Synthesis, insecticidal activity, structure–activity relationship (SAR) and density functional theory (DFT) of novel anthranilic diamides analogs containing 1,3,4-oxadiazole rings

Abstract

A series of anthranilic diamides analogs (5a–x) containing 1,3,4-oxadiazole rings were synthesized and characterized by ¹H NMR, ¹³C NMR and mass spectrometry. The structure of N-(4-chloro-2-methyl-6-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)methacrylamide (5u) was determined by X-ray diffraction crystallography. The insecticidal activities of these new compounds against diamondback moth (Plutella xylostella) were evaluated. Preliminary bioassays indicated that some of these compounds exhibited good insecticidal activities against P. xylostella, especially 3-bromo-N-(4-bromo-2-methyl-6-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (5d), which displayed 100%, 80.95% and 57.14% activity against P. xylostella at 40 μg mL⁻¹, 10 μg mL⁻¹ and 4 μg mL⁻¹, respectively. The relationship between structure and insecticidal activity was discussed. The density functional theory (DFT) studies could be helpful to understand the various insecticidal activities.

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Introduction

To discover a new type of environmentally friendly insecticide with high activity, low toxicity as well as low residue has become an urgent subject for science researchers. Recently, the emergence of commercial insecticides that target insect ryanodine receptors, i.e., the anthranilic diamides (Chlorantraniliprole¹ Fig. 1a and Cyantraniliprole² Fig. 1b), has inaugurated a new era of synthetic insecticides. The anthranilic diamides exhibit exceptional broad-spectrum, high activity and low toxicity. Especially, chlorantraniliprole, the first anthranilic diamide insecticide, accounts for its low mammalian toxicity and favorable environmental profile.³ They act by activating the insect ryanodine receptor, which is a non-voltage-gated calcium channel to affect calcium release from intracellular stores by locking channels in a partially opened state, an assignment based on electrophysiological and Ca²⁺-release studies.^4,5 Owing to their prominent insecticidal activity, unique mode of action, and good environmental profiles, anthranilic diamide analogues have attracted more and more interest in this field.

Fig. 1 Chemical structures of compounds a–e.

Generally, the chemical structure of anthranilic diamides could be characterized by three parts (Fig. 2a): an aromatic bridge moiety (A), a N-pyridylpyrazole amide moiety (B) and an aliphatic amide moiety (C). In the previous work, most modifications for chlorantraniliprole were related to part (A)^2,6–8 and part (B).^9–14 As for part (C), structural modifications, such as cyano,¹⁵ hydrazone,¹⁶ and heterocyclic groups,¹⁷ were reported. Recently, a novel pyrazolecarboxamide with a thiadiazole group in the ortho position (JS9117 Fig. 1c) has been reported with high insecticidal activity.¹⁸ Compound d (Fig. 1d) containing an oxazoline group reported by Kang et al. showed good larvicidal activity against beet armyworm (Spodoptera exigua),¹⁹ indicating that part (C) is attractive in further modifications. Considering the inspiring studies^17–19 and bioisosterism,²⁰ the aliphatic amide part (C) of anthranilic diamides could be concealed in the 1,3,4-oxadiazole ring (Fig. 2b), which is an efficient pharmacophore extensively used in pesticides and drug molecule design.^17,21–23 Therefore, we suggest that a high activity 1,3,4-oxadiazole, the possible bioisostere of the aliphatic amide, is introduced into the o-heterocyclic phenylformamide structure, which might attain the satisfying activity. Thus, it is worthy for us to explore the investigation.

Fig. 2 General structure of anthranilic diamides and design strategy of the target compounds.

According to frontier molecular orbital theory, HOMO and LUMO are the two most important factors that affect the bioactivities of compounds.^14,24–27 They establish the correlation in various chemical and biochemical systems.^28,29 Recently, Zhengming Li research group^14,24,26,27 and Xing-hai Liu research group^25,30 have reported studies on frontier orbital energy, which could provide useful information about the biological mechanism. Thus, DFT studies could possibly be used for insecticidal activity investigating.

Taking all these into account, we successfully designed and synthesized a series of new anthranilic diamides derivatives containing 1,3,4-oxadiazole. The single crystal structure of one target compound has been verified, which could stimulate a better understanding of the binding nature of these compounds, and might help explore new structures to enhance their biological activities. The larvicidal activities against Plutella xylostella (P. xylostella) were tested accordingly, and their preliminary structure–activity relationships were also discussed. Moreover, the DFT studies were used for the insecticidal activity investigating.

Results and discussion

Synthesis

The key intermediate 3 was synthesized from 2-amino-5-halo-3-methylbenzoic acid referring to the literature (Schemes 1, see ESI† for details).^17,31

Scheme 1 Reagents and conditions: (a) ClCOOEt, dioxane, reflux, ClCOCH₃, 55 °C; (b) 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride, anhydrous pyridine, anhydrous acetonitrile, 60 °C; (c) methacrylic anhydride/benzoic anhydride, pyridine, reflux.

The synthesis of final compounds 5 was accomplished by using the pathway illustrated in Scheme 2. The condensation reaction of compound 3 with the aromatic hydrazide compound in the presence of sodium hydroxide or potassium hydroxide, gave diacylhydrazine derivatives 4. Once the formation of compounds 4 reached completeness, triethylamine (TEA) and 4-methylbenzenesulfonyl chloride (PTSC) were charged to afford the final compounds 5.³²

Scheme 2 Reagents and conditions: (d) R₂CONHNH₂, NaOH, DMF, r.t.; (e) Et₃N, PTSC, DMF, r.t.

Through our study, we found that a suitable dehydrating agent played an important role in the cyclodehydration reaction of diacylhydrazines derivatives 4. Among the variety of available dehydrating agents, we tried trifluoroacetic anhydride (TFAA)³³ first, since their yields in other reported studies were lower than 20%. In addition, according to the literature,³² we chose PTSC, which is a non-toxic and cheap reagent. As was the case with the PTSC, the cyclodehydration reaction of diacylhydrazines derivatives 4 proceeded well at room temperature, giving isolated yields of up to 85.2% (Table 1).

Table 1 XPS parameters of the different contributions of Ni 2p_3/2 obtained for NiO–MoO₃/γ-Al₂O₃ sulphided at different temperatures

Cmpd.	Yield (%)	Cmpd.	Yield (%)	Cmpd.	Yield (%)
5a	80.4	5i	62.2	5q	47.2
5b	40.7	5j	43.5	5r	46.9
5c	73.0	5k	47.9	5s	20.7
5d	51.3	5l	61.6	5t	46.1
5e	77.2	5m	63.8	5u	45.1
5f	85.2	5n	51.2	5v	33.7
5g	67.1	5o	42.1	5w	28.3
5h	44.8	5p	31.7	5x	37.2

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Structure

The structures of all synthesized title compounds were confirmed by ¹H NMR, ¹³C NMR and mass spectrometry. The single peak appearing at the lowest field of δ 10.66–9.58 ppm in the ¹H NMR can be assigned to the aromatic amide hydrogen (–NH–C=O) of the target compounds. The chemical shift of Ph-CH₃ appears at δ 2.13–2.42. In addition, compound 5u was recrystallized from dichloromethane to give colourless crystals (0.30 mm × 0.20 mm × 0.10 mm) suitable for X-ray single-crystal diffraction with the following crystallographic parameters: a = 9.774(2) Å, b = 9.830(2) Å, c = 9.908(2) Å, α = 91.70(3)°, β = 110.52(3)° and γ = 106.41(3)°. The detailed crystallographic data for 5u can be found in the ESI (Table S1†). The single crystal structure diagram of 5u is shown in Fig. 3. The bond lengths of possible intramolecular hydrogen bonds (H3C⋯N1, H8A⋯O1, H13A⋯O2 and H13A⋯N3) were 2.36 Å, 2.39 Å, 2.51 Å and 2.49 Å, respectively. In addition, the intramolecular hydrogen bonds resulted in the formation of two planar pseudo rings A (C13/H13A/N3/C12/C11) and B (C8/H8A/O1/C6/C7), and two non-planar pseudo rings C (C13/H13A/O2/C14/N3/C12/C11) and D (N3/H3/N1/C6/C7/C12), which may be effective in the stabilization of the structure.³⁴ The bridge benzene ring (C7 to C12) and the terminal thiophene ring (C1/C2/C3/C4/S1) were connected with the 1,3,4-oxadiazole ring, which twisted 8.38° and 3.58°, respectively, and the three rings were almost located in the same plane. Meanwhile, in the molecular packing of 5u, offset face-to-face π-stacking interactions between neighbouring molecular 1,3,4-oxadiazole units are observed in Fig. 3 and the intermolecular distance is 3.72 Å. These crystallographic data might provide the basis for elucidating the effect on their biological activities.

Fig. 3 Molecular structure of 5u obtained from X-ray crystallography.

Biological activities and structure–activity relationships

The larvicidal activity of compounds 5a–x and commercial chlorantraniliprole against P. xylostella is summarized in Table 2. All of the compounds were initially tested at a concentration of 100 μg mL⁻¹, and consequently the compounds with high insecticidal potency were investigated further at lower concentrations. The bioassay results indicated that most of the compounds showed moderate to good insecticidal activities. Especially compounds 5d and 5h showed more than 57.14% and 52.38% larvicidal activities at the concentration of 4 μg mL⁻¹. Although it is difficult to find a specific structure–activity relationship from these data, they still appear to be following a general trend.

Table 2 Larvicidal activity against P. xylostella and physicochemical properties of compounds 5a–x

Cmpd	X	R1	R2	pKa^a	Log P^b	Larvicidal activity 3 d (%) at
						100 μg mL^−1	40 μg mL^−1	10 μg mL^−1	4 μg mL^−1	1 μg mL^−1
a Calculated pKa was predicted by using ACD/labs version 6.0.b Calculated log P (n-octanol/water partition coefficients) was predicted by using ChemBioOffice Ultra version 12.0 from CambridgeSoft Corporation.
5a	Br	N-Pyridylpyrazole	2-Thienyl	10.65	6.60	100.00	76.19	47.62	19.05	4.76
5b	Br	N-Pyridylpyrazole	Phenyl	10.66	6.62	100.00	85.71	52.38	28.57	4.76
5c	Br	N-Pyridylpyrazole	3-Pyridyl	10.63	5.28	90.00	77.78	57.14	28.57	23.81
5d	Br	N-Pyridylpyrazole	2-Pyrazinyl	10.60	4.37	100.00	100.00	80.95	57.14	38.10
5e	Cl	N-Pyridylpyrazole	2-Thienyl	10.65	6.33	86.36	76.19	23.81	0.00	0.00
5f	Cl	N-Pyridylpyrazole	Phenyl	10.66	6.35	100.00	95.45	60.00	4.76	0.00
5g	Cl	N-Pyridylpyrazole	3-Pyridyl	10.63	5.01	100.00	100.00	71.43	9.52	4.76
5h	Cl	N-Pyridylpyrazole	2-Pyrazinyl	10.60	4.10	100.00	100.00	71.43	52.38	4.76
5i	Br	Phenyl	2-Thienyl	11.84	5.37	5.56	—	0.00	—	—
5j	Br	Phenyl	Phenyl	11.85	5.39	18.75	—	0.00	—	—
5k	Br	Phenyl	3-Pyridyl	11.82	4.05	16.67	—	0.00	—	—
5l	Br	Phenyl	2-Pyrazinyl	11.79	3.14	28.57	—	0.00	—	—
5m	Cl	Phenyl	2-Thienyl	11.84	5.10	5.26	—	0.00	—	—
5n	Cl	Phenyl	Phenyl	11.85	5.12	16.67	—	4.76	—	—
5o	Cl	Phenyl	3-Pyridyl	11.82	3.78	47.62	—	4.76	—	—
5p	Cl	Phenyl	2-Pyrazinyl	11.79	2.87	66.67	—	0.00	—	—
5q	Br	Isopropenyl	2-Thienyl	12.08	4.51	4.76	—	0.00	—	—
5r	Br	Isopropenyl	Phenyl	12.10	4.53	4.76	—	0.00	—	—
5s	Br	Isopropenyl	3-Pyridyl	12.07	3.19	0.00	—	0.00	—	—
5t	Br	Isopropenyl	2-Pyrazinyl	12.03	2.28	18.75	—	4.76	—	—
5u	Cl	Isopropenyl	2-Thienyl	12.08	4.24	9.52	—	0.00	—	—
5v	Cl	Isopropenyl	Phenyl	12.10	4.26	0.00	—	0.00	—	—
5w	Cl	Isopropenyl	3-Pyridyl	12.07	2.92	16.67	—	4.76	—	—
5x	Cl	Isopropenyl	2-Pyrazinyl	12.03	2.00	4.76	—	0.00	—	—
Chlorantraniliprole				10.77	4.26	100.00	100.00	100.00	100.00	100.00

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From Table 2, we can see that at the concentration of 100 μg mL⁻¹, N-pyridylpyrazole group substituted compounds 5a–h showed 86.36–100% larvicidal activities against Plutella xylostella, phenyl group substituted compounds 5i–p exhibited 5.26–66.67% activities, and isopropenyl group substituted compounds 5q–x possessed 0.00–16.67% activities, respectively. When the concentration of the test compounds was reduced to 10 μg mL⁻¹, most of N-pyridylpyrazole group substituted compounds (5a–h) could still exhibit better mortality against P. xylostella, for example, 5d displayed 80.95% mortality, 5g and 5h possessed 71.43% larvicidal activities. This revealed that the compounds with N-pyridylpyrazole could show a much more remarkable mortality than the compounds with a phenyl group or an isopropenyl group. This may be due to the more hydrophobic nature of N-pyridylpyrazole group, resulting in an appropriate overall log P value (around 5). Moreover, the appropriate ionization constants (pK_a 10.60–10.65), which were close to the value of chlorantraniliprole (pK_a 10.77), also contributed to drug absorption.³⁵ To understand which substituent on the bridge benzene ring appears to be more active in larvicidal activity, the benzene ring was fixed as Cl or Br. As illustrated in Table 2, structure–activity relationship of all compounds, where X varied as Cl or Br, suggested the trend Cl ≈ Br.

Moreover, to investigate the influence of different substitutions on the 1,3,4-oxadiazole ring, 2-thienyl group, phenyl group, 3-pyridyl group and 2-pyrazinyl group were introduced into R₂. Although it is hard to construct a clear structure–activity relationship from the data shown in Table 2, we can also conclude that the general trend in larvicidal activity is 2-pyrazinyl group > 3-pyridyl group > phenyl group > 2-thienyl group. For example, at the concentration of 10 μg mL⁻¹, compound 5a (R₂ = 2-thienyl group, log P = 6.60), 5b (R₂ = phenyl group, log P = 6.62), 5c (R₂ = 3-pyridyl group, log P = 5.28) and 5d (R₂ = 2-pyrazinyl group, log P = 4.37) exhibited 47.62%, 52.38%, 57.14% and 80.95% activity against P. xylostella, respectively. This revealed that the introduction of electron-withdrawing and weak hydrophobic substituents R₂ might contribute to the insecticidal activity increase against P. xylostella. In addition, when the concentration was reduced to 4 μg mL⁻¹ and 1 μg mL⁻¹, 5d displayed 57.14% and 38.10% mortality. This result implied that the 1,3,4-oxadiazole connected pyrazinyl group might be a potential pharmacophore against P. xylostella.

DFT calculation

The frontier molecular orbitals play an important role in several chemical and pharmacological processes.³⁶ HOMO (Highest Occupied Molecular Orbital) has the priority to provide electrons, whereas LUMO (Lowest Unoccupied Molecular Orbital) accepts electrons first.^37,38 Thus, study of the frontier orbital may help in the insecticidal activity investigating. Three compounds (5a, 5d and 5t) having relatively greater difference in activity were selected for DFT comparison.

The optimized geometry corresponding to the minimum of the potential energy surface has been obtained by solving the self-consistent field equation iteratively. Generally, the compounds 5a, 5d and 5t showed that the phenyl ring was not coplanar with the 1,3,4-oxadiazole ring; while the R₂ group was nearly planar with the 1,3,4-oxadiazole ring. The pyridyl group showed a deviation from the pyrazolyl group. The detailed geometrical parameters of the compounds calculated can be found in the ESI (Tables S2–S4†).

LUMO and HOMO energies and HOMO−LUMO (H−L) Gaps (in eV) of 5a, 5d and 5t are listed in Table 3. Comparing the H-L gap of the three molecules, the order was: 5t > 5a > 5d. The narrow HOMO−LUMO gap implies a high chemical reactivity because it is energetically favorable to add electrons to a low-lying LUMO or extract electrons from a high-lying HOMO, and so to form an activated complex in any potential reaction.³⁹ This suggested that compound 5d might possess a relatively high activity, which correlated well with our experimental results. The HOMO and LUMO maps are shown in Fig. 4. In the HOMO of 5a, 5d, and 5t, electrons are mainly delocalized on the benzene ring (including those of the bromine atom), the amide bridge and 1,3,4-oxadiazole ring; in addition, electrons are also delocalized on R₁ and R₂ groups in varying degrees. When electron transitions take place, some electrons in the HOMO will enter into the LUMO;²⁶ then, in the LUMO of 5a, 5d, and 5t, the electrons were similarly delocalized on three aromatic rings (1,3,4-oxadiazole ring and two aromatic rings attached to it). The different electron distributions among 5a, 5d, and 5t may possibly cause the large difference in larvicidal activity.

Table 3 LUMO and HOMO energies and HOMO–LUMO (H–L) gaps (in eV) of 5a, 5d and 5t

	R1	R2	HOMO	LUMO	H–L gaps
5a	N-Pyridylpyrazole	2-Thienyl	−6.30	−2.16	4.14
5d	N-Pyridylpyrazole	2-Pyrazinyl	−6.47	−2.53	3.94
5t	Isopropenyl	2-Pyrazinyl	−6.53	−2.32	4.21

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Fig. 4 LUMO and HOMO maps for compounds 5a, 5d and 5t from DFT calculations. The green parts represent positive molecular orbitals, and the red parts represent negative molecular orbitals.

The amide bridge group can be observed in the HOMO maps of three molecules (5a, 5d, and 5t). The amide bridge can play an important role in insecticidal activity through hydrophobic interactions.¹⁴ Although exact binding site(s) on insect ryanodine receptor have not been confirmed and are still unclear, researchers found that the hydrophobic C-terminal domain of the RyR 1 protein had a strong effect on the properties of the calcium release channel.⁴⁰ Thus, the distribution of the frontier orbitals may be related to the hydrophobic interaction of the molecule with the target receptor.

As Fig. 4 shows, in HOMO maps, three molecules showed different degrees of electron delocalization. The general trend according to electron delocalization was 5t > 5a > 5d, which represented a negative correlation with their insecticidal activity. As reported,^14,24,27 the frontier molecular orbitals are located on the main groups, the atoms of which can easily bind with the receptor. Moreover, the different degrees of delocalization may affect the orbital interaction.⁴¹ Thus, it seemed that the high electron delocalization of 5t or 5a in HOMO might possibly make the orbital interactions limited, which might bring about a decrease in activity. In addition, the orbital interactions between selected compounds (5a, 5d and 5t) and a side of residue chains of receptors might be dominated by hydrophobic interactions of the amide bridge among the frontier molecular orbitals.

Materials and methods

Analytical methods

Unless otherwise mentioned, reagents were purchased from commercial suppliers like Aladdin, Energy Chemical and Sinopharm Chemical Reagent Co., Ltd. and they were used without further purification, while all solvents were redistilled before use. Analytical thin layer chromatography was performed on silica gel GF254. Silica gel (200–300 mesh) was used for flash column chromatography. Melting points (mp) were taken on an X-4 microscope electrothermal apparatus (Taike China) and were uncorrected. The nuclear magnetic resonance (¹H NMR and ¹³C NMR) spectra were recorded on a Bruker AV-100 spectrometer at 100 MHz or a Bruker AV-400 spectrometer at 400 MHz, using CDCl₃ or DMSO-d₆ as the solvent, with tetramethylsilane (TMS) as an internal standard. Mass spectra were recorded with an Agilent 1100 Series LC/MSD Trap SL. The synthetic procedures, detailed characterization data of intermediates 3a–f and different amidoximes can be found in the ESI.†

Chemical synthesis

General procedure for the synthesis of compounds 5a–x. A mixture of 3a–f (20.0 mmol), solid aromatic hydrazide compound (24.0 mmol) and N,N-dimethylformamide (100 mL) was stirred at r.t. for 15 min. Then, solid sodium hydroxide (10.0 mmol) was added into the solution. Once the formation of intermediates 4a–x reached completeness, more liquid triethylamine (2 equiv.) and solid 4-methylbenzenesulfonyl chloride (3 equiv.) were charged to afford the pyrazinyl group substituted 1,3,4-oxadiazole rings. The mixture was poured into 500 mL saturated sodium bicarbonate solution. The solid was filtered, washed with water, and dried to afford solid 5a–x. The crude product was purified by flash chromatography.

X-ray diffraction crystallography. A suitable single crystal of compound 5u was obtained by dissolving the compound in dichloromethane and evaporating the solvent slowly at r.t. for about 7 d. The diffraction data were collected on a Nonius CAD4 single crystal diffractometer with graphite-monochromated MoKα radiation (λ = 0.71073 Å) by using a ω/2θ scan mode at 293 K. The crystal structure was solved by the direct method and refined by the full-matrix least-squares procedure on F² using the SHELXL-97 program.⁴² All non-hydrogen atoms were refined anisotropically, and hydrogen atoms were introduced at calculated positions.

Insecticidal activities assay. The larvicidal activities of the title compounds (5a–x) against Plutella xylostella were evaluated by a dipping method according to literature procedures.⁴³ Cabbage leaf disks (8 cm in diameter) were dipped into a test solution for 10 s and air-dried on filter paper. The treated diet was released into the Petri dish, and twenty-one third-instar P. xylostella were released into the Petri dish. P. xylostella affected by this treatment were assessed for 3 days after the treatment.

P. xylostella with abnormal symptoms such as body contraction, feeding cessation, or paralysis were included in the number of dead.⁴³ The results are listed in Table 2, in which the mortality percentage was expressed as the mean of values obtained in three independent experiments. Chlorantraniliprole, the lead compound, was used as a control.

Computational methods. The structures of compounds 5a, 5d and 5t were selected as the initial structures, whereas the DFT-B3LYP/6-31G*^44–50 method in the Gaussian 09 ⁵¹ package, used to optimized structures, was in accordance with the minimum points on the potential energy surfaces. pK_a was predicted by using ACD/labs version 6.0.⁵² Log P (n-octanol/water partition coefficients) was predicted by using ChemBioOffice Ultra version 12.0 from CambridgeSoft Corporation.⁵³ All calculations were carried out on the supercomputer in Nanjing Tech University.

Conclusions

In summary, a series of new anthranilic diamide analogs containing a substituted 1,3,4-oxadiazole ring was designed and synthesized. Preliminary bioassays indicated that some of the compounds showed good larvicidal activities against P. xylostella. In particular, compounds 5d against P. xylostella were 57.14% and 38.10% active at 4 μg mL⁻¹ and 1 μg mL⁻¹, respectively. The preliminary structure–activity relationship (SAR) of the title compounds indicated that compound attached N-pyridylpyrazole showed a much more remarkable mortality than compound attached phenyl group or isopropenyl group. The compounds with electron-withdrawing and weak hydrophobic substituents on the 1,3,4-oxadiazole ring can display better insecticidal activity than others. In addition, through density functional theory (DFT) studies, it seemed that the high electron delocalization of 5t or 5a in HOMO might possibly make the orbital interactions limited, which might bring about a decrease in activity. Furthermore, the orbital interactions between the selected compounds (5a, 5d and 5t) and a side of residue chains of the receptors might be dominated by hydrophobic interactions among the frontier molecular orbitals. With the expectation of finding more new 1,3,4-oxadiazole containing anthranilic diamide analogs, further structural optimization and larvicidal activity tests are under way.

Acknowledgements

This work is financially supported by the National key technology R&D program of the Ministry of Science and Technology (2011BAE06B01-11), the Technology R&D Program of Jiangsu province (BE2012363), and the Postgraduate innovation fund of Jiangsu province (2013, CXLX13_399). We thank Jiangsu Pesticide Research Institute Co., Ltd. for the test of biological activities.

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Footnote

† Electronic supplementary information (ESI) available: Characterization data of compounds 5a–x, general synthetic methods and schemes for intermediates 3a–f, crystal and structure refinement data of compound 5u, ¹H NMR spectra and mass spectra for all target compounds 5a–x, and the data for DFT calculation. CCDC 990869. See DOI: 10.1039/c4ra06356b

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