10/15/2016

Nucleophilic Substitution of
Haloalkanes

Guanine base
of DNA
Leaving group
Nucleophile
Nucleus

Toxic

1
 10/15/2016

+ -
Haloalkanes C X

Names: Halo-, as a substituent

3 1 F I
4 2
CH3
Cl R Br
S
1-Chlorobutane
(1S,2R)-1-Bromo-2- 2-Iodo-2-
fluorocyclohexane methylbutane

2
 10/15/2016

The C-
C-X Bond is Polarized

+ -

CH3 Cl
Electrophilic

3
10/15/2016

4
 10/15/2016

Electronegativity

(4.0) (3.2) (3.0) (2.7)

Trends are a function of dipole-

dipole and London forces

5
 10/15/2016

Halogenation of Alkanes
heat or R–X + HX
R–H + X2 —→ a substitution reaction
light

Reactivity: F2 > Cl2 > Br2 > I2

too common too

reactive unreactive
(endothermic)

Cl2 Cl2 Cl2 Cl2

CH4 → CH3Cl → CH2Cl2 → CHCl3 → CCl4
hn hn hn hn
+ HCl + HCl + HCl + HCl

Problem: mixture of products

Solution: use large excess of CH4 (and recycle it)

6
 10/15/2016

Halogenation of Alkanes
A. Free-radical chain mechanism
species with an odd (unpaired) electron

Step 1: Cl2 → 2Cl• (homolytic cleavage) Initiation

Step 2: Cl• + CH4 → HCl + CH3•

Propagation
Step 3: CH3• + Cl2 → CH3Cl + Cl•
-determines
1000’s of cycles = “chain” reaction net reaction
net: CH4 + Cl2 → CH3Cl + HCl

Sometimes: Cl• + Cl• → Cl2 Termination

CH3• + CH3• → CH3–CH3 (infrequent due
CH3• + Cl• → CH3Cl to low [rad•])

7
10/15/2016

8
 10/15/2016

Halogenation of Alkanes
B. Stability of free radicals: bond dissociation energies
R–H → R• + H• DH = BDE

BDE
CH3—H 104 kcal
easier to break bonds
CH3CH2—H 98 kcal
∴ free radical more stable
CH3CH2CH2—H 98 kcal (any 1º)
(CH3)2CH—H 95 kcal (any 2º)
(CH3)3C—H 91 kcal (any 3º)

CH3CH2CH2• •
CH3CHCH3 lower energy, more stable,
easier to form
98 kcal 95 kcal
∴Reactivity of C–H:
3º > 2º > 1º > CH3–H
CH3–CH2–CH3 9

9
10/15/2016

10
10/15/2016

11
10/15/2016

12
10/15/2016

13
10/15/2016

14
10/15/2016

15
10/15/2016

16
10/15/2016

17
 10/15/2016

Halogenation of Alkanes
C. Higher alkanes: regioselectivity
Some alkanes give only one monohalo product:
Cl2
CH3 CH3 CH3 CH2 Cl
hν

Cl2
hν Cl Synthetically
useful.
Cl
Cl2
hν

Cl Not as
Cl2 useful.
But: CH3CH2CH3 CH3CH2CH2Cl + CH3CHCH3
hν
find: 43% 57%
even though statistically: 75% 25%
(6 H) (2 H) 18

18
 10/15/2016

Halogenation of Alkanes
C. Higher alkanes: regioselectivity

Reactivity of C–H: 3º > 2º > 1º

-for Cl2, relative reactivity is 5.2 : 3.9 : 1

Predicting relative amounts of monochloro product:

Cl
Cl2
CH3CH2CH3 CH3CH2CH2Cl + CH3CHCH3
hν

2º product reactivity of 2º H number of 2º H’s

= x
1º product reactivity of 1º H number of 1º H’s

3.9 x 2 7.8 57%

= = =
1x6 6 43%

19

19
 10/15/2016

Halogenation of Alkanes
C. Higher alkanes: regioselectivity
Question 4-7. What would be the expected distribution of
monochlorinated products in the following reaction? Click
on the arrow to check your answer.

Cl2
hν

Check Answer

20

20
 10/15/2016

Halogenation of Alkanes
C. Higher alkanes: regioselectivity
Answer 4-7. First, draw all of the different isomers that could be
formed. Then count the number of hydrogens could be replaced by
chlorine to give that isomer. Then classify each as primary, secondary,
or tertiary, and multiply #H by reactivity factor. Divide each by the sum
of all and express as a percent.
CH 3 H CH 3 CH 3 H CH 3 CH 3 H CH 3 CH 3 H CH 3
Cl2
CH 3 C C C CH 3 CH 3 C C C CH2 Cl CH 3 C C C CH 3 CH 3 C C C CH3
hv
H H H H H H H H Cl H Cl H

1-chloro-2,4-dimethylpentane 2-chloro-2,4-dimethylpentane 3-chloro-2,4-dimethylpentane

12 H, primary 2H, tertiary 2H, secondary

#H 12 2 2
reactivity factor x1 x 5.2 x 3.9
12 10.4 7.8
sum = 12+10.4+7.8 = 30.2

percent 12/30.2 x 100 = 39.7% 10.4/30.2 = 34.4% 7.8/30.2 = 25.8

21

21
 10/15/2016

Halogenation of Alkanes
C. Higher alkanes: regioselectivity

Bromine is much more selective:

Cl
Cl2 Cl +
hν
43% 57%
Br2
3% 97% Synthetically
hν
more useful.

Relative reactivities for Br2: 3º 2º 1º

1640 82 1

Br 2
hν
22

22
 10/15/2016

Halogenation of Alkanes
C. Higher alkanes: regioselectivity

X
X2 + + +
hν
X
X X
Cl2: 28% 23% 35% 14%
Br2: ~0% 90% 9% ~0%

23

23
 10/15/2016

Halogenation of Alkanes
Question 4-8. Indicate which reagent you would use to
convert the indicated starting material to the specified
product. Click on the arrow to check your answers.

OH Cl

Br

OH Br

OH Br

Check Answer

Deana Wahyuningrum 24

24
 10/15/2016

Halogenation of Alkanes
Answer 4-8. Indicate which reagent you would use to
convert the indicated starting material to the specified
product. Click on the arrow to check your answers.
SOCl2, pyridine
OH Cl

Br2, heat or hv Br

OH Br
HBr

OH Br

PBr3

25

25
 10/15/2016

Nucleophilic Substitution:
General

Color scheme: Nu, E, L, and curved arrows: e-Flow

- -
Nu + C X Nu C + X
Nucleophile
Electrophile Leaving
(Nu)
(E) group (L)

26
 10/15/2016

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.

27
 10/15/2016

Note: no (simple) ∆H º calculations

possible on ionic reactions; bond
strengths refer to homolytic, not
heterolytic, dissociation.

28
 10/15/2016

Note: Tertiary halides are notably absent from this list.

29
 10/15/2016

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

30
 10/15/2016

Kinetics
- -
For HO + CH3 Cl CH3OH + Cl
-
Rate = k [CH3Cl][ OH] 2nd order

Points to bimolecular mechanism (TS)

Hence name: SN2 bimolecular,

nucleophilic substitution

31
 10/15/2016

Transition State
―
[HO···CH3Cl]‡ ? What is TS
structure?
E
CH3Cl We can look at
+ -OH
CH3OH + Cl- stereochemistry.

Two extreme approaches of Nu : C X

Back Front

32
 10/15/2016

Frontside attack: Retention of

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

33
 10/15/2016

Frontside Displacement

Frontside

34
 10/15/2016

Backside Displacement

Backside

35
 10/15/2016

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

36
 10/15/2016

PotEnergy
Holiday
Lipshutz

37
 10/15/2016

Chemical Consequences of Inversion

1. Retention: By double inversion

- - H
H H
+ I +H S
C Br - I C - C SH
R - Br R - I R
CH3 CH3 CH3
2. Inversion does not necessarily mean: R S
CH3Sb a SCH3
- S a b S -
+ X
CH3CH2O + C Br CH3CH2O C
H H
H3C c c CH3

38
 10/15/2016

3. Diastereoisomerization
CH3 CH3
S
- R
H Br I I H
CH3CH2 R
H - Br - CH3CH2
R
H

CH3 CH3
Br H H CN
-CN
S S S R
- Br -
H3C H H3C H
Br - I
I R
S
R - Br- R
Cis Trans
CH3 CH3

39
 10/15/2016

Leaving Group Ability “L”

(kinetic parameter)

-
Nu + C L 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)

40
 10/15/2016

Halides as L
- - - -
F < Cl < Br < I Increasing, going down periodic
table (PT). Same trend as HX:

HF HCl HBr HI
Why?
pKa 3.2 -2.2 -4.7 -5.2 Because:
DHº 135 103 87 71 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).

41
 10/15/2016

Along a row of PT: L increases to the right

(same trend as acidity)
R L or H A:
Electronegativity
CH3< NH2< OH< F : wins !

pKa 50 35 15.7 3.2 decreases, but

DHº 105 107 119 135 increases

And: Size of orbital decreases.

In practice: only F - is a reasonable leaving group in
this row. Hydroxide can be, in special cases.

42
 10/15/2016

Generally: L increases to the right and

down PT.
But, superimposed on these trends:
Resonance.
-
For example, for same leaving atom, e.g., RO :

O O
- - -
CH3O < CH3CO < CH3S O
O
pKa : 15.5 4.7 -1.2
(of acid)

43
 10/15/2016

Neutral L are good: relatively nonbasic

1. Protonated alcohols: L = H2O

+ +H Nu -
R OH + H R O R Nu + H2O
H
Use ROH plus HBr, or HI, or H2SO4
2. Diazonium ions: L = N2 , a superleaving group
+ -
R N N + Nu R Nu + N N

44
 10/15/2016

For practical purposes:

Here is where L- ability
ends (going down PT)

45
 10/15/2016

Nucleophilicity “Nu”
(kinetic parameter)

Affected by charge, basicity, solvent,

polarizability, sterics.

1. Charge (for same atom):

- - 2- -
HO > H2O ; H2N > H3N ; SO4 > ROSO3
The more charged, the more nucleophilic

46
 10/15/2016

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

47
 10/15/2016

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
Nu ) have a strong influence.
For charged Nu- :
+ - +
Protic solvents have acidic H ; e.g., RO H or
- +
N H. They surround charged Nu ,-using
R
hydrogen bonds: Nu - H OR

48
 10/15/2016

Protic Solvents: Fluoride is a Worse

Nucleophile Than Iodide

δ-
δ-
δ+
δ- δ+
δ- δ+
δ+
δ-
Hydrogen
bonds

Solvent shell increases “size” of Nu - ,

hence Nu increases going down PT.

49
 10/15/2016

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.

50
 10/15/2016

Increasing Polarizability
Improves Nucleophilicity

More polarizable

Less polarizable

51
 10/15/2016

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

52
 10/15/2016

SolventMeOH SolventDMF

53
 10/15/2016

Review: Range of
Nucleophilicities
Depends on:

• charge
• basicity
• polarizability
• H-bonding

54
 10/15/2016

Summary Trends in the

Periodic Table
e-Negativity > DHº and orbital size

e-Negativity
or < DHº and
orbital size
Nu-
Protic solvent, “Naked” anions,
polarizability aprotic solvents

55
 10/15/2016

Steric Effects
Sterics for L: Larger = better
Sterics for Nu: Larger = worse,
- -
e.g., CH3O > (CH3)3CO

Sterics around E are the most

significant.

56
 10/15/2016

Sterics around electrophilic C L

R Br + I - R I + Br- relative rates

Alpha versus beta branching:
CH3 CH3CH2 (CH3)2CH (CH3)3C
α:
145 1 0.078 0
Mechanism
changes
CH3CH2 CH3CH2CH2 (CH3)2CHCH2 (CH3)3CCH2
β:
1 0.8 0.03 slow! 10-5

57
10/15/2016

58
10/15/2016

59
10/15/2016

DireStr
Walba

60
 10/15/2016

SN1, E1, E2,

E2, not
just SN2

SN2, SN1
E1, E2
- H E1, E2 - Relative “rates”
B: : Nu
C C of 4 arrows
differ
L
SN2, SN1, E1, E2

“Lingo”: α position, ß position; further away: γ, δ, and so on.

SolventMeOH SolventDMF

61
 10/15/2016

Recall: SN2 slows with weak Nu

(and branching). For example:
CH3Br + H2O
Weak Nu

(CH3)3CBr
But or react!
(CH3)2CHBr
Despite being α-branched

Acetone
(CH3)3C Br + H OH (CH3)3C OH + H Br
Hydrolysis

DMF
(CH3)2CH Br + H OCH3 (CH3)2CH OCH3 + H Br
Methanolysis

Generally: Solvolysis

62
 10/15/2016

Mechanism:

1. Rate = k[R-L], 1st order unimolecular, only

R-L in rate-determining TS: “bottleneck”.

2. Stereochemistry: Racemization (extensive,

although often not complete).

Both observations inconsistent with

SN2 mechanism

63
 10/15/2016

3. Accelerates with polar (best with protic, in

contrast to SN2) solvents: O
Hexane < CHCl3 < CH3CCH3 < CH3OH
4. Accelerates with better L
L: Cl < Br < I < OSO2R
5. Product determining steps after
“bottleneck”: Competition between Nu’s.
+ - k1
+
(CH3)3CCl CH3OH + Na N3 Intermediate
.. + N :-
- :N N
:

CH3OH
.. k
k3 > k2 > k1 2 k3
..
(CH3)3OCH
.. 3 wins (CH3)3CN3

64
 10/15/2016

Mechanism
1.

Electron deficient!

65
 10/15/2016

2.

66
 10/15/2016

3.

67
 10/15/2016

Mechanism explains data:

• 1st Order rate law • Acceleration

with better L
• Racemization
• Fast product
• Acceleration in polar
determining step
solvents

Unimolecular nucleophilic substitution:

SN 1
SN1

68
 10/15/2016

“Bottleneck”

Bottleneck:
SN1PE

69
 10/15/2016

Incomplete Racemization
May stay close
to form an ion pair

Planar and achiral,

but both sides not
equally accessible
in ion pair with Br-

Ideally; in
SN1Racem
practice: Slight
enantiomer excess

70
 10/15/2016

The Strong Effect of Polar

Solvents on the SN1 Reaction

Increasing solvent polarity Increasing solvent polarity

speeds reaction retards reaction

71
 10/15/2016

What makes SN1 possible? 1. SN2 is slow.

2. α-Branched carbocations are stabilized
by hyperconjugation
H + + + +
+ CH3 < CH3CH2 (CH3)2CH (CH3)3C
C C
Too unstable The only cations
feasible in solution

Bonding MO Stabilizing (2e)!

of neighboring C H 2p Better than
bond interacts with E radical (3e).
empty 2p orbital

72
 10/15/2016

Hyperconjugation

73
 10/15/2016

X-Ray Structure of the

1,1-
1,1-Dimethylethyl Cation
(Laube, 1993)

Django
LipshutzSN1

74
 10/15/2016

Summary : Rprim- L : no SN1, only SN2

Rtert- L : only SN1, no SN2
Rsec- L : both,
SN2/SN1 ratios difficult to predict, except in
“extreme" cases, such as:
- DMF -
(CH3)2CH Cl + CH3S (CH3)2CHSCH3 + Cl
S N2

(CH3)2CH OSO2CF3 + H2O (CH3)2CHOH +

S N1
Solvent CF3SO3H

75
 10/15/2016

Reactivity of R-
R- X

76
 10/15/2016

Problem:

OH

H2O
S + HBr
-(CH3)2S
Br−

S N2 or SN 1 ?

77
 10/15/2016

Elimination: E1 and E2
(-) (-)
When Nu : acts as B: : Cations are deprotonated
Therefore: Elimination E1, a side reaction of SN1.
Same first dissociation step to cation:
+ -
:B
(CH3)3C L - C C C C
–L
H Then proton
loss to base
(solvent)

Normally B: acts as Nu: to give SN1.

78
 10/15/2016

Mechanism of the E1 Reaction

We usually omit the base in deprotonations and

Caruso
simply write “-H+ ”. E1Lipshutz

79
 10/15/2016

Ratios of SN1 to
E1 products are
independent of L

80
 10/15/2016

E1 Gives Mixtures
All C H at β-positions in cation are acidic:
: :

: :
CH3OH CH3OH
. Cl
- +
+ H
Mixture
Cl CH3 CH3O
H

+ + +

“Regio-” and
+ stereoisomers
(“cis/trans”)

81
 10/15/2016

E1/SN1 ratios are difficult to predict

Generally: Increasing amounts of E1 products
are formed with:
1. Higher T, because entropy of elimination is
positive: (RX is converted to alkene plus HX).
Recall: ∆G° = ∆H º– T∆Sº, hence positive ∆Sº
makes ∆G° more negative.
2. Very poorly nucleophilic medium (slows SN1),
e.g: Acetone solvent.

Why not base? Base (unless very weak) changes

the mechanism once again.

82
 10/15/2016

Bimolecular Elimination E2
With strong base: Mechanism changes, base attacks
R-L directly at β-H: E2 (faster than SN1/E1)
Mechanism:
-
1. Rate = k [R-L][:B] 2nd order bimolecular TS

2. L leaves in TS: RCl RBr RI

3. H + removed in TS: Deuterium isotope

L
effect kH/kD~ 7 * *
Anti-TS C C
4. Stereochemistry: -
B: H

83
 10/15/2016

The E2 Reaction is Stereospecific

One diastereomer of RX (e.g. R,R/S,S below) gives
only one stereoisomer of alkene product:

84
 10/15/2016

Or the S,R-R,S pair:

85
 10/15/2016

Mechanism of the E2 Reaction

TS: staggered, best overlap, least e-repulsion

Cream Ray
E2 Walba Lipshutz

86
 10/15/2016

E2 in Cyclic Systems

87
 10/15/2016

Hindered Base Ensures E2

88
 10/15/2016

Summary

89
 10/15/2016

Factors that Affect the Competition

between SN and E
Factor 1: Base strength of the nucleophile
Weak Bases Substitution more likely
- - - -
H2O , ROH , PR3 , halides , RS , N3 , NC , RCOO

Strong Bases Likelihood of elimination increased

- - - -
HO , RO , H2N , R2N

Factor 2: Steric hindrance around the reacting

carbon
Sterically unhindered Sterically hindered
Primary haloalkanes Branched prim, or sec and tert haloalkanes
Substitution more likely Likelihood of elimination increased

90
 10/15/2016

Factor 3: Steric hindrance in nucleophile

(strong base)

Sterically unhindered Sterically hindered

- - - - - -
HO , CH3O , CH3CH2O , H2N (CH3)3CO , [(CH3)3CH]2N

Substitution may occur Elimination strongly favored

91
 10/15/2016

Problem:

H+, CH3OH, 100°C

(CH3)3COH An alkene
-H2O

1. Mechanism: SN2 SN1 E2 E1?

2. At lower temperatures one of the following ratios will increase:

SN2 / SN1 SN1 / E1 E2 / E1 SN2 / E2

92
 10/15/2016

Reactivity of Prim Haloalkanes

R-X with Nucleophiles (Bases)
For unhindered primary R X :
SN2 with good nucleophiles that are not strongly basic
- Acetone
CH3CH2CH2Br + CN CH3CH2CH2CN + Br-

SN2 with good nucleophiles that are also strong bases

- CH3OH
CH3CH2CH2Br + CH3O CH3CH2CH2OCH3 + Br-
But E2 with strong, hindered bases
CH3
- (CH3)3COH
CH3CH2CH2Br + CH3CO CH3CH CH2
HBr
CH3
No (or exceedingly slow) reaction with poor nucleophiles (CH3OH)

93
 10/15/2016

For branched primary R X :

SN2 with good nucleophiles (although slow compared with

unhindered RX)

CH3 CH3
- Acetone
CH3CCH2Br + I CH3CCH2I + Br-
H H

E2 with strong base (not necessarily hindered)

CH3 CH3
- CH3CH2OH
CH3CCH2Br + CH3CH2O CH3C CH2
HBr
H
No (or exceedingly slow) reaction with poor nucleophiles or
neopentyl systems (in which E is not possible)

94
 10/15/2016

Reactivity of Sec Haloalkanes R-

R-X with
Nucleophiles (Bases)

SN1 and E1, when X is a good leaving group in a

highly polar medium with weak nucleophiles

CH3 CH3
CH3CH2OH
CH3CBr CH3COCH2CH3 + CH3CH CH2
HBr
H H
Major Minor (more on
increasing T)

95
 10/15/2016

SN2 with high concentrations of good, weakly basic

nucleophiles

CH3 CH3
- CH3CH2OH
CH3CBr + CH3S CH3CSCH3 + Br-
H H

E2 with high concentrations of strong base

- -
(for example, HO or RO in alcohol solvent)

CH3
- CH3CH2OH
CH3CBr + CH3CH2O CH3CH CH2
HBr
H

96
 10/15/2016

Reactivity of Tert Haloalkanes R-

R-X
with Nucleophiles (Bases)
SN1 and E1 in polar solvents when X is a good leaving group
and only dilute or no base is present
CH3 CH3
HOH, acetone
CH3CH2CBr CH3CH2COH + alkenes
HBr
CH3 CH3

E2 with high concentrations of strong base

H3C CH2 - H3C CH2
CH3O, CH3OH
CH3CH2CCl CH3CH2C
HCl CHCH3
H3C CH2

97
 10/15/2016

Summary

98