Synthetic Attempts towards ‘Aromatic’ Nonafulvenes

According to their spectroscopic behavior, four classes of nonafulvenes may be distinguished, but, so far, only three classes have been identified. Type-A nonafulvenes (including parent 1a ) are typically olefinic molecules with strongly alternating bond lengths and a nonplanar nine-membered ring. Type-B nonafulvenes are characterized by four pairs of equivalent ring H-atoms and ring C-atoms. Spectra of both Type-A and Type-B nonafulvenes are not dependent on temperature and solvent polarity. However, spectra of Type-C nonafulvenes (including prototype 1d with R¹ = R² = NMe₂) are strongly influenced by temperature and solvent polarity due to an equilibrium 1?1 ^± between the nonpolar olefinic 1 and dipolar planarized 1 ^±. So far, Type-D nonafulvenes occurring exclusively in the dipolar form 1 ^± were unknown. Synthetic attempts towards nonafulvenes of Type D are described and problems encountered in nonafulvene syntheses are discussed. Several new cyclononatetraenes and four new nonafulvenes (or nonafulvalenes) 31, 1n, 3 , and 5 have been synthesized. Spectroscopic evidence shows that 11,12-bis(diethylamino)nonatriafulvalene 5 is the first Type-D nonafulvene.     

1H- and 13C-NMR Investigation of Nonafulvenes

¹H- and ¹³C-NMR spectra of a series of nonafulvenes 1 have been investigated. Most nonafulvenes are olefinic molecules with alternating bond lengths, their nine-membered ring deviating strongly from planarity. The 10-monosubstituted nonafulvenes contain 2 sterically different ring segments with a nearly planar (E)-diene system consisting of C(7), C(8), C(9), C(10), and R. Substituents R are influencing C(9) > C(7) > C(5). In symmetrically substituted nonafulvenes a fast process equilibrating olefinic conformers is operating so that pairs of ring protons and ring C-atoms are equivalent and only average substituent effects are observed for C(9) > C(7,2). ¹H- and ¹³C-NMR chemical shifts are not significantly influenced by changes of solvent or temperature. On the other hand, new ¹³C- and ¹H-NMR experiments completing previous investigations by Hafner and Tappe confirm that NMR spectra of 10,10-bis (dialkylamino)nonafulvenes are strongly dependent on solvent polarity and temperature. At ambient temperature and in unpolar solvents, nonplanar conformers are predominant, their spectral data fitting into the series of other nonafulvenes. At low temperature and/or in polar solvents, dipolar conformers are favoured which are characterised by charge separation and a planarised (but not necessarily completely planar) nine-membered ring with negative excess charge. The spectroscopic behaviour of nonafulvenes is reasonably explained by a qualitative scheme (Fig. 7) which is based on a model proposed by Boche for nonafulvenolates.     

Substituent Effects on π‐Bond Delocalization of Fulvenes and Fulvalenes. Are Fulvenes Aromatic?

The influence of exocyclic substituents on π‐delocalization of pentafulvenes 2 , heptafulvenes 3 , and nonafulvenes 4 has been investigated. Pentafulvenes 2 : Changes of bond lengths (induced by exocyclic substituents R¹ and R² of 2 ) are reflected by systematic changes of ³J(H,H) (Fig. 2) as well as of ¹J(C,C) coupling constants (Fig. 4), so that linear correlations of σ_p⁺ vs. ³J(H,H) and ¹J(C,C) coupling constants were obtained. Plots of that type are very useful for determining the extent of π‐delocalization of various pentafulvalenes 5 – 8 (Figs. 6 and 12). Charge density effects of pentafulvenes and pentafulvalenes were observed by substituent‐induced shifts of the ring C‐atoms (Fig. 5). Heptafulvenes 3 : Contrary to planar pentafulvenes, heptafulvenes did not show any linear correlations of σ_p⁺ vs. ³J(H,H)‐plots (Fig. 8) or σ_p⁺ vs. δ(¹³C)‐plots (Fig. 9), although substituents R¹, R² clearly influenced ³J(H,H)‐coupling constants as well as ¹³C chemical shifts of the ring H‐atoms and ring C‐atoms. In the NMR spectra of ‘heptafulvenes with inverse ring polarization’ (in the lower range of Fig. 8), ³J(H,H)‐coupling constants were strongly alternating and were barely influenced by exocyclic substituents. This supported a boat conformation of the corresponding heptafulvenes. In the range of Hammett σ_p⁺‐values above ?0.5 to 0, strong substituent effects started to be effective, and a nearly linear approach of ³J(H,H)‐coupling constants J(2,3)/J(4,5) and J(3,4) was observed. This meant that, as soon as heptafulvenes were planar or nearly planar, there existed similar substituent effects as for planar pentafulvenes. – A similar ‘turning point’ was observed in plots of σ_p⁺ vs. ¹³C‐chemical shifts around σ_p⁺=0 (Fig. 9): In the range of strong electron‐accepting groups (above σ_p⁺=1), there was a marked substituent‐induced high‐frequency shift which strongly decreased in the series C(7)>C(2)/C(5)>C(3)/C(4), while C(1)/C(6) was barely influenced. Nonafulvenes 4 : Most nonafulvenes are non‐planar olefins with strongly alternating vicinal H,H‐coupling constants. This has been convincingly shown by the high‐resolution ¹H‐NMR spectrum of 10‐dimethylaminononafulvene ( 4c , Fig. 10), which was not planar but contained a nearly planar (E)‐dienamine substructure of the segment C(7)?C(8)? C(9)?C(10)? NMe₂ according to the NMR data. Only with very strong π‐donors (like two dimethylamino groups in 4b ), planarization of the nine‐membered ring could be observed at low temperatures (Fig. 10). Finally, the first stable nonatriafulvalene (11,12‐bis(diethylamino)nonatriafulvalene ( 10 )) existed in the planar dipolar form in the whole temperature range and even in unpolar solvents.     

Nonapentafulvalen

Nonapentafulvalene ( 1 ) has been prepared by oxidative coupling of sodium cyclopentadienide ( 6 ) and sodium cyclononatetraenide ( 7 ) with CuCl₂ in THF, two-fold deprotonation of cyclopentadienyl-cyclononatetraene 8 to give dianion 16 , and oxidative treatment of 16 with CuCl₂ (Schemes 2 and 3). Compound 1 is a highly reactive and thermally instable molecule, since valence isomerisation 1 → 17 proceeds easily even at low temperature (the half-life of 1 is ca. 30 min at ?15° in CDCl₃). NMR investigations show that nonapentafulvalene is an olefinic molecule with strongly alternating bond lengths, its nine-membered ring deviating strongly from planarity. Comparison of the NMR data of 1 with those of a series of sterically similar pentafulvenes 18 and nonafulvenes 19 (Tables 1 and 2) demonstrates that (a) with regard to the pentafulvene unit of 1 , the cyclononatetraene ring acts as very weak electron-donating group, while (b) with regard to the nonafulvene unit of 1 , the cyclopentadiene ring acts as weak electron-accepting group. So nonapentafulvalene may be regarded as a ‘nonafulvene of inverse π-polarisation’.     

The conformation of (1R,2S,4R,5S)-2,4-dimethoxybicyclo[3.3.1]nonan-9-one and some related compounds

A mixture of stereoisomers of 2,4-dimethoxybicyclo[3.3.1]nonan-9-one was prepared, separated by column chromatography and characterized by 60 MHz ¹H NMR spectroscopy using Eu(fod)₃. A double chair conformation with axial methoxyl groups is established for (1R,2S,4R,5S)-2,4-dimethoxybicyclo[3.3.1]-nonan-9-one on the basis of the J(12), J(2,H-3 exo) and J(2,3 endo) values and the chemical shifts for H-2(4). The conformation of some related compounds is subsequently inferred.     

High resolution 1H NMR spectra of 2,2′-biquinoline

From analysis and refinement by the LAOCOON III program of the 220 MHz ¹H spectrum of 2,2′-biquinoline, recorded as a saturated solution in carbon disulphide, most derived chemical shifts and coupling constants are close to corresponding values in quinoline. However, H-3 is at 1.5 ppm lower field in 2,2′-biquinoline than in quinoline and the ortho-coupling ³J(34) in the heterocyclic ring is 0.5 Hz larger in 2,2′-biquinoline than in quinoline; fairly free rotation about the 2,2′ bond is inferred.     

3J(H,H) Coupling Constants as a Simple Criterion for π Delocalization of Pentafulvenes and Pentafulvalenes

A simple criterion for estimating the extent of π delocalization in the five-membered ring of pentafulvenes and pentafulvalenes is described. It is based on the fact that changes of bond lengths (induced by exocyclic substituents R¹-R² of 1 ) are reflected by systematic changes of ³J(H,H) values, so that linear correlations of σ vs, ³J(H,H)are obtained. Plots of that type (Fig. 1) are very useful for determining the extent of π delocalization of various pentafulvalenes 2 – 5 (Fig. 3) which show a very similar behavior to pentafulvenes. In principle, these plots could additionally be used for estimating substituent constants σ or for approximating the extent of π overlap between exocyclic substituents and the π system of pentafulvenes. Charge-density effects of pentafulvenes and pentafulvalenes are observed by substituen-induced shifts of the ring C-atoms (Fig. 4).     

31P-NMR-Daten heterocyclischer phosphine. Diastereomerenzuordnung an 1,3-Oxa-, 1,3-Aza- und 1,3-thiaphospholanen

The diastereomers of 16 1,3-oxa-, 1,3-aza- and 1,3- thiaphospholanes were assigned by means of the coupling constants ²J(P? C? H) and ³J(P? C? CH₃) and the linewidths of the ³¹P signals and ¹H chemical shifts of CH₃ groups. It is shown that the change in the ³¹P chemical shifts allows the estimation of the relative configuration in these compounds.     

Protonenresonanz-Spektroskopie ungesättigter Ringsysteme—XVI 7,7-Difluor-benzo-cyclopropen

The NMR-spectrum of 7·7-difluoro-benzo-cyclopropene ( 2 ) has been analysed to obtain chemical shifts and spin, spin-coupling constants: δ_AA′ = 7·6026, δ_BB′ = 7·4834 ppm; J_AB = 6·86, J_AA′ = 7·45, J_AB′ = 0·34 and J_BB′ = 1·89 Hz. Heteronuclear double resonance experiments have been used to establish a positive sign for ⁴J(H? F) (3.64 Hz) and a negative sign for ⁵J(H? F) (?0·33 Hz) in this molecule. The results are discussed with reference to the structure of 2 and the NMR data found for benzo-cyclopropene.     

Covalent‐Bond Formation in the Course of the Inhibition of δ‐Chymotrypsin with trans‐Decalin‐Type Organophosphates: 31P‐NMR Evidence

Earlier investigations have shown that the irreversible inhibition of δ‐chymotrypsin with the axially substituted trans‐3‐(2,4‐dinitrophenoxy)‐2,4‐dioxa‐3λ⁵‐phosphabicyclo[4.4.0]decan‐3‐one (=2‐(2,4‐dinitrophenoxy)hexahydro‐4H‐1,3,2‐benzodioxaphosphorin 2‐oxide) proceeds under inversion of the configuration at the P‐atom. Since this assignment is based on the comparison of the respective chemical shifts with model compounds, the covalent nature of the binding interaction between enzyme and inhibitor was formulated in analogy. To prove this assumption, inhibition experiments were performed with the deuterated inhibitor (±)‐trans‐3‐(2,4‐dinitrophenoxy)‐2,4‐dioxa‐3λ⁵‐phospha(1,5,5‐²H₃)bicyclo[4.4.0]decan‐3‐one ((±)‐ 6a ). ³¹P{²H}‐NMR‐Spectroscopic monitoring of the reaction of stoichiometric amounts of the enzyme with (±)‐ 6a at pH 7.8 yielded the diastereoisomeric adducts 9 (−3.88 ppm) and 9′ (−3.96 ppm). Comparing the ³¹P chemical shifts of the corresponding deuterated covalent phosphoserine model compounds 8a/8a′ (−6.70 ppm, axial) and 8b/8b′ (−4.11/−4.13 ppm, equatorial) confirmed the inversion of the configuration at the P‐atom. ¹H‐Correlated ³¹P{²H}‐NMR spectra revealed a cross peak of the Ser¹⁹⁵‐H₂ (4.45 ppm) with the P‐atom of the inhibitor at −3.88/−3.96 ppm, thus establishing the covalent nature of the Ser¹⁹⁵−O−P bond.     

The first automated 470.59 MHz 19F NMR‐controlled titration: dissociation constants and ion‐specific chemical shifts of 2‐amino‐4‐fluoro 2‐methylpent‐4‐enoic acid

2‐Amino‐4‐fluoro‐2‐methylpent‐4‐enoic acid, obtained as a 1 : 1 salt with trifluoro‐acetic acid, was characterized by ¹H and ¹⁹F high‐resolution NMR spectroscopy. High‐precision potentiometry led to the dissociation constants pK = 1.879 and pK = 9.054. The first automated 470.59 MHz ¹⁹F NMR‐controlled titration yielded the dynamic chemical shift 〈δ_F〉 as a function of pcH or τ and the ion‐specific chemical shifts: δ_F(H₂L⁺) = ?94.81 ppm, δ_F(HL) = ?94.21 ppm, δ_F(L^?) = ?92.45 ppm. The deprotonation gradients were found to be Δ₁ = ?0.60 ppm and Δ₂ = ?1.76 ppm. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthese und NMR-Spektren einiger 13C-markierter Thio- und Seleno-äther, -acetale und -orthoester

Synthesis and NMR Spectra of Some ¹³C-Labelled Thio- and Seleno-ethers, -acetals, and -orthoesters Twenty-seven different open-chain and cyclic derivatives (RX)_nCH_4-n and (RX)_nCH_3-nR′ with n = 1?3, X = S or Se, R,R′ = alkyl or aryl, 1,3,5-trithiane, and bis-(dimethylsulfonio)methane and -methanide with single or multiple ¹³C-labelling have been synthesized. The ¹³C-NMR spectra of the sulfur and selenim compounds have been measured, and the dependence of the chemical shifts (δ_c) and coupling constants [′J(C,H), ′J(Se,C)] from the substitution pattern in discussed (Fig. 1) and compared with the polyhalogeno-methanes (Fig. 2).     

1H NMR spectra of the 2-trifluoroacetyl derivatives of benzo[b]furan and benzo[b]thiophene

The ¹H NMR spectra of the 2-trifluoroacetyl derivatives of benzo[b]furan and benzo[b]thiophene were recorded at 200MHz in two solvents, chloroform and acetone. A long-range coupling constant, 5J(HF), between the fluorine nuclei of the trifluoroacetyl group and H-3, of a value higher than 1 Hz, was measured. From the comparison of the ¹H chemical shifts of, and the solvent effects on, the trifluoroacetyl compounds and those of the corresponding 2-acetyl derivatives, and on the basis of an empirical interpretation of the ⁵J(HF) coupling constant, a predominant Z conformation was tentatively assigned to these derivatives.     

1H, 13C and 77Se NMR spectra of substituted selenoanisoles

The ¹H, ¹³C and ⁷⁷Se chemical shifts and the ¹J[C(Me)H(Me)], ^1.2J(SeC) and ²J(SeH) coupling constants in 14 para- or meta-substituted selenoanisoles, R? C₆H₄? Se? CH₃, have been measured and the dependence of these parameters on the electronic effects of the substituent R is discussed. A significant (up to 6 ppm) deviation from additivity of the substituent influence on the shielding of the ¹³C ring carbons has been found.     

1H‐NMR Analysis of Intra‐ and Intermolecular H‐Bonds of Alcohols in DMSO: Chemical Shift of Hydroxy Groups and Aspects of Conformational Analysis of Selected Monosaccharides,Inositols, and Ginkgolides

The interpretation of ¹H‐NMR chemical shifts, coupling constants, and coefficients of temperature dependence (δ(OH), J(H,OH), and Δδ(OH)/ΔT values) evidences that, in (D₆)DMSO solution, the signal of an OH group involved as donor in an intramolecular H‐bond to a hydroxy or alkoxy group is shifted upfield, whereas the signal of an OH group acting as acceptor of an intramolecular H‐bond and as donor in an intermolecular H‐bond to (D₆)DMSO is shifted downfield. The relative strength of the intramolecular H‐bond depends on co‐operativity and on the acidity of OH groups. The acidity of OH groups is enhanced when they are in an antiparallel orientation to a C−O bond. A comparison of the ¹H‐NMR spectra of alcohols in CDCl₃ and (D₆)DMSO allows discrimination between weak and strong intramolecular H‐bonds. Consideration of IR spectra (CHCl₃ or CH₂Cl₂) shows that the rule according to which the downfield shift of δ(OH) for H‐bonded alcohols in CDCl₃ parallels the strength of the H‐bond is valid only for alcohols forming strong intramolecular H‐bonds. The combined analysis of J(H,OH) and δ(OH) values is illustrated by the interpretation of the spectra of the epoxyalcohols 14 and 15 (Fig. 3). H‐Bonding of hexopyranoses, hexulopyranoses, alkyl hexopyranosides, alkyl 4,6‐O‐benzylidenehexopyranosides, levoglucosans, and inositols in (D₆)DMSO was investigated. Fully solvated non‐anomeric equatorial OH groups lacking a vicinal axial OR group (R=H or alkyl, or (alkoxy)alkyl) show characteristic J(H,OH) values of 4.5 – 5.5 Hz and fully solvated non‐anomeric axial OH groups lacking an axial OR group in β‐position are characterized by J(H,OH) values of 4.2 – 4.4 Hz (Figs. 4 – 6). Non‐anomeric equatorial OH groups vicinal to an axial OR group are involved in a partial intramolecular H‐bond (J(H,OH)=5.4 – 7.4 Hz), whereas non‐anomeric equatorial OH groups vicinal to two axial OR form partial bifurcated H‐bonds (J(H,OH)=5.8 – 9.5 Hz). Non‐anomeric axial OH groups form partial intramolecular H‐bonds to a cis‐1.3‐diaxial alkoxy group (as in 29 and 41 : J(H,OH)=4.8 – 5.0 Hz). The persistence of such a H‐bond is enhanced when there is an additional H‐bond acceptor, such as the ring O‐atom ( 43 – 47 : J(H,OH)=5.6 – 7.6 Hz; 32 and 33 : 10.5 – 11.3 Hz). The (partial) intramolecular H‐bonds lead to an upfield shift (relative to the signal of a fully solvated OH in a similar surrounding) for the signal of the H‐donor. The shift may also be related to the signal of the fully solvated, equatorial HO−C(2), HO−C(3), and HO−C(4) of β‐D ‐glucopyranose ( 16 : 4.81 ppm) by using the following increments: −0.3 ppm for an axial OH group, 0.2 – 0.25 ppm for replacing a vicinal OH by an OR group, ca. 0.1 ppm for replacing another OH by an OR group, 0.2 ppm for an antiperiplanar C−O bond, −0.3 ppm if a vicinal OH group is (partially) H‐bonded to another OR group, and −0.4 to −0.6 for both OH groups of a vicinal diol moiety involved in (partial) divergent H‐bonds. Flip‐flop H‐bonds are observed between the diaxial HO−C(2) and HO−C(4) of the inositol 40 (J(H,OH)=6.4 Hz, δ(OH)=5.45 ppm) and levoglucosan ( 42 ; J(H,OH)=6.7 – 7.1 Hz, δ(OH)=4.76 – 4.83 ppm; bifurcated H‐bond); the former is completely persistent and the latter to ca. 40%. A persistent, unidirectional H‐bond C(1)−OH⋅⋅⋅O−C(10) is present in ginkgolide B and C, as evidenced by strongly different δ(OH) and Δδ(OH)/ΔT values for HO−C(1) and HO−C(10) (Fig. 9). In the absence of this H‐bond, HO−C(1) of 52 resonates 1.1 – 1.2 ppm downfield, while HO−C(10) of ginkgolide A and of 48 – 50 resonates 0.5 – 0.9 ppm upfield.     

1H NMR parameters of the N-terminal 13-residue C-peptide of ribonuclease in aqueous solution

The ¹H NMR chemical shifts and the spin-spin coupling constants of the non-exchangeable protons of the N-terminal 13-residue C-peptide of ribonuclease A, obtained by cleavage of the enzyme with cyanogen bromide, have been measured in a 5 mM solution in D₂O (pH 3.0, 24°C) at 360 MHz. The titration parameters for end groups (Lys-1 and homo-Ser-13) and side chains (Lys-1, Glu-2, Lys-7, Glu-9 and His-12) have been determined. The chemical shifts, their temperature coefficients and the vicinal coupling constants, ³J(HNCH-α), for the exchangeable NH protons have been measured in a 5 mM solution in D₂O/H₂O (1:9 v/v) at pH 3.0. An assignment of observed signals to individual residue protons based on characteristic shifts, standard double resonance experiments, spectral simulations and titration shifts is proposed. All experimental evidence indicates that under the conditions studied the C-peptide is in a random coil form.     

1H NMR spectra part 31: 1H chemical shifts of amides in DMSO solvent

The ¹H chemical shifts of 48 amides in DMSO solvent are assigned and presented. The solvent shifts Δδ (DMSO‐CDCl₃) are large (1–2 ppm) for the NH protons but smaller and negative (?0.1 to ?0.2 ppm) for close range protons. A selection of the observed solvent shifts is compared with calculated shifts from the present model and from GIAO calculations. Those for the NH protons agree with both calculations, but other solvent shifts such as Δδ(CHO) are not well reproduced by the GIAO calculations. The ¹H chemical shifts of the amides in DMSO were analysed using a functional approach for near ( ≤ 3 bonds removed) protons and the electric field, magnetic anisotropy and steric effect of the amide group for more distant protons. The chemical shifts of the NH protons of acetanilide and benzamide vary linearly with the π density on the αN and βC atoms, respectively. The C=O anisotropy and steric effect are in general little changed from the values in CDCl₃. The effects of substituents F, Cl, Me on the NH proton shifts are reproduced. The electric field coefficient for the protons in DMSO is 90% of that in CDCl₃. There is no steric effect of the C=O oxygen on the NH proton in an NH…O=C hydrogen bond. The observed deshielding is due to the electric field effect. The calculated chemical shifts agree well with the observed shifts (RMS error of 0.106 ppm for the data set of 257 entries). Copyright © 2014 John Wiley & Sons, Ltd.     

Deuterium-isotopieeffekte auf die 13C-chemischen verschiebungen und kohlenstoff-deuterium kopplungskonstanten in deuterierten verbindungen

The isotope effects on the ¹³C NMR chemical shifts and coupling constants (¹³C¹H and ¹³C¹H) have been determined by pulse Fourier transform ¹³C NMR investigation at 22·63 MHz for more than 30 common deuterated and protonated solvents. The observed isotope effects correlate with hybridization and electron withdrawal at the coupling carbon within the series of comparable compounds. In agreement with MO-theoretical calculations a linear correlation between the J_CD values of CD_x groups and the J_CH values of the corresponding CH_x groups was found. The experimentally determined J_CD values show an average deviation from the calculated line J_CD = (γ_D/γ_H)J_CH = 0·154 ×J_CH on the order of± 1 Hz.     

17O NMR study of isomeric 2-R-2-oxo-1,3,2-dioxaphosphorinanes

Oxygen-17 NMR spectra were obtained from the four pairs of isomeric 2-R-2-oxo-1,3,2-dioxaphosphorinanes, where R=OMe (2), NMe₂ (3), H (4) or Me (5). The isomerism has been previously shown to be configurational at phosphorus, with one isomer of each pair having an equatorial phosphoryl oxygen (a isomer), and the other an axial orientation for phosphoryl oxygen (b isomer). Only data for the phosphoryl oxygen are reported. Substitution of OMe or NMe₂ for H or Me produced upfield shifts of 27.9-41.8 ppm. In all cases, the chemical shifts of the a isomers were upfield of the b analogs, with differences of 7.9, 18.0, 20.3 and 8.6 ppm for 2—5, respectively. The absolute values of ¹J(³¹P¹⁷O) were 5–9 Hz larger for the a isomers.     

Complete assignments of the 1H and 13C NMR spectra of 15 limonoids

Unambiguous and complete assignments of ¹H and ¹³C NMR chemical shifts for 15 limonoids, eight of them found in natural sources and seven other synthetic derivatives, are presented. The assignments are based on 2D shift‐correlated [¹H,¹H‐COSY, ¹H,¹³C‐gHSQC‐¹J(C,H), ¹H,¹³C‐gHMBC‐ⁿJ(C,H) (n = 2 and 3)] and NOE experiments. Copyright © 2003 John Wiley & Sons, Ltd.