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Jones Oxidation. Because acyclic ketones are relatively stable to Cr(VI) oxidations,
acetone is frequently used as the solvent for Cr(VI) oxidations of alcohols. In these
reactions,
a CrO3/H2SO4/H2O mixture is slowly added to an acetone solution of the alcohol, or the
alcohol is mixed with an acetone solution of CrO3/H2SO4/H2O. Both the
CrO3/H2SO4/H2O
mixture and that mixture in acetone are called the Jones reagent while the resultant
oxidation
reaction is called a Jones oxidation.
Modified Cr(VI) Reagents are weaker oxidizing agents than the Jones reagent and
permit the formation of aldehydes without their subsequent oxidation to carboxylic
acids
5
This summary shows there are intermediate Cr(V) and Cr(IV) species,
and intermediate organic free radicals on the paths from alcohol to
ketone or aldehyde.
MnO2: This Mn(IV) reagent selectively oxidizes allylic and benzylic alcohols to ketones
Or aldehydes and the Mn(IV) is reduced to Mn(II).
6
OH groups that are not allylic or benzylic are not oxidized, and the aldehyde
products do not further oxidize to carboxylic acids.
Baeyer-Villiger rearrangement
Ketones to Esters
8
A key step is migration of the R' group with its bonding
electron pair from C to O (fourth
step).
9
This migration selectivity has synthetic utility. For example, we can convert compounds
of
the structure R-C(=O)-CH3 exclusively into the alcohols R-OH by the sequence of
reactions.
In contrast the facile migration ability of H transforms aldehydes R-C(=O)-H into the
corresponding carboxylic acids R-C(=O)-OH.
10
The key step is the transfer of an H with its bonding electron pair (a hydride transfer)
from
the intermediate anion to another molecule of aldehyde.
11
Both the alkoxide species (R2CHO-) and acetone are bonded to Al in an aluminum
trialkoxide molecule (Figure 17.027) formed by reaction of R2CHOH with a molecule
such as Al(O-C(CH3)3).
12
Oxidation of Carbon-Carbon Multiple Bonds
There are a variety of oxidation reactions in which C=C bonds add oxygen or
are cleaved to oxygenated products
13
These reactions give stereospecific syn addition of the two OH groups
Osmium tetratoxide gives excellent yields of 1,2-diols, but it is toxic (it causes
blindness) and
expensive. Potassium permanganate is inexpensive and safer to use, but it gives much
lower
yields of diols.
Formation of anti-1,2-Diols.
14
Cleavage Using Ozone (O3). The mechanism of the reaction between ozone (O3)
and an
alkene involves direct addition of O3 to give an unstable intermediate that decomposes
to an
ozonide intermediate
We do not isolate the ozonide (it usually is an explosive compound), but react it with
zinc
metal in acetic acid to give the product carbonyl compounds
Aldehyde products do not oxidize to carboxylic acids under these reaction conditions.
We obtain the highest yields of carbonyl compound products using KMnO4 dissolved in
benzene containing a Crown ether. It permits KMnO4 to dissolve in benzene by
solvating
15
the K+ ion
KMnO4 in basic solution yields 1,2-diols without cleavage of the original C=C bond.
These 1,2-diols are likely intermediates when we react CrO3, or KMnO4, with alkenes in
neutral or acidic solution.
However, under these reaction conditions they further oxidize to ketones and/or
aldehydes, and aldehydes further oxidize to carboxylic acids.
Cleavage of 1,2-Diols Using HIO4 or Pb(OAc)4. We can also oxidatively cleave C=C
bonds using the sequence of two reactions
The aldehyde products do oxidize further when they arise in reactions of alkenes with
the powerful oxidizing agents CrO3, or KMnO4 in neutral or acidic solution. These
reagents cleave the C=C bond, and oxidize each of the C=C carbons to the highest
oxidation state consistent with their substitution patterns
This sequence of two separate reactions gives high yields of relatively pure products in
each step. Once again, aldehydes are stable to further oxidation under these reaction
conditions.
16
Oxidation Using Singlet Oxygen.
Molecular oxygen (O2) in air is an oxidizing agent and one of its
oxidation reactions ("autoxidation") is oxidation of alkyl groups.
Atmospheric O2 exists in i) a "triplet" electronic state (3O2) (with an
unpaired electron on each O atom and acts as a free radical .O-O.).
ii) can also exist in a "singlet" electronic state (1O2) that has no
unpaired electrons.
We show three types of reactions of singlet oxygen with molecules
containing C=C bonds:-
17
Metal Oxide Oxidations :
Oxidizing agents include potassium permanganate (KMnO4), chromium trioxide
(CrO3),chromyl chloride (Cl2CrO2), and selenium dioxide (SeO2).
KMnO4 and CrO3. The strong oxidizing agents KMnO4 or CrO3 oxidize alkyl groups on
aromatic rings to carboxylic acid groups (directly attached to the ring) if there is at
least one H
on the C attached to the ring.
These reagents are so powerful that we limit their use to simple aromatic systems with
no
other oxidizable functional groups.
Cl2CrO2. In contrast, the milder oxidizing agent chromyl chloride (Cl 2CrO2)
oxidizes methyl groups on aromatic rings to aldehyde groups without
further oxidation to carboxylic acids.
SeO2 Oxidations. Even more selectively, selenium dioxide (SeO2) oxidizes allylic R
groups to alcohols, and benzylic R groups to alcohols or carbonyl compounds.
18
This reagent is particularly useful because it does not oxidize other functional groups
that
may be oxidized by KMnO4 or CrO3. For example, the double bonds in the allylic
systems
above are easily oxidized by either KMnO4 or CrO3 as we previously described, but are
stable to SeO2. SeO2 also selectively oxidizes CH2 groups attached () to carbonyl
groups
Formation of Phenols
It is difficult to directly add an OH group to a benzene ring, so we usually synthesize
phenols by transforming another functional group, already on an aromatic ring, into an
OH
group.
20
In each case, we form the intermediate substituted benzene directly or indirectly by an
electrophilic aromatic substitution reaction on benzene.
From Cumene.
Organic chemists prepare phenol commercially by autoxidation of cumene.
Cumene comes from the Friedel-Crafts alkylation of benzene
While it appears that HO- might displace Cl- by nucleophilic substitution, this reaction
has an elimination-addition mechanism in which benzyne (C6H4) is an intermediate.
21
From Arylsulfonic Acids. When we "fuse" arylsulfonic acid salts (Ar-SO3-Na+) with
sodium hydroxide at high temperatures, we replace the SO3- group with an O- group.
Subsequent protonation with acid gives phenols
We synthesize arylsulfonic acids from the aromatic compound by electrophilic aromatic
sulfonation.
From Diazonium Ions. The most general method for substituting OH on an aromatic
ring is replacement of an N2+ group (a diazonium group) by an OH group
We form N2+ groups from NH2 groups by a nitrosation reaction.
22
While there is no synthetically useful direct method to place an NH2 group on an
unsubstituted aromatic ring, we can synthesize amino benzenes and other amino
arenes by
reducing a nitro group on an aromatic ring
23
Swern Oxidation
The Swern Oxidation of alcohols avoids the use of toxic metals such as chromium, and can be carried out under very
mild conditions. This reaction allows the preparation of aldehydes and ketones from primary and secondary alcohols,
resp. . Aldehydes do not react further to give carboxylic acids. A drawback is the production of the malodorous side
product dimethyl sulphide.
Deprotonation of this intermediate gives a sulphur ylide, which undergoes intramolecular deprotonation via a five-
membered ring transition state and fragmentation to yield the product and DMS (odour!):
If the temperature is not kept near -78C, mixed thioacetals may result:
Recent Literature
24
New odorless method for the CoreyKim and Swern oxidations utilizing dodecyl methyl sulfide (Dod-S-Me)
S.-I. Ohsugia, K. Nishidea, K. Oonob, K. Okuyamab, M. Fudesakaa, S. Kodamaa, M. Node, Tetrahedron, 2003, 59,
8393-8398.
The oxidation of primary and secondary alcohols with ion-supported methyl sulfoxide and oxalyl chloride in the
presence of triethylamine in dichloromethane efficiently gives carbonyl compunds in good yields with high purity.
Isolation of the product was achieved very easily by simple diethyl ether extraction of the reaction mixture.
Furthermore, ion-supported methyl sulfide was recovered in good yield and re-oxidized.
D. Tsuchiya, K. Moriyama, H. Togo, Synlett, 2011, 2701-2704.
Mechanism:
25
Criegee Mechanism
26
Mechanism of Ozonolysis
The mechanism was suggested by Criegee (Angew. Chem. Int. Ed., 1975, 87, 745. DOI) and has been recently
revisited using 17O-NMR Spectroscopy by the Berger Group (Eur. J. Org. Chem., 1998, 1625. DOI).
First step is a 1,3-dipolar cycloaddition of ozone to the alkene leading to the primary ozonide (molozonide, 1,2,3-
trioxolane, or Criegee intermediate) which decomposes to give a carbonyl oxide and a carbonyl compound:
The carbonyl oxides are similar to ozone in being 1,3-dipolar compounds, and undergo 1,3-dipolar cycloaddition to the
carbonyl compounds with the reverse regiochemistry, leading to a mixture of three possible secondary ozonides (1,2,4-
trioxolanes):
27
These secondary ozonides are more stable than primary ozonides. Even if the peroxy bridge is shielded by steric
demanding groups leading to isolable products, they should not be isolated from an unmodified ozonolysis, because
still more explosive side products (tetroxanes) may have been formed:
As endoperoxides are investigated as antimalarial compounds, more selective methods have been developed for their
preparation (for example the Griesbaum Coozonolysis). Some reactions can be found here: V. D.B. Bonifacio, Org.
Chem. Highlights 2004, October 25. Link
28
The Criegee mechanism is valid for reactions in hydrocarbons, CH 2Cl2, or other non-interactive solvents. Alcohols react
with the carbonyl oxide to give hydroperoxy hemiacetals:
Sarett reagent:CrO3.2Py
Election of Oxidant
29
The following guidelines can help in the election of a certain
chromium-based oxidant in the laboratory:
. Jones oxidation is very easy to carry out, because of the absence
of need to keep anhydrous conditions. Furthermore, it is very cheap.
It is the oxidation of choice for robust substrates on a big scale. It is
neither suitable for very acid sensitive substrates, nor for the
preparation
of many aldehydes.
. Collins oxidation is very cheap, but has the added experimental
difficulty of having to work under anhydrous conditions. Although
sometimes it lacks the selectivity of PDC or PCC, it can produce
very good yields of aldehydes and ketones in uncomplicated
substrates.
. PDC and PCC are more expensive reagents that normally guarantee
the best results in difficult cases.
Chromium trioxide (CrO3) is a strong oxidizing agent that appears in
the form of deep-red hygroscopic crystals. Upon solution in water, it
forms chromic acid that equilibrates with polymeric anhydrides.
K2Cr2O7, Na2Cr2O7
CrO3/H2SO4/H2O.
30
i) Mofatt and Pfitzner (1963) first published the oxidation using
activated DMSO
Mechanism
, and in 1967, Doering and Parikh disclosed the use of the complex
SO3 _ Py.8 The following years witnessed the exploration of
numerous activators, belonging to almost any conceivable
electrophile kind. Thus, the Swern team carried out a very active
search for an ideal activator that led to the proposal of triXuoroacetic
anhydride9 in 1976, and culminated with the predication of oxalyl
chloride in 1978,10 as the activator of choice in what became known
as the Swern oxidation.
31
Strong activators, such as oxalyl chloride or trifluoroacetic
anhydride, produce highly reactive activated DMSO,
able to oxidize alcohols at very low temperature.
The resulting forms of highly reactive activated DMSO will also
have a tendency to decompose to the methylene sulfonium salt 12 at
relatively low temperatures.
Thus, strong activators must necessarily be used at low
temperatures for best yields.
Nomenclature of Reactions Involving Activated DMSO
32
The CoreyKim procedure is the oxidation method of choice for the
transformation of -hydroxycarbonyl compounds into 1,3-dicarbonyl
compounds.
Treatment of -hydroxycarbonyl compounds under CoreyKim
conditions leads to an intermediate 1,3-dicarbonyl compound 33 that
reacts in situ with activated DMSO, resulting in the generation of a
stable sulphur ylide 34.
This sulfur compound can be transformed into the desired 1,3-
dicarbonyl compound by reduction with zinc in acetic acid.
33
With Dess-Martin periodinane(DMP), the alcohols are oxidized to the
corresponding aldehydes and ketones, DMP is transformed into the
organic iodinane (38) and acetic acid.
34
The o-iodosobenzoic or o-iodobenzoic acids, recovered from the
work-up of oxidations with Dess-Martin periodinane, can be recycled
back to this oxidant by oxidation to IBX, followed by transformation
of IBX into Dess-Martin periodinane.
when tert-butyl alcohol is used for the acceleration of Dess-Martin periodinane oxidation
35
This confusing state of affairs was clarified in 1994 by Meyer and
Schreiber, in a very elegant paper, in which they proved that reaction
of Dess-Martin periodinane with water results in the formation of the
acetoxyiodinane oxide (44), that is able to oxidize alcohols much
quicker and efficiently than Dess-Martin periodinane.
39
m-Chloroperbenzoic acid oxidizes TEMPO (55) to an oxoammonium
salt 56. This oxoammonium salt can react with the alcohol
producing an intermediate 57, which can deliver a carbonyl
compound by a Cope-like elimination.
40
Fetizons Reagent: Silver Carbonate on Celite*
2,3-Dichloro-5,6-dicyano-p-quinone (DDQ)
41
Selective Oxidations of Secondary Alcohols via Protection of
Primary Alcohols
It is possible to perform the regioselective protection of primary
alcohols in the presence of secondary ones with almost any
protecting group, thanks to the substantially less crowded
environment of primary alcohols.
Examples of this strategy include the use of silyl and trityl
ethers.
The employment of trityl trifluoroborate is particularly interesting.
This reagent is able to introduce trityl groups on both primary and
secondary alcohols and to selectively oxidize secondary trityl ethers
to ketones in the presence of primary trityl ethers.
43
MnO2: ((CH3)2S=O)
((CH3)2C=O)
44
We can think of phenols, hydroquinones, and quinones
(Figure 17.052), as successive oxidation products of
benzene.
Cumene hydroperoxide to phenol mechanism
45
methylthiomethyl ether
The activated DMSO 9 can also suffer an elimination, resulting in the highly reactive
H2C=S(+)-CH3 species that can react with the alcohol, yielding a methylthiomethyl ether 13
as a side compound. Fortunately, this elimination demands a higher temperature than the
normal temperature of oxidation, and a proper control of the temperature minimizes the
formation of the methylthiomethyl ether side compound.
46
The regiochemistry of the reduction is dramatically influenced by the presence
of the lanthanide in the reaction.
Mechanism of DIBAL-Reduction:
Acidic
media!!
Not a
good
method
for H+
sensitive groups and compounds.
49
50
51
Selective Oxidation of Allylic Alcohols
52
CrO3 on Celite MnO2
53
CrO3/Et2O/CH2Cl2/Celite
Oxidation of 1 allylic alcohols to -unsaturated esters
Ruthenium Tetroxide
- effective for the conversion of 1 alcohols to RCO2H and 2
alcohols to ketones.
- oxidizes multiple bonds and 1,2-diols.
54
55
56
RuO4
57
R2 = H > 3 > 2 > benzyl = phenyl > 1 >> CH3.
Reductions:-
1. Hydrogenation using metal catalyst
2. Boron Reagents
3. Aluminium Reagents
4. Tin Hydrides
5. Silanes
6. Dissolving Metal Reductions
Hydrogenations
Heterogeneous Catalytic Hydrogenation
Transition metals absorbed onto a solid support
metal: Pd, Pt, Ni, Rh
support: Carbon, alumina, silica
solvent: EtOH, EtOAc, Et2O, hexanes, etc.
- Reduction of olefins & acetylenes to saturated hydrocarbons.
58
- Sensitive to steric effects and choice of solvent
- Polar functional groups, i.e. hydroxyls, can sometimes direct the
delivery of H2.
- Cis addition of H2.
59
60