Sucralose

Sucralose was discovered in 1989 as part of a collaboration between researchers and the

Queen Elizabeth College in London and the Tate & Lyle Chemical Company. Researchers were

conducting studies on nontraditional uses of sucrose and the sweetness of its derivatives.10 As the

story goes, a graduate student named Shashikant Phadnis misunderstood a request to ‘test’ the

substance he was working with as a request to ‘taste’ it – the rest, one could say, is history.11

OCl

OH

OH

O

OH

O

OHOH

Cl

Cl

Figure 7. The structure of sucralose closely resembles that of sucrose, with three chlorine atoms substituting for three of the oxygen atoms in the molecule.

Sucralose, or more formally 1,6-Dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-

deoxy-α-D-galactopyranoside, is now made by modifying sucrose in a large scale, industrial

process. Although many processes have been developed and patented to produce sucralose, few

are well documented in scientific literature. According to a technical review from 1990,

sucralose can be produced from sucrose in a five step process. In step one trityl chloride is added

to sucrose in the presence of multiple catalysts and the product is then mixed with acetic

anhydride. Steps two, three, and four involve the addition of multiple reactants and catalysts, as

well as heat, to produce an intermediate known as sucralose pentaacetate. In the final step of the

reaction, methanol is used in the presence of sodium methoxide to produce the final sucralose

product.12 Unfortunately, no diagrams or specific mechanisms of this process are currently

available.

Often being derived from sucrose, it comes as no surprise that the structure of sucralose is

almost identical to that of sucrose. Sucralose is a sucrose molecule in which one of the functional

groups on the glucose monomer and two of the functional groups on the fructose monomer have

been replaced with chlorine atoms.

Although the exact mechanism of sweetness is still not fully understood for any of the

major sweeteners, sucralose is believed to utilize the same mechanism as many other sweet

substances. This mechanism, described previously, relies on a combination of hydrophobic and

electronic interactions between the molecule and the ‘sweet’ taste receptors of the tongue. For

sucralose specifically, the two chlorine on the ‘fructose’ region of the molecule activate the

hydrophobic ‘X’ site while the ‘glucose’ region activates the ‘AH’ and ‘B’ sites without

interference of the third chlorine atom.10

A metabolic study in humans revealed that an average of 92.8% of sucralose consumed at

a dose of one milligram per kilogram of body weight will pass out of the body within five days

of consumption. Of the total dose, an average of 14.5% passes in the urine and 78.3% is excreted

in the feces. The vast majority of sucralose consumed passes through the body unchanged, but an

average of 2.6% of the total dosage passes through the urine as other metabolic products.

Through the use of thin lay chromatography and gas chromatography-mass spectrometry, the

metabolic products found in the urine have been identified as glucuronide conjugates.13

As with any food additive, one of the greatest concerns with sucralose is safety and the

effects it has on the body. A review of dozens of toxicology studies, published in 2000,

examined sucralose for carcinogenic, neurotoxic, genotoxic, and reproductive toxic effects.

Virtually all studies examined found no negative effects of sucralose in groups as diverse as rats,

mice, rabbits, dogs, and humans. Some studies revealed morphological changes in the thymus

glands – an important component of the immune system – of rats that were fed diets containing

five percent sucralose, but it is believed that these changes were caused by reduced feeding as

the result of the food simply being too sweet and unpalatable. Tests in rats also found

enlargement of the cecum of the large intestine at doses of three to eight percent of their total

diet; researchers attribute this not to toxicity but to the osmotic action of the poorly absorbed

compound. Minor changes in offspring were noted, but only in mothers receiving doses of

sucralose hydrolysis products equivalent to 40,000 times the maximum estimated daily human

intake. Taken as a whole, sucralose is shows great promise as a very safe and well studied

artificial sweetener.14

Saccharin

Saccharin, or more properly 1,1-Dioxo-1,2-benzothiazol-3-one, is the oldest of the

artificial sweeteners and was discovered in the laboratory of Ira Remsen at Johns Hopkins

University in 1878. Although there is some controversy as to who actually discovered its

sweetness and how this discovery was made, the generally accepted account is that Constantine

Fahlberg, a post doc working in Remsen’s lab, spilt some of the compound he was working with

on his hand and realized its sweet nature that evening at. Despite publishing their data jointly, the

two later grew apart and began fighting over who should have revived credit for the discovery.15

NHS

O

OO

Figure 8. The structure of saccharin consists of joined five and six member rings with three double bonded oxygens attached to the five member ring.

Due to its age and successful long-term use as a commercially viable sweetener, a great

many reactions are know that can synthesize saccharin with varying levels of yield and purity.

The original reaction published by Fahlberg and Remsen in the American Chemical Journal used

a three step process. In step one, toluene was mixed with sulfuric acid and phosphorus

pentachloride to give a toluene ring with ClSO2 attached in the number two position. A further

reaction, for which the reactant is not available, substitutes an NH2 group for the chlorine. In the

final step, the previous intermediate is mixed with potassium permanganate to give saccharin.15

Figure 9: The original process for creating saccharin, as given by Fahlberg and Remsen in 1879. Extraneous portions of the image have been removed.15

Saccharin follows the same basic pattern of taste receptor activation as other common

sweeteners, binding with the receptor via hydrophobic and electronic interactions. Studies have

shown that the AHS site on the receptor is hydrogen bonded to an S→O on the saccharin and the

Br site of the receptor is hydrogen bonded with the N-H of the saccharin molecule. In addition to

these hydrogen bonds, the fourth, fifth, and sixth carbons of the saccharin molecule engage in

hydrophobic bonds with the fourth, fifth, and eighth amino acid residues of the receptor, further

creating and strengthening the sensation of sweetness.16

Figure 10. The annotated structure of saccharin, indication the sites of the various interactions. In this example, the nitrogen has been deprotonated creating a sodium saccharin

salt.

Studies in rats have demonstrated that saccharin is easily absorbed by the body and is

largely excreted in the urine. Significant amounts, however, have also been shown to be

reabsorbed from the bladder and placed back into the bloodstream – this leads to an increased

concentration of saccharin in the bladder tissues, creating what is known as a high-retention

compartment. Studies in humans have shown similar results, indicating what appears to be long-

term retention of saccharin in the body. In one such study, a daily user of saccharin and a non-

user were given one-hundred milligram doses and their urine and blood monitored for 24 hours.

In the non-user, approximately 85% of the ingested dose was excreted within a day. The average

rate of renal clearance for the non-user was more than twice that of the daily user, suggesting that

accumulation in the body is a very real possibility with saccharin.17 In tests using rats, the

metabolic products of saccharin, accounting for only a small amount of the total excretion, were

identified as o-sulfamoylbenzoic acid and ammonium o-sulfamoylbenzoic acid.18

Again due in a large part to its age and widespread commercial use, saccharin has seen

extensive safety testing over the years. For the most part, these studies have shown saccharin to

be relatively safe and acceptable as food additive – one particular study, however, suggested that

things may not have been as good as they seemed. A Canadian study conducted in 1977 showed

that rats fed high doses of saccharin on a regular basis for two years had elevated rates of bladder

cancer in the second generation.19 These results led to a ban on saccharin as a food additive in

Canada in the same year and attempts by the FDA to ban it in the United States (these attempts

proved futile, however, when Congress placed a moratorium on the ban).10

Studies in mice, hamsters, monkeys, and humans have shown no conclusive link between

the use of saccharin and an increased risk of cancer. Despite the increased risk of cancer in rats,

no genotoxic effects have been shown and the only symptom that seems capable of leading to

cancer is an increased proliferation of the urothelial cells. Even these changes, without leading to

cancer, occur at a threshold level many, many times that which any human will consume in

normal daily activities. One study, in 1977, showed a possible link between saccharin

consumption and the rates of bladder cancer in adult males, but the study is now believed to have

been flawed and did not offer sufficient analysis of potential confounding factors. Despite the

efforts of what one might consider to be overzealous government regulators, the simple fact

remains that the current scientific data supports saccharin as a safe and effective sugar

substitute.19

Conclusion

As is the case with all tastes experienced by humans, the sensation of sweetness is caused

by molecules of a substance binding to and interacting with receptors on the tongue. Over the

years, a series of experiments have revealed that the sweetness receptor functions based on a

three site binding model. This model states that molecules bind and interact with an A-H site, a B

site, and an X site in different ways and in different degrees to produce varying levels of

sweetness. Beginning with the saccharin in 1878, including aspartame in 1965, sucralose in

1989, and continuing to present day, many molecules have been discovered that activate the

receptors and produce a sweet sensation. All of these substances have potential risks, and many

have shown potentially toxic carcinogenic effects in high doses in animals, but through careful

study and close government regulation, those which are allowed for human consumption are safe

at and far beyond the levels even the most prodigious consumers encounter on a regular basis.

Whether being used to reduce calorie intake as part of a diet, to cut costs by replacing more

expensive sweeteners, out of other health concerns, or simply for personal preference, artificial

sweeteners provide relatively safe and low calorie alternatives to sucrose and other natural

sweeteners when used in moderation.

Works Cited

(10) Knight I. The development and applications of sucralose, a new high-intensity sweetener. Canadian J. of Physiology and Pharmacology, 1993, 72, 435-439.

(11) Walters D.E. The History of High Potency Sweeteners: Tales of Discovery. http://www.rosalindfranklin.edu/dnn/chicagomedicalschool/home/CMS/biochem/Faculty/Walters/Sweeteners/History/tabid/1188/Default.aspx (9 May 2008).

(12) SRI Consulting. Sucralose - A High Intensity, Noncaloric Sweetener. http://www.sriconsulting.com/PEP/Reports/Phase_90/RW90-1-4/RW90-1-4.html (9 May 2008)

(13) Roberts A.; Renwick A.G.; Sims J.; Snodin D.J. Sucralose Metabolism and Pharmacokinetics in Man [Online]. Food and Chemical Toxicology, 2000, 38 (Suppl. 2), S31-S41.

(14) Grice H.C.; Goldsmith L.A. Sucralose—An Overview of the Toxicity Data [Online]. Food and Chemical Toxicology, 2000, 38 (Suppl. 2), S1-S6.

(15) Tarbell, S.; Tarbell, A.T. The Discovery of Saccharin [Online]. J. of Chemical Education, 1978, 55, 161-162.

(16) Suami, T.; Hough, L.; Machinami, T. Molecular mechanisms of sweet taste 8: saccharin, acesulfame-K, cyclamate and their derivatives. Food Chemistry, 1998, 63, 391-396.

(17) Colburn, W.A.; Bekersky, I/; Blumenthal, H.P. A Preliminary Report on the Pharmacokinetics of Saccharin in Man: Single Oral Dose Administration. J. Clinical Pharmacology, 1981, 21, 147-151.

(18) Pitkin, R.M.; Andersen, D.W.; Renyolds, A.; Filer, L.K.; Bradbury, J.T. Saccharin Metabolism in Macaca mulatta. Proceedings of the Society of Experimental Biology and Medicine, 1971, 137, 803-806.

(19) Ellwein, L.B.; Cohen, S.M. The Health Risks of Saccharin Revisited. Critical Reviews in Toxicology, 1990, 20, 311-326.