Acids and Bases.

Answers to Problems

Daniel Palleros

Acids and Bases. Additional Problems

Answers
Problem 1
In order of decreasing acidity (approximate pKa given in parenthesis): sulfonic acids (R-SO3H; 0-1) > arylammonium salts (Ar-NH3+; 4-5) carboxylic acids (R-CO2H and Ar-CO2H; 4-6) > alkylammonium salts (R-NH3+, 9-10) imides (R-CO-NH-CO-R; 9-10) sulfonamides (R-SO2NH2; 9-10) phenols (Ar-OH; 9-11) > amides (R-CO-NH2; 15-16) > alcohols (R-OH; 16-18) > aldehydes and ketones (R-CH2-CO-R; 19-21) > terminal acetylenes (R-CCH; 25-27) > amines (R-NH2; 35-40) Keep this order in mind. Make an effort to memorize it. It will be of great help in solving the rest of the problems.

Problem 2
a)
H 3C N H3CO CH3 H 3C N H3CO N H CH2OH CH3 CH2O N CH3 CH3

alcohol; pKa 16-18

alkylammonium salt; pKa 9-10

OH2

OH O S NH O O S O N

protonated phenol; pKa ! "7

N-arylsulfonamides; pKa 6-7

b) To draw the conjugate acid, a proton must be added on the most basic atom. Ketones are extremely weak Lewis bases. They can be protonated on the oxygen atom by very strong acids at high concentration.
O H O

+ HA

+ A-

protonated ketone pKa -2 to -8

The following molecule is the conjugate base of an amide; it is a strong base.

Acids and Bases. Answers to Problems

Daniel Palleros

O NH

+ HA

NH2

+ A-

an amide; pKa 15-16

In the following molecule the two nitrogen atoms display different basicities. The nitrogen outside the ring (alkylamine) is more easily protonated. The nitrogen in the ring is forming part of the aromatic pyrrole system. The lone electron pair forms part of the aromatic electron cloud and, therefore, is not available for protonation.
aliphatic amine, basic
NH2 N H

pyrrole ring, nonbasic

NH2 N H

+ HA
N H

NH3

+ A-

an alkylammonium salt; pKa 9-10

The following molecule is the enolate of a ketone. Enolates are strong bases and can be easily protonated.
O O

+ HA

+ A-

the ! hydrogens of ketones are weakly acidic; pKa 19-21

Problem 3
a) Sulfonic acids are more acidic than carboxylic acids because the conjugate base of the former (sulfonates) is more stabilized by resonance than the conjugate base of the latter (carboxylates). sulfonic acids
O R-S OH O + H2O O R-S O O O R-S O O

O
R-S O O + H3O+

conjugate base stabilized by three resonance forms

Acids and Bases. Answers to Problems

Daniel Palleros

carboxylic acids
O R-C OH + H2O R-C O O R-C O O + H3O+

conjugate base stabilized by two resonance forms b) Arylammonium salts are more acidic than alkylammonium salts because the conjugate base of the former (aromatic amine) is stabilized by resonance. The lone electron pair is delocalized in the aromatic ring.
ArNH3+ ArNH2 + H3O+
aromatic amines: stabilized by resonance

+ H2O

arylammonium salts

NH2

H2N

H2N

NH2

H2N

RNH3+

+ H2O

RNH2

+ H3O+ aliphatic amines: not stabilized by resonance

alkylammonium salts

Problem 4
a) Sulfonamides. The conjugate base of sulfonamides is stabilized by three resonance forms.

O R-S NH2 O + H2O

O R-S NH O

O R-S NH O

O
+ R-S NH + H3O

Acids and Bases. Answers to Problems

Daniel Palleros

Amides. The conjugate base of amides is less stabilized than the conjugate base of sulfonamides because there are only two resonance forms.

O R-C NH2 + H2O

O R-C NH

O R-C NH + H3O+

b) N-arylsulfonamides are more acidic than sulfonamides because N-arylsulfonamides conjugate bases are more stabilized by resonance by virtue of electron delocalization in the aromatic ring.
O R-S NH-Ar + H2O O H3O+ + O R-S N O O R-S N O

O R-S O N

O R-S O N

O R-S O N

O R-S O N

O R-S N O

O R-S N O

O R-S O N

Problem 5
a) The compounds in question are an alcohol (neutral in water), a carboxylic acid, a phenol (weak acid) and a carboxylic acid substituted with a nitro group (a strong e-WD group). Least acidic: the alcohol; most acidic p-nitrobenzoic acid.
OH O OH OH O2N O OH

b) The compounds in question are alcohols with different degree of substitution. Halogens are e-WD groups by inductive effect, which is the main effect in these alcohols (they lack orbitals and therefore show no resonance effects). The closer the halogen to the alcohol, the more acidic the OH group. The larger the number of halogens, the more acidic the OH group.
OH OH Cl Cl Cl Br OH OH

Acids and Bases. Answers to Problems

Daniel Palleros

c) The compounds in question are all substituted phenols. The OCH3 and the NO2 groups from the meta position are e-WD by inductive effect, and thus increase their acidity. There is no important resonance effect from the meta position. The -NO2 group from the para position is a strong e-WD group by inductive effect and resonance, thus pnitrophenol is the most acidic. The methyl group from the para position is e-donor (by inductive effect), thus p-methylphenol is the least acidic.

OH

OH

OH H 3C

OH O2N

OCH3

NO2

d) The compounds in question are arylammonium salts. The CN and the -Cl are both eWD overall. Of the two groups, the CN is a stronger e-WD group because it is e-WD by both inductive and resonance effects while the Cl is e-WD by inductive and e-donor by resonance. Therefore p-cyanoaniline is the least basic (p-cyanoanilinium ion the most acidic). The methyl group is e-donor by inductive effect, thus p-methylanilinium ion is the least acidic.

NH3 NC

NH3 H 3C

NH3 Cl

NH3

e) The compounds in question differ in the hybridization of the C atoms. The terminal acetylene (sp-hybridized) is the most acidic; ethylcyclohexane with all sp3-hybridized carbon atoms, is the least acidic.

f) The compounds in question show a very wide range of acidity. They are a terminal acetylene (very weak acid), a thiol (weak acid), a sulfonic acid (strong acid) and a phenol (weak acid). The sulfonic acid is the most acidic and the acetylene the least acidic.

Acids and Bases. Answers to Problems

Daniel Palleros

H SH SO3H OH

g) The functional groups are amide, amine and imide. All three compounds are slightly acidic; the H attached to the N can be removed by strong bases. The imide is the most acidic because the conjugate base is stabilized by the presence of two carbonyl groups (eWD groups by inductive effect and resonance). The alkylamine is the least acidic because the conjugate base (CH3CH2NH-) has the negative charge localized on the N.

CH3CONH2 amide

CH3CH2NH2 amine

CH3CO-NH-COCH3 imide

Problem 6
a) The functional groups involved are carboxylic acid (more acidic; pKa 4-6) and phenol (less acidic; pKa 9-11). Trichloroacetic acid, a carboxylic acid with three chlorine atoms close to the OH, is the most acidic (pKa 0.52), followed by m-fluorobenzoic acid (fluorine is an e-WD group), pKa 3.87, and then by p-methylbenzoic acid (methyl is e-donating). pKa 4.37. The most acidic of the two phenols is m-bromophenol (bromine is e-WD), pKa 8.87.
OH OH COOH COOH H 3C F

Cl3CCOOH

Br

8.87

10.0

3.87

4.37

0.52

b) The functional groups involved are arylammonium salts (more acidic) and alkylammonium salts (less acidic). Methylammoniun is the least acidic of the four compounds, pKa 10.62. Of the remaining three, all arylammonium ions, the most acidic is the one with the NO2 group (e-WD), pKa 1.00 and the least acidic the one with the methyl group (e-donor), pKa 5.08.
NH3 NH3 NH3 H3C

CH3NH3
O2N

4.63

10.62

1.00

5.08

c) Maleic acid is the most acidic, pKa 1.92, because the conjugate base is stabilized by the formation of an intramolecular H-bond. Fumaric acid cannot form such a bond and its less acidic than maleic acid. cis-2-Butenoic acid (isocrotonic acid) is less acidic (pKa

Acids and Bases. Answers to Problems

Daniel Palleros

4.44) than fumaric acid because the methyl group is an electron donor whereas the second carboxyl group in fumaric acid is not.
isocrotonic acid
O OH

maleic acid
O OH HO OH O

fumaric acid
O OH

maleic acid, conjugate base

O O

CH3

H O O

4.44

1.92

3.02

Problem 7
When only one equivalent of acid or base is used, the most basic or acidic group reacts. To solve this problem you must first identify those reactive groups. The rank of acidity given in Problem 1 will help. a)
O OH O

+ NaOH ( 1 eq.)
OH OH

Na

+ H2O

b)
NH2 NH3

+ HCl (1 eq.)
N N

Cl

c)
OCH3 OCH3

+
N

SO3H N H

SO3

d)
NH3 NH2

+ NaOH (1 eq.)
OH OH

+ H2O + Na

e)
O NH O O

+ NaOH
O

Na

+ H2O

f) Alkylammonium salts and phenols have similar pKa values. Thus, treatment with one equivalent of base produces a mixture of conjugate bases.

Acids and Bases. Answers to Problems

Daniel Palleros

NH3

NH2

NH3

+ NaOH (1 eq.)
OH OH

+
O

+ H2O

+ Na

g)
NH3 NH2

+ NaOH (2 eq.)
OH O

+ 2 H2O + 2 Na

Problem 8
To determine the direction in which the equilibrium is shifted, first find the acids on both sides of the reaction and look for their pKa values (Table 1 is a good source; the supplemental material text is another). If you cannot find the exact pKa value use an approximate one. Identify the stronger acid. The reaction is shifted in the direction from the stronger acid to the weaker acid (low pKa to high pKa). a)
OH O- Na+

+ NaHCO3 alcohols: pKa 16-18

+ H2CO3 carbonic acid: pKa 6.38

b)
NH2 NH- Li+

+ amines: pKa 35-40

Li

+ alkanes: pKa 50-60

c)
+ CF3COOH
N N

+ CF3COOH

pKa 0.59

pyridinium ions: pKa 3-6

Problem 9
a) According to Table 1, the estimated pKa values for the functional groups in 8hydroxyquinoline are: for the conjugate acid of the pyridine, pKa 3-6; phenols, pKa 9-11. Thus, the observed pKa values of 5.02 and 9.81 can be assigned to the pyridinium cation and the phenol, respectively.

Acids and Bases. Answers to Problems

Daniel Palleros

N OH

N OH H

phenol: weakly acidic

pyridine: weakly basic

pKa2 9.81

pKa1 5.02

b) At pH 2, pH < pKa1, 8-hydroxyquinoline is found mainly in its protonated, ionic form. At pH 7, an intermediate pH between both pKa values, pKa1 < pH < pKa2, the main form of the compound has no charge. At pH 10, pH > pKa2, it is found mainly in the anionic form.

N OH H OH

N O

pH 2

pH 7

pH 10

Problem 10
a), b) The presence of the Cl and I on the quinoline ring is expected to increase the acidity of both the pyridinium and phenolic groups because Cl and I are electron withdrawing elements. Thus, the following assignment of pKa values can be made:
Cl

I OH

N H

pKa 7.24

pKa 2.10

Problem 11
a) The estimated pKa values are given below.
aryl halide: neutral
O F CO2H

ketone: neutral

aromatic amine: weakly basic pKaBH+ 4-5

carboxylic acid: acidic pKa 4-6

N H

aromatic amine: weakly basic pKaBH+ 4-5

aliphatic amine: basic pKaBH+ 9-10

b) At pH 2, a pH lower than all the estimated pKa values, Ciprofloxacin will be protonated, even on the weakly basic aromatic amine nitrogens. At pH 7, all the

Acids and Bases. Answers to Problems

10

Daniel Palleros

hydrogens with pKa < 7 will go (aromatic ammonium ions, carboxylic acids), and at pH 11, the alkylammonium ion (pKa 9-10) also gets deprotonated.
O F H N N H H H CO2H F O CO2 F O CO2

N H N H

N N H

pH 2

pH 7

pH 11

Problem 12
a), b)
carbamate: neutral
H3C O HN CH3 O N CH3 N

alkylamine: basic
CH3

aromatic amine: weakly basic

The functional groups in Physostigmine are: An alkylamine, basic; an aromatic amine, weakly basic, and a carbamate, neutral (think of a carbamate (R-NH-CO-OR) as a functional group comprised of an ester and an amide that share the carbonyl; carbamates are neutral because both the ester and the amide groups are neutral). The group that will first get protonated is the alkylamine.
H 3C O HN CH3 O N CH3 H N CH3

SO42-

c) The pKa of the ammonium salt is 8.4. At the pH of blood, pH 7.4, pH < pKa, the drug will be protonated. Thus, the major form at this pH is the ionized form as shown above.

Problem 13
a) Histamine has two functional groups, an alkylamine and an imidazole ring. According to Table 1 the pKa values are 9-10 and 5-7, respectively. Thus, pKa1 = 5.80 must correspond to the imidazole and pKa2 = 9.40 to the alkylammonium group.
NH3

alkylammonium ion: pKa 9-10

H N N H

imidazole ring; pKa 5-7

b) The imidazole ring is aromatic. There are two major resonance forms in which the positive charge is delocalized between the two nitrogens of the ring. Other resonance

Acids and Bases. Answers to Problems

11

Daniel Palleros

forms can also be drawn but they are not as important because they involve energetically unfavorable separation of charges inside the ring.
NH3 NH3 NH3

N H

N H H

important resonance forms

NH3

NH3

N H

N H H

N H

c) If it wasnt for the side chain, the two imidazole hydrogens would be identical. They are expected to have very similar pKa values. In fact, it is impossible to assign pKa1 to either hydrogen in particular. d) When the first equivalent of HO- is added, a mixture of two tautomers (in similar amounts) is produced. When the second equivalent of base is added the alkylammonium group gets deprotonated.

NH3

NH3

N
H

N H

pKa 5.80

HO1 eq. pKa 9.40

NH3 NH3

+
H N N

+ H2O

HO1 eq.
NH2

NH2

+
H N H N

+ H2O

Note that once the protonated imidazole ring loses its first proton, the removal of the second proton from the ring becomes much more difficult taking place only at very high pH values (pKa of the imidazole H is approximately 14.5).
pKa 14.5
N N H

+ H2O

+ H3O+

Acids and Bases. Answers to Problems

12

Daniel Palleros

Problem 14
a) The conjugate acid of Warfarin is:
O OH

b) The high acidity of the OH group (pKa 4.50) is due to the great stabilization of the anion by resonance. The stabilization by resonance is less important in the anions of phenols and lacking altogether in the anions of alcohols. In Warfarin, the negative charge is delocalized between two oxygen atoms which are very tolerant of negative charges (while in phenolates the negative charge is delocalized on the carbons of the ring see Supplemental Material p. 15 which are much less tolerant of negative charges than the oxygens). The kind of delocalization found in Warfarin is similar to that of the carboxylate anion where the negative charge is delocalized between two oxygen atoms, see Problem 3. Therefore, it is not surprising that the pKa of Warfarin is similar to those of carboxylic acids. Warfarin has also a third resonance form (absent in carboxylic acids) in which the negative charge is on a carbon atom, but its contribution to the stability of the anion is less important.
O O O O

O O

Problem 15
a) Etomidate
imidazole: basic

ester: neutral
O N O

The two functional groups are the basic imidazole ring and the neutral ester group. The imidazole ring is aromatic. The pKa of the conjugate acid of the imidazole is approximately 5-7. The N atom with the electron pair outside the ring is the most basic one. The other N is not basic because the electron pair forms part of the aromatic cloud and it is not available for protonation (protonation destroys the aromaticity).

Acids and Bases. Answers to Problems

13
nonbasic

Daniel Palleros

basic

Reaction of Etomidate with one equivalent of HCl produces the Etomidate hydrochloride shown below.
N O N H N

Cl
O N O

HCl , 1 eq.
O

There is no acid-base reaction between Etomidate and NaOH. b) Clopidogrel

aryl chloride: neutral

Cl N

thiophene: neutral

OCH3

alkylamine: basic

ester: neutral

The functional groups are: The aryl chloride which is neutral; the alkylamine which is basic (the pKa of its conjugate acid is 9-10); the ester group which is also neutral; and the heterocyclic thiophene, which despite the sulfurs two electron pairs is neutral. In thiophene, one electron pair is inside the ring and is involved in the aromaticity of the ring and thus not available for protonation; the second electron pair is not likely to get protonated because it is rather stabilized being spread over the large volume of the big sulfur atom. When Clopidogrel reacts with one equivalent of HCl the following hydrochloride is formed:
Cl N H O OCH3 S

Cl

Clopidogrel does not have an acid-base reaction with NaOH.

Acids and Bases. Answers to Problems

14

Daniel Palleros

c) Captopril
amide: neutral
O N CH3 CO2H

HS

thiol: acidic

carboxylic acid: acidic

Captopril has three functional groups: An amide group which is neutral; a carboxylic acid group with an estimated pKa from Table 1 of 4-6 (experimental pKa 3.7); and a thiol group which is mildly acidic (estimated pKa from Table 1, 10-11; experimental pKa 9.8). Captopril does not react with HCl. The reaction with one equivalent of NaOH gives the following carboxylate:
O N CH3 CO2 Na

HS

Problem 16
a)
alcohol: neutral aryl fluoride: neutral
HO OH F N O OH

carboxylic acid: acidic

NH O

pyrrole: neutral

amide: neutral

b) The only group with acid-base properties in water is the carboxylic acid. According to Table 1, estimated pKa 4-6 (experimental value 4.3). c) At pH 3 (pH < pKa) the acid is in its protonated, undissociated form as shown in the structure above. At pH 8 (pH > pKa) the acid is dissociated as shown below:

Acids and Bases. Answers to Problems

15
O OH O

Daniel Palleros

HO

F N

NH O

Problem 17
a) According to Table 1, the estimated pKa values for the two functional groups with acid/base properties are: conjugate acid of pyridine, pKa 5-7; conjugate acid of alkylamine, pKa 9-10. Thus, the observed pKa values of 4.2 and 8.6 can be assigned to the pyridinium cation and the alkylammonium cation, respectively.
alcohol: neutral ether: neutral

HO CH3O

N HO CH3O
alkylamine: basic

N
H

N
pyridine: weakly basic

N
H

pKa2 8.6

pKa1 4.2

b) When quinine reacts with the first equivalent of HCl, the most basic N (the alkylamine) gets protonated. With the second equivalent, the less basic pyridine N also gets protonated.

HO CH3O N

N HO HCl 1 eq. CH3O N

H

N Cl

HCl 1 eq.

HO CH3O N
H

N
H

Cl

Cl

Acids and Bases. Answers to Problems

16

Daniel Palleros

Problem 18
For an acid of the type HA, the degree of ionization is given by equation 27, rewritten below:

"=

1 1+ 10 pK a # pH

a) If the pH is at least two units above the pKa, then pKa pH - 2. Therefore,

"#

1 1 = = 0.99 $2 1+ 10 1+ 0.01

This means that at a pH at least two units more basic than the pKa, the acid is at least 99% ionized in the A- from. ! b) If the pH is at least two units below the pKa, then pKa pH 2. Therefore,

"#

1 1 = = 0.0099 2 1+ 10 1+ 100

This means that at a pH at least two units more acidic than the pKa, the acid is less than 0.99 % ionized, or in other words, the acid is more than 99% undissociated, in the HA form. !

Problem 19
a), b) Saccharin has a rather low pKa value (pKa = 1.6). The saccharins high acidity is due to the stabilization of the conjugate base by resonance. The functional group in saccharin is a sulfonimide: the NH group is surrounded by two electron-withdrawing groups, the carbonyl and the sulfone groups. This makes the hydrogen atom particularly acidic.
O NH S O O
O O N S O O

+ H2O

H3O+ +
S O

N O

O N S O O O

O N S O

c) For HA-type acids, such as saccharin, the degree of ionization, , can be calculated with the help of equation 27, rewritten below:

Acids and Bases. Answers to Problems

17

Daniel Palleros

"=

1 1+ 10 pK a # pH

At pH 1.4 (empty stomach), the degree of ionization is:

"=

1 1 = = 0.39 1.6#1.4 1+ 10 1+ 10 0.2

% ionization = 39%

At pH 4.0 (full stomach), the degree of ionization is:

"=

1 1 = = 0.996 1.6#4.0 1+ 10 1+ 10#2.4

% ionization = 99.6%

At pH 8.0 (in the intestine), the degree of ionization is:

"=

1 1 = = 1.000 1.6#8.0 1+ 10 1+ 10#6.4

% ionization = 100%

! d) No. Saccharin is largely ionized, especially in the intestine and the full stomach, and therefore not easily absorbed. This is a plus because after eliciting the sweet taste in the mouth, saccharin is excreted from the organism without being absorbed. This reduces its potential side effects.
e) The sodium salt is used to increase its solubility in water.

Problem 20
a)
alcohol: neutral
H O N O

pyridine: weakly basic

amide: neutral

Acids and Bases. Answers to Problems

18

Daniel Palleros

b)
H O N O N H O N N O H

+ H2O

HO-

pKa = 5.2

c) The degree of ionization for ammonium salts, BH+, is given by eq. 28, rewritten below.

"=

1 1+ 10 pH # pK a

At pH 4, the pH of the buffered eye drops, the degree of ionization is:

"=

1 1 = = 0.941 4.0#5.2 1+ 10 1+ 10#1.2

At pH 4, more than 94% of the Tropicamide molecules are ionized. This high degree of ionization makes Tropicamide soluble in water and ensures an easy delivery to the eye. ! At pH 7.4, the physiological pH of the eye fluid, the degree of ionization is only about 0.6%.

"=

1 1 = = 0.006 7.4#5.2 1+ 10 1+ 10 2.2

At this pH, Tropicamide is largely nonionized and thus insoluble in water, making its delivery to the eye difficult. This is why Tropicamide is applied in a buffered solution at ! pH 4.

Problem 21
a)
H O N N O O O H H N N O O O O H N N O

+ H2O

H O N N O O

+ H3O+

b) The degree of ionization for HA-type acids is:

Acids and Bases. Answers to Problems

19

Daniel Palleros

"=

1 1+ 10 pK a # pH

At pH 1.8, in the empty stomach, the degree of ionization of Phenobarbital is close to zero: ! 1 1 "= = $0 7.5#1.8 1+ 10 1+ 10 5.7 At pH 8.0, in the intestine, the degree of ionization of Phenobarbital is 76%:

"=

1 1 = = 0.76 7.5#8.0 1+ 10 1+ 10#0.5