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VX and VG chemical warfare agents bidentate complexation with lanthanide ions† Genevieve H. Dennison,*ab Mark R. Sambrook*c and Martin R. Johnston*b

Received 3rd September 2013, Accepted 24th October 2013 DOI: 10.1039/c3cc46712k www.rsc.org/chemcomm

Investigations into V-agent interaction with 1,10-phenanthroline nitrate Ln(III) complexes (Eu and Tb) were carried out using luminescence and UV-Vis spectroscopy. Addition of several equivalents of agent resulted in the loss of luminescence intensity and the observation of free 1,10-phenanthroline by UV-Vis. We propose a displacement mechanism in which the V-agent acts as a bidentate ligand to the lanthanide ion. Association constants were determined by luminescence titrations and found to be 105 mol

1

dm3.

The organophosphorus nerve agents, comprised of the G- and V-series agents, are highly toxic chemical warfare agents (CWAs) that cause incapacitation and death through inhibition of acetylcholine esterase, and the history of their development and use throughout the twentieth century up to the present time has been well documented.1 There has been a recent resurgence of interest in exploiting molecularly based chemical sensing approaches for the detection of CWAs.2 Although molecular sensing approaches based upon chemical reactivity are relatively well-known3 the exploitation of non-covalent interactions (including metal–ligand coordination) to drive the association is reported less frequently.4 Lanthanide ions such as Eu(III) and Tb(III) exhibit dramatically increased luminescence emission in the presence of UV-light-absorbing sensitising moieties via the antenna effect.5 Such lanthanide complexes have been utilised as chemical sensors6 when CWA simulants have competitively interacted with either the lanthanide ion or the ligand resulting in a displacement of the sensitising ligand and switching off of the lanthanide-based emission.7,8

Fig. 1

Structures of VX, VG and agent simulant DMMP.

We have used luminescent lanthanide complexes as a means to probe the fundamental interactions between V-series CWAs (Fig. 1) and lanthanide metal ions that are postulated to be mediated by PQO  Ln coordinative bonds.9 Herein, we report our preliminary studies into the interaction of agents VX and VG with simple complexes of the type [Ln(phen)2(NO3)3(H2O)x] where phen = 1,10-phenanthroline and 1 Ln = Eu(III), x = 3 and 2, Ln = Tb(III), x = 2 (Fig. 2). We demonstrate rapid quenching of the lanthanide luminescence emission, determine complexation affinities, and propose a bidentate chelation mechanism (Fig. 2). In this work we show that there is a considerable difference between simulant and agent interaction with lanthanide complexes. Such a bidentate interaction mechanism has only previously been theoretically proposed10,11 and highlights the need for careful interpretation of simulant binding studies. Lanthanide complexes 1 and 2 were prepared according to modified literature methods12 and characterised by elemental and infra-red analyses.13 Solutions of the complexes (1  10 3 mol dm 3) were prepared in 1 : 9 DMF : MeCN. These solutions were further diluted in MeCN ([complex] = 1  10 5 mol dm 3) and the emission spectra

a

Human Protection and Performance Division, Defence Science and Technology Organisation, Fishermans Bend, Melbourne, Australia. E-mail: [email protected], [email protected] b Flinders Centre for Nanoscale Science and Technology, School of Chemical and Physical Sciences, Flinders University, Adelaide, Australia. E-mail: [email protected]; Fax: +61 8 820 12905; Tel: +61 8 820 12317 c Detection Department, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, UK. E-mail: [email protected] † Electronic supplementary information (ESI) available: Synthetic procedure, IR and elemental characterisation data, titration methods, fluorescence, UV-Vis spectral and Stern–Volmer plots. CWA NMR spectra. See DOI: 10.1039/c3cc46712k

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Fig. 2 (a) Lanthanide complexes 1 and 2 used in this study, (b) proposed coordination mode between bidentate V-agent and lanthanide to form a seven membered chelate ring.

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Fig. 3 Quenching of the luminescence emission of 1 upon addition of VX; inset: luminescence quenching titration profile 1, upon addition of VX (+), VG (X) where lem = 617 nm; [complex]initial = 1  10 5 mol dm 3, 293 K.

recorded. Strong emission bands at 617 nm and 545 nm were observed for 1 and 2, respectively.14 The addition of either VX or VG into solutions of the lanthanide complexes resulted in rapid quenching of the luminescence emission (Fig. 3), and almost complete quenching occurred at addition of 7–10 molar equivalents of agent (Fig. 3, inset). Analogous UV-Vis titrations of VX and VG solutions into solutions of 1 and 2 were conducted with changes in the spectra observed immediately at low V-agent concentrations. In the case of 1, the complex absorption band centered at 268 nm is seen to undergo a shift towards a band centered at 262 nm, with an isosbestic point seen at 266 nm indicating the presence of two absorptive species in solution. This lower wavelength absorption band at 262 nm corresponds to the free phen absorption spectrum (Fig. 4). The UV-Vis absorption data suggests that the observed luminescent quenching is a result of ligand displacement by competitive binding, and thus a disruption of the antenna affect. As this is a ground state effect it allows for assignment of a static quenching mechanism, and thus Stern–Volmer (SV) analysis was undertaken.15 A plot of I0/I (where I0 is the complex emission intensity, and I is the intensity in the presence of quencher) versus the concentration of the V-agent guest did not yield a straight line and thus static SV quenching constants KSV (and thus Kassoc) could not be determined. Fig. 5 shows the SV plot for 1 with VX and VG over the full titration range studied. Qualitative interpretation of the plot does, however, provide further mechanistic insight.15 The significant upward (positive) curvature away from the x-axis at high V-agent concentration could be indicative of a sphere of effective quenching mechanism16 being

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Fig. 5 Full Stern–Volmer plot for the quenching of 1 luminescence emission (lem = 617 nm) by VX (+) and VG (X) up to 10 molar equivalents of V-agent added; inset: selected region of the Stern–Volmer plot for the quenching of luminescence emission of complex 1 by VX (+) and VG (X); [complex]initial = 1  10 5 mol dm 3, 293 K.

present, however, a slight upward curvature (more pronounced for VG than VX) is still seen at low V-agent concentrations (Fig. 5) and thus indicates the presence of both static and dynamic quenching components across the whole concentration range. Attempts to fit the luminescence data to an extended SV plot were unsuccessful, and may be further complicated by fractional accessibility to binding sites as indicated by dimethyl methyl phosphonate (DMMP) data (vide infra). The UV-Vis spectral titration data was fitted to a 1 : 1 binding mode; using the software package HypSpec17 (Table 1). There was no indication of a 1 : 2 complex stoichiometry, in agreement with the observation of a single isosbestic point, suggesting a lack of cooperativity effects (negative or positive) between the two displacement sites. As such, the concentration of the binding sites was treated as 2[complex], effectively [phen]bound.18 There is little discrimination between the two V-series agents and between the two metal centres (Table 1). Consideration of the Lewis basicities of the coordinating functionalities within the two agents suggests the greater basicity of the tertiary amine in VX relative to that in VG is compensated for by the lower basicity of the phosphonyl bond compared to phosphoryl, and vice versa in VG, and may account for the lack of discrimination between the two agents.19 Similarly, the affinity of phen ligands for europium and terbium is similar, and is likely to be the reason for the similarity in binding between the metal ions.20 In order to further elucidate the mechanism of ligand displacement observed above, a series of additional experiments were conducted with the commonly used organophosphorus nerve agent simulant DMMP, the CWA bis-2-chloroethylsulfide (sulfur mustard, or HD) and triethylamine (TEA). These additional putative guests were used to provide information regarding the likely coordination behaviour of the three key functional groups found

Table 1 log Kassoc values for 1 : 1 complexation of V-agents by complexes 1 and 2 determined from UV-Vis spectral titration data

Complex

Fig. 4 Selected spectra from the titration of 1 with VX: complex, 1.0, 2.0, 5.0 and 10.0 mol equiv. VX. The low absorbance red trace is the spectrum of free phen; [complex]initial = 1  10 5 mol dm 3, 293 K.

196 | Chem. Commun., 2014, 50, 195--197

1 2

VX log Kassoc a

5.1  0.12 5.2  0.12

VG log Kassoc 4.5  0.03 5.2  0.13

a

Standard deviation of the refined parameters from the least squares fitting of binding isotherms.

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in the V-series agents, namely phosphoryl, sulfide and tertiary amine. Interestingly, titration of 10 molar equivalents of DMMP into solutions of 1 and 2 did not result in the rapid luminescence quenching noted with VX and VG at low molecular equivalents (Fig. S7, ESI†). Upon the addition of 10 molar equivalents of DMMP to 1 the extent of quenching of luminescence emission intensity is less than 15%. Analysis of the UV-Vis absorption spectrum revealed no changes, indicating no interaction between the ground state of 1 and DMMP in solution, i.e. phen was not displaced. SV analysis at low DMMP concentration (o1.5  10 5 mol dm 3) yields a linear plot of I0/I against [DMMP], and the determination of a KSV value of approximately 4500 M 1. The combined UV-Vis and luminescence emission data suggests that this is solely a dynamic quenching process and that PQO  Ln coordination is not occurring under the conditions studied. This might be surprising in light of reports demonstrating ligand displacement by TEP PQO coordination,7 and yet Shunmugam and Tew demonstrated a lack of complex perturbation, and thus a lack of PQO  Ln coordination, with similarly non-reactive organophosphorus nerve agent simulants.8 The DMMP data supports the combined static and dynamic quenching observed in the presence of VX and VG. It should also be noted that with increasing concentrations (up to 1.2  10 4 mol dm 3) of DMMP the SV plot was observed to undergo negative curvature (towards the x-axis), which is often assigned to inaccessible binding sites/luminescent species. This potentially further complicates the luminescent emission behaviour of the V-agent complexation if it is also present as a factor within the dynamic quenching component.15 Similarly, addition of HD or TEA to solutions of the complexes did not result in changes to the UV-Vis absorption spectra. In the case of luminescence emission, either zero (with HD) or minimal (with TEA) decrease was observed demonstrating that both the sulfur and nitrogen centres alone of the V-series CWA are unlikely to play a role in the competitive binding process. The amine centres of the V-agents may contribute an additional quenching mechanism, as TEA is a known photoinduced electron transfer (PET) quencher.10 Our model for VX or VG sensing by these simple lanthanide complexes is through displacement of a sensitising phen ligand by coordination of the target agent, and thus luminescence emission quenching through disruption of the antenna effect. Individually, none of the potential donor sites of the V-agents appear to bind strongly enough to displace the ligand, and yet clearly VG and VX are effective ligands. The studies conducted therefore suggest that coordination of the V-series agents to the Ln metal centre, and concurrent displacement of the phen ligands, is driven by a chelate effect. We propose that complexation is through phosphoryl and nitrogen coordination to form a seven membered chelate ring (Fig. 2). This [OP, N] chelation mode was proposed as the most stable out of the possible coordination modes in a theoretical study of metal–VX complexation (for group I and II metal cations) by Churchill and co-workers.11 Similarly, de Sousa et al. reported the possibility of a [OC, N]

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seven-membered chelate, albeit it with binding driven primarily by N–Ln coordination.10 The sensitivity of lanthanide coordination complex emission to the presence of UV-Vis absorbing antenna ligands provides the opportunity to use these complexes to interact with CWAs. We have successfully demonstrated the binding of V-series nerve agents to simple lanthanide complexes of the type [Ln(phen)2(NO3)3(H2O)x] (Ln = Eu(III), Tb(III)) in which a sensing response is reported by rapid disruption of the antenna effect. We propose that complexation of the V-agent by the lanthanide centre and displacement of the sensitising phenanthroline ligand by competitive binding is driven by a bidentate [OP, N] chelate effect. With an enhanced understanding of this interaction we are now in a position to construct more efficient CWA sensor systems.

Notes and references 1 K. Kim, O. G. Tsay, D. A. Atwood and D. G. Churchill, Chem. Rev., 2011, 111(9), 5345. 2 (a) M. Burnworth, S. J. Rowan and C. Weder, Chem.–Eur. J., 2007, ´n ˜ez, F. Sanceno ´n, 13, 7828; (b) S. Royo, R. Martı´nez-Ma A. M. Costero, M. Parra and S. Gil, Chem. Commun., 2007, 4839. 3 (a) S.-W. Zhang and T. M. Swager, J. Am. Chem. Soc., 2003, 125, 3420; (b) T. J. Dale and J. Rebek Jr., Angew. Chem., Int. Ed., 2009, 48, 7850. 4 (a) J. F. Brinkley, M. L. Kirkey, A. D. S. Marques and C. T. Lin, Chem. Phys. Lett., 2003, 367, 39; (b) M. R. Sambrook, J. R. Hiscock, A. Cook, A. C. Green, I. Holden, J. C. Vincent and P. A. Gale, Chem. Commun., 2012, 48, 5605; (c) R. C. Knighton, M. R. Sambrook, J. C. Vincent, S. A. Smith, C. J. Serpell, J. Cookson, M. S. Vickers and P. D. Beer, Chem. Commun., 2013, 49, 2293. ¨nzli and C. Piguet, Chem. Rev., 2002, 102, 1897. 5 J.-C. Bu 6 (a) N. Sabbatini, M. Guardigli and J.-M. Lehn, Coord. Chem. Rev., 1993, 123, 201; (b) S. Lis, J. Alloys Compd., 2002, 341, 45. 7 D. Knapton, M. Burnworth, S. J. Rowan and C. Weder, Angew. Chem., Int. Ed., 2006, 45, 5825. 8 (a) R. Shunmugam and G. N. Tew, Chem.–Eur. J., 2008, 14, 5409–5412; (b) S. Sarkar, A. Mondal, A. K. Tiwari and R. Shunmugam, Chem. Commun., 2012, 48, 4223. 9 A. E. Hargrove, S. Nieto, T. Zhang, J. L. Sessler and E. V. Anslyn, Chem. Rev., 2011, 111, 6603. 10 M. de Sousa, B. de Castro, S. Abad, M. A. Miranda and U. Pischel, Chem. Commun., 2006, 2051. 11 I. Bandyopadhyay, M. J. Kim, Y. S. Lee and D. G. Churchill, J. Phys. Chem. A, 2006, 110, 3655. 12 R. C. Grandey and T. Moeller, J. Inorg. Nucl. Chem., 1970, 32(1), 333. 13 V. Tsaryuk, V. Zolin, L. Puntus, V. Savchenko, J. Legendziewicz, J. Sokolnicki and R. Szoztak, J. Alloys Compd., 2000, 300–301, 184. 14 D. Parker, Coord. Chem. Rev., 2000, 205, 109. 15 C. D. Geddes, Meas. Sci. Technol., 2001, 12, R53. 16 The concentration of the quencher is so high that dynamic quenching can occur without the need for diffusion of species in solution. 17 P. Gans, A. Sabatini and A. Vacca, Talanta, 1996, 43, 1739. 18 It should also be noted that the addition of phen to solutions of complex 1 resulted in a linear increase in absorption at 268 nm indicating formation of Eu(phen)x(NO3)3 complexes, where x 4 2. This suggests that the intermediate complex Eu(phen)(V-agent)(NO3)3 has an absorption spectrum identical to 1 except with an extinction coefficient approximately half the value. This further precludes the identification of a 1 : 2 binding mode, and supports the lack of cooperativity effects. 19 C. Laurence and J.-F. Gal, Lewis Basicity and Affinity Scales, Wiley, 2009. 20 S. Yakima and Y. Hasegawa, Bull. Chem. Soc. Jpn., 1998, 71(12), 2825.

Chem. Commun., 2014, 50, 195--197 | 197

VX and VG chemical warfare agents bidentate complexation with lanthanide ions.

Investigations into V-agent interaction with 1,10-phenanthroline nitrate Ln(III) complexes (Eu and Tb) were carried out using luminescence and UV-Vis ...
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