Consider the following general substitution reaction:
Nu + R LG R Nu + LG
How might this reaction proceed?
We can imagine three different mechanisms:
•the nucleophile Nu-R bond forms first then the R-LG bond breaks.
• the Nu-R bond forms at the same time as the R-LG bond breaks.
•the R-LG bond breaks first then the Nu-R bond forms.
Are all these mechanisms reasonable?
Substitution reactions are reactions in which a nucleophile displaces an atom or
group of atoms (the leaving group) from a tetrahedral carbon atom.
Substitution Reactions
S stands for substitution
N stands for nucleophilic
The number refers to the number of reacting molecules in the rate determining step.
In substitution reactions the RDS is the step where the leaving groups leaves.
The two mechanisms that are operative in substitution reactions are the SN1
and SN2 reactions.
•Reactions in which the leaving group leaves before the attack of the
nucleophile are referred to as SN1 reactions.
•Reactions in which the nucleophile attacks at the same time as the
leaving group leaves are referred to as SN2 reactions.
Consider the two different mechanisms for a substitution reaction. What factors
would favour one pathway over the other?
C ClH3 CH2 C
H
H3 C
CH3S- Na+
CH3CNCH3 CS
CH2 CH3
H
CH3
+ NaCl
C OHH3 C
H3 C
H3 C
HBr, ²
C BrH3 C
H3 C
H3 C
+ H2O
H3 CH2 C Br:N(CH3)3
OSO2 CH3
NaI, acetone
I + NaOSO2CH3
H3 CH2 C N(CH3 ) 3Br
Substitution Reactions of Alkyl Halides
All of these reactions:
• involve displacement of a heteroatom from carbon -- the "leaving group"
• have a leaving group that is more EN than carbon making the carbon electrophilic
• have an electrophilic carbon that is sp3 hybridized
• have a nucleophile present, which is either -ve or -
Remember: Good leaving groups are weak bases!
Alkyl halides and alcohols SN1 or SN2?
3°, benzylic and allylic substrates undergo SN1 reactions because THEY
FORM RELATIVELY STABLE CARBOCATIONS.
1°, substrates undergo SN2 reactions because they DO NOT FORM STABLE
CARBOCATIONS and THE REACTION SITE IS STERICALLY
ACCESSIBLE.
2°, substrates can undergo both types of reaction, but do so slowly.
SN1 reactions in which the solvent participates as a nucleophile are
called solvolysis reactions.
Th e SN1 Re actio n
H3 C
C
H3 C
H3 C BrH2 O
H3 C
C
H3 C
H3 C OH + HBr
Sketch a reaction profile diagram for the following reaction:
Substitution Reactions – SN1
I (H3C)3C Br C(CH3)3I Br+ +
Substitution Reactions – SN1
SN1 reactions predominate when:
•A relatively stable carbocation is formed.
•The solvent is polar and protic.
•Weak nucleophile (e.g. a neutral molecule such as H2O, ROH, etc.).
Carbocation Stability
Carbocation stability is dependent on:
•Coulombic stabilization
•Inductive stabilization
•Delocalization (resonance)
•Hyperconjugation.
Carbocation Stability – Resonance Delocalization
Since SN1 reactions involve carbocation intermediates, only those species that form
reasonable carbocations will undergo this reaction is a timely fashion (this lifetime).
C C
H
H H2C
H
Br
H3CO
H2C
Cl
CH2 Cl
Aryl and vinyl carbocations cannot be stabilized by resonance. The empty
orbital is orthogonal to the π-system and as such cannot be delocalized:
Carbocation Stability – Resonance Delocalization
Alky l ca r b o ca t io n s a r e st a b ilized b y e le ct r o n d o n a t io n fr o m a d ja cen t C-H b o n d s,
so m e th in g t h a t is kn o wn a s h y p er co n ju ga t io n .
H
C
H
HC
H
H
1 ° 3 °H
C
H
HC
C
C
H
H
HH
H
H
1 9 .5 °
Alkyl carbocations are also stabilized by electron donation from adjacent C–H
bonds. This phenomenon is known as hyperconjugation.
3° > 2° > 1°
Recall that inductive and field arguments suggest carbocation stability is:
Vin y l a n d a r y l ca r b o ca t io n s ca n n o t b e st a b ilize d b y r e so n a n ce ...
C CHH
H C
H
H
C H
Vinyl and aryl carbocations CANNOT be stabilized by resonance.
Thus, the order of carbonium ion stability is:
Benzylic ~ allylic > 3° > 2° > 1° > CH3 > vinyl ~ aryl
Usually, SN1 reactions are practical for benzylic allylic and 3° substrates.
H
o r b y h y p e r co n ju ga t io n .
6 0 °
or by hyperconjugation!
• One consequence of reactions proceeding via carbocation intermediates is the
occurrence of rearrangement side reactions. Consider the following reaction:
• The substitution product is a constitutional isomer of the product expected. Propose
a mechanism for the above reaction:
SN1 - Rearrangements
It is worth noting that carbocation
rearrangements can involve
shifting either a hydride ion or a
methyl anion. In either case, you
will always be forming a more
stable carbocation.
SN1 - Rearrangements
Pay close attention to the way
curly arrows are drawn when
proposing a hydride or methyl
shift. We should be able to tell if
you are proposing a hydride shift
or generation of a pi bond.
The SN1 Reaction - Kinetics.
•What happens to the rate of production of (CH3)3CI if the concentration of I- is
held constant and the concentration of (CH3)3CBr is increased?
Consider:
•What happens to the rate of production of (CH3)3CI if the concentration of
(CH3)3CBr is held constant and the concentration of I- is increased?
I - + (CH3)3CBr → (CH3)3CI + Br -
The Stereochemistry of the SN1 reaction
C
Ph
CH2CH3H3C
BrNaI/Acetone
CPhCH2CH3H3C
C
Ph
CH2CH3H3C
I
C
CH2CH3
PhH3C
I
The nature of the intermediate is such that the nucleophile can attack from either
side with equal likelihood.
Reactions in which the configuration of a chiral centre is scrambled are said to
occur with RACEMIZATION.
The Stereochemistry of the SN1 reaction
C
Ph
CH2CH3H3C
BrNaI/Acetone
CPhCH2CH3H3C
C
Ph
CH2CH3H3C
I
Br-
C
CH2CH3
PhH3C
I
Sometimes (depending on conditions) reactions occur with only partial
racemization.
14
SN1 reactions – Solvent Effects
SN1 reactions are typically done in polar protic solvents. Polar protic solvents
are used because they help stabilize the transition state during the process of
forming the carbocation intermediate. The more stabilized the transition state, the
faster the carbocation will form.
Some common polar protic solvents:
H3CC
OH
OOH
CH3CH2OH CH3OH H2OOH
t-Butanol(t-BuOH)
Isopropanol(iPrOH)
Ethanol(EtOH)
Methanol(MeOH)
WaterAcetic AcidAcOH
The SN2 reaction is favoured for 1° and methyl substrates.
The SN2 Reaction.
Sketch a reaction profile diagram for the above reaction.
I H3C Br CH3I Br
The SN2 Reaction - Kinetics.
•What happens to the rate of production of CH3I if the concentration of CH3Br is
held constant and the concentration of I- is increased?
I H3C Br CH3I Br
Consider:
•What happens to the rate of production of CH3I if the concentration of I- is held
constant and the concentration of CH3Br is increased?
The Stereochemistry of the SN2 reaction
The reaction geometry is such that the collision must occur with the nucleophile
attacking the back side of the C—LG bond.
When attack occurs at an asymmetric carbon, the reaction occurs exclusively with
inversion of the absolute stereochemistry.
H3C Br CH3I BrI + +
C Br
H3CH3CH2C
H
CS
CH3CH2CH3
H
Br
H3CCH3S + +
Stereospecific: A reaction in which the mechanism dictates that different steroisomeric reactants give different stereoisomeric products.
Why backside attack?
C Br
HH
H
H3C S CS
HH
H
BrH3C
The Stereochemistry of the SN2 reaction
Substrate Relative rate
CH3Br
0.004
CH3CH2CH2Br
C
H3C
H3C
Br
H
C
H3C
H3C
Br
CH3
100
1.31
0.81
0.015
CH3CH2Br
CH3Br
CH3CH2CH2Br
100
1.31
0.81
CH3CH2Br
CH3CH2CH2CH2Br 0.52
C
CH3
H3CH2
CBr
H
C
CH3
H3CH2
CBr
H3C
0.052
0.00001
Relative rateSubstrate
SN2 reactions - Reactivity
Substrate dependance:
SN2 reactions – Solvent Effects
SN2 reactions are typically done in polar aprotic solvents. These solvents are
polar enough to solubilize the nucleophile but do not stabilize the nucleophiles
enough to prevent reaction.
Some common polar aprotic solvents:
H3CC
CH3
O
H3C C N CH3OCH2CH2OCH3
HC
N(CH3)2
O
H3CS
CH3
O
H3CH2CO
CH2CH3
N
O
AcetoneAcetonitrile
(MeCN)Dimethoxyethane
(DME) Dimethylformamide(DMF)
Dimethyl sulfoxide(DMSO)
Ethyl ether(Et2O) Pyridine
(Pyr)Tetrahydrof uran
(THF)
SN2 reactions - Reactivity
When evaluating SN2 reactions, you have to consider everything involved in the
reaction. This includes the substrate, the nucleophile, the leaving group and the
solvent.
For each set of reactions, draw the SN2 products. Then indicate which reaction
should proceed faster and why.
A
B
SN2 reactions - Reactivity
For each set of reactions, draw the SN2 products. Then indicate which reaction
should proceed faster and why.
C
SH+
Br
SHBr
SN1 vs. SN2 reactions – Comparison
Minimum # Steps 1 or more steps 2 or more steps
Intermediates? No carbocation
Reaction Order second order reaction first order reaction
Stereochemical stereospecific inversion of racemization (full or partial)
Consequences configuration at electrophilic site at electrophilic site
Importance of very important; no reaction unimportant
Nucleophile Strength for weak nucleophiles like H2O
Importance of very important; no reaction for very important; no reaction for
Leaving Group weak leaving groups like HO- weak leaving groups like HO-
Substrate Structure avoid steric hindrance; need carbocation stabilization;
Dependence CH3 > 1 > 2(slow) > 3 (no); 3 > 2 (slow) > 1 (no);
no reaction for aryl/vinyl resonance stabilization helps;
no reaction for aryl/vinyl
Solvent polar aprotic polar protic
Competing Reactions E2 E1, E2, rearrangement
SN1SN2
NaIacetone
NaIacetone
Ag+Ag+
SN1 vs. SN2 reactions
Would you expect the following reactions to proceed via SN1, SN2, both, or neither?
Draw the expected product(s) for each reaction.