Organic Chemistry CHE 275 Chapter 8 Nucleophilic Substitution

Nucleophilic 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
Substrate cannot be an a vinylic halide or an aryl halide, except under specific conditions to be discussed in Chapter 12. X C C X

Examples of Nucleophilic Substitution

Alkoxide ion as the nucleophile R' .. O .. : + R X

gives an ether R' .. O .. R + :X

Example
(CH3)2CHCH2ONa + CH3CH2Br

Examples of Nucleophilic Substitution

Carboxylate ion as the nucleophile O .. + R X R'C O .. : gives an ester

Isobutyl alcohol

(CH3)2CHCH2OCH2CH3 + NaBr Ethyl isobutyl ether (66%)

O R'C .. O .. R + :X

Example
O CH3(CH2)16C OK + CH3CH2I

Examples of Nucleophilic Substitution

Hydrogen sulfide ion as the nucleophile H acetone, water .. S ..: + R X

O CH3(CH2)16C O CH2CH3 + KI

gives a thiol H .. S .. R + :X

Ethyl octadecanoate (95%)

Example
KSH + CH3CH(CH2)6CH3 Br

Examples of Nucleophilic Substitution

Cyanide ion as the nucleophile :N ethanol, water C: + R X

CH3CH(CH2)6CH3 + KBr SH 2-Nonanethiol (74%) gives a nitrile :N C R + :X

Example
NaCN + Br

Examples of Nucleophilic Substitution

Azide ion as the nucleophile :N .. DMSO + N N .. : + R X

CN

NaBr gives an alkyl azide + :N N N .. .. +

Cyclopentyl cyanide (70%)

:X

Example
NaN3 + CH3CH2CH2CH2CH2I 2-Propanol, water

Examples of Nucleophilic Substitution

Iodide ion as the nucleophile .. : .. I: + R X

CH3CH2CH2CH2CH2N3 + NaI Pentyl azide (52%) gives an alkyl iodide .. : .. I R + :X

Example
CH3CHCH3 + NaI Br acetone

Reactivity of Leaving Groups

Reactivity of halide leaving groups in nucleophilic substitution is the same as for elimination.

RI RBr

most reactive

CH3CHCH3 + NaBr I 63%

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

RCl RF least reactive

Problem
A single organic product was obtained when 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product? BrCH2CH2CH2Cl + NaCN Br is a better leaving group than Cl :N C

Problem
A single organic product was obtained when 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product? BrCH2CH2CH2Cl + NaCN

CH2CH2CH2Cl + NaBr

Kinetics and the SN2 Mechanism

Many nucleophilic substitutions follow a second-order rate law. CH3Br + HO CH3OH + Br rate = k[CH3Br][HO ] inference: rate-determining step is bimolecular

Bimolecular Mechanism
HO CH3 Br

transition state

one step HO + CH3Br HOCH3 + Br

Stereochemistry
Nucleophilic substitutions that exhibit second-order kinetic behavior are stereospecific and proceed with inversion of configuration.

Inversion of Configuration

nucleophile attacks carbon from side opposite bond to the leaving group

three-dimensional arrangement of bonds in product is opposite to that of reactant

Stereospecific Reaction
A stereospecific reaction is one in which stereoisomeric starting materials give stereoisomeric products. The reaction of 2-bromooctane with NaOH (in ethanol-water) is stereospecific. (+)-2-Bromooctane ()-2-Octanol ()-2-Bromooctane (+)-2-Octanol

Stereospecific Reaction
CH3(CH2)5 H NaOH C CH3 (S)-(+)-2-Bromooctane Br HO C CH3 (R)-()-2-Octanol H (CH2)5CH3

Problem
The Fischer projection formula for (+)-2-bromooctane is shown. Write the Fischer projection of the ()-2-octanol formed from it by nucleophilic substitution with inversion of configuration.

Problem
The Fischer projection formula for (+)-2-bromooctane is shown. Write the Fischer projection of the ()-2-octanol formed from it by nucleophilic substitution with inversion of configuration.

CH3 H Br CH2(CH2)4CH3 H

CH3 Br CH2(CH2)4CH3 HO

CH3 H CH2(CH2)4CH3

Steric Effects on SN2 reactions: Crowding at the Reaction Site

The rate of nucleophilic substitution by the SN2 mechanism is governed by steric effects. Crowding at the carbon that bears the leaving group slows the rate of bimolecular nucleophilic substitution.

Reactivity toward substitution by the SN2 mechanism

RBr + LiI RI + LiBr Alkyl bromide CH3Br CH3CH2Br (CH3)2CHBr (CH3)3CBr Class Methyl Primary Secondary Tertiary Relative rate 221,000 1,350 1 too small to measure

Decreasing SN2 Reactivity

CH3Br CH3Br

Decreasing SN2 Reactivity

CH3CH2Br (CH3)2CHBr (CH3)3CBr

CH3CH2Br (CH3)2CHBr (CH3)3CBr

Crowding Adjacent to the Reaction Site

The rate of nucleophilic substitution by the SN2 mechanism is governed by steric effects. Crowding at the carbon adjacent to the one that bears the leaving group also slows the rate of bimolecular nucleophilic substitution, but the effect is smaller.

Effect of chain branching on rate of SN2 substitution

RBr + LiI RI + LiBr Alkyl bromide Ethyl Propyl Isobutyl Neopentyl Structure CH3CH2Br CH3CH2CH2Br (CH3)2CHCH2Br (CH3)3CCH2Br Relative rate 1.0 0.8 0.036 0.00002

Interactive Question
What is the major product of the reaction of the dihalide at the right with 1 equivalent of NaSH in dimethyl sulfoxide?

Nucleophiles and Nucleophicity

The nucleophiles described in the book have mostly been anions. .. .. .. : : N C: : : HS HO O CH 3 .. .. ..

etc.

A) C)

B) D)

Not all nucleophiles are anions. Many are neutral. .. .. : NH3 for example CH3OH HOH .. .. All nucleophiles, however, are Lewis bases.

Nucleophiles
Many of the solvents in which nucleophilic substitutions are carried out are themselves nucleophiles.

Solvolysis

The term solvolysis refers to a nucleophilic substitution in which the nucleophile is the solvent.

.. HOH ..

.. CH3OH ..

for example

Solvolysis
substitution by an anionic nucleophile RX + :Nu solvolysis RX + :NuH step in which nucleophilic substitution occurs + RNuH + :X RNu + :X

Solvolysis
substitution by an anionic nucleophile RX + :Nu solvolysis RX + :NuH + RNuH + :X RNu + :X

products of overall reaction

RNu + HX

Example: Methanolysis
Methanolysis is a nucleophilic substitution in which methanol acts as both the solvent and the nucleophile. CH3 RX + : O: H CH3 + H+ R O: H The product is a methyl ether. CH3 R O .. :

Typical solvents in solvolysis

solvent water (HOH) methanol (CH3OH) ethanol (CH3CH2OH) O formic acid (HCOH) O acetic acid (CH3COH) product from RX ROH ROCH3 ROCH2CH3 O ROCH O ROCCH3

Nucleophilicity
compare the relative rates of nucleophilic substitution of a variety of nucleophiles toward methyl iodide as the substrate. The standard of comparison is methanol, which is assigned a relative rate of 1.0.

Major factors that control nucleophilicity

basicity solvation small negative ions are highly solvated in protic solvents large negative ions are less solvated

Rank strong good fair weak very weak

Nucleophile I-, HS-, RSBr-, HO-, RO-, CN-, N3NH3, Cl-, F-, RCO2H2O, ROH RCO2H

Relative rate >105 104 103 1 10-2

Nucleophilicity
Rank good fair weak Nucleophile HO, RO Relative Rate 104 103 1

Major factors that control nucleophilicity

basicity solvation small negative ions are highly solvated in protic solvents large negative ions are less solvated

RCO2 H2O, ROH

When the attacking atom is the same (oxygen in this case), nucleophilicity increases with increasing basicity.

Solvation
Rank strong good fair
Solvation of a chloride ion by ion-dipole attractive forces with water. The negatively charged chloride ion interacts with the positively polarized hydrogens of water.

Nucleophilicity
Nucleophile IBrCl-, FRelative Rate >105 104 103

A tight solvent shell around an ion makes it less reactive. Larger ions are less solvated than smaller ones and are more nucleophilic.

The SN1 Mechanism

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. CH3

CH3 C CH3

Hydrolysis of tert-butyl bromide.

H .. : Br .. + : O: H CH3 CH3 H

+ C
CH3

O: H

+
CH3 CH3 C CH3 .. OH .. + H .. Br : .. .. : Br : ..

Hydrolysis of tert-butyl bromide.

CH3 CH3 C CH3 .. Br : .. + : O: H H CH3 CH3 H

Hydrolysis of tert-butyl bromide.

CH3 CH3 C H CH3 .. Br : .. + : O: H H CH3 CH3 H

+ C
CH3

O:

+ C
CH3

O: H

+
This is the nucleophilic substitution stage of the reaction; the one with which we are concerned. .. : Br : .. The reaction rate is independent of the concentration of the nucleophile and follows a first-order rate law. rate = k[(CH3)3CBr]

+
.. : Br : ..

Hydrolysis of tert-butyl bromide.

CH3 CH3 C CH3 .. : Br .. + : O: H H CH3 CH3 H

Kinetics and Mechanism

rate = k[alkyl halide] First-order kinetics implies a unimolecular rate-determining step. Proposed mechanism is called SN1 (Substitution Nucleophilic unimolecular)

+ C
CH3

O: H

+
The mechanism of this step is not SN2. It is SN1 and begins with ionization of (CH3)3CBr. .. : Br : ..

CH3

CH3 C CH3 unimolecular slow .. : Br ..

Mechanism

H3C

+ C CH3

CH3 : O:

Mechanism

bimolecular fast
CH3 CH3 H

H3C

+ C CH3

CH3 +

.. : Br : ..

+ C
CH3

O: H

carbocation formation

R+

carbocation capture

Characteristics of the SN1 mechanism

first order kinetics: rate = k[RX] proton transfer unimolecular rate-determining step carbocation intermediate rate follows carbocation stability rearrangements sometimes observed reaction is not stereospecific

RX + ROH2 ROH

Significant racemization in reactions of optically active alkyl halides

Electronic Effects Govern SN1 Rates

The rate of nucleophilic substitution by the SN1 mechanism is governed by electronic effects. Carbocation formation is rate-determining. The more stable the carbocation, the faster its rate of formation, and the greater the rate of unimolecular nucleophilic substitution.

Reactivity toward substitution by the SN1 mechanism

RBr solvolysis in aqueous formic acid Alkyl bromide CH3Br CH3CH2Br (CH3)2CHBr (CH3)3CBr Class Methyl Primary Secondary Tertiary Relative Rate 1 2 43 100,000,000

Decreasing SN1 Reactivity

Generalization
Nucleophilic substitutions that exhibit first-order kinetic behavior are not stereospecific.

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

Interactive Question
Which alkyl halide will react faster with CH3OH under SN1 conditions? A) B)

Stereochemistry of an SN1 Reaction

CH3
R-()-2-Bromooctane

C CH3(CH2)5

Br

H C) D) HO C

CH3

CH3 H H2O C CH3(CH2)5

(R)-()-2-Octanol (17%)

OH

(CH2)5CH3
(S)-(+)-2-Octanol (83%)

Ionization step gives carbocation; three bonds to chirality center become coplanar

Leaving group shields one face of carbocation; nucleophile attacks faster at opposite face.

Carbocation Rearrangements in SN1 Reactions Because...

Carbocations are intermediates in SN1 reactions, rearrangements are possible. CH3

Example
CH3 C H CHCH3 Br H2O CH3 CH3 C OH CH2CH3 (93%)

H2O CH3 CH3 C H CHCH3 + CH3 CH3 C + CHCH3 H

Solvent Effects
SN1 Reaction Rates Increase in Polar Protic Solvents

SN1 Reactivity versus Solvent Polarity

Solvent Dielectric constant 6 33 58 78 Relative rate 1 4 5,000 150,000
Fastest rate

acetic acid methanol formic acid water

Most polar

transition state stabilized by polar solvent

transition state stabilized by polar solvent

activation energy decreases; rate increases

R+ R+ energy of RX not much affected by polarity of solvent energy of RX not much affected by polarity of solvent

RX

Ea

RX

Ea > Ea

In general...
SN2 Reaction Rates Increase in Polar Aprotic Solvents

SN2 Reactivity vs. Type of Solvent

CH3CH2CH2CH2Br + N3 Solvent CH3OH H2O DMSO DMF Acetonitrile Type polar protic polar protic polar aprotic polar aprotic polar aprotic Relative Rate 1 7 1300 2800 5000

An aprotic solvent is one that does not have an OH group.

Interactive Question
The reaction of butyl iodide with NaSCH3 will proceed at a faster rate in which solvent? A) acetone B) acetic acid C) propanol D) water

Mechanism Summary SN1 and SN2

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) in a protic solvent SN2 mechanism in the presence of a good nucleophile in an aprotic solvent

Interactive Question
What combination is the best choice in order to prepare 3-chloro-1-iodobutane? A) 1-iodobutane + Cl2 (400C) B) 1,3-dichlorobutane + NaI (1 equiv) in acetone C) 1,3-iodobutane + NaCl (1 equiv) in acetone D) 3-bromo-1-iodobutane + NaCl (1 equiv) in acetone

Interactive Question
The best combination of reactants for preparing (CH3)3CSCH3 is: A) (CH3)3CCl + CH3SK B) (CH3)3CBr + CH3SNa C) (CH3)3CSK + CH3OH D) (CH3)3CSNa + CH3Br

Substitution and Elimination as Competing Reactions

Two Reaction Types

Alkyl halides can react with Lewis bases by nucleophilic substitution and/or elimination.
-elimination C C X + :Y

Two Reaction Types

How can we tell which reaction pathway is followed for a particular alkyl halide?
-elimination

H C

C + H Y + :X

H C C X + :Y

C + H Y + :X

H C C Y nucleophilic substitution + :X

H C C Y nucleophilic substitution + :X

Elimination versus Substitution

A systematic approach is to choose as a reference point the reaction followed by a typical alkyl halide (secondary) with a typical Lewis base (an alkoxide ion). The major reaction of a secondary alkyl halide with an alkoxide ion is elimination by the E2 mechanism.

Example
CH3CHCH3 Br NaOCH2CH3 ethanol, 55C CH3CHCH3 OCH2CH3 (13%) (87%)

CH3CH=CH2

Example: E2

Example: SN2

CH3CH2

Br

CH3CH2

Br

When is substitution favored?

Given that the major reaction of a secondary alkyl halide with an alkoxide ion is elimination by the E2 mechanism, we can expect the proportion of substitution to increase with: 1) decreased crowding at the carbon that bears the leaving group

Uncrowded Alkyl Halides

Decreased crowding at carbon that bears the leaving group increases substitution relative to elimination. primary alkyl halide CH3CH2CH2Br NaOCH2CH3 ethanol, 55C CH3CH2CH2OCH2CH3 + CH3CH=CH2 (91%) (9%)

But a crowded alkoxide base can favor elimination even with a primary alkyl halide.
primary alkyl halide + bulky base CH3(CH2)15CH2CH2Br KOC(CH3)3 tert-butyl alcohol, 40C

Interactive Question
Which one of the following alkyl halides would be expected to give the highest ratio of substitution to elimination on treatment with sodium ethoxide in ethanol (50C)? A) 1-bromopentane B) 2-bromopentane C) 3-bromopentane D) 2-bromo-3-methylbutane

CH3(CH2)15CH2CH2OC(CH3)3 + CH3(CH2)15CH=CH2 (13%) (87%)

When is substitution favored?

Given that the major reaction of a secondary alkyl halide with an alkoxide ion is elimination by the E2 mechanism, we can expect the proportion of substitution to increase with: 1) decreased crowding at the carbon that bears the leaving group 2) decreased basicity of the nucleophile

Weakly Basic Nucleophile

Weakly basic nucleophile increases substitution relative to elimination secondary alkyl halide + weakly basic nucleophile CH3CH(CH2)5CH3 Cl KCN DMSO CH3CH(CH2)5CH3 (70%) CN pKa (HCN) = 9.1

Weakly Basic Nucleophile

Weakly basic nucleophile increases substitution relative to elimination secondary alkyl halide + weakly basic nucleophile I NaN3 pKa (HN3) = 4.6

Tertiary Alkyl Halides

Tertiary alkyl halides are so sterically hindered that elimination is the major reaction with all anionic nucleophiles. Only in solvolysis reactions does substitution predominate over elimination with tertiary alkyl halides.

N3

(75%)

Example

(CH3)2CCH2CH3 Br

Interactive Question
CH3 CH3C=CHCH3 Which of the following is not a good nucleophile for an SN1 reaction? A) NaOCH3 B) CH3OH C) CH3CH2OH D) H2O

CH3 CH3CCH2CH3 OCH2CH3 ethanol, 25C 64% +

CH3 CH2=CCH2CH3 +

36%

2M sodium ethoxide in ethanol, 25C 99% 1%

Interactive Question
Which one of the following compounds gives the highest subtitution-to-elimination ratio (most substitution least elimination) on reaction with 2-bromobutane? A) NaOCH3 B) NaNH2 C) NaCN D) NaCCH

Leaving Groups
We have seen numerous examples of nucleophilic substitution in which X in RX is a halogen However, halogens are not the only possible leaving groups

Other RX compounds
O ROSCH3 O Alkyl methanesulfonate (mesylate) O ROS O Alkyl p-toluenesulfonate (tosylate) CH3

Preparation
Tosylates are prepared by the reaction of alcohols with p-toluenesulfonyl chloride (usually in the presence of pyridine)

ROH + CH3 O ROS O CH3

SO2Cl

pyridine

undergo same kinds of reactions as alkyl halides

(abbreviated as ROTs)

Tosylates undergo typical nucleophilic substitution reactions

H CH2OTs

KCN
ethanolwater

H CH2CN (86%)

The best leaving groups are weakly basic

Approximate Relative Reactivity of Leaving Groups

Leaving Group F Cl Br I H2 O TsO CF3SO2O Relative Rate 10-5 1 10 102 101 105 108 Conjugate acid pKa of of leaving group conj. acid HF HCl HBr HI H3 O + TsOH CF3SO2OH 3.5 -7 -9 -10 -1.7 -2.8 -6

Approximate Relative Reactivity of Leaving Groups

Leaving Group F Cl Br I H2 O TsO CF3SO2O Relative Rate 10-5 1 10 102 101 105 108 Conjugate acid pKa of of leaving group conj. acid HF HCl HBr HI H3 O + TsOH CF3SO2OH 3.5 -7 -9 -10 -1.7 -2.8 -6

Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.

Tosylates can be converted to alkyl halides

NaBr DMSO

Tosylates allow control of stereochemistry

Preparation of tosylate does not affect any of the bonds to the chirality center, so configuration and optical purity of tosylate is the same as the alcohol from which it was formed. CH3(CH2)5 H C CH3 OH CH3(CH2)5
TsCl pyridine

CH3CHCH2CH3 OTs

CH3CHCH2CH3 Br (82%)

H C CH3 OTs

Tosylate is a better leaving group than bromide.

Tosylates allow control of stereochemistry

Having a tosylate of known optical purity and absolute configuration then allows the preparation of other compounds of known configuration by SN2 processes. H TosO C
SN2

Secondary alcohols react with inversion

H CH3 Br H H3 C C OH H 13% H3 C C CH3(CH2)5 Br 87% HBr C (CH2)5CH3

CH3
Nu

CH3 H C CH3(CH2)5 Nu

CH3(CH2)5

(CH2)5CH3

Secondary alcohols react with inversion

Most reasonable mechanism is SN1 with front side of carbocation shielded by leaving group

Rearrangements can occur

CH3 Br C (CH2)5CH3

OH HBr
H

H H3 C C CH3(CH2)5 OH

87% HBr

13%

H3 C C CH3(CH2)5 Br

Br + Br
93% 7%

Rearrangements can occur

HBr

Tosylates also undergo Elimination

NaOCH3 CH3OH heat CH2=CHCH2CH3 + CH3CH=CHCH3 E and Z

OH
7%

+ Br

CH3CHCH2CH3 OTs

+
93%

Br +

Br

Br

Summary: Chapter 8
Summary: Chapter 8 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 Nucleophilic Substitution Relative Reactivity of Halides The SN2 Mechanism Steric Effects in SN2 Nucleophiles and Nucleophilicity The SN1 Mechanism Carbocation Stability and SN1 Rate Stereochemistry of SN1 Reactions Carbocation Rearrangements in SN1 Reactions 8.10 8.11 8.12

Summary: Chapter 8
Summary: Chapter 8 Solvent Effects on Nucleophilic Substitution Substitution vs. Elimination Sulfonate Esters as Substrates in SN1 and SN2