The document summarizes computational analysis of the anomeric effect in heterocyclic compounds containing CH/O or CH/X hydrogen bonds. Key findings include: 1) Ab initio calculations show the axial conformer of 1,2-substituted oxanes and 1,3-dioxanes has lower Gibbs energy than the equatorial conformer when Z is electron-withdrawing. 2) Non-bonded distances between axial hydrogens and Z are shorter than van der Waals distances, suggesting CH/n hydrogen bonds stabilize the axial conformation. 3) NBO charges reveal the axial conformer has more positive charge on axial hydrogens and more negative charge on carbons, compared to

1. アノマー効果再訪 CH/ n (CH/O, CH/X) 水素結合による解釈 高橋 修，山崎勝義（広大） 河野雄次，上田一義（横国大） 末澤裕子（文科省），西尾元宏（ CHPI 研）

2. Anomeric effect of glucosides

3. Anomeric effect of six-member heterocyclic compounds X, Y = O, S; Z = O, halogens, etc.

4. Generalized anomeric effect

5. Theory of the anomeric effect The equatorial conformation is unstable due to the dipolar interaction (well explains the solvent effect ). (2) The axial conformation is stabilized by the donation of lone pair electrons to the  * orbital of the C-X bond ( shortening of the CH 2 -O bond in gauche or axial conformers) Radom, Hehre, Pople, J. Am. Chem. Soc . 1971 , 93 , 289

6. Our hypothesis The CH/ n ( CH/O, CH/halogen , etc.) hydrogen bond is important

7. Computational method MP2/6-311++G(d,p)//MP2/6-31G(d) Vibrational frequencies were calculated using the analytical second derivatives at the same level of the geometry optimization for each conformer. Using these results, the thermal energy corrections were added to the total Gibbs energy at 298.15 K and 1 atmosphere of pressure. NBO: B3LYP/3-21G* by NBO 3.1 program 13 C chemical shifts: B3LYP/6-31G*//B3LYP/6-311++G** relative to TMS

8. Difference in the Gibbs energy between ax and eq conformers G eq – G ax (  G eq-ax ) of 2-substituted oxanes 1 and 1,3-dioxanes 2

9. Bond lengths d O -C 2 and d C 2 - Z in 1

10. Bond lengths d O-C 2 and d C 2 -O and  d ax-eq in 2-methoxy oxane, glucose and glycosides

11. Non-bond distances between axial hydrogens H 4ax and H 6ax vs. Z, calculated for 2-substituted oxanes

12. Conformation of simple aliphatic molecules (5-member CH/O hydrogen bond)

13. NBO charges of the axial and equatorial conformers of in 2-methoxy oxane

14. Differences in the NBO charges between the axial and equatorial conformers of the relevant atoms in 2-substituted oxanes

15. Calculated 13 C NMR chemical shifts and the difference between the axial and equatorial conformers for C 4 and C 6 in 2-substituted oxanes (  -effect )

16. CH/O 水素結合による解釈 Eliel, J. Org. Chem . 1968 , 33 , 3754

17.  -Anomers of glycosides Lichtenthaler, Liebig Ann. Chem. 1990 , 1001

18.  -Anomers of glycosides Horton, J. Org. Chem . 1965 , 30 , 3387

19. Conclusions Ab initio MO calculations have revealed that the Gibbs energy of the axial conformer in 1 and 2 is smaller than that of the corresponding equatorial conformer, when Z is an electron-withdrawing group. The non-bonded distance between the 2-substituent and an axial C-H has been shown shorter than the van der Waals distance , suggesting the importance of 5-member CH/ n hydrogen bonds. Analysis of the natural bonding orbital (NBO) charge of the relevant protons and carbons have revealed an appreciable difference between the conformers: more positive for H and more negative for C in the axial conformer than in the corresponding equatorial conformer. The CH/ n (CH/O, CH/X) hydrogen bond has been suggested to be an important factor in stabilizing the axial conformations of these compounds. This mechanism is compatible with the solvent effect .