Density Functional Theory Computational Reexamination of the

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Density Functional Theory Computational Reexamination of the Anomeric Effect in 2-Methoxy- and 2-Cyano-1,3-Dioxanes and 1,3-Dithianes. Stereoelectronic Interactions Involving the Cyano (C#N:) Group Revealed by Natural Bond Orbital (NBO) Analysis. Eusebio Juaristi, and Rafael Notario J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01458 • Publication Date (Web): 19 Jul 2018 Downloaded from http://pubs.acs.org on July 19, 2018

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The Journal of Organic Chemistry

Density Functional Theory Computational Reexamination of the Anomeric Effect in 2-Methoxy- and 2-Cyano-1,3-Dioxanes and 1,3-Dithianes. Stereoelectronic Interactions Involving the Cyano (C≡N:) Group Revealed by Natural Bond Orbital (NBO) Analysis. Eusebio Juaristi*,1,2 and Rafael Notario*,3 1

Departamento de Química, Centro de Investigación y de Estudios Avanzados, Avenida

IPN # 2508, 07300 Ciudad de México, Mexico. 2El Colegio Nacional, Donceles # 104, Centro Histórico, 06020 Ciudad de México, Mexico. 3Instituto de Química Física Rocasolano, CSIC, Serrano 119, 28006 Madrid, Spain. E-mail: [email protected] and/or [email protected]

Abstract. The present study reports DFT geometry optimization of the anancomeric (ring conformationally anchored) axial r2-methoxy-trans-4,trans-6-dimethyl- and r2cyano-trans-4,trans-6-dimethyl-1,3-dioxanes (1-ax and 3-ax), the equatorial isomers (2eq and 4-eq), the axial r2-cyano-trans-4,trans-6-dimethyl-1,3-dithianes (5-ax and 7-ax) and the equatorial isomers (6-eq and 8-eq). The computational results do reproduce the anomeric effect in 1-8, and most importantly Weinhold’s NBO analysis supports the contribution of n(X) → σ*(C−Y) stereoelectronic interactions that stabilize the axial isomers. Furthermore, NBO analysis of the delocalization energy E(2) of properly aligned filled/empty orbitals in these isomeric 2-polar substituted heterocycles reveals that n(O) → σ*(C−Hax) is responsible for the increased charge density at C(2)−Hax in the equatorial isomers, providing an explanation for the computational observation that very recently led Wiberg, Bailey, Lambert and Stempel [J. Org. Chem. 2018, 83, 52425255] to discard a potential contribution of n(X) → σ*(C−Y) stereoelectronic interactions that stabilize the axial isomers. Interestingly, during the course of this study two relevant stereoelectronic interactions involving the cyano group were revealed, n(N) → σ*(NC−C) and σ(C(2)−H) → σ*(C−N). Keywords.

Anomeric

effect,

Stereoelectronic

effects,

Hyperconjugation,

Conformational analysis, Density functional theory, Natural bond orbitals.

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Page 2 of 22

Introduction Six decades ago, the unanticipated preference of electronegative substituents to occupy the axial rather than the equatorial orientation at anomeric positions in pyranose derivatives was termed the “anomeric effect” by Lemieux and Chu.1 From the beginning, this conformational effect caught the attention of chemists as it turns out to be relevant in order to explain the peculiar structural properties and reactivity of heterocyclic systems, as well as open-chain analogs containing anomeric X−C−Y segments. Most frequently, the anomeric effect has been explained in terms of dipole-dipole repulsion in the equatorial isomer2 (Scheme 1a), or as a consequence of a stabilizing interaction between the axial lone electron pair on the ring heteroatom “X” and the antiperiplanar antibonding orbital of the axial C(2)−Y bond, that is n(X) → σ*(C−Y) hyperconjugation (Scheme 1b).3 Nevertheless, the underlying fundament of the anomeric effect continues to be a matter of debate,4,5 and it is evident that further investigation of this important effect is still required.

(a)

X

C2

Y

C2

X

Y

(b)

X

X

X+ Y−

Y Y Incorrectly aligned for stabilizing orbital ovelap

Correctly aligned for stabilizing orbital overlap

Double bond-no bond resonance

Scheme 1. Interpretation of the anomeric effect in terms of (a) dipole-dipole repulsive interaction in the equatorial isomer, and (b) two orbital-two electron stabilization of the axial conformer by n(X) → σ*(C−Y) stereoelectronic interaction, which is effective in the antiparallel orientation of the donor and acceptor orbitals.


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In this regard, very recently Wiberg, Bailey, Lambert and Stempel6 reported the chemical equilibration of ring conformationally anchored (anancomeric) axial r2methoxy-trans-4,trans-6-dimethyl-1,3-dioxane (1-ax) and axial r2-cyano-trans-4,trans6-dimethyl-1,3-dioxanes (3-ax), and the equatorial isomers (2-eq and 4-eq) (Scheme 2). The two isomeric pairs were equilibrated in solution under Brønsted or Lewis acid catalysis, and both equilibria exhibited in non-polar solvents a preference for the axial isomers. In particular, free energy difference between 1-ax and 2-eq in Et2O and cyclohexane was determined as +0.40 kcal·mol-1 and +0.51 kcal·mol-1, respectively, favoring the axial isomer. By comparison, the conformational equilibria of 2-cyano analogs 3-ax and 4-eq show an even larger predominance of the axial isomers, ∆Gº = +0.93 kcal·mol-1 in Et2O and ∆Gº = +1.34 kcal·mol-1 in cyclohexane. The experimental study of Wiberg, Bailey, and coworkers summarized above was complemented by a computational study (MP2/6-311+G* followed by reexamination at MP2/aug-cc-pVTZ using the MP2/6-311+G* geometries) of 1,3-dioxanes 1-4, which was further extended by similar computational analysis of axial r2-cyano-trans-4,trans6-dimethyl-1,3-dithianes (5-ax and 7-ax), and the equatorial 1,3-dithiane isomers (6-eq and 8-eq) (Scheme 2).6



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OCH3

O

H3C

O H3C

OCH3

O

H3C

O H3C

2-eq

1-ax CN

H3C

O

H3C O

CN

O O

H3C

H3C

4-eq

3-ax OCH3

H3C H3C

S

H3C S

OCH3

S S

H3C

5-ax

6-eq CN

H3C

S

CN

S

H3C

S

S H3C

H3C

8-eq

7-ax

Scheme 2. Chemical equilibration of anancomeric 2-methoxy- and 2-cyano-1,3dioxanes (1-4) and 1,3-dithiane analogs (5-8). The calculated (in the gas phase) data are summarized in Table 1. Most salient is the significant axial preference predicted for the four equilibria, which is consistent with the anticipated anomeric effect in O−C−Y and S−C−Y (Y = OCH3, CN) segments. Wiberg, Bailey, et al. also calculated relevant bond lengths for the substituted 1,3-dioxanes (1-4) and 1,3-dithianes (5-8) of interest.6 The calculated structural changes are in line with anticipation in terms of n(X) → σ*(C−Y) hyperconjugation: the axial C−Y bond is lengthened, the carbon to ring heteroatom bond is shortened, and the adjacent equatorial C−H bond is also shortened in the isomer having an axial substituent. Nevertheless, calculated Hirshfeld charges were interpreted as contrary to the operation of n(X) → σ*(C−Y) hyperconjugation. In particular, the authors were surprised by the calculated 4 ACS Paragon Plus Environment

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decreased charge density at the equatorial hydrogen in the axially substituted heterocycles.6

Table 1. Axial

⇌

Equatorial Conformational Energy Differences Calculated at the

MP2/aug-cc-pVTZ Level in kcal·mol-1.6 _________________________________________________________________________________________________________________

entry heterocycle ring 2-substituent ∆G° ______________________________________________________________________ 1 1,3-dioxane OCH3 +0.78 2

1,3-dioxane

CN

+1.89

3

1,3-dithiane

OCH3

+3.57

4 1,3-dithiane CN +2.82 ______________________________________________________________________

In the present work, we report a theoretical re-examination [with Natural Bond Orbital (NBO) theory – a method of choice for quantifying stereoelectronic interactions]7,8 of the conformational behavior of 1,3-dioxanes 1-4 and 1,3-dithianes 5-8.

Computational methods. The package of Gaussian 09 programs was used to carry out all calculations.9 Molecular structures of minimum energy were fully optimized at the B3LYP/aug-cc-pVTZ level of theory. Potential hyperconjugative interactions were evaluated with Natural Bond Orbital analysis, NBO program (version 3.1).10 All calculations were performed for isolated molecules in the gas phase, and no corrections for solvent effects were made.

Results and Discussion Figure 1 presents the structures of minimum energy for axial and equatorial ring anchored 2-methoxy-1,3-dioxanes (1-ax and 2-eq), 2-cyano-1,3-dioxane (3-ax and 4eq), 2-methoxy-1,3-dithiane (5-ax and 6-eq), and 2-cyano-1,3-dithiane (7-ax and 8eq). Figure 2 collects the corresponding delocalization energies for the most relevant two orbital-two electron hyperconjugative interactions in these heterocycles. (For a more complete listing see Table S-2 in the Supporting Information).



Page 6 of 22

Figure 1. Optimized structures and relative energies for 1-ax, 2-eq, 3-ax, 4-eq, 5-ax, 6eq, 7-ax, and 8-eq at B3LYP/aug-cc-pVTZ level of theory.

1-ax, Erel = 0.0 kcal·mol-1

2-eq, Erel = +0.29 kcal·mol-1






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Figure 2. Most relevant delocalization energies, E(2), for 1-ax, 2-eq, 3-ax, 4-eq, 5-ax, 6-eq, 7-ax, and 8-eq at B3LYP/aug-cc-pVTZ level of theory . CH3 8

O7 4

3

9

H3C

6

2

O

H

1

O

5

H3C

10

2-eq 1-ax Interaction

E(2)/kcal·mol-1

∆E/Hartrees

E(2)/kcal·mol-1

∆E/Hartrees

n(O1) → σ*(C2‒H)

2.62

0.93

5.53

0.66

n(O3) → σ*(C2‒H)

2.43

0.94

5.53

0.66

n(O1) → σ*(C6‒Hax)

6.45

0.69

6.26

0.67

n(O3) → σ*(C4‒Hax)

6.58

0.68

6.26

0.67

n(O7) → σ*(C2‒H)

4.76

0.67

2.81

0.91

n(O7) → σ*(C2‒O3)

12.28

0.60

11.39

0.59



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n(O7) → σ*(C2‒O1)

3.63

0.90

11.42

0.59

n(O1) → σ*(C2‒O7)

11.94

0.59

3.71

0.93

n(O3) → σ*(C2‒O7)

11.82

0.59

3.71

0.93

n(O1) → σ*(C2‒O3)

9.60

0.60

11.37

0.60

n(O3) → σ*(C2‒O1)

8.77

0.63

11.36

0.60

σ(C2‒H) → σ*(O1‒C6)

4.29

0.80

---

---

σ(C2‒H) → σ*(O3‒C4)

4.12

0.80

---

---

σ(C2‒H) → σ*(O7‒C8)

---

---

5.15

0.81


E(2)/kcal·mol-1

∆E/Hartrees

E(2)/kcal·mol-1

∆E/Hartrees

n(O) → σ*(C2‒H)

2.95

0.95

5.55

0.65

n(O) → σ*(C6‒Hax)

6.07

0.69

5.43

0.67

n(O) → σ*(C2‒C)

7.65

0.68

1.73

1.00

n(O) → σ*(C2‒O)

10.27

0.61

12.92

0.60

n(N) → σ*(C‒C)

11.76

0.89

12.41

0.93

σ(N‒C) → σ*(C‒C2)

2.50

1.43

3.55

1.46

σ(N‒C) → σ*(C2‒H)

2.07

0.71

2.33

0.68

σ(N‒C) → σ*(C2‒O)

2.67

0.64

2.84

0.63


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σ(C2‒C) → σ*(C‒N)

2.57

1.62

3.92

1.64

σ(C2‒H) → σ*(C‒N)

6.93

0.64

6.62

0.65

σ(O‒C2) → σ*(C‒N)

2.49

1.76

2.64

1.77

σ(C2‒H) → σ*(O‒C4)

3.82

0.80

---

---

CH3 8

O7 4

3

9

H3C

6

2

S

H

1

S

5

H3C

10


E(2)/kcal·mol-1

∆E/Hartrees

E(2)/kcal·mol-1

∆E/Hartrees

n(S1) → σ*(C2‒H)

---

---

3.13

0.63

n(S3) → σ*(C2‒H)

---

---

3.13

0.63

n(S1) → σ*(C6‒Hax)

4.05

0.62

3.58

0.62

n(S3) → σ*(C4‒Hax)

3.94

0.62

3.58

0.62

n(O) → σ*(C2‒H)

4.19

0.68

3.21

0.95

n(O) → σ*(C2‒S3)

12.88

0.44

9.98

0.44

n(O) → σ*(C2‒S1)

1.08

0.46

9.99

0.44

n(S1) → σ*(C2‒O)

8.40

0.51

---

---

n(S3) → σ*(C2‒O)

7.95

0.52

---

---

n(S1) → σ*(C2‒S3)

4.94

0.36

6.40

0.37

n(S3) → σ*(C2‒S1)

4.39

0.39

6.40

0.37

σ(C2‒H) → σ*(S1‒C6)

1.55

0.69

---

---



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σ(C2‒H) → σ*(S3‒C4)

1.41

0.69

---

---

σ(C2‒H) → σ*(O‒C8)

---

---

5.31

0.81

σ(C5‒Heq) → σ*(C6‒S1)

5.40

0.64

5.49

0.64

σ(C5‒Heq) → σ*(C4‒S3)

5.42

0.64

5.49

0.64


E(2)/kcal·mol-1

∆E/Hartrees

E(2)/kcal·mol-1

∆E/Hartrees

n(S) → σ*(C2‒H)

---

---

3.44

0.62

n(S) → σ*(C4‒Hax)

4.04

0.63

3.51

0.63

n(S) → σ*(C2‒C)

4.39

0.66

---

---

n(S) → σ*(C2‒S)

5.08

0.37

6.57

0.38

n(N) → σ*(C‒C)

12.26

0.94

12.37

0.95

σ(N‒C) → σ*(C‒C2)

5.64

1.48

6.03

1.49

σ(N‒C) → σ*(C2‒H)

3.16

0.73

2.93

0.72

σ(N‒C) → σ*(C2‒S)

2.69

0.47

2.49

0.48

σ(C2‒C) → σ*(C‒N)

5.87

1.64

6.51

1.64

σ(C2‒H) → σ*(C‒N)

5.69

0.66

5.85

0.66

σ(S‒C2) → σ*(C‒N)

4.23

0.71

4.75

0.70

σ(C2‒H) → σ*(S‒C4)

1.28

0.69

---

---


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σ(C5‒Heq) → σ*(C‒S)

5.48

0.64

5.40

0.64

NBO analysis of 1-ax and 2-eq 2-methoxy diastereomers (Figure 1) provided several important observations: (1) E(2) values support the importance of hyperconjugative n(O) → σ*(C−Oax) interactions that are in accordance with Altona’s model explaining the stabilization of the axial orientation of the methoxy group in anomeric carbons,3 (2) the significant delocalization energy for the n(O1) → σ*(C−O3) stereoelectronic interaction is in line with the existence of an intramolecular anomeric effect, and (3) the significant magnitude of the E(2) value for the n(O) → σ*(C2−Hax) hyperconjugative interaction in 2-eq implies electron delocalization and therefore an increase in charge at C2−Hax. A similar n(O) → σ*(C2−Heq) stereoelectronic interaction is much less important 1-ax because of the gauche rather than antiperiplanar orientation of the donor oxygen lone pair and the acceptor antibonding σ*(C(2)−H) bond. Thus, the calculated6 decreased charge density at the equatorial hydrogen in the axially substituted heterocycles is in line with the relevance of two orbital-two electron stabilizing interactions in properly aligned (antiperiplanar) and cannot be used as an argument to discard the potential importance of n(X) → σ*(C−Y) stereoelectronic interactions that stabilize the axial orientation of the polar 2-methoxy substituent. NBO analysis of the 3-ax and 4-eq 2-cyano diastereomeric pair (Figure 2) confirm the salient observations made in the 1-ax/2-eq pair: (1) E(2) values support the importance of hyperconjugative n(O) → σ*(C−CNax) interactions explaining the stabilization of the axial orientation of the cyano group at anomeric carbon C2, (2) the existence of an intramolecular anomeric effect as evidenced by the significant delocalization energy for the n(O1) → σ*(C−O3) stereoelectronic interaction, and (3) the significant E(2) value for the n(O) → σ*(C2−Hax) hyperconjugative interaction in 4-eq indicates electron delocalization and therefore an increase in charge at C2−Hax. By contrast, n(O) → σ*(C2−Heq) stereoelectronic interaction is much less important in 3-ax as a consequence of the gauche rather than antiperiplanar orientation of the donor oxygen lone pair and the acceptor antibonding σ*(C2−H) bond. In our opinion, this observation explains the calculated decreased charge density at the equatorial hydrogen in the axially substituted heterocycles observed by Wiberg, Bailey, et al.,6 ruling out the 11 ACS Paragon Plus Environment


Page 12 of 22

argument against the potential importance of an n(X) → σ*(C−Y) stereoelectronic interaction that is based on this electron charge difference. Additional theoretical support for the operation of the n(O) → σ*(C2−Hax) hyperconjugative interaction in 2-eq and 4-eq was obtained from estimation of 1JC-H coupling constant in 1-ax, 2-eq, 3-ax and 4-eq (Table 2). As anticipated in terms of the so-called Perlin effect, two-electron/two-orbital stereoelectronic interactions weaken the acceptor (or donor) C–H bonds and attenuate the Fermi contribution to the onebond 13C–1H coupling constants, affording smaller coupling constants.11 In the system at hand, 1JC-H for the axial C(2)-H bonds in equatorial 2-eq and 4-eq are indeed smaller than 1JC-H for the equatorial C(2)-H bonds in axial 1-ax and 3-ax, ∆Jeq/ax = 6.2 and 15.6 Hz, respectively (Table 2). It is worth mentioning that earlier studies on the Perlin effect do support the decreased charge of Heq relative to Hax in six-membered heterocycles.11b Table 2. B3LYP/aug-cc-pVTZ-calculated 1JC(2)-H coupling constants in 1-ax, 2-eq, 3-ax and 4-eq, in Hz.

Species

1

JC(2)-H

∆Jeq/ax

1-ax

199.0

6.2

2-eq

192.8

3-ax

183.6

4-eq

168.0

15.6

In this regard, although the absolute values for the NBO natural charges calculated for the hydrogens in C(2)-H differ to some extent from the Hirshfeld charges obtained by Wiberg, Bailey, Lambert and Stempel, the relative differences agree quite well, showing decreased charge when passing from C(2)-Heq to C(2)-Hax (Table 3). Table 3. Natural charges at the H joined to C(2).

1-ax

Hax

Heq

---

0.147


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2-eq

0.125

---

3-ax

---

0.214

4-eq

0.166

---

5-ax

---

0.193

6-eq

0.185

---

7-ax

---

0.269

8-eq

0.240

---

The computational data presented in Figure 2 also provide evidence for two relevant stereoelectronic interactions involving the cyano group: n(N) → σ*(NC−C) and σ(C2−H) → σ*(C−N). These interactions are anticipated to result in a lengthening of the C2−H bond, shortening of the C2−CN bond, and lengthening of the CN bond (Scheme 3). N X

C

N−

σC-H

σ*C-N

H

X

A

X

C

X

H+

B

X = O, S N X

C

X

H

N+

nN

σ*C-C

A

X

C

X

H−

C



Page 14 of 22

Scheme 3. Stereoelectronic interactions involving the cyano group, uncovered during the present NBO computational study.

It is worth pointing out that the stereoelectronic interactions involving the cyano group exhibited by the present NBO study and depicted in Scheme 3 should not influence the conformational equilibria 3-ax

⇌

4-eq and 7-ax

⇌

8-eq; nevertheless, they are rather

interesting in the context of the present study of stereoelectronic interactions and warrant their inclusion in this report. The delocalizing energies calculated for 1,3-dithianes 5-8 collected in Figure 2 are also in accordance with the stereoelectronic interactions disclosed in the 1,3-dioxane derivatives 1-4. Nevertheless, the relative magnitude of the corresponding E(2) values shows that sulfur is not as efficient donor as oxygen. For example, the n(O) →

σ*(C2−Oax) stereoelectronic interaction in 1-ax associated to a delocalization energy E(2) = 11.94 kcal·mol-1, whereas n(S) → σ*(C2−Oax) in 5-ax exhibits E(2) = 8.40 kcal·mol-1. By the same token, n(O1) → σ*(C2‒Hax) in 2-eq is associated to an E(2) value equal to 5.53 kcal·mol-1, whereas n(S1) → σ*(C2‒Hax) in 6-eq is associated to E(2) = 3.13 kcal·mol-1.

Interestingly, 1JC-H for the axial C(2)-H bonds in equatorial 6-eq and 8-eq are larger than 1JC-H for the equatorial C(2)-H bonds in axial 5-ax and 7-ax, ∆Jeq/ax = −18.1 and

−7.6 Hz, respectively (Table 4); that is, C(2)-Heq are weaker than C(2)-Hax in the 1,3dithiane derivatives. Examination of the delocalization energies E(2) collected in Figure 2 suggests a plausible interpretation in terms of dominant σ(C2-Heq) → σ*(SC4,6) hyperconjugation.

Table 4. B3LYP/aug-cc-pVTZ-calculated 1JC(2)-H coupling constants in 5-ax, 6-eq, 7-ax and 8-eq, in Hz. Species

1

JC(2)-H

∆Jeq/ax


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5-ax

167.6

6-eq

185.7

7-ax

160.0

8-eq

167.6

-18.1

-7.6

Evidence indicating that sulfur is not as good donor as oxygen comes from comparison of the intramolecular X−C−Y anomeric effect in 1,3-dioxane versus 1,3-dithiane derivatives. Indeed, the delocalization energy for the n(O1) → σ*(C2−O3) in 4-eq (Figure 2) is significantly larger, E(2) = 12.92 kcal·mol-1, than the corresponding E(2) = 6.57 kcal·mol-1for n(S1) → σ*(C2−S3) in 8-eq (Figure 2). By contrast and not surprisingly, the stereoelectronic interactions involving the cyano group are quite similar in magnitude in the 1,3-dioxanes and 1,3-dithianes. Compare for example, the σ(C2‒H) → σ*(C‒N) two orbital-two electron interaction in 4-eq, E(2) = 6.62 kcal·mol-1 (Figure 2) with the same interaction in 7-ax, E(2) = 5.69 kcal·mol-1 (Figure 2). By the same token, the E(2) value for the n(N) → σ*(C‒C) stereoelectronic interaction in 3-ax is equal to 11.76 kcal·mol-1 (Figure 2), whereas the corresponding E(2) value for the nN → σ*(C‒C) stereoelectronic interaction in 8-eq is calculated as 12.37 kcal·mol-1 (Figure 2).

The interpretations advanced above are supported by deletion of the key NBO interactions followed by re-optimization of the geometries with these interactions switched off (NBODEL). The results are summarized in Table 5. In all cases, application of NBODEL while switching off the key hyperconjugative interactions led to lengthening of the C2−CN bonds and simultaneous shortening of the C−N and C2−H bonds, as anticipated in terms of n(N) → σ*(NC−C) and σ(C2−H) → σ*(C−N).

Table 5. Comparison of Structural Parameters in the Optimized Geometries of 3-ax, 4eq, 7-ax, and 8-eq with Those Optimized Geometries Obtained by NBODEL, When Switching Off Key NBO Interactions. Bond Lengths, in Å, at the HF/6-31G(d) Level 15 ACS Paragon Plus Environment


Page 16 of 22

of Theory. Values in Parentheses Are the Differences in the Bond Lengths with and without Deletion. CN

O

H3C

O

H3 C

3-ax

Optimized structure

Without n(N) → σ*(NC−C)

Without σ(C2−H) → σ*(C−N)

C−CN

1.509

1.533 (0.024)

1.559 (0.050)

Without both n(N) → σ*(NC−C) and σ(C2−H) → σ*(C−N) 1.580 (0.071)

C−N

1.134

1.129 (−0.005)

1.135 (0.001)

1.129 (−0.005)

C2 −H

1.078

1.077 (−0.001)

1.071 (−0.007)

1.070 (−0.008)

4-eq

CN

O

H3C

O

H3C

Optimized structure



C‒CN

1.483

1.503 (0.020)

1.518 (0.035)


C‒N

1.133

1.128 (−0.005)

1.133 (0.000)

1.128 (−0.005)

C2‒H

1.090

1.088 (−0.002)

1.084 (−0.006)

1.083 (−0.007)


Page 17 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


CN

S

H3C

S H3C

7-ax

Optimized structure



C‒CN

1.472

1.491 (0.019)

1.523 (0.051)


C‒N

1.135

1.129 (−0.006)

1.135 (0.000)

1.129 (−0.006)

C2‒H

1.082

1.081 (−0.001)

1.077 (−0.005)

1.077 (−0.005)

8-eq

CN

S

H3C

S

H3C

Optimized structure



C‒CN

1.467

1.485 (0.018)

1.507 (0.040)


C‒N

1.134

1.128 (−0.006)

1.134 (0.000)

1.128 (−0.006)

C2‒H

1.082

1.082 (0.000)

1.077 (−0.005)

1.076 (−0.006)

Conclusions High level DFT calculations at the B3LYP/aug-cc-pVTZ level of theory do reproduce the significant preference for the axial orientation of the polar substituents 2-methoxy and 2-cyano both in 1,3-dioxane and 1,3-dithiane frameworks. The Natural Bond Orbitals (NBO) method developed by Weinhold and co-workers12 is a very useful theoretical method for the study of hyperconjugative interactions present in 2-polar 17 ACS Paragon Plus Environment


Page 18 of 22

substituted 1,3-dioxanes 1-4 and 2-polar-substituted 1,3-dithianes 5-8. In particular, NBO analysis provided the energies of the delocalizing interactions that weaken the axial C2−OCH3 and C2−CN bonds of interest (endo anomeric effect). Furthermore, two orbital-two electron hyperconjugative interactions in the O−C−O and S−C−S segments (intramolecular anomeric effect) are also confirmed. NBO analysis also exhibited the operation of n(O) → C2−Hax and n(S) → C2−Hax hyperconjugation and provided an explanation for the decreased charge density at the equatorial hydrogen in the axially substituted heterocycles observed by Wiberg, Bailey, and coworkers,6 which is not at odds with the existence of the n(X) → σ*(C−Y) stereoelectronic interactions that stabilize the axial isomers in equilibria involving ring anchored 2-methoxy-1,3-dioxanes (1-ax 2-methoxy-1,3-dithianes (5-ax

⇌ 2-eq), 2-cyano-1,3-dioxanes (3-ax ⇌ 4-eq),

⇌ 6-eq), and 2-cyano-1,3-dithianes (7-ax ⇌ 8-eq) (X =

O, S; Y = OCH3, CN). Additional evidence supporting the proposed n(O) → C2−Hax hyperconjugative interaction was obtained by NBO estimation of natural charges at the hydrogens bound to C(2) and by comparison of calculated 1JC-H coupling constants in 1-4. Indeed, the estimated Perlin effects do support electron transfer to the C(2)-Hax in 2-eq and 4-eq. Also relevantly, this study revealed two relevant stereoelectronic interactions involving the cyano group, n(N) → σ*(NC−C) and σ(C2−H) → σ*(C−N).

Supporting Information. B3LYP/aug-cc-pVTZ-optimized geometries of 1-ax, 2-eq, 3ax, 4-eq, 5-ax, 6-eq, 7-ax, and 8-eq (Table S-1). Most relevant NBO hyperconjugative interactions in 1-ax, 2-eq, 3-ax, 4-eq, 5-ax, 6-eq, 7-ax, and 8-eq (Table S-2). This material is available free of charge via the Internet at http://pubs.acs.org

Acknowdegment. Financial support from Consejo Nacional de Ciencia y Tecnología, CONACYT grant number 220945, is gratefully acknowledged. We are also grateful to the reviewers, for helpful comments.

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] and/or [email protected] 18 ACS Paragon Plus Environment

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ORCID Eusebio Juaristi: 0000-0003-0936-7020 Rafael Notario: 0000-0003-2957-8183

Notes. The authors declare no competing financial interest.

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For selected applications of NBO method for analysis of chemical bonding see: a) A. E. Reed, F. Weinhold, Natural Bond Orbital Analysis of Internal Rotation Barriers and Related Phenomena. Isr. J. Chem. 1991, 31, 277-285. b) L. Goodman, V. T. Pophristic, Hyperconjugation Not Steric Repulsion Leads to the Staggered Structure of Ethane. Nature 2001, 411, 565-568. c) J. Podlech, Stereoelectronic Effects in α-Carbanions of Conformationally Constrained Sulfides, Sulfoxides, and Sulfones. J. Phys. Chem. A 2010, 114, 8480-8487. d) M. P. Freitas, The Anomeric Effect on the Basis of Natural Bond Orbital Analysis. Org. Biomol. Chem. 2013, 11, 2885-2890. e) E. Juaristi, R. Notario, Theoretical Examination of the S-C-P Anomeric Effect. J. Org. Chem. 2015, 80, 2879-2883. f) D. Vidhani, M. Krafft, I. V. Alabugin, Gold(I)-Catalyzed Allenyl Cope

Rearrangement:

Evolution

from

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Trappable

Intermediates Assisted by Stereoelectronic Switching. J. Am. Chem. Soc., 2016, 138, 2769-2779. g) E. Juaristi, R. Notario, Theoretical Evidence for the 20 ACS Paragon Plus Environment

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Relevance of n(F) → σ*(C-X) (X = H, C, O, S) Stereoelectronic Interactions. J. Org. Chem. 2016, 81, 1192-1197. h) Juaristi, E.; dos Passos Gomes, G.; Terent’ev, A. O.; Notario, R.; Alabugin, I. V. Stereoelectronic Interactions as a

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Graphical abstract




Density Functional Theory Computational Reexamination of the

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