preview of chapter 7 alkyl halides and nucleophilic substitution alkyl halides : r-x - properties...

Preview of Chapter 7

Alkyl Halides and Nucleophilic substitution

Alkyl Halides : R-X

- properties and reactions, preparation

Substitution reaction

- mechanism SN1 v.s. SN2

- Properties and Selectivity

Assignment for the March 27th Class.

1. What is Hammond postulation?2. What is the product and stereochemical outcome

of the reaction of (S)-2-bromobutane with -OH a) through SN1 mechanism? b) through SN2 mechanism?

Your answers should be submitted to your TAOn Thursday.

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Chapter 7Alkyl Halides

andNucleophilic Substitution

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• Alkyl halides : organic molecules containing a halogen atom bonded to an sp3 hybridized carbon atom.

• Alkyl halides are classified as primary (1°), secondary (2°), or tertiary (3°), depending on the number of carbons bonded to the carbon with the halogen atom.

• The single most important factor that determines the reactivity of alkyl haide.

Introduction to Alkyl Halides

Alkyl Halides and Nucleophilic Substitution

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• Allylic halides : X bonded to the carbon atom adjacent to a C—C double bond.

• Benzylic halides have X bonded to the carbon atom adjacent to a benzene ring.


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• Vinyl halides have a halogen atom (X) bonded to a C—C double bond.

• Aryl halides have a halogen atom bonded to a benzene ring.


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Alkyl Halides and Nucleophilic SubstitutionNomenclature

F: fluoroCl: chloroBr: bromoI: iodo

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Common names are often used for simple alkyl halides.

Nomenclature


2-iodo-2-methylpropane chloroethane

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• weak polar molecules

• dipole-dipole interactions

• incapable of intermolecular hydrogen bonding.

Physical Properties

Alkyl Halides

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Physical Properties

Alkyl Halides

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Interesting Alkyl Halides

Alkyl Halides

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Alkyl Halides

Interesting Alkyl Halides

DichloroDiphenylTrichloroethane

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The Polar Carbon-Halogen Bond

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• Three components are necessary in any substitution reaction.

General Features of Nucleophilic Substitution

Lewis acid Lewis base

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• Since the identity of the counterion is usually inconsequential, it is often omitted from the chemical equation.


• When a neutral nucleophile is used, the substitution product bears a positive charge.

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• when the substitution product bears a positive charge and also contains a proton bonded to O or N,


• To draw any nucleophilic substitution product:

Find the sp3 hybridized carbon with the leaving group.

Identify the nucleophile, the species with a lone pair or bond.

Substitute the nucleophile for the leaving group and assign charges (if necessary) to any atom that is involved in bond breaking or bond formation.

•the initially formed substitution product readily loses a proton in a BrØnsted-Lowry acid-base reaction, forming a neutral product.

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The Leaving Group

• For example, H2O is a better leaving group than HO¯ because H2O is a weaker base.


•The more stable the leaving group X:¯, the better able it is to accept (accommodate) an electron pair.

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• There are periodic trends in leaving group ability:

The Leaving Group

Equilibrium will favor products of nucleophilic substitution when the leaving group is a weaker base than the in-coming nucleophile.

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The Leaving Group


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The Leaving Group

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The Leaving Group

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• Nucleophiles v.s. bases

structurally similar: both have a lone pair or a bond. They differ in what they attack.

The Nucleophile

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Basicity : a measure of how readily an atom donates its electron pair to a proton.

It is characterized by an equilibrium constant, Ka in an acid-base reaction, making it a thermodynamic property.

Nucleophilicity: a measure of how readily an atom donates its electron pair to other atoms.

It is characterized by a rate constant, k, making it a kinetic property.


The Nucleophile

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• Nucleophilicity parallels basicity in three instances:

1. For two nucleophiles with the same nucleophilic atom, the stronger base is the stronger nucleophile.

The relative nucleophilicity of HO¯ and CH3COO¯, two oxygen nucleophiles, is determined by comparing the pKa values of their conjugate acids (H2O = 15.7, and CH3COOH = 4.8). HO¯ is a stronger base and stronger nucleophile than CH3COO¯.

2. A negatively charged nucleophile is always a stronger nucleophile than its conjugate acid. HO¯ is a stronger base and stronger nucleophile than H2O.

3. Right-to-left-across a row of the periodic table, nucleophilicity increases as basicity increases:

The Nucleophile

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• Nucleophilicity does not parallel basicity when steric hindrance becomes important.

• Steric hindrance : a decrease in reactivity resulting from the presence of bulky groups at the site of a reaction.

• Steric hindrance decreases nucleophilicity but not basicity.• Sterically hindered bases that are poor nucleophiles are called

nonnucleophilic bases.

The Nucleophile – steric factor

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• If the salt NaBr is used as a source of the nucleophile Br¯ in H2O,

the Na+ cations are solvated by ion-dipole interactions with H2O molecules, and the Br¯ anions are solvated by strong hydrogen bonding interactions.

The Nucleophile – solvent effect

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• In polar protic solvents, nucleophilicity increases down a column of the periodic table as the size of the anion increases. This is the opposite of basicity.


• protic solvents : compounds with OH or NH bond

• polar protic solvents

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• Polar aprotic solvents also exhibit dipole—dipole interactions, but they have no O—H or N—H bonds. Thus, they are incapable of hydrogen bonding.


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• Polar aprotic solvents solvate cations by ion—dipole interactions.

• Anions are not well solvated because the solvent cannot hydrogen bond to them. These anions are said to be “naked”.


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• In polar aprotic solvents, nucleophilicity parallels basicity, and the stronger base is the stronger nucleophile.

• Because basicity decreases as size increases down a column, nucleophilicity decreases as well.

CH3CH2CH2CH2-Br + N3- CH3CH2CH2CH2N3 + Br-

Solvent CH3OH H2O DMSO DMF CH3CN HMPA

Rel. rate 1 7 1300 2800 5000 2x105

example

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The Nucleophile

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In a nucleophilic substitution:

Mechanisms of Nucleophilic Substitution

Possible mechanisms

In this scenario, the mechanism is comprised of one step. In such a bimolecular reaction, the rate depends upon the concentration of both reactants, that is, the rate equation is second order.

[1] Bond making and bond breaking occur at the same time.

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In this scenario, the mechanism has two steps and a carbocation is formed as an intermediate. Because the first step is rate-determining, the rate depends on the concentration of RX only; that is, the rate equation is first order.

[2] Bond breaking occurs before bond making.

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This mechanism has an inherent problem. The intermediate generated in the first step has 10 electrons around carbon, violating the octet rule. Because two other mechanistic possibilities do not violate a fundamental rule, this last possibility can be disregarded.

[3] Bond making occurs before bond breaking.

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Kinetic data show that the rate of reaction [1] depends on the concentration of both reactants, which suggests a bimolecular reaction with a one-step

mechanism.

SN2 (substitution nucleophilic bimolecular) mechanism.

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Kinetic data show that the rate of reaction [2] depends on the concentration of only the alkyl halide. This suggests a two-step mechanism in which the rate-determining step involves the alkyl halide only.

SN1 (substitution nucleophilic unimolecular) mechanism.



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SN2 Mechanism

Kinetics

Rate = k[CH3Br][CH3COO-]

one step mechanism

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SN2 Mechanism

backside attack

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SN2 Mechanism -- stereochemistry

B

A

(R)(S)

Inversion of configuration

Backsideattack Br

_+CH3CO2 C

CH3H

D+ BrC

CH3H

D

_CH3CO2

Retention of configuration

(S)(S)

+_

CCH3

H

D

O2CCH3_

O2CCH3+Frontsideattack BrBrC

CH3H

D

Frontside attack : Nu approaches from the same side as the leaving group

Backside attack : Nu approaches from the opposite side as the leaving group

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• All SN2 reactions proceed with backside attack of the nucleophile, resulting in inversion of configuration at a stereogenic center.


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S R

S R

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Influence of Identity of R group on SN2 reactions

• Methyl and 1° alkyl halides undergo SN2 reactions with ease.

• 2° Alkyl halides react more slowly.

• 3° Alkyl halides do not undergo SN2 reactions.

• This order of reactivity can be explained by steric effects. Steric hindrance caused by bulky R groups makes nucleophilic attack from the backside more difficult, slowing the reaction rate.


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Alkyl Halides and Nucleophilic SubstitutionInfluence of Identity of R group on SN2 reactions

Substrate (CH3)3CBr (CH3)3CCH2Br (CH3)2CHBr CH3CH2Br CH3Br

3o hindered 1o 2o 1o methyl (neopentyl)Rel. rate <1 1 500 4 x 104 2 x 106

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Application: Useful SN2 Reactions

Fluoxetine (trade name: Prozac

O NHCH3

CF3

one step

..OH

NHCH3

Nucleophile

CH3NH2

Leaving group

I

OH

..

..

ClCl

Ethambutol (trade name: Myambutol)

OH

NHNH

HO

Nucleophiles

Leaving groups

++

OH

H2NHO

NH2

OH

Cl2/H2O

OH

Cl

Cl

ClCH2CO2H

Nucleophile

pH > 7

Leaving group

:..

Cl

Cl

OCH2CO2H

2,4-Dichlorophenoxyethanoic acid(selective weed killer)

(anti-tuberculosis drug)

(antidepressant)

CH3

ClSO3H

CH3

S

Cl

OO

NH3

..Nucleophile

Leaving group

CH3

SO

H2N

O

Oxidation of CH3

to CO2H, thencyclization

S

NHO

O

O

Saccharin (sweetener)

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SN2 reaction in Nature

Nucleophilic substitution reactions are important in biological systems as well.

methylation


Application: Useful SN2 Reactions

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two step mechanism, carbocations -- reactive intermediates.

SN1 Mechanism

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SN1 Mechanism

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geometry of the carbocation intermediate.


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racemic mixture


1 : 1 mixtureracemization

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• The rate of an SN1 reaction is affected by the type of alkyl halide involved.

• This trend is exactly opposite to that observed in SN2 reactions.


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SN1 Mechanism

Why?

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Carbocation Stability

i.e. alkyl groups act as electron donor

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How ?

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Carbocation Stability• The order of carbocation stability can be rationalized

through inductive effects and hyperconjugation.

• Inductive effects : electronic effects that occur through bonds -- the pull of electron density through bonds caused by electronegativity differences between atoms.

• Alkyl groups are electron donating groups that stabilize a positive charge.

• In general, the greater the number of alkyl groups attached to a carbon with a positive charge, the more stable will be the cation.

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Carbocation Stability• Hyperconjugation : the spreading out of charge by the

overlap of an empty p orbital with an adjacent bond. • This overlap (hyperconjugation) delocalizes the positive charge on the

carbocation, spreading it over a larger volume, and this stabilizes the carbocation.

• Example: CH3+ cannot be stabilized by hyperconjugation, but

(CH3)2CH+ can.

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The rate of an SN1 reaction

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• The Hammond postulate relates reaction rate to stability.

• It provides a quantitative estimate of the energy of a transition state.

• The Hammond postulate : the transition state of a reaction resembles the structure of the species (reactant or product) to which it is closer in energy.

in an endothermic step, TS resembles the products,in an exothermic step, TS resembles the reactants.

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The Hammond Postulate

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• endothermic reaction

• the transition state resembles the products more than the reactants --- anything that stabilizes the product stabilizes the transition state also.

i.e. lowering the energy of the transition state decreases Ea, which increases the reaction rate.

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Alkyl Halides and Nucleophilic SubstitutionThe Hammond Postulate

•If there are two possible products in an endothermic reaction, but one is more stable than the other, the transition state that leads to the formation of the more stable product is lower in energy, so this reaction should occur faster.

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• exothermic reaction

• the transition state resembles the reactants more than the products.

• lowering the energy of the products has little or no effect on the energy of the transition state.

• Since Ea is unaffected, the reaction rate is unaffected.

• The conclusion is that in an exothermic reaction, the more stable product may or may not form faster, since Ea is similar for both products.

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• In an exothermic reaction, the more stable product may or may not form faster, since Ea is similar for both products.

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Alkyl Halides and Nucleophilic SubstitutionThe Hammond Postulate and SN1 reactionThe stability of the carbocation determines the rate of its

formation.

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SN1 Reactions, Nitrosamines and Cancer

• SN1 reactions are thought to play a role in how nitrosamines act as toxins and carcinogens.

RN

RH + NaNO2

RN

RN O

sodium nitrite nitrosamine

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Alkyl Halides and Nucleophilic SubstitutionPredicting the Likely Mechanism of a Substitution Reaction.

When is the mechanism SN1 or SN2 ?

1. Allkyl halides

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• Strong nucleophiles (which usually bear a negative charge) present in high concentrations favor SN2 reactions.

• Weak nucleophiles, such as H2O and ROH favor SN1 reactions by decreasing the rate of any competing SN2 reaction.


2. Nucleophile

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• The strong nucleophile favors an SN2 mechanism.

• The weak nucleophile favors an SN1 mechanism.

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• A better leaving group increases the rate of both SN1 and SN2 reactions.


3. Leaving group

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• Polar protic solvents like H2O and ROH favor SN1 reactions

because the ionic intermediates (both cations and anions) are stabilized by solvation.

• Polar aprotic solvents favor SN2 reactions because nucleophiles are not well solvated, and therefore, are more nucleophilic.


4. Solvent

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SN2

Strong Nu andpolar aproticsolvent

SN1

Weak Nu andpolar proticsolvent

Strong Nu neededStrong Nu not needed

or SN2SN1

SN2SN1

3o

2o

1o

Alkyl Halide

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Vinyl Halides and Aryl Halides.

• Vinyl and aryl halides do not undergo SN1 or SN2 reactions, because heterolysis of the C—X bond would form a highly unstable vinyl or aryl cation.SN1 and SN2 reactions occur only at sp3 hybridized carbon atoms.

for now!

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In organic synthesis

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In organic synthesis

Organic synthesis : systematic preparation of a compound (the target molecule, TM) from readily available starting material.

main goals of synthetic organic chemistry : to prepare physiologically active natural products (or their analogs) from simpler starting materials

O

OH

O

OO

O

OHN

O

HO OO

OH

O

OH

HO

O O

O

Taxol

aspirin

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Nucleophilic Substitution and Organic Synthesis.

• To carry out the synthesis of a particular compound, we must think backwards, and ask ourselves the question: What starting material and reagents are needed to make it?

“retrosynthesis”

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Nucleophilic Substitution and Organic Synthesis.

7.47, 7.51, 7.52, 7.54, 7.55, 7.57, 7.61, 7.63, 7,.67, 7.68,

7.71, 7.73, 7.76, 7.79

Homework

Preview of Chapter 8

Alkyl Halides and Elimination reactions

Alkyl Halides : R-X

Alkenes

Substitution reaction

- mechanism E1 v.s. E2

- When is the reaction SN1, SN2, E1 or E2?

There will be 10 minute quiz on following questions.

On the April 17th (Thursday)

1. What is Zaitsev rule ?2. Which halide undergo elimination reaction faster than others a) under E1 mechanism? b) under E2 mechanism? R3CX,, R2CHX, RCH2X

And there will be no classOn April 15th (Tuesday)!

preview of chapter 7 alkyl halides and nucleophilic substitution alkyl halides : r-x - properties...

Documents

simple alkyl halides

aryl halides

benzylic halides

nomenclaturealkyl halides

nucleophilic substitutionthe

nucleophilic substitutionsince

reactivity of alkyl

halogen atom x