19-1 Naming the Carboxylic Acids CHAPTER 19 动 Carboxylic Acids 伪 2 03. Dicarbox 君2器on8cc " 19-2StrycPropies f Cabyic and for hydroge mic acid is plana lcacidsupto butaocaid are completelyublin 2RC0OH→R- 1
1 CHAPTER 19 Carboxylic Acids 19-1 Naming the Carboxylic Acids Chemical Abstracts retains the common names for the two simplest carboxylic acids, formic acid and acetic acid. The IUPAC system derives the name of carboxylic acids by replacing the ending –e in the parent alkane by the ending –oic acid. The carbonyl group and the functional groups of its derivatives take precedence in naming over any other groups discussed so far: The alkanoic acid stem is numbered by assigning 1 to the carbonyl carbon and labeling any substituents along the longest chain incorporating the CO2H group accordingly. When other functional groups are present, the main chain is chosen to include other functional groups as much as possible. Saturated cyclic acids are named as cycloalkanecarboxylic acids. Aromatic acids are named benzoic acids. Dicarboxylic acids are referred to as dioic acids. Structural and Physical Properties of Carboxylic Acids 19-2 Formic acid is planar. The molecular structure of formic acid is roughly planar, which is characteristic of carboxylic acids in general. The carboxy group is polar and forms hydrogenbonded dimers. The carboxy function is strongly polar and forms hydrogen bonds to other polarized molecules such as water, alcohols and other carboxylic acids. Carboxylic acids up to butanoic acid are completely soluble in water. As neat liquids, and even in fairly dilute solutions, carboxylic acids form hydrogen-bonded dimers (6–8 kcal mol-1)
19-3 NMR and IR Spectroscopy of Carboxylic Acids The carboxy hydrogen and carbon are deshie 9品 0 CH.CH.CH.CH.COR 822to咖 一一 The carboxy group shows two important IR bands. stretching frequences for both the carbonyl group and the 2
2 Carboxylic acids have relatively high melting and boiling points due to hydrogen bonding in both the solid and liquid states. Volatile carboxylic acids (low MW) exhibit characteristically strong odors (butanoic acid, cheese; (E)-3-methyl-2-hexenoic acid, human sweat). 19-3 NMR and IR Spectroscopy of Carboxylic Acids The carboxy hydrogen and carbon are deshielded. Hydrogens on a carbon next to a carbonyl group are slightly deshielded. The effect diminishes rapidly with increasing distance from the carbonyl. The hydroxyl proton resonates at very low field (δ = 10-13 ppm). Its chemical shift varies strongly with concentration, solvent and temperature because of its involvement in hydrogen bonding. The 13C NMR chemical shifts of carboxylic acids are similar to those of aldehydes and ketones. The amount of deshielding is smaller because of the presence of the extra OH group. The smaller deshielding can be attributed to the extra resonance form present in carboxylic acids: The carboxy group shows two important IR bands. Stretching frequencies for both the carbonyl group and the hydroxy substituent are seen in the IR spectra of carboxy groups. The O-H bond exhibits a very broad band at 2500–3300 cm-1, lower than for alcohols because of strong hydrogen bonding. Mass spectra of carboxylic acids show three modes of fragmentation. Fragmentation of carboxylic acids occurs in several ways, which results in a fairly weak molecular ion peak
19-4 Acidic and Basic Character of Carboxylic Acids Carboxylic acids are relatively strong acids. Carods havemcvaleshano +t gyategoup r一w一a一k-na tncrea the two pk sgoepgcnetwhegroupscdosetohe oxylic acids may be protonated on the carbony 19-5 Carboxylic Acid Synthesis in Industry artonloryoenoacatboyticacdmaybeprotonatedby Formic Acid Synthesis NOH+C0Cm巴，HCO0-O,He00 btethatheprotonationreactionsnotprticuhrtystiorg 3
3 19-4 Acidic and Basic Character of Carboxylic Acids Carboxylic acids are relatively strong acids. Carboxylic acids have much lower pKa values than do alcohols. The lowered pKa values are due to the electron-withdrawing effect of the positively polarized carbonyl carbon and the resonance stabilization of the carboxylate group. Two of the three resonance forms of the carboxylate ion are equivalent, leading to a symmetrical ion with equal carbonoxygen bond lengths (1.26 Å), midway between a carbon-oxygen double bond (1.20 Å) and a carbon-oxygen single bond (1.34 Å). Electron-withdrawing substituents increase the acidity of carboxylic acids. The inductive effect of electron-withdrawing groups close to the carboxy group causes an increase in acidity. Three electron-withdrawing groups on the α-carbon sometimes results in acidity near that of some inorganic acids. The dioic acids have two pKa values. In ethanedioic and propanedioic acids, the first pKa is lowered by the electron-withdrawing effect of the second. In higher dioic acids, both pKa values are close to monocarboxylic acids. Carboxylate salts of carboxylic acids can be prepared by treatment of the acid with a base, such as NaOH, Na2CO3 or NaHCO3. These salts are much more water soluble than the corresponding acids. Carboxylate salts are named by specifying the metal and then replacing “ic acid” with “ate”. Carboxylic acids may be protonated on the carbonyl oxygen. The carbonyl oxygen of a carboxylic acid may be protonated by strong acids to give alkyloxonium ions. The carbonyl oxygen is more basic than the –OH group of alcohols due to resonance stabilization of the alkyloxonium ion. Note that the protonation reaction is not particularly strong. 19-5 Carboxylic Acid Synthesis in Industry Formic acid and acetic acid are manufactured on a large scale industrially
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4 Other important industrial carboxylic acids include the two dicarboxylic acids: •Hexanedioic acid Nylon •1,4-benzenedicarboxylic acid Plastics Methods for Introducing the Carboxy Functional Group 19-6 Oxidation of primary alcohols and of aldehydes furnishes carboxylic acids. Primary alcohols oxidize first to aldehydes, which then may further oxidize to carboxylic acids. Oxidants include CrO2, KMnO4 and HNO3. Nitric acid is often chosen as the oxidant because it is one of the cheapest strong oxidants. Organometallic reagents react with carbon dioxide to give carboxylic acids. Carbonation, or reaction of an organometallic reagent with CO2 (dry ice), produces a carboxylate salt, which yields a carboxylic acid upon protonation in aqueous acid. A two step synthesis allows the conversion of an alkyl halide into the corresponding carboxylic acid having one more carbon. Nitriles hydrolyze to carboxylic acids. A second method for preparing a carboxylic acid with an additional carbon is through the synthesis and hydrolysis of a nitrile, RC≡N. Nitrile hydrolysis is preferable to Grignard carbonation when the substrate contains other functional groups capable of reacting with the Grignard reagent (hydroxy, carbonyl, nitro). Substitution at the Carboxy Carbon: the Addition-Elimination Mechanism 19-7 The carbonyl carbon is attacked by nucleophiles. Carboxylic acids and their derivatives of the form RCOL (L = leaving group) can be attacked by nucleophiles. Unlike the reactions with aldehydes and ketones, the attacking nucleophile displaces the leaving group resulting in an additionelimination reaction. An addition-elimination reaction proceeds through a tetrahedral intermediate
Addition-elimination is catalyzed by acid or base. m n:-vinon 1 8rtieatiogooapggtheaatpnobheabyd sogegaaa a26w 39w Competing Reactlons of a Carbexyli Acld witha Nacleophile 。0 0: 19-aboryic Acid Derivatves:Akanoy (Acy) hepo8cieavgtpr82nb82o5ah他hggugonod Ak2nomMaeWahaeeefrtowCbgidin9 ng92hsS0c。2 Pred1 from xylic acids by 一。 5
5 Addition-elimination is catalyzed by acid or base. Acid catalysis of an addition-elimination reaction proceeds by initial protonation of the carbonyl group and subsequent protonation of the leaving group. Base catalysis proceeds by deprotonating the nucleophile. Substitution in carboxylic acids is inhibited by a poor leaving group and the acidic proton. Two problems can be encountered when trying to convert a carboxylic acid into one of its derivatives by the additionelimination process. •Hydroxide ion is a poor leaving group. •Carboxylic proton is acidic and most nucleophiles are bases. An alternate acid-base reaction may occur. With less basic nucleophiles, especially under acidic conditions, substitution through the addition-elimination mechanism may occur. In the esterification of a carboxylic acid, an alcohol and a carboxylic acid react in the presence of acid to form an ester and water. The acid serves to protonate both the carbonyl oxygen, activating the carbonyl towards nucleophilic addition, and the carboxy OH, converting it into a better leaving group. Carboxylic Acid Derivatives: Alkanoyl (Acyl) Halides 19-8 Alkanoyl (acyl) halides are formed by using inorganic derivatives of carboxylic acids. Alkanoyl (acyl) halides can be prepared from carboxylic acids by using reagents such as SOCl2 or PBr3. The reaction with either reagent begins with the conversion of the poor leaving group, -OH, into a good leaving group
Acid ieSarmeoeeeangaeaaReaeparedysmpe aanoythalde5actvatedoatcktyweakernudieophie C3ogmcoalkya2dehaideswthcartoytcacdse3tsto 。c 99 ng the prepa of other compo 19-9 Carboxylic Acid Derivatives:Esters Carboxylic acids react with alcohols to form esters recesingthecholthe 5tatiomiGcntthoughacd-catalvzed
6 Acids combine with alkanoyl halides to produce anhydrides. An alkanoyl halide is activated to attack by weaker nucleophiles by the electronegative power of its halogen atom. Treatment of alkanoyl halides with carboxylic acids leads to carboxylic anhydrides. 5- or 6-membered cyclic anhydrides can be prepared by simple heating of the corresponding dicarboxylic acids. Because the halogen in an alkanoyl halide and the RCO2 group in an anhydride are good leaving groups, alkanoyl halides and anhydrides are often useful intermediates during the preparation of other compounds. 19-9 Carboxylic Acid Derivatives: Esters Carboxylic acids react with alcohols to form esters. Esters can be formed in an equilibrium process by combining a carboxylic acid and an alcohol in the presence of catalytic amounts of a mineral acid. ΔHo is usually close to 0 for an esterification reaction. Since ΔSo is also close to zero, ΔGo will be close to zero and the equilibrium constant for the reaction will be close to 1. The equilibrium can be shifted in the direction of the products by using an excess of one of the starting materials, or by removing either water or the ester from the reaction mixture. Esterifications are most often carried out using the alcohol as the solvent. Esterifications are most often carried out using the alcohol as the solvent. Etherification proceeds through acid-catalyzed addition-elimination. Acid catalysis in an esterification reaction functions first to protonate the carbonyl oxygen, making the carbonyl carbon a better electrophile, and then to protonate the –OH group in the tetrahedral intermediate making it a better leaving group. All of the steps are reversible. Addition of alcohol or removal of water favors esterification
eare2,iohnmg30tonergolhtramoleculbar 19-10 Carboxvlic Acid Derivatives:Amides 2 K better b well as better ncdeophiles-than 公 10 -1at. Dicarboxylic acids react with amines to give imides. oeaiognesdbongaa8S6amc8asn89nmona Amino acids cyclize to lactams. 19-1 Redudbyum 7
7 Hydroxy acids may undergo intramolecular esterification to lactones. Hydroxy carboxylic acids may form 5- or 6-membered cyclic esters, or lactones, when treated with catalytic amounts of mineral acid through a process called intramolecular esterification. 19-10 Carboxylic Acid Derivatives: Amides Amines react with carboxylic acids as bases and as nucleophiles. Amines are better bases—as well as better nucleophiles—than alcohols. Because of this, the competing acid-base reaction becomes a problem when trying to prepare carboxylic amides. The ammonium carboxylate salt is very resistant to nucleophilic attack. The ammonium salt formation is reversible. Upon heating, a slower but thermodynamically more favorable reaction between the carboxylic acid and the amine takes place. Dicarboxylic acids react with amines to give imides. Imides, or the nitrogen analogs of cyclic anhydrides, can be formed through the reaction of a dicarboxylic acid and ammonia or a primary amine. Amino acids cyclize to lactams. Some amino acids can undergo an intramolecular cyclization to the corresponding cyclic amide, or lactam. The penicillin class of antibodies derives its biological activity from a lactam function. Reduction of Carboxylic Acids by Lithium Aluminum Hydride 19-11 Carboxylic acids are converted to their corresponding primary alcohols by reduction with LiAlH4
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8 Bromination Next to the Carboxy Group: the Hell-Volhard-Zelinsky Reaction 19-12 Monobromination of alkanoic acids at the α-carbon can be accomplished by treatment with Br2 in the presence of catalytic amounts of PBr3. The PBr3 is usually generated in situ by adding a little red phosphorous to the starting materials, which is then converted into PBr3 by the bromine present. Halogenation at the α-carbon of a carboxylic acid is a useful intermediate in the synthesis of 2-hydroxy- and 2-amino acids. 19-13 Biological Activity of Carboxylic Acids Fatty acids are derived from the coupling of acetic acid. Acetic acid is the primary building block for the biosynthesis of more naturally occurring compounds than any other single precursor substance. The substance 3-methyl-3-butenyl pyrophosphate is the crucial intermediate in the synthesis of terpenes: Fats are esters of long-chain carboxylic acids. Hydrolysis of fats, or saponification, yields the corresponding fatty acids. The most important fatty acids are between 12 and 22 carbons long and may contain cis carbon-carbon double bonds. Most fatty acids contain an even number of carbon atoms since they are derived directly from the polymerization of acetic acid units. Reduction of the ketone to a methylene follows. The resulting acid replaces the acetic acid in step 1 and the process repeats until the carbon chain is 16 carbons long
Arachidonicadisbioocally important Nature also produces complex polycyclic carboxylic aea8snboa Cabg9CaCagelepalyactvensturalpoduascortan activity.but may: may not contribute directly to the biologica or ion tra 19 Important Concepts 19 Important Concepts Nomenclature-Carboyicdm Spectroscopy- nedio oxy gro 9
9 Arachidonic acid is a biologically important unsaturated fatty acid. Arachidonic acid is an essential fatty acid which is enzymatically converted into many important biological molecules: Nature also produces complex polycyclic carboxylic acids. Many complex, biologically active natural products contain carboxylic acid groups. The carboxylic acid may not contribute directly to the biological activity, but may: •Confer water solubility •Allow for salt formation or ion transport •Enable micellar-type aggregation 19 Important Concepts 1. Nomenclature – Carboxylic acids are named as alkanoic acids. • Carbonyl carbon is numbered 1 in the longest chain incorporating the carbonyl group. • Dicarboxylic acids are named as alkanedioic acids. • Cyclic systems are named cycloalkanecarboxylic acids. (Ring carbon bearing the carboxy group is number 1.) • Aromatic systems are named benzoic acids. (Ring carbon bearing the carboxy group is number 1.) 2. Geometry – Carboxy group is trigonal planar. • Carboxylic acids form hydrogen bonded dimers except in very dilute solution. 19 Important Concepts 3. Spectroscopy – • NMR: Proton shift is high due to hydrogen bonding: (δ ~ 10 – 13). Carbonyl carbon is deshielded (not as much as in aldehydes and ketones) • IR: C=O band at ~1710 cm-1, O-H broad band between 2500 and 3300 cm-1 4. Carbonyl Reactivity – Carbonyl group subject to attack by nucleophiles giving unstable tetrahedral intermediates. These may decompose by elimination of the resulting hydroxy group. 5. LiAlH4 – Can reduce carboxylic acids to primary alcohols