First observable CD spectra from n-σ * excitation: TD-DFT calculation and determination of absolute configuration of

Recently we reported that 2,6-dithiaspiro[3.3]heptane 2,6-dioxide 1a exists as enantiomers at ambient temperature and is able to be resolved. This is because the lone pair(s) on the sulfur atom(s) are rich in s-character, which results in high barrier for flipping the conformation of the four-membered ring, i.e., racemization of the spiro framework of 1a . During the HPLC analysis, we noticed considerably strong absorption of UV at 210 nm. We expected that the absorbance comes from n-σ * excitation. The acute bond angle of C-S-C leads to high p-character of the C-S bond(s), which lowers the σ * orbital energy. We performed the TD-DFT calculations of a model, constrained dimethylsulfoxide (DMSO) and 1a . The strong UV absorption of 1a is reproduced with the TD-DFT calculation. However, there are two sulfoxide groups arranged with chiral position in 1a , we could expect that the circular dichroism (CD) spectra are observable by coupling of two sulfoxide groups. The TD-DFT calculation showed that the Cotton effects should appear in the observable UV range. We separated the enantiomers of 1a by HPLC equipped with a chiral stationary phase column. The enantiomers are subjected to the CD analysis. We determined the absolute configuration of 1a , comparing the calculation and the obtained spectra. This is the first report of the CD spectra of n-σ * excitation.


Introduction
Recently, we reported that 2,6-dithiaspiro [3.3]heptane 2,6-dioxide 1a 1,2 exists as enantiomers at ambient temperature. 1The spiro [3.3]heptane framework is chiral due to puckering of two four-membered ring.If flipping of the four-membered ring is quite facile, it racemizes very easily at ambient temperature.For example, commercially available 2,6-diazaspiro [3.3]heptane 2a is calculated to racemize only with the enthalpy of activation of 5.2 kcal/mol at the B3LYP/6-311+G(d)//B3LYP/6-31G(d) level. 2 However, if the lone pairs of the heteroatom at the 2,6positions are rich in s-character, the inversion barrier at the heteroatom is high to maintain the absolute configuration without racemization.These circumstances are easily achieved by substitution with heavy atoms.We showed that substitution with phosphorus (2b), arsenic (2c) and sulfoxide (1a), selenoxide (1b) and telluroxide (1c) led to high barrier for racemization.
Our initial experiments confirmed that sulfoxide substituted 1a exists as enantiomers at ambient temperature and is able to resolve with HPLC equipped with a chiral stationary phase column for analytical scale and a preparative scale.However, we wondered that UV absorbance is extremely high at 210 nm in comparison with sulfoxides, such as DMSO.If the absorbance comes from the sulfoxide groups, we expected that we could observe the CD spectra of 1a because two sulfoxide groups are arranged with chiral position.Previously, the CD spectra with n-σ* excitation was predicted by theoretical calculation 3 , and there are some observations of the CD spectra with π-π* excitation of the non-aromatic amides. 4To date, however, there are no reports on observation of CD spectra of n-σ* excitation.Here we demonstrate the first observation of CD spectra of n-σ* excitation.We performed the TD-DFT calculations to show the possibility of observation of CD spectra, and prepared 1a, which was resolved into enantiomers.The CD spectra of enantiomers of 1a were measured to determine the absolute configuration.

Results and Discussion
First, we calculated a model compound, constrained dimethyl sulfoxide (DMSO) (Figure 1).With the narrower bond angles, the bond becomes richer in p-character.Thus, the energy of the σ* orbital should decreased, and the UV absorbance should shift to longer wave length.Hush 5 and Baker 6 calculated 1a to examine the remote through-bond interaction, and measured the photoelectron spectra.To probe the chirooptical properties of 1a, we performed the TD-DFT calculations to show whether the UV and CD spectra are observable.Initially, the calculations of constrained DMSO were performed with the dihedral angle of C-S-O-C fixed, which is equivalent to fixation of the C-S-C bond angle.We used the RHF/6-31G(d)//B3LYP/6-311+G** level for the bond orbital energies and the B3LYP/6-311+G** level for TD-DFT calculations (Table 1). 7,8The σ* orbital energy was obtained using Bond Model Analysis (BMA) 9 and NBO analysis. 10The σ* energy level is estimated with the diagonal element of a Fock matrix of the bond orbitals (Fii) for BMA.TD-DFT calculations showed that the UV absorbance results from n-σ* excitation.As expected, we noticed that the smaller bond angle of C-S-C resulted in enhanced absorbance with a longer wave-length.A more acute bond angle gives the C-S bond more p-character, which leads to lowering of the σ* energy level of the C-S bond.We optimized the structure of 1a, and performed the TD-DFT calculations using the optimized structure at the M06-2X/6-311+G** level (Figure 2).The solvent effect from acetonitrile is included in the calculation with the PCM model.The calculated UV absorbance clearly indicates the absorption (local) maximum at 220 nm, which should be in the observable range of the UV spectra.The HOMO and LUMO of 1a are shown in Figure 3.The LCBO-MO expression by the BMA analysis showed that the HOMO consists of the lone pair(s) on the oxygen(s) coupled with the lone pair(s) on the sulfur(s) out of phase, and the σ C-S and σ C-C orbitals out of phase.On the other hand, the LUMO mainly consists of the in-phase combination of four each of σ* C-S and σ* C-C orbitals.Thus, the UV absorbance resulted from n-σ* excitation.Furthermore, there are two sulfoxide groups in 1a, which are arranged in a chiral position.Thus, we could expect that the two sulfoxide groups interact with each other to show CD. 11To date, there have been many reports on CD spectra from π-π* excitation.However, we believe that there have been no observations of CD spectra from n-σ* excitation.The calculated dihedral angle of O2-S2-S6-O6 for (axS)-1a is 122.9°, and that for (axR)-1a is -122.9°(B3LYP/6-311+G**). 12Thus, a first negative Cotton effect and second positive Cotton effect are expected for (axR)-1a, and a positive first Cotton effect and second negative Cotton effect should be observed for (axS)-1a.In fact, the TD-DFT calculations showed CD active.We recalculated 1a at the PCM-TD-M06-2X/6-311+G** (solvent = acetonitrile) level.The exo,exo-1a is the most stable and the relative energies of other conformers are shown in Figure 4. From the calculation, the exo,exo-(axR)-isomer of 1a should show a negative first Cotton effect at 220 nm (∆ε = -18) and a positive Cotton effect at 188 nm (∆ε = 18), while the (axS)-isomer should show a positive first Cotton effect at 220 nm (∆ε = 18) and a negative Cotton effect at 188 nm (∆ε = -18).The simulation weighted on the conformers is shown in Figure 5.Although the simulated CD spectrum is somewhat outside of the observable range (190 nm<), it clearly showed that the absolute configuration could be determined with the CD spectrum.To confirm our calculations, we prepared 1a from 2,6-dithiaspiro[3.3]heptane 3. 1,16,17 Treatment of 3 with NaIO 4 and repeated recrystallization gave 1a as a clear solid.As expected, 1 H NMR showed two doubled doublets and two doublets.Only one large w-shaped coupling constant (5.1 Hz) is observed (Figure 6).This large coupling constant can be attributed to coupling between the hydrogens at the equatorial 1,3-positions.This is because of the acute bond angle of 94.7° for C1-C4-C3 and the large dihedral angles of 145.2° for H1eq-C1-C4-C3 and -145.2° for C1-C4-C3-H3eq; the other values are too small to observe using a 400 MHz NMR instrument. 18This observation is in quite contrast of 1 H NMR of 3, which showed only one averaged singlet in toluene-d 8 even at -70 °C.It is because the racemization barrier (inversion barrier of the thietane ring) was calculated to be 1.1 kcal/mol at the BMK/6-311+G(d,p)//B3LYP/6-31G(d) level.The recrystallized 1a was examined with a UV spectrometer to obtain the UV absorbance (Figure 2).Although the observed absorbance agrees only qualitatively with the calculation, the maximum absorbance at 216 nm is in accordance with the calculation.

Conclusions
In conclusion, we have reported the first CD spectra for n-σ* excitation.Due to the high pcharacter of the σ C-C bond, the σ* C-C orbital becomes low in energy, which makes the CD spectra in the observable range.We determined the absolute configurations of the enantiomers of 1a.

Figure 8 .
Figure 8. Observed Cotton effect of the enantiomer of 1a (in acetonitrile).