Organic Chemistry I Laboratory Ambident Nucleophiles: Reaction of Sodium Saccharin with Iodoethane

Background Reading Zubrick, J. W. The Organic Chem Lab Survival Manual, 4 edition, Wiley & Sons, Inc., New York, 1997. Scenario: Saccharin is a nonnutritive sweetener, meaning that it is not metabolized by the body to produce energy. But saccharin is usually mixed with fructose or other Calorie laden sweeteners to mask its bitter aftertaste, giving the mixture about half as many Calories as sucrose and thus making it less attractive as a sugar substitute. Dulcinea Petty IV directs a product development team at Sweet Nothings Ltd., which manufactures saccharin. She has learned that substances with N-H bonds often have bitter tastes, so she wonders if converting the N-H bond of saccharin to an N-C bond by alkylating it will mask the bitter taste and thus yield a better sweetener. Saccharin is converted to its more nucleophilic sodium salt proir to alkylation, but resonance structures of the salt reveal that it is an ambident nucleophile; that is, it has two potentially nucleophilic atoms, the nitrogen atom and an oxygen atom. Before their quest for a better sweetener can be pursued, Sweet Nothings needs to know whether or not alkylation will occur mainly on the nitrogen atom. Your assignment is to carry out the alkylation of sodium saccharin with iodoethane and analyze the product mixture to determine the structure of the major product.
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Experiment 8 Week 8

O NH S O O Saccharin
Saccharin, an Accidental Sweetener

N N S S O O O O Resonance Structures of Sodium Saccharin

One rule that chemists follow scrupulously is to never, ever, taste anything they make in the laboratory. A chemist should not even eat or drink anything else while working in the lab because of possible contamination by toxic chemicals. During the nineteenth century, however, chemists were not so fastidious. It was a common practice to perform a "taste test" on any new chemical, sometimes with unfortunate results; but occasionally an accidental or deliberate tasting paid off with a new discovery. Ira Remsen, a Johns Hopkins University chemistry professor, studied chemistry under a student of the "father of organic chemistry," Friedrich Whler, and became the most famous American chemist of the nineteenth century. (Scientists are always facinated by someone's pedigree. Who did they work under and can they follow that lineage back to a famous scientist) In 1878 a German student working in Remsen's research group, Constantin Fahlberg, prepared some white crystals of a previously unknown compound starting from otoluenesulfonamide. He later ate a piece of bread (probably without washing his hands) and was astonished to find that it tasted intensely sweet. It didn't take Fahlberg long to trace the sweet taste to the new compound he had just handled, which he named saccharin after the Latin word for sugar, saccharum. Saccharin is about 500 times sweeter than sucrose, common table sugar. Its sweetness came as a surprise because no one was looking for a synthetic sweetener at the time. In fact, at that time, most scientists believed that only natural compounds could be sweet. Fahlberg recognized the commercial possibilities of a nonfattening sweetener, so he applied for a patent and began to manufacture saccharin. Despite its somewhat bitter aftertaste, saccharin was the most popular artificial sweetener during most of the twentieth century, outselling other synthetic sweeteners such as dulcin (from the Latin dulcis, meaning sweet), which was discovered just six years after saccharin. Concerns about the safety of saccharin cropped up from time to time, inspiring Theodore Roosevelt to proclaim, "anyone who says saccharin is injurious to health is an idiot." Roosevelt, who liked to sweeten his chewing tobacco with saccharin, was no authority on the safety of commercial products, but his words must have
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Lehman, J. W. Operational Organic Chemistry: A Problem-Solving Approach to the Laboratory Course, 3 Ed., Prentice-Hall, Inc., Upper Saddle River, New Jersey, 1999, 150-155.

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reassured many Americans about saccharin. Then in 1977 a Canadian study showed that some rats developed bladder tumors when they were fed a diet containing 5% saccharin. Although the rats' diet was equivalent to a human consuming about 1000 cans of diet soda per day, saccharin was promptly removed from the GRAS (generally recognized as safe) list and later banned in the United States. Reacting to protests by diabetics and overweight Americans, for whom consuming sugar was a far greater risk than the remote possibility of saccharin induced cancer, Congress suspended the ban in 1979. As a result, you can still buy Sweet 'n Low at your local grocery store, but the packets carry a mandatory warning label. Because of the cancer scare and competition from aspartame (NutraSweet), saccharin use has declined sharply in recent years. Lacking the bitter aftertaste of saccharin, aspartame has become our most popular artificial sweetener, but it may face some tough competition in the near future. A French sweetener called superaspartame is 300 times sweeter than aspartame and -unlike aspartame- can be used in baking and frying. The natural sweetener, thaumatin, which is extracted from the west African plant ketemfe, is reported to be nearly 100,000 times sweeter than sucrose, making it the sweetest natural substance ever discovered. Thaumatin is actually a basic protein mixture containing five different forms of thaumatins, named thaumatin I, II, III, b, and c, which all have molecular weights of about 22,000. Thaumatin is also (like aspartame) a flavor enhancer, so it has been used to persuade farm animals to eat more. For example, pigs gain up to 10% more weight when thaumatin is added to their feed. Understanding the Experiment In this experiment you will carry out the reaction of sodium saccharin with iodoethane in the solvent N,Ndimethylformamide (DMF). This is a nucleophilic substitution reaction in which the nucleophilic atom can be either nitrogen or oxygen and the leaving group is iodide ion (I ). The rate of a nucleophilic substitution can be very sensitive to the solvent used. Polar protic solvents (solvents capable of H-bonding) such as water and alcohols form bulky solvation shells around a charged nucleophile, reducing its nucleophilic strength. Polar aprotic solvents such as DMF (Figure 1) do not solvate the nucleophile strongly, leaving it free to attack the substrate (electrophile). Thus they accelerate the rates of many substitution reactions, particularly SN2 reactions in which the strength of the nucleophile has a large effect on the reaction rate. O H N CH 3 H3C O S CH 3 H3C CN Acetonitrile

CH 3 DMF

Dimethyl Sulfoxide DMSO

Figure 1. Common Polar Aprotic Solvents The composition of the product will depend on whether nitrogen or oxygen acts as the nucleophilic atom most of the time. As shown in the reaction scheme below (Figure 2), nucleophilic attack by nitrogen will yield Nethylsaccharin, while attack by oxygen will yield O-ethylsaccharin. Predicting the major product is not easy beecause a number of competing factors may come into play. N-Ethylsaccharin is more stable than Oethylsaccharin so it should be the major product if the reaction reaches thermal equilibrium (thermodynamic product favored). However, the oxygen of sodium saccharin has a higher elecreonegativity than nitrogen and oxygen will have a higher partial negative charge than the nitrogen atom. Therefore, a reaction involving oxygen as the nucleophile might occur faster than one involving nitrogen (kinetic product favored). For example, the reaction of potassium saccharin with 2-bromopropane in DMF yields mainly O-isopropylsaccharin. You will determine the composition of your product by using proton nuclear magnetic resonance spectroscopy 1 ( H-NMR), IR, and GC-MS. An oxygen atom has a stronger deshielding effect on nearby protons than a nitrogen atom, so the signal for the methylene protons of an OCH2CH3 group will appear farther downfield ( = 4.7 ppm) 1 than the corresponding signal for an NCH2CH3 group ( = 3.9 ppm) in the H-NMR spectrum. Because the methylene protons have three adjacent methyl protons as neighbors, their signal in either case will be a quartet. By measuring the integrated signal areas for both quartets (assuming the product is a mixture) you will be able to determine the percentages of N-ethylsaccharin and O-ethylsaccharin in your product. The infra-red spectrum of the product may also shed some light on the product distribution. N-Ethylsaccharin -1 contains a carbonyl group which will have a strong absorbance in the range for amides (1600-1700 cm ). In O-

ethylsaccharin, there is no carbonyl stretch. Instead, there may be an observed C=N stretch. The intensity of this -1 stretch would be much weaker than the C=O stretch but it typically occurs in the range from 1640-1690 cm . Therefore, the presence of a strong absorbance for the C=O stretch may indicate that the major product is Nethylsaccharin while the absence of a strong C=O stretch may indicate that O-ethylsaccharin is the major product. O N S O O Na DMF I 80oC O S O N-Ethylsaccharin Na O DMF N S O O I 80 C O
o

O N + Na-I

O N S O O-Ethylsaccharin + Na-I

Figure 2. Mechanism of Alkylation of Sodium Saccharin The mass spectra of the isomeric products will have distinct differences. Both isomers should have prominent M-29 peaks due to the loss of the ethyl group. O-Ethylsaccharin will also have a peak at M-45, due to the loss of the OCH2CH3 fragment. N-Ethylsaccharin does not have any easy way to lose a mass of 45 so will show no M-45 peak in its mass spectrum. Therefore, the GC-MS can be used to distinguish between the two possible products. The GC will allow us to determine the percent composition of O-ethylsaccharin and N-ethylsaccharin once the MS has been used to correlate a structure with a peak at a specific retention time. O N S O O O O-Ethylsaccharin M+ = 211 O N S O O O O-Ethylsaccharin M+ = 211 S O M-45 (166 peak) N + O Neutral fragment S O M-29 (182 peak) O N + H2C CH 3 Neutral fragment

Figure 3. Mass Spectral Fragmentation Reactions of O-Ethylsaccharin O N S O O S O O M-29 (182 peak) O N + H2C CH 3

Neutral fragment N-Ethylsaccharin + M = 211 Figure 4. Mass Spectral Fragmentation Reaction for N-Ethylsaccharin

The melting point of the product will be the final check on the product composition. N-Ethylsaccharin and Oo ethylsaccharin have different melting points. The melting point of N-ethylsaccharin is 95 C while the melting point o of O-ethylsaccharin is 211 C. If your product is a mixture you should expect a wide melting point range. However, you should be able to determine whether the major component is the high or low melting compound. For example, if N-ethylsaccharin is the major product, then you would expect the majority of your mixture to melt o o before 100 C and only a small amount to hang around until the temperature reached 200 C. On the other hand, if o O-ethylsaccharin is the major product, then you would expect to observe very little material melting before 200 C. Procedure: Weigh out 10 mmol of sodium saccharin (MW = 205.2) and add it to 5 mL of DMF in a 125 mL Erlenmeyer o flask. Heat the mixture in an 80 C water bath (in the hood) with swirliong until the solid dissolves. Add 0.80 mL (~10 mmol) of iodoethane using a micropipet. Seal the Erlenmeyer flask with Parafilm and heat the mixture in the o water bath for 10 minutes, keeping the temperature around 80 C. Remove the reaction flask from the water bath and let the reaction mixture cool to room temperature, add 75 mL of water, and shake the stoppered flask until any liquid residue that forms has solidified. Cool the flask in an ice water bath, breaking up the solids with a stirring rod or spatula. Collect the solid product by vacuum filtration and wash the solids twice with 5 to 10 mL portions of cold water. Dry the product and measure its mass and melting point range. Obtain an IR spectrum of the dry product in a KBr pellet and as a nujol mull. Obtain a GC-MS of your sample, making a typical GC sample consisting of one 1 small speck of solid dissolved in methanol. Obtain a H NMR of your product in CDCl3. Your report should include a statement of the problem, a calculated product yield, the determination of the identity of the major product and the exact percentages of isomers formed. Questions: 1. Assuming that the reaction was SN2 and that the major product was the one that formed faster, which atom appears to be more nucleophilic, N or O? 2. Write a mecanism showing the transition state of the reaction that led to your major product. 3. Most compounds containing N-H bonds are basic but saccharin is acidic. Explain why, using resonance structures.