Protonation Of Ligand Research Articles

Quantum Mechanical Study of Oxygen Ligands Protonation for the Stable States of the Laccase Active Site.

Laccases are enzymes catalyzing the oxidation of a wide range of organic and inorganic substrates accompanied by molecular oxygen reduction to water. Recently, oxygen reduction by laccases has been studied by single-crystal serial X-ray crystallography with increasing absorption doses at subatomic resolution. There were two determined structures corresponding to the reduced and oxidized stable states of the laccase active site. However, the protonation of the oxygen ligands involved cannot be determined even at subatomic resolution. In the present work, the protonation of oxygen ligands in the active site of laccase for the two stable states determined in the X-ray study was explored using quantum mechanical and continuum-electrostatics calculations. This is important for understanding the reaction of the oxygen reduction mechanism in laccases. The high precision of X-ray data at subatomic resolutions allowed us to optimize the quantum mechanical calculations.

Comparative paraCEST effect of amide and hydroxy groups in divalent cobalt and nickel complexes of tripyridine-based ligands.

Co(II) and Ni(II) complexes of two tri-pyridine-based ligands with two hydroxy and two amide exchangeable protons (TDTA) and with six amide exchangeable protons (TMTP) were investigated for application as paraCEST-based magnetic resonance imaging (MRI) contrast agents. The two hydroxy groups present in the TDTA ligand were found to be passive while the amide group was active towards the CEST process. In the case of the Co(II) and Ni(II) complexes of the TMTP ligand, all three coordinated amide groups participated in the exchange process, and excellent CEST signals were observed. The X-ray structure of the four complexes revealed the seven-coordinate geometry of Co(II) complexes and the six-coordinate geometry of Ni(II) complexes. The presence of amide protons and hydroxy protons in the complexes was detected by the NMR method. The stability of the complexes in solution at high temperatures, in different pH ranges and acidic conditions, in the presence of competing cations, and biologically relevant anions was investigated. Potentiometric titrations were carried out to determine the ligand's protonation constants and the complexes' thermodynamic stability constant at 25.0 °C and I = 0.15 mol L-1 NaClO4. ParaCEST studies of [Co(TMTP)]2+ and [Ni(TMTP)]2+ at variable pH and variable pulse power are highlighted.

The acid-mediated isomerization of iridium(III) complexes with cyclometalated NHC ligands: kinetic vs. thermodynamic control.

The isomerization of iridium(III) complexes with metalated N-heterocyclic carbene (NHC) ligands was studied. The fac isomers of complexes with 1-phenyl-3-methylbenzimidazolin-2-ylidene or 1-phenyl-3-benzylbenzimidazolin-2-ylidene ligands are transformed cleanly into the mer isomers when solutions of the complexes are treated with first HNTf2 and then NEt3. The transformation can be accomplished within a few minutes and the side product (NEt3H)(NTf2) is easy to separate. Spectroscopic and structural analyses indicate that the isomerization proceeds by protonation of the carbene ligand at the metalated phenyl group, accompanied by a fac → mer rearrangement of the carbene donors. An iridium complex with a 1-phenyl-1,2,4-triazolo[4,3-f]phenanthridine-based carbene ligand could not be isomerized under similar conditions, most likely because of its reduced conformational flexibility.

Determination of Stability Constant of Flurosubstituted Chlconemines for its Medicinal Efficiency

The good activity of drug is depending upon its stability constant i.e. proton ligand stability constant and metal ligand stability constant. If the stability constant is fairly very good then it should use as a good and effective medicine .In content to this in present work the proton ligand stability constant and metal ligand stability constant of fluro substituted chalconeimines L5 = 2-Hydroxy naphthalene 4-dimethyl aniline 4- fluro chalconeimine [FN] are studied with highly reactive transition metal like (Cu (II), Co(II),Cr(II) and Fe(III)). The 70% dioxane water solvent system used in the present investigation. The presence of –OH group confirmed by using of 0.1 M ionic strength. The transition metal (Cu (II),Co (II),Cr(II)and Fe(III)) used and the ligand form 1:1 and 1:2 complex with all values of log k1 and log k2 positive.

Electrocatalytic hydrogen evolution of manganese corrole

A series of manganese corroles bearing different substituents had been prepared and characterized by UV–vis, 1H NMR, 19F NMR, HRMS and XPS. These manganese corrole complexes were applied to electrocatalytic hydrogen evolution reaction (HER) for the first time. The results showed that manganese corroles are effective catalysts for HER in DMF solvent by using acetic acid (AcOH), trifluoroacetic Acid (TFA) and p-toluenesulfonic acid (TsOH) proton sources, and strong acid leads to higher electrocatalytic activity. When using TsOH as proton source, protonation of corroles ligand may be involved in HER. The electrocatalytic HER activity can be improved by increasing the electron-withdrawing substituent of the corrole macrocycle in both organic and aqueous media.

Metal Coordination and Biological Screening of a Schiff Base Derived from 8-Hydroxyquinoline and Benzothiazole.

Designing new metallodrugs for anticancer therapy is a driving force in the scientific community. Aiming to contribute to this field, we hereby report the development of a Schiff base (H2L) derived from the condensation of 2-carbaldehyde-8-hydroxyquinoline with 2-hydrazinobenzothiazole and its complexation with transition metal ions. All compounds were characterised by analytical and spectroscopic techniques, which disclosed their structure: [Cu(HL)Cl], [Cu(HL)2], [Ni(HL)(acetate)], [Ni(HL)2], [Ru(HL)Cl(DMSO)], [VO(HL)2] and [Fe(HL)2Cl(H2O)]. Different binding modes were proposed, showing the ligand's coordination versatility. The ligand proton dissociation constants were determined, and the tested compounds showed high lipophilicity and light sensitivity. The stability of all complexes in aqueous media and their ability to bind to albumin were screened. Based on an antiproliferative in vitro screening, [Ni(HL)(acetate)] and [Ru(HL)Cl(DMSO)] were selected for further studies aiming to investigate their mechanisms of action and therapeutic potential towards colon cancer. The complexes displayed IC50 < 21 μM towards murine (CT-26) and human (HCT-116) colon cancer cell lines. Importantly, both complexes exhibited superior antiproliferative properties compared to the clinically approved 5-fluorouracil. [Ni(HL)(acetate)] induced cell cycle arrest in S phase in CT-26 cells. For [Ru(HL)Cl(DMSO)] this effect was observed in both colon cancer cell lines. Additionally, both compounds significantly inhibited cell migration particularly in the human colon cancer cell line, HCT-116. Overall, the therapeutic potential of both metal complexes was demonstrated.

Syntheses of Group 5 Amide Amidinates and Their Reactions with Water: Different Reactivities of Nb(V) and Ta(V) Complexes.

Chemistries of Nb(V) and Ta(V) compounds are essentially identical as a result of lanthanide contraction. Hydrolysis of M(NMe2)5 (M = Nb, Ta), for example, yields [M(μ3-O)(NMe2)3]4 (M = Nb, 1; Ta, 2) reported earlier. The similar reactivities of Nb(V) and Ta(V) compounds make it challenging, for example, to separate the two metals from their minerals. We have found that the reactions of H2O with amide amidinates M(NMe2)4[MeC(NiPr)2] (M = Nb, 3; Ta, 4) show that the niobium and tantalum analogues take different principal paths. For the Nb(V) complex 3, the amidinate and one amide ligand are liberated upon treatment with water, yielding [Nb(μ3-O)(NMe2)3]4 (1). For the Ta(V) complex 4, the amide ligands are released in the reaction with H2O, leaving the amidinate ligand intact. [Ta(μ3-O)(NMe2)3]4 (2), the analogue of 1, was not observed as a product in the reaction of 4 with H2O. To our knowledge, this is the first example of the formation of two different complexes that maintain the (V) oxidation state in both metals. The new complexes M(NMe2)4[MeC(NiPr)2] (M = Nb, 3; Ta, 4) have been prepared by the aminolysis of M(NMe2)5 (M = Nb, Ta) with iPrN(H)C(Me)=NiPr (5). The hydrolysis of 3 and 4 has been investigated by DFT electronic structure calculations. The first step in each hydrolysis reaction involves the formation of a hydrogen-bonded complex that facilitates a proton transfer to the amidinate ligand in 3 and protonation of an axial dimethylamide ligand in 4. Both proton transfers furnish an intermediate metal-hydroxide species. The atomic charges in 3 and 4 have been computed by Natural Population Analysis (NPA), and these data are discussed relative to which of the ancillary ligands is protonated initially in the hydrolysis sequence. Ligand exchanges in 3 and 4 as well as the exchange in iPrN(H)C(Me)=NiPr (5) were probed by EXSY NMR spectroscopy, giving rate constants of the exchanges: 0.430(13) s-1 (3), 0.033(6) s-1 (4), and 2.23(7) s-1 (5), showing that the rate of the Nb complex Nb(NMe2)4[MeC(NiPr)2] (3) is 13 times faster than that of its Ta analogue 4.

Oxidative addition of 8-bromo-9-ethyl-1,N6-ethenoadenine to d10 metals

The 8-bromoadenine derivative 8-bromo-9-ethyl-1,N6-ethenoadenine 3 was prepared from adenine in three steps. Treatment of 8-bromo-9-ethyl-1,N6-ethenoadenine 3 with the zero-valent metal precursors [M0(PPh3)4] (M = Pd, Pt) in the presence of NH4BF4 as proton source gave exclusively the compounds trans-[4]BF4 and trans-[5]BF4. The obtained complexes bear a modified C8-bound adenine derivative with a protonated endocyclic nitrogen atom N7. A stepwise reaction sequence consisting of an initial oxidative addition of the C8–Br bond of 3 to [Pt0(PPh3)4] followed by treatment with HBF4·Et2O as proton source led to the dinuclear complex [6]2+ after a reaction time of several days. This complex features two adenine-derived NHC ligands coordinating to two PtII ions in a µ-κC8:κN7 bridging fashion. Protonation of the NHC ligands occurred at the nitrogen atom N6 instead of N7 of the purine scaffold. The molecular structures of the three complexes were determined by X-ray diffraction studies.

Manganese(II) complexes of 1,1′-bis[(pyridin-2-yl)methyl)]-2,2′-bipiperidine (PYBP): Synthesis, structure, catalytic properties in alkene epoxidation with hydrogen peroxide, and related mechanistic studies

Several manganese(II) complexes with the stereoisomers of ligand PYBP (1,1′-bis[(pyridin-2-yl)methyl]-2,2′-bipiperidine) and different anions were prepared and characterized by X-ray diffractometry. Complex [MnII(rac-PYBP)]2+ (1) was found to be an efficient catalyst of alkene epoxidation by hydrogen peroxide in the presence of acetic acid in acetonitrile at room temperature. Cyclooctene was converted to its epoxide with up to 91 % yield, 99.6 % selectivity, and the turnover number of 180 within 5 min. Fast epoxidations of cyclohexene, 1-decene, styrene, and cis-stilbene were also achieved. Isomeric complex [MnII(meso-PYBP)]2+ (2) was catalytically inactive under the same experimental conditions. Stopped-flow spectrophotometry and freeze-quenched EPR spectra show that complex 2 is not oxidized by H2O2 in the presence of acetic acid (AcOH) but instead undergoes partial ligand protonation and liberation of the Mn2+ cations due to the relatively poor chelating ability of ligand meso-PYBP. The rac-PYBP isomer acts as a better ligand and retains the coordinated Mn center when complex 1 is treated with the H2O2/AcOH mixture in acetonitrile solution yielding a mixture of intensely colored intermediates likely involving MnIII, MnIV, and MnV complexes. Magnetic susceptibility measurements, UV–vis and EPR spectra suggest that dinuclear complexes [MnIII2(μ-O)(μ-OAc)(rac-PYBP)2]3+ and [MnIIIMnIV(μ-O)2(rac-PYBP)2]3+ gradually accumulate in the reaction mixture as inactivated states of the catalyst. Complex 1 also causes fast decomposition of hydrogen peroxide into O2 gas and H2O, which competes with the epoxidation of alkenes and requires gradual addition of H2O2 for its efficient use. The catalytic activity of complex 1 is strongly influenced by its counterions and decreases in order ClO4− ≈ SbF6− > NO3– > Cl− indicating that labile ligands in the coordination sphere of Mn are required for the activation of H2O2.

Improvement of electrochemically mediated atom transfer radical polymerization: Use of aluminum as a sacrificial anode in water

The simplest electrolytic devices are undivided electrochemical cells without any separator between anodic and cathodic compartments. These simple yet efficient electrochemical cells often require the use of sacrificial metal counter electrodes, which, however, are incompatible with many electrocatalytic systems. In this article, we investigate the effect of the presence of an Al anode on an electrocatalytic reaction in water, namely electrochemically-mediated atom transfer radical polymerization (eATRP) catalyzed by common Cu complexes with amine ligands. It was found that the sacrificial anode could undermine the reactivity of the aqueous Cu catalysts in two ways: i) protonation of the amine ligand promoted by the release of acidic Al3+ ions; ii) spontaneous deposition of Cu0 on the Al metal surface. Both pathways led to decomposition of the original copper catalyst. To avoid undesired side reactions arising from the Al anode, simple strategies involving the use of appropriate amine ligands and pH buffers are described.

A europium metal–organic framework for dual Fe3+ ion and pH sensing

Metal–organic frameworks (MOFs) with ratiometric sensing properties are desirable for many applications due to their intrinsic self-calibration. We report the re-assessment of the sensing properties of a MOF, originally reported as containing europium(III) and 2-hydroxyterephtalic acid, and having fluorescent ratiometric iron(III) sensing properties. Synchrotron single-crystal X-ray diffraction and proton nuclear magnetic resonance (1H NMR) spectroscopy revealed that the MOF is composed of 2-methoxyterephthalate, not 2-hydroxyterephthalate as originally reported. We found that the MOF exhibits a sensor turn-off response towards Fe3+ ion concentrations in the range 0.5–3.7 ppm (band 425 nm), and a turn-on response towards a decrease of pH from 5.4 to 3.0 (band 375 nm), both resulting from the addition of acidic Fe3+ salt solution to a MOF suspension. Thus, the ratiometric sensing properties and the originally proposed mechanism no longer apply; our work reveals a dynamic quenching mechanism for the fluorescence turn-off response due to the presence of Fe3+ ions, and a ligand protonation mechanism for the turn-on response to a decrease in pH. Our work highlights the importance of a thorough investigation of the structure of any newly synthesized MOF, and, in the case of potential sensors, their selectivity and any environmental effects on their sensing behavior.

Temperature dependence studies and microscopic protonation constants of L-alanine and β-alanine in acetonitrile – water mixtures

Abstract L-alanine and β-alanine are important biological molecules and have zwitterion structure. In this study, L- alanine and β-alanine’s microscopic protonation constants and thermodynamic parameters (enthalpy, entropy, and free energy changes) for the proton–ligand systems of L-alanine methyl ester, β-alanine and β-alanine methyl ester have been determined at 5; 20; 35 °C, in ACN-water (25% ACN and 50% ACN (v/v)) mixtures at constant ionic strength of 0.1000 mol L–1 NaClO4 by potentiometric method. The results shown that, L-alanine and β-alanine’s microscopic protonation constants generally tend to decrease with temperature rise and their protonation reactions in ACN-water mixtures generally favor enthalpy-driven.

Dissociation of Pyridinethiolate Ligands during Hydrogen Evolution Reactions of Ni-Based Catalysts: Evidence from X-ray Absorption Spectroscopy.

The protonation of several Ni-centered pyridine-2-thiolate photocatalysts for hydrogen evolution is investigated using X-ray absorption spectroscopy (XAS). While protonation of the pyridinethiolate ligand was previously thought to result in partial dechelation from the metal at the pyridyl N site, we instead observe complete dissociation of the protonated ligand and replacement by solvent molecules. A combination of Ni K-edge and S K-edge XAS of the catalyst Ni(bpy)(pyS)2 (bpy = 2,2′-bipyridine; pyS = pyridine-2-thiolate) identifies the structure of the fully protonated catalyst as a solvated [Ni(bpy)(DMF)4]2+ (DMF = dimethylformamide) complex and the dissociated ligands as the N-protonated 2-thiopyridone (pyS-H). This surprising result is further supported by UV–vis absorption spectroscopy and DFT calculations and is demonstrated for additional catalyst structures and solvent environments using a combination of XAS and UV–vis spectroscopy. Following protonation, electrochemical measurements indicate that the solvated Ni bipyridine complex acts as the primary electron-accepting species during photocatalysis, resulting in separate protonated ligand and reduced Ni species. The role of ligand dissociation is considered in the larger context of the hydrogen evolution reaction (HER) mechanism. As neither the pyS-H ligand nor the Ni bipyridine complex acts as an efficient HER catalyst alone, the critical role of ligand coordination is highlighted. This suggests that shifting the equilibrium toward bound species by addition of excess protonated ligand (2-thiopyridone) may improve the performance of pyridinethiolate-containing catalysts.

CuI/AgI‐containing coordination compounds as advanced catalysts for selective oxidation of styrene to benzaldehyde

AbstractFour coordination compounds, [Cu(Hmthd)2Cl]n (1), [Cu3(mthd)2Br]n (2), [Ag(mthd)]n (3), and [Ag2(mthd)I]n (4) (Hmthd = 2‐mercapto‐5‐methyl‐1,3,4‐thiadiazole), were synthesized and characterized by inductively coupled plasma (ICP) elemental analyses, powder X‐ray diffraction (PXRD), and Fourier transform infrared (FT‐IR) spectroscopies. These resulting coordination compounds can act as efficient catalysts for the oxidation of olefins with tert‐butyl hydroperoxide (TBHP) as oxidant. Wherein, compound 2 performed extremely enhanced catalytic activity for oxidation of styrene at 80°C. Moreover, the addition of an appropriate amount of acid can promote the protonation of ligands and activate the two Ag‐containing catalysts to improve their catalytic efficiencies. Experimental results indicate that catalyst 2 has a low activation energy and excellent recycle catalytic property. Radical trap experiments were performed to verify that free radicals participate in the oxidation of styrene.

Design of 4‐Coordinate Ti Imido Aryloxide on the Surface of Silica for Catalytic Oxo/Imido Heterometathesis

AbstractWe report here the synthesis of 4‐coordinate Ti imido complexes Ti(=NtBu)(OArtBu)2(py) (2) and Ti(=NtBu)(OArtBu)(Me2Pyr)(py) (3) (ArtBu=O‐2,6‐tBu2‐4‐MeC6H2, Me2Pyr=2,5‐dimethylpyrrolyl) and study their grafting onto the surface of partially dehydroxylated silica with the aim to prepare 4‐coordinate Ti imido aryloxide surface species. Study of the resulting materials with IR, solid‐state NMR, elemental and mass balance analyses demonstrates that grafting of bis‐aryloxide complex 2 leads to a predominant formation of silica‐supported Ti amide (≡SiO)Ti(NHtBu)(OArtBu)2(py) resulting from the protonation of the imido ligand with the surface silanols and only a smaller fraction of the desired imido species (≡SiO)Ti(=NtBu)(OArtBu)(py). The use of the tailored complex 3 where one of the aryloxides is replaced with a more reactive pyrrolyl ligand significantly increases the selectivity of grafting leading to the formation of the Ti imido aryloxide (≡SiO)Ti(=NtBu)(OArtBu)(py) as major surface species. The obtained materials show high activity in catalytic oxo/imido heterometathesis supporting the previously proposed hypothesis that electron‐donating environments are favorable for this transformation.

Structural Insights on the Conversion of Cytochrome P450 to P420.

A characteristic feature of cytochromes P450* is that the complex formed between the ferrous heme iron and carbon monoxide generates an intense absorption band at 450 nm. This unique feature of P450s is due to the proximal thiolate Cys ligand coordinated to the heme iron. Various harsh treatments shift this band to 420 nm, thereby giving P420 which is most often associated with an inactive form of the enzyme. Various explanations have been put forward to explain the P450-to-P420 change ranging from protonation of the Cys heme ligand, displacement of the Cys ligand, or replacement of the Cys ligand with His. There are two crystal structures of the well-studied cytochrome P450cam that have a high fraction of P420. In one, P450cam is cross-linked to its redox partner, putidaredoxin (Pdx), and the second is P450cam crystallized in the absence of substrate. In both of these structures, a significant part of the substrate pocket is disordered and the poor quality of the electron density for the substrate indicates substantial disorder. However, in both structures there is no detectable change in the Cys-iron ligation or surrounding structure. These results indicate that the P450-to-P420 switch is due primarily to an opening and disordering around the substrate binding pocket and not ligand displacement or ligand swapping. Since it remains a possibility that ligand swapping could be responsible for P420 in some cases, we mutated to Gln the 3 His residues (352, 355, and 361) close enough to the proximal side of the heme that could possibly serve as heme ligands. The triple variant forms P420 which indicates that swapping Cys for His is not a requirement for the P450-to-P420 switch.

Experimental and Molecular Modeling Studies on the Complexation of Chromium(III) with the Angiotensin-Converting Enzyme Inhibitor Captopril.

Captopril (CPT) is an inhibitor of angiotensin I converting enzyme, used as a medication for the treatment of people with high blood pressure, renal insufficiency, and cardiovascular diseases. It inhibits the angiogenesis process, vasoconstriction, and tumor metastasis. Some metal–captopril complexes exhibit antimicrobial activities. In the current work, the formation of the CrIII–CPT complex was studied spectrophotometrically and potentiometrically in aqueous solution. Kinetics of CrIII–CPT complex formation was spectrophotometrically studied over the pH range 3.20–4.20, at an ionic strength of 0.3 M at 30–50 °C. CrIII–CPT complex formation was potentiometrically studied at 25 °C, where ligand protonation constants and complexes’ overall stability constants were calculated. UV–vis absorption spectra were executed to confirm the complex formation. Density functional theory and molecular dynamics simulation were performed to search the geometries of the CrIII–CPT complex. Atoms in molecules and interaction region indicator calculations are used to investigate intermolecular interactions for the formation of CrIII–CPT complex. The antimicrobial activity of the CPT ligand and CrIII–CPT complex on the prevention and control of environmental pathogenic bacteria, as tested on both Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative bacteria Escherichia coli (E. coli) via agar disc diffusion method, assess the ability to use as an antimicrobial agent. CPT had shown good antimicrobial activity against both types of bacteria, which had increased slightly the zone of inhibition in Cr-CPT that indicates the increased efficacy due to Cr(III) antimicrobial activity via its oxidative damage to the bacterial cell wall. No previous study tested the CPT antimicrobial activity against Gram-positive ones such as S. aureus

Speciation Study on O-Phosphorylethanolamine and O-Phosphorylcholine: Acid-Base Behavior and Mg2+ Interaction.

In the present study, the acid–base behavior of compounds constituting the headgroups of biomembranes, O-phosphorylethanolamine (PEA), and O-phosphorylcholine (PPC) was investigated by potentiometric titrations in NaCl aqueous solutions at different temperatures (15 ≤ t/°C ≤ 37) and ionic strength (0.15 ≤ I/mol L−1 ≤ 1) values. The complexation properties and the speciation of these ligands with Mg2+ were defined under different temperatures (15 ≤ t/°C ≤ 37) and I = 0.15 mol L−1. The results evidenced the formation of three species for PEA, namely, MLH2, MLH, and ML and two species for PPC, namely, MLH and ML. 1H-NMR titrations were performed on solutions containing ligand and metal–ligand solutions at t = 25°C and I = 0.15 mol L−1. The estimated values of ligand protonation and complex formation constants and the speciation model are in accordance with the potentiometric data. The enthalpy changes were also determined at t = 25°C and I = 0.15 mol L−1 by the dependence of formation constants on the temperature, confirming the electrostatic nature of the interactions. Matrix-assisted laser desorption mass spectrometry (MALDI-MS) was applied for the characterization of Mg2+-L systems (L = PEA or PCC). MS/MS spectra of free ligands and of Mg2+-L species were obtained. The observed fragmentation patterns of both Mg2+-L systems allowed elucidating the interaction mechanism that occurs via the phosphate group generating a four-membered cycle.

Prospects and limitations of paramagnetic chemical exchange saturation transfer agents serving as biological reporters in vivo.

The concept of using paramagnetic metal ion complexes as chemical exchange saturation transfer agents (paraCEST) for molecular imaging of various biological processes first appeared in the literature about 20 years ago. The first paraCEST agent was based on a highly shifted, inner-sphere, slowly exchanging water molecule that could be activated at a frequency far away from bulk water, a substantial advantage for selective activation of the agent alone. Many other paraCEST agent designs followed that were based on activation of exchanging -NH or -OH proton on the chelate itself. Both types of paraCEST designs are attractive for molecular imaging because the rates of water molecule or ligand proton exchange can be designed to be sensitive to a biological or physiological property such as pH, enzyme activity, or redox. Hence, the intensity or frequency of the resulting CEST signal provides a direct readout of that property. Many molecular designs have appeared in the literature over the past 20 years, mostly reported as proof-of-concept designs but, unfortunately, only a few reports have explored the limitations of paraCEST agents for imaging a biological process in vivo. As a community, we now know that the sensitivity of paraCEST agents is lower than one might anticipate based upon simple chemical exchange principles and, in general, it appears the sensitivity of paraCEST agents is even lower in vivo than in vitro. In this short review, we address some of the factors that contribute to the limited sensitivity of paraCEST agents in vivo, offer some thoughts on approaches that could lead to dramatically improved paraCEST sensitivity, and challenge the scientific community to perform more in vivo experiments designed to test these ideas.

Crystallographic and Computational Characterisation of the Potential PET Tracer 1,4,7‐Triazacyclononane‐1,4,7‐tri(methylenephosphonato)gallium(III)

AbstractThe macrocyclic chelator 1,4,7‐triazacyclononane‐1,4,7‐tri(methylenephosphonic acid) (H6NOTP) has shown significant promise for use in positron emission tomography with the positron‐emitting radionuclide 68Ga3+. We report the X‐ray crystal structure of the neutral complex 1,4,7‐triazacyclononane‐1,4,7‐tri(methylenephosphonato)gallium(III) ([Ga(H3NOTP)]), which crystallised in the centrosymmetric space group P21/n. The coordination geometry of the Ga3+ ion is distorted octahedral with three macrocyclic amine N donor atoms and three singly deprotonated phosphonato O donor atoms. Two discrete enantiomers, Δ(λλλ)‐SSS and Λ(δδδ)‐RRR, are present as a racemate within the unit cell. Intermolecular hydrogen bonds between phosphonic acid groups of adjacent complexes form a two‐dimensional sheet network. Density functional theory (DFT) calculations supported the observation of complexes with low electric field gradient values with slight but significant deviations from ideal octahedral geometry. The DFT calculations were also used to investigate the influence of intermolecular interactions and ligand protonation states on the coordination environment and surface charge distribution.