The History, Synthesis, Metabolism and Uses of Artificial Sweeteners

Greg Hodgin

Introduction
The Purpose of Artificial Sweeteners
History
Advantages/Disadvantages
Structures
Synthesis
Metabolism
Current Taste Theories
Conclusion
References

Introduction

"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 models.
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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: This is what glucose and fructose look like.

This is what glucose and fructose look like.

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This is what sucrose looks like:

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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.

History

    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.
    Aspartame was 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 studies₃ 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.
    A third 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.
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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.
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Structures

This is what saccharin looks like:

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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 ester.

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.
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Synthesis

Saccharin is made like this: Synthesis of saccharin.

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: This is the synthesis of aspartame. 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 produce aspartame.

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.

Metabolism

    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.
    All 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 the molecule.
    A general model of the taste receptor has been constructed, which looks like this: This is the current generic model of the taste receptor region of the tongue.

This is the current generic model of the taste receptor region of the tongue.

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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:
This is the fit of aspartame in the receptor site. ₅

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 receptor model:

This is what saccharin looks like in the receptor model. ₅

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 appropriate model.

Conclusion

Artificial sweeteners 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.

Footnotes

1. FDA
2. "The History of Artificial Sweeteners". http://www.trufax.org/research/f18.html
3. International Food Information Council Foundation. http://ificinfo.health.org/insight/janfeb98/lowcalsweet.htm
4. What is Saccharin? http://crystal.biol.csufresno.edu:8080/projects98/540.htm
5. Sweeteners: Discovery, Molecular Design and Chemoreception.
6. McGilvery, R.W. Biochemistry. W.B. Saunders, Philidelphia, PA 1970
7. Personal Notes
8. Sweet One.

References

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. Saunders Company.
Solomon, Eldra P., Linda Berg, Dian W. Martin, Claude Villee, 1993. Biology, 3^rd Ed. New York: Saunders College Publishing.
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, pg. 43.
Sweet One.
"The History 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, 4^th edition. Dubuque, IA: Wm. C. Brown Publishers.