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Oxidation of Alcohols by Dioxygen Catalysed with Transition
Metal Complexes
Petro Lahtinen
Laboratory of Inorganic Chemistry
Department of Chemistry
University of Helsinki
Academic Dissertation
To be presented, with the permission of the Faculty of Science of the University of Helsinki,
for public critisism in the auditorium of Arppeanum (Snellmanninkatu 3), on 11th of March,
2005 at 13 o´clock.
2
Supervisor Professor Markku Leskelä Laboratory of Inorganic Chemistry Department of Chemistry University of Helsinki Finland Reviewers Dr. Jussi Sipilä Laboratory of Organic Chemistry Department of Chemistry University of Helsinki Finland Professor Björn Åkermark Department of Organic Chemistry University of Stockholm Sweden Opponent Professor Dr. Karl Wieghardt Max Planck Institute for Bioinorganic Chemistry Mülheim and der Ruhr Germany ISBN 952-91-8375-5 (paperback) ISBN 952-10-2358-9 (PDF) http://ethesis.helsinki.fi Yliopistopaino Helsinki 2005
3
Abstract
The catalytic oxidation with dioxygen in aqueus solutions offers an aconomic and
environmentally safe alternative for oxidation reactions performed in synthetic laboratories
and chemical industry. Applications where oxidation reactions are required are diverse,
ranging from pulp and textile bleaching to production of fine chemicals. At the moment, most
of these processes are carried out by using stoichiometric oxidants, such as peroxides,
chlorine-bearing compounds and high valent transition metal oxides. In addition these
oxidants function often in hydrocarbon solvents which are harmful and sometimes require
special arrangements from the reactor set-up. By using molecular oxygen as oxidant and
aqueous reaction medium the amount of waste produced in the process can be minimized. At
the same time also the cost of the reaction is reduced since molecular oxygen and water are
easy to come by.
In this thesis complexes of iron, copper and cobalt have been investigated as catalysts for
oxidation of alcohols in aqueous solution. In order to find new catalyst for this kind oxidation
reaction, a parallel screening method for screening potential catalysts was developed. The
screening method proved to be very efficient for this task and several new catalysts were
found. The veratryl alcohol (3,4-dimethoxybenzyl alcohol) which was used in the oxidation
tests, is an model compound for lignin. Therefore, the catalysts found in this work can be
considered not only as oxidation catalysts for benzyl alcohol oxidation but also as pulp
bleaching catalysts.
4
Preface
The experimental work for this thesis was made in the Laboratory of Inorganic Chemistry at
the University of Helsinki during years 2001-2004.
I want to express my deepest gratitude to Professor Markku Leskelä and Docent Timo Repo
who have provided me with the opportunity to work under their guidance. I also want to thank
my colleagues in and outside the department for all the help they have given me. Especially,
my closest colleagues, Kaisa Kervinen and Heikki Korpi have set the scene for my work.
Help from Elina Lankinen and Jukka Hamunen in experimental work is also greatfully
acknowledged.
My parents, Eero and Leena, deserve the biggest thanks for supporting me both mentally and
financially during my long years of studies. I could not have done this without your help.
Milli, my darling, above all I want to thank you for believing in me when I did not. Your
lovely and respectful words have helped me in my work more than you believe.
Special thanks to my friends for good conversations and encouragement during these years.
Also the financial support from the Academy of Finland, Association of Finnish Chemical
Societies and Tekniikanedistämissäätiö (Foundation for Advancing Technology) is greatfully
acknowledged.
February 2005, Helsinki
Petro Lahtinen
5
List of Original Publications
The thesis includes five publications and they are refered in the text with their roman
numerals.
I. Kervinen, K., Lahtinen, P., Repo, T., Svahn, M. and Leskelä, M.: ‘The effect of reaction
conditions on the oxidation of veratryl alcohol by cobalt salen-complexes’ Catalysis
Today 75 (2002) 183.
II. Korpi, H., Lahtinen, P., Sippola, V., Krause, O., Leskelä, M. and Repo, T.: ‘An efficient
method to investigate metal-ligand combinations for oxygen bleaching’ Applied
Catalysis A: General 268 (2004) 199.
III. Lahtinen, P., Korpi, H., Haavisto, E., Leskelä, M. And Repo, T.: ‘Parallel screening of
homogeneous copper catalysts for oxidation of benzylic alcohols with molecular oxygen
in aqueous solutions’ Journal of Combinatorial Chemistry 6 (2004) 967.
IV. Lahtinen, P., Lankinen, E., Leskelä, M. and Repo, T. ‘Insight into copper oxidation
catalysts: Kinetics, catalytic active species and their deactivation’ Submitted to Journal
of Catalysis.
V. Lahtinen, P., Leskelä, M. and Repo, T.: ‘A Non-heme Iron Catalyst for Oxidation of
Alcohols by Dioxygen’ Submitted to Advanced Synthesis and Catalysis.
6
Table of Contents
Abstract 3
Preface 4
List of Original Publications 5
Table of contents 6
Abbreviations 7
1. Introduction 8
2. Background 9
2.1 Cobalt catalysts 10
2.2 Copper catalysts 15
2.2.1 The Mechanisms of alcohol oxidation catalysed by Copper complexes 15
2.2.2 Copper dioxygen adducts and their use as stoichiometric oxidants 17
2.2.3 Copper catalysts used in catechol oxidation 19
2.2.4 Copper oxidation catalysts used in alcohol oxidation 22
3. Iron catalysts 27
4. Combinatorial Chemistry 31
4.1 The concept of combinatorial chemistry 32
4.2 Library synthesis 32
4.3 Screening Experiments 33
5. Experimenta 33
5.1 Cobalt-salen Catalysed Oxidations 34
5.2 Parallel Screening Method 35
5.3 Effect of Reaction Conditions on Conversion and Reaction Optimization 37
5.4 Reaction Kinetics 39
5.5 Reaction Termination 41
5.6 Pulp Bleaching Experiments 43
5.7 Iron Catalyst 44
6. Conclusions 46
References 47
7
Abbreviations Acac anion of acetylacetone Acacen N,N'-ethylenebis(acetylacetonylideneiminate) MeCN acetonitrile Atm atmospheric pressure bbmhe N,N-bis(2-benzimidazolylmethyl)-1-hydroxy-2-aminoethane bdpdz 3,6-bis(di-2-pyridylmethyl)pyridazine Co(4-hydroxySalen) N,N´-bis(4-hydroxy salisylidene)ethylenediamine cobalt(II) Co(DACHSalen) (R,R)-(-)-N,N'-Bis(3,5-di-tert.-butylsalicylidene)-1,2-cyclohexane-
diamino-cobalt(II) CoSANPE bis[2-[{1-phenylethyl)imino}methyl]phenolato-N,O]Cobalt DACH 1,2-diaminocyclohexane DAPHEN 9,10-diaminophenantrene DBAD di-tert-Butylazodicarboxylate DBADH2 di-tert-Butylazohydrazine DMF dimethylformamide DMG dimethylglyoxime DTBC 3,5-di-tert-butylcatechol DTBQ 3,5-di-tert-butylquinone EtOAc ethylacetate GC Gas chromatography HPLC High pressure liquid chromatography HT High Through-put KOH potassium hydroxide L Ligand mbdpdz 3,6-bis[(6-methyl-2-pyridyl)(2-pyridyl)methyl]pyridazine MeOH methanol MS Mass spectrometry NBA p-nitrobenzoic acid pzmhe N,N-bis(3,5-dimethylpyrazol-1-ylmethyl)-1-hydroxy-2-aminoethane Pzmhp N,N-bis(3,5-dimethylpyrazol-1-ylmethyl)-1,3-diamino-2-
hydroxypropane RhB Rhodamine B RT Room temperature Salen N,N´-bis(salisylidene)ethylenediamine t-BuOK potassium salt of tert-butanol TEMPO 2,2,6,6-tetramethylpiperidine N-Oxyl(radical scavenger) THF tetrahydrofuran TMEDA N,N,N´,N´-tetramethyl ethylenediamine TOF Turn over frequency (catalytic cycles/moles of catalyst) TON Turn over number TPP tetraphenylporphinato
8
1. Introduction
The oxidation of organic compounds is an important and widely used reaction in laboratory
scale organic synthesis as well as in large scale chemical industry.1,2 There are hundreds of
different reagents and methods available for the oxidation of organic chemicals. Even though
these methods exist and are very applicable for a laboratory scale, most of them share
common disadvantages from an industrial point of view. Many industrial oxidation reactions
are currently performed with a stoichiometric amounts of oxidants such as peroxides or high
oxidation state metal oxides. These oxidants are expensive and the processes where these
oxidants are used generate organic and heavy metal waste.3 When reactions are scaled to tons
instead of grams, the use of stoichiometric oxidants is not an attractive option. For these kind
of reactions an alternative and environmetally benign oxidant is welcome.
An ideal oxidant for any large scale oxidation reaction should be easily accessible, cheap and
non-toxic. As it happens, the best oxidant to fit this description is dioxygen.4 It is easily
available since it is present in air and the only by-product produced from its decomposition is
water. There are few things however which make the use of molecular oxygen challenging: 1)
although dioxygen has a high oxidation potential, it is not very reactive towards organic
molecules, 2) the reactions where dioxygen is present are often radical reactions, which are
hard to control. What is needed for efficient use of dioxygen is the appropriate catalyst which
activates the dioxygen molecule and mediates the oxidation potential to right oxidation
reaction.
Currently dioxygen is in use in several large-scale oxidation reactions, catalysed by inorganic
heterogenous catalysts.5 Typically these reactions are carried out at high temperatures and
pressures, often in the gas phase. Unfortunately, these heterogenous oxidation methods are not
suitable for reactions required by fine chemical industry, where selectivity and mild reaction
conditions are favoured in the production of high value products. If the stoichiometric
oxidants are to be replaced by dioxygen, catalysts which are able to activate dioxygen at mild
reaction conditions and in solution phase are required. The most promising solution to this
challenge is homogeneous transition metal complexes which are able to catalyse selective
oxidation reactions under mild conditions by using dioxygen.
9
The aim of this work was to find and study transition metal complex catalysts, which are able
to promote the selective oxidation of benzylic alcohols to aldehydes by dioxygen in aqueous
solutions. This reaction is important for two reasons: 1) the oxidation of alcohols, including
benzylic alcohols, is an important reaction to the fine chemical industry. Aldehydes made by
selectively oxidizing alcohols are used in great quantities as flavours, fragrances and
pharmaceuticals, not to mention food additives and crop protection agents. 2) the veratryl
alcohol (3,4-dimethoxybenzyl alcohol, Figure 22) used in this work is a lignin model
compound. This means that the compounds able to catalyse the oxidation of veratryl alcohol
should also be active as pulp bleaching catalysts. The interest in water soluble homogeneous
catalysts arises from the environmental and economical benefits of using dioxygen based
methods, compared to traditional methods described above.
An introduction to principles of combinatorial methods along with a survey of the current
state of transition metal complex catalyzed oxidation research is given in the Background
section. The area of homogeneous catalytic oxidations is vast and it is too extensive to be
discussed here thoroughly. Therefore only the catalysts which are able to activate dioxygen
and contain cobalt, copper or iron are discussed herein. In the Experimental part, research
methods used in the experimental work of this thesis and the key results are introduced. The
significance of the findings made in the experimental work and its importance to the field of
catalytic oxidation research is summed up in the Conclusions section.
2. Background
Although dioxygen has the thermodynamical potential required from a good oxidant, the
kinetic and thermodynamic restrictions caused by the spin conservation rule and its one-
electron reduction reaction pathways make it rather inert towards organic molecules.6
Therefore, in order to get dioxygen to efficiently react with organic molecules, the electronic
configuration of the dioxygen molecule (a triplet in ground state) has to be changed to match
the electronic configuration of the organic molecules (a singlet ground state). This can be
done either physically with light excitation6 or chemically by letting the dioxygen react with,
for example, transition metals. This is the basis for using transition metal complexes as
oxidation catalysts.
Copper and iron are essential metals for living organisms, since they are present in active sites
of many oxygen activating enzymes. A good example of a such enzyme is cytochrome c
oxidase, which plays a key part in cell respiration.7 The reactions catalyzed by cytochrome c
10
oxidase and other similar enzymes are the same as those sought for in homogeneous oxidation
catalysis. The active sites of these enzymes serve as good structural models for catalysts. The
fact that transition metals are already in efficient use in nature, as oxidation catalyst gives
motivation to search for synthetic transition metal oxidation catalysts.
2.1 Cobalt catalysts
The reactivity of cobalt(II) complexes toward dioxygen has long been recognized.8,9 An
extensive record about the ability of cobalt complexes to activate dioxygen has accumulated.10
By far the most widely used cobalt catalysts are cobalt complexes of salen, porphyrin and
acacen (Figure 1). Salen and acacen ligands have two nitrogen and two oxygen donor atoms.
This is typical for cobalt complexes used as oxidation catalysts.
N N
OOCo
NN
N NCo
N N
OOCo
II
R
NN
N N
R
R
R
N
O
N
OCo
Co
OMe
N
ON
OCo
N N
OOCo
O
O O
OCo
Co
NO
NO
H
NO
NO
H
Co(Salen) Co(Acacen) (2) Co(Porphyrin) (3)
Co(DMISalen) (4) R=
3-MeO-TPP (5)
CoPEIMP (6)
Co(DACHSalen) (7)"Jacobsen ligand"
Co(acac)2 (8)
Cobaloxime(II) (9)
(1)
Figure 1. Structures of Cobalt complexes as discussed in the text.
11
The mechanism of oxidation reactions, catalysed by cobalt complexes and using dioxygen as
oxidant have been widely studied. Reaction pathways for oxidation of different substrates
have been suggested.11,12,13,14,15,16 The active intermediate of cobalt catalysts depends on the
type of oxidation reaction. Two most commonly encountered active intermediates are the
superoxocobalt(III) and oxocobalt(IV) complexes. 10,17,18,19 The oxygen atoms in the
superoxocobalt(III) complex are as a superoxoradical. This is formed when dioxygen is
oxidatively coordinated to the cobalt center of the catalyst. The oxocobalt(IV) complex is
formed when the superoxocobalt(III) complex reacts with a carbonyl compound to give a
carboxylic acid (Figure 2). Generally, it is thought that the active intermediate in
dehydrogenation reactions is a superoxocobalt(III) complex and in O-insertion reactions the
oxocobalt(IV) complex is responsible for the oxidation of the substrate, hence a sacrificial
aldehyde is added to oxidation reactions where oxygen insertion is required.
Co(III)L O O O C
O
C
Co(III)L OHO
O2Co(II)L Co(III)L O O
Co(IV)L
O
Superoxocobalt(III) species
+R1
H
R1
+
Oxocobalt(IV) species
RCOOH
Figure 2. Schematic representation of the formation of catalytically active intermediates of cobalt complexes, which are formed in oxidation reactions involving dioxygen as oxidant.
The properties of cobalt catalysts can easily be changed by modifying substituents of the
ligand frame. For example the solubility of the complexes can be changed by adding either
hydrophilic or hydrophobic groups. Stereoselectivity of the catalyst can be influenced by
adding chiral structures to the ligand.20
Typical oxidation reactions catalysed by cobalt complexes are epoxidations, oxidation of
phenols, hydroxylation of alkenes and oxidation of alcohols to aldehydes.10 The selection of
oxidants used in these reactions is diverse but only the catalytic reactions involving dioxygen
are discussed here. Presented next are some examples from the most efficient oxidation
reactions catalysed by various cobalt complexes, with dioxygen as oxidant.
12
Co(Salen) (Figure 1) and its analogues have been used for catalysing the oxidation of phenols
and alcohols (mostly lignin sub-structures)21 with dioxygen as oxidant. Reports about
oxidation of alkenes also exist.10,22 In order to efficiently bind dioxygen and to be catalytically
active, Co(Salen) needs an axial ligand (Figure 3). The dioxygen is coordinated orthogonally
to the square planar coordination sphere of Co(Salen). The axial ligand is needed to fill the
sixth coordination site, opposite to dioxygen. Pyridine21 is the most common axial ligand used
in the Co(Salen) catalysed oxidation reactions. Other bases, for example, imidazole and
pyrimidine have also been used.23 An alternative way to provide an axial ligand is to use
modified salen structure, which has an extra nitrogen, for intramolecular axial coordination in
the ligand frame.21
Co
N
NNH N
O O
Co
NN
OO
(10)
Figure 3. On the left, a coordination sphere of Co(Salen) with axial pyridine ligand and on right, a five dentate modification of Co(Salen).
Co(acac)2 (Figure 1) is an unusual cobalt catalyst in the sense that it has only oxygen donors
in the ligand. It is similar to Co(Salen) in its catalytic properties and has been reported to
catalyse the oxidation of hydroxyketones,24 phenols25 and alcohols,26 with dioxygen.
Reactions are typically carried out in close to ambient conditions with moderate to high
conversion rates however, unlike in Co(Salen) catalysed reactions, no axial ligand is required
by Co(acac)2.
Cobaloxime(II) (Figure 1) complexes have been reported to catalyze oxidative
dehydrogenations and oxygen insertions into some organic substrates, under ambient
conditions.27 The complex has two dimethylglyoxime (DMG) ligands bound together with
hydrogen bonds, making the coordination sphere square planar. Addition of axial ligand
(pyridine, imidazole, Ph3P, etc.) to the fifth coordination site increases the activity.27 It has
been reported to catalyse the oxidation of 3,5-di-tert-butylcathechol to the 1,2-
13
benzoquinone,28 as well as the oxidative cleavage of a stilbene double bond with
dioxygen.29,30
Cobalt(II)porphyrin is not an effective oxidation catalyst for the oxidation of organic
substrates, due to the reactivity of the porphyrin itself 31,32 but when the ligand is halogenated
or otherwise substituted, it can be used as an efficient and versatile oxidation catalyst.35,33,34
Substituted cobalt(II)porphyrins are reported to be efficient catalysts for oxygen insertions to
hydrocarbon substrates under ambient conditions.35 In these cases, as mentioned previously,
carbonyl compounds are needed as sacrificial additives. Selected oxidation reactions catalysed
by cobalt complexes are given in Table 1.
14
Table 1. Selected results of oxidations, made with dioxygen and catalysed by cobalt complexes.
Catalyst Temperature, O2 pressure,
Reaction time
Medium Additives Substrate Product Conversion
(%) TON
Reference
1 RT 1 atm 2.5 h
DMF Pyridine OH
O
O 98 %
20
36
4 RT 1 atm 1 h
DMF Pyridine OH
O
O 100 %
20
36
5 RT 1 atm 3 h
CH3CN 2-methylpropanal
O
100 %
40
35
5 RT 1 atm 3 h
CH3CN 2-methylpropanal
1O
+3+
OH
1.2
O
84 %
33
35
6 RT 1 atm 5.5 h
anhydrous CH3CN
-
OH
O
94 %
20
37
6 RT 1 atm 3 h
anhydrous CH3CN
- OH
O
96 %
20
37
7 20 oC 1 atm
Over night
CH3CN propanal
4O
+
1
O
98 % total
196
38
8 40 oC 1 atm 6 h
1,2-dichloroethane
2-methylpropanal OH
OHO
96 %
58
26
9 40 oC 1 atm 48 h
1,2-dichloroethane
3-methylbutanal OH
O
O 61 % yield
20
25
15
2.2 Copper catalysts
Typically, commercially used copper oxidation catalyst systems are heterogenous and are
composed of copper salts or oxides, and are often mixed with other metals.39,40 The Wacker
Process, where a catalyst containing palladium and copper chlorides, is used for converting
alkenes into alcohols and is a good example of an industrially important large scale oxidation
reaction.1
The homogeneous copper based oxidation catalysts have not found their place in large scale
industry yet but they are very important to academic research. Since the 1990´s a significant
number of the publications concerning copper complexes, as models for active sites of oxygen
activating enzymes, have been published.41 The information obtained about the ability of
copper complexes to activate dioxygen has also benefitted oxidation catalysis research and
thus most copper catalysts reported are similar to the complexes used in enzyme research.
Introduced here are the most efficient and elegant copper oxidation catalyst systems, which
use dioxygen as oxidant.
2.2.1 The mechanisms of alcohol oxidation catalysed by copper complexes
Most ligands used in homogeneous copper complex catalysts have nitrogen as donor atoms
but few exceptions exist where also oxygen serves as donor atom. Copper catalysts can be
divided into mononuclear and binuclear complexes by the number of copper atoms in their
structure.42 The mononuclear complexes are more common in oxidation catalysis research and
binuclear complexes are typically encountered in catechol oxidase enzyme research.
In cells, the enzymatic reaction where alcohol is selectively oxidized to aldehyde, by
dioxygen, is catalyzed by galactose oxidase enzyme.43,44 The oxidation reaction catalyzed by
galactose oxidase is a two electron reduction of dioxygen to hydrogen peroxide, with
concomitant oxidation of alcohol to aldehyde.43 The aldehyde produced is released together
with the hydrogen peroxide and in living cells, catalase enzyme further degrades it to
dioxygen and water. The structure and the reaction mechanism of the galactose oxidase is
well known44 but the reaction mechanisms of the synthetic counterparts are not equally clear.
It seems that the reaction mechanisms change between these synthetic catalysts, although the
reactions catalysed by them, the oxidation of alcohol to aldehyde by dioxygen, are the same.
The two most important mechanisms for oxidation of alcohols to aldehydes with dioxygen,
catalysed by copper complexes, are the ones suggested by Wieghardt et al 45 and Markó et al
16
(Figure 4).46 The net reaction observed by Wieghardt et al is the same as in the galactose
oxidase catalysed reactions. In other words, hydrogen peroxide is formed in a 1:1 ratio with
the aldehyde. In this mechanism not only the copper is oxidized and reduced but also the
ligand is involved in the transportation of electrons during the catalytic cycle. This is a unique
feature since usually only the metals are considered to participate in the electron transport
between dioxygen and substrate. In the reaction mechanism suggested by Markó et al the
dioxygen molecule is reduced to water, peroxide is present only as a bridge between two
copper phenanthroline complexes and it is not released to reaction solution (Figure 4). This
mechanism involves auxiliary hydrazine which, according to suggested reaction mechanism,
serves as hydrogen acceptor. But it has to be kept in mind that a Cu(I) hydroxy species, which
in said to occur in the mechanism, is not known in the literature and no direct evidence for it
is presented by the group. Therefore the exact catalytic cycle is still left unclear.
R H
O
O H
HR
OC
R
H
NOO
C N
OO
NOO
N
N
N
N
N
N
N NEE
N NEE
H
N NEE
H
N NEE
Cu
Cu
Cu
N
NCu
OR1
R2H
OR1
R2
O O
OH
OHR1
R2H
OR1
R2
[CuII(L2)(NEt3)]
CuII(L2H)(NEt3)
CuII(L3H2)(NEt3)
[CuI(L3H2)(NEt3)]
[CuI(L3H)][(NEt3H)]
[CuII(L3H2)(O2*-)(NEt3)]
RCH2OH
or
R=CH3, Ph
O2
H2O2
L1= L2=
L3=
H2O
O2
copper-alkoxide/azo
hydrazino-copper
Cu(II) peroxide
Cu(I) hydroxy
R1;R2=alkyl, aryl, heteroaryl, HE=COOEt, COOBut
Figure 4. The reaction mechanisms for oxidation of alcohols to aldehydes as suggested by Wieghardt et al (left) and Markó et al.45,46
17
2.2.2 Copper dioxygen adducts and their use as stoichiometric oxidants
The binding of dioxygen to the copper centers of enzymes have been studied by synthesizing
dioxygen adduct copper complexes. The ligands used are often pyridyl or imidazole
compounds where the dioxygen forms a bridge between two copper atoms. An example of a
mononuclear copper complex is presented in Figure 5, with the binuclear dioxygen adduct
and the reaction scheme of oxidation of organic substrates.47 The dioxygen adduct copper
complex 13a has been used as a stoichiometric oxidant in oxidation of 2,4-di-tert-butyl
phenol, dihydroanthracene and 1,4-cyclohexadiene substrates. The dioxygen adduct
complexes are stable only at reduced temperatures and therefore the oxidation experiments
were made at -80 oC. The substrates were observed to donate hydrogen atoms to the dioxygen
adduct complex in a reaction where dioxygen bridge is transformed into a hydroxyl bridges.
N
N
N
R
R
Cu(I)
AcCN
N
N
N
O
N
N
N
R
R
CuO
N
N
N
R
R
Cu
OH
N
N
N
R
R
CuOH
N
N
N
R
R
Cu
MePY2 (11)
+ 2+
2+
-80oC
O2, AcCN
R=H, MeO, Me2N (12a,12b,12c)
Reduced substrate
Oxidized Substrate
(13a,13b,13c)
(14a,14b,14c)
Figure 5. The copper complexes of bis[2-(2-pyridyl)ethyl]methylamine (11) and their reaction scheme studied by Karlin and Zuberbühler. The 13a, 13b, 13c have been used as stoichiometric oxidants toward organic substrates.47
In a later study this same copper complex 13a with few modified versions 13b and 13c were
observed to oxidize THF, methanol and some other relatively inert substrates.48 It was also
shown that if there is no exogenous substrate available, an intramolecular oxidation which
inactivates the catalyst may occur (Figure 6).49,50 This was observed for example with m-xylyl
18
bridged binuclear copper complex 15, presented in Figure 6. The m-xylyl backbone of the
ligand is hydroxylated by the coordinated dioxygen yielding a stable hydroxylated ligand 18.
CuCuNN
PY PYPYPY
O
OCuCu
NN
PY PYPYPY
O
OCuCu
NN
PY PYPYPY
OHNN
YP YPPYPY
O2
PY=2-pyridyl
(18)
(15) (16)
(17)
Figure 6. The reaction scheme for the irreversible intramolecular oxidation of the ligand in the complex 15. The first step is a reversible dioxygen binding and the second is irreversible ligand hydroxylation.49
Mukherjee et al have also studied oxygen binding to m-xylyl bridged binuclear copper
complexes. Their m-xylyl-bridged complexes of copper(I) were first reported to show same
intramolecular oxidation of the ortho position of the xylyl backbone, as was discussed above
(Figure 6).51 By adding a fluorine atom to the xylyl-backbone, the intra molecular oxidation
of the ligand can be prevented and thereby enabling the oxidation of exogenous substrates
(Figure 7). The compound 19, a dioxygen adduct of the complex obtained by letting the
complex react with dioxygen, was used as stoichiometric oxidant in phenol oxidation.52 In the
oxidation reaction the phenols are oxidatively coupled to yield dimerized quinones and the
dioxygen in the complex is hydrogenated to give a hydroxyl bridge.
Cu(II)
NHNH
NN
F
Cu(II)O
O
2+
2 ClO4-
(19)
Figure 7. The dioxygen adduct of binuclear copper complex, which has been used as catalyst in oxidation of substituted phenols by Mukherjee et al.52
19
Stack et al have studied dioxygen binding properties of copper(I) complexes with n-
alkyldiamine ligands which are structurally similar to those used in the experimental work of
this thesis. The ligand structures were observed to be critical in controlling the formation of
the copper-oxygen complex and the subsequent reactivity of the complex. The copper
complexes react with dioxygen to form either a µ-η2:η2-peroxodicopper(II) species or bis-µ-
oxodicopper(III)species, depending on the substituents on the nitrogen donors (Figure 8).53,54
These oxo-copper complexes of ethylenediamine type ligands can be used as stoichiometric
oxidants in phenol and alcohol oxidations.55,56
CuN
NNCMe
CuN
N
OCu
N
N OH
H H
H
CuN
N
OCu
N
N OCu
N
N
OCu
N
N O
N
NCu NCMe Cu
N
N
OCu
N
N O
O2, -80 oC
THF
THF
O2, -80 oC
+
O2, -80oC
CH2Cl2
(20) (21)
(22)
(23)
(24b)(24a)
Figure 8. The structures of complexes and copper-oxygen cores reported by Stack et al.53,54
2.2.3 Copper catalysts used in catechol oxidation
The 3,5-di-tert-butylcatechol is a common substrate in catechol oxidase enzyme research
(Figure 9). Several papers have been published concerning binuclear copper complexes, as
active models for catechol oxidase. In Figure 10, a selection of ligands used in catechol
oxidase research is displayed.57,58,59,60 Typically, polar solvents were used as reaction
medium. In these studies mostly MeOH, MeCN and water. The progress of the catechol
oxidation reaction can be conveniently followed by monitoring the strong absorbance peak of
quinone in the UV/Vis spectrophotometer. This means that in most cases, the final yield of
the reaction is not determined but only the initial reaction rate is reported.
20
OH
OH OO
RT, O2
SolventCatalyst
Figure 9. Catechol oxidation reaction, catalyzed by catechol oxidase model compounds, in presence of oxygen.
NN
NNN N
NN
NNN N
N
NO
N
N
OCuCu
AcCn
AcCn
OO
N
N
NNH
ON
Cu Cu
N
N
N
NN
OH
NN
NN
NOH
NN N
HNN
NH
OH
2+
(25) (26)
(27) (28)
(29)
(31)
2+
(30)
Figure 10. Nitrogen donor ligands and some complexes used as catechol oxidase model compounds, as discussed in the text.
The mononuclear copper(II) complexes of 25 (pzmhe, N,N-bis(3,5-dimethylpyrazol-1-
ylmethyl)-1-hydroxy-2-aminoethane), 26 (bbmhe, N,N-bis(2-benzimidazolylmethyl)-1-
hydroxy-2-aminoethane) and 27 (pzmhp, N,N-bis(3,5-dimethylpyrazol-1-yl methyl)-1,3-
diamino-2-hydroxypropane) have been studied as catalysts in the oxidation of 3,5-di-tert-
catechol (Figure 10).58,61 The copper complexes of 25 and 26 are ones of the few catecholase
active catalysts reported, which are not binuclear. The ligands are coordinated from four
donor nitrogens to copper atom and the fifth coordination site is occupied by a readily
dissociative anion. It was observed that the catalytic activity of the complexes are not only
dependent on the organic ligand but also on the type of inorganic anion coordinated to copper
center. Generally, the complexes with pyrazol ligands were more active and the complex with
21
molecular formula of [Cu(pzmhe)N3]BF4 was observed to be the most active complex, with
reaction rate of 0.186 µmol of product per mg of catalyst in one minute.58 The oxidation
experiments were carried out at room temperature in MeOH solutions.
As examples of binuclear copper complexes capable of catalysing 3,5-di-tert-butylcatechol
oxidation with dioxygen, the complexes of 28 (bdpdz, 3,6-bis(di-2-pyridylmethyl)pyridazine)
and it´s methyl substituted modification 29 (mbdpdz, 3,6-bis[(6-methyl-2-pyridyl)(2-
pyridyl)methyl]pyridazine) can be mentioned together with asymmetric binuclear copper
complexes 30 (binuclear copper complex of (N,N,N´-tris-(2-pyridylmethyl)-1,3-
diaminopropan-2-ol) and 31 (binuclear copper(II) complex of (2-pyridylmethyl)(1-
hydroxypropyl)amine). 57,59,60,62,63 The oxidation reactions with copper complexes of 28 and
29 were made in MeOH at close to room temperature, with dioxygen as oxidant. The largest
reaction rate constant was recorded for [Cu2(mbdpdz)Cl(H2O)]Cl3, while other complexes,
although active, showed lower rate constants. Interestingly, the addition of two equivalents of
base (KOH), in respect to complex, was observed to enhance the reaction rate but no reason
for this phenomenon is given in the literature. Also complex 30 is active only above pH 8 in
water/MeOH solution. This is a unique feature of the catalyst system since usually water is
carefully excluded from the reaction solutions in which catechol is oxidised. The oxidation
reactions with 31 were made in MeCN solutions under atmospheric pressure and at room
temperature. The initial reaction rate was determined with UV/Vis measurents and the
maximum TOF observed for this catalyst was 32.
Complexes with more complicated ligand structures have also been used as catalysts, in
catechol oxidation. Some examples of such ligands are presented in Figure 11.64,65 The
copper complexes of ligands 32, 33 and 34 catalyse the oxidation of 3,5-di-tert-butylcatechol
(DTBC), in oxygen saturated buffered methanol/water solution and at pH 5.1. The copper
complex of 34 was observed to be the most active, although all copper complexes with
ligands 32, 33 and 34 were able to catalyze the oxidation of catechol. The reaction is
suggested to proceed in two steps; the first step involves electron transfer between catechol
and the dicopper(II) centers, the second step involves oxygenation of the dicopper species and
the electron transfer from the catechol anion to the dioxygen moiety. Recently a modified
version of 34 was reported to catalyze the stereo selective oxidation of L- and D-Dopa and
Dopa-OMe.66
22
NNN N
N
NNN N
N N N NN
N
N N NN
N
NN
N
NN
N
NN
NN
Cu(II)Cu(II)NN
bz bzbz bz
bz=1-methyl-benzimidazole
(32) (33) (34)
(32a)
Figure 11. The ligands of the copper complexes used for catechol oxidation.65
2.2.4 Copper oxidation catalysts used in alcohol oxidation
Copper complexes of 1,10-phenanthroline (phen) and 2,2´-bipyridine (bipy) have been
reported to be efficient catalysts in the selective oxidation of alcohols, by dioxygen. Several
patents have emerged concerning their use as catalysts. The catalytic activity of the copper
complexes of 2,2´-bipyridine (bipy) and 1,10-phenanthroline (phen) are similar and therefore
they are often discussed together. The complexes of bipy and phen the are most active and
versatile copper oxidation catalysts reported so far. Structures of these ligands are presented
in Figure 12. Copper phenanthroline complexes have been found to catalyse the oxidation of
alcohols,67 MeCN68 and pyridine.69 The common denominator in these reactions is the need
for basic conditions. The oxidation rates are also higher in nonaqueos solutions, which is
explained by the change in the oxidation mechanism from aqueous radical to nonradical. For
example, in basic aqueous solution the 1-propanol is converted into acids and aldehydes,
formic acid being the main product (45-65 %). The same reaction in basic DMF solution
proceeds two orders of magnitude faster. Same kind of behavior is observed when benzyl
alcohol is used as substrate.
23
NN NN
1,10-phenantroline 2,2´-bipyridine(33) (34)
Figure 12. Structures of phenanthroline and bipyridine.
In the 1980´s, selective oxidation of primary alcohols, including MeOH and EtOH, to
corresponding acids, in basic aqueous solutions by dioxygen and catalyzed by copper
phenanthroline was reported.70,71 Reactions were carried out in 1 M NaOH solutions at 60-100 oC, under 2-4 atm dioxygen pressure. Maximum conversion of 55 % was observed with
EtOH. This corresponds to a TON of 55. Since then, a number of papers concerning copper
phenanthroline and bipyridine have been published. Sawyer et al have made catalytic
oxidations of alcohols, catalysed by copper bipyridine.72 They oxidised primary, secondary
and benzylic alcohols to corresponding aldehydes, in basic MeCN solutions. The highest
conversions of 37 % and 38% were observed with unsubstituted and 4-methoxy substituted
benzylalcohols, respectively. These conversions correspond to a TON of approximately 75.
The reaction mechanism is suggested to be similar to what is observed with a galactose
oxidase system, without the accumulation of hydrogen peroxide.
Another oxidation method using copper-phenanthroline complex, as catalyst in oxidation of
benzylic and secondary alcohols, was published in 1996 by Markó et al46 In their system,
carboxylate and hydrazine compounds were used as additives, with copper(I)phenanthroline
in order to enhance the rate and total TON of the reaction.73 The hydrazine acts as hydrogen
acceptor. It receives a hydrogen atom from the substrate and donates it to oxygen during the
catalytic reaction. Reactions were carried out under basic conditions, at temperature of 70-90 oC and in toluene. They were observed to reach high conversions in short period of time. The
suggested reaction mechanism was discussed earlier and can be found in Figure 4. The
general reaction scheme is presented in Figure 13 and key results are displayed in Table 2.
OHH
R1R2 O
H
R1R2
5 mol% CuCl, 5 mol% Phen2 equiv. K2CO3
5 mol % Additive (DBADH2)O2, toluene, 70o or 90o C
Figure 13. The oxidation reaction and reaction conditions used in the work of Markó et al.46
24
Table 2. Results from copper(I)phenanthroline oxidations of various alcohols.46
Entry Substrate Product Yield a
(Conversion)
Time
(min.)
TONb
1
Cl
OH
Cl
O
83
(100)
90 20
2 OH
O
89
(100)
60 20
3 OH
O
71
(75)
60 15
4 OHC9H19
OC9H19
88
(90)
120 18b
5 C9H19 OH
C9H19 O
73
(87)
45 9b
6
N
OH
N
O
81
(87)
60 18
7 OH
t-Bu
O
t-Bu
84
(87)
120 9c
a Yield is the amount of recovered product, 100 % conversion means no substrate is left. b Calculated from the conversion. c DBAD was used instead of DBADH2.
A similar system to that published by Markó et al was recently reported by Gamez and
coworkers with bipyridine ligands. In their study the oxidation reactions were carried out at
room temperature under basic MeCN/water solution with air used as dioxygen source. The
copper(II) bipyridine system uses 2,2,6,6-tetramethylpiperidine N-Oxyl (TEMPO, a radical
scavenger) as additive and is able to catalyse selectively the oxidation of primary and benzylic
alcohols to aldehydes, with high conversions. For example, benzyl alcohol is converted to
25
benzaldehyde with 100 % conversion and octanol with 95 % conversion.74 Interestingly this
catalyst system is not able to catalyse the oxidation of secondary alcohols. The authors
suggest that this is due to steric hindrance in the coordination of the secondary alcohols to
copper but this is an unlikely reason since secondary alcohols are oxidised in a similar copper
phenanthroline system, reported by Markó et al discussed above.
NN
R OH R O
5 mol% CuBr2
5 mol%
5 mol % TEMPO5 mol % t-BuOKCH3CN:H2O 2:1air, 25 oC
Figure 14. The reaction system used by Gamez and coworkers for the oxidation of primary alcohols.74
A modification of a previous bipyridine system, where perfluoroalkylated bipyridine ligand
35 with copper bromide in biphasic chlorobenzene and perfluoroctane solution is used, for
catalysing oxidation of various alcohols to corresponding aldehydes and ketones has been
reported (Figure 15).75 This method also uses TEMPO as radical scavenger.76 The ligand 35
and it´s corresponding copper complex, formed in situ, are soluble in perfluoroctane phase
while the substrate and the products are soluble in chlorobenzene. The conversions recorded
with various primary and secondary alcohol substrates varied between 70 % to 96 %. The
summarised results of this work are collected in Table 3. The TONs were not recorded in the
original publications and have been calculated afterwards. The most significant benefit of this
method is that the catalyst is easily separable and recyclable, without any loss of activity.
NN
C8F17C8F17 44
OH
NO2
O
NO2
L=
L, CuBr*Me2S(2 mol%)TEMPO(2,5 mol%)
C8F18/C6H5Cl90oC, 1 atm O24 h (35)
Figure 15. The oxidation reaction scheme used by Knochel et al.75
26
Table 3. The oxidation results obtained with the biphasic catalytic system, using the reaction scheme presented in the Figure 15.
Entry Substrate Product Yield TON
1
O3N
OH
O3N
O
93 % 47
2 OH
Br
O
Br
96 % 48
3 OH
OMeMeO
O
OMeMeO
93 % 47
4 OH
O
79 % 40
5 OH
O
91 % 46
6 OH O 73 % 37
7 OH O 71 % 36
8 OH O
31 %a 16
a Conversion after 17 h
Wieghardt et al have published a series of copper complexes capable of catalysing the aerial
oxidation of alcohols, including EtOH and MeOH, to corresponding aldehydes at ambient
conditions (Figure 16). 45,77,78,79 The catalysts are reported to function in certain organic
solvents (THF, MeCN) or in pure substrate solutions, for example, in pure benzyl alcohol.
The selected results from oxidation experiments, performed with these complexes, have been
collected in Table 4. As discussed earlier, the catalysts behave similarly to galactose oxidase
enzyme. This means that the reduction product of dioxygen is hydrogen peroxide and it is
formed stoichiometrically to the aldehyde formed in the reaction.
27
Cu
NN
OO
R
OO
Cu
NEt3
(36) R=N(37) R=S (38) R=Se
(39)
Figure 16. The schematic structures of complexes, used as catalysts, in the oxidation of alcohols, by Wieghardt et al. The active form of 37 is a dimer of the complex.45,77,78,79
Table 4. The selected results of oxidation experiments from the work of Wieghardt et al.
Catalyst Substrate Product Conversion TON Reference
36
37
39
Ethanol Acetaldehyde
63 %a
55 %b
~50 %c
315
2600
~5000
76
44
78
36
37
38
OH
O
60 %a
55 %b
~10 %d
300
2600
95
76
44
77
37
OH
O
68 %a 340 76
a 12 h, air atmosphere, RT, THF. b 20h, air atmosphere, RT, THF. c 45 h, air atmosphere, RT, THF. d 24 h, air atmosphere, RT, CH3CN, Bu4OCH3 as base.
3. Iron catalysts
Many iron complexes have been reported to possess catalytic properties in the oxidation of
alcohols, alkenes and other substrates. However, most of these iron catalysts reported so far
are not able to use dioxygen as oxidant without sacrificial additives (e.g. aldehydes) or light
excitation and therefore in many cases activated oxygen (peroxides etc.) are used as
oxidants.80,81 On the other hand, most enzymes with iron complexes in their active sites use
explicitly dioxygen as oxidant.82 This fact gives motivation to search for new iron complexes
28
which are capable of using dioxygen as oxidant although so far only few such catalysts are
known.
N
N
Fe
N
N
O O
C
C
C
C
O O
C
C
(40)
Figure 17. Structure of Heme (Fe-Protoporphyrin IX).
Iron complexes with catalytic oxidation properties can be divided roughly into two groups;
heme (Figure 17) and non-heme complexes. The heme complexes are found in the active sites
of some iron-containing enzymes where the heme serves as binding site for dioxygen. The
cytochrome P-450 being maybe the best known example.83 Synthetic analogues of heme are
the complexes of substituted porphyrin and phtalocyanins. The non-heme iron complexes are
the rest of iron complexes which do not contain porphyrin as the ligand. Most published non-
heme iron complexes are products of studies where functional models of non-heme iron
enzymes have been synthesized. Several different types of non-heme iron complexes are
reported to catalyse the oxidation of catechols and alkenes, by dioxygen. These catalysts are
mainly variations from few general structural themes, which are the tripodal and macrocyclic
ligands shown in Figure 18.10
29
N
RR
R NN
N
N
R
R(41) R=Py(42) R=Ac
(43) R=Me(44) R=H
Figure 18. Examples from stuctures of tripodal and macrocyclic ligand frames common in nonheme iron catalysts.
Iron containing enzymes can be divided into two categories. Mono-oxygenases and
dioxygenases. The reactions catalysed by these two type of enzymes differ by the products
formed and active species involved in the catalytic reaction.83,84 Mono-oxygenases catalyze
the oxidative insertion of single oxygen atom to substrate and is typically associated with
heme catalyzed reactions.83 The active species in monodioxygenase type reactions is a high
oxidation state Fe(IV)=O species. A typical dioxygenase is catechol dioxygenase which
catalyzes the intradiol (Fe2+ in active site, the 1,2-catechol is cleaved between hydroxyl
groups) or extradiol (Fe3+ in active site, the 1,2-catechol is cleaved next to hydroxyl group)
cleaving oxygenations. Most of the non-heme iron complexes are used for modeling catechol
dioxygenases but some complexes have been used for other oxidation reactions as well.85,86
Discussed next are some of the most important iron enzyme models and catalyst, systems
which are able to activate dioxygen in the oxidation of hydrocarbon substrates. The
emphasize is on the catalytic oxidation methods, which do not need any auxiliary agents or
outside excitation of the dioxygen molecule.
A catalyst designed for oxidative pollutant degradation, using air as source of dioxygen, was
recently reported by Deng et al.87 The catalyst used in their work is a porphyrin like complex.
Iron(II) tetra(1,4-dithin)porphyrazine immobilised on a ion-exhange resin. This catalysts
system is able to catalyze the degradative aerial oxidation of Rhodamine B (RhB) and p-
nitrobenzoic acid (NBA), in alkaline aqueous solutions under a broad pH range. The catalyst
does not need light excitation or sacrificial additives for dioxygen activation, as is normally
required from iron catalysts. The reaction conditions are also very mild. The substrates are
degraded to lower molar mass aldehydes, ethers and carboxylic acids with over 50 %
30
conversion. The catalyst is also robust enough for recycling, which is not common for
homogeneous iron porphyrin catalysts.
Simándi et al have reported catecholase activity of iron complexes of dimethylglyoxime
(DMG) 45 and it´s derivatives 46, 47 (Figure 19).27 The complexes are able to catalyse
oxidation of 3,5-di-tert-butylcatechol to the corresponding quinone by dioxygen, in MeOH
solution at room temperature. The reaction rate was determined only for Fe(DMG)2 complex
(7.30*10-3 s-1) which corresponds to TOF of 26 cycles/h.
NH
NN
NNO O
Fe2+
H
N
NO
N
NO
Fe2+
H
NNOO
N NO O
Fe2+H H
(45) (46) (47)
Figure 19. Iron complexes of dimethylglyoxime and it´s Schiff base derivatives used by Simandi et al.27
Guo et al have reported the oxidative catalytic activity of a µ-oxo dimeric ferroporphyrin
complex 48, (µ-oxo-bis(tetraphenylporphinato)iron [(TPPFe)2O]).88 The complex 48 is able to
catalyse the oxidation of ethylbenzene to acetophenone and phenylethanol by dioxygen. The
reactions were carried out in pure ethylbenzene at 60 oC and under atmospheric pressure of
air. This catalyst is one of the few heme catalysts which work without any additives or light
excitation. Although the recorded conversions are low, the TONs (TON= 878) are one of the
highest observed in transition metal complex catalysed oxidations.
31
Fe
N
N N
N
O
Fe
N
N N
N
(48)
Figure 20. µ-oxo -bis (tetra-phenyl porphinato) iron complex 48 used by Guo et al, as catalyst in oxidation of ethylbenzene.88
The iron complex of bipyridine has been reported to activate dioxygen without additives in
the oxidation of cyclohexene by Sawyer et al89,90 The [Fe(bipy)2]2+/O2/MeCN system
catalyses the oxidation of cyclohexene to cyclohexanone, cyclohexanol and
cyclohexenepoxide. The ratio of the products formed depends on the dioxygen pressure
applied. The reaction has to be carried out in dry conditions since water is reported to supress
the reaction. The highest observed TON was 230 for a one hour reaction.
Several efficient catalysts for oxidation of olefins to yield carboxylic compounds, alcohols
and epoxides, with molecular oxygen, have been reported but as yet no iron catalysts for
selective oxidation of alcohols to aldehydes are known. There are some examples of iron
catalysts which are able to oxidize alcohols to aldehydes but these systems are not able to use
dioxygen, as oxidant.91,92,93 The iron bipyridine catalyst published, by Sawyer et al, is an
example of a catalyst which uses H2O2 to oxidize veratryl alcohol selectively to the
corresponding aldehyde.94 The same oxidation reaction is discussed in the experimental part
of this thesis with the exception that our system uses dioxygen as oxidant.V This is the first
example where an iron complex is able to catalyse the selective oxidation of alcohol to
aldehyde, with dioxygen as oxidant.
4. Combinatorial Chemistry
Combinatorial chemistry is a relatively new area of chemistry. Combinatorial methods have
been first used for drug discovery and from pharmaceutical applications, the technique has
found its way to other branches of chemistry.95 Combinatorial methods enable the synthesis
and testing of a large group of substances. For example, synthetic chemistry and catalyst
32
research96,97 have benefitted greatly from combinatorial techniques and in the future more and
more research will be done with combinatorial methods.
4.1 The concept of combinatorial chemistry
By definition combinatorial chemistry is “Using a combinatorial process to prepare sets of
compounds from sets of building blocks”.98 In practice, all methods where a number of
reactions are carried out simultaneously, all in a short period of time, are considered as high-
throughput (HT) methods and these all fall under the term of combinatorial chemistry. The
combinatorial techniques consist roughly of two phases, synthesis of compounds to be studied
and the testing of these compounds for a certain activity. The set of compounds obtained by
combinatorial synthesis are called libraries or combinatorial libraries. The operation in which
the activity of the members of a given library is determined is called screening. Lead
compounds are compounds which have shown activity in the screening experiments and are
used as basis for further experiments.
4.2 Library synthesis
The synthesis of libraries is done either in solid or liquid phase in parallel synthesis or with
the split and combine methods.99,100,101 The most simple way to synthesize a library is from
two types of starting materials, which are known to react with each other. Starting materials
can be named for instance, compounds An and Bm. These can be, for example, metal-ligand
pairs or organic molecules, with certain functional groups. When starting materials are
combined in an array of reaction vessels, it results in a library with n*m members. The
formation of such a library is exemplified in Figure 21. More complexed libraries can be
made by mixing three or more compounds together in several stages or by split and combine
methods.
A1 A2 A3 A4 A5 A6 A7 A8
B3
B2
B1
B6
B5
B4
B8
B7
A1 A2 A3 A4 A5 A6 A7 A8
B3
B2
B1
B6
B5
B4
B8
B7
Figure 21. By combining A1-8 with B1-8 a library of 64 members is created. Each small square represent a member of a library.
33
4.3 Screening Experiments
The screening experiments are typically carried out parallel in an array of isolated reaction
vessels.95 The most important factors determining the size of an array is the analysis method
used for identifying the lead compounds and the degree of automation in the procedure used.
If the screening and analysis is done manually by GC, HPLC or some other relatively slow
method, the size of a reactor array is usually counted in dozens but advanced automated
screening methods, based on robots and visual identification with digital cameras, enable the
simultaneous analysis of hundreds of samples.
5. Experimental
The focus of experimental work was to find catalysts for oxidation of benzylic alcohols to
aldehydes (mainly veratryl alcohol, a lignin model), with dioxygen as oxidant (Figure 22).
The interest for this particular reaction is in its application in pulp bleaching and in the
applications in fine chemical industry(see Introduction). Veratryl alcohol which is the main
substrate used in this work is a known model compound for lignin, a wood component which
is oxidatively degraded during pulp bleaching.102 The working hypothesis in this research was
that if we can find compounds which catalyse the oxidation of veratryl alcohol, with
dioxygen, we would also have a catalyst for pulp bleaching and for selective alcohol
oxidation. Described next is the research activities performed in order to find such catalysts.
Figure 22. Oxidation of veratryl alcohol.
34
5.1 Cobalt-salen Catalysed Oxidations
The cobalt-salen 1 and it´s derivatives 2 and 48-51, shown in Figure 23, were used as
catalysts for oxidation of veratryl alcohol by dioxygen.I The catalyst 1 and 48-50 were
selected, in order to study the effects of substituents in the ligand on the activity of the
catalyst. Cobalt-salen needs an axial base, for example pyridine, in order to promote the
coordination of dioxygen to the cobalt center of the catalysts. The purpose of the third amine
on catalyst 51 is to eliminate the need for an axial base in the reaction solution. The oxidation
reactions were carried out in 50 ml flasks equipped with dioxygen balloon. The reaction
conditions (80-100 oC, pH 12,5) were derived from those used in pulp bleaching process. For
determination of conversion, the substrate and product were extracted from the aqueous
reaction solution and dried for 1H-NMR analysis.
Unsubstituted Co(Salen) 1 with an equimolar amount of pyridine, as axial ligand, was
observed to be the most effective catalyst of those studied here. Catalysts 2 and 48-50 showed
a varying degree of activity and the order of superiority was observed to be dependent upon
the applied reaction temperature. The catalyst 51 was observed to be virtually inactive under
all reaction conditions. In general, higher temperatures were observed to increase the
conversion, but above 80 oC, the conversion starts to decrease. This might be due to decreased
solubility of dioxygen in water and/or instability of the catalytically active species at high
temperatures. The highest conversion with 1 was observed at pH 14 and in general, a higher
pH was observed to increase the final conversion with every catalyst. The key results from the
first publication are displayed in Table 5.
N N
OOCo
R1
R3R2
R1
R2R3
N
O
N
OCo
NN N
OOCo
1 R1=R2=R3=H 48 R1=Me, R2=R3=H49 R1=R2=H, R3=OH50 R1=R3=H, R2=SO3Na
2 Co(acacen)
Co(Salen)
51
Figure 23. Cobalt catalysts used for the published results.I
35
Table 5. Key results from oxidation experiments, catalysed by Cobalt complexes. Substrate to catalyst ratio was 10 in these experiments.I
Catalyst Conversion, % S/Cat=10
80 oC 100 oC
1 100 70
2 30 35
48 8 70
49 20 43
50 64 54
5.2 Parallel Screening Method
In order to efficiently test a large group of potential catalysts, a parallel screening method was
developed.III A 1 liter autoclave with 14 small reaction vessels was used as test reactor (Figure
24). The catalysts were prepared insitu by adding a metal salt and a ligand directly to a
reaction solution of the desired pH. The substrate (e.g. veratryl alcohol) and a magnetic
stirring bar were then added and the reaction vessels were loaded to the autoclave. Dioxygen
pressure (10 atm) was set from a gas cylinder and the autoclave was placed into an oil bath of
desired temperature. The reaction time was typically 3-4 hours after, which the autoclave was
opened. 0.5 mL samples were taken from the reaction solutions and extracted with 1.5 mL of
EtOAc, in a GC sample bottle. The conversion of the reaction was determined by GC or
GC/MS, directly from the EtOAc phase. This method proved to be very efficient and accurate
in determination of the activity of potential catalysts.
36
Figure 24. The reaction autoclave used in parallel screening of oxidation catalysts.II,III
The parallel screening method was used in two different studies. In the first, different metal
salts and nitrogen donor ligands were studied, with the described method.II In the secon, only
copper sulphate was used as metal source together with a different set of nitrogen donor
ligands.III Copper turned out to form catalytically the most active compounds with the
nitrogen donor ligands tested here. The ligands which formed the most active catalysts with
copper sulphate, for the oxidation of veratryl alcohol with dioxygen, are presented in Figure
25.
NH2NH2
N N
NH2 NH2
N N N N OH N N OH
9,10-Diaminophenantrene(DAPHEN) (52)
N,N,N´,N´-tetramethyl ethylenediamine(TMEDA) (53)
Phenantroline(phen) (33)
2,2´-Bipyridine(bipy) (34)
Dimethylglyoxime(dmg) (51)
rac-1,2-diminocyclohexane(DACH) (54)
Figure 25. Ligands which form the most active oxidation catalysts with copper. The activity was established with parallel screening method described in the text.II,III
37
5.3 Effect of Reaction Conditions on Conversion and Reaction Optimization
The effect of reaction conditions on the activity of the copper complexes of ligands presented
in Figure 25 was studied. In Figure 26 and Figure 27, the effects of reaction conditions on the
activity of the Cu(DACH), Cu(TMEDA), Cu(DAPHEN), CuSO4-phen, CuSO4-bipy and
CuSO4-dmg catalyst are presented. In general, temperature, dioxygen pressure and substrate
concentrations were observed to have a rather direct effect on the conversions which means
that the higher the value of the reaction parameter, the higher the activity is. The decrease in
conversions observed in Cu(TMEDA) and Cu(DAPHEN) catalysed reactions, at high
temperatures, is propably due to increased decomposition of ligands. The anion and the initial
oxidation state of the copper does not have significant effect on the conversion although the
pH and ligand to metal ratio (L/M) have more intricate effect on the reaction outcome. This is
caused by the nature of the catalysts. In aqueous solutions, the structure of the catalyst is
determined mainly by the concentrations of metal and ligand in the solution and also the pH.
Figure 26. The effect of reaction conditions on the activity of Cu(DACH), Cu(TMEDA) and Cu(DAPHEN) catalysts. Catalyst load (calculated by mole amount of copper in the reaction solution) was 5 mol-%, except when the amount of substrate was studied.III The default reaction temperature was 80 oC and dioxygen pressure 10 atm.
38
Figure 27. The effect of copper compound used, temperature, ligand to metal ratio and pH on the activity of the CuSO4-phen, CuSO4-bipy and CuSO4-dmg catalysts.II On upper left, grey columns are for phen, black for bipy, white for dmg and (1) CuSO4·5 H2O, (2) CuCl2·2 H2O, (3) Cu(CH3COO)2·5 H2O, (4) Cu(NO3)2·3 H2O, (5) CuSO4, (6) CuCl and (7) Cu2O. In other graphs CuSO4-phen is solid line with squares, CuSO4-bipy is dotted line with circles and CuSO4-dmg is dash line with triangles.
The optimum reaction conditions in respect to pH and L/M ratio for CuSO4-phen, CuSO4-
bipy and CuSO4-dmg catalysts were determined by optimising these reaction parameters, one
reaction parameter at a time. The limitation in this method is that not all possible reaction
conditions are tested. A thorough way to optimise this kind of reaction is to simultaneuosly
vary the pH and L/M ratio of the reaction solution. This was done for Cu(TMEDA),
Cu(DACH) and Cu(DAPHEN) catalysts, in the veratryl alcohol oxidation. The results of this
are presented in Figure 28. Cu(DAPHEN) was observed to convert veratryl alcohol to veratral
aldehyde in 100 % conversion with L/M ratio of 1.8 at pH 13.2. The maximum conversion
observed for Cu(TMEDA) and Cu(DACH) were 40 % and 32 %, respectively. The optimum
L/M ratio for Cu(TMEDA) is 8-11 at pH 11 and for Cu(DACH) the optimum L/M ratio is
1.5-3.5 at pH 13.5-14. The reactions were carried out at 80 oC in 10 atm dioxygen pressure.
The concentration of copper (c(CuSO4)= 1 g/L) and veratryl alcohol (10 g/L) was kept
constant.
39
Figure 28. The opimization of ligand to metal ratio vs pH with Cu(TMEDA), Cu(DACH) and Cu(DAPHEN) catalysts, in the oxidation of veratryl alcohol. The reactions were carried out at 80 oC with 10 atm dioxygen pressure. The concentration of copper (c(CuSO4)= 1 g/L) and veratryl alcohol (10 g/L) was kept constant.
In general, the optimum reaction conditions are dictated by the stability constants of the
complexes. The oxidation of veratryl alcohol requires basic conditions and therefore due to
the tendency of copper to hydrolyse at basic solutions, the hydroxyl ions and ligand molecules
are competing to coordinate to copper. As a result from this competing coordination, if a
complex with metal to ligand ratio of 2 is desired, an excess of ligand is needed to
compensate for the coordination of hydroxyl ions to metal. The opposite is also true, the
higher the stability constant of the ligand, the higher concentration of hydroxyl ions (pH) is
needed. According to solution distribution calculations, based on the known stability
constants of TMEDA, the catalytic precursor in Cu(TMEDA) catalysed reactions is a
hydroxyl bridged complex, with molecular formula of L-Cu-(µ-OH)2-Cu-L.
5.4 Reaction Kinetics
The TOFs (reaction rates) were determined for Cu(DACH), Cu(TMEDA) and Cu(DAPHEN)
catalysts, at five different substrate concentrations.IV This was done in a reaction autoclave
which made it possible to take samples during the reaction. The initial reaction rates were
observed to be fairly high but after approximately a two hour reaction time, the reaction rates
had reduced to a fraction of the initial values. This is visualised in Figure 29 where the
conversions are plotted as a function of time. The reasons for reaction termination are
discussed latter.
40
Figure 29. The conversions and turn over numbers of the reactions, as a function of time, in Cu(DACH), Cu(TMEDA) and Cu(DAPHEN) catalysed reactions.IV The reaction temperature was 80 oC and dioxygen pressure 10 atm.
The value of TOF generally increased with the substrate concentration, until the maximum
TOF of a catalyst is reached. Above the point where the change in substrate concentration
does not effect the TOF, the rate limiting factor should be the catalytic cycle itself and
therefore this is the maximum TOF of a given catalyst. Cu(DAPHEN), which is the most
active catalyst of the studied, shows it´s maximum initial TOF at substrate concentration 0.69
M. The maximum TOF of Cu(TMEDA) is approximately 11, which is observed in 0.33 M
veratryl alcohol solution. The initial TOF of Cu(DACH) reacts slowly to substrate
concentration until very high substrate concetrations are present. The maximum measured
TOF of Cu(DACH) is 45, at substrate concentration 2.07 M. This is also the highest
accessible substrate concentration for this reaction system. The initial turn over frequencies at
different substrate concentrations are presented in Table 6.
41
Table 6. The initial TOFs (catalytic cycles/hour) at different substrate concentrations in Cu(DACH), Cu(TMEDA) and Cu(DAPHEN) catalysed reactions. The TOFs are calculated from graphs presented in Figure 29.IV
Substrate/Catalyst ratio
(substrate concentration)
Cu(DACH)
Initial TOF (TON/h)
Cu(TMEDA)
Initial TOF (TON/h)
Cu(DAPHEN)
Initial TOF
(TON/h)
10 (0.064 M) 2 3 11
30 (0.20 M) 3 7 36
50 (0.33 M) 6 10 44
100 (0.69 M) 13 11 49
300 (2.07 M) 45 12 50
5.5 Reaction Termination
Although the initial TOFs were observed to be high, the conversions and overall TONs of the
reactions are in most cases low, as can be seen from Figure 29. The reasons for this were
investigated. The possible reasons for reaction termination are neutralisation of the reaction
solution, catalyst decomposition and/or inhibition of the reaction by the products formed in
the reaction.
The pH of the reaction solution changes during the reaction. This is most likely a result from
veratric acid formation and neutralisation of the reaction solution by the dissolved dioxygen.
If the change in pH of the reaction solution would be the major reason for termination of the
catalytic reaction, then the catalysts should be reactivated by adding base to the reaction
solution. This is infact the case with phenanthroline and bipyridine ligands which are
chemically robust enough to withstand the reaction conditions. With amine type ligands, the
catalysts cannot be reactivated by adding base. So the main reason for deactivation must be
inhibitioin by the reaction products or decomposition of the catalysts.
42
The effect of reaction products (veratral aldehyde and veratric acid) on the activity of the
catalysts was studied by adding these compounds to reaction solutions, prior to reaction. The
kinetics of the reactions was determined together with reaction solution compositoins, after
the reactions. The analysis were made with GC/MS and EI-MS.IV The added veratric acid did
not significantly effect the outcome of the reaction but veratral aldehyde inhibited the
oxidation of veratryl alcohol severely. When equimolar amounts of aldehyde and alcohol
were added to reaction solution, prior to reaction, only little oxidation of alcohol occurred. In
the Cu(DACH) catalysed reaction, the amount of alcohol was increased which means that
aldehyde is actually reduced back to alcohol (Figure 30). Cu(TMEDA) and Cu(DAPHEN) are
not able to promote this reduction of aldehyde. Extended experiments showed that
Cu(DACH) is even able to convert other aldehydes (benzaldehydes) to alcohols in addition to
veratral aldehyde. The ratio of aldehyde and alcohol (2:1) in the reaction solutions, after a 24
hour Cu(DACH) catalysed reaction, seems to be independent on their initial concentrations.
The reaction outcome is therefore presumed to be determined by the equilibrium constant for
the reaction.
Figure 30. The kinetics of Cu(DACH), Cu(TMEDA) and Cu(DAPHEN) catalysed oxidation reactions in various initial reaction substrate and product concentrations.IV
A closer analysis of the Cu(TMEDA) and Cu(DACH) reaction solutions, after the reactions,
revealed that imines are formed from the veratral aldehyde and ligands during the oxidation
reaction (Figure 31). This is suggested to be the ultimate reason for catalyst deactivation in
these reactions. In the case of Cu(DAPHEN) however, the major reason for catalyst
deactivation is ligand dimerization.
43
Figure 31. The reaction products of DACH, TMEDA and DAPHEN ligands which are formed during oxidation of veratryl alcohol.IV
5.6 Pulp Bleaching Experiments
The ability of copper complexes to catalyse pulp bleaching with dioxygen was tested in actual
pulp bleaching experiments.II The ideal pulp bleaching catalyst would reduce the kappa value
and increase brightness of the bleached pulp but would not effect the viscosity of the pulp. In
other words, catalyst should be active towards lignin species and inactive towards cellulose
fibres. In general, the catalyst were able to catalyse pulp bleaching with dioxygen but no
selectivity towards lignin was observed. The results from pulp bleaching experiments are
displayed in Table 7 and Table 8. The kappa value, brightness and viscosity in CuSO4
catalysed pulp bleaching experiment are virtually the same as in uncatalysed experiment. This
proves that the complexes are actually needed for catalytic activity and that copper by itself is
not able to catalyse the pulp bleaching with dioxygen. The kappa values of CuSO4-phen and
CuSO4-bipy catalysed reactions are significantly lower than in the uncatalysed reaction.
Unfortunately the viscosity of the pulp is also decreased in the experiments. The reductions in
kappa values are only moderate in CuSO4-dmg, Cu(DACH) and Cu(DAPHEN) catalysed
pulp bleaching experiments and the Cu(TMEDA) seems to be completely inactive in pulp
bleaching. In the CuSO4-dmg, Cu(DACH), Cu(TMEDA) and Cu(DAPHEN) catalysed pulp
bleaching experiments, no viscosity was measured but presumably the results are similar to
those observed in CuSO4-bipy and CuSO4-phen catalysed reactions.
44
Table 7. Pulp bleaching results for CuSO4-phen and CuSO4-bipy catalysts. Metal–ligand molar ratio 1:2, temperature 90 °C, reaction time 60 min, initial O2 pressure 8 bar, kappa of pulp 31.8 and viscosity 1230 dm3/kg.
No catalyst CuSO4 CuSO4-phen CuSO4-bipy
Kappa 20.1 20.1 16.1 15.0
ISO brightness 30.5 29.6 31.6 32.4
Intrinsic viscosity / [dm3/kg] 1070 1050 630 620
Table 8. The results from bleaching experiments made with Cu-dmg, Cu(TMEDA), Cu(DACH) and Cu(DAPHEN) catalysts. The reaction conditions are derived from reaction parameter optimizations described above. Metal–ligand molar ratio 1:1-8, temperature 90 °C, reaction time 60 min, initial O2 pressure 8 bar.
Cu-dmga Cu(DACH)b Cu(DAPHEN)c Cu(TMEDA)d
Kappa
(Reference)
15.5
(17.2)
16.6
(17.2)
16,6
(17.2)
27.0
(26.2)
ISO brightness
(Reference)
32.6
(32.6)
32.2
(32.6)
31,5
(32.6)
25.6
(26.5)
a Ligand to metal ratio was 1:5 b Ligand to metal ratio was 1:2 c Ligand to metal ratio was 1:1 d Ligand to metal ratio was 1:7
5.7 Iron Catalyst
The activity of the iron complex Fe(DAPHEN) in the oxidation of alcohols, by dioxygen, was
observed in screening studies made with the parallel screening method, as reported above.III
Fe(DAPHEN) is one of the few iron catalysts known which is able to activate dioxygen
without light excitation and/or additives. To the best of our knowledge this is the first
occasion where iron based catalyst is used in the selective oxidation of alcohols to aldehydes
by dioxygen.V Also the use of aqueous solution makes this an interesting catalyst system,
since usually iron catalysts are active only in organic solvents. A 100 % conversion from
alcohol to aldehyde is observed only with high catalysts loads. With veratryl alcohol 10 mol-
% of Fe(DAPHEN) and with 4-nitrobenzaldehyde 5 mol-% in 24 hour reactions. The
Fe(DAPHEN) catalyst is able to catalyse the oxidation of other alcohols as well but with
lower conversions. The results from these oxidation experiments are presented in Table 9. The
45
reaction conditions are 100oC, 10 atm dioxygen pressure and 0.25 M NaOH as solvent. The
solubility of the substrate in the aqueous reaction solution seems to correlate with the
conversions observed in the oxidation experiments, with different substrates. The highest
conversions are obtained with the most soluble substrates, veratryl alcohol and 4-
nitrobenzylalcohol.
Table 9. The results from oxidation experiments made with Fe(DAPHEN).V
Substrate Product
Conversion
5 mol-%
24 h
Conversion
2 mol-%
3 h
OH
OMe
O
OMe
10 % 10 %
NO2
OH
O
O
100 % 45 %
OH
OMeOMe
O
OMeOMe
90 % 74 %
OH
O
33 % 10 %
OH
O
6 % 5 %
OH
OMe
OMe
O
OMe
OMe
30 % 20 %
46
The structure of the Fe(DAPHEN) catalyst is unclear. The catalyst is suggested to be
homogeneous on the grounds that a filtered sample of the 0.25 M NaOH solution of
Fe(DAPHEN) is capable to catalyse the oxidation of veratryl alcohol, with dioxygen. The iron
concentration in the reaction solution is very low (approximately 0.3 µg/mL) according to
atomic absorption spectrophotometric measurements. In an experiment where a filtered
Fe(DAPHEN) reaction solution was used, as catalyst, in veratryl alcohol oxidation, the value
of the TON number was observed to be approximately 3500. This is very high for this kind of
reaction. Since the catalytic reaction requires basic conditions, iron and DAPHEN ligand, we
suggest that the catalytically active species is a iron complex with hydroxyl and DAPHEN
ligands.
6. Conclusions
The transition metal complex catalysed oxidation offers attractive opportunities for industry
which seeks to develop more environmentally benign manufacturing processes. So far, most
of the oxidation catalysts reported have only academic interest and their true value is to show
the way for future research in this area. This is also the case with the catalysts presented in
this thesis. Although hundreds of different transition metal complexes capable of catalysing
oxidations of organic substrates have been reported, the number of such catalytic methods is
substantially decreased if only methods which use dioxygen, as oxidant and without any
sacrificial additives, are taken into account. The catalysts presented in the experimental part of
this work are exactly such catalysts and that makes these findings significant.
Combinatorial methods have become an established field of chemistry and it proved to be a
fruitful technique in our work also. All the major results in this work were obtained with the
developed parallel screening method, described above. The catalysts are obtained by insitu
complexation which makes this a fast method but also at the same time it makes the
characterization of catalytically active species difficult. Therefore, the structures of the
catalysts were left unclear in most cases. However, with solution chemistry calculations, the
active species of the Cu(TMEDA) and Cu(DACH) catalysts are suggested to be hydroxyl
bridged binuclear complexes.
The same reaction set-up, as was used in parallel screening, was also found to be useful when
the effects of the reaction conditions were studied in order to optimize the conversion in the
reactions. The catalysts presented here have relatively high initial TOFs, but unfortunately the
conversions are less than 100 % in most experiments. In the reactions where TMEDA, DACH
47
and DAPHEN ligands are used, the primary reason for termination of the catalytic reaction
was observed to be the reactivity of diamine type ligands. All of the studied catalysts were
observed to have characteristic optimum reaction conditions where the maximum conversion
is reached. The pH of the reaction solution significantly effects the reaction outcome with all
catalysts studied here. In cases where catalyst is obtained by in situ complexation, the
stoichiometry between ligand and metal is also important. The Cu(DACH) also differs from
the rest of catalysts for it´s ability to catalyse the reduction of aldehydes to alcohols. This is a
remarkable feature which requires further study.
In conclusion it can be said that the goal to find complexes capable of catalysing the oxidation
of benzylic alcohols and pulp bleaching have been partially reached. The complexes presented
here are infact able to catalyse the above mentioned reactions but the drawbacks are the low
conversions exhibited by the catalysts in alcohol oxidations with high substrate concentrations
and the lack of selectivity in the pulp bleaching experiments.
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