Modular preparation of cationic bipyridines and azaarenes via C–H activation

Bipyridines are ubiquitous in organic and inorganic chemistry because of their redox and photochemical properties and their utility as ligands to transition metals. Cationic substituents on bipyridines and azaarenes are valuable as powerful electron-withdrawing functionalities that also enhance solubility in polar solvents, but there are no general methods for direct functionalization. A versatile method for the preparation of trimethylammonium- and triarylphosphonium-substituted bipyridines and azaheterocycles is disclosed. This methodology showcases a C–H activation of pyridine N-oxides that enables a highly modular and scalable synthesis of a diverse array of cationically charged azaarenes. The addition of trimethylammonium functionalities on bipyridine derivatives resulted in more anodic reduction potentials (up to 700 mV) and increased electrochemical reversibility compared to the neutral unfunctionalized bipyridine. Additonally, metallation of 4-triphenylphosphinated biquinoline to make the corresponding Re(CO)3Cl complex resulted in reduction potentials 400 mV more anodic than the neutral derivative.


Introduction
Bipyridines and their derivatives are a broadly useful class of small molecules for applications ranging from electrochemistry 1 and photochemistry 2 to medicinal chemistry. 3They are also ubiquitous ancillary ligands in transition metal chemistry. 4unctionalizing bipyridyls is critical to ne-tuning their specic redox and photophysical properties as isolated species and for their corresponding metal complexes.Among these, charged functional groups are oen desirable because of their electronwithdrawing properties 5 and their favorable impact on solubility in polar solvents. 6Charged functionalities impart significant electrostatic effects that can be used to create amphiphilic and phase transfer catalysts, 7 impact regiochemical control over reactivity, 8 and inhibit aggregation. 9espite the utility of cationic bipyridines and related ligands, there are no general methods for the preparation of trimethylammonium groups directly bound to the azaarenes.Instead, preparation of isolated cationic bipyridines most commonly occurs through N,N-dialkylation (Fig. 1).These molecules, commonly called viologens, are widely applicable because of their multiple accessible oxidation states and unique photochemical properties. 10In photochemistry and photoredox catalysis, viologens are used as oxidative quenchers of photocatalysts. 11Electrochemically, they are common anolytes in both aqueous 12 and nonaqueous 13 redox ow batteries and are used as mediators for (bio)electrocatalysis because of their stability in electrochemical cycling. 14As these derivatives easily gain electrons, they can also act as herbicides, as they interfere with photosynthesis by disrupting electron transfer reactions and producing harmful radical oxygen species. 15btaining cationic bipyridines to use as transition metal ligands has been more challenging since they cannot be alkylated at the nitrogen metal-binding site.Instead, the charged functional group is typically tethered to the 2,2 ′ -bipyridyl (bpy) metal complexes through a multi-step synthesis because direct attachment to the azaarene has been generally inaccessible.Meyer and coworkers investigated benzylic trimethylaminium functionalized bpy to study ion pairing in the corresponding iridium and ruthenium complexes. 16The same ligand was applied by Thoi and coworkers in aqueous electrocatalytic rhenium-catalyzed carbon dioxide (CO 2 ) to carbon monoxide (CO). 17Likewise, Tsai and coworkers used this ligand for a palladium-catalyzed Mizoroki-Heck reaction under phasetransfer conditions. 18Ertem, Manbeck, and coworkers have shown that even when the trimethylaminium is further separated from the metal center, the impact of the charge has benecial properties on catalysis. 19o expand the series of accessible non-N methylated cationic bipyridines and azaarenes, we sought a modular and facile preparation for the direct attachment of trimethylaminium functionalities to azaarenes.Using 6-trimethylaminium-2,2 ′bipyridyl 1 as the target molecule, we initially envisioned synthetic access through either methylation of 6-dimethylamino-2,2 ′ -bipyridyl (Scheme 1), 20 or nucleophilic aromatic substitution of 6-halo-2,2 ′ -bipyridyl with trimethylamine (NMe 3 ) (Scheme 1). 21While these approaches have been used to access relatively simple trimethylaminated pyridines, their application to bipyridines would require pre-functionalized bipyridyl precursors that are either expensive ‡ or challenging to prepare.Keeping these limitations in mind, we opted to try a pyridine N-oxide C-H trimethylamination approach (Scheme 1).This method is inspired by prior work by Xiong and Hoye and coworkers for the uorination of pyridines. 22In their work, a series of functionalized pyridine N-oxides were selectively trimethylaminated using trimethylamine (NMe 3 ) as a nucleophile and triuoroacetic anhydride (TFAA) as an activating agent.Since the goal of their study was to use the trimethylaminated pyridines as intermediates in the preparation of uoropyridines, Xiong and Hoye only isolated two of the trimethylaminated pyridine salts. 22This approach was of interest because pyridine N-oxides are easy to access with a diverse array of functional groups and substitution patterns.While applying this method to bipyridines is a logical extension of their work, the additional pyridine ring adds complexity.Namely, pyridines are known to be competent nucleophiles under analogous conditions of using TFAA to activate pyridine N-oxides. 22,23Further, at the outset we were not certain if the products could be easily isolable without the use of reverse phase high performance liquid chromatography (HPLC), which would limit our method's scalability and broad accessibility.In this study, we demonstrate a general and facile method for isolating trimethylaminated and triarylphosphinated bipyridines.Furthermore, we show this approach can be expanded to other azaheterocyclic ligands, including phenanthrolines, terpyridines, and quaterpyridines.
Because the electrochemical properties of bipyridines and their corresponding complexes are a key factor in their widespread utility, the redox properties of the monocationic and dicationic bipyridines were also examined and compared to the neutral bipyridine.Of note is that the cationic bipyridines have both anodically-shied and more available reduction events, as well as improved overall stability of the reduced species.Additionally, a rhenium complex with a 4-triphenylphosphinated biquinoline was prepared.The presence of the cationic group resulted in an anodic shi to the metal-based reduction potential.

Synthesis of cationic bipyridyls
The reaction of 2,2 ′ -bipyridyine N-oxide with 5 equiv. of NMe 3 and 3 equiv.of TFAA in methylene chloride (CH 2 Cl 2 ) at room temperature furnished 1 in 100% yield, as determined by 1 H NMR spectroscopic analysis (Table 1).Fewer equivalents of amine or anhydride led to lower reaction yields.Isolation of pure 1 as the triuoroacetate salt proved to be challenging because the concomitantly generated trimethylammonium tri-uoroacetate was difficult to separate from 1. Various methods of purication were attempted, including extractions, recrystallizations, bases, and alternative activating groups.§ Fortunately, salt metathesis with aqueous sodium tetrauoroborate (NaBF 4 ) allowed for the isolation of spectroscopically pure 1, albeit in slightly diminished yields (70-80%) due to its partial solubility in water.{and k With these optimized conditions in hand, the scope of tolerated azaarene N-oxides was tested (Table 1).Each reaction was performed on 1 mmol scale or higher.As noted above, the tetrauoroborate salt of 1 was generated in 79% yield on 1 mmol scale and 69% yield on 10 mmol scale.This approach was easily scaled, as 1 was isolated in 75% yield on 5 g scale with respect to the starting bipyridyl N-oxide.This method is not limited to converting mono N-oxides into mono trimethylaminated bipyridyls, as 2,2 ′ -bipyridyl N,N ′ -bis-N-oxide formed the bis trimethylaminated 2 in 52% isolated yield on 1 mmol scale and 63% isolated yield on 10 mmol scale.Substitution in the 4position of the bipyridine was also tolerated, as the mono and bis trimethylaminated analogues of 4,4 ′ -di-tert-butyl-2,2 ′ -bipyridyl, 3 and 4, were obtained in 89% and 47% yield, respectively.In the case of 4, the triuoroacetate ( − OTFA) salt can be isolated spectroscopically pure in 61% yield.Further, the electron-decient 4,4 ′ -bis-esterbipyridyl and more sterically encumbered 5,5 ′ -dimethylbipyridyl were successful under the reaction conditions, furnishing 5 in 78% and 6 in 48% yield.In the case of 7, perdeuteration did not impact the reaction.Additionally, these conditions are not limited to the trimethylamination of bipyridyls; N-oxides of phenanthroline (8), 2-phenylpyridine (9), Scheme 1 Potential approaches to trimethylaminated bipyridyls.benzo[h]quinoline (10), terpyridine (11), and quaterpyridine (12) all afforded the desired salt in moderate to great yields.
One limitation of this method is for substrates based on 4,4 ′and 6,6 ′ -dimethylbipyridyl.Here, we postulate that a Boekelheide reaction proceeds instead of our desired salt formation, as triuoroacetylation of the N-oxide causes signicant acidication of the protons on the 4-or 6-methyl groups, which can be deprotonated by trimethylamine and lead to undesired reactions. 24In an attempt to prepare cationic salts of these substrates, we hypothesized that a heavier pnictogen congener should still have adequate nucleophilicity while having attenuated basicity.Thus, we turned to triarylphosphines, which Bugaenko, Karchava, and coworkers have shown to react with pyridine N-oxides using TFAA as an activating agent. 25Using slightly modied conditions (1.5 equiv. of tri(para-tolyl)phosphine and 1.5 equiv. of TFAA), complete conversion of 4,4 ′ -dimethyl-2,2 ′ -bipyridyl N,N ′ -dioxide to the corresponding bisphosphonium salt 13 (Table 2) was achieved.Due to the lowered basicity of triarylphopshines, no triarylphosphonium tri-uoroacetate forms in the reaction, allowing for easy isolation of spectroscopically pure 13 in 95% yield as the triuoroacetate salt without the need for an aqueous salt metathesis.

Electrochemistry
The electrochemical behavior of the cation-bearing bipyridines was investigated using cyclic voltammetry (CV) and compared to both uncharged and N,N ′ -dialkyl bipyridiniums commonly utilized in electrochemical and other redox processes.All potentials are reported versus an internal Fe(C 5 H 5 ) 2 +/0 standard.
The neutral, parent 2,2 ′ -bipyridine in acetonitrile exhibits one reduction event, bpy/bpyc − at −2.60 V in acetonitrile (MeCN) using tetrabutylammonium hexauorophosphate (TBAPF 6 ) as the supporting electrolyte (Fig. S1 †), which matches known values in both tetrahydrofuran and N,N-dimethylformamide. 27,28The one electron reduced species is unstable, as the feature is irreversible at slow scan rates but becomes reversible at fast scan rates (>500 mV s −1 ) (Fig. S2 †).Incorporation of trimethylaminium group(s) results in signicant changes to the bipyridine's redox (electrochemical) properties.For monocationic 1, where there is one trimethylaminium group, two different one electron redox features can be observed (Fig. S3 †).The rst event is the bpy/bpyc − redox cycle, which is now anodically shied by almost 400 mV to −2.22 V (Table 3).This singly reduced species is still unstable; however, reversibility is again observed at scan rates of 500 mV s −1 and above (Fig. S4 †).The second reduction event, which is not present within the solvent window for the parent 2,2 ′ -bipyridine, is quasireversible for 1 with a reduction potential at −2.58 V (Fig. S5 †).
An even more dramatic effect is observed when multiple trimethylaminium groups are installed.In the case of dicationic 2, where the nitrogen of each pyridyl ring is anked by a trimethylaminium, the rst reduction occurs at −1.92 V and the peak cathodic current for the second irreversible reduction (E pc ) is at −2.38 V (Fig. S6 †).Most notably, not only is the rst reduction shied anodically by nearly 700 mV with respect to the unsubstituted 2,2 ′ -bipyridine, the one electron reduced species is more stable, as the redox event is completely reversible even at scan rates as low as 5 mV s −1 (Fig. S7 †).This redox behavior shows the impact that installing trimethylaminiums and other cationic functional groups has on accessing stable reduced states of bipyridine derivatives.
To complete the series of charged 2,2 ′ -bipyridines, N,Ndimethylated 2,2 ′ -bipyridinium ( 19) was also prepared.As expected, both redox features are at even more anodic potentials, where the rst reduction proceeds at −1.14 V and the second reduction at −1.60 V (E pc , Fig. S8 †).Surprisingly, while the related N,N-dialkylated 4,4 ′ -bipyridiniums (viologens) are stable and redox events are reversible, both reduction features of 19 are irreversible.
The installation of trimethylaminium(s) modies the rst reduction of the bipyridines by nearly 700 mV.For comparison, the rst reduction event for dimethyl 2,2 ′ -bipyridine-4,4 ′carboxylate occurs at −2.03 V, or only a 600 mV change with respect to 2,2 ′ -bipyridine. 28The profound change in reduction is clearly tuned by charge, as the reduction events become more positive with increasing charge (Fig. 2).Further, incorporating the trimethylaminium(s) improves the stability of the one electron reduced species by cyclic voltammetry, enhancing their utility as redox-ow battery anolytes or redox mediators.The potential for each reduction is summarized in Table 3.

Ligand properties
The impact of the cationic groups on transition metal complexes was also explored.As large functionalities such as tert-butyl and dimethylphenyl groups in the 2-or 6-position of bpy or phenanthroline ligands oen inhibit metal binding at the pyridine or require C-H activation to bind, 29 we opted to use 4-triphenylphosphinated biquinoline (18) to obtain desired pyridine binding.Since the cationic functional group is in the 4position relative to the transition metal, it decouples the electronic impact of the phosphonium from any steric bias that it might impart.Additionally, the ligand inuence has the potential to be analyzed in the context of Hammett studies. 30he reaction of 18 with pentacarbonylchlororhenium(I) [Re(CO) 5 Cl] readily forms the rhenium tricarbonyl complex 20 in 84% yield (Scheme 2).
The electrochemical and photochemical inuence of the phosphonium group on the metal center was investigated by comparing 20 to the uncharged biquinoline bound rhenium   complex (biq)Re(CO) 3 Cl ( 21) via CV and UV-visible (UV-Vis) spectroscopy.Electrochemically, complexes of the type (bpy) Re(CO) 3 Cl are known to have two one-electron reductions: a metal-centered reduction at −1.78 V followed by a ligandcentered reduction event at −2.16 V in acetonitrile. 31Similarly, the neutral biquinoline-ligated 21 exhibits a reversible reduction at −1.30 V and an irreversible reduction at −1.84 V in N,N-dimethylformamide (DMF) (Fig. S10 †).We attribute these to metal-centered and ligand-centered events based on the similar structure of the biquinoline complex to the bipyridine congener.The more anodic values reect the more electronwithdrawing nature of the biquinoline ligand compared to bipyridine.
In contrast, the cationic triphenylphosphonium complex 20 shows a signicant anodic shi for both reductive features compared to the neutral analogue.By installing the charged functional group on the biquinoline, the reversible rst reduction occurs at −0.86 V and the second reduction, now reversible, occurs at −1.42 V (Fig. 3, S11 and S12 †).This Re(I/0) reduction potential of −0.86 V for 20 is particularly noteworthy as it is 300 mV more anodic than the analogous Re(I/0) redox event (−1.19 V) for the related electron decient (4,4 ′ -CN-bpy) Re(CO) 3 Cl. 29The potential for each reduction is summarized in Table 3.
The impact of installing the phosphonium group on the metal's photophysical properties was investigated.In DMF, 21 is known to exhibit an absorption at 426 nm that is characterized as a d / p* transition. 32In the case of 20, this absorbance is red shied by 45 nm, to a l max of 471 nm, while having a slightly higher molar absorptivity (3 = 3970 vs. 3548 for 21, Fig. 4).The l max and molar absorptivities of the other absorbances remained relatively constant (Fig. S13 and 14 †).
Finally, the Re complexes contain carbonyl ligands that are useful infrared spectroscopic probes for the electronic effects of ligands (see ESI †).The parent complex (biquinoline)Re(CO) 3 Cl exhibits infrared vibrational spectra resonances at 2012, 1895, and 1866 cm −1 while the cationic derivative 21 has features at 2013, 1899, and 1884 cm −1 .While we do not assign these resonances to specic carbonyls, we note that the rst two are similar, while the third increases by 18 wavenumbers in the cationic species, indicating less p-backbonding.

Conclusions
The synthesis of a series of previously synthetically inaccessible bipyridyls and azaheterocycles bearing cationic pnictogens is reported.As their preparation involves C-H activation of pyridine N-oxides, this method is highly modular and allows for facile trimethylamination and diversication of commercial and existing bipyridyls and azaarenes without requiring de novo syntheses for each target molecule.The method is scalable, as products can be prepared on a 5 gram scale.The impact of the cationic functionalities on the derivatives, as well as the physical properties of the corresponding complexes, were investigated.The strong electron-withdrawing nature of the cationic pnictogens resulted in signicant anodic shis in the reduction events while also improving the stability of the reduced species.This general synthetic method and the charged azaarenes will have a positive impact on a wide range of applications, from new amphiphilic metal-based photo-and electrocatalysts to  organic materials with benecial electrochemical and optical properties.

Fig. 1
Fig.1Previous approaches to accessing charged bipyridines and the approach reported herein.

Fig. 4
Fig. 4 Overlay of UV-vis of 20 (blue trace) and 21 (black trace) showing d / p* transition at room temperature in DMF.

Table 3
Summary of reduction potentials for 2,2 ′ -bipyridine and selected new cationic derivatives.Potential values are reported vs. Fe(C 5 H 5 ) 2 +/0 and are E 1/2 for reversible and quasireversible events and E pc for irreversible events b 19 −1.14 (irrev.