C ClH3CH2C

H

H3C

CH3S- Na+

CH3CNCH3CS

CH2CH3H

CH3

+ NaCl

C OHH3C

H3C

H3C

HBr, ∆C Br

H3CH3C

H3C

+ H2O

H3CH2C Br:N(CH3)3

OSO2CH3NaI, acetone

I

+ NaOSO2CH3

H3CH2C N(CH3)3Br

Substitution Reactions of Alkyl Halides

• involve displacement of a heteroatom from carbon -- the "leaving group"

• the leaving group is always more EN than carbon making the carbon electrophilic

• the carbon is always sp3 hybridized

• there is always a nucleophile present, either -ve or d -

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

C CH3C C CH3C CH3

Important Synthetic Reactions that are Substitutions

Many important functional groups can be prepared by using Substitution reactions.

O2N CH2

Examples involving C-C bond formation: Result

CH3CH2Br + NaCN CH3CH2CN

Nucleophile

CH3I +

Examples involving C-O bond formation:

PhCH2Cl +

CH3I + PhO CH3OPh

CH3CH2CH2CH2Cl + HO CH3CH2CH2CH2OH

Examples involving C-S bond formation:

CH3CH2Br + NaSH CH3CH2SH

CH3I + CH3CH2CH2S

PhCH2CH2NO2

CH3CH2CH2SCH3

(CH3)3C—Br + H2O (CH3)3C—OH

(CH3)3C—Br + HOCH3 (CH3)3C—OCH3

Examples involving C-H bond formation:

CH3(CH2)8CH2Cl + LiAlH4 CH3(CH2)8CH3

Examples involving C - halogen bond formation:

CH3CH2CH2CH2Cl + KNCO CH3CH2CH2CH2NCO

Examples involving C-N bond formation:

CH3CH2CH2CH2Cl + H3N CH3CH2CH2CH2NH3

PhCH2Cl + N(CH3)3 PhCH2N(CH3)3 Cl

CH2Br + NaI CH2I

+ NaN3

Br N3

What makes a good nucleophile?

It is hard to derive an accurate order of nucleophilic strength because, among other things, solvent plays an important role in SN2 reactions. Having said that, the following trends are a useful guide.Strong bases are good nucleophiles... so:

A nucleophile with a negative charge is always a more powerful nucleophile than its conjugate acid. So, HO- is more nucleophilic than H2O, and H2N- is more nucleophilic than H3N:.

Overall: R3C- > H2N- > RO- > HO- > R2NH > AcO- > ArO- > H3N: > F- > H2O.

For the same atom with the same charge, nucleophilicity parallels basicity:

CH3CH2O > HO > PhO > CH3CO2 > H2O

For atoms in the second row of the periodic table, and with the same charge, nucleophilicity parallels basicity:

H3C > H2N > HO > F

Going down the periodic table, nucleophilicity increases, though basicity decreases. Therefore, for halides:

I- > Br- > Cl- > F-

Group VIA: RSe - > RS - > RO -

Group VA: R3P > R3N

Steric bulk around the basic atom suppresses nucleophilicity...

CH3CH2O > CH3C

H3CH3C

Ot-butoxide

H2N >N

Diisopropylamide(LDA)

pKa conj. acid:

CH3CH2CH2OH CH3CH2CH2ClH3CH2C

BrH

CH3 H3CC

CH3H3C

OH

CH2Cl CH2OH

C CH

H CH2Br

HC C

H

H C

H

H3CCH3

OH

CH3C

CH3

OHCH2CH2Cl Br

C CH

H

H

Br

To determine which, if either, mechanism is operating, you must learn to...

Alkyl halides and alcohols undergo substitution by two mechanisms: SN1 and SN2.

The SN1 reaction involves a the formation of a carbocation reaction intermediate in rate determining step. SN2 involves the collision of the nucleophile with the carbon that bears the leaving group.

3°, benzylic and allylic substrates undergo SN1 reactions because they form relatively stable carbocations.

1° substrates undergo SN2 reaction because they are sterically uncluttered at the reaction site.

2° substrates undergo both reaction types but slowly.

The SN1 Reaction

H3C

C

H3CH3C Br

H2O

H3C

C

H3CH3C OH + HBr

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

The Mechanism...

H3C

CH3C

H3C Br

H3CC CH3

H3C

BrOH

HH3C

CH3C

H3C OH

H

H3C

CH3C

H3C OH

HBr

Br

HOH3C

Br

HO CH3

HO

H3C

HO

CH3H3C C

CH3

CH3

HO

CH3

HO

H3C

The reaction profile...

This mechanism operates when:• the substrate forms a relatively stable carbocation• the nucleophile is a weak base, preferably a neutral molecule like H2O, ROH etc.• the reaction is done in a polar, protic (OH)solvent (water, alcohols, acetic acid etc.)

Factors that stabilize carbocations.

Since the SN1 reaction involves the formation of carbocations in the rate determining step, only those species that form relatively stable carbocations will undergo this reaction in a timely fashion.

H2C

C C

H

H H2C

H

Br

H3CO

H2C

Cl

Cl

Alkyl carbocations are stabilized by electron donation from adjacent C-H bonds, something that is known as hyperconjugation.

H

C

HH

CHH

1° 3° H

C

HH

CC

C

H

H

HH

HH

So for alkyl carbocations, the order of stability is...

Vinyl and aryl carbocations cannot be stabilized by resonance...

C CHH H

C

H

H

C H

H

or by hyperconjugation.

So, the order of stability of carbocations is:

Usually, SN1 reactions are practical for benzylic, allylic and 3° substrates.

The Hammond Postulate - a useful and oft used tool to rationalize the relative rates of analogous reactions.

"The structure of a transition state tends to resemble that species to which it is closer in energy."For endothermic reactions... For exothermic reactions...

the transition state is closer in energy to the products and therefore said to be "product-like" in structure. From this, we infer something about the energy of the transition state from the stability of the product.

the transition state is closer in energy to the reactants and therefore said to be "reactant-like" in structure. From this, we infer something about the energy of the transition state from the stability of the reactants.

H3C

C

H3C

H3C Br

H3CC CH3

H3C BrNu:

H3CC

H3CH3C Nu

H3CC

H

H3C BrH3C

C CH3H

Br

H3CC

HH3C Nu

Nu:

Therefore, when comparing reactions that involve the formation of carbocation intermediates in the RDS, the one involving the more stable carbocation intermediate will be formed ...

H3C

C

H3CH3C Br

H3C

C CH3

H3C

O

H

H

Br

Reactions Involving Carbocations

H3C CC

CH3

H

HH

H3C CC

CH3

H

H

H3C

C CH3

H3C H2C C

CH3

CH3 H3CC

CH3

H3C H2C C

CH3

CH3

H3CC

CH3

H3C HC CH3

H3C C

CH3

CH3

CHCH3

Substitution (SN1 - the last step is a Lewis acid/base reaction).

Elimination (E1 - the last step is a Brønsted acid/base reaction.)

Addition

Rearrangement

H3CC

CH3

H CH2 ClAlCl3

H3CC

CH3

H CH2 Cl AlCl3

Carbocation rearrangements are often promoted by the presence of Lewis acids. In this case, the intermediates are said to be "carbocation-like" if not actual carbocations.

H3C C

CH3

CH3AlCl4

C

H3C

H3CCH3

C

CH3I

H

H2O/CH3OH, ∆ C

H3C

H3CCH3

C

CH3OH

HC

H3C

H3COH

C

CH3H

CH3

C

H3C

H3CCH3

C

CH3I

H

C

H3C

H3CCH3

C

CH3

H

C

H3C

H3CCH3

C

CH3OH

H

C

H3C

H3CC

CH3H

CH3

C

H3C

H3COH

C

CH3H

CH3

Carbocation rearrangements are always possible when group migration can lead to a more stable carbocation. Generally this is an unwanted complication.

Another case...

Cl H2O/CH3OH, ∆

H H H

Yet another case...

AlCl3C

CH3

CH3

CH3

C

H3CH3C

H3C

Cl C

H3CH3C

H

CH2Cl

AlCl3C

CH3

CH3

CH3

Stereochemistry of the SN1 Reaction

C

PhCH2CH3H3C

BrNaI/Acetone

C PhCH2CH3H3C

C

PhCH2CH3H3C

I

C

PhH3CH2C CH3

I

Reactions in which the configuration of an asymmetric center is scrambled are said to occur with...

Sometimes (depending on conditions) reactions occur with only partial racemization.

C

PhCH2CH3H3C

BrNaI/Acetone

C PhCH2CH3H3C

C

PhCH2CH3H3C

I

C

PhH3CH2C CH3

I

Br-

The SN2 reaction

Best for 1° and methyl substrates.

I H3C Br CH3I Br

The mechanism consists of a single elementary process.

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.

H3C Br CH3I Br

When attack occurs at an asymmetric carbon, the reaction occurs exclusively with inversion of the absolute stereochemistry. This is an example of a stereospecific reaction.

C Br

H3CH3CH2C

HCS

CH3CH2CH3

H

BrH3C

Why backside attack?

C Br

HH

HH3C S CS

HH

H

BrH3C

Substrate structure and the rate of SN2

Substrate Relative rate

CH3Br

0.004

CH3CH2CH2Br

C

H3C

H3CBr

H

C

H3C

H3CBrCH3

100

1.31

0.81

0.015

CH3CH2Br

So the substrate structure dependence on rate is...

More data...

CH3Br

CH3CH2CH2Br

100

1.31

0.81

CH3CH2Br

CH3CH2CH2CH2Br 0.52

C

CH3

H3CH2C

Br

H

C

CH3

H3CH2C

Br

H3C

0.052

0.00001

Neopentyl substrates are prone to rearrangement.

C

CH3

H3CH2C

OTs

H3C H2O/CH3OH, ∆

C

OH

H3CH2C

CH3

H3C

CH3C

CH2

CH3

H3C

The effect of solvent on the rate of SN1 and SN2 reactions...

SN1 processes are fastest in polar, protic solvents due to ion-dipole stabilization of the developing charge in the transition state.

Polar protic solvents...

H3CC

OH

OOH CH3CH2OH CH3OH H2OOH

t-Butanol (t-BuOH)

Isopropanol (iPrOH)

Ethanol (EtOH)

Methanol(MeOH)

WaterAcetic AcidAcOH

Polar aprotic solvents are best for SN2 because the nucleophile is not as solvated.

H3CC

CH3

O

H3C C N CH3OCH2CH2OCH3 HC

N(CH3)2

O

H3CS

CH3

O

H3CH2CO

CH2CH3

N

O

Acetone Acetonitrile(MeCN)

Dimethoxyethane(DME) Dimethylformamide

(DMF)

Dimethyl sulfoxide(DMSO)

Ethyl ether(Et2O)

Pyridine(Pyr) Tetrahydrofuran

(THF)

OK for the preparation of 3° amines from 2° amines...

NHCl

OH

N

OH

70%

and quaternary ammonium compounds...

NCH3

CH3

CH3I N CH3

CH3

CH3

I

Preparation of Amines vis SN2

But pitfalls in the synthesis of 1° or 2° amines...

H3N: CH3CH2Br CH3CH2NH3Br

CH3CH2NH3Br H3N: CH3CH2NH2 NH4Br

CH3CH2NH2 CH3CH2Br CH3CH2NH2CH2CH3 Br

Wtih 16 eq. NH334% 1°57% 2°1% 3°

Comparing SN2 and SN1

No. Steps 1 2 or 3

SN2 SN1

Reactionorder

2nd 1st

Substrate structure dependence

CH3, 1° best. 2° OK but slow.Watch for b-branching.3°, vinyl, aryl do not react.

Allylic, benzylic > 3°.2° very slow. 1°, vinyl, aryldo not react.

Intermediate None Carbocation.

Stereochemical consequences StereospecificInversion

Racemization orpartial racemization

Solvent Polar, aprotic. Polar protic

Competing reaction E2 E1, E2, rearrangement.

Importance of nucleophile on rate

Very important.NR for weak nucleophileslike H2O, ROH.

Unimportant.

Substrateclassification

Weak base/good Nu

Moderate/strong base/good Nu

Weak base/weak Nu

Methyl, CH3X SN2 SN2 NR

1°

2°

3°

SN2

SN2 and SN1

SN1

SN2

E2

SN1

E2

SN1

SN1

1° Benzylic

2° Benzylic

3° Benzylic

1° Allylic

2° Allylic

3° Allylic

Aryl

Alkenyl(Vinyl)

NR NR NR

NRNRNR

SN2 and SN1

SN1

SN1

E2

E2

SN1SN2

SN1

SN1

SN2 and SN1

SN1

SN1

E2

E2

SN1SN2

SN1

SN1