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Carboxylic Acids and the Acidity of the O—H Bond

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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
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 cm-1. In the 1H NMR: -The O—H proton absorbs between ppm. -The  protons absorb between ppm. In the 13C NMR, the C=O appears at 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
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
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
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.

51 The mechanism illustrates why two different products are possible.

52 Carboxylic acids are reduced to 1° alcohols with LiAlH4.
LiAlH4 is too strong a reducing agent to stop the reaction at the aldehyde stage, but milder reagents are not strong enough to initiate the reaction in the first place.

53 Unlike the LiAlH4 reduction of all other carboxylic acid derivatives, which affords 1° alcohols, the LiAlH4 reduction of amides forms amines. Since ¯NH2 is a very poor leaving group, it is never lost during the reduction, and therefore an amine is formed.



56 Oxidation of Aldehydes
A variety of oxidizing agents can be used, including CrO3, Na2Cr2O7, K2Cr2O7, and KMnO4. Aldehydes can also be oxidized selectively in the presence of other functional groups using silver(I) oxide in aqueous ammonium hydroxide (Tollen’s reagent). Since ketones have no H on the carbonyl carbon, they do not undergo this oxidation reaction.

57 Organometallic Reagents
Other metals in organometallic reagents are Sn, Si, Tl, Al, Ti, and Hg. General structures of the three common organometallic reagents are shown:

58 Since both Li and Mg are very electropositive metals, organolithium (RLi) and organomagnesium (RMgX) reagents contain very polar carbon—metal bonds and are therefore very reactive reagents. Organomagnesium reagents are called Grignard reagents. Organocopper reagents (R2CuLi), also called organocuprates, have a less polar carbon—metal bond and are therefore less reactive. Although they contain two R groups bonded to Cu, only one R group is utilized in the reaction. In organometallic reagents, carbon bears a - charge.

59 Organolithium and Grignard reagents are typically prepared by reaction of an alkyl halide with the corresponding metal. With lithium, the halogen and metal exchange to form the organolithium reagent. With Mg, the metal inserts in the carbon—halogen bond, forming the Grignard reagent.

60 Grignard reagents are usually prepared in diethyl ether (CH3CH2OCH2CH3) as solvent.
It is thought that two ether O atoms complex with the Mg atom, stabilizing the reagent.

61 Organocuprates are prepared from organolithium reagents by reaction with a Cu+ salt, often CuI.

62 Acetylide ions are another example of organometallic reagents.
Acetylide ions can be thought of as “organosodium reagents”. Since sodium is even more electropositive than lithium, the C—Na bond of these organosodium compounds is best described as ionic, rather than polar covalent.

63 An acid-base reaction can also be used to prepare sp hybridized organolithium compounds.
Treatment of a terminal alkyne with CH3Li affords a lithium acetylide. The equilibrium favors the products because the sp hybridized C—H bond of the terminal alkyne is more acidic than the sp3 hybridized conjugate acid, CH4, that is formed.

64 Organometallic reagents are strong bases that readily abstract a proton from water to form hydrocarbons. Similar reactions occur with the O—H proton of alcohols and carboxylic acids, and the N—H protons of amines.

65 Since organolithium and Grignard reagents are themselves prepared from alkyl halides, a two-step method converts an alkyl halide into an alkane (or other hydrocarbon). Organometallic reagents are also strong nucleophiles that react with electrophilic carbon atoms to form new carbon—carbon bonds. These reactions are very valuable in forming the carbon skeletons of complex organic molecules.

66 Examples of functional group transformations involving organometallic reagents:
[1] Reaction of R—M with aldehydes and ketones to afford alcohols [2] Reaction of R—M with carboxylic acid derivatives

67 [3] Reaction of R—M with other electrophilic functional groups

68 Reaction of Organometallic Reagents with Aldehydes and Ketones.
Treatment of an aldehyde or ketone with either an organolithium or Grignard reagent followed by water forms an alcohol with a new carbon—carbon bond. This reaction is an addition because the elements of R’’ and H are added across the  bond.

69 This reaction follows the general mechanism for nucleophilic addition—that is, nucleophilic attack by a carbanion followed by protonation. Mechanism 20.6 is shown using R’’MgX, but the same steps occur with RLi reagents and acetylide anions.

70 Note that these reactions must be carried out under anhydrous conditions to prevent traces of water from reacting with the organometallic reagent.

71 This reaction is used to prepare 1°, 2°, and 3° alcohols.

72 Protecting Groups Addition of organometallic reagents cannot be used with molecules that contain both a carbonyl group and N—H or O—H bonds. Carbonyl compounds that also contain N—H or O—H bonds undergo an acid-base reaction with organometallic reagents, not nucleophilic addition.

73 Solving this problem requires a three-step strategy:
[1] Convert the OH group into another functional group that does not interfere with the desired reaction. This new blocking group is called a protecting group, and the reaction that creates it is called “protection.” [2] Carry out the desired reaction. [3] Remove the protecting group. This reaction is called “deprotection.” A common OH protecting group is a silyl ether.

74 tert-Butyldimethylsilyl ethers are prepared from alcohols by reaction with tert-butyldimethylsilyl chloride and an amine base, usually imidazole. The silyl ether is typically removed with a fluoride salt such as tetrabutylammonium fluoride (CH3CH2CH2CH2)4N+F¯.

75 The use of tert-butyldimethylsilyl ether as a protecting group makes possible the synthesis of 4-methyl-1,4-pentanediol by a three-step sequence.

76 Figure 20.7 General strategy for using a protecting group

77 Reaction of Organometallic Reagents with Carboxylic Acid Derivatives.
Both esters and acid chlorides form 3° alcohols when treated with two equivalents of either Grignard or organolithium reagents.


79 To form a ketone from a carboxylic acid derivative, a less reactive organometallic reagent—namely an organocuprate—is needed. Acid chlorides, which have the best leaving group (Cl¯) of the carboxylic acid derivatives, react with R’2CuLi to give a ketone as the product. Esters, which contain a poorer leaving group (¯OR), do not react with R’2CuLi.

80 Reaction of Organometallic Reagents with Other Compounds
Grignards react with CO2 to give carboxylic acids after protonation with aqueous acid. This reaction is called carboxylation. The carboxylic acid formed has one more carbon atom than the Grignard reagent from which it was prepared.

81 The mechanism resembles earlier reactions of nucleophilic Grignard reagents with carbonyl groups.

82 Like other strong nucleophiles, organometallic reagents—RLi, RMgX, and R2CuLi—open epoxide rings to form alcohols.

83 The reaction follows the same two-step process as opening of epoxide rings with other negatively charged nucleophiles—that is, nucleophilic attack from the back side of the epoxide, followed by protonation of the resulting alkoxide. In unsymmetrical epoxides, nucleophilic attack occurs at the less substituted carbon atom.

84 ,-Unsaturated Carbonyl Compounds
,-Unsaturated carbonyl compounds are conjugated molecules containing a carbonyl group and a C=C separated by a single  bond. Resonance shows that the carbonyl carbon and the  carbon bear a partial positive charge.

85 This means that ,-unsaturated carbonyl compounds can react with nucleophiles at two different sites.

86 The steps for the mechanism of 1,2-addition are exactly the same as those for the nucleophilic addition of an aldehyde or a ketone—that is, nucleophilic attack, followed by protonation.


88 Consider the conversion of a general enol A to the carbonyl compound B
Consider the conversion of a general enol A to the carbonyl compound B. A and B are tautomers: A is the enol form and B is the keto form of the tautomer. Equilibrium favors the keto form largely because the C=O is much stronger than a C=C. Tautomerization, the process of converting one tautomer into another, is catalyzed by both acid and base.




92 Summary of the Reactions of Organometallic Reagents
[1] Organometallic reagents (R—M) attack electrophilic atoms, especially the carbonyl carbon.

93 [2] After an organometallic reagent adds to the carbonyl group, the fate of the intermediate depends on the presence or absence of a leaving group. [3] The polarity of the R—M bond determines the reactivity of the reagents: —RLi and RMgX are very reactive reagents. —R2CuLi is much less reactive.

94 Synthesis Figure 20.8 Conversion of 2–hexanol into other compounds

95 Give the IUPAC name for each compound.
3,3’-dimethylhexanoic acid b) 4-chloropetanoic acid c) 2,4-diethylhexanoic acid

96 d) 4-isopropyl-6,8-dimethylnonanic acid

97 Draw the structure corresponding to the IUPAC name.
a) 2-bromobutanoic acid b) 2,3-dimethylpentanoic acid c) 3,3’,4-trimethylheptanoic acid

98 d) 2-secbutyl-4,4’-diethylnonanoic acid
e) 3,4-diethylcyclohexanecarboxylic acid

99 f) 1-isopropylcyclobutanecarboxylic acid

100 5) Give the IUPAC name for each metal salt.
C6H5CO2-+Li Lithium benzoate b) HCO2-+Na Sodium methanoate c) (CH3)2CHCO2-+K Potassium 2-methylpropanoate

101 d) (CH3CH2)2CHCH2CHBrCH2CH2CO2-+Na
Sodium 4-bromo-6-ethyloctanoate

102 7) Explain how you would distinguish between these compounds using IR spectroscopy.
2 peaks C=O 1710 -OH 1 peak C=O 1700 1 peak -OH

103 Propose a compound with the formula, C4H8O2 and the following date:
0.95 (triplet, 3H) 1.65 (multiplet, 2H) 2.30 (triplet, 2H) 11.8 (singlet, 1H)

104 Identify the starting material in each reaction.
b) c)

105 d)

106 19.13) Which of the following bases are strong enough to deprotonate CH3COOH?
a) F- pka of CH3COOH is 4.8. b) (CH3)3CO- b) has a pka of 18 c) has a pka of 50 d) has a pka of 38 c) CH3- d) NH2- pka of conjugate acid must be greater than that of the carboxylic acid being deprotonated. e) Cl-

107 19.14) Rank the labeled protons in order of increasing acidity.
Ha<Hb<Hc The more stable the conjugate base the more acidic the proton.

108 19. 15) Match each pka value with each carboxylic acid. (3. 2, 4
19.15) Match each pka value with each carboxylic acid.(3.2, 4.9 and 0.2) CH3CH2COOH CF3COOH ICH2COOH 4.9 0.2 3.2 Electron withdrawing groups make acids more acidic.

109 19.16) Why is formic acid more acidic than acetic acid?
The methyl group is electron donating and stabilizes the acid while destabilizing the conjugate base thus making it less acidic.

110 19.17) Rank the compounds within each group in order of decreasing acidity.

111 19.18) Rank each group of compounds in order of decreasing acidity.

112 19.19) Is the following compound more or less acidic than phenol?
The more electron donating groups present, the less acidic a compound is. This compound has an additional hydroxy and alkyl group, both electron donating. So it is less acidic.

113 19.22) Comparing CF3SO3H and CH3SO3H, which has the weaker conjugate base? Which conjugate base is the better leaving group? Which of these acids has the higher pka? CF3SO3H is the weaker conjugate base. CF3SO3H is the better leaving group because it is the weaker conjugate base. CH3SO3H, with the electron donating methyl group, has the higher pka and is thus a weaker acid.

114 20. 1) What type of orbitals make up the indicated bonds
20.1) What type of orbitals make up the indicated bonds? And in what orbitals do the lone pairs on the oxygen lie? a. sp3-sp2 b. sp2-sp2, p-p c. sp3-sp2 The lone pairs lie in sp2 hybridized orbitals.

115 20.2) Which compounds undergo nucleophilic addition and which substitution?

116 20.3) Which compound in each pair is more reactive toward nucleuphilic attack?
b) c) d)

117 20.4) What alcohol is formed when each compound is treated with NaBH4 in MeOH?

118 20.5) What aldehyde or ketone is needed to synthesize each alcohol by metal hydride reduction?

119 20.6) Why can’t 1-methylcyclohexanol be prepared from a carbonyl by reduction?
Tertiary alcohols can not be made by reduction of a carbonyl because there are no hydrogens on the carbon with the -OH.

120 20.7) Draw the products of the following reactions?
b) c) d)

121 e) f)

122 20.8) Draw the products when the following compounds are treated with NaBH4 in MeOH.

123 20.9) What reagent is needed to carry out the reaction below?
Two reagents are needed to carry out this reaction. First, the (S)-CBS reagent to produce the R-enantiomer. Followed by H2O to protonate the alcohol.

124 20.10) Draw a stepwise mechanism for the following reaction.

125 20.11) Draw an acid chloride and an ester that can be used to produce each product.

126 20.12) Draw the products of LiAlH4 reduction of each compound.
b) c)

127 d)

128 20.13) What amide will form each of the following amines when treated with LiAlH4?
b) c)

129 20.14) Predict the products of these compounds when treated with the following reagents.
b) No reaction

130 c)

131 20.15) Predict the products in the following reactions.
No Reaction b)

132 20.16) Predict the products of the compound below when reacted with each reagent.

133 c) d) e)

134 20.17) Write out the rea tions needed to convert CH3CH2Br to each of the following reagents.

135 20.18) 1-octyne reacts readily with NaH, forming a gas that bubbles out of the reaction mixture. 1-octyne also reacts with CH3MgBr and a different gas is produced. Write out balanced equations for each reaction.

136 20.19) Draw the product of the following reactions.
b) c)

137 d)

138 20.20) Draw the product formed when each compound is treated with C6H5MgBr followed by H2O.

139 d)

140 20.21)Draw the products of each reaction.
b) c)

141 d)

142 20.22) Draw the products (including stereochemistry) of the following reactions.

143 20.23) What Grignard and carbonyl are needed to prepare each alcohol?

144 d)

145 20.24) Tertiary alcohols with three different R groups on the carbon attached to the OH can be prepared in three different ways using the Grignard reagent. Show them. a)

146 b)

147 c)

148 20.25) Show the steps for the following reaction.

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