Review from 1st Year Organic Chemistry: Nucleophilic

Review from 1st Year Organic Chemistry: Nucleophilic Substitutions &
& Eliminations
at o s
Ch
Chapters 11 (excluding 11.1, 11.6, 11.8 and 11.11) 11 ( l di 11 1 11 6 11 8 d 11 11)
1
Substitution and Elimination Reactions
SN1 or SN2
E1 or E2
2
SN2 : Mechanism and Energetics
(S)
(S) (R)
(R)
Rate = k [Nu
R
k [N ‐] [substrate]
][ b
]
En
nergy
• Concerted, single‐step • Bimolecular
Bi l l (nucleophile ( l
hil
and substrate participate in rate limiting step) • No intermediates
• Occurs with inversion of configuration
Progress of reaction
3
SN2 : Substrate Structure
Steric effects slow down SN2 reactions:
Br
H3C
C
H
methyl
y
"sterically unhindered” fastest SN2 reactions
H3C
1°
“somewhat unhindered” fast SN2 reactions
H3C
Br
C
H3C
H3C
H
Br
C
CH3
3°
2°
“somewhat hindered” slow SN2 reactions
H
4
“very hindered”
No SN2 reaction
SN2 : Effect of Nucleophile
Nucleophilicity
Notable Trends:
‐ Anions are better nucleophiles than their neutral conjugate acids
‐ Within a group (I > Br > Cl & S > O), more polarizable orbitals give better nucleophiles
give better nucleophiles
‐ Stronger bases are generally better nucleophiles:
Same attacking atom: HO > CH
k
3CO2
5
SN2 : Effect of Leaving Group
• Better leaving groups are those which can stabilize the negative charge in the transition state (enhanced stability leads to lower transition state energy). • Generally, weaker bases (conjugate bases of ll
k b
( j
b
f
strong acids) are better leaving groups: O
O
S
O
Leaving group reactivity
6
SN2 : Effect of Solvent
SN2 reactions are the fastest in polar aprotic solvents:
2
ti
th f t t i
l
ti
l t
Polar Protic → solvated anion → less reac ve Nu− → slow
e.g. H2O, MeOH, EtOH Polar Aprotic → poorly solvated anion → more reactive Nu−→ fast
7
SN1 : Mechanism and Energetics
Rate Limiting Step
Rate = k [substrate]
En
nergy
• Two‐step
Two step mechanism mechanism
• Unimolecular (only the substrate participates in rate limiting step) t li iti
t )
• Carbocation intermediate
• Occurs with racemization of configuration
Progress of Reaction
8
SN1 : Substrate Structure
Substrates that produce more stable carbocations will undergo faster SN1 reactions:

<
methyl/1°

allylic
2°
<
benzylic
3°
Increasing carbocation stability and rate of SN1 reaction
Note: Carbocation stability review: Chapter 7 Section 7.9
9
SN1: Nucleophile and Leaving Group Effects
The rate of the reaction does not depend upon the nucleophile!
RS  CN  I  RO  HO  Br
 Cl  NH3  CH3CO2  H2O
The best leaving groups are those that are weak bases:

<
<
< < <
Leaving group reactivity
10
SN1: Effect of Solvent
SN1 reactions are favoured by polar protic solvents:
Polar Protic → solvated ca ons/anions → more stable ions → fast
/
e.g. H2O, MeOH, EtOH Polar Aprotic → poorly solvated ions → unstable ions → slow
11
Summary of SN1 vs SN2
SN2
Structure of R‐X 1
Structure of R‐X
1° > 2
> 2° > 3
> 3°
Kinetics
3° > 2
3
> 2° > 1
> 1°
rate = k[Nuc][substrate] rate = k[substrate]
St
Stereochemistry
h i t Inversion
I
i
Nucleophile
Leaving Group
Leaving Group
Solvent
SN1
R
Racemization
i ti
Wide range of Polarizable anionic nucleophiles (Nuc
nucleophiles (Nuc nucleophiles preferred doesn’t affect rate)
Stabilized leaving group Stabilized leaving
(weak base)
group (weak base)
Polar aprotic preferred
12
Polar protic preferred
E2: Mechanism and Energetics
Energy
Rate = k [base] [substrate]
Progress of Reaction
13
• Concerted, single step
• Bimolecular (base and substrate participate in
substrate participate in rate limiting step) • No intermediates
• Anti‐periplanar geometry A i
i l
required E2: Stereochemistry
E2 reactions must proceed through an anti‐periplanar geometry:
anti‐periplanar
14
E2: Regiochemistry
Zaitsev's rule: The major product of an elimination reaction is the more stable alkene (more highly substituted)
Both E1 and E2 reactions follow Zaitsev’s rule
(where possible for E2!)
15
E1: Mechanism and Energetics
Rate
Rate Limiting Step
Rate = k [substrate]
En
nergy
• Two‐step
Two step mechanism mechanism
• Unimolecular (only the substrate participates in rate ti i t i
t
limiting step) • Carbocation intermediate
Progress of reaction
16
E1: Stereochemistry
Anti‐periplanar geometry is not required for E1.
Major product formed via less sterically‐hindered carbocation:
j p
y
(minor product)
17
(major product)
Summary of E1 vs E2
E2
Kinetics
E1
rate = k [base] [substrate] rate = k [substrate]
Stereochemistry H‐C‐C‐X anti‐periplanar
No anti‐periplanar requirement
Regiochemistry
Zaitsev’s Rule where
possible
Base
The stronger the base, the faster the reaction
Leaving Group
Stabilized leaving group
((weak base)
ea base)
Wide range of bases (base doesn’t affect rate)
t )
Stabilized leaving
ggroup
oup ((weak base)
ea base)
Solvent
Polar aprotic preferred
Polar protic preferred
18
Zaitsev’s Rule
Summary of Substitution & Elimination Reactions
Alkyl halide
CH3 3 X
Substitution (SN)
Elimination (E)
SN2 only
cannot occur
RCH2X
SN2: main reaction with most nucleophiles
p
SN1: will not occur
SN2: weakly basic nucleophiles in polar aprotic solvent
in polar aprotic solvent
SN1: weakly basic nucleophiles in polar protic solvent
SN2: will not occur
will not occur
R2CHX
R3CX
E2: main reaction with strong, bulky bases (ex. tBuOK)
y
(
)
E1: will not occur
E2: main reaction with strong bases (bulky base increase E2)
bases (bulky base increase E2)
E1: weakly basic nucleophiles in polar protic solvents
E2: strong bases such as HO
strong bases such as HO‐
and RO‐
SN1: main reaction in polar E1: main reaction in polar protic solvents; nucleophiles
protic solvents; nucleophiles protic solvents; weakly basic protic solvents; weakly
basic
that are extremely weak bases
conditions
19
Take‐Home Activity
Which substrate would react fastest in an SN2 reaction?
20
Take‐Home Activity
Which substrate would react fastest in an SN1 reaction?
21
Take‐Home Activity
Draw the mechanisms of the following SN1‐type reactions:
What is the driving force for the shift step in each reaction?
*Hint: if you are unsure, review Chapter 7 Section 7.11
22
In Class Problem
Take‐Home Activity
Draw the major product of the following transformations and describe as either SN1, SN2, E1 or E2:
23
In Class Problem
Take‐Home Activity
Propose reagents for the following transformation. More than one step may be required.
24
Take‐Home Activity
Draw the product(s) of the following E2 reactions. If more than D
h
d ( ) f h f ll i E2
i
If
h
one product is possible, identify the major product:
25

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