A ACID ANHYDRIDES FIELDS OF STUDY anhydrides are also possible and are, in fact, essential components of certain biochemical cycles. Acid an- Organic Chemistry hydrides can also be thought of as esters formed from an acyl group. Generally, acid anhydrides are repre- SUMMARY sented as follows: O O O O The characteristic properties and reactions of acid | | | | | | | | anhydrides are discussed. Acid anhydrides are useful C C C C compounds in organic synthesis reactions, helping R O R Ar O Ar to form complex molecular structures from simple The generic placeholders R− and Ar− indicate an starting materials. alkyl group substituent and an aryl group substituent, respectively. PRINCIPAL TERMS Acid anhydrides of linear molecules are generally used to add single substituents to a molecular struc- acyl group: a functional group with the formula − ture. Acid anhydride compounds with a cyclic struc- RCO, where R is connected by a single bond to the ture are also commonly used in synthetic procedures carbon atom of the carbonyl (C=O) group. to elaborate a molecular structure. In principle, an carboxylic acid: an organic compound containing anhydride can be formed from any carboxylic acid. a carboxyl functional group and having the gen- However, in practice, very few acid anhydrides are eral formula RC(=O)OH. available, and other carboxylic-acid derivatives are functional group: a specifi c group of atoms with a more readily obtained for particular purposes. Thus, characteristic structure and corresponding chem- linear carboxylic acids are seldom prepared or uti- ical behavior within a molecule. lized. Dicarboxylic acids, in which the formation organic acid: an acid derived from an organic com- of the anhydride produces a fi ve- or six-membered pound. ring structure, are more readily converted to their R (generic placeholder): a symbol used primarily anhydride form and are generally more useful in in organic chemistry to represent a hydrocarbon synthetic methods. side chain or other unspecifi ed group of atoms in The most common acid anhydride is acetic anhy- a molecule; can be used specifi cally for an alkyl dride. Because of its relative ease of handling and group, with Ar used to represent an aryl group. because it does not release hydrogen chloride (HCl) gas as a product of the reaction, it is the preferred re- The Nature of Acid Anhydrides agent for forming acetate esters. In pure form, acetic The term “ anhydride” indicates the absence of ei- acid tends to absorb atmospheric moisture. It is a ther water or its components, oxygen and hydrogen, common laboratory practice to add a small amount of from a molecular structure. Acid anhydrides are com- acetic anhydride to pure acetic acid to counteract this pounds in which a bond has been formed between effect, as any moisture consumed by the hydrolysis of two acid functional groups by the virtual elimination acetic anhydride simply produces more acetic acid, of −H from one acid group and −OH from the other. which would not be a contaminant in the reagent. Most common acid anhydrides are formed from car- boxylic acids, but they can also be formed from any organic acid and many inorganic acids. Mixed acid 1 Acid Anhydrides Principles of Chemistry ACID ANHYDRIDES dioxide and water to produce the less strained compound cyclopentanone. Generic Formula ethanoic anhydride Reactions of Acid Anhydrides Acid anhydrides are reactive com- pounds widely used for the formation CH3 O CH3 of esters. By far the most common R1 O R2 commercial use of acetic anhydride C C C C is in the formation of acetate esters of carbohydrate compounds such as O O O O sugars, starches, and celluloses. The O carbonyl (C=O) groups of an acid anhydride readily interact with nu- (R C=O)2O cleophiles, which are chemical species O O that are attracted to positively charged species. This happens partly because (CH CO) O 3 2 the electronegative oxygen atoms of the carbonyl groups tend to draw electron density away from the carbon atoms, causing the carbon to behave Formation of Acid Anhydrides as though it were positively charged, and partly be- Simple acid anhydrides are never formed by dehy- cause the way the bonds are arranged around the dration reactions. Acetic anhydride is produced com- carbon atoms makes it easier for nucleophiles to ap- mercially by the reaction of acetic acid with ethenone proach and interact. After the nucleophile is added in the gas phase, according to the following equation: and the leaving group is eliminated, the carbonyl groups re-form in the new molecule. This same basic O O O mechanism permits acid anhydrides to be converted | | | | | | C + H2C C O C C into different acid derivatives. Reaction with water H3C OH H3C O CH3 reconverts the anhydride into its acid form, which al- The anhydrides of larger linear carboxylic acids lows other types of reactions to occur after an anhy- are more diffi cult to prepare, but in some cases, they dride group has been added to a substrate molecule. can be formed by heating the acid in the presence of For example, maleic anhydride is commonly used a strong dehydrating agent, such as phosphorus pent- in a Diels-Alder reaction, which is a type of reaction oxide (P2O5), and separating the anhydride from that results in the addition of a six-membered ring the reaction mixture as it forms. Cyclic anhydrides structure to the substrate molecule. Hydrolysis of such as maleic anhydride and succinic anhydride the resulting molecule produces two carboxylic acid form readily when their parent acids are heated. The functional groups (−COOH) that can be modifi ed by process is assisted by the removal of water from the other reactions to produce a desired product. reaction as it is formed, which prevents the reverse Acid anhydrides also react well with ammonia to reaction from occurring. Ring size is vitally important produce the corresponding amide of one carboxylic for this process: fi ve- and six-membered rings are well acid group and the ammonium salt of the other. The suited to the geometric constraints of the electron or- reaction of acetic anhydride with ammonia, for ex- bitals in carbon and oxygen atoms, while seven-mem- ample, would produce acetamide and ammonium bered rings are more diffi cult to form because of the acetate: strain that the bond angles of such a ring impose on O O O O | | | | | | | | + 2NH the molecule. Adipic acid, or 1,6-hexanedioic acid, C C 3 C + C í + O H C NH H C O NH4 does not form the corresponding cyclic anhydride; H3C CH3 3 2 3 instead, it eliminates a molecule of both carbon 2 Principles of Chemistry Acid Anhydrides A reaction with a substituted amine such as ethyl- amine would produce the corresponding substituted SAMPLE PROBLEM amide compound. Anhydrides are also able to act as acylating agents Given the chemical name isobutyric anhydride, draw the skeletal structure of the molecule. in the Friedel-Crafts acylation of benzene and ben- zene-like aromatic compounds. One half of the an- hydride function bonds chemically to the aromatic Answer: ring as an acyl substituent, while the other half is The name indicates that the material is the anhydride of reconverted into the acid. The reaction is typically isobutyric acid, which has the structure catalyzed by a Lewis acid, such as aluminum trichlo- O ride (AlCl3) or ferric chloride (FeCl3). Phthalic anhy- | | dride, for example, can be used to acylate benzene, C producing the corresponding benzoic acid deriva- OH tive, according to the following equation: Isobutyric anhydride must therefore have the structure O O | | | | C C O O AlCl3 | | | | O + C C C HO C O | | | | O O Diels-Alder, Friedel-Crafts, and similar reactions are useful in organic synthetic chemistry because mixed anhydride of acetic acid and phosphoric acid they allow the chemist to easily and quickly build would be named acetic phosphoric anhydride. Such a complex molecular structure from very simple mixed anhydrides sometimes appear in enzyme- starting materials. The reactions typically produce mediated biochemical processes. hydrogen chloride as well, but this is an inconsequen- tial by-product and is seldom, if ever, shown in struc- Richard M. Renneboog, MSc tural formula equations. Bibliography Nomenclature of Acid Anhydrides Hendrickson, James B., Donald J. Cram, and George Acid anhydrides are named according to the S. Hammond. Organic Chemistry. 3rd ed. New York: parent acid from which they are formed, simply by McGraw, 1970. Print. adding “ anhydride” to the name of the parent acid. Jones, Mark Martin. Chemistry and Society. 5th ed. Phil- Accordingly, the anhydride of butyric acid would be adelphia: Saunders College Pub., 1987. Print. named butyric anhydride, while maleic acid and suc- Morrison, Robert Thornton, and Robert Neilson. cinic acid readily form maleic anhydride and succinic Boyd. Organic Chemistry. 7th ed. Englewood Cliffs, anhydride. Mixed anhydrides, though uncommon, N.J.: Prentice Hall, 2003. Print. are also known. For a mixed anhydride, the names Wuts, Peter G. M., and Theodora W. Greene. of the two parent acids are used, with the “higher” Greene’s Protective Groups in Organic Synthesis. 4th acid being named in second place. For example, the ed. Hoboken: Wiley-Interscience, 2007. Print. 3 Acid Chlorides Principles of Chemistry ACID CHLORIDES FIELDS OF STUDY O O | | | | Organic Chemistry; Inorganic Chemistry C C R Cl Ar Cl SUMMARY Acid chlorides are the most reactive derivatives of carboxylic acids. This relatively high reactivity and The characteristic properties and reactions of acid the ease with which acid chlorides can be prepared chlorides are discussed. Acid chlorides are useful make them extremely versatile reagents in many ap- compounds in both organic and inorganic synthesis plications.