Cyclic Forms of Carbohydrates

Fischer projections and hexose isomerism

The study of carbohydrate structure traditionally begins with linear models. The carbon skeleton is always numbered starting from the aldehyde group ($C^1$). The reference structure is $D$-glucose, whose hydroxyl groups are arranged in a strictly defined manner:

• at $C^2$ — on the right;
• at $C^3$ — on the left;
• at $C^4$ — on the right;
• at $C^5$ — on the right.

Any deviation from this scheme leads to the formation of a different substance. If the positions of absolutely all $OH$ groups are mirror-reflected, the complete optical antipode is formed — $L$-glucose (enantiomer).

Carbohydrates that differ from glucose in the configuration of only a single carbon atom are frequently encountered. Such isomers are called epimers.

• $D$-galactose is an epimer of glucose at $C^4$ (the hydroxyl group is on the left).
• $D$-mannose is an epimer at $C^2$ (the hydroxyl group is also on the left).

Mechanism of glucose cyclization

The carbon chain of hexoses possesses pronounced conformational flexibility. Due to free rotation around single $\sigma$-bonds, the molecule can bend, bringing the ends of the chain spatially close together. This creates ideal conditions for a key chemical reaction — intramolecular nucleophilic addition across the carbonyl group.

The transition from the linear to the cyclic form proceeds through the following stages:

1. The oxygen atom of the hydroxyl group at $C^5$ (acting as a nucleophile) attacks the electrophilic center — the carbonyl carbon $C^1$.
2. The $C=O$ double bond breaks.
3. A hydrogen atom from the fifth hydroxyl migrates to the oxygen of the aldehyde group, forming a new functional group — the glycosidic hydroxyl.
4. The six-membered ring closes.

The resulting ring is called a pyranose ring (by analogy with the oxygen-containing heterocycle pyran). Furthermore, the resulting ring is not planar: in space, atom $C^4$ is shifted slightly upward from the mean plane, and atom $C^1$ is displaced downward.

Anomers and Haworth formulas

Upon ring closure, a new asymmetric center is formed at the hemiacetal carbon ($C^1$). Depending on the direction in which the oxygen of the aldehyde group was pointed at the moment of attack, spatial isomers — anomers — are formed:

• $\beta$-form: the glycosidic hydroxyl is directed upward relative to the plane of the ring (in the same direction as the $-CH_2OH$ side chain in $D$-hexoses).
• $\alpha$-form: the glycosidic hydroxyl is directed downward (below the plane).

For convenient graphical representation of complex spatial conformations, Haworth formulas are used. The pyranose ring is conventionally drawn as a flat hexagon, depicting the oxygen atom, the positions of the $OH$ groups, and the $C^6$ side fragment (usually $-CH_2OH$). To simplify the diagram, hydrogen atoms ($H$) are often omitted. If the spatial position of the glycosidic hydroxyl is unknown or the substance is a mixture of anomers, the chemical bond is designated by a wavy line.

Note: when constructing a cyclic enantiomer (e.g., $\beta$-$L$-glucose), the configuration of absolutely all asymmetric centers must be inverted, including the anomeric carbon atom $C^1$.

Tautomerism and equilibrium in solutions

In carbohydrate solutions, tautomerism is observed — a reversible intramolecular transformation in which several isomeric forms of the molecule are simultaneously present in the system in dynamic equilibrium.

For glucose, the equilibrium scheme is as follows: $\alpha$-glucose $\rightleftarrows$ acyclic glucose $\rightleftarrows$ $\beta$-glucose

The composition of the equilibrium mixture in aqueous solution is stable:

• the $\beta$-form predominates, accounting for about $64\%$;
• The $\alpha$-form accounts for about $36\%$;
• the acyclic (open) form accounts for less than $1\%$ (five-membered rings may also occur in trace amounts).

Interestingly, crystallization conditions directly determine which anomer will be isolated in solid form. If crystallization is carried out from an aqueous solution, the $\alpha$-form precipitates. If a solution in pyridine is used instead, the $\beta$-form crystallizes.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Principles of transition from linear Fischer formulas to cyclic Haworth formulas
• Properties and reactivity of the glycosidic hydroxyl
• Spatial conformations of six-membered rings: boat and chair
• Formation of furanose (five-membered) rings in carbohydrate solutions
• Chemical properties of alcohols and aldehydes using intramolecular reactions as an example

Other topics in "Chapter 18. Major Classes of Bioorganic Compounds"

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