Saccharin

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Saccharin[1]
Saccharin.svg
Saccharin-from-xtal-3D-balls.png
Identifiers
CAS number 81-07-2 YesY
PubChem 5143
ChemSpider 4959 YesY
UNII FST467XS7D YesY
KEGG D01085 YesY
ChEBI CHEBI:32111 N
ChEMBL CHEMBL310671 YesY
Jmol-3D images Image 1
Properties
Molecular formula C7H5NO3S
Molar mass 183.18 g mol−1
Appearance White crystalline solid
Density 0.828 g/cm3
Melting point 228.8-229.7 °C
Solubility in water 1 g per 290 mL
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N (verify) (what is: YesY/N?)
Infobox references

Saccharin[2] is an artificial sweetener with effectively no food energy which is approximately 300 times as sweet as sucrose or table sugar, but has a bitter or metallic aftertaste, especially at high concentrations. It is used to sweeten products such as drinks, candies, cookies, medicines, and toothpaste.

Origins[edit]

Saccharin derives its name from the word "saccharine", meaning of, relating to, or resembling sugar.[3]

Properties[edit]

Sodium salt of saccharin: A white powder

Saccharin is unstable when heated but it does not react chemically with other food ingredients. As such, it stores well. Blends of saccharin with other sweeteners are often used to compensate for each sweetener's weaknesses and faults. A 10:1 cyclamate:saccharin blend is common in countries where both these sweeteners are legal; in this blend, each sweetener masks the other's off-taste. Saccharin is often used together with aspartame in diet carbonated soft drinks, so that some sweetness remains should the fountain syrup be stored beyond aspartame's relatively short shelf-life. Saccharin is believed to be an important discovery, especially for diabetics, as it goes directly through the human digestive system without being digested.

In its acid form, saccharin is not water-soluble. The form used as an artificial sweetener is usually its sodium salt. The calcium salt is also sometimes used, especially by people restricting their dietary sodium intake. Both salts are highly water-soluble: 0.67 grams per milliliter water at room temperature.[4][5]

Safety and health effects[edit]

Saccharin has no food energy. It has been suggested that it may trigger the release of insulin in humans and rats, as a result of its taste, but this has not been confirmed in controlled studies."[6][7][8] This is similar for aspartame (another artificial sweetener).[9] However large amounts of saccharin (corresponding to 4L of sweetened soft drinks per day) has been shown to lead to significantly increased glucose intolerance in mice and in some humans, likely due to interactions between saccharin and gut bacteria.[10]

History[edit]

Saccharin, historical wrapping; Sugar Museum (Berlin)

Saccharin was produced first in 1878 by Constantin Fahlberg, a chemist working on coal tar derivatives in Ira Remsen's laboratory at the Johns Hopkins University. (As discussed below, the relative contributions of Fahlberg and Remsen to the discovery were later contested, with no final resolution in sight; the 1879 paper announcing the discovery lists both names as authors, with Fahlberg's name first.) Fahlberg noticed a sweet taste on his hand one evening, and connected this with the compound that he had been working on that day.[11][12] Fahlberg and Remsen published articles on benzoic sulfimide in 1879 and 1880.[4][13] In 1884, then working on his own in New York City, Fahlberg applied for patents in several countries, describing methods of producing this substance that he named saccharin.[14] Two years later he began production of the substance in a factory in a suburb of Magdeburg, Germany. Fahlberg would soon grow wealthy, while Remsen merely grew irritated, believing that he deserved credit for substances produced in his laboratory. On the matter, Remsen commented, "Fahlberg is a scoundrel. It nauseates me to hear my name mentioned in the same breath with him."[15]

Although saccharin was commercialized not long after its discovery, it was not until sugar shortages during World War I that its use became widespread. Its popularity further increased during the 1960s and 1970s among dieters, since saccharin is a calorie-free sweetener. In the United States, saccharin is often found in restaurants in pink packets; the most popular brand is "Sweet'n Low".

Government regulation[edit]

Starting in 1907, the USDA began investigating saccharin as a direct result of the Pure Food and Drug Act. Harvey Wiley, then the director of the bureau of chemistry for the USDA, viewed it as an illegal substitution of a valuable ingredient (sugar) by a less valuable ingredient. In a clash that had career consequences, Wiley told President Theodore Roosevelt that "Everyone who ate that sweet corn was deceived. He thought he was eating sugar, when in point of fact he was eating a coal tar product totally devoid of food value and extremely injurious to health." But Roosevelt himself was a consumer of saccharin, and, in a heated exchange, Roosevelt angrily answered Wiley by stating, "Anybody who says saccharin is injurious to health is an idiot."[16] The episode proved the undoing of Wiley's career.

In 1911, the Food Inspection Decision 135 stated that foods containing saccharin were adulterated. However, in 1912, Food Inspection Decision 142 stated that saccharin was not harmful.

More controversy was stirred in 1969 with the discovery of files from the FDA's investigations of 1948 and 1949. These investigations, which had originally argued against saccharin use, were shown to prove little about saccharin being harmful to human health.[citation needed] In 1972, the USDA made an attempt to completely ban the substance.[17][full citation needed] However, this attempt was also unsuccessful, and the sweetener continued to be widely used in the United States. It is now the third most popular artificial sweetener behind sucralose and aspartame.

In the European Union, saccharin is also known by the E number (additive code) E954.

The current status of saccharin is that it is allowed in most countries, and countries like Canada have lifted their previous ban of it as a food additive.[18] The claims that it is associated with bladder cancer were shown to be unfounded in experiments on primates.[19] (It is, however, prohibited to mail saccharin tablets or packets to France.)[20]

Saccharin was formerly on California's list of chemicals known to the state to cause cancer for the purposes of Proposition 65, but it was delisted in 2001.[21]

Warning label addition and removal[edit]

In 1958, the United States Congress amended the Food, Drugs, and Cosmetic Act of 1938 with the Delaney clause to mandate that the Food and Drug Administration not approve substances that "induce cancer in man, or, after tests, [are] found to induce cancer in animals." Studies in laboratory rats during the early 1970s linked saccharin with the development of bladder cancer in rodents. As a consequence, all food containing saccharin was labeled with a warning meeting the requirement of the Saccharin Study and Labeling Act of 1977.[22]

However, in 2000, the warning labels were removed because scientists learned that rodents, unlike humans, have a unique combination of high pH, high calcium phosphate, and high protein levels in their urine.[23][24] One or more of the proteins that are more prevalent in male rats combine with calcium phosphate and saccharin to produce microcrystals that damage the lining of the bladder. Over time, the rat's bladder responds to this damage by over-producing cells to repair the damage, which leads to tumor formation. Since this does not occur in humans, there is no elevated risk of bladder cancer.

The delisting of saccharin led to legislation, known as the Sweetness Act; which was signed into law on December 21, 2000, repealing the warning label requirement for products containing saccharin.[citation needed] In 2001, the U.S. Food and Drug Administration and the state of California reversed their positions on saccharin, declaring it safe for consumption.[25] The FDA's decision followed a 2000 determination by the U.S. Department of Health and Human Services' National Toxicology Program to remove saccharin from its list of carcinogens.

The EPA has officially removed saccharin and its salts from their list of hazardous constituents and commercial chemical products. In a December 14, 2010 release, the EPA stated that saccharin is no longer considered a potential hazard to human health.[26]

Chemistry[edit]

Saccharin can be produced in various ways.[27] The original route by Remsen & Fahlberg starts with toluene; another route begins with o-chlorotoluene.[28] Sulfonation by chlorosulfonic acid gives the ortho and para substituted sulfonyl chlorides. The ortho isomer is separated and converted to the sulfonamide with ammonia. Oxidation of the methyl substituent gives the carboxylic acid, which cyclicizes to give saccharin free acid:[29]

Remsen-Fahlberg synthesis of saccharin.png

In 1950, an improved synthesis was developed at the Maumee Chemical Company of Toledo, Ohio. In this synthesis, anthranilic acid successively reacts with nitrous acid (from sodium nitrite and hydrochloric acid), sulfur dioxide, chlorine, and then ammonia to yield saccharin:[29]

Maumee synthesis of saccharin.png

The free acid of saccharin has a low pKa of about 2 (the acidic hydrogen being that attached to the nitrogen).[30][31] Saccharin can be used to prepare exclusively disubstituted amines from alkyl halides via a nucleophilic substitution,[32] followed by Gabriel synthesis.[33]

See also[edit]

Notes and references[edit]

  1. ^ Merck Index, 11th Edition, 8282.
  2. ^ The word saccharin (as above) has no final "e". The word saccharine, with a final "e", is much older and is an adjective meaning "sugary" – its connection with sugar means the term is used metaphorically, often in a derogative sense, to describe something "unpleasantly over-polite" or "overly sweet".[1] Both words are derived from the Greek word σάκχαρον (sakcharon, German "ch" sound), which ultimately derives from Sanskrit for sugar, sharkara (शर्करा), meaning "gravel" [2]
  3. ^ "Saccharine, Wiktionary". 
  4. ^ a b Fahlberg, C. and Remsen, I. (1879). "Über die Oxydation des Orthotoluolsulfamids". Berichte der Deutschen chemischen Gesellschaft zu Berlin 12: 469–473. doi:10.1002/cber.187901201135. 
  5. ^ P. M. Priebem, G. B. Kauffman (1980). "Making governmental policy under conditions of scientific uncertainty: A century of controversy about saccharin in congress and the laboratory". Minerva 18 (4): 556–574. doi:10.1007/BF01096124. PMID 11611011. 
  6. ^ Just T, Pau HW, Engel U, Hummel T (November 10, 2008). "Cephalic phase insulin release in healthy humans after taste stimulation?". Appetite 238 (4): 622–7. doi:10.1016/j.appet.2008.04.271. PMID 18556090. 
  7. ^ E Ionescu, F Rohner-Jeanrenaud, J Proietto, RW Rivest and B Jeanrenaud (1988). "Taste-induced changes in plasma insulin and glucose turnover in lean and genetically obese rats". Diabetes 37 (6): 773–9. doi:10.2337/diabetes.37.6.773. PMID 3289998. 
  8. ^ H. R. Berthoud, E. R. Trimble, E. G. Siegel, D. A. Bereiter and B. Jeanrenaud (April 1, 1980). "Cephalic-phase insulin secretion in normal and pancreatic islet-transplanted rats". American Journal of Physiology-Endocrinology and Metabolism 238 (4): E336–40. PMID 6769337. 
  9. ^ Ferland A, Brassard P, Poirier P (July 2007). "Is aspartame really safer in reducing the risk of hypoglycemia during exercise in patients with type 2 diabetes?". Diabetes Care 30 (7): e59. doi:10.2337/dc06-1888. PMID 17596482. 
  10. ^ Suez J, Korem T, Zeevi D, et al. (September 2014). "Artificial sweeteners induce glucose intolerance by altering the gut microbiota". Nature 514 (7521): 181–6. doi:10.1038/nature13793. PMID 25231862. 
  11. ^ Fahlberg's account of how he discovered the sweetness of saccharin appears in: (Anon.) (July 17, 1886) "The inventor of saccharine," Scientific American, new series, 60 (3) : 36.
  12. ^ Myers, Rusty L.; Myers, Richard L. (2007). The 100 most important chemical compounds: a reference guide. Westport, Conn: Greenwood Press. p. 241. ISBN 0-313-33758-6. 
  13. ^ Remsen Ira, Fahlberg C. (February 1880). "On the oxidation of substitution products of aromatic hydrocarbons. IV. - On the oxidation of orthotoluenesulphamide". American Chemical Journal 1 (6): 426–439.  From pages 430-431: "It possesses a very marked sweet taste, being much sweeter than cane-sugar. The taste is perfectly pure. The minutest quantity of the substance, a bit of its powder scarcely visible, if placed upon the tip of the tongue, causes a sensation of pleasant sweetness throughout the entire cavity of the mouth. As stated above, the substance is soluble to only a slight extent in cold water, but if a few drops of the cold aqueous solution be placed in an ordinary goblet full of water, the latter then tastes like the sweetest syrup. Its presence can hence easily be detected in the dilutest solutions by the taste."
  14. ^ Constantin Fahlberg and Adolph List, "Manufacture of saccharine compounds," U.S. Patent no. 319,082 (filed: August 7, 1884).
  15. ^ Getman, Frederick Hutton (1940). The life of Ira Remsen. Easton, Pa: Journal of chemical education. p. 66. OCLC 2640159 
  16. ^ "Sugar: A Cautionary Tale". www.fda.gov. Retrieved 2010-06-20. 
  17. ^ Preibe and Kauffman, 2,3,4,6,7
  18. ^ [3], Health Canada
  19. ^ Takayama, S.; Sieber, SM.; Adamson, RH.; Thorgeirsson, UP.; Dalgard, DW.; Arnold, LL.; Cano, M.; Eklund, S.; Cohen, SM. (Jan 1998). "Long-term feeding of sodium saccharin to nonhuman primates: implications for urinary tract cancer". J Natl Cancer Inst 90 (1): 19–25. doi:10.1093/jnci/90.1.19. PMID 9428778. 
  20. ^ http://pe.usps.com/text/imm/fh_005.htm USPS Mailing Conditions
  21. ^ Chemicals Delisted Effective April 6, 2001 as Known to the State to Cause Cancer, California Office of Environmental Health Hazard Assessment
  22. ^ "Saccharin warning". AP via Telegraph-Herald. 1973-05-22. Retrieved 2011-06-09. 
  23. ^ Whysner, J.; Williams, GM. (1996). "Saccharin mechanistic data and risk assessment: urine composition, enhanced cell proliferation, and tumor promotion". Pharmacol Ther 71 (1–2): 225–52. doi:10.1016/0163-7258(96)00069-1. PMID 8910956. 
  24. ^ Dybing, E. (Dec 2002). "Development and implementation of the IPCS conceptual framework for evaluating mode of action of chemical carcinogens". Toxicology. 181-182: 121–5. doi:10.1016/S0300-483X(02)00266-4. PMID 12505296. 
  25. ^ Conis, Elena. "Saccharin's mostly sweet following." Los Angeles Times. December 27, 2010, accessed January 14, 2011.
  26. ^ "EPA Removes Saccharin from Hazardous Substances Listing." December 14, 2010, accessed January 14, 2011.
  27. ^ David J. Ager, David P. Pantaleone, Scott A. Henderson, Alan R. Katritzky, Indra Prakash, D. Eric Walters (1998). "Commercial, Synthetic Nonnutritive Sweeteners". Angewandte Chemie International Edition 37 (13–24): 1802–23. doi:10.1002/(SICI)1521-3773(19980803)37:13/14<1802::AID-ANIE1802>3.0.CO;2-9. 
  28. ^ Bungard, G. (1967) Die SusStoffe Der Deut Apotheker, 19, 150.
  29. ^ a b Gert-Wolfhard von Rymon Lipinski (2005), "Sweeteners", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a26_023 
  30. ^ WHO food additives series 17
  31. ^ pKa data compiled by R. Williams
  32. ^ Ervithayasuporn, V.; Yingsukkamol, Pa-Kwan; Phurat, Chuttree; Somsook, Ekasith; Osotchan, Tanakorn; Ervithayasuporn, Vuthichai (2012). "Synthesis and Reactivity of Nitrogen Nucleophiles-Induced Cage-Rearrangement Silsesquioxanes". Inorg. Chem. 51 (22): 12266–12272. doi:10.1021/ic3015145. 
  33. ^ Sugasawa, S.; Abe, K. (1952). J. Pharm. Soc. Jpn. 72: 270. 
    Chem Abstr 47: 1626c. 1953.