Functional Group Transformation notebook

Functional Group Transformation Notebook M. Huffstickler, K. Syler, and H. Wayland For Organic Chemistry I and II

2012

Huffstickler, Syler, and Wayland Henderson State University

8/3/2012

2

Table of Contents

Alkene and Alkyne Chemistry

p.5 Acid-Catalyzed Addition of an Alcohol to an Alkene

p.6 Addition of Halogen to an Alkyne

p.7 Addition of Peroxyacid to an Alkene

p.8 Addition of Halogen to an Alkene

p.9 Addition of Hydrogen Halide to an Alkyne

p.10 Addition of Hydrogen to an Alkene

p.11 Addition of Hydrogen to an Alkyne

p.12 Addition of Water to an Alkyne

p.13 Alkoxymercuration of an Alkene

p.14 Alkylation of Alkynes

p.15 Addition of Hydrogen Halide to an Alkene

p.16 Addition of Water to an Alkene

Benzene Chemistry

p.17 EAS Electrophiles

p.18 EAS

p.19 More Benzene Chemistry

Carbonyl Compounds I

p.20 Activating Carboxylic Acids

p.21 Ethers

p.22 Hydrolysis of Nitriles

p.23 Reactions of Acid Anhydrides

p.24 Reactions of Acyl halides

p.25 Reactions of Amides

p.26 Reactions of Carboxylic Acids

p.27 Reactions of Esters

Carbonyl Compounds II

p.28 Acetal or Ketal Formation

3

p.29 Alcohol Protecting Groups

p.30 Amino Protecting Groups

p.31 Carbonyl Compounds with Acetylide Ions

p.32 Carbonyl Compounds with Amines

p.33 Carbonyl Compounds with Hydride Ions

p.34 Carbonyl Compounds with Hydrogen Cyanide

p.35 Carbonyl Compounds with Water

p.36 Carbonyl Oxygen Protecting Groups

p.37 Wittig Reaction

Carbonyl Compounds III

p.38 Acid-Catalyzed Alpha-Carbon Halogenation

p.39 Aldol Condensation and Dehydration e1cB

p.40 Base-Catalyzed Alpha-Carbon Halogenation

p.41 Claisen Condensation

p.42 Dieckmann Condensation

p.43 Haloform Reaction

p.44 Hell-Volhard-Zelinski Reaction

p.45 Intramolecular Aldol Addition

p.46 Keto-Enol Interconversion

p.47 LDA to Form Enolates

p.48 Michael Reaction

p.49 Nucleophilic Addition to Unsaturated Ketones

Elimination Reactions

p.50 Alkyl Fluorides

p.51 Dehydration of Alcohols

p.52 E1

p.53 E2

Organometallic Chemistry

p.54 Carbonyl Compounds Grignard Reactions

p.55 Gilman Reaction

4

p.56 Grignardlithium

p.57 Palladium

Other

p.58 Diels-Alder Ring Formation

Oxidation

p.59 Hydroboration-Oxidation of an Alkene – Part 1

p.60 Hydroboration-Oxidation of an Alkene – Part 2

p.61 Hydroboration-Oxidation of an Alkyne

p.62 Oxidation of Alcohols

p.63 Oxidation of Aldehydes and Ketones

p.64 Oxidation of Alkenes to 1,2-Diols

p.65 Oxidative Cleavage of 1,2-Diols

p.66 Oxidative Cleavage of Alkenes

Radicals

p.67 Addition of Radicals to an Alkene

p.68 Formation of Explosive Peroxides

p.69 Radical Halogenation of Alkanes

p.70 Radical Substitution of Benzylic and Allylic Hydrogens

Reduction

p.71 Catalytic Hydrogenation

p.72 Dissolving Metal Reduction

p.73 Metal Hydride Reduction

p.74 Oxymercuration-Reduction of an Alkene

Substitution Reactions

p.75 Nucleophilic Substitution of Epoxides

p.76 Sn1

p.77 Sn2

p.78 Substitution of Alcohols

5

Acid catalyzed Addition of Alcohol to an Alkene

general scheme:

R

R 1H2SO4

R2

OHR

R 1

OH

Mechanism:

H2SO4

OHO H

H

OH

OH

OH

H

O

O

H

H

Key Points:

alcohol quick to deprotonate the protonatedether- pH of solution is greater than pka ofprotonated ether

regiospecific, Markovnikov

f unctional group transformation:

alkene ether

6

Addition of Halogen to an Alkyne


alkyne halogenated alkane

general scheme:

R 1

R

X X

R

R 1

X

X

X

X

mechanism:

Br Br

Br

Br

Br

Br

Br Br

Br

Br

Br

BrBr Br

Br Br

Key Points:

solvent is typically CH2Cl2anti addition

7

Addition of a Peroxyacid to an Alkene


alkene epoxide + carboxylic acid

general scheme:

R + R1

C

OOH

O

R

O

+R1

C

OH

O

mechanism:

R

O

OO

H

O

OH

O

Key Points:

concerted reactionsyn addition

epoxide

carboxylic acid

8

Addition of a Halogen to an Alkene

general scheme:

R

R 1 X2R

R 1

X

X

"X" is any halogen

Mechanism:

Br Br

Br

Br-

Br

Br

Key Points:

forms cyclic intermediatestereospecific, anti-additionracemic mix


alkene viscinal halogenated alkane

9

Addition of Hydrogen Halide to an Alkyne


alkyne geminal dihalide

general scheme:

R 1

R

H X

R

R 1

X

X

mechanism:

H Br

Br

Br

H Br

Br

Br

BrBr

Key Points:

anti additionH+ adds to sp carbon bonded to the hydrogenresults in geminal (on same carbon) dihalide

10

The Addition of a Hydrogen to an Alkene


Alkene Alkane

general scheme:

R R

H2

Pd/C

mechanism:

R

RH

H

R

R

H

H

Key Points:

don't know precise mechanismconcerted reactionsyn additionreduction reaction

11

Addition of Hydrogen to an Alkyne


alkyne alkane or alkene

general scheme:

R R 1H2 R R 1

R R 1

mechanism:

Lindler's catalyst

Na or Li

NH3 (liquid)

(cis)

( trans)

H2

Pd/C

Na or Li

NH3 (liquid)Na + Na

H

NH2

H

Na

+ NH2

H

+ Na

H

NH2

H

H

+ NH2

Key Points:

Linder's catalyst causes syn additioncis alkene

Na or Li in NH3 cause trans alkenebecause is most stable radicalf ormation

12

Addition of Water to an Alkyne


alkyne ketone

general scheme:

R 1

H2O

H2SO4R 1

R

R

O

mechanism:

O

HH

H2SO4

OH

O

enol

O

H

H

H

H

keto-enoltautomerization

ketone

Key Points:

an enol is unstable and will tautomerizemost, if not all, of the product will be a ketone

H H

H

13

Alkoxy-Mercuration Reduction of an Alkene

general scheme:


Alkene Ether

R1.) Hg(O2CCF3)2 , CH3OH

2.) NaBH4R

OCH3

Mechanism:

1.) Hg(O2CCF3)2 , CH3OH

2.) NaBH4

F3CCO2

Hg

O2CCF3

Hg

O2CCF3

HO

CH3

Hg

O

H3C

O2CCF3

NaBH4

O

H3C

+ Hg + CF3CO2-

H

HO

CH3

Hg

O

H3C

O2CCF3

Key Points:

regiospecific, anti-Markovinikovsyn addition

R1

R 1

14

Alkylation of Alkynes

Functional Group Transformation: terminal alkyne to internal alkyne

General Scheme:

R CHNaNH2

R C-RX

R CR

Reaction Mechanism:

CH3C CHNaNH2

CH3C C + NH2H

H3CC C + NH3CH3BrCH3C CCH3 + Br

Notes:

-an alkylation reaction is the attachment of an alkyl group to a species by selection of an alkyl halide of

the appropriate structure

-actual alkylation is second step, f irst step is the removal of a hydrogen from the terminal sp2 carbon by

NaNH2

-negatively charged acetylide ion (nucleophile) is attracted to the partially positively charged carbon

(electrophile) of the alkyl halide, represented as RX in General Scheme

15

Addition of Hydrogen Halide to an Alkene

general scheme:

R

(Z) HX

R R 1

X

"X" is any halogen

Mechanism:( E)

H

Cl

+ Cl

+ Cl

Cl

Key Points:

regiospecific, Markovnikov addition

racemic mixture

carbocation intermediate subject to 1,2 hydride/methyl shifts

R1


alkene alkyl halide

16

Acid Catalyzed addition of Water to an Alkene

general scheme:

R

R 1 H2SO4

H2O R

R 1

OH

Mechanism:

H2SO4

H

O

HH

O

H

O

HH

O

HH

OH

O

HH

H

Key Points:

regiospecif ic, Markovnikov

carbocation intermediate subject to 1,2 hydride/methyl shifts


alkene alcohol

17

Electrophilic Aromatic Substitution

Functional Group Transformation:

Benzene Substituted Benzene

General Reaction Mechanism:

E+

H

E

BE

Notes:

Benzene does not undergo nucleophilic substitution due to its cloud of pi electrons repelling anyincoming nucleophiles

The intermediate carbocation is stabilized by resonance

The hydrogen attached to the same carbon as the incoming electrophile is eliminated to restorearomaticity to the benzene ring

Where multiple electrophiles will be directed onto a benzene ring depends on the substituents alreadyon the ring

Activating substituents have electrons pairs to push into the benzene ring and stabilize theintermediate carbocation, these substituents are ortho-para directors; alkyl chains and halogens donot push electrons into the benzene ring, but they still ortho-para direct

Deactivating substituents draw electron density from the benzene ring and they direct electrophiles tothe electron dense meta positions

Benzene can only be reduced with Nickel at 225 degrees celsius and 25 atmospheres of pressure

18

Generation of EAS Electrophiles

Halogenation:

Br Br FeBr3 Br Br FeBr3+

Also works with chlorine. The reagents are Br2 and FeBr3

Iodination:

I2 2I+H2O2

H2SO4

Nitration:

HO NO2 H OSO3H+ HOH NO2 NO2

Reagents are HNO3 and H2SO4

Sulfonation:

HO SO3H + H OSO3H HOH SO3H SO3H

Reagents are Sulfuric acid and heat, reversible

Friedel-Crafts Acylation:

Cl

O

AlCl3

O

Friedel-Crafts Alkylation:

R Cl AlCl3R+

Friedel-Crafts Reagents are the acyl chloride, or haloalkane and AlCl3

Notes:

Friedel-Crafts chemistry can not be done on deactivated rings or aniline

Aniline can not be nitrated safely

19

More Benzene Chemistry

To remove the carbonyl group af ter acylation the Wolff -Kishner or Clemmensen reductions can beused.

Wolff-Kishner Reagents: H2NNH2

-OH, Heat

Clemmenson Reagents: Zn(Hg), HCl

Heat

Conditions for the Clemmenson reduction will react with double bonds.

Arenediazonium Salts:

NH2NaNO2

HCl, 0oC

N N

N N

CuX X

X=Br, Cl, CN

Also works with KI for X=I, H3O+ for X=OH, HBF4 for X=F, and H3PO2 for X=H

Arenediazonium salts can also act as electrophiles with benzene to form azo linkages that consist of twobenzene rings conected by N N

Mechanism for Nucleophilic Aromatic Substitution:

O2N NO2

Cl

O

NO2O2N

Cl O O

NO2O2N

For substitution to take place the benzene ring must be highly deactivated

20

Activation of Carboxylic Acids

Functional Group Transformation: Carboxylic Acid to Acyl Halide or Acid Anhydride

General Scheme:

R OH

O

R Cl

O

or

R O R

O O

Reactions:

R OH

O

SOCl2

R Cl

O

+ SO2 + HCl

R OH

O

PCl3

R Cl

O

+ H3PO3

R OH

OP2O5

R O R

OO

+ H2O

Notes:-Converting a carboxylic acid into an acyl halide or an acid anhydride is a priceless tool in the laboratory,as carboxylic acids are the most used type of compound and changing them into something more reactiveincreases the number of things that they can be used for.

21

Nucleophilic Substitution Reactions of Ethers


Ether Alkyl Nucleophile

General Scheme:

R

O

R

HXR X

Reaction Mechanism:

OH Br

OH

+

Br+ Br-+

OH

Notes:

Ethers can only undergo nucleophilic substitution with HBr and HI

Heat

Heat Heat

If a secondary or tertiary carbocation would be formed, the reaction will proceed through the SN1

mechanism

If an unstable carbocation would be formed the reaction will proceed through the SN2 mechanism

(methyl, vinyl, aryl, primary)

Only substitution occurs, because any elimination product would react with HBr or HI to form thesubstitution product

Ethers can also be activated by tosyl chlorides, SOCl2, and PCl3 in the same way as alcohols to form

an alkyl chloride

22

Hydrolysis of Nitriles

Functional Group Transformation: Nitrile to Carboxylic Acid

General Scheme:

R N + H2O

R OH

O

+ NH4Cl

Reaction Mechanism:

R N

H B

R NH + H2O

R O

NH

H

H

B

R OH

NH

H B

R OH

NH2

R OH

NH2

H2O

R O

OH

Notes:-Nitriles are harder to hydrolyze than amides, but it can be done by the above mechanism when water, acid,and heat are used.

23

Reactions of Acid Anhdrides

Functional Group Transformation: Acid Anhydride to Ester and Carboxylic Acid via AlcoholAcid Anhydride to Amide and Carboxylate Ion via Amine

General Scheme:

R O

O

R

O

+ H R 1

R R 1

O

+

R OR/OH/N

O

Reaction Mechanism:

R O

O

R

O

+ R OH R O

O

OR

R

O

HB

R O

O

OR

R

O

R OR

O

+

O R

OB

HO R

O

Notes:-Acid anhydrides do not react with sodium chloride or bromide because the incoming halide is a weaker basethan the departing carboxylate ion.-All of the mechanisms follow the general mechanistic scheme of the nucleophilic addition-eliminationreaction with a neutral nucleophile.

24

Reactions of Acyl Halides

Functional Group Transformation: Acyl Halide to Anhydride via Carboxylate IonAcyl Halide to Ester via AlcoholAcyl Halide to Carboxylic Acid via WaterAcyl Halide to Amide via Amine

General Scheme:

R Cl

O

+ H R

R R

O

H Cl+

Reaction Mechanism:

R Cl

O

R O

O

+R Cl

O

OR O R

O O

+ Cl

R Cl

O

+ R OH R Cl

OH

OR

H

OR

B

R Cl

O

OR

+ B

R OR

O

+ Cl

Notes:-The mechanisms shown are for the conversions of acyl chlorides to anhydride and ester, respectively.-The reaction of an acyl chloride with an amine to form an amide calls for twice as much amine as acylchloride because the HCl formed as a byproduct will protonate any amine that has not reacted yet.-In each mechanism, the incoming nucleophile is a stronger base than the departing chloride ion, so thereaction is a nucleophilic substitution.

25

Reactions of Amides

Functional Group Transformation: Amide to Carboxylic AcidAmide to Nitrile

General Scheme:

R NH2

O

R OH

O

R NH2

O

R2CN

Reaction Mechanism:

R NH2

OH B

R NH2

OH

H2O R NH2

OH

O

H H

B

R NH2

OH

OH H B

R NH3

OH

OH BR OH

OH

NH3

R OH

O

NH4+ +

Notes:-Amides cannot be hydrolyzed without catalysts.-The mechanism is similar to that of the acid catalyzed hydrolysis of an ester.

26

Reactions of Carboxylic Acids

Functional Group Transformation: Carboxylic Acid to Ester via Alcohol

General Scheme:

R OH

O

+ R1 OH

R OR'

O

+ H2O

Reaction Mechanism:

R OH

OH B

R OH

O

H

+ CH3OH

B

R OCH2

OH

OH

R OCH3

OH

OH H B

R OCH3

OH

O

H H

BR OCH3

O

H

H2O

H B

R OH

O

Notes:-The mechanism is the exact reverse of the acid catalyzed ester hydrolysis.-Carboxylic acids have approximately the same reactivity as esters, therefore they do not react with halideions or carboxylate ions either.

27

Reactions of Esters

Functional Group Transformation: Ester to Carboxylic Acid and Alcohol via WaterEster to New Ester and New Alcohol via AlcoholEster to Amide via Amine

General Scheme:

R OR

O

+ R1 H

R R 1

O

+ R OH

Reaction Mechanism:

Acid Catalyzed Ester Hydrolosis:

R OCH3

O

H B

R OCH3

O

H

+ H2O R OCH3

OH

OH

H

B

OH

OCH3R

OH H B

OCH4R

OH

OH

R OH

OH

+ CH3OH

B

R OH

O

Notes:-Curiously enough, this mechanism is the exact reverse of the mechanism for the acid catalyzed reactionof a carboxylic acid and an alcohol to form an ester.-The reaction of an ester with an amine is not as slow as the reaction of an ester with water or alcoholbecause amine is a better nucleophile.-Transesterif ication is also acid catalyzed.

28

Acid-Catalyzed Acetal or Ketal Formation

Functional Group Transf ormation:

aldehyde hemiacetal acetal

ketone hemiketal ketal

Reaction Scheme:

R

O

H

+ CH3OHHCl

R H

O

OHCH3OH, HCl

R H

O

O

R

O

R

CH3OH HCl

R

OH

R

O CH3OH, HCl

R R

O

O

Reaction Mechanism:

R R

O

H

B

R R

OH

CH3OHR R

OH

O

HB

R R

OHH

O

RR

O

CH3OH

R R

O

O

HB

R R

O

O

Notes:

acid catalyst is required

one equivalence of alcohol is added to the aldehyde or ketone, goes to hemiacetalor hemiketal

two equivalence of alcohol takes aldehyde or ketone all the way to acetal or ketal

29

Alcohol Protecting Groups


OH of an alcohol triethylsilyl ether OH of an alcohol

OH of carboxylic acid ester OH of carboxylic acid

Reaction Scheme:

OH

Br

Si

Cl (CH3CH2)3NOSi(CH2CH3)3

Br

H3O

Br

OH

HO

OH

O

OHexcess

HClHO

O

O

alcohol

carboxylic acid

HCl, H2Oheat

HO

OH

O

30

Amino Protecting Group

Functional Group Transformation:amino amide amino

Reaction Scheme:

NH2

Cl

O HN

O

1. HCl, H2O, heat

2. HO

31

Reactions of Carbonyl Compounds with Acetylide Ions

Functional Group Transformation: Aldehyde or Ketone to Alkoxide

General Scheme:

R R

O

1. acetylide ion

2. H3O+ R

OH

R

R

Reaction Mechanism:

R R

O

+

R R

O

H+

R R

OH

Notes:-As a method of making carbon-carbon double bonds, this reaction is extremely important to chemists.-The acetylide ion forms a nucleophilic addition product.

32

Reactions of Carbonyl Compounds with Amines

Functional Group Transformation: Aldehyde or Ketone to Imine

General Scheme:

R R 1

O

+ H2NR"H+

R R 1

NR"

+ H2O

Reaction Mechanism:

R R 1

O

R"NH2+ R R 1

NH2R"

OH B

R R 1

OH

NHR"

HB

R R 1

OH

NHR"

B H

R R 1

O

NHR"

H H

R R'

NR"

HB

R R 1

NR"

Notes:-Imine formation is reversible, with equilibrium favoring the nitrogen protonated tetrahedral intermediate.-Overall the addition of an amine to an aldehyde or ketone is nucleophilic addition-elimination.-Other amine reactions are possible, which are not mentioned here, but which include formation ofderivatives such as oxime, semicarbazone, and Wolff -Kishner reduction.

33

Reactions of Carbonyl Compounds with Hydride Ions

Functional Group Transformation: Aldehyde, Ketone, Acyl Chloride, or Carboxylic Acid to AlcoholEster to AldehydeAmide to Amine

General Scheme:

R R

O

1. NaBH4

2. H3O+

R R

OH

Reaction Mechanism:

R R

O

+ H BH3 R R

O

H

H3O+

R R

OH

H

Notes:-The mechanism shown above is specif ically for a ketone or aldehyde, but the other reactions follow thesame pathway.-Sodium borohydride will reduce aldehydes, ketones, and acyl chlorides.-Lithium aluminum hydride is required to reduce carboxylic acids, esters, and amides.

34

Reactions of Carbonyl Compounds with Hydrogen Cyanide

Functional Group Transformation: Aldehyde or Ketone to Cyanohydrin

General Scheme:

R R

O

CN

HClR

OH

R

N

Reaction Mechanism:

R R

O

+ N R

O

R

NN

R

OH

R

N

+ N

Notes:-The hydrogen cyanide is generated in situ by adding copius amounts of HCl to a mixture of the aldehydeor ketone in excess sodium cyanide.-Only ketones and aldehydes react with hydrogen cyanide.-The catalytic addition of hydrogen to the cyanohydrin will form a primary amine.

35

Carbonyl Compounds with Water

Functional Group Transformation: Aldehyde or Ketone to Hydrate

General Scheme:

R R 1

O

+ H2OHCl

R R 1

OH

OH

Reaction Mechanism:

R R 1

OH OH

HR R 1

OH

+ H2OR R 1

OH

O

H H

H2O

R R 1

OH

OH+ H3O

+

Notes:-Water is a poor nucleophile, so addition is sped up by addition of an acid catalyst.-The hydrate product is also known as a geminal-diol.

36

Ketone or Aldehyde Protecting Groups

Functional Group Transf ormation:Ketone or Aldehyde 5 or 6-membered ring ketal or acetal ketone or aldehyde

Reaction Scheme:

R R

O

HO

OH

HO OH

HS SH

, HCl

, HCl

, BF3

R R

O

O

R

O

R

O

R

S

R

S

R R

O

R R

O

R R

O

H3O

H3O

HgSO4

H3O

Notes:

aldeydes and ketones can be protected by being converted into acetals

can be brought back by use of aq acid or mercury sulfate in aq acid

thioketal can be reduced to an alkyl group through Raney Nickel

37

Wittig Reaction


aldehyde or ketone alkene

Reaction Scheme:

R R

O

(C6H5)3P

R'

R'

(C6H5)3P

O

Phosphoniumylide

Reaction Mechanism:

R R

O

H2C

P(C6H5)3

R R

O

CH2

P(C6H5)3

R R

CH2

O

P(C6H5)3

Notes:

concerted cycloaddition reaction

Horner-Wittig Reaction uses but gives same product

RP

O

OO

38

Acid- Catalyzed Halogenation of Alpha Carbon

f uncitonal group transformation

aldehyde or ketone halogenated aldehyde or ketone

Reaction Scheme:

R

O

R

HO

H

H

RR

O H

H

H

OHH

RR

H

OH

BrBr

RR

O

Br

H

HO

HRR

O

Br

Reaction Mechanism:

O O

Cl

+ HClH3O

Notes:

can add to either alpha carbon

each successive halogenation is slower than the previous

-basicity of carbonyl oxygen is decreased, making protonation of O less favorable

Cl2

39

Aldol Condensation and Dehydration, E1cB


Aldehydes or Ketones Beta-hydroxyaldehydes or Beta-hydroxyketones

Reaction Scheme:

H

O

R

OH, H2O

H

O

R

OH

RH3O

R

R

H

O

OOH, H2O

OOH

OH

heat

heat

O

Reaction Mechanism:

R

O

R

OH

H

H

B

R

OH

R

O

R

OH

R

OH

B

R R

O

Notes:

heating the aldol addition product leads to dehydration which produces an enone

base catalyzed deyhdration reaction represents E1cB reaction

condensation:

dehydration:

E1cB mechanism

40

Base-Catalyzed Halogenation of an AlphaCarbon


aldehyde or ketone halogenated aldehyde or ketone

Reaction Scheme:

O

OH

Br2

O

Br

BrO

Br

Br

Br

Br

Reaction Mechanism:

R

R

O

H

H

OH

RR

OH

R

R

O

Br

Br

Repeat first 2 steps

RR

O

Br

Br

+ H20

RR

O

Br

+ Br

Notes:

each successive halogenation is more rapid than the previous-acidity of remaining H's is increased

41

Claisen Condensation


Ester Beta-keto ester

Reaction Scheme:

O

O

21. CH3CH2O

2. HCl

O

O

O

HO+

Reaction Mechanism:

O

O

R

H

H CH3O R

O

O RO

O

R

O

O

R

O

O

R

O

R

O

O

Notes:

nucleophilic addition-elimination reaction

crossed claisen condensation reaction is between two different esters, will form amixture of products

42

Dieckmann Condensation


1,6- Diester 5-membered ring beta-keto ester

1,7- Diester 6-membered ring beta-keto ester

Reaction Scheme:

O

O

O

O

1.CH3O

2.HCl

O

O

O

1,6-diester beta-keto ester

O

O

O

O

1. CH3O

2. HCl

O

O

O

1.7-diester beta-keto ester

Reaction Mechanism:

O

O

O

O

OCH3O

O

O

OO O

O

O

O

O

O

Notes:

intramolecular Claisen condensation

43

Haloform Reaction


methyl ketone carboxylate ion + halof orm

Reaction Scheme:

R CH3

O

+ Br2

excess

OH

O

O

HC

BrBr

Br

Reaction Mechanism:

R CH3

O

HO

I2 excess R CI3

O

O

H

HO CI3

R

O

R OH

O

C I

I

I

HC

II

IO

O

Notes:

only works with methyl ketone

44

Hell-Volhard-Zelinski Reaction


Carboxylic Acid Alpha-brominated carboxylic acid

Reaction Mechanism:

OH

R

OPBr3 R

Br

O

R

Br

OH

Br

Br

Br

R

OH

Br

R

Br

Br

O

R

OH

O

Br

H2O

Reaction Scheme:

R

OH

O

Br

OH

O

1. PBr3 (or P), Br2

2. H2O

Notes:

Alpha substitution occurs because acyl bromide is undergoing the substitution,not the carboxylic acid

45

Intramolecular Aldol Addition


1,4- diketone or 1,6-diketone f ive membered ring

1,5-diketone or 1,7-diketone six membered ring

Reaction Scheme:

O

O

OH, H2O

O

O

O

O

H2O, HO OH

O

1,4-diketone

O

O

OH

O

OH, H2O

OO

1,5-diketone

OH

O

Reaction Mechanism:

Notes:

can potentially f orm a different numbered ring but most stable ring will form

46

Keto-Enol Interconversion

functional group transformation:keto tautomer enolate ion enol tautomer

Mechanism: (base-catalyzed interconversion)

R

O

R

OH

H

HR

R

O

H

R

R

O O

HH

R

R

OH

+ OH

Mechansim: (acid -catalyzed interconversion)

R

R

O

O

HH

H

R

R

OH

H

H

H

O

H

R

R

OH

+ O

HH

Key Points:

47

Using LDA to form an Enolate Ion


carbonyl compound enolate ion

Reaction Scheme:

OO

LDA/THF

Notes:

LDA is a very strong base so all of carbonyl compound is converted to the enolate ion

48

The Micheal Reaction


alpha, beta-unsaturated carboxylic acid derivative nucleophilic addition productor conjugate addition product

Reaction Scheme:

R

O

RR R

OH

Nu1. Nu

2. H3O

Reaction Mechanism:

an alpha, beta-unsaturatedaldehyde or ketone

direct additionR R

ONu

Hconjugate addition

R R

OOHO

H2O R R

OO

R R

O

R R

O

R

O

R

O

O

H H

R R

O

RR

OO

Notes:

if either of reactants has an ester group, the base used to remove the alpha protonmust be same as leaving group of the ester

form 1,5-dicarbonyl compounds

use enolate ions of : beta-diketones, beta-diester, beta-keto esters, beta-keto nitriles

49

Nucleophilic Addition to Alpha, Beta-Unsaturated Ketones and Aldehydes

alpha, beta-unsaturated carbonyl compound

R

O

R

Direct Addition:

Y

R R

O

Y

H3OR R

OH

Y

Conjugate Addition:

R R

O

alpha, beta-unsaturated carbonyl compound

Y

H3O R R

OY

R R

OHY

ketotautomer

enoltautomer

Usually direct addition:

Usually Conjugate addition:

R-MgX

R-Li

C C

(R)2CuLi

HO-R, H

H2N-R

H-X

CN

50

Reactivity of Alkyl Fluorides


Alkyl Fluoride Anti-Zaitsev Elimination Product

General Scheme:

F

Conc. Base

Polar Protic Solvent

Heat /

Reaction Mechanism:

F

H

Conc. NaOEt

Heat/EtOH

Notes:

Anti-Zaitsev product is formed because the reaction mechanism goes through a carbanion liketransition state

The mechanism for this reaction is E2

Reaction conditions are E2 conditions

The carbanion like transition state occurs because f luorine is a relatively strong base and a very poor leavinggroup; the reason the product is anti-Zaitsev is because the carbanion transition state does not want tohyperconjugate with the neighboring carbon-hydrogen bonds. It wants to avoid additional electron density dueto its partial negative charge.

*

*

51

Dehydration of Alcohols


Alcohol Alkene

General Scheme:

OH

H2SO4

Heat

Reaction Mechanism:

OH

+ H OSO3H

OH2

H

+

+

Heat Heat

Heat

Notes:

H2O +

Secondary and Teriary alcohols react through the E1 mechanism, and Primary alcohols reactthrough the E2 mechanism

To prevent reformation of the alcohol f rom the product and H2O, the alkene is distilled from the

reaction mixture because it boils at a lower temperature than the alcohol

The reagents POCl3/pyridine, 0 degrees celsius also convert an alcohol to an alkene through the

E2 reaction mechanism

52

Elimination Unimolecular Reactions, E1


Alkyl Halide Alkene

General Scheme:

X

Reaction Mechanism:

X

+

H

Low conc. Base

Polar Protic Solv.

Low conc.

NaOEt

EtOH

Low conc.

NaOEt

EtOH

Notes:

Two step mechanism, Rate=k[alkyl halide][Base]

Heat Heat

Heat

E2 can go through a syn-periplanar or anti-periplanar mechanism, the major product will have themost stable stereochemistry (E or trans/Zaitsev product)

If a bulky enough base or substrate is used an anti-Zaitsev product will be the major product

Reactivity of Alkyl Halides: Benzyl, Allyl, Tertiary, Secondary, [Primary] (Only when a bulkybase/substrate is used)Bases: NaOEt, NaOR, NaOH

Protic Polar Solvents: H2O, EtOH, ROH

Elimination is favored by heat, EtOH, conjugation, and a good base

Mechanism involves formation of a carbocation, rearrangement can occur

53

Elimination Bimolecular Reactions, E2


Alkyl Halide Alkene

General Scheme:

Strong Base, conc.

Polar Protic/Aprotic Solvent

X

Reaction Mechanism:

Br

NaOt

tOH, heat

H

Notes:

Concerted Mechanism, Rate=k[alkyl halide][Base]

H and X must be anti-periplanar to eliminate through E2

When reacting a cycloalkyl halide the H and X must be in axial positions

When two H's are present on the beta carbon two stereoisomers will be formed, but the more stabletrans or E isomer will be the major product (Zaitsev Product).

If only one H is present on the beta carbon the stereochemistry will be determined by the substrate'sconfiguration.

Strong Base: NaOH, NaNH2, NaOR

Ethanol as a solvent, heat, and conjugation favor Elimination

If a bulky base or substrate is used Elimination is more likely to occur (anti-Zaitsev)

Reactivity of Alkyl Halides: Benzyl, Allyl, Tertiary, Secondary, [Primary] (favors substitutionunless a bulky base or substrate is used)

54

Reactions of Carbonyl Compounds with Grignard Reagents

Functional Group Transformations: Aldehyde, Ketone, Ester, or Acyl Chloride to AlcoholCarbon Dioxide to Carboxylic Acid

General Scheme:

(H) R R (H)

O

1. R'MgBr

2. H3O+

(H) R R(H)

R(H)

1

OH

Reaction Mechanism:

R R

O

+ R1 MgBr R R

O

R1

MgBr+

H3O+

R R

OH

R1

Notes:-Although only the mechanism for the reaction of a ketone with a Grignard reagent is shown, they allreact by the same pathway, forming primary, secondary, or tertiary alcohols depending on the number ofhydrogens in place of the R groups and the number of potential leaving groups the compound has.

55

Gilman Coupling Reactions

Reaction Scheme:

Organolithium Reagent Alkyl Chain

General Scheme:

Li2 + CuITHF

( )2CuLi + LiI

Sample Reaction:

( )2CuLi +Br

THF

Notes:

Couples any two alkyl, aryl, or vinylic groups

Alkyl Fluorides will not undergo this reaction

The precise mechanism for this reaction is not known

Gilman reagents, dialkyl lithium cuprates, react with primary secondary, vinylic, or aryl,halides

This reaction works even if the halogenated compound contains other functional groups(without acidic protons)

If a vinylic halide is reacted, it will maintain its E or Z conf iguration

56

Organolithium and Organomagnesium Reactions


Haloalkane Carbon Nucleophile

General Scheme:

Br Li, Hexanes

or

Mg, THF

Li or MgBr

Reaction Mechanism:

Sample Reaction of Organolithiums and Grignard Reagents

MgBr +O

O OHH+THF

Notes:

Organolithiums and Grignard (Organomagnesium) reagents react in the same way, as a source ofcarbon nucleophile

The solvent for these reactions is important, an aqueous solvent, or any solvent with acidichydrogens, would destroy the reagent

57

Palladium Based Coupling Reactions: Heck, Suzuki


Couples two alkyl pieces, at least one of them with a halogen attached to an aryl or vinyl position.

General Scheme:

X + Ar B

OR

OR

ArPdL2

HO-

X

+ PdL2

TEA

Reaction Mechanism

Suzuki

Heck

R XPdL2

R Pd X

BAr

OR

OR

R Pd R' R R'

R XPdL2

R Pd X

Z

R

Pd

Z

H

X

R

Z

B

Suzuki

Heck

Notes:

The organopalladium compoud can not have beta hydrogens, or an elimination reaction will occurinstead of the couplingThe suzuki boron ester must have an aryl group

Triethyl amine is a necessary reagent for the heck reaction; it reduces the Pd2 to Pd0

58

Diels-Alder Reactions


Diene + Dienophile Substituted Cylohexene, or Cyclohexadiene

General Scheme:

+

W

W-electron withdrawing group

Heat

W

Reaction Mechanism:

OH

O

OH

O

+Heat

Notes:

The diene is the nucleophile and the dienophile is the electrophile

A six memebered ring is always formed

The reaction will not occur if the diene is locked in the s-trans configuration

[4+2] cycloaddition reaction: 4 pi electrons from the diene, and 2 from the dienophile

Concerted reaction mechanism

If a stereocenter is formed, the product will be a racemic mixture

Syn addition reaction, stereochemistry of substituents is conserved

59

Hydroboration-Oxidation of an Alkene


Alkene Alcohol

general scheme:

R

1.) BH3 / THF

2.) OH- , H2O , H2O2 R

OH

mechanism:

RB

HH

H

H BH

partial positive

partial negative

BH2

x3

B

OH- , H2O2 , H2OB

RR

O

R

OHHO

OB

RR

OR

OH

B

ORRO

OR

B

ORRO

OR

OH

B

RO

OR

OH

O

RO

HH

60

Hydroboration-Oxidation of an Alkene Part 2

R

OH

OH+ B(OH)4 +R

OH

Key Points:

no carbocation rearrangementconcerted reactionsyn addition

continuation of mechanism:

61

Hydroboration-Oxidation of an Alkyne


alkyne ketone or aldehyde

general scheme:

R

R 1

BH3/THF

OH-, H20, H2O2

O

R

R 1

BH3/THF

OH-, H20, H2O2

O

aldehyde

ketone

mechanism:

+ BH3THF

B

R

R HO- , H2O2

H2O

OHH

H

3

O

3

Key Points:

mechanism basically same as hydroboration of alkeneelectrophile (BH3) adds to C with most H's

product is ketone due to keto-enol tautomerizationif terminal alkyne then aldehyde is produced

62

Oxidation of Alcohols

Functional Group Transformation: Primary Alcohol to AldehydeSecondary Alcohol to Ketone

General Scheme:

R OH R H

O

or

R R

OH

R R

O

Reaction Mechanism:

SWERN Oxidation:

R

R(H)

OH

H

+S+

Cl

R

R(H)

H

O S

H

B

R

R

O S

H

N

O

R

R+S

Notes:-Chromic acid (H2CrO4) is used to oxidize secondary alcohols to ketones, but it will oxidize primaryalcohols all the way to carboxylic acids.-SWERN is CH3SCH3, ClCOCOCl, and TEA at 60 degrees Celcius

63

Oxidation of Aldehydes and Ketones

Functional Group Transformation: Aldehyde to Carboxylic AcidKetone to Ester

General Scheme:

R R(H)

O

R O/R(H)

O

Reaction Mechanism:

Baeyer-Villager Oxidation:

R R

O

+

F

F

F

O

OO

R

O R

O O

O

F

F

F

R OR

O

+

O

O

F

F

F

Notes:

-Tollens reagent: oxidizes an aldehyde, too mild for anything else, it is (1) Ag2O, NH3 (2) H3O+

-Any reagent used to oxidize primary alcohols to carboxylic acids can be used to oxidize aldehydes to

carboxylic acids.

-Ketones do not react with most of the reagents used to oxidize aldehydes, but both can be oxidized by

conjugate base of a peroxyacid, i.e. a Baeyer-Villager reaction.

64

Oxidation of Alkenes to 1,2-Diols

Functional Group Transformation: Alkene to 1,2-Diol (vicinal diol)

General Scheme:

OH

OH

Reaction Mechanism:

+Os

OO

O O

H

H

O

OOs

O

O

H2O2

OH

OH

+ OsO4

Notes:-Syn addition-Forms cyclic intermediate-Hydrogen peroxide reoxidizes osmium reagent

65

Oxidative Clevage of 1,2-Diols

Functional Group Transformation: 1,2-Diol to Ketone or Aldehyde

General Scheme:

OH

OH

H

O

+

H

O

Reaction Mechanism:

OH

OH

HIO4

HO O

I

O O

+ H2O

O

+

H

O

+ HIO3

Notes:-Periodic acid is used to form a cyclic intermediate f rom the diol, and when the intermediate breaks down,the bond between the two carbons bonded to the oxygens breaks as well.-It is called an oxidative clevage because it cuts a reactant into two pieces.

66

Oxidative Clevage of Alkenes

Functional Group Transformation: Alkene to Aldehyde or Ketone

General Scheme:

O

+

O

Reaction Mechanism:

H

O

O

O

H

O O

O

O

OH

O

O

HOO

Zn, H2O

or (CH3)2SH

OO

H2O2

OH

OO

Notes:-When an alkene is treated with ozone at low temperatures, the double bond breaks and the carbons aredoubly bonded to oxygens instead of to each other, known as ozonolysis.-The immediate reaction results in a molozonide, which is unstable and therefore quickly rearranges intoan ozonide.-Ozonide treated with reducing conditions yields ketones and aldehydes.-Ozonide treated with oxidizing conditions yields ketones and carboxylic acids.

67

Addition of Radicals to an Alkene

Functional Group Transformation: alkene to alkyl halide

Reaction Mechanism:

H3CO OCH3

light

or

2 CH3O

H3C O + H Br H3C OH + Br

H2C CHCH3+Br BrCH2CHCH3

+ H BrBrCH2CHCH3BrCH

2CH

2CH

3 + Br

Br + Br Br Br

BrCH2CHCH3+ Br

Br CH2CHCH3

Br

BrCH2CHCH3 + BrCH2CHCH3

CH3CH CHCH3

CH2 H2CBr Br

General Scheme:

CH

CH

R R H Br

peroxide

R CH2CH2 R Br+

Notes:-mechanism is divided into three groups of reactions: initiation, propagation, and termination-this is known as a radical addition reaction-in the presence of peroxide, Br becomes the electrophile which adds to the less substituted carbon, causing anti-Markovnikovaddition of the Br

68

Formation of Explosive Peroxides

Functional Group Transformation: ether to peroxide

General Scheme:

R O CH R

H+ O2

R O CH

O O H

R

Reaction Mechanism:

Y H3C O CH CH3 + HY

H3C O CH CH3+O OH3C O CH

O O

CH3

H3C O CH CH3

H

H3C O CH CH3

H

+

H3C O CH

O OH

CH3 + H3C O CH CH3

+

O2

Notes:

-must have chain initiating radical (i.e., Y) to remove H from ether

-a peroxide is simply a compound with an O-O bond, which is easily cleaved homolytically to formradicals that can propogate further radical production

-a peroxide is a radical initiator

-ethers contain stabilizers to trap chain-imitating radicals to prevent explosive situations

69

RCHn

Radical Halogenation of Alkanes

Functional Group Transformation: alkane to alkyl halide

General Scheme:

+ X2

heat

or hv

RCHn-1X + HX

Reaction Mechanism:

Cl Cl

heat

or hv2 Cl

Cl + H CH3 HCl +

CH3 + Cl Cl CH3Cl + Cl

Cl Cl+ Cl2

Cl CH3+ CH3Cl

CH3 CH3+ CH3CH3

CH3

Notes:

-heat or UV light supplies energy to break dihalide bond homolytically; that is, so that each atomretains one of the two bonding electrons, forming radicals

-the specif ic reaction above is called the monochlorination of methane, where the chlorine radicalremoves a hydrogen atom from methane, the alkane, making HCl and a methyl radical

-in any radical reaction such as this, there are three types of steps: initiation (f irst above), propogation(second and third above), and termination (fourth through sixth above)

-any step that continues the radical cycle started in the initiation step(s) is a propogation step, while anystep that combines two radicals to form a product with all paired electrons is termination

70

Radical Substitution of Benzylic and Allylic Hydrogens

Functional Group Transformation: alkene to halogenated alkene

General Scheme:

CH2R

+ X2

CHR

X

+ X2X

Reaction Mechanism:

+OO

N

Br

hv or

H2O2

+ Br

+ Br

CH3CH3

CH3 CH2

+ HBr

CH2

+ Br2

CH2Br

+ Br

CH2

Br+

CH2Br

Notes:-Bromine radical f rom NBS removes allylic H, but bromine radical f rom HBr + H2O2 adds to doublebond

71

Catalytic HydrogenationFunctional Group Transformation:

General Scheme:

or

Reaction Mechanism:

H H +Pd/C

or PtO2

H H +Lindlar

Catalyst

R H

O

H H

Raney NiR

C+

H

O-

R OH

R R

O

R

C+

R

O-

H H

Raney NiR R

OH

R Cl

O

R

C+

Cl

O-

H H

PartiallyDeactivatedPd R H

O

Alkene or Alkyne to AlkaneAldehyde to Primary AlcoholEster to Secondary AlcoholAcyl Halide to Aldehyde

72

Dissolving Metal Reductions

Functional Group Transformation: Alkyne to Trans Alkene

General Scheme:

Reaction Mechanism:

+ NaC-

+ Na

H NH2

H

+NaC-

H

H2N H

H

H

Notes:

-Na or Li in liquid NH3 cannot reduce double bonds-Na and Li have a strong tendency to lose single electron in outer shell s-orbital-Radical anion is strong enough base to deprotonate NH3, as is vinylic anion

73

Metal Hydride Reduction

Functional Group Transformation: Carbonyl group to Alcohol

Acyl chloride to Aldehyde or Alcohol

Amide to Amine (*doesn't use H3O+)

General Scheme:

R R

O

R R

OH

Reaction Mechanism:

R R

ONaBH4

HR R

H

O-

H3O+

H+R

OH

R

H

Notes:

-metal hydrides: sodium borohydride (NaBH4) or lithium aluminum hydride (LiAlH4) in H3O+

-metal-hydrogen bonds in LiAlH4 are more polar than NaBH4, making LiAlH4 a stronger reducing agent

-both NaBH4 and LiAlH4 reduce aldehydes, ketones, and acyl halides, but NaBH4 is a safer choice

-LiAlH4 used to reduce carboxylic acids, esters, and amides

-replacing some hydrogens of LiAlH4 with alkoxy groups decreases reactivity of metal hydrides; lithium

tri-tert-butoxyaluminum hydroxide reduces acyl chlorides to aldehydes

-metal hydride reduction will not reduce alkynes or alkenes

74

Oxymercuration- Reduction of an Alkene

general scheme:

R

R 1 1.) Hg(O2CCH3)2 , H2O, THF

2.) NaBH4R

R 1

OH

Mechanism:

1.) Hg(O2CCH3)2 , H2O, THF

2.) NaBH4

H3CO2

Hg

O2CH3

Hg

O2CH3

H

O

H

O

Hg

HH

O2CH3

H

O

H

OH

Hg

O2CH3

NaBH4

+ Hg + CH3CO2-

Key Points:

regiospecific, anti-Markovnikovsyn addition

OH

functional group transformation:

alkene alcohol

75

Nucleophilic Substitution of Epoxides


Epoxide Vicinal Alcohol/Nucleophile

General Scheme:

R

O Acidic Conditions

Or Neutral/Basic ConditionsR

OH

Nu

or

OH

Nu

R

Acidic Neutral/Basic

Racemic Mixture of Conditional Product

Reaction Mechanism:

OH+

CH3OH

O

OH

OCH3

H

+

CH3OH

Notes:

If the conditions are acidic, the nucleophile will attack the more substituted carbon; if conditions areneutral or basic the nucleophile will attack the less substituted carbon because of reduced sterichindrance

This reaction is an anti-addition because the epoxide blocks one face of the reactive site

Stereochemistry is a racemic mixture if a stereocenter is formed

Epoxides can be formed from the addition of a peroxy acid (RCO3H) to a double bond, or through the

addition of Cl2 and H2O to a double bond followed by HO-

76

Substitution Nucleophilic Unimolecular Reactions, SN1


Alkyl Halide Alkyl Nucleophile

General Scheme:

X Weak Nucleophile

Polar Protic Solvent

Nu

+ Enantiomer

Reaction Mechanism:

ClEtOH

+EtOH

OEt

Notes:

Two step mechanism, Rate=k[alkyl halide]

Racemic mixture, due to Sp2 carbocation intermediate

Carbocation formation, carbocation rearrangement is possible

Alkyl Halide Reactivity: Tertiary, Secondary, Primary and Methyl do not react

Weak Nucleophile: EtOH, MeOH, H2O

Protic Polar Solvent: H2O, Acetic Acid, EtOH

77

Substition Nucleophilic Bimolecular Reactions-SN2

General Scheme:

XPolar Aprotic Solvent

R R

NH2

Reaction Mechanism:

Br

Good Nucleophile

NaOEt

DMSO


Alkyl Halide Alkyl Nucleophile

+ Br-

Notes:

100% Inversion of Stereochemistry through Back Side Attack

Reactivity of Alky Halides: Methyl, Primary, Secondary, Tertiary will not react

Concerted Mechanism, Rate=k[alkyl halide][nucleophile]

Polar Aprotic Solvents: DMSO, DMF, Acetone

Strong Nucleophiles: NaOEt, NaOMe

OEt

78

Nucleophilic Substitution of Alcohols


Alcohol Alkyl Nucleophile

General Scheme:

R OHHX

HeatR X

Reaction Mechanism:

OH OH2

+Br

H

Heat

HBr

Heat

BrBr-

Notes:

This reaction can proceed through either an SN2 or SN1 mechanism, depending on the degree of

the alcohol

Primary goes through SN2, Secondary and Tertiary go through SN1

The same reaction can also proceed using PX3/Pyridine as reagents

Alcohols can also be made into good leaving groups by reacting them with pyridine/tosCl, andthen a good nucleophile (ex. NaCN, SMe)

Functional Group Transformation notebook

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