Download DEVELOPMENT OF GREEN AND OF POLYMER

DEVELOPMENT OF GREEN AND OF POLYMER-SUPPORTED
OXIDIZING AGENTS FOR OXIDATION OF ALCOHOLS
by
SYED JAVED ALI, M.Tech., B.Tech.
A THESIS
IN
CHEMISTRY
Submitted to the Graduate Faculty
of Texas Tech University in
Partial Fulfillment of
the Requirements for
the Degree of
MASTER OF SCIENCE
Approved
David Birney
Chairperson of the Committee
Satomi Niwayama
Accepted
John Borrelli
Dean of the Graduate School
May, 2006
ACKNOWLEDGEMENTS
I would like to express my sincere gratitude to my mentor, Dr. David Birney, for
his ever-inspiring scientific guidance, for his constant encouragement and support and for
his unfathomable patience. I hold him in very high esteem for being such an excellent
teacher and a wonderful human being. Words would only depreciate my admiration and
my gratitude for all that he has done. I would like to thank Dr. Satomi Niwayama for
agreeing to be my thesis committee member and for her valuable comments on my work.
My thanks are also due to Dr. Pramod Chopade for helping me understand some of the
chemistry, Ms. Paramakalyani Martinelango for being a great friend and for help with
this manuscript. I thank my very best friend, Pradip, and Anwesa for their moral support
and always being there for me. I would like to thank my parents for their love, sacrifice
and continued prayers and blessings, and my friends back home who I know genuinely
care for my well-being.
ii
TABLE OF CONTENTS
ACKNOWLEDGEMENTS……………………………………………………………….ii
LIST OF SCHEMES……………………………………………………………………...v
LIST OF TABLES………………………………………………………………………..vi
LIST OF FIGURES……………………………………………………………………...vii
CHAPTER
1. INTRODUCTION…………………………………………………………………...…1
1.1 An Overview of Oxidizing Agents for Alcohols……………………………...1
1.1.1 With Strong Oxidizing Agents……………………………………....1
1.1.1.1 Chromium Compounds…………………………………….1
1.1.1.2 Manganese Compounds……………………………………3
1.1.1.3 Ruthenium Compounds……………………………………4
1.1.1.4 Other Metal-Based Oxidants……………………………….5
1.1.2 By Catalytic Dehydrogenation………………………………………5
1.1.3 The Oppenauer Oxidation…………………………………………...7
1.1.4 With Dimethyl Sulfoxide Reagents…………………………………8
1.1.5 With Hypervalent Iodine Reagents………………………………….9
1.2. Use of Nitroxyl Radicals…………………………………………………….11
1.2.1 Structure and Stability……………………………………………...11
1.2.2 Synthesis of Nitroxyl Radicals……………………………………..12
1.2.3 Redox Reactions…………………………………………………...13
1.2.4 Mechanistic considerations………………………………………...14
1.2.5 Significance of this research……………………………………….18
2. EXPERIMENTAL…………………………………………………………………….19
2.1 General Methods……………………………………………………………..19
2.2 Synthesis of PEG-supported TEMPO………………………………………..19
2.3 General procedure for oxidation of alcohols with PEG-TEMPO……………24
2.4 General procedure for TEMPO-TCCA oxidation of alcohols……………….25
iii
3. RESULTS AND DISCUSSION………………………………………………………26
3.1 Factors Affecting Frequency of Absorption of the C=O Group……………..26
3.1.1 Inductive and Resonance Effects…………………………………..26
3.1.2 Effects of Conjugation……………………………………………..27
3.1.3 Steric Effects……………………………………………………….27
3.1.4 Ring strain effects………………………………………………….28
3.2 Discussion of experimental data……………………………………………..28
3.2.1 Oxidation of benzylic alcohols to aromatic ketones……………….28
3.2.2 Oxidation of alcohols to aliphatic and unsaturated ketones……….32
3.2.3 Oxidation of alcohols to cyclic aliphatic ketones………………….33
3.2.4 Oxidation of alcohols to form aromatic aldehydes………………...35
3.2.5 Oxidation of alcohols to form aliphatic/ unsaturated aldehydes…..39
4. CONCLUSION………………………………………………………………………..41
REFERENCES…………………………………………………………………………..42
iv
LIST OF SCHEMES
1.1 Oxidation of alcohols to carbonyl compounds……………………………............. ..1
1.2 Preparation of pyridinium chlorochromate (PCC)………………………………......2
1.3 Oppenauer oxidation of an alcohol to a carbonyl compound……………………... ..7
1.4 Alcohol oxidation with DMSO…………………………………………………… ..8
1.5 Synthesis of the Dess-Martin periodinane………………………………………....10
1.6 Disproportionation of a nitroxyl radical with an α- hydrogen………………….…..12
1.7 Redox reactions of TEMPO………………………………………………………. 13
1.8 Disproportionation of the nitroxyl radical……………………………………….....14
1.9 Possible mechanistic pathways for oxidation with TEMPO……………………… 15
1.10 Mechanism of the TEMPO-TCCA oxidation system…………………………….17
2.1 Synthesis of PEG-supported TEMPO…………………………………………….. 20
2.2 Synthesis of mesylate of modified PEG……………………………………….…...23
v
LIST OF TABLES
3.1 Oxidation of Alcohols to form Aromatic Ketones...................................................30
3.2 Oxidation of Alcohols to form Aliphatic and Unsaturated Ketones........................32
3.3 Oxidation of Alcohols to form Cyclic Aliphatic Ketones........................................33
3.4 Oxidation of Alcohols to form Aromatic Aldehydes...............................................35
3.5 Oxidation of Alcohols to form Aliphatic/Unsaturated Aldehydes...........................39
vi
LIST OF FIGURES
1.1 Structures of some chromium based oxidizing agent.................................................2
1.2 Structure of IBX........................................................................................................10
1.3 Resonance structure of the nitroxyl radical..............................................................11
1.4 Conjugated and non-conjugated nitroxyl radicals....................................................11
1.5 Complex formation in the acyclic intermediate........................................................16
3.1 Inductive and resonance effects influencing C=O shift…........................................27
3.2 Effect of conjugation.................................................................................................27
3.3 A resonance structure for 4-methoxybenzaldehyde showing decreased double
bond character...........................................................................................................38
3.4 s-cis conformation for (Z)-hex-2-enal......................................................................40
vii
CHAPTER 1
INTRODUCTION
The selective oxidation of primary alcohols and secondary alcohols into their
corresponding aldehydes (or carboxylic acids) and ketones is one of the most important
transformations in modern organic synthesis. A myriad of oxidizing agents have been
developed to affect this transformation shown in Scheme 1. Tertiary alcohols resist
oxidation by conventional oxidizing agents unless they are dehydrated in acidic media to
alkenes, which subsequently undergo oxidation.
In modern synthetic chemistry there is still a demand for mild and selective
reagents for the oxidation of alcohols in presence of other oxidizable groups.
R1
CHOH
R1
O
C
R2
O
R2
R1= H, Alkyl or Aryl
R2= Alkyl or Aryl
Scheme 1.1 Oxidation of alcohols to carbonyl compounds
1.1 An overview of oxidizing agents for alcohols
Primary and secondary alcohols can be oxidized to the corresponding carbonyl
compounds in five main ways1
1.1.1 With strong oxidizing agents
1.1.1.1 Chromium compounds
Traditionally, the reagents most commonly used are based on high oxidation state
transition metals, particularly Cr(VI). Chromic acid (H2CrO4), a strong oxidizing agent,
can be prepared by acidification of sodium or potassium salts of chromate (CrO42-) or
dichromate (Cr2O72-).
Oxidation of primary alcohols by this method leads to the
1
formation of carboxylic acids in most instances, due to the rapid hydration and
subsequent oxidation of aldehydes with chromic acid. Pyridinium chlorochromate (PCC),
prepared by dissolving chromium trioxide in aqueous HCl and adding pyridine2 (Scheme
2), was developed for the oxidation of primary alcohols to aldehydes. Secondary alcohols
are oxidized to ketones by chromic acid as well as by PCC.3
CrO3 + HCl +
CrO3Cl
N
N
H
Scheme 1.2 Preparation of pyridinium chlorochromate (PCC)
Pyridinium chlorochromate, tetra-n-butylammonium hydrogen chromate (Fig 1a)
and pyridinium dichromate (Fig 1b) are typical representatives of an important series of
chromium (VI) oxidants that may be formally regarded as lipophilic derivatives of the
monomer form of chromic acid H2CrO4 or of the dimeric form H2Cr2O7. They find
increasing use as mild reliable oxidants for alcohols.4
n-Bu4N-O
O
Cr2O72-
Cr
HO
O
N
2
b
c
Figure 1.1 Structures of some chromium based oxidizing agents
2
O
Cr
N
H
a
N
O
O
Jones’ reagent is a solution of chromium trioxide in dilute H2SO4 which also
affects the oxidation of primary allylic alcohols to aldehydes and secondary alcohols to
ketones. Other chromium trioxide reagents have been prepared by adsorption of
chromium trioxide on Celite, silica gel, or on anion exchangers. Among non-acidic
reagents which are suitable for oxidations of acid-sensitive substrates, is Collin’s reagent
(Fig 1c), a complex of chromium trioxide with two molecules of pyridine. It is prepared
by the addition of chromium trioxide in small portions to pyridine, with continuous
stirring and cooling the mixture in an ice bath.2 The disadvantages of this reagent are that
a) it is very hygroscopic and is easily converted into the insoluble dipyridinium
dichromate b) a six fold quantity of the reagent might be required to obtain best yields in
some instances and c) saturated aliphatic alcohols often give low yields.
Though chromium based oxidations are effective, they are relatively expensive
and have serious drawbacks in terms of green chemistry and environmental impact. They
generate stoichiometric amounts of heavy-metal waste and Cr(VI) is a proven
carcinogen.5,6
1.1.1.2 Manganese compounds
The best known manganese based oxidants are manganese dioxide and the
permanganate ion. Manganese dioxide is used as a suspension in petroleum ether,
hexane, benzene, chloroform or CCl4. Saturated alcohols are less readily oxidized
compared to allylic, benzylic alcohols and α-keto alcohols.4 The reactions are carried out
at room temperature and yields vary widely depending on the substrate, ratio of substrate
to oxidant, solvent and reaction time.
Manganates and permanganates are seldom used for the conversion of alcohols to
aldehydes as permanganate oxidizes aldehydes to carboxylic acids. Aldehydes can be
obtained using potassium permanganate if adsorbed on molecular sieves and the reaction
is done in benzene at 70 ºC. However, saturated alcohols give very low yields of
aldehydes. Barium manganate has also been used in certain instances as an alternative to
manganese dioxide.
3
1.1.1.3 Ruthenium compounds
Among the earliest known ruthenium based oxidizing agents was ruthenium
tetroxide,2,4 which was successfully used for the oxidation of secondary alcohols to
ketones. Though it was used to oxidize benzyl alcohol to benzaldehyde,4 aliphatic
primary alcohols were oxidized to the corresponding carboxylic acids. It is a strong and
effective oxidant which may be used under mild conditions for the conversion of
secondary alcohols to ketones. This reagent has been specifically useful in the field of
carbohydrate chemistry, where the oxidation of alcohol groups in partially protected
derivatives of saccharides poses a problem. Ruthenium tetroxide oxidation of such
compounds provides a viable route to the corresponding keto-sugars, subsequently used
in the synthesis of many important derivatives whose syntheses are based on the
chemistry of the carbonyl group. In order to minimize difficulties in the handling of pure
ruthenium tetraoxide, it has been prepared and used in solution. Chloroform and
dichloromethane are the solvents of choice for the reaction medium, though carbon
tetrachloride is preferable. It reacts violently with diethyl ether, benzene and pyridine. An
alternative to ruthenium tetraoxide, which is rather expensive and required in
stoichiometric amounts, is the use of ruthenium trichloride in catalytic amounts with
sodium hypochlorite as reoxidant.
Sodium ruthenate and potassium ruthenate, synthesized respectively from
ruthenium dioxide and sodium periodate in sodium hydroxide and from ruthenium
trichloride and potassium persulfate, effect the oxidation of secondary alcohols to ketones
at room temperature. Tetrapropylammonium perruthenate (also known as TPAP) can be
used to convert some primary alcohols to aldehydes. TPAP is prepared by the initial
formation of RuO4 by the reaction of hydrated ruthenium chloride and sodium periodate
in water, and then transferring the product into a solution of tetra-n-propylammonium
hydroxide containing sodium hydroxide. N-methyl morpholine oxide (NMO) was used as
the co-oxidant. Another ruthenium compound, RuCl2(PPh3)3 in benzene, was found to be
highly effective for the selective oxidation of primary alcohol groups in presence of a
secondary one : 1-dodecanol was oxidized fifty times faster than 4-dodecanol.7
4
1.1.1.4 Other metal-based oxidants
Cerium (IV) salts are strong oxidants that show selectivity for the oxidation of
secondary alcohols relative to primary alcohols.4 Cerium (IV) sulfate oxidation, done in
acidic media, is a selective oxidant for the preparation of quinones. Ceric ammonium
nitrate (CAN) in water or in 50% acetic acid oxidizes benzylic alcohols at 90 ºC in very
good yields. NaBrO3 used in stoichiometric amounts with catalytic amounts of CAN
selectively oxidizes secondary alcohols in presence of primary ones.
Commercial silver carbonate in excess of 300 mol% has been found to be a
satisfactory oxidant if the reaction was performed in refluxing toluene. Precipitating
silver carbonate in the presence of Celite results in a supported reagent, commonly
known as Fetizon’s reagent. It is a very versatile and useful oxidizing agent, its chief
advantages being its ease of use, selectivity and mild conditions under which it is used.
Lead tetraacetate finds major application in the cleavage of 1,2-diols. The reaction
is virtually quantitative and leads to the formation of two carbonyl compounds. In the
oxidation of primary and secondary monohydric alcohols, product composition depends
upon the structure of the substrate and the reaction solvent. Aldehydes and ketones are
formed in good yields for reactions performed with an excess of the alcohol or in polar
solvents such as pyridine. For reactions carried out in non-polar solvents, fragmentation
reactions and formation of cyclic ethers, if the substrate is of suitable structure, are more
often observed. Molar equivalents of lead tetraacetate are required, and the reaction time
varies from 10-20 h at room temperature. The reaction medium acts as its own indicator,
turning from deep red to pale yellow when all the oxidant has been reduced. An
important feature of this oxidation is that the reaction stops at the aldehyde or the ketone
stage, and the product is stable under the reaction conditions for several days.
1.1.2. By catalytic dehydrogenation
Catalytic dehydrogenation is much more valuable as an industrial method than on
a laboratory scale. It is especially advantageous in the oxidation of primary alcohols2 as it
prevents their over-oxidation to carboxylic acids. This method is also useful for the
5
oxidation of secondary alcohols as ketones are more stable at the higher temperatures at
which the reactions are usually conducted, resulting in higher yields and fewer byproducts. Besides, secondary alcohols are more reactive towards the dehydrogenation
process than primary alcohols. The catalytic dehydrogenation of alcohols to yield
carbonyl compounds can generally be performed either in the absence or in the presence
of a hydrogen acceptor. In the absence of a hydrogen acceptor, the process is endothermic
and is favored by high temperatures. In the latter case, oxygen may be used as a hydrogen
acceptor and the reaction is exothermic.
An extremely large number of dehydrogenation catalysts have been described,
copper chromite being the most commonly used. Reactions can be carried out in the gas
phase or in the liquid phase. Aliphatic alcohols with three to eight carbons are converted
to aldehydes using copper chromite on Celite at 300-350 ºC. Quantitative yields can be
obtained when reactions are carried out over copper, silver or both in an insufficient
amount of air or oxygen at 300-380 ºC. For aldehydes which are stable at high
temperatures of 250-300 ºC, vapor-phase dehydrogenation of the corresponding alcohol
can be done over cupric oxide in a current of helium. Besides copper chromite, catalysts
that have found laboratory use include Raney nickel, platinum, palladium and coppersilver on pumice.
Liquid phase reactions are operationally simpler than gas phase reactions for
laboratory use, though convenient experimental arrangements that use a simple heated
reaction tube are available. For alcohols that cannot be vaporized and that contain double
bonds, a catalytic oxidation can be carried out by passing a current of air or oxygen
through solutions of alcohols in solvents like heptane or ethyl acetate, in the presence of
platinum, or preferably platinum oxide, or active cobalt oxide. Aliphatic, aromatic and
unsaturated alcohols can be oxidized in the liquid phase from -10 to 60 ºC with argentic
oxide in nitric or acetic acid. Benzylic alcohols can be oxidized in very good yields at 90
ºC in water or in 50% acetic acid with ceric ammonium nitrate.
6
1.1.3. The Oppenauer oxidation
The Oppenauer oxidation is essentially the reverse of the Meerwein-PonndorfVerley reduction.4 This method involves the use of a carbonyl compund as a hydrogen
acceptor in the presence of a base. Aluminum alkoxides such as aluminum isopropoxide
and aluminum phenoxide are bases used often; aluminum tert-butoxide being the most
commonly used. Carbonyl compounds used as hydrogen acceptors are acetone,
cyclohexanone, benzaldehyde, cinnamaldehyde and benzophenone. Fluorenone can also
be used as the hydrogen acceptor as it effects a considerable reduction in time and
temperature of the reaction. The oxidation potential of the carbonyl compound affects its
efficiency as a hydrogen acceptor, which can be overcome by using the oxidant in large
excess.
The metal alkoxide converts the alcohol into its corresponding alkoxide, which is
converted into a carbonyl compound by hydride ion transfer to a carbonyl compound as
shown in Scheme 3. The reaction is reversible and leads to an equilibrium and systematic
removal of the product drives the reaction to completion. The product or byproduct is
removed by distillation or azeotropic distillation. Hence, high boiling alcohols such as
hydroxy steroids may be oxidized with considerable selectivity; equatorial hydroxyl
groups are oxidized more rapidly than axial ones.
R1
OH
C
R2
t-BuO
R3R4C=O
H
R1
-
R1
O
C
R2
C
H
R2
+
R3
O
+
R3
C
CH
O
O
R4
R4
Scheme 1.3 Oppenauer oxidation of an alcohol to a carbonyl compound
7
Only catalytic amounts of the metal alkoxide base are needed to initiate the
reaction, as the byproduct R3R4CH-O- formed acts as a strong base. Carbonyl compounds
containing α-hydrogen atoms can undergo self-condensation under the alkaline
conditions of the oxidation, and can also undergo condensation reactions with the
product. The use of inert solvents can minimize these reactions in instances where it is
desirable. Commonly used oxidant-solvent combinations are acetone-benzene and
cyclohexanone-toluene. For compounds which are sufficiently stable to heat, reaction
times may be significantly reduced in the cyclohexanone-toluene system by conducting
the oxidations under reflux conditions. In general, the Oppenauer oxidation finds better
application in the oxidation of secondary alcohols than primary alcohols.
1.1.4 With dimethyl sulfoxide based reagents
Dimethyl sulfoxide (DMSO) is a versatile and mild reagent for the oxidation of
alcohols of widely different structural types and complexities to carbonyl compounds.
Successful use of DMSO as an oxidant for alcohols requires8 a) activation of DMSO by
a suitable electrophilic reagent (E+A-) below the rearrangement temperature of the
requisite intermediate 1; b) facile attack by an alcohol on the electropositive sulfur atom
of
intermediate
1
with
the
departure
of
a
leaving
group
to
form
a
dimethylalkoxysulfonium salt 2; c) reaction of the salt 2 with a base, typically
triethylamine, to form dimethyl sulfide and the carbonyl product; and d) isolation of the
carbonyl product from by-products.
Me2S
O
+
E+A-
Me2S
O
E A-
1 "activated" DMSO
R1R2CHOH
Me2S + R1R2C
base
O + R1R2CHOCH2SCH3
Me2S
Scheme 1.4 Alcohol oxidation with DMSO
8
O
2
CHR1R2 A-
Most oxidations involving DMSO are accomplished at temperatures well below 0
ºC and require an acid catalyst. The Moffatt oxidation involves the oxidation of an
alcohol with DMSO, dicyclohexylcarbodiimide (DCC) and anhydrous phosphoric acid. It
provides a method for the conversion of a primary alcohol to an aldehyde without the
formation of the carboxylic acid. There are a number of variants to this reaction, where
DCC is replaced with other reagents. The use of oxalyl chloride with DMSO, where the
oxidizing species, (CH3)2S+Cl is generated by the reaction between these two reagents, is
known as the Swern oxidation. A major drawback of the Swern oxidation is that it suffers
from the use of activated DMSO as a reagent and very low temperatures, and mainly
from the presence of dimethyl sulfide as a byproduct. Moreover, the oxidation is not
chemoselective.
In the Corey-Kim modification9, the oxidizing species is generated using dimethyl
sulfide and N-chlorosuccinimide, as the latter is more convenient to use on a laboratory
scale. The formation of HCl is avoided which results in a milder and a more generally
useful method, and the reaction products appeared somewhat cleaner. Some of the other
reagents used in place of DCC are acetic anhydride, SO3-pyridine-triethylamine,
trifluoroacetic anhydride, methane sulfonic anhydride, tosyl chloride, trichloromethyl
chloroformate and trimethylamine N-oxide.
1.1.5 With hypervalent iodine reagents
The Dess-Martin periodinane10 is an iodine containing oxidizing agent by treating
2-iodobenzoic acid with KBrO3 in sulfuric acid, and then heating the resultant product
with acetic acid and acetic anhydride to 100 ºC. The reagent so formed is stable, with an
indefinite shelf life. However, it can be shock sensitive under some conditions and can be
explosive at temperatures exceeding 200 ºC.11
9
O
OH
KBrO3
H2SO4
I
I
HOAc
Ac2O
OAc
AcO
I
100 ºC
O OAc
O
COOH
O
O
Scheme 1.5 Synthesis of the Dess-Martin periodinane
Another iodine containing reagent that can affect smooth oxidations of primary as
well as secondary alcohols at room temperature is o-iodoxybenzoic acid12 (Fig 2). 1,2Diols can also be oxidized to α-ketols or α-diketones without any oxidative cleavage of
the glycol bond.
HO
O
I
O
O
Figure 1.2 Structure of IBX
However, these reactions can only be conducted in DMSO as IBX is sparingly
soluble in commonly used solvents such as dichloromethane, acetonitrile, chloroform,
acetone, THF and DMF. THF can be used as a co-solvent for compounds that are not
readily soluble in DMSO. In contrast to the Dess-Martin periodinane, IBX is not sensitive
to moisture and the oxidations can be carried out in an open flask without the need for an
inert atmosphere or a dry solvent. However, like the Dess-Martin periodinane, it is also
explosive upon heavy impact and heating over 200 ºC.
A newer oxidation protocol that involves the use of [bis(acetoxy)iodo]benzene
(BAIB) as the stoichiometric oxidant with catalytic quantities of TEMPO has also been
developed.13 The reaction worked well at room temperature in dichloromethane, but no
oxidation process was observed in the absence of TEMPO. Oxidation of alcohols in high
10
yields under solvent-free conditions has been achieved by using iodobenzene diacetate
supported on alumina, the reaction being accelerated by microwaves.14
1.2. Use of Nitroxyl Radicals
1.2.1 Structure and stability
Nitroxyl radicals are compounds containing the N-O group with one unpaired
electron15. Resonance structures for this fragment can be drawn as shown in Fig 2.
N
O
N
O
Figure 1.3 Resonance structure of the nitroxyl radical
The major contributing structure depends on the polarity of the medium and the effects of
conjugation.
In conjugated nitroxyl radicals (Fig 4a), the unpaired electron is delocalized over
the entire molecule. Such radicals, unlike non-conjugated radicals, are not used for the
oxidation of alcohols. In non-conjugated nitroxyl radicals (Fig 4b and 4c), the unpaired
electron is only delocalized over the nitrogen-oxygen bond. The high stability of the non
conjugated radicals is demonstrated by the fact that these radicals underwent chemical
reactions without involving the unpaired electron.16 Similar radicals have been
synthesized and used in the biological field as spin labels and spin trapping agents.
N
N
N
O
O
O
a
b
c
Figure 1.4 Conjugated and non-conjugated nitroxyl radicals
11
In general, these radicals are stable only in molecules lacking α-hydrogens. The
presence of one or more hydrogens in the α-position results in a disproportionation
reaction leading to the formation of a hydroxylamine and a nitrone as shown in Scheme
6. Either or both of the species so formed may undergo further reaction.
2
+
N
N
H
H
OH
O
N
O
Scheme 1.6 Disproportionation of a nitroxyl radical with an α- hydrogen
The most stable nitroxyl radicals among the piperidine series are the ones where the αpositions are completely substituted. The most simple radical of this class, 2,2,6,6tetramethylpiperidin-1-oxyl (Fig 4b), commonly known as TEMPO, was the first nonconjugated nitroxyl radical to be synthesized.
1.2.2 Synthesis of nitroxyl radicals
In general, nitroxyl radicals have been obtained by the dehydrogenation of
hydroxylamines, oxidation of amines, reduction of nitro or nitroso compounds and
addition of free radicals to nitrones.15 Preparation of nitroxyls by the oxidation of amines
is particularly useful in the preparation of cyclic dialkyl nitroxyls.
The oxidative method was first reported when an ESR signal resulted from the
diphenylnitroxyl radical when oxygen was bubbled into a diphenylamine solution.17
Following this result, a number of nitroxyls were prepared by oxidation of the
corresponding aromatic, aromatic-aliphatic, aliphatic and alicyclic amines. Oxidation of
secondary amines with hydrogen peroxide in the presence of tungstates is among the
more convenient methods for the synthesis of nitroxyls. Highly stable nitroxyls of
piperidines, pyrolidines, hydrogenated pyrrols, tetrahydroquinoline derivatives and
tetrahydrobenzoquinoline derivatives, besides other cyclic compounds and biradicals
have been synthesized by this method. The oxidation of suitable amines with
12
phosphotungstic acid and ammonium molybdate as catalyst also readily yields nitroxyl
radicals. TEMPO was prepared by this method. Phototungstic acid accelerated the
oxidation, but resulted in decreased nitroxyl yields. It was shown mechanistically that the
pertungstate ion is the oxidizing agent.
1.2.2.1 Synthesis of TEMPO
Among
the
earliest
syntheses,18
reported
a
solution
of
2,2,6,6-
tetramethylpiperidine (1 mol), ethylenediamine-N,N,N',N'-tetraacetic acid (0.05 mol),
800 ml of 45% methanol, 0.3 g of sodium tungstate, and 250 ml of 30% hydrogen
peroxide was cooled in a flat-bottomed flask. The mixture was left at room temperature
for 10 days. It was then diluted two fold with water, saturated with potassium carbonate
and extracted with ether. The ether extract was dried with magnesium sulfate. The ether
was evaporated and the residue was sublimed in vacuum to obtain the radical in a 61%
yield. The product was dark red, transparent prisms.
1.2.3 Redox reactions
The nitroxyl radical represents only one stage in a series of compounds
interrelated by oxidation and reduction products as shown, for TEMPO, in Scheme 7.19,20
These are: the secondary amine (a), the hydroxyl amine (b), the nitroxyl radical (c) and
the nitrosonium salt (d).
-2e-
-1e-
-1e-
N
N
N
N
H
OH
O
O
a
b
c
d
Scheme 1.7 Redox reactions of TEMPO
Mild reducing agents like phenylhydrazine or ascorbic acid react with the radical
to give the hydroxylamine, while stronger reducing agents like sodium sulfide yield the
13
secondary amine. Two of the above species, the radical (c) and the nitrosonium salt (d),
are oxidizing agents, the latter being much stronger of the two. The oxammonium salt is
the reactant in the oxidation of primary and secondary alcohols.
Yet another redox reaction of significant importance is the reversible and acid
catalyzed disproportionation of the radical to yield the hydroxylamine and the
nitrosonium salt19 as shown in Scheme 8. In acidic media, the equilibrium is shifted to the
right as the hydroxylamine is basic enough to form a salt and the hydroxide ion formed
can be neutralized. This reaction is favored at a pH below 2.0.
2
+ OH-
+
+ H2 O
N
N
N
O
OH
O
Scheme 1.8 Disproportionation of the nitroxyl radical
At a pH above 3.0, the reverse of the disproportionation reaction occurs, i.e. a syn
proportionation between the oxammonium salt and the hydroxylamine occurs to give two
nitroxyl radicals.
1.2.4 Mechanistic considerations
Many functional groups such as amines, phosphines, phenols and anilines can be
oxidized using nitroxyl radicals. Nitroxyl radicals, as shown earlier, are oxidized into
nitrosonium salts which, in turn, function as oxidizing agents and have been used as
oxidants for alcohols (to form aldehydes or ketones), primary amines (to form aldehydes,
and in some cases RCH2NH2 to nitriles), ketones (to α-diketones), and phenols (to
quinones).21 The use of nitroxyl radicals has recently emerged as a metal-free alternative
for the oxidation of alcohols.
Two possible mechanistic pathways for the TEMPO oxidation of alcohols have
been considered as shown in Scheme 9. Initial mechanistic investigations by Semmelhack
and co-workers favored the formation of 2.22 The possibility of a radical mechanism as
14
well that of a direct hydride abstraction were excluded. It was suggested that a Cope-like
cyclic elimination could be expected in this transition state. An alternate mechanism with
an acyclic transition state 4 was proposed by Ma and Bobbit.23 The acyclic form was
considered more favorable for two reasons. First, the acyclic form appeared sterically less
confining than the cyclic form and it seemed that fewer steric effects were involved in
oxammonium oxidations.
N
O
O
-H+
R2
H
R1
2
H
+
N
O
N
OH
HO
R1
H
R2
3
1
+
O
N
OH
O
H
B
R1
R2
R1 R2
4
Scheme 1.9 Possible mechanistic pathways for oxidation with TEMPO
Secondly, the acyclic intermediate also shows how a β-oxygen may hinder the reaction
by complexing with the positively charged nitrogen as shown in Fig 5, which is less
likely to occur in the cyclic intermediate because of a negatively charged oxygen. The
complex formation may hinder or slow the reaction in two ways. It may reduce the
positive charge on the
nitrogen and decrease the driving force of the reaction.
Alternatively, complex formation may force the hydrogen out of the anti-periplanar
conformation required for the reaction.
15
O
H
H
N
OH
δ−
O
H
H
R
Figure 1.5 Complex formation in the acyclic intermediate
Steric effects become more important in nitroxyl radical based oxidations under
alkaline conditions.24 Reactions rates are comparable for primary and secondary alcohols
under acidic conditions, while under alkaline conditions, the more sterically hindered
secondary alcohols are oxidized at a slower rate. It was proposed by van Bekkum and coworkers that a sterically confining cyclic reaction mechanism as proposed by
Semmelhack could be possible under alkaline conditions, while an acyclic mechanism as
proposed by Bobbit could be possible under acidic conditions. Also, under acidic
conditions, the primary hydrogen isotope effect (kH/kD) was 3.1 while under alkaline
conditions, it was 1.8, and is hence consistent with the pathways suggested. Abstraction
of the α- proton is expected to be the rate limiting step in acidic conditions while under
basic conditions equilibrium formation of the complex might occur at a rate comparable
with that of elimination.
TEMPO can be used in catalytic amounts with 1,3,5-trichloro-2,4,6triazinetrione25 (trichloroisocyanuric acid – TCCA), a relatively inexpensive reagent to
provide an oxidation system that operates rapidly, and gives near quantitative yields of
aldehydes and ketones at room temperature. A proposed mechanism26 for this reaction is
as shown in Scheme 10.
16
TCCA
R
N
N
O
O
OH
1
Cl
H
N
O
N
O
Cl
N
O
N
N
Cl
O
O
Cl
H
N
O
OH
N
Cl
H
Cl
O
R
H
H2O
O
R
N
2
OH
H
N
O
N
+
N
Cl
OH
O
R
HOCl
O
H
+
R
HCl
O
O
Scheme 1.10 Mechanism of the TEMPO-TCCA oxidation system
17
1.2.5 Significance of this research
The purpose of this research is to find at least one oxidation system that can
oxidize a wide variety of alcohols within a reasonable time frame so it can used in an
Organic Chemistry teaching lab. The oxidation systems explored would be mild and
environmentally friendly methods that would introduce to students comparatively newer
and modern oxidation techniques, thereby replacing traditional oxidation experiments
which are over half a century old. These experiments would enable students to prepare a
different aldehyde or a ketone from a primary or a secondary alcohol. Using the infrared
(IR) spectra of the resultant carbonyl products, the pedagogical goal can be further
extended to enable students study trends in carbonyl peak shifts based on the structure of
the compound. These experiments would be similar to a parallel combinatorial synthesis
of esters that has been previously developed.27
18
CHAPTER 2
EXPERIMENTAL
2.1 General methods
All commercially available materials were used as received, unless otherwise
mentioned. Tetrahydrofuran was dried over anhydrous MgSO4 and distilled from sodium
and benzophenone under N2. Diethyl ether was refluxed with sodium and benzophenone
and distilled immediately before use. Acetone and N,N-dimethylformamide were distilled
with 4Å molecular sieves onto 4Å molecular sieves just before use. Polyethylenegylcol
monomethylether was dried by melting at 80 °C under vacuum until the disappearance of
bubbles. All glassware used for the reactions was oven dried and cooled in desiccators
prior to use.
IR spectra of all compounds were recorded as films cast on a salt plate from
solutions in CH2Cl2. A Thermo Nicolet IR100 spectrometer with a resolution of 4 cm-1
was used for this purpose. NMR spectra were obtained on a Varian UNITYplus 300
instrument. All spectra were obtained using CDCl3 as the NMR solvent with residual
CHCl3 as the internal reference. Mass spectra were done on a Finnigan AQA Mass
Spectrometer by the electrospray ionization (ESI) method.
2.2 Synthesis of PEG-supported TEMPO
The synthesis of polymer supported TEMPO is accomplished by a convergent
synthesis by the reaction of products 5 and 6 as depicted in Scheme 2.1. The reaction
scheme for the synthesis of the mesylate of modified PEG (product 6) is provided in
Scheme 2.2. This is a modification of the published procedure.28
19
O
OH
OH
O
Br
N
CBr4, PPh3
K2CO3, KI
Acetone, reflux 24h
O
THF, 0 C, 30min
aq NaOH, Bu4NBr
OH
OH
1
4
Br
2
3
OH
O
Pd(OAc)2, PPh3
+
EtOH
O
OMs
O
O
7
N
N
O
O
6
5
Cs2CO3
O
DMF
O
O
8
= CH3O-(CH2CH2O)n-CH2-CH2-
Polyethyleneglycol monomethylether
Mw = 5000 Da
Scheme 2.1 Synthesis of PEG-supported TEMPO (8)
20
N
O
Synthesis of p-(Allyloxy)benzyl Alcohol (2)
A mixture of 4-hydroxybenzyl alcohol (1) (12.41 g, 100 mmol), potassium
carbonate (17.91 g, 130 mmol) and potassium iodide (0.22g, 1.3 mmol) was weighed in a
three-necked flask and dry acetone (80 mL) was added. Allyl bromide (11.3 mL, 130
mmol) dissolved in dry acetone (60 mL) was added dropwise with continuous stirring.
The reaction mixture was refluxed for 24 h under nitrogen. The reaction was then cooled
to room temperature and an insoluble portion was filtered off. The filtrate was dried over
MgSO4 and the solvent was evaporated to give a yellow liquid. The yield of 2 was 15.86
g (96.6%). 1H NMR (CDCl3) δ = 6.91, 7.21 (d, J= 7.8 Hz, ArH, 4H), 6-6.2 (m, -CH=,
1H), 5.3, 5.5 (dd, J= 18.1, 1.9, 11.4, 1.3 Hz =CH2, 2H), 4.61 (s, -CH2-, 2H), 4.51 (d, J =
5.5 Hz, -CH2-, 2H).
Synthesis of p-(Allyloxy)benzyl Bromide (3)
p-(Allyloxy)benzyl alcohol (9.16 g, 56 mmol) and tetrabromomethane (23.22 g,
70 mmol) in THF (60 mL) were placed in a three-necked flask under nitrogen and cooled
in an ice bath. Triphenylphosphine (18.36 g, 70 mmol) was added dropwise with
continuous stirring. The reaction mixture was stirred for 30 min in the ice bath. The
solution was filtered and the filtrate was evaporated. The residue, a thick brown liquid,
was transferred to a separatory funnel. The crude product was extracted from the residue
with 4 x 25 mL washes of hexane. An insoluble portion remained, and the organic layer
was dried over MgSO4. Removal of solvent provided 11.39 g of crude material. Purified
3 was obtained by vacuum distillation. An aliquot of 1.23 g of the crude material gave
0.15 g of pure product.
1
The yield was extrapolated to be 1.38 g (10.85 %).
H NMR (CDCl3) δ = 6.79, 7.23 (d, J= 8.2 Hz, ArH, 4H), 6-6.2 (m, -CH=, 1H), 5.31,
5.53 (dd, J= 19.3, 1.6, 11.5, 1.8 Hz, =CH2, 2H), 4.61 (d, J= 5.3 Hz, -CH2-, 2H), 4.5 (s, CH2-, 2H).
21
Synthesis of 4-(p-(Allyloxy)benzyloxy)-2,2,6,6-tetramethyl piperidinyl-1-oxy (5)
Hydroxy-TEMPO (4) (1.17 g, 5.16 mmol) was dissolved in dry toluene (1 mL),
and p-(allyloxy)benzyl bromide (3) (0.89 g, 5.16 mmol), tetrabutylammonium bromide
(0.08 g, 0.258 mmol) and a two-fold excess of 50% aq. NaOH were added. The mixture
was stirred and heated at 70 °C for 20 h. The solution was cooled to room temperature
and stirred with the addition of toluene (5 mL), hexanes (5 mL) and H2O (10 mL). The
organic phase was separated, dried over Na2SO4 and the solvent evaporated under
vacuum. Purification was done by flash chromatography on a silica gel column (hexanes :
ethyl acetate 9:1) to obtain product 4. The yield was 1.64 g. (12.7 %). IR (selected
peaks): 2875, 2937, 1612, 1512, 1241, 1083 cm-1.
Synthesis of product 6
Product 5 (0.21 g, 0.6 mmol) was dissolved in ethanol (10 mL).
Triphenylphosphine (0.07 g, 0.27 mmol) and palladium(II) acetate (0.013 g, 0.06 mmol)
were added, and the mixture was refluxed for 2 h with stirring. The mixture was cooled to
room temperature, SiO2 (1 g) was added and the contents were stirred for 60 min. The
mixture was stirred through Celite and the solvent evaporated under vacuum. The residue
was purified by flash chromatography on a silica gel column (hexanes : ethyl acetate 4:1)
to yield product 6. The yield was 0.17 g (70.3 %).
IR (selected peaks): 3000, 2975,
2937, 1614, 1517, 1462, 1354, 1239, 1173, 1081 cm-1. ESI MS: m/z was found at 277.8;
formula weight calculated for [C16H24NO3]+ was 278.18.
Synthesis of product 7
Product 7 was synthesized in three steps as depicted in Scheme 2.2. Polyethylene
glycol monomethylether (MW=5000 Da) (9) (5.0 g, 1 mmol) was dissolved in dry
CH2Cl2 (15 mL) and tri-n-octylamine (0.53 mL, 1.2 mmol) was added. The mixture was
stirred for 5 min before the addition of methanesulfonyl chloride (0.09mL, 1.2 mmol).
The mixture was stirred for 20 h. The resultant PEG-mesylate (10) was precipitated by
the addition of diethyl ether (200 mL), and filtered over a Büchner funnel. The precipitate
22
was washed thrice with diethyl ether (150 mL) and any residual ether was removed under
vacuum. The yield was 4.78 g (95.6%). 1H NMR (with presaturation of methylene signals
at δ =3.6, relaxation delay = 6 s, acquisition time = 4 s) MeSO2 signal resonated at δ
=3.08.
To a solution of (10) (4.22 g, 0.83 mmol) in dry DMF (30 mL) were added
cesium carbonate (0.87 g, 2.7 mmol) and 3-(4-hydroxyphenyl)-1-propanol (11) (0.38 g,
2.49 mmol) and stirred for 18 h at room temperature. The mixture was concentrated to
half its original volume under vacuum. Addition of diethyl ether (80 mL) resulted in a
oily product at the bottom of the flask. Evaporation of ether by blowing a stream of N2
over the mixture induced the formation of a precipitate. The process was continued till no
significant increase in the formation of precipitate was observed. The precipitate was
washed with diethyl ether (150 mL) after filtration over a Büchner funnel. Residual ether
was dried over vacuum, resulting in a 2.08 g yield (48.2%) of product (12).
The modified PEG (12) (2.21 g, 0.42 mmol) was dissolved in CH2Cl2 (20 mL)
and stirred with trioctylamine (0.88 mL, 2 mmol) and methanesulfonyl chloride (0.16
mL, 2 mmol) for 18 h. The mesylate was precipitated by the addition of diethyl ether (80
mL), filtered over a Büchner funnel and washed with ether (100 mL). The residual
solvent was evaporated and 2.15 g of 7 was obtained (99.5 %).
OH
HO
CH3SO2Cl, TOA
OH
11
OSO2CH3
CH2Cl2
Cs2CO3, DMF
9
10
O
OH
CH3SO2Cl, TOA
O
OMs
CH2Cl2
12
7
= CH3O-(CH2CH2O)n-CH2-CH2Polyethyleneglycol monomethylether
Mw = 5000 Da
Scheme 2.2 Synthesis of mesylate of modified PEG
23
Synthesis of product 8
A solution of the modified PEG-mesylate 7 (1.31 g, 0.25 mmol) was dissolved in
dry DMF (6 mL) and stirred at 50 °C under N2. The TEMPO-attached phenol 6 (0.083 g,
0.3 mmol) and cesium carbonate (0.24 g, 0.75 mmol) were added and stirred for 72 h at
70 °C. Most of the DMF was evaporated under vacuum, and after cooling to room
temperature, CH2Cl2 (6 mL) was added. The solution was filtered to remove an insoluble
portion, and diethyl ether (120 mL) was added to precipitate PEG-supported TEMPO 8.
Again, evaporation of ether by blowing a stream of N2 resulted in an increased amount of
precipitate, which was filtered over a Büchner funnel and washed with ether. Any
residual solvent was evaporated and the yield was found to be 0.89 g (64 %).
IR (selected peaks): 2882, 1646, 1511, 1467, 1467, 1359, 1280, 1241cm-1
2.3 General procedure for oxidation of alcohols with PEG-TEMPO
In a reaction vial equipped with a stirrer, 1 mmol of the alcohol was weighed and
CH2Cl2 (1-2 mL) was added to completely dissolve the alcohol. The solution was cooled
to 0 °C. To the cold solution, PEG-TEMPO (varying from 0.01 mmol to 0.001 mmol)
was added and stirred for 5 min. Trichloroisocyanuric acid (TCCA) (0.244 g, 1.05 mmol)
was added and the mixture was stirred for 15 min. The progress of the reaction was
monitored by TLC (before spotting on the TLC plate, an aliquot of the reactant solution
was filtered through a Celite plug) until the alcohol was completely oxidized. Reaction
times are indicated in the table below. At the end of the reaction, the CH2Cl2 solution was
filtered through Celite, and cold ether (10 mL) was added. The polymer precipitate was
collected on a Büchner funnel, and the filtrate was collected in a test tube placed at the
bottom of the funnel inside the suction flask. A TLC of the filtrate was done to ensure no
residual polymer catalyst was present in the ether. The ether layer was then dried over
MgSO4 and the solvent was removed under vacuum. An IR spectrum of the product was
obtained by dissolving it in CH2Cl2 and casting a thin film on a salt plate.
24
2.4 General procedure for TEMPO-TCCA oxidation of alcohols
In a round bottomed flask containing a magnetic stirrer, a solution of alcohol (2.5
mmol) and the solvent dichloromethane (10 mL) was prepared.
The oxidant,
trichloroisocyanuric acid, was added to the solution in excess (2.6 mmol, 0.6043 g). The
flask was then cooled in an ice water bath and stirred in a nitrogen atmosphere. TEMPO,
or 2,2,6,6-tetramethyl-1-piperidinyloxy, was weighed out in a shell vial (0.025 mmol,
0.0040 g). TEMPO was then dissolved in about 1-2 mL of dichloromethane and added to
the solution at approximately 0˚C. After the addition of TEMPO, the solution was
removed from the ice bath and allowed to warm to room temperature while stirring. The
solution was then allowed to stir for 20 to 25 minutes and filtered over Celite. The
mixture was washed with 15 mL of Na2CO3, followed by HCl, and brine in a separatory
funnel. The organic layers were combined and dried over MgSO4. The solvent was
evaporated under vacuum and an IR spectrum of the product was obtained by dissolving
it in CH2Cl2 and casting a thin film on a salt plate.
25
CHAPTER 3
RESULTS AND DISCUSSION
Functional groups such as ketones, aldehydes, carboxylic acids, esters, lactones,
acid halides, anhydrides, amides and lactams show a strong C=O stretching absorption
band in the region of 1870 to 1540 cm-1. The C=O stretching mode is always intense
owing to the large dipole moment of the carbon-oxygen double bond. The absorption
frequency occurring at approximately 1715 cm-1 for a saturated aliphatic ketone is often
referred to as the “normal” absorption frequency.29 Changes in the environment of the
carbonyl group effect an increase or a decrease in the absorption frequency from this
“normal” value. Conversely, changes in the observed absorption frequency can be
interpreted as reflecting changes in the environment of the carbonyl group.
3.1 Factors affecting frequency of absorption of the C=O group
The position of the C=O stretching band is determined by a number of factors29
including: (1) the physical state, (2) electronic and mass effects of neighboring
substituents,
(3)
conjugation,
(4)
hydrogen
bonding30
(intermolecular
and
intramolecular), and (5) ring strain.
Intermolecular hydrogen bonding between the carbonyl group and a hydroxylic
solvent causes a slight decrease in the absorption frequency. The physical state of the
carbonyl compound, ex. the crystal packing structure can effect a slight increase in the
absorption frequency.
3.1.1 Inductive and resonance effects
The C=O absorption frequency shifts when the alkyl group in a saturated aliphatic
ketone is replaced by a heteroatom (G). The direction of the shift is determined by the
predominance of the inductive effect or the resonance effect.29
26
G
G
C
O
C
R
O
R
(a)
(b)
Figure 3.1 Inductive and resonance effects influencing C=O shift
A strongly electronegative group attached to the C=O group results in the
predominance of the inductive effect (Figure 3.1 a). This reduces the length of the C=O
bond and increases the force constant, resulting in a higher frequency of absorption. On
the other hand, electron donation via the resonance effect (Figure 3.1 b) decreases the
double bond character in the carbonyl group, thereby weakening the bond. The C=O
bond length consequently increases, and the frequency of absorption is reduced.
3.1.2 Effects of conjugation
Conjugation of the C=O group with a C=C bond of an alkene or phenyl group
results in delocalization of the π electrons of both the unsaturated groups (Figure 3.2).
Again, delocalization of the π electrons of the C=O group diminishes its double bond
character31, thus causing conjugated C=O groups to have lower absorption frequencies
than their saturated counterparts.
O
C
O
C
C
C
C
C
Figure 3.2 Effect of conjugation
3.1.3 Steric effects
The effect of conjugation is reduced by sterically bulky groups that reduce the
coplanarity of the system. A conjugated system tends towards a planar conformation in
27
the absence of steric hindrance. Inductive and/or resonance effects from the neighboring
group affect the frequency of absorption as described above.
3.1.4 Ring strain effects
Ring strain can be interpreted as changing the hybridization of atoms in the ring.
In a small, and hence more strained ring, σ bonds should have more p- orbital character
and thus, exocyclic σ bonds should have more s- orbital character. This makes the C=O
stronger and results in an increase in absorption frequency.
3.2 Discussion of experimental data
The following sections provide a list of alcohols that have been oxidized by both the
TEMPO-TCCA system, as well as by the PEG-TEMPO method. The carbonyl frequency
used in the discussion is the observed value, recorded by taking an IR of a liquid film.
The observed values reported have been obtained after the TEMPO-TCCA oxidation.
Selected alcohols were oxidized by the PEG-TEMPO oxidation system, and IR
absorptions obtained from this system have been indicated. The reference value, unless
otherwise indicated, is that of a liquid film of the compound.
3.2.1
Oxidation of benzylic alcohols to aromatic ketones
Table 1 lists the alcohols that were oxidized in quantitative yields to their
corresponding ketones. The oxidation of 1-phenylethanol (entry 1) results in the
formation of acetophenone. The absorption frequency of acetophenone (1686 cm-1) is
lower than that of an aliphatic saturated ketone due to the electron withdrawing effect of
the phenyl group. Propiophenone, formed by the oxidation of 1-phenylpropan-1-ol (entry
2), has a comparable absorption frequency (1687 cm-1) as the neighboring ethyl group
does not have a significant effect on the C=O group. A comparatively more significant
change
in
the
absorption
frequency
is
observed
in
the
case
of
1-(2-
methoxyphenyl)ethanone, obtained by the oxidation of 1-(2-methoxyphenyl)ethanol
(entry 3). The lowered absorption frequency of 1678 cm-1 can be explained by the
28
combined electron withdrawing effects of the benzene ring and the methoxy group,
present in the ortho position. The absorption frequency of 1-(4-fluorophenyl)ethanone
and 1,2-diphenyl ethanone (entries 5 and 6 respectively) are similar to that of
acetophenone. In the case of 1-(4-fluorophenyl)ethanone, the presence of a fluorine atom
in the para position does not affect the absorption frequency. Similarly, the C=O group of
1,2-diphenyl ethanone is affected only by the neighboring benzene ring, as the second
benzene ring is one carbon atom away, accounting for the comparable absorption
frequency. For 1-(2,4-dichlorophenyl)ethanone (entry 7), a substantial increase in
absorption frequency – 1698 cm-1 is observed. It is possible that the relatively bulkier
chlorine atom in the ortho position causes the C=O group to bend out of plane of the
benzene ring, thereby decreasing the conjugation with the ring, resulting in an increase of
absorption frequency. Another contributing factor is that chlorine, though electron
withdrawing by induction, is electron donating by resonance, resulting in a higher
frequency of absorption as explained in Section 3.1.1.
Both
1-(2-chlorophenyl)propan-1-one
and
2-chloro-1-(2,4-dichlorophenyl)
ethanone (entries 8 and 9 respectively) have comparable absorption frequencies, but
higher than that of acetophenone. Again, this can be explained by the loss of co-planarity
of the system owing to the Cl atom and also due to its electron donating effect.
29
Table 3.1 Oxidations of Alcohols to form Aromatic Ketones
Entry
Alcohol
Frequency (cm-1)
of Carbonyl peak
Product
1
1686,
1687@
1686 32
1687,
1687@
1688 32
1678
1675 32
1681
(orig),
1709
-
1686,
1688@
1687,
1698 32
1686,
1686@
1686 32
1698,
1698@
1698 32
O
OH
2
O
OH
3
O
O
OH
O
O
4
O
OH
5
F
F
6
OH
O
O
OH
7
Cl
Reference
O
OH
O
Observed
Cl
Cl
30
Cl
Table 3.1 Continued
Entry
Alcohol
Product
OH
Cl
OH
Cl
Reference
1702,
1705@
-
1703,
1703@
1699 32
1722
1660 32
O
Cl
9
Observed
O
Cl
8
Frequency (cm-1)
of Carbonyl peak
Cl
Cl
Cl
Cl
OH
O
10
O
O
@ Obtained by PEG-TEMPO oxidation
31
3.2.2 Oxidation of alcohols to aliphatic and unsaturated ketones
Table 3.2 Oxidation of alcohols to form aliphatic and unsaturated ketones
Entry
Alcohol
Frequency (cm-1)
of Carbonyl peak
Product
Observed
Reference
1710
1685,
1704 32
12
1712,
1714@
-
13
1712,
1712@
1730 33
14
1716,
1717@
1717 32
15
1716
1716 32
1758
1722 32
1759,
1770
1708 32
11
O
O
OH
OH
OH
O
OH
O
O
O
HO
OH
16
O
OH
17
@ Obtained by PEG-TEMPO oxidation
The absorption of pent-1-en-3-one (entry 11), hept-1-en-4-one (entry 12) and
heptane-3-one (entry 16) occur, as expected in the “normal” absorption region.
1-
Phenylpropan-2-one and 4-phenylbutan-2-one (entries 13 and 14) also exhibit absorption
frequencies closer to the “normal” value of 1715 cm-1. Evidently, the C=O group is away
from the influence of the benzene ring in both cases, resulting in an absorption frequency
similar to that of a saturated aliphatic ketone. However, the absorption frequencies for
32
butan-2-one and 3,3-dimethylbutan-2-one do not fit the anticipated trends, and have
unexpectedly high absorption values.
3.2.3 Oxidation of alcohols to cyclic aliphatic ketones
Table 3.3 Oxidation of alcohols to form Cyclic Aliphatic Ketones
Entry
Alcohol
Frequency (cm-1)
of Carbonyl peak
Product
OH
OH
20
OH
HO
O
O
CH3
1716 32
1718,
1720@
1712 32
1717
1721@
1723* 32
1724,
1724@
1711
1717
1722# 32
1742,
1742@
1744 32
CH3
21
(H3C)2HC
(H3C)2HC
H3C
H3C
H3C
H3C
CH3
H
23
1714,
1716@
O
19
HO
Reference
O
18
22
Observed
CH3
H
H
H
O
H
H
H
OH
O
* Absorption frequency determined by Nujol Mull method
# Absorption frequency determined by KBr method
@ Obtained by PEG-TEMPO oxidation
33
In cyclic ketones, the C=O stretch is affected by the adjacent C-C stretch. The
bond angle of the –C-CO-C- group influences the absorption frequency of the C=O
group. In acyclic ketones and in ketones with a 6-membered ring, this angle is nearly
120°. In rings where the angle is less than 120°, ring strain results in increased scharacter at the C=O carbon, and strengthens the C=O bond because of increased overlap
between orbitals on C and O atoms. The force constant increases, resulting in an
increased frequency of absorption. Cyclohexanone, 2-methylcyclohexanone and 4-tertbutyl cyclohexanone (entries 18, 19 and 20 respectively) are some examples of 6membered rings where there is no ring strain. Hence, they show absorption frequencies
similar to that of aliphatic ketones. The same can be said of ketones formed by the
oxidation of (2S,5R)-2-isopropyl-5-methyl cyclohexanol and cholesterol (entries 21 and
22), where the change in absorption frequency is negligible. A drastic increase in the
absorption frequency to 1742 cm-1 is observed in the oxidation of borneol to camphor
(entry 23). As explained earlier, the ring strain in the system causes an increase in energy
required to produce the C=O stretch, resulting in an increased frequency of absorption.
34
3.2.4 Oxidation of alcohols to form aromatic aldehydes
Table 3.4 Oxidation of alcohols to form aromatic aldehydes
Entry
Alcohol
Product
OH
O
Observed
Reference
F
1691,
1690@
1702 33
NO2
1694,
1697@
1699 32
H
F
24
O
OH
H
NO2
25
Frequency (cm-1)
of Carbonyl peak
O
O
26
H
OH
34
1695
~1700
1698
1699# 32
1696,
1699@
-
1715
1676# 32
O
O
O2N
OH
27
O2N
H
Cl
Cl
O
OH
28
H
I
I
O
Br
OH
29
Br
H
OH
OH
35
Table 3.4 Continued
Entry
Alcohol
Frequency (cm-1)
of Carbonyl peak
Product
Observed
Reference
1713,
1693* 32
1728
1702 32
1721,
1721@
1724 32
1709
1745 33
1720
-
1727
-
1723
-
O
OH
30
H
HO
HO
OCH3
OCH3
H
OH
O
31
OCH3
OCH3
OH
H
32
O
O
OH
33
H
+
acid
OH
O
34
H
H3CO
H3CO
O
OH
35
F
F
H
H
36
OH
O
36
Table 3.4 Continued
Entry
Alcohol
Frequency (cm-1)
of Carbonyl peak
Product
37
O
H3CO
OH
38
Reference
1721,
1721@
-
1724,
1724@
1724,
1734 32
1726
-
H
OH
H3CO
Observed
O
H
O
OH
39
Cl
H
Cl
* Absorption frequency determined by Nujol Mull method
# Absorption frequency determined by KBr method
@ Obtained by PEG-TEMPO oxidation
2-Fluorobenzaldehyde (entry 24) shows a decreased frequency of carbonyl
absorption at 1691 cm-1 due to a bulky halogen, viz. a fluorine atom, at the ortho position
causing the aldehyde to have some electrostatic interaction. The absorption frequencies of
2-nitrobenzaldehyde, 4-phenoxybenzaldehyde and 2-iodobenzaldehyde (entries 25, 26
and 28) are, within instrumental error, at relatively the same position as that of 2fluorobenzaldehyde.
In the case of 2-chloro-5-nitrobenzaldehyde (entry 27), the carbonyl absorption
frequency is slightly increased (1698 cm-1). It would appear that the presence of the nitro
group at the meta position has little effect, while the presence of a bulky Cl atom, at the
ortho position, accounts for the observed increase. A significant increase in absorption
frequency is observed in 5-bromo-2-hydroxybenzaldehyde (1715 cm-1) and 4-hydroxy-3methoxybenzaldehyde (1713 cm-1) (entries 29 and 30 respectively). In both instances, it
37
appears that the substituents at the meta position has little effect on the absorption
frequency, while the presence of an OH group in the ortho and para position can result in
a decrease of double bond character of the carbonyl group as explained using Fig 3.3. A
still sharper increase in absorption frequency is observed in the case of 4methoxybenzaldehyde (entry 31) and a resonance structure that contributes to this effect
is shown in Fig 3.3. In all three cases, the absorption frequency should be expected to
decrease; the increased frequency does not fit the anticipated trend.
H
O
H
OCH3
O
OCH3
Figure 3.3 A resonance structure for 4-methoxybenzaldehyde showing decreased double
bond character
Oxidation of 2-p-tolylethanol (entry 33) resulted in the formation of 2-ptolylacetaldehyde and 2-p-tolylacetic acid, as observed by TLC and NMR. The resultant
intermolecular hydrogen bonding could cause the observed decrease in absorption
frequency. 2-4-(Methoxyphenyl)-acetaldehyde (entry 34) and the aldehydes in entries 35
through 39 exhibit absorption frequencies in the range of 1721 cm-1 to 1727 cm-1. In all
these cases, the aldehyde functionality is at least one C atom away from the benzene ring,
and the neighboring alkyl group caused the absorption frequency to occur at slightly
above the “normal” range.
38
3.2.5 Oxidation of alcohols to form aliphatic/ unsaturated aldehydes
Table 3.5 Oxidation of alcohols to form aliphatic/unsaturated aldehydes
Entry
Alcohol
Frequency (cm-1)
of Carbonyl peak
Product
Observed
Reference
1668,
1670@
-
1717
-
1729
1695 32
1729
1694 32
1724
-
1711,
1715@
1729 32
1730
-
H
HO
O
40
41
O
OH
H
H
42
HO
O
H
43
HO
O
H
OH
O
44
H
45
HO
O
H
46
HO
OH
O
O
H
@ Obtained by PEG-TEMPO oxidation
The absorption frequency of (E)-3,7-dimethylocta-2,6-dienal (entry 40) is
observed at a sharply decrease value of 1668 cm-1 due to the effect of conjugation as
explained in Section 3.1.2. However, in (Z)-hex-2-enal (entry 41), (E)-hex-2-enal (entry
42), and (E)-oct-2-enal (entry 43), there is an increase in absorption frequency, possibly
due to the s-cis conformation of the α,β-unsaturated aldehyde as shown in Fig 3.4.
39
H
O
Figure 3.4 s-cis conformation for (Z)-hex-2-enal
Octanal (entry 45) shows the absorption frequency expected for an aliphatic aldehyde, at
1711 cm-1, while decanedial (entry 46) shows an unanticipated higher absorption
frequency.
40
CHAPTER 4
CONCLUSION
The oxidation of alcohols to their corresponding carbonyl compounds was carried
out by the TEMPO-TCCA oxidation system as well as by the PEG-supported TEMPO.
The reactions proceeded to completion without over-oxidation to the corresponding
carboxylic acid in most cases. Polymer supported catalysts are being currently regarded
as amenable alternatives to improve the efficiency of a catalytic process in that they allow
catalyst recovery and recycling. Removal of the catalyst can be achieved by mere
precipitation, making the purification of the product much easier. Both methods provide
mild conditions for oxidation of alcohols, and are viable alternatives to metal based
oxidants. The IR spectra of the carbonyl compounds obtained have been studied, and
trends in absorption frequencies of the carbonyl group have been discussed.
41
REFERENCES
1. Smith, M. B.; March, J. Advanced Organic Chemistry. 5th ed. Wiley-Interscience,
2001.
2. Hudlicky, M. Oxidations in Organic Chemistry, ACS Monograph 186,1990.
3. Atkins, R.C.; Carey, F.A. Organic Chemistry, 2nd ed. McGraw-Hill, 1987.
4. Haines, A. H. Methods for the Oxidation of Organic Compounds - Alcohols, Alcohol
derivatives, Alkyl Halides, Nitroalkanes, Alkyl Azides, Carbonyl Compounds,
Hydroxyarenes and Aminoarenes, Academic Press, 1988.
5. Bagchi, D.; Stohs, S.J.; Downs, B.W.; Bagchi M.; Preuss, H.G. Toxicology, 2002,
180, 5.
6. de Flora, S. Carcinogenesis, 2000, 21, 533.
7. Tomioka, H.; Oshima, K.; Nozaki, H. Tetrahedron Lett., 1982, 23, 539.
8. Omura, K.; Swern, D. Tetrahedron, 1978, 34, 1651.
9. Corey, E. J.; Kim, C. U. J Am. Chem. Soc, 1972, 94, 7586.
10. Dess, D.B.; Martin, J.C. J. Org. Chem., 1983, 48, 4155.
11. Ireland, R.E.; Liu, L.J. J. Org. Chem., 1993, 58, 2899.
12. Friegrio, M.; Santagostino, M.; Tetrahedron Lett. 1994, 35, 8019.
13. DeMico, A.; Margarita, R.; Parlanti, L.; Vescovi, A,; Piancatelli, G. J. Org. Chem.
1997, 62, 6974.
14. Varma, R. S.; Saini, R. K.; Dahiya, R. J. Chem. Res., 1998, 120.
15. Rozantsev, E.G.; Sholle, V. D. Synthesis, 1971, 190.
16. Neiman, M. B.; Rozantsev, E. G.; Mamedova, Y. G. Nature, 1962, 196, 472.
17. Hoskins, R. J. Chem. Phys., 1956, 25, 788.
18. Rozantsev, E.G. Free Nitroxyl Radicals, Plenum press, 1970.
19. Bobbit, J.M.; Flores, C. L. Heterocycles, 1988, 27, 509.
20. Yamaguchi, M.; Miyazawa, T.; Takata, T.; Endo, T. Pure Appl. Chem. 1990, 62,
217.
21. de Nooy, A.E. J.; Bessemer, A.C.; van Bekkum, H. Synthesis 1996, 1153.
22. Semmelhack, M. F.; Schmid, C. R.; Cortes, D.A. Tetrahedron Lett. 1986, 27, 1119.
23. Ma, Z.; Bobbitt, J. M. J. Org. Chem. 1991, 56, 6110.
42
24. de Nooy, A.E. J.; Bessemer, A. C.; van Bekkum, H. Tetrahedron, 1995, 51, 8023.
25. De Luca, L.; Giacomelli,G.; Porcheddu, A. Org. Lett. 2001, 3, 3041.
26. De Luca, L.; Giacomelli, G.; Masala, S.; Porcheddu, A. J. Org. Chem. 2003, 68,
4999.
27. Birney, D. M.; Starnes, S., J. Chem. Educ. 1999, 76, 1560
28. Pozzi, G.; Cavazzini, M.; Quici, S.; Benaglia, M.; Dell’Anna, G. Org. Lett., 2004, 3,
441.
29. Silverstein, R.M.; Webster, F.X. Spectrometric Identification of Organic
Compounds. 6th ed. Wiley-Interscience, 1996.
30. Stuart, B. Infrared Spectroscopy : Fundamentals and Applications. Wiley, 2004.
31. Sorrell, T.N. Interpreting Spectra of Organic Molecules. University Science Books,
1988.
32. Spectral Database for Organic Compounds, SDBS,
http://www.aist.go.jp/RIODB/SDBS
33. The NIST Chemistry WebBook, http://webbook.nist.gov/chemistry/
34. Pouchert, C.J. Aldrich Library of Infrared Spectra, Ed. III, Aldrich Chemical
Company, Inc., 1981.
43
PERMISSION TO COPY
In presenting this thesis in partial fulfillment of the requirements for a master’s
degree at Texas Tech University or Texas Tech University Health Sciences Center, I
agree that the Library and my major department shall make it freely available for
research purposes. Permission to copy this thesis for scholarly purposes may be granted
by the Director of the Library or my major professor. It is understood that any copying
or publication of this thesis for financial gain shall not be allowed without my further
written permission and that any user may be liable for copyright infringement.
Agree (Permission is granted.)
Syed Javed Ali
Student Signature
4/20/2006
Date
Disagree (Permission is not granted.)
_______________________________________________
Student Signature
_________________
Date