1. PHCM 331 – Organic and Medicinal/Pharmaceutical Chemistry I
Handout # 3 Winter 2015 / 2016
The objectives of the 3rd handout are to know about:
Functional groups: Definition, Most common functional groups neutral, acidic, and
basic functional groups, pKa values
Some Typical Reactions of Hydrocarbons
Radical Substitution Reactions, course, stability, and reactivity of radicals
Some free radical reaction mechanisms, Halogenation of alkanes, NBS alllylic substitution,
Free radical addition to alkenes (HBr / Peroxide addition), Radical polymerization of
alkenes
Addition Reactions of Alkenes; Hydrohalogenation, Halogenation, Halohydrin
Formation , Alcohols from, Syn addition of hydrogen
Addition to alkynes
Addition to dienes
Relative stabilities of conjugated and isolated dienes.

2. 1.5 Functional groups 1.5.1 Definition
It is the part of a molecule where most of its chemical
reactions occur. Alkanes pKa 50 do not have a functional
group. It is the part that effectively determines the
compound’s chemical and most of its physical properties.
1.5.2 Most common functional groups; examples
Alkene
Alkyne
pKa 40
pKa 25
Alcohol
CH3OH
pKa 16
Ether
pKa alpha COOH 2.4
Amino acid

3. Aldehyde
Carboxylic ester
Ketone
Carboxylic acid
Amine
Amide 3

4. Average values of pKa Alkanes 51 Amines 33-35 Esters 23-25
Ketones and aldehydes
18-20
Alcohols
15-19
b-Ketoesters 11
b-Diketones 10
Carboxylic acids
3-5
Average values of pKa

5. 1.6 Some Typical Reactions of Hydrocarbons
1.6.1 Substitution radical Reactions
In a substitution reaction one atom is replaced by another
Introduction
Addition reaction
1, 2-Dibromocyclohexane
however
substitution reaction
h or 
i.e. energy
Bromocyclohexane

6. Mechanism: How a given reaction takes place?
In a chemical reaction some bonds are broken and others are formed via movement of electrons.
In explaining a mechanism, movement of a pair of electrons is
represented as follows:
Movement of one electron as follows: h
1.6.2 course, stability, and reactivity of radicals
Why?
The energy needed to break C  H bond depends on the type of C atom i.e. tert-(3), sec-(2), primary-(1) or methyl.

7. More than 100 k cal/mol needed to break the C-H bond
The higher the amount of energy needed to break C  H bond, the less stability of the intermediate (free radical) hence, the greater the tendency of the intermediate to recombine with hydrogen i.e.
Highly unstable
More than 100 k cal/mol needed to break the C-H bond
98 k cal/mol 7 7

8. 1.6.3 Halogenation of Alkanes
(monosubstitution only)
1.6.3 Halogenation of Alkanes
Mechanism:
(unstable, one ē short)

9. Some examples 1) 2)
The relative yield of products is dictated by the relative intermediates stabilities. 3)

10. 1.6.4 Addition Reactions
General Equation
The addition to alkenes is electrophilic.
Mechanism.

11. i.e. Addition to a double bond proceeds via two steps:
1- An electrophile starts the reaction to produce an intermediate.
2- A nucleophile reacts with the intermediate to yield a neural molecule (product).
Hydrohalogenation of Alkenes
Hydrogen halide
e.g.

12. Mechanism: (Electrophilic addition; H+ then Br-)
However
Mechanism: (Electrophilic addition; H+ then Br-) 12

13. Problem: What is the major product when HCl reacts with 3-Methyl-2-Pentene?
Halogenation of Alkenes (Br2 and Cl2)
F2 is too reactive)
I2 is too slow
General Equation

14. This is an electrophilic anti addition reaction. Why? Bridge!
Mechanism: One chlorine (or Bromine) atom acts as the electrophile.
Bridge

15. example
cyclopentene
Halohydrin Formation (Addition of X and OH)
Mechanism is similar to however, water molecule is the nucleophile rather than bromide ion

16. 1.6.4.4 Alcohols from Alkenes (Hydration i.e. addition of H2O)
problems
Alcohols from Alkenes (Hydration i.e. addition of H2O)
Types of Alcohols
(1) alcohol [Ethyl alcohol; Ethanol]
(2) alcohol [Isopropyl alcohol; Isopropanol]
(3) alcohol [tert-Butyl alcohol; tert-Butanol]

17. Markovnikov’s Rule: on addition to double bonds, H is
attached to the carbon with the most hydrogens.
Negatively charged ion is considered a nucleophile. However, neutral H2O molecule (or ROH) may react as a nucleophile also using lone pair’s electrons of oxygen atom.
Addition of X2 or X & OH: anti-addition (trans product).
Acidic water addition of H, OH follows Mark.Rule (with possible rearrangement ).(hydride or methyl shift)
Oxymercuration reaction is anti addition of H, OH that follows Mark.Rule (However, no rearrangement occurs).
Hydroboration Method
For the preparation of all types of alcohols 1°, 2°, 3°
Syn addition i.e. both H and OH are added to the same face of double bond. 17
- Anti-Markovnikov’s addition
-NO possible rearrangement.

18. A) The acidic water method
[H+  trace of inorganic acid e.g. HCl]
Mechanism:
(1) alcohol since OH is attached to a (1) carbon atom.

19. However
(2°) alcohol
also
(3°) alcohol

20. Rearrangement Problem:
In some cases, addition of water to alkenes is not a simple process.
e.g.
major

21. B) Oxymercuration Method
To avoid rearrangement problem, the following reagents are used instead of acidic water.
Reagents
1) Mercuric acetate in water
2) Sodium Borohydride: NaBH4 (strong reducing reagent)

22. The reaction is anti addition of H, OH that follows Mark
The reaction is anti addition of H, OH that follows Mark.Rule (no rearrangements).
OH drives from water and H, (produced from NaBH4) replaces the electrophile HgOAc after it adds.
Mechanism:
The actual picture of the intermediate:
i.e. (Anti) addition

23. Conclusion:

24. C) Hydroboration Method (Nobel Prize 1979)
For the preparation of all types of alcohols 1°, 2°, 3°by
choosing the right alkene
Syn addition i.e. both H and OH are added to the same
face of the double bond.
- Anti-Markovnikov’s addition due to what is called the steric effect.
-NO possible rearrangement.
Reagents 1) 2)

25. Mechanism:
The electrophile attacks the less substituted carbon atom. Why?
The electrophile BH3 coordinates with the solvent THF and the actual attacking species is of a larger size:
e.g.

26. General Examples:
(1°) Alc.
(2°) Alc.
(3°) Alc.

27. (2°) alcohol (3°) alcohol
(Review)
(2°) alcohol
(3°) alcohol
Intermediates may rearrange for more stability by moving a hydride or methyl group. The move should be 1,2 shift ONLY. 27

28. Free Radical Addition to Alkenes
Free Radical Addition to Alkenes
i.e. Addition of HBr in the presence of an organic peroxide ROOR.
Don’t confuse organic peroxide e.g. CH3OOCH3 with inorganic peroxide e.g. HOOH (hydrogen peroxide).
Recall:
However in the presence of organic peroxide and light the addition is
free radical .
In this case Br. adds first instead of H.
e.g.
Why?

29. The mechanism
free radicals
Steps 2 and 3 are repeated over and over
Conclusion:

30. On the other hand, while O2 is used as oxidizing reagent,
General Information:
H2 gas is used for hydrogenation (reduction) however, under high pressure and the presence of a catalyst such as Pt, Pd, or Ni.
Hydrogen-rich molecules are also used as a good source of hydrogen e.g. Sodium Borohydride: NaBH4 , LiAlH4 (strong reducing reagents)
On the other hand, while O2 is used as oxidizing reagent,
oxygen-rich molecules are also useful for the oxidation of
organic molecules. e.g. O3 , H2O2 (hydrogen peroxide), and
KMnO4 (potassium permanganate)
Lone pair of electrons may be transferred into a single bond
and vice versa i.e. a single bond may be transferred into
lone pair. 30

31. 1. 6. 4. 6. Hydrogenation (reduction) of Alkenes. i. e
Hydrogenation (reduction) of Alkenes i.e. addition of HH molecule (Syn)

32. 1.6.5 Addition to Alkynes (H2, X2, HX and H2O)
A) Reduction of Alkynes
B) Halogenation
(recall )

33. C) Hydrohalogenation of Alkynes
D) Addition of water to Alkynes : Tautomerism
i.e. the product is a mixture of the enol and keto forms.
Tautomer: Isomeric equilibrium of 2 structures that differ in the arrangement of atoms.
The acidic water method is used in making a ketone from
an alkyne with the same # of C atoms.

34. 1.6.6 Addition to Dienes (Electrophilic Addition)
Why?
Mechanism (as in )

35. There are three types of Dienes; conjugated, cumulated, & isolated.
Relative stabilities of conjugated and isolated dienes.
There are three types of Dienes; conjugated, cumulated, & isolated. s h o r t e a n b d , w v l g .
Why?
1, 3-Butadiene (conjugated)

36. Less stable and of a higher energy than conjugated due to the absence of resonance.
Cumulated diene is the least stable (of highest energy) among other dienes. Why?
Tutorial (molecular orbital picture)