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The Anomeric Effect

Cody F. BenderCharles E. Price

University of Utah

The anomeric effect was discovered in 1955 with the work of J.T. Edward, N.-J. Chu, and R.U. Lemieux.

Edward’s observed axial preference

Edward notice alkoxypyranose rings favored axial positioning, which contradicted previous notions1

He was the first to state lone pairs affected conformation by suggesting the cyclic oxygen’s lone pairs interacted with substituents1

Discovery of the Anomeric Effect

1Edward, J.T. Chem. Ind. (London) 1955, 1102.2Lemieux, R.U. Explorations with Sugars-How Sweet It Was, In Profiles, Pathways, and Dreams, Seeman, J.I., Ed.; American Chemical Society: Washington D.C., 1990.3Lemieux, R.U.; Chu, P. Abstracts of Papers; 133rd National Meeting of the American Chemical Society, San Francisco, CA.; American Chemical Society: Washington D.C., 1958; 31N.

Discovery of the Anomeric Effect

1Edward, J.T. Chem. Ind. (London) 1955, 1102.2Lemieux, R.U. Explorations with Sugars-How Sweet It Was, In Profiles, Pathways, and Dreams, Seeman, J.I., Ed.; American Chemical Society: Washington D.C., 1990.3Lemieux, R.U.; Chu, P. Abstracts of Papers; 133rd National Meeting of the American Chemical Society, San Francisco, CA.; American Chemical Society: Washington D.C., 1958; 31N.

Chu and Lemieux’s acetylated aldohexopyranose results

Chu and Lemieux noticed a similar effect while observing equilibrium of acetylated aldohexopyranose rings2

The measured energy difference of α- and β-pyranose rings to be 0.94 kcal/mol, favoring the α-conformer (Figure 3)2

It was also measured that the free energy difference was 1.48 kcal/mol for α-xylose2.

The term anomeric effect was first coined at an ACS meeting in 1958 due to the frequent occurrence of this phenomenon on the anomeric

carbon of sugar molecules3

The Anomeric Effect Defined

The anomeric effect describes the tendency for electronegative substituents geminally bound to other heteroatoms within a cyclohexyl system to prefer the axial position.

Hyperconjugation

Hyperconjugation is believed to be the prominent factor for the anomeric effect4

Shown is where the cyclic heteroatom’s lone pairs donate electron density to the σ* oribtal of the adjacent carbon-substituent bond, known as a σ*-π interaction4

Due to orbital alignment, this interaction is not possible with equatorial subsitution4

π-σ* interaction

4Cuevas, E.; Juaristi, G. (1995). The Anomeric Effect. Boca Raton: CRC Press.

The Anomeric Effect Defined

The anomeric effect describes the tendency for electronegative substituents geminally bound to other heteroatoms within a cyclohexyl system to prefer the axial position.

4Cuevas, E.; Juaristi, G. (1995). The Anomeric Effect. Boca Raton: CRC Press.

Dipole minimization

Dipole Minimization Another contributing argument is the

result of a reduced dipole of the molecule due to lone pair orientation4 (Figure 5)

Overcoming the Anomeric EffectSince the anomeric effect only gives a benefit of 1-2 kcal/mol, it can easily be overcome by solvent and in synthesis.

Solvent ε % Axial

CCl4 2.2 83

C6H6 2.3 82

CS2 2.6 80

CHCl3 4.7 71

CH3COCH3 20.7 72

CH3OH 32.6 69

CH3CN 37.5 68

H2O 78.5 52

Solvent Effects Since equatorial conformers give

larger dipoles, solvents with larger dielectric constants, or polarity, can aid in overcoming the anomeric effect5

The table shows this trend using 2-methoxytetrahydropyran in various solvents

Solvent effects on axial preference

5Lemieux, R.U.; Pavia, A.A.; Martin, J.C.; Watanabe, K.A. Can. J. Chem. 1969, 47,4427.6Koenigs, W.; Knorr, E. Eur. J. Inorg. Chem. 1901, 34, 957.

Overcoming the Anomeric EffectSince the anomeric effect only gives a benefit of 1-2 kcal/mol, it can easily be overcome by solvent and in synthesis.

5Lemieux, R.U.; Pavia, A.A.; Martin, J.C.; Watanabe, K.A. Can. J. Chem. 1969, 47,4427.6Koenigs, W.; Knorr, E. Eur. J. Inorg. Chem. 1901, 34, 957.

Koenigs-Knorr Reaction5

Anti-Anomeric Synthesis Various reactions have been

developed to produce products that evade the anomeric effect due to low relative energetic benefits, coming from high energy contributions of sterics in the case of a ring flip.6

Example of the Anomeric Effect in Avermectin 1bThe avermectins are a class of 16-membered macrocyclic lactones with anthelmintic and insecticidal properties. They are natural products that can be isolated from the bacteria Streptomyces avermitilis.7,8 William C. Campbell and Satoshi Omura were awarded the Nobel Prize for Medicine in 2015 for these molecules’ discovery.

The avermectins show three different examples of the anomeric effect, highlighted in red. Two occur in the disaccharide moiety and the third occurs in the spiroketal structure, in which the anomeric effect is not entirely observed. The external ring of the spiroketal follows the anomeric effect as a substituent. But, the isopropyl group on this ring disrupts the ability for the internal ring to occupy the axial position.9

7Omura, S.; Shiomi, K. Pure and App. Chem. 2007. 79. 581.8Pitterna, T. et al. Bioorg. Med. Chem. 2009. 17. 4085.9Springer, J.; Arison, B.; Hirshfield, J.; Hoogsteen, K. J. Am. Chem. Soc. 1981. 103. 4221.

Structure of avermectin 1b3

Practice Problems1) Predict the Keq for the following equilibrium.

2) What is the preferred position of the allyl substituted anomeric carbon on this tri-methoxybenzylpyranose ring?

3) What is the position of the vinyl group in the product of the given reaction?

a) Keq > 1b) Keq = 1c) Keq < 1

a) Axialb) Equatorialc) No preference

a) Racemicb) Axialc) Equatorial

10Shuto, S. Angew. Chem. Int. Ed. 2003. 42. 1021-1023.

11Aponick, A. Chem. Eur. J. 2013. 19. 11613-11621.

Solutions: 1) C, 2) A, 3) B

This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.

Contributed by: Cody F. Bender, Charles E. Price (Undergraduates)

University of Utah, 2016