Anisotropy Effect of Three-Membered Rings in 1H NMR Spectra

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The Anisotropy Effect of Three-Membered Rings in H NMR Spectra -Quantification by TSNMRS and Assignment of the Stereochemistry Erich Kleinpeter, Stefanie Krüger, and Andreas Koch J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.5b03078 • Publication Date (Web): 10 Apr 2015 Downloaded from http://pubs.acs.org on April 22, 2015

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The Anisotropy Effect of Three-Membered Rings in 1H NMR Spectra−Quantification by TSNMRS and Assignment of the Stereochemistry Erich Kleinpeter,* Stefanie Krüger and Andreas Koch Universität Potsdam, Institut für Chemie, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam(Golm), Germany

ABSTRACT: The spatial magnetic properties (Through Space NMR Shieldings - TSNMRS) of cyclopropane, of the hetero-analogeous oxirane, thiirane and aziridine, and of various substituted mono-, dis- and tris-cyclic analogues have been computed by the GIAO perturbation method employing the Nucleus Independent Chemical Shift (NICS) concept and visualized as Iso-Chemical-Shielding Surfaces (ICSS) of various size and direction. The TSNMRS values, thus obtained, can be employed to visualize the anisotropy (ring current) effect of the cyclopropane ring moiety. This approach has been employed to qualify and quantify substituent influences and contributions of appropriate ring heteroatoms O, NH and S on the anisotropy (ring current) effect of three-membered ring moieties, and to assign the stereochemistry of mono-, bis- and tris-cyclic structures containing cyclopropane as structural element. Characteristic examples will be given. Keywords: Anisotropy effect; Ring-current effect; 1H NMR, TSNMRS; ICSS; Theoretical calculations; NICS; Assignment of Stereochemistry

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1. INTRODUCTION Nucleus independent chemical shifts (NICS)1 prove to be a quantitative measure of aromaticity. When computed for a grid around molecules (through-space NMR shieldings − TSNMRS)2 and visualized as iso-chemical-shielding surfaces (ICSSs)2 these TSNMRS values can be employed successfully to quantify the anisotropy effects of functional groups and hereby to assign the position of protons close to studied functional groups2-14 along proton NMR assignment procedures. There are comprehensible concerns15 to qualify and quantify molecular response properties (as e.g. the anisotropy effect of functional groups in 1H NMR spectroscopy) by theoretical and unobservable quantities as NICS,16 however, our results obtained by TSNMRS (spatial NICS)2-14 prove the latter to be definitely evaluated as the molecular response property of spatial NICS.17 In addition, TSNMRS values have been utilized to successfully indicate planar,18 spherical19 and chelatoaromaticity;20 antiaromaticity with reversed ICSS (deshielding above/below the plane, shielding in-plane), was qualified and quantified in cyclobutadiene and pentalene,2 suggested partial antiaromaticity of the seven-membered ring moieties in fulvenes and fulvalenes21 was confirmed, too. In the assembly of three-membered rings only the anisotropy effect of the oxirane ring was computed by our approach2 and employed to assign the stereochemistry of 3-arylidene-1thioflavan-4-one epoxides.22 However, there have been synthesized a large variety of substituted three-membered rings, heterocyclic analogues and three membered rings as structural components of bis- and also tris-cyclic aliphatic and heterocyclic compounds. For this reason, this assembly has been studied in detail by our approach2 along the present paper in order to highlight, qualify and quantify the potential of the anisotropy effect of the saturated three-membered ring moiety for assignment purposes in 1H NMR spectroscopy. Chemical shifts δ(1H)/ppm of cyclopropane protons are something special in view of the fact of the extraordinary high field position in proton NMR spectroscopy; early was realized that the reason therefore proves to be the anisotropy effect of the cyclopropane moiety23 which was first calculated by the McConnell equation24 and was later upgraded by empirical parameters for better coincidence with experimental δ(1H).25 Also empirical models26 have been employed. In 2007 Fowler et al.27 computed and visualized the anisotropy effect of cyclopropane, which actually is a ring current effect due to σ-aromaticity, corroborated by the computations of Carion et al.28 The cyclopropane magnetic anisotropy


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was also empirically modelled by three equivalent dipoles perpendicular to the ring at each carbon atom.29

2. COMPUTATIONAL DETAILS The quantum chemical calculations were performed using the Gaussian 09 program package.30 The structures of cyclopropane 1, substituted cyclopropanes 2–17, the heterocyclic (18−23), bis- and tris-cyclic analogues (24−36) were fully geometry optimized at the MP2/aug-cc-pVTZ level of theory. NICS values1 and δ(1H)/ppm (also the reference TMS) were computed using the GIAO method31 at the B3LYP/6-311G** theory level32 on SGI workstations and LINUX clusters. To calculate spatial NICS (TSNMRS), ghost atoms were placed on a lattice of −10 Å to +10 Å with a step size of 0.5 Å in the three directions of the Cartesian coordinate system. The resulting 68,921 NICS values, thus obtained, were analyzed and adjusted by the SYBYL 7.3 molecular modeling software;33 different ICSS of –0.1 ppm (red) deshielding, and 5 ppm (blue), 2 ppm (cyan), 1 ppm (greenblue) and 0.1 ppm (yellow) shielding were used to visualize TSNMRS of 1–36 in the various figures.

3. RESULTS AND DISCUSSION 3A. Mono-substituted cyclopropanes and heteroanalogues−Structures, δ(1H) chemical shifts and anisotropy effect of the cyclopropyl moiety. Structural peculiarities of the monosubstituted cyclopropanes were not indicated. Both experimental and computed δ(1H)/ppm of 1−15 are given in Table 1. Up to very few exceptions (−Br, −I, −C≡N, −CH2OH) the margin of error add up to less than ∆δ < 0.2 ppm which prove the useful quality of the structures obtained true. Substituent influences (±M/±I) are remarkable (cis protons more than trans analogues), probably, because of steric proximity.



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Table 1. 1H Chemical shifts δ/ppm in monosubstituted cyclopropanes 1−15 ___________________________________________________________________________ Substituent Cyclopropyl protons (Substituent effect) ipso cis trans No. δcalc. δexp. δcalc. δexp. δcalc. δexp. ___________________________________________________________________________ 2 −Me(+I)34 0.58 0.55 −0.17 −0.10 0.35 0.31 1.06 1.01 −0.10 0.17 0.40 0.46 7 −CH2OH(+I)35 1 −H26 0.14 0.22 0.14 0.22 0.14 0.22 10 −NH2(+M)35 2.27 2.24 0.26 0.22 0.23 0.33 1.30 1.38 0.37 0.38 0.49 0.68 15 −CH=CH2(+I)36 8 −OH(+M)35 3.45 3.36 0.60 0.48 0.30 0.40 35 1.67 1.83 0.59 0.65 1.00 0.89 13 −Ph(+I) 3 −F(−I/+M)37 4.47 4.32 0.70 0.69 0.33 0.27 4 −Cl(−I/+M)35 2.75 2.93 0.55 0.78 0.69 0.87 2.51 2.79 0.58 0.85 0.82 0.96 5 −Br(−I/+M)35 6 −I(−I/+M)35 1.65 2.27 0.47 0.78 0.89 1.04 11 −COCH3(−M)35 1.74 1.83 1.07 0.93 0.70 0.77 12 −COOCH3(−M)35 1.50 1.61 0.97 0.98 0.67 0.86 14 −CHO(−M)35 1.84 1.79 1.28 1.03 0.86 0.99 35 9 −C≡N(−M) 0.98 1.29 0.83 1.04 0.73 0.96 __________________________________________________________________________

Next the anisotropic (ring current) effect of cyclopropyl was studied: First, cyclopropane (C3) and the effect of unique substituents in 2−15 was studied. The alikeness of both the ring current effect of cyclopropane, especially above/below the ring plane, and benzene is striking; the in-plane deshielding belt which is completed in benzene proved to be reduced to dots in between the CH2−CH2 moieties of cyclopropane (cf. Fig. 1). From the center of C3 the corresponding deshielding dots of ICSS(−0.1 ppm) (red) prove to be ca. 3 to 3.5 Å away, a distance only scarcely applicable for δ(1H)/ppm assignment purposes. The shielding ring rurrent effect of C3 above/below the C3 plane looks more promising: ICSS(+0.1 ppm) lasts up to more than 5 Å, a sufficed displacement to please as adequate δ(1H)/ppm assignment tool. In Figs. 2-4 are the corresponding C3 ring current effects of some mono-substituted (2, 4, 8, 14 and 15 (others cf. Supporting Information), of exo-methylene C3 and cyclopropanone (16, 17) and the heteroanalogues oxirane 18, aziridine 19 and thiirane 20 visualized. The deshielding dots are heavily distorted by the additional anisotropy effects of attached substituents; comparable are the shielding ICSS(+0.1 ppm) and ICSS(+0.5 ppm) below the C3 ring plane (in the figures the structures are adequately and comparable pictured). It can be concluded that single substituents are of negligible influence on the C3 anisotropy/ring


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current effect only. The same is true for exo-methylene C3 and cyclopropanone (16, 17). Of the heteroanaloges 18−20, only the ring current effect of oxirane proves to be slightly different; while the ring current effect of aziridine 19 and thiirane 20 are comparable to the one of C3, shielding above/below oxirane proves to be least prolonged, probably due to strongest electronegativity of the oxygen heteroatom compared with −NH−, −S− or −CH2− (cf. Fig. 4). An additional methyl group in 2-position to the heteroatom does not change the anisotropy behavior of the three-membered ring moieties in 2-methyloxirane 21, 2methylaziridine 22 and 2-methyl-thiirane 23 (cf. Supporting Information).

Figure 1. Structures and TSNMRS (visualized as ICSSs: blue represents 5 ppm shielding, cyan 2 ppm shielding, greenblue 1 ppm shielding, green 0.5 ppm shielding, yellow 0.1 ppm shielding and red represents −0.1 ppm deshielding) of benzene (left) and cyclopropane 1. Thus, the anisotropy behavior of the three-membered ring, with a single substituent, or a single heteroatom as ring-member, proves to be only little susceptible: shielding above/below the ring plane up to distances of more than 5Å can be definitely provided as hard criterion for assignment purposes in proton NMR spectroscopy.



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The corresponding usability, in this regard, will be tested in a number of bis- and triscyclic hydrocarbons (cf. Scheme 1).

24

27

25

28

30

31a

33a

35s

26a

29

31s

33s

26s

32s

34s

35a

32a

34a

36s

36a

Scheme 1: Structures of studied cis- and trans-, bis- and tris-cyclic structures 24 – 36syn/anti.


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7

1

4

2

15

Figure 2. Structure and TSNMRS (visualized as ICSSs: blue represents 5 ppm shielding, cyan 2 ppm shielding, greenblue 1 ppm shielding, green 0.5 ppm shielding, yellow 0.1 ppm shielding and red represents −0.1 ppm deshielding) of cyclopropane 1 and the mono-substituted analogues 2, 4 and 15.



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8

8

14

17

16

Figure 3. Structure and TSNMRS (visualized as ICSSs: blue represents 5 ppm shielding, cyan 2 ppm shielding, greenblue 1 ppm shielding, green 0.5 ppm shielding, yellow 0.1 ppm shielding and red represents −0.1 ppm deshielding) of cyclopropanol 8, cyclopropyl carboxaldehyde 14, methylene cyclopropane 17 and cyclopropanone 16.


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9

1

18

19

20

Figure 4. Structure and TSNMRS (visualized as ICSSs: blue represents 5 ppm shielding, cyan 2 ppm shielding, greenblue 1 ppm shielding, green 0.5 ppm shielding, yelloe 0.1 ppm shielding and red represents −0.1 ppm deshielding) of cyclopropane 1, oxirane 18, aziridine 19 and thiirane 20.



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3B.

Bis-

and

tris-cyclic

structures

containing

cyclopropane

and/or

oxirane

1

moieties−Stereochemistry, δ( H) chemical shifts and anisotropy effect of C3 as estimated by TSNMRS.

As the mono-cyclic C3 structures were processed, the bis- and tris-cyclic analogues were computed and optimized at the MP2/aug-cc-pVTZ level of theory. The ones with the five-membered ring moiety 24−26, proved to develop the envelope conformation for the latter; the C5−C1−C2−C3 entity is planar with C4 out-of-plane syn to the cyclopropane moiety (cf. Fig. 5). The corresponding anti-position is destabilized by the axial protons in 3,5positions. If additionally considering the attached three-membered ring the whole molecules 24−26 appear as boat conformers which was found already previously38 for 26syn,anti by 1H NMR spectroscopy.

Figure 5. Preferred conformer of 26syn.

If, in addition to the C3 moiety, the second ring moiety proves to be 6-membered, again the C6−C1−C2−C3 entity is planar; the C4−C5 moiety is twisted forming all-to-gether the characteristic half-chair conformer (cf. Fig. 6). In case of cyclohexene as the second moiety (29 and 30) with even more steric rigidity only one boat and one completely flat conformer were found, the latter more stable for steric reasons; the preferred conformer of 30 is slightly twisted. Also the tris-cyclooctanes 31−35 prefer the boat conformer (cf. Fig. 6); the two threemembered ring moieties now in one structure are positioned syn or anti to each other (for preferred conformers of 24 to 36syn/anti cf. Supporting Information).


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Figure 6. Preferred conformer of 27(above) and 32(syn) (below).

Both experimental and computed δ(1H)/ppm of 24−36 are given in the Supporting Information. Up to very few exceptions [olefinic proton in 29 and 30;39 H3b/6b in 31syn;40 H7endo in 34syn29and H5b in 36syn/anti],41 the margin of error add up to less than ∆δ < 0.3 ppm only which prove the useful quality of obtained structures. The δ(1H)/ppm sequence proves to be correctly reproduced by present computations. Substituent influences (±M/±I) are remarkable (cis protons more than trans analogues), obviously due to steric proximity. In case of missing experimental data (due to the latter results) computed δ(1H)/ppm have been applied for further discussions. The strong influence of the cyclopropane anisotropic (ring current) effect is apparent, e.g. in 26syn/anti: The syn-proton H4 in 26anti proves to be strongly high-field shifted [26anti: δ(H4) = 3.79 ppm (comp.); 3.97 ppm (exp.)42] with respect to the same proton in 26syn [(H4) = 4.33 ppm (comp.); 4.34 ppm (exp.)42]. When comparing the anisotropy effects of cyclopropane and oxirane (24 and 25, respectively) the latter above/below the plane of the three-membered ring proved to be remarkably lower (vide supra, cf. Fig. 4): The stronger shielding of the syn-C4 protons in cyclopropane [24: δ(H4syn) = 1.13 ppm (comp.); 1.02 ppm (exp.)43 and 25: δ(H4syn) = 1.52 ppm (comp.); 1.36 ppm (exp.)44] confirm the latter ascertainment. The same result is obtained if the sixACS Paragon Plus Environment


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membered ring analogues 27 and 28, respectively [27: δ(H4,5syn) = 0.97 and 1.40 ppm (comp.) and 28: δ(H4,5syn) = 1.50 and 1.46 ppm (comp.); 1.41 ppm (exp.)45], as well as 31syn/anti,40 32syn/anti29 and 33syn/anti46 have been compared: generally the more severe upfield anisotropy/ring current effect of cyclopropane is observed, and, obviously, can be of potential assignment use. There are a number of further examples of the δ(1H)/ppm assignment-efficient applicability of the cyclopropane anisotropy effect (see Supporting Information). In the bis- and tris-cyclic structures studied the computed anisotropic/ring current effect of the three-membered rings is superimposed by the remaining anisotropic effects the residual bonds within the studied molecules (cf. Supporting Information). The studied structures were tried to be viewed in a way to visualize relevant information, however, only small differences compared with the situation in the mono-cycles could be found: as a general result can be concluded that changes of the anisotropic effect of cyclopropane and oxirane (in the cases were it could be isolated and is not covered completely by the anisotropic effects of the remaining structural moieties) are not significant in the studied bis- and tris-cyclic structures. Thus, in order to quantify this anisotropy effect, the TSNMRS values have been employed (vide infra). The ring current/anisotropy effect of the three-membered rings is put inside the bis- and tris-cyclic structures at the correct position, protons in the studied molecules were included as ghost atoms at their correct positions in the studied structures and the corresponding anisotropy/ring current effect on their δ(1H)/ppm values is quantitatively calculated (cf. Fig. 7).

Figure 7. Stereochemistry of 24 (left), ghost atoms (green) without (middle) and within the computed structure (right) for which δ(1H)/ppm values subject to the anisotropy effect of cyclopropane were calculated as TSNMRS values.


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Hereby, the isolated shielding/deshielding effect of cyclopropane or/and oxirane on the remaining protons of the studied molecules can be quantified, and subsequently related to experimental ∆δ(1H)/ppm variations.47 A number of comparable structures among the bisand tris-cyclic analogues are available with differences in δ(1H)/ppm which can be subjected mainly or partly to the anisotropy/ring current effect of cyclopropane and oxirane

(cf.

Supporting Information):

(i) Firstly in bicyclo[3.1.0]hexane 24 and 6-oxabicyclo[3.1.0]hexane 25, chemical shift differences ∆δ(1H)/ppm between the protons at C4 can be calculated and compared with the ring current effect of cyclopropane and oxirane, respectively, as computed TSNMRS values: 24: ∆δ(1H)/ppm: 0.49 ppm (TSNMRS) and 0.40 ppm (exp. value); 25: ∆δ(1H)/ppm: 0.38 ppm (TSNMRS) and 0.19 ppm (exp. value). 0.55 0.75 0.26

24

0.35 0.25 0.54

25

0.16 0.64

The sequence proves correct in both cases: the 4-proton syn to the three-membered ring is high-field shifted. The agreement in case of cyclopropyl (24) is excellent−obviously the chemical shift difference between the protons at C4 are dominated by the cyclopropane anisotropy effect. The anisotropy effect of oxirane proves to be smaller (vide supra) and the computed anisotropy effect in 25 is larger than experimental ∆δ(1H)/ppm; obviously, participation of other influences on ∆δ(1H)/ppm increases.

(ii) Protons H4 in the syn/anti isomers of 3-bicyclo[3.1.0]hexanol 26 are another unequivocal proof (vide supra): 26syn (H4 = 4.33 ppm (calc.); 4.34 ppm (exp.); 26anti(H4 = 3.79 ppm (calc.); 3.97 ppm (exp.) − ∆δ(1H)/ppm: 0.54 ppm (TSNMRS) and 0.37 ppm (exp. value)



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in correct sequence with the H4 proton in 26anti at high-field. Again the computed anisotropy effect proves larger, other structural influences contribute either. 0.53

26syn

0.27 0.22 0.34 0.51 0.76

26anti

0.08 0.34

(iii) ∆δ(1H)/ppm differences between H4,5 proton in 27 and 28 as well as between H5 protons in 30 from both TSNMRS as well as experimental shift differences are negligible only (cf. Supporting Information) − any severe anisotropic offect of cyclopropane and oxirane moieties, respectively, cannot be reported. (iv) The remaining syn/anti isomers of tricyclo[5.1.0.03,5]octanes 31 and heterocyclic analoges 32-35 are excellent examples as well to check the stereochemistry assignmentusability of the anisotropy effect of three-membered rings. Experimental chemical shift differences e.g. of the H4,5 protons between 32syn and 32anti are negligible [∆δ(1H) = 0.02 ppm]; the anisotropy effect was computed to be 0.07 ppm in correct order (in 32anti at highfield). Similar ∆δ(1H)/ppm differences were computed and experimentally found in 33-35; in these cases, obviously the anisotropy effect of the three membered rings proves to be not the dominating effect.

(v) Differently behave the exo/endo protons at C7 when comparing 31syn/anti, 32syn/anti and 34syn/anti, respectively: if e.g. in 31syn compared with 31anti the two C7 protons are subjected to the C3 anisotropy/ring current effect, on the H7endo proton a highfield shift of 0.55 ppm (on the corresponding H7exo proton 0.19 ppm also to high-field) can be reported:


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0.55 0.19 0.11

31syn

0.36 0.33 0.37 0.31 0.13

31anti

0.10 0.34

This is both in direction and amount in agreement with the experiment:48 31syn: δ(H7endo) = −0.19 ppm; δ(H7exo) = 0.64 ppm); experimental δ(1H)/ppm of the protons in 31anti are not reported yet.

(vi) The same anisotropy/ring current effects of the three-membered ring moieties were computed when comparing 32syn/anti49,50 [32syn/32anti − ∆δ(H7endo) = 0.95 ppm (computed 0.55 ppm) and ∆δ(H7exo) = 0.40 ppm, computed 0.15 ppm], however, only if the experimental assignment of the syn/anti isomers in 32 is reversed (cf. Supporting Information).51-53

Thus, computed TSNMRS values of the anisotropy/ring current effect of the threemembered ring moieties proved to be both in size and direction in agreement with the experimental ∆δ(1H)/ppm values. There are still small differences which can be, however, definitely assigned to (i) the margin of error of the computation of the anisotropy/ring current effect but also (ii) to parallel steric effects in these highly strained structures which point in terms of ∆δ(1H)/ppm values into the same direction.54 On the corresponding usability of the computed anisotropy/ring current effect of three membered ring moieties for assignment purposes in proton NMR spectroscopy of relevant structures can be concluded.



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4. SUMMARY AND CONCLUSIONS The spatial magnetic properties (Through Space NMR Shieldings - TSNMRS) of cyclopropane, of the hetero-analogeous oxirane, thiirane and aziridine, and of various substituted mono-, dis- and tris-cyclic analogues have been computed by the GIAO perturbation method employing the Nucleus Independent Chemical Shift (NICS) concept and visualized as Iso-Chemical-Shielding Surfaces (ICSS) of various size and direction. These TSNMRS values were employed to visualize the anisotropy (ring current) effect of the cyclopropane ring (and aziridine, oxirane, and thioxirane). In addition, the following results were obtained: (i) The anisotropy effect of the three-membered ring moiety, with a single substituent attached to, or a single heteroatom as ring-member, proves to be only less susceptible: shielding above/below the ring plane up to distances of more than 5Å (ICSS = 0.10 ppm highfield from centre) can be definitely provided as hard criterion for assignment purposes in proton NMR spectroscopy. (ii) Both structures and ring current (anisotropy) effect of the three membered ring moiety on the protons of a number of bis- and tris-cyclic compounds containing one and two cyclopropane and oxirane ring moieties were computed. (iii) When comparing computed (as TSNMRS values) and experimental ∆δ(1H)/ppm values, on the corresponding usability of the computed anisotropy/ring current effect of three membered ring moieties for assignment purposes in proton NMR spectroscopy of relevant structures can be concluded; characteristic examples are given.

■ ASSOCIATED CONTENT Supporting information. Absolute energies, Cartesian coordinates of 1–36 computed at the MP2/aug-cc-pVTZ level of theory, computed and experimental 1H and 13C chemical shifts of 24−36, structures (preferred conformers) and TSNMRS (visualized as ICSSs: blue represents 5 ppm shielding, cyan 2 ppm shielding, greenblue 1 ppm, green 0.5 ppm shielding, yellow 0.1 ppm shielding and red −0.1 ppm deshielding) of the same compounds 24−36 and preferred conformers of the studied bis- and tris-cyclic structures 24-36 syn/anti and the ring current effect of the three-membered ring [as TSNMRS δ(1H)/ppm] on relevant protons in these bisand tris-membered structures. This information is available free of charge via the Internet at http://pubs.acs.org.


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■ AUTHOR INFORMATION Corresponding Author *E-mail: [email protected].

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Kleinpeter, E.; Klod, S.; Rudorf, W.-D. Electronic State of Push-Pull Alkenes: An Experimental Dynamic NMR and Theoretical ab Initio MO Study. J. Org. Chem. 2004, 69, 4317−4329.

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Kleinpeter, E.; Klod, S. Separation of Anisotropic and Steric Substituent Effects NCS Analysis of H-4 and C-4 in Phenanthrene and 11-Ethynylphenanthrene. J. Am. Chem. Soc. 2004, 126, 2231−2236.

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Szatmári, I.; Martinek, T. A.; Lázár, L.; Koch, A.; Kleinpeter, E.; Neuvonen, K.; Fülöp, F. Stereoelectronic Effects in Ring-Chain Tautomerism of 1,3Diarylnaphth[1,2-e][1,3]oxazines and 3-Alkyl-1arylnaphth[1,2-e][1,3]oxazines. J. Org. Chem. 2004, 69, 3645−3653.



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Ryppa, C.; Senge, M. O.; Hatscher, S. S.; Kleinpeter, E.; Wacker, Ph.; Schilde, U.; Wiehe, A. Synthesis of Mono- and Disubstituted Porphyrins: A- and 5,10-A2-Type Systems. Chem. Eur. J. 2005, 11, 2427−3442.

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Kleinpeter, E.; Schulenburg, A.; Zug, I.; Hartmann, H. The Interplay of Thio(seleno)amide/Vinylogous Thio(seleno)amide “Resonance” and the Anisotropic Effect of Thiocarbonyl and Selenocarbonyl Functional Groups. J. Org. Chem. 2005, 70, 6592−6602.

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Kleinpeter, E.; Schulenburg, A. Quantification of the Push-pull Effect in Tolanes and a Revaluation of the Factors Affecting the 13C Chemical Shifts of the Carbon Atoms of the C≡C Triple Bond. J. Org. Chem. 2006, 71, 3869−3875.

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Kleinpeter, E.; Koch, A.; Seidl, P. R. Visualization and Quantification of the Anisotropic Effect of C=C Double Bonds in Highly Congested Hydrocarbons–Indirect Estimates of Steric Strain. J. Phys. Chem. A 2007, 112, 4989−4995.

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Baranac-Stojanovic, M.; Koch, A.; Kleinpeter, E. Is the Conventional Interpretation of the Anisotropic Effect of C=C Double Bonds and Aromatic Rings in NMR Spectra in Terms of π-Electron Shielding/Deshielding Contributions Correct? Chem. Europ. J. 2012, 18, 370−376.

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Baranac-Stojanovic, M.; Koch, A.; Kleinpeter, E. Density Functional Calculations of the Anisotropic Effects of Borazine and 1,3,2,4-Diazaboretidine. ChemPhysChem 2012, 13, 3803−3811.

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(a) Lazzeretti, P. Assessment of Aromaticity via Molecular Response Properties. Phys. Chem. Chem. Phys. 2004, 6, 217−223; (b) Pelloni, St.; Lazzeretti, P.; Zanasi, R. Assessment of σ-Diatropicity of the Cyclopropane Molecule. J. Phys. Chem. A 2007, 111, 8163−8169; (c) Stanger, A. What is ... Aromaticity: a Critique of the Concept of Aromaticity−Can it Really be Defined? Chem. Commun. 2009, 1939−1947.

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(a) Fallah-Bagher-Shaidaei, H.; Wannere, C. S.; Corminboeuf, C.; Puchta, R.; von Ragué Schleyer, P. Which NICS Aromaticity Index for Planar π Rings Is Best? Org. Lett. 2006, 8, 863−866; (b) Corminboeuf, C.; Heine, T.; Seifert, G.; von Ragué Schleyer, P.; Weber, J. Induced Magnetic Fields in Atomatic [n]Annulenes−Interpretation of NICS Tensor Components. Phys. Chem. Chem. Phys. 2004, 6, 273−276.

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Kleinpeter, E.; Lämmermann, A.; Kühn, H. The Anisotropic Effect of Functional Groups in 1H NMR Spectra is the Molecular Response Property of Spatial NICS. Org. Biomol. Chem. 2011, 9, 1098−1111; (b) Kleinpeter, E.; Koch, A. The Anisotropic


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Effect of Functional Groups in 1H NMR Spectra is the Molecular Response Property of spatial NICS–the Frozen Conformational Equilibria of 9-Arylfluorenes. Tetrahedron 2011, 67, 5740−5743. (18)

Kleinpeter, E.; Klod, S.; Koch, A. Visualization of Through Space NMR Shieldings of Aromatic and anti-Aromatic Molecules and a Simple Means to Compare and Estimate Aromaticity. J. Mol. Struct. (THEOCHEM) 2007, 811, 45-60 − Computational Organic Chemistry, a special issue edited by Otilia Mó and Manuel Yáñez.

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Kleinpeter, E.; Klod, S.; Koch, A. Endohedral and External Through-Space Shieldings of the Fullerenes C50, C60, C606-, C70 and C706- − Visualization of (Anti)Aromaticity and Their Effects on the Chemical Shifts of Encapsulated Nuclei. J. Org. Chem. 2008, 73, 1498−1507.

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Kleinpeter, E.; Koch, A. Chelatoaromaticity–Existing Yes or No? An Answer Given by Spatial Magnetic Properties. Phys. Chem. Chem. Phys. 2011, 13, 20593−20601.

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Kleinpeter, E.; Holzberger, A.; Wacker, Ph. Quantification of the (Anti)Aromaticity of Fulvalenes Subjected to π-Electron Cross-Delocalization. J. Org. Chem. 2008, 73, 56−65.

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(a) Tóth, G.; Kovács, J.; Lévai, A.; Koch, A.; Kleinpeter, E. NMR and QuantumChemical Study of the Stereochemistry of Spiroepoxides Obtained by Oxidation of (Z)-3-Arylidene-1-thioflavan-4-ones. Magn. Reson. Chem. 2001, 39, 251−258; (b) Kovács, J.; Tóth, G.; Simon, A.; Lévai, A.; Koch, A.; Kleinpeter, E. 1H, 13C, 17O NMR and Quantum-Chemical Study of the Stereochemistry of the Sulfoxide and Sulfone Derivatives of 3-Arylidene-1-thioflavan-4-one Epoxides. Magn. Reson. Chem. 2003, 41, 193−201.

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Only protons with a minimal distance of 2.5 to 3 Å to the three-membered ring were considered; more proximate protons would lie within the electronic cloud of cyclopropane and oxirane, and δ(1H)/ppm values were no longer determined substantially by the anisotropy/ring current effect only.

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Abraham, R. J.; Leonard, P.; Tormena, C. F. 1H NMR Spectra. Part 28: Proton Chemical Shifts and Couplings in Three-Membered Rings. A Ring Current Model for



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Cyclopropane and a Novel Dihedral Angle Dependence for 3JHH couplings Involving the Epoxy Proton. Magn. Reson. Chem. 2012, 50, 305−313. (51)

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Kleinpeter, E.; Szatmári, I.; Lázár, L.; Koch, A.; Heydenreich, M.; Fülöp, F. Visualization and Quantification of Anisotropic Effects on the 1H NMR Spectra of 1,3-Oxazino[4,3-a]isoquinolines−Indirect Estimates of Steric Compression. Tetrahedron 2009, 65, 8021−8027.


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Table of contents graphic: Erich Kleinpeter, Stefanie Krüger and Andreas Koch: The Anisotropy Effect of ThreeMembered Rings in 1H NMR Spectra−Quantification by TSNMRS and Assignment of the Stereochemistry


Anisotropy Effect of Three-Membered Rings in 1H NMR Spectra

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