2. WWU- Chemistry Substituent Effects on the Acidities of Carboxylic Acids

3. WWU- Chemistry When substituents are attached to a molecule, such as a carboxylic acid, they can influence the acidity (or basicity) of that substance. Some substituents strengthen acids and weaken bases; other substituents have the opposite effect, the weaken acids and strengthen bases. Substituents exert their effects on acidity or basicity through a combination of resonance and inductive effects. REVIEW: Lecture Textbook, Chapter 7, especially sections 7.6 through 7.8.

4. WWU- Chemistry The essential idea is this: if a substituent removes electrons from the negative oxygen of a carboxylate ion, it will stabilize the ion. This effect shifts the equilibrium to the right and increases acidity. If a substituent pours electrons toward the negative oxygen of a carboxylate ion, it will destabilize the ion. This effect will shift the equilibrium to the left and decrease acidity.

5. WWU- Chemistry Electron-withdrawing Effects: –strengthen acids –weaken bases Electron-releasing Effects: –weaken acids –strengthen bases

6. WWU- Chemistry Resonance Effects on the Acidities of Carboxylic Acids

7. WWU- Chemistry Resonance Effects of Substituents Consider a substituent that contains multiple bonds. Let represent such a substituent, where B is more electronegative than A.

8. WWU- Chemistry In other words, let’s compare the acidities of: Which acid is stronger, and why?

9. WWU- Chemistry The substituent will be a hybrid of two or more resonance forms of the type: The presence of the substituent on a molecule will influence the electron distribution throughout the entire structure. This type of effect, called a resonance effect, can be seen most clearly when the substituent is attached to a benzene ring.

10. WWU- Chemistry To illustrate, consider a para-substituted benzoic acid. We can draw resonance forms:

11. WWU- Chemistry For the carboxylate ion, the corresponding resonance forms would be:

12. WWU- Chemistry The resonance forms that are the most important in our discussion are those forms where the positive charge is located on the carbon atom that also bears the functional group. The ionization of the substituted benzoic acid can thus be analyzed by examining the following equilibrium:

13. WWU- Chemistry The positive charge in the ring attracts the electrons on the carboxylate group. The resonance effect of the substituent thus acts to stabilize the anion and shift the equilibrium to the right. Remember that we are comparing the substituted benzoic acid with unsubstituted benzoic acid. In the unsubstituted benzoic acid, we are assuming that the substituent (H) makes no difference in the electron distribution in the ring. Thus, we would expect the -A=B substituted benzoic acid to be a stronger acid than benzoic acid itself.

14. WWU- Chemistry A specific example of the -A=B type of substituent is the nitro group (-NO 2 ). A nitro group in the para position of a benzoic acid strengthens the acidity by a factor of six (0.8 log units).

15. WWU- Chemistry The nitro group stabilizes the carboxylate anion and shifts the equilibrium to the right. NOTE: The nitro group also has an electron-withdrawing inductive effect; this has been ignored in this discussion. Inductive effects will be examined later.

16. WWU- Chemistry The resonance effect of a substituent of the -A=B type reduces the electron density in the benzene ring. The resonance forms shown here represent this reduction of electron density by showing positive charge in the ring. As a result, these substituents exert an electron- withdrawing resonance effect. This is sometimes represented as a -R effect. The following table shows several substituent groups that exert an electron-withdrawing resonance (-R) effect.

17. WWU- Chemistry Substituents with Electron- Withdrawing Resonance Effects

18. WWU- Chemistry The resonance forms show that positive charge is located at the ortho and para positions with respect to the substituent. A functional group that is located ortho or para to the substituent will be influenced by the resonance effect. A substituent located meta to the substituent will be affected to a much smaller degree. Therefore, we would expect that whenever a -R substituent is located ortho or para to a carboxyl group, the acidity of the benzoic acid should be increased.

19. WWU- Chemistry -R substituents strengthen acids and weaken bases

20. WWU- Chemistry Resonance Effects of Substituents (Part Two) Consider a substituent that contains an atom that bears one or more unshared pairs of electrons. Let represent such a substituent.

21. WWU- Chemistry In other words, let’s compare the acidities of: Which acid is stronger, and why?

22. WWU- Chemistry When this substituent is attached to the benzene ring, the unshared electron pairs will be shifted into the ring through resonance. Once again, the presence of the substituent on a molecule will influence the electron distribution throughout the entire structure. This is another example of a resonance effect.

23. WWU- Chemistry To illustrate, consider a para-substituted benzoic acid. We can draw resonance forms:

24. WWU- Chemistry For the carboxylate ion, the corresponding resonance forms would be:

25. WWU- Chemistry The resonance forms that are the most important in our discussion are those forms where the negative charge is located on the carbon atom that also bears the functional group. The ionization of the substituted benzoic acid can thus be analyzed by examining the following equilibrium:

26. WWU- Chemistry The negative charge in the ring repels the electrons on the carboxylate group. The resonance effect of the substituent thus acts to destabilize the anion and shift the equilibrium to the left. Remember that we are comparing the substituted benzoic acid with unsubstituted benzoic acid. In the unsubstituted benzoic acid, we are assuming that the substituent (H) makes no difference in the electron distribution in the ring. Thus, we would expect the -Y substituted benzoic acid to be a weaker acid than benzoic acid itself.

27. WWU- Chemistry A specific example of the -Y type of substituent is the methoxy group (-OCH 3 ). A methoxy group in the para position of a benzoic acid weakens the acidity by a factor of 1.9 (0.27 log units).

28. WWU- Chemistry The methoxy group destabilizes the carboxylate anion and shifts the equilibrium to the left. NOTE: The methoxy group also has an electron- withdrawing inductive effect; this has been ignored in this discussion. Inductive effects will be examined later.

29. WWU- Chemistry The resonance forms show that electron density is increased at the ortho and para positions with respect to the substituent. A functional group that is located ortho or para to the substituent will be influenced by the resonance effect. A substituent located meta to the substituent will be affected to a much smaller degree. Therefore, we would expect that whenever a +R substituent is located ortho or para to a carboxyl group, the acidity of the benzoic acid should be decreased.

30. WWU- Chemistry Substituents with Electron- Releasing Resonance Effects

31. WWU- Chemistry The resonance effect of a substituent of the -Y type increases the electron density in the benzene ring. The resonance forms shown here represent this increase of electron density by showing negative charge in the ring. As a result, these substituents exert an electron-releasing resonance effect. This is sometimes called an electron- donating resonance effect. This is sometimes represented as a +R effect. The following table shows several substituent groups that exert an electron-releasing resonance (+R) effect.

32. WWU- Chemistry +R substituents weaken acids and strengthen bases

33. WWU- Chemistry In the case of the alkyl substituents (which have no unshared pairs of electrons), their electron-releasing resonance effect arises from hyperconjugation. p-Methylbenzoic acid is less acidic than benzoic acid by a factor of 1.5 (0.17 log units)

34. WWU- Chemistry Inductive Effects on the Acidities of Carboxylic Acids

35. WWU- Chemistry Let’s now compare the acidities of two aliphatic carboxylic acids: where X is an electronegative element.

36. WWU- Chemistry Electronegative substituents attract electrons. When electronegative elements are present in a molecule that can act as an acid, they enhance the acidity of the bond because they lower the electron density in that bond and because they stabilize the conjugate base. Substituents of this type are said to have an electron- withdrawing inductive effect. This type of effect is often known as a -I effect. The following table lists a number of substituents that have -I inductive effects:

37. WWU- Chemistry Substituents with Electron- Withdrawing Inductive Effects

38. WWU- Chemistry As before, whenever we consider the resonance or inductive effect of a substituent, we are comparing it with a reference substituent, hydrogen. When hydrogen is the substituent, it is treated as if it had no resonance or inductive effect.

39. WWU- Chemistry -I substituents strengthen acids and weaken bases

40. WWU- Chemistry And one last case, again comparing two aliphatic carboxylic acids: The alkyl substituent (R) is weakly electropositive with respect to a hydrogen.

41. WWU- Chemistry When an electropositive substituent is placed in a molecule, we should see the opposite type of effect than we saw when electronegative substituents were present. An electropositive substituent should show an electron- releasing (or electron-donating) inductive effect. An electron-releasing inductive effect is sometimes known as a +I effect. The following table lists several +I substituents.

42. WWU- Chemistry Substituents with Electron- Releasing Inductive Effects

43. WWU- Chemistry +I substituents weaken acids and strengthen bases

44. WWU- Chemistry To illustrate the resonance and inductive effects described in this unit, consider the following examples:

45. WWU- Chemistry The following table illustrates electron-withdrawing resonance effects. Notice how the pK a values compare with the reference compound, acetic acid.

46. WWU- Chemistry

47. The next table shows the effect on acidity that results from multiple substitution. Both electron- withdrawing and electron-releasing examples are included. Again, acetic acid is used as a reference.

48. WWU- Chemistry

49. In the next table, the effect of a chlorine substituent on the strength of a benzoic acid is shown. The reference compound is benzoic acid. -Cl has two competing effects: +R and -I In the case of the chloro group, the -I effect is larger than the +R effect, so we see the -I effect. As the chloro group moves farther away from the carboxyl group, the acid becomes weaker.

50. WWU- Chemistry In the case of the nitro substituent, both the inductive and resonance effects are electron- withdrawing (acid strengthening). But the nitro group is more effective from the para position than from the meta position. This is because the resonance effect is contributing in the para position.

51. WWU- Chemistry Benzoic Acid: pK a = 4.19

52. WWU- Chemistry In the next example, we see the larger +R effects of the methoxy and hydroxy groups predominating over the smaller -I effects. We can see that the substituted benzoic acids are significantly weaker when the -OH or -OCH 3 groups are in the para positions than when they are in the meta positions (where the +R effect is not significant). But we see that when we compare the two ortho- substituted benzoic acids, there is an anomaly. ortho-Hydroxybenzoic acid (salicylic acid) is much stronger than we would predict.

53. WWU- Chemistry Benzoic Acid: pK a = 4.19 2.97

54. WWU- Chemistry When there is a hydroxy group ortho to the carboxylic acid functional group, the carboxylate ion is stabilized through intramolecular hydrogen bonding.

55. WWU- Chemistry Finally, we see the acid-weakening effect (both +R and +I) of a methyl substituent. When the methyl group is in the para position, it is more effective in weakening the benzoic acid. This is because the +R effect is operating from the para position (when the methyl group is in the meta position, we only see the +I effect).

56. WWU- Chemistry Benzoic Acid: pK a = 4.19