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.