Fragmentation of pure and hydrated clusters of 5Br-uracil by low energy carbon ions: observation of hydrated fragments

M. C. Castrovilli a, P. Markush a, P. Bolognesi a, P. Rousseau b, S. Maclot b, A. Cartoni ac, R. Delaunay b, A. Domaracka b, J. Kočišek bd, B. A. Huber b and L. Avaldi *a
aCNR-ISM, Area della Ricerca di Roma 1, Monterotondo Scalo, Italy. E-mail: lorenzo.avaldi@ism.cnr.it
bNormandie Université, ENSICAEN, UNICAEN, CEA, CNRS, CIMAP, 14000 Caen, France
cDipartimento di Chimica, Sapienza Università di Roma, Roma, Italy
dJ. Heyrovský Institute of Physical Chemistry, The Czech Academy of Sciences, Prague, Czech Republic

Received 6th April 2017 , Accepted 8th June 2017

First published on 13th June 2017


The fragmentation of the isolated 5-bromouracil (5BrU) molecule and pure and nano-hydrated 5BrU clusters induced by low energy 12C4+ ions has been studied. A comparison indicates that the environment, on the one hand, protects the system against the complete break-up into small fragments, but, on the other hand, triggers ‘new’ pathways for fragmentation, for example the loss of the OH group. The most striking result is the observation of several series of hydrated fragments in the hydrated cluster case, with water molecules bound to hydrophilic sites of 5BrU. This highlights the strong interaction between 5BrU and water molecules and the blocking of specific fragmentation pathways, such as the loss of the BrC2H group for example.


1. Introduction

Exposure of living organisms to ionizing radiation causes alterations that begin at the DNA level1,2 and evolve in biological malfunctioning as well as mutations and cellular death. On the other hand, the same pathogenic effects of radiation damage are proficiently used in radiotherapy for cancer treatment. The major drawback in radiotherapy is the production of unselective damage in both tumour and healthy cells, with significant side effects for the patients. This led to the search for new strategies with targeted drugs, the radiosensitizers,3–7 that can enhance the lethal effects of radiation specifically on tumour rather than on normal cells.

Among the different classes of radiosensitizers, the halosubstituted pyrimidinic bases and their nucleosidic analogues have reached the stage of clinical trials.8–11 Their effectiveness12 has been attributed to different processes: (i) intense cascade of Auger electrons triggered by the removal of deeply bound core electrons from the halogen atom13,14 (ii) secondary damage due to the emission of low energy electrons15 and the production of reactive radicals from the surrounding medium16,17 (iii) ‘peculiar’ fragmentation processes.18 Among halopyrimidine nucleobases, 5-bromouracil (5BrU)19,20 is the fundamental building block of bromo-deoxyuridine that, thanks to the similar steric hindrance of the Br atom and the methyl group, can replace thymine in the DNA of fast replicating tumour cells, where it ‘selectively’ introduces harmful effects such as mutagenesis21 and radiosensitization.22,23

The fragmentation of isolated 5BrU molecules has been investigated via theoretical calculations24,25 as well as using proton,26 multiply charged ion,26,27 photon28 and electron impact29,30 experiments. Gas phase studies of biomolecules have an important value, as they allow accessing the intrinsic properties of the molecules, free from effects due to the presence of solvents or different types of substrates.31–33 Nevertheless, this fundamental understanding needs to be extended towards more realistic biomolecular systems, to unveil ‘how’ the intrinsic molecular properties are affected by the surrounding medium when the biomolecule is incorporated into a natural environment.34–40 In the present work, we have investigated the 36 keV 12C4+ ion induced fragmentation of 5BrU embedded in clusters of molecules of the same species (pure clusters) or with bound water molecules (nano-hydrated clusters). Both situations mimic ‘realistic’ biological media, because of the planar bonding of nucleobases in the cluster,34,35 similar to the base pairing configuration in DNA, as well as the presence of water, the main constituent of human bodies.

2. Experimental methods

The experiments were performed in a crossed beam set-up where a 36 keV energy 12C4+ ion beam interacts with a neutral molecular target beam. The COLIMACON apparatus has been described previously41,42 and here only the information relevant to the present measurements is reported. The ion beam is produced by an electron cyclotron resonance ion source at ARIBE, the low-energy ion beam facility of GANIL (Caen, France).43 The projectile beam is pulsed in bunches of a 500 ns temporal width, transported and focused in the interaction zone of the apparatus where it collides with the target beam of free molecules/clusters.

The cationic products of the interaction are extracted into a Wiley-McLaren time-of-flight (TOF) spectrometer and detected with constant efficiency over a wide mass range thanks to a Daly-type detector.44 After the field-free region of the spectrometer, the cations are post-accelerated impacting a conversion plate leading to the emission of secondary electrons, which are then deflected by a weak magnetic field towards a microchannel plate detector giving the time-of-flight signal. This signal is digitized using a time-to-digital converter with multi-hit capability for ion–ion coincidence measurements.

Two different types of neutral target beams have been produced via independent sources, using commercial powder of 5BrU with 98% purity (Aldrich): (i) an effusive beam of isolated molecules is obtained by heating at 170 °C a molybdenum oven located 20 cm away from the interaction region; (ii) clusters are formed in a gas aggregation source45 mounted on the opposite side of the interaction zone, where an oven is resistively heated at 250 °C, and carried through a liquid nitrogen cooled condensation channel by a flow of He buffer gas. The long residence time (ms timescale) in the condensation channel produces the cooling of the clusters at a temperature between 80–100 K by collisions with the He buffer gas. Two skimmers define a differential pumping stage and collimate the cluster beam through the interaction zone. The interaction zone itself is surrounded by a liquid nitrogen cooled trap that prevents contamination of the apparatus. The gas aggregation source produces a log-normal distribution of neutral clusters. Under the usual conditions, the formation of small clusters (monomers, dimers, trimers) is small. The maximum usually occurs at a few tens (30–50) of molecules. The observed monomers, dimers and trimers are fragments of larger clusters as shown by the peak width. In order to produce hydrated species, a mixture of He/H2O flows into the condensation channel with the 5BrU molecules. The water vapour pressure is obtained by heating purified water (>18 MOhm cm) under primary vacuum at 55–60 °C.

3. Results and discussion

In this work, we follow previous studies on 5BrU26–30 as well as our previous study on uracil (U)34 as for the assignment of the peaks and only highlight the features relevant to the present discussion. In Sections 3.1 and 3.2 the new results are discussed in terms of the role of the environment and the observation of several series of hydrated fragments, respectively. Along the text, the mass over charge ratio (m/z) is given in units of amu and the m(m + 2) notation indicates the isotopic contribution of Br containing fragments of mass m.

The mass spectra of 5BrU (C4H3N2O2Br, m/z 190(192)), considered as an isolated molecule or embedded in the environment provided by pure and nano-hydrated clusters, are shown in Fig. 1 for the m/z region up to the monomer.


image file: c7cp02233f-f1.tif
Fig. 1 Mass spectra of 5BrU molecules after collisions with 36 keV C4+ ions in the m/z region up to the monomer (M+): (a) isolated molecule (b) pure 5BrU clusters and (c) hydrated 5BrU clusters. Singly charged fragments containing the Br atom display the typical 79Br(81Br) isotopic structure and are highlighted as green areas in (a). The peaks belonging to the protonated water clusters (H2O)nH+ and hydrated [HCNH/CO](H2O)nH+ series are indicated in (c).

The well resolved and high intensity feature at m/z 147(149) represents the BrC3ONH2+ fragment ion, due to the HNCO (m/z 43) loss from the parent ion. The relative intensity of this fragment is significantly larger than that of the ‘equivalent’ fragment in U (C3ONH3+m/z 69)34 suggesting a more likely ring breaking due to the HNCO loss in 5BrU. There are three possible fragmentation pathways for its formation and, depending on the location of the bond breakage, a second HNCO loss is possible, leaving the BrC2H+ fragment at 104(106). Its complementary charged part, 2(HNCO)+ with m/z 86, is not observed. Several fragmentation pathways are possible: (i) the species is ejected as a neutral moiety, (ii) two steps or the concerted loss of separate charged/neutral fragments, (iii) fragment m/z 86 decays further, likely into two HNCO species. The last assumption is supported by the high intensity of the HNCO+ fragment ions in the mass spectrum.

The BrC2NH+ and BrC2OH+/BrC2NH3+ fragment ions are responsible for the features at m/z 118(120) and 120(122), respectively, where the peaks at m/z 120(122) can only be explained by the intramolecular hydrogen migration towards O7, to give BrC2OH+, or N1, to give BrC2NH3+, see Fig. 2 and ref. 27. In comparison with the 5BrU case, the ‘equivalent’ patterns in U are at m/z 40 and 4234 and can be attributed to fragments that may or may not involve H migrations. This provides evidence that the isotopic peculiarity of the halogen atom can be exploited to reveal intramolecular processes, like the H migration before fragmentation.


image file: c7cp02233f-f2.tif
Fig. 2 The different processes leading to the fragments at m/z 118(120) (process 1 in a) and 120(122) (processes 2 in a and 3 in b).

The features at m/z 91–94 and 79–82 are assigned to the CBr+–CBrH+ and Br+–BrH+ fragments, respectively. In all cases, the peaks are broader than the other Br containing fragments, indicating that a large amount of kinetic energy is released in their formation.26 The H migration to the Br atom is likely to originate from the N3 site according to the photoelectron–photoion coincidence (PEPICO) results of Itälä et al.46

As in the U34 case in the smallest m/z region, several low intensity peaks can be clearly and unambiguously attributed to doubly charged ions. This is the case for the atomic species at m/z 6 [C2+], 7 [N2+], 8 [O2+] and fragments characterized by non-integer m/z values, such as 59.5(60.5) [BrC2O2+/BrC2NH22+], 39.5(40.5) [Br2+] and 35.5 [C2H3N2O2+].27 Interestingly BrC2O+/BrC2NH2+ is absent in the mass spectrum, which indicates that either this fragmentation pattern is not open or undergoes fragmentation following its formation. The formation of doubly charged fragments is not observed in electron and photon impact experiments. Thus it seems to be a peculiarity of the multi electron capture occurring in the ion collision experiments.47–49

3.1. The role of the environment

The mass spectra of pure and nano-hydrated clusters in the m/z region up to the monomer are shown in Fig. 1b and c, respectively. Typical characteristics of the cluster spectra are the broad peak shapes, due to a large amount of kinetic energies involved in the fragmentation process of clusters and successive monomer evaporation occurring in the cluster, as well as to the presence of protonated species. Important differences in the relative intensity of some fragments, new fragmentation pathways as well as the presence of hydrated fragments in the nano-hydrated cluster spectrum (Fig. 1c) can immediately be observed.

In Fig. 1b and c the parent ion is represented by a broad feature where the contribution of the two Br isotopes is no longer resolved due to the presence of protonated species with a protonated/unprotonated ratio of 1.83 and 0.75 for pure (Fig. 1b) and nano-hydrated (Fig. 1c) clusters, respectively.

The new fragment centred at m/z 174 in the pure cluster mass spectrum can be assigned to [MH − OH]+. In the case of clusters of U34 and other DNA bases,35 this fragment ion can be associated with the fragmentation of a cluster in a planar configuration with hydrogen bonds between two adjacent O and H atoms. Its assignment to the [MH − NH3]+ channel due to the fragmentation of the protonated molecule, MH+, with sufficient internal energy, has also been considered, as pointed out by the joint theoretical and experimental results of collision induced dissociation studies of protonated U produced by electrospray ionization.50–52 However, this pattern would invoke the presence of a tautomeric form different from the canonical keto–eno and not likely to exist in the gas phase. Therefore, also in view of the large width of the feature, we consider the assignment of the m/z 174 feature as more likely related to the OH loss from cluster fragmentation.

The new fragment centered at m/z 84 can be assigned to [MH − BrCO]+ or [MH − H2CNBr]+, suggesting the Br atom to be involved in hydrogen bonding of the cluster network. This assumption is consistent with the decreased intensity of the Br+/HBr+ (m/z 79–82) and BrC2H+ (m/z 104(106)) fragments and the increased intensity of the [MH − Br]+ fragment (m/z 112) in the pure cluster spectrum (Fig. 1b) compared to the isolated 5BrU molecule (Fig. 1a), where the behaviour of these features is opposite.

Another fragmentation pathway that is inhibited by the presence of the environment is the loss of N2CO, responsible for the peaks at m/z 134(136) in Fig. 1a, which disappear in the mass spectrum of the cluster (Fig. 1b). This emphasizes the involvement of oxygen and nitrogen atoms in the hydrogen bonding between the molecular species.

In the region of light masses, the number and relative intensity of the peaks in the pure cluster spectrum is smaller compared to the isolated molecule, suggesting a “protective effect” against the monomer fragmentation due to the intermolecular environment. This phenomenon, already observed in the ion induced fragmentation of amino acids and other biomolecules,36,38 can be explained considering that the energy transferred in the collision with the cluster can be dissipated by breaking hydrogen bonds among monomers. Conversely, in the isolated molecule the only way to dissipate the energy is the fragmentation and/or molecular rearrangement of the molecule itself. No evidence of doubly charged fragments is observed in the mass spectra of the clusters as their larger size and higher charge mobility allow efficient charge redistribution, contributing to the “protecting effect” of the environment.39

In Fig. 3 the mass spectra of pure and nano-hydrated cluster ions are reported versus their size/charge ratio, k/z. These spectra do not show any evidence of doubly charged species or magic numbers in the cluster fragmentation as the intensity of the peaks decreases monotonically. This is likely due to the limited cluster size observed in the present experiments, compared with the long progression detected in the U case.34 Both pure and nano-hydrated cluster spectra display the [5BrUk–Br]+channel (and its protonated equivalent) for k up to 8, providing further evidence of the Br atom involvement in hydrogen bonding in the cluster, with a correspondingly low amount of Br atom released (see Fig. 1).


image file: c7cp02233f-f3.tif
Fig. 3 The 12C4+ ion induced mass spectra of nano-hydrated (a) and pure (b) 5BrU clusters versus their size/charge ratio, k/z. The series of fragment ions due to the Br loss is indicated by vertical bars. In the insets, an expanded view of the region between the monomer and the dimer is shown.

Except for the dimer, larger clusters that have lost more than one Br atom are not observed. The inset of Fig. 3 shows that the region between the monomer and the dimer is congested with the presence of higher n terms of hydrated fragment series observed below the monomer (see also Fig. 1c), a few terms of the hydrated monomer as well as fragments originating from larger clusters. Due to the large number of possible contributions a complete assignment of all the features cannot be proposed for this region.

3.2. Formation of hydrated fragments

The most striking characteristic of the mass spectrum of the nano-hydrated clusters is the presence of several features separated by 18 amu and assignable to a series of hydrated fragments, i.e. molecular fragments bound to an increasing number, n, of water molecules. All the other fragments that are also observed in the pure cluster case have smaller intensities, unless they accidentally overlap with a member of a hydrated series.

According to the theoretical predictions by Wang et al.53 and Hu et al.54 for the U and 5BrU molecules, respectively, three hydrophilic, hydration sites exist in 5BrU where the water molecules can form two H-bonds, namely the regions of N1–C2, C2–N3 and N3–C4 (see Fig. 2 for the numbering of atoms). However at variance with the U case, in 5BrU due to the steric hindrance by the Br atom the regions C4–C5 and C5–C6 are precluded.

In our case the first series observable in Fig. 1c is the one due to protonated water clusters [H2O](H2O)nH+ at m/z 19, 37, 55, 73 and 91 for n = 0–4.

In the same region, the [HCNH/CO](H2O)nH+ hydrated series built on the [HCNH/CO] molecular fragment can be observed (Fig. 1c). Similar to the water case, this series turns out to be protonated because the first member at m/z 47 can only be obtained by adding a protonated water molecule (H2O)H+. Higher members of the series can be observed at m/z 65, 83, 101 and 119 with a maximum of 5 water molecules.

It is important to mention that peaks in the spectrum are completely resolved up to m/z 73. Above that, the peaks broaden with asymmetric line shapes and shoulders that hint to the presence of several contributions as shown in Fig. 4, where the region m/z 115–235 is reported. In this region we can assign peaks to the protonated hydrated series of [BrC3ONH2] 147(149), [BrC2NH] 118(120), [BrC2N] 117(119), [BrC4N2H2O] 173(175), [BrC2O/BrC2NH2] 119(121) and [C4N2O2H2] (110) fragments, the formation of which is already observed in the isolated molecule. A fitting procedure has been established to disentangle the different contributions to each feature of the spectrum. In this procedure, all the possible fragments, m+, that can contribute to the selected m/z peak are identified; for each [m]+, its protonated, [m]H+, and hydrated and protonated, [m](H2O)nH+, fragments have been taken into account, while the contribution due to hydrated (but not protonated) charged fragment, [m]+(H2O)n, was not observed and therefore not included in the analysis. In this fitting procedure, each peak has been represented by a Gaussian function, the Br isotopic distribution was also included and each fragment and its respective protonated form were constrained to equal width. Kinetic energy values for different members of hydrated series were in the range 0.2–3.4 eV (Fig. 5a).


image file: c7cp02233f-f4.tif
Fig. 4 The 36 keV 12C4+ ion induced mass spectrum of the nano-hydrated 5BrU clusters in the m/z region between 115 and 235. The peaks belonging to hydrated series of protonated [BrC3ONH2] 147(149), [BrC2NH] 118(120) and [BrC2N] 117(119) fragments are indicated in (a) and the ones belonging to the hydrated series of protonated [BrC4N2H2O] 173(175), [BrC2O/BrC2NH2] 119(121) and [C4N2O2H2] (110) fragments in (b).

image file: c7cp02233f-f5.tif
Fig. 5 Best fit of the two features of the nano-hydrated cluster spectrum centered at m/z 156 (a) and 174 (b) with the contribution of the several hydrated fragments. In (b) the assignment is achieved by adding one water molecule to the series observed in (a) and by the introduction of three new fragments ([MH − H2O]+,51 [MH − OH]+/[M − O]+ and [MH − O]+/[M − O]H+).

Fig. 5 shows the example of the deconvolution procedure of two features in the mass spectrum of the nano-hydrated clusters, whose centers of mass are separated by 18 amu and therefore can be associated with the same hydrated fragments series.

The contributions due to the [BrC2NH](H2O)2H+, [BrC2N](H2O)2H+ and [BrC2NH2/BrC2O](H2O)2H+ ions determine the observed lineshape of the feature centred at m/z 156. The same three contributions with an additional water molecule contribute to the feature at around m/z 174. However, in order to achieve a reasonable representation of this last feature other peaks due to the loss of O, OH and H2O51 from the protonated monomer have to be considered. A complete list of all the protonated hydrated series disclosed and considered in the fitting procedure is shown in Table SI.1 of the ESI.

The intensity distributions of the different members of the most relevant series have been reported on a logarithmic scale together with their linear fitting, in Fig. 6, versus the number of bound water molecules, n. In the cases of the protonated water clusters, [HCNH/CO], [BrC3ONH2], [BrC4N2H2O], [BrC2N], [BrC2NH], [BrC2O] and [C4N2O2H2] protonated and hydrated fragments the intensities display a decay well represented by an exponential function, which supports the present assignments to series of hydrated fragments formed in the fragmentation of 5BrU nano-hydrated clusters. In the case of protonated water clusters (Fig. 6a) there is no clear evidence of magic numbers. Therefore, considering that the term n = 4 is well known to be a magic number in the fragmentation of pure water clusters,55 we deduce that their formation in our experiment is dominated by the fragmentation of mixed 5BrU–water clusters, even though the presence of pure water clusters cannot be excluded due to the unselected nature of the cluster source. The intensity distribution shows a different behavior for the [C4O2N2H2](H2O)2H+ hydrated series, Fig. 6h, which cannot be represented by a single decay component. This could be explained by the contribution of three different hydrophilic sites, each one with its own probability that could be involved in the formation of these hydrated fragments.


image file: c7cp02233f-f6.tif
Fig. 6 The exponential decays of the areas of the peaks used for the deconvolution of the spectrum reported in Fig. 5 (see the text) and corresponding to the protonated water clusters (a) and hydrated fragment (b–h) series. The peaks corresponding respectively to three water molecules (a–f) and two water molecules (g) have not been included in the fitting procedure. Results of the fittings are shown by red curves. The intensity distribution shows a different behavior in (h), likely because the three different hydrophilic sites can be involved in the formation of the hydrated fragments. The insets show the possible fragmentation pathways and the probable hydrophilic sites are indicated by the arrows.

In the region above m/z 235 the identification of the hydrated fragments series becomes more uncertain due to the large number of possibilities for the relative contributions, which may also derive from the fragmentation of larger clusters.

The absence in the nano-hydrated cluster spectrum of the m/z 104(106) fragment due to BrC2H+, see Fig. 1, suggests that the presence of water molecules inhibits this fragmentation channel. Van Mourik et al.56 and Hu et al.54 showed that the water molecules do not access the region between the Br and O7 atoms because of the steric hindrance of the halogen atom. For the same reason, it is reasonable to assume that the region between the Br and C6 is not accessible to the water molecules too. This would prevent the formation of the BrC2H hydrated series.

The observation of hydrated fragments, even though more sporadic, was already reported in the ion induced fragmentation of nano-hydrated clusters of U34 and in the photodissociation of protonated and hydrated leucine-enkephalin (Leu-Enk) peptide dimers, i.e. the [2Leu-Enk + 3H2O + H]+ precursors.57 As already observed in the U nano-hydrated clusters34 the hydrated fragments may originate from a non-statistical process, perhaps associated with a localized energy deposition in the 5BrU molecule followed by ultrafast dissociation that prevents the energy redistribution leading to water molecule evaporation. The observation of hydrated fragments shows that the cleavage of covalent molecular bonds is preferred with respect to the breaking of intermolecular hydrogen bonds with evaporation of water molecules from the cluster. In such a case the presence of the water molecules would be only ‘instrumental’ to the observation of this ultrafast process. The weakening of the molecular bonds might also be due to the perturbation of the charge distribution of the 5BrU molecule induced by the water. This would suggest an active role in the charge localization due to the water environment. In any case, the observed ‘non-statistical’ fragmentation leading to the formation of hydrated fragments seems to play a much more relevant role in the halosubstituted than in the natural U base.34 Indeed, while only the [HCNH/CO] hydrated fragment series was observed in the U case, at least seven different series (see Fig. 1c and 5) are identified in 5BrU, leading to the conclusion that intramolecular fragmentation seems to be more efficient than intermolecular fragmentation in 5BrU with respect to U. This is consistent with the larger ‘fragility’ of 5BrU upon radiation exposition, as might be expected for a radiosensitizer.

4. Conclusions

We have investigated the fragmentation processes occurring during the interaction of 12C4+ ions with 5BrU molecules as well as their alteration due to the presence of an environment that, in the form of pure and nano-hydrated 5BrU clusters, mimics a ‘realistic’ biological medium.

The effects of intermolecular environments have been unravelled by the comparison of the mass spectra of the molecule considered as isolated or embedded in clusters. It is observed that on the one hand the environment has an overall ‘protecting’ effect reducing the formation of small fragments as well as the release of Br cations and, therefore, reducing the damage to individual molecules. On the other hand, it is also responsible for the opening of new fragmentation channels and the formation of new species as a result of the altered molecular bonding conditions. A planar arrangement of the 5BrU cluster, with the involvement of the Br atom in the cluster network, has been proposed.

The most striking result is the observation of a large number of hydrated fragments most likely due to a strong water–5BrU molecule interaction. Since in the fragmentation mass spectrum of nano-hydrated clusters of U measured under similar conditions34 the formation of so many hydrated fragments has not been observed, the present phenomenon can be clearly related to the presence of the Br atom favouring intramolecular rather than intermolecular bond breaking in the halosubstituted base. There is strong evidence, in the formation of the hydrated fragments, that water molecules will be located in specific hydrophilic sites favouring or preventing specific fragmentation channels.

Authors contributions

M. C. C., P. B., P. R., S. M., R. D., A. D., B. A. H. and L. A. participated in the preparation and performed the experiment; M. C. C. and P. M. contributed to the data analysis. The main text was written by M. C. C., P. M., P. B. and L. A. All the authors contributed to the paper with discussions and edits.

Acknowledgements

This work is partially supported by the Ministero degli Affari Esteri e della Cooperazione Internazionale with the Serbia – Italy Joint Research Project PGR00220 “A nanoview of radiation-biomatter interaction” and CNRS-PICS 2016 “BIFACE – Biomolecular Ions:Fundamental and Apllied scienCE”. The support by the COST Actions XLIC and nano-IBCT via the STSM scheme and MIUR FIRB RBFR10SQZI is acknowledged. Financial support received from the INCa-ITMO (no. PC201307) within the Programme Plan Cancer 2009–2013 (Inserm) is gratefully acknowledged.

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Footnote

Electronic supplementary information (ESI) available. See DOI: 10.1039/c7cp02233f

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