1. Carboxylic Acids and Nitriles

2. Introduction Carboxylic Acids
Carboxylic acids are abundant in nature and in pharmaceuticals

3. Introduction Carboxylic Acids
The US produces over 2.5 million tons of acetic acid per year, which is primarily used to produce vinyl acetate
Vinyl acetate is used in paints and adhesives
Carboxylic acid derivatives such as vinyl acetate are very common and play a central role in organic chemistry

4. Structure and Properties of Carboxylic Acids
The carbon atom of the carboxylic acid has a trigonal planar geometry.
The acid moiety is capable of strong hydrogen bonding including H-bonding between acid pairs
As a result, carboxylic acids generally have high boiling points – consider the BPs of acetic acid (118 °C) and isopropanol (82 °C)

5. Structure and Properties of Carboxylic Acids
In water, the equilibrium generally favors the acid
pKa values mostly range between 4 and 5.

6. Dissociation of Carboxylic Acids
Carboxylic acids are proton donors toward weak and strong bases, producing metal carboxylate salts, RCO2 +M
Carboxylic acids with more than six carbons are only slightly soluble in water, but their conjugate base salts are water-soluble

7. Acidity Constant and pKa
Carboxylic acids transfer a proton to water to give H3O+ and carboxylate anions, RCO2, but H3O+ is a much stronger acid
The acidity constant, Ka,, is about 10-5 for a typical carboxylic acid (pKa ~ 5)

8. Structure and Properties of Carboxylic Acids
Electron withdrawing substituents have a great effect on acidity (including synergistic effects with multiple substituents)
Fluoroacetic, chloroacetic, bromoacetic, and iodoacetic acids are stronger acids than acetic acid

9. Substituent Effects on Acidity
Electronegative substituents promote formation of the carboxylate ion

10. Aromatic Substituent Effects
Electron-withdrawing (EW) groups increase acidity by stabilizing the carboxylate anion. Electron-donating (activating) groups decrease acidity by destabilizing the carboxylate anion
We can use relative pKa’s as a calibration for effects on relative free energies of reactions with the same substituents

11. EW Substituent Effects on Acidity

12. Biological Acids and the Henderson-Hasselbalch Equation
If pKa of given acid and the pH of the medium are known, % of dissociated and undissociated forms can be calculated using the Henderson-Hasselbalch eqn
Example problems
Henderson-Hasselbalch equation

13. Preparing Carboxylic Acids
Oxidation of a substituted alkylbenzene with KMnO4 or Na2Cr2O7 gives a substituted benzoic acid (see Section 16.9)
1° and 2° alkyl groups can be oxidized, but tertiary groups are not

14. From Alkenes
Oxidative cleavage of an alkene with KMnO4 gives a carboxylic acid if the alkene has at least one vinylic hydrogen (see Section 7.9)

15. Preparation of Carboxylic Acids
In earlier chapters, we have already learned some methods to synthesize carboxylic acids

16. From Alcohols
Oxidation of a primary alcohol or an aldehyde with CrO3 in aqueous acid

17. Hydrolysis of Nitriles
Hot acid or base yields carboxylic acids
Conversion of an alkyl halide to a nitrile (with cyanide ion) followed by hydrolysis produces a carboxylic acid with one more carbon (RBr  RCN  RCO2H)
Best with primary halides because elimination reactions occur with secondary or tertiary alkyl halides

18. Carboxylation of Grignard Reagents
Grignard reagents react with dry CO2 to yield a metal carboxylate
Limited to alkyl halides that can form Grignard reagents
The organomagnesium halide adds to C=O of carbon dioxide
Protonation by addition of aqueous HCl in a separate step gives the free carboxylic acid

19. Reactions of Carboxylic Acids
LiAlH4 is a strong reducing agent that can convert an acid to a primary alcohol
The LAH acts as a base first
Then, an aldehyde is produced

20. Reactions of Carboxylic Acids
LiAlH4 is a strong reducing agent that can convert an acid to a primary alcohol
The aldehyde is further reduced to the alcohol

21. Reactions of Carboxylic Acids
The more mild borane reagent can also be used to promote the reduction
Reduction with borane is selective compared to LAH reduction

22. Reactions of Carboxylic Acids: An Overview
CA can transfer a proton to a base (produces good nucleophile).
CA can be reduced by LAH.
Nucleophile can add to carbonyl carbon of CA.
In addition, carboxylic acids undergo other reactions characteristic of neither alcohols nor ketones

23. Carboxylic Acid Derivatives
Carboxylic acids can be modified without changing the oxidation state: CA Derivatives
Because it has the same oxidation state, a nitrile is also an acid derivative despite not having a carbonyl group.
Nitriles and CA’s are electrophiles.

24. Carboxylic Acid Derivatives
Acid halides and anhydrides are relatively unstable, so they are not common in nature
Some naturally occurring esters are known to have pleasant odors
Amides are VERY common in nature

25. Carboxylic Acid Derivatives
To name an acid halide, replace “ic acid” with “yl halide”

26. Carboxylic Acid Derivatives
Alternatively, the suffix, “carboxylic acid” can be replaced with “carbonyl halide”

27. Carboxylic Acid Derivatives
Symmetrical acid anhydrides are named by replacing “acid” with “anhydride”
Asymmetrical acid anhydrides are named by listing the acids alphabetically and adding the word anhydride

28. Carboxylic Acid Derivatives
Esters are named by naming the alkyl group attached to the oxygen followed by the carboxylic acid’s name with the suffix “ate”

29. Carboxylic Acid Derivatives
Amides are named by replacing the suffix “ic acid” or “oic acid” with “amide”

30. Carboxylic Acid Derivatives
If the nitrogen atom of the amide group bears alkyl substituents, their names are placed at the beginning of the name with N as their locant

31. Carboxylic Acid Derivatives
Nitriles are named by replacing the suffix “ic acid” or “oic acid” with “onitrile”

32. Reactivity of Carboxylic Acid Derivatives
CA derivatives have electrophilic carbonyl carbons
Reactivity can be affected by
Induction
Resonance
Sterics
Quality of leaving group

33. Reactivity of Acid Chlorides
The electronegative chlorine enhances the electrophilic character of the carbonyl.
There are 3 resonance contributors to the acid chloride
Chloride affects the sterics of the nucleophilic attack on the carbonyl
The chloride is a good leaving group, which also enhances its reactivity

34. Amides are the least reactive acid derivative
Reactivity of Amides
Amides are the least reactive acid derivative
Examine the factors below to explain amide reactivity
Induction
Resonance
Sterics
Quality of leaving group

35. Reactivity of Aldehydes and Ketones
Aldehydes and ketones are also electrophilic, but they do not undergo substitution
– H and –R do not qualify as leaving groups.

36. Reactivity of Carboxylic Acid Derivatives
Nucleophilic acyl substitution is a two-step process
Because C=O double bonds are quite stable, the “loss of leaving group” step should occur if a leaving group is present
A nucleophile that is a weaker leaving group can replace a stronger leaving group.

37. Reactivity of Carboxylic Acid Derivatives
Not an SN2 mechanism
Sometimes a proton transfer will be necessary in the mechanism

38. Reactivity of Carboxylic Acid Derivatives
Under acidic conditions, (-) charges rarely form
The first step will NOT be nucleophilic attack
The electrophile and nucleophile are both low in energy

39. Reactivity of Carboxylic Acid Derivatives
H3O+ is unstable and drives the equilibrium forward by starting the reaction mechanism
Now that the electrophile carries a (+) charge, it is much less stable (higher in energy.

40. Reactivity of Carboxylic Acid Derivatives
Under basic conditions, (+) charges rarely form
The OH- is the most unstable species in the reaction and drives the equilibrium forward
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e

41. Preparation of Esters
Fischer esterification combines a carboxylic acid and an alcohol using an acid catalyst, with multiple proton transfers

42. Preparation of Esters

43. Ester Reaction Products
Relatively Poor Yields

44. Specific Reactions with Acid Chlorides/Anhydrides
Seager SL, Slabaugh MR, Chemistry for Today: General, Organic and Biochemistry, 7th Edition, 2011

45. Saponification Products
Reaction of ester with water to break ester linkage and produce alcohol and carboxylic acid
isopropyl propanoate
sodium propanoate
ethyl benzoate
potassium benzoate
Seager SL, Slabaugh MR, Chemistry for Today: General, Organic and Biochemistry, 7th Edition, 2011

46. Amines Form Amides
Amides are formed through reaction of primary and secondary amines with acid chlorides and acid anhydrides.
Similar to esterification reactions.
Seager SL, Slabaugh MR, Chemistry for Today: General, Organic and Biochemistry, 7th Edition, 2011

47. Reaction of Acid Chlorides
Esters and acid chlorides can be attacked by Grignard nucleophiles

48. Reaction of Acid Chlorides
Two equivalents of the Grignard yield a 3° alcohol

49. Reaction of Acid Chlorides with LAH
Acid chlorides can be reduced using LAH
To stop the aldehyde from being reduced to the alcohol, a bulky reducing agent can be used

50. Reactions of Esters
Esters can be fully reduced using reagents such as LiAlH4
Two equivalents of reducing agent are required
Two alcohols are produced
When performed at low temperature, reduction with DIBAH yields an aldehyde.

51. Reactions of Amides
LiAlH4 can reduce an amide to an amine

52. Reactions of Acid Chlorides

53. Reactions of Acid Anhydrides
Acetic anhydride is often used to acetylate an amine or an alcohol

54. Reactivity of Carboxylic Acid Derivatives
Neutral nucleophiles are generally less reactive, but they can still react if given enough time
An intermediate with both (+) and (-) charge forms

55. Preparation of Nitriles by Dehydration
Reaction of primary amides RCONH2 with SOCl2 or POCl3 (or other dehydrating agents)
Not limited by steric hindrance or side reactions (as is the reaction of alkyl halides with NaCN)

56. Mechanism of Dehydration of Amides
Nucleophilic amide oxygen atom attacks SOCl2 followed by deprotonation and elimination

57. Reactions of Nitriles
RCºN is strongly polarized and with an electrophilic carbon atom
Attacked by nucleophiles to yield sp2-hybridized imine anions

58. Hydrolysis: Conversion of Nitriles into Carboxylic Acids
Hydrolyzed in with acid or base catalysis to a carboxylic acid and ammonia

59. Mechanism of Hydrolysis of Nitriles
Nucleophilic addition of hydroxide to CN bond
Protonation gives a hydroxy imine, which tautomerizes to an amide
A second hydroxide adds to the amide carbonyl group and loss of a proton gives a dianion
Expulsion of NH2 gives the carboxylate

60. Reduction: Conversion of Nitriles into Amines
Reduction of a nitrile with LiAlH4 gives a primary amine
Nucleophilic addition of hydride ion to the polar CN bond, yielding an imine anion
The C=N bond undergoes a second nucleophilic addition of hydride to give a dianion, which is protonated by water

61. Reaction of Nitriles with Organometallic Reagents
Grignard reagents add to give an intermediate imine anion that is hydrolyzed by addition of water to yield a ketone

62. Spectroscopy of Carboxylic Acids and Their Derivatives
Recall that C=O stretching is a prominent peak in IR spectra
Recall that conjugated carbonyl signals appear at lower wavenumbers (about 40 cm-1 less)

63. Spectroscopy of Carboxylic Acids and Their Derivatives
The O-H stretch of an acid gives a very broad peak ( cm-1)
The CΞN triple bond stretch appears around 2200 cm-1
Carbonyl 13C peaks appear around ppm
Nitrile 13C peaks appear around ppm
The 1H peak for a carboxylic acid proton appears around 12 ppm
Practice with conceptual checkpoint 21.38

64. Spectroscopy of Carboxylic Acids and Their Derivatives
Predict the number and chemical shift of all 13C peaks for the molecule below
Predict the number, chemical shift, multiplicity, and integration of all 1H peaks for the molecule below