Substitution Reactions Substitution reactions are reactions in which a nucleophile displaces an atom or group of atoms (the leaving group)

from a tetrahedral carbon atom. Consider the following general substitution reaction:
Nu

LG

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?

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.

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.

Consider the two different mechanisms for a substitution reaction. What factors would favour one pathway over the other?

Substitution Reactions of Alkyl Halides H H 3 CH 2 C H3 C H3 C H3 C C H3 C :N(CH3)3 H 3 CH 2 C NaI, acetone I + NaOSO2CH3 N( CH 3 ) 3 C Cl CH3S- Na+ CH3CN HBr, OH H 3 CS H C CH 2 CH 3 CH 3 H3 C H3 C C H3 C Br + NaCl

Br

+ H2O

H 3 CH 2 C

Br

OSO 2 CH 3

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.
Th e SN 1 Re ac tio n H3 C H3 C C Br H3 C H3 C C OH + HBr

H2 O

H3 C

H3 C

SN1 reactions in which the solvent participates as a nucleophile are called solvolysis reactions.

Substitution Reactions SN1 Sketch a reaction profile diagram for the following reaction:

+ (H3C)3C

Br

C(CH3)3

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).
CH2 Cl

H C H

H2C C H

Br

H3C O

H2 C Cl

Carbocation Stability Resonance Delocalization Aryl and vinyl carbocations cannot be stabilized by resonance. The empty orbital is orthogonal to the -system and as such cannot be delocalized:

 Alkyl carbocations are also stabilized by electron donation from adjacent CH Alk y l ca This r b o caphenomenon t io n s a r e st a b ilize d b y e leas ct r o n d o n a t io n fr o m a d ja ce n t C-H b o n d s, bonds. is known hyperconjugation.
so m e t h in g t h a t is k n o wn a s h y p e r co n ju ga t io n .

1 9 .5
1 H H H C H C H H 3 H C H C

H C C H H H HH

Recall that inductive and field arguments suggest carbocation stability is: Vinyl and aryl carbocations CANNOT be stabilized by resonance.
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 ... H H H C C H H C C H

3 > 2 > 1
H
60

oor r bby y hhyperconjugation! y p e r co n ju ga t io n .

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.

SN1 - Rearrangements 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.

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. I - + (CH3)3CBr (CH3)3CI + Br Consider: 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?

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?

The Stereochemistry of the SN1 reaction

Br NaI/Acetone C H3C CH2CH3 Ph H3C C CH2CH3 Ph

I C H3C H3C CH2CH3 Ph C I

CH2CH3 Ph

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 Sometimes (depending on conditions) reactions occur with only partial racemization.
Br Br NaI/Acetone C H3C CH2CH3 Ph H3C C CH2CH3 Ph

I C H3C CH2CH3 Ph H3C C I CH2CH3 Ph

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:

O OH C H3C OH Acetic Acid t-Butanol AcOH (t-BuOH) OH Isopropanol (iPrOH) CH3CH2OH Ethanol (EtOH) CH3OH Methanol (MeOH) H2O Water

The SN2 Reaction. The SN2 reaction is favoured for 1 and methyl substrates.

H3C

Br

CH3

Br

Sketch a reaction profile diagram for the above reaction.

The SN2 Reaction - Kinetics.

I
Consider:

H3C

Br

CH3

Br

What happens to the rate of production of CH3I if the concentration of CH3Br is held constant and the concentration of I- is increased?

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 CLG bond.

+ H3C

Br

CH3

Br

When attack occurs at an asymmetric carbon, the reaction occurs exclusively with inversion of the absolute stereochemistry.
H3C H3CH2C C + H CH3 CH2CH3 C + H

CH3S

Br

H3C

Br

Stereospecific: A reaction in which the mechanism dictates that different steroisomeric reactants give different stereoisomeric products.

The Stereochemistry of the SN2 reaction Why backside attack?

H H H3C S H C Br H3C S H H C H Br

SN2 reactions - Reactivity Substrate dependance:

Substrate CH3Br CH3CH2Br CH3CH2CH2Br H3C C H3C H3C C H3C CH3 Br H Br 0.015 H H3C C 0.004 CH3 H3C H3C C CH3 H2 C Br H2 C Br 0.052 Relative rate 100 1.31 0.81 Substrate CH3Br CH3CH2Br CH3CH2CH2Br CH3CH2CH2CH2Br Relative rate 100 1.31 0.81 0.52

0.00001

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:

O C H3C CH3 Acetone O S H3C CH3 Dimethyl sulfoxide (DMSO) O H3CH2C CH2CH3 N Pyridine (Pyr) Tetrahydrof uran (THF) Ethyl ether (Et2O) O H3C C N CH3OCH2CH2OCH3 Dimethoxyethane (DME) H O C N(CH3)2 Dimethylformamide (DMF)

Acetonitrile (MeCN)

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.

SN2 reactions - Reactivity For each set of reactions, draw the SN2 products. Then indicate which reaction should proceed faster and why. C
SH + Br

SH Br

SN1 vs. SN2 reactions Comparison SN2

Reaction Order Minimum # Steps Intermediates? second order reaction 1 or more steps No

S N1
first order reaction 2 or more steps carbocation

Stereochemical Consequences
Importance of Nucleophile Strength Importance of Leaving Group

stereospecific inversion of configuration at electrophilic site

very important; no reaction for weak nucleophiles like H2O very important; no reaction for weak leaving groups like HO-

racemization (full or partial) at electrophilic site

unimportant very important; no reaction for weak leaving groups like HO-

Substrate Structure Dependence

avoid steric hindrance; CH3 > 1 > 2(slow) > 3 (no); no reaction for aryl/vinyl
polar aprotic E2

need carbocation stabilization; 3 > 2 (slow) > 1 (no); resonance stabilization helps; no reaction for aryl/vinyl
polar protic E1, E2, rearrangement

Solvent Competing Reactions

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.

NaI

acetone

Ag+