Theoretical Evidence for the Relevance of n(S) - American Chemical

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Chapter 1

Theoretical Evidence for the Relevance of n(S) → σ*(C-P), σ(C-S) → σ*(C-P), and n(F) → σ*(C-X) (X = H, C, O, S) Stereoelectronic Interactions Eusebio Juaristi*,1,2 and Rafael Notario*,3 1Departamento

de Química, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional 2508, Colonia Zacatenco, 07360 Ciudad de México, México 2El Colegio Nacional, Luis González Obregón 23, Centro Histórico, 06020 Ciudad de México, México 3Instituto de Química Física “Rocasolano”, CSIC, c/ Serrano 119, 28006 Madrid, Spain *E-mail: [email protected]; [email protected]

Three decades after the discovery of a strong S-C-P anomeric effect in 2-diphenylphosphinoyl-1,3-dithiane (1), a suitable interpretation was pending; nevertheless, very recent DFT geometry optimization of 1-ax and 1-eq did reproduce the S-C-P anomeric effect in 1, worth 5.45 kcal/mol (in chloroform solvent). Furthermore, NBO computational analysis suggests the involvement of n(X) → σ*(C-P(O)Ph2) stereoelectronic interactions that stabilize the axial conformer. Along similar lines, theoretical calculations on r-1,c-3,c-5trifluorocyclohexane (2), r-2,c-4,c-6-trifluoro-1,3,5-trioxane (3) and r-2,c-4,c-6-trifluoro-1,3,5-trithiane (4) confirm the relevance of n(F) → σ*(C-X)gem hyperconjugative interactions, where X = H, C, O, S. Thus, contrary to generally accepted concepts, fluorine is a good lone pair electron donor towards geminal sigma bonds.

© 2017 American Chemical Society Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Introduction Since its discovery six decades ago, the so-called ‘anomeric effect’ has turned into one of the most frequently used concepts employed to explain conformational preferences, structural properties, and even the reactivity of organic molecules (1). Nevertheless, the origin of the anomeric effect is still a matter of controversy (2), and it is thus apparent that further studies of this important effect are necessary. As demonstrated by E. L. Eliel in the 1960s and 1970s (3–5), the presence of lone electron pairs in substituted saturated heterocyclic compounds can have pronounced effects on their conformation. In this context, the interaction of electron-withdrawing anomeric substituents [electronegative groups localized at C(1)] with endocyclic lone electron pairs induces a preference by these substituents to adopt the axial instead of the equatorial orientation. This conformational effect was initially discovered by Edward (6) and Chü and Lemieux (7), and attracted much attention. This phenomenon became to be known as the anomeric effect (Scheme 1).

Scheme 1. Counter-intuitive (according to prevailing concepts in the early times of conformational analysis) preference of electronegative substituents at the anomeric position to adopt the axial orientation. Reproduced with permission from ref. (8). Copyright [2015] ACS.

In an imaginative, remarkable interpretation of this conformational effect, a stabilizing interaction between a lone electron pair on the ring heteroatom “X” and the low-energy antiperiplanar antibonding orbital of the bond connecting the axial electronegative substituent “Y” at the anomeric carbon [n(X) → σ*(C-Y)app hyperconjugation] was proposed. Because of the double bond-no bond canonical structure associated with this hyperconjugative interaction, a lengthening of the axial C-Y bond, as well as a shortening of the endocyclic C-X bond are anticipated (9, 10). Entirely by chance, while working in the very first research project undertaken in our laboratory, proton NMR spectroscopic data showed significant deshielding of the syn-axial protons at C(4,6) in 2-diphenylphosphinoyl-1,3-dithiane (1), which suggested an axial conformation of the diphenylphosphinoyl group (Scheme 2) (11). In order to quantitate this conformational effect, conformationally fixed diastereomeric models were synthesized, and their chemical equilibration under basic catalysis (ethanolic EtO−Na+) afforded ΔG° = +1.0 kcal/mol, the axial conformer being more stable than the equatorial conformer (11). 4 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Scheme 2. Predominance of the axial conformation in the conformational equilibrium of 2-diphenylphosphinoyl-1,3-dithiane (1). Reproduced with permission from ref. (11). Copyright [2015] ACS.

This conclusion was very intriguing in view of the rather large size of the diphenylphosphinoyl group. Nevertheless, X-ray diffraction data from suitable crystals of 2-diphenylphosphinoyl-1,3-dithiane (1) provided the structure and conformation shown in Figure 1.

Figure 1. X-Ray diffraction structure of 1-ax, exhibiting the axial orientation of the diphenylphosphinoyl group. Reproduced with permission from ref. (11). Copyright [2015] ACS.

Surprisingly, comparison of the structural data of 1-ax (Figure 1) and its conformationally-fixed equatorial analog did not exhibit the expected (in terms of a n(S) → σ*(C-P)app hyperconjugative interaction, see above) contraction of the endocyclic S-C(2) bond and lengthening of the exocyclic C(2)-P bond in 1-ax (11). With the advent of powerful computational equipment and software in recent years, it was decided to explore whether theoretical calculations could reproduce the anomeric effect manifested experimentally in the conformational behavior of 2-diphenylphosphinoyl-1,3-dithiane (1-ax ⇌ 1-eq, Scheme 2). Furthermore, the question was posed as to whether natural bond order (NBO) calculations could provide support for stereoelectronic interactions at the origin of this conformational equilibrium. 5 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

Computational Methods


All calculations were carried out with Gaussian 09 programs (12). The structures of interest were fully optimized at the B3LYP/6-311+G(d,p) level of theory (13). Electronic structures were examined with Natural Bond Orbital (NBO) analysis (14), and hyperconjugative interactions were evaluated by means of the NBO program (version 3.1) (15). Simulation of solvent was accomplished according to the polarizable continuum model developed by Tomasi and co-workers (16).

Results and Discussion Anomeric Effect in the S-C-P Segment The lowest energy geometries of axial and equatorial 1 at the B3LYP/6311+G(d,p) level of theory, are shown in Figure 2 and Table 1.

Figure 2. B3LYP/6-311+G(d,p)-optimized structures of 2-diphenylphosphinoyl1,3-dithiane, in the axial conformation, 1-ax, and in the equatorial conformation, 1-eq. Reproduced with permission from ref. (8). Copyright [2015] ACS.

According to the calculations summarized in Table 1 (8), the C(2)-P(O) bond in the axial isomer 1-ax (1.867 Å) is exactly similar to the C(2)-P(O) bond in equatorial 1, 1.867 Å. By the same token, the endocyclic C(2)-S bonds in 1-ax and 1-eq are essentially identical, 1.836 ± 0.002 Å in both isomers. Experimentally (11), the X-ray crystallographic data afforded 1.825 Å for axial C(2)-P and 1.840 Å for equatorial C(2)-P. On the other hand, the C(2)-S bond lengths are 1.809 Å in 1-ax and 1.809 Å in the anancomeric (conformationally fixed) equatorial model. As indicated in the Introduction, both the experimental and calculated structural data are not in line with the anticipated consequences of n(S) → σ*(C-P) stereoelectronic interaction; i. e., one would expect a substantial shortening of the S-C(2) endocyclic bond as well as a lengthening of the C(2)-P(O) bond in 1-ax relative to 1-eq.

6 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Table 1. B3LYP/6-311+G(d,p)-optimized geometrical parameters of 2-diphenylphosphinoyl-1,3-dithiane, in the axial conformation, 1-ax, and in the equatorial conformation, 1-eq. Bond distances in Å, and bond angles in degrees. Bond

1-ax

1-eq

C(2)-P

1.867

1.867

C(2)-S

1.835-1.836

1.837-1.838

P=O

1.505

1.497

C(4)-S

1.841-1.842

1.837-1.838

C(4)-C(5)

1.528-1.529

1.529

S-C(2)-S

114.7

114.0

C(2)-P-O

113.0

114.8

C(2)-S-C(4)

100.8-100.9

98.0

SC(4)-C(5)

114.1-114.2

114.4-114.5

C(4)-C(5)-C(6)

113.4

113.8

In the most relevant result from the theoretical calculations (8), DFT calculations do reproduce the S-C-P anomeric effect in diphenylphosphinoyl1,3-dithiane 1; that is, the preference of the phosphorus substituent to adopt the axial orientation instead of the equatorial orientation. Indeed, as revealed by B3LYP/6-31G(d) and B3LYP/6-311+G(d,p) calculations, in ethanol solvent at 294 K the conformer with the diphenylphosphinoyl group in the axial position (1-ax in Scheme 2) is lower in energy, ΔG° +1.36 kcal/mol and +1.30 kcal/mol, respectively. These values are rather close to the experimentally observed ΔG°294 K = +0.99 kcal/mol in ethanol (11). Nevertheless, at the B3LYP/6-311+G(d,p) level of theory, the calculated ΔG°298 K = +3.80 kcal/mol in the gas phase seems too large, probably as the result of overestimated hydrogen bonding interactions between the phosphoryl oxygen and the axial hydrogens at C(4,6), which stabilize the axial isomer. As it has been shown by Alabugin (17), the NBO method developed by Weinhold (18) is a quite useful for the study of hyperconjugation. In our work, NBO analysis afforded an estimate of the magnitude of the delocalizing interaction that weakens the axial C-P bond. In particular, the energies of delocalization (Edel) were obtained by deletion of the corresponding Fock elements, followed by the recalculation of the wave function. Table 2 lists Edel for the main hyperconjugative interactions in dithianes 1-ax and 1-eq. Table 2 includes also the energy difference between the corresponding donor and acceptor orbitals, which (as anticipated) shows an inverse relationship between energy gap and the magnitude of the two-electron/two-orbital hyperconjugative interaction.


Table 2. Selected hyperconjugative interactions (Edel) in axial and equatorial 2-diphenylphosphinoyl-1,3-dithiane, 1-ax and 1-eq.


1-ax

1-eq

Donor orbital

Acceptor orbital

Edel (kcal/mol)

ΔEdonor/acceptor (Hartrees)

n(Sax)

σ*(C-Pax)

3.86

0.41

n(Seq)

σ*(C-Pax)

1.65

0.81

n(Seq)

σ*(C(2)-S)

5.31

0.37

n(Sax)

σ*(C(2)-S)

1.97

0.77

σ(C(4,6)-S

σ*(C-P)

---

---

n(S)

σ*(C-Peq)

---

---

n(Seq)

σ*(C(2)-S)

6.88

0.37

n(Sax)

σ*(C(2)-S)

1.29

0.77

σ(C(4,6)-S)

σ*(C-Peq)

1.87

0.76

The most salient observations are the following: 1) n(S) → σ*(C-P)app stereoelectronic interactions are observed in 1-ax but not in 1-eq. This observation is in agreement with anticipation in terms of an efficient stereoelectronic interaction in the axial conformation, where the donor and acceptor interacting orbitals are antiperiplanar to each other. Such antiperiplanar orientation of the donor/acceptor orbitals in not possible in equatorial 1. As discussed in the Introduction, this stereoelectronic interaction is responsible for the S-C-P anomeric effect, i.e., the axial predominance of the phosphorus substituents at C(2) in the 1,3-dithiane ring in 2-diphenylphosphinoyl-1,3-dithiane 1. 2) Interestingly, n(S) → σ*(C(2)-S)app stereoelectronic interactions are present both in the axial and equatorial isomers, so that this two orbitals-two electrons stabilizing interaction is equally effective in both orientations of the phosphorus group and has no consequence in the conformational free energy difference of the 2-P-substituted 1,3-dithianes 1. 3) Most interestingly, antiperiplanar σ(C(4,6)-S) → σ*(C-P)app stereoelectronic interactions are effective in equatorial 1-eq, but are not operative in 1-ax. This hyperconjugative stereoelectronic interaction 8 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


apparently weakens the equatorial C(2)-P bonds, which are rendered longer. This may help explain the “anomalous” structural observation discussed in the Introduction, that the C(2)-P bond distances are of the same length in the axial and equatorial isomers of 1. That is, n(S) → σ*(C-P)app stereoelectronic interactions are responsible for the longer C(2)-P axial bonds, but σ(C(4,6)-S) → σ*(C-P)app hyperconjugation gives rise to longer C(2)-P equatorial bonds. The interpretations advanced above are supported by deletion of the key hyperconjugative interactions followed by reoptimization of the geometries with those interactions switched off by means of NBODEL (15). In all cases, application of NBODEL while switching off the key hyperconjugative interactions resulted in lengthening of the C(2)-S bonds and simultaneous shortening of the antiperiplanar C(2)-P bonds, as anticipated in terms of n(S) → σ*(C-Pax)app in 1-axial. By the same token, NBODEL results were in line with σ(C(4,6)-S) → σ*(C-Peq)app and n(S) → σ*(C(2)-S)app stereoelectronic interactions operative in the equatorial analog. In summary, DFT calculations do reproduce the S-C-P anomeric effect in diphenylphosphinoyl-1,3-dithiane 1, i.e., the preference of the phosphorus substituent to adopt the axial orientation. The Natural Bond Orbitals (NBO) method developed by Weinhold and co-workers (15) turned out to be a very useful theoretical strategy for the study of the hyperconjugative interactions present in 1. In particular, NBO analysis afforded the estimated energies of the delocalizing interactions that weaken the axial C-P bonds of interest. Specifically, n(S) → σ*(C-P)app stereoelectronic interactions are observed in 1-ax but not in 1-eq, as anticipated in terms of an efficient hyperconjugative interaction in the conformation where the donor and acceptor interacting orbitals are antiperiplanar to each other (Scheme 3a). This stereoelectronic interaction gives rise to the S-C-P anomeric effect, that is manifested as the axial predominance of the diphenylphosphinoyl substituent in 1. On the other hand, antiperiplanar σ(C(4,6)-S) → σ*(C-P)app stereoelectronic interactions are only effective in equatorial 1-eq (Scheme 3b). The combination of the two stereoelectronic effects helps explain the “anomalous” structural observation that the C(2)-P bond distances are quite similar in length in the axial and equatorial isomers of 1.

n(F) → σ*(C-X) (X = H, C, O, S) Stereoelectronic Interactions In contrast to orbitals associated with lone pairs of electrons at the electronegative elements nitrogen and oxygen, which turn out to be rather good donor orbitals, the orbitals associated with lone electron pairs on fluorine usually exhibit poor electron donating power (1). Interestingly, O’Hagan and coworkers recently provided structural and theoretical data supporting the existence of significant n(F) → σ*(C-X)gem stereoelectronic interactions in the geminal F-C-H and F-C-C segments present in all-cis-1,2,3,4,5,6-hexafluorocyclohexane (19). 9 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Scheme 3. a) n(S) → σ*(C-P)app stereoelectronic interaction in 1-ax. b) σ(C(4,6)-S) → σ*(C-P)app stereoelectronic interaction in 1-eq.

Intrigued by this report, we carried out theoretical calculations of the conformational behavior of r-1,c-3,c-5-trifluorocyclohexane (2-ax ⇌ 2-eq, Scheme 4), r-2,c-4,c-6-trifluoro-1,3,5-trioxane (3-ax ⇌ 3-eq, Scheme 4) and r-2,c-4,c-6-trifluoro-1,3,5-trithiane (4-ax ⇌ 4-eq, Scheme 4). We were able to confirm the importance of n(F) → σ*(C-X)gem stereoelectronic interactions in 2, 3 and 4. Furthermore, the relevance of “anomeric” type n(X) → σ*(C-F)app (X = O, S) stereoelectronic interactions in the axial conformations of heterocycles 3 and 4 was also established.

r-1,c-3,c-5-Trifluorocyclohexane, 2 The optimized geometries of axial and equatorial 2 at the MP2/6-311+G(d,p) level of theory, are presented in Figure 3 and Table 3.



Scheme 4. Conformational equilibria of fluorinated compounds examined in the present study: r-1,c-3,c-5-trifluorocyclohexane (2-ax ⇌ 2-eq), r-2,c-4,c-6-trifluoro-1,3,5-trioxane (3-ax ⇌ 3-eq), and r-2,c-4,c-6-trifluoro-1,3,5-trithiane (4-ax ⇌ 4-eq). Reproduced with permission from ref. (20). Copyright [2015] ACS.

Figure 3. MP2/6-311+G(d,p)-optimized structures of r-1,c-3,c-5trifluorocyclohexane, in the axial conformation, 2-ax, and the equatorial conformer, 2-eq. Reproduced with permission from ref. (20). Copyright [2015] ACS.


Table 3. MP2/6-311+G(d,p)-optimized geometrical parameters of r-1,c-3,c-5-trifluorocyclohexane, in the axial, 2-ax, and equatorial, 2-eq, conformations. Bond distances in Å.


a

2-axial

2-equatorial

C-Fax

1.395

---

C-Feq

---

1.397

C-C

1.522

1.521

C-Hax

1.098

1.096(1.097)a

C-Heq

1.094 (1.096)a

1.094

H geminal to F.

As it could be anticipated in terms of strong dipole-dipole repulsion originated from the 1,3-diaxial orientation of the C-F bonds, 1-axial is calculated to be 3.6 kcal/mol less stable than 1-equatorial. This result is in line with the value calculated recently by Schaefer, et al. (ΔE = 3.45 kcal/mol) (21). Table 4 summarizes the delocalization energies (E(2)) for the most relevant hyperconjugative interactions operative in trifluorocyclohexanes 2-ax and 2-eq. Table 4 presents also the calculated energy difference (energy gap, ΔE) between the donor and acceptor orbitals of interest. As anticipated, an inverse relationship between donor/acceptor energy gap and the magnitude of the two-electron/twoorbital hyperconjugative interaction is observed. Salient observations are the following: n(Fax) → σ*(C-Heq)gem with an interaction energy of 9.17 kcal/mol; n(Feq) → σ*(C-Hax)gem with an interaction energy of 8.93 kcal/mol; n(Fax) → σ*(C-C)gem with an interaction energy of 5.21 kcal/mol; and n(Feq) → σ*(C-C)gem with an interaction energy of 4.82 kcal/mol. These results seem to confirm the suggestion advanced by O’Hagan et al. (19) in the sense that the donor character of the fluorine lone pair towards the geminal sigma bonds is significant. In this regard, in our calculations the σ*(C-H) antibonding orbital is estimated to be a better acceptor orbital relative to σ*(C-C), as it could be anticipated on the basis of the accepted interpretation of the gauche effect (1). The calculations also show quite strong σ(C-Hax) → σ*(C-Fax)app hyperconjugative interactions, worth 6.12 kcal/mol (Table 4).


Table 4. Selected hyperconjugative interactions in r-1,c-3,c-5trifluorocyclohexane, 2-ax and 2-eq.


2-axial

2-equatorial

E(2)/kcal/mol

ΔE/Hartrees

E(2)/kcal/mol

ΔE/Hartrees

n(Fax) → σ*(C-Heq)

9.17

1.23

---

---

n(Feq) → σ*(C-Hax)

---

---

8.93

1.22

σ(C-Hax) → σ*(C-Fax)

6.12

1.19

---

---

n(Fax) → σ*(C-C)

5.21

1.24

---

---

n(Feq) → σ*(C-C)

---

---

4.82

1.25

σ(C-Heq) → σ*(C-C)

3.59a 3.38b

1.33a 1.31b

3.22

1.31

3.50c 3.29d

1.27c 1.32d

3.55

1.33

σ(C-Hax) → σ*(C-Hax) σ(C-C) → σ*(C-Feq) a Heq geminal to Fax.

--b Heq geminal to Hax.

---

c Hax geminal to Heq.

d Hax geminal to Feq.

r-2,c-4,c-6-Trifluoro-1,3,5-trioxane, 3 The lowest energy structures of axial and equatorial 3 at the MP2/6311+G(d,p) level of theory, are presented in Figure 4 and Table 5.

Figure 4. MP2/6-311+G(d,p)-optimized structures of r-2,c-4,c-6-trifluoro-1,3,5trioxane, in the axial, 3-ax, and equatorial, 3-eq, conformations. Reproduced with permission from ref. (20). Copyright [2015] ACS.



Table 5. MP2/6-311+G(d,p)-optimized structural parameters of r-2,c-4,c-6-trifluoro-1,3,5-trioxane, in the axial, 3-ax, and equatorial, 3-eq, conformations. Bond distances in Å. 3-axial

3-equatorial

C-Fax

1.363

---

C-Feq

---

1.334

C-O

1.390

1.395

C-Hax

---

1.099

C-Heq

1.086

---

In strong contrast with the conformational energies calculated for r-1,c-3,c5-trifluorocyclohexane (2), the all-axial conformer 3-ax was predicted to be 7.0 kcal/mol lower in energy (more stable) than the equatorial isomer 3-eq. That is, replacement of the methylene groups in 2 for oxygen atoms in 3 is accompanied by 10.6 kcal/mol stabilization of the axial conformer, in spite of the strong dipoledipole repulsive interactions between syn-diaxial C-F bonds. Very likely, this conformational is the consequence of the n(O) → σ*(C-Fax)app and σ(C-Hax → σ*(C-Fax)app stereoelectronic interactions present in 3-ax but not in 3-eq. In line with this interpretation, the structural data estimated for the optimized structures of 3-ax and 3-eq (Table 5) show that the axial C-F bonds are significantly longer (1.363 Å) than the equatorial C-F bonds (1.334 Å), as anticipated in terms of the proposed interactions that weaken the axial C-F bonds (1). Application of the NBO analysis gives evidence for the salient hyperconjugative interactions present in 3-ax and 3-eq (Table 6). Quite significant are the rather large interaction energies involving fluorine as a lone electron pair donor. As it can be appreciated in Table 6, the strongest hyperconjugative interaction results from n(O) → σ*(C-Fax)app, with 19.07 kcal/mol interaction energy. Quite strong is also the hyperconjugation involving the fluorine lone electron pairs: n(Fax) → σ*(C-O)gem (10.75 kcal/mol interaction energy) and n(Feq) → σ*(C-O)gem (11.03 kcal/mol interaction energy). Most important is also the “anomeric-type” n(O) → σ*(C-O)app hyperconjugative interaction, with 7.1 to 13.1 kcal/mol interaction energies (Table 6).

r-2,c-4,c-6-Trifluoro-1,3,5-trithiane, 4 The optimized structure of axial and equatorial 4 at the MP2/6-311+G(d,p) level of theory, are presented in Figure 5 and Table 7.


Table 6. Selected hyperconjugative interactions in r-2,c-4,c-6-trifluoro-1,3,5trioxane, 3-ax and 3-eq.


3-axial

3-equatorial

E(2)/kcal/mol

ΔE/Hartrees

E(2)/kcal/mol

ΔE/Hartrees

n(O) → σ*(C-Fax)

19.07

1.03

---

---

n(O) → σ*(C-Feq)

---

---

6.88

1.39

n(Fax) → σ*(C-O)

10.75 4.04

1.19 1.19

---

---

n(Feq) → σ*(C-O)

---

---

11.03 4.34

1.19 1.19


9.24

1.24

---

---


---

---

10.20

1.20

n(O) → σ*(C-O)

7.10 3.71

1.08 1.39

13.10

1.08

σ(C-Heq) → σ*(C-O)

3.92

1.31

n(O) → σ*(C-Hax)

---

---

7.58

1.08

n(O) → σ*(C-Heq)

3.46

1.43

---

---

σ(C-O)→σ*(C-Fax)gem

1.24

1.65

---

---

σ(C-O)→σ*(C-Feq)gem

---

---

2.48

1.66

Figure 5. MP2/6-311+G(d,p)-optimized structures of r-2,c-4,c-6-trifluoro-1,3,5trithiane, in the axial, 4-ax, and equatorial, 4-eq, conformations. Reproduced with permission from ref. (20). Copyright [2015] ACS.



Table 7. MP2/6-311+G(d,p)-optimized geometrical parameters of r-2,c-4,c-6-trifluoro-1,3,5-trithiane, in the axial, 4-ax, and equatorial, 4-eq, conformations. Bond distances in Å. 4-axial

4-equatorial

C-Fax

1.351

---

C-Feq

---

1.339

C-S

1.804

1.815

C-Hax

---

1.080

C-Heq

1.080

---

Table 8. Selected hyperconjugative interactions in r-2,c-4,c-6-trifluoro-1,3,5trithiane, 4-ax and 4-eq. 4-axial

4-equatorial

E(2)/kcal/mol

ΔE/Hartrees

E(2)/kcal/mol

ΔE/Hartrees

n(S) → σ*(C-Fax)

15.38

0.82

---

---

n(S) → σ*(C-Feq)

---

---

1.06

1.28

n(Fax) → σ*(C-S)

8.31 2.91

0.98 1.02

---

---

n(Feq) → σ*(C-S)

---

---

6.96 2.66

0.99 1.01


9.84

1.24

---

---


---

---

9.53

1.23

n(S) → σ*(C-S)

5.41 3.38

0.72 1.18

9.74

0.73

σ(C-Heq) → σ*(C-S)

1.82

1.10

n(S) → σ*(C-Hax)

---

---

4.24

0.94 ---

n(S) → σ*(C-Heq)

0.83

1.39

---

σ(C-S) →σ*(C-Fax)gem

1.50

1.29

---

---

σ(C-S) →σ*(C-Feq)gem

---

---

2.18

1.27

Most interesting is the much larger stability of the axial conformer 4-axial relative to 4-equatorial. The calculated structural data, specially the longer C-Fax (1.351 Å) by comparison with C-Feq (1.349 Å), as well as the shorter encocyclic C-S bond in 3-axial (1.804 Å) relative to the same bond in 4-equatorial (1.815 Å) are in line with n(S) → σ*(C-F)app hyperconjugation. 16 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Indeed, application of the NBO analysis provides evidence for the relevant hyperconjugative interactions (Table 8), which confirm the rather strong n(S) → σ*(C-Fax)app stereoelectronic interaction, worth 15.38 kcal/mol. While the magnitude of this stereoelectronic interaction involving sulfur tends to be smaller than the corresponding one with oxygen [E(2) = 19.07 kcal/mol, Table 6] it contrasts with early theoretical studies from the Schleyer group suggesting that sulfur is an ineffective donor in S-C-X anomeric segments (22). The data collected in Table 8 also support the existence of significant interactions involving fluorine as a lone pair donor in n(Fax) → σ*(C-S)gem, n(Feq) → σ*(C-S)gem, n(Fax) → σ*(C-Heq)gem, and n(Feq) → σ*(C-Hax)gem stereoelectronic interactions.

Conclusions Theoretical calculations confirm the donor ability of fluorine lone electron pairs in hyperconjugative interactions involving geminal sigma bonds as acceptors. This is in agreement with the recent proposal by O’Hagan and coworkers from examination of the structural characteristics of all-cis-1,2,3,4,5,6-hexafluorocyclohexane. In particular, compelling evidence supporting the importance of n(F) → σ*(C-C)gem, n(F)→σ*(C-H)gem, n(F)→σ*(C-O)gem, and n(F)→ σ*(C-S)gem was gathered from the study of r-1,c-3,c-5-trifluorocyclohexane (2), r-2,c-4,c-6-trifluoro-1,3,5-trioxane (3) and r-2,c-4,c-6-trifluoro-1,3,5-trithiane (4). The Natural Bond Orbital (NBO) method developed by Weinhold and co-workers (18) was a convenient theoretical method for the study of the hyperconjugative interactions present in 2-4. MP2/6-311+G(d,p) calculations on the conformational equilibria of 2-4 indicate that 2-ax ⇌ 2-eq is shifted to the right by 3.6 kcal/mol, while 3-ax ⇌ 3-eq and 4-ax ⇌ 4-eq equilibria strongly favor the axial isomer by 7.0 and 10.1 kcal/mol, respectively. The strong axial preference for 3-ax and 4-ax originates from dominant n(X) → σ*(C-F)app hyperconjugative interactions, where X = O or S.

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Theoretical Evidence for the Relevance of n(S) - American Chemical

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