organic chemistry 2 notes
TRANSCRIPT
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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
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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.
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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
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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
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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
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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
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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
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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
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Organometallic Coupling Reactions
RLi reacts with copper iodide to give lithium dialkylcopper (Gilmanreagents)
Lithium dialkylcopper reagents react with alkyl halides to give alkanes
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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
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20. Conjugated Dienes and
Ultraviolet Spectroscopy
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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
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Measuring Stability From heats of hydrogenation, we can compare relative stabilities of conjugated
and unconjugated dienes.
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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
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Electrophilic Additions to Conjugated Dienes:
Allylic Carbocations
Review: Markovnikov regiochemistry via more stable carbocation
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Carbocations from Conjugated Dienes
Addition of H+ leads to delocalized secondary allylic carbocation
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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.
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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
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Stereochemistry of the Diels-Alder Reaction
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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
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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)
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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
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21. Benzene and Aromaticity
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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
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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
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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.
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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
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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
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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
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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
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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
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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.
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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.
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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
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If it is conjugated planar comformation
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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
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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+
+
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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
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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
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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
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Naphthalene Orbitals Three resonance forms and delocalized electrons
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Naming Aromatic Compounds Many common names are retained.
Toluene CumeneEthylbenzene Styrene
Phenol Aniline Benzoic acid Anisole
COOHNH2 OCH3OH
Benzaldehyde
CHO
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Naming Aromatic Compounds Monosubstituted benzenes systematic names as hydrocarbons with
benzene
C6H5Br = bromobenzene C6H5NO2 = nitrobenzene, and C6H5CH2CH2CH3 is propylbenzene
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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
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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)
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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)
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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
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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
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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
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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
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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
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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
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22. Chemistry of Benzene:
Electrophilic Aromatic Substitution
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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
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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
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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?
1: Electrophilic substitution
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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
1: Electrophilic substitution
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Bromination of Aromatic Rings
1: Electrophilic substitution
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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
1: Electrophilic substitution
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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:
1: Electrophilic substitution
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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
1: Electrophilic substitution
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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
1: Electrophilic substitution
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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
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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
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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+
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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
1: Electrophilic substitution
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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
1: Electrophilic substitution
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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
1: Electrophilic substitution
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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
1: Electrophilic substitution
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Meta-Directing Deactivators Inductive and resonance effects reinforce each other
Ortho and para intermediates destabilized by deactivation from carbocationintermediate
Resonance cannot produce stabilization
1: Electrophilic substitution
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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
1: Electrophilic substitution
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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
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Summary Table: Effect of Substituents in
1: Electrophilic substitution
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Aromatic Substitution
Important Application
1: Electrophilic substitution
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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
1: Electrophilic substitution
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y
If the directing effects of the two groups are the same, the result is additive
Substituents with Opposite Effects
1: Electrophilic substitution
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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
1: Electrophilic substitution
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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
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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
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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
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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
3: Benzyne intermediated substitution
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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
3: Benzyne intermediated substitution
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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
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Reactions at the Benzylic position:
Oxidation
Halogenation
Hydrogenolysis
E+ = X+ N+ S+ C+
Mechanism #1: Mechanism #2: SNAr
Mechanism #3:
Benzylic Oxidation
Reactions at the Benzylic posit ion:
Oxidation
Halogenation
Hydrogenolysis
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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
Reactions at the Benzylic posit ion:
Oxidation
Halogenation
Hydrogenolysis
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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
Reactions at the Benzylic posit ion:
Oxidation
Halogenation
Hydrogenolysis
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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
Reactions at the Benzylic posit ion:
Oxidation
Halogenation
Hydrogenolysis
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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
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Chapter 10
Alcohols and Phenols
Alcohols and Phenols
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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
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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
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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
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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
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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
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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
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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
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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
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Weakly basic and weakly acidic
Alcohols are weak Brnsted bases
Protonated by strong acids to yield oxonium ions, ROH2+
Acidity of Alcohols
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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
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Electron-withdrawing groups make an alcohol a stronger acid by stabilizing
the conjugate base (alkoxide)
Phenol Acidity
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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
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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
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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
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Phenols. Reactions
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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
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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
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Reactions of Alcohols
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Two general classes of reaction
At the carbon of the CO bond
At the proton of the OH bond
Alcohols to alkoxides
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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
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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.
Alcohols to alkyl halides
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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.
Alcohols to alkyl halides
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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:
Alcohols to alkyl halides
Thion l chloride is the most idel sed reagent for the con ersion of 1 and 2
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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
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Alcohols to alkenes
A id t l d l h l d h d ti d lk h d ti ti
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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
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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
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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.
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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
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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,
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p y g g 4 3and Na2Cr2O7 or by more selective, expensive reagents
Oxidation of Primary Alcohols
To aldehyde: pyridinium chlorochromate (PCC
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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
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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
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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
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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
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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
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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
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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
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Protection-Deprotection
Another example of TMS-alcohol protection in a synthesis
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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
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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
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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
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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.
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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
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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+
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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
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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
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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
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HI, HBr produce an alkyl halide from less hindered component by SN2(tertiary ethers undergo S
N1)
Reactions of Ethers: Claisen rearrangement
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Claisen Rearrangement Mechanism
Concerted pericyclic 6-electron, 6-membered ring transition state
Mechanism consistent with 14C labelling
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Cyclic Ethers: Epoxides
Cyclic ethers behave like acyclic ethers, except if ring is 3-membered
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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
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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
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Epoxides from Halohydrins
Addition of HO-X to an alkene gives a halohydrin
Treatment of a halohydrin with base gives an epoxide
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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
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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
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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
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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:-
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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
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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 )
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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Mass Spectrometry
Aliphatic aldehydes and ketones that have hydrogens on their gamma ()carbon atoms rearrange as shown
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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)
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Oxidation of Aldehydes
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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.
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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
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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
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Reduction: Clemmensen Reaction
Refluxing an aldehyde or ketone with amalgamated zinc in concentratedHCl converts the carbonyl group to a methylene group.
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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)
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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
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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
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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:
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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
-
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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
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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
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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
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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
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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
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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
+
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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)
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(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
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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.
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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
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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
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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
+
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Role of Acid or Base
The base-catalyzed
hydration nucleophile is the
hydroxide ion, which is a
much stronger nucleophile
than water
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Protonation of C=O makes it
more electrophilic
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Fischer Projection and Mutarotation
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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
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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
+
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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)
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Uses of Acetals As Protecting Groups
H+THP group
Tetrahydropyranyl (THP) protecting group.
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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)
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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++
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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
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(conjugateaddition, or 1,4addition)
The initialproduct is aresonance-stabilizedenolate ion,
which is thenprotonated
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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
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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
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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
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Acid OR Base Catalysis of Enolization
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O
Ph
OH
Ph
O
Ph
An achiralenol
(R)-3-Phenyl-2-butanone
(S)-3-Phenyl-2-butanone
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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
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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
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ot uc eop c
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Halogenation of Enolate Ions: The
Haloform Reaction Base-promoted reaction occurs through an enolate ion intermediate
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Application:
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Alkylation of Enolate Ions
Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic
alkyl halide or tosylate and displaces the leaving group
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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
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Condensation Reactions
Carbonyl compounds are both the electrophile and nucleophile in
carbonyl condensation reactions
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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
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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
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