lecture 4_ nucleophilic substitution
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Dr. Doan Duy Tien
Organic ChemistryFor USTH Students
Lecture 4: Nucleophilic Substitution
at a saturated carbon atom
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Classification of alkyl halides according to the class of the
carbon that the halogen is attached to.
RCH2-X R2CH-X R 3C-X
1o 2o 3o
InterestingAlkyl Halides
(Natural Compounds)
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InterestingAlkyl Halides
(Synthetic Compounds)
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Interesting alkohol
A renewable fuel source
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Eplerenone (trade name Inspra) is prescribed to reduce
cardiovascular risk in patients who have already had a heart attack.
Tiotropium bromide (trade name Spiriva) is a long-acting
bronchodilator used to treat the chronic obstructive pulmonary
disease of smokers and those routinely exposed to secondhand smoke
Interesting Epoxide
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Contents
+ The Leaving Group
+ The Nucleophile
+ Nucleophilicity Versus Basicity
+ Steric Effects and Nucleophilicity
+ Possible Mechanisms for Nucleophilic Substitution
+ Two Mechanisms for Nucleophilic Substitution: SN1 and SN2
+ Stereochemistry of the SN2 Reaction
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1. Nucleophilic substitution R-X + :Z- R-Z + :X-
2. Preparation of Grignard Reagent
R-X + Mg RMgX
3. Reduction
R-X + Mg RMgX + H2O R-H
R-X + Sn, HCl R-H
Nucleophilic substitution of alkyl halides
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Nucleophilic Substitution of alkyl halides
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Nucleophilic substitution of alkyl halides
good nucleophile strong base
good leaving group weak base
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Examples
Nucleophilic substitution of alkyl halides
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Living groups
Nucleophilic substitution of alkyl halides
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Good Living groups
Nucleophilic substitution of alkyl halides
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Poor living groups
Nucleophilic substitution of alkyl halides
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Reactions of Alkyl Halides (R-X):[SN1, SN2, E1, & E2 reactions]
When a nucleophile (electron donor, e.g., OH-) reacts with an
alkyl halide, the halogen leaves as a halide
There are two competing reactions of alkyl halides with nucleophiles.
1) substitution
2) elimination
C C
H
X
Nu:-
+ C C
H
Nu
+ X-
+ C C
H
X
Nu:- C C + X
- + Nu H
The Nu:- replaces the halogen on the -carbon.
The Nu:- removes an H+ from a -carbon &
the halogen leaves forming an alkene.
BrR..
.. :
..
.. ::BrNu:
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R-X + :OH- ROH + :X- alcohol
R-X + H2O ROH + HX alcohol
R-X + :OR - R-O-R + :X- ether
R-X + -:CCR R-CCR + :X- alkyne
R-X + :I- R-I + :X- iodide
R-X + :CN- R-CN + :X- nitrile
R-X + :NH3 R-NH2 + HX primary amine
R-X + :NH2R R-NHR + HX secondary amine
R-X + :SH- R-SH + :X- thiol
R-X + :SR R-SR + :X- thioether
Etc.
Best when R-X is CH3 or 1o!
Nucleophilic substitution
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CH3CH2CH2-Br + KOH CH3CH2CH2-OH + KBr
CH3CH2CH2-Br + HOH CH3CH2CH2-OH + HBr
CH3CH2CH2-Br + NaCN CH3CH2CH2-CN + NaBr
CH3CH2CH2-Br + NaOCH3 CH3CH2CH2-OCH3 + NaBr
CH3CH2CH2-Br + NH3 CH3CH2CH2-NH2 + HBr
CH3CH2CH2-Br + NaI, acetone CH3CH2CH2-I + NaBr
Nucleophilic substitution
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Giving this reaction
CH3 CH3
CH3CCH3 + OH-
CH3CCH3 + Br-
Br OH
Kinetics
rate = k [ tert-butyl bromide ]
SN1
Nucleophilic substitution
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Nucleophilic substitution
(SN1) mechanism:
Kinetics: rate = k [R-W ]; only R-W is involved in the RDS!
C WRDS
C + :W
C + :Z C Z
carbocation
1)
2)
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CH3 CH3 CH3
H Br + NaOH HO H + H OH
(SN1 conditions)
C6H13 C6H13 C6H13
(-)-2-bromooctane (+)-2-octanol (-)-2-octanol
SN1 proceeds with partial racemization. The intermediate carbocation is
sp2 hybridized. The nucleophile can attack the carbocation from either the
top or the bottom and yield both enantiomeric products.
Nucleophilic substitution
SN1 stereochemistry
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SN1 reactivity: 3o > 2o > 1o > CH3
RBr R+ + Br-
CH3Br H = 219 Kcal/mole CH
3+
CH3CH2Br H = 184 Kcal/mole 1o
CH3CHBr H = 164 Kcal/mole 2o
CH3
CH3CH3CBr H = 149 Kcal/mole 3
o
CH3
Nucleophilic substitution SN1 reactivity
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SN1 order of reactivity = 3o > 2o > 1o > CH3
Stability of carbocations = 3o > 2o > 1o > CH3+
RDS in SN1: RW R+ + :W-
RX [ R---------X ] R+ + X-
+ -
Nucleophilic substitution SN1 reactivity
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Nucleophilic substitution SN1
Application: Nitrosamines, and Cancer
SN1 reactions are thought to play a role in how nitrosamines,compounds having the general structure R2NN=O, act as toxins
and carcinogens. Nitrosamines are present in many foods,
especially cured meats and smoked i sh, and they are also found in
tobacco smoke, alcoholic beverages, and cosmetics. Nitrosaminescause many forms of cancer
Formation of nitrosamine
Nucleophilic substitution S 1
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Nucleophilic substitution SN1
Application: Nitrosamines, and Cancer
+ In the presence of acid or heat, nitrosamines are converted to diazonium
ions, a very good leaving group, N2.
+ With certain R groups, these diazonium compounds form carbocations,
which then react with biological nucleophiles (such as DNA or an enzyme)in the cell.
+ If this nucleophilic substitution reaction occurs at a crucial site in a
biomolecule, it can disrupt normalcell function leading to cancer or cell
death. This two-step process-loss of N2 as a leaving group and reaction with
a nucleophile is an SN1 reaction
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Mechanism for nucleophilic substitution:
substitution, nucleophilic, bimolecular
SN2
Z: + C W Z C + :W
RDS
Kineticsstudy of the effect of changes in concentration on
rates of reactions.
CH3Br + NaOH
CH3OH + NaBrrate = k [ CH3-Br ] [ OH
- ]
CH3-Br and OH- are involved in the rate determining step of
the mechanism. bimolecular
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SN2 stereochemistry
CH3 CH3
H Br + NaOH HO H
(SN2 conditions)
C6H13 C6H13
(S)-(-)-2-bromooctane (R)-(+)-2-octanol
100% optical purity
SN2 proceeds with 100% inversion of configuration! (backside attack
by the nucleophile)
SN2 100% backside attack by the nucleophile
Evidence: stereochemistry = 100% inversion of configuration
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Relative rates for alkyl halides in SN2
CH3-X > 1o > 2o > 3o
37 : 1.0 : 0.2 : 0.0008
The transition state has five groups crowded around the carbon. If
the substrate is CH3X then three of the the five groups are
Hydrogens. If the alkyl halide is 3o then there are three bulky alkylgroups crowded around the carbon in the transition state. Steric
factors explain the relative reactivity of alkyl halides in the SN2
mechanism.
Z: + C W Z C + :W
Z C W
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Nucleophilic Substitution
Application: Useful SN2 Reactions
The SN2 reaction is a key step in the laboratory synthesis of manydrugs including ethambutol (trade name: Myambutol), used in the
treatment of tuberculosis, and fluoxetine (trade name: Prozac), an
antidepressant.
N l hili S b tit ti
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Nucleophilic Substitution
Application: Useful SN2 ReactionsNucleophilic substitution by an SN2 mechanism is common in
biological systems.
SN2 ReactionsNucleophilic substitution at the CH3 group
S-adenosylmethionine or SAM.
SAM is the cells equivalent of CH3I. The many polar functional
groups in SAM make it soluble in the aqueous environment in the cell.
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Adrenaline (epinephrine) is a hormone
synthesized in the adrenal glands fromnoradrenaline (norepinephrine) SN2
using SAM. When an individual senses
danger or is confronted by stress, the
hypothal-amus region of the brainsignals the adrenal glands to synthesize
and release adrenaline, which enters the
bloodstream and then stimulates a
response in many organs. Stored
carbohydrates are metabolized in the
liver to form glucose, which is further
metabolized to provide an energy
boost. Heart rate and blood pressure
increase, and lung passages are dilated.
Biosynthesis of Adrenaline
Nucleophilic Substitution S 1 and S 2
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Competing mechanisms for nucleophilic substitution
SN2
Z: + C W Z C + :WRDS
SN1
C WRDS
C + :W
C + :Z C Z
Nucleophilic Substitution SN1 and SN2
Reactions
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stereochemistry 100% inversion Partial racemization
Kinetic order Rate = k[RX][Z-] Rate = k[RX]
Rearrangements None Possible
Rates CH3,1o,2o,3o CH3>1
o>2o>3o 3o>2o>1o>CH3
Rates RCl,RBr,RI RI>RBr>RCl RI>RBr>RCl
Rate? temp. Increases rate Increases rate
Rate? 2 x [RX] Doubles rate Doubles rate
Rate? 2 x [Z-] Doubles rate No effect
SN2 SN1
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R-X + Z- R-Z + X- which mechanism?
SN2 -
CH3 1o 2o 3o
- SN1
SN2 steric factors CH3 > 1o > 2o > 3o
SN
1 carbocation stability 3o > 2o > 1o > CH3
Nucleophilic Substitution
SN1 and SN2 Reactions
Nucleophilic Substitution
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Effect of solvent polarity on SN1/SN2:
water = polar ethanol = less polar
Solvent: mixture of ethanol/water
Add more water = more polar; add more ethanol = less polar.
SN1: R-W R+ + W-
ionization favored by polar solvents
SN2: Z:- + R-W Z-R + :X-
solvent polarity does not affect rate
Nucleophilic Substitution
SN1 and SN2 Reactions
N l hili S b tit ti S 1 d S 2
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Alkyl halide + base SN1 or SN2
SN2: best with CH3 or 1o RX, concentrated, strong base
(SN1: 2o or 3o, dilute, weak base, polar solvent;
rearrangements are possible, alkene by-products)
Nucleophilic Substitution SN1 and SN2
Reactions
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Nucleophilic substitution of the alkohol
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Nucleophilic substitution of the alkohol
Reaction of 2 and 3 ROH with HX: An SN1 Mechanism
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Nucleophilic substitution of the alkohol
Reaction of 1 with HX: An SN2 Mechanism
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Nucleophilic substitution of the alkohol
Application: S 2 reaction of the Epoxide
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Application: SN2 reaction of the EpoxideThe reaction of epoxide rings with nucleophiles is important for the synthesis
of many biologically active compounds, including salmeterol and albuterol,
two bronchodilators used in the treatment of asthma
A key step in each synthesis is the opening of an epoxide ring with a
nitrogen nucleophile to form a new CN bond
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Reaction of Carbocations
R ti f C b ti
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Structure Formation
Stability
FormationEmpty obital
Reaction of Carbocations
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Rearrangement of carbocations
Carbocations can rearrange:
by 1,2-hydride or by 1,2-methyl shifts:
[1,2-H] --CC-- --CC
+ +H H
[1,2-CH3]
--CC-- --CC+ +
CH3 CH3
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Carbocations can rearrange by 1,2-hydride or 1,2-methyl shifts but only do so when the resultant
carbocation is more stable.
1o carbocation will rearrange to 2o
1o carbocation will rearrange to 3o
2o carbocation will rearrange to 3o
(only goes down hill)
Rearrangement of carbocations
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CH3 C
H
CHCH3
Br
CH3H2O
CH3 C
OH
CH2CH3
CH3
(93%)
Example
Rearrangement of carbocations
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CH3 C
H
CHCH3
CH3
CH3 C CHCH3
CH3
CH3 C
H
CHCH3
Br
CH3
H2O
CH3 C
OH
CH2CH3
CH3
(93%)
+
H
+
Example
Rearrangement of carbocations
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CH3 CH3CH3CCH2CH3 + NaCN (SN1 conditions) CH3CCH2CH3
Br CN
CH3 [ 1,2-H shift ] CH3
CH3CCH2CH3 CH3CCH2CH3 + CN-
+ +
2o carbocation 3o carbocation
Rearrangement of carbocations.
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Carbon-Carbon Bond Formation
in Terpene Biosynthesis
Reaction of Carbocations
Carbon-Carbon Bond Formation
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Carbon-Carbon Bond Formation
via carbocation intermediate
The key process involves the double bond of
isopentenyl pyrophosphate acting as a
nucleophile toward the allylic carbon of
dimethylallyl pyrophosphate.
+OPP
OPP
Carbon-Carbon Bond Formation via
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Carbon Carbon Bond Formation via
carbocation intermediate
+OPP
OPP
+OPP
OPP
H+
OPP
Carbon-Carbon Bond Formation
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OPP
OH
Geraniol
H2O
Carbon-Carbon Bond Formation
via carbocation intermediate
Carbon-Carbon Bond Formation
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10 Carbons to 15
+OPP
OPP
Geranylpyrophosphate
+OPP
OPP
Carbon-Carbon Bond Formation
via carbocation intermediate
Carbon-Carbon Bond Formation
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From 15 Carbons to 20
OPP
Farnesyl pyrophosphate is extended by another isoprene
unit by reaction with isopentenyl pyrophosphate.
OPP
Carbon-Carbon Bond Formation
via carbocation intermediate
Carbon-Carbon Bond Formation
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Cyclization: Rings form by intramolecular
carbon-carbon bond formation.
OPP
OPP
+
Edouble
bond
Zdouble
bond
Carbon-Carbon Bond Formation
via carbocation intermediate
Carbon-Carbon Bond Formation
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+
H+
H2
O
Limonene
a-Terpineol
Cyclization
Carbon Carbon Bond Formationvia carbocation intermediate
Carbon-Carbon Bond Formation
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+
+
+
b-Pinene
+
a-Pinene
Carbon Carbon Bond Formation
via carbocation intermediate
Carbon-Carbon Bond Formation
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via carbocation intermediateCholesterol biosynthesis
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Keyconcept
Keyconcept
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Keyconcept
Keyconcept
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Keyconcept
Keyconcept
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Keyconcept
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Problems
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Problems
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Problems
Rank the carbocations in each group in
order of increasing stability
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Problems
Rank the alkyl halides in each group in
order of increasing SN1 reactivity
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Problems
SN1 or SN2 products
Problems
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Muscalure, the sex pheromone of the common housefly, can be
prepared by a reaction sequence that uses two nucleophilic
substitutions.
Identify compounds AD in the following synthesis of muscalure.
Problems
Problems
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Problems
Draw the products of each reaction
Problems
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Benzalkonium chloride (A) is a weak germicide used in topical
antiseptics and mouthwash. A can be prepared from amines B orCby SN2 reaction with an alkyl chloride.
(a) What alkyl chloride is needed to prepare A from B?
(b) What alkyl chloride is needed to prepare A from C?
Problems
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