Tailoring the Binding Properties of Phosphazane Anion Receptors and

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Tailoring the Binding Properties of Phosphazane Anion Receptors and Transporters Alex J. Plajer, Jinbo Zhu, Patrick Proehm, Andrew D. Bond, Ulrich F Keyser, and Dominic S. Wright J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00504 • Publication Date (Web): 11 May 2019 Downloaded from http://pubs.acs.org on May 11, 2019

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Journal of the American Chemical Society

Tailoring the Binding Properties of Phosphazane Anion Receptors and Transporters Alex J. Plajer,† Jinbo Zhu,‡ Patrick Proehm,ψ Andrew D. Bond,† Ulrich F. Keyser‡ and Dominic S. Wright.*,† † Chemistry Department, Cambridge University, Lensfield Road, Cambridge CB2 1EW (U.K.). ‡ Cavendish Laboratory, Department of Physics, Cambridge University, J. J. Thomson Avenue, Cambridge CB3 0HE (U.K.) ψ

Institut fuer Chemie und Biochemie, Freie Universitaet Berlin, Fabeckstr. 34 -36 14159 Berlin

KEYWORDS phosphazanes, anion receptors, anion sensing, X-ray, ion transport, small unilamellar vesicles

ABSTRACT: The binding and sensing of anions is an important cross-disciplinary field, which impacts on broad areas such as biology, supramolecular chemistry and catalysis. To date, however, this area has been dominated by organic architectures which function as H-bonding, anion receptor molecules. Inorganic anion receptors have largely been based on Lewis acidic metals, with very few examples of H-bonding counterparts of organic systems having being systematically studied. This paper develops strategies for enhancing the anion binding properties of phosphazanes of the type [(RNH)(E)P(µNtBu)]2 (E = O, S, Se) which are bench-stable, H-bond receptors that can be regarded as inorganic analogues of squaramides (a key class of organic anion receptor). The distinct advantages of these inorganic receptors over organic counterparts is the ease by which their functionality and electronic character can be altered (by means of the R-groups, chalcogenide or metal present). Se-substitution at the P-centers, the presence of electron withdrawing R-groups and metal coordination to the soft donor centers can be used to modulate and enhance anion binding. The water stability and superior anion binding properties of the seleno-phosph(V)azanes gives them applications as synthetic anion transporters through phospholipid layers.

Introduction Anion binding and sensing using small organic receptor molecules containing H-bonding functionality is a rapidly developing area of research.1–3 Owing to their ease of synthesis, chemical robustness and high binding constants, ureas and squaramides are among the most popular classes of small organic receptors used in the field (Figure 1), and have broad ranging applications in anion-sensing, anion-transport and counterion-catalysis.4–7 However, inorganic counterparts based on non-carbon frameworks have received less attention, largely because of their common thermodynamic and kinetic instability, which makes them generally unsuitable for applications under ambient and aqueous conditions. There are several potential advantages in using inorganic alternatives in this area, not least greater flexibility in modulating the spatial and electronic characteristics of the host without the need for

elaborate synthesis and the relative ease by which different functionalities can be introduced. Urea

Squaramide

X

R

H N

X H N

E

R

H R N O

H N R O

Figure 1 The structures of ureas and squaramides and their binding to anions (X-) via H-bonding to the N-H groups.

A commonly employed strategy for main group anionreceptors has been the incorporation of Lewis acidic metal atoms, such as B and Sb, for anion binding.8–11 A range of Hbond donor functionalities containing a variety of p-block functionalities has also recently emerged, including phosphoramides [R2P(=O)NHR, sulfonamide [RS(=O)2NHR], boronic acids [RB(OH)2], borinic acids (R2BOH), silanols (R3SiOH), phosphoric acid RO2P(=O)OH and phosphonium cations (RN2)2P(RNH)2+.12–18 The acidity of the H-bond donor N-H and O-H groups increases when bonded to heavier main group elements, due to transfer of electron density from the lone-pairs on N or O into the σ*- or p-orbitals of the main group center, e.g., the proton acidity of C-OH is less than Si-OH.16,19– 21 Changing the main group element therefore provides the potential means of tuning the strength of anion binding and affinity. The overarching requirement for any useful inorganic anion host is high bond energy and low polarity of the framework bonds (resulting in thermodynamic and kinetic stability). These requirements are met in particular in the P-N single bond, with a bond energy of ca. 290 kJ mol-1 which is relatively close to that of the C-C single bond (346 kJ mol-1), and a difference in electronegativity (Pauling) of 0.85.22 As a result, a number of P-N bonded phosphazane-based supramolecular arrangements and H-bond donor receptors have recently emerged.23–28 In our own research, we have explored the N-H functionalized macrocyclic phosph(III)azane [{P(-NtBu)}2(-NH)]5 (Figure 2) which exhibits size-selective coordination of a range of anions and a marked preference for Cl-.29,30

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t

BuN P

P

P

colorimetric reagents for the detection of F- and anion transport through phospholipid layers have also been explored. H H H H t t R N R N Bu N R Bu N R N N P P P P N N t t E Bu Bu E A B

P

NtBu t t BuN N Bu H P

N H

N

Page 2 of 10

H N

P t t N Bu BuN BuN NtBu H H t P N Bu N P N P P N t Bu

t

Figure 4 Structures of [RNHP(µ-NtBu)]2 (A) and selenocyclodiphosph(V)azanes [RNH(E)P(µ-NtBu)]2 (B) (E = O, S, Se).

Figure 2 Structure of the anion-receptor macrocycle [{P(NtBu)}2(-NH)]5.

Directly relevant to the study presented here, Goldfuss and coworkers have investigated the anion binding properties of the air-stable phosph(V)azane dimers [ArNH(E)P(-NtBu)]2 (E = O (1a), S (1b), Ar = 3,5-(CF3)2C6H3) (Figure 3), whose bidentate H-bond donor arrangements are conceptually related to ureas and squaramides.31–33 Phosph(V)azane 1a binds particularly strongly to Cl-, with logK = 5.43 being significantly higher than the corresponding diaryl urea (logK = 4.25 M-1) and squaramide (logK = 5.13 M-1) (containing the same 3,5(CF3)2C6H3 groups). This high anion affinity makes 1a useful in counterion-catalysis of the N-acyl-Mannich reaction. The sulfur derivative 1b has a significantly lower affinity for Cl-. This difference was ascribed, on the basis of structural and DFT studies, to the effect of stabilizing ortho-C-H•••O=P interactions in the O-analogue 1a on the conformation of the dimer, making the chelating N-H ‘in-in’ conformation (necessary for bifurcated Cl- coordination) more energetically accessible (Figure 3). It can be noted, however, that the calculated differences in energy between the various conformers is no more than ca. 5 kcal mol-1, and that the effect of the electronegativity of the chalcogen on the polarization of the NH bonds was not considered.

Results and Discussion 1.1 The Qualitative Effects of Oxidation, Ligand Substitution and Metal Coordination on Phosph(III)azane Anion Binding Our initial aim in the current work was to gain a qualitative understanding of how the H-bond donor properties of phosph(III)azanes of the type [(RNH)2P(-NtBu)]2 (A) can be modified by oxidation of the PIII centers to phosph(V)azanes (B), by changing the endocyclic NR groups (C) or by coordination to metal atoms (D) (Figure 5). For this purpose, a series of new anion receptors in each class was prepared (shown in Figure 5) (see Supporting Information, Section 1). In this study we chose to explore Se-oxidation of the phosphazane framework in B since, as noted in the introduction, the effects of descending group 16 had not been assessed previously. This subject is returned to in the next section of this paper, where the effects of O-, S- and Se-substitution at PIII are examined quantitatively. N

F 3C

H

H R

N

t

P

Bu N N t Bu

R

P

N

H

P

F 3C

F3C

H

H F3C

Cl

H N

H

P E

H H t Bu N N P H N t Bu E

R

CF3 H CF3

Cl- complex of 1a (E = O) Goldfuss 1b (E = S)

N

H

P E

N t Bu

R

N

t

Bu N

P

F 3C

F 3C

E

P

Figure 3 Coordination of a Cl- anion by 1a and 1b.

R N N R

N

R

P

F 3C

H

CF3

P N P N

F 3C F 3C

N P

[M]

t

Bu N N t Bu D

N CF3

CF3 2

F 3C

H

H R

CF3

H

F 3C

N

C

In this paper we develop fundamental tools for the activation and tuning of the anion-receptor behavior of cyclodiphosph(III)azanes of the type [RNHP(µ-NtBu)]2 (A) (Figure 1). Phosph(V)azane anion receptors [RNH(Se)P(µNtBu)]2 (B) are found to not only to be synthetically more accessible and hydrolytically more stable than oxygen counterparts but, surprisingly, also to have similar if not greater binding constants for Cl-. Coordination of the PIII atoms of A to metal centers or substitution of the endocyclic tBu groups for electron withdrawing substituents also enhance Cl- binding by the N-H groups, to a similar level to that found in B. By harnessing the anion-binding properties of selenocyclodiphosph(V)azanes of type B, new applications as

CF3

1c H

H N

CF3

H N tBu N N P P N t Se Bu Se H

B

R

CF3

A-1

A H

CF3

H Bu N N P N t Bu t

N

H

R

P

N P

F 3C [M]

Au Cl

H Bu N N P N t Bu Au

CF3

t

A-1(AuCl)2

CF3

Cl

Figure 5 The main types of receptor (A-D) examined in the initial stages of the current study and the individual compounds explored (with their numbering schemes).


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3.07

3.04 shorter

3.38 Se

A-1.Et3NHCl Endo Derivatization

1c.Et3NHCl 2 eq (Me2S)AuCl longer shorter

3.05 shorter

3.21

3.16 3.19

3.23

A-1(AuCl)2.Et3NHCl

2.Et3NHCl

Figure 6 Comparison of the structural effects on the Et3NHCl adducts of oxidation of the PIII centers of A-1 by Se in 1c, substitution of the P2N2-bridging tBuN-groups in A-1 by (CF3)2C6H3N-groups, and coordination of the PIII atoms of A-1 by AuCl. Displacement ellipsoids with 40% probability at 180(2) K. Selected bond length [Å] and angles [°]: A-1•Et3NHCl, Nendo-P av. 1.71, Nexo-P av 1.70, (receptor)N···Cl av. 3.38, Et3N(H)···Cl 3.04, Nexo-P-Nendo av. 102.8, P-N-P av. 97.9; 1c•Et3NHCl, Nendo-P av. 1.68, Nexo-P av. 1.65, P-Se av. 2.08, (receptor)N···Cl av. 3.21, Et3N(H)···Cl 3.07, Nexo-P-Nendo av. 107.2, P-N-P av. 96.4, Nendo-P-Se av. 113.6; 2•Et3NHCl, NendoP av. 1.73, Nexo-P av. 1.67, (receptor)N···Cl av. 3.23, Et3N(H)···Cl 3.05 Nexo-P-Nendo av. 104.5, P-N-P av. 101.2. A-1(AuCl)2•Et3NHCl, Nendo-P av. 1.68, Nexo-P av. 1.64, P-Au av. 2.20, (receptor)N···Cl av. 3.19, Et3N(H)···Cl 3.16, Nexo-P-Nendo av. 108.6, P-N-P av. 97.1, Nendo-P-Au av. 120.3. Color code, P (orange), N (magenta), Se (orange), N (magenta), Cl (green), F (yellow), Au (yellow).

In order to provide qualitative understanding of the trends in anion binding we prepared a series of discrete host-guest complexes via established synthetic protocols (see Supporting information, Section 1). Figure 6 compares the single-crystal Xray structures of the Et3NCl adducts of each of these anion receptors, in which the Cl- anions are coordinated by the N-H groups. Oxidation of the PIII centers of A-1 by Se results in significant shortening of the N-H•••Cl H-bonds in the PV adduct 1c•Et3NHCl by ca. 0.17 Å (from N•••Cl av. 3.38 Å in A1•Et3NHCl to av. 3.21 Å in 1c•Et3NHCl), signifying the greater H-bond donor properties of the receptor 1c. The increased Clreceptor interaction is accommodated by the reorientation of the 3,5-(CF3)2C6H3 units, which are mutually coplanar and perpendicular to the P2N2 mean plane in A-1•Et3NHCl but tilted significantly from perpendicular in 1•Et3NHCl (by av. 52o) (Figure 6). This change allows the closer engagement of the Et3NHCl guest with the receptor pocket of 1c, but has the effect of reducing the potential for any stabilizing ortho-C-H•••Se interactions with the 3,5-(CF3)2C6H3 groups. Such interactions have been proposed previously to be crucial to the ‘in-in’ conformation of the N-H groups in the closely related O- and Sreceptors 1a and 1b (Figure 3).32 However, these interactions

are at best weak in 1c•Et3NHCl (2.87-2.93 Å, cf. 3.10 Å for the sum of van der Waals radii of Se and H), and the analysis of the structures of A-1•Et3NHCl and 1c•Et3NHCl strongly suggests that steric factors are more important in dictating the orientation of the 3,5-(CF3)2C6H3 groups in the Se receptors.34 The effects of H-bonding in A-1•Et3NHCl and 1c•Et3NHCl are also observed in their solution 1H NMR spectra in CDCl3 at room temperature. The strengthening of the phosphazanechloride interactions causes deshielding of the phosphazane NH proton from  7.13 ppm in A-1•Et3NHCl to  8.80 ppm in 1c•Et3NHCl and the concurrent weakening of the Et3NH+···Clinteractions, resulting in shielding of the ammonium NH resonances from  11.85 ppm in A-1•Et3NHCl to  10.98 ppm in 1c•Et3NHCl. Therefore oxidation can be seen to amplify the receptor properties of phosphazanes not only in the solid state but also in solution. Similar receptor enhancement to selenium oxidation is also caused by replacing the endocyclic, electron-rich tBu substituents by electron withdrawing 3,5-(CF3)2C6H3 substituents in the phosh(III)azane 2 (Figure 6). The result of the incorporation of this electron-withdrawing group within the P2N2 ring unit is the shortening of the N-H•••Cl H-bonds in



2•Et3NHCl by ca. 0.15 Å compared to those in A-1•Et3NHCl, i.e., of a similar magnitude to the effect of Se-oxidation of A-1. Interestingly, no tilting of the exocyclic 3,5-(CF3)2C6H3 substituents of the receptor 2 is observed, presumably because of the lower steric demands of the endo 3,5-(CF3)2C6H3 groups compared to the tBu substituents in A-1. Therefore close approach of the Et3NHCl guest can occur without significant distortion of the receptor ligand in this case. The potential effect of metal coordination of the receptors on anion binding of phosphazanes has not been explored previously. Indeed, only a few studies of this effect have been published with conceptually-similar organic receptors. 35–38 An increase in the H-bond donor properties of the phosphazane A1 on coordination to AuI is seen in the solid-state structure of the Et3NCl adduct of A-1(AuCl)2 (Figure 6), in which there is a large increase in the Et3N-H•••Cl distances (by ca. 0.12 Å with respect to the N•••Cl contact) and a corresponding large decrease in the N-H•••phosphazane H-bonding interactions (by ca. 0.19 Å with respect to the N•••Cl contact) compared to the Et3NHCl adduct of A-1. This strengthening of the NH•••Cl interactions is also consistent with the large down-field shift of the receptor NH protons from  7.13 to  9.38 in the 1H NMR spectra comparing the Et3NHCl adducts of A-1 and A-1(AuCl)2 (in CDCl3). The extent of the strengthening of the H-bonding resulting from coordination of AuI is at least on a par with the effect of Se-oxidation seen in 1c•Et3NHCl, on the basis of a comparison of their solid-state structures. However, the 1H NMR spectrum of the Et3NCl adduct of A-1(AuCl)2 in solution might actually suggests that coordination of the P-atoms amplifies the binding properties to a greater extent than Seoxidation, with the NH proton resonance for the Et3NHCl adduct of A-1(AuCl)2 ( 9.38 ppm) being significantly downfield of that for 1c ( 8.80 ppm). This is also accompanied by a large reduction of ca. 0.90 ppm in the Et3NH N-H resonance moving to A-1(AuCl)2. This initial work helped us to pinpoint the phosha(V)zanes B as the most viable candidates for further studies. These species are not only the most soluble in a range of organic solvents and indefinitely air-, moisture- and light-stable (unlike all the other receptors containing phosph(III)azanes investigated), but are also extremely easily prepared. We found in the current work that the reactions of Se-powder with a range of phosp(III)azanes (A) at room temperature in THF as the solvent give exclusively the cis-isomers of phosh(V)azanes (B) in > 90% yields, without the formation of the trans-isomers or other products (Figure 7) (see Supporting Information). This approach therefore provides a simple, modular strategy to a broad family of receptors starting from the readily prepared The phosph(III)azane precursors [ClP(-NtBu)]2.39–43 regioselectivity of these reactions contrasts with previous studies of O- or S-oxidation of phosph(III)azanes which have normally been performed in toluene at reflux, with the cis- and trans- products formed being separated by, e.g., column chromatography, and resulting in overall yields of the cisisomers in 3b ( 3.74) > 3a ( 3.15) (Supporting Information).

H

t

Bu N P E

3a (E = O) H Bu N tBu N 3b (E = S) P N t 3c (E = Se) Bu E t

Increase in Binding Affinity

Figure 8 The dimers 3a, 3b and 3c.

The binding constants of 3a-3c with Cl- in ACN were measured by titration with a standard solution of [nBu4N]Cl (TBACl). The change in the N-H resonances was monitored by 1H NMR spectroscopy and could all be fitted to a 1 : 1 binding model (Supporting Information, Section 2).45 In accordance with our initial NMR spectroscopic observations, the binding constants (K) follow the same order of 3c (235 ± 7 M-1) > 3b (155 ± 3 M-1) > 3a (18 ± 2 M-1).


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3a

3b

3c

Figure 9 Top: ESPs of 3a, 3b and 3c plotted on the electron density at an isovalue of 0.03, calculated on B3LYP-D3-BJ/def2-TZVPD. Bottom: The LUMO of 3a, 3b and 3c obtained at B3LYP-D3-BJ/def2-TZVPD level of theory at an isovalue of 0.03 and associated HOMO-LUMO gaps.

The order of the binding constants for 3b (E = S) and 3c (E = O) is the opposite of that observed by Goldfuss and coworkers for 1a and 1b, i.e., 1a > 1b (Figure 3). Intrigued by this difference, we determined the binding constant for the Sereceptor 1c using UV-visible titration in ACN with a standard solution of TBACl at 25oC. Again we were able to fit the data to a 1 : 1 binding isotherm with logK = 5.74 ± 0.05. This value can be compared to the previously reported value of logK for the O-receptor 1a of 5.43 ± 0.02 in ACN. The increase in Claffinity is in line with the larger 1H NMR N-H chemical shift in 1c compared to 1a at room temperature in ACN. The value of logK reported for the S-receptor is 5.17 ± 0.02. On this basis, the binding constants for Cl- in ACN follow the order 1a ≈ 1c > 1b. The significant point being that the Se-receptor has a binding constant that is at least as high if not higher than the Oreceptor. DFT calculations at the B3LYP-D3-BJ/def2-TZVPD level of theory were used to investigate the proton acidities and, hence, the relative anion binding properties of 3a, 3b and 3c. A systematic decrease of the electron density at the bond critical point of the N-H bonds is found moving from 3a (ρ = 0.3406 e/Å3) to 3b (ρ = 0.3393 e/Å3) to 3c (ρ = 0.3387 e/ Å3), which is in line with the observed greater acidity of the N-H bonds, favorable for hydrogen bonding. However, this increased acidity is not reflected in the charges on the N and H atoms, which remain almost the same in 3a, 3b and 3c (N, ca. 1.01e, H ca. +0.40e) despite a significant decrease in the charge at the P atoms along this series (Figure S32). The LUMO of 3a, 3b and 3c (Figure 9, lower panel) is located at the position where anion binding occurs, with the main contribution to the LUMO being from the σ* C-H and NH orbitals, and with the chalcogen contribution increasing going from 3a to 3b to 3c. The energy of the LUMO decreases going from 3a (-0.517 eV) to 3b (-0.571 eV) to 3c (-0.629 eV). This means that occupation of the LUMO with the electron density of a chloride anion upon binding will release more energy for 3c than 3b and 3a, consistent with the observed order of chloride binding constant. The lowering of the LUMO energies is a direct consequence of decreasing the HOMOLUMO gap when moving from chemically hard to soft atoms

(HOMO-LUMO gap 3c (5.07 eV), 3b (5.33 eV) and 3a (5.72 eV)).46 The greater delocalisation of the chalcogen electron density moving from O to S and Se is seen in the electrostatic potential (ESP) maps (Figure 9, top panel), which show a decrease in the electron density of the chalogen and a more homogeneous charge distribution moving from 1a to 1b and 1c, suggesting greater delocalization and polarisability. A similar trend is observed for the natural charges (see Supporting Information). Here, the O-atom of 1a is calculated to carry a negative charge of -1.085e, significantly higher that the S-atom of 1b (-0.576e) and the Se-atom of 1c (-0.489e). Although we are not able to provide a simple (pictorial) explanation for the ‘selenium effect’, the calculations suggest that the selenium derivatives are the most potent anion receptors on the basis of electronic factors associated with the inorganic framework. A possible explanation for the different behavior of 1a, 1b and 1c (with experimental binding constants in the order 1a ≈ 1c > 1b) is that the effect of the chalcogen (O, S or Se) on the framework bonding and the polarity of the N-H groups (seen in 3a-3c) is off-set in 1a by the preorganization due to ortho-CH•••O=P interactions (see Figure 3). 2 eq (tBu)3P

R N

H

P Se

2 eq (tBu)3P Se

H Bu N R N P N t Bu Se

R N

t

A

H

P 2 eq Se

H Bu N R N P N t Bu B t

Enhanced Chloride Binding

Figure 10 Binding modulation by oxidation and reduction of seleno-cyclodiphosphazanes. An interesting side issue to the use of these Se-receptors is that the receptor enhancement induced by selenium oxidation of the phosph(III)azane framework can be reversed by



reduction. In situ reaction of the phosph(V)azanes 1c and 3c with excess tBu3P results in quantitative generation of the phosph(III)azanes together with tBu3P=Se (see supporting information) (Figure 10). In the case of 3c reduction switches chloride binding of Cl- off completely. The ability to modulate anion binding in this way is uniquely different from organic receptors like thiorureas and squaramides.

2

Page 6 of 10

experiments.53 Since all of the receptors 1c, 3a, 3b and 3c are indefinitely stable under benchtop conditions, we aimed to investigate their properties as anion transporters. The closest work to the transporter ability of phosphazanes reported here is the investigation of the phosphoric triamide receptors (E=)P(NHAr)3 (E = O, S; Ar = 3,5-(CF3)2C6H3) by Gale and coworkers.54

Applications of Phosphazanes in Anion Sensing and Membrane Transport

We next looked at how the effects of anion binding might be used for anion sensing and the transport of anions through phospholipid layers. Although the P2N2 ring unit of [tBuNH(O)P(-NtBu)]2 (1a) remains intact upon coordination of Cl-, previous in situ 1H and 31P NMR spectroscopic studies showed that the P2N2 ring unit does not survive in the presence of F-, presumably due to nucleophilic attack of the P-atoms and ring opening.31,47 We wondered whether this effect could be harnessed as a means of sensing F- anions. For this purpose Sephosph(V)azane 4 (Figure 11), containing chromophoric benzoxadiazole groups, was chosen as a candidate for investigation. In accord with the previously published report, addition of excess TBAX containing less nucleophilic X = Cl-, Br-, I- to solutions of 4 in MeCN does not result in any significant color change. However, addition of excess TBAF gives an immediate red color change (Figure 11), so that 4 functions as a colorometric reagent for F-.

N

O

N

N H N P

Se

O

N

-

-

-

X = NO3 , HCO3 , SO4

2-

Figure 12 Schematics of (a) the lucigenin assay (POPCLUVs⊃LU) used to assess anion carrier ability into a LUV, (b) the lucigenin assay exchange of Cl- (inside) and other anions (X- = NO3-, HCO3-, SO42-) outside the LUV.

H t Bu N N P N t Bu Se 4

Figure 11 Structure of 4 (see Scheme 1 for synthesis) and the observed effect of the addition of excess TBAX (X = F, Cl, Br, I) to MeCN solutions of 4.

The titration of TBAF into a MeCN solution of 4 was monitored by UV-vis spectroscopy. Addition of 0.1- 7.6 equivalents of TBAF reveals that multiple transformations occur during the addition of F-, with the appearance of isosbestic points at different stages of the titration (see Supporting Information). In situ 31P NMR spectroscopy in CD3CN supports the conclusion that 4 reacts with F- at higher concentration, with the chemical shift changing by ca. 15 ppm on addition of 10 equivalents of TBAF. The single product formed contains one 31P environment with isotopic coupling to a single 77Se atom (and no 31P-19F coupling), indicating breakdown of the P2N2 ring of 4 in to a mononuclear phosphorus species (in line with the previous report51). The fact that the phosphazane receptors can strongly bind Cland are also soluble in a range of organic solvents (owing to the presence of apolar organic substituents) suggested that they may be of value as synthetic anion transporters through phosphospholipid layers, an area extensively investigated with organic receptors.48–52 Although recent studies have identified halogen, chalcogen and pnictogen Lewis acids as aniontransporters, the use of more complex main group receptors has been widely ignored as such systems are rarely robust enough under the aqueous conditions used in membrane-transport

Ion transport was assessed using lucigenin (LU, a chloridesensitive fluorescent dye) or 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS, a pH sensitive fluorescent dye) encapsulated large unilamellar vesicles (LUVs) composed of 2-oleoyl-1palmitoyl-sn-glycero-3-phosphocholine (POPC). The lucigenin assay (POPC-LUV⊃LU) was used to assess Cl- transport (Figure 12a) and Cl-/X- exchange (Figure 12b) into and out of the LUVs, mediated by the phosph(V)azane anion carriers.55,56 While the HPTS assay (POPC-LUV⊃HPTS) was used to assess the ion transport activity and selectivity of cation and anion transport through the membrane (Figure S27). 57,58 All of the experiments were performed in aqueous media. From Figure 13 it can be concluded that the Sephosph(V)azane 1c (containing electron-withdrawing 3,5(CF3)2C6H3 groups) is a better Cl- anion carrier than 3c (containing electron-donating tBuNH substituents). The anion transport behavior can at least in part be explained by the relative anion binding properties, with the values of LogK being in the same order as the observed Cl- carrier ability (1c > 3c). However, fluorination of synthetic anion transporters has also been previously reported to increase transport activity.50 In order to allow more accurate comparison of the most active phosphazane receptor 1c with organic counterparts, we determined the EC50 values (the concentration of transporter needed for 50% chloride efflux in 270s) of 1c and the corresponding thiourea and squareamide containing 3,5(CF3)2C6H3 substituents (Figure S29) using HPTS assay. The Se-phosph(V)azane 1c has very similar activity to the thiourea,


Page 7 of 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


with the squaramide being the most active (1c EC50 = 8.56 nM, thiourea = 8.02 nM, squaramide = 0.35 nM), in line with previous reports.59 Only a limited number of topologicallysimple anion transporters with competitive EC50 values to those of thioureas and squaramides have been reported previously. We employed an HPTS assay to investigate the cation dependency of the transport of anions, and hence to determine whether a cation-anion symport or anion-anion antiport transport mechanism across the membrane is involved. The POPC-LUVs⊃HPTS assay shows that changing the cation from Li+ to Na+, K+, Rb+ or Cs+ has little effect on 1c-assisted transport of H+ or OH- through the membrane (Figure S30a), so that a symport mechanism is therefore unlikely. By following the fluorescence intensity of vesicles containing Cl- upon addition of different anions outside the vesicle (Figure 14a), transport of Cl- anions outside the vesicle can clearly be observe upon NO3- addition. However, addition of SO42- resulted in no fluorescence change and addition of HCO3- in only a minor change. The selectivity for nitrate and chloride over sulfate was confirmed in a separate HPTS assay (Figure S30b). Such clear anion dependence is a strong indication of an anion-anion antiport mechanism and is similar to the transport mechanism observed for thioureas, squareamides and (E=)P(NHAr)3 [E = O, S; Ar = 3,5-(CF3)2C6H3].4

increase in anion affinity as well as the greater hydrophobicity of the heavier congeners. This is in line with the development of partial charges we observe in the DFT analysis of 3a, 3b and 3c (see Supporting Information). Our study is the first to identify the large dependence in transport activity on descending Group 16, and should have a direct impact on the design of related main group transporters in the future.

3a 3b 3c

Figure 13 Chloride influx into POPC-LUVs⊃lucigenin mediated by different carriers added at 1.5 min with the same concentration (200 nM). FI = Fluorescence intensity. 10 µL of acetonitrile was added as the blank control. 1 mM lucigenin was encapsulated in the LUVs and 20 mM NaCl was in the extravesicular buffer solution.

Finally, since our previous studies had identified significant differences in Cl- binding to phosph(V)azanes of the type [RNH(E)P(-NtBu)]2 (B), containing different chalcogens (E = O, S, Se), we also looked at the effect of varying the chalcogen substitution on membrane transport. Comparing 3a, 3b and 3c, we observe an increase in transport activity moving to the heavier chalcogens (3c > 3b > 3a) (Figure 14b), with the Otransporter having almost no activity. Apart from the inherently lower anion binding ability of 3a which we determined previously in this report, a further reason for the poor transport properties of 3a is its’ hydrolytic sensitivity. Whereas solid 3c is completely insoluble but stable in D2O at room temperature, contrary to previous reports 3a rapidly hydrolyses under these condition (Figure S31).60 The greater transport activity of the Se-receptor 3c over the S-receptors 3b can be attributed to the

Figure 14 a) Ion transport activity of 1c (0.1 µM) across NaCl contained POPC-LUVs⊃lucigenin compared in different extravesicular solution conditions. Inside: 100 mM NaCl, 1 mM lucigenin, PB buffer; outside: 100 mM NaX (X= NO3- HCO3-, SO42-), PB buffer. The NaCl contained POPC-LUVs⊃lucigenin was diluted by NaX-PB buffer before measurement and 1c was added at 1 min b) Chloride influx into POPC-LUVs⊃lucigenin mediated by carriers 3a-c (0.5 µM). Carriers were added at 1.5 min and Triton X-100 was added at 6 min.

Conclusions In the current study we have found that selenophosph(V)azanes [RNH(Se)P(µ-NtBu)]2 (B), which are more easily synthesized and functionalized than the O- or Scounterparts, have superior anion binding and anion transport properties. Se-substitution at the PIII-atoms of t phosph(III)azanes [RNH(Se)P(µ-N Bu)]2 (A) has a similar effect to the introduction of electron-withdrawing groups within the P2N2 rings or metal coordination by the P-lone pairs. The selective lability of the P2N2 ring units of selenophosph(V)azanes B to ring cleavage by strong nucleophiles can be harnessed to develop F- sensing capability by the incorporation of chromophoric substituents (R), while their water stability, hydrophobic character and strong anion binding



properties lead to applications as synthetic anion transporters through phospholipid layers (which are competitive with organic variants). Importantly, our study shows just how significant substitution of the chalcogen can be in regard to transport activity. By providing the tools for modulating anion binding, this work sets the stage for the development of highly active, adaptive main group anion receptors in catalysis and membrane transport. Exciting prospects in this area are chiral anion receptors (i.e., containing endo-cyclic chiral groups) and tandem catalysis involving anion binding and metal activation. ASSOCIATED CONTENT Supporting Information. Synthesis and characterization and Xray data on A-1•Et3NHCl, 1c•Et3NHCl, 2•Et3NHCl, A1(AuCl)2•Et3NHCl. Binding constant measurements on 1c, 3a, 3b and 3c and associated NMR spectroscopic data. Protocol, synthetic aspects and conditions for ion transport in POPCLUVs. This material is available free of charge via the Internet at http://pubs.acs.org.” Corresponding Author Prof. D. S. Wright, Chemistry Department, Cambridge University, Lensfield Road, Cambridge CB2 1EW (U.K.); e-mail [email protected].

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Funding Sources Cambridge Trust, Engineering and Physical Sciences Research council (EPSRC), U.K.

Notes The authors state that there are no financial or other conflicts of interest.

ACKNOWLEDGMENT We thank the Cambridge Trust (Vice Chancellor Scholarship for AJP) and the EPSRC (J.Z., U.F.K. EP/M008258/1) for financial support. We also thank the ZEDAT and FU Berlin.

ABBREVIATIONS 2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine (POPC), small unilamellar vesicle (LUV), lucigenin (LU), 8-hydroxypyrene1,3,6-trisulfonic acid (HPTS), EC50 (concentration of transporter needed for 50% chloride efflux in 270s). (1) Gale, P. A.; Busschaert, N.; Haynes, C. J. E.; Karagiannidis, L. E.; Kirby, I. L. Anion Receptor Chemistry: Highlights from 2011 and 2012. Chem. Soc. Rev. 2014, 43, 205–241. (2) Wenzel, M.; Hiscock, J. R.; Gale, P. A. Anion Receptor Chemistry: Highlights from 2010. Chem. Soc. Rev. 2012, 41, 480–520. (3) Gale, P. A.; Howe, E. N. W.; Wu, X. Anion Receptor Chemistry. Chem 2016, 1, 351–422. (4) Wu, X.; Howe, E. N. W.; Gale, P. A. Supramolecular Transmembrane Anion Transport: New Assays and Insights. Acc. Chem. Res. 2018, 51, 1870–1879. (5) Amendola, V.; Bergamaschi, G.; Boiocchi, M.; Fabbrizzi, L.; Milani, M. The Squaramide versus Urea Contest for Anion Recognition. Chem. - A Eur. J. 2010, 16, 4368–4380. (6) Blažek Bregović, V.; Basarić, N.; Mlinarić-Majerski, K. Anion Binding with Urea and Thiourea Derivatives. Coord. Chem. Rev. 2015, 295, 80–124.

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Tailoring the Binding Properties of Phosphazane Anion Receptors and

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