Cyclamate

Cyclamate (cyclohexylsulfamic acid and its calcium and sodium salts) were discovered in the United States in 1937. They are 30 to 80 times as sweet as sucrose and were widely used until late 1969, when it was 

Cyclamate is produced by reacting cyclohexylamine with sulfonating agents, followed by reactions with sodium or calcium hydroxides to produce cyclamates and free cyclohexylamine as follows  

With the general name of cyclohexylsulphamate, this sweetener was discovered in 1937 by Michael Sveda at the University of Illinois. The sodium salt is the most commonly used form. It is a white crystalline salt with good solubility. The relative sweetness of cyclamate is comparatively low, at approximately 35, in most food systems (Bakal, 1983). The taste quality of cyclamate as a sole sweetener has a slow onset time and can have a sweet/sour aftertaste at high concentrations (Franta et al., 1986). Sweetness quality is greatly unproved in combination with other sweeteners. Cyclamate is synergistic with acesulfame K (Von Rymon Lipinsky, 1985), aspartame (Searle, 1971), saccharin (Von Rymon Lipinsky, 1987) and sucralose (Tate Lyle Pic, 2002). 

Cyclamate is stable under conditions likely to be encountered in soft drinks, that is, pH range 2-7, pasteurisation and UHT treatments. Analysis is usually using HPLC. Owing to differences in chemistry between cyclamate and other intense sweeteners, cyclamate requires derivatisation before analysis by HPLC (MacArthur et al., 2002). 

Cyclamates are non-cariogenic and non-caloric (Bakal, 1983). The majority of people metabolise less than 10% of cyclamate intake. However, approximately 47% of the population have the ability to metabolise 20-85% cyclamate (via the gut microflora) into cyclohexylamine, in which form it is excreted (Kasperson Primack, 1985 Renwick, 1985 TNO BIBRA, 2000). 

Historically, cyclamate was used in soft drinks in the United States from 1958 and in the United Kingdom from 1964, in combination with saccharin. In 1969, it was banned in the United States for use in general purpose foods on the basis of studies suggesting it may cause bladder tumours in laboratory animals. Several other countries, including the United Kingdom, followed suit. The ban on cyclamates was controversial and the original rat study has been heavily criticised. Subsequent studies on safety have implicated cyclohexylamine (the 

The FDA has, so far, refused to lift the ban on cyclamate, despite several petitions from Abbot Laboratories. Cyclamate is permitted in the European Union and came back into use in the United Kingdom via the harmonised EU Sweetener Regulations 1991. Use of cyclamate in the UK soft drinks industry is almost non-existent 10 years after its re-approval. 

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Other Sweeteners. Two other sweeteners, sucralose and cyclamates, are approved for use outside of the United States. Sucralose, a chlorinated derivative of sucrose which is 500—600 times as sweet as sugar, has received limited approval in Canada, and petitions for its approval are pending in the United States and Europe (71). Cyclamate sweeteners, once available in the United States, but now baimed because they caused bladder cancer in animals, are stiU available in Canada and Europe. Table 7 gives several examples of nonnutritive sweeteners that have been developed. 

Before a 1/1 /70 FDA ban (rescission proposed in early 1990), cyclamate noncaloric sweeteners were the major derivatives driving cycloliexylamine production. The cyclohexylsulfamic acid sodium salt (39) [139-05-9J and mote thermally stable calcium cyclohexylsulfamic acid (40) [139-06-1] salts were prepared from high purity cyclohexylamine by, among other routes, a reaction cycle with sulfamic acid. 

Sucrose occupies a unique position in the sweetener market (Table 3). The total market share of sucrose as a sweetener is 85%, compared to other sweeteners such as high fmctose com symp (HFCS) at 7%, alditols at 4%, and synthetic sweeteners (aspartame, acesulfame-K, saccharin, and cyclamate) at 4%. The world consumption of sugar has kept pace with the production. The rapid rise in the synthetic sweetener market during 1975—1995 appears to have reached a maximum. 

In 1969, a chronic toxicity study on a cyclamate saccharin (10 1) blend indicated bladder cancer problems in rats. Cyclamate was soon banned by the FDA, but saccharin remained an approved sweetener. In 1977, the FDA proposed a ban on saccharin because of the discovery of bladder tumors in some male rats fed with high doses of saccharin. Because no other nonnutritive sweetener was available at that time, the proposed ban faced strong opposition. 

Saccharin imparts a sweetness that is pleasant at the onset but is followed by a lingering, bitter aftertaste. Sensitivity to this bitterness varies from person to person. At high concentration, however, most people can detect the rather unpleasant aftertaste. Saccharin is synergistic with other sweeteners of different chemical classes. For example, saccharin—cyclamate, saccharin—aspartame, saccharin—sucralose, and saccharin—aUtame combinations all exert synergy to various degrees. The blends, as a rule, exhibit less aftertaste than each of the component sweeteners by themselves. 

Cyclamate. Sodium cyclamate [139-05-9] (6), the sodium salt of cyclamic acid [100-88-9] was so widely used that it was often just called cyclamate. The other common salt, calcium cyclamate [139-06-0] is useful in low sodium diets. 

Abbott Laboratories, which has conducted additional toxicity and carcinogenicity studies with cyclamate, a 10 1 mixture of cyclamate—saccharin, and cyclohexylamine, claimed to be unable to confirm the 1969 findings. Abbott then filed a food additive petition for cyclamate in 1973, which was denied by the FDA in 1980. In 1982, the Calorie Control Council and Abbott Laboratories filed a second food additive petition containing the results of additional safety studies (73). That petition was stiU pending as of 1996. Cyclamate is, however, allowed for use in any or all three categories, ie, food, beverage, and tabletop, in about 50 countries. Sweet n Low, known in the United States as a saccharin-based table-top sweetener, contains exclusively cyclamate in Canada. 

Cyclamate is about 30 times (8% sucrose solution sweetness equivalence) more potent than sugar. Its bitter aftertaste is minor compared to saccharin and acesulfame-K. The mixture of cyclamate and saccharin, especially in a 10 1 ratio, imparts both a more rounded taste and a 10—20% synergy. Cyclamate (6) is manufactured by sulfonation of cyclohexylamine (7). Many reagents can be used, including sulfamic acid, salts of sulfamic acid, and sulfur trioxide (74—77). 

To meet consumer demands, manufacturers are developing new nonnutritive sweeteners that more closely match the taste and mouthfeel of sucrose. There are several nonnutritive sweeteners currentiy pending FDA approval for use in soft drinks. They include sucralose [56038-13-2] aUtame [80863-62-3] encapsulated aspartame, cyclamates, and acesulfame-K [55589-62-3] also known as paUtinit. 

The concentration of the flavor in the dentifrice and the nature of substances added to bring out specific flavor notes and thereby make the flavor unique are significant concerns. The flavor must not be excessive it must not bum too strongly. Also, the flavor must not be a sensitizer. Synthetic sweeteners are usually added, although regulatory concerns limit their selection for example, cyclamate [100-88-9] is not used in the United States. 

Tabushi and Fujiyoshi have prepared alkylated cyclam derivatives for the purpose of suspending these systems from a polymer backbone. They have utilized a malonic ester alkylation reaction followed by cyclization and reduction to accomplish this end. ... 

Fig. 1 Fluorescence scan of a chromatogram track with 3 gg each of acesulfame and saccharin and 2.25 ig of cyclamate per chromatogram zone. Cyclamate (1), saccharin (2), acesulfame (3).

Examine the structures oisucrose, the natural sweetener, and saccharin, sodium cyclamate and aspartame (Nutrasweet), three of the most common artificial sweeteners. What, if any, structural features do these molecules have in common Compare electrostatic potential maps for the different sweeteners. Are there any significant features in common Based on yom findings, do you think it is likely that entirely different artifical sweeteners might be discovered Explain. 

Phethenylate sodium Ammonium chloride Cyclofenil Methionine Ammonium sulfate Aminobenzoic acid Fibrinolysin Ammonium sulfamate Cyclamate calcium Ammonium thiocyanate Acetazolamide Clonidine HCl Tolonidine nitrate 2oxazo lamina d-Amphetamine Tanphetamin Ampicillin Mezlocillin Talampicillin... 

Cadmium chloride Naproxen Calcium bisulfite obesilate calcium Calcium carbonate Caraspirin calcium Medazepam Calcium chloride Docusate calcium Fibrinolysin Calcium ferricyanide Sulfamethizole Calcium hydroxide Cyclamate calcium Inositol... 

Hydroxyprogesterone caproate Cyclohexylacetone Droprenilamine HCl Propylhexedrine Cyclohexylamine Clorexolone Cyclamate calcium 1 -Cyclohexylamino-2-propanol Hexylcaine HCl Cyclohexyl bromide Cetiedll... 

Sodium cyanoborohydride. reductive ami nation with, 931 Sodium cyclamate, LP50 of, 26 Sodium hydride, reaction with alcohols, 605... 

With a tridentate ligand Au(terpy)Cl3.H20 has, in fact, AuCl(terpy)2"1" with weakly coordinated chloride and water while Au(terpy)Br(CN)2 has square pyramidal gold(III) the terpyridyl ligand is bidentate, occupying the axial and one basal position [124]. Macrocyclic complexes include the porphyrin complex Au(TPP)Cl (section 4.12.5) cyclam-type macrocyclic ligands have a very high affinity for gold(III) [125],... 

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