lecture 4_ nucleophilic substitution

8/10/2019 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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good nucleophile strong base

good leaving group weak base


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Examples



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Living groups



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Good Living groups



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Poor living groups



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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



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Giving this reaction

CH3 CH3

CH3CCH3 + OH-

CH3CCH3 + Br-

Br OH

Kinetics

rate = k [ tert-butyl bromide ]

SN1



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(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.


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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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

N l hili S b tit ti


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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


SN1 and SN2 Reactions



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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


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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Reaction of 2 and 3 ROH with HX: An SN1 Mechanism


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Reaction of 1 with HX: An SN2 Mechanism


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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



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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



(only goes down hill)



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CH3 C

H

CHCH3

Br

CH3H2O

CH3 C

OH

CH2CH3

CH3

(93%)

Example



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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



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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




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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



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OPP

OH

Geraniol

H2O





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10 Carbons to 15

+OPP

OPP

Geranylpyrophosphate

+OPP

OPP





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From 15 Carbons to 20

OPP

Farnesyl pyrophosphate is extended by another isoprene

unit by reaction with isopentenyl pyrophosphate.

OPP





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Cyclization: Rings form by intramolecular

carbon-carbon bond formation.

OPP

OPP

+

Edouble

bond

Zdouble

bond





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+

H+

H2

O

Limonene

a-Terpineol

Cyclization

Carbon Carbon Bond Formationvia carbocation intermediate



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+

+

+

b-Pinene

+

a-Pinene

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

lecture 4_ nucleophilic substitution

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