Quantification and Visualization of the Anisotropy Effect in NMR Spectroscopy by Through-Space NMR Shieldings

CHAPTER THREE

Quantification and Visualization of the Anisotropy Effect in NMR Spectroscopy by Through-Space NMR Shieldings Erich Kleinpeter Chemisches Institut der Universita¨t Potsdam, Karl-Liebknecht-Str. 24-25, D-14476, Potsdam (Golm), Germany

Contents 1. Introduction 2. Computation and Visualization of the Anisotropy Effect by TSNMRS 3. Anisotropy Effects of CdC, C]C, C^C Bonds, Benzene and the Corresponding Heteroanalogues 4. Anisotropy Effects of Carbonyl, Heteroanalogues and of the Nitro Group 5. Anisotropy Effects as the Molecular Response Property of Spatial NICS (TSNMRS) 5.1 The Exo/Endo Configuration and Syn/Anti Conformation of Dicyclopentadiene (DCPD) Derivatives 5.2 The Frozen Conformational Equilibria of 9-Arylfluorenes 5.3 Antiaromaticity Proved by the Anisotropy Effect in 1H NMR Spectra the 9-Dioxaanthracene Dianion 102 6. Application of TSNMRS in Structural Chemistry 6.1 Stereochemical Applications 6.2 Position in the Binding Pocket of Enzymes and Other Host Compounds 7. Application of TSNMRS in Quantification and Characterization of (Anti)Aromaticity, Pseudo-, Spherical, Captodative, Homo- and Chelatoaromaticity 7.1 General 7.2 Aromaticity of Fulvenes, Fulvalenes, Dehydroannulenes and Fullerenes 7.3 Homo- and Antiaromaticity 7.4 Aromatic Versus Quinonoid Structures 7.5 Chelatoaromaticity and Miscellaneous Aromaticity 8. Résumé References

116 118 121 128 130 130 132 135 136 136 143 145 145 149 153 155 157 160 161

Abstract The anisotropy effect of functional groups (respectively the ring-current effect of aryl moieties) in 1H NMR spectra has been computed as spatial NICS (through-space NMR chemical shieldings) and visualized by iso-chemical-shielding surfaces of various Annual Reports on NMR Spectroscopy, Volume 82 ISSN 0066-4103 http://dx.doi.org/10.1016/B978-0-12-800184-4.00003-5

#

2014 Elsevier Ltd All rights reserved.

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size and low(high)field direction. Hereby, the anisotropy/ring-current effect, which proves to be the molecular response property of spatial NICS, can be quantified and can be readily employed for assignment purposes in proton NMR spectroscopy— characteristic examples of stereochemistry and position assignments (the latter in supramolecular structures) will be given. In addition, anisotropy/ring-current effects in 1H NMR spectra can be quantitatively separated from the second dominant structural effect in proton NMR spectra, the steric compression effect, pointing into the reverse direction, and the ring-current effect, by far the strongest anisotropy effect, can be impressively employed to visualize and quantify (anti)aromaticity and to clear up standing physical-organic phenomena as are pseudo-, spherical, captodative, homo- and chelatoaromaticity, to characterize the p-electronic structure of, for example, fulvenes, fulvalenes, annulenes or fullerenes and to differentiate aromatic and quinonoid structures. Keywords: Through-space NMR shielding (TSNMRS), Anisotropy effect, Stereochemistry, Ring-current effect, Aromatic or quinonoid, Aromaticity, Chelatoaromaticity, Binding pocket position, Supramolecular compounds, Diastereomers assignment

1. INTRODUCTION The diamagnetic anisotropy Dw of any functional group with axial symmetry is defined as difference between the susceptibilities parallel and perpendicular to the axis (cf. Eq. 3.1). The corresponding magnetic contribution to the chemical shift of proximate protons can be quantitatively estimated by employing the point dipole approximation via the McConnell Eqs. (3.2A and 3.2B): Dw ¼ wk  w?

(3.1)


Ds ¼ 1=3 Dw 1  3cos 2 y R3

(3.2A)

ðDs ¼ DdÞ

(3.2B)

which is actually a function of both the distance (R) of any proximate proton Hi to the point dipole centre C and the angle y between the line HiC and the direction of the induced magnetic moment. This anisotropic contribution to the chemical shift of Hi [d(Hi)] gets zero at the magic angle of y ¼ 54.7 ; otherwise shielding or deshielding contributions (cf. Eq. 3.2B) to d(Hi) in the vicinity of the functional group will be observed (the anisotropy effect) and are well-nigh dependent on the geometric position of Hi in the molecule studied with respect to the magnetically anisotropic functional group. For this reason, the anisotropy effect proves to have significant

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assignment capacity in proton NMR spectroscopy; for heavier nuclei, it is of only minor impact because their d ranges are usually larger and the anisotropy effect remains the same. In textbooks, anisotropy effects of functional groups are visualized by anisotropy cones (cf. Fig. 3.1 for C]O and C^C) and can be employed in many structural 1H NMR spectroscopic studies to assign the structure but especially the conformation and configuration of the molecules studied and often in cases where other assignment tools failed [2]. A particular anisotropy effect proves to be the ring-current effect of arene moieties (cf. Fig. 3.1). Due to 4n + 2 (aromatic) or 4n cyclically conjugated p electrons (antiaromatic compounds) the ring-current effect is by far the strongest anisotropy effect and, for this reason, of exceptional assignment potency. The diatropic ring current, induced in the applied magnetic field, develops an especially strong second magnetic field (cf. Fig. 3.1) which leads to shielding/deshielding regions around the aromatic moiety; aromatic protons and protons in-plane with the arene ring system are deshielded (at the same time the unequivocal assignment criterion to differ olefinic from aromatic protons in 1H NMR spectroscopy), nuclei above/below the aromatic moiety are shielded. By the same simple depiction, the inversed paratropic ring-current effect (shielding in-plane and deshielding above/below the plane) of antiaromatic ring moieties can be explained and employed accordingly. The ring-current effect can be visualized by an anisotropy cone similar to those of the multiple bonds given in Fig. 3.1 (vide infra). The quantitative computation of the ring-current effect has been reviewed by Paolo Lazzeretti [3]. The low-field shift of aromatic protons but also the even abnormal chemical shifts of in-plane protons in the centre of enlarged aromatic ring systems or of protons bridging aromatic ring

Figure 3.1 Anisotropy cones [1], classically used for signal assignment.

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moieties could be employed to quantitatively notify aromaticity of the ring systems studied. Paul von Rague´ Schleyer et al. [4] computed the absolute magnetic shieldings (nucleus-independent chemical shifts—NICS) at the centre or ˚ ) of p-conjugated ring systems with the GAUSSIAN above the centre (1 A 94 program [5] and used the corresponding NICS and NICS(1) values to quantify aromaticity (positive NICS) and antiaromaticity (negative NICS); the most fundamentally grounded aromaticity index based on NICS proved later to be NICS(0)pzz with the easily computable NICS(1)zz as a useful alternative [6]. Thus, a simple and efficient criterion was found to measure quantitatively the diamagnetic/paramagnetic effects of ring currents associated with (anti)aromaticity. Based on Paul von Rague´ Schleyer´s NICS criterion [4], we computed the absolute magnetic shieldings in the proximity of relevant functional groups and aromatic ring systems [1] [spatial NICS—through-space NMR shieldings (TSNMRS)] and employed the TSNMRS values (i) to classify, quantify and visualize the corresponding anisotropy effects, and (ii) to apply the definite TSNMRS values to assign stereoisomerism but also to study quantitatively physical-organic items as are aromatic versus quinonoid structures or, for example, chelatoaromaticity but also other physicalorganic problem statements. This is the topic of this chapter.

2. COMPUTATION AND VISUALIZATION OF THE ANISOTROPY EFFECT BY TSNMRS The quantum chemical calculations were carried out using the GAUSSIAN 94 program package [5] or upgrades. All compounds were fully optimized using sufficient levels of theory [7]. The absolute magnetic shieldings in the proximity of anisotropic functional groups (anisotropy effect) and arene moieties (ring-current effect) were computed on basis of the NICS index [4]. Spatial NICS values (TSNMRS) in ppm [4,6] were computed on the basis of the ab initio MO geometries using the GIAO method [8,9] at the HF/6-31G* theory level [10]. The molecule is posi˚ to tioned in the centre of a grid of “ghost” atoms ranging from 10 A ˚ ˚ +10 A in the three dimensions with a step width of 0.5 A resulting in a cube of 68,921 lattice points (NICS values; cf. Fig. 3.2). The symmetry of the molecules was taken into account. Both coordinates and absolute shielding values (TSNMRS) of the “ghost” atoms (lattice points) around the molecules were transferred into SYBYL [11] contour files

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Figure 3.2 Lattice points of a grid of “ghost” atoms ranging from 10 Å to +10 Å (left) and in-plane ICSS of 0.1 ppm low-field shift (right) of the thiocarbonyl group.

and visualized by iso-chemical-shielding surfaces (ICSS) of different size and direction, thereby providing a 3D map of spatial extension, sign and scope of the anisotropy/ring-current effect of the moiety studied at each point of the space (cf. Fig. 3.2, right) [1]. The TSNMRSs obtained by our approach were in excellent accordance with data obtained by application of the classical model of Bovey and Johnson [12] and Haigh and Mallion [13] if the distances were more than ˚ from the anisotropic functional group. This provided us with a 2.5–3 A new method to quantitatively ab initio MO calculate both the through-space effects of certain bonds and functional groups and of aromatic moieties as well on proximal nuclei. The ring-current effect of benzene and the anisotropy effects of ethylene and acetylene, thus obtained [1], as visualized by ICSS of different size and direction, are given in Fig. 3.3. To represent spatial NICS in the space, further techniques or approaches have been employed. Sebastiani and Parker [14] presented NICS maps which consist of 2D slices of the 3D space of NICS values; NICS were made visible by different isosurfaces. Rodrı´guez-Otero et al. [15] based on our approach [1], studied the aromaticity of fulvalenes using a 3D representation of the NICS within the electron density surface of 0.05 au. And Elguero et al. [16] studied the aromaticity of a series of carbocycles and heterocycles by the 3D isosurfaces of the electron density. A similar approach to estimate TSNMRS around the CdC single bond has been published by Alkorta and Elguero [17]. They ab initio computed the

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Figure 3.3 Computed ring-current effect of benzene (left) and the anisotropy effects of ethylene (middle) and acetylene (right) visualized by ICSS of different size and direction. Reproduced by permission of The Royal Society of Chemistry [1]. H3 C CH3

H CH3 1

H H

2

H

H

H

H

3

Scheme 3.1 Structure of supramolecules ethane...methane 1, H−H...benzene 2 and CH3−H...benzene 3, respectively.

supramolecule ethanemethane 1 (cf. Scheme 3.1) and used the distance dependence of the proximate methane proton to probe the anisotropy effect of the CdC single bond in ethane. At the same time, the identical approach was employed by Martin et al. [18]. They computed various supramolecules employing one hydrogen in H2 or methane (models 2 and 3 in Scheme 3.1) as sensors; the shielding of the corresponding Hi was computed by the GIAO method and evaluated as the TSNMRS of a number of functional groups and arene moieties. In both cases, shieldings of similar size and direction, comparable with the results of our model [1], were obtained.

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3. ANISOTROPY EFFECTS OF CdC, C]C, C^C BONDS, BENZENE AND THE CORRESPONDING HETEROANALOGUES The computed anisotropy effect of the CdC single bond in ethane, employing our approach [1], is visualized in Fig. 3.4 and proves to be ˚ from the censhielding in the bond direction [ICSS(0.1 ppm) at ca. 4.3 A tre of this bond] [19]. Around the CdC single bond are deshielding areas [ICSS(+0.1 ppm)], however, not a completed deshielding belt. This result reverses the classical picture but is in line with the computations of Alkorta and Elguero [17]. The anisotropy effect of the single bond does not change much if a heteroatom instead of one carbon atom is introduced; the anisotropic effects of CdO, CdN and CdS single bonds were computed and visualized [19]. As obtained for ethane, in the direction of the single bonds again high-field shifts but now of different intensity [ICSS(0.1 ppm) were ˚ ] were obtained [17]; also the deshielding regions ICSS extended to 5–6 A (+0.1 ppm) are enlarged, in case of the CdO bond, they are closed to a ˚ extension [19]. deshielding belt of ca. 4 A As the reason for the high-field position of the axial protons in cyclohexane with respect to the equatorial ones, the anisotropy effect of the CdC single bonds was assigned previously; however, employing our model [1], both the axial and the equatorial protons are found in the shielding region of the CdC anisotropy effect [19]. The chemical shift difference Ddaxial–equatorial (per CdC single bond of 0.24 ppm) proved to be in excellent agreement with the experiment; actually, the equatorial protons are

Figure 3.4 Computed anisotropy effect of ethane visualized by ICSS of different size and direction. Reproduced by permission of The Royal Society of Chemistry [19].

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more high-field shifted by the CdC single bond anisotropy effect than the axial protons. Thus, the anisotropy effect of the CdC single bond is not the reason for Ddaxial–equatorial and the high-field position of the axial protons (instead hyperconjugation seems to dominate this experimental result) [19]. The anisotropy effect of the C]C double bond (cf. Fig. 3.3) is rather ˚ from the centre, only the ICSS of +0.1 ppm dessmall as well: At ca. 4 A hielding in-plane with the double bond and 0.1 ppm shielding above/ below to this plane was calculated [1]. Thus, the anisotropy effect of the C]C double bond is small only; assignment possibilities of little account only can be expected. Though, conjugation of C]C double bonds strengthens the anisotropy effect [1]. But the anisotropy effect of the C]C double bond has been computed and quantitatively employed to detect the influence on the proton NMR spectra of norbornene, substituted norbornenes and a number of tetracyclic norbornene analogues [20]. These nonpolar compounds were studied because electric field and solvent effects on d(Hi) values were absent and the interplay of the remaining anisotropy effect of the C]C double bond and the “steric compression” effect [deshielding Hi and shielding Ci in highly congested (RHiCi) hydrocarbons] on d(Hi) values can be investigated. First, the anisotropy effect of C]C double bond(s) was visualized by ICSS and quantified with respect to proximate protons in norbornene (cf. Fig. 3.5); second, the anisotropy effects on the various d(Hi) values (cf. Fig. 3.6) were compared with experimental chemical shifts Dd(olefin–hydrocarbon) and the differences were analyzed in terms of distortions in the molecular geometry via steric compression as reflected by bond lengths and bond angles. Hereby, differences in steric strain between

Figure 3.5 Quantification of the anisotropy effect of the 1,6-C]C double bond on the 1 H chemical shifts of norbornene protons. Copyright 2008 American Chemical Society [20].

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123

Figure 3.6 The C]C double bond anisotropy effect in exo-4-Me-norbornene and in endo-4-Me-norbornene as visualized by ICSS of different deshielding and shielding. Copyright 2008 American Chemical Society [20].

olefins and hydrocarbons could be readily evaluated [20]: Even the part(moiety) of the molecules of strongest steric strain could be clearly identified applying this approach [20]. The classical anisotropy cone of the C^C triple bond displays deshielding around and shielding along the bond axis (cf. Fig. 3.3) [1,21]. ˚ , the deshielding ranges While the shielding effect reaches up to 4 A prove to be small only and punctually proximate to the principal molecular axis. This computational result is, on the one hand, in line with the classical model which can be found in all text books of NMR spectroscopy, but on the other hand, the deshielding zones around the triple bond are small and limited to certain dots of +0.1 ppm deshielding only. In text books of NMR spectroscopy, the anisotropy effect of the C^C triple bond is usually specified by chemical shift differences of H-4 in phenanthrene and in 11-ethynylphenanthrene (Dd ¼ 1.71 ppm) [21]. But the weak and spatially limited computed anisotropic effect of +0.1 ppm only actually contradicts the latter assignment; obviously steric compression and not the anisotropy effect of the C^C triple bond is the reason for the low-field shift of the phenanthrene proton in 11-ethynylphenanthrene (cf. Fig. 3.7) [21]. The latter conclusion is proved by the distorted geometry of 11-ethynylphenanthrene, the misshappened orbitals of the triple bond and the strong high-field position of C-4 with respect to d(C-4) in phenanthrene, and could be quantified by a parallel NCS-NBO study [21]. This result illustrates how a long-held belief, though intuitively sound, can be erroneous.

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Calc. Dd(H) = +0.06 ppm

Figure 3.7 Anisotropy effect of the C^C triple bond [shielding (ICSS ¼ 0.1 ppm) in line with principal C^C triple bond axis and deshielding (ICSS ¼ + 0.1 ppm) around the bond axis. Copyright 2004 American Chemical Society [21]. N

Ph 5

NMe2 S

H O

O

Me

Me 4

Scheme 3.2 Structure of Meldrum's acid derivative 4 [22].

A similar large difference was obtained between the anisotropy effect of the carbonyl group on the ring proton H-5 (cf. Scheme 3.2) in the Medrum´s acid derivative 4, computed by our approach (0.3 ppm high field), and the experiment (+1.83 ppm low field) [22]. This is another spectacular example of overestimating anisotropy effects but heavily underestimating steric effects in 1H NMR spectroscopy. Also the triple bond anisotropy effect is strengthened if heteroatoms are introduced into it (cf. Fig. 3.8 (left)); in case of the cyano group dC^N, ˚ and the deshielding shielding in line with the bond axis is extended to 4–5 A zone develops into a deshielding belt around the C^N triple bond [1]. On the other hand, the anisotropy effect of the cyano group was deemed to be too small to differentiate the E/Z isomers of a large variety of push-pull alkenes [23]; chemical shift differences between the isomers are dominated by the electronic donor/acceptor substituent effects at the central partial

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125

Figure 3.8 Computed anisotropy effect of HdC^N (and for comparison purposes, of acetylene, left) visualized by ICSS of different size and direction. Reproduced by permission of The Royal Society of Chemistry [1].

C]C double bond. Thus, it was left to the computation of the 13C chemical shifts to render a distinction between the E/Z isomers [23]. In these strongly polarized molecules, also the anisotropy effect of the thiocarbonyl group proved only minor and could not account for the observed chemical shift differences [23]. In another manuscript [24], the computation, visualization by ICSS and, finally, quantification of the anisotropy effects of dC^N and C]O functional groups (but also of dCH3 and dCF3) as ortho substituents in a number of tolanes (cf. Fig. 3.9) could be convincingly employed to prove that they are only negligible and do not dominate the 13C chemical shift difference of the central dC^Cd triple bond carbon atoms (DdC^C). Quite in contrary, the latter parameter DdC^C proved to be an excellent parameter to quantify the push-pull effect in tolanes [24]. The ring-current effect of benzene is already pictured in Fig. 3.3 (together with the anisotropy effects of both the C]C and C^C triple bonds). This

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Figure 3.9 Preferred conformer of o-C^N tolane and computed anisotropy effects of the o-CN substituent on the carbons of the triple bond. Copyright 2006 American Chemical Society [24].

common and comparing presentation imposingly expresses the different scales and the outstanding dimension and importance of this anisotropy effect for assignment proposes in 1H NMR spectroscopy [1]. Deshielding ˚ in-plane and shielding ICSS ¼ 0.1 ppm ICSS ¼ +0.1 ppm at already 7 A ˚ above/below the plane of the ring system were computed. at 9 A The ring-current effect of aryl moieties, because of the extraordinary size, has been often employed for proton assignment in 1H NMR spectroscopy (vide infra); see, for example, the rather complicated and challenging assignment of the proton NMR spectra of phenyl-substituted porphyrins [25], where it did a good and useful job. In annelated aromatic ring systems, the global ring-current effect is increased along with the number of fused rings (benzene < naphthaline < anthacene < pentacene, etc.) based on intramolecular interactions of the various ring currents, confirmed by the Lazzeretti study [3], and the ring-current effects of the 5-membered heteroaromatic ring systems are strengthened with the donor power of the heteroatom (furan < pyrrol < thiophene) [1], demonstrating hereby the similarity of benzene and thiophene not only in this but also other physical and physical-organic properties [1]. Antiaromatic ring systems with [4n]p-electrons (like cyclobutadiene in Fig. 3.10) exhibit the reversed (paratropic) ring-current effect of decreased intensity (deshielding regions above/below and shielding regions in-plane with the ring system) and ready for assignment purposes in 1H NMR spectroscopy (vide infra) [1].

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127

Figure 3.10 Ring-current effects of benzene and of the antiaromatic cyclobutadiene (left). Reproduced by permission of The Royal Society of Chemistry [1].

In a parallel study [26], it was found out that the conventional interpretation of the anisotropy effects of aromatic/antiaromatic rings (and also of the C]C double bonds) in terms of the p-electron shielding/deshielding effects is correct assuming only a perpendicular external magnetic field, but should not be applied to the interpretation of the chemical shift values obtained in an NMR spectroscopy experiment, which implies the external field in all space directions, that is, isotropic (average) chemical shifts. In fact, it could be shown that p-shielding/deshielding contributions only agree with the conventional explanations for the antiaromatic cyclobutadiene and it can be said that they arise from the paratropic ring current, mainly coming from the frontier p orbital. The total p contribution overcomes the opposing s contribution. On the contrary, for both aromatic ring systems and C]C double bonds, the p-electron effects are quite opposite to those predicted by the

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anisotropy cone depictions, that is, p electrons shield the in-plane directions and, depending on the number of electrons and the degree of aromaticity, can deshield the out-of-plane direction. The familiar in-plane deshielding/ out-of-plane shielding effect for these functional groups should be attributed to s contributions. The important difference in p contributions for the antiaromatic system on one side and the aromatic systems and the C]C double bond on the other side is that in the former the p contribution dominates, whilst for the latter at most points in space, the s effect dominates [26].

4. ANISOTROPY EFFECTS OF CARBONYL, HETEROANALOGUES AND OF THE NITRO GROUP As in case of the hetero CdX single bonds, the C]X double bonds (imine, carbonyl and thiocarbonyl moieties) are significantly strengthened if one of the carbon atoms is replaced by the heteroatom (cf. Fig. 3.11). The shielding/deshielding regions of the anisotropy cones at ICSS ¼ 0.1 ppm ˚ for the are extended to 5 A˚ for the carbonyl and even more than 6 A thiocarbonyl group [1].

Figure 3.11 Calculated anisotropy effect of double bonds: (A) ethylene, (B) formaldehyde and (C) thioformaldehyde; presentation by ICSS of different size and direction; view from perpendicular to the molecules (above) and in the plane of the molecules (below). Reproduced by permission of The Royal Society of Chemistry [1].

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129

The anisotropy effect of the carbonyl group was successfully employed to fully understand the proton NMR spectrum of camphor [27] and was studied, in case of a number of trinuclear metal carbonyl compounds, dependent on transition-metal influences [28]. This effect on the carbonyl anisotropy cone was found to change subject to the different metals and could be associated with p-back donation from the metal to the carbonyls. Actually, the anisotropy effect of the carbonyl moieties in the trinuclear metal-carbonyl compounds of group 8 is able to reflect the distinct arrangements of the carbonyl groups in these organometallic compounds [28]. The anisotropy effects of thiocarbonyl [1] and selenocarbonyl groups [29] are rather similar and not too far reaching (ICSS ¼ 0.1 ppm at ca. ˚ ; cf. Fig. 3.11), and, therefore, not very useful for stereochemical appli5A cations when comparing thiocarbonyl and selenocarbonyl compounds. This is in strong contrast to studies where the anisotropy effect of carbonyl was compared with thione analogues [1,30]. In the latter case, the difference could be readily employed for assignments in 1H NMR spectroscopy [31,32]. Differences in C]S and C]Se anisotropy effects are only marginal, consequences for correct assignments in 1H NMR spectroscopy are obvious [33]. The anisotropy effect of the nitrate anion, finally, is visualized in Fig. 3.12 [34]. Above and below the plane of the planar nitrate anion proves ˚ from the central to be the high-field shift region [ICSS(0.1 ppm), at 5.1 A nitrogen of the molecule]; the plane of the nitrate anion reveals the deshielding region of the anisotropy effect, however, only along the OdNdO

Figure 3.12 Visualization of the anisotropy effect (TSNMRS) of the nitrate anion by ICSS of different size and direction. Copyright 2008 Elsevier [34].

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˚ from nitrogen centre]; the effect bisectors [ICSS(+0.1 ppm) at 5.0 A towards the oxygens along the NdO bonds is negligible only. The ICSS of 0.1 ppm (cf. Fig. 3.12) have been calculated and were employed to visualize the anisotropy effect of the nitrate anion; however, the complete grid of ˚ in all three dimensions is availghost atoms ranging from –10.0 to +10.0 A able and can be employed to determine quantitatively this effect in complexes and supramolecules including nitrate anions [34]. This anisotropy effect (together with the ring-current effect of the 4-methylpyridyl aromatic moiety) was employed to manifest the different chemical shifts of a-bispyridyl protons in a number of palladium complexes and of the amino protons of the ethylene analogues. The calculated chemical shift sequences (due to the anisotropy effects of nitrate and 4-methylpyridyl, respectively) of both classes of protons are in agreement with experimental differences; however, in addition to the anisotropy effects, intramolecular hydrogen bonding NdHOdN, as the dominating effect, had been taken into account. Due to the theoretical quantification of the anisotropy effects with our approach [1], both effects on the chemical shifts of the amino protons could be separated [34].

5. ANISOTROPY EFFECTS AS THE MOLECULAR RESPONSE PROPERTY OF SPATIAL NICS (TSNMRS) In spite of the numberless successful application of the various NICS indices to quantify aromaticity, it should be pointed out that there are still serious reservations with regard to qualifying molecular response properties by unobservable quantities such as NICS [3]. However, we found definitive examples of the application of spatial NICS (TSNMRS) to unequivocally assign diastereoisomers and also preferred conformers even if a basic dynamic process is still too fast on the NMR timescale (vide infra). This led us to the conclusion that the anisotropy effects of functional groups on the signals in 1 H NMR spectra are the molecular response property of spatial NICS. Three examples to prove will be given.

5.1. The Exo/Endo Configuration and Syn/Anti Conformation of Dicyclopentadiene (DCPD) Derivatives The interconversion of the 5-membered ring moiety (syn/anti) in exo/endo diastereomers of DCPD derivatives could not be frozen even at 103 K; parallel computations provided ring inversion barriers of 3–5 kcal/mol and strongly one-sided conformational equilibria for the anti conformer of exo

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Anisotropy Effect in NMR Spectroscopy

N

N

N N Exo/anti

Exo/syn N

N N

N

Endo/anti

Endo/syn

Scheme 3.3 Preferred conformers of exo/endo isomer of DCPD derivative.

Table 3.1 Experimental 1H chemical shift differences opposed to the ring-current effect of the quinoxalyl moiety in the exo/endo isomers of the quinoxalyl-DCPD derivative Proton Ddexpa Exo/antib Exo/synb Endo/antib DDdc Endo/synb DDdd

H-4,5

0.84

0.16

0.21

0.34

0.50

- 0.34

0.55

0.55 H-1,3

-0.55

0.28

0.26

0.92

1.20

0.24

0.14

0.08

0.08

0.22

0.13

-0.80

0.1

0.01

0.14

0.24

0.50

0.25

0.12

0.72

0.97 0.84

0.60 0.51

0.15 -1.93

0.27 0.21

0.16 H-2

0.52 0.50

1.18 -0.11

0.50

2.62

2.87 2.74

a

Experimental chemical shift differences of the corresponding protons between exo/endo isomers. Ring-current effect (cf. Fig. 3.13) of the quinoxalyl moiety in the four conformers (cf. Scheme 3.3) of exo/endo isomers. c Chemical shift differences of the ring current effect of the quinoxalyl moiety between the conformers endo/anti and exo/anti and exo/syn, respectively. d Chemical shift differences of the ring current effect of the quinoxalyl moiety between the conformers endo/syn and exo/anti and exo/syn, respectively. b

and surprisingly the syn conformer of the endo isomer [35] (cf. Scheme 3.3) in line with the experiment. The spatial NICS (TSNMRS) of the attached quinoxalyl moiety (cf. Table 3.1) in the four stereoisomers (cf. Fig. 3.13) proved the conformations to be the preferred ones by agreement with the experimental chemical shift differences; the result was

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Endo/anti

Exo/anti

Endo/syn

Exo/syn

Figure 3.13 Structures of syn/anti conformers of exo/endo isomers together with the ring-current effect of the quinoxalyl moiety visualized as ICSS of various size and direction. Reproduced by permission of The Royal Society of Chemistry [35].

impressively corroborated by employing computed H,H coupling constants for the same purpose [35]. In the corresponding diketones [35], although remarkable carbonyl anisotropy effects on the various protons in the 1H NMR spectra could be expected, it is not possible to compare the latter values (in competition with steric compression) with the experimental chemical shift differences in the light of syn/anti conformation of the attached DCPD 5-membered ring. The outstanding position of phenyl (aryl) in this sense is in turn corroborated.

5.2. The Frozen Conformational Equilibria of 9-Arylfluorenes Both the structures of the preferred conformers of various 9-methylsubstituted arylfluorenes 5–9 (Scheme 3.4) and the spatial magnetic properties (TSNMRS) of the fluorene moiety (cf. Fig. 3.14) have been ab initio MO calculated [36]. In the ground-state conformers, the planes of the aryl and

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R2 R4

HC R3

R2⬘

R2

R2⬘

5

CH3

H

H

H

6 7

CH3 CH3

CH3 CH3

H H

H CH3

8

H

H

CH3

H

9

H

H

H

CH3

No.

R3

R4

Scheme 3.4 Structures of methyl-substituted 9-arylfluorenes 5–9 [37].

Figure 3.14 Ground state conformer of 9-arylfluorene 7 (right) and visualization of the magnetic properties (TSNMRS, left) of the fluorene moiety as ICSS of different direction and size. Copyright 2011 Elsevier [36].

fluorene moieties are perpendicular to each other. The experimental 1H chemical shifts of the methyl protons located at the ortho, meta and para positions on the aryl moiety [37] in 5–9 were examined with respect to the spatial magnetic properties (TSNMRS) of the fluorene moiety (cf. Table 3.2) and were found to be controlled by the ring-current effect of the fluorene moiety and by the steric hindrance present in the molecules. Both contributions could be quantified by the TSNMRS and geometry variations in 5–9 (cf. Table 3.3) [36]. In a separate manuscript [38], it was possible to quantitatively separate steric compression and the anisotropic/ring-current effect. For the series of 1,3-oxazino[4,3-a]isoquinolines, the minimum-energy isomers/conformers were determined by NMR spectroscopy and theoretical calculations. On the basis of these structures, the ring-current effects of the

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Table 3.2 Experimental 1H chemical shifts [37] of the methyl protons and proton H-9 at the sp3-hybridized carbon atom connecting the aryl and fluorene moieties compared with TSNMRS of the fluorene anisotropic effect in 9-arylfluorenes 5–9 Anisotropy effect of the fluorene d(1H) (ppm) moiety No. Ortho Ortho0 Meta/para H-9

Ddexp (ppm)

Ddcalc Ortho Ortho0 Meta/para (ppm)

5

1.13

2.63

–

5.30 1.50 (4.90)a

1.79

0.41 –

2.20

6

1.13

2.69

–

5.50

1.56

1.80

0.34 –

2.14

7

1.10

2.64

2.25

5.47

1.54

1.81

0.34 0.02

2.15

8

–

–

2.21

4.97

–

–

–

0.26

–

9

–

–

2.27

4.98

–

–

–

0.04

–

a

Conformer with the ortho methyl above the plane and, in parentheses, in-plane with the fluorene moiety.

Table 3.3 Geometrical data (dihedral angles ( ), distances r (Å)) of 9-arylfluorenes 5–9 r[H–C(sp3)C r[H–C(sp3)C ∠H–C(sp3)–C ∠C(f )–C(sp3)–C ∠plane 1, a a b (i)–C(o) plane 2 (o)]a (Å) (o0 )]a (Å) No. (i)–C(o)

5

14.5 (0.0 )c

45.3 (59.2 )c

83.7 (90.0 )c

2.655 (2.527)c 3.409 (3.436)c

6

0.0

59.2

90.0

2.527

7







0.0



59.5  d



90.0  d



3.436

2.574

3.434

8

0.0 (0.0 )

57.4 (57.3 )

90.0 (90.0 )d

2.607 (2.613) 3.417 (3.416)d

9

0.0

57.4

90.0

2.613

a

0

d

3.418

3

Aryl moiety: i (ipso), o,o (ortho); fluorene moiety: f, adjacent to C(sp ). Angle between the planes of the aryl and fluorene moieties. Conformer with the ortho methyl above the plane and, in parentheses, in-plane with the fluorene moiety. d Conformer with the meta methyl above the plane and, in parentheses, in-plane with the fluorene moiety. b c

aromatic moieties (phenyl, a-naphthyl and b-naphthyl) on the isoquinoline and methoxy protons were computed by our approach [1]. While the more distant ring and OMe protons proved to be excellent indicators of the anisotropy effects in these compounds, the values of the more proximate ring and OMe protons in these structures were found to be smaller than the experimental Dd values. As the reason for the differences between Dd and the anisotropy effects of the aromatic moieties, steric compression was identified, in agreement with the parallel structural changes of the geometries.

135

Anisotropy Effect in NMR Spectroscopy

This approach for the quantitative separation of the anisotropy effects and the steric compression of the functional groups on the 1H chemical shifts could be recommended as a generally applicable method. Both quantitative ring-current effects and steric substituent effects were employed to determine also the stereochemistry of naphthoxazinobenzoxazine [39] and naphthoxazinoquinazolinones [40].

5.3. Antiaromaticity Proved by the Anisotropy Effect in 1H NMR Spectra the 9-Dioxaanthracene Dianion 102With these encouraging results in hand we studied, employing our approach [1], the relative antiaromaticity of the oxaanthracene anion 11 and dioxaanthracene dianion 102 (Scheme 3.5) which proved to be unclear [41] employing the ring-current effect of these antiaromatic moieties. The antiaromaticity of one half of the dianion 102 compared with the one of the anion 11 was found to be consistent with the magnetic susceptibility data of 11 compared with a single ring moiety of 102 (cf. Table 3.4) [42]. In the latter case, the paratropic ring-current effect of the antiaromatic molecules (cf. Fig. 3.15) strongly deshields the protons H-1,8 above the 5

O 6

O

4 3 2

7 8

9

1

H O 102-

11-

Scheme 3.5 Oxaanthracene anions 10

2-

-

and 11 studied [42].

Table 3.4 Theoretical chemical shifts of the protons in 102 and 11 (quantification of the anisotropic effect of the paratropic ring current) d(1H) (ppm) Proton

102

11

Dd(1H) (ppm)

Anisotropy effect (Ds) (ppm)a

H-1,8

5.51

4.45

+1.06

-0.71

H-2,7

5.25

5.42

-0.16

-0.12

H-3,6

4.23

4.44

-0.21

-0.02

H-4,5

4.55

4.80

-0.25

-0.005

a

Minus for deshielding, plus for shielding.

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Figure 3.15 Both structure and paratropic ring-current effect of the antiaromatic dianion 102 [3]. Copyright 2012 American Chemical Society [42].

antiaromatic moiety by 1.08 ppm in excellent agreement with the TSNMRS value of 0.71 ppm. The small difference to the experimental shift values can be again attributed to partial “steric compression”. Especially this last example [42] of a paratropic ring-current effect of antiaromatic molecules strengthened our grading of the ring-current effect of arene moieties (anisotropy effects of functional groups) on the signals in 1H NMR spectra are the molecular response property of spatial NICS.

6. APPLICATION OF TSNMRS IN STRUCTURAL CHEMISTRY 6.1. Stereochemical Applications In opposite to the 11-ethynylphenanthrene result [21], concerning the anisotropy effect of the dC^Cd triple bond (vide infra), the strong shielding of the bridge dCH2d protons [d(CH2) ¼ 0.51 ppm] in 1,6methano[10]annulene, which is supposed to result from the ring-current effect of the 10 p-electron system, could be readily proved. We computed the ring-current effect of the 10 p-electron moiety (visualized in Fig. 3.16) [1] and found the CH2 bridge protons located in the ICSS ¼ 2 ppm. Together with the d-value of ca. 1.5 ppm for this kind of saturated

Anisotropy Effect in NMR Spectroscopy

137

Figure 3.16 Stereochemistry and ring-current effect of the 10 p-electron aromatic ring system 1,6-methano[10]annulene: only the shielding surface at 2 ppm of the global minimum conformation of 1,6-methano[10]annulene is visualized; the bridge methylene protons are positioned within this shielding area. Reproduced by permission of The Royal Society of Chemistry [1].

protons in the 1H NMR spectra of hydrocarbons, the high-field position of d(CH2) ¼ 0.51 ppm can be readily explained [1]. The ring-current effect of the ortho-disubstituted phenyl moiety in ortho,meta-cyclophanes (cf. Fig. 3.17 for N,N-ditosyldiaza[2.2] orthometacyclophane) proved to be a very useful tool in conformational analysis [1]: At low temperature (180 K), the 1H NMR spectrum shows for the H-2 proton of the meta-disubstituted aryl moiety two signals at 7.18 and 4.59 ppm. The two signals (together with the respective resonances) could be assigned to both the boat and the chair conformers (cf. Fig. 3.17) which were found as the only preferred conformers as result of a parallel ab initio MO study. Considering the ring-current effect of the ortho-disubstituted phenyl moiety the assignment proved easy: the H-2 high-field signal belongs to the chair conformer respect to the ring-current effect of ca. 2 ppm compared with the boat conformer in fine agreement with the experimental chemical shift difference of Dd ¼ 2.59 ppm [43]. The conformation of some molecules in a large variety of biologically active hydantoin derivatives, especially of 5-benzyl hydantoin (cf. Fig. 3.18) was not clear from NMR spectra [44]. For the latter compound, a folded conformation seems to be preferred because the NdH(3) proton is 0.5 ppm high-field shifted with respect to other 5-substituted hydantoins.

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Figure 3.17 Calculated ring-current effect of boat and chair conformers of N,Nditosyldiaza[2.2]orthometacyclophane (1.5 ppm shielding surface and 0.5 ppm deshielding surface (in-plane) of the ortho-disubstituted phenyl ring): H-2 of the meta-disubstituted phenyl ring positioned in the shielding area of the orthodisubstituted phenyl ring in the chair conformer (right) but in its deshielding area in the boat conformer (left). Reproduced by permission of The Royal Society of Chemistry [1].

Figure 3.18 Conformational analysis of 5,5-disubstituted hydantoins: the NdH(3) of 5-benzyl-5-methylhydantoin (A) and the ortho-protons of the N(3)-phenyl ring of 3-phenyl-5-benzylhydantoin (B) on the 0.5 ppm shielding surface of the benzyl phenyl ring-current effect; the deshielding of NdH(1) in 5-methyl-5-phenylhydantoin (C) due to the position on the 0.5 ppm deshielding area of the 5-phenyl ring-current effect. Reproduced by permission of The Royal Society of Chemistry [1].

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Anisotropy Effect in NMR Spectroscopy

In the 5-phenyl-substituted derivatives, however, NdH(1) is 0.5 ppm deshielded compared with the same proton in the former compound. Computations employing our approach cleared up the situation [1]: NdH(3) in 5-benzyl hydantoin was found inside the ICSS ¼ 0.5 ppm shielding surface of the benzyl phenyl ring and NdH(1) in the 5-phenyl-substituted derivatives along the ICSS ¼ + 0.5 ppm deshielding area of the 5-phenyl ring-current effect (cf. Fig. 3.18), both in excellent agreement with the experiment and unequivocally clearing up the conformational behaviour of the studied compounds [1]. Employing our approach [1], the anancomeric chair conformation of the 10-membered ring in the 3,12-diaza analogue of [3.3]-ortho-cyclophane (cf. Fig. 3.19), which was initially assigned as boat conformer [46], could be proved [45] by the position of the aromatic protons within the various ICSS (cf. Fig. 3.19); in addition, the dynamic exchange phenomena as obtained along the low-temperature NMR study could be assigned to result from a combined process of 10-membered ring interconversion and restricted rotation about the exo-cyclic partial C]N double bond [45]. For establishing structure, configuration and conformation of a variety of new di-exo-oxa-norbornane-fused 1,3-heterocycles [47] (Scheme 3.6) a number of NOE experiments proved equivocal; the ring-current effect of the phenyl ring, however, as computed for the lowest energy structure of 12, cleared up the stereochemistry: The high-field shift of H-3

O 7.23 ppm

O

S

6.86 ppm

N

6.69 ppm

N

6.46 ppm

S

O O

Shielding: 0.9 ppm 0.4 ppm 0.1 ppm

Figure 3.19 Visualization of the ring-current effect of the tosyl aromatic moieties on the aromatic proton chemical shifts of the [3.3]-ortho-cyclophane system. Copyright 2001 Elsevier [45].

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Erich Kleinpeter

O O N

H3 H4 Ph

(CH2)n

O R

n=1, 2

R=H, Me

12 Scheme 3.6 Molecular 1,3-heterocycles [47].

CH3 H3C

structure

of

some

X

di-exo-oxa-norbornane-fused

CH3

CH3

N

new

H3C

N X

N

N

H

H

CH3

S(Se)

S(Se) N3,Ph(s-cis) N3,Ph(s-trans)

CH3 CH3

N X

N

H S(Se)

CH3

H3C

CH3

N X

N

H

CH3

S(Se)

Scheme 3.7 Stereochemistry of N(Me)Ph-substituted thio(seleno) acrylamides 13.

(1.29 ppm) agreed excellently with the experimental values of the trans isomer confirming, in addition, the trans position of phenyl and H-4(endo). For the cis analogue, the two parameters are strongly different [47]. The ring-current effect of phenyl was also employed to unequivocally assign the preferred conformers of the N(Me)Ph-substituted thio(seleno) acrylamides 13 (cf. Scheme 3.7), mentioned already [29]. When comparing the ring-current effect on the alkene and N-methyl protons in 1H NMR spectra with experimental chemical shift differences, only N1,Ph(s-trans) and N3,Ph(s-trans) proved to be the preferred conformers in the N(Me)Phsubstituted thio(seleno) acrylamides [29]. The combined anisotropy effect of the carbonyl group and the ringcurrent effect of phenyl, computed by our method [1], were applied to assign both configuration and conformation of epoxides of Z-3arylidene-1-thioflavan-4-ones [48] which, due to three chiral centres, could exist as four isomers. Initially, two sets of signals were detected and could be

Anisotropy Effect in NMR Spectroscopy

141

Figure 3.20 trans,trans and trans,cis isomers of the epoxides of Z-3arylidene-1-thioflavan-4-ones in solution (A), signal assignment of the H-3 protons in the two isomers via the computed anisotropy effect of the carbonyl group (above/ below ring plane 0.4 ppm shielding, in-plane 0.4 ppm deshielding) (B) and signal assignment of the C-2 ortho-phenyl protons in the trans,trans isomer (C). Reproduced by permission of The Royal Society of Chemistry [1].

assigned by 3J(H-2,C-8a) to the trans,cis- and trans,trans-epoxides. These two isomers could be differentiated by the chemical shift difference of the H-30 protons (Dd ¼ 0.8 ppm) [48]. Computing the anisotropy effect of the carbonyl group on the protons H-30 in the two isomers, the latter could be assigned unequivocally (cf. Fig. 3.20). The computed ring-current effect of the 30 phenyl ring corroborates this assignment: Only in the trans,trans-epoxides get the ortho-protons of the 2-phenyl ring spatially proximate to the C-30 phenyl and are high-field shifted hereby (cf. Fig. 3.20) [48]. Employing the anisotropy effects of the oxirane ring system and of the sulfoxy group both the configuration and conformation of the corresponding sulfoxides and sulfones could be unequivocally assigned [49]. Also the anisotropy effect of cyano group was successfully applied to assign the cis/trans isomers of substituted quinazoline derivatives [50] (cf. Fig. 3.21). Two sets of NH signals were obtained in the 1H NMR spectrum: the low field set of signals could be assigned to the conjugated (to the annelated phenyl) NH protons via NOE measurement; the chemical shift difference, however, within the two sets was at ca. 0.2 ppm rather small to assign to the cis/trans isomers unequivocally. The anisotropy effect

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Figure 3.21 cis/trans-Isomerism at the exo-cyclic C]N double bond of a quinazoline derivative (A), calculated anisotropy effect for the two isomers as a whole (B) and separately calculated anisotropy effects of the nitrile group (C), NH-3 in the cis isomer and NH-1 in the trans isomer are located in the shielding area of the calculated anisotropy effect of the cyano substituent. Reproduced by permission of The Royal Society of Chemistry [1].

calculated for the whole molecules of the two isomers is given in Fig. 3.21B. It is easy to see that the anisotropy effects of the benzene ring and the nitrile group, as calculated as single fragments, reproduce the anisotropy effect of the molecule as a whole. The superposition of the ICSS obtained for the fragments and obtained as calculated for the whole molecule proved excellent both in shape and scope. Therefore, it was decided to calculate only fragmental anisotropy effects in order to save calculation time and make the representations clearer and more illustrative [1]. In the case of the quinazoline derivative, the anisotropy effect of the nitrile group attached to the exo-cyclic double bond proves N(1)dH in the 0.1 ppm shielding ICSS in the cis isomer and N(3)dH in the 0.1 ppm shielding ICSS for the trans isomer (cf. Fig. 3.21C), both excellently in line with the experimental chemical shifts of the two sets of NH protons. The corresponding assignment of the signals to the cis and trans isomers could be readily concluded [1].

Anisotropy Effect in NMR Spectroscopy

143

6.2. Position in the Binding Pocket of Enzymes and Other Host Compounds Based on NMR spectroscopic information about the allosamidin–hevamine complex (1H and 13C NMR spectra, H,H-COSY and phase-sensitive H,CCOSY (HMQC), HMBC as well as HMQC–TOCSY NMR experiments; trNOESY and STD measurements) [51] ab initio MO calculations of the ring-current effect of the aromatic moieties of Trp255, Tyr183, Tyr6 and Phe32 of the chitinase inhibitor hevamine were carried out to investigate the role of these amino acid residues in binding interactions with the chitinase allosamidine in solution. The geometry of the binding pocket with the mentioned relevant amino acid residues was taken from the X-ray analysis, the ring-current effects of the indole and phenyl residues in the four amino acid residues were computed by our method [1] and visualized by the various ICSS (cf. Fig. 3.22) [52]. Then, the chemical shifts of the protons of the allosamidine moiety were analyzed with respect to both sign and intensity of the present ring-current effect of the mentioned amino acid residues and compared with the experimental complexation-induced shifts (cf. Table 3.5). Coincidence of computation and experimental chemical shift differences supports a very similar structure of the hevamine–allosamidine complex both in solution and in the solid state. Deviations of H-8 and H-11 indicate high steric compression confirming that the allosamidine is strongly in contact with hevamine in these positions. In addition, deviations between computational and experimental results had to be discussed in the

Figure 3.22 Calculated ring-current effect of Trp255 (shielding ICSSs of 0.2, 0.3 and 1 ppm, Tyr6 and Phe32 (deshielding ICSS of +0.1 ppm) and Tyr6 (shielding ICSS of 0.5 ppm) [52].

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Table 3.5 Experimental and calculated complexation-induced 1H chemical shifts [52] Calc. Dd(1H) Proton Exp. Dd(1H)

H-7

- 0.13

- 0.15

H-8

- 0.28

- 0.5

H-9

- 0.25

- 0.25

H-11

+0.42

- 0.20

H-12

- 0.19

- 0.45

H-13

- 0.03

- 0.05

H-14,15

- 0.15

- 0.2

light of present hydrogen bonding, charge polarizations and van der Waals forces which, actually, determine both the binding conformation and the position in the binding pocket of the enzyme [51,52]. Both position and docking conformation of allosamidine in hevamine was detected by tr-NOE and STD NMR measurement [52]. Employing our approach [1], also the anisotropy effects of C]O, CdX (X]C, N, S) bonds, of the NH]C(NH2)dNHd moiety and of the aromatic moieties indole, toluene, p-methoxy-toluene and imidazole, which could potentially exist in amino acid residue side chains, were computed [53]: Hereby, quantitative information about spatial extension, sign and scope of the corresponding anisotropy/ring-current effects could be obtained. While the anisotropy effects of the mentioned functional groups proved to be not long ranging enough, the ring-current effects of the aryl moieties were found to be extended sufficiently to influence the 1H NMR spectra of docked substrates in the binding pockets of proteins. As a summary of this chapter, it can be concluded: If the amino acid residues of phenylalanine, tryptophane, histidine and tyrosine are involved in the amino acid sequence of a protein in its binding pocket, the ring-current effects can be readily employed in order to identify the position of potential substrates; if more than two of these amino acid residues are present, the exact position of the substrate could be optimized by considering the various ring-current influences on the 1H NMR spectrum of the docked substrate [53]. The successful application of our approach [1] has been also established along the coordination NMR study of hexaazasulfinate ligands in dinuclear transition-metal complexes 14 of bowl-shaped binding cavities (cf. Scheme 3.8) [54].

145

Anisotropy Effect in NMR Spectroscopy

+ tBu [(L1)M2(m-L)]+ Me

Me N Me N

M N

N

S L S

Me

N

M

Me

N Me

tBu

Scheme 3.8 Structure of the bowl-shaped dinuclear transition-metal complexes 14.

To investigate the solution structures, the zinc complex of 14 was characterized by 1H and 13C NMR spectroscopy which exists as a single isomer in solution as [(L2)Zn2(m-OAc)]+ cation. The appearance of a 1H NMR signal at d ¼ 0.59 ppm, which can be assigned to the methyl protons of the bridging acetate ion, is worthy of note. The observed high-field shift [14: Dd ¼ 1.24 ppm, relative to NaOAc (d ¼ 1.83 ppm)] can be explained by the ring-current effect of the aryl moieties within the molecule. As can be seen from Fig. 3.23, the methyl protons of the coordinated acetate group are positioned above the centre of the two phenyl rings in the shielding region; the Dd value of 1.92 has been computed by our approach [1] which is in good agreement with the experiment, considering the difference caused by steric compression.

7. APPLICATION OF TSNMRS IN QUANTIFICATION AND CHARACTERIZATION OF (ANTI)AROMATICITY, PSEUDO-, SPHERICAL, CAPTODATIVE, HOMO- AND CHELATOAROMATICITY 7.1. General As mentioned and discussed already in Section 1, the various punctual NICS indices [NICS(0), NICS(1), NICS(0)pzz and NICS(1)zz] [4,6] can be each employed as a simple and efficient criterion to measure quantitatively the diamagnetic/paramagnetic effects of ring currents associated with (anti)aromaticity. As the result of our approach [1], the corresponding diamagnetic/ paramagnetic ring currents are visualized by ICSS of different size and

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Mean value: –1.92 ppm –1.59 ppm –2.32 ppm –1.85 ppm

Figure 3.23 Calculated chemical shielding values at the positions of the three methyl protons of the bridging acetate ions in 14 (atomic coordinates were taken from the crystal structure) are as follows: Dd (ppm) ¼  2.32, 1.59, 1.85 ppm (mean value ¼1.92 ppm) in the gas phase. Copyright © 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim [54].

˚ in-plane and perpendicular-todirection, and we employed as distances in A centre (cf. Scheme 3.9) of the (anti)aromatic system at ICSS ¼ 0.1 ppm shielding/deshielding as a relative parameter of (anti)aromaticity; the ben˚ in-plane, 8.9 A ˚ above/below the plane) and the zene values (7.2 A ˚ in-plane, 6.2 ppm above/below the plane cyclobutadiene values (5.5 A but, due to antiaromaticity of inverted sign) were set as reference values [55]. Deviations from these reference values were discussed as relative (anti)

147

Anisotropy Effect in NMR Spectroscopy

Perpendicular-to-center (Å)

In-plane (Å)

Scheme 3.9 Estimation of aromaticity by ICSS [1].

Figure 3.24 Visualization of the TSNMRSs of benzene, naphthalene, anthracene, butacene and pentacene (from left to right; ICSSs: above/below plane outward represents declining shielding from 5 ppm via 2 ppm, 1 ppm and 0.5 ppm to 0.1 ppm, and in-plane 0.1 ppm deshielding. Copyright 2004 Elsevier [55].

aromaticity and ICSS were employed to visualize the diamagnetic/paramagnetic ring currents and respective (anti)aromaticity as well [55]. In this respect, aromaticity of benzene derivatives subject to donor/ acceptor substituents, subject to linear and helical annelation of only aromatic but also aromatic and antiaromatic moieties and subject to the number of 4n + 2 conjugated p-electrons (annulenes) could be visualized and studied quantitatively [55]. For visualization, the corresponding results obtained for the annulenes (Fig. 3.24) and the alternating aromatic and antiaromatic moieties (Fig. 3.25) are given. Similar quantifying results were obtained for 5- and 6-membered aromatic heterocycles, their benzo analogues, of the cyclopropenylium cation, azulene, ferrocene, the [14]- and [18]-annulenes, and of the helicenes were published [55]. While for linear annelation of benzene moieties (cf. Fig. 3.24) both shielding above/below the ring system increases (as well as the corresponding in-plane deshielding) due to the rising common ring-current effect, this changes in dibenzocyclobutadiene, terphenylene, zig-zag[4] phenylene and triangular[4]phenylene, respectively (cf. Fig. 3.25).

Figure 3.25 Visualization of the TSNMRSs of both aromatic and antiaromatic moieties: benzocyclobutadiene, dibenzocyclobutadiene, terphenylene, zig-zag[4]phenylene and triangular[4]phenylene (from left to right; ICSSs: above/below plane outward represents declining shielding from 5 ppm via 2 ppm, 1 ppm and 0.5 ppm to 0.1 ppm, and in-plane 0.1 ppm deshielding. Copyright 2004 Elsevier [55].

Anisotropy Effect in NMR Spectroscopy

149

Common and nearly constant ICSS above/below the benzene moieties (indicating the corresponding intact ring-current effects), were obtained, disconnected by holes of indefinite shielding/deshielding above/below the 4-membered ring moieties [55]. On this way, aromaticity of tris-cyclobutabenzene derivatives but the complete 1,3,5-cyclohexatriene structure of the central 6-membered ring of [4n]annulene[4n + 2]annulene could be proved [56]. Further, the planar 4c,6p aromaticity in the cyclobutadiene dianion and the interplay with partial spatial 6c,6p aromaticity of the corresponding di-Li+ complex could be visualized [57]; the latter spatial (spherical) aromaticity was studied and interpreted when studying a number 2(N + 1) [3] homoaromatic compounds [58]. The corresponding TSNMRS were really useful also in differentiation 5- or 6-membered aromatic ring formation in heterocyclic chemistry via estimation of the corresponding partial aromaticity via ring-current quantifications [59].

7.2. Aromaticity of Fulvenes, Fulvalenes, Dehydroannulenes and Fullerenes The ring currents of the (anti)aromatic fulvenes [60] and fulvalenes [61] were studied and related to this inherent property: It was found that, due to the ring-current effects, 3- and 5-membered ring moieties remain always planar and attain partial aromaticity via cross conjugation (cf. Fig. 3.26). As to the 7-membered ring moieties, they demonstrate different behaviour in this respect: in [5,7]- and [7,7]-fulvalenes, no aromaticity at all is attained due to steric hindrances, whereas in [3,7]- and [7,9]-fulvalenes, they become partly antiaromatic (cf. Fig. 3.27). 9-Membered ring moieties, finally, prove generally to be twisted due to steric hindrance and show no partial aromaticity or antiaromaticity at all [61]. The same is true for the corresponding tris-, penta-, hepta- and nonafulenes [60]. Proved by the anisotropy/ring-current effect of the macrocyclic ring of carbo-benzene on the phenyl protons in 1H NMR in mono-phenyl carbobenzene 15 and of the same effect of the 14-membered macrocyclic ring of dehydro[14]annulene on the phenyl protons of o,o0 -ring included para-cyclophane protons in 1H NMR (which are the molecular response property of spatial NICS—TSNMRS) the aromaticity of dehydro[10]-, dehydro[14]- (cf. Fig. 3.28) and dehydro[24]annulenes and the antiaromaticity of dehydro[12]-, dehydro[16]- and dehydro[20] annulenes was quantified [62]. The (anti)aromaticity of the macrocyclic ring and the aromaticity of the o,o0 -included phenyl residues are competing. The larger

Figure 3.26 Structure and TSNMRS cone of calicene (ICSSs: above/below plane outward represent declining shielding from 5 ppm via 2 ppm, 1 ppm and 0.5 ppm to 0.1 ppm, and in-plane 0.1 ppm deshielding. Copyright 2008 American Chemical Society [61].

Figure 3.27 Structure and TSNMRS cone of sesquifulvalene (ICSSs: above/below plane outward of the three-membered ring represent declining shielding from 5 ppm via 2 ppm, 1 ppm and 0.5 ppm to 0.1 ppm, and in-plane 0.1 ppm deshielding, and above/ below plane outward of the seven-membered ring 0.5 ppm and 0.1 ppm deshielding. Copyright 2008 American Chemical Society [61].

Anisotropy Effect in NMR Spectroscopy

151

Figure 3.28 Visualization of the spatial magnetic properties (TSNMRS) of the dehydro [14]annulene derivatives with increasing number of annelated phenyl moieties as ICSS (+2 ppm) shielding. Copyright 2013 Elsevier [62].

the aromaticity of the 10-, 14- and 24-membered and the higher the antiaromaticity of the 12-, 16- and 20-membered conjugated ring systems, the lower proves to be the aromaticity of the o,o0 -included phenyl residues. This latter result is in complete agreement with the 1,3,5-cyclohexatriene electronic structure of the central ring in ([4n]annuleno[4n + 2]annulene) [56]. Since the discovery of fullerenes, the NMR chemical shifts of nuclei inside and outside the carbon sphere have proven to be very interesting for characterizing these compounds with respect to either the aromaticity

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or antiaromaticity present. Experimental chemical shifts of both enclosed magnetically active nuclei and external protons proximal to the fullerene surface excellently corroborate the TSNMRS and exactly reproduce the local aromaticity endohedrally and on the surface of fullerenes [63]: (i) Shielding (aromaticity) inside the carbon cages (e.g. of C60 in Fig. 3.29) proves to be not homogeneous but heterogeneous; the position of magnetically active nuclei in the cavities determines their chemical shift subject to spherical (anti)aromaticity. (ii) Differences in (anti)aromaticity of 5- and 6-membered ring moieties of the fullerenes C50, C60, C60 6 , C70 and C70 6 were determined quantitatively by the ICSS at 0.1 ppm (e.g. of C60 in Fig. 3.30); the results are in excellent agreement with magnetic susceptibilities and theoretical calculations. (iii) Experimental 1H chemical shifts in fullerene derivatives are in excellent agreement with ab initio calculated chemical shifts and in good agreement with TSNMRS values at the certain positions; thus, ring-current effects

Figure 3.29 Visualization of the endohedral TSNMRS of C60 by various shielding ICSS. Copyright 2008 American Chemical Society [63].

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153

Figure 3.30 Visualization of the TSNMRS of C60 (ICSS light grey: 0.1 ppm shielding, dark grey: 0.1 ppm deshielding. Copyright 2008 American Chemical Society [63].

(aromaticity/antiaromaticity) strongly but not exclusively determine the 1H chemical shifts of external protons in fullerene derivatives. A parallel study dealt with the C20 derivatives [64]; in case of the hydrocarbon dodecahedrane C20H20 the exohedral magnetic properties are rather small, comparable with the anisotropic effects of CdC single bonds [19,58]. Fullerene C20 exhibits the exohedral shielding/deshielding zones as known from the larger fullerenes (cf. Fig. 3.30) [63] and the spatial magnetic properties of dodecahydrotetraenes (C20H12 with four double bonds) simply show a combination of C]C double bond anisotropic effect [64]. Thus, TSNMRS, as in the case of fullerenes in C60, C60 6 , C70 and C70 6 [63], are generally applicable to quantify and visualize combined anisotropic effects of CdC single and C]C double bonds, respectively, local and spherical 2(N + 1) [3] homoaromaticity [58], and overall (4n + 2) Hu¨ckel aromaticity of molecules with curved p-conjugation [64].

7.3. Homo- and Antiaromaticity Representative examples of molecules with potential homoaromaticity have been studied by our approach [1] and the inherent ring currents were visualized. From the ICSS of the TSNMRS, the latter compared with the cone of benzene, the answer on the question, homoaromaticity existing yes or no, can be readily given. Strong support up to complete disagreement with previous studies was obtained [65]. As representative an example from neutral homoaromaticity will be given: In tris(bismethano)benzene 16, on the one hand, which is homoaromatic [66], the three C]C double bonds are

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Figure 3.31 Structures and TSNMRS (visualized as ICSSs of various size and direction of tris(bismethano)benzene 16. (left), of triquinacene 17 (middle) and the combined anisotropic effects of three isolated C]C double bonds 17a, identically positioned as the double bonds in 17 (right). Copyright 2009 Elsevier [65].

˚ ) to interact appropriately and the additional sufficiently proximate (1.79 A 4-membered ring units are not sterically strained; TSNMRS of this compound (16) display a perfect 6p-electron ring current similar to benzene (cf. Fig. 3.31); the corresponding ICSS ¼ –0.1 ppm (9.5 A˚) and ICSS ¼ ˚ ) of 16 prove to be even something larger than in the ben+ 0.1 ppm (7.9 A ˚ , respectively). zene reference (8.9 and 7.2 A In comparison, triquinacene 17 was studied, which lacks homoaromaticity due to the three double bonds which are too far apart ˚ ) to get conjugated in a homoaromatic manner and can be the ref(2.52 A erence for non-existing homoaromaticity [67]. Examination of the ˚ below the corresponding ICSS result in uniform ICSS(+0.1 ppm) ¼ 6.1 A ring system and completely separated ICSS above the 5-membered ring moieties (cf. Fig. 3.31). The TSNMRS of triquinacene 17, as reference for non-existing homoaromaticity, were simulated by the combined anisotropy effects of the three isolated C]C double bonds in 17a at the same position as are the three C]C double bonds in 17 (cf. Fig. 3.31). The TSNMRS of both triquinacene 17 and the model 17a are practically identical and prove the correctness of the homoaromaticity model proposed on the basis of TSNMRS values. Antiaromaticity, as proved by paratropic ring-current effects with deshielding above/below and shielding in-plane of the ring system, has been mentioned and pictured already for cyclobutadiene, the oxaanthracene anion 11– and dioxaanthracene dianion 102– (vide supra) [1,42]. Several other molecules with potential antiaromaticity were studied [42] by our approach [1] with striking success. For example, any expected homoantiaromaticity in

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155

Figure 3.32 Structure and TSNMRS (visualized as ICSSs; above/below plane (0.5 ppm shielding), in-plane 0.1 ppm deshielding) of 3H-cyclonona[def]biphenylene 18—different views. Copyright 2009 Elsevier [65].

3H-cyclonona[def]biphenylene 18 [68] was proved to be absent [65] (cf. Fig. 3.32—the spatial magnetic properties of 18 are dominated by the ring currents of the two separated benzene moieties with usual shielding above/below the units and deshielding in-plane; a completed paratropic ring current in the 9-membered ring unit in 18 containing the 4n (eight p electrons) is not generated) [65]. Thus, the indication of antiaromaticity by ICSS of TSNMRS in certain conjugated molecules proved to be possible and applicable for these purposes as is aromaticity employing the inversed TSNMRS values (shielding above/ below the ring system) of aromatic compounds [55].

7.4. Aromatic Versus Quinonoid Structures The differentiation of aromatic and quinonoid structures by our approach [1] proves impressive: Benzenoid structures show identical behaviour as benzene [shielding above/below the ring plane and deshielding in-plane] in line with active ring-current effects. Quinonoid structures generate magnetic properties completely different from aromatic moieties but in line with the anisotropy effects of the quinonoid isolated C]C double bond moieties. Thus, TSNMRS are a recommendable alternative for the identification of benzenoid/quinonoid structures if 1H NMR spectra are too complex [69] or X-ray structures are not available due to insufficient crystal quality [70]. As pictured example, the TSNMRS of hydroquinone and benzophenone are given in Fig. 3.33. The difference between aromatic and quinonoid structures is visible at first glance: While the in-plane behaviour changes only slightly (closed deshielding belt in the quinonoid structure; due to the CdN single bond anisotropic effect), the shielding zones above and below the plane of resonance

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Figure 3.33 Visualization of the magnetic properties (TSNMRS) of the benzenoid compound hydroquinone (left) and the quinonoid compounds p-benzoquinone (right) as ICSS of different direction and size. Copyright 2010 American Chemical Society [71,72].

˚ only (compare with more than 5 A˚ in drop decisively and achieve 3.5–4 A the benzenoid structure). In addition, the shielding effect is no longer strongest above/below the centre of the aromatic moieties but above/below the two O]CdCH]CHdC]O delocalized moieties. Actually, there is deshielding in the centre of the quinonoid structure corroborating complete absence of any ring-current effect/aromaticity but presence of the two delocalized quinonoid moieties. Employing the same approach, the benzenoid/quinonoid structure of a number of tetraazapentacene derivates [71], the keto-enol tautomerism of a,b,b-disubstituted phenazines and bridged bisphenazine analogues [72], and the first stable phenylogous enol tautomer of benzofuranotrione 3 could be readily assigned [73].

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7.5. Chelatoaromaticity and Miscellaneous Aromaticity Since Calvin’s and Wilson’s [74] idea of potential chelatoaromaticity [74], this physical-organic phenomenon was employed from time to time to predict and comprehend properties, and to study the corresponding influences on reactions of chelato complexes. Results obtained so far have been reviewed [75,76]; both experimental and theoretical methods were employed to judge the phenomenon. The spatial magnetic properties of the chelate ring of various complexes with assumed chelatoaromaticity were computed as TSNMRS and visualized as usual by ICCS [77]. From the corresponding values only in the vanadium complex of phenyl substituted dithiolene 20b (cf. Scheme 3.10 and Fig. 3.34), the existence of chelatoaromaticity can be proved from the perspective of spatial magnetic properties and even in the latter case, experimentally measured Dd values with respect to the free ligand are not induced by the chelate ring-current effect. H H

S S

n–

S H

X/3 S

H0 19

20a X = Mo(n=0) 20b X = V(n=−1)

Scheme 3.10 Structure of dithiolene derivative 19 and of the corresponding Mo/V complexes 20a,b [77].

Figure 3.34 Visualization of the spatial magnetic properties (TSNMRS) of the vanadium tris-phenyldithiolene complex 20b as ICSS of different direction and size. Reproduced by permission of the PCCP Owner Societies [77].

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In other complexes studied and where chelatoaromaticity was assumed (acetylacetonato chelato complexes, metallobenzenes complexes, orthohydroxy-para-pyrone chelato complexes and the molybdenum dithiolene complex 20a) [77] as well as in the corresponding free ligands chelatoaromaticity could not be identified [77]. In addition to energetic and structural criteria of the aromaticity of the 9-membered ring in the lithium and sodium salts of N-(2-hydroxyphenyl) salicylaldimine 22 and 23 (cf. Scheme 3.11), the magnetic criteria (spatial magnetic properties—TSNMRS) were studied in order to compare with previous results (cf. Fig. 3.35) [79] and complete the topic. It was found out that p-electron delocalization in the 9-membered ring in 22 and 23 generates partial aromaticity but by far less than in [10]annulene and in pyrano [2,3-b]pyrrole. Herefrom can be concluded that approving the lithium and sodium salts of N-(2-hydroxyphenyl)salicylaldimine as the first example of H H

O C

H

H

N

H

H H

21

H

O

H

O C H

X H

O

N

H H

22 (X = Li) 23 (X = Na)

Scheme 3.11 Structure of N-(2-hydroxyphenyl)salicylaldimine 21 and of the corresponding Li/Na complexes 22 and 23 [78].

Figure 3.35 Visualization of the magnetic properties (TSNMRS) of the sodium salt of N-(2-hydroxyphenyl)salicylaldimine 23 as ICSS of different direction and size. Reproduced by permission of the PCCP Owner Societies [78].

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metalla-hetero[10]annulene goes too far [78] and when evaluating aromaticity [80,81], which is a multidimensional characteristic [81] dependent on energetic, geometric and magnetic criteria [82,83], that all items must be considered. The same result was obtained when studying the spatial magnetic properties of 1,3-dihydroxy-naphthyl-2-aldehyde 24 (cf. Scheme 3.12) and analogues: previously [84], it was concluded that the fragment of the resonance-assisted hydrogen bond that contains six delocalized p-electrons adopts partially the role of a typical aromatic ring [85]. Actually, in 24, there is no indication of aromaticity (in the centre of the exo-cyclic H-bonded 6-membered ring there is even ICSS(–0.1 ppm)) [78]; the spatial magnetic properties are dominated by the anisotropy effects of the conjugated partial double bonds in the exo-cyclic 6-membered ring moiety (cf. Fig. 3.36).

O

H

O

O H 24

Scheme 3.12 Preferred structure of 1,3-dihydroxynaphthyl-2-aldehyde 24 [84].

Figure 3.36 Visualization of the magnetic properties (TSNMRS) of N-(2-hydroxyphenyl) salicylaldimine 21 (left) and 1,3-dihydroxy-naphthyl-2-aldehyde 24 as ICSS of different direction and size. Reproduced by permission of the PCCP Owner Societies [78].

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Figure 3.37 Structure and ring-current effect of planar [1,2]dithiolo[1,5-b][1,2,4] dithiazole moiety of 25 (ICSSs of different shielding or deshielding). Copyright 2007 Elsevier [86].

In opposite, due to intramolecular non-bonded SO interactions, the presence of an aromatic 10p-electron system in the 1,2-dithiol-3-imino species 25 could be identified subject to the ring-current effect visualized in Fig. 3.37 as usual [86]. Subject to the ring-current effects, as visualized by our approach [1], in addition, also partial push-pull aromaticity [59,73] and captodative aromaticity [87] could be visualized and quantified. Further was our approach [1] employed to quantify the electronic structure of ring-closed push-pull allenes [88]: besides polar and carbene-like also carbone-like canonical structures could be identified. And, when studying the local aromaticity of pyrazolo[1,5-a]quinoxalines with the same approach [1], the preferred conjugation via the NdN]C link and much less via the N]CdC]CdC connection could be readily identified [89].

8. RÉSUMÉ Since 2001, a new approach is available [1] to compute (as TSNMRS), quantify and visualize (as ICSS) the anisotropic/ring-current effect in 1H

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NMR spectroscopy. This method, characteristic applications are reviewed in this chapter, is based on spatial NICSs and can be readily employed (i) for stereochemical (syn/anti, exo/endo, cis/trans, preferred conformers, position assignments in supramolecules) and (ii) electronic [conjugation, (anti)aromaticity, quinonoid structures, homo- and chelatoaromaticity] structure characterization along with 1H NMR spectroscopy. Hereby, the experimental anisotropic/ring-current effects in proton NMR spectra prove to be the molecular response property of spatial NICS (TSNMRS).

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[30] S.N. Balasubrahmanyam, S.N. Bharathi, N. Narasimha, G. Usha, The shielding of H-a in the stabilized rotameric forms of a, a-di-tert-butylthioacetic esters. The electric and magnetic anisotropic effects of the thione group, Org. Magn. Reson. 21 (1983) 474. [31] G. Szalontai, J. Dudas, 13C and 1H NMR study of tetrahydro-3,5-dialkyl-1,3,5thiadiazin-2-thiones, Acta Chim. Hung. 119 (1985) 7. [32] O. Kalinowski, W. Lubosch, D. Seebach, 1H- und 13C-NMR-spektroskopische Untersuchungen an Thioamidderivaten; Ringstromeffekt in der 13C-NMRSpektroskopie, Chem. Ber. 110 (1977) 3733. [33] I.A. Rae, M.J. Wade, Differences in anisotropic effects of thio- and selenocarbonyl functional groups, Int. J. Sulfur Chem. 8 (1976) 519. [34] E. Kleinpeter, A. Koch, H.S. Sahoo, D.K. Chand, Anisotropic effect of the nitrate anion—manifestation of diamagnetic proton chemical shifts in the 1H NMR spectra of NO3- coordinated complexes, Tetrahedron 64 (2008) 5044. [35] E. Kleinpeter, A. La¨mmermann, H. Ku¨hn, The anisotropic effect of functional groups in 1H NMR spectra is the molecular response property of spatial NICS, Org. Biomol. Chem. 9 (2011) 1098. [36] E. Kleinpeter, A. Koch, The anisotropic effect of functional groups in 1H NMR spectra is the molecular response property of spatial NICS–the frozen conformational equilibria of 9-arylfluorenes, Tetrahedron 67 (2011) 5740. [37] T.H. Siddall III, W.E. Stewart, Proton magnetic resonance studies of slow rotation in 9-arylfluorenes, J. Org. Chem. 34 (1969) 233. [38] E. Kleinpeter, I. Szatma´ri, L. La´za´r, A. Koch, M. Heydenreich, F. Fu¨l€ op, Visualization and quantification of anisotropic effects on the 1H NMR spectra of 1,3-oxazino[4,3-a] isoquinolinesIndirect estimates of steric compression, Tetrahedron 65 (2009) 8021. [39] M. Heydenreich, A. Koch, S. Klod, I. Szatmari, F. Fu¨l€ op, E. Kleinpeter, Synthesis and conformational analysis of naphth[1´,2´:5,6][1,3]oxazino[3,2-c][1,3]benzoxazine and naphth[1´,2´:5,6][1,3]oxazino[3,4-c][1,3]benzoxazine derivatives, Tetrahedron 62 (2006) 11081. [40] R. Csu¨t€ ort€ oki, I. Szatma´ri, A. Koch, M. Heydenreich, E. Kleinpeter, F. Fu¨l€ op, Syntheses and conformational analyses of new naphth[1,2-e][1,3]oxazino[3,2-c] quinazolin-13-ones, Tetrahedron 68 (2012) 4600. [41] M. Black, C. Woodford, N.S. Mills, Antiaromatic dianions: dianions of dixanthylidene by reduction and attempted excited-state deprotonation, J. Org. Chem. 76 (2011) 2286. [42] E. Kleinpeter, A. Koch, Antiaromaticity proved by the anisotropic effect in 1H NMR spectra, J. Phys. Chem. A 116 (2012) 5674. [43] E. Kleinpeter, J. Hartmann, W. Schroth, O. Hofer, H. Kalchhauser, G. Wurz, Synthesis and conformational behaviour of ditosyldiaza[2.2]orthometacyclophanes, Monatsh. Chem. 123 (1992) 823. [44] (a) R. Benassi, A. Bregula, A. Henning, M. Heydenreich, G. Kempter, E. Kleinpeter, F. Taddei, NMR spectroscopic and theoretical structural analysis of 5-benzyl substituted hydantoins in solution, J. Mol. Struct. 475 (1999) 105. (b) E. Kleinpeter, M. Heydenreich, L. Kalder, A. Koch, D. Henning, G. Kempter, R. Benassi, F. Taddei, NMR spectroscopic and theoretical structural analysis of 5,5-disubstituted hydantoins in solution, J. Mol. Struct. 403 (1997) 111. [45] E. Kleinpeter, A. Holzberger, Theoretical study of conformation and dynamic behaviour of [3.3]orthocyclophane and heterocyclic analogues, Tetrahedron 57 (2001) 6941. [46] E. Kleinpeter, H. Hartmann, W. Schroth, Conformational study of the 4,9-dihetero (Z, Z)cyclodeca-1,6-diene ring system, the mono- and the dibenzo analogues, Magn. Reson. Chem. 28 (1990) 628. [47] F. Miklos, I. Kanizsai, St Thomas, E. Kleinpeter, R. Sillanpa¨a¨, G. Stajer, Preparation and structure of di-exo-oxanorbornane-fused 1,3-heterocycles, Heterocycles 63 (2004) 63.

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