Pyridine Modifications Regulate Electronics and Reactivity of Fe-Pyridinophane Complexes

Abstract

12-membered pyridinophanes are the focus of many studies as biological mimics, chelators, and catalytic precursors. Therefore, the desire to tune the reactivity of pyridinophanes to better control the applications of the derivative metal complexes has inspired many structure-activity relationship studies. However, separation of structural versus electronic changes imparted by ligand modification have made these structure-activity relationship studies of transition metal catalysts challenging to define. However, in this work we show that 4-substitution of the pyridine ring in 12-membered tetra-aza pyridinophanes successfully provides a regulatory handle on the electronic properities of the metal center and, therefore, the catalytic C-C coupling activity of the respective iron complexes. The C-C coupling reaction catalyzed by Fe(L1-L6) provides a range of yields (32–58%) that directly correlate to iron redox potentials (ΔE_1/2 = 152 mV) and metal binding constants (Δlog β = 3.45), while the geometry of the complexes were virtually indistinguishable. These are the first results to definitively show redox potential and metal binding as independent properties from the coordination chemistry in one ligand series. Adjustments to these chemical properties was then shown to provide a regulatory handle for the C-C coupling reactivity tuned via pyridine substitution in pyridinophanes.

Introduction

Metalloenzymes incorporate earth abundant metals, such as iron, to facilitate a wide range of biological transformations with great efficiency under mild conditions. Inorganic chemistry often draws inspiration from biological catalysts such as cytochrome p450 and has led to the development of a large library of ligands. Tetra-aza macrocyclic frameworks have shown promise as biological catalytic mimics in both the structure of the corresponding metal catalyst and activity of the complex compared to enzymes.^1–9 Several studies of synthetic biomimetic ligands revealed that mirroring the metal coordination environment and geometry of an enzyme are not the only factors that impact the reactivity. Rather, electronic properties of the ligand should also be considered.

Metal-binding tetra-aza macrocyclic ligands at large have been developed varying in ring size, rigidity, and amine functionalization.^{4, 6, 10–12} However, the coordination chemistry and electronics within this family of complexes has not been deconvoluted, particularly as it relates to reactivity. For example, N-atom modified macrocycles have been used for catalytic reactions. Prat et. al showed that substitution on the pyridine appendages on the N-1,4,7-triazacyclononane scaffold regulate the spin-state of iron complexes.¹³ Interestingly, the resulting iron complexes were found to be highly efficient catalysts for C–H and C═C oxidation reactions with H₂O₂ and functionalization of the pyridine ring provided selectivity for olefin cis-dihydroxylation. Costas et. al also investigated key design principles through ligand modifications to tune the reactivity of the iron complexes. In this example a library of ligand designs developed over several years was explored to also tune, not only reactivity, but also selectivity in the oxidation of C-H and C=C bonds.^14–15 While these examples employ modifications that change the coordination environment of the metal center, they also suggest that pyridine modifications may be a fruitful route to access electronic control of reactivity.

The introduction of the pyridine moiety into the skeleton of tetra-aza macrocycles resulted in a class of molecules known as pyridinophanes. This functionalization with pyridine introduced conformational rigidity and a handle for tuning ligand basicity, the latter has only recently been recognized.^16–19 These ligands were first explored to meet the need for fast forming complexes with divalent transition metal ions. They have been studied extensively as the backbone for contrast agents due to the inertness of the resulting complexes as well as mimics for metalloenzymes such as superoxide dismutase.^20–24 More recently, they have found applications in a range of catalytic reactions.^25–27

As a result of our group’s contributions to expanding the number of pyclen (1,4,7,10-tetraaza-2,6- pyridinophane) congeners with different substituents on the pyridine moiety, this modification method had only recently been observed to offer a unique opportunity of electronic control without change to the coordination environment.^28–29 The results of the series of studies described herein will focus on the characterization of iron(III) pyridinophane complexes, specifically, and their use for a C-C coupling reaction to demonstrate the impact of pyridine modification on catalytic activity of these complexes.

The direct Suzuki-Miyaura C-C coupling reaction is most commonly facilitated by Pd-based catalysts with moderate yields (60–80%).¹ However, iron complexes featuring pyridinophane ligands have also been reported to catalyze various examples of the Suzuki-Miyaura coupling reactions with similar success.^{7, 2, 5–6, 30–32} Wen and co-workers established iron-based, direct C-C coupling reactions using 12-membered tetra-aza macrocycles and iron-salts.³³ They showed that pyridine and pyrrole could each be coupled with phenylboronic acid to produce 2-phenylpyridine (41%) and 2-phenylpyrrole (66%), respectively. Our team has previously focused on the relationship between catalytic reaction yields for the coupling of pyrrole and phenylboronic acid with N-atom functionalization of tetra-aza macrocyclic ligands (Figure 1, top left), including the pyridinophane system, as well as incorporation of rigidity, achieved via cross-bridging within tetra-aza macrocyclic ligands, i.e. Me₂BCyclen and Me₂EBC.^{13–14, 34} We showed that the tetra-azamacrocycle alone, as well as Fe(ClO₄)₃ alone, produce either no or trace amounts of 2-phenylpyrrole.^34–35 This work also showed that the reaction does not proceed through a radical mechanism but most likely uses a high valent iron species in the mechanism that involves C-H activation, transmetalation, and reductive elimination.³² Lastly, μ-oxo iron dimers of the pyridinophane complexes were identified to form as off-cycle species that resulted in a decrease in catalytic yields.³²

Figure 1.

12-Membered tetra-aza pyridinophanes, varying in functional groups, and Fe(OTf)3 were used to catalyze the reaction between phenylboronic acid and pyrrole to form 2-phenyl pyrrole.

The scaffolds studied previously ranged in ring size and substitutions that lack functionalization to the pyridine ring (Figure 1, top left).^{13–14, 34} It was found that the redox activity of the complexes derived from the tetra-aza macrocycle series provided a handle by which the catalytic activity could be controlled. However, the impact of ligand modification on the observed redox behavior within the series of iron complexes, could not be attributed to the donor strength of the ligand alone. In the series previously investigated, the electronic properties of the complexes could not be separated from the range of geometric and coordination chemistry differences.

Here we hypothesize that the pyridine ring provides the unique opportunity to have a structure-activity relationship study without impacting the coordination chemistry. A preliminary communication introduced a series of ligands modified with electron withdrawing groups (EWG) on the pyridine ring and resulted in a large shift to more positive redox potentials of the metal complex as the strength of the withdrawing group increased. However, the complexes were not studied for catalysis.³⁶ These results inspired the current work here with a significantly expanded series that ranges from electron donating groups (EDG) (L1(NMe₂), L2(OMe)) and unsubstituted (pyclen, L3(H)) to electron withdrawing groups (EWG) (L4(I), L5(Cl), L6(CN)) (Figure 1, top right). The library of ligands was produced to study the impact of functionalizing the pyridine ring on electronic properties of the resulting iron(III) complexes and their use as catalysts for the direct Suzuki-Miyaura C-C coupling between the pyrrole and phenylboronic acid to yield 2-phenylpyrrole as a readout to demonstrate how the electronic changes impact the reactivity.

Results and Discussion

Synthesis.

Details for the synthesis of novel ligands L1 and L4 along with the new iron(III) complexes derived from L1, L2, and L4 are described in the Experimental and Supporting Information. The synthesis of this class of ligands typically involves the isolation of the 2,6-functionalized lutidine precursor with a leaving group to be used for the cyclization step. Ligands L1 and L4 share a common starting material produced using the methods shown in Scheme 1, which streamlined synthetic methods by minimizing divergent starting materials. Dimethyl 4-iodopyridine-2,6-dicarboxylate (1) and 4-Iodo-2,6-bis(hydroxymethyl)pyridine (2) were synthesized using previously published procedures (Scheme S1).^{3, 28} A tosylation reaction with 2 in basic THF at low temperature yielded 3. A Richman-Atkins type cyclization reaction between 3 and N,N’,N”-Tris(p-toluenesulfonyl)diethylenetriamine (4) produced the protected macrocycle 5. Precursor 5 can be converted into 6 by mixing with dimethylamine at high temperature in a pressure vessel for three days (Scheme 1). The product precipitates upon cooling and requires no further purification after filtration from the mother liquor. This reaction is one example where 5 serves as a molecule that can be easily converted into other species of interest and this reactivity is being actively explored. Deprotection of both 5 and 6 with H₂SO₄, followed by isolation as the HCl salts yields solid materials of L4 and L1, respectively, in good yields. The ligands used in this series provide a balanced range of electron donating and withdrawing substituents to best understand the impact of this change on the metal center. First, we will present the results of catalysis to provide a point-by-point comparison to the chemical characterizations within the series and reactivity observed.

Scheme 1.

Synthetic route used to obtain L1 and L4.

Catalysis.

Conversion yields for 2-phenyl pyrrole derived from phenylboronic acid and neat pyrrole ranged from 32–58% (Table 1) when catalyzed by iron(III) complexes (10% loading) formed in-situ (Fe(III)(OTf)₃ + L1-L6). EWGs in the 4-position of the pyridine ring resulted in higher yields in comparison to the ED functionality. The relationship observed between the Hammett Parameter, σ_p, for each pyridine substitution is directly proportional to C-C coupling reaction yield catalyzed by iron(III) with L1-L6. While the yields within the EWGs do not vary extensively, the differences between the EWGs and the EDGs indicate that reactivity of the metal center can be controlled using substitutions to the pyridine ring. It is hypothesized that these results can be attributed to the electron deficient metal center resulting from the EWGs rendering it more reactive, consistent with the recently proposed mechanism.³² Catalytic yields obtained when L4 was employed, do deviate from the series trend. This is due to the iodine group being sufficiently activated for cross-reaction with the substrates, thus decreasing the yield of the target 2-phenyl pyrrole. This reactivity engenders the ligand to compete with the reactants. A full study of the relationship between the conversion yields and the fundamental properties of the iron complex series will be detailed herein. This approach will allow us to investigate if the pyridine modifications impact the electronic properties of the metal center without a change in the coordination environment, as evidenced by the SC-XRD results described below.

Table 1.

Coupling reaction conversions for Fe(OTf)₃ and L1-L6 at 10% catalyst loading versus phenylboronic acid in neat pyrrole.

	R	σp	Conversiona (%)
L1	NMe2	−0.83	32 (±4)
L2	OMe	−0.27	47 (±4)
L3	H	0	54 (±2)
L4	I	0.18	49 (±6)
L5	Cl	0.23	56 (±2)
L6	CN	0.66	58 (±3)

^aDetermined by ¹H NMR. Internal standard: dimethyldiphenylsilane.

Ligand or Fe(OTf)₃ alone resulted no measurable yields.²⁸ Yields are comparable between forming catalyst in-situ vs. isolated complexes.

Synthesis and Characterization of Iron (III) Complexes.

To understand the impact of the electronic properties imparted by substitutions on the pyridine ring of L1-L6, bona fide iron(III) complexes were obtained as crystalline materials. The iron complexes were produced by mixing the respective HCl salt ligands with iron(III) triflate in methanol. Slow evaporation of methanol solutions of each complex yielded materials suitable for analysis. The models resulting from XRD diffraction analysis (Table 2) are consistent with the results reported previously for FeL3, FeL5, and FeL6.^{34, 36} Each complex adopts a six coordinate, distorted octahedral geometry (N(2)-Fe-N(4) = 84–87°; N(1)-Fe-N(3). = 147–148°). The coordination sphere consists of four ligand-based nitrogen donor (2 axial and 2 cis) in addition to two chloride ions at the remaining cis positions derived from the HCl salt of the ligand used. The geometry and Fe-N bonds of the macrocycle are largely unaffected. The observed, distorted octahedral geometry and coordination environment are conserved throughout the Fe(L1-L6)³⁺ series indicating that electronic control provided by pyridine substitution is the largest contributor to any changes in the reactivity of the complexes studied.

Table 2.

Selected bond angles (°) and lengths (Å) from single crystal X-ray diffraction analysis of FeL1-FeL6.

	N(4)-Fe-N(2)	Fe-N(2)	Fe-N(4)
FeL1 (NMe2)	87.2 (4)	2.18(1)	2.047(9)
FeL2 (OMe)	84.6(1)	2.189(3)	2.099(3)
FeL3 (H)a	85.21(4)	2.20(1)	2.11(1)
FeL4 (I)	83.9(1)	2.188(4)	2.121(3)
FeL5 (Cl)a	84.45(6)	2.201(2)	2.116(2)
FeL6 (CN)a	85.9(1)	2.157(4)	2.105(4)

^aRef.³⁶

Electrochemistry.

The electrochemical behavior of a chelated metal-ion serves as a clear indicator of electronic changes within a ligand series. Therefore, cyclic voltammetry of the iron(III) complexes was used to identify a correlation between electronic control and substitution of the pyridine ring and how this might relate to reactivity in catalysis (Figure 2 and Table 3). The iron(III/II) redox couple shifted from −540 mV (FeL1) to more positive potentials (−388 mV, FeL6) as the EW character increased with substitutions on the pyridine ring of L1-L6. The EWG on the pyridine ring allowed the iron(III) complexes to be more easily reduced. The redox potential had been previously postulated to be a key factor in controlling the C-C catalytic activity for the iron(III) tetra-aza macrocyclic complexes shown in Figure 1 (top, left)³⁷, which is further supported by these results. These results indicate that there is a narrow range of control observed for the redox potentials of complexes with EW substitution (ΔE_1/2=65 mV, FeL3-FeL6), but this range of control is much larger for the ED series (ΔE_1/2=87 mV, FeL1-FeL3). On the other hand, the EDGs offer more sensitive regulation on the redox potential and ultimately on the electronic properties and reactivity of these complexes.

Figure 2.

Cyclic voltammogram overlay of the iron(III/II) redox couple of FeL1-FeL6 in DMF (3–4 mM complex; [Bu₄N][BF₄] (100 mM), Scan rate = 100 mV/s). Potential values have been normalized to Fc⁺/Fc, E_1/2 = 0.00 V.

Table 3.

The oxidation (E_Pa) and reduction (E_Pc) potentials vs Fc⁺/Fc (E_1/2 = 0.00 V), ΔE (mV), and E_1/2 (mV) for FeL1-FeL6.

Complexes	EPa (mV)	EPc (mV)	ΔE (mV)	E1/2 (mV)
FeL1 (NMe2)	−488	−593	105	−540
FeL2 (OMe)	−461	−577	116	−519
FeL3 (H)	−404	−502	98	−453
FeL4 (I)	−399	−495	96	−447
FeL5(Cl)	−365	−466	95	−416
FeL6 (CN)	−347	−432	85	−388

Formation constants.

Finally, metal binding stabilities were then evaluated to determine their relationship to regulation by pyridine substitutions on L1-L6. Potentiometric titrations were used to model the speciation of these complexes (Figure S9–S11) and log β for iron(II) with L1-L6, the latter of which was used to derive the iron(III) values using the redox data (Table 4) and the Nernst equation.^38–40 The log β with iron(III) complexes decreases from ED (L1, log β = 14.85) to EW (L6, log β = 11.40). Interestingly, this trend parallels the results from XRD studies that indicated a stronger interaction between ED ligands (L1-L2) with iron compared to the EW counterparts but the results are much more pronounced in terms of the range of control for the log β as a result of pyridine modification. The EDGs favor interactions with iron(III) compared to EWG having larger log β with iron(II). This indicates that a ligand with stronger donor ability has an increased interaction with the higher valent iron(III) compared to iron(II). Conversely, iron(II) complexes with EW ligands have larger formation constants than the iron(III) analogues. Therefore, one explanation for the results observed could be that the EDGs produce higher stability with the iron(III) complexes and higher accessibility to oxidized form like the μ-oxo species, rendering them less reactive, resulting in lower yields for the catalytic transformations presented herein. Moreover, there is a clear relationship between the log β iron(III) and electrochemical potentials compared to catalytic yields (Figure 3). For the pyridinophane series studied, the more positive redox potentials correspond to ligands with lower log β iron(III) and higher yields. These results support our previously postulated mechanism that involved a high valent iron(V)=O species, which would be more readily reduced under the oxidizing conditions of the catalytic reaction with the EWGs on the pyridinophane scaffold.³²

Table 4.

Formation constants (log β) of the ML species for Fe(II)/(III).

	log ß Fe(II)[a]	log ß Fe(III)[b]
[FeL1 (NMe2)]	13.14 (4)	14.85
[FeL2 (OMe)]	13.01(4)	14.38
[FeL3 (H)]	14.02(5)	14.26
[FeL4 (I)]	13.71(3)	13.85
[FeL5 (Cl)]	12.53(2)	12.14
[FeL6 (CN)]	12.26(2)	11.40

^[a]I = 0.15 M NaCl and T = 25.0 °C.

^[b]Derived from Nernst equation^38–40 and (Fe²⁺)_aq, E°, Fe^III/Fe^II = −0.439 vs. Fc⁺/Fc.

Figure 3.

Fe(III/II) potentials and log β versus catalytic yields for iron(III) complexes.

Conclusions

Cumulatively, the results of catalysis, XRD, CV, and metal-binding studies of iron(III) complexes of L1-L6 indicate that a controlled regulator of chemical properties and reactivity can be installed by functionalization of the pyridine ring in 12-membered tetra-aza macrocyclic pyridinophanes. The changes to electrochemical behavior and log β_Fe was directly correlated to pyridine substitution. Interestingly the geometry around the metal center did not change in the series. To evaluate the connection between these observations and their impact on reactivity, a C-C coupling reaction was explored. Further, the results indicate that EDGs provide a prominent influence yielding a broad range of potentials for the iron(III/II) couple [ΔE_1/2 ED = 87 mV, EW = 65 mV], which is also reflected in the range of catalytic activity [Yield range ED = 22% vs. EW = 4%]. The EDGs offer a better handle of modification on reactivity and electronic properties of the metal center. However, the EWGs have proven to increase the catalytic activity of the complex.

The correlation between catalytic yields, iron(III/II) redox potentials, and iron(II) complex formation constants supports the recently proposed mechanism that incorporates the formation of high valent iron-oxo species with ligands of this type.³² First, it is important to consider that the reaction takes place under oxidizing conditions. The catalytic mechanism, which involves a final reductive elimination step, would be facilitated by complexes that prove to be more easily reduced, i.e. FeL1-FeL3 with more positive iron(III/II) redox potentials. Also, our recent work indicated that a complex that forms off-cycle μ-oxo dimers can be a pathway that results in a decrease of reaction yields compared to catalysts that do not form dimers.³² This observation could be an additional pathway responsible for decreasing yields observed with EDG ligands. The redox potentials of the iron complexes with EDGs are indicative of stabilized oxidized species, including μ-oxo dimers. Consistent with these results and during our work on this project, it was qualitatively observed that ligands L1 and L2 were more prone to form such dimers compared to L3-L6. This should be an area of further exploration and a consideration when designing catalysts for C-C coupling reactions with iron.

As shown in Figure 4A, molecules studied in previous work did not allow for a separation of geometric and redox properties and resulted in a non-linear relationship between yields and redox-potential. However, this work shows that the electronic properties provide a direct regulation of reactivity (Figure 4B), when geometry is kept constant. As a result of this, it was determined that a balance of complex stability and redox potential is key to controlling the reaction. The EWGs in the series have shown the extent, and apparent limits, to which this balance can be manipulated through pyridine modifications and serves as a foundation to design other systems to expand on these findings.

Figure 4.

(A) Previous work showed that C-C yields can be correlated to redox control of the iron but the redox potential could not be decoupled from geometry.⁴¹ (B) In the present work, the geometry is held constant and redox potential varied using pyridine substitutions, leading to a direct relationship between C-C yield and redox potential. Open symbols represent ligands focused on this study.

Experimental

General Methods.

Pyrrole (98% Purity) was distilled under reduced pressure prior to use; all other reagents, including anhydrous iron(III) triflate (Sigma-Aldrich), were obtained from commercial sources and used as received, unless noted otherwise. ¹H NMR spectra were obtained with a 400 MHz Bruker Avance spectrometer using deuterated solvents and were referenced using the corresponding solvent resonance (in parts per million; e.g. CDCl₃, δ= 7.26 ppm).⁴² For proper identification of the NMR signals, the following abbreviations were used: s = singlet, d = doublet, t = triplet, m =multiplet. Elemental analysis was performed by Atlantic Microlab Inc. Synthesis of ligands L1 and L4 is detailed in Supporting Information. Ligands L2, L3, L5 and L6 and complexes FeL3, FeL5 and FeL7 were synthesized using previously published procedures.^28–29

Potentiometric methods.

The concentration of each ligand, as well as stability constants of the iron(II) complexes, were determined via pH-potentiometric titrations. A Metrohm 888 Titrando equipped with a Metrohm 6.0234.100 combined electrode was used to measure the pH in the titration experiments. For the calibration of the electrode, KH-phthalate (pH 4.008) and borax (pH 9.177) buffers were used.^43–44 The calculation of [H⁺] from the measured pH values was performed with the use of the method proposed by Irving et al. by titrating a 0.02 M HCl solution with a standardized NaOH solution (0.2 M).⁴⁵ The differences between the measured and calculated pH values were used to obtain the [H⁺] concentrations from the pH-data collected in the titrations. The ion product of water was determined from the same experiment in the pH range 11.40–12.00. The ionic strength in the titrated and thermostat controlled (at 25 °C) samples of 6.00 mL was kept constant and set to 0.15 M NaCl. A magnetic stirbar was used to mix each sample, which were kept under an inert gas atmosphere (N₂) to avoid the effect of CO₂. The protonation constants of the ligands were obtained from previously reported data.²⁸ The stability constants of the metal complexes were determined using the direct pH-potentiometric method by titrating samples with 1:1 metal-to-ligand ratios (the number of data pairs were between 100–250), allowing 1 min for sample equilibration to occur. The protonation and stability constants ((log β) = [ML]/([M][L])) were calculated from the titration data with the PSEQUAD program.⁴⁶ formation constants and speciation diagrams for L3, L5 and L6 were previously reported.³⁶

Catalytic Reactions.

Phenylboronic acid (24 mg, 0.20 mmol), ligand (0.02 mmol) and Fe^III(OTf)₃ (9.9 mg, 0.02 mmol) were added to a 2−10 mL flask equipped with a stir bar. Pyrrole (1 mL) was added to flask, and the mixture was heated to 130°C for 10 h as previously reported.

Yield Determination.

Reactions were cooled to room temperature, and the pyrrole was removed in vacuo until no visible liquid was present. The reaction was dissolved in a minimum amount of CDCl₃, and 10 μL of dimethyldiphenylsilane was added as an internal reference. The solution was filtered through a 0.2 μm nylon filter. Yield determinations were performed using three resonances 6.875, 6.532, and 6.307 ppm, corresponding to 2-phenylpyrrole and a resonance at 0.533 ppm corresponding to dimethyldiphenyl silane. The reported values are averages of all resonances; each reaction was run in triplicate.

X-ray Crystallography.

Crystal diffraction data for FeL1, FeL2 and FeL4 were collected at 100 K on a Bruker D8 Quest Diffractometer. Data collection, frame integration, data reduction (multi-scan), and structure determination were carried out using APEX2 software.⁴⁷ Structural refinements were performed with XSHELL (v 6.3.1), by the full-matrix least-squares method.⁴⁸ All non-hydrogen atoms were refined using anisotropic thermal parameters, while the hydrogen atoms were treated as mixed. The ORTEP molecular plots (50%) were produced using APEX2 (Version 2014.9–0).

Electrochemistry.

Cyclic voltammetry experiments for the FeL1, FeL2 and FeL4 complexes used 3–4 mM complex and 100 mM [Bu₄N][BF₄] as the supporting electrolyte in DMF and were carried out under a blanket of N₂. The electrochemical cell was composed of a working glassy carbon electrode, a Pt auxiliary electrode, and a silver wire as the reference electrode. The potential values presented here have been normalized to the half-wave potential of the Fc⁺/Fc = 0.00 mV.

Synthesis of 2.

4-iodo-2,6-dimethylcarboxylate pyridine (1) was synthesized using previously published procedure.⁴⁹ A 250 mL two-necked round bottom flask was charged with 1 (8.08 g, 25.1 mmol), finely powdered CaCl₂ (2.79 g, 25.2 mmol), and anhydrous MeOH (150 mL) under N₂ atmosphere. NaBH₄ (1.89 g, 50.6 mmol) was added portion-wise for ca. 10 min to the suspension at room temperature and stirred. During the addition, the color of the white suspension changed to bright pink and then orange. The reaction was monitored by TLC [R_f (1) = 0.53, R_f (2) = 0.1 (diethyl ether)]. After 5 h, the resulting colorless suspension was filtered through silica gel (3 cm × 2 cm, rinsing with MeOH). The solvents of the filtrate were removed by rotary evaporation and the residual colorless solid was dissolved in 1 M HCl (100 mL). The pH of the solution was raised to pH 12 by the addition of 1.0 M aqueous NaOH, resulting in a solid precipitate. The tan precipitate was isolated by filtration, washed with water (200 mL), and dried using rotary evaporation. After drying for 5 d in a lyophilizer, 1 (5.21 g, 19.7 mmol, 78%) was obtained as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.70 (s, 2H), 5.52 (t, J=4.11 Hz, 2H), 4.48 (d, J=4.01 Hz, 4H).

Synthesis of 3.

A procedure for a similar intermediate was adapted.³ A 250 mL round bottom flask was charged with 2 (5.22 g, 19.7 mmol), NaOH (3.21 g, 80.2 mmol), H₂O (20 mL), and THF (20 mL) at 0° C and stirred. A solution of tosyl chloride (16.9 g, 88.8 mmol) in THF (30 mL) was added dropwise to this mixture for ca. 10 min. The mixture was stirred at 0 °C for 2 h, and at room temperature for 2 h. The mixture was concentrated using rotary evaporation and H₂O (60 mL) was added. The mixture was extracted with CH₂Cl₂ (3X50 mL). The organic layer was dried (anhydrous Na₂SO₄) and filtered. The solvent was evaporated using rotary evaporation to obtain tan solid crystals, which were washed with diethyl ether (200 mL). The residual solvent was removed using an oil pump vacuum to obtain 2 (10.4 g, 18.1 mmol, 92%) as white crystals. ¹H NMR (400 MHz, CDCl₃) δ: 7.81 (d, J=8.04 Hz, 4H), 7.64 (s, 2H), 7.36 (d, J=8.13 Hz, 4H), 5.01 (s, 4H), 2.47 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ: 154.1, 145.4, 132.5, 130.4, 130.0, 128.1, 107.0, 70.4, 21.7.

Synthesis of 5.

N,N’,N”-Tris(p-toluenesulfonyl)diethylenetriamine (4) was produced using previously reported procedures.²⁸ A 250 mL two-necked round bottom flask was charged with (1.98 g, 3.55 mmol), Cs₂CO₃ (3.42 g, 10.5 mmol), and anhydrous DMF (150 mL) under an N₂ atmosphere. 2 (2.04 g, 3.55 mmol) in DMF (25 mL) was added dropwise to the mixture for ca. 10 min and stirred. After 16 h, the solvent was removed using rotary evaporation to obtain a tan solid. Water (50.0 mL) was added and the mixture was extracted with CH₂Cl₂ (3 × 30 mL). The solvent was removed from the organic phase by rotary evaporation to obtain 5. (2.49 g, 3.13 mmol, 88%) as a tan powder. Note: This product was >95% pure (¹H NMR). To obtain a pure sample, the final product obtained can be washed multiple times with small amounts of EtOAc. Since the desired product is slightly soluble in EtOAc, a small yield is lost. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.72 – 7.68 (m, 8H), 7.48–7.44 (m, 6H), 4.31 (s, 4H), 3.60 (t, J=4.06 Hz, 4H), 3.11 (t, J=4.12 Hz, 4H) 2.43 (s, 6H) 2.42 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ:157.8, 144.1, 143.8, 138.4, 135.4, 131.1, 130.5, 127.5, 127.1, 108.4, 54.5, 49.7, 46.1, 21.52, 21.48. Elemental analysis: Calc. (Found) for L4-Ts₃: C, 48.36 (48.32); H, 4.44 (4.40); N, 7.05 (6.97). HRMS: calc. (found) (M+H⁺, m/z) 795.0836 (795.0845).

Synthesis of L4⸱3HCl.

Previously reported deprotection (or detosylation) methods were used to design the synthesis of L4.⁵ A 100 mL round bottom flask was charged with 5 (0.641 g, 0.811 mmol) and cc. H₂SO₄ (10 ml). The mixture was stirred at 120 °C. After 3 h, the oil bath was removed, and the mixture was allowed to cool to room temperature. The mixture was then washed with diethyl ether (200 mL) to remove the organic impurities. 1 M NaOH was added to the aqueous fraction until the pH of the solution reached 12. CH₂Cl₂ (100 mL) was added to the flask and the mixture was extracted with CH₂Cl₂ (2 × 50 mL). The solvent was removed from the organic extracts using rotary evaporation to obtain a tan oil. The least amount of cc. HCl (1 mL) was added to the mixture. Anhydrous EtOH (5 mL) and diethyl ether (20 mL) were then added dropwise to the flask, and a white solid precipitated. The solid was collected by filtration, washed with CH₂Cl₂ (20 mL), and dried using an oil pump vacuum to obtain L4⸱3HCl (0.232 g, 0.532 mmol, 65%) as white crystals. ¹H NMR (400 MHz, D₂O) 7.89 (s, 2H), 4.50 (s, 4H), 3.27 (t, J=8.10 Hz, 4H), 3.13 (t, J=7.96 Hz, 4H); ¹³C (101 MHz, D₂O) 150.2, 132.8, 108.8, 48.5, 44.6, 43.4. Elemental analysis: Calc. (Found) for C₁₁H₂₁IN₄Na₄Cl₈: C, 18.56(18.82); H, 2.97(3.16); N, 7.87(7.83). HRMS: calc. (found) (M+H⁺, m/z) 333.0571 (333.0559).

Synthesis of 6.

Methods previously reported were used to design the synthesis of 6.⁵⁰ A 75 mL pressure flask was charged with 5 (0.618 g, 0.755 mmol), in 40% aqueous dimethyl amine solution (10.0 mL, 75.6 mmol) the flask was sealed and placed under 160 °C. After 3 days the mixture was left to cool to room temperature, resulting in a white precipitate. The solid was collected by filtration, washed with CH₂Cl₂ (20 mL), and dried using an oil pump vacuum to obtain 6 (0.338 g, 0.462 mmol, 61%) as white crystals. ¹H NMR (400 MHz, CDCl₃) 7.71 (d, J=8.24 Hz, 3H), 7.67 (d, J=8.24 Hz, 3H), 7.33 (d, J=7.96 Hz, 3H), 7.28(d, J=8.00 Hz, 3H) 6.56 (s, 2H), 4.14 (br s, 4H), 3.33 (br, 4H), 2.99 (s, 6H) 2.75 (s, 4H), 2.44 (s, 6H), 2.42 (s, 3H); ¹³C NMR (101 MHz, CDCl₃); Elemental analysis: Calc. (Found) for C₃₄H₄₁N₅O₆S₃: C, 57.36(56.71)*; H,5.81(5.75); N, 9.84(9.76). HRMS: calc. (found) (M+H⁺, m/z) 712.2292 (712.2290). *The found C percentage deviated from the calculated value, but based on other characterization methods we have proceeded to the next step with this product.

Synthesis of L1⸱3HCl.²⁸

A 100 mL round bottom flask was charged with L1-Ts₃ (0.743 g, 1.04 mmol) and cc. H₂SO₄ (10 ml). The mixture was stirred at 120 °C. After 3 h, the oil bath was removed and the mixture was allowed to cool to room temperature. The mixture was then washed with diethyl ether (200 mL) to remove the organic impurities. 1 M NaOH was added to the aqueous fraction until the pH of the solution reached 12. CH₂Cl₂ (100 mL) was added to the flask and the mixture was extracted with CH₂Cl₂ (2 × 50 mL). The solvent was removed from the organic extracts using rotary evaporation to obtain a tan oil. The least amount of cc. HCl (2 mL) was added to the mixture. Anhydrous EtOH (5 mL) and diethyl ether (20 mL) were added dropwise to the flask, and a white solid precipitated. The solid was collected by filtration, washed with CH₂Cl₂ (20 mL), and dried using an oil pump vacuum to obtain L1⸱3HCl (0.224 g, 0.630 mmol, 60%) as white crystals. ¹H NMR (400 MHz, D₂O) 6.63 (s, 2H), 4.31 (s, 4H), 3.39–3.41 (m, 4H), 3.32–3.34 (m, 4H), 2.93 (s, 6H); ¹³C NMR(101 MHz, D₂O) 156.7, 149.1, 133.1, 106.2, 49.1, 43.0, 38.8. Elemental analysis: Calc. (Found) for C₂₇H₅₈N₁₀OCl₈: C, 39.43(39.14); H, 7.11(7.46); N, 17.25(17.03). HRMS: calc. (found) (M+H⁺, m/z) 250.2026 (250.2019).

Synthesis of complexes.

[Fe^IIIL1(Cl)₂]CF₃SO₃.

Fe(CF₃SO₃)₃ (101 mg, 0.20 mmol) was dissolved in 6 mL of methanol and added dropwise to L1·3HCl(150 mg, 0.22 mmol) dissolved in a minimal volume of water. The reaction was allowed to stir overnight. A fine precipitate was removed by filtration through a 0.2 μm nylon filter and the yellow solution was transferred to a test tube for slow evaporation at room temperature. The resulting purple, X-ray quality crystals were isolated via filtration and washed with a small amount of cold methanol. Yield: 56% (58.8 mg, 0.11 mmol). Elemental Analysis: Calc. (Found) for C₁₄H₂₃Cl₂F₃FeN₅O₃S: C, 32.01 (31.76); H, 4.41 (4.42); N, 13.34 (13.13). [Fe^IIIL2(Cl)₂]CF₃SO₃ and [Fe^IIIL4(Cl)₂]CF₃SO₃ were produced in an identical manner using 100–250 mg of ligand in each reaction.

[Fe^IIIL2(Cl)₂]CF₃SO₃.

Orange Crystals. Yield: 60% (58.4 mg, 0.114 mmol). Elemental Analysis: Calc. (Found) for C₁₃H₂₀Cl₂F₃FeN₄O₄S: C, 30.49 (30.40); H, 3.94 (3.88); N, 10.94 (10.80).

[Fe^IIIL4(Cl)₂]CF₃SO₃.

Orange Crystals. Yield: 70% (90 mg, 0.340 mmol). Elemental Analysis: Calc. (Found) for C₁₂H₁₇Cl₂F₃FeIN₄O₃S: C, 23.82 (24.14); H, 2.33 (2.65); N, 9.23 (9.25). (CCDC#: 2126621).