Part 3CHM1C3

Substitution Reactions

R1

R2R3

ClNu

R1

R2R3

Nu

Inversion of

Configuration

Racemisation of

Configuration

R1

R2R3

Nu

R1

R2R3

Nu

Rate = k [R-Cl][Nu]

SN2

Rate = k [R-Cl]

SN1

Content of Part 3

Part 3i. The Role of Kinetics and Chirality in Determining

Mechanisms of the Substitution Reaction

Part 3ii. Effect of Solvent on the Substitution Reaction

Part 3iii. Effect of Structure on the Substitution Reaction

Part 3iv. Nature of the Attacking Nucleophile

Part 3v. Nature of the Leaving Group

Part 5i

Substitution Reactions:Mechanisms

Bimolecular substitution (SN2) (and elimination (E2)) reactions and transition states

Unimolecular substitution (SN1) (and elimination (E1)) reactions and reactive intermediates

Content of Part 5i

The SN2 Reaction Mechanism

The SN1 Reaction Mechanism

Reaction Rates/Chirality in Determining the Mechanism

Transition States

Reactive Intermediates

After completing PART 4i of this course you should have an understanding of, and be able to demonstrate, the following

terms, ideas and methods.

(i) Understand how by considering both the reaction kinetics and the stereochemical outcome of substitution

reactions the SN2 and SN1 mechanisms were devised,

(ii) Understand the difference in timings of the arrow-pushing in the mechanisms of the SN2 and SN1 reaction,

(iii) Understand the terms bimolecular and unimolecular,

(iv) Understand the reaction energy profile for a reaction in which a transition state leads to the formation of the

products – a SN2 reaction, and

(vi) Understand the reaction energy profile for a reaction in which a reactive intermediate leads to the formation

of the products – a SN1 reaction.

– Learning Objectives Part 5i –

Substitution Reactions:Mechanisms

CHM1C3– Introduction to Chemical Reactivity of Organic

Compounds–

Nucleophililic Substitution Reactions at sp3 Carbons

It is found that there are two possible stereochemical outcomes, each described by a different rate equation, and different stereochemical outcomes.

Descriptor Rate Equation Stereochemical Outcome

SN2 rate = k[R-Hal][Nu] Inversion

SN1 rate = k[R-Hal] Racemisation

Stereochemistry

Rate

EquationNu

R

R'"R

XX

R

R'"R

Nu

Clearly, two different reaction mechanisms must be in operation.

It is the job of the chemists to fit the experimental data to any proposed mechanism

Reaction Mechanisms

The mechanism of a reaction consists of everything that happens as the starting materials are converted into products.

In principle, therefore, writing (or drawing) the mechanism means describing everything that happens in the course of the reaction.

However, providing an exact description of a reaction on paper is an impossible goal.

Instead, a proposal for the mechanism of a reaction should include certain types of information about the course of the reaction. Thus, the reaction mechanism should:

[1] Account for the number of reaction steps as indicated by the rate equation

[2] Account for reactive intermediates or transition states

[3] Account for any stereochemical relationships between starting materials and products

SN2

The SN2 Reaction Mechanism

Cl

R1

R3R2

Nu

Transition State – Energy Maxima

BondForming

2

1–2

1–

sp2

BondBreaking

R1

R2

R3Nu Cl

Inversion of Configuration

Nucleophile attacks from behind the C-Cl -bond.

This is where the *-antibonding orbital of the C-Cl bond is situated.

Rate = k[R-Hal][Nu]

R1

R2R3

ClNu

sp3

Bimolecular Process

Rate Determinig

Step

http://chemistry.boisestate.edu/rbanks/organic/sn2.gif

http://www.personal.psu.edu/faculty/t/h/the1/sn2.htm

http://www.bluffton.edu/~bergerd/classes/CEM221/sn-e/SN2-1.html

Transition States: See SN2 and E2 Reaction Mechanisms

A transition state is the point of highest energy in a reaction or in

each step of a reaction involving more than one step.

The nature of the transition state will determine whether the reaction

is a difficult one, requiring a high activation enthalpy (G‡), or an easy

one.

Transition states are always energy maxima, I.e. at the top of the

energy hill, and therefore, can never be isolated.

A transition states structure is difficult to identify accurately. It

involves partial bond cleavage and partial bond formation.

Transition States

A + B

Energy

Reaction Coordinate

A + B

C + D

[A.B]‡

Transition State

Energy Maxima

Rate = k[A][B]

See SN2 and E2Reaction Mechanisms

G‡

Go

Energy

Reaction Coordinate

R1

R2R3ClNu

R1

R2R3Nu Cl

Cl

R1

R3R2

Nu

Transition State – Energy Maxima

BondForming

2

1–2

1–

sp2

BondBreaking

SN1

The SN1 Reaction Mechanism

R1

R2R3

Nu

R1

R2R3

Nu

Racemisation of

Configuration

R1

R2R3

Cl

sp3

UnimolecularProcess

Rate = k[R-Hal]

RateDetermining

State

R1

R3 R2

Nu Cl

Reactive Intermediate – Energy Minima

sp2

Nucleophile attacks from either side of the carbocationic intermediate.

Reactive Intermediates: See SN1 and E1 Reaction Mechanisms

Reactive intermediates are energy minima, i.e. at the bottom of the energy hill,

and therefore, can be isolated.

A reactive intermediate structure is much easier to identify and in certain cases

these high energy species can be isolated and structurally characterised.

Go

Energy

G‡ G‡

Energy

Reaction Coordinate

A + B

D + E

C + B

Reactive Intermediate

Energy Minima

Reactive Intermediates

Rate = k[A]

See SN1 and E1Reaction Mechanisms

And Radical Chain Reaction

Energy

Reaction Coordinate

R1

R2R3

Cl

R1

R3 R2

R1

R2R3

Nu

R1

R2R3

Nu

Reactive Intermediate

– Summary Sheet Part 3i –

Substitution Reactions:Mechanisms

The difference in electronegativity between the carbon and chlorine atoms in the C-Cl sigma () bond result in a polarised bond,

such that there is a partial positive charge (+) on the carbon atom and a slight negative charge (-) on the halogen atom. Thus,

we can consider the carbon atom to be electron deficient, and therefore electrophilic in nature (i.e. electron liking). Thus, if we

react haloalkanes with nucleophiles (chemical species which have polarisable lone pairs of electrons, which attack electrophilic

species), the nucleophile will substitute the halogen atom.

The difference in electronegativity between the carbon and chlorine atoms in the C-Cl sigma () bond result in a polarised bond,

such that there is a partial positive charge (+) on the -carbon atom and a slight negative charge (-) on the halogen atom, which

in turn is transmitted to the -carbon atom and the protons associated with it. Thus, the hydrogen atoms on the -carbon atom are

slightly acidic. Thus, if we react haloalkanes with bases (chemical species which react with acids), the base will abstract the

proton atom, leading to carbon-carbon double bond being formed with cleavage of the C-Cl bond.

Substitution (and elimination) reactions can be described by two extreme types of mechanism. One mechanism is a concerted

and relies on the starting materials interacting to form a transition state, and the other is a step-wise process in which one of the

starting material s is converted into a reactive intermediate, which then reacts with the other reagent.

Discussions of transition states and reactive intermediates in the course of a reaction is very useful when proposing an organic

reaction mechanism, which takes into account the experimental evidence for a reaction, such as rate equations and

stereochemical outcomes.

CHM1C3– Introduction to Chemical Reactivity of Organic

Compounds–

Exercise 1: Substitution Reactionscis-1-Bromo, 3-methylcyclopentane reacts with NaSMe (MeS— is an excellent nucleophile) to afford a product with molecular formulae C7H14S. The rate of the reaction was found to be dependent on both the bromoalkane and the NaSMe.

(i) Identify the product, and(ii) propose an arrow pushing mechanism to account for the product formation.

Answer 1: Substitution Reactionscis-1-Bromo, 3-methylcyclopentane reacts with NaSMe (MeS— is an excellent nucleophile) to afford a product with molecular formulae C7H14S. The rate of the reaction was found to be dependent on both the bromoalkane and the NaSMe.

(i) Identify the product(s), and(ii) propose an arrow pushing mechanism to account for the product formation.

BrMe

Me Br

MeS

MeBr

MeS

Me

SMe

SMeMe

Starting material molecular formula = C6H11Br

Product molecular formula = C7H14S

Lost Br, Gained SMe, Substitution Reaction

Rate equation indicates bimolecular process, SN2

Envelope Conformation of Cyclopentane

Exercise 2: Substitution ReactionsCompounds A and B when treated with a weak base are deprotonated to form the carboxylate anion. One of these carboxylate anions then reacts further to afford the lactone P, whilst the other carboxylate anion is does not lead to P.

Identify the carboxylate anion which affords P, and rationalise its formation with an arrow pushing mechanism, as well as rationalising why the other carboxylate anion does not afford P.

I

IHO O HO O O O

A B P

Answer 2: Substitution ReactionsCompounds A and B when treated with a weak base are deprotonated to form the carboxylate anion. One of these carboxylate anions then reacts further to afford the lactone P, whilst the other carboxylate anion is unaffected.

Identify the carboxylate anion which affords P, and rationalise its formation with an arrow pushing mechanism, as well as rationalising why the other carboxylate anion does not afford P.

I

IHO O HO O O O

I

IO O O O

BaseBase

* orbital of C-I bond

A B P

HO O

H

Reaction must be SN2 type, because if it was SN1 like the carbocation below would be generated from both S1 and S2. Therefore both S1 and S2 would afford P