Acid-Base ChemistryChapter 5

The equilibrium constant (Keq) gives quick insight into whether the reactant or productis more stable, and the extent to which the reactant or product is preferred.Brønsted acid: a proton donor, Brønsted base: a proton acceptor

5.1 Brønsted Acid-Base Chemistry

R ← P→

base acid

acid baseWhen in solution, all four species will be solvated, and solvation is one of the major Factors controlling which side of the equilibrium is preferred. Pyridine -> pyridinium, ROH -> ROH2

+, H3O+

5.2 Aqueous solutions5.2.1 pKa

The pKa values reflect the relative stabilities of the species on the different sides.

5.2.2 pH

Henderson-Hasselbalch equation

[A-] = [HA] -> pH = pKa

The pH gives the proton donor ability of the solution, and the pKa gives the proton donor ability of an acid.

1. When the pH is the same as the acid’s pKa, the solution has the same ability to protonatethe conjugate base A- as the acid HA has the ability to protonate the solvent, andhence the acid exists as a 1:1 ratio of its HA and A- form.

2. When the pH is above the pKa, the solution does not have enough donor ability to protonate the conjugate base, and therefore the acid exists mostly in its conjugate base form A-.

3. When the pH is below the pKa, the donor ability of the solution is strong enough to protonate A-, and mostly HA exists.

pH indicators: molecules that change color as a function of their protonation state.

C-H protonation

C-C protonation

:C O:

5.2.6 Super acids : extremely strong acidSolution formed from BF3, PF5, AsF5 and especially SbF5 in liquid HF, often diluted with FSO3H and SO2ClF. This creates acids of the extremely non-nucleophilic and non-coordinating anions BF4

-, PF6-, AsF6

- and SbF6-. Such solutions can protonate bases

as weak as benzene or alkanes to create persistent carbocations.

5.3 Nonaqueous systemsMost of the times pKa values change significantly when measured in different solvents, although there are examples where acidities are nearly identical in different solvents.2,4,6-trinitrophenol: DMSO and H2O, similar pKa valuesHCN is stronger acid than malonitrile (NCCH2CN) in H2O, but HCN is weaker acid than malonitrile (NCCH2CN) in DMSO.-> solvation has a large influence in altering the intrinsic ability of a compound to act as

a proton donor.1. The pKa values are almost always in the organic solvent than in water.2. The pKa differences are accentuated in the organic solvent, meaning that they tend

to spread out over a larger pKa range. The lower the polarity of the solvent, the higher the pKas of the various acids.

The lower the polarity of the solvent, the higher the pKas of the various acids.-> organic solvents are not very effectively stabilizing the charges created

when the acid donates its proton to the solvent.

Deprotonated anions of picric acid and malononitrile are highly delocalized, thus solvation effects would be expected to be less important -> similar pKa values in both solvents.

Strong solvating nature -> effectively stabilizes the anionicconjugate bases -> making the intrinsic stability of the bases less important -> the corresponding acidity differences between acids becomes smaller.

5.3.1 pKa shifts at enzyme active sitesOrganic solvents generally lower acidity, whereas polar solvents increase acidity.Electrostatic interactions influence acidity. The second pKa of a dicarboxylic acid is higher than the first pKa due to the formation of a distance with the associated electrostatic repulsion.

The active site of enzymes are not identical to water, and in fact are often considered quite organic in nature. However, they also can possess charges. Therefore, acids at enzyme active sites often have pKa that are quite different than the normal pKa for those acids in water.If a neutral acid, such as carboxylic acid, is placed in proximity to a positive charge, the acid willbecome more acidic because the resulting anionic conjugate base is stabilized due to electrostatic attraction. Conversely, when a positive acid, such as ammonium, is placed near a negative charge, it will become less acidic. Now the electrostatic attraction is lost when the acid donates its protonand becomes neutral. These effects can be quite large, and changes in acidity strength of four to five orders of magnitude are common.

5.4 Predicting acid strength in solution

- Electronegativity

Acidity: HF > ROH > R2NH > R3CH C CO

O H

HH

H

C COH

HH

pKa = 4.8 (DMSO) 19 (DMSO)

C CO

O

HH

H

C COH

HH H

- Inductive effects: when electronegativity effects arise from electron withdrawal by a remote group via sigma bonds, it is referred to as an inductive effect.

Alkyl substituents on localized carbanions are destabilizing.

PhSO2HCH

H PhSO2HCH

CH3

pKa = 29 (DMSO) 31 (DMSO)

- Resonance

Acetic acid: 4.76 (O에의한 inductive effect가더중요한 factor임)

10.02

CH3-OH 16.0

o-nitrophenol: 7.22m- : 8.36p- : 7.15Phenol: 10.02

Acetone: 20

CH3COCH2COCH3: 8.84

참조, Cyclohexanol: 17

Acidity of α-H: ketone > ester > amide > carboxylate

- Electrostatic effects

Neighboring charges greatly influence the ability to create further charges in close proximity.

+NH3CH2CO2H : 2.31, CH3CH2CO2H : 4.82

ylides

22.4

8.3(CH3)S+-CH2COPh

- Hybridization

Acidity:

pKa: 24 44 50

pKa: -12 5.23 (pyridinium) 10-11

sp > sp2 > sp3

sp > sp2 > sp3

- Aromaticity pKa: 16 61

- Solvation

The bulkier the alkyl group, the more difficulties it is for the solvent molecules to make close contact with and thereby to stabilize the O- in the alkoxide or carboxylate.

- Cationic organic structures

pKa: -15 -0 -12

A positive charge on a very electronegative group

5.5 Acids and bases of biological interestIsoelectric points

NH3+

NH2+

NH+

Positive nitrogen

pKa of α-H of mandelic acid: 22HO2C OH

H

pKa of lysine-NH3+: 10

How can a base (Lys) in enzyme abstract a-H of mandelic acid?1. Raise the pKa of the conjugate acid of the base bt changes in the environment

around this base, making it more basic.2. Present a microenvironment around the anionic conjugate base of the mandelate that is

so stabilizing that it induces the large increase in acidity. -> low barrier HB, ionic pairing effects and metal coordination

triple helical DNA

5.6 Lewis acids/bases and electrophiles/nucleophiles

Lewis acid (electrophile): an electron pair acceptorLewis base (nucleophile): an electron pair donor

Principle of hard and soft acids and bases (앞에서언급)

Lewis acid decreases pKa.