By Yasine Malki 馬建生
Artificial sweeteners are commonly found in many “diet” varieties of food and drinks: from soft drinks to bakery goods, canned fruits and syrups. These sweeteners are synthetic substitutes of sugar, with little to no caloric content. You might see the common ones, like sucralose or aspartame among the ingredients of your favorite snack or drink! But did you know that the discovery of the first artificial sweetener, saccharin, came from experiments with coal tar and an accidental laboratory spillage?
Ira Remsen was a passionate German chemist who flourished in his work on sulfobenzoic compounds1  at Johns Hopkins University. Around 1877, a Russian chemist, Constantin Fahlberg, had joined his lab and they were working together to oxidize a coal-tar sulfobenzoic derivative , o-toluenesulfonamide .
One day when Fahlberg went home for dinner and took a bite at a piece of bread, he was shocked to find it tasted incredibly sweet! He also detected that both his hands and arms also tasted sweet, even though he had washed them thoroughly! He concluded that the sweetness came from insoluble remnants of an earlier chemical spillage over his hands. Being desperate for answers, he returned to the lab and tasted all the glassware on his bench until he found the substance with “eminent sweetening power.”  This turned out to come from an overboiled mixture of o-toluenesulfonic acid, phosphorus pentachloride and ammonia, which resulted in o-benzosulfimide. Remsen and Fahlberg published their discovery in 1879, describing the compound as “even sweeter than cane sugar.” 
However, this is where the sweet story took a bitter turn. After Fahlberg left Remsen’s lab, he started to realize the commercial potential of o-benzosulfimide and further optimize its synthesis for large-scale production, even conducting safety tests by feeding the compound to animals and himself . He realized that the compound was not metabolized by the body and was eliminated in the urine unchanged — meaning that it could probably be a replacement of sugar for diabetics and dieters, because it did not alter blood sugar levels nor provide any calories. Fahlberg filed patents2 for this substance in several countries under the name “saccharin” without Remsen’s knowledge or permission, and even claimed to be its sole discoverer. These actions left Remsen feeling betrayed and furious.
Saccharin quickly gained popularity in the US nevertheless, becoming a nation-wide success and a booming industry. Its increased consumption soon drawn the attention of health experts. After studies revealed a link between saccharin consumption to the development of bladder cancer in male rats , its use became highly scrutinized. For around 19 years, saccharin had to be sold with a warning label  until further research showed that those male rats had had unique physiological conditions (high levels of urinary proteins and calcium phosphate) that triggered their tumor formation by producing microcrystals with saccharin [6, 7], and these conditions do not apply to humans at all .
You may be wondering how can a molecule like saccharin, that is not sugar, tastes sweet? This is actually a result of its specific molecular shape, allowing it to trigger sweet taste receptors on the tongue through a lock-and-key mechanism. These receptors transmit electrical impulses to the brain, creating the perception of sweetness. The structural requirement for molecules that act as “keys” to the sweet taste receptor “lock” is described as a “triangle of sweetness” : it needs to contain two sites for forming hydrogen bonds3 with the receptor — one with an O–H or N–H group and one with an O or N atom — and a third site of a water-repelling group (e.g. hydrocarbon), forming a triangular geometry within specific dimensions (Figure 1(a)). This configuration is demonstrated in saccharin (Figure 1(b): an N–H group, one of the oxygen atoms on sulfur and the hydrophobic benzene ring) , allowing it to bind perfectly into the sweet taste receptor’s cavity. This same phenomenon also occurs for other sweet-tasting substances, such as glucose, sucrose or aspartame.
However, evidence suggests that saccharin also activates other taste receptors on the tongue, including the T2R bitter taste receptor and the vanilloid receptor 1 (TRPV1). These may explain the bitter and metallic aftertaste of saccharin, respectively .
This first commercialized artificial sweetener, saccharin (Sweet’N LowTM), had inspired the development of similar products with improved tastes, such as aspartame (EqualTM) and sucralose (SplendaTM). More recently, sugar alcohols (e.g. erythritol and xylitol) and plant extracts (e.g. Stevia and Monk Fruit) are trending as “healthier” natural sugar substitutes. Consumers today should be content that such a wide range of sweetening options are available in the market, offering them the sweetness of sugar without the risks of weight gain or developing diabetes!
|WARNING: NEVER TRY THIS IN YOUR SCHOOL LAB!
Although it may seem tempting to touch and taste the chemicals and biological samples in your school lab, and you might make great discoveries…most chemicals are not safe to consume or handle. It is always a good practice to wear gloves in the laboratory and to wash your hands thoroughly afterwards. Most importantly, NEVER taste or consume any laboratory chemicals!
Figure 1(a). The “triangle of sweetness” showing the structural requirements to activate the sweet taste receptors on the tongue . The numbers shown are the ideal distances between the three sites (picometer (pm): 10-12 meter).
Figure 1(b). The “triangle of sweetness” in saccharin . The electron-rich region between the two oxygen atoms can form a hydrogen bond with the sweet taste receptor.
1 Sulfobenzoic compounds: Compounds containing a sulfoxide group attached to a benzene ring (Ph–SO2R)
2 Patent: A right or ownership to protect a certain invention by preventing others from making, using and selling it, which usually lasts 20 years from the filing date.
3 Hydrogen bond: A relatively weak, non-covalent intermolecular interaction between an electronegative atom (N, O, F) and the hydrogen atom covalently bonded to another electronegative atom (N, O, F)
 Hicks, J. (2010). The Pursuit of Sweet. Retrieved from https://www.sciencehistory.org/distillations/the-pursuit-of-sweet.
 US Government Printing Office. (1963). United States Import Duties (1963).
 The Editors of Encyclopaedia Britannica. (2017). Saccharin. In Encyclopædia Britannica. Retrieved from https://www.britannica.com/science/saccharin.
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 National Cancer Institute. (2016). Artificial Sweeteners and Cancer. Retrieved from https://www.cancer.gov/about-cancer/causes-prevention/risk/diet/artificial-sweeteners-fact-sheet.
 Elmore, S. A., & Boorman, G. A. (2013). Environmental Toxicologic Pathology and Human Health. In W. Haschek, C. Rousseaux, & M. Wallig (Eds), Haschek and Rousseaux’s Handbook of Toxicologic Pathology (pp. 1029-1046). London, UK: Academic Press.
 Cohen, S. M., Cano, M., Earl, R. A., Carson S. D. & Garland, E. M. (1991). A proposed role for silicates and protein in the proliferative effects of saccharin on the male rat urothelium. Carcinogenesis, 12(9), 1551-1555. doi: 10.1093/carcin/12.9.1551
 U.S. Department of Health and Human Services. (2016). 14th Report on Carcinogens. Retrieved from https://ntp.niehs.nih.gov/ntp/roc/content/appendix_b.pdf.
 Emsley, J. (1994). The consumer’s good chemical guide: A jargon-free guide to the chemicals of everyday life. Oxford, UK: W.H. Freeman.
 Guley, P., & Uhing, J. (n.d.). Comparison of Relative Sweetness to Molecular Properties of Artificial and Natural Sweetners. Retrieved from http://shodor.org/succeed-1.0/compchem/projects/fall00/sweeteners/index.html
 Riera, C. E., Vogel, H., Simon, S. A., & le Coutre, J. (2007). Artificial sweeteners and salts producing a metallic taste sensation activate TRPV1 receptors. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 293(2), R626-R634. doi: 10.1152/ajpregu.00286.2007