26.2.

We have met several classes of organic compounds in previous chapters. Chapter 4 introduced ethanol as the primal member of the alcohols. Alcohols can be distinguished by the presence of an "-OH" functional group, 2/3 of a water molecule, hanging off of various and assorted carbon atoms. Subsequently, Chapter 19 gave us glycerol, a tri-alcohol. As you look on ingredient labels around your house, you can recognized the names of alcohols because they always end in "-ol;" you might find "biglongnamanol," for example.

In Chapter 16 we saw our first organic acid, acetic acid, the compound which makes vinegar sour. Subsequently, Chapter 19 introduced the fatty acids, oleic acid, palmitic acid, and stearic acid. Organic acids are characterized by the peculiar "-COOH" functional group and their names end in "-ic acid;" you might find "biglongnamic acid" or its sodium salt, "sodium biglongnamate" as ingredients in shampoos.

An important concept from Chapter 18 was the acid anhydride. Carbon dioxide, for example, is the anhydride of carbonic acid:

H2CO3 = CO2 + H2O

Sulfur trioxide is the anhydride of sulfuric acid:

H2SO4 = SO3 + H2O

The same idea gives us acetic anhydride, the anhydride of acetic acid:

2 CH3COOH = (CH3CO)2O + H2O

You can think of acetic anhydride as a kind of "super vinegar." It smells like vinegar, tastes like vinegar, and turns into vinegar when you add it to water.

Chapter 22 started us off on a new class of compounds, the amines, of which aniline and toluidine are examples. Just like an alcohol has an "-OH" hanging off of it, an amine has an "-NH2" hanging off of it. You can tell that something is an amine because its name ends in "-ine" or "-in;" biglongnamine would be an example. In fact, if you look back to the beginning of this chapter you will find a whole bunch of natural drugs and poisons—nicotine, morphine, cocaine, quinine—all of them amines. Like ammonia, the amines are bases, or alkalis, and participate in the same kinds of reactions as inorganic bases.

Chapter 7 introduced metathesis reactions, in which inorganic chemicals swapped first and last names. One kind of metathesis reaction was the acid-base reaction, in which a base and an acid combine to produce a salt. Ammonia, for example, reacts with hydrochloric acid to form ammonium chloride. The amines can also form salts with acids; while aniline and the toluidines are insoluble in water their salts, aniline hydrochloride and toluidine hydrochloride, are soluble in water. This is a common trick for making pharmaceuticals soluble in water; look at the ingredients of cold remedies and you may find things that look like "biglongnamine hydrochloride," the hydrochloride salt of the otherwise insoluble biglongnamine.

Equation 26-1. From Aniline to Acetanilide

The reaction of an amine with an acid produces a salt, but the reaction of an amine with an acid anhydride produces an amide. Such a reaction, one in which two molecules join together by spitting out a smaller molecule, is called a condensation reaction. Equation 26-1, for example, shows the reaction of aniline with acetic anhydride to produce acetic acid and acetanilide, the drug trademarked as Antifebrin. The dotted lines show where the new bonds will form when acetic anhydride and aniline react. You can imagine half of the acetic anhydride sticking to the nitrogen atom on the amine, while the other half takes off with one of the hydrogen atoms. The acetic acid product is, of course, quite soluble in water, while the acetanilide product is not very soluble and falls out of solution as a precipitate. Thus the acetanilide can be separated from the acetic acid by filtration.

Acetanilide has passed into pharmaceutical oblivion because of its side effects but its near cousin, acetaminophen, has survived as the analgesic trademarked, Tylenol. As a matter of fact, acetanilide is converted into acetaminophen in the body and this latter molecule is responsible for the analgesic effects of the former. We can get the analgesic benefit while avoiding the side effects of acetanilide by taking acetaminophen directly. The structure of acetaminophen is the same as that of acetanilide except that the hydrogen atom marked "-H*" in Equation 26-1 is replaced by an "-OH." In fact, it's this group, characteristic of alcohols, which puts the ol in Tylenol.

The chapter would not be complete without a discussion of the big daddy of analgesics, acetylsalicylic acid, trademarked, Aspirin. Figure 26-1 gives a process schematic for the synthesis of Aspirin beginning with the coal-tar distillate, phenol, an aromatic alcohol. You may be familiar with the aroma of phenol, the active ingredient in Chloraseptic throat spray. Reaction of phenol, structure (a), with sodium hydroxide produces sodium phenolate, structure (b). Reaction of sodium phenolate with carbon dioxide produces sodium salicylate, structure (c), and reaction of sodium salicylate with sulfuric acid produces salicylic acid, structure (d). Notice that salicylic acid is a curious beast: it is both an aromatic acid and an aromatic alcohol. Sodium sulfate stays in solution while salicylic acid precipitates and can be filtered out.

Just as the condensation of an amine with an acid anhydride produces an amide, the condensation of an alcohol with an acid anhydride produces an ester. In this case, reaction of salicylic acid with acetic anhydride in toluene solution produces acetylsalicylic acid, structure (e). Acetic acid is soluble in toluene while acetylsalicylic acid precipitates and can be filtered out. Most of the reactants in the Aspirin synthesis, sodium hydroxide, carbon dioxide, and sulfuric acid, are familiar from previous chapters. Similarly, most of the processes are variations on familiar themes, the reaction of an acid with a base and the absorption of carbon dioxide. Only the final reaction, the condensation, is entirely new. This reaction is common to the syntheses of both Aspirin and Antifebrin and is the one we'll explore in this project.

Figure 26-1. The Aspirin Process

WarningMaterial Safety
 

Locate MSDS's for aniline (CAS 62-53-3), acetic anhydride (CAS 108-24-7), and acetanilide (CAS 103-84-4). Summarize the hazardous properties in your notebook, including the identity of the company which produced each MSDS and the NFPA diamond for each material.[1]

Your most likely exposure is inhalation of acetic anhydride vapor; if your eyes begin to water, you should go someplace to get fresh air. You should also be aware that aniline may be absorbed through the skin. In case of contact wash the affected area immediately with soap and water.

You should wear safety glasses and rubber gloves while working on this project. All activities should be performed in a fume hood or with adequate ventilation. Leftover aniline should be dissolved in vinegar and flushed down the drain with plenty of water. Leftover acetic anhydride may be dissolved in water and flushed down the drain. Your acetanilide product may be thrown in the trash when you're finished with it.

NoteResearch and Development
 

Before you get started, you should know this stuff.

  • You better know all the words that are important enough to be indexified and glossarated.

  • You should know all of the Research and Development stuff from Chapter 21 and Chapter 22.

  • You should know the structures of the coal-tar distillates, aniline and phenol.

  • You should know the difference between aniline acetate and acetanilide.

  • You should know the structure of acetanilide, acetylsalicylic acid, and acetaminophen.

  • You should know the hazardous properties of aniline, acetic anhydride, and acetanilide.

  • You should know the stories of how acetanilide became Antifebrin and how Aspirin went over-the-counter.

Notes

[1]

The NFPA diamond was introduced in Section 15.2. You may substitute HMIS or Saf-T-Data ratings at your convenience.