJ), considering these distances as a measure of the
A search in the Cambridge Structural Database (CSD, Version
5.39, updated August 2018; only the corresponding Refcode are
given) [11] shows that the structures of 1 (UJUNOC) [12] and 4
ring size. This larger void can either host a solvent molecule inside
(NEWHIJ) [13] have previously been described, which contain
the cavity or can form a catenane, like in the closely related com-
two DMSO and one unknown crystallization solvent molecules,
pound UJUNUI. As a result of that conformation, the main interac-
respectively (Fig. 4a). Examples of rotaxanes containing the macro-
tion in UJUNOC takes place between the NH and CO groups
cycle 1 and DMSO have been reported (IHIFOU, IHIGEL [14]; UJU-
(pointing outwards in an anti-conformation) of neighboring
SAT, UJUVEA [12]) as well as a derivative of 4 with DMSO but
macrocycles instead with the solvent leading to the final arrange-
ment of the network.
In summary, the above-mentioned features oblige us to con-
sider the importance not only of the cavity size, which should be
with four methyl groups on each para-phenylenediamide [15]. This
is perhaps not surprising as sulfoxides are powerful H-bond accep-
tors for benzylic amide macrocycles [16].
NEWHIJ is very similar to 6 with small differences mainly aris-
adequate to host the solvent, but also of the type of the intermolec-
ing from the para substitution on the xylyl groups. In both cases,
ular interactions in the final crystal arrangement. Furthermore, all
the molecule adopts a chair conformation presumably due to the
of these compounds have in common the presence of crystalliza-
steric effect of the t-butyl groups. This fact favors the location of
tion solvent molecules, which are proposed to have a key role in
voids above and below the ring that can accommodate the DMSO
preventing the formation of the expected catenanes, since there
solvent molecules, which also interacts with the amido groups of
is competition concerning the intermolecular interaction of a
the nearest ring stabilizing the whole entity (Fig. 4b).
macrocycle with the solvent or with other rings. Therefore, the sol-
By contrast, UJUNOC shows a more planar shape allowing the
vent coordinative capability, the molecular conformation of the
formation of a void inside the ring, leading to a longer than average
Table 1
Hydrogen bonds (Å and °) for macrocycle 6.
D–Hꢂ ꢂ ꢂA
Symmetry operations
d(D–H)
d(Hꢂ ꢂ ꢂA)
d(Dꢂ ꢂ ꢂA)
<(DHA)
N1–H1ꢂ ꢂ ꢂO3
0.93
0.89
2.28
2.24
3.206(3)
3.125(2)
173.5
171.9
N2–H2ꢂ ꢂ ꢂO3#1
#1 1 ꢁ x, 1 ꢁ y, 1 ꢁ z
Please cite this article as: D. Santa María, R. M. Claramunt, M. C. Torralba et al., Synthesis of a new 24-membered tetramide macrocycle and X-ray crystal
structure determination, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.03.066

4
D. Santa María et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 4. Crystal structures of 4 (NEWHIJ) and 1 (UJUNOC). (a) View of the macrocycles with their solvent molecules; (b) View of the voids generated in both macrocycles.
(b) R. Ahmed, A. Altieri, D.M. D’Souza, D.A. Leigh, K.M. Mullen, M. Papmeyer, A.
M.Z. Slawin, J.K.Y. Wong, J.D. Woolins, J. Am. Chem. Soc. 133 (2011) 12304–
12310;
ring, and the type of intermolecular interactions should be taken
into account in the formation of catenanes.
(c) M.R. Panman, B.H. Bakker, D. den Uyl, E.R. Kay, D.A. Leigh, W.J. Buma, A.M.
Brouwer, J.A.J. Geenevasen, S. Woutersen, Nat. Chem. 5 (2013) 929–934;
(d) D.A. Leigh, V. Marcos, T. Nalbantoglu, I.J. Vitorica-Yrezabal, F.T. Yasar, X.
Zhu, J. Am. Chem. Soc. 139 (2017) 7104–7109;
Acknowledgement
This work was carried out with financial support from the Span-
ish Ministerio de Ciencia, Innovación y Universidades (Projects
PGC2018-094644-B-C2 and RTI2018-097416-B-C21).
(e) M.R. Panman, C.N. van Dijk, A. Huerta-Viga, H.J. Sanders, B.H. Bakker, D.A.
Leigh, A.M. Brouwer, W.J. Buma, S. Woutersen, Nat. Commun. (2017) 2206.
[6] N.S. Simpkins, D.F. Weske, L. Male, S.J. Coles, M.B. Pitak, Chem. Commun. 49
(2013) 5010–5012.
[7] P. Rajakumar, R. Padmanabhan, Tetrahedron Lett. 51 (2010) 1059–1063.
[8] C. Heim, A. Affeld, M. Nieger, F. Voegtle, Helv. Chim. Acta 82 (1999) 746–768.
[9] CCDC 1896044 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[10] S. Gehrke, R. Macchieraldo, B. Kirchner, Phys. Chem. Chem. Phys. 21 (2019)
4988–4997.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.03.066.
[11] C.R. Groom, I.J. Bruno, M.P. Lightfoot, S.C. Ward, Acta Crystallogr. B 72 (2016)
171–179.
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Please cite this article as: D. Santa María, R. M. Claramunt, M. C. Torralba et al., Synthesis of a new 24-membered tetramide macrocycle and X-ray crystal
structure determination, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.03.066