Reductively Stable Hydrogen-Bonding Ligands Featuring Appended CF₂-H Units

Abstract

We present the development of ligands featuring the unconventional hydrogen bond donor, –CF₂H, within a metal’s secondary coordination sphere. When metalated with palladium, o-CF₂H functionalized 1,10-phenanthroline provides highly directed H-bonding interactions with Pd-coordinated substrates. Spectroscopic and computational analyses with a series of X-type ligand acceptors (–F, –Cl, –Br, –OR) establish the H-bonding interaction strength for the –CF₂H group (~3 kcal/mol). Synthesis of Pd°/Ni° complexes and subsequent coupling (Ni) highlight the unique reductive and base compatibility of the –CF₂H hydrogen bond donor group.

INTRODUCTION

Prearranged hydrogen bonding interactions that facilitate substrate capture and activation are ubiquitous in enzyme active sites. These secondary-sphere interactions are critical to many biological transformations including nitrogen fixation,^1-3 hydrogenation,^4-7 and CO₂ reduction.⁸ To develop an understanding of how these noncovalent interactions facilitate small molecule activation, synthetic complexes featuring appended hydrogen bond (H-bond) donors are increasingly used in biomimetic design,^9-12 and catalytic transformations.^13-20 In almost all cases, these studies are limited to mid- to high- oxidation state transformations. H-bond donors are generally incompatible with low valent metal complexes because they undergo proton-transfer to the metal,^21-23 which presents a fundamental challenge for evaluating H-bonding induced reactivity at highly reduced metal sites.²⁴ Although biologically relevant H-bond donors (e.g. amines, thiols, or water) are often incompatible with reduced metal complexes,^25-28 metalloenzymes have evolved to overcome this limitation by: (1) isolating their active-sites,²⁹ (2) employing highly specific H⁺/e⁻ transport systems,³⁰ and/or (3) operating at or above the proton reduction limit through charge delocalization (e.g. [FeS]_n clusters; E° > −0.8 V vs SHE).^31-32 An alternative approach within synthetic systems, where common reducing agents used to access biological model complexes exceed −2 V (vs SHE),³³ is to use H-bond donors that are resistant to proton transfer.

The –CF₂H functional group is a robust³⁴ bioisostere for amines and thiols, exhibiting comparable H-bond donor strength.³⁵ Although H-bonding effects of this unit have been identified using metal-free systems,^36-37 the –CF₂H unit has not been incorporated within a metal’s secondary coordination sphere for H-bonding to a metal coordinated substrate. To address this gap, we targeted ligands that accommodate appended –CF₂H groups as a key design element. Ortho- functionalized pyridines provide high directionality to enforce H-bonding to metal bound substrates,^{13-14, 38-47} especially when constrained within a rigid chelating ligand (Figure 1). To probe secondary coordination sphere effects of –CF₂H H-bonding to a metal bound substrate, we targeted 2-(difluoromethyl)-1,10-phenanthroline⁴⁸ (phen^CF₂H).^43-49 Herein we disclose the –CF₂H group as a viable H-bond donor when appended to a ligand scaffold to evaluate (1) directional H-bond strength and (2) reductive stability.

Figure 1.

2-Pyridyl ligand frameworks for –OH and –CF₂H H-bonds.

RESULTS AND DISCUSSION

Synthesis and characterization of complexes featuring secondary-sphere –CF₂H hydrogen bonds.

Treatment of phen^CF₂H with PdCl₂ in refluxing acetonitrile afforded PdCl₂(phen^CF₂H) (1-Cl) in 55 % yield as confirmed by X-ray crystallography (Figure 2). The primary coordination sphere of 1–Cl features a square-planar geometry (τ= 0.08) at Pd, with equivalent Pd-Cl distances (Pd-Cl1 = 2.290(16) Å; Pd-Cl2 = 2.299(17) Å) and inequivalent Pd-N distances (Pd-N1 = 2.005(9) Å; Pd-N2 = 2.149(11) Å). We attribute the ligand binding asymmetry to a steric interaction of the ortho- group of the phen^CF₂H ligand. Importantly, the crystallographic characterization of 1-Cl (Figure 2B) reveal the –CF₂H proton is oriented toward the neighboring –Cl at a distance of 2.339 Å (C-Cl = 3.15(2) Å) ⁵⁰ within the sum of the van der Waals radii(vdW),^51-52 consistent with formation of a –CF₂H⋯Cl H-bond. To assess the –CF₂H group as a secondary-sphere H-bond donor,^{13-14, 38-44} we evaluated the interaction energy, solution behavior, and donor strength of the H-bond.

Figure 2.

(A) Synthesis of complexes 1-X and 2, and (B) crystal structure of 1-Cl; Cl1-H11 = 2.339, Cl1-C11 3.15(2) Å with side view (50% probability ellipsoids; protons not involved in H-bonds are removed for clarity).

To interrogate the extent to which the –CF₂H H-bond is retained in solution, we examined a series of 1-X complexes (X= F, Cl, Br): congeners featuring coordinated halides of varied H-bond acceptor strength.⁵³ We prepared PdBr₂(phen^CF₂H) (1-Br) in 80 % yield, analogous to 1-Cl, while PdF₂(phen^CF₂H) (1-F) was accessed by oxidation of in situ prepared Pd(dba)(phen^CF₂H) (2) (dba = dibenzylideneacetone) with XeF₂.^54-59,60 Relative to the free ligand, phen^CF₂H, the ¹H NMR spectra of complexes 1-X exhibit shifts of the –CF₂H group (²J_FH = 52-55 Hz) downfield from 7.01 to ≥ 8.3 ppm, and corresponding modest ¹⁹F NMR shifts (≤ Δδ 4.5 ppm). For 1-F, the –CF₂H ¹H NMR signal at 8.38 ppm is a triplet of doublets, with coupling constants of 53 and 25 Hz, which we attribute to both –CF₂H ¹⁹F ²J_FH coupling as well as a through-space –CF₂H⋯F interaction (¹J_FH). Selective ¹H{¹⁹F} decoupling of the Pd-F signal at −383 ppm collapsed the triplet of doublets to a triplet (²J_FH = 53 Hz), further supporting assignment of ¹J_FH coupling; a hallmark of –F⋯H H-bond formation. The magnitude of ∣¹J_FH∣ of 25 Hz is consistent with “weak” H-bond formation.^61-62 In general, the ¹H chemical shift of H-bond donors (E-H) provides a spectroscopic handle to interrogate H-bond interactions, where strong H-bond interactions generally have a large deshielding effect.⁶³ However, for the 1-X series, the induced H-bond chemical shift of –CF₂H (X = F, Cl, Br; 8.38, 8.73, 8.73 ppm), is inverted relative to the predicted H-bond acceptor strength (F > Cl > Br).⁵³

To understand why the –CF₂H proton resonance undergoes an upfield rather than downfield shift in the ¹H NMR spectra as the H-bond acceptor strength for 1-X increases, we used computational methods. Structures of 1-X were optimized and analyzed at the M062x/6-311++(2d,2p) SDD//M062x/def2tzvp PCM=(CH₂Cl₂) level of theory. 1-X undergoes geometric distortion as the size of X increases, forcing the phen^CF₂H ligand out of the PdX₂ plane (Figure 3). The distortion of the close-contact for the –CF₂H⋯X proton is an additional factor that may convolute the effect of NMR shielding. To determine whether the -CF₂H⋯X close-contact is attractive or repulsive and the relative magnitude of the interaction, we employed a noncovalent interaction (NCI)⁶⁴ analysis of 1-X. The NCI plots (Figure 3) demonstrate that the X⋯H interaction is attractive (sign(λ₂)ρ < 0) for all X, and largest in magnitude for 1-F (Figure 3) (sign(λ₂)ρ_min: F= −0.034; Cl = −0.021; Br = −0.019). For context, the interactions of H-bond donors H₂O, NH₃, and CH₂F₂ interacting with a reference acceptor molecule, NH_3, are −0.028 (H₂O), −0.016 (NH₃), and −0.013 (CH₂F₂) (Figure 3C). To further characterize the –CF₂H H-bond, we examined charge transfer via a natural bond orbital (NBO) analysis. A comparison of 1–F and 1–Br revealed the C-H bond of –CF₂H has a higher H charge for 1–F (Δe⁻ = 0.03) with a concomitant decrease in C charge (Δe⁻ = −0.02). These results are consistent with increased polarization induced by H-bond formation to the stronger acceptor (F).⁶⁵ The computational analysis of 1–X supports an H-bonding interaction of Pd-X with the –CF₂H unit and underscores the importance of geometric constraints of the H-bond acceptor.

Figure 3.

DFT optimized structures with NCI analysis (isosurface s = 0.5) of the X-H interaction of (A) 1-F, 1-Cl, and 1-Br, (B) side-view of 1-X distortion of Pd-N1-C3 angle, and (C) NCI analysis of H-bond interactions of H₂O, NH₃, and CH₂F₂ with NH₃.

The geometric distortions that convolute analysis of the H-bonding effects in 1-X can be mitigated by comparing isostructural H-bond acceptors. When substituted in the para position, phenoxides provide tunable H-bond acceptor strength, that can be quantified by the Hammett parameter (where H-bond acceptor strength tracks as NMe₂ > OMe > ^tBu > H > Br > NO₂).⁶⁶ Salt metathesis of 1-Cl with 2 equiv. thallium phenoxides resulted in the formation of Pd(OArR’)₂(phen^CF₂H) (3-OArR’, R’= NMe₂, OMe, ^tBu, H, Br, NO₂) (Figure 4A). ¹H NMR analyses of 3-OArR’ feature small shifts of the phen^CF₂H ligand resonances and a pair of corresponding aryl resonances, consistent with an identical primary coordination sphere across the series. X-ray analysis of 3-OArNO₂ and 3-OArH provided clear support that the primary coordination sphere is not altered (Figure 4B; primary sphere geometry overlay RMS = 0.111; see SI). Across the series, the ¹H NMR –CF₂H resonance shifted downfield with increasing H-bond acceptor strength of the phenoxide (Figure 5A); consistent with an H-bond strength induced chemical shift. When the Δδ of the –CF₂H resonance is plotted as a function of Hammett parameter (σ_p), the data are linear up to σ_p = −0.268 (3-OArOMe), with deviations from linearity observed for σ_p = −0.83 (3-OArNMe₂).

Figure 4.

(A) Synthesis of complexes 3-OArR’ and 5-OArR’, (B) crystal structures of 4-Cl, 3-OArNO₂, and 3-OArH (50% probability ellipsoids; protons not involved in H-bonds are removed for clarity). Dihedral angles shown between H13-C13-C10-N2. (C) Steric (1 vdW radii) and electrostatic potential surface (at 0.004 au) comparisons for appended groups of phen^CR₂H.

Figure 5.

Hammett plots of (A) –CR₂H Δδ and (B) calculated Δν_C-H of 3-OArR’ and 5-OArR’.

To clarify the reasons that govern the nonlinear behavior described above, we interrogated the solid state structures of 3-OArR’. Both structurally characterized products, 3-OArNO₂ and 3-OArH, exhibit close –CF₂H⋯O heavy-atom –C⋯O distances consistent with H-bonding interactions (2.820(5) and 2.93(2) Å respectively) (Figure 4B). For an sp³ carbon atom, the heavy atom positions (C-CF₂) provide an accurate –H atom position and orientation (riding model) even without location from a difference electron map.⁶⁷ Using this treatment, the H⋯O contacts of 3-OArNO₂ and 3-OArH are 2.197 and 2.002 Å, respectively. Importantly, these distances are flipped relative to the heavy atom O⋯C treatment. The difference between the H⋯O contacts of the riding model protons is the result of –CF₂H rotation (3-OArNO₂ = 11.8°; 3-OArH ≤ 1°) about the C_py-CF₂H torsion angle, with a stronger H-bond interaction exhibiting a shorter H-bond contact (Figure 6). The consequence of –CF₂H coplanarity for 3-OArH is that as the H-bond strength is increased, a closer contact is not possible and the ¹H NMR response becomes entirely due to through-space C-H polarization and charge transfer. Computational analysis of the series supports the angular constraint of the H-bond distance on H-bond acceptor strength and that coplanar geometry (R’= –^tBu, –OMe, –NMe₂) affords an H-bond with a maximum directionality (∠O-H-C) of 158° (Figure 6).⁶⁸

Figure 6.

Analysis of the impact of H-bond donor strength on directionality. (A) NCCH dihedral and H⋯O contact as a function of H-bond acceptor strength (p-OArR’) and (B) Hammett plots of calculated NCCH dihedral angle (°) and O---H contact of 3-OArR’.

There are two competing factors that could generate the short H⋯X contacts from the –CF₂H group; (1) an attractive interaction or (2) the minimization of steric repulsion from the –F substituents. With few exceptions, the identification of H-bond interactions with –CF₂H units rely exclusively on crystallographic analyses. Assessment of close contacts does not necessitate an attractive interaction. However, in many of these structures,^{36, 69-70,71} rotation of the –CF₂H group is hindered due to the steric repulsion from the –F groups, a factor noted above to control H-bond strength. To examine the steric component of the –CF₂H unit to influence close contacts, we targeted an isosteric analogue of –CF₂H that has similarly hindered –CR₂H rotation but does not contain an acidic C-H group. Although –CH₃ is a common control group for –CF₂H (Charton parameter⁷² (ν): –CF₂H = 0.68; –CH₃ = 0.52), it does not capture the steric bias contributing to C-H orientation.⁷³ Furthermore, fast rotation of the –CH₃ group averages the H-bond interactions with non-interacting protons on the NMR timescale, resulting in a diminished ¹H NMR response. Instead, we targeted an ⁱPr group (ν = 0.76) as a structurally faithful model⁷⁴ (phen^iPr) to assess the C-H polarization contribution to H-bond formation (Figure 4C).

Metalation of the control ligand, phen^iPr, with PdCl₂(PhCN)₂ afforded PdCl₂(phen^iPr) (4-Cl) in 82 % yield. X-ray diffraction of 4-Cl (Figure 4C) revealed a CH⋯Cl contact of 2.496 Å (riding model treatment) and C-Cl contact of 3.256(3) Å), which are a longer contacts than for the –CF₂H analogue (1-Cl: H⋯Cl = 2.339 Å; C-Cl = 3.15(2) Å). To rigorously compare the H-bond contributions of –C(CH₃)₂H group vs –CF₂H, we prepared analogous Pd^II phenoxide complexes. Salt metathesis of 4-Cl afforded the phenoxide complexes (5-OArR’).⁷⁵ The ¹H NMR spectra of the complexes 5-OArR’ each contain a characteristic septet peak between 4.50 and 5.30 ppm (Δδ = 0.80) assignable to the methine proton (H-C(CH₃)₂).

In comparison to –CF₂H (Δδ of 3-OArR’ = 0.95), the Δδ of the –C(CH₃)₂H resonance is similar for weak H-bond acceptors (R’= –NO₂ – –^tBu; ΔΔδ ≤ 0.08) and larger only for strong H-bond acceptors (R’= –OMe – –NMe₂; ΔΔδ ≤ 0.15) where through-space interactions are expected to dominate over –CR₂H rotation effects (Table 1). These results were supported by computational analysis of the 3-OArR’ and 5-OArR’ series, which exhibit a phenoxide-dependent –CR₂H dihedral orientation for –CF₂H, but not for –C(CH₃)₂H (see SI). This result is consistent with weaker attractive noncovalent interactions for the non-polar –C(CH₃)₂H, compared to –CF₂H. Together, the combined ¹H NMR/computational analyses support the notion that the unique ability of the –CF₂H group to form H-bonds is an electronic rather than a steric effect.

Table 1.

H-bonding and primary-sphere comparisons between Pd–phen^CR₂H compounds. X_b: H-bond acceptor; X_a: non-interacting X-type ligand on Pd.

Compound	1H –CR2H (ppm)	Xb⋯H (Å)	Pd-Xa (Å)	Pd-Xb (Å)	DFT: Xb⋯H (Å)	DFT: Pd-Xa (Å)	DFT: Pd-Xb (Å)	DFT: νC-H (cm−1)
–CF2H
1-F	8.38				1.829	1.947	1.956	3128
1-Cl	8.73	2.339	2.290(16)	2.299(17)	2.364	2.294	2.304	3205
1-Br	8.73				2.533	2.431	2.441	3210
3-OArNO2	8.02	2.197	1.983(3)	1.993(3)	2.088	2.000	2.006	3186
3-OArBr	8.47				2.051	1.998	2.004	3184
3-OArH	8.72	2.002	2.002(9)	2.020(8)	1.995	1.993	1.999	3173
3-OArtBu	8.81				1.948	1.992	2.006	3145
3-OArOMe	8.86				1.948	2.002	2.007	3141
3-OArNMe2	8.97				1.955	2.003	2.010	3135
6-I	9.08				2.772	1.941	2.665	3149
6-F	8.68	1.895a	1.977(5)a	1.957(7)a	1.869	1.946	1.996	3110
–C(CH3)2H
4-Cl	5.07	2.496	2.2796(7)	2.2891(7)	2.430	2.300	2.314	3172
5-OArNO2	4.49				2.118	2.005	2.012	3120
5-OArBr	4.82				2.125	2.023	2.029	3118
5-OArH	4.93				2.116	1.996	2.002	3116
5-OArtBu	4.95				2.066	1.994	2.005	3115
5-OArOMe	5.20				2.106	1.997	2.005	3116
5-OArNMe2	5.25				2.112	1.998	2.013	3121
7-I	5.28				2.794	1.943	2.681	3106
7-F	5.01				2.073	1.949	1.994	3102

^a)Distances reported are for one individual molecule in the unit cell.

Although the computational and experimental studies above indicate that phen^CF₂H ligand engages in H-bond interactions, quantifying the interaction strength is intrinsically difficult. In contrast to classic H-bond donors (OH, NH) that undergo a hypsochromic (blue) shift of the ν_E-H mode upon formation of an H-bond, H-bonds to C-H donors may exhibit distinct shifts: the ν_C-H may either undergo a hypsochromic (blue), no, or bathochromic (red) shift.⁷⁶ As a result, it is difficult to identify ν_C-H shifts for even simple systems,³⁶ and there are no reported correlations between C-H H-bond energy and ν_C-H.

To ascertain the influence of the –CR₂H group on the H-bond interaction, the vibrational dependence (Δν_C-H) of the donor was analyzed computationally for 3-OArR’ and 5-OArR’. We found that the ν_C-H for 3-OArR’ exhibits bathochromic (red) shifts with increasing H-bond acceptor strength.⁷⁷ The important difference between the two modeled complexes is that for R = CF₂H, the Δν_C-H tracks with H-bond acceptor strength, while there is no systematic trend for R = C(CH₃)₂H (Figure 5B).⁷⁸

To experimentally establish the relative strength of the CR₂H⋯X interaction (for CF₂H and C(CH₃)₂H, we interrogated the through-space H-F coupling interaction by NMR spectroscopy. Despite efforts to prepare Pd difluoride compounds (1-F, Figure 2), we found that they were generally unstable toward further chemical manipulations including isolation and crystallization. To overcome this limitation, we targeted the isolation of palladium aryl fluoride complexes because they exhibit higher stability relative to palladium difluorides.^54-59 The addition of phen^CF₂H or phen^iPr to Pd(Ph)I(Py)₂ in CH₂Cl₂ afforded Pd(Ph)I(phen^CF₂H) (6-I) or Pd(Ph)I(phen^iPr) (7-I) in good yields (84, 76%) (Figure 7A). Sonication of 6-I and AgF in CH₂Cl₂ while cooling in an ice bath facilitated halide exchange to produce Pd(Ph)F(phen^CF₂H) (6-F). The major isomer observed (>95%) exhibited H⋯F H-bonding interactions, vide infra.

Figure 7.

(A) Synthesis of complexes 6-I, 7-I, 6-F, and 7-F, (B) crystal structure of 6-F (30% probability ellipsoids; for clarity a single molecule from the unit cell is shown and protons not involved in H-bonds are removed), and (C) ¹H and selective decoupled ¹H{¹⁹F} NMR of 6-F and 7-F.

¹H NMR spectra of 6-I and 6-F exhibit –CF₂H resonances at 9.08 and 8.68 ppm respectively.⁷⁹ Similar to 1-F, the –CF₂H⋯F interaction in 6-F exhibits a through-space coupling interaction; ∣¹J_FH∣ = 23 Hz. This value is smaller than ∣¹J_FH∣ coupling to stronger H-bond donors (–OH = 50 Hz;⁴³ –NH₂ = 50-64 Hz⁸⁰). To examine a direct comparison using stronger H-bond donors within this system, we targeted bpy^OH as a related bidentate ligand. In contrast to the stable complex obtained using phen^CF₂H, we found that metalation of this ligand under analogous conditions produced benzene (via protonation of Pd-Ph) as a primary product: a reaction liability introduced by acidic H-bond donors (–OH).

To further interrogate the electronic requirements needed to visualize a through space ¹J_FH coupling to Csp³-H units, we analyzed the isostructural complex with phen^iPr. The ¹H NMR spectrum of the analogously prepared Pd(Ph)F(phen^iPr) (7-F) complex does not feature detectable through-space ¹J_FH coupling, but is broadened.⁸¹ Selective Pd-F decoupling ¹H{¹⁹F} NMR collapses the broadened resonance to a sharp septet, which is consistent with a very weak through-space H⋯F interaction of ∣¹J_FH∣ ≤ 3 Hz. The contrast between the ¹J_FH of 6-F and 7-F provides further support that the C-H bond in –CF₂H is uniquely polarized and capable of strong attractive interactions and electronic communication via H-bonding. Similar to 1-X and 3-OAr, the –CF₂H vibrations of 6-I/F were unable to be identified even with isotopic labeling of the –CF₂H(D) group. An NCI analysis of 6-F indicated a stronger attractive interaction than found in 7-F (sign(λ₂)ρ for s=0.5: 6-F = −0.029; 7-F = −0.021), consistent with polarization serving as the dominant factor in forming the non-conventional H-bonds (Table S13). Although preorganization can serve to structurally enforce H-bonding interactions to unconventional H-bond donors, the results of our combined experimental/computational investigations indicate that, even with structurally similar environments, the –CF₂H group imparts significantly stronger interactions, when compared to an –ⁱPr group.

Determination of –CF₂H hydrogen bond strength.

To determine the strength of the unconventional –CF₂H⋯X H-bonds for the strongest H-bond acceptor (F), we applied computational methods.⁸² We approximated the H-bond enthalpy (ΔH_H-F) of the –CR₂H⋯F-Pd bond of 1-F as the difference between the formation enthalpy of the Pd-F bond (ΔH_Pd-F) of 1-F and a reference compound that cannot H-bond.⁸³ The –CF₂H substituent, when placed in the para- position of the pyridine ring (phen^4-CF₂H), removes the attractive H-bond interaction for enthalpy analysis, but also imparts a geometric distortion relative to the para- substitution (overlay RMS = 0.111, See SI page S82). As such, the ΔH_Pd-F difference between ortho- vs para- does not simply reflect the H-bond contribution of the group, but also a primary-sphere perturbation (2-CF₂H vs 4-CF₂H; ΔPd-N = 0.095 Å; ΔPd-F < 0.011 Å; ΔH_Pd-F < 1.8 kcal/mol). To minimize the primary-sphere distortion and assess the electronic effect of the –CF₂H group, we compared the isostructural pair PdF₂(phen^4-CF₂H) and PdF₂(phen) (overlay RMS = 0.006). The minimal structural changes and small enthalpic differences between –H and –CF₂H (4-H vs 4-CF₂H; ΔPd-N = 0.002 Å; ΔPd-F < 0.002 Å; ΔH_Pd-F < 0.8 kcal/mol) demonstrates that the –CF₂H group exerts a modest electron withdrawing effect on the Pd center, which we expect to be similar in the case of ortho- substitution. After establishing the electronic effect of the –CF₂H group, we evaluated differences between phen^CF₂H and phen^iPr. Importantly, phen^CF₂H and phen^iPr exhibit identical primary coordination sphere environments (Figure 8; RMS = 0.0159),⁸⁴ which indicates that an enthalpy comparison between –CF₂H and –C(CH₃)₂H should appropriately model the H-bond interaction effects (2–CF₂H vs 2–C(CH₃)₂H; ΔPd-N < 0.007 Å; ΔPd-F < 0.003 Å). From this method (Figure 8), the –CF₂H⋯F H-bond strength is ~ −3.2 kcal/mol, which highlights the use of a preorganized ligand scaffold to bias cooperative interactions using the –CF₂H group.⁸⁵

Figure 8.

(A) Calculation of H-bond formation enthalpy ΔH_HF and (B) optimized structure overlay of 1-F and PdF₂(phen^iPr).

Reductive stability of –CF₂H H-bond donors.

The characterization of a stable Pd° intermediate en route to 1-F (vide supra) indicates compatibility between secondary-sphere –CF₂H H-bond donors and a low valent metal center. To further evaluate the stability of the –CF₂H group to low valent metal compounds, we investigated intermediate 2. Combining phen^CF₂H with the Pd° precursor, Pd₂(dba)₃, afforded a dark orange solution. The resulting ¹H and ¹⁹F NMR spectra feature broad ligand phen^CF₂H resonances at 7.21 and 8.88 ppm, consistent with Pd(phen^CF₂H)(dba) (2). Although no coordinated dba resonances were observed at room temperature, these were resolved upon cooling (– 30 °C) at 4.87, 4.56, and 4.33 ppm, consistent with fluxional behavior.⁸⁶ Similar preparations with dihydroxybipyridine (bpy^OH) were not successful and resulted in formation of a black precipitate. This result indicates that phen^CF₂H is compatible with Pd° in a complex that would otherwise not tolerate an H-bond donor containing ligand.⁸⁷

To complement the stability of phen^CF₂H in the presence of a reduced metal, described above, we performed electrochemical experiments. Electrochemical reduction of phenol has an onset potential of –1.8 V, while for Ph-CF₂H, no reduction is observed within the electrolyte window < −2.65 V (0.1 M [NBu₄][PF₆], CH₃CN vs Fc⁺/Fc).⁸⁸ Although certain reductants (i.e. KC₈) defluorinate the R-CF₂H group, the electrochemical analysis indicated alternative reductants or reduced metal precursors are expected to be compatible with –CF₂H containing ligands.⁸⁹ In support, solutions containing either Co(Cp*)₂ or KFe(Cp)(CO)₂ (E_1/2 > −1.98 vs Fc)³³ and Ph-CF₂H are stable and do not undergo defluorination (see SI page S61).

Low valent metal complexes are often precursors and/or intermediates during common organometallic reactions, such as cross coupling. To assess the ability of the appended –CF₂H containing ligand to tolerate reduced metal complexes competent for cross-coupling we investigated metalation of Ni°. Addition of phen^CF₂H to Ni(COD)₂ (COD = 1,4 cyclooctadiene) resulted in an immediate color change to dark purple. The UV-vis spectrum of the resultant complex features absorbances at 434, 545, and 686 nm, consistent with previously reported bipyridine Ni(COD) complexes,^90-91 which supports formation of Ni(phen^CF₂H)(COD) (8).^92-93 Similar to related phenanthroline complexes, 8 promotes phenyl halide coupling.⁹⁴ Addition of 1 equivalent PhI affords biphenyl in 90 % yield. A new paramagnetic species also forms, which was identified as NiI₂(phen^CF₂H)(THF) (9-THF) by an X-ray diffraction experiment as well as independent synthesis (Figure 9).⁹⁵ Formation of biphenyl by Ni° requires stability of the ligand with both the low valent metal center, and strongly basic groups (e.g. Ni-Ph).⁹⁴ Solutions of 8 (THF 25°C) were stable for ~ 20 h, while similar preparations with a protic appended H-bond donor ligand (bpy^OH) decompose and form a mirror on reaction vessel walls over < 1 h. Although the in situ reaction to form biphenyl proceeds with many aprotic polypyridyl ligands, when bpy^OH is used the reaction proceeds in very low yield (< 10 % biphenyl). These results indicate incompatibility between protic ligands and the phenyl halide coupling reaction, even for stoichiometric reactivity, and contrasts with the results obtained for phen^CF₂H. Overall, the combined electrochemical measurements and compatibility with reactions involving low valent complexes demonstrate an unexplored important property of –CF₂H units as H-bonding groups: reductive stability.

Figure 9.

(A) Phenyl halide coupling with in situ generated Ni° polypyridyl complexes and (B) isolated inorganic side product of phen^CF₂H reaction (9-THF) with crystal structure (50% probability ellipsoids; protons not involved in H-bonds are removed for clarity).

CONCLUSION

The investigation of the H-bond donor/acceptor interaction within the phen^CR₂H ligands revealed an unusual dependence on the H-bond acceptor. In addition to electronic considerations, the size contributes to geometric distortions of the primary coordination sphere as summarized by comparing ¹H NMR shifts and calculated bond metrics in Table 1. Key differences between more common H-bond donors (e.g. 2-hydroxypyridine) and phen^CF₂H ligands are illustrated by their geometric requirements. In contrast to coplanar H-bonds formed with even large acceptors (X = Cl, Br, I) in similar geometries,^44-45 the weaker H-bond donor –CF₂H counterparts require a larger X⋯H contact which is accommodated by phen^CF₂H binding distortions. Smaller acceptor groups, X = F, OAr, maintain similar primary-sphere bond distances and exhibit trends with increasing H-bond acceptor strength for the –CR₂H⋯X contact and ¹H shift. Exploiting the unique H-bond properties of the –CF₂H group, namely base and reductive tolerance, may require appending the group to more flexible polypyridyl ligands or ligands of smaller ring size to better facilitate coplanar H-bond donor interactions.

In summary, we have demonstrated that appended –CF₂H groups, such as those positioned in the 2-position of phen (phen^CF₂H) can engage in intramolecular H-bonding interactions to a metal-coordinated substrate with moderate strengths (~ 3 kcal/mol). This unit is stable, even when incorporated into highly reducing and/or basic organometallic reactions that are incompatible with most traditional H-bond donor groups. The ability of the –CF₂H group to form H-bonds, in addition to tolerating reducing and highly basic conditions, provides unique opportunities to develop and study synthetic systems capable of H-bonding in the presence of highly reduced metal centers, areas that we are currently pursuing.