organic chemistry 2 notes

8/11/2019 Organic Chemistry 2 notes

1/328

Chapter 15

Introduction to Organometallic Compounds

William H. Brown Beloit College

William H. Brown

Christopher S. Foote

Brent L. Iverson

Eric Anslynwww.cengage.com/chemistry/brown

15-1


2/328

Organometallic Compounds Organometallic compound:A compound that contains a carbon-

metal bond.

In this chapter, we focus on organometallic compounds of Mg, Li,

and Cu.

These classes illustrate the usefulness of organometallics in

modern synthetic organic chemistry.

They illustrate how the use of organometallics can bring about

transformations that cannot be accomplished in any other way.


3/328

3

Other Reactions of Alkyl Halides:

Grignard Reagents Reaction of RX with Mg in ether or THF

Product is RMgX an organometallic compound (alkyl-metal bond)

R is alkyl 1, 2, 3, aryl, alkenyl X = Cl, Br, I


4/328

RLi

Organolithium reagents

Prepared by reaction of an alkyl, aryl, or alkenyl

halide with lithium metal.

Cl + +1-Chlorobutane Butyllithium

pentane2 Li L iClL i


5/328

RMgX and RLi RMgX and RLi are valuable in synthesis as nucleophiles.

The carbon bearing the halogen is transformed from an electrophile

to a nucleophile.

Their most valuable use is addition to the electrophilic carbon of the

C=O group of aldehydes, ketones, carboxylic esters, and acid

chlorides to form a new carbon-carbon bonds.

Br -C Br

CH3 CH2 CH2

H

HC -

CH3 CH2 CH2

H

HMg 2 +

+ -

carbon is anelectrophile

carbon is anucleophile


6/328

RMgX and RLi

Reaction with proton acids

RMgX and RLi are strong bases. RLi are extremely strong bases.

They remove these types of acidic protons readily.

CH3 CH2-MgBr H-OH CH3 CH2 -H Mg2 +

OH-

Br-

Weakerbase

Stronger

base Weaker

acid

Stronger

acid

pKa51pKa15.7

+++-

pKe q = -35-+

+ +

R2NH ArOH RSH RCOOHROH HOHRC CH

1 and 2Amines

Alcohols Water Phenols Thiols Carboxylicacids

pKa4-5pKa8-9pKa9-10pKa15.7pKa16-18pKa38-40

Terminalalkynes

pKa25


7/328

RMgX and RLi

Reaction with oxiranes (epoxides)

Reaction of RMgX or RLi with an oxirane followed by

protonation gives a primary alcohol with a carbon chain two

carbons longer than the original chain.

H3 O+ OH

Mg Br O

O Mg Br+

+

Butylmagnesiumbromide

Ethyleneoxide

A magnesiumalkoxide

1-Hexanol


8/328

RMgX and RLi Reaction with oxiranes (epoxides)

The major product corresponds to SN2 attack of RMgX or RLion the less hindered carbon of the epoxide.

Mg Br

H2 O

HCl

Methyloxirane

(Propylene oxide)

(racemic)

A magnesium

alkoxide

1-Phenyl-2-propanol

(racemic)

+

Phenyl-

magnesium

bromide

OHO-MgBr+

O


9/328

9

Organometallic Coupling Reactions

RLi reacts with copper iodide to give lithium dialkylcopper (Gilmanreagents)

Lithium dialkylcopper reagents react with alkyl halides to give alkanes


10/328

10

Utility of Organometallic Coupling in Synthesis

Coupling of two organometallic molecules produces larger molecules of defined structure

Aryl and vinyl organometallics also effective

Coupling of lithium dialkylcopper molecules proceeds through trialkylcopper intermediate


11/328

11

20. Conjugated Dienes and

Ultraviolet Spectroscopy


12/328

12

Conjugated and Nonconjugated Dienes

Compounds can have more than one double or triple bond

If they are separated by only one single bond they are conjugatedand their orbitals interact

The conjugated diene 1,3-butadiene has properties that are verydifferent from those of the nonconjugated diene, 1,5-pentadiene


13/328

13

Measuring Stability From heats of hydrogenation, we can compare relative stabilities of conjugated

and unconjugated dienes.


14/328

14

Molecular Orbital Description of 1,3-Butadiene

The single bond between the conujgated doublebonds is shorter and stronger than sp3- sp3 C-C. It isstrengthened by overlap ofp orbitals

The bonding -orbitals are made from 4p orbitals thatprovide greater delocalization and lower energy than

in isolated C=C


15/328

15

Electrophilic Additions to Conjugated Dienes:

Allylic Carbocations

Review: Markovnikov regiochemistry via more stable carbocation


16/328

16

Carbocations from Conjugated Dienes

Addition of H+ leads to delocalized secondary allylic carbocation


17/328

17

Kinetic and Thermodynamic Control

Kinetic

control:The

distribution

of products

is

determined

by their

relative

rates of

formation.

Thermodynamic

control:

The

distribution of

products is

determined bytheir relative

stabilities.


18/328

18

The Diels-Alder Cycloaddition Reaction

Conjugate dienes can combine with alkenes to form six-membered cyclic compounds

The formation of the ring involves no intermediate (concerted formation of two bonds)

Discovered by Otto Paul Hermann Diels and Kurt Alder in Germany in the 1930s


19/328


20/328

20

Stereochemistry of the Diels-Alder Reaction


21/328

21

SummaryConjugate systems are more stable than non-conjugate system

Experimental evidence: (a) measurement of heat of formation (H)

(b) bond lengthTheoretical rationale: Energy calculation based on MO theory

Chemical properties:

1. Kinetic control vs. thermodynamic control 2. [4+2] reaction


22/328

22

UV-Visible Spectroscopy

Region ofSpectrum

Wavelength (nm)

kcal/mol

near ultravioletvisible

200-400400-700

71.5 - 14340.9 - 71.5

EnergykJ/mol

299-598171-299

724 (173)

552 (132)

448 (107)

385 (92)290

268

217

165

max

Structural FormulaName

(3E,5E)-1,3,5,7-Octatetraene

(3E)-1,3,5-Hexatriene

1,3-Butadiene

Ethylene

(nm)

Energy

[kJ (kcal)/mol]

max: wavelength where UV

absorbance for a compound is

greatest

max increases as conjugationincreases (lower energy)


23/328

23

Quantitative Use of UV Spectra

Beer-Lambert law: The relationship between absorbance, concentration,

and length of the sample cell (cuvette):

A = absorbance (unitless): A measure of the extent to which a

compound absorbs radiation of a particular wavelength.

= molar absorptivity (M-1cm-1): A characteristic property of a

compound; values range from zero to 106 M-1cm-1.

I = length of the sample tube (cm)

Beer-Lambert Law: A = c l

I

IoAbsorbance (A) = log

Absorbance for a particular compound in a specific solvent at a specified wavelengthis directly proportional to its concentration

You can follow changes in concentration with time by recording absorbance at thewavelength


24/328

24

21. Benzene and Aromaticity


25/328

25

Benzene Aromaticwas used to described some fragrant compounds in early 19th century

Current: distinguished from aliphatic compounds by electronic configuration

In 1872, August Kekul proposed the following structure for benzene. Thisstructure, however, did not account for the unusual chemical reactivity of

benzene.

CH

CH

CH

CHC

H

C

H

CC

CC

C

C

H

H

HH

HH

We often represent benzene as a hybrid of two equivalent Kekul structures.

Each makes an equal contribution to the hybrid and thus the C-C bonds are

neither double nor single, but something in between.

Benzene as a hybrid of two equivalentcontributing structures


26/328

26

Benzene The concepts of hybridization of atomic orbitals and the theory of resonance,

developed in the 1930s, provided the first adequate description of benzenes

structure. The carbon skeleton is a planar regular hexagon. All its C-C bonds are

the same length: 139 pm between single (154 pm) and double (134

pm) bonds.

All C-C-C and H-C-C bond angles 120.

Electron density in all six C-C bonds is identical.

sp2-sp

2

sp2-1s109 pm

120

120

120

139 pm

C

C

C

C

C C

H

H H

H

H H


27/328

27

Benzene

The carbon framework with the six 2p orbitals. Each C is sp2 and

has ap orbital perpendicular to the plane of the six-memberedring

Overlap of the parallel 2p orbitals forms one torus above the plane

of the ring and another below it. This orbital represents the lowest-

lying pi-bonding molecular orbital.


28/328

28

Drawing Benzene The two benzene resonance forms can be represented by a single structure

with a circle in the center to indicate the equivalence of the carboncarbonbonds

This does not indicate the number of electrons in the ring but reminds usof the delocalized structure

We shall use one of the resonance structures to represent benzene for easein keeping track of bonding changes in reactions


29/328

29

Structure and Stability of Benzene

Benzene reacts slowly with Br2 to give bromobenzene (where Br replaces H)

This is substitution rather than the rapid addition reaction common to compoundswith C=C, suggesting that in benzene there is a higher barrier


30/328

30

Heats of Hydrogenation as Indicators of Stability

Resonance energy: The

difference in energy between aresonance hybrid and the

most stable of its hypothetical

contributing structures in

which electrons are localized

on particular atoms and inparticular bonds.

One way to estimate the

resonance energy of

benzene is to compare the

heats of hydrogenation ofbenzene and

cyclohexene. Benzene has about 150 kJ more

stability than an isolated set ofthree double bonds


31/328

31

Concept of Aromaticity The underlying criteria for aromaticity were recognized in the early 1930s

by Erich Hckel, based on molecular orbital (MO) calculations.

To be aromatic, a compound must Be cyclic.

Have onep orbital on each atom of the ring.

Be planar or nearly planar so that there is continuous or nearly

continuous overlap of allp orbitals of the ring. Have a closed loop of (4n + 2) pi electrons in the cyclic arrangement of

p orbitals. (n is 0,1,2,3,4). For n=1: 4n+2 = 6; benzene is stable and

the electrons are delocalized


32/328

32

Molecular Orbital Description of Benzene

The 6 p-orbitals combine to give

Three bonding orbitals with 6 electrons,

Three antibonding orbitals with 0 electrons

Orbitals with the same energy are degenerate


33/328

33

Molecular Orbital Description of BenzeneFrost circle:A graphic method for determining the relative order of pi MOs in

planar, fully conjugated monocyclic compounds.Inscribe in a circle a polygon of the same number of sides as the ring to be

examined such that one of the vertices of the polygon is at the bottom of the circle.The relative energies of the MOs in the ring are given by where the vertices of the

polygon touch the circle.

Those MOsBelow the horizontal line through the center of the ring are bonding MOs,

on the horizontal line are nonbonding MOs,above the horizontal line are antibonding MOs.


34/328

34

Concept of Anti-aromaticity Antiaromatic hydrocarbon:A monocyclic, planar, fully conjugated

hydrocarbon with 4n pi electrons (4, 8, 12, 16, 20...).

An antiaromatic hydrocarbon is especially unstable relative to an open-chain fully conjugated hydrocarbon of the same number of carbon

atoms.

Cyclobutadiene is antiaromatic.


35/328

35

Compounds With 4n Electrons Are Not

Aromatic (May be Antiaromatic)

4- and 8-electron compounds are not delocalized(single and double bonds)

Cyclobutadiene is so unstable that it dimerizes by aself-Diels-Alder reaction at low termperature

Cyclooctatetraene:

with 8 pi electrons is not aromatic; it shows

reactions typical of alkenes.

X-ray studies show that the most stableconformation is a nonplanar tub conformation.

Although overlap of 2p orbitals occurs to form pi

bonds, there is only minimal overlap between sets

of 2p orbitals because they are not parallel.

has four double bonds, reacting with Br2, KMnO4,and HCl as if it were four alkenes.

cyclobutadiene

cyclooctatetraene


36/328

36

If it is conjugated planar comformation


37/328

37

Aromatic Ions Any neutral, monocyclic, unsaturated hydrocarbon with an odd number of

carbons must have at least one CH2 group and, therefore, cannot be

aromatic.

Cyclopropene, for example, has the correct number of pi electrons to be

aromatic, 4(0) + 2 = 2, but does not have a closed loop of 2p orbitals.

Cyclopropene Cyclopentadiene Cycloheptatriene

CH2 CH2CH2


38/328

38

Aromatic Ions If, however, the CH2 group of cyclopropene is transformed into a CH

+

group in which carbon is sp2 hybridized and has a vacant 2p orbital, the

overlap of orbitals is continuous and the cation is aromatic.

Cyclopropenyl cation represented as a hybridof three equ ivalen t contributin g structures

+

H

H

H

H

H

H

H

H

H+

+


39/328

39

Aromatic Ions The 4n + 2 rule applies to ions as well as neutral species

Both the cyclopentadienyl anion and the cycloheptatrienyl cation are

aromatic The key feature of both is that they contain 6 electrons in a ring of

continuous p orbitals


40/328

40

Aromaticity of the Cyclopentadienyl Anion

1,3-Cyclopentadiene contains conjugated double bonds joined by a CH2 thatblocks delocalization

Removal of H+

at the CH2 produces a cyclic 6-electron system, which is stable Removal of H- or H generate nonaromatic 4 and 5 electron systems

Relatively acidic (pKa = 16) because the anion is stable


41/328

41

Aromatic Hydrocarbons

[14]Annulene

(aromatic)

HH

H H

H

H

H

H

HH

H

H

H H

[18]Annulene

(aromatic)

H

H

H

H

H

H

H

H

HH

H

H

H

H

H

H

H

H [10]Annulene

Nonplanar: not aromatic


42/328

42

Naphthalene Orbitals Three resonance forms and delocalized electrons


43/328

43

Naming Aromatic Compounds Many common names are retained.

Toluene CumeneEthylbenzene Styrene

Phenol Aniline Benzoic acid Anisole

COOHNH2 OCH3OH

Benzaldehyde

CHO


44/328

44

Naming Aromatic Compounds Monosubstituted benzenes systematic names as hydrocarbons with

benzene

C6H5Br = bromobenzene C6H5NO2 = nitrobenzene, and C6H5CH2CH2CH3 is propylbenzene


45/328

45

The Phenyl Group When a benzene ring is a substituent, the termphenyl is used (for

C6H5)

You may also see Ph or in place of C6H5 Benzyl refers to C6H5CH2


46/328

46

Disubstituted Benzenes Relative positions on a benzene ring

ortho- (o) on adjacent carbons (1,2)

meta- (m) separated by one carbon (1,3) para- (p) separated by two carbons (1,4)

Describes reaction patterns (occurs at the para position)


47/328

47

Naming Benzenes With More Than Two Substituents

Choose numbers to get lowest possible values

List substituents alphabetically with hyphenated numbers

Common names, such as toluene can serve as root name (as in TNT)


48/328

48

Aromatic Heterocycles: Pyridine and Pyrrole

Heterocyclic compounds contain elements other than carbon in a ring, such

as N,S,O,P

Aromatic compounds can have elements other than carbon in the ring There are many heterocyclic aromatic compounds and many are very

common

Cyclic compounds that contain only carbon are called carbocycles (not

homocycles)

Nomenclature is specialized


49/328

49

Pyridine A six-membered heterocycle with a nitrogen atom in its ring

electron structure resembles benzene (6 electrons)

The nitrogen lone pair electrons are not part of the aromatic system(perpendicular orbital)

Pyridine is a relatively weak base compared to normal amines butprotonation does not affect aromaticity


50/328

50

Pyrrole A five-membered heterocycle with one nitrogen

electron system similar to that of cyclopentadienyl anion

Four sp2-hybridized carbons with 4p orbitals perpendicular to the ring and4 p electrons

Nitrogen atom is sp2-hybridized, and lone pair of electrons occupies aporbital (6 electrons)

Since lone pair electrons are in the aromatic ring, protonation destroysaromaticity, making pyrrole a very weak base


51/328

51

Spectroscopy of Aromatic Compounds

IR: Aromatic ring CH

stretching at 3030 cm1

and peaks 1450 to1600 cm1

UV: Peak near 205 nm

and a less intense

peak in 255-275 nm

range


52/328

52

Spectroscopy of Aromatic Compounds

1H NMR: Aromatic Hs strongly deshielded by ring and absorb between 6.5

and 8.0

Peak pattern is characteristic positions of substituents Aromatic ring oriented perpendicular to a

strong magnetic field, delocalized electrons producing a small local magneticfield

Opposes applied field in middle of ring

reinforces applied field outside of ring

Results in outside Hs resonance atlower field


53/328

53

13

C NMR of Aromatic Compounds Carbons in aromatic ring absorb

at 110 to 140

Shift is distinct from alkane

carbons but in same range as

alkene carbons


54/328

54

22. Chemistry of Benzene:

Electrophilic Aromatic Substitution


55/328

55

Reactions at aromatic skeleton:

Mechanism #1: Electrophilic substitution

Mechanism # 2: Nucleophilic substitutionMechanism #3: Benzyne intermediated substitution

Evidence of benzyne mechanism

Structure of benzyne

Overview

Reactions at the Benzylic position:

Oxidation

Halogenation

Hydrogenolysis


56/328

56

Comparison of Reactivity in Reduction

Aromatic rings are inert to catalytic hydrogenation under conditions that reducealkene double bonds

Can selectively reduce an alkene double bond in the presence of an aromatic ring

Reduction of an aromatic ring requires more powerful reducing conditions

1: Electrophilic substitution


57/328

Substitution Reactions of Benzene and Its Derivatives

Reactions of benzene lead to the retention of the aromatic core

Electrophilic aromatic substitution replaces a proton on benzene with

another electrophile

General question: What is the electrophile and how is it generated?



58/328

ChlorinationStep 1: Formation of a chloronium ion.

Step 2: Attack of the chloronium ion on the ring.

Cl Cl Cl

Cl

Cl

Fe

Cl

Cl

ClFeClCl Cl FeCl4

+

A molecular complex

with a positive charge

on chlorine

Ferric chloride

(a Lewis

acid)

Chlorine

(a Lewis

base)

++

An ion pair

containing a

chloronium ion

+

+

+

Resonance-stabi lized cation in termediate; the positive

charge is delocalized onto three atoms of the ring

+

slow, ratedetermining

Cl

HH

Cl

H

Cl

Cl

Step 3: Proton transfer regenerates the aromatic character of the ring.

Cl

HCl-FeCl3 Cl HCl FeCl3

Chlorobenzene

fast

Cationintermediate

++

+-

+

Wheland

Intermediate



59/328

59

Bromination of Aromatic Rings



60/328

Substitution Reactions of Benzene and Its Derivatives

+Benzenesulfonic acid

Sulfonation:

H SO3 HSO3

H2SO4

++

An alkylbenzene

Alkylation:

RRXA lX

3 HX

++

Acylation:

An acylbenzene

H RCX A lX3 HX

OCRO

H



61/328

61

Aromatic Nitration The combination of nitric acid and sulfuric acid produces NO2

+ (nitronium ion)

The reaction with benzene produces nitrobenzene

COOH

NO2

3 H2Ni

COOH

NH2

2H2O

4-Aminobenzoic acid4-Nitrobenzoic acid

+(3 atm)

+

Application:



62/328

62

Aromatic Sulfonation Substitution of H by SO3 (sulfonation)

Reaction with a mixture of sulfuric acid and SO3 Reactive species is sulfur trioxide or its conjugate acid

Reaction occurs via Wheland intermediate and is reversible

Alk l i f A i Ri



63/328

63

Alkylation of Aromatic Rings: The FriedelCrafts Reaction

Step 1: Formation of an alkyl cation as an ion pair.

Step 2: Attack of the alkyl cation on the aromatic ring.

Step 3: Proton transfer regenerates the aromatic ring.

R Cl ClAl

Cl

ClR Cl

Cl

Cl

Al Cl R+

AlCl4-

An ion pair containinga carbocation

+

-+

A molecularcomplex

+ R+

R

H

R

H

R

H

A resonance-stabilized cation

+

+

+

H

RCl AlCl3 R AlCl3 HCl+ ++

Li it ti f th F i d l C ft Alk l ti



64/328

64

Limitations of the Friedel-Crafts Alkylation

Only alkylhalides can be used (F, Cl, I, Br)

Aryland vinylichalides do not react (their carbocations are too hard to form)

Will not work with rings containing an amino group substituent or a stronglyelectron-withdrawing group

Reactions at the Benzylic posit ion:

Oxidation

Halogenation

Hydrogenolysis


65/328

65

Synthetic Application Aromatic ring activates neighboring carbonyl group toward reduction

Ketone is converted into an alkylbenzene by catalytic hydrogenation over Pd

catalyst

Hydrogenolysis

R i


66/328

Review1: Electrophilic substitution

Cl Cl Cl

Cl

Cl

Fe

Cl

Cl

ClFeClCl Cl FeCl4

+

A molecular complex

with a positive charge

on chlorine

Ferric chloride

(a Lewis

acid)

Chlorine

(a Lewis

base)

++

An ion pair

containing a

chloronium ion

R Cl ClAl

Cl

Cl

R Cl

Cl

Cl

Al Cl R+AlCl4-

An ion pair containinga carbocation

+ -

+

A molecularcomplex

E+ = X+

E+ = N+

E+ = S+

E+ = C+


67/328

67

O

C

O

O

OC

H

OO OH

CO

O

A cyclohexadienoneintermediate

+

Sodiumphenoxide

Salicylate anion

keto-enoltautomerism

(1) (2)

OH

NaOH

H2 O

O-Na

+

CO2

H2 O

OH

CO-Na

+O

HCl

H2 O

OH O

COH

Phenol Sodiumphenoxide

Sodium salicylate Salicylic acid

Kolbe Carboxylation Aspirin

Substituent Effects in Aromatic Rings



68/328

68

Substituent Effects in Aromatic Rings

-OCH3 is ortho-para directing.

-COOH is meta directing.

OCH3

HNO3 CH3COOH

OCH3NO2

OCH3

NO2

H2 O

p-Nitroanisole (55%)

o-Nitroanisole (44%)

Anisole

+++

COOH

HNO3H

2SO

4

NO2

COOH COOH

NO2NO2

COOH

100C

m-Nitro-benzoic

acid(80%)

Benzoicacid

+ ++

o-Nitro-benzoic

acid(18%)

p-Nitro-benzoic

acid(2%)

An Explanation of Substituent Effects



69/328

69

An Explanation of Substituent Effects

Weaklyactivating

Ortho-paraD

irecting

Weaklydeactivating

Moderately

activating

Stronglyactivating NH2 NHR NR2 OH

NHCR NHCAr

OR

OCArOCR

R

F Cl Br I

: : : : :

::

: : :

:

:

:

:

:

:

:

:

:

:

:

::::

Stronglydeactivating

Moderatelydeactivating

CH

O O

CR COH

SO3 H

CORO

CNH2

NO2 NH3+

CF3 CCl3MetaDirecting

C N

O O O O

OO

Alkyl, phenyl, and all other substituents in which the atom

bonded to the ring has an unshared pair of electrons are

ortho-para directing. All other substituents are meta

directing.

All ortho-para directing groups except the halogens are

activating toward further substitution. The halogens are

weakly deactivating.

Ortho and Para Directing Activators: OH and NH



70/328

70

Ortho- and Para-Directing Activators: OH and NH2

Alkoxyl, and amino groups have a strong, electron-donating resonanceeffect

Most pronounced at the ortho and para positions



71/328

71

Meta-Directing Deactivators Inductive and resonance effects reinforce each other

Ortho and para intermediates destabilized by deactivation from carbocationintermediate

Resonance cannot produce stabilization



72/328

72

Origins of Substituent Effects An interplay of inductive effects and resonance effects

Inductive effect - withdrawal or donation of electrons through a bond

Resonance effect - withdrawal or donation of electrons through a bond

due to the overlap of ap orbital on the substituent with ap orbital on the

aromatic ring

Resonance Effects Electron Donation



73/328

73

Resonance Effects Electron Donation

Halogen, OH, alkoxyl (OR), and amino substituents donate electrons

electrons flow from the substituents to the ring

Effect is greatest at ortho and para


74/328

Summary Table: Effect of Substituents in



75/328

75

Aromatic Substitution

Important Application



76/328

76

po ta t pp cat o

CH3

K2 Cr2 O7

H2SO4

HNO3

H2 SO4

CH3

NO2

COOH

H2SO4

HNO3

K2 Cr2O7

H2SO4

COOH

NO2

COOH

NO2

m-Nitrobenzoicacid

p-Nitrobenzoicacid

Trisubstituted Benzenes: Additivity of Effects



77/328

77

y

If the directing effects of the two groups are the same, the result is additive

Substituents with Opposite Effects



78/328

78

Substituents with Opposite Effects

If the directing effects of two groups oppose each other, the more

powerful activating group decides the principal outcome

Usually gives mixtures of products

Meta-Disubstituted Compounds Are Unreactive



79/328

79

The reaction site is too hindered

To make aromatic rings with three adjacent substituents, it is best to start withan ortho-disubstituted compound

Nucleophilic Aromatic Substitution

2: Nucleophilic substitution


80/328

80

p

Aryl halides with electron-withdrawing substituentsortho and para react with nucleophiles

Form addition intermediate (Meisenheimer

complex) that is stabilized by electron-withdrawal Halide ion is lost to give aromatic ring

Aryl halides do not undergo

nucleophilic substitution by

either SN1 or SN2pathways.

They do undergo

nucleophilic substitutions,

but by mechanisms quite

different from those ofnucleophilic aliphatic

substitution.

Nucleophilic aromatic

substitutions are far less

common than electrophilicaromatic substitutions.

Application: Alkali Fusion of Aromatic Sulfonic Acids

2: Nucleophilic substitution


81/328

81

pp

Sulfonic acids are useful as intermediates

Heating with NaOH at 300 C followed by neutralization with acid

replaces the SO3

H group with an OH

Example is the synthesis ofp-cresol

Benzyne

3: Benzyne intermediated substitution


82/328

82

y

Phenol is prepared on an industrial scale by treatment of chlorobenzenewith dilute aqueous NaOH at 340C under high pressure

The reaction involves an elimination reaction that gives a triple bond

The intermediate is called benzyne

Evidence of Benzyne Intermediate



83/328

83

y

3-Methylphenol(m-Cresol)

2-Methylphenol(o-Cresol)

+

CH3Cl OH

CH3 CH3

OH

1. NaOH, heat, pres sure

2. HCl, H2O

Structure of Benzyne



84/328

84

y

Benzyne is a highly distorted alkyne

The triple bond uses sp2-hybridized carbons, not the usual sp

The triple bond has one bond formed bypp overlap and by weak sp2

sp2 overlap

Reactions at aromatic skeleton:

Mechanism #1: Electrophilic substitution

Mechanism # 2: Nucleophilic substitution

Mechanism #3: Benzyne intermediated substitution

Review


85/328

85

Reactions at the Benzylic position:

Oxidation

Halogenation

Hydrogenolysis

E+ = X+ N+ S+ C+

Mechanism #1: Mechanism #2: SNAr

Mechanism #3:

Benzylic Oxidation


Oxidation

Halogenation

Hydrogenolysis


86/328

86

Benzene is unaffected by strong oxidizing agents such as H2CrO4 and KMnO4

An alkyl group with at least one hydrogen on its benzylic carbon is oxidized to

a carboxyl group.

1,4-Dimethylbenzene

(p-xylene)1,4-Benzenedicarboxylic acid (terephthalic acid)

CH3 H2SO4

K2 Cr2 O7

H3 C COH

O

HOC

O

li i


Oxidation

Halogenation

Hydrogenolysis


87/328

87

Benzylic Halogenation Reaction of an alkylbenzene with N-bromo-succinimide (NBS) and

benzoyl peroxide (radical initiator) introduces Br into the side chain

CH3

Cl2+CH2 Cl

HCl+

Toluene

heator light

Benzyl chloride

M h i f NBS (R di l) R i


Oxidation

Halogenation

Hydrogenolysis


88/328

88

Mechanism of NBS (Radical) Reaction

Abstraction of a benzylic hydrogen atom generates an intermediatebenzylic radical

Reacts with Br2 to yield product

Br radical cycles back into reaction to carry chain Br2 produced from reaction of HBr with NBS

Benzylic Hydrogenolysis


Oxidation

Halogenation

Hydrogenolysis


89/328

89

Hydrogenolysis: Cleavage of a single bond by H2 Among ethers, benzylic ethers are unique in that they are cleaved under

conditions of catalytic hydrogenation.

O H2Pd/ C

OH

Me+

Benzyl butyl ether Toluene1-Butanol

+

this bondis cleaved


90/328

90

Chapter 10

Alcohols and Phenols

Alcohols and Phenols


91/328

91

Alcohols contain an OH group connected to a a saturated C (sp3)

They are important solvents and synthetic intermediates

Phenols contain an OH group connected to a carbon in a benzene ring

Methanol, CH3OH, called methyl alcohol, is a common solvent, a fuel additive,produced in large quantities

Ethanol, CH3CH2OH, called ethyl alcohol, is a solvent, fuel, beverage

Phenol, C6H5OH (phenyl alcohol) has diverse uses - it gives its name to thegeneral class of compounds

General classifications of alcohols based on substitution on C to which OH is

attached

Methyl (C has 3 Hs), Primary (1) (C has two Hs, one R), secondary (2) (C

has one H, two Rs), tertiary (3) (C has no H, 3 Rs),

Nomenclature of Alcohols


92/328

92

IUPAC names The parent chain is the longest chain that contains the OH group.

Number the parent chain to give the OH group the lowest possiblenumber.

Change the suffix -e to -ol.

Common names

Name the alkyl group bonded to oxygen followed by the word alcohol.

1-Propanol

(Propyl alcohol)

2-Propanol

(Isopropyl alcohol)

1-Butanol

(Butyl alcohol)

OH

OH

OH

2-Butanol(sec-Butyl alcohol)

2-Methyl-1-propanol(Isobutyl alcohol)

2-Methyl-2-propanol(tert-Butyl alcohol)

OH

OHOH

More Names


93/328

93

cis-3-Methylcyclohexanol

OH

OH

Bicyclo[4.4.0]decan-3-ol

14

58

10

91

22

3

3

4

56 76

Numbering of the

bicyclic ring takesprecedence overthe location of -OH

1

2 3

4 5

6

(E)-2-Hexene-1-ol

(t rans-2-Hexen-1-ol)

HO

Properties of Alcohols and Phenols: Hydrogen Bonding


94/328

94

The structure around O of the alcohol or

phenol is similar to that in water, sp3

hybridized

Alcohols and phenols have much higherboiling points than similar alkanes and alkyl

halides. WHY?

bp -24CEthanolbp 78C

Dimethyl ether

CH3 CH2OH CH3 OCH3

Alcohols Form Hydrogen Bonds


95/328

A positively polarizedOH hydrogen atom from one moleculeis attracted to a lone pair of electrons on a negatively polarizedoxygen atom of another molecule

This produces a force that holds the two molecules together

These intermolecular attractions are present in solution but notin the gas phase, thus elevating the boiling point of the solution

Alcohols Form Hydrogen Bonds


96/328

Hydrogen bonding:When the positive end of one dipole is an H bonded to F, O, or N

(atoms of high electronegativity) and the other end is F, O, or N.

Alcohols Form Hydrogen Bonds with water


97/328

Alcohols are more soluble in water.

The presence of additional -OH groups in a

molecule further increases solubility in water.

sugar

Spectroscopy of Alcohols and Phenols


98/328

98

Characteristic OH stretching absorption at 3300 to 3600 cm1 in the

infrared

Sharp absorption near 3600 cm-1 except, if H-bonded: then broad

absorption 3300 to 3400 cm1 range

Strong CO stretching absorption near 1050 cm1

Phenol OH absorbs near 3500 cm-1

13C NMR: C bonded to OH absorbs at a lower field, 50 to 80

1H NMR: electron-withdrawing effect of the nearby oxygen, absorbs at 3.5 to 4

Usually no spin-spin coupling between OH proton and neighboringprotons on C due to exchange reactions with moisture or acids

Spinspin splitting is observed between protons on the oxygen-bearing carbon and other neighbors

Phenol OH protons absorb at 3 to 8

Basicity of alcohols


99/328

99

Weakly basic and weakly acidic

Alcohols are weak Brnsted bases

Protonated by strong acids to yield oxonium ions, ROH2+

Acidity of Alcohols


100/328

100

In dilute aqueous solution, alcohols are weakly acidic.

CH3 O H : HO

H

[ CH3OH]

[ CH3O-] [H3O

+]

CH3 O:

O

H

HH+

+

= 10- 15.5

pKa = 1 5.5

Ka =

+

( CH3) 3COH

( CH3) 2CHOH

CH3 CH2 OH

H2O

CH3 OH

CH3 COOH

HClHydrogen chloride

Acetic acid

Methanol

Water

Ethanol

2-Propanol

2-Methyl-2-propanol

Structural

Formula

Stronger

acid

Weaker

acid

Also given for comparison are p Kavalues for

water, acetic acid, and hydrogen chloride.

Compound pKa

-7

15.5

15.7

15.9

17

18

4.8

Simple alcohols are about asacidic as water

Alkyl groups make an alcohol aweaker acid

The more easily the alkoxideion is solvated by water themore its formation isenergetically favored

Steric effects are important

Alkoxides are basesused as reagents inorganic chemistry

Inductive Effects


101/328

101

Electron-withdrawing groups make an alcohol a stronger acid by stabilizing

the conjugate base (alkoxide)

Phenol Acidity


102/328

102

Phenols (pKa ~10) are much more acidic than alcohols (pKa ~ 16) due toresonance stabilization of the phenoxide ion

Phenols react with NaOH solutions, forming soluble salts that are soluble indilute aqueous

A phenolic component can be separated from an organic solution byextraction into basic aqueous solution and is isolated after acid is added tothe solution

Phenol Acidity


103/328

103

These 2 Kekulstructures are

equivalent

HH

OO O O

H

O

These three contrib uting s tructuresdelocalize the negative chargeonto carbon atoms of the rin g

H

OO O O

H

O

The greater acidity of phenols compared with alcohols is due to the

greater stability of the phenoxide ion relative to an alkoxide ion.

Substituted Phenols


104/328

104

Can be more or less acidic than phenol itself

An electron-withdrawing substituent makes a phenol more acidic by

delocalizing the negative charge

Phenols with an electron-donating substituent are less acidic because these

substituents concentrate the charge

pKa Values for Typical OH Compounds


105/328

105

Phenols. Reactions


106/328

106

no reaction+X RO-Na

+

OH CH2 =CHCH2 ClNaOH, H2 O, CH2 Cl 2

OCH2 CH=CH2

Phenyl 2-propenyl ether(Allyl phenyl ether)

+

Phenol 3-Chloropropene(Allyl chloride)

Phenols. Oxidation/Reduction


107/328

107

H2Cr O4

Phenol 1,4-Benzoquinone(p-Quinone)

O

O

OH

OH

OH K2Cr2 O7

OH

OH

H2 SO4

K2Cr2 O7

H2 SO4

O

O

O

O

1,4-Benzoquinone (p-Quinone)

1,2-Benzenediol (Catechol)

1,2-Benzoquinone (o-Quinone)

1,4-Benzenediol(Hydroquinone)

1,4-Benzoquinone(p-Quinone)

(reduction)

1,4-Benzenediol(Hydroquinone)

O

O

OH

OH

Na2 S2O4 , H2 O

Sodium dithionite

Chromic acid

Potassium dichromate

Preparation of Alcohols: an overview and review


108/328

108

Reactions of Alcohols


109/328

109

Two general classes of reaction

At the carbon of the CO bond

At the proton of the OH bond

Alcohols to alkoxides


110/328

110

Alcohols react with Li, Na, K, and other active metals to liberate hydrogen

gas and form metal alkoxides.

Alcohols are also converted to metal alkoxides by reaction with basesstronger than the alkoxide ion.

One such base is sodium hydride.

Sodium methoxide(MeO Na+)

+2 CH3 O Na + H22 CH3 OH + 2 Na

Ethanol Sodium ethoxide

CH3 CH2 OH CH3 CH2 O Na ++ + H2Na+ H

Sodiumhydride

Alcohols to alkyl halides


111/328

111

3 alcohols react very rapidly with HCl, HBr, and HI.

Low-molecular-weight 1 and 2 alcohols are unreactive under these

conditions. 1 and 2 alcohols require concentrated HBr and HI to form alkyl

bromides and iodides.

OH + H2 O+HCl25C

Cl

2-Methyl-2-propanol

2-Chloro-2-methylpropane

reflux1-Bromobutane1-Butanol

++ HBr H2 O

H2 O

OH Br

simple 1 alcohols react with HX by an SN2 mechanism.



112/328

112

2-Bromopentane3-Bromopentane(major product)

3-Pentanolheat

+ +HBr + H2 O

OH Br

Br

a product ofrearrangement

2-Bromo-2-methylbutane(a product of rearrangement)

2,2-Dimethyl-1-propanol

+ +HBr H2 OOHBr

reaction of 2 and 3 alcohols with HX occurs by an SN1 mechanism, and

involves a carbocation intermediate.

These alcohols react by a concerted loss of HOH and migration of an alkyl group.



113/328

113

An alternative method for the synthesis of 1 and 2 bromoalkanes is

reaction of an alcohol with phosphorus tribromide.

This method gives less rearrangement than with HBr.

PBr3 H3 PO30

Phosphorous

acid

+ +

2-Methyl-1-propanol(Isobutyl alcohol)

Phosphorus

tribromide

1-Bromo-2-methylpropane(Isobutyl bromide)

OH Br

BrO PBr2R-CH2

H

P BrBr

Br

R-CH2 -O-H + +

a good leaving group

+

Br- O PBr2R-CH2

H

R-CH2 -Br HO-PBr2+

++SN 2

Step 1:

Step 2:


Thion l chloride is the most idel sed reagent for the con ersion of 1 and 2


114/328

114

Step 1:

Step 2:

Thionyl chloride is the most widely used reagent for the conversion of 1 and 2

alcohols to alkyl chlorides.

A base, most commonly pyridine or triethylamine, is added to catalyze the

reaction and to neutralize the HCl.

OH

SOCl2

Cl

SO2 HCl+3 amine

+ +

(S)-2-Octanol Thionylchloride

(R)-2-Chlorooctane

C

R1

HR2

OH Cl-S-Cl

O

C

R1

H

R2

O S

O

ClH-Cl+ +

An alky l

chlorosulfite

C

R1

HR2

O S

O

ClCl +C

R1

HR2

Cl + Cl+ O S

OSN2

Alcohols to sulfonates


115/328

115

Alcohols to alkenes

A id t l d l h l d h d ti d lk h d ti ti


116/328

116

Tertiary alcohols are readily dehydrated with acid

Secondary alcohols require severe conditions (75% H2SO4, 100C) -sensitive molecules don't survive

Primary alcohols require very harsh conditions impractical

Reactivity is the result of the nature of the carbocation intermediate

An alkene An alcohol

C C C C

H OH

+ H2O

acidcatalyst

Acid-catalyzed alcohol dehydration and alkene hydration are competing processes.

Alcohols to alkenes

H2SO4


117/328

117

180CCH3 CH2OH

2 4CH2 = CH2 + H2 O

140C

Cyclohexanol Cyclohexene

OH

+ H2OH2SO4

CH3 COH

CH3

CH3

H2SO4CH3 C=CH2

CH3+ H2O

50C

2-Methyl-2-propanol

(tert- Butyl alcohol)2-Methylpropene

(Isobutylene)

Alcohols to alkenes

Where isomeric alkenes are possible the alkene having the greater


118/328

118

Where isomeric alkenes are possible, the alkene having the greater

number of substituents on the double bond (the more stable alkene)

usually predominates (Zaitsev rule).

1-Butene

(20%)

2-Butene

(80%)

2-Butanol

+

heat

8 5 % H3 PO4

CH3 CH=CHCH3

CH3 CH2CHCH3

CH3 CH2CH= CH2 + H2 O

OH

Alcohols to alkenes. Mechanism

Step 1: Proton transfer to the -OH group gives an oxonium ion.


119/328

119

Step 2: Loss of H2O gives a carbocation intermediate.

O

H O

H

H

O

O

H

H

H HH

+

+

rapid and

reversible

+

+

A 2 carbocation

intermediate

O

H H+ slow, rate

determining

H2 O+

Step 3: Proton transfer from a carbon adjacent to the positively charged carbon to water. The

sigma electrons of the C-H bond become the pi electrons of the carbon-carbon doublebond.

rapid andreversible

O

H

H

HH

+ + O

H

+

+ H H

Pinacol Rearrangement

OHHOO


120/328

120

H2 SO4 H2O

2,3-Dimethyl-2,3-butanediol

(Pinacol)

3,3-Dimethyl-2-butanone

(Pinacolone)

+

OHHO +

H

H HO+

rapid andreversible OHO

+ H

H

O

HH

An oxonium ion

OHO HH

HO

+ H2O

A 3ocarbocationintermediate

A resonance-stabilized cation intermediate

OH

OH

OH

++

+

OH

H2 O + O

+H3 O+

1 2

3

4

Oxidation of Alcohols

Can be accomplished by inorganic reagents, such as KMnO4, CrO3,


121/328

121

p y g g 4 3and Na2Cr2O7 or by more selective, expensive reagents

Oxidation of Primary Alcohols

To aldehyde: pyridinium chlorochromate (PCC


122/328

122

To aldehyde: pyridinium chlorochromate (PCC,

C5H6NCrO3Cl) in dichloromethane

Other reagents produce carboxylic acids

Oxidation of Secondary Alcohols

Effective with inexpensive reagents such as Na2Cr2O7 (sodium


123/328

123

Effective with inexpensive reagents such as Na2Cr2O7 (sodiumdichromate) in acetic acid

PCC is used for sensitive alcohols at lower temperatures

Mechanism of Chromic Acid Oxidation

Alcohol forms a chromate ester followed by elimination with electron transfer


124/328

124

to give ketone

The mechanism was determined by observing the effects of isotopes on rates

Mechanism of Chromic Acid Oxidation

Chromic acid oxidizes a 1 alcohol first to an aldehyde and then to a


125/328

125

O

R-C-H H2 O H2 CrO4 R-C-OH

O-CrO3 H

HH2 O

R-C-OH

OH

H

R-C-OH

O

HCrO3-

+

An aldehyde An aldehyde hydrate

fast andreversible

A carboxylicacid

+ H3 O++

Chromic acid oxidizes a 1 alcohol first to an aldehyde and then to a

carboxylic acid.

In the second step, it is not the aldehyde per se that is oxidized but

rather the aldehyde hydrate.

Oxidation of diol

OH

+ HIOCHO

+ HIO3


126/328

126

OH

+ HIO4 CHO+ HIO3

cis- 1,2-Cyclo-hexanediol

HexanedialPeriodicacid

Iodicacid

A cyclic periodate

+C

C

OH

OH IO

OOC

CO

OO

O

IOH OH+ H

2O

OC

C O

I

O

OH

O

C O

C O

O

O

I OH+OC

C O

I

O

OH

O

C O

C O

O

O

I OH+

Step 1

Step 2

Protection of Alcohols

Hydroxyl groups can easily transfer their proton to a basic reagent


127/328

127

This can prevent desired reactions

Converting the hydroxyl to a (removable) functional group without an

acidic proton protects the alcohol

Si Cl

Me

Me

Me

Si Cl

Me

Me

Si ClSi Cl

Et

Et

Et

Trimethylsilylchloride(TMSCl)

t -Butyldimethylsilylchloride

(TBDMSCl)

Triisopropylsilylchloride(TIPSCl)

Triethylsilylchloride(TESCl)

Methods to Protect Alcohols

Reaction with chlorotrimethylsilane in the presence of base yields an unreactivetrimethylsilyl (TMS) ether


128/328

128

trimethylsilyl (TMS) ether

The ether can be cleaved with acid or with fluoride ion to regenerate the alcohol

Protection-Deprotection

An example of TMS-alcohol protection in a synthesis


129/328

129

Protection-Deprotection

Another example of TMS-alcohol protection in a synthesis


130/328

130

OH

H

O

H2. Na

+NH2

-

3. Br

4-Heptyn-1-ol

4-Pentyn-1-ol

Si

OSi CH3OH

+

1 . ( CH3 )3 SiCl

CH3CH3

CH3

CH3

CH34. Bu4 N

+F

-

FSi CH3CH3

CH3


131/328

131

11. Ethers and Epoxides;

Thiols and Sulfides

Ethers and Their Relatives

An ether has two organic groups (alkyl, aryl, or vinyl) bonded to the sameoxygen atom, ROR


132/328

132

Diethyl ether is used industrially as a solvent

Tetrahydrofuran (THF) is a solvent that is a cyclic ether

Thiols (RSH) and sulfides (RSR) are sulfur (for oxygen) analogs ofalcohols and ethers

Naming Ethers

Simple ethers are named by identifying the two organic substituents

and adding the word ether


133/328

133

and adding the word ether

If other functional groups are present, the ether part is considered an

alkoxy substituent

Physical properties

Boiling points of ethers are

lower than alcohols of comparable MW.


134/328

134

p

close to those of hydrocarbons of comparable MW.

Ethers are hydrogen bond acceptors. They are more soluble in H2O than are hydrocarbons.

Preparation: The Williamson Ether Synthesis

Reaction of metal alkoxides and primary alkyl halides and tosylates

Best method for the preparation of ethers


135/328

135

Best method for the preparation of ethers

Alkoxides prepared by reaction of an alcohol with a strong base such as

sodium hydride, NaH

Preparation: Acid-catalyzed dehydration of alcohols

2CH3CH2 OHH2SO4140C

CH3CH2OCH2CH3 H2 O+


136/328

136

3 2 140C 3 2 2 3 2Ethanol Diethyl ether

CH3CH2 -O-H

O

O

H-O-S-O-H CH3CH2 -O-H

H O

O-

O-S-O-H+

+

An oxonium ion

+

fast andreversible

CH3 CH2 -O-H CH3 CH2 -O-H

H

SN2

H

CH3 CH2 -O-CH2 CH3

H

O-H

A new oxonium ion

++

++

1

2

Preparation:Acid-catalyzed addition of alcohols to alkenes

+

acidcatalyst

CH3 CH3

CH3 C=CH2 CH3 OH CH3 COCH3


137/328

137

1

2

2-Methoxy-2-methylpropane

CH3

3 3 3 3

CH3

CH3 C=CH2 H O

H

CH3

CH3

CH3 CCH3 O

H

CH3++

+

+

CH3 CCH3

CH3

HOCH3O

CH3 CCH3

H

CH3

CH3

++

+

Preparation: Alkoxymercuration of Alkenes

React alkene with an alcohol and mercuric acetate or trifluoroacetate

Demercuration with NaBH4 yields an ether


138/328

138

4 y

Overall Markovnikov addition of alcohol to alkene

Reactions of Ethers:Acidic Cleavage

Ethers are generally unreactive

Strong acid will cleave an ether at elevated temperature


139/328

139

HI, HBr produce an alkyl halide from less hindered component by SN2(tertiary ethers undergo S

N1)

Reactions of Ethers: Claisen rearrangement


140/328

140

Claisen Rearrangement Mechanism

Concerted pericyclic 6-electron, 6-membered ring transition state

Mechanism consistent with 14C labelling


141/328

141

Cyclic Ethers: Epoxides

Cyclic ethers behave like acyclic ethers, except if ring is 3-membered


142/328

142

Oxirane(Ethylene oxide)

Oxolane(Tetrahydrofuran)

Oxane(Tetrahydropyran)

1,4-Dioxane

OO1

2 3

O

O

OO

Oxetane

Although cyclic ethers have IUPAC names, their common names are more

widely used.

IUPAC: prefix ox- shows oxygen in the ring.

The suffixes -irane, -etane, -olane, and -ane show three, four, five, and

six atoms in a saturated ring.

Epoxides (Oxiranes)

Three membered ring ether is called an oxirane (root ir from tri for 3-membered; prefix ox for oxygen; ane for saturated)

Also called epoxides


143/328

143

p

Ethylene oxide (oxirane; 1,2-epoxyethane) is industrially important as an

intermediate Prepared by reaction of ethylene with oxygen at 300 C and silver oxide

catalyst

Na+

CN-

CH3 NH2

C C-Na

+CH3

OH

ON

OH

CH3H

N COH

N OCH3

O

H2 SO4

H2 / M

N

OH

CH3

OH

N N-HCH3

OH

H2 N

SOCl2

NH3

N

Cl

CH3

Cl

(1)(2)

(3) (4) (6)

(8)(5) (7)

Preparation of Epoxides Using a Peroxyacid

Treat an alkene with a peroxyacid: Stereospecific


144/328

144

Epoxides from Halohydrins

Addition of HO-X to an alkene gives a halohydrin

Treatment of a halohydrin with base gives an epoxide


145/328

145

Intramolecular Williamson ether synthesis

Ring-Opening Reactions of Epoxides

Water adds to epoxides with dilute acid at room temperature

Product is a 1,2-diol (on adjacent Cs: vicinal)

Mechanism: acid protonates oxygen and water adds to opposite side


146/328

146

p yg pp(trans addition)

Regiochemistry of Acid-Catalyzed Opening of Epoxides

Nucleophile preferably adds to less hindered site if primary and secondary Cs

Also at tertiary because of carbocation character


147/328

147

Nucleophilic Epoxide Opening

Strain of the three-membered ring is relieved on ring-opening

Hydroxide cleaves epoxides at elevated temperatures to give trans 1,2-diols


148/328

148

Adds CH2CH2OH to the Grignard reagents hydrocarbon chain

Acyclic and other larger ring ethers do not react

Nucleophilic Epoxide Opening

Treatment of an epoxide with lithium aluminum hydride, LiAlH4, reduces the

epoxide to an alcohol.

The nucleophile attacking the epoxide ring is hydride ion H:-


149/328

149

The nucleophile attacking the epoxide ring is hydride ion, H:

Phenyloxirane(Styrene oxide)

1-Phenylethanol

CH2

O

CH

OH

1 . L iA lH4

2 . H2 OCH-CH3

Crown Ethers

Complexes between crown ethers and ionic salts are soluble in nonpolarorganic solvents

Creates reagents that are free of water that have useful properties


150/328

150

Inorganic salts dissolve in organic solvents leaving the anionunassociated, enhancing reactivity

Thiols and Sulfides

Thiols (RSH), are sulfur analogs of alcohols Named with the suffix -thiol

SH i ll d t ( t f )


151/328

151

SH group is called mercapto group (capturer of mercury)

Sulfides

Sulfides (RSR), are sulfur analogs of ethers

Named by rules used for ethers, with sulfide in


152/328

152

place of etherfor simple compounds and alkylthioin place of alkoxy

Thiolates (RS) are formed by the reaction of a thiol with a base

Thiolates react with primary or secondary alkyl halide to give sulfides (RSR)

Thiolates are excellent nucleophiles and react with many electrophiles

Thiols: Formation and Unique Reactions


153/328

153

Spectroscopy of Ethers

Infrared: CO single-bond stretching 1050 to 1150cm1 overlaps many other absorptions.

Proton NMR: H on a C next to ether O are shifted


154/328

154

Proton NMR: H on a C next to ether O are shifted

downfield to 3.4 to 4.5 The 1H NMR spectrum of dipropyl ether shows the

these signals at 3.4

In epoxides, these Hs absorb at 2.5 to 3.5 d intheir 1H NMR spectra

Carbon NMR: Cs in ethers exhibit a downfield shiftto 50 to 80

16.Aldehydes and Ketones

Aldehydes and ketones are characterized by the the carbonyl functional group

(C=O)

The compounds occur widely in nature as intermediates in metabolism and


155/328

155

biosynthesis

They are also common as chemicals, as solvents, monomers, adhesives,

agrichemicals and pharmaceuticals

The carbonyl group consists of

one sigma bond formed by the

overlap of sp2 hybrid orbitals

and one pi bond formed by the

overlap of parallel 2p orbitals

Naming Aldehydes

Aldehydes are named by replacing the terminal -e of the corresponding alkanename with al

The parent chain must contain theCHO group

The CHO carbon is numbered as C1


156/328

TheCHO carbon is numbered as C1

H

O

3-Methylbutanal 2-Propenal(Acrolein)

(2E)-3,7-Dimethyl-2,6-octadienal(Geranial)

1

2

3

4

5

6

7

8H

O

H

O

CHOC6 H5CHO

t rans-3-Phenyl-2-propenal(Cinnamaldehyde)

Benzaldehyde

The IUPAC naming retains the

common names benzaldehyde and

cinnamaldehyde, as well

formaldehyde and acetaldehyde.

Naming Ketones

Replace the terminal -e of the alkane name with one

Parent chain is the longest one that contains the ketone group

Numbering begins at the end nearer the carbonyl carbon


157/328

157

Propanone(Acetone)

Benzophenone 1-Phenyl-1-pentanoneAcetophenone

O O OO

The IUPAC retains the common names acetone, acetophenone, and benzophenone.

Ketones and Aldehydes as Substituents

The RC=O as a substituent is an acyl group is used with the suffix -yl fromthe root of the carboxylic acid

CH3CO: acetyl; CHO: formyl; C6H5CO: benzoyl

The prefix oxo is used if other functional groups are present and the doubly


158/328

158

The prefix oxo- is used if other functional groups are present and the doubly

bonded oxygen is labeled as a substituent on a parent chain

Order of Precedence

For compounds that contain more than one functional group indicated by a suffix.

FunctionalExample w hen thefunctional group h as

Suffix if

higherPref ix iflower


159/328

159

H COOH

O

COOH

O

COOHHO

OHHS

COOH

NH2

Functional

Group

Carb oxyl -oic acid

Aldehyde -al oxo-

Ketone -one oxo-

Alcohol -ol hydroxy-

Amino -amine amino-

3-Oxopropanoicacid

3-Oxobutanoic acid

4-Hydroxybutanoicacid

3-Aminobutanoicacid

functional group h as

a lower priority

Sulfhydryl -thiol mercapto 2-Mercaptoethanol

g e

priority

owe

priority

Increasing precedence

Physical Properties

Oxygen is more electronegative than carbon (3.5 vs 2.5) and, therefore, a

C=O group is polar.

-+ +

C O +

C O


160/328

160

C O C O

More importantcontributing

structure

C O C O C O

Polarity ofa carbonyl

group

C O

Aldehydes and ketones are polar

compounds and interact in the pure

state by dipole-dipole interaction.

They have higher boiling points and

are more soluble in water thannonpolar compounds of comparable

molecular weight.

Spectroscopy of Aldehydes and Ketones

Infrared Spectroscopy

Aldehydes and ketones show a strong C=O peak 1660 to 1770 cm1

aldehydes show two characteristic CH absorptions in the 2720 to 2820cm1 range.


161/328

161

NMR Spectra of Aldehydes

Aldehyde proton signals are at 10 in 1H NMR - distinctive spinspincoupling with protons on the neighboring carbon, J 3 Hz

Slightly deshielded and normally absorb near 2.0 to 2.3

Methyl ketones always show a sharp three-proton singlet near 2 1


162/328

162

Methyl ketones always show a sharp three-proton singlet near 2.1

13C NMR of C=O

C=O signal is at 190 to 215

No other kinds of carbons absorb in this range


163/328

163

Mass Spectrometry

Aliphatic aldehydes and ketones that have hydrogens on their gamma ()carbon atoms rearrange as shown


164/328

164

Cleavage of the bond between the carbonyl group and the carbon

Yields a neutral radical and an oxygen-containing cation

Preparing Ketones/Aldehydes

pyridinium chlorochromate

(PCC, C5H6NCrO3Cl)


165/328

165

Oxidation of Aldehydes


166/328

166

Silver oxide, Ag2O, in aqueous ammonia (Tollens reagent) oxidizes

aldehydes (no acid)

Oxidation of Aldehydes

Aldehydes are oxidized by O2 in a radical chain reaction.

Liquid aldehydes are so sensitive to air that they must be stored under N2.


167/328

167

Benzoic acidBenzaldehyde

+CH

O O

COH2O22

Undergo slow cleavage with hot, alkaline KMnO4

CC bond next to C=O is broken to give carboxylic acids

Reaction is practical for cleaving symmetrical ketones

Oxidation of Ketones


168/328

168

Reduction: WolffKishner Reaction

Treatment of an aldehyde or ketone with hydrazine, H2NNH2 and KOHconverts the compound to an alkane

Originally carried out at high temperatures but with dimethyl sulfoxide assolvent takes place near room temperature


169/328

169

Reduction: Clemmensen Reaction

Refluxing an aldehyde or ketone with amalgamated zinc in concentratedHCl converts the carbonyl group to a methylene group.


170/328

170

Zn(Hg), HCl

OH O OH

Cannizzaro Reaction

The adduct of an aldehyde and OH can transfer hydride ion to anotheraldehyde C=O resulting in a simultaneous oxidation and reduction(disproportionation)


171/328

171

Reduction with Hydrogen

+25 oC, 2 atm

Pt

CyclohexanoneC l h l

O OH

H21-Butanoltrans- 2-Butenal

(C t ld h d )

2 H2

NiH

O

OH


172/328

172

Cyclohexanol

By careful choice of experimental conditions, it is often possible to

selectively reduce a carbon-carbon double in the presence of an

aldehyde or ketone.

O OH

RCH=CHCR' RCH=CHCHR'1. NaBH4

2. H2O

ORCH=CHCR' H2

RhRCH2 CH2CR'

O+

(Crotonaldehyde)

Reduction with Hydride

Convert C=O to CH-OH

LiAlH4 and NaBH4 react as donors of hydride ion

Protonation after addition yields the alcohol


173/328

173

Hydride ionLithium aluminum

hydride (LAH)

Sodium

borohydride

H

H H

H

H-B-H H-Al-HLi +Na+

H:

Summary

Preparing Ketones/Aldehydes

from alcohols, alkenes, alkynes, and aromatics/RCOCl

Reactions of Ketones/Aldehydes:


174/328

174

Reactions of Ketones/Aldehydes:[O]: common for aldehydes (CrO3, or Tollens reagent, air, but uncommon for

ketones unless KMnO4/OH-)

[H]: (a) completely remove O: Wolff-Kishner, Clemmensen

(b) interesting self-oxidation: Cannizzaro

(c) increase # of H by using H2 (w/ help of transition metal catalyst) or H-Addition reactions (some also belong to [H])Relative Reactivity of Aldehydes and Ketones

Tetrahedral carbonyl

addition compound

+ C

R

R

O CNu

O -

RR

Nu -

Reaction Themes

One of the most common reaction themes of a carbonyl group is addition of a

nucleophile to form a tetrahedral carbonyl addition compound.

+ C

R

O CNu

O -

RNu

-


175/328

175

Tetrahedral carbonyladdition compound

+ CR

O CNu RR

Nu

Often the tetrahedral product of addition to a carbonyl group is a new chiral center.

If none of the starting materials is chiral and the reaction takes place in an achiralenvironment, then enantiomers will be formed as a racemic mixture.

Nu-

C O

R

R'

Nu

OR'

R

Nu

OR

R'

+

H3 O+

Nu

OHR

R'

Nu

OHR'

R+

A racemic mixtureA new chiral

center is created

Approach from

the bottom face

Approach from

the top face

Relative Reactivity of Aldehydes and Ketones

Aldehydes are generally more reactive than ketones in nucleophilic addition reactions

The transition state for addition is less crowded and lower in energy for an aldehyde (a)than for a ketone (b)

Aldehydes have one large substituent bonded to the C=O: ketones have two


176/328

176

Aldehyde C=O is more polarized than ketone C=O

As in carbocations, more alkyl groups stabilize + character

Ketone has more alkyl groups, stabilizing the C=O carbon inductively

Relative Reactivity of Aldehydes and Ketones


177/328

177

Reactivity of Aromatic Aldehydes

Less reactive in nucleophilic addition reactions than aliphatic aldehydes

Electron-donating resonance effect of aromatic ring makes C=O less reactiveelectrophilic than the carbonyl group of an aliphatic aldehyde


178/328

178

Addition of C Nucleophiles

Addition of carbon nucleophiles is one of the most important types of

nucleophilic additions to a C=O group.

A new carbon-carbon bond is formed in the process.

We study addition of these four types of carbon nucleophiles


179/328

179

We study addition of these four types of carbon nucleophiles.

RMgX RLi -

CRC C-

N

A Grignardreagent

An organolithiumreagent

An alkyneanion

Cyanide ion

Carbanion:An anion in which carbon has an unshared pair of

electrons and bears a negative charge.

A carbanion is a good nucleophile and adds readily to the

carbonyl group of aldehydes and ketones.

Nucleophilic Addition of Grignard Reagents and

Hydride Reagents: Alcohol Formation

Treatment of aldehydes or ketones with Grignard reagents yields an

alcohol


180/328

180

Given the difference in electronegativity between carbon and magnesium (2.5 -

1.3), the C-Mg bond is strongly polarized, so a Grignard reagent reacts for all

practical purposes as R : MgX +.

In its reactions, a Grignard reagent behaves as a carbanion.

Grignard Reaction: examples

CH3 CH2-MgBr

O

H-C-H

O - [MgBr ]+ OH

ether

Formaldehyde

+


181/328

181

O [MgBr]

CH3 CH2-CH2HCl

H2O

OH

CH3 CH2-CH2 Mg2+

1-Propanol

(a 1 alcohol)

+

A magnesium

alkoxide

Ph-MgBrO

Ph

O - [ MgBr ]+ HCl

H2O Ph

OHMg2+

+

Acetone

(a ketone)

ether

+

A magnesium

alkoxide

2-Phenyl-2-propanol

(a 3 alcohol)

Phenyl-

magnesium

bromide

Addition with other reagents

Li O

O-

Li+

HCl

H2O

OH

3,3-Dimethyl-2- butanone 3,3-Dimethyl-2-phenyl-2-butanol

+

Phenyl-lithium A lithium alkoxide(racemic)


182/328

182

(racemic)lithium (racemic)

C:-

Na+

HC

OC O -Na+HC

HCl

H2O

C OHHC

1-Ethynyl-cyclohexanol

A sodiumalkoxide

+

CyclohexanoneSodium

acetylide

Review: Hydration ofTerminal Alkynes

2-Hydroxypropanenitrile(Acetaldehyde cyanohydrin)

+ HC N CH3 C-C NCH3 CH

OH

H

O

Wittig ReactionThe Wittig reaction is a very versatile

synthetic method for the synthesis of

alkenes from aldehydes and ketones.

Triphenyl-phosphine oxide

Methylene-cyclohexane

A phosphoniumylide

++-+

CH2 Ph3P=OPh3 P-CH2

Cyclohexanone

O


183/328

183

Phosphonium ylides are formed in two steps:

Step 1: Nucleophilic displacement of iodine by triphenylphosphine.

Step 2: Treatment of the phosphonium salt with a very strong base, most

commonly BuLi, NaH, or NaNH2.


184/328

Wittig Reaction and modification

HPh

O

Ph3 P Ph Ph Ph3 P= O

Phenyl-

acetaldehyde

+ +

(Z)-1-Phenyl-2-

butene

(87%)

(E)-1-Phenyl-2-

butene

(13%)

+

O O O


185/328

185

HPh

O

+ OEtPh3 P

O

PhOEt

O

Ph3 P= O

Ethyl (E)-4-phenyl-2-butenoate

(only the E isomer is formed)

+

Phenyl-

acetaldehyde

Horner-Emmons-Wadsworth modification

( MeO)2 P-CH2 -C-OEt

OO

O

H

OEt

O

MeO-P-O-

O

OMe

1. strong base

2.Only theEisomer

is formed

+

Dimethylphosphate

anion

Reaction Themes

Nu-

C OR

R'

NuO

R'R

Nu

OR

R'+

H3 O+

Nu

OHR

R'

NuOH

R'R

+

Approach from

Approach from

the top face


186/328

186

A racemic mixtureA new chiral

center is created

Approach from

the bottom face

RMgX RLi -

CRC C-

N

A Grignardreagent

An organolithiumreagent

An alkyneanion

Cyanide ion

Triphenyl-phosphine oxide

Methylene-cyclohexane

A phosphoniumylide

++-+

CH2 Ph3P=OPh3 P-CH2

Cyclohexanone

O

O H-OEtOH

OEt+

acid orbase

A hemiacetalOH

OEtH-OEt

H+

OEt

OEtH2O

A diethyl acetal

+

A hemiacetal

+


187/328

Role of Acid or Base

The base-catalyzed

hydration nucleophile is the

hydroxide ion, which is a

much stronger nucleophile

than water


188/328

188

Protonation of C=O makes it

more electrophilic


189/328

Fischer Projection and Mutarotation


190/328

190

In solution, -D-glucose is in equilibrium with -D-glucose. Mutarotation involves the conversion of the cyclic anomers into the open chain.

At any time, there is only a small amount of open chain.

-D-glucose D-glucose (open) -D-glucose(36%) (trace) (64%)

Fischer Projection and Mutarotation

A Fischer

projection: Is a 2-dimensional

representation of a 3-

dimensional

molecule. Places the most

oxidized group at the


191/328

191

oxidized group at the

top.

Uses vertical lines in

place of dashes for

bonds that go back.

Uses horizontal linesin place of wedges

for bonds that come

forward.

Addition of alcohol to C=O:

hemiacetal and acetal

Hemiacetals react with alcohols to form acetals.

Acetal:A molecule containing two -OR or -OAr groups bonded to the same

carbon.OH

OEt

H-OEt H

+OEt

OEt

H2O

A diethyl acetal

+

A hemiacetal

+


192/328

192

y

HO

R-C-OCH3

H

H A

HHO

H

R-C-OCH3 A:-

+

An oxonium ion

+

+

R-C OCH3

H

OHH

H

R-C OCH3 R-C

H

OCH3 H2 O+

A resonance-stabilized cation

++

+

Step 1: Proton transfer from HA gives an oxonium ion.Step 2: Loss of water gives a resonance-stabilized cation .

CH3 -OHH

R-C OCH3 R-C OCH3H

OCH3H

A p rotonated acetal

+

+

+

A:

-

R-C OCH3H

OCH3H OCH3

HR-C-OCH3 H-A+

(4)

An acetal

+

+

Step 3: Reaction of the cation (an electrophile) withmethanol (a nucleophile) gives the conjugate acid of the

acetal.

Step 4: Proton transfer to A- gives the acetal andgenerates a replacement acid catalyst.

Uses of Acetals As Protecting Groups

Acetals can serve as protecting groups for aldehydes and ketones

It is convenient to use a diol, to form a cyclicacetal (the reaction goes

even more readily)


193/328

193

Uses of Acetals As Protecting Groups

H+THP group

Tetrahydropyranyl (THP) protecting group.


194/328

194

RCH2 OH +

OO RCH2 O

Dihydropyran A tetrahydropyranylether

H

The THP group is an acetal and, therefore, stable to neutral and basic

solutions, and to most oxidizing and reducing agents.

It is removed by acid-catalyzed hydrolysis.

Nucleophilic Addition of Amines:

Imine and Enamine Formation

RNH2 adds to C=O to form imines, R2C=NR (after loss of HOH)

R2NH yields enamines, R2NCR=CR2 (after loss of HOH)

(ene + amine = unsaturated amine)


195/328

195

Nucleophilic Addition of Amines:

Imine and Enamine Formation

Formation of an imine occurs in two steps:

Step 1: Carbonyl addition followed by proton transfer.

CO

H2N-R

H

C

O:-

N-RO

H

N-RC++


196/328

196

Step 2: Loss of H2O and proton transfer to solvent.

H H

O H

H

H H

C

O H

N-R N-R

H

C

OHH

O

H

H

C N-R OH

H

H An imine

+

+

++

++H2 O

Conjugate Nucleophilic Addition to ,-

Unsaturated Aldehydes and Ketones

A nucleophilecan add to theC=C doublebond of an,-

unsaturatedaldehyde orketone


197/328

197

(conjugateaddition, or 1,4addition)

The initialproduct is aresonance-stabilizedenolate ion,

which is thenprotonated


198/328

Conjugate Addition of Alkyl Groups:Organocopper Reactions

Reaction of an , -unsaturated ketone with a lithium diorganocopperreagent

Diorganocopper (Gilman) reagents from by reaction of 1 equivalent ofcuprous iodide and 2 equivalents of organolithium

1, 2, 3 alkyl, aryl and alkenyl groups react but not alkynyl groups


199/328

199

The carbon next to the carbonyl group is designated as being in the position

Electrophilic substitution occurs at this position through either an enolorenolate ion

Reaction Theme 2: The Position


200/328

200

Tautomers Are Not Resonance Forms

Enols

The enol tautomer is usually present to a very small extent and cannot be isolated

However, it can serve as a reaction intermediate


201/328

201

Acid OR Base Catalysis of Enolization


202/328

202

O

Ph

OH

Ph

O

Ph

An achiralenol

(R)-3-Phenyl-2-butanone

(S)-3-Phenyl-2-butanone


203/328

Acidity of Alpha Hydrogen Atoms:

Enolate Ion Formation

Carbonyl compounds canact as weak acids (pKa ofacetone = 19.3; pKa of

ethane = 60)

The conjugate base of a


204/328

204

The conjugate base of aketone or aldehyde is anenolate ion - the negative

charge is delocalized ontooxygen

Reagents for Enolate Formation

Ketones are weaker acids than the OH of alcohols so a a more powerful

base than an alkoxide is needed to form the enolate

Sodium hydride (NaH) or lithium diisopropylamide [LiN(i-C3H7)2] are strong

enough to form the enolate

LDA is from butyllithium (BuLi) and diisopropylamine (pKa 40)

Not nucleophilic


205/328

205

ot uc eop c


206/328

Halogenation of Enolate Ions: The

Haloform Reaction Base-promoted reaction occurs through an enolate ion intermediate


207/328

207

Application:


208/328

Alkylation of Enolate Ions

Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic

alkyl halide or tosylate and displaces the leaving group


209/328

209

SN2 reaction:, the leaving group X can be chloride, bromide, iodide, ortosylate

R should be primary or methyl and preferably should be allylic or benzylic

Secondary halides react poorly, and tertiary halides don't react at allbecause of competing elimination

-Dicarbonyls Are More Acidic

When a hydrogen atom is flanked by two carbonyl groups, its acidity is

enhanced

Negative charge of enolate delocalizes over both carbonyl groups


210/328

210

Condensation Reactions

Carbonyl compounds are both the electrophile and nucleophile in

carbonyl condensation reactions


211/328

211

Condensations of Aldehydes and Ketones:

The Aldol Reaction

Acetaldehyde reacts in basic solution (NaOEt, NaOH) with another moleculeof acetaldhyde

The -hydroxy aldehyde product is aldol(aldehyde + alcohol)

This is a general reaction of aldehydes and ketones


212/328

212

The aldol reaction is reversible, favoring the condensation product only

for aldehydes with no substituent

Steric factors are increased in the aldol product

Aldehydes and the Aldol Equilibrium

organic chemistry 2 notes

Documents