Solution and Solid-Phase Halogen and C–H Hydrogen Bonding to Perrhenate

Abstract

¹H NMR spectroscopic and X-ray crystallographic investigations of a 1,3-bis(4-ethynyl-3-iodopyridinium)benzene scaffold with perrhenate reveal strong halogen bonding in solution, and bidentate association in the solid state. A nearly isostructural host molecule demonstrates significant C–H hydrogen bonding to perrhenate in the same phases.

With similar structural and electronic characteristics,¹ perrhenate (ReO₄⁻) is a tractable surrogate² for the medically ubiquitous and environmentally pernicious³ oxoanion, pertechnetate (TcO₄⁻).⁴ The metastable form of technetium⁵ and its long half-life⁶ decay product ⁹⁹Tc are standards for radiolabeling⁷ and in situ radiotherapy. Considering the high mobility of ⁹⁹TcO₄⁻, its stability,⁸ and increasing production,⁹ the need for synthetic receptors to function as strong and selective chelating agents, liquid-liquid extractants,² and ion-exchange stationary phases¹⁰ is pressing.

ReO₄⁻ and TcO₄⁻ are challenging targets due to their low hydration energies and diffuse charge densities.¹¹ To combat these difficulties, a number of hydrogen bonding (HB) scaffolds and hosts have been developed.^{1, 11–12} Elegant HB examples include aza-cryptands with pH-tunable cavities,^12a–c and charge neutral pyrrole-based macrocycles.^12d–e In contrast, bidentate halogen bonding (XB) and unconventional C–H¹³ HB receptors for ReO₄⁻ or TcO₄⁻ have not been reported. XB¹⁴ in particular offers an exciting competitive¹⁵/cooperative¹⁶ alternative with the benefit of soft-soft HSAB complementarity.¹⁷ Herein, we report the first two receptors that exhibit strong XB and C–H HB with ReO₄⁻ in solution, and the first bidentate and tridentate structures of each in the solid state.

We have developed two bidentate receptor molecules based on a diethynyl benzene core (1 and 2, Scheme 1). 1 is designed to direct two XB donors towards one anionic guest in a planar conjugated conformation.¹⁹ Molecule 2—which lacks XB donors—was prepared to quantify C–H HB to ReO₄⁻, and serve as a comparison. Both receptor scaffolds were synthesized by Sonogashira²⁰ cross-coupling of 1,3-diethynyl benzene with either 3-bromo-4-iodopyridine or 4-bromopyridine hydrochloride. The XB donor iodines of 1 were installed by lithium halogen exchange followed by quenching with I₂. Alkylation of the pyridines with octyl triflate activated the XB and HB donors of 1 and 2, respectively, and enhanced solubility in organic solvents. To minimize competitive intramolecular interactions, triflate counteranions were exchanged by metathesis for non-coordinating [BAr^F₄]⁻ anions.²¹ Methyl derivatives 1b and 2b were synthesized in a similar manner for X-ray diffraction studies.

Scheme 1.

a) 3-Bromo-4-iodopyridine, CuI, Pd(PPh₃)₂Cl₂, DMF, DIPEA, rt, 24 h, 88%; b) n-BuLi, THF, −78°C, I₂, 24 h, 41%; c) prepared according to literature procedure,¹⁸ 22% d) octyl triflate or methyl triflate, DCM, rt, 24 h, 98%; e) vapor diffusion of ether into DCM solution of TBA⁺Cl⁻, 55–75%; Na⁺[BAr^F₄]⁻, DCM, rt, 30 min, 59–75%.

The crystal structure of 1b²⁺•2ReO₄⁻ represents the first bidentate XB²² to ReO₄⁻ in the solid state. Yellow single crystals of 1b²⁺•2ReO₄⁻ suitable for X-ray diffraction were grown by diffusing DCM into a DMF/MeOH solution of receptor 1b and tetra-n-butylammonium perrhenate (TBA⁺ReO₄⁻).²³ 1b²⁺•2ReO₄⁻ crystallized in space group P2₁/c, forming bidentate XB to separate oxygens of a ReO₄⁻ anion (Figure 1, top). The C–I···O⁻ distances 2.97 and 3.06 Å correspond to 84 and 86% of the Σ VdW radii, and corroborate strong XB interactions. To accommodate the size of ReO₄⁻, both pyridinium rings rotate 11° from coplanarity. As a result, the observed C–I···O⁻ bond angles of 175 and 168° also confirm strong XB interactions. Examination of the crystal packing reveals C–H HB and electrostatic contacts between ReO₄⁻ and five additional molecules of 1b (see ESI). The second ReO₄⁻ participates in seven C–H HB interactions, and two weak σ contacts with electron-deficient pyridinium rings.²⁴ A head-to-tail π-stacking dimer (3.4 Å) is also observed.²⁵ This arrangement produces columns of 1b with each ReO₄⁻ on alternating sides of the receptor.

Figure 1.

X-ray crystal structures of 1b²⁺•2ReO₄⁻ (top) highlighting bidentate XB to ReO₄⁻ in the solid state (red). Crystal structure of 2b²⁺•2ReO₄⁻ (bottom) illustrating tridentate C–H HB to ReO₄⁻ (black).

In contrast, the crystal structure of 2b²⁺•2ReO₄⁻ illustrates unique C–H HB to ReO₄⁻. Colorless single crystals of 2b²⁺•2ReO₄⁻ were obtained by diffusing ether into a MeOH solution of receptor 2b and TBA⁺ReO₄^−.26 2b²⁺•2ReO₄⁻ crystallized in space group P2₁/n. Notably, tridentate C–H HB to ReO₄⁻ is formed using two Hc hydrogens and Hd (Figure 1, bottom), with C–H···O⁻ distances of 2.64, 2.71 and 2.31 Å. In addition, four intermolecular C–H²⁷ and two weak σ²⁸ contacts with ReO₄⁻ are present. The second ReO₄⁻ is involved in nine C–H HB and two weak σ interactions. To enable tridentate binding to ReO₄⁻, both pyridinium rings adjust 9° from coplanarity, and one ethynyl spacer deviates 8° from linearity. An off-centered head-to-tail π-stacking dimer (3.3 Å) is also noted (see ESI).²⁵ Together, the crystal structures of 1b²⁺•2ReO₄⁻ and 2b²⁺•2ReO₄⁻ illustrate the importance of bidentate/tridentate XB and HB coordination to ReO₄⁻ in the solid state.

¹H NMR spectroscopic titrations involving 1a and 2a were conducted to probe their corresponding XB and C–H HB capabilities in solution. Both 1a, 2a and TBA⁺ReO₄⁻ were independently soluble in CDCl₃; however, precipitation of host-guest complexes necessitated a CDCl₃/(CD₃)₂CO (3:2 v/v) mixed solvent. Titrating TBA⁺ReO₄⁻ produced noteworthy shifts for the pyridinium (Ha, Hb, and Hc) and phenyl (Hd) hydrogens for both 1a and 2a (Figure 2).²⁹

Figure 2.

Partial ¹H NMR spectra of 1a (top, 0–4.78 equiv) and 2a (bottom, 0–4.62 equiv) upon titrating TBA⁺ReO₄⁻ (equivalents from bottom to top).

The significant upfield shifting of Ha and Hb (Δδ = −0.099 and −0.082 ppm, respectively) on 1a is indicative of strong XB in solution.³⁰ The dominant XB conformation as suggested by the crystal structure of 1b²⁺•2ReO₄⁻ is distinctly bidentate (Figure 1, top). Further evidence of XB in solution can be seen in the downfield ¹³C NMR shifting of 1a’s C–X carbons (Δδ = 0.150 ppm) upon titrating ReO₄⁻ (see ESI). Additionally, facile rotation of alkynyl-aromatic C–C bonds enables a second XB mode. Constructive bidentate XB-HB involving a single halogen and Hc/Hd is consistent with the downfield shifting of these hydrogens (Δδ = 0.038 and 0.154 ppm).³¹ Taken together, the greater upfield (Ha and Hb) and greater downfield (Hc and Hd) shifting of 1a is explained by strong bidentate XB in solution as well as XB-HB synergy.

For 2a, C–H HB and electrostatic contacts are the prevailing interactions in solution. Specifically, a tridentate binding site involving two Hc hydrogens and Hd proves the most active as evidenced by the crystal structure of 2b²⁺•2ReO₄⁻ and the downfield progression of these hydrogens (Δδ = 0.019 and 0.139 ppm, respectively). Upfield shifting of 2a’s Ha/b (Δδ = −0.071 ppm) is indicative of anion-HB augmentation of ring electron density.³²

HypNMR 2008³³ was used to fit changes in shift to a stepwise association model:

$$\mathbf{H}+\mathbf{G}\rightleftharpoons \mathbf{HG},{\mathbf{K}}_{\mathbf{1}}=\frac{[\mathbf{HG}]}{[\mathbf{H}][\mathbf{G}]}$$ (1)

$$\mathbf{HG}+\mathbf{G}\rightleftharpoons \mathbf{H}{\mathbf{G}}_{\mathbf{2}},{\mathbf{K}}_{\mathbf{2}}=\frac{[\mathbf{H}{\mathbf{G}}_{\mathbf{2}}]}{[\mathbf{HG}][\mathbf{G}]}$$ (2)

Iterative and simultaneous refinement of multiple isotherms provided stability constants (K_a) for both 1a and 2a with ReO₄^−.34 For receptor 1a, the K₁ of 8990 M⁻¹ represents the first quantification of XB to ReO₄⁻ in solution, highlighting XB’s effectiveness at targeting this challenging oxoanion.³⁵ Alternatively, 2a exhibits C–H HB and electrostatic interactions with ReO₄⁻, which result in a K₁ of 7390 M⁻¹. Both 1a and 2a display modest K₂ values of 172 and 145 M⁻¹, respectively, that likely result from a combination of weak mono- and bidentate HB, and weak σ bonding.

The earliest quantification of XB and C–H HB to ReO₄⁻ in solution, and their corresponding bidentate/tridentate complexation in the solid state have been reported. The enhanced association of 1a to ReO₄⁻ when compared directly to a nearly isostructural and potent C–H HB molecule validates XB’s place alongside HB in an ongoing effort to design rational and selective receptors for ReO₄⁻ and TcO₄⁻. Future work with 1a and 2a will include liquid-liquid extraction of ReO₄⁻ from aqueous phase, and exploration of XB and C–H HB with other anionic guests.