The History, Synthesis, Metabolism and Uses of Artificial
Purpose of Artificial Sweeteners
"Anyone who thinks saccharin is dangerous is an idiot" was
something that Teddy Roosevelt said when people questioned saccharin's use as an
artificial sweetener. However, even presidents have been wrong
before. Indeed, saccharin is one of the most studied molecules in society
today. This paper will begin with why artificial sweeteners are needed,
including what happens to the main sweetener, sucrose, when it enters the body
and why artificial sweeteners are important. Then this paper will first
look at the history of 3 of the major artificial sweeteners: saccharin,
aspartame, and acesulfame K. Then this article will look at what each
artificial sweetener is, and how it is produced in the lab and in
industry. It will then look at what happens to each sweetener as it enters
the body. It will then show the current taste models for the taste
receptors themselves, and will show how each of these molecules fits these
Purpose of Artificial
Sweeteners The purposes of artificial sweeteners
are many fold. Sucrose's chemical formula is
C12H22O11. In essence,
sucrose is a glucose molecule bonded to a fructose molecule. This is what
fructose and glucose look like: 6
This is what sucrose looks like: 6
The problems for sucrose are many fold. When
sucrose is metabolized by the body, the body breaks the molecule down into
fructose and glucose, which both go into either glycolysis or they are changed
into adipose tissue, which is fat. Sucrose has 9 calories per gram, making
it very fattenening in essence. Another major problem for sucrose is that
people with diabetes can go into diabetic shock if they eat any products with
sucrose in it. This is due to the fact that diabetics do not have
sufficient levels of insulin, a hormone which controls sugar uptake in the
bloodstream. If sugar levels become to high, a person will enter into
shock. Another problem of sucrose is that it promotes tooth decay due to
the fact that bacteria that naturally occur in the human oral cavity are able to
efficiently use sucrose as a food source, releasing wastes that degrade
enamel. This can be a considerable problem for children, who are not able
to make rational decisions and usually base decisions on sensory input as
opposed to cognitive processes. For these reasons, artificial sweeteners
have come into use.
Saccharin was the first artificial sweetener
discovered. It was accidentally found in 1879 by a chemistry research
assistant Constantine Fahlberg. Fahlberg was working on new food
preservatives when he accidentally spilled some of the compound he had
synthesized on his hands. When he went back home that night and ate his
dinner that night, he noticed the intense sweetness of the compound. He
named the compound saccharin after the Latin saccharum which means
sugar. He went back to the lab, tracing his steps until he was able to
synthesize saccharin in bulk.
Saccharin was used as a
sweetener only sporadically until the advent of World War I. During World
War I, most of the sugar was rationed, and saccharin use increased dramatically
as the sugar was sent to the troops in Europe. By 1917, the little pink
packets were seen all over tables in America and in Europe, as saccharin was
exported to Europe with the troops in 1917. After the war, the consumption
of saccharin increased and the number of products that used saccharin also
increased. When World War II hit, sugar rationing started again, leading
to another significant increase in saccharin use and a proliferation of products
that used the sweetener. Saccharin use continued upward during World War
II and afterwards.
In 1960, studies that were conducted
on saccharin suggested that it caused cancer in rats. When tests began to
suggest that saccharin caused bladder cancer in lab rats, the FDA1
moved to limit its use. This caused an immediate uproar due to the fact
that at the time saccharin was the only artificial sweetener. Its use was
banned in Canada in 1977. The FDA considered banning it in 1977 based on
this animal research. However, Congress placed a moratorium on the ban to
allow for more research on saccharin's safety. This moratorium has been extended
seven times due to continued consumer demand. The FDA withdrew the ban in
1991, but the moratorium is still in effect until the year 2002.
While numerous studies since 1977 have clearly shown that saccharin does not
cause cancer in humans in the doses that people take it in, labels on products
with saccharin must still carry a statement that says saccharin has caused
cancer in laboratory animals.
Aspartame was the next
major artificial sweetener to be discovered. Aspartame was discovered in
1965 by Mr. James Schlatter while he was working for G.D. Searle and Co.
Schlatter was working on new drugs to treat ulcers when he stumbled on this
compound. Surprisingly, he found the sweet taste of aspartame in about the
same way as Fahlberg when Fahlberg discovered saccharin: Schlatter licked his
fingers to pick up a piece of paper, and tasted the intense sweetness of the
compound he synthesized. By working backwards, he determined what he had
done, and managed to determine what he had.
approved for use as a table-top sweetener and in powdered mixes in 1981 by the
FDA. Since then, a number of people have questioned2
the studies that led to this decision. However, repeated
done on aspartame show that it is harmless to people in the amount that it is
ingested. In 1996, it was approved for use in all foods and beverages,
including products such as syrups, salad dressings and certain snack foods where
prior approval had not yet been obtained.
artificial sweetener, acesulfame potassium, was discovered in 1967 by Hoechst
AG. It was approved for use in the US by the FDA in 1992 for gums and dry
foods, and it was finally approved for liquid use in 1998. As soon as it
was approved, Pepsi announced that it would be used in a new drink, Pepsi One.
Advantages and Disadvantages
Saccharin has a number of advantages. Saccharin is
easy to make, it is stable when heated up, and is approximately 300 times
sweeter than sugar. However, there have been a large number of questions
about saccharin's role in causing cancer in rats. A large number of
studies have been done about this issue; however, it seems that some studies
show that saccharin does increase bladder in cancer, while other studies show
that there is no correlation between the amount of saccharin and the rate of
cancer in rats.
Aspartame also has a number of
advantages. Aspartame is also relatively easy to make, and it hasn't been
shown to cause cancer in anything. Aspartame is also 200 times sweeter
than sugar. However, aspartame has a shelf life of about 6 months, after
which it breaks down into its constituent components and looses its sweetness
abilities. Also, aspartame breaks down in temperatures above 85 degrees F,
which means that aspartame cannot be used in hot baking foods due to the fact
that heating it will destroy its sweetness abilities.
Acesulfame potassium, in essence, has no disadvantages. Acesulfame K
doesn't break down in high temperatures, it has a very long shelf life (about
3-4 years), and hasn't been shown to ever show cancer. It's only other
problem is that it isn't advertised all that much, thereby effectively limiting
consumer's choices to saccharin and aspartame.
This is what saccharin looks like: 4
Saccharin's chemical formula is
C7H5O3NS. As can be seen, saccharin is 2
fused rings: one phenyl ring and another, 5 membered ring with a carboxyl group,
a nitrogen in the ring (making the ring heterocyclic), and a sulfone group next
to the nitrogen.
This is what aspartame looks like: 5
Aspartame's chemical formula is
C13H18O5N2. As can be seen
from the picture, aspartame contains the amino acids phenylalanine and aspartate
with the end of the aspartate residue methylated by methanol to form a methyl
This is what acesulfame K looks like: 8
This molecule is a single heterocyclic ring with a
carboxyl group coming off of the gamma carbon, a double bond at the alpha and
beta carbons, and a methyl group off of the alpha carbon. Next to the
alpha carbon is an oxygen atom, and next to the oxygen atom is a sulfone
group. Next to the sulfone group is a nitrogen atom, completing the ring.
Saccharin is made like this:
The synthesis of saccharin first starts with
toluene. Then Cl2SO2OH is added, forming 2 products:
one with the SO2Cl group attached at the ortho site of the phenyl
group, and one with the SO2Cl group at the para site of the phenyl
group. The ortho product is used in the next reaction, where ammonium
carbonate is added to the reaction mix. The ammonium carbonate can be
added to the original reaction mix due to the fact that the reaction will be
pulled towards the products because of Le Chatelier's principle. The
ammonium replaces the chlorine in the molecule, forming ammonium chloride and
the next molecule. The reaction is purified and separated. The
molecule is then placed in a high concentration of potassium permanganate and
heated to approximately 150 degrees centigrade. The methyl group in the
molecule is changed from a methyl group to a carboxyl group, COOH. When
this happens, the molecule self-cyclizes, releasing water and producing
saccharin. After this, a base is added to exchange the hydrogen on the
nitrogen atom with a metal ion, like sodium or calcium.
Aspartame is even more simple to make than saccharin, as
can be seen: Simply add phenylalanine and
aspartate together. After these two have finished reacting, esterify the
end of the amino acid with a methyl group by adding methanol and this will
Acesulfame is made from acetoacetic acid. However,
due to the fact that the company that first made acesulfame K still holds the
patents to it, it isn't possible to get a representation of what the synthesis
of acesulfame K looks like.
Saccharin and acesulfame potassium both go directly
through the human digestive system without being digested at all.
Acesulfame actually does release its potassium into the bloodstream, but the
amount is negligible.
Aspartame, on the other hand, has a
more complicated history in the body. When the body ingests aspartame, it
breaks down into its three constituent components: phenylalanine, aspartate, and
methanol. The phenylalanine and aspartate are handled by enzymes in the
stomach and in the small intestine, while the methanol is transported to the
liver for detoxification. Although methanol is a very dangerous substance,
so little is produced in the metabolism of aspartame (10% by weight) that the
result on the body is negligible.
Another problem with
aspartame is the phenylalanine that is produced in the breakdown of it. A
small portion of the population has a genetic disorder called phenylketonuria
(PKU). As can be seen by this diagramatic representation of the metabolism
of phenylalanine, people who have PKU cannot change phenylalanine into tyrosine,
another amino acid: 7 Tyrosine in
the body is changed into L-Dopa, which is then converted into the basic
neurotransmitters. Someone with phenylketonuria, however, lacks the enzyme
that converts phenylalanine into tyrosine. This causes a buildup of
phenylalanine in the neural tissue, which leads to mental retardation.
Because of this, all food products that contain aspartame contain a warning that
tells people with PKU not to use this product. For this reason, pregnant
women should also not use aspartame due to the chance that the fetus may have
PKU. This will help reduce the chances of retardation in the child.
Current Taste Models
Taste models have had an evolution from simplistic,
one-dimensional analysis to complex three-dimensional structures which include
electrostatic interactions and size parameters. The first models tried to
find common features among the sweet molecules themselves. This approach
ignored the three-dimensional shape of the molecules themselves and the
electrostatic interactions between the molecules and the receptor
molecules. This model fell into disfavor due to the inefficiency of its
predictions; i.e. it wasn't able to predict effectively what would and what
wouldn't taste sweet.
The next postulate was given by
Shallenberger and Acree. They pointed out that nearly all sweet molecules
have a hydrogen bond donor and a hydrogen bond acceptor separated by about 0.3
nanometers. Therefore, it can be implied that the ability to create a
sweet taste is the ability of the molecule to form two hydrogen bonds with a
complementary donor or acceptor in the receptor.
three of the major sweeteners included in this paper due indeed have this
characteristic. Acesulfame has a hydrogen bond donor at the SO2
side of the molecule, and a bond acceptor at the nitrogen on the ring.
Saccharin also has a bond donor at the SO2 side, and also has a bond
acceptor at the nitrogen of the ring. Aspartame has a bond acceptor at the
CO2 end, and has a bond donor at the amino (NH3) end of
A general model of the taste receptor has
been constructed, which looks like this: 5
As can be seen, the receptor has both hydrophobic and
hydrophilic portions. Acesulfame can fit with the methyl group oriented
towards the methyl ester site, the ring sitting over the aryl region, the
SO2 group fitting into the carboxylate site, and the nitrogen fitting
into the major NH site.
From computer modeling, this is
how much scientists think aspartame fits into the receptor model:
As can be seen, aspartame fits rather well into the
receptor site, making it extremely sweet (i.e. 200-300 times sucrose).
This is what saccharin is believed to look like in the
The bromine molecule was used to see if halogenated
molecules were sweeter than non-halogenated ones. As can be seen, they
were due to the fact that they fit into the receptor site more
effectively. In fact, halogenated saccharins were 2-5 times sweeter than
plain saccharin. This gives credence to the theory that this is an
have only come onto the scene within the last century. However, ever since
their introduction, they have shown their importance not only for people
attempting to decrease caloric intake, but also for diabetics who cannot eat
simple sucrose. Each of the major artificial sweeteners that have been
released have at least one problem (some more): saccharin and acesulfame both
might be carcinogens, and aspartame breaks down at high temperatures and can't
be used by a segment of the population at all (people with PKU). Because
of this, the quest for a non-carcinogenic, thermally stable, easily produceable
artificial sweetener continues.
2. "The History of Artificial Sweeteners". http://www.trufax.org/research/f18.html
3. International Food Information Council Foundation.
4. What is Saccharin? http://crystal.biol.csufresno.edu:8080/projects98/540.htm
5. Sweeteners: Discovery, Molecular Design and
6. McGilvery, R.W.
Biochemistry. W.B. Saunders, Philidelphia, PA 1970
7. Personal Notes
8. Sweet One.
Barber, Susana. Question: What is Saccharin? http://crystal.biol.csufresno.edu:8080/projecets98/540.html
Brewer, M. Susan and Edlefsen, Miriam. Saccharin. http://www.foodsafety.org/il/il096/htm
Food and Drug Administration. FDA.
International Food Information Council Foundation. http://ificinfo.health.org/insight/janfeb98/lowcalsweet.htm
McGilvery, R.W., 1970. Biochemistry. Philadelphia: W.B.
Solomon, Eldra P., Linda Berg, Dian W. Martin, Claude
Villee, 1993. Biology, 3rd Ed. New York: Saunders
Sweeny, James G. et al. Discovery and Synthesis
of a New Series of High-Potency L-Aspartyl-D-a-alkylbenzylamide
Sweeteners. Journal of Agricultural and Food Chemistry, 1995,
of Artificial Sweeteners". http://www.trufax.org/research/f18.html
Walters, D. Eric, Frank t. Orthoefer, Grant E. Dubois. Sweeteners:
Discovery, Molecular Design and Chemoreception. Washington, DC: ACS
Symposium Series, 1997.
Zubay, Geoffrey, 1996. Biochemistry,
4th edition. Dubuque, IA: Wm. C. Brown Publishers.