Internal reactions that occur spontaneously
As a preliminary preparation to understand how an open chain structure is converted into a cyclic ring structure, we looked at electronegativity and nucleophiles/electrophiles in detail in the previous article. Now, using glucose—the most abundant and widely used monosaccharide, and the most discussed molecule of the 21st century—as an example, let us explore the process of cyclization.
The open-chain linear structure of glucose is best represented by the Fischer projection, which clearly shows the chiral centers. In contrast, the cyclic form of glucose in aqueous solution is best depicted by the Haworth projection. While the Fischer projection displays groups to the left and right of the carbon backbone (as seen in the D/L nomenclature), the Haworth projection shows the substituents positioned above and below the plane of the ring.
Let's imagine a long chain rope in front of us. If we connect one end to the other, it forms a ring and can be used as a necklace. If we connect one end to the middle of the chain instead, it will form a ring shape, but the size of the ring is smaller so it would be difficult to make a necklace, but it could make a bracelet. Similarly, if we think of the Fischer projection of glucose as a long chain, it can form a ring when one part connects to another part on the opposite end of the molecule. This connection is the result of a spontaneous, intramolecular chemical reaction that occurs without the aid of any external catalyst.
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Cyclization is extremely important because it is the first step in extending simple monosaccharides into more complex and diverse carbohydrates. Through cyclization, an additional chiral center is created, and the monosaccharide can now be further classified into two new mirror-image isomers created from this new chiral center. Plants connect countless monosaccharides to form starch, while animals and humans store energy efficiently in the form of glycogen. To create rigid, fibrous structures like cellulose or the exoskeletons of insects and crustaceans, endless numbers of monosaccharides are also linked together. During these connections, the new chiral center created through cyclization and its resulting two isomeric ring forms play essential roles in determining the types of linkages that occur. As the first step in understanding how monosaccharides expand, let’s explore how to convert the linear structure represented by the Fischer projection into its cyclic form.
Let's tilt the Fischer projection and rotate the substituent on carbon 5.
Fischer projections are designed to visually represent the chiral centers of monosaccharides. We know that if the hydroxyl group (–OH) on carbon 5 is on the right, it is a D-form glucose; if on the left, it's an L-form. This left/right directionality is crucial. When glucose cyclizes, substituents that were on the right in the Fischer projection appear below the plane in the Haworth projection. This becomes easier to understand if we tilt the Fischer projection to the right.
Now, let’s rotate the –OH group on carbon 5 so it positions outward. Maintaining the positions of carbons 4 and 5, slightly rotate the other three substituents. Because all these connections are single sigma bonds, such rotation is possible. With this adjustment, it becomes clearer why the hydrogen attached to carbon 5 appears below the plane in the Haworth projection. The glucose in the example below is D-type glucose because the OH group on carbon 5, which is the chiral carbon furthest from the aldehyde group on carbon 1, is located to the right.
After rotating the substituents on carbon 5, the OH group has shifted to the end of the chain and now approaches the carbonyl group (C=O) on carbon 1. Just like in the photo of the chain, the linear structure begins to bend and gradually forms a ring. The shape of the ring depends on which parts of the chain connect.
In the Haworth projection, the side of the ring closer to the observer is shown with a thick wedge, while the far side is drawn with a thinner line to express perspective. Don't forget that the substituents that were on the right in the Fischer projection now all appear below the ring plane in the Haworth projection.
The Nucleophilic attack on the electrophile
Now, in order to understand the internal reaction that will close the ring, we learned about electronegativity and the behavior of nucleophiles and electrophiles in the previous article. The oxygen and carbon of the carbonyl group at carbon number 1 form a double bond (C=O). At this time, carbon is in an sp2 hybridized state, forming one sigma bond and one pi bond with oxygen. (Hybridization and Sigma/Pi Bonds were discussed in detail in separate articles.)
Due to oxygen's much greater electronegativity, it pulls the shared electrons toward itself, becoming partially negatively charged (δ–), while the carbon, having lost electron density, becomes an electron-deficient electrophile with a partial positive charge (δ+).
So what about the OH group on carbon 5? The oxygen of this OH group has two covalent bonds and two lone pairs of electrons. This oxygen is a nucleophile that wants to form a covalent bond with the electrophile by donating one of its two lone pairs of electrons. The nucleophilic oxygen "attacks" the electrophilic carbon of the carbonyl group.
The birth of anomeric carbon
Let's pay attention to the carbon of the carbonyl group. Since carbon can only form four bonds, it cannot accept a fifth bond from the incoming oxygen. One existing bond must be broken. As expected, the pi bond is weaker than the sigma bond and is thus broken to allow the new bond with the nucleophile to form.
At this time, as the pi bond breaks, the electrons in the pi bond are pushed toward oxygen of the carbonyl group, making this oxygen even more negatively charged. This negatively charged oxygen then attracts a nearby proton in aqueous solution and forms a new OH group.
It is important to note that carbon number 1 was not a chiral center in the open-chain structure because it has double bond(carbonyl carbon). But now, with the formation of a new bond, it becomes a chiral center. The moment the double bond of the carbonyl group is broken and combined with oxygen, carbon number 1 becomes a chiral carbon, and this newly created chiral carbon is called an anomeric carbon. This point will be the starting point for the infinite march of monosaccharides that will take place in the future. Let's learn more about the two new forms that this anomeric carbon creates in the next article.
What happens to the nucleophile’s oxygen?
Meanwhile, what happens to the oxygen on carbon 5 that initiated the nucleophilic attack? Normally, an oxygen atom is stable with two covalent bonds and two lone pairs of electrons (with a formal charge of zero). But as shown in the diagram(6), after forming a third covalent bond during the reaction, it now has only one lone pair—giving it a formal charge of +1 and an unstable, electron-deficient state.
The electron density has also been lowered, resulting in a partial positive charge, but thankfully(?) the hydrogen leaves its electrons to oxygen and leaves as a proton (H+), so the oxygen that received the electrons becomes neutral and becomes stable again. At this time, this free protons combine with another surrounding water molecules in an aqueous solution to form hydronium ions. This is part of understanding why cyclization occurs stably in aqueous solution. Glucose now formed a stable ring structure.
Chair conformation
The process by which glucose is cyclized from its chain structure was examined in detail. The Fischer projection, which represents monosaccharides with an open linear structure before cyclization, places the carbon skeleton in the vertical (vertical) direction and shows the substituents (OH and H) connected to this skeleton positioned to the left and right, and when the carbon skeleton is closed and cyclized, the Haworth projection is specialized to clearly represent whether the cyclized structure is a 6-membered ring or a 5-membered ring. The Haworth projection takes the substituent positions of the Fischer projection before cyclization and displays them so that the substituents on the right side of the Fischer projection are facing downwards and the substituents on the left side are at the top. However, right/left and top/bottom as used here do not mean the absolute direction in the 3D structure of the actual molecule, but rather the relative direction based on the carbon skeleton, which may be different from the actual space position. In this way, both the Fischer projection and the Haworth projection express the structure in a very simplified way as if it were placed on a two-dimensional plane, so neither can explain the actual three-dimensional structure of monosaccharides.
However, despite these limitations, the two projection methods each have important uses and advantages because they have clear purposes and uses. In the case of the Fischer projection, it intuitively shows the stereochemical structure resulting from various chiral carbons in the carbon skeleton. The Fisher projection not only shows the relationship between various stereoisomers and makes it easy to distinguish between them, but is also optimized to distinguish between L-type and D-type. The Haworth projection also has the advantage of making it easy to identify how many element ring structures there are and intuitively distinguishing between the two anomeric (α, β) forms resulting from cyclization, thereby neatly showing how glycosidic bonds occur when combining monosaccharides, including disaccharides. (α and β anomers are discussed in detail in the next article.)
In that case, a method is needed to show the actual three-dimensional structure as realistically as possible, considering both accurate bond angles and spatial orientation within the molecule. For this, we use chair conformation for six-membered ring structure monosaccharide (pyranose) such as glucose, and an envelope conformation for five-membered ring structure (furanose) such as fructose, which will be discussed in the next article.
When the chiral carbons of a monosaccharide are connected to four surrounding substituents, sp3 hybridization occurs, maintaining the bond angle of 109.5° between molecules and trying to have the most stable ring structure. However, to maintain this bond angle, it actually takes a slightly twisted form, so the six-membered ring structure becomes chair-shaped and the five-membered ring structure becomes envelope-shaped. These two forms are the most stable and low-energy structures. It looks a bit similar to a camping folding chair to me... hmm...
Axial and equatorial position
In chair conformation, using the ring plane as a reference, substituents are drawn either perpendicular to the ring (axial) or nearly parallel to the ring (equatorial). By convention, the ring oxygen(red) is placed at the upper right. When substituents are located in the equatorial positions, steric hindrance is minimized and the molecular structure is more stable, especially when large substituents are located in the equatorial position. Simply put, steric hindrance is a phenomenon in which substituents in a molecule are too close to each other and collide with each other. Just as we try to avoid bumping into people in a crowded elevator, molecules also use energy to avoid getting caught up in the ‘battle for space,’ so we can imagine a more peaceful and stable state if there are fewer seat obstacles.
In glucose, the most stable form is β-D-glucose, where all bulky substituents (–OH, –CH₂OH) are in equatorial positions. In contrast, α-D-glucose, where the anomeric –OH group is axial, is less stable. Chair conformations thus help us understand molecular stability and reactivity more accurately. Note that hydrogen atoms are usually omitted in these diagrams for clarity unless necessary.
Hexagonal Pyranose Vs Pentagonal Furanose
With cyclization comes new terminology: pyranose and furanose. Let’s think back to the chain photo above. The size of the ring depends on which parts of the chain connect. If carbon 6’s –OH attacked carbon 1 instead of carbon 5’s –OH, a 7-membered ring could theoretically form—but such rings are too unstable to exist. A 5-membered ring (furanose) can form if carbon 4’s –OH attacks carbon 1, but this too is less stable and rarely occurs compared to the 6-membered ring.
A furanose contains 4 carbon atoms and 1 oxygen in its ring, while a pyranose contains 5 carbon atoms and 1 oxygen. These names are derived from organic compounds called furan (five-membered ring) and pyran (six-membered ring), and the “-ose” suffix indicates a sugar. Thus, the term pyranose refers to six-membered sugar rings, and furanose to five-membered ones. In the glucose example, a six-membered ring forms, so we could use the more specific name D-gluco-pyranose. The longer the name, the more descriptive and informative it becomes.
Having explored in detail the cyclization of glucose—representative of six-carbon aldoses—and its more realistic chair conformation, we’ll now move on in the next article to learn about the anomeric carbon and the two stereoisomers (α and β) it produces.
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