8
1
General Principles
⊡ Figure 3
The A value for a methyl group at position 3 of tetrahydropyran is less than that of cyclohexane, 6.0 vs
7.5 kJ mol −1
⊡ Figure 4
The anomeric effect: the axial conformer is more stable than predicted based on the A value of the methoxy
group. The exoanomeric effect: the preferred rotamers about the exocyclic C–O bond are those with the methyl
gauche to the endocyclic oxygen atom and to H-1
Edwards [54] and named by Lemieux [33]. This effect is due to electronic interactions
between the exocyclic and endocyclic oxygen atoms and their C–O bonds (see later). It had
been recognized that cyclohexane A values were not appropriate as reference values for the size
of the anomeric effect because of the different geometry in the heterocycle [55]. Franck [56]
suggested that the cyclohexane A values for polar substituents be scaled to obtain reference
heterocyclic A values by using a line defined by the relationship of heterocyclic to cyclohexane
A values for non-polar substituents such as methyl and using hydrogen as the zero point. The
resulting equation is G(2-thp) = 1.53 × G(Cyhx) + 0.04 kJ mol −1 . This suggestion has
now been generally accepted [50,53]. Thus, an observed equatorial to axial free energy difference for a methoxy group at position-2 in tetrahydropyran of -3.3 kJ mol −1 in a non-polar
solvent [57] and the cyclohexane A value of 2.7 kJ mol −1 scaled to 4.2 kJ mol −1 (see above)
gives an anomeric effect for methoxy of 7.5 kJ mol −1 in tetrahydropyran ( > Fig. 4).
Two explanations have been advanced to account for the anomeric effect. The first involves
the stabilizing effect of bonding interactions between n electrons on one oxygen atom and
the σ * orbital of the bond connecting the other oxygen atom and the central anomeric carbon
atom [58]. The second involves destabilizing dipole-dipole repulsion between the two oxygen
atoms and their lone pairs [54]. The relative importance of these factors has been difficult to
establish.
Complicating the discussion are the two different descriptions of the nature of the lone pairs
involved. In the traditional view, the lone pairs on oxygen are depicted as sp 3 hybridized.
However, these lone pairs would be equivalent for water, which is not compatible with the
photoelectron spectra, where the lone pair orbitals are very different in energy [59,60]. In the
correct description, the two orbitals differ in their extent of p character; the higher energy
orbital of HOMO, n p is close to being a pure p orbital, while the lower energy orbital, n σ
has much more a s character, resulting in a picture that resembles sp 2 hybridization, with the
n p orbital perpendicular to the plane containing the two substituents bonded to the oxygen
1
General Principles
⊡ Figure 3
The A value for a methyl group at position 3 of tetrahydropyran is less than that of cyclohexane, 6.0 vs
7.5 kJ mol −1
⊡ Figure 4
The anomeric effect: the axial conformer is more stable than predicted based on the A value of the methoxy
group. The exoanomeric effect: the preferred rotamers about the exocyclic C–O bond are those with the methyl
gauche to the endocyclic oxygen atom and to H-1
Edwards [54] and named by Lemieux [33]. This effect is due to electronic interactions
between the exocyclic and endocyclic oxygen atoms and their C–O bonds (see later). It had
been recognized that cyclohexane A values were not appropriate as reference values for the size
of the anomeric effect because of the different geometry in the heterocycle [55]. Franck [56]
suggested that the cyclohexane A values for polar substituents be scaled to obtain reference
heterocyclic A values by using a line defined by the relationship of heterocyclic to cyclohexane
A values for non-polar substituents such as methyl and using hydrogen as the zero point. The
resulting equation is G(2-thp) = 1.53 × G(Cyhx) + 0.04 kJ mol −1 . This suggestion has
now been generally accepted [50,53]. Thus, an observed equatorial to axial free energy difference for a methoxy group at position-2 in tetrahydropyran of -3.3 kJ mol −1 in a non-polar
solvent [57] and the cyclohexane A value of 2.7 kJ mol −1 scaled to 4.2 kJ mol −1 (see above)
gives an anomeric effect for methoxy of 7.5 kJ mol −1 in tetrahydropyran ( > Fig. 4).
Two explanations have been advanced to account for the anomeric effect. The first involves
the stabilizing effect of bonding interactions between n electrons on one oxygen atom and
the σ * orbital of the bond connecting the other oxygen atom and the central anomeric carbon
atom [58]. The second involves destabilizing dipole-dipole repulsion between the two oxygen
atoms and their lone pairs [54]. The relative importance of these factors has been difficult to
establish.
Complicating the discussion are the two different descriptions of the nature of the lone pairs
involved. In the traditional view, the lone pairs on oxygen are depicted as sp 3 hybridized.
However, these lone pairs would be equivalent for water, which is not compatible with the
photoelectron spectra, where the lone pair orbitals are very different in energy [59,60]. In the
correct description, the two orbitals differ in their extent of p character; the higher energy
orbital of HOMO, n p is close to being a pure p orbital, while the lower energy orbital, n σ
has much more a s character, resulting in a picture that resembles sp 2 hybridization, with the
n p orbital perpendicular to the plane containing the two substituents bonded to the oxygen