Stereochemical Effects on 1H Chemical Shifts in 2,3-Diazabicyclo[2.2.1]Hept-2-Ene (DBH), 2,3-Diazabicyclo[2.2.2]Oct-2-Ene (DBO) and Related Molecules

¹H-NMR spectra of DBH (1), DBO (2) and of the synthetic precursor to 1, 1,4-phenyl-2,4,6-triazatricyclo[5.2.1.0^2,6]heplanc-3,5-dione (3), were recorded in acetone-d₆ and C₆D₆ at 500 MHz. Assignment was aided by complete resolution of signals of 1 and 3 in C₆D₆ by aromatic solvent-induced shifts (ASIS). The effect of the change from phenyllriazolinedione to a diazene functional group on the chemical shifts of the exo,endo and syn,anti protons was investigated. The chemical shifts of the exo,endo protons of 1 are exceptionally sensitive to the functional group at the hetero substituted bridge in the DBH skeleton. However, the relative chemical shift of the syn,anti proton pair is independent of the nature of the functional group. The role of stereochemical effects on these chemical shifts is discussed.     

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.     

Electronic Spectral Studies and Determination of the First Excited Singlet-State Dipole Moments of New Benzo[a]phenothiazine Derivatives

The room temperature (298 K) electronic absorption, and fluorescence excitation and emission spectra of seven new, pharmacologically-important benzo[a]phenothiazines (12H-benzo[a]phenothiazine ( 1 ), 9-methyl-12H-benzo[a] phenothiazine ( 2 ), 10-methyl-12H-benzo[a] phenothiazine ( 3 ), 11-methyl-12H-benzo[a]phenothiazine ( 4 ), 5-oxo-5H-benzo[a]phenothiazine ( 5 ), 6-hydroxy-5-oxo-5H-benzo[a]phenothiazine ( 6 ) and 6-methyl-5-oxo-5H-benzo[a] phenothiazine ( 7 ):) were measured in several solvents of different polarities and hydrogen bonding abilities. In combination with the ground state dipole moments of these benzo[a]phenothiazines, the spectral data were used to determine their first excited singlet-state dipole moments by means of the solvatochromic shift method. These excited singlet-state dipole moments were found to be significantly higher (1.9 to 2.5 Debye units) than their ground-state counterparts.     

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.     

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.     

Studies of Hindered Rotation and Magnetic Anisotropy by 1H, 13C and 19F NMR. The Diels-Alder Adduct of N- Pentafluorophenylmaleimide and Phencyclone: A Model for Drugs.

The potent Diels-Alder diene, phencyclone, 1, reacts with N-pentafluorophenylmaleimide, 2, to form an adduct, 3, characterized by ¹H, ¹³C, and ¹⁹F NMR at 300, 75 and 282 MHz, respectively. The one-dimensional (1D) and two-dimensional (2D) ¹H and ¹³C NMR spectra of 3 at ambient temperatures imply a slow exchange limit (SEL) regime with respect to rotation of the unsubstituted bridgehead phenyl groups about severely hindered C(sp²)-C(sp³) bonds. Major non-bonded interactions are expected between the ortho protons of the C₆H₅ groups and H-1, 8 of the phenanthrenoid moiety of 3. ¹⁹F 1D and 2D (COSY) NMR spectra show that the SEL regime also obtains for rotation about the N-C₆F₅ bond of 3, with five separate fluorine signals seen, consistent with a preferred conformation in which the C₆F₅ may lie roughly perpendicular to the plane of the pyrrolidinedione moiety, and may be in the mirror symmetry plane of 3. The results are considered relevant to hindered aryl rotations in numerous Pharmaceuticals. Selected spectral data for 2 and precursors are also presented.     

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

The ¹H NMR spectra of the potent anti-hypertensive drug, lofexidine, 1, have been studied in CDCl₃ at 60 and 300 MHz. Both the achiral shift reagentr tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionatol-europium(III), 2 and the chiral reagents1 tris[3-(heptafluoropropylhydroxymethylenel-d-camphoratoleuropium(III), 3 and tris[3-(trifluoromethylhydroxymethylenel-d-camphoratoleuropium(III), 4, were employed. Substantial lanthanide induced shifts were observed with 2, 3 or 4, with the largest shifts seen for the methine at the chiral centerr followed by the signal of the NH. Enantiomeric shift differences for the CH₃ signal of 1 were seen with 3 OK 4, with 4 inducing larger values of potential analytical utility. Using a non-racemic sample of 1, the (-) enantiomer was shown to have a downfield sense of magnetic nonequivalence for the methyl resonance in the presence of added 4.     

Binuclear NMR Shift Reagents. An Apparent Anomalous Effect with Vinclozolin

The 60 MHz ¹H NMR spectra of racemic vinclozolin, 1, have been studied at 28° in CDC1₃ solution with the chiral reagent tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium(III), 2, by incremental additions of (6,6,7,7,8,8,8-heptafluoro-2,2-di-methyl-3,5-octanedionato)silver(I), 3. Although the solution of 1 with 2 displayed substantial downfield lanthanide-induced shifts, Δδ, and enantiomeric shift differences, ΔΔδ, for selected nuclei, relative to the spectrum of unshifted 1, additions of 3 to the solution of 1 and 2 were unexpectedly found to dramatically reduce the magnitudes of both Δδ and ΔΔδ.     

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.     

1 H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Tocainide. Method for Direct Optical Purity Determination and Observation of an “Anomalous” Shift

The 60 MHz ¹H NMR spectra of racemic tocainide, 1, have been studied in CDCL₃ solution at 28° with the achiral shift reagent, tris(6,6,7,7,8,8,8-heptafluor-2,2-dimethyl-3,5-octanedionato)europiumIII), 2, and the chiral reagent, tris[3- (heptafluoropropylhydroxymethylene)-d-canphorato]- europium(III), 3. Substantial lanthanide induced shifts, Δδ, were served with both 2 and 3, A significant “anomalous” upfield shift for the CH signal of 1 was seen with added 2. The chiral reagent 3 led to appreciable emtiomeric shift differences for the CH₃CH and amide NH signals. The potential for direct optical purity determinations of 1 using 3 was demonstrated for a non-racemic (“spiked”) sample of 1, based on the CH₃ resonance. The sense of magnetic non-equivalence for these resonances was also determined.     

1H NMR Spectral Simplification with Chiral Solvating Agents and with Achiral and Chiral Lanthanide Shift Reagents. Cis-4,5-Dihydro-4-Methyl-5-Phenyl-2-Oxazolamine, “Cis-4-Methylaminorex,” a Potent Stimulant and Anorectic

Abstract

The 60 MHz ¹H NMR spectra of racemic (+)-cis-4,5-dihydro-4-methyl-5-phenyl-2-oxazolamine, 1, have been studied at 28° in CDC1₃, solution 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?(heptafluoropropylhydroxymethy1ene)-d-camphor-ato]europium(III), 3. Additional NMR studies were performed at 400 MHz in CDC1, solution at 24° using the chiral solvating agents (CSA), (E)-(-)-2,2,2-trifluoro-1- (9-anthryl) ethanol, 4, and (R) - (+) -α-methoxy- α-(trifluoromethy1)phenylacetic acid, 5. Substantial enantiomeric shift differences, for the CH₃, signal of 1 using 3 or 5, and for the ortho aryl protons using4, which should make possible direct optical purity determinations of 1. Accurate 400 MHz data f o r chemical shifts and vicinal coupling constants of, of racemic cis-1 are presented, and compared with values for (optically active) (-)-trans-1; some dfferences are seen compared to previously reported data. solution. The LSR and CSA results are compared and Some additional data were obtained in C₆D₆ discussed.     

Studies on Cyclitols. XIV. Methyl Group Signals of gem-Dimethyldioxolanes as Indicators of Anisotropy

In connection with our interest in nmr spectroscopy of cyclopentanoid and 2, 4-dioxabicyclo[3. 3. 0] octane systems³ we have synthesized a large number of gem-dimethyldioxolanes^2,4 and have examined their spectra. The spectra of all the compounds showed two distinct singlets, representing the two methyl groups, in the region δ 1. 2-1. 5. Similar values have been reported in the case of derivatives of 1, 2-O-isopropylidene-α-D-xylohexofuranose by Abraham et al.⁵ Perlin⁶ has reported similar differences in the chemical shift of the endo- and exo- C-methyl groups of the diastereoisomeric orthoacetates of D-mannose, and Baggett et al.⁷ observed a difference of 0. 30 ppm between the chemical shifts of endo- and exo-benzyl protons of O-benzylidene sugars. Our studies permit the assignment of the lower field resonance to the endo-methyl group and the higher field resonance to the exo-methyl group of the dimethyldioxolanes.     

An Example of Crossed Ship Conformation: The Tetrahydropyran Ring in Trioxa-bis-Spirocital Series

Abstract

The three ³J_HH coupling constants observed in the ¹H NMR spectra (500 MHz) of trioxa-bis-spirocital 1 and 2 serve to calculate the dihedral angles Ψ(8,9) and Ψ(9,10) of these two molecules. The values obtained, 54° for 1, 25° for 2, reflect the change in conformation: chair → crossed ship when passing from 1 to 2. This change in conformation corresponds in ¹³C NMR to strong shielding (?3.6 to ?5.5 ppm) of the lines of the carbons C₈, C₉ and C_10.     

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.     

1H, 13C and 19F NMR Studies of the Diels-Alder Adduct of p-Fluoranil with Phencyclone. II. Hindered Phenyl Rotations and Anisotropic Effects in a Model Compound for Drugs

Abstract

The Diels-Alder adduct of phencyclone, compound 1, with p-fluoranil, compound 3, has been prepared in refluxing toluene. The adduct, compound 2, has been examined by ¹H, ¹³C and ¹⁹F NMR spectroscopy at 300, 75 and 282 MHz, respectively. At ambient temperature, the unsubstituted bridgehead phenyl groups in adduct 2 are found to exhibit hindered rotation, resulting in slow exchange limit (SEL) ¹H NMR spectra. Full aryl proton assignments are made based on 1D and 2D (COSY45) NMR. The ¹⁹F NMR (proton coupled) reveals one of the two ¹⁹F signals to be a triplet. This resonance collapses to a singlet in the proton decoupled ¹⁹F spectrum, implying an unexpected long range ¹H-¹⁹F coupling. For the ¹³C NMR spectrum, tentative assignments are presented. Data for compound 2 as a model compound for drugs are discussed in terms of the hindered aryl rotation and evidence of magnetic anisotrppic effects.     

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. Application of a Chiral Lanthanide Shift Reagent for Potential Direct Determination of Enantiomeric Excess of Methsuximide

The 200 MHz ¹H NMR Spectra of methsuximide, 1,3-dimethy1-3-ogebt1-2,5-otrrikudubeduibem 1, havebeen studied in CDC13 solution with the chiral reagent, tris[3-(heptafluoropropy1-hydroxymethylene)-d-camphorato] europium (III), 2, Eu(HFC)3. Substantial lanthanide-induced shifts are seen. In addition, significant enantiomeric shift differences are observed for several of the nuclei of 1. With a 2:1 molar ratio near 1.0, the CCH3 and NCH3 signals show nearly baseline resolution between the peaks from each enantiomer, providing excellent potential for direct determinations of enantiomeric excess of samples of 1. As little as 2% of a minor enatiomer should be readily detectable.     

Captopril and Its Disulfide Metabolite: 13C NMR Assignments and Preferred Conformations

The ¹³C nmr assignments for captopril (1) and its disulfide mammalian metabolite (2) were made. Evidence was presented for the preferred conformations of these compounds to be in the trans forms.     

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 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.