This document summarizes key aspects of nucleophilic substitution reactions of haloalkanes. It discusses the polarization of the C-X bond, with X (the leaving group) being electrophilic and carbon being polarized partially positively. The ability of a substituent to be a good leaving group (L) or nucleophile (Nu) depends on trends in electronegativity, bond strength, and orbital size down the periodic table. Steric effects are also important, with bulky groups hindering frontside attack. Solvent effects influence nucleophilicity, with protic solvents enhancing nucleophiles through hydrogen bonding.

1. Chapter 6: Nucleophilic
Substitution of Haloalkanes
Guanine base
of DNA
Leaving group
Nucleus
Nucleophile
Toxic

2. Haloalkanes
Names: Halo-, as a substituent
1-Chlorobutane
(1S,2R)-1-Bromo-2-
fluorocyclohexane
2-Iodo-2-
methylbutane
C
+ -
X
Cl
4
3
2
1 F
BrR
S
I CH3

3. The C-X Bond is Polarized
ClCH3
+ -
Electrophilic

5. Trends are a function of dipole-
dipole and London forces
Electronegativity
(4.0) (3.2) (3.0) (2.7)

6. Nucleophilic Substitution:
General
Color scheme: Nu, E, L, and curved arrows: e-Flow
C XNu + C XNu
-
+
Nucleophile
(Nu)
Leaving
group (L)
Electrophile
(E)
-

7. Remember: Acid-base reactions
B + H A B H + A
- -
conjugate
acid base
-
B = Nu
-
when H is attacked, we call it base B.
When C (or other nuclei) attacked, we call it
nucleophile Nu.

8. Note: no (simple) H º calculations
possible on ionic reactions; bond
strengths refer to homolytic, not
heterolytic, dissociation.

9. Note: Tertiary halides are notably absent from this list.

10. Mechanism
In general: how do we study it ?
1. Kinetics
2. Stereochemistry
3. Modify substituents: look for electronic and
steric effects
4. Isotope effects: Usually H/D
DHº C--H < C—D
5. Modify reagents/subtrates: Nu, E, L, solvent

11. Kinetics
For HO + CH3 Cl CH3OH + Cl
--
Rate = k [CH3Cl][ OH] 2nd order
Points to bimolecular mechanism (TS)
Hence name: SN2 bimolecular,
nucleophilic substitution
-

12. [HO···CH3Cl]‡ ?
CH3Cl
CH3OH
E
What is TS
structure?
We can look at
stereochemistry.
Two extreme approaches of Nu : C X
Back Front
+ Cl-
+ -OH
Transition State
―

13. Frontside attack: Retention of
configuration.
Backside attack: Inversion of
configuration.
Which one is it?
C X
chiral
*
Test: Use enantiomerically pure

14. Frontside Displacement
Frontside

15. Backside Displacement
Backside

16. C Br
S
H
H3C
CH3CH2
+
-
I C BrI
-
+
H
CH3
CH2CH3
R
Result: Inversion (no S -product)

17. PotEnergy
Lipshutz
Holiday

18. Chemical Consequences of Inversion
1. Retention: By double inversion
C
CH3
R
H
Br C
CH3
R
H
SHCI
CH3
R
H
I
-
Br
-
I
-
H S
-
+
- -
+
2. Inversion does not necessarily mean: R S
CH3CH2O + C
CH3S
H
H3C
Br C
X
CH3CH2O
-+
SCH3
H
CH3
S
c
b
ab
c
a- S

19. 3. Diastereoisomerization
CH3
Br
H
CH3
CH3CH2
H
CH3
H
H
CH3
CH3CH2
II
- Br R
R
R
S
-
-
Br H
H3C H
SS
H CN
H3C H
RSCN
- Br -
-
CH3
Br
R
S
I
-
CH3
R
R
I
Cis Trans
- Br-

20. Leaving Group Ability “L”
(kinetic parameter)
C LNu + B + H A
-
What makes a good L- (A-) ?
Remember from the discussion on acidity:
1. Ability to accommodate e-pair (charge) :
e-Negativity + resonance
2. Size of the orbital describing the e-pair.
3. Indirectly: Bond strength C—L (H—A)

21. F < Cl < Br < I Increasing, going down periodic
table (PT).
HF HCl HBr HI
pKa 3.2 -2.2 -4.7 -5.2
DHº 135 103 87 71
Why?
Because:
Goes down in PT
And: Orbital size increases from 2p to 3p to 4p…
As noted earlier: This trend is opposite that
expected on the basis of electronegativity (goes
down in PT).
Same trend as HX:
- - - -
Halides as L

22. pKa 50 35 15.7 3.2
DHº 105 107 119 135 increases
In practice: only F is a reasonable leaving group in
this row. Hydroxide can be, in special cases.
-
CH3< NH2< OH< F :
Electronegativity
wins !
decreases, but
And: Size of orbital decreases.
R L or H A:
Along a row of PT: L increases to the right
(same trend as acidity)

23. For example, for same leaving atom, e.g.,
Generally: L increases to the right and
down PT.
But, superimposed on these trends:
Resonance.
pKa : 15.5 4.7 -1.2
-
- -
O O
O
-
CH3O < CH3CO < CH3S O
RO :
(of acid)

24. Neutral L are good: relatively nonbasic
1. Protonated alcohols: L = H2O
Use ROH plus HBr, or HI, or H2SO4
2. Diazonium ions: L = N2 , a superleaving group
R OH + H R O
H
H
Nu-+
R Nu + H2O
R N N + Nu R Nu + N N
-+
+

25. For practical purposes:
Here is where L- ability
ends (going down PT)

26. Nucleophilicity “Nu”
(kinetic parameter)
Affected by charge, basicity, solvent,
polarizability, sterics.
1. Charge (for same atom):
The more charged, the more nucleophilic
HO > H2O ; H2N > H3N ; SO4 > ROSO3
- - 2- -

27. 2. Basicity: Decreases to the right
in PT, so does Nu:
H3N > H2O ; H2N > HO ; HO > F
- - - -
Comparison of neutral and charged Nu: (See
pKa table)
H2N > HO > H3N > F > H2O
- - -
As expected: Trend opposite L
ability

28. Protic solvents have acidic H ; e.g., RO H or
N H. They surround charged Nu , using
hydrogen bonds:
+ +-
+-
-
-
R
Down the PT: Murky! Basicity goes down,
hence Nu should too (opposite L). But not
true: Nu increases!
The reason: Solvent effects and
polarizability (deformability of orbital of
) have a strong influence.
For charged Nu- :
Nu
Nu H OR

29. Protic Solvents: Fluoride is a Worse
Nucleophile Than Iodide
Hydrogen
bonds
-
-
-
-
-
+
+
+
+
Solvent shell increases “size” of Nu ,
hence Nu increases going down PT.
-

30. For uncharged Nu , same trend, but
now due to polarizability
H2O < H2S < H2Se (CH3)3N < (CH3)3P
Polarizability operates also for
charged Nu, which already benefit
from lesser solvation: especially fast.

31. Increasing Polarizability
Improves Nucleophilicity
More polarizable
Less polarizable

32. The Story Changes In
Polar Aprotic
Solvents,
Which
• dissolve salts
• do not form H bonds
• enable formation of
“naked” anions
cause huge rate increases
with all Nu
follow trends in basicity

33. SolventMeOH SolventDMF

34. Review: Range of
Nucleophilicities
• charge
• basicity
• polarizability
• H-bonding
Depends on:

35. Summary Trends in the
Periodic Table
L
Nu-
“Naked” anions,
aprotic solvents
or
Protic solvent,
polarizability
e-Negativity > DHº and orbital size
e-Negativity
< DHº and
orbital size

36. Steric Effects
Sterics for L: Larger = better
Sterics for Nu: Larger = worse,
e.g., CH3O > (CH3)3CO
- -
Sterics around E are the most
significant.

37. Sterics around electrophilic C L
R Br + I R I + Br relative rates
CH3 CH3CH2 (CH3)2CH (CH3)3C
145 1 0.078 0
Mechanism
changes
CH3CH2 CH3CH2CH2 (CH3)2CHCH2 (CH3)3CCH2
1 0.8 0.03 slow! 10-5
- -
α :
β :
Alpha versus beta branching:

40. Walba
DireStr