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Substitution Reactions of Alkyl Halides

Paula Yurkanis BruiceUniversity of California,

Santa Barbara

Chapter 9

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The Compounds in Group II Are Electrophiles

All the compounds in Group II have an electron withdrawing atom or group

that is attached to an sp3 carbon.

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Because Group II Compounds are Electrophiles,They React with Nucleophiles

Substitution reaction—the electronegative group is replaced by another group.

Elimination reaction—the electronegative group is eliminated along with a hydrogen.

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Nucleophilicity

Basicity

NUCLEOPHILES AND BASES

All nucleophiles are bases …... and all bases are nucleophiles.

THE FUNDAMENTAL DISTINCTION

A good base is not necessarily a good nucleophile, and vice versa.HOWEVER :

kinetic (or rate) parameter

thermodynamic (or equilibrium) parameter.

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Alkyl Halides

This chapter discusses the substitution reactions of alkyl halides.

Alkyl halides have good leaving groups.

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A Substitution Reaction

More precisely called a nucleophilic substitution reaction because the atom replacing the halogen is a nucleophile.

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What is the Mechanism of the Reaction?

an SN2 reaction

The kinetics of a reaction—the factors that affect the rate of the reaction—can help determine the mechanism.

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Relative Rates of an SN2 Reaction

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Inverted Configuration

If the halogen is bonded to an asymmetric center, the product will have the inverted configuration.

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Summary of the Experimental Evidence for the Mechanism of an SN2 Reaction

1. The rate of the reaction is dependent on the concentration of both the alkyl halide and the nucleophile.

2. The relative rate of the reaction is primary alkyl halide > secondary alkyl halide > tertiary alkyl halide.

3. The configuration of the product is inverted compared to the configuration of the reacting chiral alkyl halide.

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The Mechanism

back-side attack

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Why Bimolecular?

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Why Back-Side Attack?

RULE - bond formation requires HOMO-LUMO interaction - HOMO is filled nonbonding MO of Nu:, LUMO is empty * antibonding orbital of C-Br bond

RULE - for an SN2 reaction, the best overlap of interacting orbitals is achieved through back-side attack

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If Front-Side Attack• In a potential retention mechanism, there would be

poor overlap between the HOMO of the nucleophileand the LUMO of R–L.

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Why Do Methyl Halides React the Fastest and Tertiary the Slowest?

steric hindrance© 2014 Pearson Education, Inc.

Why Steric Hindrance Decreases the Rate

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Both are Primary Alkyl Halides but They React at Different Rates

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Although it is Primary, it Reacts Very Slowly

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Why the Configuration of the Product is Inverted

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The Weakest Base is the Best Leaving Group

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The Rate of an SN2 Reaction is Affected by the Leaving Group

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The SN2 Reaction: Leaving Group Stability

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The Leaving Group

• The more stable the anion, the better the leaving ability– the most stable anions are the conjugate bases of

strong acids

I- > Br- > Cl- > H2 O >> F- > CH3 CO- > HO- > CH3 O- > NH2-

Reactivity as a leaving group

Stability of anion; strength of conjugate acid

rarely function as leaving groups

O

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Base Strength and Nucleophile Strength

If atoms are in the same row, the strongest base is the best nucleophile.

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Base Strength and Nucleophile Strength

A negatively charged atom is a stronger base and a better nucleophile than the same atom that is neutral.

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Charged Nucleophiles

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Nucleophilicity and Basicity

A + H2O AH + OHK

K = Equilibrium Constant

Nu + R-X Nu-R + Xk

k = rate constant

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NUCLEOPHILE VERSUS BASE

Nu2 is a betternucleophile

Nu1 is a better base

( FASTER RATE )

( STRONGER BOND )

Nucleophilicity = Kinetic

Basicity = Thermodynamic

Rate = k2[RX][Nu]

B:- + H+ B-H

Nu1

Nu2

strong baseshifts equilib.

good nucleophileincreases k2(I.e., the rate)

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Nucleophilicity isdetermined here

activation energyand rate (kinetics)

Basicity isdetermined here

strength of bondsand position ofequilibrium

DIFFERENT PLACES ON THE ENERGY PROFILE DETERMINE NUCLEOPHILICITY AND BASICITY

faster is better

lower energy is better

NUCLEOPHILES

BASES

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C

R

Br:

RR

Y: :....

WHAT IS THE IDEAL NUCLEOPHILE ?

no way ! badSTERIC PROBLEMS

Smalleris better !

LARGE

SMALL

SN2 REACTIONS

For an SN2 reaction the nucleophile must find the back lobe of the sp3 hybrid orbital that the leaving group is bonded to.

:....X:

-good

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FF Cl Br I

1.36 A 1.81 A 1.95 A 2.16 A

-- - - -

smallestion

and we would expect the smallest one (fluoride) to be the best nucleophile,

….. however, that is not usually the case.

OUR NAÏVE EXPECTATION

We would expect the halides to be good nucleophiles:

ionic radii:

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F- 5 x 102

Cl- 2.3 x 104

Br- 6 x 105

I- 2 x 107

slowest

fastest

k

CH3-I + NaX CH3-X + NaI

Rate = k [CH3I] [X-]

RELATIVE RATES OF REACTION FOR THE HALIDES

MeOH

* MeOH solvates like water but dissolves everything better.

EXPERIMENTAL RESULTS

SN2

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Ion–Dipole Interactions

Stronger bases form stronger ion–dipole interactions.

Ion–dipole interactions have to be broken before the nucleophile can react.

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SMALL IONS SOLVATE MORE HEAVILY THAN LARGE ONES

solventshell

- -...smaller

solvent shell

...escapeseasily

…morepotential energy

BETTERNUCLEOPHILE

IF - -

“Effective size” is larger.

H OH

H OHH

O

HH

O

H

HO

H H

OH

HO H

H OH

H OHH

O

H

Heavy solvation lowers the potential energy of the nucleophile.

It is difficult for the solvated nucleophileto escape the solvent shell.

This ion is less reactive.

strong interactionwith the solvent

weak interactionwith the solvent

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FF Cl Br I

1.36 A 1.81 A 1.95 A 2.16 A

HALIDE IONS

Heats ofsolvationin H2O - 120 - 90

Kcal / mole

- 65

X(H2O)n-

-- - - -

increasing solvation

- 75

SMALL IONS SOLVATE MORE THAN LARGE IONS

smallestion

larger n smaller n

IONICRADIUS

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PROTIC SOLVENTS

water methanol ethanol amines

CH3CH2 OH

H OH

NRH

HCH3 O

H

Water is an example of a “protic” solvent.

Protic solvents are those that have

Protic solvents can form hydrogen bonds and can solvate both cations and anions.

O-H, N-H or S-H bonds.

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APROTIC SOLVENTS

SCH3 CH3

O

CH N

O

CH3

CH3

N P N

O

N

H3C

H3C

CH3

CH3

CH3H3C

CCH3 CH3

O

CH3 C N

dimethylsulfoxide

dimethylformamide

hexamethylphosphoramide

acetone acetonitrile

if scrupulouslyfree of water

+

- -+

APROTIC SOLVENTSDO NOT HAVE

OH, NH, OR SH BONDS

“DMSO”

“DMF”

“HMPA”

They do not form hydrogen bonds.

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DMF and DMSO

They can solvate a cation (+) better than they can solvate an anion (–).© 2014 Pearson Education, Inc.

APROTIC SOLVENTS SOLVATE CATIONS,BUT NOT ANIONS (NUCLEOPHILES)

The nucleophile is“free” (unsolvated),and therefore is smalland not hindered by a solvent shell.

-

-

+

+

X-M+

S

O

CH3 CH3

S

O

H3C CH3

SO

CH3

CH3

S O

H3C

H3C

crowded

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CH N

O

CH3

CH3

M+

CH3

H3C

O

N HC

X-

DIMETHYLFORMAMIDE

nucleophile is “free”(unsolvated)

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+

-

++

+

-

++

+-

++

+ -++

Na+

+

-

++

+

-

++

+-

++

+ -

++Cl-

Polar aprotic solvents solvate cations well, anions poorly

good fit! bad fit!

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Base Strength and Nucleophile Strength

The strongest base is the best nucleophile unless1.they differ in size.2.they are in a protic polar solvent.

F– is the best nucleophile in an aprotic solvent because it is the strongest base.

I– is the best nucleophile in a protic solvent because it more polarizable and it is poorly solvated.

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The Solvent - SN2

Br N3-

CH3C N

CH3OH

H2 O

(CH3 )2S=O

(CH3 )2NCHO

N3 Br-

SolventType

polar aprotic

polar protic

500028001300

71

k(methanol)

k(solvent)

Solvent

+solvent

SN 2+

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SN2 mechanism promoted by moderately polar & polar aprotic solvents

destabilize Nu–s, makethem more nucleophilic

e.g., OH– in H2O: strong H-bonding to water makes OH– less reactiveOH– in DMSO: weaker solvation makes OH– more reactive (nucleophilic)

RX + OH–

ROH + X–

in DMSO

in H2O

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Polarizability

As you go down a row in the periodic table the larger atoms are more polarizable, so they are betternucleophiles but they are weaker bases.

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Steric Hindrance Decreases Nucleophilicity

Even though the tert-butoxide ion is a stronger base, it is a poorer nucleophile because nucleophilic attack is more sterically hindered than proton removal.

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The SN2 Reaction: Nucleophile Size and TypeNucleophilicity ~ both size and basicity

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SN2 Reactions Can Be Used to Makea Variety of Compounds

The reactions are irreversible because a strong base displaces a weak base.© 2014 Pearson Education, Inc.

Synthesizing an Amine

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Reversibility of SN2 ReactionsHow to determine the direction of an SN2 reaction

RULE - an SN2 reaction proceeds in the direction that allows the stronger base to displace the weaker base

What if the basicities of the Nu: and the LG are similar?

RULE - an SN2 reaction proceeds in the direction that allows the stronger base to displace the weaker base - this reaction will be reversible if the base strengths are similar

pKa = -9.0pKa = -10

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Reversibility of SN2 Reactions

A reversible reaction can be driven towards products by removing one of the products as it is formed:

Le Châtelier’s principle - if an equilibrium is disturbed, the system will adjust to offset the disturbance:

The rapid deprotonation of a protonated ether drives the reaction towards products© 2014 Pearson Education, Inc.

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A Substitution Reaction

A tertiary alkyl halide and a poor nucleophile

The reaction is surprisingly fast, so it must be taking place by a different mechanism.

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The Rate Depends Only on the Concentration of the Alkyl Halide

an SN1 reaction

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Relative Rates of an SN1 Reaction

Generally only tertiary alkyl halides undergo SN1 reactions.

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If the halogen is bonded to an asymmetric center, the product will be a pair of enantiomers.

The Product is a Pair of Enantiomers

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Summary of the Experimental Evidence for the Mechanism of an SN1 Reaction

1. The rate of the reaction depends only on the concentration of the alkyl halide.

2. Tertiary alkyl halides react the fastest.

3. If the halogen is attached to an asymmetric center the product will be a pair of enantiomers.

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The Mechanism

Most SN1 reactions are solvolysis reactions; the nucleophile is the solvent.

The leaving group departs before the nucleophile approaches.

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The Slow Step is Formation of the Carbocation

Tertiary alkyl halides react the fastest; they form the most stable carbocations.

Secondary and primary alkyl halides do not undergo SN1 reactions.© 2014 Pearson Education, Inc.

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Why a Pair of Enantiomers?

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Stereochemistry of SN2 and SN1 Reactions

inverted product ~50 -70%

retained configuration ~ 30 - 50%

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Why More Inverted Product

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The Front Side is Partially Blocked

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The Weakest Base is the Best Leaving Group

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Benzylic and Allylic Halides Undergo SN2 Reactions

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Allylic and Benzylic Halides

• Allylic and benzylic intermediates stabilized by delocalization of charge

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Delocalized Carbocations• Delocalization of cationic charge enhances stability• Primary allyl is more stable than primary alkyl• Primary benzyl is more stable than allyl

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Benzylic and Allylic Halides Undergo SN1 Reactions

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The SN1 Reaction of Allylic Halides Can Form Two Products

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Vinylic and Aryl Halides Cannot Undergo SN2 Reactions

SN2 - Nu: approach to the backside of the sp2 carbon is repelled by electron cloud

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Vinylic and Aryl Halides Cannot Undergo SN1 Reactions

SN1 - vinylic and aryl cations are even more unstable than 1° carbocations (6.5 -placing charge on more electronegative sp carbon is unstable)

SN1 - sp2 carbon atoms form stronger bonds than sp3 carbons (1.14) so the halogen bond to a sp2 carbon is harder to break.

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Comparing SN2 and SN1 Reaction

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Summary of Alkyl Halide Reactivity

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Rate Law for an SN2 Reaction + Rate Law for an SN1 Reaction

The rate law for a reaction that can undergo both SN2 and SN1 reactions.

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Common Solvents

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Solvation

The dielectric constant is a measure of how the solvent can insulate(solavate) opposite charges from one another.

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One of the Reactants is Charged

If a reactant is charged, the charge on the reactants will be greater than the charge on the transition state.

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If One of the Reactants is Charged,Increasing the Polarity of the Solvent Decreases the Rate

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The Reactants are Neutral

If the reactants are neutral, the charge on the reactants will be less than the charge on the transition state.

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If the Reactants are Neutral,Increasing the Polarity of the Solvent Increases the Rate

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Neutral Nu:

• This a general phenomenon for SN2 reactions© 2014 Pearson Education, Inc.

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Influence of the solvent

• The transition state is a highly chargedintermediate, which is more stabilized in apolar environment

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Effects of Solvent on Energies• Polar solvent stabilizes transition state and

intermediate more than reactant and product

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Solvent Is Critical in SN1

• Stabilizing carbocation also stabilizes associated transition state and controls rate

Solvation of a carbocation by water

SN1: Ionizing Ability of Solvent is CriticalPolar Protic Solvents Best (Solvate Cations and Anions)

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The Rate of an SN1 Reaction of an Alkyl Halide Increases as the Polarity of the Solvent Increases

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0

20

40

60

80

Dielectric Constant

Water

Methanol

Aceticacid

Protic Solvent

SN1

DMSO

Acetone

DichloromethaneDiethyl ether

Aprotic Solvent

SN2

DMFHMPA

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Role of Solvent in SN1 & SN2If Nu: is charged - will not dissolve in nonpolar solvents (problem)

Solution - use aprotic polar solvents

Why polar - dissolve charged Nu:

Why aprotic - not H-bond donor - although not as good as protic solvent at solvating charges this is a good thing, because we don’t want our solvent to sufficiently stabilize our reacting Nu:

If Nu: is neutral - polar solvents increase the rate of the reaction

Solution - use protic polar solvents

Why polar - increase reaction rate

Why protic - better than aprotic at solvating

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RX + OH–

ROH + X–

in polar aprotic

in polar protic

Role of Solvent in SN1 & SN2

Charged NucleophileNeutral Nucleophile

Problem: solubility!!!

Solution:Polar Aprotic Solvent!!!

Polar Protic Solvent!!!Polar Protic Solvents Best(Solvate Cations and Anions)

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Competition Between SN2 and SN1 Reactions

• When a halide can undergo both an SN2 and SN1 reaction:

– SN2 will be favored by a high concentration of a good (negatively charged) nucleophile

– SN2 will be favored in a polar aprotic solvent– SN1 will be favored by a poor (neutral)

nucleophile in a polar protic solvent

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Intermolecular versus Intramolecular SN2 Reactions

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The Intramolecular Reaction is Favored When a Five- or Six-Membered Ring Can Be Formed

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3-Membered and 4-Membered Rings are Less Stable

Three-membered rings are generally formed faster than 4-membered rings.© 2014 Pearson Education, Inc.

Methylation by a Chemist

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Methylation by a Cell

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Nordrenaline to Adrenaline

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One Phospholipid is Converted to Another Phospholipid