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Mechanisms in iron, nickel, and manganese, catalysis with small molecule oxidantsPadamati, Sandeep

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Chapter 1 Activation of NaOCl by transition metal complexes

Abstract NaOCl is a widely used oxidant, which is synthesized by passing electrochemically

generated Cl2 through cold alkali. The speciation of NaOCl is highly pH dependent and -

generally oxidizes substrates rapidly, which in turn limits the selectivity and specificity

that can be achieved in such reactions. Despite this, nature generates hypochlorite

enzymatically, either through oxygen activation to form Fe(III)-OOH or Fe(IV)=O species,

which further react with Cl- to give hypochlorite. The hypochlorite formed is used

further for selective oxidation or halogenation of the substrates. In this chapter, we

review briefly the chemistry of NaOCl and halogenases/haloperoxidases followed by a

review of biomimetic metal complexes that have been applied to control the reactivity

of NaOCl and achieve selectivity in oxidation or halogenation of substrates. Complexes

of manganese, iron and nickel, have seen most application and it is clear that control of

acidity is critical to the reactivity achieved and species formed, in particular high valent

intermediates and in the latter sections attention is turned to their study.

Sandeep K. Padamati, Apparao Draksharapu, Wesley R. Browne to be submitted.

1

Chapter 1

1.1 Introduction Sodium hypochlorite (NaOCl or bleach) is viewed as a ‘strong oxidant’ in colloquially,

primarily due to its reactivity in comparison to other oxidants such as H2O2 or O2 rather

than for thermodynamic reasons. It is used widely as a cheap and readily available

aqueous bleach, primarily due to the ease of its production, handling and storage, and

because the by-product it forms is predominantly NaCl. The use of hypochlorite,

domestically and medically, as a disinfectant has become widespread ever since the

development of moderately efficient methods of production in the 1900s. The

production of hypochlorite is a major industrial activity, carried out primarily using the

chloro alkali process developed by E. S. Smith in the late 1800s, in which brine is

electrolyzed to produce sodium hydroxide and gaseous chlorine which are then mixed to

form alkaline solutions of NaOCl.1 The Hooker process is used currently in which chlorine

is passed into cold aqueous sodium hydroxide (the low temperature is necessary to

reduce formation of chlorate). From a synthetic perspective, the primary detractors in

using NaOCl is that commercial NaOCl is supplied as an aqueous solution, which in turn,

limits its application to systems that are insensitive to water and its relatively wide

substrate scope. The taming of such a versatile and powerful oxidant presents many

challenges in comparison with the isoelectronic oxidant H2O2, not least due to the orders

of magnitude higher rate constants for its direct reaction with organic substrates. In this

chapter the first steps towards the use of transition metal catalyst to direct the

oxidation chemistry of hypochlorite will be discussed with a focus on efforts to

characterize reactive intermediates and to achieve selectivity. However, before

discussing these aspects, it is pertinent first to review briefly the basic inorganic

chemistry of hypochlorite and the several enzymes in which chlorine chemistry is

important, specifically halogenases and haloperoxidases.

1.2 pH dependence of the chemistry of aqueous NaOCl

The chemistry of chlorine is dominated by pH dependent equilibria and especially com-

and disproportionation reactions between the six oxidation states that chlorine can

achieve from perchlorate to chloride.1 The Latimer diagram for chlorine2 and the

Pourbaix plot shown below (Scheme 1) highlight the complexity of the chemistry of

chlorine and the need to consider carefully the pH of solutions in which reactions

involving chlorine species occur.

Cl2 gas and NaOH are prepared industrially by electrolysis of NaCl and both are used in

the Hooker process, currently in which chlorine gas is passed into cold aqueous sodium

hydroxide (the low temperature is necessary to prevent formation of chlorate).3

However, this reaction leads to many side products and additional reactions meaning

that commercially available sources of hypochlorite are contaminated with other species

such as perchlorate.1

2

Introduction

In the context of the present chapter NaOCl, in which chlorine has the formal oxidation

state of +1, pH dependent comproportionation and disproportionation reactions are of

interest, which can be deduced from the Latimer diagrams shown below.

Scheme 1 Latimer diagrams for chlorine under (a) acidic (pH 0), and (b) basic (pH 14) conditions.

Figure 1 Percentages of active chlorine species as a function of pH.1

At pH < 4 Cl2 gas is the dominant species present in terms of thermodynamical stability,

however, at pH 5 the major species is HClO, and at pH > 7 it is ClO-. The pH dependence

of the redox potentials relevant to these species is indicated in the Pourbaix plot below

for hypochlorite species, which shows that at all pH values hypochlorite is able to oxidize

water and the pKa for HOCl/OCl- is ca. 7.5.

Figure 2 Pourbaix diagram of hypochlorites in the chlorine-water system.1

In the Hooker process, mentioned above, chlorine gas is passed into cold aqueous

sodium hydroxide (equations 4 to 6 below). The yields of NaOCl depend critically on the

3

Chapter 1

pH as both it and HOCl undergo a complex set of reactions in solution (Scheme 2,

equations 5, 7-10) to form other chlorinated compounds and O2 (equations 7, 9, 10),

which is problematic industrially.1

Scheme 2 Reactions occurring in the production of NaOCl.1

1.3 Reactivity of NaOCl with alkanes, alkenes, and alcohols, and the

effect of acids The reactivity of NaOCl with organic substrates is well established and indeed there are

numerous reports of its use especially in the oxidation of alkenes to epoxides. Although

the focus of this chapter is on efforts towards metal catalyzed reactions with NaOCl, a

brief survey of the non-metal catalyzed reactions and their possible mechanisms in the

oxidation or chlorination of organic substrates will be made.

Scheme 3 Reactions of NaOCl at low pH condition.

The pH dependent chemistry of chlorine reagents means that with aqueous NaOCl, pH

control is essential. The equilibrium composition of NaOCl (aq) is pH-dependent (Scheme

3,), and under alkaline conditions (pH > 7), OCl- is the dominant species present and is

relatively stable (hence commercial hypochlorite bleach is sold as alkaline solutions). The

insolubility of NaOCl in organic solvents, however, presents practical problems in the

oxidation of organic substrates and hence phase transfer catalysts are required with two

4

Introduction

phase reactions (vide infra). Below pH 7 HOCl, is the significant form, which is soluble in

polar organic solvents such as CH2Cl2 circumventing the need for phase-transfer

catalysts in two phase reactions in the pH range 4-7. Below pH 4, Cl2 is a major

component of the aqueous hypochlorite solutions, and its reactivity will dominate the

organic oxidations performed.4

1.3.1 Oxidation of alkanes under acidic conditions

The oxidations of alkanes with hypochlorite is typically catalyzed by metal ions, vide

infra, however, acid catalyzed reactions have been reported, typically with acetic acid, in

which the reaction is likely to proceed through a radical pathway involving hypochlorous

acid formed in-situ. Hypochlorous acid, present in equilibrium with dichlorine monoxide

and water decays to form chloride and chlorine oxide radicals.5 Chlorine oxide radicals

chlorinate alkanes (Scheme 4).

Scheme 4 Proposed mechanism for acid catalyzed reactions with hypochlorite.5,6

Although of limited synthetic use as an alkane oxidant, an example of the use of bleach

for soil remediation is in the recent report by Chaouki and co-workers in the oxidation of

aliphatic petroleum contaminants (C10-C50) in a calcareous soil (average 5473 ppm C10-

C50, 15 wt% Ca).7 In this approach, decontamination was improved by using CO2 for

acidification to boost the oxidation with NaOCl and desorbing organic matter. It should

be noted that the reactivity may be affected strongly by the presence of transition

metals, such as manganese, although this was not investigated.

1.3.2 Oxidation of Alkenes

Alkenes, enones, and in particular chalcones, react readily with NaOCl to yield epoxides

(Scheme 5). The epoxidation of alkenes is typically highly pH dependent, not least due to

subsequent epoxide ring opening reactions and alkene chlorination reactions, to yield,

e.g., halohydrans.8 Typically the ClO• radical is invoked as the reactive species due to the

occurrence of hydrocarbon chlorination (vide supra), and from Hammett ρ values for the

chlorination of toluene.5

5

Chapter 1

Scheme 5 Epoxidation of enones at pH 8 - 8.5 with NaOCl.3

The enantioselective epoxidation of α,β-unsaturated ketones using NaOCl as the

terminal oxidant can be accomplished with high selectivity through the use of chiral

phase transfer catalysts (PTCs).9

1.3.3 Oxidation of alcohols

The oxidation of secondary alcohols to ketones with solutions of NaOCl10 proceeds

relatively cleanly with added acetic acid (Scheme 6).11 Excess hypochlorite is quenched

with sodium bisulfite, and essentially pure ketone is obtained simply by extraction of the

product into dichloromethane or ether, thus providing a convenient approach to highly

selective oxidation of secondary alcohols in the presence of primary alcohols,12 and

without epimerization of alcohols bearing β-stereocenters (Scheme 6). Kinetic studies

indicate that Cl2 is the active oxidant at the low pH in which these reactions are

performed.13 A detailed review of the oxidation of aldehydes and nitriles with NaOCl is

given elsewhere.4

Scheme 6 Oxidation of secondary alcohols to ketones with NaOCl and acetic acid.4

1.3.4 Phase transfer catalyzed reactions

The insolubility of NaOCl in organic solvents has prompted the use of phase transfer

catalysts (typically tetraalkyl ammonium salts) in reactions carried out at pH > 8. Lee and

co-workers have proposed that the PTC – OCl- ion pair partitions into the organic layer.14

In the absence of the PTC, little if any oxidation is observed, consistent with the absence

of significant interfacial reactivity. The ion pair shows increased reactivity in the organic

phases enabling clean and rapid oxidation, with the products recovered by phase

separation and solvent stripping.

The mechanistic study of these reactions was considered by Hossein and co-workers in

the study of the oxidation of various hydrocarbons with NaOCl, together with a phase-

transfer catalyst (PTC).5 They concluded that a free-radical mechanism was involved

rather than an electrophilic or heterolytic mechanism, since both light and oxygen affect

6

Introduction

the rate of reaction and product distribution, the product distribution with alkyl

aromatics and alkenes was typical of radical reactions and the relative reactivity of

primary, secondary, and tertiary C-H groups was as expected for a radical mechanism.

Furthermore azaphenanthrenes were converted to epoxides rather than the

corresponding N-oxides.15 Hence ClO• is likely to be the reactive reagent in the NaOCl-

PTC system, with its formation possible via the reactions shown in Scheme 7.

Scheme 7 Proposed reactions for the formation of ClO• under alkaline PTC conditions.5

It is notable that the NaOCl-PTC system does not show product distributions expected

for reactions involving chloride radicals, and hence the reaction of chloride radicals with

hypochlorite is efficient as well as being thermodynamically more favored. Hence the

oxidation of alkanes, alkenes and chlorination of anisoles were proposed to follow the

mechanisms shown in the Scheme 8.

Scheme 8 Proposed mechanisms for oxidation and chlorination of (a) alkenes, (b)

alkanes and (c) anisoles by NaOCl-PTC.5

For the reactions to proceed efficiently the concentration of Cl2O (for pathways b and c)

and ClO⁻ (for pathway a) should be constant in order to consume Cl• and regenerate

ClO•. Hence, a PTC will not only increase the concentration of ClO⁻ in the organic phase

but also increase the rate of mass transfer between the phases.16 Furthermore, the PTC

will stabilize the hydroxide ions formed in these reactions and remove them to the

aqueous phase efficiently. The observation that oxidation of azaphenanthrene (7,8-

benzoquinoline) in a two-phase reaction results in a mixture of the N-oxide and epoxide

products, whereas only the N-oxide is formed under single phase conditions, indicates

7

Chapter 1

that the mechanisms proceeding in the two-phase reactions are distinct from those

(possibly electrophilic) mechanisms occurring in aqueous solutions.15

1.4 Halogenases and haloperoxidases Halocarbons are common motifs in marine natural products, such as antibiotics,

hormones of pharmaceutical interest, agrichemicals, and are key reagents in organic

synthesis.17 Current methods for the late stage halogenation of complex compounds

present challenges as great as the corresponding challenges in late stage hydroxylation

of C-H bonds, with the reactivity needed to cleave a C-H bond incompatible with many

functional groups. Despite these challenges, nature has hijacked peroxidases and

oxygenases to achieve late stage halogenation with excellent selectivity and

specificity.18,19 A number of structures of haloperoxidases have been reported already20

and they are classified based on the nature of the terminal oxidant used into

haloperoxidases and halogenases.18 Vanadium and heme dependent enzymes employ

H2O2 to generate the reactive intermediates needed for C-H halogenations and are

classified as haloperoxidases. Non-heme and flavin dependent enzymes that use O2 by

contrast are referred to as halogenases.

I.4.1 Halogenases

1.4.1.1 Flavin dependent halogenases

The class of halogenases that require a flavin cofactor, such as PrnA (tryptophan 7-

halogenase) and PrnC, are not dependent on transition metal ions and engage in highly

regiospecific chlorination reactions. The high specificity precludes involvement of

HOCl/OCl- and points towards the generation of X+ (X = Cl or Br) equivalents to

halogenate electron rich substrates.

Scheme 9 Mechanistic proposal for the formation of dichloropyrrolyl-S-PltL. A proposed FAD-4α -OCl intermediate is formed from the attack of Cl- on FAD-4 α -OOH. The FAD-4 α

-OCl intermediate then reacts with substrate pyrrolyl-S-PltL in a two-electron electrophilic aromatic substitution to first form the 5-chloropyrrolyl intermediate and

then the 4,5-dichloropyrrolyl product.22(b)

Van Pée and co-workers have proposed the involvement of a 4α-hydroperoxy flavin

intermediate, which epoxidize alkenes and incorporate halogens regioselectively as

8

Introduction

halohydrins followed by removal of water to form the final chlorinated product.21 Walsh

and co-workers have proposed a FAD-4α-OCl intermediate,22 generated by reaction of

FADH2 with O2 and Cl to form an O-Cl intermediate in the active site which then reacts

with substrates (via electrophilic aromatic substitution) to yield chlorinated products

(Scheme 9). An alternative mechanism proposed by Naismith and co-workers23 was

based on the crystal structure of PrnA (with FAD, tryptophan and chloride bound).

Scheme 10 Mechanism for halogenation by Flavin dependent haloperoxidases proposed by Naismith and co-workers (formation of HOCl is followed by protein mediated

electrophilic aromatic substitution).18,24

Overall the halogenation involves HOCl equivalents, produced by reaction of Cl- anions

with the FAD-OOH intermediate formed by reaction of FADH2 with O2. However, the FAD

cofactor provides control of its reactivity by holding it within the active site through H-

bonding (Scheme 10).24,25

1.4.1.2 Non-heme iron dependent halogenases

Iron dependent halogenases, such as SyrB1 and CmaA, use non-heme Fe(II)/α-

ketoglutarate with O2 for halogenation of the inert aliphatic C-H bonds (Scheme 11).18,26

These enzymes are related to oxygenases based on a non-heme Fe(II)/αKG active site

except that a chlorido ligand replaces an aspartate moiety,18,26 and contrast with flavin

dependent enzymes in that they use chloride anions rather than Cl+ equivalents. The

general mode of action of this class of enzyme involves binding of a substrate within the

active site close to an Fe(II) center which facilitates dissociation of an aqua ligand and

coordination of O2 to form an Fe(III)-OOH intermediate and, through O-O bond cleavage

coupled with a decarboxylation, to form an Fe(IV)=O species. The later species has been

identified by Mössbauer and (resonance)Raman spectroscopy. Reaction of the Fe(IV)=O

intermediate with a C-H group in the substrate yields a Cl-Fe(III)-OH intermediate and an

alkyl radical, followed by formal reaction of a chlorine radical (Cl•) with the alkyl radical

(R-CH2•) to form the C-Cl bond.26 Although attack by a hydroxyl radical can compete with

chloride radicals, this pathway is less thermodynamically favourable.20d,27

9

Chapter 1

Scheme 11 Proposed mode of action of Fe(II) and αKG-dependent halogenases. R =

CH2-L-CH(NH2)-CO-S-CytC2; R’ = (CH2)2CO2.26

1.4.2 Haloperoxidases

1.4.2.1 Vanadium dependent haloperoxidases

Vanadium bromo peroxidase is one of the better known haloperoxidases owing to its

likely involvement in the biosynthesis of several halogenated natural products.28 In these

enzymes the vanadium ion is coordinated by histidine residue’s imidazole,18 and is able

to halogenate electron rich substrates using a combination of H2O2 and X- (where X- = Cl-,

Br- and I-), Scheme 12.29 Formation of a side on vanadium peroxy species is followed by

two electron oxidation of a halide to form V-O-X. Although the details of the mechanism

by which the vanadium dependent haloperoxidases halogenate substrates remain

unclear, it is generally accepted that they produce X+ (X = Cl, Br and I) equivalents, which

further halogenates electron rich substrates.

10

Introduction

Scheme 12 Formation of hypochlorite intermediate in vanadium-dependent haloperoxidases.18

1.4.2.2 Heme dependent haloperoxidases

As with the vanadium dependent haloperoxidases, heme dependent haloperoxidases

use a combination of H2O2 and halide ions (Scheme 13). A few examples of heme

dependent haloperoxidases are chloroperoxidase (CPO),30 myeloperoxidase (MPO),

thyroid peroxidase (TPO), lactoperoxidase (LPO) and eosinophil peroxidase (EPO), and as

with flavin dependent halogenase, they generate X+ (X = Cl or Br) equivalents and

therefore halogenate electron rich substrates. Reaction of heme Fe(III) with H2O2 leads

to formation of an Fe(IV)=O species, the so called Compound I.31,32 Inner sphere two

electron oxidation of a halide ion by Compound I yields heme-Fe(III)-O-X (where X = Cl,

Br and I),32 and hence a Fe(III) hypohalite species is proposed to engage in substrate

halogenation.

Scheme 13 Proposed mechanism in heme-dependent halogenation reactions.18

Direct spectroscopic evidence for a heme-Fe(III)-OCl adduct in heme dependent

haloperoxidases is thus far elusive, with only the observation of a heme-Fe(III)-OCl

adduct made recently by Fujii and co-workers.33 Reaction of OCl- with [(TPFP)Fe(III)(OH)]

in CH3CN/CH2Cl2 generated an intermediate assigned as [(TPFP)Fe(III)(OCl)2]-, that was

stable for 1 h at -60 °C, decomposing to [(TPFP)Fe(IV)(O)]. Indeed, only recently was a

non-heme Fe(III)-OCl reported by Draksharapu et al. at room temperature under

biological relevant conditions (vide infra).34 The transient nature of such species and the

potential to tame the reactivity of, especially OCl-, has prompted recent efforts in the

exploration of biomimetic complexes.

1.5 Reaction of biomimetic metal complexes with NaOCl Despite that it is isoelectronic with H2O2, the reactivity of metal complexes with

HOCl/NaOCl has received little attention primarily due to its intrinsic reactivity with

organic substrate. Nevertheless, recently the number of reports dealing with this topic

has increased with attention focused on manganese, iron and nickel complexes

primarily, in particular those bearing porphyrin ligands.35 In this section, the systems

reported with each metal will be discussed in turn.

11

Chapter 1

1.5.1 Manganese based complexes

1.5.1.1 Manganese porphyrins

Tabushi et al. reported the reactivity of manganese porphyrin complexes with NaOCl

over two decades ago in the context of generating intermediates relevant to the water

oxidation center of PSII,36,37 and noted that the combination could be used to oxidize

benzyl alcohol to benzaldehyde. Meunier et al. reported, as early as 1984, the use of

manganese porphyrin complexes with NaOCl in the epoxidation of olefins.38 These early

reports highlighted the need for PTCs, as styrene conversion to its epoxide was

negligible in the absence of PTCs. Furthermore, control of pH is essential as mentioned

above at low pH uncatalyzed oxidation to halohydrins and allylic chlorination is

observed.39 A key aspect of porphyrin chemistry is the involvement of proximal ligands

(such as pyridine ligand), Indeed, pyridine coordination to manganese centers was

accompanied by an increase in catalytic activity. Furthermore, increase in OCl-

concentration in the organic phase due to the PTCs leads to the formation of a Mn(III)-

OCl species, followed by heterolytic O-Cl bond cleavage to generate a reactive Mn(V)=O

species, which further reacts with 3-carene. The formation of -epoxide from 3-carene

in the presence of the catalyst, in contrast to the formation of -epoxide by the

uncatalyzed reaction supports this mechanism (Scheme 14).

Scheme 14. Formation of -epoxide of 3-carene by using Mn(TPP)OAc and NaOCl.38

Saturation kinetics were reported by Collman et al. for the epoxidation of various olefins

(styrene, cyclic olefins, or aliphatic alkenes) with Mn(TPP)Cl or Mn(TMP)Cl (where TPP

(meso-tetraphenylporphyrinato) and TMP (meso-tetramesitylporphyrinato) and 4'-

(imidazol-1-yl) acetophenone as axial ligand (Scheme 15).40 The data obtained was

consistent with the mechanism proposed by Tabushi et al.(vide supra).

12

Introduction

Scheme 15 Proposed catalytic cycle for olefin epoxidations by "OCl-/Mn(Porphyrin)Cl/L” where L is an axial ligand.40a

The intermediacy of the Mn(III)-OCl species was more recently supported by similar

species in the oxidation and chlorination of C-H bonds proposed by Groves and co-

workers.41 They proposed a mechanism in which formation of a LMn(IV)-OH or a

O=Mn(V)=O species occurred prior to substrate oxidation.42 Following hydrogen atom

abstraction the alkyl radical forms the product by chlorine atom transfer from L-Mn(IV)-

OCl to regenerate the O=Mn(V)=O species. In order for the chain reaction to proceed,

alkyl radical has to diffuse out of the [O=Mn(IV)-OH •R] cage, and the rearrangements

observed in the chlorination of norcarane indicate that this occurs (Scheme 16).

Scheme 16 Proposed C-H chlorination mechanism.41

1.5.1.2 Manganese salen complexes

The synthetic accessibility of salen complexes together with their similarity (in terms of

planar coordination) with porphyrins has prompted considerable interest in their

complexes over the last decades. Manganese salen complexes have been applied widely

in alkene epoxidations, most notably by Kochi,43 Jacobsen and co-workers. Jacobsen and

co-workers reported the use of Mn-salen complexes in epoxidations with NaOCl,44 and

considerable effort has been directed towards comparing the reactivity of Mn-salen

13

Chapter 1

complexes with a broad range of oxidants, such as PhIO, m-CPBA.45 Several mechanisms

have been proposed for the mode of action of Mn-salen complexes with NaOCl based on

species observed, product distributions and the effect of pyridines on catalytic activity,

and have raised key questions, in regard to catalyst degradation, and of phase transfer

agents in increasing reactivity and selectivity.

Reider and co-workers,46 reported the 4-(3-phenylpropyl)pyridine N-oxide (P3NO) as an

axial ligand to achieve higher yield, and enantioselectivity in the asymmetric epoxidation

of indene using aqueous NaOCl, catalyzed by Jacobsen’s chiral manganese salen

complex. It was proposed that P3NO increased the rate of mass transfer of HOCl to the

organic layer, where HOCl oxidizes Mn(III) to Mn(V)=O, which forms the rate limiting

step in the reaction based on kinetic data, which show that the rate of epoxidation is

independent of indene concentration but is dependent on the concentration of HOCl.

Furthermore, control of the concentration of OCl- in the organic layer and the

observation that the rate of oxidation of a redox indicator, diphenylbenzidine, resembles

the rate of epoxidation support this conclusion. Nevertheless mass transfer (e.g., stirring

speed) effects in the two phase system in the absence of axial ligand indicate that

oxidation can occur in the interfacial region. Thus, the axial ligand is proposed to play at

least two roles in the epoxidation of indene: it stabilizes the catalyst, presumably by

ligation, and it increases the epoxidation reaction rate by drawing the active oxidant,

HOCl, into the organic layer.46

Polymeric catalysts are also one of the ways to improve the catalytic efficiency. Many

groups have reported the use of polymeric Mn(III)-salen complexes to give high yields

and selectivity in the oxidation of alkenes using NaOCl as oxidant.47,53 Jasra and co-

workers has reported polymer immobilized chiral Mn(III)-salen complexes prepared

from 1S,2S-(+)-1,2-diaminocyclohexane, and 1R,2R-(+)-l,2-diphenyl ethylenediamine

with 5,5-methylene-di-3-tert-butylsalicylaldehyde.48 These complexes provided the

enantioselective epoxidation of styrene, indene and chromenes in presence of pyridine-

N-oxide (PyNO) as an axial base and NaOCl as oxidant and were recycled several times.

The polymeric Mn(III)-salen complexes used in the present study can be easily separated

from the reaction system and reused effectively.

Although several mechanisms have been proposed to rationalize the chemistry of Mn-

salen complexes with NaOCl, it is generally accepted that the initial step is the formation

of a Mn(III)-OCl intermediate that undergoes heterolytic O-Cl bond cleavage to liberate

Cl- and form a Mn(V)=O species. The latter intermediate is believed to be responsible for

the oxidation of alkenes (Scheme 17).46,49 This mechanism is essentially analogous to the

mechanisms proposed for the structurally related Mn-pophyrin complexes (vide supra).

14

Introduction

Scheme 17 Proposed mechanism for oxidation of alkenes with manganese salen complexes.45

A key challenge in mechanistic studies is the identification of reactive intermediates and

several intermediates were proposed to form upon reaction of Mn-salens with PhIO,

mCPBA, and NaOCl (Chart 1).

Chart 1 Intermediates proposed to be involved in catalytic cycles.45

Recent evidence for multiple oxidants or oxidation pathways in these (Mn(salen))

reactions has challenged the paradigm of a common mechanism with the formation of

adducts between the terminal oxidants and Mn(salen) species proposed to compete

with O=Mn(V)-(salen) as oxygen transfer agents. Seebach and co-workers have proposed

that with oxidants such as NaOCl, XO-Mn(III)(salen) species are involved in a concerted

pathway in the oxidation of substrates. In contrast with oxidants such as PhIO,

O=Mn(V)(salen) species lead to formation of radical intermediates and thereby affect

the trans/cis-epoxide ratio (i.e. loss of stereochemistry).50 Brauman and co-workers have

proposed that oxidants such as PhIO lead to a mixture of PhIO-Mn(III)(salen) adducts

and O=Mn(V)(salen), and the data supports the opposite mechanisms (Seebach and co-

workers) for these two types of species.51 Radical trapping and free energy studies show

a nonlinear Eyring plot for PhIO, while with mCPBA and NaOCl the corresponding plots

are linear, consistent with a single oxidant, O=Mn(V)(salen), in the latter cases. Further

15

Chapter 1

support for this conclusion is the lower levels of trans-epoxide obtained from cis-alkenes

(stilbene) with NaOCl.45

1.5.2 Iron complexes as models for halogenases and haloperoxidases Iron dependent halogenases and haloperoxidases play a key role in halogenation

reactions in nature (vide supra). Bio-mimetic complexes can provide insight into the

mechanisms by which these enzymes operate and open opportunities for novel catalytic

reactivity. In the case of halogenases, the reaction of H2O2 with the Fe(II) center leads to

formation of an Fe(IV)=O species with a porphyrin π-cation radical ligand (compound

I).52 Reaction of compound I with chloride results in the formation of an Fe(III)-OCl

species transiently, which releases OCl-.33 Such Fe-OCl species have been proposed as

key intermediates in catalytic oxygenation reactions and hence their formation is of

substantial wider interest.50,53

Despite that the formation of a putative Fe(III)-OCl species rationalizes the reactivity

observed, its direct detection has not been achieved for enzymatic systems and hence

generation of such species in model complexes is of interest.54,33 Alexander and co-

workers proposed the formation of an Fe(III)-OCl species during the oxidation of alkanes

with NaOCl and Fe(III) tetramesityl-porphyrin chloride (TMPFeCl).55 Under basic

conditions, the 3/1 alcohol/ketone ratio was obtained with a remarkably high KIE

observed.

Hypochlorito iron(III) porphyrin complexes have received relatively little attention in

comparison with those species formed from other terminal oxidants such as H2O2 or

iodosylarene.56,41 Recently, Cong and co-workers reported the spectroscopic

characterization of an intermediate species assigned the structure TPFPFe(III)-(OCl)2

(where TPFP is 5,10,15,20- tetrakis(pentafluorophenyl)porphyrinat), formed during the

reaction of (TPFP)Fe(III)-OH with TBAOCl (tetrabutyl ammonium hypochlorite), which

reacted with thioanisole to give (TPFP)Fe(III)-Cl and (TPFP)Fe(III)-OH. TPFPFe(III)-(OCl)2

reacted with cyclohexene to form a transient TPFP Fe(IV)=O and also showed reactivity

in sulfoxidations, chlorinations, and epoxidations.33

In contrast to heme systems, relatively little attention has been given to non-heme iron

complexes reactivity with NaOCl. Balland and co-workers noted the appearance of a

transient intermediate with absorbance maximum at 440 nm when generating a non-

heme Fe(IV)=O species from the corresponding Fe(II) L(L= N-methyl-N,N’,N’-tris(2-

pyridylmethyl)propane-1,3-diamine) with NaOCl, which they tentatively assigned as

Fe(II)-OCl intermediate.57

The first non-heme Fe(III)-OCl species was characterized spectroscopically by

Draksharapu et al. recently.34 Addition of near stoichiometric NaOCl to

[Fe(II)(Cl)(MeN4Py)]2+ (where MeN4Py = 1,1-di(pyridin-2-yl)-N,N-bis(pyridin-2-

ylmethyl)ethanamine) under acidic conditions (pH 2-5) resulted in formation of

16

Introduction

[Fe(III)(OCl)(MeN4Py)]2+, which undergoes homolysis of the OCl bond to yield

[Fe(IV)(O)(MeN4Py)]2+.34 The non heme Fe(III)-OCl intermediate is stable at room

temperature and shows a weak visible absorption band (max 480 nm), resonantly

enhanced Raman bands (580, 653, and 673 cm-1), and an EPR spectrum characteristic of

a mononuclear S = ½ Fe(III) complex (g = 2.26, 2.15, and 1.97).33 However, DFT

calculations indicate the formation of an intermediate Fe(II)-OCl species also, that

undergoes rapid heterolytic O-Cl bond to yield the corresponding Fe(IV)=O species

(Scheme 18). It is notable, in the context of iron dependent haloperoxidases, that the

Fe(IV)=O species reacts with Cl- to form an Fe(III)-OCl.

Scheme 18 The reaction mechanism for the formation of [Fe(III)(OCl)(MeN4Py)]2+ and [Fe(IV)(O)(MeN4Py)]2+ with the free energies (ΔG) calculated for each step. Reproduced

with permission from ref. 34. Copyright Wiley (2015).

Although the observation of Fe(III)-OCl species is still rare, Sen Gupta and co-workers

demonstrated the formation of Fe(V)=O complexes upon reaction of the corresponding

Biuret-amide-modified Fe(III)−TAML complex (where TAML is tetra amido macrocyclic

ligand) upon reaction with NaOCl. Reaction with 0.5 equiv. of NaOCl in CH3CN, resulted

in initial formation of a Fe(IV)2(μ-O) complex, with a second 0.5 equiv. of NaOCl

producing the Fe(V)=O species.58 Collins and co-workers have shown recently that Fe(III)-

TAML (beheaded) complexes show a pH dependence in their reaction with NaOCl

forming either Fe(V)=O and Fe(IV)=O species, at low and high pH, respectively (Scheme

19).59

17

Chapter 1

Scheme 19 pH-Dependent transformations of Fe-TAML species generated with NaOCl in water.59

Scheme 20 Oxidation of organic substrates with catalytic nickel(II) salts and aqueous bleach (a-d), and (e) proposed mechanism for the oxidation of 3-butenoic acid to

fumaric acid.62

Although nickel dependent enzymes are uncommon, there are some examples such as

Ni-SOD, and there has been some effort, especially recently, towards the study of Ni(II)

complexes as catalysts for organic oxidations with a wide range of oxidants including

bleach.

18

Introduction

1.5.3 Reactivity of Nickel complexes with HOCl/NaOCl

Interest in nickel complexes as oxidation catalysts with a wide range of oxidants has

increased, the use of simple nickel salts with NaOCl was already studied in the 1970s.

The reaction of stoichiometric nickel oxides and hydroxides60 with organic substrates

was well established for example Bekkum and coworkers noted that diol cleavage of

some sugars could be achieved with nickel oxides and bleach to yield carboxylic acids.61

It should be noted that reaction of bleach with nickel(II) salts leads to rapid formation of

nanoparticulate nickel oxides with high surface areas that are useful as heterogeneous

catalysts.62 Recently, Grill et al. have shown that NaOCl can be used synthetically with

catalytic amounts of nickel salts (ca. 2 mol%) such as nickel(II)acetate and

nickel(II)chloride in the oxidation of primary and secondary alcohols to ketones and

acids,and the epoxidation of α,β-unsaturated carboxylic acids (Scheme 20).62

1.5.3.1 Ni(II) salen complexes in oxidations with NaOCl

In the mid-1980s, Burrows and co-workers, and thereafter Kureshy and coworkers

demonstrated that cyclam and salen based nickel complexes catalyzed the epoxidation

of alkenes with NaOCl.63,64,65 In these studies the formation of a fine black suspension

during the reaction was noted indicating formation of NiO(OH)2.60,62 However, the

involvement of such inorganic particulate species in the oxidation was excluded as only

trace epoxidation was observed under the same conditions with Ni(II) acetate, and the

recovered black precipitate did not oxidize the substrate. Similar conclusions were

drawn later by Draksharapu et al. (vide infra).72

Scheme 21 Proposed mechanism for epoxidation of (E) and (Z)-stilbene with Ni(II) salen complexes and NaOCl.64

The formation of Ni(IV)-oxo intermediates were proposed for the cyclam catalysts with

PhIO and an analogous mechanism was proposed to occur with NaOCl (Scheme 21).

19

Chapter 1

Notably, the oxidation of olefins proceeded without stereospecificity, indicating the

formation of radical intermediates.64

Subsequently, Burrows and co-workers proposed a mechanism based on the effect of

pH and additives on the reaction.65 At pH 9.3, the rate of epoxidation was highest, which

indicated that at that pH, sufficient concentrations of chlorine monoxide, the proposed

terminal oxidant, formed (Scheme 22). Indeed the reaction of Cl2O with Mn(TPP)Cl and

with [Ni(CN)4]2- has been reported already, with [Ni(CN)4]2- reacting with Cl2O 107 times

faster than with HOCl. It was proposed that a NiIV(CN)4(Cl)(H2O)- intermediate formed.66

Scheme 22 Formation of Cl2O from HOCl.65

Oxidation of the Ni(II) salen complex to the Ni(III) state with Cl2O followed by exchange

of Cl- for OCl- and homolytic Ni(III)-OCl bond cleavage would generate ClO•, a known

epoxidizing reagent (Scheme 23).5,67

Scheme 23 Proposed mechanism for generation of ClO• (epoxidation) and Cl• (chlorination) with NiII complexes. Ligands are omitted for clarity.65

An alternative pathway involves the intermediacy of a LNiIII-oxo radical formed by

reaction with HOCl (equation 16) or by cleavage of the O-Cl bond (Scheme 24). The LNiIII-

O• formed could engage in H atom abstraction and epoxidation.68

20

Introduction

Scheme 24 Generation of salen NiIII ClO• species.65

Freire and co-workers69 noted that methyl substituents on the salen ligand on Ni-salen

complex did not affect selectivity trans-β-methyl styrene, however O2 increased

conversion prompting the proposition of two pathways; a mechanism in which a Ni-oxo

complex is generated by reaction with radical species formed from NaOCl in the

presence of O2, which leads to faster alkene conversion but not a change in selectivity,

analogous to the rebound mechanism proposed for Cytochrome P450.70 Recently, it has

been shown that short-lived radicals are not bound to metal complexes.71 In an

alternative mechanism, substrate binding to the metal oxo complex occurs lowering

conversion but increasing epoxide selectivity (Scheme 25).

Scheme 25 Mechanisms for the oxidation of trans-β-methyl styrene with NaOCl and Ni(II) (salen) complexes.69

1.5.3.2 Ni(II) triazacyclononane based catalysts for oxidations with NaOCl.

Recently Draksharapu et al. reported a Ni(II) catalyst based on the facial coordinating

triazacyclononane scaffold (PyTACN = 1-(2-pyridylmeth-yl)-4,7-dimethyl-1,4,7-

triazacyclononane) for the chlorination of alkanes with NaOCl as both oxidant and halide

transfer agent.72 Although activity under basic conditions was low, addition of acetic acid

21

Chapter 1

increased the rate of cyclohexane chlorination beyond that (marginally) of the

background reaction. The inhibition seen by simple Ni(II) salts, indicated that the

Ni(II)(PyTACN) complex was playing an active role in the reactions observed, and several

intermediates were characterized spectroscopically.

However, the KIE measured through a competition reaction between cyclohexane-H12

and cyclohexane-D12 was 2, which, together with the product distribution obtained with

cis-1,2-dimethylcyclohexane and decalins, is consistent with a highly reactive hydrogen

atom abstracting reagent, e.g., a chlorine radical. The increase in reaction rate (catalyzed

and non-catalyzed) upon addition of acetic acid, is expected given that under acidic

conditions HOCl forms ClO• species (vide supra), which was confirmed by the

appearance of an band at ca. 320 nm upon addition of acetic acid to NaOCl in

acetonitrile. Nevertheless despite that the role of the catalyst appeared to be to

accelerate the formation of the chlorine species responsible for substrate chlorination

(Scheme 4),5,73 several species of interest in the development of Ni(II) catalysts are

worth mentioning. A low spin Ni(III) species was observed (EPR signals at g⊥ = 2.13, and

g// = 2.03)74 with resonantly enhanced Raman bands at 724 cm-1 for Ni(III)-OH and 1682

cm-1 for a Ni(III)-OOCCH3 species. However, as with other Ni(III)-OR species reported

recently75 it is unlikely that these species are oxidants in the case of cyclohexane, as they

are only capable of undergoing hydrogen atom transfer (HAT) with weak O−H bonds.

Scheme 26 Proposed mechanism for C-H chlorination by Ni(II)-PyTACN complexes reaction.72

The mechanism proposed is shown in Scheme 26, in which [(L)Ni(II)-OCl(S)]+ (A) is

formed by reaction of Ni(II)PyTACN with NaOCl and subsequently decays to

[(L)Ni(III)−OH(S)]2+ (B) (where S is solvent), possibly through homolytic cleavage of the

O−Cl bond. This mechanism rationalizes the release of Cl• atoms. Notably, the hydrolysis

22

Introduction

of acetonitrile to acetic acid was observed resulting in the formation of [(L)Ni(III)-

OOCCH3 (S) ]2+(C), and thereafter [(L)Ni(II)-OOCCH3 (S)]2+(D), presumably via oxidation of

ClO2− to form ClO2. Coordination of NaOCl to [(L)Ni(II)-OOCCH3(S)]2+ (D) regenerates

[(L)Ni(III)-OH(S)]2+ (B) more rapidly than from the original complex. Acids, such as acetic

and triflic acid, increase the rate and extent of formation of [(L)Ni(III)-OH(S)]2+(B),

indicating proton acceleration of O−Cl homolytic cleavage. Ultimately, these reactions

generate Cl• atoms and ClO2 in a catalytic cycle in which the nickel complexes undergo a

Ni(II) - Ni(III) cycle liberating chlorine atoms which react with the C−H bonds of alkanes,

forming alkyl radicals that are trapped by Cl• to form alkyl chlorides. Since alkane

functionalization is not a metal-based process, the regioselectivity of these reactions is

limited to that expected for chlorination with chlorine radicals.

1.5.3.3 Ni(II) catalysts with anionic ligands

Recently, Company and co-workers reported the formation of Ni(IV)-OCl intermediate

from a Ni(II) complex bearing a dianionic macrocyclic ligand (with two amidate, one

pyridine, and one aliphatic amine) upon reaction with NaOCl in the presence of acetic

acid.76

Scheme 27 Possible formulations of compound Ni(IV)-OCl derived from the reaction of 1(Ni-L) with NaOCl in the presence of AcOH. Free energies are given in parentheses in

kcal·mol-1 at -30°C in MeCN.76

The Ni(IV)-OCl intermediate reacted rapidly with substrates including those with strong

aliphatic C−H bonds, and they concluded that in contrast to the previous example

reported by Draksharapu et al. (where nickel generated chloride radicals involved in

chlorination),72 the Ni(IV)-OCl species was directly involved in the oxidation/chlorination

reactions. DFT studies, together with a combination of UV/Vis absorption, EPR, ESI-MS,

Raman, EXAFS spectroscopy enabled the characterization of the intermediate as

23

Chapter 1

formally in the Ni(IV) oxidation state, but in reality it is more accurately formulated as a

Ni(III) complex with one unpaired electron delocalized over the ligand ( Scheme 27).

1.6 Conclusions In summary, NaOCl is a useful oxidant and a high energy species, which can be used in

wide range of functional group transformations. A drawback of hypochlorite is its

reactivity; it reacts rapidly, but with limited specificity. Nevertheless, it has been applied

often with stereo- and chemo-selectivity and its diverse pH chemistry has enabled the

control of its reactivity allowing access to various mechanisms and to tune the reactivity

in the presence of metal complexes as catalysts. A catalyst is typically viewed as a

species that provides a pathway with a lower activation energy than the uncatalyzed

reaction. For example, despite being a high energy molecule, H2O2 does not oxidize

substrates on its own but requires a catalyst. By contrast, NaOCl is highly reactive as the

various oxidation states and species of chlorine act as their own catalyst. Therefore the

challenge is not to accelerate the reaction of NaOCl with substrates but instead to tame

it with a catalyst. In this review it is shown by using various complexes, such as

manganese, iron, and nickel, that NaOCl can be used to generate reactive intermediates,

which have some analogies with natural systems, such as halogenases, haloperoxidase.

Nature produces hypohalites and controls their reactivity with substrates through

hydrogen bonding, proximity effects etc. Alternatively, in case of halogenases,

hypohalites are not formed, but instead an Fe(IV)=O with a chlorido ligand co-ordinates

to the metal center, and a rebound reaction with the chloride ligand involved in the

chlorination of substrates. It is difficult to achieve conditions comparable to those found

in these enzymes, however we can potentially mimic by formation of Fe(IV)=O with a

chlorido ligand present.

Although iron and nickel catalysts have been applied with NaOCl as early as the 1990s,

these system have received little attention compared to manganese complexes,

however over the last decade, high valent iron and nickel intermediates formed with

NaOCl have been characterized. The real challenge, however, is to tame NaOCl, to

generate the active species faster than NaOCl reacts with the substrate directly, which

can be achieved with high concentrations of the catalyst and maintaining low

concentrations of hypochlorite, such that hypochlorite can be reacted to form active

species before having a chance with the substrate and the activated form of the catalyst

can react with substrate. In conclusion, although there are many challenges in the use of

NaOCl in catalyzed reactions, there are also many opportunities provided that we

recognize that activating NaOCl is not the goal but rather taming its reactivity with

suitable metal complexes.

1.7 Outline of the thesis Chapter 1 discusses briefly the production and basic chemistry of the oxidant NaOCl,

focusing on the pH dependence of its reactivity, and enzymes such as halogenases,

24

Introduction

haloperoxidases. The potential for transition metal complexes, based primarily on

manganese, iron and nickel, to tame NaOCl is explored in regard to efforts to use NaOCl

activated species to oxidize the alkanes or alkenes. The aim of chapter 1 is to gain insight

into the high valent intermediates formed with NaOCl and how these complexes can be

applied effectively in selective oxidations.

In chapter 2 the reaction of H2O2 with [(MeN3Py)FeII(CH3CN)2]2+ is studied primarily at

room temperature in acetonitrile. The data reported in the chapter highlight the role of

ligand exchange reactions in the activation of Fe(II), and the importance of the

formation of thermodynamically stable dinuclear Fe(III)−O−Fe(III) species under catalytic

conditions.

In chapter 3 the involvement of high valent iron intermediates in the reaction of

[(MeN3Py)FeII(CH3CN)2]2+ with H2O2 and oxidation of alkenes is discussed. In particular,

the role of solvent (acetonitrile vs acetone) in the chemoselectivity observed, and

especially the role played by the sixth ligand at iron center. It is shown that H2O2 reacts

with [(MeN3Py)FeII(CH3CN)2]2+ in acetone at room temperature and low temperatures (-

15 ºC, -30 ºC, and -80 ºC) results in the formation of Fe(IV)=O as well as Fe(III)-OOH

species, and importantly that the Fe(IV)=O species formed in acetone is distinct from

that formed in acetonitrile. The implications of these differences is discussed in regard

to the differences in chemoselectivity.

Acetic acid is frequently employed in oxidation catalysis with non-heme iron catalysts

and in chapters 2 and 3 its formation in situ and involvement was apparent. In chapter 4,

the goal is to understand the role acetic acid plays in reactivity of

[(MeN3Py)FeII(CH3CN)2]2+ with H2O2 in terms of both the species formed and its influence

on the chemoselectivity of the oxidation of alkenes. Evidence for the formation of an

Fe(IV)=O species in the presence of acetic acid is coupled with an increase in selectivity

towards epoxide products.

In Chapter 5, the aim is to characterize a novel reactive intermediate formed when a

nickel(II) complex of the robust ligand TMTACN reacts with NaOCl. DFT methods

together with time resolved spectroscopy are used to show that reactive species is the

high valent intermediate [(TMTACN)2NiIV2(O)3]2+. Furthermore, initial studies to gain

insight into the reaction mechanism for its formation are reported.

In Chapter 6 the focus shifts to the activation of molecular oxygen and in particular the

application of time resolved resonance Raman spectroscopy to understand the

activation of O2 by Mn(II)dpeo complex. The activation of oxygen by the Mn(II) complex

was followed by a stepwise oxidation of its own ligand at the methylene position to form

a ketone. Importantly, it is shown that the reaction is in fact catalytic and

intermolecular, opening up the possibility for the activation of oxygen beyond ligand

oxidation.

25

Chapter 1

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