Carboxylic Acids and the Acidity of the O—H Bond

1. Carboxylic Acids and the Acidity of the O—H Bond Structure and Bonding • Carboxylic acids are compounds containing a carboxy group (COOH). • The structure of carboxylic acids is often abbreviated as RCOOH or RCO2H, but keep in mind that the central carbon atom of the functional group is doubly bonded to one oxygen atom and singly bonded to another.

2. Structure and Bonding • The C—O single bond of a carboxylic acid is shorter than the C—O bond of an alcohol. • This can be explained by looking at the hybridization of the respective carbon atoms. • Because oxygen is more electronegative than either carbon or hydrogen, the C—O and O—H bonds are polar.

3. Nomenclature—The IUPAC System • In the IUPAC system, carboxylic acids are identified by a suffix added to the parent name of the longest chain with different endings being used depending on whether the carboxy group is bonded to a chain or a ring. • If the COOH is bonded to a chain, find the longest chain containing the COOH, and change the “e” ending of the parent alkane to the suffix “oic acid”. • If the COOH is bonded to a ring, name the ring and add the words “carboxylic acid”. • Number the carbon chain or ring to put the COOH group at C1, but omit this number from the name. • Apply all the other usual rules of nomenclature.

5. Greek letters are used to designate the location of substituents in common names. • The carbon adjacent to the COOH is called the  carbon, followed by the  carbon, followed by the  carbon, the  carbon and so forth down the chain. • The last carbon in the chain is sometimes called the  carbon. • The  carbon in the common system is numbered C2 in the IUPAC system.

6. Compounds containing two carboxy groups are called diacids. Diacids are named using the suffix –dioic acid. • Metal salts of carboxylate anions are formed from carboxylic acids in many reactions. To name the metal salt of a carboxylate anion, put three parts together:

7. Figure 19.2 Naming the metal salts of carboxylate anions

8. Physical Properties • Carboxylic acids exhibit dipole-dipole interactions because they have polar C—O and O—H bonds. • They also exhibit intermolecular hydrogen bonding. • Carboxylic acids often exist as dimers held together by two intermolecular hydrogen bonds. Figure 19.3 Two molecules of acetic acid (CH3COOH) held together by two hydrogen bonds

9. Spectroscopic Properties • Carboxylic acids have very characteristic IR and NMR absorptions. • In the IR: • -The C=O group absorbs at ~ 1710 cm-1. • -The O—H absorption occurs from 2500-3500 cm-1. • In the 1H NMR: • -The O—H proton absorbs between 10-12 ppm. • -The  protons absorb between 2-2.5 ppm. • In the 13C NMR, the C=O appears at 170-210 ppm.

10. Figure 19.4 The IR spectrum of butanoic acid, CH3CH2CH2COOH

11. Preparation of Carboxylic Acids [1] Oxidation of 1° alcohols [2] Oxidation of alkyl benzenes

12. [3] Oxidative cleavage of alkynes

13. Reactions of Carboxylic Acids The most important reactive feature of a carboxylic acid is its polar O—H bond, which is readily cleaved with base.

14. The nonbonded electron pairs on oxygen create electron-rich sites that can be protonated by strong acids (H—A). • Protonation occurs at the carbonyl oxygen because the resulting conjugate acid is resonance stabilized (Possibility [1]). • The product of protonation at the OH group (Possibility [2]) cannot be resonance stabilized.

15. The polar C—O bonds make the carboxy carbon electrophilic. Thus, carboxylic acids react with nucleophiles. • Nucleophilic attack occurs at an sp2 hybridized carbon atom, so it results in the cleavage of the  bond as well.

16. Carboxylic Acids—Strong Organic BrØnsted-Lowry Acids • Carboxylic acids are strong organic acids, and as such, readily react with BrØnsted-Lowry bases to form carboxylate anions.

17. An acid can be deprotonated by a base that has a conjugate acid with a higher pKa. • Because the pKa values of many carboxylic acids are ~5, bases that have conjugate acids with pKa values higher than 5 are strong enough to deprotonate them.

19. Carboxylic acids are relatively strong acids because deprotonation forms a resonance-stabilized conjugate base—a carboxylate anion. • The acetate anion has two C—O bonds of equal length (1.27 Å) and intermediate between the length of a C—O single bond (1.36 Å) and C=O (1.21 Å).

20. Resonance stabilization accounts for why carboxylic acids are more acidic than other compounds with O—H bonds—namely alcohols and phenols. • To understand the relative acidity of ethanol, phenol and acetic acid, we must compare the stability of their conjugate bases and use the following rule: • - Anything that stabilizes a conjugate base A:¯ makes the starting acid H—A more acidic.

21. Ethoxide, the conjugate base of ethanol, bears a negative charge on the O atom, but there are no additional factors to further stabilize the anion. Because ethoxide is less stable than acetate, ethanol is a weaker acid than acetic acid. • Phenoxide, the conjugate base of phenol, is more stable than ethoxide, but less stable than acetate because acetate has two electronegative O atoms upon which to delocalize the negative charge, whereas phenoxide has only one.

22. Figure 19.7 Summary: The relationship between acidity and conjugate base stability for acetic acid, phenol, and ethanol • Note that although resonance stabilization of the conjugate base is important in determining acidity, the absolute number of resonance structures alone is not what is important!

23. The Inductive Effect in Aliphatic Carboxylic Acids

25. Substituted Benzoic Acids Recall that substituents on a benzene ring either donate or withdraw electron density, depending on the balance of their inductive and resonance effects. These same effects also determine the acidity of substituted benzoic acids. [1] Electron-donor groups destabilize a conjugate base, making an acid less acidic—The conjugate base is destabilized because electron density is being donated to a negatively charged carboxylate anion.

26. [2] Electron-withdrawing groups stabilize a conjugate base, making an acid more acidic. The conjugate base is stabilized because electron density is removed from the negatively charged carboxylate anion.

27. Figure 19.8 How common substituents affect the reactivity of a benzene ring towards electrophiles and the acidity of substituted benzoic acids

28. Sulfonic Acids • Sulfonic acids have the general structure RSO3H. • The most widely used sulfonic acid is p-toluenesulfonic acid. • Sulfonic acids are very strong acids because their conjugate bases (sulfonate anions) are resonance stabilized, and all the resonance structures delocalize negative charge on oxygen.

29. Introduction to Carbonyl Chemistry; Organometallic Reagents; Oxidation and Reduction Introduction Two broad classes of compounds contain the carbonyl group: [1] Compounds that have only carbon and hydrogen atoms bonded to the carbonyl [2] Compounds that contain an electronegative atom bonded to the carbonyl

30. The presence or absence of a leaving group on the carbonyl determines the type of reactions the carbonyl compound will undergo. • Carbonyl carbons are sp2 hybridized, trigonal planar, and have bond angles that are ~1200. In these ways, the carbonyl group resembles the trigonal planar sp2 hybridized carbons of a C=C.

31. In one important way, the C=O and C=C are very different. • The electronegative oxygen atom in the carbonyl group means that the bond is polarized, making the carbonyl carbon electron deficient. • Using a resonance description, the carbonyl group is represented by two resonance structures.

32. General Reactions of Carbonyl Compounds Carbonyls react with nucleophiles.

33. Aldehydes and ketones react with nucleophiles to form addition products by a two-step process: nucleophilic attack followed by protonation.

34. The net result is that the  bond is broken, two new  bonds are formed, and the elements of H and Nu are added across the  bond. • Aldehydes are more reactive than ketones towards nucleophilic attack for both steric and electronic reasons.

35. Carbonyl compounds with leaving groups react with nucleophiles to form substitution products by a two-step process: nucleophilic attack, followed by loss of the leaving group. The net result is that Nu replaces Z, a nucleophilic substitution reaction. This reaction is often called nucleophilic acyl substitution.

37. Nucleophilic addition and nucleophilic acyl substitution involve the same first step—nucleophilic attack on the electrophilic carbonyl carbon to form a tetrahedral intermediate. • The difference between the two reactions is what then happens to the intermediate. • Aldehydes and ketones cannot undergo substitution because they do not have a good leaving group bonded to the newly formed sp3 hybridized carbon.

38. Preview of Oxidation and Reduction • Carbonyl compounds are either reactants or products in oxidation-reduction reactions.

39. The three most useful oxidation and reduction reactions of carbonyl starting materials can be summarized as follows:

40. Reduction of Aldehydes and Ketones • The most useful reagents for reducing aldehydes and ketones are the metal hydride reagents. • Treating an aldehyde or ketone with NaBH4 or LiAlH4, followed by H2O or some other proton source affords an alcohol.

41. The net result of adding H:¯ (from NaBH4 or LiAlH4) and H+ (from H2O) is the addition of the elements of H2 to the carbonyl  bond.

42. Catalytic hydrogenation also reduces aldehydes and ketones to 1° and 2° alcohols respectively, using H2 and a catalyst. • When a compound contains both a carbonyl group and a carbon—carbon double bond, selective reduction of one functional group can be achieved by proper choice of the reagent. • A C=C is reduced faster than a C=O with H2 (Pd-C). • A C=O is readily reduced with NaBH4 and LiAlH4, but a C=C is inert.

43. Thus, 2-cyclohexenone, which contains both a C=C and a C=O, can be reduced to three different compounds depending upon the reagent used.

44. The Stereochemistry of Carbonyl Reduction • Hydride converts a planar sp2 hybridized carbonyl carbon to a tetrahedral sp3 hybridized carbon.

45. Enantioselective Carbonyl Reductions • Selective formation of one enantiomer over another can occur if a chiral reducing agent is used. • A reduction that forms one enantiomer predominantly or exclusively is an enantioselective or asymmetric reduction. • An example of chiral reducing agents are the enantiomeric CBS reagents.

46. CBS refers to Corey, Bakshi and Shibata, the chemists who developed these versatile reagents. • One B—H bond serves as the source of hydride in this reduction. • The (S)-CBS reagent delivers H:- from the front side of the C=O. This generally affords the R alcohol as the major product. • The (R)-CBS reagent delivers H:- from the back side of the C=O. This generally affords the S alcohol as the major product.

47. These reagents are highly enantioselective. For example, treatment of propiophenone with the (S)-CBS reagent forms the R alcohol in 97% ee.

48. Reduction of Carboxylic Acids and Their Derivatives • LiAlH4 is a strong reducing agent that reacts with all carboxylic acid derivatives. • Diisobutylaluminum hydride ([(CH3)2CHCH2]2AlH, abbreviated DIBAL-H, has two bulky isobutyl groups which makes this reagent less reactive than LiAlH4. • Lithium tri-tert-butoxyaluminum hydride, LiAlH[OC(CH3)3]3, has three electronegative O atoms bonded to aluminum, which makes this reagent less nucleophilic than LiAlH4.

49. Acid chlorides and esters can be reduced to either aldehydes or 1° alcohols depending on the reagent.

50. In the reduction of an acid chloride, Cl¯ comes off as the leaving group. • In the reduction of the ester, CH3O¯ comes off as the leaving group, which is then protonated by H2O to form CH3OH.