Chapter 3

An Introduction to Organic Reactions and Their Mechanisms

Acids and Bases
Created by Professor William Tam & Dr. Phillis Chang
Ch. 3 - 1

About The Authors

These Powerpoint Lecture Slides were created and prepared by Professor William Tam and his wife Dr. Phillis Chang. Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem. Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.

Ch. 2 - 2

1.

Reactions and Their Mechanisms

Almost all organic reactions fall into one of four categories: Substitutions Additions Eliminations Rearrangements

Ch. 3 - 3

Substitutions: one group replaces another

H3C Br + NaOMe
alkyl halides

MeOH

H3C

OMe + NaBr

H
alkane

+ Br

Br

Br

+ HBr

H + CH3Cl
aromatics

CH3 AlCl3 + HCl

Ch. 3 - 4

Additions: two molecules become one

H C H C H H + Br Br CCl4 H Br H C H C Br H

Cl Cl HC CH + 2 Cl Cl CCl4 H C C H Cl Cl

with multiple bonds

Ch. 3 - 5

Eliminations: one molecule loses the

elements of another small molecule
CH3 NaOMe MeOH heat H C H C CH3 H H C H CH3 C Br CH3

+ MeOH + NaBr
H H C H C H NaNH2 heat H C C H

Br Br

preparing double and triple bonds

+ 2H

NH2
Ch. 3 - 6

+ 2 NaBr

Rearrangements: reorganization of its

constituent parts
H H C C CH3 C H

H3C C H3C C

CH3 CH3

H3C

H3C

Ch. 3 - 7

1A. Homolysis and Heterolysis of Covalent Bonds

Homolysis

A B

homolytic bond cleavage

A + B
radicals

Ch. 3 - 8

Heterolysis

A B

heterolytic bond cleavage

A + B
ions

A B

A +B
Ch. 3 - 9

 Normally requires the bond to be polarized d+

A
d-

d-

Usually occurs with assistance

d+

A B

Y A +B
Ch. 3 - 10

2.

AcidBase Reactions

Many of the reactions that occur in organic chemistry are either acidbase reactions themselves or they involve an acidbase reaction at some stage Two classes of acidbase reactions are fundamental in organic chemistry BrnstedLowry Lewis acidbase reactions
Ch. 3 - 11

BrnstedLowry Acids and Bases Conjugate Acid of H2O

Cl
d-

Base (H+ acceptor)

d+

O H

+ H

O H

H +

Cl

Acid (H+ donor)

Conjugate Base of HCl

Ch. 3 - 12

2B. Acids and Bases in Water Hydronium ion (H3O+) is the strongest acid that can exist in water to any significant extent: Any stronger acid will simply transfer its proton to a water molecule to form hydronium ions Hydroxide ion (HO-) is the strongest base that can exist in water to any significant extent: Any base stronger than hydroxide will remove a proton from water to form hydroxide ions

Ch. 3 - 13

Total ionic reaction

H O H + H Cl
H O H
H + Cl + Na O H 2H O + Na + Cl H

H +

Cl

O H

Net reaction
H O H H +

Spectator ions
O H 2H O H

3.

Lewis Acids and Bases

Lewis Acids are electron pair acceptors Lewis Bases are electron pair donors Lewis Base (e pair donor)
dCl H d+ + NH3

Cl

+ H

NH3

Lewis Acid (e pair acceptor)

Ch. 3 - 15

Lewis Base (e pair donor)

d+ Cl Al d d
-

d-Cl + NH3 Cl

Cl Cl Al Cl NH3

Lewis Acid (e pair acceptor)

In Lewis acidbase theory, the attraction of oppositely charged species is fundamental to reactivity

Ch. 3 - 16

Ch. 3 - 17

4.

Heterolysis of Bonds to Carbon: Carbocations and Carbanions

d+ C Z dheterolysis C + Z

carbocation

dC

d+

heterolysis

carboanion
Ch. 3 - 18

Carbocations are electron deficient. They have only six electrons in their valence shell, and because of this, carbocations are Lewis acids
C carbocation (a Lewis acid) + B C B

anion (a Lewis base)

C carbocation (a Lewis acid)

O H

H water (a Lewis base)

Ch. 3 - 19

All Lewis acids are electrophiles. By accepting an electron pair from a Lewis base, a carbocation fills its valence shell
C + B C B

anion carbocation (a Lewis base) (a Lewis acid and electrophile)

Ch. 3 - 20

Carbon atoms that are electron poor because of bond polarity, but are not carbocations, can also be electrophiles

d+ dC O

Lewis base

Lewis acid electrophile

Ch. 3 - 21

Carbanions are Lewis bases &nucleophile

Ch. 3 - 22

Carbanions are Lewis bases A nucleophile is a Lewis base that seeks a positive center such as a positively charged carbon atom

Nu + d+ dC O electrophile Nu C O

nucleophile

C electrophile

Nu nucleophile

Nu
Ch. 3 - 23

5.

How to Use Curved Arrows in Illustrating Reactions

HO

NOT
NOT H

HO

N H

d-O C d+

N H

dO C d+

O H3C O H+ OH H3C

O O +H O
Ch. 3 - 24

6.

The Strength of BrnstedLowry Acids and Bases: Ka and pKa In contrast to strong acids such as HCl and H2SO4, acetic acid is a much weaker acid
O H3C OH + H2O H3C O O + H O H H

At 25oC, in a 0.1 M acetic acid solution, only about 1% of the acetic acid molecules ionize

Ch. 3 - 25

6A. The Acidity Constant, Ka

O H3C OH + H2O H3C O O + H O H H

Equilibrium constant (Keq)

Keq =

[CH3CO2 ]

[H3O ]

[CH3CO2H][H2O]
Ch. 3 - 26

For dilute aqueous solutions, the concentration of water is essentially constant (~55.5M); and the Keq expression can be written in terms of the acidity constant (Ka)
[CH3CO2 ]

Ka = Keq [H2O] =

[H3O ]

[CH3CO2H]

At 25C, the acidity constant for acetic acid is 1.76 x 10-5

Ch. 3 - 27

For any weak acid dissolved in water

HA + H2O

H3O
[H3O ] [A ] [HA]

+ A

Ka =
An An

acid with a large value of Ka a strong acid acid with a small value of Ka a weak acid
Ch. 3 - 28

6B. Acidity and pKa pKa = - log Ka pH = - log [H3O ]

For acetic acid the pKa is 4.75

pKa = - log [1.76 x 10-5] = - [- 4.75] = 4.75
Ch. 3 - 29

The larger the value of the pKa, the weaker the acid Increasing acid strength

CH3CO2H pKa = 4.75

Weak acid

>

CF3CO2H pKa = 0

>

HCl pKa = -7
Very strong acid
Ch. 3 - 30

6C. Predicting the Strength of Bases The stronger the acid, the weaker its conjugate base The larger the pKa of the conjugate acid, the stronger the base

Increasing base strength

Cl

CH3CO2

HO

Very weak base pKa (HCl) = -7

Weak base pKa (CH3CO2H) = 4.75

Strong base pKa (H2O) = 15.7

Ch. 3 - 31

Example
Base CH3OH H3C O H -2.5 H H H2O O H -1.74 H

Conjugate Acid pKa

Since CH3O H2 is a stronger acid than H3O , H2O is a stronger base than CH3OH

Ch. 3 - 32

 1. 2.

Explaining the differences in base strengths The factors to consider Two of the factors which influence the strength of a base are: the ease with which the lone pair picks up a hydrogen ion, the stability of the ions being formed.

In the methylammonium ion, the positive charge is spread around the ion by the "electron-pushing" effect of the methyl group. The more you can spread charge around, the more stable an ion becomes. In the ammonium ion there isn't any way of spreading the charge.

pKb CH3NH2 CH3CH2NH2 CH3CH2CH2NH2

3.36 3.27 3.16

Why are aromatic primary amines much weaker b

the lack of intense charge around the nitrogen, and the need to break some delocalisation - this means that phenylamine is a very weak base indeed.

7.

How to Predict the Outcome of AcidBase Reactions

Acidbase reactions always favor the formation of the weaker acid and the weaker base Acidbase reactions are under equilibrium control Reactions under equilibrium control always favour the formation of the most stable (lowest potential energy) species

Ch. 3 - 37

stronger base
O R O H + Na OH R

weaker base
O O Na + H O H

stronger acid pKa ~3-5

weaker acid pKa = 15.7

Ch. 3 - 38

7A. Water Solubility as the Result of Salt Formation Most carboxylic acids containing more than 5 carbons are insoluble in water However, due to their acidity, they are soluble in aq. NaOH
O R O H + Na OH R O O Na + H O H

(R>5 carbons) Insoluble in water

Soluble in water (due to its polarity As a salt)

Ch. 3 - 39

Similarly, amines with high molecular weights are insoluble in water However, due to their basicity, they are soluble in aqueous acids

NH 2 + H

O H

Cl

N H

Cl + H2O

Water Insoluble

Water Soluble (salt)

Ch. 3 - 40

8.

Relationships between Structure and Acidity

Two of the factors which influence the ionization of an acid are:

1.
2.

the strength of the bond being broken, the stability of the ions being formed.

8.

Relationships between Structure and Acidity

HF HCl HBr HI

Bond Length ()
pKa

0.92
3.2

1.28
-7

1.41
-9

1.60
-10

Increasing acidity

The strength of HX bond HF > HCl > HBr > HI 1. The stronger the HX bond, the weaker the acid. Ch. 3 - 42

Thus acidity increases as we descend a vertical column in a group in the Periodic Table
HF F
Cl Br
-

Increasing acidity

HCl HBr

Increasing basicity

HI

The stronger the acid, the weaker the conjugate base.

Ch. 3 - 43

H3CH H3NH

d-

d+

d-

d+

d-

d+

d-

d+

HOH

FH

Electro2.5 2.1 3.0 2.1 3.5 2.1 4.0 2.1 negativity

pKa

48

38

15.7

3.2

2. The higher the electronegativity of an atom, the easier it will acquire a negative charge. Ch. 3 - 44

Thus acidity increases from left to right when we compare compounds in the same row of the Periodic Table
Increasing acidity H3CH
CH 3

H2NH
NH 2

HOH
OH

FH
F

Increasing basicity
Ch. 3 - 45

Acidity increases within a given row (electronegativity effect)

Hydride pKa C (H3CH) 48 N (H2NH) 38 O (HOH) 15.7 S (HSH) 7.0 Se (HSeH) 3.9 F (FH) 3.2 Cl (ClH) -7 Br (BrH) -9

Acidity increases within a given column (bond strength effect)

Ch. 3 - 46

I (IH) -10

8A. The Effect of Hybridization

(50% s character) sp
H C C H H

(33.3% s character) sp2 H H

C C H

(25% s character) sp3 H H H C C H H H

pKa = 25

pKa = 44

pKa = 50

3. Having more s character means that the electrons of the anion will, on the average, be lower in energy, and the anion will be Ch. 3 - 47 more stable

Relative Acidity of the Hydrocarbons

H C C H > H C C H H > H H C H C H H H

Relative Basicity of the Carbanions

H C H C H H > H H C C H
Ch. 3 - 48

>

8B. Inductive Effects

Inductive effects are electronic effects transmitted through bonds The inductive effect of a group can be electron donating or electron

withdrawing

Inductive effects weaken as the distance from the group increases

Ch. 3 - 49

H3C

CH3

The CC bond is nonpolar.

H3C
2

d+

CH2
1

d+

dF

The positive charge that the fluorine imparts to C1 is greater than that imparted to C2 because the fluorine is closer to C1
Ch. 3 - 50

9.

Energy Changes The two fundamental types of energy are kinetic energy and potential energy Kinetic energy is the energy an object has because of its motion; it equals one-half the objects mass multiplied by the square of its velocity KE = m2
Ch. 3 - 51

Potential energy is stored energy. It exists only when an attractive or repulsive force exists between objects Chemical energy is a form of potential energy The more potential energy an object has, the less stable it is

Ch. 3 - 52

Potential energy exists between objects that either attract or repel each other. In the case of atoms joined by a covalent bond, the lowest potential energy state occurs when atoms are at their ideal internuclear distance (bond length). Lengthening or shortening the bond distance raises the potential energy.

Ch. 3 - 53

9A. Potential Energy and Covalent Bonds

Atoms and molecules possess potential energy often called chemical energy that can be released as heat when they react Because heat is associated with molecular motion, this release of heat results from a change from potential energy to kinetic energy
Ch. 3 - 54

Potential Energy and Covalent Bonds

Potential energy in molecules is stored in the form of chemical bond energy Enthalpy DHo is a measure of the change in bond energies in a reaction Exothermic reactions DHo is negative and heat is evolved Potential energy in the bonds of reactants is more than that of products Endothermic reactions DHo is positive and heat is absorbed Potential energy in the bonds of reactants is less than that of products

Chapter 3

55

H + H

DH o = - 436 kJ mol-1

The relative potential energies of hydrogen atoms and a hydrogen molecule

H + H
Potential Energy

436 kJ mol-1
H H
Ch. 3 - 56

10. The Relationship between Keq and DG

DG = - RT ln Keq
R is the gas constant = 8.314 J K-1 T is the absolute temperature in kelvins (K)

For a reaction to favor the formation of products when equilibrium is reached it must have a negative value for DG For reactions with a positive DG, the formation of products at equilibrium is unfavorable Ch. 3 - 57

DG = DH - T DS
DH is the enthalpy energy DS is the entropy energy
A negative value for DH will contribute to making DG negative and will consequently favour the formation of products The more random a system is, the greater is its DS A positive entropy change (from order to disorder) makes a negative contribution to DG and is energetically favourable for the formation of products

In many cases DSo is small and DGo is approximately equal to DHo

Ch. 3 - 58

11. The Acidity of Carboxylic Acids

O H3C OH CH3CH2 OH

Acetic acid

Ethanol

pKa = 4.75 DG = 27 kJ/mol

pKa = 16 DG = 90.8 kJ/mol

DG values are for OH proton ionization

Deprotonation is unfavorable in both cases but much less favorable for ethanol Ch. 3 - 59

CH3CH2O2

+ H3O

Free Energy Change

CH3CO2 + H3O

DG = 90.8 kJ/mol

DG = 27 kJ/mol CH3CO2H + H2O CH3CH2O2H + H2O

Ch. 3 - 60

O CH3 O H + H2O

O CH3 O + H3O

acetic acid

acetate

CH3CH2

H + H2O

CH3CH2

+ H3O

ethanol

ethoxide
Ch. 3 - 61

When comparing acidity of organic compounds, we compare the stability of their conjugate base. The more stable the conjugate base, the stronger the acid
CH3COOH pKa 4.75 CH3CH2OH 16
Ch. 3 - 62

11A. The Effect of Delocalization

The conjugate base acetate is more stable (the anion is more delocalized) than ethoxide due to resonance stabilization
O O O CH3 O CH3 O O

CH3

Thus, acetic acid is a stronger acid than ethanol

Ch. 3 - 63

11B. The Inductive Effect

O

<
CH3 O <H CH3CH2 O <H Acetic acid Ethanol

Stronger acid

Weaker acid
Ch. 3 - 64

11C. Summary and a Comparison of Conjugate AcidBase Strengths

The greater acidity of a carboxylic acid is predominantly due to the ability of its conjugate base (a carboxylate ion) to stabilize a negative charge better than an alkoxide ion, the conjugate base of an alcohol The conjugate base of a carboxylic acid is a weaker base than the conjugate base of an alcohol

Ch. 3 - 65

O CH3 O H + H2O

O CH3 O + H3O

acetic acid
STRONGER ACID

acetate
WEAKER BASE (stabilization of the anion through resonance + inductive e withdrawal)

CH3CH2

H + H2O

CH3CH2

+ H3O

ethanol
WEAKER ACID

ethoxide
STRONGER BASE
Ch. 3 - 66

Both acetic acid and acetate are stabilized by resonance Acetate is more stabilized by resonance than acetic acid This decreases DGo for the deprotonation

Neither ethanol nor its anion is stabilized by resonance There is no decrease in DGo for the deprotonation

Chapter 3

67

11D. Inductive Effects of Other Groups O O <

CH3 O <H pKa = 4.75
O Cl CH2 O H + H2O
dCl

<

Cl

CH2

O <H

pKa = 2.86
dO CH2 d O + H3O
Ch. 3 - 68

O Cl O Cl

O O

The Cl further stabilizes the carboxylate anion due to negative inductive effect of the Cl
Ch. 3 - 69

Organic acids

In an ethanoate ion, one of the lone pairs on the negative oxygen ends up almost parallel to these p orbitals, and overlaps with them.

Delocalisation the single oxygen atom is still the most electronegative thing present, and the delocalised system will be heavily distorted towards it. What delocalisation there is makes the phenoxide ion more stable than it would otherwise be, and so phenol is acidic to an extent. However, the delocalisation hasn't shared the charge around very effectively. There is still lots of negative charge around the oxygen to which hydrogen ions will be attracted - and so the phenol will readily reform. Phenol is therefore only very weakly acidic.

HCOOH CH3COOH CH3CH2COOH

pKa 3.75 4.76 4.87

Alkyl groups have a tendency to "push" electrons away from themselves. That means that there will be a small amount of extra negative charge built up on the -COO- group. Any build-up of charge will make the ion less stable, and more attractive to hydrogen ions.

CH3COOH CH2ClCOOH CHCl2COOH CCl3COOH

pKa 4.76 2.86 1.29 0.65

pKa CH3CH2CH2COOH CH3CH2CHClCOOH CH3CHClCH2COOH CH2ClCH2CH2COOH 4.82 2.84 4.06 4.52

CH2FCOOH CH2ClCOOH CH2BrCOOH CH2ICOOH

pKa 2.66 2.86 2.90 3.17

12. The Effect of the Solvent on Acidity

In the absence of a solvent (i.e., in the gas phase), most acids are far weaker than they are in solution In solution, solvent molecules surround the ions, insulating them from one another, stabilizing them, and making it far easier to separate them than in the gas phase Solvation of any species decreases the entropy of the solvent because the solvent molecules become much more ordered as they surround molecules of the solute
Ch. 3 - 75

O H3C OH + H2O H3C

O O + H O H H

Water molecules solvate both the undissociated acid (CH3CO2H) and its anion (CH3CO2) by forming hydrogen bonds to them However, hydrogen bonding to CH3CO2 is much stronger than to CH3CO2H because the water molecules are more attracted by the negative charge Acetic acid has pKa of 130 in the gas phase

Ch. 3 - 76

13. Organic Compounds as Bases

If an organic compound contains an atom with an unshared electron pair, it is a potential base

H3C

O H

+ H

Cl

H3C

O H

H +

Cl

Methanol

Methyloxonium ion (a protonated alcohol)

Ch. 3 - 77

O H

+ H

O H

H +

Alcohol

Strong acid

Alkyloxonium ion Weak base

O R

+ H

O R

H +

Ether

Strong acid

Dialkyloxonium Weak ion base

Ch. 3 - 78

O R R

+ H

A
R

H + R Weak base A

Ketone

Strong acid

Protonated ketone

Proton transfer reactions like these are often the first step in many reactions that alcohols, ethers, aldehydes, ketones, esters, amides, and carboxylic acids undergo
Ch. 3 - 79

14. A Mechanism for an Organic Reaction

CH3 H3C C CH3 tert-Butyl alcohol (soluble in H2O) OH + H O H Concentrated HCl
CH3 H3C C CH3 tert-Butyl chloride (insoluble in H2O)
Ch. 3 - 80

H +

Cl

H2O

Cl + 2 H2O

Step 1
CH3

CH3 H
O H + H O H H

H3C

C CH3

H3C

C CH3

H O H

+ H

Step 2
CH3 H CH2 H H3C C CH3 + H O H
Ch. 3 - 81

H3C

C CH3

Step 3
CH3 CH3 + Cl H3C C CH3 Cl

H3C

C CH3

Ch. 3 - 82

15. Acids and Bases in Nonaqueous Solutions

H C C H + NH2
H C

. +H C.

NH2

pKa = 25

(stronger base) (weaker base) pKa = 38

This reaction cannot be carried using water as solvent

H O H + NH2

... HO.

NH2

pKa = 15.7

pKa = 38
Ch. 3 - 83

Alkyl lithium reagents in hexane are very strong bases o The alkyl lithium is made from the alkyl bromide and lithium metal

Since water is a stronger acid than ethyne, NH2 will react with water first instead of ethyne

When NaNH2 is used, solvent such as hexane, Et2O or liquid NH3 can be used instead of water

Ch. 3 - 85

16. AcidBase Reactions & The Synthesis of 2H- & 3H-Labeled Compounds

Li

D + OD + Li

Deuterium (stronger acid) Isopropyl lithium (stronger base)

salt (weaker base)

2-Deuteriopropane (weaker acid)

Ch. 3 - 86

Ch. 3 - 87

 END OF CHAPTER 3

Ch. 3 - 88