1. Pharmaceutical Organic ChemistryBy
Dr. Mehnaz Kamal
Assistant Professor
Pharmaceutical Chemistry
Prince Sattam Bin Abdulaziz University

2. WELCOME

3. 1-What is Substitution reaction?
2-What are Nucleophilic Substitution Reaction?
3-SN1 reaction.
4-SN2 reaction.
5- Mechanisms of SN1 & SN2.

4. 1- Substitution reactions

5. 1-Substitution Reaction
In this type of reaction one atom, ion, or group is substituted for another.
Its two types:
Nucleophilic Substitution Reaction
Electrophilic Substitution Reaction

6. X is called leaving group, a term meaning any group that can be displaced from a carbon atom.
Halide ions are good leaving groups as they are very weak bases.
Strong bases such as OH- are very poor leaving group.
In substitution reaction of alkyl halides, the Iodide ion is the halide most easily displaced.

7. The species that attacks an R “usually alkyl” in substitution reaction is called a nucleophile (abbreviated Nu:-).
Generally, a nucleophile is any species that is attracted to positive center. It is a Lewis base.
Most nucleophiles are anions, however, some neutral polar molecules such as H2O, CH3OH, CH3NH2 can also act as nucleophiles by their unshared electrons that can be used to form sigma bonds.

8. Some common electrophiles and nucleophiles
Substitutions by nucleophiles are called nucleophilic substitution or nucleophilic displacement.
The electrophile (abbreviated E+) is any species that is attracted toward a negative center. It is a Lewis acid.
Some common electrophiles and nucleophiles

9. Nucleophilic Substitution Reaction
Q: What is nucleophilic substitution reaction?
A species which has ability to donates a pair of electrons is termed as a nucleophile
A reaction in which Nu is substituted by another Nu
can occur by an: a. SN1 path
b. SN2 path
Most common reaction of alkyl halides (RX) and alcohols (ROH)

10. Nucleophilic Substitution Reactions
The SN1 Mechanism

11. SN1 Reaction Unimolecular Nucleophilic Substitution
It is a 2 step mechanism involving:
1. Slow: (rate determining) step - ionization of the alkyl halide to form a carbocation (Carbonium ion)
2. Fast step: addition of the nucleophile to the carbocation (Carbonium ion)

12. The SN1 Mechanism
This sequence of reactions can be represented on an energy diagram. The formation of the carbocation (carbonium ion) is the high energy (slow) step. Addition of the nucleophile to the carbocation (carbonium ion) is very rapid.
(CH3)3CBr + H2O
Carbocation
intermediate
(CH3)3COH+H+
t.s.1 ?
t.s. 2 ?
Progress of reaction E
carbocation

13. SN1 Reaction: stereochemistry
50%
sp2 + -
planar
carbocation
attacks top
and bottom
equally
(R)
50%
(S)
(R)
enantiomers
RACEMIZATION

15. The SN1 Mechanism
1) The rate of SN1 reaction Is in the following order
2) 3° RX undergo SN1 reaction exclusively
3) When weak Nu such as H2O or ROH is used the rate of SN1 reaction Is in the following order:
C6H5CH2X > CH2=CHCH2X > 3° RX
4) When a strong Nu as CN- is used 3° RX undergo SN1 reaction exclusively,
C6H5CH2X or C6H5CH2OH or CH2=CHCH2OH
CH2=CHCH2X C6H5CH2CN or CH2=CHCH2CN
SN1
H2O or ROH
SN2
CN-

16. SN1 Reaction: kinetics
The 1 indicates that the reaction is unimolecular - only one reactant is involved in the slow step of the reaction. The rate depends only on the concentration of the alkyl halide, not the nucleophile.
SN1 does not involve the nucleophile in the rate determining step. Thus nucleophile has no effect on the reaction rate.

17. SN1 Reaction solvents R-X R+ + X-
Usually SN1 reactions are run in polar protic solvents, compounds with O-H groups, as Polar solvent stabilizes the carbocation!
The polar protic solvent acts as BOTH nucleophile as well as the solvent in SN1 reactions - solvolysis:.
Common solvent/nucleophiles include:
water, ethanol, methanol, acetic acid, and formic acid.
SN1 reactions prefer polar-protic solvents that can solvate the anion and cation formed in the rate-determining step.
ions
R-X
R X-
solvation of both ions
speeds the ionization
rate-determining
step
Carbocation

18. SN1 Reaction solvents SN1 SN2 Polar Protic Solvents
Nonpolar or Polar Aprotic Solvents
SN1
SN2
NONPOLAR

19. H.W -1
Q1: List the following carbocation in order of increasing stability
Q2: Which of the following compounds is more reactive toward SN1
reaction. Explain why
1. C6H5CH2Br CH3Br CH2=CHCH2Br

20. Substitution Reactions
The SN2 Mechanism
Substitution Reactions

21. Bimolecular nucleophilic substitution, one-step mechanism, which
SN2 Reactions
Bimolecular nucleophilic substitution, one-step mechanism, which
involves a transition state.
Nu attacks from back-side
Bimolecular reaction, because both Nu and RX are involved in the transition state.
Transition state

22. SN2 Reactions The SN2 mechanism: a) is a single step process
b) involves no intermediates
c) involves only one transition state, which is of low polarity
d) follows second order (bimolecular) kinetics. That is,
rate=k[substrate][nucleophile]

23. SN2 Reactions
It is second order reaction , because it is proportional to conc. Of Nu & RX
Increase the steric hindrance around the halogenated carbon Decreases
the rate of SN2 reaction.
3° RX are too hindered to undergo SN2 reaction.
CH3X RCH2X R2CHX
increasing steric hindrance , decreasing SN2 rate
CH3X…… most reactive
2 ° [R2CHX ]…… react slowly
3 ° [R3X ] …….no react by SN2
When strong Nu as CN- is used, the SN2 rate in the following order
benzylic halide > Allylic halide > Methyl halide
** CH3X and RCH2X (1° RX) undergo SN2 exclusively, irrespective of the strength of Nu-

24. SN2 Reactions Mechanism
SN2 - SUBSTRATE .. R H O : .. C : Br
large groups
introduce steric
hindrance R R H O : .. H C : Br
easy access
no steric
hindrance H H

25. SN2 Reactions Mechanism
Progress of reaction
Potential
Energy
(E)
Energy of T. S.
Average energy
of reactants
of products
∆H for reaction
Eact
transition state
one step

26. C R H CH3 Br : .. O R .. H O : C .. CH3 H SN2 Reactions Mechanism
nucleophilic attack C R H
CH3 Br : ..
(R)-config. O
attacks
back lobe R ..
H O : C ..
CH3
INVERSION
(S)-config. H

27. C R .. Cl: .. H CH3 SN2 Reactions Mechanism SN2 ANIMATION
ENERGY PROFILE
SN2 Reactions Mechanism
SN2 ANIMATION R .. C
Cl: .. H
CH3
Press the slide show button to see the animation. Press ESC to finish.

28. C R .. .. :Br: Cl: .. H CH3 SN2 Reactions Mechanism SN2 ANIMATION
ENERGY PROFILE
SN2 Reactions Mechanism
SN2 ANIMATION R
:Br: .. .. C
Cl: .. H
CH3

29. C R .. .. :Br: Cl: .. H CH3 SN2 Reactions Mechanism SN2 ANIMATION
ENERGY PROFILE
SN2 Reactions Mechanism
SN2 ANIMATION R
:Br: .. .. C
Cl: .. H
CH3

30. C R .. .. :Br: Cl: .. H CH3 SN2 Reactions Mechanism SN2 ANIMATION
ENERGY PROFILE
SN2 Reactions Mechanism
SN2 ANIMATION R
:Br: .. .. C
Cl: .. H
CH3

31. C R .. .. :Br: Cl: .. H CH3 SN2 Reactions Mechanism SN2 ANIMATION
ENERGY PROFILE
SN2 Reactions Mechanism
SN2 ANIMATION R
:Br: .. .. C
Cl: .. H
CH3

32. C R .. .. :Br Cl: H CH3 SN2 Reactions Mechanism SN2 ANIMATION d- d-
ENERGY PROFILE
SN2 Reactions Mechanism
SN2 ANIMATION R
Transition State
:Br ..
Cl: .. d- d- C H
CH3
Activated
Complex

33. C R .. .. :Br :Cl: H CH3 SN2 Reactions Mechanism SN2 ANIMATION
ENERGY PROFILE
SN2 Reactions Mechanism
SN2 ANIMATION R
:Br ..
:Cl: .. C H
CH3

34. C R .. .. :Br :Cl: H CH3 SN2 Reactions Mechanism SN2 ANIMATION
ENERGY PROFILE
SN2 Reactions Mechanism
SN2 ANIMATION R
:Br ..
:Cl: .. C H
CH3

35. C R .. .. :Br :Cl: H CH3 SN2 Reactions Mechanism SN2 ANIMATION
ENERGY PROFILE
SN2 Reactions Mechanism
SN2 ANIMATION R
:Br ..
:Cl: .. C H
CH3

36. SN2 Reactions Mechanism
ENERGY PROFILE
SN2 ANIMATION R
:Br .. C H
CH3

37. SN2 Reactions Mechanism
The rate depends on both the concentration of the R-X and the nucleophile.
Stereochemistry of SN2 Reactions
When the nucleophile attacks in an SN2  it is on the opposite side to the position of the leaving group. As a result, the reaction will proceed with an inversion of configuration.
(R)
(S)

38. Reactivity order---- fastest to slowest!
SN2 Reactions Mechanism
Effects of R-
The rate of SN2 reaction is inversely proportional to the streic hindrance around the carbon attached to the leaving group.
Reactivity order
CH3-  >  CH3CH2-  >  (CH3)2CH-  >  (CH3)3C-
Reactivity order---- fastest to slowest!

39. SN2 Reactions Mechanism
Effects of Nucleophile
Since the nucleophile is involved in the rate determining step, the nature of the nucleophile is very important in an SN2 reaction. More reactive nucleophiles will favor an SN2 reaction.
Relative Nucleophilicity
1) In general, stronger bases are better nucleophiles
2) However, iodide doesn’t fit that pattern (weak base, but great nucleophile!)
3) Cyanide is an excellent nucleophile because of its linear structure
4) Sulfur is better than oxygen as a nucleophile

40. SN2 Reaction solvents SN1 SN2 Polar Protic Solvents
Nonpolar or Polar Aprotic Solvents
SN1
SN2
NONPOLAR

41. SN2 Reaction solvents .. R : : .. C : Br R R X
SN2 reactions prefer “non-polar” solvents, or polar-aprotic solvents that do not solvate the nucleophile.
SN2 reactions are accelerated in polar aprotic solvents
SN2 reactions are retarded (slowed) in polar protic solvents .. R : : .. X C : Br
SMALL,
UNSOLVATED R R

42. Examples on SN2 Reaction
CH3CH2Cl HO CH3CH2OH Cl-
CH3CH2Br HS CH3CH2SH Br-
CH3CH2I RO CH3CH2OR I-
CH3CH2Br RS CH3CH2SR Br-
CH3CH2Cl H2N CH3CH2NH Cl-
CH3CH2Br RCC CH3CH2CCR Br-
CH3CH2I NC CH3CH2CN I- ..

43. H.W -2
Q: Outline all steps in the mechansim of each of the following reaction:
1. C6H5CH2Br + NaCN C6H5CH2CN + NaBr
2. C6H5CH2Br + H2O C6H5CH2OH + HBr
3. (CH3)3CCl CH3O-Na (CH3)3COCH NaCl

44. H.W -3 Which member of the following pairs of compounds will react
more rapidly with Nu in an SN2 reaction? Explain

45. General concepts for SN1 & SN2

46. Solvents Protic solvents: “…those that contain -OH or -NH groups
…worst solvents for SN2 reactions.”
Typical protic solvents:
water, methanol, ethanol, acetic acid, formic acid
Aprotic solvents:
“…have strong dipoles but don’t have
-OH or -NH groups. Best for SN2
reactions.”
Typical aprotic solvents:
acetone, DMF, DMSO, acetonitrile

47. Summary of SN1 & SN2 Mechanisms
A bimolecular reaction
Back-side attack
2nd order in rate
Inversion of configuration
CH3X > 1oRX > 2oRX
SN1
A unimolecular reaction
An ionization reaction
1st order in rate
No inversion of configuration
3oRX > 2oRX

48. Summary of SN1 & SN2 Mechanisms
Benzylic and allylic undergo both type of substitution
SN1 & SN2 Mechanisms
Depending on the strength of Nu
if weak Nu ……… SN1
if strong Nu ………. SN2
Energy required for 3o alkyl halide is very high, not obtained even with heating, but tertiary alkyl halide is very reactive and proceed via SN1 reaction.
Factors Regulate SN2 and SN1 Mechanism
1) Nature of the nucleophile
2) Nature of the solvent
3) Nature of the alkyl halide

49. Linkage with the life sciences
Information Enrichment

50. Medically Speaking Pharmacology And Drug Design
Pharmacology is the study of how drugs interact with biological systems, including the mechanisms that explain drug action.
Pharmacology is a very important field of study because it serves as the basis for the design of new drugs.

51. Chlorambucil