Organic Chemistry I Laboratory - North Central College

Organic Chemistry I Laboratory Experiment 8
Week 8
Ambident Nucleophiles:1
Reaction of Sodium Saccharin with Iodoethane

Background Reading
Zubrick, J. W. The Organic Chem Lab Survival Manual, 4th 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.

OO O

NH N N
S S S
OO OO OO
Resonance Structures of
Saccharin Sodium Saccharin

Saccharin, an Accidental Sweetener

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 Wöhler, 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 o-
toluenesulfonamide. 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

1 Lehman, J. W. Operational Organic Chemistry: A Problem-Solving Approach to the Laboratory Course, 3rd Ed.,
Prentice-Hall, Inc., Upper Saddle River, New Jersey, 1999, 150-155.

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,N-
dimethylformamide (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 O H3C CN
H N CH3 Acetonitrile
S
CH3 H3C CH3
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 N-
ethylsaccharin, 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 O-
ethylsaccharin 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
(1H-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 (δ = 4.7 ppm)
than the corresponding signal for an –NCH2CH3 group (δ = 3.9 ppm) in the 1H-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
contains a carbonyl group which will have a strong absorbance in the range for amides (1600-1700 cm-1). In O-

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

Na O
O
DMF N + Na-I
N I 80oC
S S
OO OO

N-Ethylsaccharin

Na O O

N DMF N + Na-I
S I 80oC
OO S
OO

O-Ethylsaccharin

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 O

N N + H2C CH3
S S
OO OO Neutral
O-Ethylsaccharin fragment
M+ = 211 M-29 (182 peak)

O

N N + O
S S
OO OO Neutral
fragment
O-Ethylsaccharin M-45 (166 peak)
M+ = 211

Figure 3. Mass Spectral Fragmentation Reactions of O-Ethylsaccharin

OO

N N + H2C CH3
S S
OO OO Neutral
fragment
N-Ethylsaccharin M-29 (182 peak)
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 O-
ethylsaccharin have different melting points. The melting point of N-ethylsaccharin is 95oC while the melting point
of O-ethylsaccharin is 211oC. 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
before 100oC and only a small amount to hang around until the temperature reached 200oC. On the other hand, if
O-ethylsaccharin is the major product, then you would expect to observe very little material melting before 200oC.

Procedure:

Weigh out 10 mmol of sodium saccharin (MW = 205.2) and add it to 5 mL of DMF in a 125 mL Erlenmeyer
flask. Heat the mixture in an 80oC 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
water bath for 10 minutes, keeping the temperature around 80oC.

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
small speck of solid dissolved in methanol. Obtain a 1H 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.