Introduction to the Developments in the Coordination Chemistry of
Introduction
The divalent oxidation states of the lanthanide ions (Ln 2+ ) are less stable compared to their well-known trivalent oxidation states (Ln 3+ ) Before the 1990s, only
Europium (Eu 2+), ytterbium (Yb 2+), and samarium (Sm 2+) are recognized in both solution and solid states The calculated reduction potentials of the lanthanides (Ln 3+/Ln 2+) are summarized in Table 1 Notably, europium exhibits the highest reduction potential, attributed to its half-filled 4f orbitals.
Table 1.1 Calculated Ln 3+ /Ln 2+ reduction potentials (versus normal hydrogen electrode) of lanthanides 5
Recently, Evans and coworkers synthesized divalent lanthanide complexes [K(2.2.2-cryptand)][(C5H4SiMe3)3Ln] (1.1) (Figure 1.1) in which Ln includes all lanthanides except the radioactive element Pm 5,6 Among these compounds, Eu 2+ ,
Yb 2+ , Sm 2+ , and Tm 2+ have 4f n+1 ground state electronic configurations; La 2+ , Ce 2+ ,
The divalent lanthanide ions Pr 2+, Gd 2+, Tb 2+, Ho 2+, Y 2+, Er 2+, and Lu 2+ possess 4f n 5d 1 ground state electronic configurations, while Dy 2+ and Nd 2+ also exhibit similar configurations, despite being traditionally classified as 4f n+1 Recent research from the Evans laboratory has challenged the long-standing belief that only Eu 2+, Yb 2+, Sm 2+, Tm 2+, Dy 2+, and Nd 2+ can be isolated as divalent lanthanide ions in molecular compounds.
Figure 1.1 Chemical Structure of complex 1.1.
Properties and applications of Eu 2+ -containing complexes
Europium stands out among the divalent lanthanides due to its highest positive reduction potential, making its divalent oxidation state the most accessible The Eu²⁺ ion, in its ground state, possesses seven unpaired electrons in its 4f orbitals and is isoelectronic with Gd³⁺, which contributes to its rapid water-exchange rate Additionally, these 4f electrons generate a significant spin magnetic moment of 7 μB Complexes containing Eu²⁺ exhibit distinctive broad emissions ranging from 390 to 580 nm, alongside sharp emission bands between 354 nm.
The luminescence of Eu 2+ in protic solvents like H2O and CH3OH can be quenched by the O–H oscillators present in the solvent's first coordination sphere However, macrocyclic ligands exhibit an "insulation effect," which enhances the emission of Eu 2+ compared to its free form by reducing the non-radiative rate constant.
Eu 2+ -containing complexes have considerable applications in synthetic chemistry, medical diagnosis, and materials science 10 For example, complex 1.2 (Figure 1.2) serves as a single-electron reductant when reacting with PhSeSePh; 12 complex 1.3
Indenyl ligands play a crucial role in initiating the polymerization of methyl methacrylate Additionally, complex 1.4 demonstrates enhanced efficiency as an MRI contrast agent at ultra-high field strengths compared to lower field strengths.
Figure 1.2 Structures of Eu 2+ -containing complexes 1.2–1.4.
Methods to stabilize Eu 2+
Despite its greater stability relative to other divalent lanthanides, Eu 2+ is prone to oxidation in solution when exposed to air, which limits its applications The effectiveness of Eu 2+ in solution is restricted by the absence of appropriate ligands that can stabilize its divalent state While Eu 2+ is extensively utilized in solid-state lighting materials, its luminescent properties in solution remain underexplored due to its tendency to oxidize to Eu 3+.
To harness the unique magnetic, catalytic, and luminescent properties of Eu 2+, it is crucial to develop effective methods to prevent its oxidation A promising approach involves utilizing macrocyclic ligands to encapsulate Eu 2+ The Allen research group has conducted studies on the oxidative stability of various Eu 2+-containing cryptates, highlighting their potential for enhanced performance.
1.10) (Figure 1.3) 16 Notably, complex 1.10 is the most oxidatively stable
The Eu²⁺-containing complex in aqueous solution exhibits an oxidative potential 35 mV higher than that of Fe²⁺ in hemoglobin This design is based on three key factors: the phenyl ring effectively reduces the cryptand cavity size, optimizing it for Eu²⁺; it also decreases the Lewis basicity of adjacent oxygen atoms, which is advantageous for the electron-rich Eu²⁺; and sulfur atoms, being softer than oxygen, provide a better match for the soft Eu²⁺ in accordance with hard–soft acid–base theory The study highlights that the stabilization of Eu²⁺ can be enhanced by adjusting the electronic and steric properties of the coordinating ligands.
Figure 1.3 Chemical structures of unfunctionalized Eu 2+ -containing cryptate 1.5 and functionalized Eu 2+ -containing cryptates 1.6–1.10 (coordinated water molecules and counter ions are not shown for clarity).
Aims of my research
The goal of my research was to synthesize new ligands which can stabilize Eu 2+ Through fine-tuning of ligand properties, we envisioned that the resulting
Eu 2+ -containing complexes have potential applications in MRI contrast agents, luminescence materials, and magnetic materials Building on previous successes with functionalized cryptands, this thesis emphasizes the modification of cryptands Chapter two details the synthesis of a cryptand linked to isophthalic acid via a thiourea bridge Chapter three covers the synthesis of an azacryptand and the progress towards its derivative Finally, chapter four discusses ligand 1.14, where two cryptands are bridged by tetraoxolene.
Figure 1.4 Chemical structures of compounds 1.11–1.14.
Synthesis of Cryptand Ligands for Eu 2+ -Containing Complexes as
Introduction
Magnetic resonance imaging (MRI) is a highly effective non-invasive diagnostic tool in medicine, known for its exceptional spatial resolution Most clinical MRI scanners operate at magnetic field strengths of 1.5 to 3 Tesla, but advancements in technology are pushing for higher field strengths to enhance both spatial and temporal resolution This trend reflects the MRI community's ongoing pursuit of improved imaging capabilities.
Gd 3+ -based contrast agents become less efficient as field strength increases 21,22 The Allen research group has investigated Eu 2+ -containing cryptates as alternatives to
Eu 2+ -containing complexes, which are isoelectronic to Gd 3+ and exhibit a faster water-exchange rate along with two inner-sphere water molecules, are ideal for ultra-high field strength MRI (≥7 T) Research by the Allen group indicates that these Eu 2+ -containing [2.2.2]cryptates (2.1–2.3) demonstrate enhanced effectiveness at ultra-high field strengths compared to lower fields.
Figure 2.1 Examples of Eu 2+ -containing [2.2.2]cryptates (2.1–2.3) that are more effective contrast agents for magnetic resonance imaging at ultra-high field strengths compared to lower fields 14
The positive charges of cryptates 2.1–2.3 may restrict their applications, as noted by Srinivasan and Sawyer, who observed that blood vessel walls and blood cells typically carry a negative charge.
2.3 might interact with the blood vessel walls and blood cells and hinder their in vivo delivery Based on this idea, ligand 2.4 was designed in which the cryptand ring and isophthalic acid are joined together by a thiourea linker The rationale for this ligand is that, upon metalation with Eu 2+ , it will produce a neutral complex 2.5 that will have a low tendency to interact with blood vessel walls and blood cells (Scheme 2.1)
Scheme 2.1 Metalation of 2.4 to form neutral Eu 2+ -containing complex 2.5
I initially synthesized cryptand 2.6, which features two methyl ester groups instead of carboxyl groups, utilizing commercially available dimethyl 5-isothiocyanatoisophthalate However, attempts at acid or base hydrolysis of 2.6 did not yield the desired product 2.4 Subsequently, I proceeded to prepare an alternative compound.
The synthesis of 5-isothiocyanatoisophthalic acid (2.7) was carried out following a previously published method, resulting in the formation of cryptand 2.4 The synthetic pathways for cryptands 2.4 and 2.6 are identical, with the exception of the final step Additionally, compounds 2.8 to 2.11 were synthesized using techniques similar to those outlined by Gansow and colleagues.
Scheme 2.2 Synthesis of cryptands 2.4 and 2.6.
Experimental Procedures
All chemicals used were of reagent-grade purity or higher and were utilized as received, unless specified otherwise Triethylamine was dried over calcium hydride and distilled in an argon atmosphere, while water was purified using a PURELAB Ultra Mk2 system Flash chromatography was conducted with silica gel 60 (230–400 mesh), and analytical thin-layer chromatography (TLC) was performed on plates precoated with silica gel 60 F254 (250 μm thickness) Visualization of TLC plates was achieved using a UV lamp or by charring with a potassium permanganate stain, prepared from 1.5 g KMnO4, 10 g K2CO3, 2.5 mL of 5% w/v aqueous NaOH, and 150 mL of water.
1H- and 13 C-NMR spectra were recorded at ambient temperature on a Varian Unity 400 spectrometer (400 MHz for 1 H and 101 MHz for 13 C) Chemical shifts were referenced to solvent residual signals (CDCl 3 : 1 H δ 7.26 ppm, 13 C δ 77.16; CD3CN:
1H δ 1.94, 13 C δ 118.26, 1.32; DMSO-d 6: 1 H δ 2.50, 13 C δ 39.52; D2O: 1 H δ 4.79, 13 C was referenced to 5% DMSO-d 6 added δ 39.52; CD2Cl2: 1 H δ 5.32, 13 C δ 53.84)
1H-NMR data is interpreted as first order, with apparent multiplicities categorized as follows: "s" for singlet, "d" for doublet, "t" for triplet, "dd" for doublet of doublets, "m" for multiplet, and "br" for broad The italicized elements indicate the shifts responsible for these designations High-resolution electrospray ionization mass spectra (HRESIMS) were obtained using a Waters LCT Premiere Xe TOF mass spectrometer, while low-resolution mass spectra of known compounds were recorded on a Shimadzu LCMS-2010EV mass spectrometer.
5-Isothiocyanatoisophthalic acid (2.7) was synthesized following established literature procedures The reaction involved dissolving 5-aminoisophthalic acid (2.12 g, 11.7 mmol), sodium acetate trihydrate (6.83 g, 50.2 mmol), and NaOH (1.05 g, 26.2 mmol) in a solvent mixture of water (50 mL) and acetone (25 mL) while stirring The solution was then cooled to 0 °C, and thiophosgene (1.50 g, 13.0 mmol) was added, resulting in a yellow suspension that turned into a white cloudy mixture after 30 minutes Following 2 hours of stirring, concentrated HCl was added dropwise to adjust the pH to 3, leading to the precipitation of the crude product as a white solid The solid was isolated through filtration using medium porosity glass frit and washed with 0.1 M hydrochloric acid.
A total of 100 mL was added to isolate and concentrate the soluble part under reduced pressure, resulting in 1.05 g (40%) of compound 2.7 as a white powder The 1H and 13C NMR spectra were assigned through comparison with existing literature The 1H NMR (400 MHz, DMSO-d6) exhibited signals at δ 13.63 (brs, 2H), 8.37 (t, J = 1.5 Hz, 1H), and 8.08 (d, J = 1.5 Hz, 2H) The 13C NMR (101 MHz, DMSO-d6) showed peaks at δ 165.4, 136.2, 133.1, 131.4, 130.2, and 128.6 The mass spectrometry analysis indicated a [M − H]− at the calculated m/z.
Dimethyl 2,2'-((4-nitro-1,2-phenylene)bis(oxy))diacetate (2.8) was synthesized following methods similar to those of Gansow and colleagues The process involved adding methyl bromoacetate to a stirred mixture of anhydrous K2CO3 in acetone, followed by the dropwise addition of a 4-nitrocatechol solution The reaction was refluxed for 12 hours, after which the mixture was cooled, filtered, and the solvent evaporated under reduced pressure The resulting solid was recrystallized from ethanol, yielding 3.34 g (84%) of compound 2.8 as a light yellow solid The structure was confirmed through 1H- and 13C-NMR spectroscopy, with specific chemical shifts reported for various protons.
3H) 13 C NMR (101 MHz, CDCl 3 ) δ 168.5, 168.3, 153.2, 147.6, 142.4, 118.9 113.2, 110.1, 66.4, 66.2, 52.7, 52.6; MS (m/z): [M + Na] + calcd for C 12 H 13 NO 8 Na, 322.0; found, 322.1
2,2'-((4-Nitro-1,2-phenylene)bis(oxy))diacetic acid (2.9): Compound 2.9 was prepared using similar methods to those described by Gansow and coworkers 27 Dowex 50WX8 (hydrogen form, 200–400 mesh, 0.22 g) was added into a mixture of
The reaction mixture, containing 2.8 (2.02 g, 6.75 mmol) in 130 mL of H2O, was heated at reflux for 20 hours and then filtered while hot This process yielded a yellow filtrate that, upon cooling to ambient temperature, produced 1.59 g (87%) of 2.9 as a white solid The 1H and 13C NMR spectra were assigned by comparing them with literature values The 1H NMR (400 MHz, DMSO-d6) showed signals at δ 13.19 (brs, 2H), 7.89 (dd, J = 9.0, 2.6 Hz, 1H), 7.69 (d, J = 2.6 Hz, 1H), 7.11 (d, J = 9.1 Hz, 1H), 4.91 (s, 2H), and 4.88 (s, 2H) The 13C NMR (101 MHz, DMSO-d6) revealed chemical shifts at δ 169.7, 169.4, 153.2, 147.0, 140.8, 117.9, 112.6, 108.4, 65.3, and 65.2 Mass spectrometry indicated a calculated [M − H]− value of 270.0 for C10H8NO8, with a found value of 270.1.
Compound 2.10, 5,6-(4-Nitrobenzo)-4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane-2,9-dione, was synthesized following the methods of Gansow et al A mixture of 2.9 (1.02 g, 3.76 mmol) in thionyl chloride (10 mL) was refluxed under argon for 3 hours, resulting in a clear light yellow solution, which was then concentrated to yield a light yellow solid In a three-neck flask, anhydrous toluene (150 mL) was added and cooled to 0 °C A solution of the light yellow solid in anhydrous toluene and CH2Cl2 was added to one funnel, while another funnel contained triethylamine (1.09 g, 10.8 mmol) and 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane (0.940 g, 3.58 mmol) in a mixture of anhydrous toluene and CH2Cl2 Both solutions were added dropwise while stirring, and the mixture was stirred at ambient temperature for 24 hours The solid was filtered, and solvents were removed under reduced pressure, yielding a yellow solid, which was purified via silica gel chromatography (20:1 CH2Cl2/CH3OH) to obtain 1.29 g (72%) of 2.10 as a light yellow fluffy solid NMR spectra confirmed the structure, with 1H NMR (400 MHz, CDCl3) showing distinct chemical shifts, and 13C NMR (101 MHz, CDCl3) provided detailed carbon signals Mass spectrometry indicated a molecular weight consistent with the formula C22H32N3O10.
5,6-(4-Nitrobenzo)-4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (2.11): Compound 2.11 was prepared using similar methods to those described by
In a study conducted by Gansow and colleagues, Compound 2.10 (1.17 g, 2.34 mmol, 1 equiv) was dissolved in 10 mL of anhydrous tetrahydrofuran (THF) under an argon atmosphere and cooled to 0 °C A syringe pump was used to add BH3 (1 M in THF, 11.0 mL, 4.7 equiv) at a rate of 30 mL/h Following the addition, the solution was refluxed for 24 hours, then cooled to room temperature, and water was added dropwise to neutralize the excess borane Subsequently, 11.0 mL of 6 M hydrochloric acid was introduced, and the mixture was refluxed for an additional 12 hours, followed by the addition of ammonium hydroxide (28% NH3).
H 2 O, 10 mL) was added to adjust the pH of the solution to 9 Solvents were removed under reduced pressure, and the residue was dissolved in CH 2 Cl 2 and washed with
H2O The organic layer was collected, and the solvent was removed under reduced pressure The crude product was purified using silica gel chromatography (20:1
CH2Cl2/CH3OH) to yield 0.891 g (81%) of 2.11 as yellow fluffy solid 1 H- and
13C-NMR spectrawere assigned by comparison with literature 30 1 H NMR (400 MHz,
CD 3 CN) δ 7.95 (dd, J = 9.0, 2.6 Hz, 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.16 (d, J = 9.0 Hz, 1H), 4.30 (dd, J = 9.1, 4.0 Hz, 4H), 3.68–3.46 (m, 12H), 3.44–3.32 (m, 4H), 2.85–
2.77 (m, 4H), 2.75–2.55 (m, 8H); 13 C NMR (101 MHz, CD3CN) δ 153.1, 147.2, 142.6, 118.9, 112.8, 108.5, 68.7, 68.2, 67.2, 66.8, 53.3, 53.1, 53.0; MS (m/z): [M + H] + calcd for C22H36N3O8, 470.3; found, 470.3; TLC: R f = 0.11 (20:1 CH2Cl2/CH3OH)
The synthesis of 5,6-(4-(3-(3,5-Dicarboxyphenyl)thioureido)benzo)-4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (2.4) began with a degassed solution of 2.11 in methanol, to which 10% Pd/C was added for hydrogenation under reflux for 12 hours After removing the Pd/C with a hydrophobic filter, the filtrate was concentrated to yield a pink paste, which was then dissolved in acetone and dichloromethane Following the addition of 5-isothiocyanatoisophthalic acid, the mixture was stirred under argon for 24 hours, filtered, and the resulting off-white solid was washed and recrystallized from boiling water The final product was obtained as a white solid with a yield of 38% The structural characterization of 2.4 was confirmed using advanced NMR techniques, including DEPT, GCOSY, GHMQC, and GHMBC.
(400 MHz, D 2 O) δ 8.13 (s, CH, 1H), 7.84 (s, CH, 2H), 7.05–6.86 (m, CH, 3H), 4.35 (d, J = 24.9 Hz, CH 2, 4H), 3.92–3.35 (m, CH 2, 28H); 13 C NMR (101 MHz, D2O– DMSO-d 6) δ 181.2, 174.7, 147.6, 146.4, 139.4, 139.0, 133.1, 129.5 (CH), 128.6 (CH), 120.7 (CH), 113.8 (CH), 112.3 (CH), 71.40 (CH2), 71.38 (CH2), 65.7 (CH2), 63.4 (CH 2 ), 57.4 (CH 2 ), 57.3 (CH 2 ), 57.0 (CH 2 ); HRESIMS (m/z): [M + Na] + calcd for
A solution of 5,6-(4-(3-(3,5-Dimethoxycarbonylphenyl)thioureido)benzo)-4,7,13,16,21,24-hexao xa-1,10-diazabicyclo[8.8.8]hexacosane (2.6) was prepared by dissolving 0.128 g (0.273 mmol) of 2.11 in 30 mL of degassed CH3OH, followed by the addition of 0.0202 g (0.0190 mmol) of 10% Pd/C The mixture underwent hydrogenation with a hydrogen balloon and reflux heating for 12 hours After hydrogenation, the Pd/C was filtered out using a 0.2 μm hydrophobic filter, and the resulting pink paste was concentrated under reduced pressure This paste was then dissolved in 10 mL of CH2Cl2 under an argon atmosphere, and a solution of dimethyl 5-isothiocyanatoisophthalate (0.0801 g, 0.319 mmol) was added to the mixture.
CH 2 Cl 2 (5 mL) dropwise The reaction was stirred at ambient temperature under Ar for 24 h The solvent was removed under reduced pressure, and the resulting solid was purified using silica gel chromatography (15:1 CH2Cl2/CH3OH) to yield 0.109 g (58%) of 2.6 as light yellow solid 1 H- and 13 C-NMR spectrawere assigned using DEPT, GCOSY, GHMQC, and GHMB experiments 1 H NMR (400 MHz, CD2Cl2) δ 11.45 (s,
NH, 1H), 11.40 (s, NH, 1H), 8.60 (d, J = 1.5 Hz, CH, 2H), 8.34 (t, J = 1.5 Hz, CH,
1H), 7.68 (d, J = 2.3 Hz, CH, 1H), 7.25 (dd, J = 8.7, 2.3 Hz, CH, 1H), 6.87 (d, J = 8.7
Hz, CH, 1H), 4.21 (t, J = 4.7 Hz, CH 2 , 2H), 4.13 (t, J = 4.7 Hz, CH 2 , 2H), 3.92 (s,
CH 3, 6H), 3.64–3.38 (m, CH 2, 16H), 2.87 (t, J = 4.7 Hz, CH 2, 2H), 2.80 (t, J = 4.7 Hz,
CH 2, 2H), 2.73– 2.57 (m, CH 2, 8H); 13 C NMR (101 MHz, CD2Cl2) δ 181.2, 166.5, 145.5, 143.6, 141.3, 134.7, 130.9, 128.8 (CH), 126.1 (CH), 117.1 (CH), 112.6 (CH), 110.9 (CH), 68.8 (CH 2 ), 68.7 (CH 2 ), 68.2 (CH 2 ), 68.1 (CH 2 ), 65.9 (CH 2 ), 65.8 (CH 2 ), 53.7 (CH 2 ), 53.4 (CH 2 ), 53.2 (CH 2 ), 52.6 (CH 3 ); HRESIMS (m/z): [M + Na] + calcd for C33H46N4O10SNa, 713.2832; found, 713.2829; TLC: R f = 0.11 (15:1
2.3 1 H- and 13 C-NMR Spectra of 2.4 and 2.6–2.11
Synthesis of Azacryptand Ligands for Luminescence Studies of
Introduction
The unique stability of half-filled 4f orbitals allows europium to adopt both divalent (Eu 2+) and trivalent (Eu 3+) oxidation states In its first excited state, Eu 2+ exhibits an electron configuration of 4f^6 5d^1 Unlike the 4f orbitals, which are shielded by full 5s and 5p orbitals, the 5d orbitals are significantly influenced by ligands This accessibility to d orbitals results in distinct luminescent properties for Eu 2+, which is characterized by broad emissions ranging from 390 nm.
The study of Eu 2+ coordination compounds is hindered by its susceptibility to oxidation into Eu 3+, necessitating the use of macrocyclic ligands in protic solvents to prevent luminescence quenching Recent research by the Allen group indicates that modified cryptands can effectively stabilize Eu 2+, suggesting potential for further enhancements in stabilization techniques Notably, sharp emission bands between 354 and 376 nm, akin to those of Eu 3+, are observed, highlighting the importance of these findings in advancing the application of Eu 2+ in luminescent materials.
Figure 3.1 Unfunctionalized cryptand 3.1 and modified cryptands 3.2–3.6
Eu 2+ is characterized as soft and electron-rich, prompting the substitution of oxygen atoms in the cryptand ring with softer nitrogen atoms Additionally, the introduction of electron-withdrawing phenyl groups near the donors was employed as a strategy to enhance stability.
Eu 2+ Based on these ideas the azacryptand ligands 3.7 and 3.8 were the targets of my research (Figure 3.2)
Figure 3.2 Structures of ligands 3.7 and 3.8
Ligand 3.7 was prepared according to the published procedures 31,32 The synthetic procedures are shown in Scheme 3.1 Briefly, tris(2-aminoethyl)amine and glyoxal solution were reacted in the presence of triethylamine to give the imine intermediate This imine was reduced by NaBH 4 to give the azacryptand as a white solid
The synthetic procedures for compound 3.8 are illustrated in Scheme 3.2 Following established literature methods, I synthesized compound 3.10 While attempting to replicate the synthesis method used for compound 3.7, the reaction was unsuccessful Subsequently, I employed oxalyl chloride, which resulted in the formation of compound 3.11, albeit with a very low yield of only 5% The low solubility of compound 3.11 necessitated the use of high-resolution electrospray ionization mass spectrometry for analysis.
(HRESIMS) was performed for characterization of this compound
Scheme 3.2 Proposed synthetic procedures for azacryptand 3.8
The reduction of compound 3.11 using LiAlH4 resulted in an unclean reaction, as evidenced by mass spectrometry showing both the desired product peak and multiple peaks from partially reduced byproducts Attempts to improve the reaction by extending the reaction time and increasing the amount of LiAlH4 were unsuccessful In contrast, the reduction with BH3-THF yielded fewer partially reduced products, as indicated by the mass spectrometry analysis.
All chemicals used in this study were of reagent-grade purity or higher and were utilized as received, unless specified otherwise Triethylamine was dried over calcium hydride and distilled in an argon atmosphere Water purification was achieved using a PURELAB Ultra Mk2 system Flash chromatography employed silica gel 60 with a mesh size of 230–400, while analytical thin-layer chromatography (TLC) utilized silica gel 60 F 254 plates with a thickness of 250 μm Visualization of TLC plates was performed using a UV lamp or by charring with a potassium permanganate stain, prepared from 1.5 g KMnO4, 10 g K2CO3, 2.5 mL of 5% w/v aqueous NaOH, and 150 mL of water.
Nuclear Magnetic Resonance (NMR) spectra for both 1H and 13C were obtained at room temperature using a Varian Unity 400 spectrometer, operating at 400 MHz for 1H and 101 MHz for 13C The chemical shifts were calibrated against the residual signals of the solvents, with CDCl3 showing 1H at δ 7.26 ppm and 13C at δ 77.16, while D2O had 1H at δ 4.79 and 13C referenced to 5% DMSO-d6 at δ 39.52 The 1H-NMR data were interpreted under the assumption of first-order behavior, and the observed multiplicities were categorized as follows: "s" for singlet.
High-resolution electrospray ionization mass spectra (HRESIMS) were obtained using a Waters LCT Premiere Xe TOF mass spectrometer, while low-resolution mass spectra of known compounds were recorded on a Shimadzu LCMS-2010EV mass spectrometer for identity confirmation In this context, 'd' denotes doublet, 't' signifies triplet, 'm' indicates multiplet, and 'br' refers to broad.
Compound 3.7, Octaazabicyclo[8.8.8]hexacosane, was synthesized using established literature methods A mixture of tris(2-aminoethyl)amine (1.95 g, 13.3 mmol) and triethylamine (5.0 mL) in isopropanol (90 mL) was cooled to –78 °C Subsequently, a dropwise addition of glyoxal (40% in H2O; 2.91 g, 20.0 mmol) dissolved in isopropanol (50 mL) was performed while stirring.
The reaction mixture was warmed to room temperature, and the solvent was removed under reduced pressure, yielding a yellowish-brown solid that was subsequently extracted with 100 mL of CHCl3 After further solvent removal, a yellow solid was obtained and dissolved in 80 mL of CH3OH To this solution, 2.58 g (68.2 mmol) of NaBH4 was added, and the mixture was stirred under argon at ambient temperature for 4 hours Following solvent removal, a white powder was produced, which was recrystallized twice from water, resulting in 0.702 g (28%) of the final product, 3.7, as a white solid The 1H and 13C NMR spectra were assigned by comparison with literature values, with 1H NMR (400 MHz, D2O) showing δ 2.76 (s, 12H), 2.69 (br s, 12H), and 2.51 (br s, 12H); and 13C NMR (101 MHz, D2O–DMSO-d6) displaying δ 53.7, 50.4, and 47.7 The calculated [M + H]+ for C18H43N8 was 371.4, which matched the found value of 371.4.
Tris(2-nitrophenyl)amine (3.9) was synthesized using a literature method, involving the reaction of 2-nitroaniline (1.99 g) with 2-fluoro-nitrobenzene (8.16 g) and K2CO3 (12.2 g) in dimethyl sulfoxide (DMSO) at 145 °C for 84 hours under an argon atmosphere After cooling, the mixture was diluted with water, sonicated, and filtered to yield a brown solid This solid was then dissolved in methanol, refluxed for 20 minutes, filtered while hot, washed with methanol, and dried under vacuum, resulting in 3.61 g (66%) of the desired yellow solid product.
1H- and 13 C-NMR spectrawere assigned by comparison with the literature 33 1 H NMR
(400 MHz, CDCl 3 ) δ 7.83 (d, J = 8.2, 3H), 7.53 (t, J = 7.8, 3H), 7.30 (t, J = 7.8, 3H), 7.21 (d, J = 8.2, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 144.0, 138.9, 134.0, 128.5, 126.4, 126.2; [M + Na] + calcd for C18H12N4O6Na, 403.1; found, 403.1
Tris(2-aminophenyl)amine (3.10) was synthesized following a literature procedure, starting with a solution of compound 3.9 (1.47 g, 3.87 mmol) in THF (100 mL) under an argon atmosphere Pd/C (10%, 0.236 g, 0.222 mmol) was added quickly, and the reaction mixture was degassed and backfilled with hydrogen After stirring at ambient temperature for 48 hours, the mixture was filtered through celite and concentrated under reduced pressure, yielding an off-white solid This solid was washed with diethyl ether and dried under vacuum, resulting in 0.842 g (75%) of compound 3.10 The 1H and 13C NMR spectra were analyzed and confirmed by comparison with literature values, showing characteristic peaks at δ 6.99, 6.91, 6.77–6.63 for 1H NMR and δ 141.4, 132.5, 125.8, 125.7, 119.0, 116.6 for 13C NMR, with a calculated [M + H]+ of 291.2, matching the found value.
2,3,8,9,11,12,17,18,19,20,25,26-hexabenzo-1,4,7,10,13,16,21,24-Octaazabicyclo[8.8 8]hexacosane-5,614,15,22,23-hexaone (3.11): Compound 3.11 was synthesized using similar methods to those described in the literature 34 A solution of compound
In a controlled reaction, 0.810 g (2.79 mmol) of compound 3.10 was added dropwise to 12.0 g (94.5 mmol) of oxalyl chloride in THF at 0 °C under an argon atmosphere The mixture was then stirred at room temperature for 12 hours, after which excess oxalyl chloride was removed under reduced pressure, yielding a yellow solid that was dissolved in 100 mL of THF Simultaneously, a solution of triethylamine (1.67 g, 16.5 mmol) and 0.732 g (2.52 mmol) of compound 3.10 was prepared in THF and added to the yellow solution at 0 °C The resulting turbid mixture was stirred for 24 hours, followed by filtration to remove solid byproducts After removing solvents under reduced pressure, a brown solid was obtained and purified via silica gel chromatography using CH2Cl2, resulting in 0.0900 g (4.8%) of compound 3.11 as a white solid High-resolution electrospray ionization mass spectrometry (HRESIMS) confirmed the molecular weight with [M + Na]+ calculated at 765.2186 and found at 765.2168, while thin-layer chromatography (TLC) indicated an Rf value of 0.08 in CH2Cl2.
3.3 1 H- and 13 C-NMR Spectra of compounds 3.7, 3.9, and 3.10
Synthesis of Tetraoxolene-Bridged Cryptand Ligands for Magnetic
Introduction
Divalent europium (Eu 2+ ) has a large magnetic moment that is partially due to its
Eu 2+ exhibits unique magnetic properties due to its half-filled 4f orbitals, making it a promising candidate for developing innovative magnetic materials A notable class of these materials is single molecule magnets (SMMs), which were discovered two decades ago and can retain magnetization after the removal of an external magnetic field While early research primarily focused on 3d transition metals like Mn 3+, advancements in SMMs faced challenges in simultaneously increasing total spin S and axial anisotropy D Recent findings emphasize the importance of single ion anisotropy for achieving high energy barrier SMMs, leading to increased interest in lanthanides and actinides, which possess exceptional single-ion anisotropies Additionally, enhancing exchange coupling through radical bridges among multiple metals offers a third approach to maximizing energy barriers Researchers, including Long and Evans, have synthesized various radical-bridged di-lanthanide complexes exhibiting SMM properties Building on these concepts, we designed ligand 4.1, where two cryptands are interconnected by tetraoxolene, a multi-electron redox-active ligand, capable of forming complexes with less-explored divalent lanthanides such as Eu 2+, Sm 2+, and Yb 2+.
Scheme 4.1 Dihydroxybenzoquinone was reduced using tin in concentrated hydrochloric acid, 40 and reacted with methyl bromoacetate to give ester 4.2 It was hydrolyzed using DOWEX to give the corresponding acid 4.3 Reaction of this acid with oxalyl chloride afforded the acid chloride which was further reacted with aza-crown ether to give the corresponding amide In the mass spectrometry I observed the peak of the amide, but I was not able to purify it using silica gel chromatography
Scheme 4.1 Proposed synthetic procedures for ligand 4.1
Experimental Procedures
Commercially available chemicals were of reagent-grade purity or better and were used as received unless otherwise noted Water was purified using a PURELAB Ultra Mk2 purification system
1H- and 13 C-NMR spectra were recorded at ambient temperature on a Varian Unity 400 spectrometer (400 MHz for 1 H and 101 MHz for 13 C) Chemical shifts were referenced to solvent residual signals (CDCl 3 : 1 H δ 7.26 ppm, 13 C δ 77.16; DMSO-d 6:
The 1H NMR data indicates first-order behavior, with apparent multiplicities noted as "s" for singlet and "br" for broad, highlighting the italicized elements responsible for the chemical shifts High-resolution electrospray ionization mass spectra (HRESIMS) were obtained using a Waters LCT Premiere Xe TOF mass spectrometer, while low-resolution mass spectra of known compounds were recorded on a Shimadzu LCMS-2010EV mass spectrometer.
Tetramethyl 2,2',2'',2'''-(benzene-1,2,4,5-tetrayltetrakis(oxy))tetraacetate (4.2):
In a stirred mixture of 2,5-dihydroxy-1,4-benzoquinone (1.98 g, 14.1 mmol) in 50 mL of 36% aqueous HCl, granular tin metal (2.12 g, 17.8 mmol) was gradually added The reaction was heated at reflux for one hour and then filtered while hot Upon cooling the filtrate to 0 °C, an off-white solid formed, which was crystallized from tetrahydrofuran, yielding 0.776 g of a white solid This solid was subsequently dissolved in 20 mL of acetone and added dropwise to a stirred mixture of K2CO3.
The synthesis involved mixing 7.80 g (56.4 mmol) of a compound with 8.56 g (56.0 mmol) of methyl bromoacetate in 130 mL of acetone, followed by stirring the reaction mixture at reflux under argon for 24 hours Upon cooling, solids were filtered out, and the solvent was evaporated under reduced pressure to yield an orange oil This oil was then dissolved in 50 mL of ethyl acetate, washed with water (three times with 50 mL), and dried over anhydrous Na2SO4 After removing the solvent, a yellow solid was obtained and recrystallized twice from ethanol, resulting in 0.508 g (8.4%) of the desired product, a white solid The structure was confirmed using 1H and 13C NMR spectroscopy, with key signals at δ 6.66 (s, CH, 2H), 4.65 (s, CH2, 8H), and 3.78 (s, CH3, 12H) for 1H NMR, and relevant carbon signals for 13C NMR at δ 169.5, 143.6, 107.8 (CH), 67.8 (CH2), and 52.3 (CH3) High-resolution electrospray ionization mass spectrometry (HRESIMS) confirmed the molecular weight with [M + Na]+ calculated as 453.1009 and found as 453.1009 for C18H22O12Na.
2,2',2'',2'''-(Benzene-1,2,4,5-tetrayltetrakis(oxy))tetraacetic acid (4.3): Dowex
In a recent experiment, 50WX8 (hydrogen form, 200–400 mesh, 0.22 g) was combined with 4.2 (1.05 g, 2.44 mmol) in 100 mL of H2O, and the mixture was heated at reflux for 24 hours After filtration while hot, the cooled filtrate yielded 0.847 g (93%) of the product 4.3 as a white solid The 1H and 13C NMR spectra were analyzed and assigned based on previously published data, revealing 1H NMR (400 MHz, DMSO-d6) signals at δ 12.90 (brs, 4H), 6.70 (s, 2H), and 4.62 (s, 8H), as well as 13C NMR (101 MHz, DMSO-d6) signals at δ 170.4, 142.0, 105.3, and 66.4.
MS (m/z): [M + Na] + calcd for C14H14O12Na, 397.0; found, 397.0
4.3 1 H- and 13 C-NMR Spectra of compounds 4.2 and 4.3
Summary and Future Outlook
Summary and Future Outlook
Coordination chemistry is a vital area of modern inorganic chemistry, with ligand synthesis through organic techniques being crucial for its development This thesis focuses on the synthesis of various cryptands for complexes containing Eu 2+ By metalating these cryptands with Eu 2+, we can create Eu 2+-containing cryptates Additionally, cyclic voltammetry experiments will be conducted to investigate the oxidative stability of these complexes.
As with the ligand for MRI application,
The compound 5,6-(4-(3-(3,5-dicarboxyphenyl)thioureido)benzo)-4,7,13,16,21,24-hexaoxa-1,10-diaz abicyclo[8.8.8]hexacosane features a cryptand unit linked by thiourea, allowing for the attachment of two carboxylic groups The positioning of these carboxylic groups on the phenyl ring can be varied, and amino acids like aspartic acid and glutamic acid are also applicable in this molecular structure.
The Allen group has investigated Eu 2+ complexes of the ligand 1,4,7,10,13,16,21,24-octaazabicyclo[8.8.8]hexacosane (aza222), discovering that it exhibits bright yellow luminescence Following this finding, a literature review revealed recent methods by Jackson and colleagues for synthesizing aza222-based polymers Future research could focus on the synthesis of Eu 2+ -containing aza222-based polymers and the evaluation of their luminescence properties.
To enhance the yield of the intermediate 2,3,8,9,11,12,17,18,19,20,25,26-hexabenzo-1,4,7,10,13,16,21,24-octaazabicyclo[8.8.8]hexacosane-5,614,15,22,23-hexaone during the synthesis of phenyl derivatives of aza222, modifications to the synthetic methods are necessary The intermediate's low solubility in common organic solvents limits further characterization, with high-resolution electrospray ionization mass spectrometry being the only viable option A potential solution to this challenge is to grow single crystals through the slow vaporization of a concentrated solution in CH2Cl2 or THF.
Efforts must be focused on synthesizing the tetraoxolene bridged dicryptand ligand, anticipating lower reaction yields than those seen with ligands featuring a single cryptand Furthermore, functionalized tetraoxolene derivatives, such as hydrochloranilic acid, can serve as effective bridging ligands in this synthesis process.
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ABSTRACT SYNTHESIS OF CRYPTANDS FOR Eu 2+ -CONTAING COMPLEXES by
May 2015 Advisor: Dr Matthew J Allen
Eu 2+ -containing complexes are valuable in synthetic chemistry, medical diagnostics, and materials science, but they are prone to oxidation in air Research by Allen and colleagues has shown that functionalized cryptands can stabilize Eu 2+ My thesis details the synthesis of various modified cryptands, which could lead to Eu 2+ -containing complexes with promising applications as magnetic resonance imaging contrast agents, luminescent materials, and magnetic materials.