Enantiomerization Process Research Articles

Bicyclic Phenyl-Ethynyl Architectures: Synthesis of a 1,4-Bis(phenylbuta-1,3-diyn-1-yl) Benzene Banister.

The novel diacetylene bridged terphenylic macrocycle 1 is presented and discussed in the context of rotationally restricted “Geländer” oligomers. The 1,4‐bis(phenylbuta‐1,3‐diyn‐1‐yl) benzene bridge of diacetylene 1 is significantly longer than its terphenyl backbone, forcing the bridge to bend around the central pylon. The synthesis of molecule 1 is based to a large extent on acetylene scaffolding strategies, profiting from orthogonal alkyne protection groups to close both macrocyclic subunits by oxidative acetylene coupling sequentially. The spatial arrangement and the dynamic enantiomerization process of the bicyclic target structure 1 are analyzed. In‐depth NMR investigations not only reveal an unexpected spatial arrangement with both oligomer strands bent alongside the backbone, but also display the limited stability of the model compound in the presence of molecular oxygen.

Sulfone "Geländer" Helices: Revealing Unexpected Parameters Controlling the Enantiomerization Process.

The two sulfonyl-bridged Geländer helices 1a and 2a are obtained by oxidation of the corresponding sulfide bridged precursors 1b and 2b. Both Geländer structures are fully characterized by NMR, high-resolution mass spectrometry, and optical spectroscopies. X-ray diffraction with a single crystal of 2a provides its solid-state structure. Both Geländer helices 1a and 2a are separated into enantiomers, and their racemizations are monitored by circular dichroism. For 1a, consisting of two equally sized macrocycles, a substantial increase in the enantiomerization barrier is observed upon going from the sulfide to the sulfone, and only a subtle rise is detected for the constitutional isomer 2a with two macrocycles of different size during the same transformation. This results not only in 1a with the highest configurational stability in the series of hitherto investigated Geländer structures but also challenges the so far hypothesized correlations between bridging structures and the Gibbs free energy of enantiomerization. The simulation of the enantiomerization process in the macrocyclic subunits suggests the proximity of the endotopic hydrogens as parameter responsible for the heights of the enantiomerization barrier.

Head to Tail Distortion Wave Characterizes the Enantiomerization of Helicenes.

A fresh look on helicenes' enantiomerization process with a focus on ring conformation reveals that it can be described as a step-by-step mechanism in which maximal distortion is consecutively transferred along the helicene skeleton, head to tail. Density functional theory methods were used to compute the enantiomerization pathway, and continuous symmetry measures were applied to quantify the distortion of even-number helicenes with 8-14 rings. Our findings show that the distortion wave is additive-the process always starts from one edge of the helicene and progresses along the rings until the other edge is reached. As more rings are added to the helicene, extra steps are appended to the distortion wave. Implications of this fundamental process are discussed in light of similar natural phenomena from polymer dynamics to snake locomotion.

Enantiomerization Barrier of all‐cis C‐Me‐tetrahydroxy p‐tert‐butylcalix[4]arene and Atropisomeric Equilibrium of its Tetraacetoxy Derivatives

All‐cis C–Me‐tetrahydroxy p‐tert‐butylcalix[4]arene (5) was prepared by exhaustive demethylation (iodocyclohexane/DMF) of its tetramethyl ether derivative 4. The molecule crystallized as a 2:1 adduct of chlorobenzene and the calix[4]arene. The calix macrocycle adopts in the crystal a pinched‐cone conformation where all methyls are located at equatorial positions of the macrocycle. The barrier for reversal of the sense of direction of the circular array of intramolecular hydrogen bonds of 5 (an enantiomerization process) is ΔG‡ = 11.1 kcal mol–1 (197 K, CD2Cl2). Acetylation (acetic anhydride, conc. H2SO4) afforded a 7:3 mixture of partial‐cone (10) and cone (11) tetraacetoxy derivatives. Both atropisomers were characterized by X‐ray crystallography. In contrast to tetraacetoxy p‐tert‐butylcalix[4]arene, equilibration studies of the tetraacetoxy derivatives of 5 ([D6]DMSO, 423 K) indicate that the cone atropisomer 11 is populated at equilibrium conditions. The relative stabilization of 11 suggests that the other atropisomeric forms of the tetraacetoxy C–Me‐calix[4]arene are destabilized by the presence of methyl substituents located at isoclinal positions of the macrocycle.

Mechanical Stabilization of Helical Chirality in a Macrocyclic Oligothiophene.

We introduce a design principle to stabilize helically chiral structures from an achiral tetrasubstituted [2.2]paracyclophane by integrating it into a macrocycle. The [2.2]paracyclophane introduces a three-dimensional perturbation into a nearly planar macrocyclic oligothiophene. The resulting helical structure is stabilized by two bulky substituents installed on the [2.2]paracyclophane unit. The increased enantiomerization barrier enabled the separation of both enantiomers. The synthesis of the target helical macrocycle 1 involves a sequence of halogenation and cross-coupling steps and a high-dilution strategy to close the macrocycle. Substituents tuning the energy of the enantiomerization process can be introduced in the last steps of the synthesis. The chiral target compound 1 was fully characterized by NMR spectroscopy and mass spectrometry. The absolute configurations of the isolated enantiomers were assigned by comparing the data of circular dichroism spectroscopy with TD-DFT calculations. The enantiomerization dynamics was studied by dynamic HPLC and variable-temperature 2D exchange spectroscopy and supported by quantum-chemical calculations.

A Chiral Macrocyclic Oligothiophene with Broken Conjugation – Rapid Racemization through Internal Rotation

AbstractA macrocyclic oligothiophene with an integrated pseudo‐para substituted [2.2]paracyclophane has been achieved. The synthetic sequence relies on alternating steps of halogenation‐ and Suzuki‐coupling conditions. By employing a modified Eglinton reaction under high dilution conditions, the macrocycle is closed and the obtained diacetylene is efficiently transferred to the corresponding thiophene. The molecule is fully characterized and its dynamic racemization is analyzed by variable temperature NMR experiments. The racemization barrier hints with 38 kJ/mol at rapid enantiomerization at room temperature by Mislow’s ‘Euclidian rubber glove’ enantiomerization process. Macrocycle formation results in red‐shifted absorption and emission spectra, hinting at increased conjugation through the oligothiophene versus the trough space conjugation through the [2.2]paracyclophane.

Determination of Ethofumesate‐2‐hydroxy Stereolability by Dynamic HPLC

AbstractEvaluating stereolability of target chiral chemical is pivotal when developing enantioselective studies. Ethofumesate‐2‐hydroxy is one of the main metabolites of ethofumesate, a chiral herbicide currently marketed as racemate. In order to perform enantioselective pharmacokinetic and metabolism studies, the stereolability of susceptible molecules should be evaluated. Based on that, dynamic high‐performance liquid chromatography experiments were performed to evaluate ethofumesate‐2‐hydroxy enantiomerization process on‐column. The thermodynamic results helped understand that ethofumesate‐2‐hydroxy enantiomerization is a bimolecular process assisted by acid and base catalysis. The enantiomerization barrier determined suggested that ethofumesate‐2‐hydroxy single enantiomers may undergo extensive racemization at ambient temperature turning ethofumesate‐2‐hydroxy enantioselective studies into an unfeasible task.

Atropisomerism in a 10-Membered Ring with Multiple Chirality Axes: (3 Z,9 Z)-1,2,5,8-Dithiadiazecine-6,7(5 H,8 H)-dione Series.

For the first time, chirality in (3 Z,9 Z)-1,2,5,8-dithiadiazecine-6,7(5 H,8 H)-dione series was recognized. Enantiomers of the 4,9-dimethyl-5,8-diphenyl analogue were isolated at room temperature, and their thermal stability was determined. X-ray crystallography confirmed the occurrence of a pair of enantiomers in the crystal. Absolute configurations were assigned by comparing experimental and calculated vibrational/electronic circular dichroism spectra of isolated enantiomers. A distorted tesseract (four-dimensional hypercube) was used to visualize the calculated enantiomerization process, which requires the rotation around four chirality axes. Conformers of higher energy as well as several concurrent pathways of similar energies were revealed.

Rate constant determination of interconverting enantiomers by chiral chromatography using a stochastic model

It may happen under the conditions employed that enantiomers interconvert to each other. In this case, obviously, the kinetics of the process is to be examined. When enantiomers dynamically interconvert to each other during the separation process, a plateau is observed between the adjacent peaks (so-called Batman peak appears). The peak shape depends on the rate constant of this dynamic reaction.A novel stochastic model was derived which takes both the separation and the interconversion into account at the molecular level – thus the effects of the parameters affecting the separation can be investigated. The novel model was used for the study of quetiapine, a drug molecule that interconverts during the separation to evaluate the rate constant based on the enantiomerization. Various flow rates and temperatures were used, and good agreement was obtained with the rate constant obtained from optical rotation experiments and with the software written by Trapp [1]. The most important result we concluded is the need of mild conditions during the separation to ascertain the rate constant the most accurately (low flow rates and temperatures where the enantiomerization process is limited to a few interconversions). The comparison of the rate constants of the on-column and the off-column experiments should be done by considering the stationary phase effects that are absent in the off-column experiments.

BITHIENOLs: Promising C2‐Symmetric Biheteroaromatic Diols for Organic Transformation

2,2′,5,5′‐Tetraphenyl‐3,3′‐bithiophene‐4,4′‐diol, the first member of a new class of chiral C2‐symmetric atropisomeric diols based on a biheteroaromatic scaffold, has been synthesized. Dynamic enantioselective HPLC experiments revealed a racemization barrier of 22.9 kcal/mol at 25 °C, which is high enough to permit the chromatographic collection of both enantiomers on a semi‐preparative scale, but at the borders of application as a promoter in asymmetric catalysis. The ground and transition states involved in the enantiomerization process have been identified through DFT calculations, which suggest the intermediacy of a tautomeric species in which a thiophen‐3‐ol unit and a 2,3‐dihydrothiophen‐3‐one ring are present. The proposed racemization mechanism is supported by the results of dynamic HPLC experiments. Calculations also suggested which substituent groups at the 2,2′‐positions of the thiophene rings could lead to an increase in enantiomerization barriers sufficient to confer full configurational stability on the 3,3′‐bithiophene framework.

Isolation, structure elucidation and racemization of (+)- and (-)-pratensilins A-C: unprecedented spiro indolinone-naphthofuran alkaloids from a marine Streptomyces sp.

Three pairs of new enantiomeric alkaloids with an unprecedented spiro indolinone-naphthofuran skeleton were isolated from a marine Streptomyces sp. The pure enantiomers had a marked difference in the enantiomerization processes for the three compounds. DFT calculations in combination with chemical derivatization were performed to corroborate the racemization process via a keto-enol-type tautomerism.

Enantiomeric determination and evaluation of the racemization process of atropine in Solanaceae seeds and contaminated samples by high performance liquid chromatography-tandem mass spectrometry

A new method has been developed for the enantioselective separation of (−) and (+) hyoscyamine in Solanaceaes seeds and contaminated buckwheat. Chromatographic separation was optimized, evaluating two chiral columns, Chirobiotic V and Chiralpal-AY3. Better resolution was obtained using a Chiralpak-AY3 column, utilizing as mobile phase ethanol (0.1% diethanolamine). An extraction procedure based on a modified QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) was applied, using water and acetonitrile containing 1% of acetic acid, and a clean-up step utilizing primary secondary amine (PSA) and graphitized carbon black (GCB) as sorbents. The extract was diluted with ethanol (50/:50, v/v) prior to chromatographic analysis, and the separation was carried out avoiding the racemization during this stage. Enantiomerization process of atropine was studied in samples at different conditions such as temperature (30, 50 and 80°C) and pH (3, 5, 7 and 9), observing that racemization occurs at high pH (9) and temperature (80°C). Stramonium and Brugmansia seeds were analyzed and the concentration of (−)-hyoscyamine was 1500mg/kg and 320mg/kg respectively. Contaminated buckwheat was also determined and (−)-hyoscyamine was detected at 170μg/kg.

Corannulene-Helicene Hybrids: Chiral π-Systems Comprising Both Bowl and Helical Motifs.

Two distinct structural elements that render π-systems nonplanar, i.e., geodesic curvature and helical motifs, have been combined into new polyarenes that contain both features. The resultant corannulene-[n]helicenes (n = 5, 6) show unique molecular dynamics in their enantiomerization processes, including inversion motions of both the bowl and the helix. Optical resolution of a corannulene-based skeletally chiral molecule was also achieved for the first time, and the influence of the bowl-motif annulation on the chiroptical properties was investigated.

An Unexpected Pathway to Enantiomerization of Hemithioketals in Toluene Involving a Dimeric Transition State: A Combined Experimental and Computational Study

Abstract5‐Alkyl‐8‐aryl‐8‐hydroxy‐8H‐[1,2,4]oxadiazolo[3,4‐c][1,4]thiazin‐3‐ones (1) and their thioketals (2) represent interesting hits as LTTC blockers as well as inhibitors of MDR1 activity. Compounds 1 contain an unstable chiral centre which can give rise to an enantiomerization process, because of the possible equilibrium with the open‐chain forms 4. We have carried out a combined experimental‐computational study on the 1/4 equilibrium in toluene by using the 8‐(4‐bromophenyl)‐5‐ethyl‐8‐hydroxy‐8H‐[1,2,4]oxadiazolo[3,4‐c][1,4]thiazin‐3‐one (1a), containing two diastereotopic hydrogen atoms. 1H‐NMR techniques have allowed to calculate the relevant energy barriers for the enantiomerization process (ca. 20 kcal mol–1). QM computations have individuated a transition state for a concerted asynchronous process occurring on a dimer of 1a with an activation barrier (ca. 23 kcal mol–1) in rather good agreement with the 1H‐NMR experimental value, thus showing how a spontaneous mutarotation process could occur in non‐polar aprotic solvent.

TlIII(dota)]−: An Extraordinarily Robust Macrocyclic Complex

The X-ray structure of {C(NH2)3}[Tl(dota)]·H2O shows that the Tl(3+) ion is deeply buried in the macrocyclic cavity of the dota(4-) ligand (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) with average Tl-N and Tl-O distances of 2.464 and 2.365 Å, respectively. The metal ion is directly coordinated to the eight donor atoms of the ligand, which results in a twisted square antiprismatic (TSAP') coordination around Tl(3+). A multinuclear (1)H, (13)C, and (205)Tl NMR study combined with DFT calculations confirmed the TSAP' structure of the complex in aqueous solution, which exists as the Λ(λλλλ)/Δ(δδδδ) enantiomeric pair. (205)Tl NMR spectroscopy allowed the protonation constant associated with the protonation of the complex according to [Tl(dota)](-) + H(+) ⇆ [Tl(Hdota)] to be determined, which turned out to be pK(H)Tl(dota) = 1.4 ± 0.1. [Tl(dota)](-) does not react with Br(-), even when using an excess of the anion, but it forms a weak mixed complex with cyanide, [Tl(dota)](-) + CN(-) ⇆ [Tl(dota)(CN)](2-), with an equilibrium constant of Kmix = 6.0 ± 0.8. The dissociation of the [Tl(dota)](-) complex was determined by UV-vis spectrophotometry under acidic conditions using a large excess of Br(-), and it was found to follow proton-assisted kinetics and to take place very slowly (∼10 days), even in 1 M HClO4, with the estimated half-life of the process being in the 10(9) h range at neutral pH. The solution dynamics of [Tl(dota)](-) were investigated using (13)C NMR spectroscopy and DFT calculations. The (13)C NMR spectra recorded at low temperature (272 K) point to C4 symmetry of the complex in solution, which averages to C4v as the temperature increases. This dynamic behavior was attributed to the Λ(λλλλ) ↔ Δ(δδδδ) enantiomerization process, which involves both the inversion of the macrocyclic unit and the rotation of the pendant arms. According to our calculations, the arm-rotation process limits the Λ(λλλλ) ↔ Δ(δδδδ) interconversion.

Lower Denticity Leading to Higher Stability: Structural and Solution Studies of Ln(III)–OBETA Complexes

The heptadentate ligand OBETA (2,2'-oxybis(ethylamine)-N,N,N',N'-tetraacetic acid) was reported to form complexes with Ln(3+) ions more stable than those formed by the octadentate and more popular congener EGTA (ethylene glycol O,O'-bis(ethylamine)-N,N,N',N'-tetraacetic acid). The structural features leading to this puzzling coordination paradox were investigated by X-ray diffraction, solution state NMR, molecular modeling, and relaxometric studies. The stability constant of Gd(OBETA) (log KGdL = 19.37, 0.1 M KCl) is 2 orders of magnitude higher than that of the higher denticity analogue Gd(EGTA) (log KGdL = 17.66, 0.1 M KCl). The half-lives (t1/2) for the dissociation reactions of Gd(OBETA) and Gd(EGTA) ([Cu(2+)]tot = 0.2 mM, [Cit(3-)]tot = 0.5 mM, [PO4(3-)]tot = 1.0 mM, and [CO3(2-)]tot = 25 mM at pH = 7.4 and 25 °C in 0.1 M KCl solution) are 6.8 and 0.63 h, respectively, reflecting the much higher inertness of Gd(OBETA) near physiological conditions. NMR studies and DFT calculations using the B3LYP functional and a large-core ECP indicate that the [Gd(OBETA)(H2O)2](-) complex most likely exists in solution as the Δ(λλ)(δδδδ)A/Λ(δδ)(λλλλ)A enantiomeric pair, with an activation free energy for the enantiomerization process of ∼40 kJ·mol(-1). The metal ion is nine-coordinate by seven donor atoms of the ligand and two inner-sphere water molecules. The X-ray crystal structure of [C(NH2)3]3[Lu(OBETA)(CO3)]·2H2O is in agreement with the predictions of DFT calculations, the two coordinated water molecules being replaced by a bidentate carbonate anion. The (1)H NMRD and (17)O NMR study revealed that the two inner-sphere water molecules in Gd(OBETA) are endowed with a relatively fast water exchange rate (kex(298) = 13 × 10(6) s(-1)). The higher thermodynamic stability and inertness of Ln(OBETA) complexes, peaking in the center of the 4f series, combined with the presence of two coordinated water molecules suggests that Gd(OBETA) is a promising paramagnetic probe for MRI applications.

Designing Molecular Flip‐Flops – DFT‐Investigations on the Enantiomerization of Hetero Helicenes

AbstractEnantiomerization of the heterocyclic compounds PyPhXPhPy, PyXXPhPy, PyXPhXPy and PyXXXPy with furan (X = O), thiophene (X = S), and selenophene (X = Se), were studied by quantum chemical calculations [B3LYP/6‐31G* and MP2(full)/6‐311+G**//B3LYP/6‐31G*]. The activation barriers for the helicene compounds and twist angle decrease in the order PyPhSePhPy > PyPhSPhPy > PySePhSePy > PySeSePhPy > PySPhSPy. Electronic and steric factors of the helicene compounds affect the enantiomerization process and activation energy barrier.

Pyridinophane Platform for Stable Lanthanide(III) Complexation

A detailed investigation of the solid state and solution structures of lanthanide(III) complexes with the macrocyclic ligand 2,11,20-triaza[3.3.3](2,6)pyridinophane (TPP) is reported. The solid state structures of 14 different Ln(3+) complexes have been determined using X-ray crystallography. The ligand is coordinating to the Ln(3+) ion by using its six nitrogen atoms, while nitrate or triflate anions and water molecules complete the metal coordination environments. The structure of the complexes in solution has been investigated by (1)H and (13)C NMR spectroscopy, as well as by DFT calculations (TPSSh model) performed in aqueous solution. The structures obtained from these calculations for the complexes with the lightest Ln(3+) ions (La-Sm) are in very good agreement with those determined by the analysis of the Ln(3+)-induced paramagnetic shifts. A structural change occurs across the lanthanide series at Sm(3+); the complexes of the large Ln(3+) ions (La-Nd) are chiral due to the nonplanar conformation of the macrocycle, and present effective C3v symmetries in solution as a consequence of a fast interconversion of two enantiomeric forms with C3 symmetry. The activation free energy for this enantiomerization process, as estimated by using DFT calculations, amounts to 33.0 kJ·mol(-1). The TPP ligand in the complexes of the heaviest Ln(3+) ions (Eu-Lu) presents a half-chair conformation, which results in C(s) symmetries in solution.

Manganese‐Enhanced MRI Contrast Agents: From Small Chelates to Nanosized Hybrids The Development of Iron(II) Complexes as ParaCEST MRI Contrast Agents Lanthanide Complexes as Paramagnetic Probes for 19F Magnetic Resonance The Solution Structure and Dynamics of MRI Probes Based on Lanthanide(III) DOTA as Investigated by DFT and NMR Spectroscopy (Eur. J. Inorg. Chem. 11/2012)

AbstractThe cover picture highlights various aspects of research in the field of metal‐based MRI probes. The picture includes graphics from four Microreviews in this Cluster Issue superimposed on an angiographic MRI image. Shown at the bottom left is a macromolecular MnII complex (D. Felder‐Flesch, M. Kueny‐Stotz, and A. Garofalo), which is an example of manganese‐enhanced MRI contrast agents. At the bottom right, the optimization of the CEST effect for a FeII complex at close to physiological pH (J. R. Morrow and S. J. Dorazio) is depicted. Right next to it is a pseudocontact shift field around a model of a lanthanide–DOTA complex (D. Parker, I. Kuprov, and P. Harvey), illustrating the physicochemical basis of probe design for 19F MRS and MRI applications. At the top left is an energy diagram for the enantiomerization process of a LnIII complex with a cyclen‐based ligand (C. Platas‐Iglesias), which reflects an improved understanding of the solution structure and dynamics of such systems. The molecular modeling representation of a typical MRI contrast agent, [Gd(DOTA)(H2O)]–, is shown next to it. We thank the authors for providing graphics for the cover and Dr. Giorgio Gatti for putting in his time and creativity to compose this insightful picture. magnified image

Rates of enantiomerization in axially chiral 2,2′-bipyridines with restricted rotation: an ab initio study

Herein, we describe our findings concerning a 6,6′-bridged-2,2′-bipyridine derivative whose dynamic properties were described by Rebek and Trend in 1978. While the enantiomerization processes of the neutral molecule, the dication and the Zn complex were correctly described by DFT calculations, those of the monoprotonated cation were in disagreement. This led us to search for possible explanations, which led us to conclude that the experimental barrier corresponds to a N–H⋯O CMe 2 hydrogen bonded complex between the cation and one solvent molecule.