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Substituent Effects on the Acidities of Carboxylic Acids 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. 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. WWU- Chemistry O R C O OH R C O + H + • Electron-withdrawing Effects: – strengthen acids – weaken bases • Electron-releasing Effects: – weaken acids – strengthen bases WWU- Chemistry Resonance Effects on the Acidities of Carboxylic Acids WWU- Chemistry Resonance Effects of Substituents Consider a substituent that contains multiple bonds. Let A B represent such a substituent, where B is more electronegative than A. WWU- Chemistry In other words, let’s compare the acidities of: O O and C B OH A C OH Which acid is stronger, and why? WWU- Chemistry The substituent will be a hybrid of two or more resonance forms of the type: A B A B 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. WWU- Chemistry To illustrate, consider a para-substituted benzoic acid. We can draw resonance forms: A B COOH A B A B COOH COOH A A B COOH B COOH WWU- Chemistry For the carboxylate ion, the corresponding resonance forms would be: A COO B A B COO A COO A B COO B A B COO 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: B B A A + H+ COOH COO 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. WWU- Chemistry A specific example of the -A=B type of substituent is the nitro group (-NO2). A nitro group in the para position of a benzoic acid strengthens the acidity by a factor of six (0.8 log units). O pKa = 4.19 C OH O O 2N pKa = 3.4 C OH WWU- Chemistry The nitro group stabilizes the carboxylate anion and shifts the equilibrium to the right. O O N O O N + H+ COOH COO NOTE: The nitro group also has an electron-withdrawing inductive effect; this has been ignored in this discussion. Inductive effects will be examined later. 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 electronwithdrawing 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. WWU- Chemistry Substituents with ElectronWithdrawing Resonance Effects O C OH carboxyl OR alkoxycarbonyl NO2 nitro O C C N cyano O C R acyl SO3H sulfo 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. WWU- Chemistry -R substituents strengthen acids and weaken bases 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 Y represent such a substituent. WWU- Chemistry In other words, let’s compare the acidities of: O O and C OH Y C OH Which acid is stronger, and why? 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. WWU- Chemistry To illustrate, consider a para-substituted benzoic acid. We can draw resonance forms: Y Y Y COOH COOH COOH Y Y COOH COOH WWU- Chemistry For the carboxylate ion, the corresponding resonance forms would be: Y Y Y COO COO COO Y Y COO COO 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: Y Y + H+ COOH COO 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. WWU- Chemistry A specific example of the -Y type of substituent is the methoxy group (-OCH3). A methoxy group in the para position of a benzoic acid weakens the acidity by a factor of 1.9 (0.27 log units). O pKa = 4.19 C OH O CH3 O pKa = 4.46 C OH WWU- Chemistry The methoxy group destabilizes the carboxylate anion and shifts the equilibrium to the left. CH3 CH3 O O + H+ COOH COO NOTE: The methoxy group also has an electronwithdrawing inductive effect; this has been ignored in this discussion. Inductive effects will be examined later. 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. WWU- Chemistry Substituents with ElectronReleasing Resonance Effects .. OH .. hydroxy .. OR .. alkoxy O .. SH .. mercapto .. O .. CH3 methyl CR3 alkyl amino .. NR2 dialkylamino fluoro .. Cl : .. chloro .. I: .. iodo .. NH2 .. F: .. .. Br : .. bromo C R acyloxy 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 electrondonating 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. WWU- Chemistry +R substituents weaken acids and strengthen bases WWU- Chemistry In the case of the alkyl substituents (which have no unshared pairs of electrons), their electron-releasing resonance effect arises from hyperconjugation. O pKa = 4.19 C OH O CH3 pKa = 4.36 C OH p-Methylbenzoic acid is less acidic than benzoic acid by a factor of 1.5 (0.17 log units) WWU- Chemistry Inductive Effects on the Acidities of Carboxylic Acids WWU- Chemistry Let’s now compare the acidities of two aliphatic carboxylic acids: O O H and CH2 C X OH CH2 C OH where X is an electronegative element. 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 electronwithdrawing 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: WWU- Chemistry Substituents with ElectronWithdrawing Inductive Effects O C OH carboxyl O C NO2 C OR alkoxycarbonyl nitro N cyano SO3H sulfo OR alkoxy O C R acyl NR2 OH SH NH2 Cl hydroxy mercapto amino chloro dialkylamino F fluoro Br bromo I iodo + N(CH3)3 trimethylammonium 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. WWU- Chemistry -I substituents strengthen acids and weaken bases WWU- Chemistry And one last case, again comparing two aliphatic carboxylic acids: O O H and CH2 C OH R CH2 C OH The alkyl substituent (R) is weakly electropositive with respect to a hydrogen. 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 electronreleasing (or electron-donating) inductive effect. •An electron-releasing inductive effect is sometimes known as a +I effect. •The following table lists several +I substituents. WWU- Chemistry Substituents with ElectronReleasing Inductive Effects CH3 methyl O CR3 alkyl O oxide C O carboxylate WWU- Chemistry +I substituents weaken acids and strengthen bases WWU- Chemistry To illustrate the resonance and inductive effects described in this unit, consider the following examples: WWU- Chemistry •The following table illustrates electron-withdrawing resonance effects. •Notice how the pKa values compare with the reference compound, acetic acid. WWU- Chemistry O CH3 C O OH pKa = 4.75 I CH2 C OH 2.66 O2N CH2 C CH2 C OH 2.86 HO OH 1.68 CH2 C OH 3.83 OH 2.34 O O Br CH2 C 3.12 O O Cl OH O O F CH2 C OH 2.86 H2N CH2 C WWU- Chemistry •The next table shows the effect on acidity that results from multiple substitution. Both electronwithdrawing and electron-releasing examples are included. •Again, acetic acid is used as a reference. WWU- Chemistry O CH3 C O OH pKa = 4.75 H CH2 C OH 2.86 CH3 C CH C OH 1.29 CH3 CH2 C Cl Cl OH 4.75 OH 4.88 OH 4.86 OH 5.05 O Cl O C C Cl 3.77 O O Cl OH O O Cl C CH3 CH C OH 0.65 CH3 CH3 O CH3 C C CH3 WWU- Chemistry •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. WWU- Chemistry •In the case of the nitro substituent, both the inductive and resonance effects are electronwithdrawing (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. WWU- Chemistry COOH COOH pKa = 2.92 2.16 Cl NO2 COOH COOH 3.82 3.47 NO2 Cl COOH COOH 3.98 Cl 3.41 O2N Benzoic Acid: pKa = 4.19 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 -OCH3 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 orthosubstituted benzoic acids, there is an anomaly. •ortho-Hydroxybenzoic acid (salicylic acid) is much stronger than we would predict. WWU- Chemistry COOH COOH pKa = 4.08 4.06 OCH3 OH COOH COOH 4.48 4.46 CH3 O HO COOH 2.97 OH Benzoic Acid: pKa = 4.19 WWU- Chemistry When there is a hydroxy group ortho to the carboxylic acid functional group, the carboxylate ion is stabilized through intramolecular hydrogen bonding. O C O H O 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). WWU- Chemistry COOH COOH H3C CH3 pKa = 4.27 4.36 Benzoic Acid: pKa = 4.19 WWU- Chemistry