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A Solid-State Dehydration Process Associated with a Significant Change in the Topology of Dihydrogen Phosphate Chains, Established from Powder X-ray ...
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CRYSTAL GROWTH & DESIGN

A Solid-State Dehydration Process Associated with a Significant Change in the Topology of Dihydrogen Phosphate Chains, Established from Powder X-ray Diffraction

2008 VOL. 8, NO. 10 3641–3645

David Albesa-Jove´,† Zhigang Pan,‡ Kenneth D. M. Harris,*,‡ and Hidehiro Uekusa§ School of Chemistry, UniVersity of Birmingham, Edgbaston, Birmingham B15 2TT, England, School of Chemistry, Cardiff UniVersity, Park Place, Cardiff CF10 3AT, Wales, and Department of Chemistry and Materials Science, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8551, Japan ReceiVed February 29, 2008; ReVised Manuscript ReceiVed June 25, 2008

ABSTRACT: The anhydrous crystalline phase of chloroquine bis-(dihydrogen phosphate) is obtained by dehydration of the corresponding hydrate phase, but in common with many solid-state dehydration processes, the product is obtained as a polycrystalline powder, thus limiting the opportunity to carry out structural characterization using single crystal X-ray diffraction techniques. Instead, structure determination of the anhydrous phase has exploited the capabilities of modern powder X-ray diffraction techniques, employing the direct-space Genetic Algorithm technique for structure solution followed by Rietveld refinement. The results reveal that the dehydration process is associated with a significant change in the topology of hydrogen bonded chains of dihydrogen phosphate anions, arising from a change in the hydrogen bonding arrangement within the chains, together with a significant change in the conformation of the chloroquine cation.

1. Introduction Chloroquine [N4-(7-chloro-4-quinolinyl)-N1,N1-diethyl-1,4pentanediamine; abbreviated CQ] has found applications as an anti-malarial agent, the mechanism of action of which may depend on its ability to form complexes with nucleic acids1,2 or by inhibiting the incorporation of orthophosphates into nucleic acids of plasmodia.3 From this applied viewpoint, as well as from fundamental structural viewpoints, it is relevant to consider the interaction between CQ and phosphate anions, and thus the structural properties of co-crystal salts containing both CQ (as a multiply protonated cation) and phosphate anions are of considerable interest. In this context, a hydrate crystalline phase of chloroquine bis-(dihydrogen phosphate) [denoted CQ(DHP)2; Scheme 1] has been reported previously,4-6 and the structural properties have been determined from single crystal X-ray diffraction data. We note7 that the three independent reports4-6 of the structure determination of the hydrate phase differ significantly in their descriptions of the level of hydration of this material. The hydrate phase of CQ(DHP)2 is known8 to undergo a solid-state dehydration process at elevated temperature, although the crystal structure of the resultant anhydrous phase of CQ(DHP)2 has not been reported previously. The anhydrous phase is reported6,8 to be stable in a dry atmosphere, but in humid atmospheres at ambient temperature the anhydrous phase takes up water to form the hydrate phase. On rapid heating, the hydrate phase melts in the same temperature region as dehydration, whereas slow heating gives an essentially complete transformation to the anhydrous phase without melting (the melting points of the hydrate and anhydrous phases are reported6 to be ca. 450 K and 480 K, respectively). For such solid-state dehydration processes, it is commonly observed that a single crystal of the parent hydrate phase becomes a polycrystalline powder upon dehydration, and under * To whom correspondence should be addressed. E-mail: HarrisKDM@ cardiff.ac.uk. † University of Birmingham. ‡ Cardiff University. § Tokyo Institute of Technology.

Scheme 1. Molecular Structure of CQ(DHP)2

such circumstances, structure determination of the dehydrated product phase cannot be carried out using single crystal X-ray diffraction techniques. In such cases, an alternative approach is required for structure determination of the anhydrous phase. Fortunately, there have been significant advances in recent years in the opportunities for carrying out complete structure determination of molecular solids directly from powder X-ray diffraction data,9 particularly through the development of the direct-space strategy for structure solution.10 These techniques now provide a viable route for structural characterization of polycrystalline powder samples produced directly by solid state processes of the type discussed above. In this paper, we have exploited this approach to determine the structure of the anhydrous phase of CQ(DHP)2, produced directly from the solid state dehydration process.

2. Background to Structure Determination from Powder X-ray Diffraction Data Among recent developments in techniques for carrying out structure solution from powder X-ray diffraction data,9 the direct-space strategy10 has become widely adopted in the case of molecular materials. In the direct-space strategy, trial structures are generated in direct space, with the quality of each trial structure assessed by comparison between the calculated powder X-ray diffraction pattern for the trial structure and the experimental powder X-ray diffraction pattern. In the present work, this comparison is made using the powder profile R-factor Rwp, which implicitly takes peak overlap into consideration. Here, direct-space structure solution has been carried out using the genetic algorithm (GA) technique11 to locate the trial structure corresponding to the global minimum in Rwp. In the

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GA technique, a population of trial structures is allowed to evolve subject to the types of rules and operations (mating, mutation and natural selection) that govern evolution in biological systems. Each structure is uniquely characterized by its “genetic code”, which represents, for each molecule in the asymmetric unit, structural variables that define the position {x, y, z} and orientation {θ, φ, ψ} of the molecule, and the molecular conformation (defined by variable torsion angles {τ1, τ2,..., τn}). New structures are generated by the mating and mutation operations, and in the GA implementation used here, each new structure is subjected to local minimization of Rwp.11c In natural selection, only the structures of highest ”fitness” (i.e. lowest Rwp) are allowed to pass from one generation to the next generation in the GA calculation. The work reported here employed a multi-population parallel genetic algorithm,11d in which the sub-populations undergo independent evolution but with occasional migration of structures allowed to occur between the sub-populations.

3. Experimental Procedures Chloroquine bis-(dihydrogen phosphate) was obtained from Aldrich and was used without further purification. The powder X-ray diffraction pattern recorded for this material at ambient temperature (on a Siemens D5000 diffractometer operating in transmission mode using Gemonochromated CuKR1 radiation) was in agreement with the powder X-ray diffraction pattern simulated for the known hydrate phase.4-6 Transformation of the hydrate phase to the anhydrous phase was studied by differential scanning calorimetry (Perkin Elmer Pyris 1 instrument) and thermogravimmetric analysis (Perkin Elmer TGA 6 instrument), which confirmed previous reports6 on the dehydration of the hydrate phase. In the present work, a polycrystalline sample of the anhydrous phase was obtained by slow heating of the hydrate phase (in the TGA instrument) to a temperature in the region of ca. 190 °C, which is above the dehydration temperature of the hydrate phase and below the melting temperature of the anhydrous phase. The resultant sample of the anhydrous phase was loaded into a 0.5 mm capillary for recording the powder X-ray diffraction data. The powder X-ray diffraction pattern confirmed that the sample was a new crystalline phase, with no detectable amounts of the original hydrate phase present. For the structure determination calculations described below, a high-resolution powder X-ray diffraction pattern of the anhydrous phase was recorded in transmission mode at ambient temperature on beamline BL-4B2 at the Photon Factory, Tsukuba, Japan (λ ) 1.207 Å; 2θ range 5°-55°; step size 0.01°; data collection time ca. 3.5 h).

4. Structure Determination The powder X-ray diffraction pattern of the anhydrous phase of CQ(DHP)2 was indexed using the program DICVOL,12 giving the following unit cell with monoclinic metric symmetry: a ) 12.54 Å, b ) 9.48 Å, c ) 20.70 Å, β ) 93.97°. From systematic absences, the space group was assigned as P21/c, and density considerations suggest that there are four CQ cations and eight DHP anions in the unit cell, corresponding to one CQ cation and two DHP anions in the asymmetric unit. For this unit cell and space group, profile fitting using the Le Bail method13 gave a good fit between calculated and experimental powder X-ray diffraction patterns (Rwp ) 4.54 %; Rp ) 3.50 %; Figure 1a). Structure solution from the powder X-ray diffraction data was carried out using the parallel implementation of our direct-space Genetic Algorithm (GA) technique described in Section 2. The structure solution calculation involved three independent molecular fragments, representing a total of 26 structural variables. The CQ cation was defined by 14 variables {x, y, z, θ, φ, ψ, τ1, τ2,..., τ8}, describing the position {x, y, z} and orientation {θ, φ, ψ} in the unit cell and with the molecular conformation defined by eight variable torsion angles {τ1, τ2,..., τ8}. Each DHP anion was defined by 6 variables, describing the position

Figure 1. (a) Le-Bail fit and (b) final Rietveld refinement for the anhydrous phase of CQ(DHP)2, showing the experimental (+ marks), calculated (solid line) and difference (lower line) powder X-ray diffraction profiles.

{x, y, z} and orientation {θ, φ, ψ} in the unit cell. For all three fragments, only non-hydrogen atoms were included (and thus the DHP anions were treated as rigid fragments), with bond lengths and bond angles taken from those reported5 for the structure of the hydrate phase of CQ(DHP)2. The bond lengths and bond angles were fixed in the direct-space structure solution calculation (but were relaxed in the subsequent Rietveld refinement calculations). The degree of protonation of the CQ cation was taken to be the same as that in the hydrate phase, as shown in Scheme 1 (as discussed below, this interpretation of the protonation of the CQ cation corresponds to a sensible hydrogen bonding arrangement in the crystal structure). The GA structure solution calculation, carried out using the program EAGER,14 involved the simultaneous evolution of two sub-populations for 200 generations, with occasional migration of structures allowed to occur between the two sub-populations. Each sub-population comprised 100 structures, and in each generation 50 offspring were generated by the mating operation (from 25 pairs of parents) and 30 mutants were generated by the mutation operation. The structure with lowest Rwp in the final generation of the GA calculation was used as the starting structural model for Rietveld refinement, which was carried out using the GSAS program.15 All atoms were included in the refinement (with hydrogen atoms added to the structural model in calculated positions). Standard geometric restraints were applied to bond lengths and bond angles, and planar restraints were applied to the atoms of the aromatic ring of the CQ cation. As shown in Scheme 1, the DHP anion has two types of phosphorus-oxygen bond, which we denote throughout this paper as P-OH for the protonated oxygen atoms and PdO for the non-protonated oxygen atoms.16 In the Rietveld refinement, the initial assign-

Topology of Dihydrogen Phosphate Chains

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ment of P-OH bonds and PdO bonds on the DHP anions was made on the basis that the oxygen atoms that are involved in two hydrogen bonds are more likely to be PdO bonds than P-OH bonds (as the oxygen atom of the PdO group17,18 is a stronger hydrogen bond acceptor than the oxygen atom of the P-OH group), whereas the oxygen atoms that are involved in one hydrogen bond were assigned as P-OH bonds. Rietveld refinement was also carried out for a structural model comprising disorder of the P-OH bonds and PdO bonds on the DHP anions (with all P-O bond lengths taken as an average of standard single and double bond lengths), but the fit obtained was slightly inferior to that for the ordered model. We note that the reported structure of the hydrate phase5 also represents an ordered arrangement of the P-OH and PdO bonds in the DHP anions. Six common isotropic displacement parameters were refined, each covering a group of similar atom types. The final Rietveld refinement (Figure 1b) gave Rwp ) 6.63 % and Rp ) 5.08 % (129 variables, 1168 reflections, 5009 data points), and the following refined unit cell: a ) 12.54365(28) Å, b ) 9.48443(13) Å, c ) 20.7000(4) Å, β ) 93.9669(18)°. The CIF file containing the final refined atomic coordinates is included as Supporting Information.

5. Results and Discussion We begin by recalling the essential structural features of the hydrate phase of CQ(DHP)25 (Figure 2), as this is necessary to allow subsequent comparison to the structure of the anhydrous phase determined here. In the hydrate structure, the DHP anions form linear hydrogen-bonded chains (Figure 2b) that run along the b-axis (21 screw axis). There are four DHP anions in the periodic repeat distance (16.81 Å) along the b-axis. Each pair of adjacent DHP anions within the chain is linked by two PO-H · · · OdP hydrogen bonds, with each DHP anion in the pair providing one PO-H group as donor and one PdO group as acceptor to form these two hydrogen bonds. All PO-H groups and all PdO groups of the DHP anions are involved in one PO-H · · · OdP hydrogen bond of this type. All three N-H bonds of the CQ cation are engaged in N-H · · · OdP hydrogen bonds to oxygen atoms within the DHP chains (Figure 2c). The two N-H bonds in the side-group of the CQ cation form N-H · · · OdP hydrogen bonds with adjacent DHP anions in the same chain, whereas the N-H bond in the aromatic ring forms an N-H · · · OdP hydrogen bond with a DHP anion in a different chain. Thus, the CQ cations effectively bridge adjacent DHP chains, and the plane of the aromatic ring is essentially perpendicular to the direction of propagation of the DHP chains. These CQ bridges between a given pair of chains are not equally spaced, but exist in pairs with a significant π · · · π interaction between the aromatic rings of the two molecules in the pair (center-to-center distance 3.55 Å). One of the four PdO bonds of the two independent DHP anions is not engaged in N-H · · · OdP hydrogen bonding with a CQ cation. The water molecules in the hydrate structure are present as a chain of four molecules (Figure 2a) located between two chains of DHP anions. Although hydrogen atoms of the water molecules were not included in the reported crystal structure, it may be inferred (from O · · · O distances) that the water molecules in the chain are hydrogen bonded to each other and also serve as donors in O-H · · · O hydrogen bonds to oxygen atoms of the DHP anions. The crystal structure of the anhydrous phase (Figure 3), determined directly from powder X-ray diffraction data in the present work, is also based on chains of DHP anions, which run along the a-axis. However, in marked contrast to the linear chains of DHP anions found in the hydrate phase (Figure 2b),

Figure 2. Crystal structure of the hydrate phase of CQ(DHP)2: (a) viewed along the a-axis, (b) the linear hydrogen-bonded chain of DHP anions running parallel to the b-axis (the two independent DHP anions are labelled A and B), and (c) hydrogen bonding between the CQ cation and two different DHP chains (which run along the direction of view). Hydrogen atoms are omitted for clarity.

the DHP chains in the anhydrous phase have a zig-zag topology (Figure 3b). The periodic repeat distance along the direction of propagation of the chain (12.54 Å) is significantly shorter than that for the hydrate phase (16.81 Å), with the same number (four) of DHP anions in the repeat unit. As in the hydrate phase, each pair of adjacent DHP anions in the chain is linked by two PO-H · · · OdP hydrogen bonds, but details of the hydrogen bonding scheme differ significantly, as elaborated below. In both the hydrate and anhydrous phases, there are four DHP anions in the periodic repeat distance along the chain and two independent DHP anions in the asymmetric unit, which we denote type A and type B. In the hydrate phase, each chain (which runs along the 21 screw axis) comprises alternating molecules of types A and B (i.e., ...ABABA..., with one AB pair related to the next AB pair by the 21 screw axis). The anhydrous phase, on the other hand, has inversion centres along thechain,andcorrespondstoanarrangementofthetype...BA•AB•BA•AB...

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Figure 4. Comparison of the conformations of the CQ cation in the hydrate (grey) and anhydrous (black) phases, with the aromatic rings overlaid on each other.

of the chains in the anhydrous phase arises from a local hydrogen bonding arrangement of the type O-H · · · O · · · H-O, in which two PO-H hydrogen bond donors share the same PdO oxygen atom as the hydrogen bond acceptor, which is the key structural feature that introduces a “bend” within the chain. Thus, for the DHP anions of type A, one PdO oxygen atom forms two PO-H · · · OdP hydrogen bonds within the chain, whereas the other PdO oxygen atom does not form any PO-H · · · OdP hydrogen bonds within the chain. For the DHP anion of type B, on the other hand, each PdO oxygen atom forms one PO-H · · · OdP hydrogen bond within the chain. In the hydrate phase, the two independent DHP anions in the asymmetric unit both interact with the adjacent DHP anions along the chain in the same manner as the DHP anions of type B in the anhydrous phase (i.e., each PdO oxygen atom forms one (and only one) PO-H · · · OdP hydrogen bond within the chain).

Figure 3. Crystal structure of the anhydrous phase of CQ(DHP)2: (a) viewed along the b-axis, (b) the zig-zag hydrogen-bonded chain of DHP anions running parallel to the a-axis (the two independent DHP anions are labelled A and B), and (c) hydrogen bonding between the CQ cation and three different DHP chains (which run along the direction of view). Hydrogen atoms are omitted for clarity.

(the symbol • denotes an inversion centre). Each pair (AA, AB or BB) of adjacent DHP anions within the chain is linked by two PO-H · · · OdP hydrogen bonds (within a given pair of adjacent DHP anions, each anion provides one PO-H group as donor and one PdO group as acceptor in forming these PO-H · · · OdP hydrogen bonds). However, the zig-zag nature

The hydrate and anhydrous structures also differ in terms of the N-H · · · O hydrogen bonding between the CQ cations and DHP chains and in the conformation of the alkyl chain of the CQ cation. In both structures, all three N-H bonds of the CQ cation are involved in N-H · · · OdP hydrogen bonds to DHP anions. However, for the anhydrous phase, these three N-H · · · OdP hydrogen bonds involve DHP anions in three different chains (Figure 3c). For a given CQ cation, one N-H · · · OdP hydrogen bond involves the PdO oxygen atom of the DHP anion (type A) that is not involved in PO-H · · · OdP hydrogen bonding within the DHP chain, whereas the other two N-H · · · OdP hydrogen bonds involve PdO oxygen atoms of DHP anions of type B that are involved in one PO-H · · · OdP hydrogen bond within the DHP chain. As shown in Figure 4, the conformation of the CQ cation differs significantly between the hydrate and anhydrous phases in terms of the orientation of the alkyl chain relative to the aromatic ring. Clearly, in each case, the formation of a suitable arrangement of N-H · · · OdP hydrogen bonds between CQ cations and DHP anions relies on the ability of the CQ cation to adopt an appropriate conformation. Finally, we note that the aromatic rings of adjacent CQ cations in the anhydrous phase do not form π · · · π interactions [the planes of the rings are not parallel (angle between planes of rings ca. 51°), and the centreto-centre distance is ca. 5 Å], again contrasting with the structure of the hydrate phase.

Topology of Dihydrogen Phosphate Chains

6. Concluding Remarks As discussed in Section 1, many materials that are prepared by solid state dehydration (or, more generally, desolvation) processes are obtained intrinsically as polycrystalline powders, and techniques that allow crystal structures to be determined directly from powder X-ray diffraction data have an important role to play in the structural characterization of new phases produced in this way. Although the number (26) of structural variables involved in the direct-space GA structure solution calculation in the present case is significant, structure solution problems of such dimensionality are nowadays well within the scope of the current generation of algorithms for direct-space structure solution. As reported here, the application of such techniques reveals that dehydration of the hydrate phase of CQ(DHP)2 leads to a substantial change in the topology of the DHP chains, together with other significant structural changes. Given the substantial structural reorganization associated with the dehydration process, it is not at all surprising that this process leads to the formation of a polycrystalline product phase. As discussed above, the final Rietveld refinement for the anhydrous phase was carried out for a model comprising an ordered arrangement of the P-OH bonds and PdO bonds of the DHP anions, based on the fact that this hydrogen bonding arrangement maximizes the number of hydrogen bonds in which the acceptor is the oxygen atom of a PdO bond. Clearly other conceivable hydrogen bonding schemes could also be proposed within the same framework of the DHP chain, but would correspond to a situation in which some P-OH oxygen atoms would serve as hydrogen bond acceptors instead of PdO oxygen atoms. From the powder X-ray diffraction data alone, we cannot rule out the possibility that the actual crystal structure may involve disorder within the hydrogen bonding arrangement, involving fractional populations of some of these different hydrogen bonding schemes, although we suggest that, if such a disordered situation does exist, then the major population should correspond to the hydrogen bonding scheme shown in Figure 3b. Clearly other techniques would be required to prove (or disprove) the existence of such disorder, including neutron diffraction (to establish the populations of hydrogen atom sites within the space-averaged and time-averaged crystal structure) and solid state 2H NMR spectroscopy19 (to establish whether dynamic inter-conversion occurs between alternative hydrogen bonding schemes). Acknowledgment. We are grateful to the University of Birmingham (studentship to D.A.J.) and EPSRC (postdoctoral fellowship to Z.P.) for financial support. Powder X-ray diffraction experiments at the Photon Factory, Tsukuba, Japan, were performed under the approval of the Photon Factory Program Advisory Committee (Proposal No. 2004G054), for which we are grateful. Financial support (to H.U.) under Grant-in-Aid for Scientific Research (KAKENHI) from MEXT in Priority Area No.432 (Molecular Nano Dynamics) is also acknowledged. Supporting Information Available: CIF file containing structural information on the anhydrous phase of CQ(DHP)2. This material is available free of charge via the Internet at http://pubs.acs.org.

References (1) (2) (3) (4) (5) (6)

Stoller, D.; Levine, L. Arch. Biochem. Biophys. 1963, 101, 335. Cohen, S. N.; Yielding, K. L. J. Biol. Chem. 1965, 240, 3123. Schellenberg, K. A.; Coatney, G. R. Biochem. Pharmacol. 1961, 6, 143. Preston, H. S.; Stewart, J. M. Chem. Commun. 1970, 1142. Karle, J. M.; Karle, I. L. Acta Crystallogr. Sect. C 1988, 44, 1605. Furuseth, S.; Karlsen, J.; Mostad, A.; Rømming, C.; Salme´n, R.; Tønnesen, H. H. Acta Chem. Scand. 1990, 44, 741.

Crystal Growth & Design, Vol. 8, No. 10, 2008 3645 (7) Although the three independent reports of the structure determination of the hydrate phase of CQ(DHP)2 from single crystal X-ray diffraction data4-6 are in agreement with regard to the main structural details, they differ in their descriptions of the level of hydration. Thus, the structure is described in one case as a monohydrate,4 in another case as a dihydrate,5 and in another case as a dihydrate but with evidence for only partial occupancy of the water sites.6 Clearly it is possible that the material may be a non-stoichiometric hydrate, which is able to exist across a range of levels of hydration, with no significant change in the remainder of the structure. Given the disagreement in the literature concerning the level of hydration of this material, we refer to it here simply as the ”hydrate phase” and our reference to the structure of this material in the present paper is focused mainly on the results presented in ref 5. As the focus of the present paper is on structural properties of the anhydrous phase, the uncertainty regarding the level of hydration of the parent material is not of direct relevance within the context of the present work. (8) Bjåen, A. K. B.; Nord, K.; Furuseth, S.; Ågren, T.; Tønnesen, H. H.; Karlsen, J. Int. J. Pharm. 1993, 92, 183. (9) (a) Harris, K. D. M.; Tremayne, M. Chem. Mater. 1996, 8, 554. (b) Harris, K. D. M.; Tremayne, M.; Kariuki, B. M. Angew. Chem. Int. Ed. 2001, 40, 1626. (c) Chernyshev, V.V. Russian Chem. Bull. 2001, 50, 2273. (d) David, W. I. F.; Shankland, K.; McCusker, L. B.; Baerlocher, C., Ed.; Structure Determination from Powder Diffraction Data, OUP/IUCr, 2002. (e) Huq, A.; Stephens, P. W. J. Pharm. Sci. 2003, 92, 244. (f) Harris, K. D. M.; Cheung, E. Y. Chem. Soc. ReV. 2004, 33, 526. (g) Tremayne, M. Phil. Trans. R. Soc. 2004, 362, 2691. (h) Favre-Nicolin, V.; Cˇerny´, R. Z. Kristallogr. 2004, 219, 847. (i) Shankland, K.; Markvardsen, A. J.; David, W. I. F. Z. Kristallogr. 2004, 219, 857. (j) Brodski, V.; Peschar, R.; Schenk, H. J. Appl. Crystallogr. 2005, 38, 688. (k) E`erny´, R. Croat. Chem. Acta 2006, 79, 319. (l) Karki, S.; Fabian, L.; Friscic, T.; Jones, W. Org. Lett. 2007, 9, 3133. (m) Tsue, H.; Horiguchi, M.; Tamura, R.; Fujii, K.; Uekusa, H. J. Synth. Org. Chem. Japan 2007, 65, 1203. (n) David, W.I.F.; Shankland, K. Acta Crystallogr. Sect. A 2008, 64, 52. (10) Harris, K. D. M.; Tremayne, M.; Lightfoot, P.; Bruce, P. G. J. Am. Chem. Soc. 1994, 116, 3543. (11) (a) Kariuki, B. M.; Serrano-Gonza´lez, H.; Johnston, R. L.; Harris, K. D. M. Chem. Phys. Lett. 1997, 280, 189. (b) Harris, K. D. M.; Johnston, R. L.; Kariuki, B. M. Acta Crystallogr. Sect. A 1998, 54, 632. (c) Turner, G.W.; Tedesco, E.; Harris, K. D. M.; Johnston, R. L.; Kariuki, B.M. Chem. Phys. Lett. 2000, 321, 183. (d) Habershon, S.; Harris, K. D. M.; Johnston, R. L. J. Comp. Chem. 2003, 24, 1766. (e) Harris, K. D. M.; Habershon, S.; Cheung, E. Y.; Johnston, R. L. Z. Kristallogr. 2004, 219, 838. (f) Kariuki, B. M.; Psallidas, K.; Harris, K. D. M.; Johnston, R. L.; Lancaster, R. W.; Staniforth, S. E.; Cooper, S. M. Chem. Commun. 1999, 1677. (g) Cheung, E. Y.; Kitchin, S. J.; Harris, K. D. M.; Imai, Y.; Tajima, N.; Kuroda, R. J. Am. Chem. Soc. 2003, 125, 14658. (h) Guo, F.; Harris, K. D. M. J. Am. Chem. Soc. 2005, 127, 7314. (i) Pan, Z.; Xu, M.; Cheung, E. Y.; Harris, K. D. M.; Constable, E. C.; Housecroft, C. E. J. Phys. Chem. B 2006, 110, 11620. (j) Hirano, S.; Toyota, S.; Toda, F.; Fujii, K.; Uekusa, H. Angew. Chemie Int. Ed. 2006, 45, 6013. (12) (a) Boultif, A.; Loue¨r, D. J. Appl. Crystallogr. 1991, 24, 987. (b) Boultif, A.; Loue¨r, D. J. Appl. Crystallogr. 2004, 37, 724. (13) Le Bail, A.; Duroy, H.; Fourquet, J. L. Mater. Res. Bull. 1988, 23, 447. (14) Zhou, Z.; Habershon, S.; Turner, G. W.; Kariuki, B. M.; Cheung, E. Y.; Hanson, A. J.; Tedesco, E.; Johnston, R. L.; Harris, K. D. M. EAGERA Program for Structure Solution from Powder X-ray Diffraction Data, Cardiff University and University of Birmingham. (15) Larson A. C.; Von Dreele R. B. GSAS, Los Alamos Laboratory Report No. LA-UR-86-748, 1987. (16) As indicated in Scheme 1, the phosphorus-oxygen bonds for the protonated oxygen atoms (i.e. those denoted P-OH) of the DHP anion are single bonds, whereas the phosphorus-oxygen bonds for the nonprotonated oxygen atoms (i.e., those denoted P)O) are intermediate between single and double bond character (with a formal bond order of 1.5). For typographical convenience, the latter are denoted throughout this paper as P)O, although it is important to emphasize that this notation is not intended to imply that these bonds are actually phosphorus-oxygen double bonds. (17) We recall, as shown in Scheme 1, that the oxygen atom of each P)O group carries a formal negative charge of -1/2. (18) We note that, due in part to polarization effects, the oxygen atom of a P)O · · · H group (i.e., a P)O group already receiving one hydrogen bond) is still expected to be a stronger hydrogen bond acceptor than the oxygen atom of a P-OH group. (19) Aliev, A. E.; Harris, K. D. M. Struct. Bonding 2004, 108, 1.

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