nucleophilic substitution. y : – rx y r + : x – nucleophile is a lewis base (electron-pair...

Nucleophilic SubstitutionNucleophilic Substitution

Y :–

R X Y R++ : X–

Nucleophile is a Lewis base (electron-pair donor),

often negatively charged and used as Na+ or K+ salt.

Substrate is usually an alkyl halide.

Nucleophilic Substitution

++

Halogens connected to sp2 carbons are not reactive under the conditions discussed in this chapter.

Effect of Hybridization of the CarbonEffect of Hybridization of the Carbon

sp2 carbons not reactive

sp3 carbon reactive

Therefore, substrate cannot be an a vinylic halide or an aryl halide, except under certain conditions to be discussed in Chapter 12.

Nucleophilic Substitution

+ R X

Alkoxide ion as the nucleophile

..O:

..R'

–

Table 8.1 Examples of Nucleophilic Substitution

gives an ether

+ : XR..O..

R' –

(CH3)2CHCH2ONa + CH3CH2Br

Isobutyl alcohol

(CH3)2CHCH2OCH2CH3 + NaBr

Ethyl isobutyl ether (66%)

Example

+ R X

Carboxylate ion as the nucleophile

..O:

..R'C

–O

..

gives an ester

+ : XR..OR'C –O


OK +CH3(CH2)16C CH3CH2I

acetone, water

O

+ KIO CH2CH3CH3(CH2)16C

Ethyl octadecanoate (95%)

O

Example

+ R X

Hydrogen sulfide ion as the nucleophile

S:–

..

..H

gives a thiol

+ : XR..S..

H –


KSH + CH3CH(CH2)6CH3

Br

ethanol, water

+ KBr

2-Nonanethiol (74%)

CH3CH(CH2)6CH3

SH

Example

+ R X

Cyanide ion as the nucleophile

–CN: :


gives a nitrile

+ : XR –CN:

DMSO

BrNaCN +

Cyclopentyl cyanide (70%)

CN

+ NaBr

Example

Azide ion as the nucleophile

.. ..–

N N N::– +

+ R X


..

gives an alkyl azide

+ : XR –..N N N:

– +

NaN3 + CH3CH2CH2CH2CH2I

2-Propanol-water

CH3CH2CH2CH2CH2N3 + NaI

Pentyl azide (52%)

Example

+ R X

Iodide ion as the nucleophile

–

..: I

..:


gives an alkyl iodide

+ : XR –....I:

NaI is soluble in acetone; NaCl and NaBr are not soluble in acetone.

acetone

+ NaICH3CHCH3

Br

63%

+ NaBrCH3CHCH3

I

Example

Alkyl iodides are most reactive since:(a) the carbon-iodine bond is weakest for the halogens;

(b) iodide is the weakest base of the halides (this implies that iodide is most stable) since HI is the strongest acid.

Relative Reactivity of Halide Leaving GroupRelative Reactivity of Halide Leaving Group

Since the rate of reaction depends on the halide the ratedetermining step must involve breaking of the carbon-halogen bond.

SSNN2 Mechanism of Nucleophilic Substitution2 Mechanism of Nucleophilic Substitution

Kinetic studies of the above reaction showed that the rate is also dependent on the hydroxide concentration:

The rate determining step therefore involves both the nucleophile and the alkyl halide.


Overall reaction.

The mechanism (one step).

The transition state.

The configuration at carbon.

From

Potential Energy Diagram for SPotential Energy Diagram for SNN2 Reaction2 Reaction

The nucleophile attacks carbon from the side opposite the bond to the leaving group. The SN2 reaction at a chirality center proceeds with inversion of configuration at the carbon bearing the leaving group.

Inversion of Stereochemistry with SInversion of Stereochemistry with SNN22

The reaction of (S)-2-bromooctane proceeds with inversion of configuration as shown in the equation:

Inversion of Configuration Inversion of Configuration

The transition state is:

Steric Effects and SSteric Effects and SNN2 Reaction 2 Reaction

RatesRates

The rate of the reaction: RBr + LiI RI + LiBr

Effect of the Alkyl Group on the RateEffect of the Alkyl Group on the Rate

decreases with increasing steric hindrance.The reaction is fastest with the least hindered methylbromide.

The rate of SN2 reactions normally decreases in the order:CH3X > primary > secondary > tertiary

Substitution on the -carbon also slows reaction by adding steric hindrance to the carbon bearing the halogen.

Effect of Effect of -Substitution on the Rate-Substitution on the Rate

Neopentyl bromide (a primaryalkyl halide) is so hindered that it is essentially unreactive.

Nucleophiles and NucleophilicityNucleophiles and Nucleophilicity

Not all nucleophiles are negatively charged. Amines (R3N), sulfides (R2S) and phosphines (R3P) are good neutral nucleophiles.

Neutral NucleophilesNeutral Nucleophiles

Solvolysis reactions with water (hydrolysis) and alcoholsalso involve neutral nucleophiles

Neutral NucleophilesNeutral Nucleophiles

SN2 hydrolysis reaction mechanism:

Nucleophilicity (nucleophile strength) is a measure of how fast a Lewis base displaces a halogen in a reaction.The table compares rates of reaction with CH3I in CH3OH.

Nucleophilic StrengthNucleophilic Strength

When comparing nucleophiles with the same nucleophilic atom then the stronger base is the stronger nucleophile.

NucleophilicityNucleophilicity

The stronger base is the conjugate base of the weaker acid.

This generalization holds when comparing nucleophilesin the same row of the Periodic table

When comparing nucleophiles that have the same nucleophilic atom the charged nucleophile is stronger.

Nucleophilic StrengthNucleophilic Strength

When comparing nucleophiles in the same group of the Periodic Table the most important factor is solvationof the nucleophile.

Iodide is the weakest base of the halogens but the best nucleophile. The smaller chloride is a stronger base but is more solvated because it has higher charge density.

Nucleophilic Strength Nucleophilic Strength

The SThe SNN1 Mechanism of 1 Mechanism of

Nucleophilic SubstitutionNucleophilic Substitution

Tertiary alkyl halides are very unreactive in substitutions that proceed by the SN2 mechanism.

Do they undergo nucleophilic substitution at all?

Yes. But by a mechanism different from SN2. The most common examples are seen in solvolysis reactions.

A question...

The reaction

(CH3)3CBr + 2 H2O (CH3)3COH + H3O+ + Br-

Nucleophilic Substitution of Tertiary Alkyl halidesNucleophilic Substitution of Tertiary Alkyl halides

follows a first order rate law:

Rate = k[(CH3)3CBr]

And the reaction is termed SN1.


Step 1: Ionization to form a tertiary cation.

Step 2: Addition of a water molecule.

Step 3: Deprotonation.

Potential Energy Graph of the SPotential Energy Graph of the SNN1 Reaction1 Reaction

first order kinetics: rate = k[RX]

unimolecular rate-determining step

carbocation intermediate

rate follows carbocation stability

rearrangements sometimes observed

reaction is not stereospecific

much racemization in reactions of optically active alkyl halides

Characteristics of the SN1 mechanism

Comparison of a series of alkyl bromides under SN1 reaction conditions (solvolysis) reveals that tertiary alkyl halides react fastest.

The Alkyl Halide and the Rate of SThe Alkyl Halide and the Rate of SNN1 Reaction1 Reaction

In general, methyl and primary alkyl halides never react by the SN1 mechanism and tertiary alkyl halides never react by SN2.

SN1 reactions proceed through the carbocation which isplanar.

Stereochemistry of the SStereochemistry of the SNN1 Reaction1 Reaction

The nucleophile can react from either side however, surprisingly a 1:1 mixture of products is not always formed.

The incomplete loss of stereochemistry is explained by a partial shielding of one side of the cation by the halideleaving group.

Stereochemistry of the SStereochemistry of the SNN1 Reaction1 Reaction

Rearrangements are evidence for carbocation intermediates and serve to confirm the SN1 reaction mechanism.

Carbocation Rearrangements in SCarbocation Rearrangements in SNN1 Reactions1 Reactions

Mechanism with RearrangementMechanism with Rearrangement

Step 2: H-shift (to form a more stable tertiary cation).

Step 1: Ionization.

Step 3: Water addition to the carbocation.

Step 4: Deprotonation.

Solvent affects the rate of a reaction not the products formed and the questions are:

1. What properties of the solvent influence the rate most?

2. How does the rate-determining step of the mechanismrespond to the properties of the solvent?

Effect of Solvent on SubstitutionEffect of Solvent on Substitution

Protic solvents are those that are capable of hydrogen bonding. Normally they have an –OH group or an N-H group.

Aprotic solvents are not hydrogen bond donors.

Polarity of a solvent is related to its dielectric constant ().Solvents with high dielectric constants are considered polar and those with low dielectric constants are non polar.

Classification of SolventsClassification of Solvents

Properties of SolventsProperties of Solvents

Polar protic solvents hydrogen bond to, and solvate, the nucleophile and suppress its nucleophilicity and reduce

the rate of reaction.

Solvents and SSolvents and SNN2 Reactions2 Reactions

Polar aprotic solvents cannot solvate the nucleophileand the nucleophile is free to react.

The table below shows the effect of solvent on this reaction.


The reaction is much faster in polar aprotic solvents.

This reaction was studied under two different conditions.


Reaction of hexyl bromide in a polar protic solvent required heating for 24 hours to form 76% of hexyl cyanide.

With a polar aprotic solvent dimethyl sulfoxide and the less reactive hexyl chloride at room temperature for 20 minutes yielded 91 % of hexyl cyanide.

Comparison of the rates of solvolysis of (CH3)3CCl and dielectric constant of the solvent shows faster reaction with more polar protic solvent.


The reaction is much faster in more polar protic solvents.

The transition state for formation of the carbocation and the halide anion is lowered in a more polar solvent.


When...

Primary alkyl halides undergo nucleophilic substitution: they always react by the SN2

mechanism.

Tertiary alkyl halides undergo nucleophilic substitution: they always react by the SN1

mechanism.

Secondary alkyl halides undergo nucleophilic substitution: they react by the

SN1 mechanism in the presence of a weak nucleophile (solvolysis).SN2 mechanism in the presence of a good nucleophile.

Substitution and Elimination as Substitution and Elimination as Competing ReactionsCompeting Reactions

Substitution and/or EliminationSubstitution and/or Elimination

Lewis bases can react as nucleophiles or bases resulting in substitution or elimination.

Examples where both substitution and elimination products are formed:

Substitution and/or EliminationSubstitution and/or Elimination

The competition between substitution and elimination is:

The balance between substitution and elimination can be affected by changing from an unhindered base to a more hindered base.

Unhindered base (CH3CH2ONa): predominantly substitution.Hindered base (CH3)3COK: predominantly elimination

Steric Effect on the SSteric Effect on the SNN2/E2 Reactions2/E2 Reactions

Nucleophiles that are weak bases tend to give higherratios of substitution. Azide (N3

-) and cyanide (CN-)are weak bases.

Basicity and SubstitutionBasicity and Substitution

Tertiary alkyl halides are very hindered and yield mixturesof substitution and elimination by SN1 and E1 mechanismswith neutral nucleophiles.

Nucleophiles and Tertiary Alkyl HalidesNucleophiles and Tertiary Alkyl Halides

Addition of stronger bases results in elimination exclusively through an E2 reaction.

Nucleophilic Substitution of Nucleophilic Substitution of Alkyl SulfonatesAlkyl Sulfonates

Sulfonic acids are very strong acids similar to sulfuric acid.

Nucleophilic Substitution of SulfonatesNucleophilic Substitution of Sulfonates

Alkyl sulfonates (ROTs) are prepared by reaction of alcohols with a sulfonyl chloride:

Sulfonates are stable anions and very weak bases because they are the conjugate bases of very strong acids.


Sulfonates are therefore excellent leaving groups.

Hydroxide (HO-) is a very poor leaving group so transforming an alcohol into a sulfonate generates a good leaving group.

Alkyl sulfonates react faster than iodides.


Sulfonates are better leaving groups than halides so theycan be used to form alkyl halides by substitution.


The formation of a tosylate does not change the configuration of the alcohol so an optically pure alcohol is transformed into an enantiopure tosylate.


Secondary tosylates undergo substitution with weak bases.


Secondary tosylates also undergo elimination with strongbases.

Nucleophilic Substitution and Nucleophilic Substitution and Retrosynthetic AnalysisRetrosynthetic Analysis

Retrosynthetic analysis works back from the targetmolecule. Here nucleophilic substitution reaction can

form the thiol.

Retrosynthetic AnalysisRetrosynthetic Analysis

Leaving group X could be a tosylate made from an alcohol.

The alcohol could be made from an alkene.

Once the retrosynthetic analysis has been developedsimply write the synthesis starting from the alkene.

Retrosynthetic Analysis to SynthesisRetrosynthetic Analysis to Synthesis

The full retrosynthetic analysis is:

Anti-Markovnikov addition of H-OH

nucleophilic substitution. y : – rx y r + : x – nucleophile is a lewis base (electron-pair...

Documents

rate of reaction

sn2 reaction ratesthe

carbon halogen bond

waterexample iodide

rate of sn2 reactions

primary alkyl halide

carboniodine bond

sn2the reaction of s