16
1
General Principles
⊡ Table 1
Destabilizing effects in pyranose and cyclitol rings in aqueous solution at room temperature in kJ/mol (22 °C
or 25 °C) [126]
1,3-Diaxial interactions Gauche interactions
Anomeric effects
C:O
10.4
C/O
1.9 for OH
if O-2 is equatorial
2.3
O:O
6.3
O/O
1.5
if O-2 is axial
4.2
C:H
3.8
C/C
3.8
if O-2 and O-3 are axial
3.6
O:H
1.9
if 2-deoxy
3.6
and gauche interactions and the anomeric effect (see > Table 1). In general, these terms are
remarkably successful for predicting which chair conformer is most populated in aqueous
solution and also for predicting anomer populations. For D-aldopyranoses, the group on the
pyranose ring with the largest A value is the hydroxymethyl group and this group causes most
derivatives to adopt the 4 C 1 conformation. In the 1 C 4 conformation, this group is axial and
has 1,3-diaxial interactions with substituents or hydrogen atoms on C-1 or C-3. Augé and
David [127] noted that the value adopted by Angyal for the 1,3-diaxial interaction of a methyl
and a hydrogen (3.76 kJ mol −1 ) gave an equatorial preference for the hydroxymethyl group
of 7.5 kJ mol −1 , similar to the cyclohexane methyl A value of 7.4 kJ mol −1 [19,20]. However,
Eliel et al. [45] found that the A value for a hydroxymethyl group at C-2 of tetrahydropyran
was 12.1 kJ mol −1 , about 4.6 kJ mol −1 greater than its cyclohexane value. Therefore, Augé
and David [127] proposed a correction termed the “proximity” correction of 4.6 kJ mol −1 for
pyranose conformations with axial hydroxymethyl or methyl substituents at C-5. This correction only increases the proportion of the already dominant 4 C 1 conformation of most sugars
and gave improved agreement for data from many substituted idopyranosyl and altropyranosyl
derivatives.
The idopyranose anomers will be considered as examples of applications of Angyal’s interaction energies. They are particularly interesting because the α-anomer is one of three α-aldohexopyranoses where both chair conformers are populated significantly (α-altropyranose and
α-gulopyranose are the others) and also because the conformations of L-iduronic acid have significance for the biological properties of heparin and other glycosylaminoglycans [128]. For
β-D-idopyranose, estimation of the destabilizing interactions by Angyal’s method [125,126]
gives: for the 4 C 1 conformer, 2 × 1.9 (O:H) + 6.3 (O:O) + 1.9 (C/O) + 1.5 (O/O) + 3.6 (anomeric
effect) = 17.1 kJ mol −1 ; for the 1 C 4 conformer, 1.9 (O:H) + 3.8 (C:H) + 10.4 (C:O) + 1.9 (C/O)
+ 3 × 1.5 (O/O) = 22.5 kJ mol −1 . Populations of conformers can be estimated from average
NMR coupling constants between vicinal hydrogen atoms, 3 J H,H , if the values for the individual conformers are known or can be estimated or calculated. These coupling constants are
known for most aldoses and ketoses [129,130,131,132]. The G value, 5.4 kJ mol −1 predicts
K( 1 C 4 / 4 C 1 ) = 0.1 at 298 K; the value derived from observed coupling constants and estimated values for J 2,3 and J 3,4 in pure conformers [131] is K = 0.33, which corresponds to G
of 2.7 kJ mol −1 . The difference between the observed and calculated equilibrium constant is
larger than for most pyranoses but the 4 C 1 conformer (20) is correctly predicted to be more
stable than the 1 C 4 conformer (21).
1
General Principles
⊡ Table 1
Destabilizing effects in pyranose and cyclitol rings in aqueous solution at room temperature in kJ/mol (22 °C
or 25 °C) [126]
1,3-Diaxial interactions Gauche interactions
Anomeric effects
C:O
10.4
C/O
1.9 for OH
if O-2 is equatorial
2.3
O:O
6.3
O/O
1.5
if O-2 is axial
4.2
C:H
3.8
C/C
3.8
if O-2 and O-3 are axial
3.6
O:H
1.9
if 2-deoxy
3.6
and gauche interactions and the anomeric effect (see > Table 1). In general, these terms are
remarkably successful for predicting which chair conformer is most populated in aqueous
solution and also for predicting anomer populations. For D-aldopyranoses, the group on the
pyranose ring with the largest A value is the hydroxymethyl group and this group causes most
derivatives to adopt the 4 C 1 conformation. In the 1 C 4 conformation, this group is axial and
has 1,3-diaxial interactions with substituents or hydrogen atoms on C-1 or C-3. Augé and
David [127] noted that the value adopted by Angyal for the 1,3-diaxial interaction of a methyl
and a hydrogen (3.76 kJ mol −1 ) gave an equatorial preference for the hydroxymethyl group
of 7.5 kJ mol −1 , similar to the cyclohexane methyl A value of 7.4 kJ mol −1 [19,20]. However,
Eliel et al. [45] found that the A value for a hydroxymethyl group at C-2 of tetrahydropyran
was 12.1 kJ mol −1 , about 4.6 kJ mol −1 greater than its cyclohexane value. Therefore, Augé
and David [127] proposed a correction termed the “proximity” correction of 4.6 kJ mol −1 for
pyranose conformations with axial hydroxymethyl or methyl substituents at C-5. This correction only increases the proportion of the already dominant 4 C 1 conformation of most sugars
and gave improved agreement for data from many substituted idopyranosyl and altropyranosyl
derivatives.
The idopyranose anomers will be considered as examples of applications of Angyal’s interaction energies. They are particularly interesting because the α-anomer is one of three α-aldohexopyranoses where both chair conformers are populated significantly (α-altropyranose and
α-gulopyranose are the others) and also because the conformations of L-iduronic acid have significance for the biological properties of heparin and other glycosylaminoglycans [128]. For
β-D-idopyranose, estimation of the destabilizing interactions by Angyal’s method [125,126]
gives: for the 4 C 1 conformer, 2 × 1.9 (O:H) + 6.3 (O:O) + 1.9 (C/O) + 1.5 (O/O) + 3.6 (anomeric
effect) = 17.1 kJ mol −1 ; for the 1 C 4 conformer, 1.9 (O:H) + 3.8 (C:H) + 10.4 (C:O) + 1.9 (C/O)
+ 3 × 1.5 (O/O) = 22.5 kJ mol −1 . Populations of conformers can be estimated from average
NMR coupling constants between vicinal hydrogen atoms, 3 J H,H , if the values for the individual conformers are known or can be estimated or calculated. These coupling constants are
known for most aldoses and ketoses [129,130,131,132]. The G value, 5.4 kJ mol −1 predicts
K( 1 C 4 / 4 C 1 ) = 0.1 at 298 K; the value derived from observed coupling constants and estimated values for J 2,3 and J 3,4 in pure conformers [131] is K = 0.33, which corresponds to G
of 2.7 kJ mol −1 . The difference between the observed and calculated equilibrium constant is
larger than for most pyranoses but the 4 C 1 conformer (20) is correctly predicted to be more
stable than the 1 C 4 conformer (21).