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Hougland CHE275 Chapter8 Slides
Hougland CHE275 Chapter8 Slides
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
Example
(CH3)2CHCH2ONa + CH3CH2Br
Isobutyl alcohol
O R'C .. O .. R + :X
Example
O CH3(CH2)16C OK + CH3CH2I
O CH3(CH2)16C O CH2CH3 + KI
gives a thiol H .. S .. R + :X
Example
KSH + CH3CH(CH2)6CH3 Br
Example
NaCN + Br
CN
:X
Example
NaN3 + CH3CH2CH2CH2CH2I 2-Propanol, water
Example
CH3CHCH3 + NaI Br acetone
RI RBr
most reactive
NaI is soluble in acetone; NaCl and NaBr are not soluble in acetone.
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
Bimolecular Mechanism
HO CH3 Br
transition state
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
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
Interactive Question
What is the major product of the reaction of the dihalide at the right with 1 equivalent of NaSH in dimethyl sulfoxide?
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
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 .. :
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.
Nucleophile I-, HS-, RSBr-, HO-, RO-, CN-, N3NH3, Cl-, F-, RCO2H2O, ROH RCO2H
Nucleophilicity
Rank good fair weak Nucleophile HO, RO Relative Rate 104 103 1
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.
CH3 C CH3
+ C
CH3
O: H
+
CH3 CH3 C CH3 .. OH .. + H .. Br : .. .. : Br : ..
+ 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 : ..
+ C
CH3
O: H
+
The mechanism of this step is not SN2. It is SN1 and begins with ionization of (CH3)3CBr. .. : Br : ..
CH3
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
RX + ROH2 ROH
Generalization
Nucleophilic substitutions that exhibit first-order kinetic behavior are not stereospecific.
Interactive Question
Which alkyl halide will react faster with CH3OH under SN1 conditions? A) B)
C CH3(CH2)5
Br
H C) D) HO C
CH3
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.
Example
CH3 C H CHCH3 Br H2O CH3 CH3 C OH CH2CH3 (93%)
Solvent Effects
SN1 Reaction Rates Increase in Polar Protic Solvents
Most polar
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
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
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
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
Example
CH3CHCH3 Br NaOCH2CH3 ethanol, 55C CH3CHCH3 OCH2CH3 (13%) (87%)
CH3CH=CH2
Example: E2
Example: SN2
CH3CH2
Br
CH3CH2
Br
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
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 CH2=CCH2CH3 +
36%
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)
SO2Cl
pyridine
(abbreviated as ROTs)
H CH2OTs
KCN
ethanolwater
H CH2CN (86%)
Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.
CH3CHCH2CH3 OTs
CH3CHCH2CH3 Br (82%)
H C CH3 OTs
CH3
Nu
CH3 H C CH3(CH2)5 Nu
CH3(CH2)5
(CH2)5CH3
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%
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