Carbohydrates

α (Alpha) – the name given to the configuration of a cyclic sugar where the oxygen on
the anomeric carbon is on the opposite face of the ring relative to the substituent on the other
carbon flanking the ring oxygen. Contrasted with beta (β) which is where the two substituents
are on the same faces of the ring.

Aldaric acid – a dicarboxylic acid derived from an aldose where both ends of the sugar have
been oxidized, e.g. from the action of nitric acid:

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Aldose – a monosaccharide with an aldehyde (or masked aldehyde) functional
group. [“Masked aldehyde” here refers to a cyclic hemiacetal that is in equilibrium with an
acyclic aldehyde through ring-chain tautomerism]. Contrast aldoses with ketoses, which are
monosaccharides with a ketone (or masked ketone) group.

Alditol – an acyclic alcohol derived from the reduction of an aldose. The alditol of
glyceraldehyde, for example, is glycerol. Sorbitol is the alditol of glucose, mannitol is the
alditol of mannose, and so forth. If these names sound familiar, it is because alditols are
commonly used as food additives and sweeteners.

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Anomer – the name given to two diastereomeric monosaccharides that are epimers at
the anomeric carbon. The two anomers are described with the terms α (“alpha”) and β
(“beta”), defined above.

Anomeric carbon – the carbon of a cyclic sugar bearing a hemiacetal or acetal (hemiketal or
ketal). This is C-1 in aldoses, and C-2 in the case of fructose.

β (beta) – the name given to the configuration of a cyclic sugar where the oxygen on the
anomeric carbon is on the same face of the ring as the substituent on the other carbon flanking
the ring oxygen. Contrast with alpha (α) where the two substituents are on the opposite faces of
the ring.

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Carbohydrate – originally just referred to monosaccharides (such as glucose) with the
empirical formula Cn(H2O)n (i.e. “hydrates of carbon”). Now used as a more generic term
referring to mono-, oligo-, and polysaccharides as well as many of their derivatives.

D- (and L-) A monosaccharide is assigned to D- or L- according to the configuration at the

highest-numbered chiral center, i.e. the bottom-most chiral center in its Fischer projection. If
the hydroxyl group of this carbon is on the right, the sugar is assigned the prefix D-; if it is on
the left, it is assigned with the prefix L- . The enantiomer of a D-sugar is always an L-sugar.
The simplest sugar is glyceraldehyde, which has one chiral center and exists in two
enantiomeric forms, called D- and L- glyceraldehyde, respectively. [See this post on D- and L-
sugars]

Disaccharide – a carbohydrate which can be hydrolyzed to give two monosaccharides. Some

prominent examples of disaccharides are lactose, sucrose, and maltose. The sugars of a
disaccharide are joined through a glycosidic bond.

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Epimer – two sugars which differ in the configuration of a single chiral center. D-Glucose and
D-Mannose are epimers, as are D-Mannose and D-Talose. [Note: generally speaking, when
using the term “epimer”, one of the atoms on the chiral center is usually hydrogen]

Furanose – a five-membered cyclic hemiacetal. The name derives from furan, a five
membered cyclic ether. Furanoses are distinct from pyranoses, which is a six-membered
cyclic hemiacetal. [See post ]

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Glycoside – fancy name for an acetal (or ketal) formed from a sugar. Formally, a glycoside is
an acetal derived from condensation of the hemiacetal (or hemiketal) carbon of a sugar with the
hydroxy group of another compound.

Glycosidic bond – the bond that links the anomeric carbon of a sugar to another compound.
[For our purposes, this is through a C–O bond, but there are also such things as nitrogen,
sulfur, and selenium glycosides (among others)]

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Haworth Projection – a graphical depiction of monosaccharides that clearly shows the
stereochemistry at each carbon (at the expense of accurately depicting its conformation). [See
this post on Haworth projections]

Hexose – a sugar with six carbons, the most familiar example being glucose. A hexose that
bears an aldehyde (or masked aldehyde) is called an aldohexose; a hexose bearing a ketone is
called a ketohexose.

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Ketose – a monosaccharide with a ketone (or masked ketone) functional group. Contrast
with aldoses.

L- (and D- ) When drawn in a Fischer projection,the highest-numbered chiral center in all L-

sugars will be pointing to the left. See D-

Monosaccharide – a sugar which cannot be hydrolyzed into simpler sugar units. Glucose,
ribose, mannose, and many other sugars (including deoxyribose) are monosaccharides.
Sucrose, by contrast, is a disaccharide which can be hydrolyzed into glucose and fructose.

Mutarotation – the change in optical rotation that occurs when a pure anomer equilibrates to
the different anomer through ring-chain tautomerism. [See this post on mutarotation]

Oligosaccharide – a carbohydrate with a moderate (~ 3 to ~10) number of monosaccharide

units bound together by glycosidic bonds. There is no firmly defined boundary between
“oligosaccharide” and “polysaccharide”, but carbohydrate with more than 10 saccharide units
starts to get into polysaccharide territory.

Pentose – a five-carbon monosaccharide, such as ribose and deoxyribose. A pentose bearing

an aldehyde is called an aldopentose; a pentose bearing a ketone is called a ketopentose.

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Polysaccharide – a carbohydrate composed of many monosaccharides linked together.
“Many” is somewhat arbitrary, but a carbohydrate with about ten or fewer monosaccharide
units is often called an oligosaccharide.

Pyranose – a six-membered cyclic hemiacetal. Derived from the name pyran, a six-membered
cyclic ether. Distinct from a furanose, which is a five-membered cyclic hemiacetal.[See post on
furanoses and pyranoses ]

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Reducing sugar – a mono- or disaccharide which gives a positive Tollens test. Practically, it
refers to any mono- or di-saccharide with a hemiacetal that can undergo ring-chain
tautomerism. Glycosides are not reducing sugars, since they are not in equilibrium with
an aldehyde or ketone. [Post: Reducing sugars]

Ring-Chain Tautomerism – the equilibrium between linear and cyclic forms that occurs in
aldoses and ketoses. [See this post on ring-chain tautomerism ] Ring chain tautomerism is
possible when the cyclic form has a hemiacetal, but is not possible in glycosides (where
the acetals and ketals are “locked”).

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Saccharide – a sugar or sugar derivative. Synonym of carbohydrate.

Tetrose – a monosaccharide with four carbons. Erythrose and threose, both aldoses, are called
aldotetroses, and tetroses bearing a ketone are called ketotetroses.

Triose – a sugar with three carbons. There are only three trioses: D- and L- glylceraldehyde
(aldotrioses), and dihydroxyacetone (a ketotriose).

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Reducing Sugars

Reducing Sugars

 Reducing sugars are small carbohydrates (usually containing one or two sugar units) that are
capable of acting as reducing agents towards metal salts such as Ag+ or Cu2+ .
 These metal salts have historically been used for testing purposes because they oxidize
aldehydes and give a clear color change after being reduced.
 The reason sugars can react with these salts is that their cyclic hemiacetal functional group
is in equilibrium with an acyclic aldehyde. Acetals do not react.
Therefore a quick way of telling if a sugar is a reducing sugar is to notice whether or not it has
a hemiacetal.

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Table of Contents

1. Before We Talk About Reducing Sugars, The Chemistry Of “Peeing On The Stick”
2. Benedict’s, Fehlings and Tollens’ Tests: Three Visual “Tests” For The Presence of
Aldehydes
3. Reducing Sugars: Sugars With A Hemiacetal Functional Group Give Positive Tests Since
They Are In Equilibrium With An Open-Chain Aldehyde
4. So What Isn’t A Reducing Sugar?
5. Saccharides Lacking A Hemiacetal Are NOT Reducing Sugars
6. Complex Polysaccharides With A single Hemiacetal Unit (e.g. Starch) Are Not Reducing
Sugars
7. Test Yourself On Reducing Sugars
8. The Chemistry Of The Benedict, Fehlings and Tollens Tests
9. Notes
10.(Advanced) References and Further Reading

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1. Before We Talk About Reducing Sugars: The Chemistry Of “Peeing On The Stick”

Q. Can you think of a situation where it might be useful to be able to measure the
concentration of glucose in a solution (especially in blood or urine) ?

A. Diabetes. Once you have a way of quickly and easily measuring the concentration of sugar,
then you can determine how much insulin is needed to counteract it.

Next question. What would be an easy, visual way to detect the presence of glucose?
Especially something that doesn’t require you to be an expert chemist?

Ideally, you’d like a chemical reaction that results in a color change.

Think about pregnancy tests: you just pee on a stick and know within a few minutes whether
you’re pregnant. You don’t need to know any chemistry. It’s brainless.

99.999% of people who use this do not know the chemistry behind how it works. And that’s
OK!
A test for blood sugar suitable for diabetics should have a similar ease of use.

This brings us (via aldehydes) to the topic of reducing sugars, since they are the basis of a
historically important color-based test for blood glucose.

2. Three Visual “Tests” For The Presence of Aldehydes: Benedict’s, Fehlings, and
Tollens’ Tests

Before we get to sugars, let’s talk about the oxidation of aldehydes.

We’ve seen previously that aldehydes are a functional group that can be oxidized relatively
easily to carboxylic acids. For example, oxidation of alcohols with a “strong” oxidant like
chromic acid (H2CrO4) results in an aldehyde that is quickly oxidized further to a carboxylic
acid.

During this process, the aldehyde is oxidized and the oxidizing agent is reduced. Another way
of framing this is to say that the aldehyde is the reducing agent in this process.

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The list of reagents that can be used to oxidize aldehydes to carboxylic acids is loooong. Of
these, a few methods stand out in providing a particularly clear visual indication that the
reaction has proceeded to completion. [Note 1]

Three “visual” tests for aldehydes that you might encounter in an introductory organic
chemistry lab are the following:

 Fehling’s solution, where an aldehyde changes the color of a blue Cu(II) solution to red
Cu(I) [as Cu2O].
 Benedict’s solution a slightly modified version of Fehling’s solution
 Tollens’ test, where aldehyde oxidation results in a beautiful “mirror” of silver metal to
precipitate on the reaction vessel.

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Importantly, ketones don’t react under any of these conditions. The above tests were also a
useful way of distinguishing aldehydes from ketones in the dark days before IR and NMR
spectroscopy made this routine.

So what does this have to do with sugars? Let’s go back to Yelling Mode:

3. Reducing Sugars: Sugars With A Hemiacetal Functional Group Give Positive Tests
Since They Are In Equilibrium With An Open-Chain Aldehyde

As we’ve seen, glucose is in equilibrium with an open-chain (or “linear”) form containing
an aldehyde.

The concentration of aldehyde at any given time is small (<1%), but long-lived enough to be
trapped with the right reagent.

This means that glucose will give a positive test with Benedicts’ reagent, Fehlings solution, or
the Tollens test, and the aldehyde will be oxidized to a carboxylic acid.
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Voila! A simple color change tells you if glucose is present!

Negative (left) and positive (right) tests for glucose using Benedict’s reagent

What about quantification?

It’s nice to have a quick visual test for glucose. But what if we want to determine the exact
concentration of glucose in a solution of, say, urine or blood?

In this case, a slightly different formulation of Benedicts solution is used [Note 2] which
results in a colourless precipitate rather than a red color. A solution of the sample to be
analyzed is added, via buret, to a flask containing a known amount of Benedicts solution until
the blue color of the Cu(II) disappears. The unknown sample is then calibrated using a 1%
solution of glucose. [Full details here]

Benedicts assay was the method of choice for quantifying glucose for over 50 years. One
researcher recalls that all inductees into the U.S. army during World War II had their urine
tested for sugar with Benedict’s Solution.

In recent times, however, the use of Benedict’s solution has been supplanted by enzymatic
methods such as glucose oxidase. Why?

The Benedict test isn’t specific for glucose; it just tells you if an aldehyde is present. So it
will also give a positive test for other reducing sugars.

In short, any sugar* (*mono- or disaccharide) with a hemiacetal will also give a positive test,
since these sugars are in equilibrium with an open-chain aldehyde. So if the blood/urine
contains common monosaccharides like mannose, galactose, or fructose, these will deliver a
positive test. In other words, those sugars are also reducing sugars.

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Hold on for a second. Et tu, fructose?

Ketones aren’t supposed to oxidize under these conditions! So why does fructose give a
positive test?

Great question. Although fructose is a keto sugar, and ketones generally give a negative test
with the Benedict, there is an exception. If the carbon adjacent to the ketone carbon (the “alpha
carbon”) contains a hydroxyl group, the ketone will be in equilibrium with an aldehyde through
tautomerization (just for the record, this is called an “enediol rearrangement”). [Note 3]

Likewise, some disaccharides such as maltose and lactose contain a hemiacetal. They are also
reducing sugars that give a positive Fehlings, Benedict, or Tollens test (picture of lactose
positive test is further below).

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The bottom line is that Benedicts’ reagent quantifies reducing sugars which includes not just
glucose but also mannose, lactose, maltose, fructose, and others. That means that the test isn’t
as specific as we’d like!

4. So what isn’t a reducing sugar?

So far, it seems like every sugar we’ve encountered is a reducing sugar. So it’s fair to ask:
when is a sugar not a reducing sugar?

Two main cases:

 mono and di-saccharides which lack a hemiacetal

 polysaccharides where the ratio of hemiacetals to acetal linkages is very low (e.g. starch)
5. Saccharides That Lack A Hemiacetal Are Not Reducing Sugars

We saw at the top of the post that hemiacetals are in equilibrium with an aldehyde or ketone. In
contrast, acetals (ketals) are locked in place and can only be converted back to
the aldehyde or ketone with aqueous acid. That’s why they make great protecting groups for
aldehydes/ketones.

The poster child for a non-reducing sugar is sucrose, a.k.a. table sugar.

Sucrose is a disaccharide of glucose and fructose. See if you can find a hemiacetal in its
structure, below:

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There isn’t one! Sucrose only has acetal groups, and since acetals don’t open up to aldehydes
under the basic conditions present in the Benedict test, sucrose isn’t a reducing sugar. [Note 4]

Sucrose gives a negative test (blue) to the Benedict solution.

Another example of a non-reducing sugar are the so-called “glucosides” of common sugars,
such as glucose methyl glucoside, below. This is obtained by heating glucose in acidic
methanol.

Lacking a hemiacetal which could open to an aldehyde, this methyl glucoside also gives a
negative Benedict’s test.

6. Complex Polysaccharides Which Only Have A Single Hemiacetal Unit Don’t Count As
Reducing Sugars (e.g. Starch)

Sugars are able to form long chains with each other in arrangements known as polysaccharides.
Common examples of polysaccharides are starch, cellulose, and glycogen.

The vast majority of individual sugar units in these polysaccharides are joined to each other
via acetal (“glycosidic“) linkages. Hemiacetals are present, but only at the termini of the
polymer.

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Starch, for example, generally has about 300-600 individual units of glucose, but only one unit
(the terminus) has a hemiacetal.

One hemiacetal “needle” in a haystack of “acetals” is not enough to give a positive test for
reducing sugars. Therefore these polysaccharides are not considered reducing sugars. For
example, starch gives a negative test (see below).

Here is an example of Benedict’s test with lactose, starch, glucose, fructose, and sucrose (

Note that starch and sucrose are blue, classifying them as non-reducing sugars.

That’s enough about what classifies a “reducing sugar” from a “non-reducing sugar”.

Here’s the last step. Test yourself. What’s a reducing sugar and what is not?

7. Test Yourself On Reducing Sugars

Make sense? Quiz yourself on whether the following sugars are reducing sugars or non-
reducing sugars.

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If you don’t need to know anything else other than “what’s a reducing sugar”, you’re done
here.

But if you want to go further down the rabbit hole, I invite you to read further to learn about…

8. The Chemistry of the Benedict, Fehlings, and Tollens tests

So what’s actually going on in the Benedict, Fehlings and Tollens tests? Let’s discuss the
details of the chemistry.

One thing about all three tests is that the active reagent is not particularly bench stable and has
to be freshly prepared.

Fehling’s Solution

For Fehling’s solution, one starts with bright blue copper(II) sulfate, sodium hydroxide, and
potassium sodium tartrate (otherwise known as Rochelle’s salt). The purpose behind using the
tartrate is that it coordinates to the copper(II) and helps prevent it from crashing out of solution.

Once prepared, the substance to be analyzed is added, and the mixture is heated for a brief
period.

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This results in a carboxylic acid and red Cu(I) which precipitates out as copper(I) oxide.

The structure of the active species in Fehling’s solution has been determined; it’s a square-
planar copper complex attached to two tartrate ligands. [link – paywall]

Benedict’s Solution

Benedict’s solution is a slight variation of Fehling’s solution that uses citrate instead of tartrate,
which provides better stability for the copper(II).

Like Fehling’s solution, it is best made fresh. The ingredients are copper(II) sulphate, sodium
carbonate (note: hydroxide is also needed! – see reference), and sodium citrate. (Note: in the
quantitative test, potassium thiocyanate is added, which results in a colourless white
precipitate).

The test is performed by adding the substance to be analyzed and heating briefly.

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Tollens’ Solution

The active ingredient in the Tollens test, [Ag(NH3)2]+ , does not have a long shelf life and like
the Fehlings’ and Benedict solutions is best prepared fresh.

The first three lines below describe the procedure. Silver nitrate is converted to silver
hydroxide, which forms silver (I) oxide, Ag2O. Then, addition of aqueous ammonia (NH3)
results in formation of the silver-ammonia complex which is the active oxidant.

The sample to be tested is then added to the freshly prepared active oxidant in a basic solution.
A positive test results in a beautiful mirror of silver metal being precipitated out on the reaction
vessel. (A variant of this procedure is used for the preparation of mirrors).

How Does It Work?

The first thing to note is that all of these procedures occur in basic solution.

Why? There’s at least two good reasons for this that we can talk about.

 First, acidic conditions might hydrolyze any acetals present to hemiacetals, giving a false
positive test.
 Secondly, base considerably speeds up the rate of ring-chain tautomerism (i.e.
interconversion between the cyclic hemiacetal form and the linear aldehyde form).

24
Bottom line here is that adding base has the effect of increasing the concentration of the
starting aldehyde.

The Mechanistic Details Are Murky And You Will Not Find Them In Any Introductory
Textbook

I can’t find a single instance of the mechanism for the Fehlings or Benedict solutions being
elucidated conclusively online. If I am wrong, please tell me (leave a comment).

There is a third reason for the use of base, although I’m not very keen on talking about it. You
might notice we haven’t mentioned the mechanisms of any of these reactions. That’s because
the exact mechanisms have been tricky to elucidate. One of the key steps involved in the
mechanism of each reaction seems to be a process called, “single-electron transfer” which is
essentially when the metal salt slurps a single electron off of the substrate, creating a free-
radical and/or carbocation.

One of the access points for the initiation of a single-electron transfer reaction is a carbon-
metal bond, which can be achieved through base-promoted formation of an enolate.

That requires that the aldehyde have a proton on the alpha carbon (i.e. be “enolizable”). It turns
out that Fehling’s solution does a crap job with testing for benzaldehyde, which lacks any
protons on the alpha-carbon and can’t be enolized. Thus it would appear that the reaction needs
to proceed through an enol.

However, Fehling’s solution also oxidizes formaldehyde to formic acid and thereon to carbon
dioxide, and this process can’t possibly proceed through an enol/enolate intermediate.

So it is likely that a variety of mechanistic pathways can be in operation.

What might a mechanism look like?

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Maybe, possibly, something like this?

To see a popup image, hover here or or click on this link to the image.

[The key step here would be generation of a carbocation on the alpha-position of the aldehyde,
which accepts a hydride from a deprotonated hydrate-like intermediate, leading to formation of
a carboxylic acid.]

If anyone else has a better idea, please feel free to comment below.

Notes

Related Articles

 Hydrates, Hemiacetals, and Acetals

 Pyranoses and Furanoses: Ring-Chain Tautomerism In Sugars
 Oxidation of aldehydes to carboxylic acids with Ag2O
 The Big Damn Post Of Carbohydrate-Related Chemistry Definitions
 Nucleophilic Addition To Carbonyls
Image sources: Benedicts solution. Fehling’s solution. Tollens test.

Note 1. This isn’t to say that they’re the most practical methods for preparing carboxylic acids
from aldehydes. When chemists want to prepare a carboxylic acid from an aldehyde in good
yield, they don’t use any of these three processes. The standard way to do it is the Pinnick
oxidation.

Note 2. The quantitative test apparently employs potassium isocyanate, which results in a
colourless precipitate.

Note 3: It’s likely that the enediol intermediate is actually the species that reacts with Cu2+ in
the initial step of the mechanism that leads to the aldehyde. See the mechanism section.

Note 4. One thing to note: if sucrose is heated with aqueous acid before a
Fehlings/Benedict/Tollens test, a positive test will result. That’s because the acetal linkages
will be hydrolyzed by aqueous acid to produce the two constituent sugars of sucrose (glucose
and fructose) which are themselves reducing sugars.

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 (Advanced) References and Further Reading

1. The Species of Fehling’s Solution

Thomas G. Hörner, Peter Klüfers
J. Inorg. Chem. 2016, 12, 1798-1807
DOI: 10.1002/ejic.201600168
Even though the reaction equation of Fehling’s test may look simple on paper, the species
involved are actually quite complex!
2. The subjection of glutaraldehyde to the Tollens test
William D. Hill
Journal of Chemical Education 1990, 67 (4), 329
DOI: 1021/ed067p329
Dialdehydes will also give a positive Tollens test (silver mirror precipitate).
3. Tollens’s test, fulminating silver, and silver fulminate
Ian D. Jenkins
Journal of Chemical Education 1987, 64 (2), 164
DOI: 10.1021/ed064p164
The Tollens test is commonly carried out in undergraduate organic chemistry laboratories,
with carefully tested procedures. The procedures have to be robust because the Tollens
reagent can be explosive, as this note explains.
4. The Fehling and Benedict tests
Ralph Daniels, Clyde C. Rush, and Ludwig Bauer
Journal of Chemical Education 1960, 37 (4), 205
DOI: 10.1021/ed037p205
This note is interesting because the authors show that the Fehling and Benedict tests are
specific for the hemiacetals in reducing sugars – they fail when used with simple aliphatic
aldehydes.
5. A correction on the Benedict test
William D. Hill
Journal of Chemical Education 1982, 59 (4), 334
DOI: 10.1021/ed059p334
Several textbooks use Na2CO3 as a base in the Benedict test, but according to this note,
NaOH is required for formation of Cu2+

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What is Mutarotation?

All About Mutarotation

 The OH group on C-1 of sugars can have two possible configurations. This gives rise to
two stereoisomers (called “anomers”) : the “α-” anomer and the “β-” anomer.
 If you take pure “α” or pure “β” and measure their optical rotation in water, an interesting
thing happens. The optical rotation slowly changes over time!
 The term “mutarotation” (literally “change in rotation”) refers to the observed change in
the optical rotation of the α- and β- anomers of glucose upon dissolution in solvent. Due
to ring-chain tautomerism, the α- and β- forms slowly interconvert until equilibrium is
established.

Table of Contents

1. Mutarotation Is The Change In Optical Rotation Observed When Pure α- Or β- Anomers

Are Dissolved In Water (or other solvents)
2. Mutarotation Is Possible When α- Or β- Anomers Can Interconvert
3. Mutarotation Is A Consequence Of Ring-Chain Tautomerism
4. Mutarotation Is A General Property Of Cyclic Sugars Bearing A Hemiacetal
5. Notes
6. (Advanced) References and Further Reading

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1. Mutarotation Is The Change In Optical Rotation Observed When Pure α- or β-
Anomers Are Dissolved In Water (or other solvents)

In the previous article on ring-chain tautomerism, we saw that there are two isomers of D-
glucose in its 6-membered ring (“pyranose”) form.

These two diastereomers – which, to make matters more confusing, are called “anomers” in the
context of sugar chemistry – differ in the orientation of the hydroxyl group on C-1. (Note that
C-1 is a hemiacetal. )

 In the “alpha” (α) anomer, the OH group on C-1 is on the opposite side of the ring as
the chain on C-5.
 In the “beta” (β) anomer, the OH group on C-1 is on the same side of the ring as the C-5
substituent.

Each of these two forms can be synthesized and isolated as pure compounds.

 The alpha (α) anomer of D-glucose has a specific rotation of +112 degrees in water.
 The beta (β) anomer of D-glucose has a specific rotation of +19 degrees. (18.7 actually, but
rounding up to 19).
Here’s the interesting thing. When either anomer is dissolved in water, the value of the
specific rotation changes over time, eventually reaching the same value of +52.5°.

 The specific rotation of α-D-glucopyranose decreases from +112° to +52.5°.

 The specific rotation of β-D-glucopyranose increases from +19° to +52.5°.
This behaviour is called mutarotation (literally, “change in rotation”).
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2. Mutarotation Is Possible When α- and β- Anomers Can Interconvert

Hold on. Isn’t specific rotation of a molecule supposed to remain the same?

Yes – if it is indeed the same molecule!

And therein lies the answer to the puzzle. For when the solutions whose specific rotations have
changed to +52.5° are analyzed, they are found to no longer consist of 100% alpha (α) or 100%
beta (β) anomers, but instead a ratio of alpha (α) (36%) and beta (β) (64% ) isomers.

Wait. What happened here? How did the alpha convert to the beta, and vice-versa?

3. Mutarotation Is A Consequence Of Ring-Chain Tautomerism

You may recall how we said in the last post on ring-chain tautomerism that the
cyclic hemiacetal forms of sugars are in equilibrium with the straight-chain (“linear”) form.

That means that even if you start with a 100% pure sample of either the alpha or beta anomer,
once it has been dissolved in water it can equilibrate, via the straight-chain form, to the other
anomer.
30
If A is in equilibrium with B, and B is in equilibrium with C, then A is in equilibrium with C.
That’s the Zeroth Law of Thermodynamics [Note 1].

The 36:64 ratio of alpha (α) to beta (β) represents the distribution of isomers when D-glucose is
in equilibrium in water at 25° C.

Is mutarotation unique to glucose?

4. Mutarotation Is A General Property Of Cyclic Sugars Bearing A Hemiacetal

No – it’s a general property of sugars, as well as (chiral) cyclic hemiacetals in general.

This phenomenon was first discovered in 1846 by French chemist Augustin-Pierre Dubrunfaut,
who founded a factory for the production of alcohol from beet sugar. While studying the
optical rotation of glucose, he noted that freshly dissolved glucose had a rotational value twice
that which was previously observed in the literature. He also studied the mutarotation of
lactose. (Interestingly, although Dubrunfaut was also the discoverer of fructose, he published
no studies on its mutarotation – perhaps because fructose is one of the most rapidly
mutarotating sugars) [Ref]

Interestingly, the structures of glucose and fructose had not been established at this point. It
was not until 1895 that Tanret first reported on the two anomers of glucose, which readily
explained Dubrunfaut’s observations.

Bonus question: given that the mechanism for the forward reaction was given in the previous
post, can you draw a mechanism for the interconversion of alpha-D-glucose to beta-D-glucose?
[A not uncommon exam question, by the way! [Note 2]

In the next post, we’ll discuss a tangent to ring-chain tautomerism: reducing sugars.
31
Notes:

Note 1. The Zeroth Law Of Thermodynamics: If A is in equilibrium with B, and B is in

equilibrium with C, then A is in equilibrium with C.

Note 2. Try and work out a mechanism for the conversion of alpha-glucopyranose to beta-
glucopyranose on your own. I’ll put a link to one solution in the comments. Hover here for a
pop-up image. or click on this link.

(Advanced) References and Further Reading

This is a very classical part of organic chemistry. The change in optical activity of glucose
solutions was first noted by Dubrunfant in 1846, and it was only in 1890 that the legendary
chemist Prof. Emil Fischer proposed that this was due to a chemical cause. In 1896, Tanret
isolated what he thought were three forms of glucose: the α form, with [α]D +105°, the β form,
with [α]D +52.5°, and the γ form, with [α]D +22°. Now we know that the α and γ forms are
distinct species (what we now know as the the α and β forms of D-glucose), and that Tanret’s β
form is the equilibrium mixture of the two forms.

1. Studies of dynamic isomerism. I. The mutarotation of glucose

T. Martin Lowry, D.Sc.
J. Chem. Soc. Trans. 1903, 83, 1314-1323
DOI: 10.1039/CT9038301314
This paper is credited with introducing the term ‘mutarotation’ in the literature to describe
the interconversion of the anomeric forms of glucose.
2. A REVIEW OF DISCOVERIES ON THE MUTAROTATION OF THE SUGARS.2
C. S. Hudson
Journal of the American Chemical Society 1910, 32 (7), 889-894
DOI: 10.1021/ja01925a009
An old review that covers early work on understanding the mutarotation of glucose, and
gives a full coverage of the development of the story up to that time.
3. STUDIES ON THE FORMS OF d-GLUCOSE AND THEIR MUTAROTATION.
C. S. Hudson and J. K. Dale
Journal of the American Chemical Society 1917 39 (2), 320-328
DOI: 10.1021/ja02247a017
This early paper contains experimental procedures for the isolation of pure a- and b-glucose.
4. Crystallization of β-d-Glucose and Analysis with a Simple Glucose Biosensor
José I. Reyes-de-Corcuera, Michael A. Teruel, and Daniel M. Jenkins
Journal of Chemical Education 2009, 86 (8), 959
DOI: 10.1021/ed086p959
This paper describes an experiment that can be carried out by undergraduates for observing
the mutarotation of glucose.

32
5. Optically Active Esters of B-Ketonic and B-Aldehydic Acids. Part II. Menthyl
Acetoacetate
Arthur Lapworth and A. C. Osborn Hann.
J. Chem. Soc. , Trans. 1903, 83, 1114-1129
DOI: 10.1039/CT9038301114
An example of mutarotation in a non-sugar system, and one of the earliest examples
containing a definitive proof of the role of acid in accelerating keto-enol tautomerism. The
authors prepared the menthyl (not methyl) ester of acetoacetic acid [(+)-menthol is an
optically active alcohol readily available from natural sources] and measured its optical
activity. They found that the menthyl ester underwent mutarotation to an extent that was
dependent on the solvent, with the rate of mutarotation being highly dependent on acid. This
demonstrates the establishment of an equilibrium between the keto and enol forms.

33
Pyranoses and Furanoses: Ring-Chain Tautomerism In Sugars

Pyranoses , Furanoses, Straight-Chain Glucose, And Ring-Chain Tautomerism

 Sugars such as glucose exist in equilibrium between their open-chain form and
various cyclic forms where an OH group and an aldehyde combine to form a
cyclic hemiacetal.
 In the case of glucose, a 5- or 6- membered ring can form, depending on which hydroxyl
group adds to the aldehyde. Equilibrium tends to favor the six-membered cyclic form, called
“pyranose” since it resembles pyran, although some of the five-membered cyclic form
(“furanose“) is also present along with the open-chain form.
 In the process of forming the hemiacetal a new chiral center is created. This gives rise to
two diastereomers which for historical reasons are called anomers and designated “alpha”
or “beta” depending on the orientation of the -OH group.

Table of Contents

1. Glucose Comes In Many Forms

2. Hydrates, Hemiacetals, and Cyclic Hemiacetals
34
3. Ring-chain Tautomerism In Glucose: The “Pyranose” Form
4. Ring-Chain Tautomerism In Glocose, II: The “Furanose” Form
5. Glucose Has Several Structures, All In Equlibrium With Each Other?
6. Conclusion: Pyranose vs Furanose vs Open-Chain Forms of Glucose
7. Notes
1. Glucose Comes In Many Forms

What’s the structure of glucose?

A simple question! but one with many “right” answers.

The first question to ask, which we covered in our recent post on D- and L- sugars, is: “Which
enantiomer are you talking about?”. If, by “glucose”, you mean the enantiomer we commonly
encounter as blood sugar, then you’re referring to D-glucose. In its open chain form, when
drawn as a Fischer projection, D-glucose looks like this:

The fact that I had to specify “open-chain form” might tip you off that something is amiss.
That’s because glucose, like a snake that bites its own tail, or a belt – can adopt a cyclic form
as well. And not just one cyclic form, but several!

Before diving into these, it’s worth a quick refresher on the two main functional groups in
glucose (and other sugars) which make this possible: hydroxyl groups and aldehydes (or
ketones, in the case of keto-sugars like fructose).

2. Hydrates, Hemiacetals, and Cyclic Hemiacetals

You may recall that aldehydes (and ketones, but we’ll focus on aldehydes here) can reversibly
react with water to form “hydrates“. (relevant article: Acetals, Hemiacetals,

35
Hydrates). Hydrates form readily in solution, but they tend not to be easy to isolate; the
equilibrium tends to favor the starting aldehyde. [Note 1].

Refresher on mechanism – hover here to bring up a picture of the mechanism or click this
link.

Similarly, aldehydes can react with alcohols to form hemiacetals.

Like hydrate formation, hemiacetal formation is an equilibrium and the equilibrium tends to
favor the starting aldehyde. [If you heat with acid, excess alcohol and sequester the water that
forms, it forms an acetal ; this is not in equilibrium with the hemiacetal, which is
why acetals are a great protecting group for aldehydes/ketones].

If you need a refresher on the mechanism, hover here or click this link.

Here’s the twist – and the relevance to glucose. If the alcohol and the aldehyde are part of the
same molecule, then it’s possible for the hemiacetal formation to be intramolecular, forming
a cyclic hemiacetal in the process. The mechanism is exactly the same as in the previous
case. Note the difference is that I’ve just drawn ONE extra bond (in blue)

36
In the case above (5-hydroxy pentanal), we form a six-membered ring.

Here’s how it works, step by step:

So, you might ask: what’s the “correct” structure of this molecule – the “linear” or the “cyclic”
form?

The answer is that since these two forms are in equilibrium, they are both “correct” structures
of this molecule, even though they are structural isomers of each other.

You might recall seeing a similar type of situation with certain ketones and aldehydes, where
a ketone is in equilibrium between a “keto-” form and an “enol” form which are themselves
structural isomers of each other. We called that keto-enol tautomerism. hover here to see an
example or click on this link

The equilibrium between the linear and cyclic form of 5-hydroxy pentanal (above) is a
different type of tautomerism we call ring-chain tautomerism.

3. Ring-Chain Tautomerism In Glucose: The “Pyranose” Form

This is exactly what happens in glucose. The alcohol on C-5 of glucose can react with
the aldehyde (C-1) to form a six-membered ring (I skipped drawing in the proton transfer in
the drawing below).

37
The linear and cyclic forms are structural isomers that exist in equilibrium with each other, so
this is another example of ring-chain tautomerism.

The 6-membered cyclic form of sugars is usually called the “pyranose” form in reference to the
cyclic ether pyran.

If you’re eagle-eyed, you might have noticed that in the process of forming a new C-O bond, a
new chiral centre is formed at C-1. This new chiral centre can have one of two configurations,
(S) or (R). Since there are other chiral centers on glucose and their R/S configurations don’t
change, that means we’ll end up with a pair of diastereomers: stereoisomers that are
not enantiomers. Rather than using the (R) and (S) descriptors, the convention with sugars is to
name them according to the orientation of the OH groups on C-1 relative to the C-5 group.
These two isomers are referred to as the alpha (α) and beta (β) isomers [Note 2] for more
detail on this]

 In the alpha (α) isomer, the OH group on C-1 is on the opposite face of the ring from the
CH2OH substituent on C-5. This can be seen from drawing the molecule as a chair, but it is
often helpful to draw a hexagonal version of a sugar in perspective (called a “Haworth
projection“) that makes the stereochemical relationships more clear.
 In the beta (β) isomer, the OH group on C-1 is on the same face of the ring relative to the
CH2OH substituent on C-5.
38
At the risk of inciting a pitchfork-wielding mob angry at the introduction of even more
terminology, these two isomers are often referred to as “anomers“, but that is a topic for
another day.

4. Ring-Chain Tautomerism In Glucose, II – The Furanose Form

But wait! that’s not all, folks!

The pyranose form of glucose is just one of the cyclic forms that glucose can adopt.

It’s also possible for the hydroxyl group on C-4 of glucose to attack the aldehyde. This forms
a five-membered ring. We call this form the furanose form, in reference to the cyclic 5-
membered ether furan. (Helpful mnemonic: Five = Furanose)

39
As with the pyranose, forming the 5-membered ring also generates a pair of diastereomers
which differ in configuration at C-1. We likewise call these the alpha and beta forms, as
above:

So what’s the structure of glucose? Not so straightforward, is it?

40
5. Glucose Has Several Structures, All In Equilibrium With Each Other

We’ve seen five separate isomers so far: the straight chain form, the pyranose form (alpha and
beta), and the furanose form (alpha and beta).

In aqueous solution, these five forms are all in equilibrium with each other!

When you dissolve glucose in water, here’s the distribution you get:

The pyranose forms dominate, with a small amount of the open-chain and furanose forms
comprising the rest of the mixture.

What about 3 and 4 (or 7) membered rings, you might ask? [ Note 3. tl;dr they are
insignificant]

6. Conclusion: Pyranose vs Furanose vs Open-Chain Forms Of Glucose

Although we’ve mainly discussed glucose in this post because it is the most familiar sugar,
ring-chain tautomerism is an important property of all 5- and 6- carbon sugars.

Another familiar example is ribose, which comprises the sugar backbone of RNA:

41
Fructose is another one.

For Next Time: A Puzzle

Understanding this property of sugars will help us untangle a mystery which baffled early
carbohydrate chemists.

 Pure α-D-glucose has a specific rotation of + 112°.

 Pure β-D-glucose has a specific rotation of + 19°.
 Yet when either of these two is dissolved in water, the optical rotation slowly changes to a
value of + 52.5° .
Can you guess why?

We’ll talk about that in the next post in this series, on mutarotation (literally, “change in
rotation”).

Notes

Note 1. Aldehydes with adjacent electron-withdrawing groups tend to form more stable
hydrates since the aldehyde carbon is much more electrophilic. Trichloroacetaldehyde (chloral
hydrate) often known as “knockout drops”, is a prominent example.

Note 2. The α / β terminology pre-dates the R/S (Cahn-Ingold Prelog) terminology by several
decades. The C-1 carbon is called the “anomeric” carbon and the α and β diastereoisomers are
referred to as “anomers”. α and β are defined according to the relationship between the
42
anomeric carbon and the anomeric reference carbon, which is the stereocenter farthest from
the anomeric carbon in the ring. In D-glucose in the pyranose form the anomeric carbon is C-1
and the reference carbon is C-5. Here’s how IUPAC defines it.

Note 3. They’re not significant. Three and four-membered rings are relatively unstable due to
their considerable ring strain, while the rate of seven-membered ring formation is extremely
slow, relative to the 5- and 6- membered ring cases. ]

Note 4. From “Ring-Chain Tautomerism of Hydroxy Aldehydes”, Hurd C. D.; Saunders, W.

H. J. Am. Chem. Soc. 1952 74, 5324.
DOI: 10.1021/ja01141a030

43
The Haworth Projection

 The Haworth Projection is a convenient notation for showing the structure of sugars.
 Since every substituent points either straight up or straight down, it is much easier to spot
differences in configuration between sugars in a Haworth than in a chair conformation.

44
 The only thing to keep in mind is that sugars are not flat hexagons or pentagons and
the Haworth is not meant to show their 3-D shape.
Table of Contents

1. The Haworth Projection

2. Pyranose “Chair” Versus Haworth
3. Converting a Pyranose “Chair” To A Haworth
4. Converting A Haworth To A Pyranose Chair
5. Notes

1. The Haworth Projection

“What!?” you may ask. Yet another drawing convention? At this late stage of the course?

And isn’t drawing glucose just like drawing cyclohexane, more or less? Didn’t we learn how to
draw cyclohexanes back in… Org 1?

Yes to all of those questions. It’s still important, however, so read on.

Haworth projections didn’t originate as some dumbed-down, simpified depiction of sugars,

even if they largely serve in that capacity today. In fact the Haworth projection pre-dates
(1929) the chair depiction of cyclohexane (1943) and represented a vast improvement from the
most common depiction of cyclic sugars at that time: the bloodyawful cyclic Fischer
projection:

The Haworth projection didn’t go away with the advent of the cyclohexane chair, however.
Here’s why.
45
Let’s look at glucose. The most stable chair conformation of glucose has the C-2, C-3, and C-4
hydroxyl groups all on equatorial positions. [Note 1] Of course, with organic chemistry fresh
in your mind, you can tell which hydroxyl groups are up and which are down in the diagram
below (right?):

But something often happens to people a few years after their last organic chemistry class: they
start to forget the details of interpreting this whole cyclohexane chair business. Plus,
conformational details are usually TMI to people who just want to look at the structure of a
sugar and be able to clearly spot the differences in configuration.

[See, one of the slightly confusing aspects beginners encounter in learning cyclohexane chair
conformations is getting used to the fact that “up” and “down” refers not merely to
the axial groups on the chair (which indeed point “straight up” and “straight down”) but
the equatorial groups as well – even though they only look like they are “somewhat up” or
“somewhat down”. [See: The Ups and Downs of Cyclohexanes]. The key point is that since
five and six-membered rings can’t turn themselves inside-out without self-destruction, no
amount of conformational twisting (or chair flips) will convert, say, cis-1,2-
dimethylcyclohexane to trans-1,2-dimethylcyclohexane, or for that matter, D-glucose to D-
galactose; each group is locked on its particular face.]

2. Pyranose “Chair” vs Haworth

A Haworth projection simply depicts a pyranose as a hexagon, and a furanose as a pentagon,

and the substituent groups are placed straight up and down. Simple as that. [Note 2] By
analogy with the Haworth, the oxygen is usually placed at the upper-right position with C-1 as
the chair’s “foot-rest” for ease of comparison between sugars. [Note 3]

46
When a sugar is drawn in the Haworth projection, there is absolutely no question as to which
groups are up or down, avoiding confusion for those who haven’t learned (or have forgotten)
the details of cyclohexane chair conformations (cough-BIOCHEMISTS-cough) . Furthermore,
there is no need to make a decision as to which chair conformation to draw. It’s standardized.
Accurate depiction of the conformation is sacrificed for ease of interpretation of the
configuration (i.e. the stereochemistry). For most applications in biochemistry, this is a good
tradeoff.[Note 4]

Plus, it’s also effective for five-membered ring sugars (furanoses), such as ribose.

3. Converting a Pyranose Chair to a Haworth

Let’s say we wanted to convert a sugar drawn in a chair form to a Haworth projection. How
would we do that?

The convention for drawing a pyranose in the chair form dictates that the ring oxygen is placed
in the upper right hand position like that depicted below (the sugar in question is β-D-mannose,
47
drawn in its pyranose form). The orientation of the chair is important: the “foot-rest” of the
chair is on the right hand side, which is to say that the axial substituent on carbon 1 points
down.

To convert a chair form to a Haworth projection, number the carbons 1 through 6 and then
draw the Haworth template next to it, similarly numbered.

The next step is to identify which groups on the chair are “up” and which are “down”. Once
this has been achieved, map the up and down groups onto the appropriate up and down
positions on the Haworth template.

48
With all the hydrogens in place, things can look crowded. It’s OK to make the hydrogens
“implicit”, which makes for a cleaner diagram:

[It’s extremely rare that you’d start with a sugar not in the “correct” chair form, but note that
this works no matter what chair conformation you start with, as during a chair flip, “up”
groups remain “up”, and “down” groups remain “down”.]

Now, let’s do a furanose. β-D-ribose is drawn below. Use the same protocol of numbering and
mapping, we can convert the “flat” form to the Haworth projection:

4. Converting a Haworth to a Pyranose Chair

Of course, we can also go in the opposite direction. The Haworth of α-D-galactofuranose is

drawn below. To convert it to a chair, we start by drawing in a chair template (foot-rest on
right) with ring oxygen at back-right and number each carbon.

49
We then assign “up and down” to each of the substituents on the Haworth and map those on to
our chair template:

The last step is to clean it up by making the hydrogens implicit, if desired.

Notes

Note 1. This is an easy way to remember how to draw glucose: it’s the sugar with all-
equatorial C-2, C-3, and C-4 hydroxyl groups when drawn according to the standard
convention. Interestingly, the sugar with all-axial hydroxyl groups, D-idose, is largely
unknown in nature.

50
Note 2. What one might call the “classic” Haworth for a pyranose employs a full hexagon with
equally spaced sides and the front three C-C bonds in bold. The Haworth used in this post is
based on a template in Chemdraw that elongates the horizontal lines and bolds the three frontal
C-C bonds. Either is acceptable.

Note 3. The “chair” form of sugars which incorporates an emboldened front three bonds is
known as a Reeves projection. Now you know. [Hat tip to Daniel E. Levy’s book, The Organic
Chemistry of Sugars].

Note 4. We are going to completely avoid the subject of the conformations of sugars here.
Levy’s book (partly available on Google Books) contains useful discussion.

(Advanced) References and Further Reading

1. A Revision of the Structural Formula of Glucose

HAWORTH, W.
Nature 116, 430 (1925).
DOI: 10.1038/116430a0
2. Nobel Lecture
Haworth won the Nobel Prize in Chemistry in 1937 (along with Karrer) for determining the
structure of Vitamin C. His Nobel Lecture briefly covers the projection.

51
1. IUPAC Gold Book reference to the Haworth projection.

52
Converting a Fischer Projection To A Haworth (And Vice Versa)

Everything you ever wanted to know about converting Fischer Projections to Haworth
Projections, And Vice Versa

 Starting with a Fischer projection, it’s not too hard to convert it to a Haworth once you
know a few tricks.
 For C-2, C-3, and C-4, if the OH is on the right hand side of the Fischer, it will be down in
the Haworth. If it is on the left hand side of the Fischer, it will be up in the Haworth.
 If the sugar is D, draw the C-5 CH2OH pointing up.
 For D-sugars, draw the C-1 OH pointing down for the alpha (and up for the beta).

Table of Contents

1. Converting A Fischer To A Haworth (The Long Way)

2. The Fischer-To-Haworth Shortcut: For C2, C3, and C4, Right = Down and Left = Up
3. What About C5 and C1?
4. Fischer To Haworth Example 1: D-Mannose
5. Example 2: L-Galactose
6. Example 3: Try Going Backwards!
53
7. What About Five-Membered Rings? (Furanoses)
8. Example 4: Fructose
9. Notes
10.(Advanced) References and Further Reading
1. Converting A Fischer to a Haworth (The Long Way)

Here’s a relatively common problem in the realm of sugar chemistry:

“Convert this (sugar) from the Fischer projection to a cyclic pyranose form as a Haworth
projection.”
(the reverse question can be asked too: “convert a sugar drawn in a Haworth to an open-
chain Fischer. “)

So…. how can we do this?

Well, there are a couple of tricks, and that’s what this post is about. (We’ll show how to deal
with furanoses too.)

Let’s start with the example of converting D-glucose drawn in a Fischer projection to a
pyranose (i.e. hexagonal) depiction in the Haworth projection – the “long way”. [The shortcut
is above, BTW. If you want to skip to some practice examples, they’re below].

We’ll start by remembering what the Fischer projection really represents.

Although all the bonds in the Fischer might be drawn “flat”, it’s not meant to be understood
that way! [See this earlier post on D and L sugars, for example].

By convention, the horizontal bonds on a Fischer projection actually point out of the page.

One way this was taught to me was to remember that “the arms come out to hug you“. In
other words, they’re “wedged”.

The first step in converting a Fischer to a Haworth is to draw in these wedges and to number
the carbons.

54
Next, let’s turn this molecule on its side, 90 degrees clockwise. [it must be clockwise –
see Note 1]

This sets us up to form a bond between the C5-OH and the carbonyl carbon (C-1), which will
make a new ring. [If this is unclear, see this earlier post on ring-chain tautomerism for more
examples.]

It’s helpful to perform a bond rotation on the C5 carbon to make the stereochemistry on the ring
clearer. Interchanging any three groups on a carbon does a bond rotation. So we’ll make
the following three “moves”:

 H → OH
 OH→ CH2OH
 CH2OH→ H
After rotation, the C5-OH is on the side rather than pointing down. In the figure below I drew it
with a “dashed” bond, owing to the tetrahedral geometry on the carbon. I also drew the C 2-
C1 bond dashed as well.

This sets us up to draw the C5-OH attacking the carbonyl carbon, forming a new O–C1 single
bond and breaking the C1-O pi bond.

After proton transfer, we now have one of two rings, which we can depict as Haworth
projections!

55
(You can imagine this as being like fastening a belt, with the OH as the “buckle” and
the carbonyl carbon as the “notch” in the belt).

Notice that all the groups that were pointing “up” in our linear molecule (e.g. the C3-OH)
also point “up” in the Haworth, and all the groups that point “down” in the linear
molecule (e.g. C2-OH and C4-OH) point “down” in the Haworth.

(The one exception is the C1 oxygen, which can be “up” (β in this case) or “down” (α)
according to which face of the carbonyl is attacked. )

Voila – there’s your conversion of a Fischer to a Haworth. If you’re keen, you can even turn
the Haworth into a chair, if you start with a template and map all the substituents as
we described in the last post.

56
2. The Fischer-to-Haworth Shortcut: For C2, C3, and C4, Right =Down and Left =Up.

Having walked through the process the long way, let’s try to come up with a shortcut for this
process.

Compare the Fischer projection of D-glucose to the final Haworth:

 C2–OH is on the right side of the Fischer and ends up on the bottom of the Haworth.
 C3–OH is on the left side of the Fischer and ends up on the top of the Haworth
 C4–OH is on the right side of the Fischer and ends up on the bottom of the Haworth
This gives us the following shortcut. If a group is on the left side of the Fischer, it will end up
on the top face of the Haworth, and if it is on the right side of the Fischer, it will end up on the
bottom face of the Haworth.

Right-down, left-up. (for C-2, C-3, and C-4, at least)

What about C5 and C1 ?

3. What About C5 and C1 ?

In our example the C5-OH was on the right side of the Fischer, which made it (by definition)
a D-sugar. We saw that C6 (the CH2OH) ended up on the top of the Haworth, so we can make a
generalization:

 for D-sugars, the C6 carbon will end up on the top of the Haworth
 for L-sugars, the C6 carbon will end up on the bottom of the Haworth.
That leaves us with C1. The hydroxyl group on C1 can end up in one of two configurations –
either “up” on our Haworth, or “down”- depending on which face of the carbonyl is attacked.

The standard terminology for these two configurations at the C-1 carbon (sometimes called the
“anomeric carbon“) uses the terms alpha (α) and beta (β).

In the “α” configuration, the C1-OH is on the opposite face of the ring as the C5 substituent
[CH2OH in this case]. For a D-sugar, therefore, the C1-OH points down.

In the β configuration, the C1-OH is on the same face as the C5 substituent. (i.e. for a D-sugar,
the C1-OH points up, as does the CH2OH attached to C5 ).

57
That’s the shortcut. So let’s do some examples, shall we?

4. Fischer to Haworth Example 1: D-Mannose

Mannose is a hexose where the configuration at C2 is flipped relative to glucose.

Using the shortcuts above, try converting it to a Haworth as an α-pyranose. (answer at the
bottom)

5. Example 2: L-Galactose

Now try a more challenging one. Starting with the structure of L-galactose, draw the Haworth
as a β-pyranose.

58
6. Example 3: Try going backwards!

If you know how to go from a Fischer to a Haworth, then you should be able to puzzle through
going from a Haworth to a Fischer (it’s actually easier).

Try it with L-idose:

7. What About Five-Membered Rings? (Furanoses)

Haworth projections can be used for five-membered ring sugars (i.e. furanoses) too.

So how do we convert a Fischer to a five-membered Haworth?

The shortcut is essentially the same, but since the C4-OH is usually forming the ring instead of
C5-OH, the mnemonic right → down and left → up only applies for the two carbons adjacent
to the carbonyl (usually C2 and C3).

So if the C4-OH is forming the ring, and if it’s on the right in the Fischer (i.e. D, for a pentose),
then the C5 will point up on the Haworth.

Alpha and beta in a furanose are assigned by comparing the orientation of the C1-OH with the
C4 substituent (not the C5 substituent, as with a pyranose).

Here’s D-ribose converted into its α-furanose Haworth projection. [Notice that the C1-OH is on
the opposite face of the molecule from the C4– substituent (CH2OH), which makes the
configuration alpha (α) ]

59
Note how the C4-OH points to the right in the Fischer and the C5 substituent
(CH2OH)points up in the Haworth.

8. Example 4: Fructose

If there was a bit torturous wording in the above paragraphs using an if… then clause, that’s
because I wanted the logic to be just as applicable to fructose, a six-carbon sugar (hexose)
which mostly exists in the furanose form.

Fructose is a particularly interesting example because it’s a ketose, not an aldose; the ring is
formed through the attack of a hydroxyl group to a ketone, not an aldehyde.

So here’s the final challenge. Given the Fischer projection, try drawing the Haworth projection
( β-furanose form) for D-fructose, below:

If you can do fructose without help, you’re in good shape for an exam.

60
Notes (and Answers)

1. D-Mannose. Just like glucose, but the C-2 OH is flipped.

2. L-galactose. A bit of a weird one. Note that if you remember “alpha” as the C1-OH being
“up”, that only works for D-sugars.

3. Going to the Fischer from L-α-idopyranose

4. Fructose drawn as a β-furanose:

It’s beta here because the OH on the anomeric carbon (C2 in this case) is on the same face
as the group on the C5 carbon (CH2OH).
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Note that whatever the sugar you are given, the mental exercise of rotating the Fischer 90
degrees clockwise is useful for determining which groups will be up and which will be down.

Related Articles

 How To Determine R and S Configurations On A Fischer Projection

 Reactions of Sugars: Glycosylation and Protection
 Converting a Fischer Projection To A Haworth (And Vice Versa)
 Pyranoses and Furanoses: Ring-Chain Tautomerism In Sugars
 What is Mutarotation?
 The Big Damn Post Of Carbohydrate-Related Chemistry Definitions
 Carbohydrates Practice (MOC Membership required)
Note 1– it’s very important that it’s clockwise and not counterclockwise, otherwise it won’t be
an accurate Haworth projection according to convention.

(Advanced) References and Further Reading

1. The conversion of open chain structures of monosaccharides into the corresponding

Haworth forms
Desmond M. S. Wheeler, Margaret M. Wheeler, and Thomas S. Wheeler
Journal of Chemical Education 1982, 59 (11), 969
DOI: 1021/ed059p969
2. Simple rule for the conversion of Fischer monosaccharide projection formulas into
Haworth representations
M. Argiles
Journal of Chemical Education 1986, 63 (11), 927
DOI: 10.1021/ed063p927
3. A mnemonic scheme for interconverting Fischer projections of open-chain
monosaccharides and Haworth projections of corresponding alpha- and beta-anomeric
forms
Jonathan Mitschele
Journal of Chemical Education 1990, 67 (7), 553
DOI: 1021/ed067p553
4. A New Method To Convert the Fischer Projection of a Monosaccharide to the
Haworth Projection
Qing-zhi Zhang and Shen-song Zhang
Journal of Chemical Education 1999, 76 (6), 799
DOI: 1021/ed076p799

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5. A Simple Paper Model Illustrates How To Cyclize Monosaccharides from Fischer
Projections to Haworth
Chi H. Mak
Journal of Chemical Education 2018, 95 (8), 1336-1339
DOI: 1021/acs.jchemed.7b00832Other useful references:
6. Rules for determining d,l configurations in Haworth structures
Jerry L. Wilson
Journal of Chemical Education 1988, 65 (9), 783
DOI: 1021/ed065p783
7. Calculation and specification of the multiple chirality displayed by sugar pyranoid ring
structures
Robert S. Shallenberger, Ronald E. Wrolstad, and Laurie E. Kerschner
Journal of Chemical Education 1981, 58 (8), 599
DOI: 1021/ed058p599
Finally, Some Reactions Of Sugars: Glycosylation And Protection

In this post we introduce some simple reactions of sugars, especially glycosylation and
protection:

 Formation of “glycosides” – just a different name for acetals when they exist at the
“anomeric” carbon of sugars
 Hydrolysis of glycosidic bonds (glycosides), which is exactly like hydrolysis
of acetals (aqueous acid)
 Reactions on the -OH groups of sugars, including protecting groups
 How to “deprotect” the anomeric (C-1) carbon selectively

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Table of Contents

1. Carbohydrates and Sugars: Finally, Some Reactions!

2. Reactions At The Hemiacetal (Anomeric) Carbon: Formation And Hydrolysis Of
“Glycosides”
3. Hydrolysis of Glycosides with Aqueous Acid
4. Formation of Disaccharides (In Theory, If Not In Practice)
5. Hydrolysis of The Glycosidic Bond Of Disaccharides
6. Reactions Of The Alcohol Groups Of Sugars: The Problem Of Selectivity
7. A Brute Force Way Around Selectivity: Excess Reagent
8. Ethers At C-1 (The Anomeric Carbon) Can Be Cleaved Selectively
9. How To Get Around The Selectivity Problem? A Glimpse Into Org 3
10.Notes
11.(Advanced) References and Further Reading

1. Carbohydrates and Sugars: Finally, Some Reactions!

If reactions are the meat of an organic chemistry course, then nomenclature is the bun – and
you’d be forgiven for thinking that the content in this chapter on sugars has been a little, er,
“carb-heavy” so far.

A lot of nomenclature and not many reactions!

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Almost none of you reading will get this reference
We’re going to try to fix this deficiency in our chemistry diet today with a discussion of the
key reactions of sugars.

The reactions of sugars we will cover really boil down to two main categories.

Part 1: Reactions of the anomeric (hemiacetal) carbon

The anomeric carbon of a sugar can form and break acetals. That’s about it.

 Formation of acetals (“glycosides”), including disaccharides and polysaccharides

 Hydrolysis (cleavage) of acetals (“glycosides”)
Part 2: Reactions of carbohydrate hydroxy groups (alcohols)

The hydroxy groups of sugars can perform all the reactions of alcohols (e.g. ether formation).
The trick is getting the right one to react! d

 Ether formation (non-selective, except in special cases with the primary (C6) alcohol)
 Ester (acetate) formation (non-selective) with Ac2O.
We’ll finish up with a few remarks about how reactions of carbohydrates really take us to the
limits of what we study in “Org 2” and how it points the way to “Org 3”.

2. Reactions At The Hemiacetal (“Anomeric”) Carbon: Formation Of Glycosides

A few chapters ago, we saw how to convert aldehydes and ketones to acetals, via hemiacetals.
In the forward direction, this is accomplished by treating the ketone (or aldehyde) with an
excess of alcohol in the presence of acid (such as H2SO4).

Simple sugars (e.g., D-Glucose) have a hemiacetal functional group due to the fact that 5- and
6- membered rings readily form between the carbonyl carbon and the hydroxyl groups, a
phenomenon known as “ring-chain tautomerism“.

So, the hemiacetal functional group on sugars can also be converted into a full acetal by
treatment with an alcohol in the presence of acid.
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In carbohydrate chemistry, these acetals have a special name: “glycosides“.

Here’s an example. Treating D-glucose with ethanol and acid provides a product called Ethyl -
D-glucopyranoside.

The new C–O bond is called a “glycosidic bond”. In the drawing above, we drew only one
anomer (the α), but in practice both will form.

Formation of the glycoside “locks” the ring closed, and it is no longer in equilibrium with the
open-chain form, and is therefore no longer a “reducing sugar” [see: Reducing Sugars]. Like
all acetals, about the only reaction of significance that it will undergo is hydrolysis back to the
starting material with aqueous acid.

3. Hydrolysis of Glycosides With Aqueous Acid

So treatment of a glycoside with water and acid results in the original sugar (as a mixture of
anomers, which we can describe with a “squiggly line”).

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4. Formation Of Disaccharides (In Theory, If Not In Practice)

A particularly important type of glycoside are those formed from the combination of two or
more sugars. Maltose, for example, is the acetal formed when C-1 of D-glucose reacts with the
C4-OH of another molecule of D-glucose to form an α- glycosidic linkage.

A quick way of describing this linkage is (α-1→4), where 1 and 4 indicate the numbers of the
carbons flanking the glycosidic bond, and “α” indicates the stereochemistry at the anomeric
carbon. [quick review of alpha and beta]

In theory, it’s possible to carry out this reaction by treating D-glucose with acid:

In practice? Well, the drawing above is a bit misleading.

In the lab, adding acid to glucose might get you some maltose, but it will also deliver a ton of
other side-products from the reaction of other hydroxy groups (C1-OH, C2-OH, etc.) with the
C-1 carbon. (it’s the kind of reaction my friend Jeff would write in his lab notebook as “BFM”,
where “M” stands for “mess”).

In nature, very specific enzymes have evolved that combine sugars together with exquisite site-
selectivity (“regioselectivity” for C4-OH in this case, versus the other possible alcohols as
nucleophiles) and stereoselectivity (α- for maltose).

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[For example, it’s very important that the orientation at the C-1 acetal is drawn alpha (α) for
maltose. The beta (β) stereoisomer is another disaccharide entirely (cellobiose).]

Similarly:

 sucrose (table sugar) is a disaccharide formed through acetal formation between C-1 of
glucose and C-2 of fructose (α-1→β-2 linkage)
 lactose is a disaccharide formed between C-1 of galactose and C4-OH of glucose (β-1→4
linkage).
 Amylose, one of the two components of starch, is a polysaccharide of glucose linked
through (α-1→4) glycosidic bonds.
All are built through formation of glycosidic bonds between sugars – in other words, good-
old acetal formation.

5. Hydrolysis of The Glycosidic Bond of Disaccharides

Just as with ethyl D-glucopyranoside, above, adding aqueous acid to a polysaccharide will
hydrolyze it back into the constitutent sugars.

D-lactose, for instance, can be hydrolyzed back into D-Galactose and D-Glucose with aqueous
acid:

In organisms, enzymes perform the hydrolysis of glycosides – these are called glycosidases .
The familiar condition of “lactose intolerance” is a result of the body lacking the necessary
enzyme (lactase) to break down the glycosidic bond of lactose.

Enzymes can be exquisitely sensitive to stereochemistry. Starch, a polymer of glucose with (α-
1→4) glycosidic bonds, is easily broken down in our bodies to units of D-Glucose, but
cellulose [with (β-1→4) glucose linkages] is not. [Fun fact: Grass-eating mammals like cows
rely on microorganisms in their gut to convert cellulose to glucose].

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6. Reactions Of The Alcohol Groups Of Sugars: The Problem Of Selectivity

What kind of reactions do the hydroxy groups of sugars undergo? They’re essentially just
alcohols, right?

We’ve explored many important reactions of alcohols previously. So let’s say we wanted to do
a meat-and-potatoes reaction of alcohols – the Williamson Ether synthesis – on the C3-OH of
glucose.

You may recall that to perform a Williamson, all we need to do is add base and an alkyl halide,
and voila – an ether forms.

What could possibly go wrong?

Well, at least four things could go wrong, actually. The C-3 OH isn’t significantly more
selective toward CH3I than any of the other four hydroxyl groups.

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The result is a mixture of products which requires a tedious separation.

Even with all the advances of modern organic chemistry, there’s no known way to get the
Williamson ether synthesis to occur selectively with, say, the C3-OH of glucose in good yields
without also forming ethers at the other hydroxyl groups.

This might seem hard to believe but it is true. The more we learn about organic chemistry, the
more we learn to appreciate just how incredible Nature is in devising extremely selective
catalysts for reactions on sugars at specific sites without the use of protecting groups.

There’s still lots to discover in organic chemistry!

[There is one reliable way to put a single ether group on a sugar like glucose. The C6-OH is
a primary alcohol, and therefore less sterically hindered than the other alcohol groups. It is
possible to use a very bulky alkyl halide like trityl chloride and have it react selectively there.
See Note 1 ]

No matter what reaction you try – oxidation, acetylation, halogenation, or silylation – you’ll
almost always run into this problem with unprotected sugars. A workaround is in order. [Note
2]

7. A Brute Force Way Around Selectivity: Use Excess Reagent

If we abandon all hopes of selectivity, good yields can be obtained by just treating the sugar
with a vast excess of a given reagent. For example if we treat glucose with excess methyl
iodide in the presence of base, we get the penta-ether in high yield. [We sometimes call this,
“exhaustive methylation”]. [Note 3]

Using an excess of acetic anhydride, one can also form the “penta-acetate”:

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Some very familiar plastics from modern life are the result of treating the polysaccharide
cellulose with various reagents under “exhaustive” conditions:

 Cellulose acetate film (“safety film”, from treating cellulose with excess acetic anhydride)
 Celluloid (the first plastic, originally used as film stock, obtained through nitration of
cellulose)
 Rayon (where cellulose is treated with excess carbon disulfide to form xanthates)
8. Ethers At C-1 (The Anomeric Carbon) Can Be Cleaved Selectively

One note. It’s possible to free up the C-1 hydroxyl group on the penta-ether through acidic
hydrolysis, because the anomeric carbon (C-1) is part of an acetal.

This might look like an ether cleavage (which usually requires a very harsh acid like H-I) but is
actually just hydrolysis of an acetal. (A good “trick” exam question!).

9. How To Get Around The Selectivity Problem?

Until we develop catalysts that rival enzymes in their ability to react selectively with the
hydroxyl groups of sugars, we’re left with protecting group strategies.
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We briefly covered protecting groups in the chapter on alcohols. [see: “Protecting Groups For
Alcohols“] With sugars, protecting group strategies are taken to a whole new level. It’s a big
topic – one we don’t have time for in this post today. [Here is a start, though.]

A Glimpse Into The Land Beyond (Org 3)

I’d argue that protecting group strategies of sugars is really a topic for what you might call
“Org 3”.

What does that mean?

Org 1 and Org 2 are courses that introduce the properties of the various functional groups and
their major reactions. The functional groups are largely treated in isolation.

It’s a bit like chess. Org 1 and Org 2 is like learning the rules of how the game is played, and
how the pieces (functional groups) move.

In Org 3, life gets more complicated. We learn how to devise strategies to deal with the many
real-life situations where a molecule has multiple reactive functional groups (like glucose!) ,
and we need to selectively form a bond at just one of them.

Or, in chess terms, it’s where you start to learn how to coordinate all your pieces together in an
overall strategy.

In the meantime, I hope this post has been more beef and less bun.

Notes

Note 1. Tritylation.

The trityl group (triphenylmethyl) is so frickin’ massive that it tends only to fit on primary
alcohols, so it will react selectively with the C-6 hydroxyl group:

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I can say from experience that it also feels really good after you put it on, since the mass of
your product skyrockets (“started with 400 mgs, and now I almost have a gram.
YESSS!”). This feeling disappears, however, when it’s removed with trichloroacetic acid.
Another option is the bulky silyl group t-butyldiphenylsilyl chloride (TBDPS).

Note 2. This is way above Org 2, but here’s a very useful protection sequence that allows for
selective functionalization of C-3 of D-glucose. Treatment with acetone and acid (one can also
use a Lewis acid, like CuSO4) ties up 4 of the 5 hydroxyl groups as “acetonides”
(acetals of acetone). This leaves the C-3 OH, which can then be selectively methylated, if
desired. [This was used in the Nicolaou synthesis of Leucomycin A to put a methyl ether on C-
3 of glucose. See “Adventures In Carbohydrate Chemistry” for many more wonderful
examples. ]

Note 3. A more reversible variant of this reaction forms benzyl ethers instead of methyl ethers
(which can be notoriously difficult to cleave). The benzyl ethers can be removed by treatment
with Pd/C and hydrogen gas.

(Advanced) References and Further Reading

1. Esterification of the primary alcoholic groups of carbohydrates with acetic acid: a

general reaction
R. B. Duff
J. Chem. Soc., 1957, 4730-4734
DOI: 10.1039/JR9570004730
An early paper showing that selective monoacetylation on the primary hydroxyl is possible,
since that is significantly more reactive.
2. Exhaustive Methylation of Glucosamine
Norbert J. Wojciechowski, Ralph Daniels, and Bernard Ecanow
Pharm. Sci. 1961, 50 (10), 888-889
DOI: 10.1002/jps.2600501024
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 The abstract states: “A reported synthesis of a glucosamine quaternary derivative was
investigated by chemical and infrared spectra methods. Under the conditions reported the
glucosamine was found to become degraded and tetramethylammonium iodide was formed”
3. Applications of Tin-Containing Intermediates to Carbohydrate Chemistry
Bruce Grindley
Adv. Carbohydrate Chem. and Biochem. 1998, 53, 17-142
DOI: 10.1016/S0065-2318(08)60043-8
The regioselective acylation and alkylation of tin acetals is very useful for the selective
protection of a number of polyol containing systems, including protection
of equatorial over axial hydroxyl groups and for differentiation between
two equatorial hydroxyl groups with different steric environments.
4. Adventures in Carbohydrate Chemistry: New Synthetic Technologies, Chemical
Synthesis, Molecular Design, and Chemical Biology
K. C. Nicolaou Prof. Dr. Helen J. Mitchell Dr.
Angew. Chem. Int. Ed. 2001, 40 (9), 1576-1624
DOI: 10.1002/1521-3773(20010504)40:9
A tour de force review by Prof. K. C. Nicolaou (now at Rice U.) that exhaustively covers
carbohydrate chemistry and its applications in natural product total synthesis.

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