Ronald Callahan

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.

Abstract 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. Sel...

19F NMR studies of the Diels-Alder adduct of N-pentafluorophenylmaleimide with phencyclone. Hindered rotation about a N-6F5 bond

Abstract N-pentafluorophenyl maleimide acts as an efficient Diels-Alder dienophile to form an adduct with phencyclone. The adduct was found to exhibit five distinct 19F NMR signals (282 MHz, ambient temperature, CDCl6) consisting of two gross doublets and three gross triplets. We interpret this as consistent with a severely hindered rotation about the N-C6F5 bond in the adduct, leading to a slow exchange limit (SEL) spectrum. The C6F5 group is thought to lie, on average, on the effective mirror plane of the adduct, perpendicular to the pyrrolidinedione ring system, to reduce steric interactions of the ortho fluorines with the imide N(CO)2 carbonyls. 19F-19F COSY45 NMR allowed assignment of vicinal fluorines in the C6F5. Comparative data is presented for the precursors, N-pentafluorophenyl maleamic acid and N-pentafluorophenyl maleimide. Variable temperature 19F NMR results for the maleamic acid are presented.

NMR Studies of Hindered Rotation. The Diels-Alder Adduct of Phencyclone with p-Benzoquinone: Restricted Motion of Bridgehead Phenyls

Abstract The Diels-Alder adduct of phencyclone with p-benzoquinone has been examined by 1H NMR at 300 MHz in CDCl3 at ambient temperatures for evidence of hindered rotation of the unsubstituted bridgehead phenyl groups. The nearly first-order spectrum exhibits four approximate doublets and five approximate triplets in the aromatic region, of roughly equal intensity (ca. 2H). This is consistent with a slow-exchange limit (SEL) spectrum of the hindered phenyls. For rapidly rotating phenyls, the predicted fast-exchange limit (FEL) spectrum would have shown two 2H doublets and one 4H doublet, in addition to three 2H triplets and one 4H triplet, in the aryl region. Full 1H assignments have been made, based on the two-dimensional 1H-1H homonuclear chemical shift correlation spectrum (COSY) and expected magnetic anisotropy effects.

NMR studies of hindered rotation, the diels-alder adduct of phencyclone with maleic anhydride : restricted motion of bridgehead phenyls

Abstract 1H NMR studies at 300 MHz have been performed for the Diels-Alder adduct of phencyclone and maleic anhydride in CDCl3 at ambient temperatures. The 1D spectrum shows four equal (2H) intensity doublets in the aryl region (in addition to other absorptions) which is fully consistent with a slow exchange limit (SEL) spectrum of a system in which the unsubstituted bridgehead phenyls exhibit hindered rotation around the C(sp2)-C (sp3) bond on the NMR timescale. These protons are assigned to H-1,8 and H-4,5 of the phenanthrene moiety and to H-2′ and H-6′ of the phenvls based on the two-dimensional (2D) homonuclear chemical shift correlation spectrum (COSY) together with arguments regarding carbonyl and aromatic ring anisotropy. Full proton assignments are given.

The solvolysis of N-acetoxy-acetanilides: the elucidation of two major reaction pathways for model ultimate carcinogens under neutral conditions

Abstract The solvolysis of a series of N-acetoxy acetanilides has been examined in aqueous dioxane. Product distributions and rate constants reveal that, in addition to a base catalyzed hydrolysis, there are two major pathways at neutral pH: NO bond cleavage to yield nitrenium ion intermediates, and acyl-oxygen cleavage which leads to hydroxamic acid.

Proton and Carbon‐13 NMR Studies of the Phencyclone Adducts of Medium Alkyl Chain‐Length N‐n‐Alkylmaleimides. Hindered Rotations and Magnetic Anisotropic Effects. Ab initio Calculations for Optimized Structures

Abstract The Diels–Alder adducts, 3a–e, of phencyclone, 1, have been prepared from a series of N‐n‐alkylmaleimides, 2, with medium chain‐length n‐alkyl groups. The maleimides were obtained by cyclodehydration of the N‐n‐alkylmaleamic acids, 4, formed from reaction of maleic anhydride with the corresponding n‐alkylamines. The five adducts prepared included derivatives from n‐heptyl, 3a; n‐octyl, 3b; n‐nonyl, 3c; n‐decyl, 3d; and n‐dodecyl, 3e. The NMR spectra of the adducts were studied in CDCl3 at ambient temperatures at 300 MHz for proton and 75 MHz for carbon‐13, with full proton assignments achieved by high‐resolution COSY45 spectra for the aryl and the alkyl regions. Slow exchange limit (SEL) spectra were observed for both 1H and 13C spectra showing slow rotation on the NMR timescales of the unsubstituted bridgehead phenyl groups. Endo Diels–Alder adduct stereochemistry was supported by striking magnetic anisotropic shielding effects in the 1H spectra of the alkyl groups, with the NCH2 CH 2 signal of each adduct appearing upfield of tetramethylsilane (TMS) at ca. −0.32 ppm. Proton NMR spectra for precursor maleamic acids and maleimides are reported, with some solvent effects found (CDCl3 vs. d 6‐acetone) for the carbon‐bound HC˭CH protons of 4. Ab initio molecular modeling calculations at the Hartree‐Fock level using the 6‐31G* basis set have been performed for two key conformers of the phencyclone adduct of N‐n‐octylmaleimide, as a representative structure for these hindered adducts, to estimate geometric parameters for the adduct. A syn conformer, with the alkyl chain directed into the adduct cavity, was found to be ca. 0.23 kcal/mol lower energy than an anti conformer (in which the alkyl chain was directed away from the phenanthrenoid moiety).

Studies of Hindered Rotation and Magnetic Anisotropy by 1H, 19F and 13C NMR in Models for Drugs. I. The Diels-Alder Adduct of Phencyclone with N-2, 2, 2-Trifluoroethylmaleimide, and Precursors

Abstract To gain understanding of hindered rotations and magnetic anisotropy in drugs, compounds of much intrinsic importance, we have investigated as a model compound the Diels-Alder adduct of phenycyclone with N-2, 2, 2-trifluoroethylmaleimide for study by 1H, 19F and 13C NMR. The N-2, 2, 2-trifluoroethylmaleamic acid and maleimide precursors were examined by 1H and 19F NMR. The phencyclone adduct is shown by 1H and 13C NMR (at 300 and 75 MHz, respectively) to exhibit slow exchange limit spectra at ambient temperatures, arising from hindered rotation of the bridgehead unsubstituted phenyl groups.

1H and 13C Nuclear Magnetic Resonance Studies of the Hindered Phencyclone Adducts of Some Smaller Branched N-Alkyl Maleimides: Rigorous Aryl Proton Assignments with High-Resolution Two-Dimensional (COSY45) Spectroscopy, and Anisotropic Shielding Effects and Ab Initio Geometry Optimizations

Phencyclone, 1, a potent Diels-Alder diene, reacts with a series of N-alkylmaleimides, 2, to form hindered adducts, 3. The 300 MHz 1H and 75 MHz 13C NMR studies of these adducts at ambient temperatures have demonstrated slow rotations on the nuclear magnetic resonance (NMR) timescales for the unsubstituted bridgehead phenyl groups, and have revealed substantial magnetic anisotropic shielding effects in the 1H spectra of the N-alkyl groups of the adducts. The selected N-alkyl groups for the target compounds emphasized smaller branched alkyls, including C3 (isopropyl, a); C4 (isobutyl, b; and t-butyl, c); C5 (n-pentyl, d; isopentyl [isoamyl], e; 1-ethylpropyl, f; t-amyl, g;) and a related C8 isomer (1,1,3,3-tetramethylbutyl [“t-octyl”], h). The straight-chain n-pentyl analog was included as a reference. This present work on the branched N-alkylmaleimide adducts appreciably extends our earlier compilation on the N-n-alkylmaleimide adducts. Key methods for proton assignments included “high-resolution” 1H–1H chemical shift correlation spectroscopy, COSY45. 13C NMR of the adducts, 3, verified the expected number of aryl carbons for slow exchange limit (SEL) spectra of the bridgehead phenyl groups. The synthetic routes involved reaction of the corresponding amines, 4, with maleic anhydride to give the N-alkylmaleamic acids, 5, which underwent cyclodehydration to form the maleimides, 2. Magnetic anisotropic shielding magnitudes for alkyl group protons in the adducts were calculated relative to corresponding proton chemical shifts in the maleimides. Geometry optimizations for the above adducts (and for the N-n-butylmaleimide adduct) were performed at the Hartree-Fock level with the 6–31G* basis set. The existence of different contributing conformers for the adducts is discussed with respect to their calculated energies and implications regarding experimentally observed anisotropic shielding magnitudes.