Anion Binding in Solution: Beyond the Electrostatic Regime Yun Liu, Arkajyoti Sengupta, Krishnan Raghavachari, Amar H. Flood  Chem  Volume 3, Issue 3, Pages 411-427 (September 2017) DOI: 10.1016/j.chempr.2017.08.003 Copyright © 2017 Elsevier Inc. Terms and Conditions

Chem 2017 3, 411-427DOI: (10.1016/j.chempr.2017.08.003) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Model System for Understanding Anion Binding in Solution (A) The 1:1 binding of shape-persistent triazolophane macrocycle with Cl–. Top view: structures of the triazolophanes examined by theory (R1 = R2 = H) and experiment (R1 = tert-butyl, R2 = triethylene glycol mono-methyl ether). Side view: optimized geometries of the triazolophane (R1,2 = H) and its 1:1 Cl− complex by M06-2X/6-31+G(d,p) level of theory. The replacement of phenylene substituents with hydrogens during computations has only a small impact on computed energies.21 See Mendeley for the raw data here and here. (B) The thermodynamic model of the 1:1 binding is pictured as a cycle. Downhill and uphill processes are represented by blue and red arrows, respectively. Chem 2017 3, 411-427DOI: (10.1016/j.chempr.2017.08.003) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 2 Electrostatic Character of 1:1 Tz:Cl– Binding (A–C) The electrostatic potential (ESP) that shows up as (A) negative around Cl– is weakened (B) by the positive ESP in the empty binding pocket (C) when a complex is formed. ESP maps are calculated at M06-2X/6-31+G(d,p) level of theory (Supplemental Information, Section 5). (D) The ESP maps calculated at the molecular surfaces of Cl–, triazolophane, and the 1:1 complex. Chem 2017 3, 411-427DOI: (10.1016/j.chempr.2017.08.003) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 3 Triazolophane:Cl– Binding across Solvents (ɛr = 4.7–56.2) (A) Chemical structures of triazolophane (Tz) and the tetra-n-butylammonium (TBA) salt. Key protons are labeled for analyzing 1H NMR spectra. (B and C) 1H NMR titration spectra of triazolophane with TBACl in (B) a nonpolar medium, chloroform-d1, and (C) a polar medium, DMSO-d6 with 10% v/v D2O. Solution species present during the course of the titrations are indicated by cartoon representations. See Figures S13 and S14 for an overview. See (B) here and (C) here for the raw data. (D and E) Calculated speciation curves (1 mM) in (D) chloroform and (E) 10% water in DMSO. See (D) here and (E) here for the raw data. (F) Speciation of triazolophane-chloride complexation across solvents simulated at 1 mM with 1 equiv of TBACl based on the equilibrium constants (Table 1); see also Figures S38 and S39. The higher-order species [Tz3⋅Cl2]2– accounts for speciation seen in the NMR data. See the raw data here. Chem 2017 3, 411-427DOI: (10.1016/j.chempr.2017.08.003) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 4 The Solvent Dependences of ΔG1 and ΔG2: Experimental and Theoretical Results (A) The 1:1 (log K1) binding affinity of triazolophane with Cl– across solvents shows the combination of dielectric effect and preferential hydration (solvation). Experimental errors are presented as two SDs. See the raw data here. (B) Solvent dependence of anion binding affinities in the global model (Equation 17). See the raw data here. (C) The cooperativity (ΔGcoop) associated with formation of the 2:1 sandwich complex is enhanced by increased solvophobic driving forces in polar solvents. The free-energy boundary between negative and positive cooperativity, RT ln 4, reflects that there is no cooperativity when the ratio of K2/K1 is 1/4. See the raw data here. (D) DFT calculation with implicit solvation models corroborates well with the experimental results for ΔG1 in pure organic solvents. Experimental errors are presented as two SDs. See the raw data here. Chem 2017 3, 411-427DOI: (10.1016/j.chempr.2017.08.003) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 5 Theoretical Analysis on the Dielectric Dependence for 1:1 Complex (A) Solvation penalties, ΣΔGsolv, trace the computed 1:1 binding free energy, ΔG1calc. See the raw data here. (B) The determination of electrostatic binding energy in gas phase, ΔWgas(binding), by extrapolation of the calculated solvation penalties, ΣΔGsolv, to infinite dielectric constant with Equation 11. See also Figures S56 and S57. Chem 2017 3, 411-427DOI: (10.1016/j.chempr.2017.08.003) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 6 Global Model for the 1:1 Tz⋅Cl– Binding Affinities (A) The semi-empirical LFER (Equation 15) is parameterized with data from the eight solvents (red circles) and then used for predicting 1:1 binding affinities in unbenchmarked media (blue circles): 1,2-dichloroethane (1,2-DCE) and water-saturated nitrobenzene (w-PhNO2). The fitting parameters are as follows: slope = 0.96, error = 0.6 kcal mol−1, and R2 = 0.95. Experimental errors are presented as two SDs. See the raw data here. (B) Application of Equation 15 for evaluating conditions under which the triazolophane can achieve certain solution affinities, ΔGsoln, in water (K = 1, ɛr = 78.4, C = 6.8, αw = 1.17, χw = 1.00). The current status of triazolophane is marked on the contour map. Chem 2017 3, 411-427DOI: (10.1016/j.chempr.2017.08.003) Copyright © 2017 Elsevier Inc. Terms and Conditions