ORGANIC CHEMISTRY

Faculty of Chemical Engineering HCMC University of Technology Office: room 211, B2 Building Phone: 38647256 ext. 5681
1

REFERENCES
[1] Nam T. S. Phan, Hoa T. V. Tran Organic chemistry, VNU-HCMC Publisher, 2011 [2] Nam T. S. Phan, Study guide to organic chemistry, VNU-HCMC Publisher, 2011 [3] Paula Y. Bruice, Organic chemistry, fifth edition, Pearson Prentice Hall, 2007 [4] Francis A. Carey, Organic chemistry, fifth edition, McGraw-Hill, 2003 [5] Paula Y. Bruice, Study guide and solutions manual Organic chemistry, fifth edition, Pearson Prentice Hall, 2007 [6] Graham T.W. Solomons, Craig B. Fryhle, Organic chemistry, eighth edition, John Wiley & Sons, 2004
2

COURSE OUTLINE
Isomerism Electronic & steric effects Introduction to reaction mechanisms Alkanes Alkenes Alkadienes Alkynes Aromatic hydrocarbons Alkyl halides Alcohols & phenols Aldehydes & ketones Carboxylic acids Amines & diazoniums

Chapter 1:

ISOMERISM

Isomers: Compounds with the same molecular formula but different structural formulas Isomers

Constitutional isomers

Stereoisomers

Conformational isomers

Configurational isomers

Geometric isomers

Optical isomers /Enantiomers & Diastereoisomers

4

CONSTITUTIONAL ISOMERS
Different compounds that have the same molecular formula but differ in their connectivity

STEREOISOMERS
Isomers that differ in the way their atoms are arranged in space
Conformational isomers Configurational isomers

CONFORMATIONAL ISOMERS
Different shapes of the same molecule resulting from rotation around a single C-C bond Conformational isomers are not different compounds

Conformations of butane

10

Conformations of cyclohexane

11

12

13

14

GEOMETRIC ISOMERS

There is no rotation around the C=C bond

15

16

The E,Z system of nomenclature

17

Cahn-Ingold-Prelog priority rules

Rule 1

Rule 2

18

Rule 3

Rule 4

19

OPTICAL ISOMERS
A chiral opbject

Nonsuperimposable mirror image

An achiral object
20

OPTICAL ISOMERS
Optical isomers are configurational isomers which are able to rotate plane-polarized light clockwise or anticlockwise plane-polarized light

21

Optically inactive

Optically active

22

Asymmetric carbon
An asymmetric carbon is a carbon atom that is bonded to 4 different groups

Optically active (chiral)

23

Isomers with one asymmetric carbon

Nonsuperimposable mirror-image molecules are 24 called enantiomers

Drawing enantiomers
Using perspective formulas:

Convention

2 bonds in the paper plane 1 bond as a solid wedge 1 bond as a hatched wedge

25

Drawing enantiomers
Using Fisher Projection formulas:

Convention

Carbon chain is drawn along the vertical line Vertical lines: bonds going into the page Horizontal lines: bonds coming 26 out of the page

NAMING ENANTIOMERS
ABSOLUTE CONFIGURATION: R-S SYSTEM
Using Cahn-Ingold-Prelog rules View the molecule with the lowest priority group pointing away If the direction from highest priority group to the next is clockwise: R If the direction is anticlockwise:S
27

Convention for perspective formulas

28

Convention for Fisher Projection formulas

Using Cahn-Ingold-Prelog rules When the lowest priority group is on a vertical bond: + If the direction from highest priority group to the next is clockwise: R + If the direction is anticlockwise:S When the lowest priority group is on a horizontal bond: + opposite answers
29

30

NAMING ENANTIOMERS
RELATIVE CONFIGURATION: D-L SYSTEM
Glyceraldehyde: the standard compound for chemical correlation of configuration

31

D-L system is only useful for naming sugars & aminoacids

32

Isomers with more than one asymmetric carbon

33

34

35

Meso compounds

36

Enantiomers vs diastereoisomers

Enantiomers: Nonsuperimposable mirror images Diastereoisomers: not mirror images of each other
37

Enantiomers vs diastereoisomers
Enantiomers normally have identical physical & chemical properties Enantiomers normally interact differently with other chiral molecules Diastereoisomers can have different physical & chemical properties Enantiomers are always chiral Diastereoisomers can be chiral or achiral (meso compounds)
38

Separating enantiomers

Racemic mixture: 1/1 mixture of 2 enantiomers

39

CHIRALITY & BIOLOGICAL ACTIVITY

40

CHIRALITY & BIOLOGICAL ACTIVITY

41

Chapter 2:

ELECTRONIC & STERIC EFFECTS

Effects

Steric

Electronic

Inductive

Hyperconjugation

Conjugation / Mesomeric
2

INDUCTIVE EFFECTS (I)

C-C bond in butane: almost completely nonpolar

C-C bond in 1fluorobutane: polarized

''+ '''+ + '+

C1 is more positive than C2 as a result of electronattracting ability of F

The more electronegative the X, the stronger the I effect

The more electropositive the Z, the stronger the +I effect

5

Through a period in a periodic table

-I
Through a group in a periodic table

-I
6

CH3CH2CH2COOH CH3CH2CH(Cl)COOH CH3CH(Cl)CH2COOH ClCH2CH2CH2COOH

Ka.105 1.5 139 8.9 3.0

Strong -I weak -I
7

CONJUGATION / MESOMERIC EFFECTS (C / M)

Electron delocalization in a conjugated system: Alternating single & multiple bonds

O is more electronegative than C Electrons move through -bond network towards C=O The conjugated system is polarized C=O has negative conjugation / mesomeric effect (-C / -M) on the conjugated system

C CH
-C

CH
+C

CH

CHR

C
-C

O R
+C

CH

CH

CH
-C

CH

O R
+C
10

OH

+C

-C

-C

+C

N
NH2
+C -C

-C

+C
11

-C groups generally contain an electronegative atom (s) or / and a -bond (s):

CHO, C(O)R, COOH, COOR, NO2, CN, aromatics, alkenes +C groups generally contain a lone pair of electrons or a -bond (s):

Cl, Br, OH, OR, SH, SR, NH2, NHR, NR2, aromatics, alkenes Aromatics or alkenes can be both +C and-C
12

Through a period in a periodic table

+C
Through a group in a periodic table

+C
13

INDUCTIVE vs CONJUGATION EFFECTS

H CH CH CH CH CH CH O C H O C H O C H
-C
14

CH

CH

CH

CH

Mobility of hydrogen atoms: almost the same

H CH

CH

INDUCTIVE vs CONJUGATION EFFECTS

C effects are generally stronger than I effects C effects can be effective over much longer distances than I effects provided that conjugation is present I effects are determined by distance, C effects are determined by relative positions
15

HYPERCONJUGATION EFFECTS (H)

Electron density from C-H flows into the vacant p orbital (in carbocation / C=C / CC) because orbitals can partially overlap

Hyperconjugation effects (H)

16

H effect of -CH3 is stronger than H effect of -CH2H effect is generally stronger than I effect

H H C CH + H CH3 CH CH2 CH3 HCl

CH Cl

CH2

CH2

CH3

Electron-donating ability of -CH3 is stronger than that of -CH2CH3 17

STERIC EFFECTS
A steric effect is an effect on relative rates caused by space-filling properties of those parts of a molecule attached at / near the reacting site Steric hindrance: the spatial arrangement of the atoms / groups at / near the reacting site hinders / retards a reaction Generally, very large & bulky groups can hinder the formation of the required transition state
18

Steric hindrance
19

Steric hindrance

20

ACIDITY & BASICITY

21

22

Electrondonating groups

Electronwithdrawing groups

23

Electrondonating groups

Electronwithdrawing groups

24

If C groups are introduced at ortho- & para position on phenol rings: + The anion (-O-) can be further stabilized by delocalization through the conjugated system as the negative charge can be spread onto the -C groups + The O-H bond is more polarized as electron density on OH can be spread onto the -C groups

Acidity of phenols is generally increased

25

If I groups are introduced on phenol rings, the effect will depend on the distance: + The closer the I group is to the negative charge (-O-), the greater the stabilizing effect is + The closer the I group is to the OH, the O-H bond is more polarized

Acidity of phenols is generally increased Note: there might be ortho-effects

26

OH > NO2 7.15 OH > CH3 pKa = 10.08

OH NO2 >

OH

NO2 pKa = 7.23 OH > CH3 10.14 8.4 OH CH3

10.28

27

OH > OCH3 pKa = 9.65 OH Cl >

OH OCH3 >

OH

OCH3 9.98 OH > Cl Cl 10.21 OH

pKa =

8.48

9.02

9.38
28

Benzoic acid derivatives pKa CH3C6H4COOH NH2C6H4COOH FC6H4COOH ClC6H4COOH BrC6H4COOH IC6H4COOH HOC6H4COOH CH3OC6H4COOH NCC6H4COOH NO2C6H4COOH

Position on benzene ring Ortho3.91 4.97 3.27 2.92 2.85 2.86 2.97 4.09 3.14 2.16 Meta4.27 4.78 3.87 3.82 3.81 3.85 4.06 4.09 3.84 3.47 Para4.36 4.92 4.14 3.98 3.97 4.02 4.48 4.47 3.55 3.41
29

-I is decreased over long distance +C dominates -I dominates

CH3CH2CH CHCOOH < CH2 CHCH2CH2COOH < CH3CH CHCH2COOH pKa = 4.83 pKa = 4.68 pKa = 4.48

+C and -I but -I dominates

+C and -I but -I dominates

HC C COOH pKa = 1.84

H3C C C COOH pKa = 2.60

30

31

X Basicity of XC6H4NH2 CH3

pKa of ammonium cation omp4.39 4.69 5.12 CH3O 4.49 4.20 5.29 C2H5O 4.47 4.17 5.25 C6H5 3.78 4.18 4.27 F 3.20 3.59 4.65 Cl 2.61 3.34 3.98 Br 2.60 3.51 3.91 I 2.60 3,61 3,78 CH3OCO 2,23 3.64 2.38 CF3 --3.50 2.60 CN --2.76 1.74 -0.29 2,50 1,02 NO2

32

33

STABILITY OF CARBOCATIONS
+H & +I

34

Allylic & benzylic carbocations

+C

+C

Allylic & benzylic carbocations are generally stable due to the electron delocalization (+C effects)
35

36

Not all allylic & benzylic carbocations have the same stability

37

Relative stability of carbocations

38

STABILITY OF RADICALS

39

STABILITY OF CARBANIONS

40

Chapter 3:

INTRODUCTION TO REACTION MECHANISMS

Reaction mechanism: the description of the step-by-step process by which reactants are changed / converted into products

Nucleophilic substitution Electrophilic substitution Elimination

Nucleophilic addition Electrophilic addition

NUCLEOPHILIC SUBSTITUTION REACTIONS (SN)

A nucleophile: an electron-rich species that can form a covalent bond by donating 2 electrons to a positive center A nucleophile is any negative / neutral molecule that has 1 unshared electron pair Substitution reaction: chemical reaction in which 1 atom / group replaces another atom / group in the structure of a molecule In a nucleophilic substitution reaction, a nucleophile attacks / bonds with the positive center
3

BIMOLECULAR NUCLEOPHILIC SUBSTITUTION REACTION (SN2)

UNIMOLECULAR NUCLEOPHILIC SUBSTITUTION REACTION (SN1)

Note: slow step is rate-determining step

ELIMINATION REACTIONS

In an elimination reaction: + Groups / atoms are eliminated from a reactant + A double bond is formed between the 2 carbons from which atoms are eliminated
8

BIMOLECULAR ELMINATION (E2)

Strong base

10

UNIMOLECULAR ELMINATION (E1)

11

Weak base

12

ELETROPHILIC ADDITION REACTIONS (AE)

Electrophilic: electron-seeking / loving Most electrophiles: + Are positively charged + Have an atom which carries a partial positive charge + Have an atom which does not have an octet of electrons An electrophilic addition reaction is an addition reaction where carbon-carbon double bonds or triple bonds are attacked by an electrophile 13

14

Not a carbocation, but a cyclic halonium ion More stable than carbocation

15

NUCLEOPHILIC ADDITION REACTIONS (AN)

The carbonyl group is polar because the oxygen, being more electronegative, has greater share of double-bond electrons The partial positive carbon can be attacked by nucleophiles

The addition of nucleophiles to the carbon atom of the carbonyl group in nucleophilic addition reactions 16

Reaction mechanism
Positive center A nucleophile
Rate-determining step

slow

fast

17

Examples:

Nucleophiles

18

ELECTROPHILIC SUBSTITUTION REACTIONS (SE)

In an electrophilic substitution reaction, an electrophile substitutes for a hydrogen of an aromatic compound

Although benzene has 3 double bonds, the overall reaction is electrophilic substitution rather than electrophilic addition 19

Reaction mechanism
Rate-determining step

An electrophile

20

Examples:

An electrophile

Rate-determining step

21

Chapter 4:

ALKANES

NOMENCLATURE OF ALKANES

ALKYL SUBSTITUENTS

IUPAC NAMES OF BRANCHED ALKANES

Determine the parent hydrocarbon the longest continuous carbon chain

 Substituents are listed in alphabetical order Carbon chain is numbered with the lowest possible number in the compound

Substituents are the same

 Di, tri, tetra, n, sec, and tert are ignored in alphabetizing substituents Iso, neo, and cyclo are not ignored

NATURAL SOURCES OF ALKANES

C1-4

C5-11

Natural gas & petroleum (fossil fuels)

C9-16 C15-25

PREPARATION OF ALKANES

Catalytic hydrogenations of alkenes / alkynes

10

Reduction reactions

11

Wurtz reactions

symmetric alkane

Limitations: + The Wurtz reaction is limited to the synthesis of symmetric alkanes from alkyl iodides & bromides + If two dissimilar alkyl halides are taken as reactants, then the product is a mixture of alkanes that is, often, difficult to separate + A side reaction also occurs to produce an alkene + The side reaction becomes more significant when the alkyl 12 halides are bulky at the halogen-attached carbon

Corey-House synthesis the reaction of a lithium dialkyl cuprate with an alkyl halide to form a new alkane

Corey-House synthesis overcomes some of the limitations of the Wurtz reaction

13

REACTIVITY OF ALKANES
Alkanes have only strong bonds Electronegativity of C & H are approximately the same None of the atoms in alkanes have any significant charge Neither nucleophiles nor electrophiles are attracted Alkanes are very unreactive
14

HALOGENATION OF ALKANES

15

16

17

PRODUCT DISTRIBUTION

It must be easier to abstract a hydrogen atom from a secondary carbon than from a primary carbon

18

Reactivity - relative rate at which a particular hydrogen is abstracted in chlorination reactions: At room temperature

19

Product distribution can be estimated:

20

Br2 is less reactive towards alkane than Cl2, but Br2 is more selective

Bromination at 125 oC

21

Too violent

Too slow

22

STEREOCHEMISTRY OF RADICAL SUBSTITUTION REACTIONS

Have no asymetric carbon

Racemic mixture
23

Already have 1 asymetric carbon

24

COMBUSTION OF ALKANES

25

Chapter 5:
An sp2 hybridized carbon

ALKENES

NOMENCLATURE OF ALKENES
The IUPAC name of an alkene is obtained by replacing the ane ending of the corresponding alkane with ene

Ethylene is an acceptable synonym for ethene in the IUPAC system Propylene, isobutylene and other common names ending in ylene are NOT acceptable IUPAC names
3

Determine the parent hydrocarbon the longest continuous carbon chain containing the C=C

Note: Alkenes can have geometric isomers

PREPARATION OF ALKENES
Dehydrations of alcohols
Acid

isomerization
6

isomerization

Eliminations of alkyl halides

Base

Alkyne hydrogenations
Pd/CaCO3 + Pb(OAc)2 / quinoline

REACTIONS OF ALKENES
Additions of hydrogen halides (AE)

More stable

Markovnikovs rule

10

Carbocation rearrangement

More stable

11

More stable

12

Stereochemistry

Racemic mixture

13

Already has 1 asymmetric carbon

14

2 asymmetric carbons are created

15

Additions of hydrogen bromide (AR) Electrophilic addition (AE)

Radical addition (AR) only for HBr

16

Reaction mechanism:

17

Additions of halogens

18

Major addition product NOT a dihalide

19

Stereochemistry

20

21

Stereochemistry
2 asymmetric carbons are created

Trans-2-butene meso compound

22

Additions of water hydration reactions

Water is too weakly acidic to allow the hydrogen to act as an electrophile

Markovnikovs rule

H2SO4, H3PO4
23

Reaction mechanism:

Carbocation rearrangement might occur

24

Alcohols by oxymercuration-reduction

Markovnikovs rule No carbocation formation, no rearrangement

25

Additions of borane: hydroboration-oxidation

26

Regioselectivity:

Anti-Markovnikov

27

Additions of hydrogen hydrogenation

28

Reaction mechanism:

Syn addition

29

Stereochemistry

30

31

Alkene epoxidations Anti hydroxylations

32

Stereochemistry

33

Reactions of epoxides

34

35

Stereochemistry

Anti additions

36

Syn hydroxylations of alkenes

37

Reaction mechanism:

Syn additions

38

Permanganate cleavage of alkenes

39

Ozonolysis of alkenes

40

In the presence of an oxidizing agent, the products will be ketones / carboxylic acids
41

Polymerizations

42

Chapter 6:

CONJUGATED ALKADIENES

A non-polar molecule

Reactions of isolated dienes are just like those of alkenes

3

NOMENCLATURE OF ALKADIENES

PREPARATION OF 1,3-ALKADIENE
Dehydrogenations

Eliminations of unsaturated alcohols & alkyl halides

ELECTROPHILIC ADDITION REACTIONS

Reaction mechanism:

10

11

12

DIELS-ALDER REACTIONS

13

Reactivity of the dienophile is increased if 1 or more electron-withdrawing groups are present

Partial positive charge

14

Stereochemistry

Racemic mixture

15

In order to participate in a Diels-Alder reaction, the diene must be in an s-cis conformation

C1 & C4 are too far apart to react with the dienophile

16

17

Polymerizations

18

Chapter 7:
An sp hybridized carbon

ALKYNES

NOMENCLATURE OF ALKYNES
The IUPAC name of an alkyne is obtained by replacing the ane ending of the corresponding alkane with yne

In common nomenclature, alkynes are named as substituted acetylenes Both ethyne & acetylene are acceptable names for C2H2
3

Lowest possible number, regardless of which functional group gets the lower number

The same low number for both directions, lower number 4 for C=C

PREPARATION OF ALKYNES
Sources of acetylene

Alkynes by elimination reactions

REACTIONS OF ALKYNES
Acidic hydrogen

Only for primary alkyl halides

Additions of hydrogen halides (AE)

Additions of halogens (AE)

10

Additions of water hydration reactions

Markovnikovs rule

Terminal alkynes are less reactive than internal alkynes, need Hg2+ as a catalyst

11

Additions of boran hydroboration & oxidation

12

Regioselectivity
Markovnikovs rule

Anti-Markovnikov

13

Additions of hydrogen hydrogenation

Product is alkane

Product is alkene

14

Ozonolysis of alkynes

Ozonolysis used to be employed in structure determination, but has been superseded by spectroscopic methods
15

Polymerizations

16

Chapter 8:

ARENES

Benzene

CRITERIA FOR AROMATICITY

To be classified as aromatic, a compound must meet both of the following criteria: It must have an un-interrupted cyclic cloud above & below the plane of the molecule The cloud must contain (4n + 2) electrons (n = 0, 1, 2)

un-interrupted cyclic cloud

6e=4x1+2
3

Aromatic:

(+)
(-)

(+)

N H

S
4

NOT aromatic:

NOT (4n + 2) e

(.)

(-)

(+)
4e

(.)

5e

7e

8e

Interrupted cyclic cloud

5

NOMENCLATURE OF MONOSUBSTITUTED BENZENES

Name of substituent + benzene

Names have to be memorized:

NOMENCLATURE OF DI- & POLYSUBSTITUTED BENZENES

Alphabetical order, 1-position for the 1st stated substituent

8

1 of the substituents can be incorporated into a name:

Names incorporating 2 substituents

9

Alphabetical order

Lowest possible numbers

10

PREPARATION OF BENZENE

Petroleum

Bezene
11

REACTIONS OF BENZENE
Halogenations of benzene

12

Reaction mechanism: electrophilic substitution

Catalyst regeneration 13

Nitration of benzene

14

Sulfonation of benzene

Reversible reaction
15

Reaction mechanism: electrophilic substitution

16

Friedel-Crafts Alkylations of benzene

17

18

Carbocation rearrangement

19

20

Friedel-Crafts Acylations of benzene

21

Reaction mechanism: electrophilic substitution

22

Rearrangement

23

REACTIONS OF SUBSTITUTED BENZENES

Relative rates of electrophilic substitutions:

Electrondonating

Electronwithdrawing
24

+I, +C, +H

Relative reactivity

- I, -C,

Electron-donating

Eelectron-withdrawing

Activating

Deactivating

ortho/para-directing

meta-direcring
25

26

27

EFFECTS OF SUBSTITUENTS ON ORIENTATION

E/D group

Only for halogen group

28

E/W group

29

E/D group

30

E/W group

31

THE ORTHO-PARA RATIO

Increase in the size of substituents

Decrease in the o/p ratio

32

ADDITIONAL CONSIDERATIONS
More deactivating than halogen, the ring is too unreactive for (only) Friedel-Crafts alkylations & acylations

33

Aniline & N-substituted anilines do NOT undergo FriedelCrafts reactions: More deactivating than halogen

Also can NOT undergo nitration primary amines are easily oxidized Phenol & anisole do undergo Friedel-Crafts reactions, orienting ortho & para oxygen does NOT complex with the Lewis acid 34

SYNTHESIS OF TRISUBSTITUTED BENZENES

More activating substituent controls the regioselectivity

35

HALOGENATIONS OF ALKYL SUBSTITUENTS

NOT Lewis acid

Can undergo E1 & E2, SN1 & SN2 reactions as usual

36

OXIDATIONS OF ALKYL SUBSTITUENTS

37

NUCLEOPHILIC AROMATIC SUBSTITUTION REACTIONS

E/W groups must be positioned ortho / para to the halogen

38

The greater the number of E/W substituents, the easier it is to carry out the reaction
39

40

Chapter 9:

ALKYL HALIDES

NOMENCLATURE OF ALKYL HALIDES

Common names: alkylhalide (chloride, bromide)

IUPAC names: halogeno + alkane (chloro, bromo)

3

Alkyl & halogen substituents are considered of equal rank

4

PREPARATION OF ALKYL HALIDES

Alkyl halides from alcohols
Only in acidic conditions

Alkyl halides from alkenes

More stable

Alkyl halides from alkanes

Chlorination is much less selective

7

REACTIONS OF ALKYL HALIDES

Very reactive

Very unreactive

With the same R

NUCLEOPHILIC SUBSTITUTION REACTIONS

SN1 vs SN2 depending on alkyl structure, nucleophile concentration & reactivity, and solvent
9

Stereochemistry of SN2 reactions

The nucleophile attacks from the back side / the side directly opposite the leaving group This attacks causes an inversion of configuration
10

11

Stereochemistry of SN1 reactions

12

However, few SN1 reactions occur with complete racemization

13

Factors affecting the rates of S N 1 & SN 2

1. The structure of the substrate 2. The concentration & reactivity of the nucleophile 3. The reaction solvent 4. The nature of the leaving group
14

Affects of substrate structure

Steric hindrance

Steric effect in the SN2 reaction

15

16

17

18

Affects of nucleophile concentration & strength

1) Neither the concentration nor the structure of the nucleophile affects the rates of SN1 reactions since the nucleophile does not participate in the rate-determining step 2) The rates of SN2 reactions depend on both the concentration and the structure of the nucleophile
19

20

Nucleophiles that have the same attacking atom: nucleophilicity roughly parallels basicity:

21

ROH, HOH

22

Affects of solvents on SN2

In polar aprotic solvent, nuceophilicity parallels basicity Polar aprotic solvents solvate cation but not anions

Rates of SN2 reactions are generally increased in polar aprotic solvent

23

24

Affects of solvents on SN1

Polar protic solvents solvate cation & anions effectively

Rates of SN1 reactions are generally increased in polar protic solvent

25

Affects of leaving group

The best leaving groups are those that become the most stable ions after they depart

The best leaving groups are weak bases

26

SN1 vs SN2

27

Functional group interconversions of 1o & 2o alkyl halides

Elimination reactions will occur for 3o alkyl halides

28

Elimination reactions will occur for 3o alkyl halides

29

Williamson ether synthesis

30

Nucleophilic substitutions

Eliminations
31

ELIMINATION REACTIONS

In an elimination reaction: + Groups / atoms are eliminated from a reactant + A double bond is formed between the 2 carbons from which atoms are eliminated
32

Stereochemistry of E2 reactions
Anti-elimination is highly favored in an E2 reaction 2 groups / atoms are removed from opposite sides of C-C bond

33

Regioselectivity of E2 reactions

Zaitsevs rule for an E2 reaction: more substituted alkene is normally obtained

34

Keep in mind that the major product of an E2 reaction is always the more stable alkene (not always the more substituted alkene)

35

In some E2 reactions, the less stable alkene is the major product due to steric effects Zaitsevs product

Hofmanns product
36

37

Rearrangements in E1 & SN1

38

39

40

Stereochemistry of E1 reactions
The carbocation formed in the 1st step is planar, so both syn & anti-elimination can occur

The major product is the more stable alkene

41

GRIGNARD REAGENTS

Strong base

Strong nucleophile

42

REACTIONS OF GRIGNARD REAGENTS

Strong base

Grignard reagents readily react with acidic groups: -OH, -NH2, -NHR, -SH, -CCH, -COOH43

Reactions of Grignard reagents with aldehydes & ketones

Only for the reaction of HCHO

44

45

46

Numbers 1 & 2 are used to indicate that the acid is not added until the reaction with the Grignard reagent is complete

47

Reactions of Grignard reagents with esters

Can NOT be isolated

48

Can be chiral

Alcohols from esters / acyl halides Can NOT be chiral

49

Reactions of Grignard reagents with nitriles

50

Reactions of Grignard reagents with carbon dioxide

51

Reactions of Grignard reagents with epoxides

52

Chapter 10:

ALCOHOLS-PHENOLS

NOMENCLATURE OF ALCOHOLS
Common names: alkyl + alcohol

IUPAC names: hydrocarbon + ol

PREPARATION OF ALCOHOLS
Alcohols from alkenes

Markovnikovs rule

H2SO4, H3PO4
6

Anti-Markovnikov

Alcohols from alkyl halides

Carbocation rearrangements may occur

8

Alcohols from aldehydes & ketones

Aldehydes & ketones can also be reduced using LiAlH4, H2/Pt, Pd, Ni, Ru 9

Alcohols from carboxylic acids & derivatives

Can NOT use NaBH4, H2/Pt, Pd, Ni, Ru for acids

10

Alcohols from Grignard reagents

11

REACTIONS OF ALCOHOLS
Reactions of proton in -OH

Can NOT react with NaOH

12

Dehydration reactions

13

isomerization
14

Primary alcohol

Internal alkene 1-alkenes can NOT be prepared using the dehydration reaction
15

Conversion of alcohols to alkyl halides

Only in acidic conditions

16

isomerization

17

PCl3, SOCl2 can also be used

NO carbocation formation, NO rearrangement

18 Can NOT work for tertiary alcohols due to steric hindrance

Conversion of alcohols to ethers

Only for symmetric ether

Only effective for primary alcohols

19

Reaction mechanism:

20

Fisher esterification reactions

Need acid catalyst

21

Reaction mechanism:

Reversible reaction

22

Oxidation reactions

23

Can NOT be isolated

PCC: pyridinium chlorochromate

24

PHENOLS
SP2 Carbon SP3 Carbon

Some naturally occurring phenols

25

NOMENCLATURE OF PHENOLS

26

PREPARATION OF PHENOLS

27

REACTIONS OF PHENOLS
Halogenation reactions
Strong activating group Non-polar solvent

Polar solvent

NO monobromination

28

Nitration reactions
NOT necessary to use mixture of concentrated HNO3 & H2SO4

Sulfonation reactions

29

FriedelCrafts Alkylation reactions

FriedelCrafts Acylation reactions

30

O-acylations of phenols
NO Lewis acid

31

The Kolbe-Schmitt reaction

32

33

Preparation of aryl ethers

Can NOT prepare aryl ether directly from the reaction of phenol & alcohol in the presence of acid catalyst

34

Cleavage of aryl ethers by hydrogen halides

35

Reaction mechanism:

SN2

NOTE:

36

Oxidation of phenols

37

Polymerization with formaldehyde

Electrophilic aromatic substitution reactions

38

39

40

Chapter 11:
C=O

ALDEHYDES-KETONES
C=C

SP2 carbon
2

NOMENCLATURE OF ALDEHYDES
Common names: carboxylic acid aldehyde is substituted for ic acid

IUPAC names: hydrocarbon + al

Lower priority than ester oxo group

NOMENCLATURE OF KETONES
Derived names: alkyls + ketone

IUPAC names: hydrocarbon + one

PREPARATION OF ALDEHYDES & KETONES

Aldehydes & ketones from alkenes

In the presence of an oxidizing agent, the products 8 will be ketones / carboxylic acids

Aldehydes & ketones from alkynes

Markovnikovs rule

Anti-Markovnikov
9

Aldehydes & ketones from alcohols

10

Can NOT be isolated

PCC: pyridinium chlorochromate

11

Aldehydes from esters, acyl chlorides

Note: LiAlH4 alcohols

12

Preparation of aromatic ketones

13

Gatterman-Koch synthesis of benzaldehyde

Can NOT be prepared & isolated

14

REACTIONS OF ALDEHYDES & KETONES I

The partial positive carbon can be attacked by nucleophiles

The addition of nucleophiles to the carbon atom of the carbonyl group in nucleophilic addition reactions
15

Reactions with Grignard reagents

Only for the reaction of HCHO

16

Numbers 1 & 2 are used to indicate that the acid is not added until the reaction with the Grignard reagent is complete

17

Reactions with acetylide ions

Weak acid, will NOT react with the triple bond

18

Reactions with hydrogen cyanide

Converted back to carbonyl in basic solutions

19

Nitriles carboxylic acids

Nitriles amines

20

Reactions with primary amines

21

Reaction mechanism:

22

Reactions with secondary amines

23

Reaction mechanism:

24

Reactions with water

25

Reactions with alcohols

26

Reaction mechanism:

27

Reactions with sulfur nucleophiles

28

Reduction reactions with hydride ion

29

 NaBH4 can reduce aldehyde, ketones, acyl chlorides, but NOT alkenes & alkynes LiAlH4 is a stronger reducing agent than NaBH4, but NOT safe to use for aldehydes & ketones

30

Reduction reactions to hydrocarbons

NOTE:

31

Oxidation reactions

Aldehydes are generally easier to oxidize than primary alcohols

32

Tollens reagent

Too weak to oxidize an alcohol or any other functional groups Should be used when oxidizing aldehydes containing double bond

33

REACTIONS OF ALDEHYDES & KETONES II REATIONS AT -C

34

Aldol additions

35

Reaction mechanism: Nucleophilic additions

Aldol additions occur more slowly with ketones

36

Aldol condensations = Additions + dehydrations

Easier to dehyrate than other alcohols because the double bond is conjugated with the carbonyl group

37

Aldol condensations sometimes occur under the aldol addition conditions without additional heating

NOT isolated

38

Mixed / crossed Aldol additions

4 addition products

NOT useful

39

Very strong base

40

Halogenations at -C
Only 1 hydrogen is replaced in acidic solution

41

The haloform reactions

Only for methyl ketones

42

Chapter 12:
C=O

CARBOXYLIC ACIDS
C=C

SP2 carbon Y=OH

2

NOMENCLATURE OF CARBOXYLIC ACIDS

IUPAC names: hydrocarbon + oic acid

Some natural occurring acids & derivatives

PREPARATIONS OF CARBOXYLIC ACIDS

From Grignard reagents

From nitriles

Have 1 more carbon as compared to the halide

8

From primary alcohols

Can NOT be isolated

PCC: pyridinium chlorochromate

9

From aldehydes

Aldehydes are generally easier to oxidize than primary alcohols

10

From alkylbenzenes

11

REACTIONS OF CARBOXYLIC ACIDS Esterification

reactions

12

IUPAC names: alkyl + carboxylate

13

Intramolecular ester formation: Lactones

14

IUPAC names: 2-oxacycloalkanone

15

Reactions of esters
Ester hydrolysis

16

Transesterification reactions

17

Acyl chloride formation

18

IUPAC names: replace ic acid with yl halide / carboxylic acid with carbonyl halide

19

Reactions of acyl chlorides

20

An amide
21

Amide formation

22

IUPAC names: replace ic acid, oic acid, ylic acid with amide

23

Reactions of amides

24

Reaction only in the presence of an acid

25

The Hell-Vohard-Zelinski reaction Only for -hydrogens

Radical substitution (halogenation) will occurs in the absence of PBr3, P

26

Reaction mechanism:

27

28

Reduction reactions

H2/Ni, Pt, Pd or NaBH4 can NOT reduce acids, esters, amides

29

LiAlH4 is used to reduce only compounds such as acids, esters, amides that can NOT be reduced by milder agents
30

Chapter 13:

AMINES-DIAZONIUM SALTS

NOMENCLATURE OF AMINES

Common names: alkyl + amine

IUPAC names: alkan + amine

Substituents are listed in alphabetical order, regardless of whether they are attached to the nitrogen or the hydrocarbon
5

PREPARATIONS OF AMINES

Alkylation of ammonia

Gabriel synthesis of primary amines

Amines by reduction

Preparation of arylamines

1:1 molar ratio

It is possible to selectively reduce just 1 of 2 nitro groups using S2 H2 /Pd, Fe/HCl will reduce both nitro groups 10

Amines by reductive amination

11

Amines by Hoffman Rearrangement

Have 1 less carbon atom

12

BASICITY OF AMINES

NOTE: pKa of conjugate acid in water at 25 oC

13

REACTIONS OF AMINES

Reactions with primary amines

14

Reactions with secondary amines

15

Reactions with carboxylic acid derivatives

16

Reactions with alkyl halides

Nucleophilic substitution reaction Excess amine

17

The Hofmann elimination reaction

Quaternary ammonium hydroxide formation

18

Different from Zaitsevs product

19

Oxidation reactions

Amines can be oxidized by hydrogen peroxide, peroxyacids, other common oxidizing agents
20

Reaction of primary amines with HNO2

HNO2 is unstable, aqueous NaNO2 / acid should be used Stable NOT stable

21

Mechanism:

22

23

Alkyl diazonium salt is NOT stable

24

REACTIONS OF DIAZONIUM SALTS

Sandmeyer reactions

KCl, KBr can NOT be used in place of CuCl, CuBr

25

This Cl is from CuCl

26

Schiemann reaction
27

Preparation of phenol from diazonium salt

28

Reductive deaminations

Anhydrous C2H5OH, NaBH4 can be used in place of H3PO2

29

Electrondonating group

Azo coupling reactions

Electrophilic aromatic substitution

Substitution will occur at 1 ortho position if the 30 para is blocked

DESIGNING A SYNTHESIS

31

32

33

34

35

36