Synthesis of self-assembling glycerotriazolophanes

Abstract

Twenty 16-membered triazole-based macrocycles possessing different pseudo-symmetry elements have been synthesized using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The formation of the macrocycles was accompanied by their spontaneous self-assembly leading to solids with distinct layered structures as confirmed by scanning electron microscopy. The self-assembling properties of the product and the “on water” reaction media seemed to form the driving force for the reaction in a t-butanol–water system. The self-assembling properties of these macrocycles was supported by quantum chemical studies using Density Functional Theory.

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Introduction

The Huisgen 1,3-dipolar cycloaddition is a widely applicable reaction for the synthesis of triazole-containing compounds.¹ Although it is a relatively new addition to the synthetic organic chemistry arsenal, it has already found wide applications in the areas of medicinal chemistry,² supramolecular chemistry,³ materials science,⁴ polymer science,⁵etc., and click chemistry has proven to be quite versatile in accessing macrocyclic frameworks.⁶ Click macrocycles possess interesting attributes like anion-binding properties,⁷ self-assembling properties,⁸ the ability to act as artificial molecular receptors,⁹ catenanes and rotaxanes,¹⁰ chemical sensors,¹¹ peptidomimetics,¹² drug carrier systems,¹³ expanded crown ethers,¹⁴ enzyme inhibitors,¹⁵ chemosensors¹⁶ and artificial receptors,¹⁷etc. Whitesides et al. have described a wide range of application possibilities for materials possessing self-assembling properties.¹⁸ Besides these applications, the important attributes of the 1,4-substituted triazole ring that attracted our attention are its metabolic stability as well as the ability to show π-stacking, unlike the trans-amide bond.¹⁹ A series of glycerol-linked triazole-based macrocycles possessing interesting self-assembling properties are described herein.

Results and discussion

The three-carbon glycerol skeleton was sourced from the readily available epichlorohydrin (ECH, 1; Scheme 1). ECH, when reacted with propargyl alcohol in the presence of sodium hydride, gave the 1,3-dipropargyl ether of glycerol (2) in high yield.²⁰ The diazide 3 was readily prepared by the reaction of 1 with sodium azide in PEG 400 as shown in Scheme 1.²¹ Treatment of 3 with 2 in the presence of CuSO₄·5H₂O and sodium ascorbate in t-BuOH–H₂O (1 : 1) gave the triazole macrocycle 5 (Scheme 1; Path A). The cyclization was tried in several organic solvents and under different dilution conditions⁶ (Table 1); and the t-BuOH–H₂O system (1 : 1) was found to be best suited for the purpose, in agreement with the observation by Sharpless et al. in which the “on water” reactions were seen to be distinctly superior.²²

Scheme 1 Synthesis of glycerotriazolophanes.

Table 1 Optimization of the solvent system for the click macrocyclization into glycerotriazolophanes

Solvent system	Reaction conditions			Yield (%)
	Time	Reagents	Temp
a Reaction was carried out at high dilution, no macrocyclisation was found. b Product was not isolated in the form of self-assembled solid (in contrast to the case in which water was used as a co-solvent); no increment in the yields were found on prolongation of the reaction time.
Toluene^a	20 d	CuI, DBU	rt	None
Acetonitrile^a	20 d	CuI, DIPEA	40 °C	None
DMF^b	30 min	CuSO4/Na ascorbate	rt	25
t-BuOH^b	30 min	CuSO4/Na ascorbate	rt	20
THF–water	15 min	CuSO4/Na ascorbate	rt	84
CH2Cl2–water	15 min	CuSO4/Na ascorbate	rt	80
t-BuOH–water	10 min	CuSO4/Na ascorbate	rt	92

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In t-BuOH–H₂O it was found that the product 5a as formed was precipitated out as a near-colourless solid. The solids on separation by filtration and evaluation for their solubility after drying were found to possess characteristically very poor solubility in most protic/aprotic as well as polar/non-polar solvents. The product was seen to be sparingly soluble in DMSO as well as neat TFA. The ¹H NMR spectrum of the compound exhibited a singlet of two protons at δ 8.05 ppm, corresponding to the hydrogen on each of the two triazole units in the structure.

Although the overall spectrum appeared to be relatively simple because of the symmetry present in the molecule, the OH-2 and the OH-2' were found to be distinctly different and were located at δ 5.69 and δ 4.92 ppm. On the other hand, H-1a, H-1b, H-1'a, H-3a, H-3b and H-3'a were observed at δ 4.50 ppm and H-1'b, H-2 and H-3'b at δ 4.17–4.16 ppm under two broad singlets. Likewise while the singlet at δ 3.55 ppm corresponded to H-2', 1-O-CH₂ and 3-O-CH₂ were located at δ 3.45–3.41 ppm, again as singlets. The assignments were based on the ¹H–¹H and ¹H–¹³C correlation spectra as well as the deuterium exchange reactions. HRMS of the compound showed the only peak at 333.1290 Da, which corresponded to the value calculated for [M + Na]⁺. Some of these observations led us to consider the possibility of the formation of organized structures in the system. Thus, compound 5a as formed was subjected to SEM analysis. The micrographs were indeed confirmatory of ordered structures for the system. Layered structures with jigsaw-like individual blocks organized into a contiguous form in each of the layers were clearly evidenced. This of course indicated a possible arrangement of the basic structural units through secondary valence bonds, which was therefore verified by molecular modelling (to be described below). Various triazole macrocycles (5b-5p) synthesized starting from their corresponding starting materials (corresponding derivatives of 2 and 3) in this manner are listed in Table 2. The pseudo-C2 symmetric macrocycles on the other hand were prepared by installing an azide residue on one end and a propargyl ether moiety on the other end of the three-carbon chain (Scheme 1; Path B). The reaction of propargyl alcohol with ECH in the presence of K₂CO₃ gave glycidyl propargyl ether which on further reaction with sodium azide in PEG 400 yielded 1-azido-1-deoxy-3-O-propargyl-glycerol (4, Scheme 1).²¹ The latter (4) on subjection to click reaction conditions led to the desired pseudo-C2 symmetric triazole-macrocycles 6. The NMR and HRMS data for this pseudo-C2 symmetric macrocycle (6a) were also in accordance with the structure shown (Scheme 1 and Table 3).

Table 2 Synthesis of Pseudo-Cs Symmetric glycerotriazolophanes

5				A typical scanning electron micrograph of the freshly prepared glycerotriazolophane 5a
Entry	R 1	R 2	Product No.	Entry	R 1	R 2	Product No
1	H	H	5a	9	Ts	OAc	5i
2	H	Ac	5b	10	Ts	Piv	5j
3	H	Bz	5c	11	Ts	Ts	5k
4	H	Bn	5d	12	Piv	H	5l
5	Ac	H	5e	13	Piv	Ac	5m
6	Ac	Ac	5f	14	Piv	Piv	5n
7	Ac	Ts	5g	15	Piv	Ts	5o
8	Ts	H	5h	16	Bz	Piv	5p

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Table 3 Synthesis of Pseudo-C2 Symmetric glycerotriazolophanes

6			A typical scanning electron micrograph of the freshly prepared glycerotriazolophane 6a
Entry	R	Product
1	H	6a
2	Piv	6b
3	Ts	6c
4	Bz	6d

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Electronic structure and interaction-analysis

In order to understand the structural details and the various intramolecular interactions, the structures of the macromolecule 5a and 6a were optimized using a Gaussian03 package employing a density functional B3LYP/6-31+G(d) method, the 3D structures of which are given in Fig. 1 (for methodology details, see supporting information†).

Fig. 1 The monomeric arrangement of representative macrocycles, 5a and 6a. The intramolecular hydrogen bond distances are given in Å units.

5a is characterized by pseudo-Cs symmetric properties. Further, a T-shaped interaction was revealed between the C–H_triazole and the nitrogen atoms on the other triazole ring in the molecule, with the former acting as the hydrogen bond donor, and involved a weak non-classical bifurcated C–H⋯N1N2 bonding interaction with the electronegative nitrogen atoms of the other triazole ring. The observed H-bond distance of 2.81 Å (CH⋯N1) and 2.88 Å (CH⋯N2) respectively were in accordance with this inference. AIM analysis^23a (Fig. S2†) shows bond critical points (BCP) corresponding to both CH⋯N1 and CH⋯N2 intramolecular H-bonding interactions. There is also a ring critical point (RCP) corresponding to a seven-membered ring involving C_triazole–N–C1′–C2′–C3′–N2–H formed due to these intramolecular hydrogen bond interactions. The images for AIM analysis showing BCP and RCP for several interactions are shown in the supporting information (Fig. S2†). In structure 6a, the T-shaped interaction is absent, instead, two weak H-bonding interactions between C–H_triazole and the ethereal oxygen were observed with H-bond distances of 2.99 and 3.00 Å.^23b

Since the macromolecule was observed to show a self-assembling property, an analysis of its ‘dimeric’ structural form that could give an indication of the possible intermolecular interactions determining their self-assembling character was undertaken. The dimeric structures were constructed from the optimized geometry of the monomer as discussed above. The optimized 3D geometries of the dimer D-5a and D-6a are shown in Fig. 2.

Fig. 2 The self-assembly of representative macrocycles in the form of dimeric structures (D-5a and D-6a) showing different interactions. The intramolecular and intermolecular hydrogen bond distances are given in Å units.

As shown in Fig. 2, there are three different intermolecular interactions in structure D-5a, namely H-bond interactions between (i) OH⋯N_triazole, (ii) CH_triazole⋯N_triazole and (iii) OH⋯O_ether. The H-bond distances for these interactions were found to be 2.69, 2.34 and 1.88 Å respectively. These H-bond interactions stabilize the dimeric structure D-5a, and suggest the possibility of a self-assembling character. The intramolecular T-shaped interactions found in 5a continued to be present in the dimeric structure D-5a, with bond distances of 2.47–2.75 Å. The intermolecular CH⋯N interactions were confirmed by AIM analysis^23c (Fig. S2†), which shows electron density at several bond critical points.

The structure D-6a represents the dimeric form of 6a, wherein it adopts a step-like (ladder) conformation due to the presence of intermolecular H-bonding interactions between the CH_triazole and the N_triazole ring. These H-bonding interactions showed characteristic bond critical point parameter values for the intramolecular hydrogen bond as observed through AIM analysis.^23d These H-bonding interactions give stabilization and a self-assembling property to this macromolecule. The intramolecular weak H-bonding CH_triazole⋯O_ether interactions continued to be present in D-6a, similar to those in 6a. The dimer D-6a with a step-like or ladder conformation can be correlated to its SEM showing a diffused pattern. Since the SEM shows the self assembly of monomers and a higher connectivity between the monomers, the pattern can be extrapolated from the dimeric arrangement, where there is a vast amount of intermolecular CH⋯N hydrogen bond interactions.

The energy details of the monomers, 5a and 6a, and the energy required for dimerization are listed in Table 4. It can be observed that the monomer 6a, which is pseudo-C2 symmetric, is marginally more stable by 1.35 kcal mol⁻¹ as compared to the pseudo-Cs symmetric monomer 5a. However, in contrast, the dimer D-5a was found to be comparatively more stable by 6.13 kcal mol⁻¹ than D-6a due to the presence of additional H-bonding interactions of OH⋯N_triazole and OH⋯O_ether in addition to the T-shaped interactions.

Table 4 The absolute energies and the relative stabilization energies of macromolecules, 5a and 6a and their dimers calculated at the B3LYP/6-31+G(d) level of theory

Macrocycle	Absolute energy (Hartree)	Relative energy (kcal mol^−1)	Dimerization energy^a (kcal mol^−1)
a Dimerization energy calculated by subtracting the summation of energies of monomer from the energy of the dimer.
Monomer 5a	−1097.431212	1.35	—
Monomer 6a	−1097.433475	0.00	—
Dimer D-5a	−2194.896536	0.00	−19.10
DimerD-6a	−2194.885194	6.13	−10.27

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The dimerization energies were calculated for both the monomers with respect to the summation of two monomers, and it was observed that the formation of D-6a releases ∼9 kcal mol⁻¹ energy less than the dimer D-5a. The dimer formation in both cases was found to be exothermic. This also provides support for the higher stability of dimer D-5a as compared to D-6a.

The NBO charges calculated for the monomeric structures 5a and 6a were found to be similar in the dimeric structures D-5a and D-6a, except for differences in the NBO charge on the CH_triazole involved in several interactions with N_triazole. It was observed that in 5a, the NBO charge on CH_triazole (0.261) increased to 0.268 for the T-shaped intramolecular interaction, and to 0.279 for the intermolecular H-bonding interaction. The charge on the N_triazole involved in the intermolecular H-bonding interaction was found to be higher (−0.287) as compared to that involved in the T-shaped interaction (−0.263).

In the structure D-6a, the two intermolecular CH–NH-bonding interactions result in an increased charge on N_triazole from −0.258 to −0.294. Moreover, the charge on the CH_triazole involved in intramolecular CH–O_ether interaction increases from 0.259 to 0.274 and the charge on O_ether from −0.606 to −0.611, indicating the strength of the interactions.

The relative and actual stabilization energies, different intra- and intermolecular interactions, NBO charges and AIM analysis confirm the self-assembling properties of these molecules. The SEM analysis of the macromolecules synthesised can be correlated to their dimeric structures, wherein the step-like arrangement of D-6a gives the impression of a flat structure akin to its diffused and flat SEM. This can be attributed to the close contact between two monomeric units via two CH_triazole–N_triazole H-bonding interactions. Similarly, the stabilization of D-5a due to the presence of several additional H-bonding interactions gives this macromolecule a distinct shape and regularity that is translated to a characteristically defined pattern in its SEM (micrographs). Thus, a relation between the polymeric arrangement of these macromolecules and their corresponding SEM patterns could be identified using Density Functional Theory calculations (Fig. S1†). The self-assembling nature of these macrocycles can be due to thermodynamic factors leading to the release of several kcal mol⁻¹ of energy, along with electrostatic factors.

Characterization by other physical methods

With a view to finding further support for molecular organization in the triazolophanes prepared, their characterization was also attempted by other physical methods. Compounds 5a and 6a possessed very low solubility in even powerful solvents such as DMF, DMSO, TFA etc. and our repeated attempts to get crystals suitable for crystallography proved unsuccessful. Efforts to generate diffractograms suitable enough for solving the structure by powder X-ray diffraction (PXRD) was also unsuccessful. Hence we turned our attention to analysis of the compound by high-resolution transmission electron microscopy (HRTEM) (Fig. 3). The micrographs (Fig. 3) clearly illustrate the ordered arrangement of the monomeric units in the macromolecular organization of compounds 5a and 6a. The small grain size observed possibly also explains the poor signal to noise ratio obtained while generating the PXRD data. Further, the endotherm at 65.6 °C for 5a and 72.2 °C for 6a observed in the thermograms (Supplementary Information 1†) obtained on subjecting compounds 5a and 6a to differential scanning calorimetry (DSC) analysis must correspond to the glass transition temperature (T_G) of the respective organic compound. The T_m (187 °C for 5a and 260.5 °C for 6a) obtained by DSC was in agreement with the value (185–187 °C for 5a and 260.5 °C for 6a) obtained on determining the melting point on a laboratory melting point apparatus.

Fig. 3 HRTEM imaging of glycerotriazolophanes. Left: compound 5a and middle: a portion of it magnified; right: compound 5b.

Experimental methodology and characterization data

Typical procedure for click macrocyclisation. Diazide (1 mmol) and dialkyne (1 mmol) were dissolved in t-butanol (5 ml) and sodium ascorbate (0.8 mmol) solution in water (2.5 ml) was added to it followed by the addition of CuSO₄ (0.4 mmol) solution in water (2.5 ml). Formation of the solid product indicated the completion of the reaction. Solvent was then decanted off and the product was purified by washing with water (3–4 times).

Analytical data for macrocycle 5a. White solid; mp: 185–187 °C; ¹H NMR δ_H (400 MHz, DMSO): 8.05 (2H, s, CH Triazole), 5.69 (1H, s, OH-2), 4.92 (1H, s, OH-2′), 4.50 (6H, m, H-1a, H-1b, H-1'a, H-3a, H-3b and H-3'a), 4.17–4.16 (3H, m, H-1'b, H-2 and H-3'b); ¹³C NMR (100 MHz, DMSO): δ 125.38, 71.75, 68.42, 68.24, 63.74, 52.89; HRMS calcd. m/z 333.1282, found m/z 333.1290 (M + Na⁺); IR (KBr) ν_max: 3412.29, 2926.25, 2862.31, 1790.44, 1732.63, 1631.45, 1457.46, 1346.03, 1226.80, 1136.48.

Analytical data for macrocycle 6a. Solid; mp (initiation of melting): 215–217 °C; ¹H NMR δ_H (400 MHz, DMSO): 8.01 (2H, s, CH Triazole), 5.33 (2H, s, OH-2), 4.54–4.23 (8H, m, H-1-OCH₂, H-3), 3.97 (2H, m, H-2); δ 3.16–3.15 (4H, m, H-1); ¹³C NMR (100 MHz, DMSO): δ 71.57, 68.20, 63.18, 61.71; HRMS calcd. m/z 333.1282, found m/z 333.1290 (M + Na⁺); IR (KBr) ν_max: 3410.55, 2927.50, 1622.62, 1429.13, 1363.37, 1229.16, 1069.58.

Computational details. ²⁴ All the Density Functional Theory (DFT) calculations were carried out using the Gaussian03 package utilizing gradient geometry (Berny) optimization. Geometry optimizations were performed using the B3LYP functional with the 6-31+G(d) basis set. Initially, the geometries of the monomers 5a and 6a were optimized using the same basis set. The optimized geometries of the monomers were utilized in constructing the geometries of the dimers D-5a and D-6a, which were further optimized. Further, the polymeric arrangements of 5a and 6a were obtained using many optimized geometries of dimers. The different polymeric arrangements of 5a and 6a were observed owing to different inter- and intramolecular interactions as described in the results section. The flow chart for the procedure as described above is given in the supporting information (Supplementary Information 2†). The vibrational frequency calculations for all the structures at the same level of geometry optimization were performed to characterize them as minima on the potential energy surface. The estimates of zero point energy values were scaled by 0.9806 before employing them in correcting the absolute energies. The charge analysis was carried out using the Natural Bond Orbital (NBO) method embedded in the Gaussian03 package. The Atoms in Molecules (AIM) method was employed to trace the bond paths associated with intra- and intermolecular interactions, using an AIM2000 software package. Several ring critical points and bond critical points were elucidated using the AIM method, indicating the inter- and intramolecular interactions. The energy and geometric parameters used in the discussion are from the B3LYP/6-31+G(d) method unless otherwise specifically mentioned.

Other physical methods. High resolution transmission electron micrographs were obtained on a Philips Technail 2 electron microscope at 120 Kv accelerating voltage. Compound 5a/6a was taken up in DMSO and aliquots were applied onto copper grids coated with carbon film (Quantifoil on 200 square mesh copper grid of hole-shape R 2/2) and after allowing to dry was mounted on the microscope for recording of the micrographs.

Differential scanning calorimetric thermograms were obtained on a Perkin Elmer Diamond DSC instrument equipped with a thermal analysis data station (Pyris software) at a heating rate of 5 °C min⁻¹. Measurements were carried out on samples after drying under vacuum. An aluminium sample pan after loading (sample weight, 2–3 mg) was closed by placing the lid over the sample in the pan and sealing. An empty pan with a lid served as a reference. The instrument was calibrated with an indium standard before starting the experiment. The area under the endotherm was converted to energy units with the help of thermal analysis software. The heat of transition has been expressed as J g⁻¹ dry wt.

Conclusions

Synthesis and characterization of a library of glycerotriazolophane-macrocycles with interesting self-assembling properties are described. The structure and properties of the compounds were rationalized by molecular modelling and quantum chemical analysis.

Acknowledgements

Financial support by the Council of Scientific and Industrial Research (CSIR), New Delhi (to MT) and the Department of Science and Technology (DST), New Delhi (to NT and PVB) is gratefully acknowledged.

References

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23. (a) AIM analysis (5a): BCPs were shown by a bond path connecting C–H⋯N1; bond critical point (BCP) is characterized by parameters typical to an intramolecular hydrogen bond, ρ_H–N = 0.051 × 10⁻¹, ∇² ρ_H—N = 0.047 × 10⁻¹. A similar C–H⋯N2 intramolecular hydrogen bond interaction is found characterized by similar values of ρ_H–N = 0.049 × 10⁻¹, ∇² ρ_H–N = 0.082 × 10⁻¹. There is also a ring critical point (RCP) (ρ = 0.038 × 10⁻¹) corresponding to a seven-membered ring formed due to these intramolecular hydrogen bond interactions.; (b) Though the distances indicate intramolecular hydrogen bond, AIM analysis does not indicate the presence of a bond critical point. Hence, this intramolecular interaction may have only electrostatic component; (c) AIM analysis (D-5a): The electron density at several bond critical points was observed, with the values of ρ_H–N = 0.038 × 10⁻¹, ∇² ρ_H–N = 0.032 × 10⁻¹. An intramolecular OH—N_triazole interaction was characterized by values of ρ_H–N = 0.34 × 10⁻¹ and ∇² ρ_H–N = 0.24 × 10⁻¹. The intramolecular hydrogen bond interaction between OH—O_ether was characterized by ρ_H–O = 0.30 × 10⁻¹ and ∇² ρ_H–O = 0.015 × 10⁻¹; (d) AIM analysis: (D-6a) The CH_triazole and N_triazole interactions showed characteristic bond critical point parameter values; ρ_H–N = 0.115 × 10⁻¹, ∇² ρ_H–N = 0.089 × 10⁻¹. Similar values were obtained for other CH_triazole⋯N_triazole intramolecular H-bond interaction, ρ_H–N = 0.115 × 10⁻¹, ∇² ρ_H–N = 0.089 × 10⁻¹.
24. See Supplementary Information 2 for more details.

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Footnote

† Electronic Supplementary Information (ESI) available: Images of polymeric structures of macromolecules and their SEM analysis; images of AIM analysis for 5a, 6a, D-5a, D-6a; Archive entries of all the optimized geometries; ¹H and ¹³C spectra of parent compounds synthesized. See DOI: 10.1039/c2ra21341a

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