Electronic influence of substitution on the pyridine ring within NNN pincer-type molecules

Article abstract of DOI:10.1039/c9dt04714j

Pincer molecules are of increasing interest due to the modular nature of modification and range of reactivity observed when coordinated to metal ions. A subset within the family of pincer molecules use a pyridine group to bridge the outer two arms as well as provide a N-donor atom for metal binding. While the arm appendages have been studied extensively, little research has been conducted on the electronic effects of the central, substituted pyridine systems. Therefore, a series of NNN pincer-type ligands with substitution on the 4-position of the pyridine ring with -OH, -OBn, -H, -Cl, and -NO₂ functional groups were synthesized and characterized through NMR spectroscopy and ESI-HRMS. Each pincer was metalated with Cu(ii) salts and evaluated through X-ray diffraction analysis, cyclic voltammetry, and density functional theory analysis. The results indicate that the relatively unstudied -OBn group demonstrates both electron-withdrawing (XRD bond lengths) and electron-donating (NMR spectroscopy) properties. The -NO₂ pincer ligand shows a redox event within experimental windows evaluated, in contrast to the other congeners studied. In addition, electron-donating groups increase the electron density around the Cu(ii) center based on DFT studies and cyclic voltammetry. These findings can be applied to other pyridine-based pincer systems when considering ligand design and warrants future characterization of 4-position substituted pyridines.

Full text of DOI:10.1039/c9dt04714j

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Electronic influence of substitution on the pyridine
ring within NNN pincer-type molecules†
Cite this: DOI: 10.1039/c9dt04714j
Timothy M. Schwartz,
Marianne E. Burnett
and Kayla N. Green
*
Pincer molecules are of increasing interest due to the modular nature of modification and range of reac-
tivity observed when coordinated to metal ions. A subset within the family of pincer molecules use a pyri-
dine group to bridge the outer two arms as well as provide a N-donor atom for metal binding. While the
arm appendages have been studied extensively, little research has been conducted on the electronic
effects of the central, substituted pyridine systems. Therefore, a series of NNN pincer-type ligands with
substitution on the 4-position of the pyridine ring with –OH, –OBn, –H, –Cl, and –NO2 functional
groups were synthesized and characterized through NMR spectroscopy and ESI-HRMS. Each pincer was
metalated with Cu(II) salts and evaluated through X-ray diffraction analysis, cyclic voltammetry, and
density functional theory analysis. The results indicate that the relatively unstudied –OBn group demon-
strates both electron-withdrawing (XRD bond lengths) and electron-donating (NMR spectroscopy) pro-
perties. The –NO2 pincer ligand shows a redox event within experimental windows evaluated, in contrast
to the other congeners studied. In addition, electron-donating groups increase the electron density
around the Cu(II) center based on DFT studies and cyclic voltammetry. These findings can be applied to
other pyridine-based pincer systems when considering ligand design and warrants future characterization
of 4-position substituted pyridines.
Received 11th December 2019,
Accepted 28th January 2020
DOI: 10.1039/c9dt04714j
rsc.li/dalton
overall tunability including electronic effects and ring size
within the inner coordination sphere. For example, the central
Introduction
Pincer molecules have been of extreme interest in the field of atom coordinating to the metal center has trans influence on
organometallic chemistry, amongst others, due to the attrac- species that may coordinate to the remaining open site of the
tive properties of these ligands. Pincers are loosely defined as metal center.1,5
terdentate ligands (three coordinating sites), with homo- or
Structural modification studies to date have largely focused
hetero-atom sites that prefer a meridional geometry upon on modification to the side arm appendages. Fig. 1 shows
metal coordination.1 van Koten described pincer systems in examples of the diversity in symmetric chiral and achiral arms
the late 80s and observed that the terdentate ligand system containing S, P, C, and N hetero-donor atoms.6–13 The broad
was highly rigid, easily tunable, and had activity involved in C– selection of these arms allow for specificity in cases like cataly-
H bond activation when bound with a variety of metal-ions sis. Aromatic rings remain a predominant, central component
including Pt, Pd, Ni, Cu, and Ir.2 While the ligand system was to pincer molecules, where benzene, pyridine, and pyrrole rep-
simple in nature, the pincer metal complexes showed stability resent the most prevalent systems. However, few studies have
and incredible versatility within organometallic chemistry.
Pincers are known for providing outer sphere effects, which
are key in organometallic and biological applications.1,3,4 In
coordination chemistry, pincers have continued to be investi-
gated as the inherent features can be easily modified.
Specifically, pincer ligands have been manipulated to focus on
Department of Chemistry and Biochemistry, Texas Christian University,
2950 S. Bowie, Fort Worth, TX 76129, USA. E-mail: kayla.green@tcu.edu
†Electronic supplementary information (ESI) available: NMR spectra, cyclic vol-
tammograms and X-ray diffraction details. CCDC 1958458, 1958460, 1958461,
1958462, 1958464 and 1958465. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c9dt04714j
Fig. 1 Notable pincer ligands in the literature.6–13
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>87%. Lower yields were obtained in DMF with equimolar
amounts of Et2NH and K2CO3 (50–60%). While higher temp-
eratures (85 °C) were used for L2–L3, ligands with electron
withdrawing groups required lower temperatures (<60 °C) in
order to avoid nucleophilic aromatic substitution. L1 was
obtained through the removal of the benzyl group of L2 using
a naphthalene-catalyzed lithiation step from lithium pellets in
anhydrous THF at −78 °C followed by hydrolysis with H2O.18,19
Care was taken to avoid an increase in temperature during the
reaction, which was observed to result in de-aromatization of
the pyridine ring. Hydrogenation with palladium catalysts were
also not successful. The L1–L5 pincers were isolated as yellow,
transparent viscous oils in the free base form. L1–L5 are
readily soluble in organic solvents. While L3 is readily soluble
in water, L1–L2 and L4–L5 require acidification to produce
aqueous solutions. These molecules were also observed to be
highly hygroscopic and were, therefore, stored under nitrogen.
The L1–L5 ligands were characterized by 1H and 13C NMR,
as well as ESI-HRMS (Fig. S1–S15†). Ligands containing elec-
tron withdrawing groups (L4–L5) have aromatic resonances
shifted further downfield, compared to L3 (neutral) and L1–L2
(electron donating). It is interesting to note that L1 has the
potential to tautomerize between the keto and enol form
Fig. 2 NNN type pincers described in this report.
focused on functional changes of these aromatic systems
within a pincer unit.14–17 These studies focused mainly on
benzene derivatives. Most notably, and specific to this report,
functional modifications to pyridine rings are difficult due to
the uneven distribution of electron density around the ring. In
order to expand the number of NNN type pincers and provide
insight into the fundamental properties of these pyridine-
derived systems, a new library of pincer ligands was produced.
The subsequent studies were used to assess how the electronic
modifications affect the coordination chemistry of chelated
metal centers.
Herein, we present the synthetic routes to the 4-substituted
(–OH (L1), –OBn (L2), –Cl (L4), –NO2 (L5)) congeners of the
symmetric NNN pincer 2,6-bis(diethylaminomethyl)pyridine
(L3) reported previously (Fig. 2).13 These molecules were
characterized through 1H and 13C NMR, and ESI-HRMS. The
Cu(II) complex of each pincer was isolated and studied through
X-ray diffraction analysis and cyclic voltammetry to evaluate
the impact of the substitution on the Cu(II) center. DFT ana-
lysis was used to further understand the observations derived
from the characterization methods of both the ligands and Cu
(II) complexes.
1
(Scheme 2).20 Based on H and 13C NMR, the keto form is the
observed tautomer in solution (Fig. S1 and S2†).
Traditionally, Hammett parameters are used to identify the
correlation between electron donor ability and an observed
result.21,22 While Hammett parameters are available for –OH,
–H, –Cl, and –NO2, data for –OBn has not been reported in the
literature. Such analysis is also challenging because of the
keto–enol tautimerization observed with L1. Therefore, density
functional theory (DFT) was used to understand the trends
observed in the NMR spectra. The keto form of L1 was
observed to be more thermodynamically stable (Δ59.9 kJ
mol−1). Therefore, only this tautomer will be discussed for the
ligand DFT comparisons in Fig. 3. The frontier molecular orbi-
Results and discussion
In order to evaluate the influence of substitution in the 4-posi-
tion of the pyridine ring with NNN pincer-type ligands, sym-
metric systems L1 (–OH), L2 (–OBn), L3 (–H), L4 (–Cl), and L5
(–NO2) were produced according to the synthetic routes
described in Scheme 1. L3 has been previously reported by
Vedernikov and co-workers using 2,6-bis(tosyloxymethyl)pyri-
dine and diethyl amine.13 However, a streamlined, new syn-
thetic approach was used and described herein (Scheme 1).
The syntheses of L2–L5 rely on a dialkylhalide precursor,
which is subjected to nucleophilic substitution with Et2NH to
produce the ligands of interest. This process was facilitated by
the use of excess Et2NH and K2CO3 in CH3CN with yields
Scheme 2 Keto–enol tautomerization of L1.
Fig. 3 Relative HOMO–LUMO gaps of ligands L1–L5 with the respect-
Scheme 1 Synthetic methods used for ligands L1–L5.
ive frontier molecular orbitals.
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tals of L1–L5 show a correlation between the relative HOMO–
LUMO gaps and substitution at the 4-position of the pyridine
ring. L1 (5.23 eV) and L3 (5.20 eV) have larger HOMO–LUMO
gaps compared to L2 (5.12 eV), L4 (5.08), and L5 (3.23 eV).
These results suggest that the –OBn substituent is more
closely related to the electron withdrawing moieties than elec-
tron donating moieties. In particular, the noticeably smaller
HOMO–LUMO gap of L5 suggests that ligand-based redox
activity could be accessible.
X-ray diffraction analysis
Given these observations, the substitution on the 4-position of
the pyridine ring suggested differences in electron donor
ability of these pincer ligands. Therefore, we synthesized Cu(II)
complexes (Scheme 3) in order to explore these implications to
coordination chemistry. Cu(II) salts were chosen because of the
straightforward synthetic procedures required, high formation
constants predicted by the Irving-Williams series, and relative
ease of crystallization within the series.23 The Cu(II) congener
of L3 has been previously reported in the solid state as
[CuL3Cl2] and was used for comparison herein.13 Likewise, crys-
talline materials suitable for XRD analysis were obtained for the
Cu(II) complexes of L1, L2, L4, and L5 using CuCl2 in DCM
(Scheme 3a and Fig. 4, 5). Pentacoordinate Cu(II) complexes
were isolated with one pincer and two chloro ligands ([CuL1Cl2],
[CuL2Cl2], [CuL4Cl2]), and a tetracoordinate Cu(II) complex was
isolated with one bound chloro ligand and a noncoordinating
[CuCl4]2− counterion ([CuL5Cl]2[CuCl4]) (Fig. 4 and 5).
In addition, BF4 salts were hypothesized to facilitate crystal-
lization as non-coordinating counter ions. Therefore, each
ligand (L1–L5) was dissolved in acidic water (pH ∼ 5), followed
by the slow addition of aqueous Cu(BF4)2 to produce the Cu(II)
complexes (Scheme 3b). X-ray quality crystals were obtained
for the Cu(II) complexes of L4–L5 by the vapor diffusion of
Et2O into an CH3CN solution of the complexes at room temp-
erature and subjected to XRD analysis. The results (Table 2
and Fig. 4, 5) indicate a coordination number of four to the Cu
Fig. 4 Solid state structures of pentacoordinate (A) [CuL1Cl2], (B)
[CuL2Cl2]a, (C) [CuL4Cl2]b, and (D) [CuL5(OH2)Cl][BF4] demonstrating
square pyramidal geometry. Counter ion and hydrogen atoms have been
removed for clarity.
Fig. 5 Solid state structures of tetracoordinate (A) [CuL4Cl][BF4] and (B)
[CuL5Cl]2[CuCl4] with square planar geometry. Counterions and hydro-
gen atoms have been removed for clarity.
(II) center comprised of one pincer (NNN donors) and one co-
ordinated chloro ligand ([CuL4Cl][BF4]) and a coordination
number of five consisting of one chloro and one aqua ligand
([CuL5(OH2)Cl][BF4]) (Fig. 4 and 5). Repeated attempts to
obtain crystalline materials of the Cu(II) complexes of L1–L3
with [BF4]− counter ions were unsuccessful.
Each of the pentacoordinate Cu(II) complexes [CuL1Cl2],
[CuL2Cl2], [CuL3Cl2], [CuL4Cl2], and [CuL5(OH2)Cl][BF4] are
observed in a distorted square pyramidal geometry. The
N-pyridine-Cu(II) bond lengths vary depending on the moiety
on the 4-position of the ring (Table 1). In general, the more
electron withdrawing groups have longer bond lengths than
the hydrogen congener L3, while the electron donating groups
have shorter bond lengths. It should be noted that while
[CuL1Cl2], [CuL2Cl2], and [CuL4Cl2] were isolated with two
chloride ligands coordinated to the Cu(II), the solid state struc-
ture of [CuL5(OH2)Cl][BF4] has one chloride ligand and one
aqua ligand. Attempts to isolate the pentacoordinate CuCl2
salts of L5 proved unsuccessful, and therefore suggest this is
an artifact of the ligand donor ability. Metalation of L5 with
CuCl2 produced the tetracoordinate complex with a [CuCl4]2−
counterion (Scheme 3a and Fig. 5). The incomplete metalation
was observed for the isopropyl congener of L3 previously.13 We
Scheme 3 General metalation procedures using (a) CuCl2 or (b) Cu
(BF4)2.
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Table 1 Selected bond lengths (Å) and angles (°) for [CuL1Cl2], [CuL2Cl2]a, [CuL3Cl2], [CuL4Cl2]b, and [CuL5(OH2)Cl][BF4]
[CuL1Cl2]
[CuL2Cl2]a
[CuL3Cl2]*
[CuL4Cl2]b
[CuL5Cl(OH2)][BF4]
N1–Cu
N2–Cu
N3–Cu
N1–Cu–N3
N2–Cu–Cl
2.174(3)
1.926(2)
2.118(2)
153.43(10)
170.98(8)
2.156(2)
1.9473(19)
2.184(2)
140.95(8)
160.65(6)
2.122(3)
1.939(2)
2.170(3)
152.99(9)
167.10(8)
2.155(5)
1.949(5)
2.159(5)
152.74(18)
163.60(14)
2.128(3)
1.945(2)
2.126(3)
157.37(7)
170.68(5)
* Ref. 13.
Table 2 Selected bond lengths (Å) and angles (°) for four coordinate
[CuL4CuCl][BF4] and [CuL5Cl]2[CuCl4]
[CuL4Cl][BF4]
[CuL5Cl]2[CuCl4]
N1–Cu
N2–Cu
N3–Cu
N1–Cu–N3
N2–Cu–Cl
2.155(9)
1.908(3)
2.037(10)
159.6(3)
178.5(13)
2.067(3)
1.920(3)
2.092(3)
166.27(12)
178.96(10)
attribute this observation to the electron withdrawing moiety
of L5. The electron withdrawing nature of the NO2 group
decreases electron density away on the N-pyridine atom and
subsequently decreases the donor capability of this ligand
making metalation more challenging. While the ethyl arms of
[CuL4Cl]BF4 were highly disordered, those of [CuL1Cl2],
[CuL2Cl2], [CuL3Cl2], [CuL4Cl2], and [CuL5(OH2)Cl][BF4] were
not. For the pentacoordinate complexes, the fifth bound
ligand forces the ethyl arms away from the coordination
sphere of the Cu(II) center and may be the origin of larger error
observed with the four coordinate complexes. It should be
noted that refinement of data from the [CuL4Cl2] material
required modeling with twin laws and resulted in lower resolu-
tion data compared to other systems described herein.
The experimental bond lengths for the tetracoordinate Cu
(II) complex of L4 are shorter than that of L5. However, the
pentacoordinate Cu(II) complex of L4 has the longest bond
(1.949(5) Å). This highlights the competitive behavior of this
moiety. While the chloro-substituent is electron-withdrawing
by induction, it is electron-donating by resonance.
Consequently, resonance overshadows the effect of induction,
leading to the electron-donating characteristics seen for the
[CuL4Cl2] complex.
Fig. 6 Electrostatic potential maps of four coordinate Cu(II) complexes
with one bound chloro ligand.
(II) complexes are denoted as follows: L1Cu, L2Cu, L3Cu,
L4Cu, and L5Cu. Each structure was optimized using B3LYP 6-
31++g(d,p) level of theory. Similar results were obtained using
the higher theory 6-311++g(d,p) for L1Cu and L3Cu, so the
former level of theory was used in order to conserve compu-
tational resources. Frequency calculations were performed for
each structure to verify a lack of imaginary frequencies. Using
the computed optimized geometries, energy profiles were
modeled for the free ligands and Cu(II) complexes in the form
of HOMO–LUMO and SOMO–LUMO diagrams, as well as
electrostatic potential maps (Fig. 3, 6 and 7). The majority of
the electron density (red) is localized around the chloro-coun-
terion within each complex, as expected. In addition, a
deficiency of electron density (blue) is centered around the Cu
Computational analysis
Density functional theory (DFT) analysis was further used to
help interpret the experimental observations. As observed with
the solid state structure of the Cu(II) complexes, multiple
forms of coordination are accessible. Therefore and for simpli-
city, only the free ligands and the tetracoordinated Cu(II) com-
plexes were modeled. The computations only accounted for
ligands coordinated to the metal center and subsequently were
modeled as a divalent species with one anionic ligand (chloro
ligand) for a total charge of +1. In order to further differentiate
Fig. 7 Relative SOMO–LUMO gaps of L1Cu–L5Cu complexes, arranged
computational and experimental complexes, the computed Cu from left to right, with the respective frontier molecular orbitals.
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(II) center for each complex (Fig. 6). Interestingly, L2Cu shows behavior of [CuL2Cl2] and [CuL3Cl2] are remarkably similar,
the greatest electron density around the Cu(II) center. We attri- which contradicts the electron-donating effects modeled in the
bute this observation to the electron-donating ability of the ESP maps (Fig. 6). We attribute this to the electron-withdraw-
oxygen atom. In contrast, L5Cu shows electron density localiz- ing capabilities of the benzene ring. No discernable data could
ation around the NO2-substituent. The electron withdrawing be obtained for [CuL5Cl2]. However, the CV of the L5 free
group pulls electron density away from the Cu(II) center. ligand (Fig. S24†) did show a reversible redox event within the
Interestingly, an unoccupied orbital situated around the nitro observable window, supporting the results from the small
group 1.8389 eV lower than the HOMO, was observed in HOMO–LUMO gap seen with the energy computations. The
Natural Bond Orbital analysis. L3Cu and L4Cu show almost irreversible reduction of [CuL1Cl2] occurred at a more negative
identical qualitative results. This observation demonstrates the potential (−786 mV) at 100 mV s−1, when compared to the
competitive behavior of induction and resonance and is sup- other Cu(II) complexes in the series, and is consistent with the
ported by the electrochemistry experiments discussed below.
expected electron donating ability of the –OH moiety on the
The fragment orbital contributions to the HOMO, SOMO, 4-position.
and LUMO of the ligands and Cu(II) complexes were also exam-
Plots of v1/2 vs. the Ipa and Ipc for each Cu(II) complex
ined with the computer program, Chemissian24 (Fig. S35– (Fig. S17, S19, S21 and S23†) show diffusion control up to
S38†). L5Cu again shows the majority of orbital contribution 100 mV s−1 for the oxidation event and up 500 mV s−1 for the
originates from the nitro-substituent. Interestingly, the OBn reduction event (the maximum value evaluated). This obser-
group within L2Cu shows similar results for the SOMO. This vation could be attributed to the inability for the complexes to
raises an interesting question regarding the electronic nature reorient from the preferred tetrahedral geometry of Cu(I) back
of the OBn substituent as a whole. As expected, L1 shows to the preferred octahedral geometry of Cu(II), but further
HOMO and LUMO contributions from mainly the N-pyridine studies would be needed to fully understand this phenom-
and substitution at the 4-position. This supports the obser- enon. The plot of v1/2 vs. the Ipa and Ipc for the L5 free ligand
vations of the electron donating properties of this ligand, even (Fig. S25†) shows diffusion control up to 500 mV s−1 (the
in the keto form. Furthermore, the NBO partial charge density maximum value evaluated) for both the oxidation and
on the N-pyridine atom were determined (Table S24†). A reduction event.
Hammett plot (Fig. S39†) was constructed for each species,
except L2Cu because no such parameter exists for the OBn
substituent. It is evident that a relationship exists for the
partial charge density and the given Hammett parameter
values.
Experimental
Physical methods and general considerations
Caution! Perchlorate salts are explosive and should be handled
with care; such compounds should never be heated as solids.
Electrochemistry
Reagents and solvents used for synthesis were purchased from
many commercials sources and used as received, unless other-
Cyclic voltammetry studies of the Cu(II) complexes, prepared
in situ, were carried out in acetonitrile using 0.1 M TBAP, a
platinum wire auxiliary electrode, glassy carbon working elec-
trode, and Ag wire reference electrode. The scan rates were
varied from 20 mV s−1 to 500 mV s−1 and referenced to Fc+/Fc
(Fig. 8, S16, S18, S20 and S22†). Notably, the Epc of [CuL2Cl2]
(−594 mV), [CuL3Cl2] (−592 mV), and [CuL4Cl2] (−593 mV)
measured at 100 mV s−1 and assigned as Cu(II)/Cu(I), are iden-
tical within experimental error. This supports the computed
results found in the ESP maps, which showed similar elec-
tronic properties between L3Cu and L4Cu. The electrochemical
1
wise noted. All H NMR and 13C spectra were completed using
a Bruker Avance III (400 MHz) High Performance Digital NMR
spectrometer in CDCl3. High resolution mass spectrometry
was completed at the University of North Texas Health Science
Center by the Advanced Mass Spectrometry and Proteomics
Laboratory (Fort Worth, TX). X-ray intensity data were collected
on a Bruker D8 Quest diffractometer equipped with a Photon
100 CMOS detector and generator operating at 50 kV and 30
A. The indexing of Bragg intensities was carried out with
APEX2 package.25 Data reduction and absorption corrections
were performed with the SAINT26 and SADABS27 software
packages, respectively. Structures were solved by the direct
method using the SHELXL-97 software and refined using
SHELXL in the WinGX package. OLEX2 software was used to
prepare material and graphics for publication.28 Cyclic voltam-
mograms were obtained in a nitrogen atmosphere at 22 °C
using a BASi EC Epsilon potentiostat equipped with a 3.0 mm
glassy carbon working electrode, a platinum wire auxiliary elec-
trode, and quasi Ag wire reference electrode. Measurements
were performed with 5 mM samples of each Cu(II) complex in
dry acetonitrile with 0.1 M TBAP as supporting electrolyte and
Fc as the internal standard (E1/2 = 0.00 mV). 4-(Benzyloxy)-2,6-
Fig. 8 CV overlay of CuCl2 and the Cu(II) complexes of L1–L4.
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bis(chloromethyl)pyridine (L2·1) was synthesized according to 171 mmol) and heated to 120 °C for 2 h. The reaction was
previous work.29
cooled to room temperature before the reaction flask was
4-(Benzyloxy)-2,6-bis(N,N-diethylaminomethyl)pyridine (L2). placed on an ice bath. The POCl3 was quenched with H2O
L2·1 (2.0 g, 7.0 mmol), produced using previously reported until effervescence ceased. NaOH pellets were added until a
methods,29 and K2CO3 (2.9 g, 21.2 mmol) were dissolved in pH of 9. The solution was extracted with dichloromethane (3 ×
50 mL CH3CN. Et2NH (1.5 mL, 14.1 mmol) was added drop- 100 mL). The organic layer was collected, dried over Na2SO4,
wise to the reaction mixture. The reaction was refluxed under and concentrated under reduced pressure. A light-yellow oil
N2 for 12 h. The reaction flask was cooled to room tempera- was isolated (L4·2, 8.6 g, 60.7 mmol, 91%). 1H NMR (400 MHz,
ture. K2CO3 was removed by vacuum filtration. The filtrate was CDCl3): 6.93 (s, 2H), 2.45 (s, 6H).
collected and concentrated under reduced pressure. The
4-Chloro-2,6-bis(bromomethyl)pyridine (L4·3). A modified
resulting oil was viscous and dark brown in color (6, 2.3 g, procedure from the literature was used.31 L4·2 (1.9 g,
6.7 mmol, 95%). 1H NMR (400 MHz, CDCl3): 7.38 (m, 5H), 13.4 mmol) was placed in a pressure flask and dissolved in
7.01 (s, 2H), 5.11 (s, 2H), 3.65 (s, 4H), 2.56 (q, 8H), 1.03 (t, 90 mL of carbon tetrachloride. N-Bromosuccinimide (NBS,
12H). 13C NMR (100 MHz, CDCl3): 166.00, 161.86, 136.18, 9.9 g, 55.6 mmol) was added to the flask, which was sealed
128.61, 128.16, 127.61, 107.08, 69.61, 59.62, 47.34, 11.96. ESI tightly and heated to 70 °C under a 200 W visible light for 6 h.
MS (m/z): Found: 356.26697[L2 + H]+, theoretical: 356.2624 [L2 Upon completion, the reaction was cooled to room tempera-
+ H]+.
ture. The reaction mixture was filtered through a pad of Celite
4-(Hydroxy)-2,6-bis(N,N-diethylaminomethyl)pyridine (L1). before being concentrated under vacuum. The resulting dark
Lithium pellets (0.40 g, 57 mmol) and naphthalene (0.90 g, red oil was collected and dissolved in 140 mL of THF and
7.0 mmol) were dissolved in 100 mL of anhydrous THF and placed on ice. DIPEA (7.2 mL, 41.3 mmol) was added dropwise
sonicated briefly to activate the lithium. The flask was placed to the flask immediately followed by the dropwise addition of
under nitrogen over a dry ice-acetone bath. L2 (1.03 g, diethyl phosphite (8.0 mL, 62.1 mmol). The flask was removed
2.89 mmol) was dissolved in a minimal amount of THF and from the ice bath and was stirred at room temperature for 3 h.
added dropwise to the lithium–naphthalene solution. Upon Water (40 mL) was added to the flask. The reaction mixture
addition of L2, the flask was allowed to come to room tempera- was concentrated under reduced pressure until the THF was
ture but continued stirring under nitrogen for 24 h. After 24 h, removed. The resulting aqueous mixture was extracted further
water was added to hydrolyze the lithium. The THF–water using dichloromethane and NaHCO3 solution. The organic
mixture was washed with diethyl ether (3 × 100 mL). The THF– layer was collected, dried over Na2SO4, and concentrated under
water layer was collected and concentrated under reduced vacuum. The resulting oil was purified by column chromato-
pressure to produce a light brown solid. The solid was lyophi- graphy (10 : 1, hexanes : ethyl acetate). The product (Rf = 0.27)
lized. The dry salts were washed with 150 mL absolute ethanol. was collected and concentrated under vacuum to afford a
The ethanol was concentrated under reduced pressure. A light, light, yellow solid (L4·3, 1.6 g, 5.3 mmol, 40%). 1H NMR
1
yellow oil was isolated (L1, 0.435 g, 1.68 mmol, 58%). H NMR (400 MHz, CDCl3): 7.39 (s, 2H), 4.48 (s, 4H).
(400 MHz, CDCl3): 6.15 (s, 2H), 3.48 (s, 4H), 2.55 (q, 8H), 2.26
4-Chloro-2,6-bis(N,N-diethylaminomethyl)pyridine (L4). K2CO3
(s, 1H), 1.04 (t, 12H). 13C NMR (100 MHz, CDCl3): 180.79, (0.126 g, 1.75 mmol) and L4·3 (76.1 mg, 0.254 mmol) were
147.97, 114.23, 54.22, 47.66, 12.27. ESI MS (m/z): Found: added to the reaction flask and dissolved in acetonitrile
266.2206 [L1 + H]+, theoretical: 266.2154 [L1 + H]+.
(10 mL). Et2NH (0.077 mL, 0.743 mmol) was added dropwise
2,6-Bis(N,N-diethylaminomethyl)pyridine (L3). An optimized to the reaction mixture, which was stirred at 60 °C for 12 h.
method was used that deviated from previously reported The reaction mixture was cooled to room temperature and sub-
studies; spectroscopic characterization were consistent with sequently filtered. The filtrate was concentrated under vacuum
1
previous reports.29,30 Compound L3·1 (1.00 g, 5.71 mmol) and to yield a light orange oil (L4, 71.5 mg, 0.252 mmol, 99%). H
K2CO3 (2.75 g, 19.9 mmol) were added to a flask with approxi- NMR (400 MHz, CDCl3): 7.38 (s, 2H), 3.67 (s, 4H), 2.56 (q, 8H),
mately 40 mL of acetonitrile. Et2NH (1.76 mL, 17.4 mmol) was 1.04 (t, 12H). 13C NMR (100 MHz, CDCl3): 161.91, 145.07,
added dropwise to the flask. The reaction mixture was refluxed 120.76, 59.28, 47.44, 11.95. ESI MS (m/z): Found: 284.1863 [L4
under N2 for 12 h. The reaction mixture was cooled to room + H]+, theoretical: 284.1815 [L4 + H]+.
temperature and subsequently filtered. The filtrate was concen-
2,6-Lutidine N-oxide (L5·2). As reported previously,31 2,6-luti-
trated under vacuum to yield a light brown oil. The oil was dine (L5·1) (21.0 mL, 180.3 mmol) was dissolved in glacial
subsequently dissolved in DCM, dried over Na2SO4, and con- acetic acid (56 mL) and H2O2 was added dropwise (35.0 mL,
centrated to yield a pale yellow oil (L2, 1.24 g, 4.97 mmol, 1132.0 mmol). The reaction mixture was heated to 100 °C for
1
86.9%). H NMR (400 MHz, CDCl3): 7.60 (t, 1H), 7.34 (d, 2H), 24 h. The flask was cooled to room temperature and concen-
3.70 (s, 4H), 2.57 (q, 8H), 1.04 (t, 12H). 13C NMR (100 MHz, trated under vacuum. The oil was basified to pH 14 with
CDCl3): 159.77, 136.56, 120.59, 59.68, 47.32, 11.92. ESI MS (m/ K2CO3 solution and extracted with dichloromethane (3 ×
z): Found: 250.2254 [L3 + H]+, theoretical: 250.2205 [L3 + H]+.
50 mL). The organic layer was collected, dried over Na2SO4,
4-Chloro-2,6-lutidine (L4·2). Methods were used based on and concentrated under vacuum to afford a light-yellow oil
the literature.31 4-Hydroxy-2,6-lutidine (L4·1, 8.5 g, 69 mmol) (L5·2, 24.1 g, 22.2 mmol, 92%). 1H NMR (400 MHz, CDCl3):
was dissolved in phosphoryl chloride (POCl3, 16 mL, 6.95 (m, 3H), 2.53 (s, 6H).
Dalton Trans.
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4-Nitro-2,6-lutidine N-oxide (L5·3). As reported in the pre- and concentrated under reduced pressure. The product was
1
viously,31 compound L5·2 (9.7 g, 78.8 mmol) was placed in a isolated as a light orange oil (L5, 72 mg, 0.24 mmol, 98%). H
100 mL flask. H2SO4 (23.0 mL, 422.0 mmol) was added drop- NMR (400 MHz, CDCl3): 8.09 (s, 2H), 3.80 (s, 4H), 2.61 (q, 8H),
wise to the flask. HNO3 (8.0 mL, 187.8 mmol) was then added 1.06 (t, 12H). 13C NMR (100 MHz, CDCl3): 164.26, 155.49,
dropwise to the flask. The mixture was heated to 85 °C for 24 h 113.01, 59.25, 47.62, 12.05. ESI MS (m/z): Found: 295.21072 [L5
and then was cooled to room temperature. The reaction + H]+, theoretical: 295.2056 [L5 + H]+.
mixture was added dropwise to a flask of water (200 mL) at
General method for metalation with CuCl2. A 1.1 : 1 molar
0 °C and a white precipitate formed. The aqueous solution was ratio of the pincer ligand to CuCl2 was used. The pincer ligand
isolated and extracted into chloroform (3 × 100 mL). The of interest was dissolved in 3 mL of DCM in a small glass vile
organic layer was collected and added to the white precipitate. with a stir bar. CuCl2 was suspended in 3 mL of DCM and
The organic layer was washed with 1 M NaOH solution (3 × added dropwise to the ligand solution with high stirring. The
100 mL). The organic layer was collected, dried over Na2SO4, yellow solution instantly changed to an aquamarine color.
and concentrated under vacuum. A white-yellow solid was iso- Upon complete addition of the CuCl2 suspension, a cap was
lated (L5·3, 9.9 g, 59.1 mmol, 75%). 1H NMR (400 MHz, placed on the glass vile and the solution was allowed to stir for
CDCl3): 8.05 (s, 2H), 2.60 (s, 6H).
12 h to ensure complete complexation. The solution was
4-Nitro-2,6-lutidine (L5·4). As reported in the literature,31 passed through a 0.45 μM syringe filter. To the collected DCM
PCl3 (8 mL, 92 mmol) was added dropwise to a flask of L5·3 was added pentanes to precipitate out the Cu(II) complexes.
(5.0 g, 29.7 mmol) dissolved in chloroform at 0 °C. The flask The light green precipitate was collected and washed with cold
was removed from the ice and heated to 62 °C for 4 h. The pentanes (2 × 5 mL).
reaction was then cooled to room temperature. The reaction
General method for metalation with Cu(BF4)2. A 1.1 : 1 molar
mixture was basified to pH 14 with 5 M NaOH. The aqueous ratio of the pincer ligand to Cu(BF4)2 was used. The pincer
mixture was extracted into chloroform and the organic layer ligands were suspended in 2 mL of H2O in a glass vile with a
was collected, dried over Na2SO4, and concentrated under stir bar and was adjusted to a pH of 5 with 0.1 M HCl. Micelles
vacuum to afford a light yellow solid (L5·5, 3.0 g, 19.9 mmol, were still present in the aqueous solution. Cu(BF4)2 was dis-
67%) 1H NMR (400 MHz, CDCl3): 7.70 (s, 2H), 2.68 (s, 6H).
4-Nitro-2,6-bis(bromomethyl)pyridine (L5·5).
solved in a minimal amount of H2O and added dropwise to
modified the pincer solution. The yellow solution changed to a deep
A
procedure from the literature was used.31 N-Bromosuccinimide blue color. A cap was placed on the vile and was set for 12 h
(15.7 g, 88.3 mmol) and L5·4 (2.1 g, 13.8 mmol) were dissolved with high stirring to ensure complete complexation. The
in benzene (100 mL). The reaction flask was stirred for 3 d at aqueous solution was passed through a 0.45 μM syringe filter.
80 °C under N2 with irradiation from a 200 W visible light. The filtrate was concentrated under reduced pressure to yield a
Solvent was removed under vacuum and the resulting solid dark blue oil. To this oil was added a minimal amount of
was dissolved in diethyl ether (60 mL) and filtered through a CH3CN and subsequently syringe filtered. The organic filtrate
Celite and Na2SO4 (1 : 1) mixture to remove any un-reacted was concentrated under reduced pressure to yield a greenish
bromine species. The filtrate was collected and concentrated blue solid.
under vacuum. The red oil was dissolved in anhydrous THF
and stirred at 0 °C. DIPEA (9.8 mL, 56.5 mmol) was added
dropwise. Next, diethyl phosphite (7.2 mL, 56.5 mmol) was
added dropwise. The reaction mixture was stirred at room
Conclusions
temperature for 30 minutes. Water was added (100 mL) to Overall, four new 2,6-bis(diethylaminomethyl)pyridine deriva-
quench the diethyl phosphite. The organic volatile solvent was tives were synthesized by the addition of varied substituents
removed under vacuum until the organic layer was removed (–OH, –OBn, –Cl, and –NO2) on the 4-position of the pyridine
and the remaining aqueous layer was washed with NaHCO3 ring and the synthesis of the –H congener was optimized. The
and extracted into diethyl ether. The organic layer was col- NNN type pincer series were characterized with combinations
lected, filtered through a Celite and Na2SO4 mixture (1 : 1), and of 1H and 13C NMR as well as ESI-HRMS. X-ray diffraction ana-
concentrated under vacuum. The crude product was purified lysis and cyclic voltammetry were used to evaluate the Cu(II)
by column chromatography (10 : 1 hexanes : ethyl acetate, Rf = complexes. DFT analysis was used to study the electronic
1
0.36) to afford a dark red oil (L5·5, 1.4 g, 4.2 mmol, 31%). H effects on both the free ligands and Cu(II) complexes. It was
NMR (400 MHz, CDCl3): 8.10 (s, 2H), 4.62 (s, 4H).
observed that the –NO2 moiety (L5) altered the electronic
4-Nitro-2,6-bis(N,N-diethylaminomethyl)pyridine (L5). K2CO3 nature of the free ligand to such an extent that non-innocent
(0.12 g, 0.87 mmol) and L5·5 (0.08 g, 0.25 mmol) were dis- redox events were observable in the experimental window of
solved in 40 mL of acetonitrile in a reaction flask. Et2NH the cyclic voltammetry experiments. NBO analysis showed the
(0.06 mL, 0.58 mmol) was added dropwise to the reaction presence of an unoccupied orbital lower in energy than the
mixture, which was then stirred at room temperature for 24 h. HOMO for both the ligand and Cu(II) complex. Additionally,
The solvent was removed under vacuum. The resulting mixture the –OBn substituent has been relatively unstudied previously.
was dissolved in dichloromethane and washed with water (3 × Some experimental methods were indicative of the electron-
50 mL). The organic layer was collected, dried over Na2SO4, donating properties (NMR of ligand, DFT) of the oxygen atom,
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Dalton Transactions
while others emphasized the electron-withdrawing (XRD of Cu
(II) complex) properties of the benzene ring. These obser-
9 G. Bauer and X. L. Hu, Inorg. Chem. Front., 2016, 3, 741–
765.
vations warrant future studies on the unique properties of this 10 A. M. Tondreau, J. M. Darmon, B. M. Wile, S. K. Floyd,
moiety.
E. Lobkovsky and P. J. Chirik, Organometallics, 2009, 28,
3928–3940.
11 D. Domyati, S. L. Hope, R. Latifi, M. D. Hearns and
L. Tahsini, Inorg. Chem., 2016, 55, 11685–11693.
12 M. Albrecht, P. Dani, M. Lutz, A. L. Spek and G. Van Koten,
J. Am. Chem. Soc., 2000, 122, 11822.
13 A. N. Vedernikov, P. Wu, J. C. Huffman and K. G. Caulton,
Inorg. Chim. Acta, 2002, 330, 103–110.
Author contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
14 J. A. Therrien and M. O. Wolf, Inorg. Chem., 2017, 56, 1161–
1172.
15 G. D. Batema, M. Lutz, A. L. Spek, C. A. van Walree,
G. P. M. van Klink and G. van Koten, Dalton Trans., 2014,
43, 12200–12209.
Conflicts of interest
There are no conflicts to declare.
16 L. A. van de Kuil, H. Luitjes, D. M. Grove, J. W. Zwikker,
J. G. M. van der Linden, A. M. Roelofsen, L. W. Jenneskens,
W. Drenth and G. van Koten, Organometallics, 1994, 13,
468–477.
17 M. Q. Slagt, G. Rodríguez, M. M. P. Grutters, R. J. M. Klein
Gebbink, W. Klopper, L. W. Jenneskens, M. Lutz, A. L. Spek
and G. van Koten, Chem. – Eur. J., 2004, 10, 1331–1344.
18 P. G. M. Wuts and T. W. Greene, Greene’s Protective Groups
in Organic Synthesis, John Wiley & Sons, Inc., Hoboken, NJ,
4th edn, 2007.
Acknowledgements
This work was funded by the National Institutes of Health
(R15GM123463 (to KG)). The authors are also grateful for gen-
erous financial support from TCU Andrews Institute of
Mathematics & Science Education (to KG), Cambridge Isotope
Laboratories, and TCU Research and Creativity Activity Grant
(to KG). The authors acknowledge the TCU High-Performance
Computing Center for providing HPC resources. The authors
would like to thank Dr. Matthias Zeller from Purdue University
for his expertise and structure refinement of [CuL4Cl]BF4.
19 E. Alonso, D. J. Ramon and M. Yus, Polyhedron, 1997, 53,
14355–14368.
20 K. N. Green, K. Pota, G. Tircsó, R. A. Gogolák, O. Kinsinger,
C. Davda, K. Blain, S. M. Brewer, P. Gonzalez,
H. M. Johnston and G. Akkaraju, Dalton Trans., 2019, 48,
12430–12439.
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