5.2. Cyclic Forms of Monosaccharides
All monosaccharides have a carbonyl (aldehyde or ketone) and multiple alcohol functional groups. If the molecule is long enough the carbonyl can combine with an alcohol from the same molecule to form a hemiacetal (see Simple Nucleophilic Attacks on Carbonyls and Catalysis of Addition Reactions; Scheme 5.1).
Scheme 5.1 – Example of D-Fructose Cyclization to 5- or 6-Membered Rings with Highlighted Preference for Cyclic Forms at Equilibrium.
Most hemiacetal functional groups are only semi-stable. However, if generating the hemiacetal forms a 5- or 6-membered ring then it is often quite stable (viz. low in energy). As a result, monosaccharides that can form 5- and/or 6-membered cyclized forms will preferentially do so. At equilibrium the overwhelming majority of the monosaccharide will be in a cyclized form. Often there are multiple possible cyclic forms (see Sections 5.2.2 and 5.2.3) making structure recognition challenging.
5.2.1. Drawing Cyclic Monosaccharides
Confusingly, there are three different styles for drawing cyclic saccharides (Figure 5.11). Some sources will preferentially use a single style and others will use all three interchangeably. Familiarity with all three is an unfortunate necessity for competent communication.
Figure 5.11 – β-D-Glucopyranose Represented Using Line-Angle, Chair, Fischer Projection, and Haworth Projection Styles.
One of the drawing styles is the standard line-angle approach (sometimes called “bond angle” or “skeletal”; Figure 5.12). This is the style preferred by many chemists. Hashed and wedged bonds are used to indicate three dimensional shapes (stereochemistry). When the ring is 6-membered it will usually adopt a chair conformation. A variation of the line-angle structures is showing the chair conformation(s) rather than the classical representation. Chair representations do not use hashed/wedged bonds to show stereochemistry and instead rely on perspective to indicate three-dimensional shape (see 6-Membered Rings).
Figure 5.12 – β-D-Glucopyranose Represented Using Line-Angle and Two Types of Chair Styles.
Remember also that the same molecule can be represented in several orientations; all of these are depictions of the exact same molecule (Figure 5.13). This is also true for any given chair conformation, which may be represented using any of 12 different perspectives. The other chair conformation of the same molecule would have another 12 different perspectives (not shown).
Figure 5.13 – Various Orientations and Perspectives of β-D-Glucopyranose Represented Using Line-Angle and Chair Styles.
By convention the preferred orientation/perspective for line-angle and chair drawings places the oxygen of the ring at the “top”/“back” of the image and the carbon of the hemiacetal on the right (as Figure 5.12). However, these are only conventions and not rules.
One of the drawing styles is the classical Fischer projection approach (Figure 5.14). This is the style preferred by some biochemists. Left/Right directionality are used to indicate three dimensional shapes (stereochemistry). The oxygen of the ring is normally connected to the central carbon of the hemiacetal using a long curved line. Rarely, some sources may use straight line segments. The connection points between line segments DO NOT represent carbons when used this way. To avoid confusion use of this approach is discouraged.
Figure 5.14 – β-D-Glucopyranose Represented Using Three Types of Fischer Projection Styles.
This style is largely a holdover from the early years of biochemistry. Outside of specific applications use of one of the other styles is heavily encouraged. However, as it is frequently used in some sources familiarity is also encouraged.
One of the drawing styles is the Haworth Projection approach (Figure 5.15). This is the other style preferred by some biochemists. Haworth projections typically use hashed/wedged bonds to indicate which atoms are closer to the viewer, though some sources omit this. Up/Down directionality are used to indicate three dimensional shapes (stereochemistry). Hydrogen atoms at carbons of the ring may or may not be explicitly shown. Often they are not shown to avoid crowding.
Figure 5.15 – β-D-Glucopyranose Represented Using Three Types of Haworth Projection Styles.
It may be helpful to view Haworth projections as simplified chair representations (Figure 5.16). The projection is functionally a “flattened” chair where groups are simplified as being directly up or down instead of showing tetrahedral geometry.
Figure 5.16 – Relating a Chair Representation of β-D-Glucopyranose to a Haworth Projection.
Haworth projections may also be used for 5-member rings (Figure 5.17).
Figure 5.17 – β-D-Fructofuranose Represented Using Line-Angle and Haworth Projection Styles.
As with chair representations, in principle there are many possible orientations/perspectives for a Haworth projection. By convention the preferred orientation/perspective places the oxygen of the ring at the “top”/“back” of the image and the carbon of the hemiacetal on the right (as Figure 5.15). Although these are only conventions the overwhelming majority of sources use this perspective. All other orientations/perspectives are heavily discouraged.
5.2.1.3. How to Convert Between Different Drawings of Cyclic Monosaccharides
The process for interconverting line-angle/chair, Fischer projection, and Haworth projection images can range from very straightforward to highly challenging. In general, interconverting styles other than Fischer projections simply requires orienting the structures correctly. Four examples where a structure is converted into each of the other styles are presented.
Reorient the structure into the “conventional” perspective. It may be helpful to number carbon positions and/or assign absolute configurations and/or class groups as axial/equatorial. Use of a molecular model is not required but may be helpful in some instances.
Draw a blank template of the structure in the new style without adding any groups. When converting from a Fischer projection number/count atoms of the ring to know whether 5-membered or 6-membered templates should be used.
Add substituents to the template of the structure in the new style. Multiple approaches may be used (assigning absolute configuration, numbering carbons, etc.). When converting between any two styles other than Fischer projections the simplest approach is to add substituents by viewing the molecule as a series of groups being towards/away from the viewer’s perspective. Working systematically (e.g. clockwise or by numbered carbons) may be helpful.
There are several methods to convert to/from a Fischer projection. Unfortunately, the best general approach is to number the atoms of the ring, assign absolute configurations, and then add substituents to match. Positions may be numbered arbitrarily but it is often helpful to number the oxygen of the ring 1, the carbon of the hemiacetal 2, and proceed systematically from there. This helps set the perspective. As before: add groups arbitrarily, assign absolute configuration, and change those that do not match. The connecting line in the template Fischer projection may need redrawn to allow the correct configuration at the last position of the ring. Other (faster) methods exist for specific interconversions, but this approach will work for any interconversion.
5.2.1.4. How to Convert Between Open Form Fischer Projections and Drawings of Cyclic Monosaccharides
A semi-common task is to draw a cyclized version of a monosaccharide given its open form. While it is possible to use the line-angle structure of the open form to generate the cyclized monosaccharide, it is usually easier to use the Fischer projection. It is possible to do this by drawing out the Fischer projection of the cyclized saccharide and converting that into a line-angle/chair/Haworth projection. However, an alternative approach involves partially converting the Fischer projection back into a line-angle structure and cyclizing this. Use of a molecular model is not required but may be helpful in some instances.
Example:
The alcohol at carbon 5 of D-galactose cyclizes intramolecularly with the carbonyl.
The new stereocentre has absolute configuration (S). Draw the cyclic form as a line-angle structure.
Examine the Fischer projection of the monosaccharide, identifying the relevant positions. Determine the size of the resulting ring. It is not necessary to (re)draw the open Fischer projection nor the cyclized Fischer projection, but it may be helpful in some cases.
Convert the Fischer projection into a line-angle structure in the “horseshoe” conformation it represents (see Section 5.1.3.1). This is fundamentally just reversing the process of converting a line-angle structure into a Fischer projection. Rotate this 90° to the right to place all carbons of the chain in the plane of the page. All groups on the “left” in the Fischer projection will be above the plane. All groups on the “right” in the Fischer projection will be below the plane. It may be helpful to number positions.
Change the conformation of the monosaccharide to place the alcohol that is doing the cyclization near the carbonyl. Rotate as few bonds (ideally only one) as possible.
Draw a template ring in the same orientation/perspective as the line-angle structure. Add substituents to the template following the line-angle structure. It may be helpful to number positions. If the new stereocentre is specified indicate it as required.
If necessary the drawing may then be rotated into the standard or required perspective/orientation.
It is NOT recommended to simply assign absolute configurations to stereocentres in the open form (Fischer projection or line-angle) structure and then add groups to the ring template to match. This method works for other tasks but may have issues when chemical reactions are occurring; the priority of some groups may change during cyclization, leading to errors.
5.2.2. Classification: Furanoses vs. Pyranoses
Depending on the structure of the monosaccharide and which alcohol forms the hemiacetal a 5- or 6-membered ring can be generated. To distinguish between the two types of rings they are given names relating them to the structures of similar cyclic compounds (Scheme 5.2). The 5-membered ring forms are classed as furanoses. The 6-membered ring forms are classed as pyranoses.
Scheme 5.2 – Example of D-Fructose Cyclization to 5-Membered (Furanose) and 6-Membered (Pyranose) Rings with Comparisons to Furan and Pyran.
Hexose monosaccharides can adopt both furanose and pyranose forms. However, shorter chain monosaccharides may not be able to generate 6-membered (pyranose) or even 5-membered (furanose) rings.
5.2.3. Classification: Alpha- (α-) vs. Beta- (β-) Anomers
Recall that simple additions to symmetrical carbonyl-containing compounds like acetone produce no stereocentres. However, additions to non-symmetrical carbonyls can produce a new stereocentre. For example, a nucleophilic attack onto butan-2-one will produce multiple stereoisomers (Figure 5.18). Specifically, attacking from the top (red arrow; towards the viewer) and attacking from the bottom (blue arrow; away from the viewer) of the ketone will produce a different absolute configuration at a new stereocentre.
Figure 5.18 – Comparison of Products from Nucleophilic Attacks on the Top and Bottom Sides of Butan-2-one.
The same process occurs during cyclization of a monosaccharide. When the monosaccharide cyclizes it generates a new stereocentre; the carbon of the carbonyl becomes a new stereocentre in either the furanose and pyranose forms. Consider two cyclizations of D-glucose to form its pyranose form (Scheme 5.3). Depending on which side of the carbonyl the alcohol attacks the new stereocentre will have a different absolute configuration (full mechanism omitted for clarity).
Scheme 5.3 – Cyclization of D-Glucose to Pyranose Form with Two Possible Stereochemical Outcomes.
To highlight this distinctive property the carbon of the new stereocentre (the carbon of the hemiacetal; the carbon that was in a carbonyl) is called the anomeric carbon (sometimes the “anomeric site” or “anomeric position”).
The relationship between these two cyclized forms is diastereomers. More specifically, they are epimers at the anomeric carbon. The term anomer is often used as an abbreviation for this; the two cyclized forms are a pair of anomers (a pair of “epimers at the anomeric carbon”).
To distinguish the two anomers they are classed as either the alpha-anomer (α-anomer) or beta-anomer (β-anomer). The IUPAC definitions of these two terms are very technical:
The molecule whose newly formed OH group is cis to the oxygen atom on the last stereocentre in a Fischer projection is the α-anomer.
The molecule whose newly formed OH group is trans to the oxygen atom on the last stereocentre in a Fischer projection is the β-anomer.
Consider the two pyranose forms of D-glucose again (Scheme 5.4). In the Fischer projection of the left structure the newly formed OH group is trans to the oxygen atom of the last stereocentre. This is the β-anomer. In the Fischer projection of the left structure the newly formed OH group is cis to the oxygen atom of the last stereocentre. This is the α-anomer.
Scheme 5.4 – Cyclization of D-Glucose to Pyranose Form with Two Possible Stereochemical Outcomes Highlighting the Fischer Projection Determination of α/β-Anomer.
The “last stereocentre” does not need to be part of the ring (Scheme 5.5).
Scheme 5.5 – Cyclization of D-Glucose to Furanose Form with Two Possible Stereochemical Outcomes Highlighting the Fischer Projection Determination of α/β-Anomer.
Cis and Trans are relative descriptors that rely on consistency in perspective, conformation, etc. to be constant. The previous examples highlight an unfortunate result of their inclusion in the definitions (Figure 5.19). The β-anomer has a trans relationship between the two relevant groups in the Fischer projection. However, it is not possible to see this in the line-angle structures. The α-anomer has a cis relationship between the two relevant groups in the Fischer projection. However, it is not possible to see this in the line-angle structures.
Figure 5.19 – Comparison of Products from Nucleophilic Attacks on the Top and Bottom Sides of Butan-2-one.
It is only possible to accurately classify α/β anomers using Fischer projections. A variety of “tricks” can be found in other sources. While these can be useful, generally these “shortcuts” work only for some cyclic monosaccharides and can lead to errors, especially with ketoses and/or furanose forms. As such their use is heavily discouraged.
5.2.3.1. How to Assign Alpha/Beta (α/β) to a Monosaccharide
To be accurate assigned as the α- or β-anomer the Fischer projection must be generated. Then, simply look for whether the OH at the anomeric carbon is cis or trans to the oxygen at the last stereocentre. The outlined process is a simplified way to do so by only depicting the two relevant stereocentres.
Identify the two relevant stereocentres: the anomeric carbon (the carbon of the hemiacetal) and the last stereocentre of the chain (the stereocentre with the highest numbered position). It is often very helpful to number the carbon positions.
Convert the structure to a simplified Fischer projection. If the only question is whether the monosaccharide is alpha or beta then only the stereochemistry of the anomeric carbon and the last stereocentre need to be represented. This makes the process much faster. Assigning and using absolute configurations is recommended.
Assign α/β. If the OH at the anomeric carbon is cis to the oxygen at the last stereocentre, then it is the α-anomer. If the OH at the anomeric carbon is trans to the oxygen at the last stereocentre, then it is the β-anomer.
Again, a variety of “tricks” can be found in other sources. While these can be useful, generally these “shortcuts” work only for some cyclic monosaccharides and can lead to errors, especially with ketoses and/or furanose forms. For example, applying the most common shortcut to the three line-angle examples above would only give the correct α/β assignment to one of them. As a result, their use is heavily discouraged.
