Francisc Potmischil

Hydroacridines: part 29. 15N NMR chemical shifts of 9-substituted 1,2,3,4,5,6,7,8-octahydroacridines and their N-oxides-Taft, Swain-Lupton, and other types of linear correlations.

The 15N NMR chemical shifts of 1,2,3,4,5,6,7,8‐octahydroacridine, 12 of its 9‐substituted derivatives, and of the corresponding N‐oxides were measured and examined in terms of the 9‐substituent effects and the effects of N‐oxidation. For the 9‐substituent effects, good linear correlations were found with the Taft and Swain‐Lupton substituent constants, for both octahydroacridines and their N‐oxides. The 15N chemical shifts of both octahydroacridines and their N‐oxides also correlate well, linearly with the 13C chemical shifts of the para‐carbons in analogously substituted benzene derivatives.

Hydroacridines. Part 17—Stereospecific influence of the N+—O‐ group on 1JC,C couplings in non‐aromatic amine oxides

The 1JC,C coupling constants of N‐epimeric pairs of amine oxides derived from (4aα, 8aβ, 9aβ, 10aα)‐ and (4aα, 8aα, 9aβ, 10aα)‐tetradecahydro‐10‐methylacridine, 1‐cis‐2,6‐trimethylpiperidine and tropine were investigated and compared with those for the parent amines. For C—C bonds adjacent to the N+—O‐ group, the couplings depend on the mutual orientation of the N+—O‐ bond and the C—C bond of interest: with the N+—O‐ bond oriented syn (gauche), the couplings are essentially as large as those in the parent amines, whereas with the N+—O‐ bond oriented anti, the couplings are about 4–5 Hz smaller. The 13C NMR chemical shifts of the N‐CH3 carbons, from which the configurations of the N‐epimeric amine oxides can be derived, are also reported.

13C GIAO DFT calculation as a tool for configuration prediction of N–O group in saturated heterocyclic N‐oxides

Tropane, tropinone, pseudopelletierine and cocaine were oxidized in situ in a nuclear magnetic resonance (NMR) tube providing mixtures of exo/endo N‐oxides. Observed 13C chemical shifts were correlated with values calculated by gauge‐including atomic orbitals density functional theory (DFT) OPBE/6‐31G* method using DFT B3LYP/6‐31G* optimized geometries. The same method of 13C chemical shift calculation was applied on series of methyl‐substituted 1‐methylpiperidines and their epimeric N‐oxides described in literature. The results show that using this undemanding calculation method enables assignment of configuration of N–O group in N‐epimeric saturated heterocyclic N‐oxides. The approach enables assigning of the configuration with high degree of certainty even if NMR data of only one isomer are available. An improved method of in situ oxidation of starting amines in an NMR tube is also described. Copyright

Experimental and theoretical study of the interaction of 3-carboxy-5,6-benzocoumarin with some 1,2,3,4,5,6,7,8-octahydroacridines and the corresponding N-oxides

The interaction of 3-carboxy-5,6-benzocoumarin (BzCum) with 1,2,3,4,5,6,7,8-octahydroacridine (OHA), 9-amino-1,2,3,4,5,6,7,8-octahydroacridine (H(2)N-OHA) and the corresponding N-oxides (OHA-NO and H(2)N-OHA-NO) was studied by fluorescence (steady state, time resolved) and absorption spectroscopy. The analysis of the fluorescence data in terms of Stern-Volmer plots indicated a predominant dynamic quenching for OHA and OHA-NO, and a more complex process for H(2)N-OHA and H(2)N-OHA-NO. The dynamic process was assigned to a photoinduced electron transfer (PET) from the acridine derivatives to the excited state of BzCum. The application of the Rehm-Weller-Marcus theory leads to a good agreement with literature data and allows for the estimation of the solvent organization energy. The presence of the PET mechanism was also supported by DFT results. The absorption spectra evidence the formation of a ground state complex assigned to a hydrogen bond complex involving the carboxylic hydrogen of BzCum.

Hydroacridines: part 30. 1H and 13C NMR spectra of 9-substituted 1,2,3,4,5,6,7,8-octahydroacridines and of their N-oxides.

The 1H and 13C NMR chemical shifts of 1,2,3,4,5,6,7,8‐octahydroacridine, 12 of its 9‐substituted derivatives, and of the corresponding N‐oxides were determined, assigned, and discussed in terms of 9‐substituent effects and effects of N‐oxidation. A good linear correlation was found between the 13C chemical shifts of the aromatic carbons in octahydroacridines and those of respective carbons in the corresponding N‐oxides. Copyright

Hydroacridines XVIII [1]. Synthesis and NMR Spectroscopic Investigation of(4aα,8aβ,9aα,10aβ)-Tetradecahydroacridine and Some of its Derivatives

Summary. The reductive amination of (R*,R*)-2,2′-methylene-bis-cyclohexanone (1) with methylamine and potassium borohydride affords a mixture of (4aα,8aβ,9aα,10aβ)- and (4aα,8aα,9aβ,10aα)-tetradecahydro-10-methylacridine (2, 3) in a ratio of approximately 1.3:1 in 57% overall yield. By N-demethylation of 2, via the N-nitrosamine 4 the first synthesis of (4aα,8aβ,9aα,10aβ)-tetradecahydroacridine (5) could be performed. The relative configurations and conformations of compounds 2–5 as well as the barrier of conformational inversion of 5 (ΔG300#=55.5±0.4 kJċmol−-1) were determined by NMR spectroscopy.Zusammenfassung. Die reduktive Aminierung von (R*,R*)-2,2′-Methylen-bis-cyclohexanon (1) mit Methylamin und Kaliumborhydrid ergibt in einer Gesamtausbeute von 57% ein Gemisch aus (4aα,8aβ,9aα,10aβ)- und (4aα,8aα,9aβ,10aα)-Tetradecahydro-10-methylacridin (2, 3) im Verhältnis von ca. 1.3:1. Durch N-Demethylierung von 2 gelang über das Nitrosamin 4 die erste Synthese von (4aα,8aβ,9aα,10aβ)-Tetradecahydroacridin (5). Die relativen Konfigurationen und die Konformationen der Verbindungen 2–5 sowie die Aktivierungsenergie der Konformationsumwandlung von 5 (ΔG300#=55.5±0.4 kJċmol−1) wurden NMR-spektroskopisch bestimmt.

Hydroacridines XXI [1]. 13C NMR Spectroscopic Investigation of the Stereoselectivities of Quaternizations of N-Alkyl Derivatives of (4aα,8aβ,9aβ,10aα)- and (4aα,8aα,9aβ,10aα)-Tetradecahydroacridine

Summary. The stereoselectivities of the quaternization reactions of (4aα,8aβ,9aβ,10aα)- and (4aα,8aα,9aβ,10aα)-tetradecahydro-10-methylacridine with methyl- and ethyl iodide as well as those of (4aα,8aβ,9aβ,10aα)- and (4aα,8aα,9aβ,10aα)-10-ethyl-tetradecahydroacridine with methyl iodide were investigated using 13C NMR spectroscopy including 13C-labelling where appropriate. The methylations of both N-methyl amines occur by predominant (60% and 75%, respectively) equatorial approach, their ethylations occur sterospecifically by equatorial approach, and the methylations of the N-ethyl amines occur by highly stereoselective (> 90%) axial approach of the quaternizing reagent.

Hydroacridines XX [1]. Stereochemical Factors Influencing the 13C NMR Protonation Shiftsof Six-membered Saturated Azaheterocyclic Tertiary Amines

Summary. The influence of stereochemical factors upon 13C NMR shifts induced by N-protonation of saturated azaheterocyclic tertiary amines was investigated using (4aα,8aβ,9aβ,10aα)-tetradecahydro-10-methylacridine, (4aα,8aβ,9aβ,10aα)-10-ethyl-tetradecahydroacridine, (4aα,8aα, 9aβ,10aα)-tetradecahydro-10-methylacridine, and (4aα,8aα,9aβ,10aα)-10-ethyl-tetradecahydroacridine as model compounds. The magnitudes of the protonation shifts depend on the following stereochemical factors: (i) whether protonation occurs through an axial or an equatorial nitrogen electron lone-pair, (ii) the relative steric orientation (γ-gauche or γ-anti) of the nitrogen and carbon atoms in γ position, and (iii) the geometry of the entire carbon skeleton. Similar stereochemical dependences were found for the protonation shifts on N-methyl-trans-decahydroquinoline, analyzed on the basis of chemical shift data from literature. The observed protonation shifts can be well rationalized in terms of the LEFS (linear electric field shift) theory.Zusammenfassung. Der Einfluß stereochemischer Faktoren auf die durch N-Protonierung von sechsgliedrigen gesättigten azaheterozyklischen tertiären Aminen hervorgerufenen 13C-NMR-Verschiebungen wurde anhand von (4aα,8aβ,9aβ,10aα)-Tetradecahydro-10-methylacridin, (4aα,8aβ,9aβ,10aα)-10-Ethyl-tetradecahydroacridin, (4aα,8aα,9aβ,10aα)-Tetradecahydro-10-methylacridin und (4aα,8aα,9aβ,10aα)-10-Ethyl-tetradecahydroacridin als Modellverbindungen untersucht. Die Größe der 13C-Protonierungsshifts ist von folgenden stereochemischen Faktoren abhängig: (i) der Protonierung über ein axiales oder ein äquatoriales unbeteiligtes Elektronenpaar des Stickstoffatoms, (ii) des relativen sterischen Verhältnisses (γ-gauche oder γ-anti) zwischen dem Stickstoffatom und den in γ-Stellung befindlichen Kohlenstoffatomen und (iii) der Geometrie des gesamten Kohlenstoffgerüsts. Gleiche stereochemische Abhängigkeiten werden für die Protonierungsverschiebungen von N-Methyl-trans-decahydroquinolin gefunden, die auf der Basis von Literaturdaten untersucht wurden. Die beobachteten Protonierungsverschiebungen können mittels der Theorie der linearen elektrischen Feldverschiebung (LEFS) gut erklärt werden.

Saturated amine oxides: part 10. hydroacridines: part 32. linear ¹⁷O/¹³C and ¹³C/¹³C chemical shift correlations between saturated azaheterocyclic N-methylamine N-oxides, and the methiodides of their parent amines.

Two kinds of good linear correlations were found between the chemical shifts of saturated six‐membered azaheterocyclic N‐methylamine N‐oxides and the chemical shifts of the methiodides of their parent amines. One of the correlations occurs between the 17O chemical shift of the N+―O– oxygen in the N‐oxides and the 13C chemical shift of the N+―CH3 methyl group analogously situated in the appropriate methiodide (r = 0.9778). This correlation enables unambiguous configuration assignment of the N+―O– bond, even if the experimentally observed 17O chemical shift of only one N‐epimer is available, provided the 13C chemical shifts of both N+―CH3 groups in the methiodide are known and assigned; furthermore, it can be used also for the estimation of 17O chemical shifts of the N+―O– oxygens in N‐epimeric pairs of N‐oxides, for which observed 17O data hardly become available. The second correlation is observed between the 13C chemical shift of the N+―CH3 methyl group in the N‐oxides and the 13C chemical shift of the N+―CH3 methyl group analogously situated in the appropriate methiodide (r = 0.9785). It can be used for safe configuration assignment of the N+―CH3 group and, indirectly, also of the N+―O– bond in an amine N‐oxide, even if no 17O NMR data, and the 13C chemical shift of only one N‐epimer is available. Copyright

Hydroacridines XIX [1]. 13C NMR Spectra of Several N-Alkyl-tetradecahydroacridines and their Protonated Species: Investigation of the N-Epimeric Equilibria of the N-Alkyl Groups in the Amines and in the Salts

Summary. (4aα,8aβ,9aβ,10aα)-Tetradecahydro-10-methylacridin, (4aα,8aβ,9aβ,10aα)-10-ethyl-tetradecahydroacridin, (4aα,8aα,9aβ,10aα)-tetradecahydro-10-methylacridine, (4aα,8aα,9aβ,10aα)-10-ethyl-tetradecahydroacridin and their products of protonation with trifluoroacetic acid were studied by 13C NMR spectroscopy. The first two amines give rise to a pair of N-diastereomeric salts, whereas the latter two yield only the salts with equatorial N-alkyl groups. The N-epimeric equilibria of the N-alkyl groups (equatorial-axial) in the salts and in the amines are discussed.Zusammenfassung. (4aα,8aβ,9aβ,10aα)-Tetradecahydro-10-methylacridin, (4aα,8aβ,9aβ,10aα)-10-Ethyl-tetradecahydroacridin, (4aα,8aα,9aβ,10aα)-Tetradecahydro-10-methylacridin, (4aα,8aα, 9aβ,10aα)-10-Ethyl-tetradecahydroacridin und deren Protonierungsprodukte mit Trifluoressigsäure wurden 13C-NMR-spektroskopisch untersucht. Die beiden erstgenannten Amine ergeben jeweils ein Paar N-diastereomerer Salze, während aus den beiden letzteren nur die Salze mit äquatorialen N-Alkylgruppen entstehen. Die N-epimeren Gleichgewichte der N-Alkylgruppen (äquatorial-axial) in den Salzen und in den Aminen werden diskutiert.