1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Mexiletine

The 60 MHz ¹H NMR spectra of mexiletine, 1-(2,6-dimethylphenoxy)-2-propanamine, 1, have been studied at 28° in CDCl₃ solution with the achiral reagent, tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium(III), 2, Eu(FOD)₃, and the chiral reagents tris[3-(trifluoromethylhydroxymethylene)-d-camphorato]europium(III), 3, Eu(FACAM)₃, and tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium(III), 4, Eu(HFC)₃. Substantial lanthanide-induced shifts were seen for the proton signals of 1 with each reagent. Appreciable enantiomeric shift differences were seen for both methyl signals and for each of the CH₂CH proton signals using 3 and 4 that should permit direct determinations of enantiomeric excess for samples of 1. A predominant conformation for 1 is suggested based on observed splittings of the CH₂ proton signals and their relative lanthanide-induced shifts.     

NMR Studies of Drugs. Sulindac Methyl Ester. Applications of Achiral and Chiral Lanthanide Shift Reagents

The potent nonsteroidal anti-inflammatory agent, sulindac, (Z) -5-fluoro-2-methyl-1-{[4-(methylsulfinyl) - phenyl]methylene} -1H-indene-3-acetic acid, has been examined by ¹H NMR as its methyl ester in CDCl₃ solution with the added achiral lanthanide shift reagent (LSR) tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium (III), Eu (FOD)₃, 2, for spectral simplification, and with the chiral LSRs, tris[3-(heptafluoropropylhydroxymethylene) - (+) - camphorato] europium (III), 3, and tris[3-(trifluoromethyl-hydroxymethylene) - (+) -camphorato] europium (III), 4, to induce enantiomeric shift differences (ΔΔδ) for several nuclei. Studies employed 60 and 300 MHz spectrometers. At the higher frequency, analytically useful ΔΔδ values were observed with added 3 for the aryl protons ortho to the methylsulfinyl group that should permit direct determinations of enantiomeric excess (% ee). By conversion of sulindac samples to the methyl ester, use of 3 would then formally constitute an ee determination of sulindac.     

NMR Studies of Drugs. Phensuximide. 1H and 13C NMR Methods with Chiral Solvating Agents and Lanthanide Shift Reagents

NMR spectra of the racemic anticonvulsant, phensuximide, 1, in CDCl₃ solution, have been studied with additives to explore methods for potential direct determination of enantiomeric excess (% ee). Proton studies at 200 MHz with the chiral solvating agent (CSA) (-)-2,2,2-trifluoro-1- (9-recommended for ee analysis due to uncertainties of contributions to the NCH₃ from the CH₂ proton absorptions.     

NMR Studies of Drugs. Applications of Achiral and Chiral Lanthanide Shift Reagents to a 5-Substituted-4-thiazolidinone

The 60 MHz ¹H NMR spectra of racemic 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone, 1, have been studied in CDCl₃ solution at 28° with the achiral lanthanide shift reagent (LSR), tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium (III), 2, and the chiral LSRs, tris[3-(heptafluoropropylhydroxymethylene)- (+)-camphoratojeuropium(III), 3, and tris[3-(trifluoromethylhydroxymethylene-(+) -camphorato]europium (III), 4, Significant enantiomeric shift differences were observed in the presence of added 3, for the aryl protons of 1 that should permit direct determination of enantiomeric excess. Relative magnitudes of lanthanide-induced shift for the different nuclei of 1 with the three LSRs are compared and discussed in terms of preferred LSR binding sites. A favored conformation of 1 with respect to rotation about the C(5)-CH₂ bond is suggested.     

NMR Studies of Drugs. Applications of Achiral and Chiral Wthanide Shift Reagents to Bupropion

Abstract

The ¹H NMR spectra of racemic samples of the antidepressant drug, bupropion, 1, have been studied in CDCl₃ solution at 60 and 200 MHz with the achiral lanthanide shift reagent (LSR), tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium (III), 2, and the chiral reagent, tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium(III), 3. Both LSR produced substantial lanthanide induced shifts consistent with ¹H assignments, but the bound complexes of 1 with 2 versus 3 may not be isostructural. With 3, substantial enantiomeric shift differences were observed for the t-butyl, CH ₃CH, NCH, and the aryl H-2 and H-6 signals, which should permit potential direct determination of enantiomeric excess.     

1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Paramethadione, 5-Ethyl-3,5-Dimethyl-2,4-Oxazolidinedione

Abstract

The 60 MHz ¹H NMR spectra of paramethadione, 5-ethyl-3,5-dimethyl-2,4-oxazolidinedione, 1, have been studied at 28° in CDCl₃ solution with the achiral reagent tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium(III), 2, and the chiral reagents tris[3-(trifluoromethylhydroxymethylene)?(+)-camphorato]europium(III), 3, and tris[3?(heptafluoropropylhydroxymethylene)?(+)-camphorato]europium(III), 4.SubstantiaΔδ values and spectral simplification are achieved with 2 or 4. Significant enatiomeric shift differences, ΔΔδ, are observed with 4 that should provide direct optical purity determinations of ? 1, using the C(5)CH3 or the NCH, signals with &;:Iratios of 1.3–1.5. Valley height for the CCH, resonance as low as 4.8% was achieved, which should allow detection of as little as 3–4% of the minor enantiomer. Results are discussed in terms of the structural features of I and of the LSR. Substantial nb values and spectral simplification     

NMR Studies of Drugs. 5-Methyl-5-phenylhydantoin. Applications of Lanthanide Shift Reagents in Polar Solvents to a Non-Chelating Substrate

The 200.1 MHz ¹H NMR spectra of 5-methyl-5-phenylhydantoin, 1, have been studied in CD₃CN solution at ambient temperatures with the achiral shift reagent, tris (6, 6, 7, 7, 8, 8, 8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium (III), 2, and the chiral reagent, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato] europium (III), 3. Although 1 cannot chelate the LSRs, use of sufficiently high LSR:1 molar ratios served to compensate for competitive binding of LSR by the polar solvent, and permitted substantial lanthanide-induced shifts to be observed with 2 or 3. With 3, significant enantiomeric shift differences were produced for the ortho aryl protons and for the CH₃ signals. The ortho proton signal appears to offer excellent potential for direct determination of enantiomeric excess of 1. These results demonstrate the utility of LSRs 2 or 3 even in a polar solvent with a nonchelating substrate.     

NMR Studies of Drugs: Antipyrine and Analogs. I. Use of Achiral and Chiral Lanthanide Shift Reagents to Examine Hindered Rotation.

The 200 MHz ¹H NMR spectra of the analgesic, antipyrine, 1, have been studied in CDC1₃ solution at ambient temperatures with the achiral lanthanide shift reagent (LSR) tris (6, 6, 7, 7, 8, 8, 8-heptafluoro-2, 2-dimethyl-3, 5-octanedionato) europium (III), Eu(FOD)₃, 2, and with the chiral LSR, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium(III), Eu(HFC)₃, 3., Lanthanide-induced shift (LIS) magnitudes and broadening of selected signals are consistent with predominant LSR binding at the carbonyl oxygen with either 2 or 3. Of the different possible conformational regimes for the N-phenyl group of 1, our results appear to rule out a slow exchange limit (SEL) system with the N-phenyl coplanar with the heterocyclic ring. Perpendicular rings in an SEL regime can not be ruled out. A rapidly-rotating N-phenyl (fast exchange limit, FEL system) would also be consistent with observed results. Accurate chemical shifts for the aryl protons (overlapped in the 200 MHz spectrum of unshifted 1) are determined from spectra with added LSR by extrapolation to zero molar ratios of [LSR]:[1]. Relative slopes in the plots of chemical shift versus [LSR]:[1] molar ratios are calculated for each proton signal of 1.     

NMR Studies of Drugs. Applications of Lanthanide Shift Reagents to Afloqualone,an Axially Chiral Quinazolinone.

The skeletal muscle relaxant, aflogualone, 1, has been studied by ¹H NMR in CDC1₃ at 60 and 300 MHz in the presence of added chiral [Eu(HFC)₃] or achiral [Eu(FOD)₃] lanthanide shift reagents (LSR). With Eu(HFC)₃, significant enantiomeric shift differences, ΔΔδ, can be induced for most of the nuclei of 1, with near-baseline resolution obtainable for the H-5 signals of each enantiomer, indicating excellent analytical potential for direct determination of enantiomeric excess of samples of 1. Observation of ΔΔδ directly confirms hindered rotation about the bond between N (3) and the 2-methylphenyl group, i.e., the N (sp²) - C(sp²) bond, leading to axial chirality in 1 with slow rotation on the NMR timescale. Assignments are supported by 2D COSY spectra at 300 MHz. Relative lanthanide-induced shift magnitudes for the protons of 1 are compared.     

NMR Studies Of Drugs. Chiral Solvating Agents for Direct Determination of Enantiomeric Excess of the Cardiac Antiarrhythmic,Mexiletine

The 400 MHz ¹H NMR spectra of the cardiac antiarrhythmic, mexiletine, 1, have been studied with different chiral solvating agents (CSA) to obtain a very promising method for direct determination of enantiomeric excess (e.e.) with limited amounts of 1. The methods included the use of β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA), and 2,2,2-trifluoro-1-(9-anthryl)ethanol (TFAE). Use of TFAE in CDCl₃ with the free base of 1 appeared to give the best results, with enantiomeric shift differences observed for the signals of the sidechain methyl, CH ₃CH, and the aryl methyls.     

1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Methastyridone, 2,2-Dimethyl-5-(2-Phenylethenyl)-4-Oxazolidinone

Abstract

The 60 MHz ¹H NMR spectra of methastyridone, 2,2-dimethyl-5-(2-phenylethenyl)-4-oxazolidinone, 1, have been studied at 28° in CDCl₃ solution with the achiral reagent tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium(III), 2, Eu(FOD)₃, and the chiral reagent tris[3-(heptafluoropropylhydroxy-methylene)-d?camphorato]europium(III), 3, Eu(HFC)₃.     

NMR Studies of Agricultural Products. Applications of Achiral and Chiral Lanthanide Shift Reagents to the Fungicide,Triadimefon.

Abstract

The 60 MHz ¹H NMR spectra of the systemic agricultural fungicide, triadimefon, 1, have been studied in CDCl₃ at 28±1° (as the racemic free base) with the added achiral lanthanide shift reagent (LSR), tris(6, 6, 7, 7, 8, 8, 8-heptafluoro-2, 2-dimethyl-3, 5-octanedionato) europium(III), Eu(FOD)₃, 2, for spectral simplification, and with the chiral LSR, tris [3-(heptafluoropropylhydroxymethylene)-(+) -camphorato)europium(III), Eu(HFC)₃, 3, to induce enantiomeric shift differences (ΔΔδ) for several nuclei. Significant ΔΔδ values were seen for the two protons of the heterocyclic ring, the OCH methine, and aryl H-2′, 6′ of the chlorophenoxy ring. For each of these nuclei exhibiting ΔΔδ with added 3, the ΔΔδ magnitudes reached maximum values with 3: 1 molar ratios ca. 0. 18–0. 29, and decreased with higher levels of 3. To confirm analytical utility of 3 for % e. e. determinations of 1, a nonracemic (“spiked”) sample of racemic 1, with added R-(?) triadimefon, was examined with 3. At low 3: 1 ratios, both triazole H-3 and H-5, as well as the OCH and aryl H-2′, 6′ protons of (?)-1 showed a downfield sense of magnetic nonequivalence with (+) -3. With 3: 1 ratios ca. 0. 8, triazole proton H-3 reversed its sense of magnetic noneguivalence. The H-3 and H-5 signals were useful for % e. e determinations at this higher 3: 1 ratio.     

NMR Studies of Drugs. Enantiomeric Excess Determination of N-acetylcathinone with Eu(HFC)3

A technique for determination of enantiomeric excess of cathinone, 2-amino-1-phenyl-1-propanone, by use of the chiral lanthanide shift reagent (LSR), tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium (III), Eu (HFC)₃, is described. The hydrochloride salt of the cathinone sample is first converted directly to the N-acetyl derivative without need for isolation of the potentially unstable cathinone free base. Addition of Eu (HFC)₃ to the crude acetylated cathinone resulted in near-baseline resolution of the CH ₃CO resonances of the enantiomers. Analytical utility and the sense of magnetic nonequivalence of this signal were demonstrated using “spiked” non-racemic samples.     

NMR Studies of Hindered Rotations in Drugs. Use of Achiral and Chiral Lanthanide Shift Reagents with Mecloqualone,an Axially Chiral Drug of Abuse. Rigorous Definition of Spin Systems.

The axially chiral sedative/hypnotic drug of abuse, mecloqualone, 1, has been studied in CDC1₃ by ¹H NMR at 60 and 300 MHz with the added achiral lanthanide shift reagent (LSR), tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5- octanedionato)europium(III), 2, and the chiral LSR, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato] europium-(III), 3. Rigorous distinctions between the two (CH)₄ spin systems of 1 with added 2 or 3 were achieved by two-dimensional homonuclear chemical shift correlation spectroscopy, COSY. Substantial up field (“anomalous”) shifts were observed for several nuclei of 1 with each LSR. Use of the chiral 3 elicited enantiomeric shift differences with baseline separations for several nuclei that should permit direct determinations of enantiomeric excess. COSY spectra allow determination of the relative sense of magnetic nonequivalence of selected nuclei of 1 with 3.     

1 H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Clenbuterol. Method for Direct Optical Purity Determination

The 60 MHz ¹H NMR spectra of clenbuterol, 1, have been studied in CDCl₃ solution with the achiral shift reagent, tris (6,6,7,7,8,8,8-hepta-fluoro-2,2-dimethyl-3,5-octanedionato)europium (III), 2, and the chiral reagent tris[3-(heptafluoropropylhydroxyn1ethyl-ene)-(+)-canphorato]europiunr(III), 3. Use of 3 resulted in observable enantiomeric shift differences, ΔΔσ, for the t-butyl, NH₂ benzylic CH and the aryl proton signals. Values of ΔΔσ as high as 135.1 Hz (2.25 ppm) and 86.5 Hz (1.44 ppn) were seen for the methine and aryl protons, respectively, with a solution 0.1035 molal in 1 and a 1:3 molar ratio of 0.551. The aryl resonance is especially well suited for direct optical purity determinations of 1.     

NMR Studies of Agricultural Compounds. Applications of Achiral and Chiral Lanthanide Shift Reagents to the Herbicide,Fenoxaprop-Ethyl

The 200 MHz H NMR spectra of the herbicide, fenoxaprop-ethyl, 1, have been studied in CDCl₃ solution at ambient temperatures as the racemic ester free base with the added chiral lanthanide shift reagent (LSR), tris [3 - (heptafluoropropylhydroxymethylene) - (+) - camphorato]europium(III), Eu(HFC)₃, 2, with some additional runs using the achiral LSR, tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium(III), Eu(FOD)₃, 3, for supplemental spectral simplification. With 2, definite enantiomeric shift differences (ΔΔδ) were observed only for the CH₃CH₂O resonance. Although increased spectral complexity for the CH₂O signal was seen with added 2, this could have resulted from anisochrony of the diastereotopic protons, H_a and H_b, of this methylene group rather than true ΔΔδ, since the achiral 3 led to near-baseline separation between the CH_aH_bO signals. Lanthanide-induced shift (LIS) magnitudes were interpreted as consistent with predominant LSR binding at the ester carbonyl.     

NMR Studies of Agricultural Compounds. Applications of Achiral and Chiral Lanthanide Shift Reagents to the Herbicide,Diclofop Methyl

The 60 MHz H NMR spectra for the herbicide, diclofop methyl, 1, have been studied in CDCl₃ solution at 28±1° with the added achiral lanthanide shift reagent (LSR) tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium(III), Eu (FOD)₃, 2, and with the chiral LSRs, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium(III)₃, Eu(HFC)₃, 3, and tris[3-(trifluoromethylhydroxymethylene)-(+)-camphorato]europium(III), Eu(FACAM)₃, 4. Both 2 and 3 produced substantial lanthanide-induced shifts (LIS) consistent with predominant LSR binding at the ester carbonyl. Much smaller LIS magnitudes were observed with 4. Modest enantiomeric shift differences (ΔΔδ) were elicited with 3 for the OCH₃ and the CCH₃ resonances of 1. The former signal appears to offer greatest potential for the direct determination of enantiomeric excess of samples of 1, with 3:1 molar ratios ca. 0.3–0.4 resulting in valley heights as low as 33% of the average peak heights of the OCH₃ signals of the two enantiomers.     

NMR Studies of Drugs. Methaqualone. Approaches to Rigorous 1H and 13C Assignments with Applications of Achiral and Chiral Shift Reagents

The ¹H and ¹³C NMR spectra of methaqualone, 1, have been extensively studied using one and two-dimensional techniques. These 300 MHz ¹H and 75 MHz ¹³C studies have allowed rigorous assignments to be made for the methyl groups and the quinazolinone nucleus. The 60 MHz ¹H spectra for 1 in CDCl₃ have been examined with     

1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Meparfynol, 3-Methyl-L-Pentyn-3-Ol. Apparent Anomalous Results with a Binuclear Shift Reagent

The 60 MHz ¹H NMR spectra of racemic meparfynol, 1, have been studied in CDCl₃ solution at 28° with the achiral shift reagentt tris(6,6,7,7,8,8,8-hepta-fluoro-2,2-dimethyl-3,5-octanedionato) europium (III), 2, and the chiral reagent, tris[3-(heptafluoropropyl-hydroxymethylene)-d-camphorat01 europium(III), 3. With 3, observable enantiomeric shift differences for the 3-methyl should make possible direct optical purity determinations. Additions of increments of (6,6,7,7,8,8,8-heptafluoro-2,2-dimenthyl-3,5-octane-dionato)silver(I) 4, to a CDCl₃ solution of 1 and 3 resulted in changes in Δδ magnitudes and in some line intensities that are discussed in terms of interactions with the ethynyl and hydroxyl groups.     

The Studies of 13C NMR Chemical Shifts and Induced Lanthanide Shift Reagent Cis-trans Isomerization of N-Cinamylidene-hexyl,t-butyl and Substituted Aryl-Amines

The Carbon-13 chemical shifts of N-Cinamylidenehexyl, t-butyl and sixteen substituted aryl amines were analysed. The lanthanide induced carbon-13 chemical shifts of the cis and trans of four N-cinamylidene substituted anilines were analysed. The spectra N-cinamylidene hexylamine showed only the trans form. The cis/trans ratio of N-cinamylidene aryl amines increased as the LSR concentration increased.