Lyn H.
Jones
*,
Nicholas W.
Summerhill
*,
Nigel A.
Swain
and
James E.
Mills
Sandwich Chemistry, World Wide Medicinal Chemistry, Pfizer Ltd., Ramsgate Road, Sandwich, United Kingdom. E-mail: lyn.jones@pfizer.com; Fax: +44-1304-651821; Tel: +44-1304-644256
First published on 11th October 2010
This review highlights the medicinal and synthetic chemistry relevance of replacing an aromatic COMPOUND LINKS
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Download mol file of compoundchloride motif with an aromatic nitrile. We explore the desirable features that this transformation can bring in a drug design sense and the recent synthetic chemistry advances that effect this replacement in a single step.
Aromatic chlorides are ubiquitous amongst high affinity protein binders and are often hits from high throughput screening efforts. There are presumably various reasons for this, including a high proportion of chloroaromatics in screening sets in the first place, possibly due to the synthetic expediency of their creation, and a variety of available binding modes, including strong hydrophobic interactions with the target protein driven by the lipophilicity of the residue (see below). Within Pfizer we have discovered through experience that replacing this moiety with an aromatic nitrile can often result in a compound with similar affinity/potency, although this transformation does not seem to have achieved widespread use, presumably in part due to the lack of publications that signpost this useful substitution. This review will explore the fundamental medicinal chemistry aspects of this switch and describe the aromatic nitrile containing drugs on the market. We will augment the analysis with data that support the generality of the conversion and the improvements seen in drug-type properties driven by modifications to the physicochemical properties of the resulting molecules. Moreover, the synthetic chemistry to effect this transformation in a single step has made significant progress in the last decade, making this a particularly apt time for review. Aromatic chlorides are in general inexpensive and much more readily available than bromides and iodides. Therefore, they are ideal starting materials for cross coupling reactions. Unfortunately, chlorides also constitute the most challenging substrates for these reactions, due to the high bond dissociation energy of the C(sp2)–Cl bond. For this reason the transition metal-catalysed cyanation reaction of aryl chlorides is an emerging but valuable field when aligned with the medicinal chemistry relevance of the conversion, and this review is anticipated to be of interest to a wide community of synthetic and medicinal chemists from both academia and industry.
Fig. 1 Aromatic nitrile-containing drugs and their corresponding COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundchloride congeners (launch date in brackets). |
For the selective COMPOUND LINKS
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Download mol file of compoundserotonin re-uptake inhibitor (SSRI) and antidepressantdrugCOMPOUND LINKS
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Download mol file of compoundcitalopram, there is a matching chloro-analogue with similar potency called LU-10-134-C (Fig. 1).2 Similarly, febuxostat, a non-purine selective xanthine oxidase inhibitor for the treatment of hyperuricemia, possesses a matching potent chlorinated derivative 1.3 Interestingly, a co-crystal structure of febuxostat with xanthine oxidase shows there to be a hydrogen bond between the nitrile moiety and the carboxamide residue of Asn768.4 In the case of the aromatase inhibitor and anticancer agent COMPOUND LINKS
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Download mol file of compoundletrozole, both nitriles can derive from chlorine substituents (molecule 2).5 Additionally, structure–activity relationships map COMPOUND LINKS
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Download mol file of compoundfadrozole to the chloro-equivalent molecule.6
COMPOUND LINKS
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Download mol file of compoundPericiazine and COMPOUND LINKS
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Download mol file of compoundcyamemazine are antipsychotic drugs from the COMPOUND LINKS
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Download mol file of compoundphenothiazine class and although the exact matching pair where the nitrile is replaced by chlorine, are not known, both drugs derive from the prototypical COMPOUND LINKS
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Download mol file of compoundchlorpromazine.7 The SAR of COMPOUND LINKS
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Download mol file of compoundbicalutamide, an oral antiandrogen for the treatment of prostate cancer, suggests that a 4-CNgroup is superior to a chloro-substituent (compound 3).8 The crystal structure of COMPOUND LINKS
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Download mol file of compoundbicalutamide with the antiandrogenreceptor ligand binding domain shows there to be a hydrogen bond between the nitrile moiety and the Arg752 residue.9
Similarly, the cyano-group in the dipeptidylpeptidase IV inhibitoralogliptin (for the oral treatment of type 2 diabetes) is able to hydrogen bond to Arg125 in the enzyme binding site.10 A corresponding chloro-derivative has also been described.11
The non-nucleosidereverse transcriptase inhibitor (NNRTI) and anti-HIV drugetravirine contains two aromatic nitrile moieties and structure–activity relationships suggest that at least one can be effectively replaced by a chlorine atom.12 A key structural component for resilience to drug resistant mutations in this class is an effective edge-to-face π-interaction with an immutable tryptophan residue in the allosteric reverse transcriptase (RT) binding pocket.13 Crystal structures of etravirine14 and capavirine15 with RT show that the hydrogen atom ortho- to the chlorine atoms in capravirine and nitrile moiety in etravirine is indeed interacting with the immutable Trp229 and both molecules possess excellent mutant viral profiles. We also have a matching pair of COMPOUND LINKS
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Download mol file of compoundimidazole NNRTIs with excellent mutant profiles from our own work16 that supports these observations (compounds 5 and 6, Fig. 2). Additionally, the nitrile moiety in these ligands points through a hole in the enzyme towards solvent, an arrangement that is ideally suited to the shape and electrostatics of this residue (see below).17
Fig. 2 Potency, lipophilic efficiency (LipE) and metabolic stability of NNRTIs. |
Fig. 3 Proportion of HTS actives containing an active ArCl or ArCN, for a) ortho- b) meta- and c) para-derivatives (unity line shown). Each point represents an HTS. |
Additionally, the plots of the propensity of an aromatic COMPOUND LINKS
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Download mol file of compoundchloride to yield an active versus an aromatic nitrile show that the chloride consistently outperforms the nitrile across the three substitutions (Fig. 4, also see Supporting Information for logarithmic plots).
Fig. 4 Propensity for an ArCl or ArCN to yield an active hit in an HTS for a) ortho- b) meta- and c) para-derivatives (unity line shown). Each point represents an HTS. |
Additionally, there is a significant difference in the number of commercially available functional building blocks for synthesis, that we refer to as monomers, containing aromatic chlorides versus nitriles (Table 1).18 It follows that an aromatic COMPOUND LINKS
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Download mol file of compoundchloride hit or lead may later be converted in a medicinal chemistry sense to a nitrile residue through bespoke synthesis, but the lack of functional monomers, and large number of chloroaromatic monomers, may also help explain the greater number of drugs containing an aromatic chloride residue.
Monomer |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundChloride |
Nitrile |
---|---|---|
RCO2H | 65705 | 3690 |
RNH2 | 134063 | 7805 |
ArOH | 36577 | 1538 |
ArB(OR)2 | 52 | 7 |
RCO2Me | 46506 | 1948 |
Fig. 5 Electrostatic potential maps for chlorobenzene and COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundbenzonitrile (red = lowest, blue = highest electrostatic potential energy)19 |
The dipole moments of these groups are also substantially different: PhCl = 1.67 debye, PhCN = 4.44 debye and reflect the higher propensity for a dipole interaction with the aryl nitrile.20 Indeed, the high dipole moment and electronic polarisability of COMPOUND LINKS
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Download mol file of compoundbenzonitrile21 imparts interesting applications for this motif in linear and non-linear optical materials.22 These values would suggest that the preferred binding environments for the aromatic nitrile residue are likely to have a complementary polar nature, compared to that of the aryl chloride (see below). The hydrogen bonding to the aromatic nitriledrugsalogliptin, COMPOUND LINKS
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Download mol file of compoundbicalutamide and febuxostat described above would appear to support this.
Fig. 6 Sub-pockets predicted to contain ArCl and ArCN moieties (on the grounds that a co-crystallised ligand in the same pocket is at least 75% similar) were analysed using an in-house method to assess burial and polarity. For each such group, a regular array of 642 vectors is sprayed out from the centroid,25 each vector terminating at the closest point at which it meets the protein surface. The proportion of such vectors with a length < 5 Å gives a measure of sub-pocket burial and the proportion of vectors terminating at a polar protein atom gives a measure of the sub-pocket polarity. Each sub-pocket was defined as preferring ArCl, ArCN or neither using a 3-fold potency window. |
The nature of the sub-pocket in the immediate vicinity of the expected area of difference in electrostatic potential between the chlorine atom (positive electrostatic potential in this region) and nitrile residue (negative electrostatic potential in this region) was also explored. This was assessed by outputting the nature of the atom contributing the closest surface point to the vector passing through the C–Cl or C–CN bond) for para-substituted phenyl rings (for ortho- and meta-substituted groups, the precise location of the substituent in the pocket is ambiguous). Although the small numbers of observations makes it difficult to generate statistically significant results, it can be seen that sub-pockets containing COMPOUND LINKS
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Download mol file of compoundH-bond acceptor, acid or π-system atoms in this position show a preference for Cl moieties and those sites that contain a donor or amphiprotic atom show more of a preference for CN moieties, again in line with the electrostatic potentials of these groups (Fig. 7).
Fig. 7 Relationship between preference and nature of binding pocket at the point (X) where the electrostatic potentials of ArCl and ArCN differ. Pockets were defined as either CN-preferring (green), Cl-preferring (red) or preferring neither (amber) using a 3-fold potency cutoff window. Pocket properties are described by the nature of the atom (A = acceptor, B=basic, C=acidic, D = donor, H=hydrophobic, M = amphiprotic, P = π-system atom, S=solvent-exposed i.e. no atom) closest to X. Number of observations giving rise to each pie chart is shown. |
Specifically relevant for the ArCl systems is halogen bonding (the non-covalent interaction between the electropositive σ-crown on the halogen and a Lewis base) and this has been reviewed regarding its importance in biologically-relevant interactions.26 Of particular interest in halogen bonding is the affinity of aromatic chlorides for π-systems, as illustrated by the serine protease factor Xainhibitors that interact in an edge-to-face manner through the chlorine atom of the inhibitor and Tyr228.27 Similarly, an analysis of the Cambridge Structural Database28 revealed 400 possible interactions between the chlorine atom on an aromatic ring and the π-system of a nearby aromatic residue (4.5 Å cut off).29
Since halogen bonding requires specific interactions with the electropositive crown on the chlorine atom, it is possible that a nitrile switch would result in an affinity reduction, particularly if a large component of the binding energy is derived from the halogen bond itself.27
To further explore the LipE relevance of the aromatic COMPOUND LINKS
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Download mol file of compoundchloride to nitrile switch, an analysis of the Targetbook database38 comparing the potency of 1074 distinctly matched ArCl-ArCN pairs across a multitude of target classes was undertaken. As expected, a direct comparison of the potency for matched pairs showed a spread of data from across enzyme, GPCR and ion channel targets (Fig. 8a). However upon normalising for lipophilicity, using calculated LogP, the plot showed a clear trend towards improved LipE for aromatic nitriles versus their corresponding aromatic COMPOUND LINKS
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Download mol file of compoundchloride congener (Fig. 8b).39 Very similar results are obtained when the Pfizer data set is interrogated in this way (see ESI†).
Fig. 8 a) Potency of ArCNversusArCl; b) LipE of ArCNversusArCl (line of unity in bold, ± 3-fold ‘error’ IC50 lines either side, translating to a ± 0.5 shift in LipE); c) Pie chart plot of data in b) (green/amber/red = ArCN better/same/worse potency than ArCl). |
A pie chart analysis of these data (Fig. 8c) clearly shows an exceptionally high probabability of aryl nitriles displaying better lipophilic efficiency relative to the corresponding aryl chloride. These statistics make a compelling case for replacing an aromatic COMPOUND LINKS
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Download mol file of compoundchloride with the nitrile derivative to improve the lipophilic efficiency, and by inference, the medicinal chemistry properties of the molecule.
An analysis of the Pfizer data set confirms the translation of improved LipE for the aromatic nitrile providing improved metabolic stability relative to the aromatic COMPOUND LINKS
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Download mol file of compoundchloride. Fig. 9 shows that the aromatic nitrile out-performs the chloride congener as assessed by an improvement in metabolic stability in human liver microsomes.
Fig. 9 Assessment of metabolic stability in human liver microsomes for matched aromatic chloride-nitrile pairs. ArCN 2-fold more stable (green), ArCl 2-fold more stable (red) or the same stability (within 2-fold, amber). Number of observations giving rise to each pie chart is shown. |
Aryl chlorides are in general much more readily available and inexpensive than bromides and iodides, and are ideal starting materials for cross-coupling reactions.44 Unfortunately, chlorides also constitute the most challenging substrates for these reactions, due to the high bond dissociation energy of the C(sp2)–Cl bond (C–Cl = 402, C–Br = 339, C–I = 272 kJ mol−1).45 For this reason the transition-metal catalysed cyanation reaction of aryl chlorides is an emerging field, and significant advances have been made in the last decade. The purpose of this synthetic review is to bring together the known methods of this transformation catalysed by palladium specifically (see below). The attractiveness of this synthetic transformation is highlighted by that of the medicinal chemistry described above, thus providing opportunities to improve drug-type properties in a single-step conversion.
Therefore, there clearly remained a need for a more general procedure suitable for all chloroarenes. This need was first addressed by Jin and Confalone from the process group in DuPont, who published the first general set of conditions for the cyanation of aryl chlorides in 2000.48 4 mol% of the Pd complex was generated from tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) and 1,1′-bis(diphenyl-phosphino)ferrocine (dppf), COMPOUND LINKS
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Download mol file of compoundzinc cyanide as the CN source, and catalyticZn powder at high temperature in dimethyl acetamide (DMA). The scope of the reaction was impressive as it was not limited to electron poor “activated” aromatic chlorides (see Scheme 1) and could be applied to the preparation of 7, an intermediate en route to the factor Xainhibitor razaxaban.49
Scheme 1
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundZinc-mediated cyanation (Jin and Confalone)48 |
The role of the COMPOUND LINKS
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Download mol file of compoundzinc powder is intriguing and worthy of further comment. Early mechanistic studies by Takagi et al.50 showed that an excess of COMPOUND LINKS
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Download mol file of compoundcyanide ions inhibits the catalytic cycle due to formation of inactive Pd(II) cyano compounds, that cannot be reduced to the catalytically active Pd(0) species; the Zn is key in reducing these compounds, thus allowing the cycle to continue. COMPOUND LINKS
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Download mol file of compoundCyanide ions can also react with Pd(0) giving species that cannot undergo oxidative addition to Ar–Cl as illustrated in red in Fig. 10. An analysis of the mechanisms by which palladium poisoning can occur in aromatic cyanations has been reported.51
It is clear that the CN− anion concentration in the reaction mixture is crucial; too much and the catalyst is deactivated as above, too little and the transmetallation (and hence reductive elimination step) is retarded. These effects also lead to solvents playing a key role in the reaction due to variation in cyanide solubility and show the importance of having a relatively insoluble cyanide source. In the above case, COMPOUND LINKS
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Download mol file of compoundzinc cyanide (originally introduced for cyanations by the Merck process group in 1994) is used, as its solubility in COMPOUND LINKS
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Download mol file of compoundDMF (at 80 °C) is only 1.8 × 10−4 g mL−1.52 Using elegant NMR studies, Beller was able to isolate the oxidative addition complex and proved that this step is rate determining, the transmetallation and reductive elimination steps being much quicker.53
In the same year Jiang et al. described dialkylcyanoboronates 8 as a novel source of cyanide for the transformation.54 However, these reagents required pre-synthesis from a diol precursor and only reacted in moderate yield with activated chlorides as shown in Scheme 2.
Scheme 3
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundTMEDA-catalysed cyanation (Beller et al.)55 |
From a mechanistic perspective, the benefits of the crown ether or amine additive are two-fold: the concentration of CN− anions is controlled and the exchange of cyanide with other ligands is facilitated. Also, crucial to the success of the reaction is the use of chelating COMPOUND LINKS
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Download mol file of compoundphosphine ligands, with COMPOUND LINKS
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Download mol file of compound1,5-bis(diphenylphosphino)-pentane (dpppe) being optimal. However, under these conditions, non-activated chlorides such as simple chlorobenzene give poor yields. Therefore, Beller investigated alternative amine co-catalysts such as those shown in Fig. 3.531-1′-methylenediperidine (COMPOUND LINKS
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Download mol file of compoundMDP) as an additive provided the best yields under these conditions (Fig. 11, Scheme 4).
Fig. 11 Amine additives used by Beller et al.53 |
Noteworthy here is the smooth reaction of COMPOUND LINKS
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Download mol file of compound4-chlorobenzaldehyde that may have been expected to undergo cyanide-catalysed benzoin condensation, reflecting the low cyanide concentration in the reaction. Also of interest are the cyanations of heteroaryl substrates, thus broadening the scope and relevance of this transformation.
Scheme 5 TMSCN cyanations (Beller et al.)57 |
Scheme 6 Microwave-assisted cyanations (Pitts et al.)60 |
In the second microwave paper, Chobanian and co-workers61 found that the key to a successful reaction in their case was the use of the Buchwald S-Phos ligand62 which was previously noted to possess “unprecedented activity” in the coupling of aryl chlorides with boronic acids and esters.63 Application of this ligand to cyanations under microwave conditions gave good results. For the first reaction shown below, use of dppf or dpppe gave no reaction at all, whereas S-Phos gave a 97% yield (Scheme 7).
Scheme 7 Microwave-assisted cyanations (Chobanion et al.)61 |
An important feature of this work is that the thermal conditions do not appear to give significantly different yields to the microwave under these conditions; even the length of reaction is comparable (30 min for MW, 1 h for thermal reaction). Also noteworthy is the poor yield in the reaction of the relatively electron rich COMPOUND LINKS
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Download mol file of compoundchlorideCOMPOUND LINKS
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Download mol file of compound10, which, apart from an isolated example in the original Confalone work,48 is a common theme in the papers described thus far.
These conditions were recently used to convert the antitumour smoothened antagonists11 as a 1:1 mixture of regioisomers into the nitrile containing derivatives 12 (Scheme 8),64 although X-Phos was the chosen ligand.65 Interestingly, the nitrile containing compounds appeared to have improved LipE, although it should be noted the biological activity was measured on the regioisomeric mixture.
Scheme 8 Smoothened antagonists and microwave-assisted cyanation64 |
Scheme 9 Reduced temperature cyanations (Littke et al.)66 |
Scheme 10 Potassium ferrocyanide and cataCXium-mediated cyanations (Beller et al.)69 |
The sterically hindered COMPOUND LINKS
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Download mol file of compound2-chloro-1,3-dimethylbenzene and electronically deactivated COMPOUND LINKS
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Download mol file of compound4-chloroanisole, both give good yields. Of particular note is the small amount of catalyst required, since reactions require only 0.2–0.5mol%. In fact, lower yields are obtained by raising the amount of catalyst; this is attributed to agglomeration of molecular palladium complexes to palladium black. A similar effect has been shown by de Vries et al. for Heck olefinations of aryl iodides.70 The low catalyst loading combined with the green credentials of the ferrocyanide suggest these conditions are ideal for larger, process scale reactions.
Finally, recent work by Beller and co-workers addresses some very demanding substrates that further expand the scope of the palladium-mediated cyanation reaction.71Learning from Littke's use of Pd(TFA)2, unprotected chloroanilines and chlorophenols can be cyanated with potassium ferrocyanide, provided the optimal ligand is chosen. However no single ligand satisfies all substrate examples, and reactions were optimised on a case-by-case basis. Additionally, the yields with these demanding substrates are only moderate (Scheme 11).
Scheme 11 Potassium ferrocyanide-mediated cyanations (Beller et al.)71 |
Significant recent progress in the synthetic conversion of aromatic chlorides to nitriles has turned a difficult transformation into one that can be effected smoothly in one step and in high yield across a variety of substrates, that include sterically hindered and electronically deactivated aryl chlorides. These advances will provide the medicinal chemist with a wider synthetic repertoire of available chemistries to facilitate this desirable transformation and the opportunity to transform an aryl chloride drug-type molecule into the corresponding nitrile in a single step.
The ability to interconvert medicinal chemistry fragments using simple and mild synthetic techniques is a powerful and efficient strategy to provide structure–activity relationships. The available toolbox contains some very useful transformations (for example, COMPOUND LINKS
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Download mol file of compoundphenol to COMPOUND LINKS
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Download mol file of compoundtrifluoromethoxybenzene,72 chloroaromatic to COMPOUND LINKS
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Download mol file of compoundtrifluoromethylbenzene,73COMPOUND LINKS
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Download mol file of compoundbenzene to COMPOUND LINKS
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Download mol file of compoundfluorobenzene and various C–H activation chemistries74) that is augmented by the aryl chloride to nitrile conversion.
Footnote |
† Electronic supplementary information (ESI) available: Supplementary figures. See DOI: 10.1039/c0md00135j |
This journal is © The Royal Society of Chemistry 2010 |