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

James P. Shanahan, Danielle M. Mullis, Matthias Zeller, and Nathaniel K. Szymczak*

Article

Reductively Stable Hydrogen-Bonding Ligands Featuring Appended

CF −H Units

Cite This: https://dx.doi.org/10.1021/jacs.0c01718

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sı Supporting Information

ABSTRACT: We present the development of ligands featuring

the unconventional hydrogen bond donor, −CF H, within a

metal’s secondary coordination sphere. When metalated with

palladium, o-CF H-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 −CF H group (∼3 kcal/mol).

The synthesis of Pd /Ni complexes and subsequent coupling (Ni)

highlight the unique reductive and base compatibility of the

−

CF H hydrogen bond donor group.

INTRODUCTION

substrate. To address this gap, we targeted ligands that

■

accommodate appended −CF H groups as a key design

Prearranged hydrogen bonding interactions that facilitate

substrate capture and activation are ubiquitous in metal-

loenzyme active sites. These secondary-sphere interactions are

critical to many biological transformations including nitrogen

element. Ortho-functionalized pyridines provide high direc-

tionality to enforce H-bonding to metal-bound sub-

13,14,38−47

strates,

especially when constrained within a rigid

−3

4−7

ﬁxation,

hydrogenation,

and CO reduction. To further

chelating ligand (Figure 1). To probe secondary coordination

understand how these noncovalent interactions facilitate small-

molecule activation, synthetic complexes featuring appended

hydrogen bond (H-bond) donors are increasingly used in

sphere eﬀects of −CF H H-bonding to a metal-bound

substrate, we targeted 2-(diﬂuoromethyl)-1,10-phenanth-

−12

13−20

CF2H

43−49

biomimetic design

and catalytic transformations.

roline (phen

Herein we disclose the −CF H

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

group as a viable H-bond donor when appended to a ligand

21−23

undergo proton transfer to the metal,

which presents a

fundamental challenge for evaluating H-bond-induced reac-

tivity at highly reduced metal sites. Although biologically

relevant H-bond donors (e.g., amines, thiols, and water) are

5−28

often incompatible with reduced metal complexes,

metalloenzymes have evolved to overcome this limitation by

(

1) isolating their active sites, (2) employing highly speciﬁc

−

H /e transport systems, and/or (3) operating at or above

the proton reduction limit through charge delocalization (e.g.,

FeS] clusters; E > −0.8 V vs SHE).

approach within synthetic systems, where common reducing

31,32

[

An alternative

Figure 1. 2-Pyridyl ligand frameworks for −OH and −CF H H-

agents used to access biological model complexes exceed −2 V

bonds.

(

vs SHE), is to use H-bond donors that are resistant to

proton transfer.

Received: February 12, 2020

The −CF H functional group is a robust bioisostere for

amines and thiols, exhibiting comparable H-bond donor

strength. Although H-bonding eﬀects of this unit have

6,37

been identiﬁed using metal-free systems,

has not been incorporated within a metal’s secondary

the −CF H unit

coordination sphere for H-bonding to a metal-coordinated

XXXX American Chemical Society

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

X-ray crystallography (Figure 2 ). The primary coordination

Article

scaﬀold and evaluate (1) directional H-bond strength and (2)

reductive stability.

H chemical shift of H-bond donors (E−H) provides a

spectroscopic handle for interrogating H-bond interactions,

where strong H-bond interactions generally have a large

RESULTS AND DISCUSSION

Synthesis and Characterization of Complexes Featur-

■

deshielding eﬀect. However, for the 1-X series, the induced

H (X = F, Cl, Br; 8.38, 8.73,

H-bond chemical shift of −CF

ing Secondary-Sphere −CF H Hydrogen Bonds. The

8.73 ppm, respectively) is inverted relative to the predicted H-

CF2H

treatment of phen

with PdCl in reﬂuxing acetonitrile

) (1-Cl) in 55% yield as conﬁrmed by

bond acceptor strength (F > Cl > Br).

CF2H

aﬀorded PdCl (phen

To understand why the −CF H proton resonance undergoes

an upﬁeld rather than a downﬁeld shift in the H 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 = (CH Cl ) level of theory. 1-X undergoes a

geometric distortion as the size of X increases, forcing the

CF2H

phen

ligand out of the PdX plane (Figure 3 ). The

Figure 2. (A) Synthesis of complexes 1-X and 2 and (B) crystal

structure of 1-Cl; Cl1−H11 = 2.339 and Cl1−C11 3.15(2) Å with

side view (50% probability ellipsoids; protons not involved in H-

bonds are removed for clarity).

sphere of 1-Cl features 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) reveals

that the −CF H proton is oriented toward the neighboring

−

Cl at a distance of 2.339 Å (C−Cl = 3.15(2) Å) within the

sum of the van der Waals radii (vdW),

Figure 3. DFT-optimized structures with NCI analysis (isosurface s =

51,52

consistent with the

.5) of the X−H interaction of (A) 1-F, 1-Cl, and 1-Br, (B) side view

formation of a −CF H···Cl H-bond. To assess the −CF H

of the 1-X distortion of the Pd−N1−C3 angle, and (C) NCI analysis

of H-bond interactions of H O, NH , and CH F with NH .

3,14,38−44

group as a secondary-sphere H-bond donor,

evaluated the interaction energy, solution behavior, and donor

strength of the H-bond.

To interrogate the extent to which the −CF H H-bond is

distortion of the close contact for the −CF H···X proton is an

retained in solution, we examined a series of 1-X complexes (X

additional factor that may convolute the eﬀect of NMR

F, Cl, Br): congeners featuring coordinated halides of varied

shielding. To determine whether the −CF H···X close contact

CF2H

H-bond acceptor strength. We prepared PdBr (phen

)

is attractive or repulsive and the relative magnitude of the

(1-Br) in 80% yield, analogous to 1-Cl, while PdF (phen

interaction, we employed a noncovalent interaction (NCI)

(

1-F) was accessed by the oxidation of in-situ-prepared

analysis of 1-X. The NCI plots (Figure 3) demonstrate that the

CF2H

Pd(dba)(phen

XeF₂.

) (2) (dba = dibenzylideneacetone) with

X···H interaction is attractive (sign(λ )ρ < 0) for all X and

4−60

CF2H

Relative to the free ligand, phen

, the H NMR

largest in magnitude for 1-F (Figure 3) (sign(λ )ρ_m_i_n: F =

spectra of complex 1-X exhibit shifts of the −CF H group ( J

−0.034; Cl = −0.021; Br = −0.019). For context, the

52−55 Hz) downﬁeld from 7.01 to ≥8.3 ppm and

interactions of H-bond donors H O, NH , and CH F

2 2

corresponding modest F NMR shifts (≤Δδ 4.5 ppm). For

interacting with a reference acceptor molecule, NH , are

-F, the −CF H H NMR signal at 8.38 ppm is a triplet of

−0.028 (H O), −0.016 (NH ), and −0.013 (CH F ) (Figure

2 2

doublets with coupling constants of 53 and 25 Hz, which we

3C). To further characterize the −CF H H-bond, we examined

attribute to both −CF H F J coupling as well as a

charge transfer via a natural bond orbital (NBO) analysis. A

through-space −CF H···F interaction ( J ). Selective H{ F}

comparison of 1-F and 1-Br revealed the C−H bond of

−

decoupling of the Pd−F signal at −383 ppm collapsed the

−CF H has a higher H charge for 1-F (Δe = 0.03) with a

−

triplet of doublets to a triplet ( J

= 53 Hz), further

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). The

supporting the assignment of J coupling, a hallmark of −F···

H H-bond formation. The magnitude of | J | of 25 Hz is

1,62

consistent with “weak” H-bond formation.

In general, the

computational analysis of 1-X supports an H-bonding

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

Br, NO ) (Figure 4 A). H NMR analyses of 3-OArR ′ feature

Article

interaction of Pd−X with the −CF H unit and underscores the

importance of geometric constraints of the H-bond acceptor.

The geometric distortions that convolute the 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 a tunable H-bond acceptor

strength that can be quantiﬁed by the Hammett parameter

(

where the H-bond acceptor strength tracks as NMe > OMe

Bu > H > Br > NO₂). The salt metathesis of 1-Cl with 2

equiv of thallium phenoxides resulted in the formation of

CF2H

Pd(OArR′) (phen

) (3-OArR′, R′ = NMe , OMe, Bu, H,

Figure 5. Hammett plots of (A) −CR H Δδ and (B) calculated

Δν

of 3-OArR′ and 5-OArR′.

C−H

to σ = −0.268 (3-OArOMe), with deviations from linearity

observed for σ = −0.83 (3-OArNMe ).

To clarify the reasons that govern the nonlinear behavior

described above, we examined the solid-state structures of 3-

OArR′. Both structurally characterized products, 3-OArNO

and 3-OArH, exhibit similar −CF H···O heavy-atom −C···O

distances consistent with H-bonding interactions (2.820(5)

and 2.93(2) Å respectively) (Figure 4B). For an sp carbon

atom, the heavy-atom positions (C−CF ) provide a relative

−

H-atom position and orientation (riding model) even

without location using a diﬀerence electron map. Using

this treatment, the H···O contacts of 3-OArNO 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

Figure 4. (A) Synthesis of complexes 3-OArR′ and 5-OArR′. (B)

Crystal structures of 4-Cl, 3-OArNO , and 3-OArH (50% probability

ellipsoids; protons not involved in H-bonds were removed for clarity).

Dihedral angles are shown for H13−C13−C10−N2. (C) Steric (1

vdW radii) and electrostatic potential surface (at 0.004 au)

comparisons for appended groups of phen^C^R²^H.

riding model protons is the result of −CF H rotation (3-

OArNO = 11.8°; 3-OArH ≤ 1°) about the C −CF H torsion

angle, with a stronger H-bond interaction exhibiting a shorter

H-bond contact (Figure 6). The consequence of −CF H

coplanarity for 3-OArH is that as the H-bond strength is

small shifts of the phen^C^F²^Hligand resonances and a pair of

corresponding aryl resonances, consistent with an identical

primary coordination sphere across the series. X-ray analysis of

increased, a closer contact is not possible and the H NMR

response is 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 with

-OArNO and 3-OArH provided clear support that the

primary coordination sphere is not altered (Figure 4B; primary

respect to H-bond acceptor strength and that coplanar

sphere geometry overlay RMS = 0.111; see the SI). Across the

geometry (R′ = − Bu, −OMe, −NMe ) aﬀords an H-bond

series, the H NMR −CF H resonance shifted downﬁeld with

with a maximum directionality (∠O−H−C) of 158° (Figure

increasing H-bond acceptor strength of the phenoxide (Figure

6).

A), consistent with an H-bond-strength-induced chemical

There are two competing factors that could generate the

shift. When the Δδ of the −CF H resonance is plotted as a

function of the Hammett parameter (σ ), the data are linear up

short H···X contacts from the −CF H group: (1) an attractive

interaction or (2) the minimization of steric repulsion from the

Journal of the American Chemical Society

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Article

group for −CF H (Charton parameter (ν): −CF H = 0.68;

−

CH = 0.52), it does not capture the steric bias contributing

to C−H orientation. Furthermore, fast rotation of the −CH

group averages the H-bond interactions with noninteracting

protons on the NMR time scale, resulting in a diminished H

NMR response. Instead, we targeted an Pr group (ν = 0.76) as

iPr

a structurally faithful model (phen ) to assess the C−H

polarization contribution to H-bond formation (Figure 4C).

iPr

Metalation of the control ligand, phen , with

iPr

PdCl (PhCN) aﬀorded PdCl (phen ) (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 a C−Cl

contact of 3.256(3) Å), which are longer contacts than for the

−

CF H analogue (1-Cl: H···Cl = 2.339 Å; C−Cl = 3.15(2) Å).

To rigorously compare the H-bond contributions of the

−

C(CH ) H group vs −CF H, we prepared analogous Pd

phenoxide complexes. Salt metathesis of 4-Cl aﬀorded the

phenoxide complexes (5-OArR′). The H NMR spectra of

the 5-OArR′ complexes each contain a characteristic septet

peak between 4.50 and 5.30 ppm (Δδ = 0.80) assignable to the

Figure 6. Analysis of the impact of the 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 the

calculated NCCH dihedral angle (deg) and O···H contact of 3-

OArR′.

methine proton (H−C(CH ) ).

3 2

In comparison to −CF H, the Δδ of the −C(CH ) H

3 2

resonance is similar for weak H-bond acceptors (R′=

−

NO ··· Bu; ΔΔδ ≤ 0.08) and larger only for strong H-

bond acceptors where through-space interactions are expected

−

F substituents. With few exceptions, the identiﬁcation of H-

to dominate −CR H rotation eﬀects (Figure 5A and Table 1).

bond interactions of −CF H units relies exclusively on

These results were supported by computational analysis of the

crystallographic analyses. An assessment of close contacts

does not necessitate an attractive interaction. However, in

many of these structures,

is hindered due to the steric repulsion from the −F groups, a

factor noted above to control H-bond strength. To examine

-OArR′ and 5-OArR′ series, which exhibit a phenoxide-

dependent −CR H dihedral orientation for −CF H but not for

−C(CH H (SI). This result is consistent with weaker

attractive noncovalent interactions for the nonpolar −C-

36,69−71

rotation of the −CF H group

)

3 2

the steric component of the −CF H unit to inﬂuence close

(CH

)

H, compared to −CF H. Together, the combined H

contacts, we targeted an isosteric analogue of −CF H that has

NMR/computational analyses support the notion that the

similarly hindered −CR H rotation but does not contain an

unique ability of the −CF H group to form H-bonds is an

acidic C−H group. Although −CH is a common control

electronic, rather than steric, eﬀect.

CR2H

Table 1. H-Bonding and Primary-Sphere Comparisons between Pd−phen

Compounds

H −CR H(ppm) X_b···H (Å) Pd−X (Å) Pd−X (Å) DFT: X ···H (Å) DFT: Pd−X (Å) DFT: Pd−X (Å) DFT: νC−H (cm⁻¹

compound

)

−

CF H

-F

-Cl

-Br

-OArNO₂

-OArBr

-OArH

-OAr Bu

-OArOMe

8.38

8.73

8.02

8.47

8.72

8.81

8.86

8.97

9.08

8.68

1.829

2.364

2.533

2.088

2.051

1.995

1.948

1.955

2.772

1.869

1.947

2.294

2.431

2.000

1.998

1.993

1.992

2.002

2.003

1.941

1.946

1.956

2.304

2.441

2.006

2.004

1.999

2.006

2.007

2.010

2.665

1.996

3128

3205

3210

3186

3184

3173

3145

3141

3135

3149

3110

2.339

2.197

2.002

2.290(16)

1.983(3)

2.002(9)

2.299(17)

1.993(3)

2.020(8)

-OArNMe₂

-I

-F

1.895

2.496

1.977(5)

1.957(7)

−

C(CH ) H

3 2

-Cl

5.07

4.49

4.82

4.93

4.95

5.20

5.25

5.28

5.01

2.2796(7)

2.2891(7)

2.430

2.118

2.125

2.116

2.066

2.106

2.112

2.794

2.073

2.300

2.005

2.023

1.996

1.994

1.997

1.998

1.943

1.949

2.314

2.012

2.029

2.002

2.005

2.013

2.681

1.994

3172

3120

3118

3116

3115

3116

3121

3106

3102

-OArNO₂

-OArBr

-OArH

-OAr Bu

-OArOMe

-OArNMe₂

-I

-F

X , H-bond acceptor; X , noninteracting X-type ligand on Pd. Distances reported are for one individual molecule in the unit cell.

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Article

Although the computational and experimental studies above

indicate that the phen^C^F²^Hligand engages in H-bond

interactions, quantifying the interaction strength is intrinsically

diﬃcult. In contrast to classic H-bond donors (OH and NH)

that undergo a hypsochromic (blue) shift of the ν_E₋_Hmode

upon the formation of an H-bond, H-bonds to C−H donors

may exhibit distinct shifts: the ν

may undergo a

C−H

hypsochromic (blue), no shift, or a bathochromic (red)

shift. As a result, it is diﬃcult to identify ν

shifts for even

C−H

simple systems, and there are no reported correlations

between C−H H-bond energy and ν_C₋_H

To ascertain the inﬂuence of the −CR H group on the H-

bond interaction, the vibrational dependence (Δν ) of the

donor was analyzed computationally for 3-OArR′ and 5-

C−H

OArR′. We found that ν

for 3-OArR′ exhibits bath-

C−H

ochromic (red) shifts with increasing H-bond acceptor

strength. The important diﬀerence between the two modeled

complexes is that for R = CF H the Δν tracks with the H-

C−H

bond acceptor strength, while there is no systematic trend for

R = C(CH ) H (Figure 5B).

To experimentally establish the relative strength of the

CR H···X interaction (for CF H and C(CH ) H), we

3 2

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

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). (C) H and selectively decoupled H{ F}

NMR of 6-F and 7-F.

4−59

CF2H

iPr

diﬂuorides.

The addition of phen

or phen to

CF2H

Pd(Ph)I(Py) in CH Cl aﬀorded Pd(Ph)I(phen

Pd(Ph)I(phen ) (7-I) in good yields (84 or 76%,

respectively) (Figure 7A). Sonication of 6-I and AgF in

) (6-I) or

−CF H(D) group. An NCI analysis of 6-F indicated a stronger

iPr

attractive interaction than found in 7-F (sign(λ )ρ for s = 0.5:

-F = −0.029; 7-F = −0.021), consistent with polarization

CH Cl while cooling in an ice bath facilitated halide exchange

serving as the dominant factor in forming unconventional 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 structur-

CF2H

to produce Pd(Ph)F(phen

) (6-F). The major isomer

observed (>95%) exhibited H···F H-bonding interactions, vide

infra.

H NMR spectra of 6-I and 6-F exhibit −CF H resonances

at 9.08 and 8.68 ppm, respectively. Similar to 1-F, the

CF H···F interaction in 6-F exhibits a through-space

ally similar environments, the −CF H group imparts

−

signiﬁcantly stronger interactions when compared to an − Pr

coupling interaction: | J | = 23 Hz. This value is smaller

group.

than | J | coupling to stronger H-bond donors (−OH = 50

Determination of −CF H Hydrogen Bond Strength.

Hz; −NH = 50−64 Hz ). To examine a direct comparison

To determine the strength of the unconventional −CF H···X

using stronger H-bond donors within this system, we targeted

H-bonds for the strongest H-bond acceptor (F), we applied

bpy as a related bidentate ligand. In contrast to the stable

computational methods. We approximated the H-bond

CF2H

complex obtained using phen

, we found that metalation of

enthalpy (ΔH ) of the −CR H···F−Pd bond of 1-F as the

H−F

this ligand under analogous conditions produced benzene (via

protonation of Pd-Ph) as a primary product, which is a

reaction liability introduced by acidic H-bond donors (−OH).

To further interrogate the electronic requirements needed to

diﬀerence between the formation enthalpy of the Pd−F bond

(ΔH

) of 1-F and a reference compound that cannot H-

Pd−F

bond. The −CF H substituent, when placed in the para

‑CF2H

position of the pyridine ring (phen

), removes the

visualize a through-space J coupling to C sp −H units, we

attractive H-bond interaction for enthalpy analysis but also

imparts a geometric distortion relative to the para substitution

iPr

analyzed the isostructural complex with phen . The H NMR

spectrum of the analogously prepared Pd(Ph)F(phen ) (7-F)

complex does not feature detectable through-space J_F_H

iPr

(overlay RMS = 0.111; SI page S82). As such, the ΔH

Pd−F

diﬀerence between ortho and para does not simply reﬂect the

H-bond contribution of the group but also a primary-sphere

perturbation (2-CF H vs 4-CF H; ΔPd−N = 0.095 Å; ΔPd−F

coupling but is broadened. Selective Pd−F decoupling

H{ F} NMR collapses the broadened resonance to a sharp

septet, which is consistent with a very weak through-space H···

< 0.011 Å; ΔH

< 1.8 kcal/mol). To minimize the primary-

Pd−F

F interaction of | J | ≤ 3 Hz. The contrast between the J of

sphere distortion and assess the electronic eﬀect of the −CF H

‑CF2H

-F and 7-F provides further support that the C−H bond in

group, we compared isostructural pair PdF (phen

) and

−

CF H is uniquely polarized and capable of stronger attractive

PdF (phen) (overlay RMS = 0.006). The minimal structural

interactions and electronic communication via H-bonding.

changes and small enthalpic diﬀerences between −H and

−CF H (4-H vs 4-CF H; ΔPd−N = 0.002 Å; ΔPd−F < 0.002

Similar to 1-X and 3-OAr, the −CF H vibrations of 6-I/F were

unable to be identiﬁed even with isotopic labeling of the

Å; ΔH

< 0.8 kcal/mol) demonstrate that the −CF H

Pd−F

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

primary coordination sphere environments (Figure 8 ; RMS =

Article

group exerts a modest electron-withdrawing eﬀect on the Pd

center, which we expect to be similar in the case of ortho

purple. The UV−vis spectrum of the resultant complex

features absorbances at 434, 545, and 686 nm, consistent

0,91

substitution. After establishing the electronic eﬀect of the

with previously reported bipyridine Ni(COD) complexes,

CF2H

−

CF H group, we evaluated diﬀerences between phen

phen . Importantly, phen

and

which supports the formation of Ni(phen

)(COD)

iPr

CF2H

iPr

92,93

and phen exhibit identical

(8).

Similar to related phenanthroline complexes, 8

promotes phenyl halide coupling. The addition of 1 equiv

of PhI aﬀords biphenyl in 90% yield. A new paramagnetic

CF2H

species also forms, which was identiﬁed as NiI (phen

(

THF) (9-THF) by an X-ray diﬀraction experiment as well as

independent synthesis (Figure 9 ). The formation of biphenyl

Figure 8. (A) Calculation of H-bond formation enthalpy ΔH and

iPr

(

B) optimized structure overlay of 1-F and PdF (phen ).

.0159), which indicates that an enthalpy comparison

between −CF H and −C(CH ) H should appropriately

3 2

model the H-bond interaction eﬀects (2−CF H vs 2−

C(CH ) H; ΔPd−N < 0.007 Å; ΔPd−F < 0.003 Å). From

this method (Figure 8), the −CF H···F H-bond strength is

∼

−3.2 kcal/mol, which highlights the use of a preorganized

ligand scaﬀold to bias cooperative interactions using the

−CF H group.

Reductive Stability of −CF H H-Bond Donors. The

characterization of a stable Pd intermediate en route to 1-F

vide supra) indicates compatibility between secondary-sphere

CF H H-bond donors and a low-valent metal center. To

(

−

further evaluate the stability of the −CF H group to low-valent

_F_i_g_u_r_e₉_.₍_A₎_P_h_e_n_y_l_h_a_l_i_d_e_c_o_u_p_l_i_n_g_w_i_t_h_i_n_-_s_i_t_u_-_g_e_n_e_r_a_t_e_d_N_i0

metal compounds, we investigated intermediate 2. Combining

polypyridyl complexes and (B) the isolated inorganic side product of

CF2H

phen

with the Pd precursor, Pd (dba) , aﬀorded a dark-

the phen

reaction (9-THF) with the crystal structure (50%

orange solution. The resulting H and F NMR spectra feature

broad ligand phen

consistent with Pd(phen

probability ellipsoids; protons not involved in H-bonds are removed

for clarity).

CF2H

resonances at 7.21 and 8.88 ppm,

CF2H

)(dba) (2). Although no coordi-

by Ni requires the stability of the ligand with both the low-

nated dba resonances were observed at room temperature,

valent metal center and strongly basic groups (e.g., Ni−Ph).

these were resolved upon cooling (−30 °C) at 4.87, 4.56, and

Solutions of 8 (THF 25 °C) were stable for ∼20 h, while

.33 ppm, consistent with ﬂuxional behavior. Analogous

reactions using dihydroxybipyridine (bpy ) in place of

similar preparations with a protic appended H-bond donor

CF2H

phen

were not successful and resulted in the formation

of a black precipitate. This result indicates that phen is

compatible with Pd in a complex that would otherwise not

ligand (bpy ) decompose and form a mirror on reaction

CF2H

vessel walls over <1 h. Although the in situ reaction to form

biphenyl proceeds with many aprotic polypyridyl ligands, when

tolerate an H-bond-donor-containing ligand.

bpy is used the reaction proceeds in very low yield (<10%

To complement the stability of phen^C^F²^Hin the presence of

a reduced metal, as described above, we performed electro-

chemical experiments. The electrochemical reduction of

phenol (a model H-bond donor) has an onset potential of

biphenyl). These results indicate the incompatibility between

protic ligands and the phenyl halide coupling reaction, even for

stoichiometric reactivity, and contrasts with the results

obtained for phen

measurements and compatibility with reactions involving low-

valent complexes demonstrate an unexplored important

CF2H

. Overall, the combined electrochemical

−

1.8 V, while for Ph−CF H, no reduction is observed within

the electrolyte window of <−2.65 V (0.1 M [NBu ][PF ],

CH CN vs Fc /Fc). Although certain reductants (i.e., KC )

property of −CF H units as H-bonding groups: reductive

stability.

deﬂuorinate the R−CF H group, the electrochemical analysis

indicated that alternative reductants or reduced metal

CONCLUSIONS

The investigation of the H-bond donor/acceptor interaction

within the phen

on the H-bond acceptor. In addition to electronic consid-

erations, the size contributes to geometric distortions of the

precursors are expected to be compatible with −CF H-

■

containing ligands. In support, solutions containing either

Co(Cp*) or KFe(Cp)(CO) (E > −1.98 vs Fc) and Ph−

CF H are stable and do not undergo deﬂuorination (SI p S61).

CR2H

ligands revealed an unusual dependence

1/2

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

primary coordination sphere as summarized by comparing H

NMR shifts and calculated bond metrics in Table 1. Key

−

CF H-containing ligand to tolerate reduced metal complexes

diﬀerences between more common H-bond donors (e.g., 2-

CF2H

competent for cross-coupling, we investigated the metalation

hydroxypyridine) and phen

ligands are illustrated by their

CF2H

of Ni . The addition of phen

cyclooctadiene) resulted in an immediate color change to dark

to Ni(COD) (COD = 1,4

geometric requirements. In contrast to coplanar H-bonds

formed to large acceptor atoms (X = Cl, Br, I) in analogous

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

(1) Spatzal, T.; Perez, K. A.; Einsle, O.; Howard, J. B.; Rees, D. C.

Article

4,45

geometries,

the weaker H-bond donor −CF H counter-

Sokol Graduate Research Fellowship. We thank Froylan Omar

Fernandez for fruitful discussions.

parts require a larger X···H contact, which is accommodated by

primary- and secondary-sphere distortions. Smaller acceptor

groups, X = F, OAr, maintain similar primary-sphere bond

distances and exhibit trends with increasing H-bond acceptor

strengths for the −CR H···X contact and H NMR shift.

Exploiting the unique H-bond properties of the −CF H group,

namely, the 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 −CF H

groups, such as those at the 2-position of phen (phen

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Nathaniel K. Szymczak − Department of Chemistry, University

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MacFaul, P. A.; Pickup, A.; Poultney, R.; Scott, J. S.; Svensson, P. H.;

Sweeney, J. Oxadiazole isomers: all bioisosteres are not created equal.

MedChemComm 2012, 3 (5), 600−604.

(

75) iPr has a closer steric Charton parameter to −CF H than to

−

CH and does not have the complicated signal averaging ( H NMR)

or vibrational mode mixing (IR) anticipated for −CH .

(76) Wang, C.; Danovich, D.; Shaik, S.; Mo, Y. A Unified Theory for

the Blue- and Red-Shifting Phenomena in Hydrogen and Halogen

Bonds. J. Chem. Theory Comput. 2017, 13 (4), 1626−1637.

(77) The ν

for 1-X features a hypso- to bathochromic shift with

C−H

increasing H-bond strength (SI).

(

78) Similar to the H NMR analysis of 3-OArR, the vibrational

analysis shows distinct behavior for stronger H-bond acceptors,

consistent with the angular dependence of the interaction.

(79) These values diverge from typical H-bond behavior analogously

to 1-X.

(80) Lee, D.-H.; Kwon, H. J.; Patel, B. P.; Liable-Sands, L. M.;

Rheingold, A. L.; Crabtree, R. H. Effects of a Nonligating Pendant

Hydrogen-Bonding Group in a Metal Complex: Stabilization of an

HF Complex. Organometallics 1999, 18 (9), 1615−1621.

(

81) Upon cooling 7-F to −80 °C, no J through-space coupling is

observed.

82) In contrast to intermolecular H-bond adducts where formation

(

enthalpies can be easily calculated, intramolecular H-bonds do not

have a corresponding formation enthalpy for association.

(83) We previously used similar approximations for secondary-

sphere H-bond interactions (ref 43).