81-07-2 Usage
Chemical Description
Saccharin is an artificial sweetener that is commonly used in food and drinks.
History
Saccharin was discovered in 1879 by chemists Constantin Fahlberg and Ira Remsen as they were researching about the oxidation of o-toluenesulfonamide. While eating, Fahlberg noticed the presence of sweetness in his food due to his arms and hands that contained saccharin. As he checked his laboratory apparatus by taste tests, Fahlberg found out that the source of this sweetness was from saccharin. Saccharin is still made of toluenesulfonamide and from phthalic anhydride.
History
Saccharin is the oldest and one of the best-known artificial sweeteners. It was accidentally discovered in 1878 by Ira Remsen (1846 1927) and his postdoctoral research fellow Constantin Fahlberg (1850 1910) at Johns Hopkins University when he was working on toluene derivatives from coal tar. He traced the taste back to the oxidized sulfonated chemicals he was working with and determined it was a sulfonated amide benzoic acid compound. Remsen and Fahlberg jointly published their findings on the compound in 1879 and 1880 in American and German journals. During the next several years, Remsen continued his academic work as one of the world's leading chemists, and Fahlberg perfected methods for commercialization of saccharin. Fours year after they published their work, Fahlberg and his uncle, Adolf List, applied for a United States patent for the compound, which was granted in 1885 (U.S. patent number 319082). Saccharin was first introduced to the public in 1885. It was initially promoted as an antiseptic and food preservative. The use of saccharin as a sweetener started around 1900 when it was marketed for use by people with diabetes. Because saccharin
was a cheap sugar substitute, it was viewed as a threat to the sugar industry. Sugar manufacturers
in Europe, Canada, and the United States lobbied for laws restricting saccharin’s
use.
Calls to regulate saccharin in foods have been present throughout its history. Early in the 20th
century, the political climate promoted legislation and government oversight to ensure that food
was safe. In 1906, the passage of the Federal Food and Drug Act gave government regulatory
authority concerning the safety of food. The Department of Agriculture’s Bureau of Chemistry,
the predecessor of the Food and Drug Administration (FDA), performed research and made
recommendations with respect to food additives. In 1907, a study by the newly created Board
of Food and Drug Inspection made claims (latter refuted) that saccharin damaged the kidneys
and other organs. The leader of the Bureau of Chemistry, Harvey W. Wiley (1844–1930), was a
member of the Board and held the view that saccharin (and other chemicals such as benzoates)
was dangerous.
Approximately 30,000 tons per year of saccharin and saccharin salts are
used globally each year, with about 5,000 tons of this used in the United States.
Questions on saccharin’s safety has followed its usage to the present day. Saccharin is banned
in Canada (except in special cases), several European countries, and many other countries.
Countries where it is legal place restrictions on its use. Saccharin has been regulated in the
United States since the beginning of the century. A Canadian study in 1977 that reported saccharin
Legislation, signed into law on December 21, 2000, repealed the warning label requirement for products containing saccharin.
The National Cancer
Institute’s position is that there is no clear evidence linking saccharin to cancer in humans.
Properties
Saccharin is stable when heated and does not chemically react with other food ingredients, therefore, it stores well. When blended with other sweeteners, saccharin often compensates for each sweetener’s faults and weakness. Commonly, saccharin is used with aspartate in diet carbonated soft drinks.
Saccharin is insoluble in water in its acid form. Its majorly used form as an artificial sweetener is its sodium salt.
Safety and Health Effects
The utilization of saccharin in human food has raised numerous health and safety concerns. In the 1970s, saccharin was linked with the development of bladder in rodents in various laboratory studies on rats. Consequently, the United States Food and Drug Administration (FDA) pushed for its ban, sighting that it is carcinogenic to humans.
However, after strong objection from the public regarding the ban, American Congress intervened and allowed the compound to remain in the food supply as long as all the manufactures libel it with a warning when packaging.
Saccharin gas been classified to have no nutritional or food energy value, as such, it safe for patients with diabetes.
Production Methods
Saccharin is prepared from toluene by a series of reactions known as the Remsen–Fahlberg method. Toluene is first reacted with chlorosulfonic acid to form o-toluenesulfonyl chloride, which is reacted with ammonia to form the sulfonamide. The methyl group is then oxidized with dichromate, yielding o-sulfamoylbenzoic acid, which forms the cyclic imide saccharin when heated.
An alternative method involves a refined version of the Maumee process. Methyl anthranilate is initially diazotized to form 2- carbomethoxybenzenediazonium chloride; sulfonation followed by oxidation then yields 2-carbomethoxybenzenesulfonyl chloride. Amidation of this material, followed by acidification, forms insoluble acid saccharin.
Preparation
Saccharin is synthesized using two methods: the Remsen-Fahlberg process and the Maumee or Sherwin-Williams method. The Remsen-Fahlberg synthesis of saccharin starts by reacting toluene with chlorosulfonic acid to give ortho and para forms of toluene-sulfonic acid (Figure 78.1). The acid can be converted to sulfonyl chlorides by treating with phosphorus pentachloride. The ortho form, o-toluene-sulfonyl chloride, is treated with ammonia to give o-toluene-sulfonamide, which is then oxidized with potassium permanganate to produce o-sulfamido-benzoic acid. On heating, the latter yields saccharin. Another synthesis was developed at Maumee Chemical Company in Toledo, Ohio, and it came to be known as the Maumee process. This process starts with phthalic anhydride, which is converted into anthranilic acid. Anthranilic acid is then reacted with nitrous acid, sulfur dioxide, chlorine, and ammonia to give saccharin. The Maumee process was further refi ned by the Sherwin-Williams Company and is therefore now referred to as the Sherwin-Williams process.
Air & Water Reactions
Slightly soluble in water.
Reactivity Profile
An amide. Acid to litmus. pH of 0.35% aqueous solution: 2.0. Organic amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).
Hazard
A questionable carcinogen. Products con-
taining it must have a warning label.
Fire Hazard
Flash point data for Saccharin are not available; however, Saccharin is probably combustible.
Flammability and Explosibility
Nonflammable
Pharmaceutical Applications
Saccharin is an intense sweetening agent used in beverages, food
products, table-top sweeteners, and oral hygiene products such as
toothpastes and mouthwashes. In oral pharmaceutical formulations,
it is used at a concentration of 0.02–0.5% w/w. It has been
used in chewable tablet formulations as a sweetening agent.
Saccharin has been used to form various pharmaceutical cocrystals.
Saccharin can be used to mask some unpleasant taste characteristics
or to enhance flavor systems. Its sweetening power is
approximately 300–600 times that of sucrose.
Biochem/physiol Actions
A sweet tastant for mammals. A glycerol taste receptor binding site specific for glucose has been proposed in drosophila.
Safety Profile
Confirmed carcinogen withexperimental neoplastigenic and tumorigenic data. Mildacute toxicity by ingestion. Experimental teratogenic andreproductive effects. Mutation data reported. Whenheated to decomposition it emits toxic NOx and SOx.
Safety
There has been considerable controversy concerning the safety of
saccharin, which has led to extensive studies since the mid-1970s.
Two-generation studies in rats exposed to diets containing
5.0–7.5% total saccharin (equivalent to 175 g daily in humans)
suggested that the incidence of bladder tumors was significantly
greater in saccharin-treated males of the second generation than in
controls. Further experiments in rats suggested that a contaminant
of commercial saccharin, o-toluene sulfonamide, might
also account for carcinogenic effects. In view of these studies, a ban
on the use of saccharin was proposed in several countries. However,
in 1977 a ban by the FDA led to a Congressional moratorium that
permitted the continued use of saccharin in the USA.
From the available data it now appears that the development of
tumors is a sex-, species-, and organ-specific phenomenon, and
extensive epidemiological studies have shown that saccharin intake
is not related to bladder cancer in humans.
The WHO has set a temporary acceptable daily intake for
saccharin, including its calcium, potassium, and sodium salts, at up
to 2.5 mg/kg body-weight. In the UK, the Committee on Toxicity
of Chemicals in Food, Consumer Products, and the Environment
(COT) has set an acceptable daily intake for saccharin and its
calcium, potassium, and sodium salts (expressed as saccharin
sodium) at up to 5 mg/kg body-weight.
Adverse reactions to saccharin, although relatively few in
relation to its widespread use, include: urticaria with pruritus
following ingestion of saccharin-sweetened beverages and
photosensitization reactions.
LD50 (mouse, oral): 17.5 g/kg
LD50 (rat, IP): 7.10 g/kg
LD50 (rat, oral): 14.2 g/kg
storage
Saccharin is stable under the normal range of conditions employed
in formulations. In the bulk form it shows no detectable
decomposition and only when it is exposed to a high temperature
(125°C) at a low pH (pH 2) for over 1 hour does significant
decomposition occur. The decomposition product formed is
(ammonium-o-sulfo)benzoic acid, which is not sweet. The
aqueous stability of saccharin is excellent.
Saccharin should be stored in a well-closed container in a dry
place.
Shipping
UN3077 Environmentally hazardous substances,
solid, n.o.s., Hazard class: 9; Labels: 9-Miscellaneous haz-
ardous material, Technical Name Required.
Purification Methods
Purify saccharin by recrystallisation from Me2CO [solubility 7.14% at 0o, 14.4% at 50o], or aqueous isoPrOH to give a fluorescent solution. It sublimes in vacuo. It is an artificial sweetner and is 500 times sweeter than sucrose. [DeGarmo et al. J Am Pharm Assoc (Sci Ed) 41 17 1952, Beilstein 27 H 168, 870, 27 I 266, 27 II 214, 27 III/IV 2649.]
Incompatibilities
Saccharin can react with large molecules, resulting in a precipitate
being formed. It does not undergo Maillard browning.
Regulatory Status
Accepted for use as a food additive in Europe. Note that the EU
number ‘E954’ is applied to both saccharin and saccharin salts.
Included in the FDA Inactive Ingredients Database (oral solutions,
syrups, tablets, and topical preparations). Included in nonparenteral
medicines licensed in the UK. Included in the Canadian List of
Acceptable Non-medicinal Ingredients.
Check Digit Verification of cas no
The CAS Registry Mumber 81-07-2 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 8 and 1 respectively; the second part has 2 digits, 0 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 81-07:
(4*8)+(3*1)+(2*0)+(1*7)=42
42 % 10 = 2
So 81-07-2 is a valid CAS Registry Number.
InChI:InChI=1/C7H5NO3S/c9-7-5-3-1-2-4-6(5)12(10,11)8-7/h1-4H,(H,8,9)
81-07-2Relevant articles and documents
Synthesis, characterization and antimicrobial evaluation of new 3-(Alkyl/Arylamino)benzo[d]isothiazole 1,1-derivatives
Kamble, Dhanraj P.,Shankarwar, Anil G.,Mane, Yogesh D.,Tigote, Radhakrishna M.,Sarnikar, Yuvaraj P.,Madje, Balaji R.
, p. 797 - 804 (2021/09/08)
The saccharine nucleus has long been recognized as a significant component in medicine. A series of pseudo-saccharine amines derivatives (7a-j) were synthesized and examined for their antibacterial activity. After testing all compounds, 7b, 7f, 7g, 7i and 7j were found most effective against Escherichia coli, Streptococcus aureus and Bacillus subtilis strains. The MIC of the compound was found from 4.6 to 16.1 μM. Further, compound 7f and 7i exhibited excellent activity against E.coli and Bacillus subtilis with MIC value 4.6 and 4.7 μM respectively. The compound 7b and 7i was found active against all the three bacteria. The zone inhibition was observed at 10 μM against Escherichia coli, Staphylococcus aureus and Bacillus subtilis at 0.9, 1.8, 3.9 respectively for 7b and 1.0, 1.8 and 2.0 cm respectively for 7i.
Adapting decarbonylation chemistry for the development of prodrugs capable ofin vivodelivery of carbon monoxide utilizing sweeteners as carrier molecules
Brewer, Maya,Cachuela, Alyssa,De La Cruz, Ladie Kimberly,Gallo, David,Ji, Xingyue,Lu, Wen,Menshikh, Anna,Otterbein, Leo,Tan, Chalet,Wang, Binghe,Wang, Minjia,Wang, Siming,Yang, Haichun,Yang, Xiaoxiao,de Caestecker, Mark
, p. 10649 - 10654 (2021/08/20)
Carbon monoxide as an endogenous signaling molecule exhibits pharmacological efficacy in various animal models of organ injury. To address the difficulty in using CO gas as a therapeutic agent for widespread applications, we are interested in developing CO prodrugs through bioreversible caging of CO in an organic compound. Specifically, we have explored the decarboxylation-decarbonylation chemistry of 1,2-dicarbonyl compounds. Examination and optimization of factors favorable for maximal CO release under physiological conditions led to organic CO prodrugs using non-calorific sweeteners as leaving groups attached to the 1,2-dicarbonyl core. Attaching a leaving group with appropriate properties promotes the desired hydrolysis-decarboxylation-decarbonylation sequence of reactions that leads to CO generation. One such CO prodrug was selected to recapitulate the anti-inflammatory effects of CO against LPS-induced TNF-α production in cell culture studies. Oral administration in mice elevated COHb levels to the safe and efficacious levels established in various preclinical and clinical studies. Furthermore, its pharmacological efficacy was demonstrated in mouse models of acute kidney injury. These studies demonstrate the potential of these prodrugs with benign carriers as orally active CO-based therapeutics. This represents the very first example of orally active organic CO prodrugs with a benign carrier that is an FDA-approved sweetener with demonstrated safety profilesin vivo.
CARBON MONOXIDE PRODRUGS FOR THE TREATMENT OF MEDICAL DISORDERS
-
Page/Page column 128-131, (2020/05/21)
The present invention provides new compounds and compositions thereof that release carbon monoxide for the treatment of medical disorders that are responsive to carbon monoxide, for example, inflammatory, pain, and dermatological disorders.
Preparation method of saccharin
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Paragraph 0128-0137; 0140-0151, (2020/10/14)
The invention discloses a preparation method of saccharin. The invention provides a preparation method of saccharin as shown in a formula 1 represented in the specification. The preparation method ischaracterized by comprising the following step: in water, in the presence of tungstate and/or tungstic acid, carrying out oxidation reaction on a compound shown in a formula 2 and hydrogen peroxide toobtain saccharin shown in a formula 1.
Synthetic method for preparing saccharin (by machine translation)
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Paragraph 0033-0076; 0081-0090, (2020/07/02)
1,2 - Benzisothiazol -3 - ketone compounds are subjected to an oxidation reaction with an oxidizing agent, and an oxidizing agent oxidizes thioether of 1,2 - benzisothiazol -3 -one compound to thioamide to obtain the O-benzoyl sulfamide compound. Compared with the traditional production technology of saccharin, the saccharin synthesis method has the advantages of simple process, low cost, high separation efficiency, low pollution and the like, and accords with the green chemistry. (by machine translation)
Method for removing saccharin in probenazole
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Paragraph 0018-0027, (2020/02/17)
The invention provides a method for removing saccharin in probenazole. The method comprises the steps: the probenazole containing saccharin impurities is suspended in an appropriate amount of water, then sodium bicarbonate or potassium bicarbonate is continuously added till no gas is generated, then centrifuge dripping is conducted, drip washing is conducted through an appropriate amount of water,and thus the saccharin in the probenazole can be removed. A water solution containing saccharin sodium is acidized, and then the saccharin can be recovered. The method is easy and convenient to operate, an organic solvent is not adopted, the three wastes (waste gas, waste water and industrial residue) are less, safety and environmental protection are achieved, an obtained product is high in purity, the production cost and the environmental protection cost are greatly saved, and industrialization is easy to achieve.
Preparation method of saccharin by using enhanced oxidation process of o-toluene sulfonamide
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Paragraph 0045-0047; 0067, (2018/08/19)
The present invention relates to a saccharin manufacturing method using an improved oxidation process of toluene sulfonamide, and more specifically, capable of economically and efficiently manufacturing saccharin through an efficient oxidation reaction of o-toluene sulfonamide using CrO_3 and H_5IO_6. The present invention is provided to improve a conventional method having a disadvantage of high costs in the oxidation reaction of the o-toluene sulfonamide such that it is possible to economically manufacture saccharin in a high yield.COPYRIGHT KIPO 2018
Aromatic Chlorosulfonylation by Photoredox Catalysis
Májek, Michal,Neumeier, Michael,Jacobi von Wangelin, Axel
, p. 151 - 155 (2017/01/17)
Visible-light photoredox catalysis enables the efficient synthesis of arenesulfonyl chlorides from anilines. The new protocol involves the convenient in situ preparation of arenediazonium salts (from anilines) and the reactive gases SO2and HCl (from aqueous SOCl2). The photocatalytic chlorosulfonylation operates at mild conditions (room temperature, acetonitrile/water) with low catalyst loading. Various functional groups are tolerated (e.g., halides, azides, nitro groups, CF3, SF5, esters, heteroarenes). Theoretical and experimental studies support a photoredox-catalysis mechanism.
A kind of processing adjacent sulfonaide method of crystallization mother liquor benzoic acid methyl ester
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Paragraph 0022; 0023, (2017/01/23)
The invention relates to a method for treating a methyl 2-(aminosulfonyl)benzoate crystallization mother solution, which comprises the following steps: performing chemical reaction on sodium hydroxide or a sodium hydroxide solution or potassium hydroxide or calcium hydroxide or calcium oxide and a methyl 2-(aminosulfonyl)benzoate crystallization mother solution generated in the concentration, crystallization or purification process during methyl 2-(aminosulfonyl)benzoate production, thus generating saccharin salt; heating to distill out methanol, cooling to 30 DEG C or below, and adding water until the Baume degree is regulated to 12Be or below; and filtering, and adding acid into the filtrate until the pH value is 1.0-2.0 to precipitate insoluble saccharin, wherein the recovered insoluble saccharin can be used as a raw material for methyl 2-(aminosulfonyl)benzoate production or saccharin sodium production. The production process of the treatment method is simple and quick in reaction and simple to operate, can lower the production cost, reduce organic substances in effluent waste water and lower the sewage treatment cost, and also can reduce environmental pollution, thereby being beneficial to environmental protection.
The Construction of 3-Methyl-4-arylpiperidines via a trans- Perhydroindolic Acid-Catalyzed Asymmetric Aza-Diels-Alder Reaction
An, Qianjin,Shen, Jiefeng,Butt, Nicholas,Liu, Delong,Liu, Yangang,Zhang, Wanbin
, p. 3627 - 3638 (2016/01/25)
An efficient trans-perhydroindolic acid-catalyzed asymmetric aza-Diels-Alder reaction of cyclic 1-azadienes and propanal was developed for the synthesis of chiral 3-methyl-4-aryldehydropiperidine derivatives (up to 98% yield and 99% ee). Such scaffolds are often found in bioactive compounds and medicines. A gram-scale reaction was carried out with a low catalyst loading to give the desired product in high yield and with excellent enantioselectivity. The resulting dehydropiperidine derivatives can be further transformed to chiral 3-methyl-4-aryl-substituted piperidines with high efficiency.
Xn:Harmful;
