Chapter 3

An Introduction to Organic Reactions and Their Mechanisms

Click to edit Master Acids and Bases subtitle style

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

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. 2Ch. 2 - 2

1.

Reactions and Their Mechanisms

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

3Ch. 3 - 3

Substitutions
t

Characteristic reactions of saturated compounds such as alkanes and alkyl halides and of aromatic compounds (even though they are unsaturated) In a substitution, one group replaces another

4Ch. 3 - 4

Examples

H3C

Br + NaOMe

MeOH

H3C

OMe + NaBr

+ Br

Br

Br

+ HBr

H + CH3Cl AlCl3

CH3 + HCl
5Ch. 3 - 5

Additions
t t

Characteristic of compounds with multiple bonds In an addition all parts of the adding reagent appear in the product; two molecules become one

6Ch. 3 - 6

Examples

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

7Ch. 3 - 7

Eliminations
t

In an elimination one molecule loses the elements of another small molecule Elimination reactions give us a method for preparing compounds with double and triple bonds

8Ch. 3 - 8

Examples

H H C H

CH3 C Br CH3

NaOMe MeOH heat

H C H C

CH3 CH3

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

Br Br

+ 2H

NH2

+ 2 NaBr
9Ch. 3 - 9

Rearrangements In a rearrangement a molecule undergoes a reorganization of its constituent parts Examples

H H3C C C CH3 C

H H

H3C C H3C C

CH3 CH3

H3C

10Ch. 3 - 10

1A.
v

Homolysis and Heterolysis of Covalent Bonds

Homolysis

homolytic bond cleavage

A + B
radicals

11Ch. 3 - 11

Heterolysis

heterolytic bond cleavage

A + B
ions

A B

A + B
12Ch. 3 - 12

Normally requires the bond to be polarized

Usually occurs with assistance

A B

Y A + B
13Ch. 3 - 13

2.

AcidBase Reactions

v v

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

14Ch. 3 - 14

2A.
v v v

BrnstedLowry Acids and Bases BrnstedLowry acidbase reactions involve the transfer of protons
A BrnstedLowry acid is a substance that can donate (or lose) a proton A BrnstedLowry base is a substance that can accept (or remove) a proton

15Ch. 3 - 15

Example

Base (H+ acceptor)

Conjugate Acid of H2O

O H

+ H

Cl

O H

H +

Cl

Acid (H+ donor)

Conjugate Base of HCl

16Ch. 3 - 16

2B.
v v

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

Acids and Bases in Water

17Ch. 3 - 17

Total ionic reaction

O H

H + Cl

+ Na

2H

O + Na + Cl H

Spectator ions

Net reaction

O H

2H

O H
18Ch. 3 - 18

3.

Lewis Acids and Bases

v v

Lewis Acids are electron pair acceptors Lewis Bases are electron pair donors

Lewis Base (e pair donor)

Cl

NH3

Cl

+ H

NH3

Lewis Acid (e pair acceptor) 19Ch. 3 - 19

Lewis Base (e pair donor)

+ Cl Al

Cl + NH3
Lewis Acid (e pair acceptor)

Cl Cl Al Cl NH3

Cl

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

20Ch. 3 - 20

4.

Heterolysis of Bonds to Carbon: Carbocations and Carbanions

+ C

heterolysis

carbocation

heterolysis

carboanion
21Ch. 3 - 21

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)

anion (a Lewis base)

C carbocation (a Lewis acid)

O H

H water (a Lewis base)

22Ch. 3 - 22

4A.
v

Electrophiles and Nucleophiles Because carbocations are electron-seeking reagents, chemists call them
electrophiles (meaning electron-loving) Electrophiles are reagents that seek electrons so as to achieve a stable shell of electrons like that of a noble gas

23Ch. 3 - 23

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

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

24Ch. 3 - 24

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

+ C O

Lewis base

Lewis acid electrophile

25Ch. 3 - 25

v v

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

Nu

+ C O electrophile

Nu

nucleophile

C electrophile

Nu nucleophile

Nu
26Ch. 3 - 26

5.

How to Use Curved Arrows in Illustrating Reactions

Curved arrows

show the direction of electron flow in a reaction mechanism point from the source of an electron pair to the atom receiving the pair always show the flow of electrons from a site of higher electron density to a site of lower electron density never show the movement of atoms. Atoms are assumed to follow the flow of the electron

27Ch. 3 - 27

Examples

HO

NOT NOT H

HO

N H
O

O C +

N H
O

O C +

H3C

H+

OH

H3C

O +H

28Ch. 3 - 28

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

O OH + H2O H3C O + H O H H

At 25oC, in a 0.1 M acetic acid solution, only about 1% of the acetic acid molecules ionize 29Ch. 3 - 29

6A.

The Acidity Constant, Ka

O H3C OH + H2O H3C

O O + H O H H

Equilibrium constant (Keq)

[CH3CO2] [H3O]
Keq =

[CH3CO2H][H2O]

30Ch. 3 - 30

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] [H3O]
Ka = Keq [H2O] =

[CH3CO2H]
At 25C, the acidity constant for acetic acid is 1.76 x 105

31Ch. 3 - 31

For any weak acid dissolved in water

HA + H2O
[H3O] [A]
Ka =

H3O

+ A

[HA]
v v

An acid with a large value of Ka a strong acid An acid with a small value of Ka a weak acid

32Ch. 3 - 32

6B.

Acidity and p Ka

pKa = log Ka

pH = log [H3O]

For acetic acid the pKa is 4.75

pKa = log [1.76 x 105] = [ 4.75] = 4.75

33Ch. 3 - 33

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

Increasing acid strength

CH3CO2H pKa = 4.75

>

CF3CO2H pKa = 0

>

HCl pKa = 7

Weak acid

Very strong acid

34Ch. 3 - 34

Relative Strength of Selected Acids & Their Conjugate Bases

Increasing acid strength

O S O pKa Conjugate Base -7 -6.5 O Cl Ph S O O -2.9 O Acid HCl Ph OH O

H H3C O

H H H -2.5 O

H HNO3 H -1.74 -1.4

CH3OH

H2O

NO3

Increasing base strength

35Ch. 3 - 35

(Cont'd)

O Acid F3C pKa Conjugate Base

Increasing acid strength

O HF OH Ph 3.2 4.21 O F Ph Ph O O OH Ph

H N H 4.63 H H3C

O OH 4.75 O

0.18 O F3C

NH2

H3C

Increasing base strength

36Ch. 3 - 36

(Cont'd)

O Acid

Increasing acid O strengthH

H H N H 9.2 O 9.9 H

OH H3C

H N H 10.6 15.7 H H O H

pKa Conjugate Base O

9.0

O NH3 CH3NH2 HO

Increasing base strength

37Ch. 3 - 37

(Cont'd)

Increasing acid strength

Acid pKa Conjugate Base OH OH 16 18 O O 19.2 O O H HC 25 HC C H H 35 H H

Increasing base strength

38Ch. 3 - 38

(Cont'd)

Increasing acid strength

H Acid H2N H H2C H pKa Conjugate Base 38 NH2 44 H2C CH H3C H3C H C H 50 CH2 H

Increasing base strength

39Ch. 3 - 39

6C.
v v

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 Very weak base pKa (HCl) CH3CO2 Weak base pKa (CH3CO2H)

HO Strong base pKa (H2O)

40Ch. 3 - 40

Example

Base

CH3OH H3C O H -2.5 H H

H2O O H -1.74 H

Conjugate Acid p Ka
v

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

41Ch. 3 - 41

7.

How to Predict the Outcome of AcidBase Reactions

v v v

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

42Ch. 3 - 42

stronger base

weaker base

O R O
stronger acid pKa ~3-5

O H + Na OH R O Na + H O H

weaker acid pKa = 15.7

43Ch. 3 - 43

7A.

Water Solubility as the Result of Salt Formation

v v

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)

44Ch. 3 - 44

v v

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

NH2 + H
Water Insoluble

O H

Cl

N H

Cl + H2O

Water Soluble (salt)

45Ch. 3 - 45

8.

Relationships between Structure and Acidity

HF Bond Length ()0.92 pKa3.2

v

HCl 1.28 -7

HBr 1.41 -9

HI 1.60 -10

The strength of HX bond HF > HCl > HBr > HI

Increasing acidity

The stronger the HX bond, the weaker the acid. 46Ch. 3 - 46

Thus acidity increases as we descend a vertical column in a group in the Periodic Table

HF Increasin g acidity HCl HBr HI

F Cl Br I Increasin g basicity

The stronger the acid, the weaker the conjugate base. 47Ch. 3 - 47

H3CH H3NH 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

The higher the electronegativity of an atom, the easier it will acquire a negative charge.

48Ch. 3 - 48

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

Increasing acidity H3CH CH3 H2NH NH2 HOH OH FH F

Increasing basicity
49Ch. 3 - 49

Acidity increases within a given row (electronegativity effect)

Hydride pKa C N (H3CH) (H2NH) 48 38 O (HOH) 15.7 S (HSH) 7.0 Se (HSeH) 3.9 F (FH) 3.2 Cl (ClH) -7 Br (BrH) -9 I (IH) -10

Acidity increases within a given column (bond strength effect)

50Ch. 3 - 50

8A.

The Effect of Hybridization

(50% s character) sp
H C C H

(33.3% s character) sp2 H H C C H H

pKa = 44

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

pKa = 50

pKa = 25

Having more s character means that the electrons of the anion will, on the average, be lower in energy, and the anion will be 51Ch. 3 - 51 more stable

Relative Acidity of the Hydrocarbons

H H C C H > H C C

H > H

H C H C

H H H

Relative Basicity of the Carbanions

H C H C H H >

H C H C H
52Ch. 3 - 52

>

8B.

Inductive Effects

v v v

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

53Ch. 3 - 53

H3C

CH3

The CC bond is nonpolar.

+ H3C
2
v

CH2
1

The positive charge that the fluorine imparts to C1 is greater than that imparted to C2 because the fluorine is closer to C1

54Ch. 3 - 54

9.

Energy Changes

v v

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 onehalf the objects mass multiplied by the square of its velocity KE = m2

55Ch. 3 - 55

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

v v

56Ch. 3 - 56

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.
57Ch. 3 - 57

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

58Ch. 3 - 58

H + H
H o = 436 kJ mol1

The relative potential energies of hydrogen atoms and a hydrogen molecule

H + H
Potential Energy

436 kJ mol1

H
59Ch. 3 - 59

10.

The Relationship between Keq and G

G = RT ln Keq

v v

R is the gas constant = 8.314 J K1 T is the absolute temperature in kelvins For reaction to favor the (K)a have a negative valueformation of products when equilibrium is reached it must for G
For reactions with a positive G, the formation of products at equilibrium is unfavorable

60Ch. 3 - 60

G = H T S

H is the enthalpy energy Svalue for H will contribute to is the entropy energy v A negative making G negative and will consequently favour the formation of products v The more random a system is, the greater is its S v A positive entropy change (from order to disorder) makes a negative contribution to G and is energetically favourable for the 61Ch. 3 - 61 formation of products

11.

The Acidity of Carboxylic Acids

O H3C OH CH3CH2 OH

Acetic acid
pKa = 4.75 G = 27 kJ/mol

Ethanol
pKa = 16 G = 90.8 kJ/mol

G values are for OH proton ionization

62Ch. 3 - 62

CH3CH2O2 + H3O Free Energy Change

CH3CO2 + H3O G = 27 kJ/mol CH3CO2 H

G = 90.8 kJ/mol

CH3CH2O2 H

63Ch. 3 - 63

O CH3 O H + H2O CH3

O O + H3O

acetic acid

acetate

CH3CH2

H + H2O

CH3CH2

+ H3O

ethanol

ethoxide
64Ch. 3 - 64

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
65Ch. 3 - 65

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

66Ch. 3 - 66

11B. The Inductive Effect

O
<
<

CH3

<

CH3CH2

<

Acetic acid
Stronger acid

Ethanol
Weaker acid

67Ch. 3 - 67

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 v The conjugate base of a carboxylic acid is a weaker base than the conjugate base of an alcohol
v
68Ch. 3 - 68

11D. Inductive Effects of Other Groups

O
<
<
<

O
<

CH3

CH2

pKa = 4.75
O Cl CH2 O H + H2O Cl

pKa = 2.86
O CH2 O + H3O
69Ch. 3 - 69

<

Cl

<

<

<

O Cl O Cl

O O

The Cl further stabilizes the carboxylate anion due to negative inductive effect of the Cl

70Ch. 3 - 70

The Effect of the Solvent on Acidity v In the absence of a solvent (i.e., in the gas phase), most acids are far weaker than they are in solution v 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 v 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
12.

71Ch. 3 - 71

O H3C
v v

O OH + H2O H3C 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

72Ch. 3 - 72

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)

73Ch. 3 - 73

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

74Ch. 3 - 74

O R R

+ H

A R

H + R Weak base A

Ketone
v

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

75Ch. 3 - 75

14.

A Mechanism for an Organic Reaction

CH3 H3C C CH3 tert-Butyl alcohol (soluble in H2O) OH + R O H Concentrated HCl CH3 H2O H3C C CH3 tert-Butyl chloride (insoluble in H2O)
76Ch. 3 - 76

H +

Cl

Cl + 2 H2O

Step 1

CH3 H3C C CH3 O H + H O H H H3C

CH3 H C CH3 O H O H

+ H

Step 2

CH3 H H3C C CH3 O H H3C

CH2 C CH3 + H O H
77Ch. 3 - 77

Step 3

CH3 H3C C CH3 + Cl H3C

CH3 C CH3 Cl

78Ch. 3 - 78

15.

Acids and Bases in Nonaqueous Solutions

H + NH2

+H

NH2

pKa = 25
v

(stronger base) (weaker base) pKa = 38

This reaction cannot be carried using water as solvent

+ NH2

HO

NH2

pKa = 15.7

pKa = 38
79Ch. 3 - 79

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

80Ch. 3 - 80

16.

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

Li + O D + OD + Li

Deuterium (stronger acid) Isopropyl lithium 2(stronger base) Deuteriopropane (weaker acid)

salt (weaker base)

81Ch. 3 - 81

 END OF CHAPTER 3

82Ch. 3 - 82