5.8. Reactions of Saccharides
The majority of the twenty-three common monosaccharides are generated on industrial scale using microorganisms. However, many synthetic monosaccharides are synthesized using more traditional methods for use in research or pharmaceutical production. These are often modified versions of the common monosaccharides, with one or more of the saccharide’s functional groups replaced with a different group. Note that the examples in this text (Sections 5.8.2-5.8.9 and subsections therein) are only some of the more traditional and straightforward methods; there are many other reactions or sequences of reactions that may be used to modify saccharides.
For convenience most schemes will show the reactant saccharide as D-glucopyranose (an aldohexose in pyranose form). Use of a specific example helps show which functional groups do/do not change, which stereocentres do/do not change, etc. Unless otherwise indicated these reactions may also be performed using other monosaccharides, furanose isomers, ketoses, other saccharide lengths (e.g. pentoses), etc.
Some of these reactions may also be performed using saccharide polymers (i.e. disaccharides, trisaccharides, etc.). This is indicated for each respective reaction.
5.8.1. (Very) Brief Refresher of the Basics
In their cyclic forms saccharides have a hemiacetal functional group. Recall that this group is made and unmade repeatedly as the isomers interconvert (e.g. Schemes 5.7 and 5.9) using acid or base catalysis.
Scheme 5.9 – Acid- and Base-Catalyzed Mechanisms for Interconversion of β-D-Glucopyranose and β-D-Glucofuranose.
Recall that acid or base catalysis may be used in general for the formation of hemiacetal functional groups from carbonyl-containing electrophiles like aldehydes and ketones (Scheme 5.13). All of the steps in either mechanism are fully reversible. As with monosaccharides, these can catalyze the formation of a hemiacetal from a carbonyl and an alcohol AND catalyze the opposite reaction (formation of a carbonyl and alcohol from a hemiacetal).
Scheme 5.13 – Reaction Mechanisms for Ethanol Attacking Acetone with Base and Acid Catalysis.
These follow the typical catalysis patterns: acid catalysts activate the electrophile (make the electrophile a better electrophile), base catalysts activate the nucleophile (make the nucleophile a better nucleophile).
Recall that when base catalysis is used the reaction ends with the formation of the hemiacetal. However, if acid catalysis is used (and there is another equivalent of alcohol in the reaction) then the hemiacetal undergoes another reaction (Scheme 5.14). This leads to the formation of an acetal. This is, in general, the same type of reaction and catalysis used in enzymes for the formation of (or breaking of) glycosidic bonds in di-/poly-saccharides.
Scheme 5.14 – Reaction Mechanism for Ethanol Attacking Acetone with Acid Catalysis Continuing Through Acetal Formation.
5.8.2. Reaction: Acid-Catalyzed Glycoside Formation
It is possible to convert the hemiacetal of a cyclic saccharide into an acetal (Scheme 5.15). This is sometimes referred to as glycoside formation. There are multiple ways of doing this, though the classical method is to use an acid catalyst and an alcohol. The alcohol is typically used as the solvent to help favour formation of the acetal (Le Chatelier’s Principle).
Scheme 5.15 – Generalized Reaction Equation for Acid-Catalyzed Acetal Formation of Saccharides using D-Glucopyranose as an Example.
For the strong acid catalyst, it is possible to use acids such as sulfuric acid (H2SO4), phosphoric acid (H3PO4), or nitric acid (HNO3) but it is much more common to use hydrochloric acid (HCl). Like sulfuric acid, phosphoric and nitric acid always contain at least some water. This water inhibits acetal formation (water is a product and the reaction is in equilibrium). However, it is possible to generate hydrochloric acid without any water in it (sometimes referred to as anhydrous hydrochloric acid).
In principle this reaction can be done on saccharide polymers (di-, tri-, etc.). In practice this affords poor yields as the catalyst also catalyzes the breaking of any pre-existing glycosidic bonds. Assume this reaction does not work with saccharide polymers.
This reaction follows the standard mechanism for acid-catalyzed acetal formation from a hemiacetal (Scheme 5.16). The acid reacts with the alcohol to form an oxonium (not shown). This is the active catalyst. First, the leaving group (OH of the hemiacetal) gets activated by the catalyst. This greatly increases its leaving group ability. Then a lone pair of the oxygen forms a π bond with the carbon, ejecting the leaving group (water). This forms an activated carbonyl electrophile. The alcohol (nucleophile) attacks the activated carbonyl (electrophile). This forms a new bond and adds a lone pair to the oxygen. The solvent then removes a proton from the oxygen (the former nucleophile), regenerating the acid catalyst.
Scheme 5.16 – Reaction Mechanism for Acetal Formation with D-Glucopyranose and Ethanol via Acid Catalysis.
5.8.2.2. Stereoselectivity – Anomeric Effect
The new acetal contains a stereocentre (the anomeric carbon).
Both the alpha (α) and beta (β) anomers will generate the same intermediate: the anomeric stereocentre becomes a non-stereogenic trigonal planar carbon (Scheme 5.17). The starting ratio of anomers does not affect the stereoselectivity of the product formation because that stereochemical information is destroyed during the reaction. However, once the hemiacetal has been converted to an acetal mutarotation and ring opening are no longer possible. Whatever ratio of anomers was generated is now permanent.
Scheme 5.17 – Loss of Anomeric Stereocentre During Acetal Formation Followed by Formation of a “New” Stereocentre.
Recall that when two orbitals overlap constructively they form a covalent bond (σ or π). However, when they overlap deconstructively they form an anti-bonding orbital (σ* or π*). Usually, in order to break a covalent bond electron density must be put into its corresponding anti-bonding orbital. During the nucleophilic attack the covalent bond being broken is the carbon-oxygen π-bond, which is broken by putting electron density from the nucleophile (alcohol) into the corresponding anti-bonding π* orbital.
The carbon and oxygen are sp2 hybridized and trigonal planar. The p orbitals which make up the π bond are located both above and below the carbonyl. This is also true for the corresponding anti-bonding orbitals (π*), which simply point in the opposite directions (Figure 5.36).
Figure 5.36 – Representations of Pi (π) Bonding and Pi* (π*) Anti-Bonding Orbitals for an Oxoniumnium.
The usual stereochemical arguments still apply: There are other stereocentres in the electrophile, so the resulting products are diastereomers (the α and β anomers). Because there is a steric and/or electronic difference between attacking from above or below in these cases, the two stereoisomers are NOT formed equally and the product is a non-one-to-one mixture of diastereomers.
However, when the ring is 6-membered (i.e. pyranose rings) another factor also affects the stereochemical outcome.
Recall that, normally, groups attached to 6-membered ring prefer to be equatorial to avoid 1,3-diaxial interactions (a type of steric interaction). The anomeric effect occurs if a six-membered ring has a heteroatom with at least one lone pair then groups attached to the carbon atoms beside it in the ring that are electronegative prefer to be axial (Scheme 5.18). This effect is not regularly encountered because of its many specific requirements but is common in saccharides because they tend to have these qualities.
Scheme 5.18 – Examples of Chair Conformations Showing Axial vs. Equatorial Preference and the Anomeric Effect.
The specific details and nature of the anomeric effect are complex and still debated by many chemists. However, it is not debated that the anomeric effect is not a steric interaction. The anomeric effect is a type of stereoelectronic effect, where the ways orbitals and electron density are distributed and shaped in a molecule has an effect on the geometry of that molecule. In general, stereoelectronic effects require a significant background in orbitals/bonding theory to conceptualize and are typically left for advanced courses on organic chemistry. They may also have multiple possible explanations. For the anomeric effect, the current leading theory involves hyperconjugation.
The anomeric effect results in a preference for the new group being added as an axial substituent to the chair conformation that is preferred by the other groups. For example, with D-glucopyranose one of the chair conformations places all of the other groups equatorial and is favoured. The new group is added preferentially as an axial substituent to this (Scheme 5.19). The result for D-glucopyranose is that the α-anomer is the major product.
Scheme 5.19 – Stereoselectivity in Acetal Formation from D-Glucopyranose.
Predicting the stereoselectivity by factoring in both the steric and stereoelectronic effects is exceptionally challenging. Depending on the specific saccharide, the α or β anomer can be preferred and the selectivity can range from high to close to 1:1. As a result, the usual approach for handling diastereomers should be taken: the two stereoisomers are NOT formed equally and the product is a non-one-to-one mixture of diastereomers. In these cases, it is important only to recognize that the product will be formed as a mixture of diastereomers. Predicting which diastereomer should be favoured is not required. However, understanding that the outcome will also be affected by the anomeric effect is required.
5.8.3. Reaction: Esterification of All OH’s
It is possible to convert all of the OH groups of a cyclic saccharide into esters (Scheme 5.15). This includes the alcohols and the OH of the hemiacetal. There are multiple ways of doing this, though the classical method is to use an acid halide or an anhydride.
Scheme 5.20 – Generalized Reaction Equation for Esterification of all OH’s of Saccharides using β-D-Glucopyranose as an Example.
As with other uses of acid halides/anhydrides, the side product of either reaction is an acid (HX or a carboxylic acid). A non-nucleophilic base is often added to remove the acid as it is generated. The base is typically pyridine because it can also perform a second function: pyridine slightly changes the mechanism for ester formation, making it faster. The exact change in mechanism is not relevant (not shown in Section 5.8.3.1) but the increase in speed has consequences for stereoselectivity (see Section 5.8.3.2).
This reaction can be done on saccharide polymers (di-, tri-, etc.).
This reaction follows the standard two step mechanism for addition-elimination reactions followed by a deprotonation (Scheme 5.21). An acid halide example is shown. The mechanism using an anhydride is identical. For convenience a generalized HO-R is shown. The same reaction, with the same mechanism, will occur for each of the OH’s of the molecule.
The nucleophile (OH) attacks the electrophile (acid halide). This forms a new bond and adds a lone pair to the oxygen. Then that lone pair comes back and reforms the π bond with the carbon, ejecting the leaving group (halide). Finally, a base (pyridine) removes a proton to generate the final product and a salt.
Scheme 5.21 – Generalized Reaction Mechanism for Ester Formation with a Generic Alcohol and Ethanoyl Chloride.
Technically, the mechanism is modified by the pyridine to involve an intermediate formed between it and the electrophile. The specific details are not relevant but some sources may show the more accurate (and lengthier) mechanism.
5.8.3.2. Stereoselectivity – Retention
The relative configurations of the alcohols are not affected by the reaction. These stereocentres remain the same relative configurations as in the starting material. The absolute configurations may change if the priorities of groups change, but the relative configurations (hashed/wedged if drawn from the same perspective) are preserved.
Once the hemiacetal has been converted to an ester mutarotation and ring opening are no longer possible. Whatever ratio of anomers was generated is now permanent. Because of the increase in reaction rate by using pyridine, esterification is faster than mutarotation. As a result, whatever ratio of anomers was present in the starting material is retained in the products (Scheme 5.22). This type of outcome is sometimes referred to as “retention of configuration”.
Scheme 5.22 – Retention of Configuration at the Anomeric Stereocentre During Per-Esterification of D-Glucopyranose.
5.8.4. Reaction: Alkylation of All OH’s
It is possible to convert all of the OH groups of a cyclic saccharide into ethers and an acetal (Scheme 5.23). Alcohols are alkylated and become ethers. The OH of the hemiacetal is alkylated and becomes as acetal. There are multiple ways of doing this, though the classical method is to use an alkyl halide and a Lewis acid catalyst.
Scheme 5.23 – Generalized Reaction Equation for Esterification of all OH’s of Saccharides using β-D-Glucopyranose as an Example.
For the Lewis acid catalyst, it is possible to use popular Lewis acids such as iron chloride/bromide (FeCl3 or FeBr3) or aluminum chloride/bromide (AlCl3 or AlBr3) but it is much more common to use silver oxide (Ag2O). The reasons for this are primarily historical.
This reaction can be done on saccharide polymers (di-, tri-, etc.).
This reaction follows the standard SN2 substitution mechanism but has an additional activation step for the catalyst and an additional deprotonation (Scheme 5.24). For convenience a generalized HO-R is shown. The same reaction, with the same mechanism, will occur for each of the OH’s of the molecule. Diethyl ether (Et2O) is shown as the solvent. Other polar aprotic solvents may be used.
The alkyl halide (nucleophile) reacts with the Lewis acid catalyst (electrophile) to form an ionic complex. This greatly increases its electrophilicity. Depending on the exact structure of the alkyl group, the ionic complex may or may not form a carbocation. Then, the oxygen of the OH (nucleophile) attacks the carbon (activated electrophile). This creates a new O-C bond. Finally, the solvent (nucleophile/base) removes the original hydrogen (electrophile/acid) to form the final product, and the chloride leaves to regenerate the catalyst. This may occur
Scheme 5.24 – Reaction Mechanism for Alkylation with a Generic Alcohol Using 1-Chloroethane and Silver Oxide.
5.8.4.2. Stereoselectivity – Retention
All stereoselectivity considerations for this reaction are identical to those for esterification of saccharides (see Section 5.8.3.2). The relative configurations of the alcohols are not affected by the reaction. The absolute configurations may change if the priorities of groups change, but the relative configurations (hashed/wedged if drawn from the same perspective) are preserved. Once the hemiacetal has been converted to an ester mutarotation and ring opening are no longer possible. Whatever ratio of anomers was generated is now permanent. The alkylation is faster than mutarotation. As a result, whatever ratio of anomers was present in the starting material is retained in the products (Scheme 5.25).
Scheme 5.25 – Retention of Configuration at the Anomeric Stereocentre During Per-Alkylation of D-Glucopyranose.
5.8.5. Reaction: Reduction of Aldehyde/Ketone (Alditol Synthesis)
It is possible to convert the carbonyl (aldehyde or ketone) of a saccharide into an alcohol (Scheme 5.26). The saccharide must be able to adopt its open form (it must still have a hemiacetal). The carbonyl is reduced into an alcohol using a moderate reducing compound such as sodium borohydride (NaBH4). Reduction using sodium borohydride requires quenching with acid or base to generate the final product. The reaction is often depicted as two steps to indicate this. This sequence of steps is sometimes called Alditol Synthesis and the product molecules are sometimes called alditols.
Scheme 5.26 – Generalized Reaction Equation for Reduction of the Carbonyl of a Saccharide using D-Glucopyranose as an Example.
For the quenching step, it is possible to use a base but it is much more common to use an acid such as ammonium chloride (NH4Cl) or dilute hydrochloric acid (HCl). This minimizes the chances of undesired side reactions (i.e. elimination) occurring.
In principle this reaction can be done on saccharide polymers (di-, tri-, etc.). In practice this is not commonly done. Assume this reaction does not work with saccharide polymers.
This reaction follows the standard borohydride mechanism (Scheme 5.27). As with all borohydride reductions, each equivalent of borohydride can deliver four equivalents of hydride; one molecule of NaBH4 can add H– to four carbonyls. Only one of these is shown.
First, a hydride (nucleophile) attacks the carbonyl (electrophile). This forms a new bond and adds a lone pair to the oxygen. Then the anionic oxygen (nucleophile) attacks the boron (electrophile). This intermediate may then perform the same reaction to another carbonyl (not shown). After the reaction is complete an acid or base is added to quench, forming the final product.
Scheme 5.27 – Reaction Mechanism for Reduction of the Aldehyde of D-Glucose Using Sodium Borohydride (NaBH4).
The relative configurations of the alcohols are not affected by the reaction. These stereocentres remain the same relative configurations as in the starting material. The absolute configurations may change if the priorities of groups change, but the relative configurations (hashed/wedged if drawn from the same perspective) are preserved.
If the monosaccharide is an aldose then no new stereocentre is formed. Only one stereoisomer is possible.
If the monosaccharide is a ketose then a new stereocentre is (usually) formed (Figure 5.37). The usual stereochemical arguments still apply. There are other stereocentres in the electrophile, so the resulting products are diastereomers. Because there is a steric and/or electronic difference between attacking from above or below in these cases, the two stereoisomers are NOT formed equally and the product is a non-one-to-one mixture of diastereomers.
Figure 5.37 – Comparison of Products from Nucleophilic Attacks from Above and Below a Generalized Unsymmetric Ketone.
In some instances the product(s) from reduction of a ketose may be the same as the product from reduction of a different aldose. For example, reduction of D-fructose yields two diastereomers, one of which is the same product obtained from reduction of D-glucose (Scheme 5.28).
Scheme 5.28 – Comparison of Products from Reduction of the Carbonyl of D-Fructose and D-Glucose.
5.8.6. Reaction: Oxidation of Aldehydes to Carboxylic Acids Using Bromine and Water (Aldonic Acid Synthesis)
It is possible to convert the carbonyl (aldehyde) of a saccharide into a carboxylic acid (Scheme 5.29). The saccharide must be able to adopt its open form (it must still have a hemiacetal) and it must be an aldose. There are multiple ways of doing this, though the classical method is to use bromine (Br2) in water (H2O). This is sometimes called Aldonic Acid Synthesis and the product molecules are sometimes called aldonic acids.
Scheme 5.29 – Generalized Reaction Equation for Oxidation of the Carbonyl of a Saccharide using D-Glucopyranose as an Example.
This reaction is functionally identical to the oxidation of alcohols using dihalides and a weak base (see Section 5.8.6.1; see Oxidation of Alcohols via Elimination). The same reaction would occur, repeatedly, under these conditions if the pH were not kept neutral/low. Because this reaction forms acid as a side product the oxidation of the alcohols is avoided.
In principle this reaction can be done on saccharide polymers (di-, tri-, etc.). In practice this is not commonly done. Assume this reaction does not work with saccharide polymers.
This reaction combines hydrate formation and the standard dihalide oxidation E2 elimination mechanism (Scheme 5.30). The exact order of steps, particularly the acid-base reactions that move hydrogens, is variable. As a result, there are several equally valid orders for the steps of this reaction. Some sources may show the same steps but in a slightly different order. Some sources may add or omit some acid-base steps.
First, water (nucleophile) attacks the carbonyl (electrophile). This forms a new bond and adds a lone pair to the oxygen. Another equivalent of water removes a proton from oxygen (the former nucleophile). This partially forms the hydrate.
Second, the oxidation occurs. The anionic oxygen of the hydrate (nucleophile) attacks the dihalide (electrophile). This creates a new O-X bond. Finally, a third equivalent of water removes a proton to cause the elimination/oxidation step.
Scheme 5.30 – Reaction Mechanism for Oxidation of the Aldehyde of D-Glucose Using the Dihalide Bromine (Br2) in Water.
5.8.7. Reaction: Oxidation of Aldehydes and Primary Alcohols Using Nitric Acid (Aldaric Acid Synthesis)
It is possible to convert the carbonyl (aldehyde) and the primary alcohol of a saccharide into carboxylic acids (Scheme 5.31). The saccharide must be able to adopt its open form (it must still have a hemiacetal) and it must be an aldose. This requires nitric acid (HNO3) in water (H2O) with mild heating. This is sometimes called Aldaric Acid Synthesis and the product molecules are sometimes called aldaric acids.
Scheme 5.31 – Generalized Reaction Equation for Oxidation of the Carbonyl and Primary Alcohol of a Saccharide using D-Glucopyranose as an Example.
Although the acid also performs the function of acid catalyst, the nitric acid is not catalytic. Three equivalents of HNO3 are reduced (consumed) as the saccharide is oxidized three times.
This reaction does not work with saccharide polymers.
The mechanism for this transformation involves several unusual intermediates (Scheme 5.32). For simplicity only the oxidation of a generic primary alcohol is shown. The oxidation of the aldehyde follows the same mechanism; the aldehyde undergoes the same reaction through the same mechanism as in the second part of the oxidation of the alcohol. Some sources show nitric acid directly reacting with itself to form the nitronium. Since water is present, this is unlikely to be accurate.
Some of the nitric acid reacts with water to form hydronium (not shown). This acts as an acid catalyst.
First, oxidation of the primary alcohol to an aldehyde occurs. The electrophile (HNO3) gets activated by the catalyst. It then ejects water and forms a nitronium ion (NO2+). This greatly increases its electrophilicity. The primary alcohol (nucleophile) attacks the nitronium (activated electrophile). This creates a new O-N bond. An equivalent of water (nucleophile/base) removes hydrogen (electrophile/acid) from the cationic oxygen, regenerating the catalyst. Finally, another equivalent of water (nucleophile/base) removes a proton to cause the elimination/oxidation step.
Second, oxidation of the aldehyde to a carboxylic acid occurs. The same mechanism applies to the newly formed aldehyde and the original aldehyde of the aldose. The carbonyl (nucleophile/base) gets activated by the catalyst. This greatly increases its electrophilicity. The anionic oxygen (nucleophile) attacks the oxonium (activated electrophile). This creates a new O-C bond. Finally, water removes a proton to cause the elimination/oxidation step.
Scheme 5.32 – Reaction Mechanism for Oxidation of a Generalized Primary Alcohol Using Nitric Acid (HNO3) in Water.
5.8.8. Reaction: Chain Lengthening (Killiani-Fischer Reaction)
It is possible to extend the chain length, adding a new CH(OH), of a saccharide (Scheme 5.33). The saccharide must be able to adopt its open form (it must still have a hemiacetal) and it must be an aldose. This occurs through a multistep sequence commonly referred to as the Killiani-Fischer Reaction.
Scheme 5.33 – Generalized Reaction Equation for Killiani-Fischer Chain Lengthening using D-Arabinose as an Example.
In principle this reaction can be done on saccharide polymers (di-, tri-, etc.) to extend the chain length of the last saccharide in the polymer. In practice this affords very poor yields. Assume this reaction does not work with saccharide polymers.
The overall reaction consists of three parts (Scheme 5.34). For simplicity a generic aldehyde is shown. The other groups (alcohols, etc.) of the saccharide are not involved in any steps of the mechanism.
First, addition to the carbonyl occurs. The electrophile (carbonyl) gets activated by the acid. This greatly increases its electrophilicity. The anionic carbon (nucleophile) attacks the oxonium (activated electrophile). This creates a new O-N bond. Some sources refer to this intermediate as a cyanohydrin (the type of functional group the aldehyde has become).
Second, hydrogenation occurs. The nitrile is hydrogenated and becomes an imine. As before (see Section 4.3.3.1) the actual mechanism for hydrogenation is complex and involves steps beyond the scope of introductory (bio)organic chemistry (not shown).
Third, the water hydrolyzes the imine. The electrophile (imine) gets activated by the acid catalyst. This greatly increases its electrophilicity. Water (nucleophile) attacks the carbon of the iminium (electrophile). This forms a new bond and adds a lone pair to the nitrogen. The amine (base) removes a proton from the oxygen (the former nucleophile) regenerating the catalyst. The acid then places a proton on the desired leaving group, the nitrogen. This greatly increases its leaving group ability. A lone pair of the oxygen forms a π bond with the carbon, ejecting the leaving group (amine). Finally, the amine removes a proton to generate the final product and regenerate the acid catalyst.
Scheme 5.34 – Generalized Reaction Mechanism for Killiani-Fischer Chain Lengthening of Saccharides.
The relative configurations of the alcohols are not affected by the reaction.
During the addition step (nucleophile attacks carbonyl) a new stereocentre is formed. The usual stereochemical arguments still apply. There are other stereocentres in the electrophile, so the resulting products are diastereomers. Because there is a steric and/or electronic difference between attacking from above or below in these cases, the two stereoisomers are NOT formed equally and the product is a non-one-to-one mixture of diastereomers.
After the full set of steps the products are a pair of diastereomers. These will be a pair of longer aldoses with one additional stereocentre “inserted” between the carbonyl and the other stereocentres. The two diastereomers formed simply have opposite absolute configurations at the new centre. For example (Figure 5.38), Killiani-Fischer chain lengthening of the aldopentose D-xylose (R,S,R) yields a non-one-to-one mixture of two aldohexoses: D-gulose (R,R,S,R) and D-idose (S,R,S,R).
Figure 5.38 – Example of Diastereomers Formed from Killiani-Fischer Chain Lengthening of an Aldopentose.
For convenience, the table of common aldoses (Figure 5.6) is organized such that the new aldoses will be the compound to the right (and lower-right) of the starting material.
5.8.9. Reaction: Chain Shortening (Wohl Reaction)
It is possible to reduce the chain length, removing a CH(OH), of a saccharide (Scheme 5.35). The saccharide must be able to adopt its open form (it must still have a hemiacetal) and it must be an aldose. This occurs through a multistep sequence commonly referred to as the Wohl Reaction.
Scheme 5.35 – Generalized Reaction Equation for Wohl Chain Shortening using D-Glucose as an Example.
The third step is a transesterification reaction. However, the compounds required (alkoxides) are also strong bases. This results in elimination of alcohol functional groups as a competitive side reaction, lowering the yield. The base may also catalyze keto-enol tautomerism of the product, destroying the desired stereoisomer and further lowering the yield. As a result, in practice the Wohl reaction often affords poor yields (typically <40%) and is not commonly used. For examples in this text, assume the Wohl reaction works as intended.
In principle this reaction can be done on saccharide polymers (di-, tri-, etc.) to reduce the chain length of the last saccharide in the polymer. In practice this affords very poor yields. Assume this reaction does not work with saccharide polymers.
Ignoring potential problems in the third step, after the full set of steps the product is a single diastereomer. This is a shorter aldose with one fewer stereocentre “removed” from between the carbonyl and the other stereocentres. For convenience, the table of common aldoses (Figure 5.6) is organized such that the new aldose will be the compound to the left (OR upper-left) of the starting material.
The overall reaction consists of three steps but five mechanistic parts (Scheme 5.36). Each individual part is straightforward, but the overall mechanism is exceptionally long. As a result, a simplified overview is presented in place of a full mechanism.
First, imine formation occurs. This does not require catalysis. Some sources refer to the intermediate that is formed as an oxime (the type of functional group the aldehyde has become). Simply referring to this as an imine is also acceptable.
Second, acetylation occurs. This follows the standard addition-elimination mechanism. All OH groups will react, including the OH of the imine/oxime.
After the OH of the imine/oxime reacts the new functional group will spontaneously eliminate acetic acid (ethanoic acid). This forms a nitrile. The mechanism for the elimination step is slightly advanced for an introductory level and does not follow the typical patterns (acid-base, nucleophile-electrophile, leaving group, etc.). It is again a rearrangement. Some sources refer to the intermediate that is formed as a cyanohydrin (the type of functional group the aldehyde has become).
Fourth, transesterification of the esters occurs. This follows the standard addition-elimination mechanism. All of the esters are converted back into alcohol functional groups.
Finally, the aldehyde forms by ejecting (eliminating) HCN. This is the reverse of the first step of the Killiani-Fischer reaction (see Section 5.8.8.1).
Scheme 5.36 – Simplified Overview for Mechanistic Steps of Wohl Chain Shortening of Saccharides.
