1. Nucleophilic Substitution overview
Mechanism of SN rxn: SN1 (stepwise) vs. SN2 (concerted):
Kinetics;
Stereochemistry outcome;
Changes involved in SN rxn:
Proton transfer;
Carbocation rearrangement;
Solvolysis
Factors affecting SN1 vs. SN2: substrate; Nuc; LG; solvent

2. Chapter Objectives
Predict the reaction pathway and draw reaction mechanism
Predict the main products
Design synthetic pathway based on chapter learning (choice of substrate, nucleophile, leaving group, and solvent)

3. Substitution Rxn One group of atoms is replaced with another
Generic example
A + B-C  A-B + C
Specific example
It involves a nucleophile and an electrophile
Very common organic chemical rxn.

4. Substitution reactions
During the substitution, one group ATTACKS (forming bond) and one group LEAVES (breaking bond):
A leaving group always takes a pair of electrons with it.
Find leaving group in the follows:

5. Substitution reactions
Substitution rxn equilibrium depends on the relative strength of base (nucleophile) involved.
Strong base (Nuc:) will react to yield weak base (as leaving group, LG)

6. Leaving Group (LG) What makes a good leaving group:
The electronegative leaving group creates a partial charge on the site of attack to attract the negative charge of the nucleophile
The Leaving Group must be able to stabilize the electrons it leaves with (conjugate base from stronger acid. ARIO)

7. Find Good LG?
Candidates as good leaving groups according to the two key criteria?
Create a positive charge to attract the nucleophile. High electronegativity
(EN > 2.1: N, O, F; P, S, Cl; Se, Br; I)
2. Be able to stabilize the electrons it leaves with, conjugate base of strong acid
What are the strong acids?
ARIO: HX (X = Cl, Br, I), oxyacids, carboxylic acids

8. Substrate I: Alkyl Halides
Alkyl halides are compounds where a carbon group (alkyl) is bonded to a halide (F, Cl, Br, or I)
Alkyl halides are important compound in substitution rxn, attacked by nucleophile. Known as substrate
Self study: refer to the end of this file for more nomenclature info. Recall from Nomenclature of Alkane
Identify and name the parent chain
Identify the name of the substituents
Assign a locant (number) to each substituents
Assemble the name alphabetically

9. Alkyl Halide Structure: a-, b-, g-
Greek letters to label the carbons of the alkyl group attached to the halide
Substitutions occur at the a-carbon
Classification of alkyl halides (here R = alkyl) based on #alkyl groups on a-carbon

10. Practice: Alkyl Halides 1, 2, 3
Lindane wased as insecticides.
For the circled atoms, label all of the alpha, beta, gamma, and delta carbons.

11. Review: Four arrow pushings Bond forming vs. Bond breaking

12. Substitution Mechanisms
EVERY nucleophilic substitution reaction will involve nucleophilic attack and loss of a leaving group
The order that these steps occur can vary
Possibility of proton transfer or rearrangement

13. SN2: a concerted mechanism
Kinetics: If the concerted rxn above is the only step in the mechanism, the rate law for this reaction will be:
rate = k[Nu:-][C-LG]
This mechanism shows a second order rate law for nucleophilic substitution, thus SN2

14. Stereochemistry of SN2
SN2 mechanism: simultaneous bond forming (attacking Nu:- and C-LG) and bond breaking of C-LG)
Being a tetrahedral carbon, with all the remaining C-Y bonds in the same order, the C-Nu is in the opposite side compared to C-LG (Inversion).
Experiments showed the agreement between kinetics and stereochemistry.

15. Transition state for SN2
Extended dotted lines to represent bonds breaking and forming
Transition state symbol

16. SN2: Potential Energy Diagram
Thermodynamically controlled reaction: high activation energy and exergonic rxn.

17. Steric Effect on SN2 kinetics
Less stericly hindered electrophiles react more readily under SN2 conditions

18. Steric Effect on SN2: Ea
3° substrates react too slow. Significant side reaction

19. Practice: SN2 rxn for alkyl halide?
SN reaction for neopentyl bromide
Is neopentyl bromide a primary, secondary, or tertiary alkyl bromide?
Predict if neopentyl bromide react by an SN2 reaction relatively quickly or relatively slowly
Exception to the common pattern! It is better to understand the concepts than to memorize rules

20. SN1 : a step-wise mechanism
The reaction begins with a unimolecular decomposition process. Thus SN1
Kinetic experiments would predict the rate law as:

21. SN1 reaction coordinate
The two-step mechanism:
Two transitions states (heterolytic bond breaking; nucleophilic attack forming bond)
Carbocation as intermediate
Nucleophile may attack from both sides

22. SN1: First step determines the rate law
First step involves large Ea, therefore is slow.
Thus the rate depends only on [electrophile] and NOT [nucleophile].

23. Kinetics: SN1 vs. SN2 Consider the following generic SN2 reaction:
[Nuc:-] affects the rate of SN2 reaction.
Consider the following generic SN1 reaction:
[Nuc:-] does NOT affect the rate of SN1 rxn

24. Structure of Substrate in SN1 rxn
The structure-rate relationship for SN1 is the opposite of what it was for SN2.
The relative stability of carbocation (hyperconjugation) affects the Transition state (Ea).

25. Carbocation as Intermediate in SN1 mechanism
A carbocation forms during the mechanism.
Hyperconjugation: Carbocation with more alkyl substitutents should be more stable.

26. Relative stability of Carbocation
Hyperconjugation: C-H orbital semiparallel with the empty p orbital in carbocation

27. More stable Intermediate, Lower Ea
Hammond postulate: proximal in reaction coordinate, similar energy and similar structure.
Primary substrates react too slowly to measure.

28. Stereochemistry of SN1
Recall the SN2 product is inversed from reactant.
Carbocation has sp2 hybridization, allowing Nu:- to attack from both sides, forming both R and S product (50% and 50%).

29. *Ion pair causes inversion in SN1
The formation of ion pairs can cause inversion to occur slightly more often than retention

30. SN2 vs. SN1: Summary

31. Protonation promotes SN1 of alcohol
SN1 demands good LG (weak base HOSO3-, I-, H2O, derived from strong acid, H2SO4, HI, H3O+, etc)
OH as poor leaving group
Protonation of C-OH gives C-+OH2 (H2O as good LG)

32. SN1 with Protonation in Mechanisms
1. Protonation; 2. Forming carbocation; 3. Nu:- attack

33. SN1 with Deprotonation
In SN1, proton transfer steps often occur after the substitution by weak nucleophile. Write mechanism:

34. Carbocation rearrangement in SN1
Carbocation in SN1 reactions may rearrange to form more stable carbocation. When carbocation is next to quartanery (4) carbon atom, rearrangement is likely.
Predict the final product(s).

35. Mechanism: SN1 vs. SN2 Summary of considerations to make
Will proton transfers be necessary?
look at the quality of the leaving group
Look at the stability of the final product
Will the mechanism be SN1 or SN2?
look at how crowded the electrophilic site is
Look at how stable the resulting carbocation would be
Are rearrangements likely?
look for ways to improve the stability of the carbocation
Will the product have inversion or racemization?
SN1=racemization while SN2=inversion

36. Protonation in SN2 Mechanisms
Proton transfer often takes place when acid is present in the SN2 reactions.

37. Protonation & Deprotonation
Proton transfer steps occur often in SN2 reactions, similar to SN1 reactions.

38. Protonation gives better LG in SN2
Protonation of three-membered ring (high energy) greatly facilitates the hydrolysis, as protonated ROH is weaker base than RO-.
Qualitatively, this reaction has negative H and negative S.

39. More SN2 Mechanisms Another example: only Deprotonation is involved.
carbocation rearrangements not possible in SN2
If rearrangement is observed, SN1 pathway more likely

40. SN1 vs. SN2: Which pathway to follow?
Four main factors to determine whether a substitution reaction is more likely to occur by SN1 or SN2 (in the order of importance from high to low):
The substrate (both STERIC effect and the stability of the CARBOCATION): sterically hindered or stable carbocation favors SN1 pathway.
The quality of the leaving group
The strength of the nucleophile
The solvent

41. Unsaturated groups in OChem
Vinyl
Allyl
Benzyl
Aryl

42. Carbocation Stability
The stability of the resulting carbocation
If a relatively stable carbocation can form when the LG leaves, the mechanism may be SN1
Stability of carbocations: ARIO
INDUCTION – electron-pulling destabilizes
RESONANCE – allylic and benzylic,  carbon is sp2

43. Resonance in Carbocation
Recall: Resonance stabilizes both allylic and benzylic carbocations
Thus allylic and benzylic halides more likely to undergo SN1

44. SN1 for Vinyl or Aryl Halides?
Consider carbocation stability from vinyl and aryl halides via SN1 pathway:
Poor stability of such carbocations due to lack of resonance: vacant sp2 orbital, not p orbital. Thus no SN1 pathway.

45. SN1 vs. SN2: Leaving Group Good Stability of LG- Makes good LG
The conjugate base of a strong acid: stable anion once dissociated WITH a pair of electrons. Conjugate base of a weak acid is bad LG.
Solvation
Examples of good LG: C2H3O2-, NO3-, RSO3-, H2O, etc.
Examples of bad LG: H-, OH-, CH3O-, NH2-, CH3-
Unstable LG is unfavorable for either SN1 or SN2.

46. Common Leaving Groups
Halide ions and sulfonate ions (from strong acids)
Sulfonate ion as LG are commonly used in organic synthesis. Tosylate often as OTs
Demo: Bromide > Chloride
Memorize the good LG!

47. Nucleophilicity Strength of nucleophile: rate of SN2 reaction
Very Good
I-, HS-, RS-
Good
Br-, HO-, RO-, CN-, N3-
Fair
NH3, Cl-, F-, RCO2-
Weak
H2O, ROH
Very Weak
RCO2H
Strength of nucleophile: rate of SN2 reaction
Stability (induction, resonance, polarizibility, solvation)
Sterics
Strong nucleophile favor SN2
Weak nucleophile incapable of SN2 but allowed in SN1, as the reaction rate of SN1 is independent of [Nu:-]
SN2 requires good nucleophile

48. Nucleophile in SN1 vs. SN2
A stronger nucleophile favors SN2 , although it may react by SN1 if the substrate is NOT sterically hindered and the leaving group is good.
A weaker nucleophile favors SN1, although it may react by SN2 if the substrate can NOT stabilize a carbocation effectively, and the leaving group is poor.
Remember these Nu:-!

49. Solvent affects Transition state
The solvent ( ) surrounds each species in the mechanism including the transition state δ+ δ- δ- δ+ δ- δ+

50. Protic vs. Polar Aprotic solvents
Protic solvents are used for SN1. Such as H2O and alcohol, as Both cation and nucleophile anion are stabilized.
Polar aprotic solvents are used for SN2. Such as DMSO, CH3CN, DMF, HMPA. Anions (nucleophile) are NOT stabilized.

51. Solvent affects Halide Nucleophilicity
The relative reactivity of halide ion (as Nu:-) depends on solvent:
In a polar, protic solvent, F- < Cl- < Br- < I-. Fluoride ion is tightly bound to the solvent shell, least available for nucleophilic substitution.
In a polar, aprotic solvent, F- > Cl- > Br- > I-. There is no solvent shell, thus smaller anions are less stable and more reactive.

52. Designing Syntheses
Organic synthesis: Convert available substrates to the target molecule (specific structure and stereochemistry)
How do we use what we have learned to set up successful reactions?
We must choose appropriate substrate, reaction condition (reagent, temperature, solvent, catalyst, etc.).

53. Syntheses via SN1 or SN2?
1° substrate adopts SN2 only (inversion product):
Good Nu:- (from weak acid)
Leaving Group: No preference.
Solvent: Polar aprotic (DMSO, DMF, HMPA, MeCN)
3° substrate goes through SN1 (racemic product):
Nucleophile Not important
Good LG
Solvent: Polar protic (water, alcohol, etc.)

54. In Between: 2° substrate
The reaction could be SN1 or SN2, depending on the desired stereochemistry for the product.
To achieve inversion product, SN2 pathway is needed.
Otherwise, both pathways are available.
The choice of the following depends on whether SN1 or SN2 pathway is chosen, like in previous slide.
Nucleophile?
Leaving Group?
Solvent?

55. Designing Syntheses
Some options and choices:

56. Example: Designing Syntheses
Design a synthesis (reagent/Nu:-, solvent, LG) for the following molecule A starting from (R)-2-chlorobutane
B. The enantiomer of A.

57. Example: Designing Syntheses
Acidic condition: -OH may be converted to –OH2+ as better LG. Rearrangement might occur due to carbocation
Sometimes convert –OH to -OTs as better LG

58. Alkyl Halide Nomenclature
For each of these examples, convince yourself that they are numbered in the most appropriate way.

59. Alkyl Halide Nomenclature
Some simple molecules are also recognized by their common names.
the alkyl group is named
as the substituent, and
the halide is treated as
the parent name
Methylene chloride is a commonly used organic solvent

60. Alkyl Halide Nomenclature
Give reasonable names for the following molecules

61. Additional Practice Problems
Give reasonable names for the following molecules
Label each halide as primary, secondary, or tertiary

62. Additional Practice Problems
Give the best set of reaction conditions to promote SN2 for the following substrate.
Describe experiments that could be done to support the proposed mechanism

63. Additional Practice Problems
Give the best set of reaction conditions to promote SN1 for the following substrate.
Describe experiments that could be done to support the proposed mechanism

64. Additional Practice Problems
Propose reaction conditions and give a complete mechanism for the following substitution reaction

65. Additional Practice Problems
Give a complete mechanism for the following substitution reaction

66. SN1 with Protonation in Mechanisms
1. Protonation; 2. Forming carbocation (Dehydration); 3. Nu:- attack

67. Carbocation rearrangement in SN1
Carbocation in SN1 reactions may rearrange to form more stable carbocation. When carbocation is next to quartanery (4) carbon atom, rearrangement is likely.
Predict the final product(s).

68. Protonation in SN2 Mechanisms
Proton transfer often takes place when acid is present in the SN2 reactions.

69. Protonation & Deprotonation
Proton transfer steps occur often in SN2 reactions, similar to SN1 reactions.

70. Protonation gives better LG in SN2
Protonation of three-membered ring (high energy) greatly facilitates the hydrolysis, as protonated ROH is weaker base than RO-.
Qualitatively, this reaction has negative H and negative S.

71. More SN2 Mechanisms Another example: only Deprotonation is involved.
carbocation rearrangements not possible in SN2
If rearrangement is observed, SN1 pathway more likely

72. Resonance in Carbocation
Recall: Resonance stabilizes both allylic and benzylic carbocations
Thus allylic and benzylic halides more likely to undergo SN1

73. SN1 for Vinyl or Aryl Halides?
Consider carbocation stability from vinyl and aryl halides via SN1 pathway:
Poor stability of such carbocations due to lack of resonance: vacant sp2 orbital, not p orbital. Thus no SN1 pathway.

74. *MO theory: HOMO vs. LUMO
Many rxns involve orbital interaction as HOMO (highest occupied MO) with LUMO (lowest unoccupied MO).
HOME is electron pair donor (nucleophile, Lewis base).
LUMO is electron pair acceptor (electrophile, Lewis acid)
When HOMO and LUMO orbitals are in phase (sharing same sign), bond may form.
Nu:- forms bond with HOMO with the LUMO from C-LG

75. *Molecular Orbital Theory on SN2:
Why nucleophile attacks from the back-side
Electron density from LG repels the attacking Nu:- from the front-side
Nu:- must approach the back-side to allow electrons to flow from HOMO of the nucleophile to LUMO of the electrophile.
Proper orbital overlap cannot
occur with front-side attack
because there is a node on
the front-side of the LUMO

76. *Example: Experiment  Mechanism
Consider the following reaction
How likely this rxn proceeds via SN1? SN2?
Which product is from inversion? Which from retention.
What accounts for the 35%/65% product ratio?
Is the reaction reacting more by SN1 or SN2?

77. Practice: Complete SN1 Mechanisms
SN1 or SN2?
Proton transfer?
Rearrangement?
Inversion/Racemization?
Predict the reagents necessary to complete this substitution.
Draw a complete mechanism

78. *Alkyl Halide in life Insecticides (DDT, etc.) Fire retardant
Polymer: Teflon, PVC
Anesthetic (chloroethane,
trichloromethane/chlorofoam)
*Drugs (anticancer, antidepressants, antimicrobial, etc.)
*Food additives (Splenda, etc.)