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MSc Chemistry

Molecular Sciences

Literature Thesis

Photochemical C-H activation of Unactivated

Alkanes via a Radical Pathway using Molecular

Systems

by

Nicole A. E. Oudhof

10780645

12 EC

January – March 2020

Examiner:

Second examiner:

Dr. J. C. Slootweg.

Dr. ir. J.I. van der Vlugt

Van’t Hoff Institute for Molecular Sciences

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Abstract

Alkanes, the main components of natural gas and petroleum, are now mostly used as energy carriers. Their use as chemical building blocks is limited due to the large bond dissociation energies of the C-H bonds, resulting in unfavourable high temperatures and harsh reaction conditions to functionalize these unactivated alkanes. Using photochemistry to produce alkyl radicals can be a strategy to functionalize hydrocarbons under relatively mild conditions with high atom-efficiency. Hence, this thesis provides the state-of-the-art methods for C-H bond activation of unactivated alkanes such as methane, ethane and cyclohexane via a radical pathway using molecular systems and photochemical activation. The emphasis lies on the mechanistic insights of alkyl radical formation and the scope of the different (catalytic) systems will be discussed. Different mechanisms to form an alkyl radical were described, such as direct hydrogen atom transfer (HAT) by the photocatalyst, multisite site-electron proton transfer, dual catalytic systems of a photocatalyst with a HAT catalyst or agent and HAT transfer in a radical chain mechanism. The described systems are commonly catalytic, although stoichiometric HAT reagents or initiators are also used in some systems. Cyclohexane was the most frequently investigated substrate and only a few catalytic systems have been found for the conversion of methane and ethane and other linear or cyclic alkanes. All reactions are performed under relatively mild conditions with temperatures below 80 °C. The most used HAT agent is the chlorine atom, but the bromine atom was also used, just as nitrogen and oxygen radicals. The most-used transition-metal based photocatalysts are cyclometalated iridium complexes, and some organic photocatalysts are described. Despite the great research efforts made in chemoselective functionalization of hydrocarbons, further research is still required to develop efficient strategies to transform the most widely available hydrocarbons, methane and ethane, in valuable products and chemical building blocks on an industrial scale.

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List of abbreviations

Abbreviation Signification

BDE bond dissociation energy

BHT butylated hydroxytoluene

bpy 2,2′-bipyridine

Cy cyclohexyl

d(CF3)bpy bis(trifluoromethyl) bipyridine

dF(CF3)ppy 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine

DMPO 5,5-dimethyl-pyrroline N-oxide

dtbbpy 4,4′-di-tert-butyl-2,2′-bipyridine

EPR electron paramagnetic resonance

EPT electron-proton transfer

FT synthesis Fischer-Tropsch synthesis

HAT hydrogen atom transfer

HOMO highest occupied molecular orbital

LMCT ligand-to-metal charge transfer

LUMO lowest unoccupied molecular orbital

Mes-Acr-Me+ 9-mesityl-10-methylacridinium

Mes-Acr-Ph+ 9-mesityl-3,6-di-tert-butyl-10-phenylacridinium

Mes-Acr-R1 Mesityl-acridinium-based

MLCT metal-to-ligand charge transfer

MS-EPT multisite site-electron proton transfer

NMR nuclear magnetic resonance

PBN N-tert-butyl-α-phenylnitrone

PCET proton-coupled electron transfer

PET photo-induced electron transfer

PFH perfluorohexane

ppy 2-phenylpyridine

SFMT reactor stop-flow microtubing reactor

SMR steam methane reforming

TBACl tetrabutylammonium chloride

TEMPO 2,2,6,6-tetramethyl piperidin-1-oxyl

TFA trifluoroacetic acid

TFE trifluoroethanol

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Table of contents

Abstract 3 List of abbreviations 4 Introduction 6 Photochemistry 10

Transition metal based photocatalysts 13

Iridium-based photocatalysts 13

Cerium based photocatalyst 24

Organic photocatalysts 25

Acridinium-based photocatalyst 25

Eosin Y 30

Pentacenetetrone 32

Iodine oxide and chloride 34

NaClO2 34 NaCl/Oxone 35 KBr/Air 36 Peroxy species 36 Amidyl radicals 37 Selectfluor 38

Conclusions and perspectives 39

Acknowledgements 41

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Introduction

Alkanes are the main components of natural gas and petroleum. As the reservoirs of crude oil are running out, the smaller alkanes in biogas and natural gas receive more attention. The production and consumption of natural gas increased over 5% in 2018, which is the highest growth rate in more than 30 years.1 More reserves of natural gas have been discovered in the last decade, making it

readily available. Unfortunately, it is mostly used as a fuel/energy carrier (Figure 1),2 even though

distribution is very energy consuming because the liquefication takes place at low temperatures or at high pressures.3 The great availability and low price make it an interesting raw material for the

production of chemicals on industrial scale.

Figure 1 Distribution of the usage of alkanes.2

However, alkanes and cycloalkanes, except cyclopropane, are the least chemically reactive class of organic compounds and thus difficult to transform. This chemical inertness is caused by strong and localized C-H and C-C bonds, that are nonpolar due to the small difference in the electronegativity of

carbon and hydrogen.4 The energy of the highest occupied molecular orbital (HOMO) of alkanes is

low, making it difficult to remove electrons from for oxidation. The lowest unoccupied molecular orbital (LUMO) lies high is energy which makes donation of electrons for reduction difficult as well. Since they have very high pKa values, they are unreactive towards both bases and acids, although

super-acids can protonate alkanes.5 Besides the aforementioned processes that involve two

electrons or a proton, one-electron processes are also difficult, shown by the high ionization potentials, low electron affinities and the high bond dissociation energies (BDEs) of the C-H bonds. The BDE is the energy that is necessary to split a bond homolytically and thus is a measure of the bond strength. The BDEs of the C-H bond of methane and ethane are higher than for most cycloalkanes such as cyclohexane (Scheme 1) because the radical intermediates are better stabilized

hence they are easier to functionalize.6 Another difficulty with the use of alkanes is their solubility.

Methane and ethane are gases under most common reaction conditions and are poorly soluble in

most solvents, while cyclohexane is more soluble.7 For these reasons, research on C-H bond

functionalization has been performed on cyclohexane and other cycloalkanes, but there is a growing interest from the scientific community that recognizes the importance of the functionalization of smaller alkanes such as methane and ethane.

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7 Scheme 1 Bond dissociation energies (BDEs) of selected unactivated alkanes in kcal mol-1.6

Considering these properties, alkanes are difficult to functionalize and due to positive Gibbs free

energies at 298 K most conversion processes are thermodynamically unfavorable.8 Nevertheless,

numerous reactions are known to convert alkanes, but these need to be performed at high temperatures and under harsh reaction conditions. The conversion of methane into larger hydrocarbons is industrially implemented through steam methane reforming (SMR) followed by Fischer-Tropsch (FT) synthesis (Scheme 2).9 Especially the SMR to produce syngas is highly energy

intensive, because it must be operated at high temperature (700-1100 °C). Research on the functionalization of alkanes is mostly focused on new methods that are less energy extensive, do not need harsh conditions and reagents and obtain high yields.

Scheme 2 Reaction equations of SMR and the FT synthesis in the formation of larger hydrocarbons from methane.

Radical reactions

A way to avoid harsh reaction conditions is the use of radical reactions. They have long been regarded as unselective and uncontrollable, although modern research more and more disproves this idea. Many natural products are formed with radical-generating enzymes in a very selective

manner.10 Especially, in polymerization and addition processes, radical pathways are proved to show

advantages over ionic pathways in the scope and the functional group tolerance.11,12 A radical

mechanism for the direct C-H bond functionalization appears to be a promising path towards functionalization with high atom- and step-economy, since protection and deprotection steps can be avoided. The reactions proceed under mild reaction conditions, which makes it extra attractive. Another advantage is the wide range of products that can be formed from the reaction of a (carbon-centered) radical with different trapping reagents (Scheme 3). Unfortunately, radical reactions suffer from some difficulties since the products and the solvent are often more reactive towards the radicals than the substrates which results in a range of side products. Some alkanes could be used as solvents, but they suffer with selectivity problems because the formation of the radicals is dictated by the BDEs of the bonds. The philicity of the radical is also important in the reactions it will perform, as radicals can also be classified in terms of electrophilicity and nucleophilicity.13 Alkyl radicals are

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8 Scheme 3 General scheme of C-H functionalization towards different products with an alkyl radical intermediate. Different methods can be used to verify the formation of radical intermediates. Since radicals are paramagnetic, electron paramagnetic resonance (EPR) spectroscopy can be used to characterize and

monitor the formation of radicals.14 The EPR spectrum can show the nature of the radical and

hyperfine coupling can indicate the neighbouring atoms. A transient radical intermediate could be reacted with a diamagnetic reactant to form a persistent radical that accumulates to make detection by EPR possible.15 This method is called spin trapping and widely used spin trapping agents are

C-nitroso compounds and nitrones such as N-tert-butyl-α-phenylnitrone (PBN) and 5,5-dimethyl-pyrroline N-oxide (DMPO) (left, Scheme 4). Radicals can also be trapped by other radical trapping agents such as 2,2,6,6-tetramethyl piperidin-1-oxyl (TEMPO) and butylated hydroxytoluene (BHT) (right, Scheme 4) that can be analysed by the other methods (mass spectrometry and NMR) to identify the radical intermediates. The involvement of radicals can also be suggested by the addition of a radical trapping agent to the reaction. If this suppresses the activity of the reaction it is very likely that radical intermediates are involved.

Scheme 4 Common spin trapping reagents and radical trapping reagents for the detection of radical intermediates.

Formation of alkyl radicals

To form an alkyl radical from an alkane, a proton and an electron must be transferred. Multiple mechanisms are possible to achieve this: in a concerted fashion with a proton-coupled electron

transfer (PCET) or by the transfer of a proton subsequent to an electron or vice versa (Scheme 5).16

The stepwise mechanisms form high-energy intermediates that bear formal charge on the carbon atoms. The concerted pathway avoids these intermediates making this pathway more favourable.

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9 Scheme 5 General mechanisms of the formation of an alkyl radical by the transfer of a proton and an electron in a concerted

or sequential fashion.

PCET is the term that is used for the whole class of reactions that simultaneously transfer a proton and an electron, but it has also subclasses: electron-proton transfer (EPT), multisite site-electron proton transfer (MS-EPT) and hydrogen atom transfer (HAT). In EPT, the proton and electron are not

sharing the same orbital in the start or final state. An example is the e-/H+ abstraction from phenol,

where the proton leaves a lone pair on the oxygen, while the electron transfers from the aromatic π-system (Scheme 6a). In a MS-PCET mechanism, the proton and electron transfer to or from different molecules or sites, which happens with the quenching of the triplet state of C60 by phenol in the

presence of pyridine (Scheme 6b), where the proton is transferred to the 3C

60*and the proton to

pyridine.17 With HAT the proton and the electron move together sharing the same donor and

acceptor as happens in radical halogenation (Scheme 6c).18 BDEs give a good indication about the

driving force of the HAT reaction, although the free bond dissociation energy is more precise because

of the inclusion of entropy changes which is especially important in metal complexes.19 A long-held

intuition is that the amount of radical character is correlated with the HAT reactivity and a good HAT reagent has a lot of radical character, but this is not the case. Spin states play an indirect role, because different spin states have different free energies and barriers for HAT.

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Photochemistry

Radicals can easily be generated by using light. Visible light can be used as a “reagent” in combination with photocatalysts, photomediators or photoinitiators to transfer photonic energy to achieve efficient and selective chemical reactions. The energy of the photons is used to access higher electronic states that have more reductive and oxidative power than the ground state. Most photochemical reactions proceed under mild conditions and have high atom-economies. These properties make it an attractive activation mechanism for the transformation of normally unreactive molecules under relatively mild conditions.

Research goal

The field of catalytic conversion of methane9,20 and ethane21 and other C-H bonds22–24 has been well

reviewed from the aspect of photocatalysis, organocatalysis, electrocatalysis and thermocatalysis with heterogeneous and homogeneous systems, but none of these focused on the formation of alkyl radical intermediates using photochemistry with molecular systems. Hence, this thesis provides the state-of-the-art methods for C-H bond activation of unactivated alkanes such as methane, ethane and cyclohexane via a radical pathway using molecular systems and photochemical activation. The emphasis will be on the mechanistic insights of alkyl radical formation. In addition, the scope of the different (catalytic) systems will be discussed. The first section of this review will provide background information on photochemical activation, which is followed by a section about transition-metal based photocatalysts and organic systems in the formation of alkyl radicals. The thesis is concluded with the most frequently seen challenges and solutions and a perspective on the direction of the research field.

Photochemistry

One way to activate strong bonds under mild reaction conditions is to use the energy of a photon to drive the reaction. This section begins with the different ways light can be used to activate substrates and will subsequently give examples of activation mechanisms of the C-H bond in unactivated alkanes in forming alkyl radicals with the use of light.

By irradiating a molecule in the UV or visible region electronically excited states can be generated of which the high energy and different electronic structure can be useful for chemical reactions. The interaction of unactivated alkanes with (visible) light is weak, but higher lying electronic states can be accessed using short wavelengths of UV light. However, this is disadvantageous because of uncontrolled photodecomposition with these high energy photons. Photocatalysts enable the use of light to drive reactions, since they absorb light with a high efficiency and at wavelengths in the visible light range. The chemical potential that is created by the absorption of a photon can be used to transform organic substrates. Other catalytic strategies to transform organic substrates can be coupled to these photocatalysts in dual-catalyst systems. In these systems different catalysts are used for the absorption of light and activation or transformation of the substrates.

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Energy transfer

There are three main photocatalytic activation pathways identified: electron transfer, atom transfer and energy transfer. The most used and well-known feature of photo-excited molecules is their ability to participate in one-electron-transfer or photoredox processes, since a molecule in the excited state is both a stronger reductant and a stronger oxidant than in the ground-state. Excitation of the photocatalyst generates an electronically excited state, which can relax back to the ground-state via different radiative or non-radiative pathways. However, the photocatalyst can also undergo photo-induced electron transfer (PET) if the lifetime of the excited state is long enough and the electron transfer fast. The excited photocatalyst can be reduced by an electron-rich donor species or oxidized by electron-deficient acceptor species, also known as reductive and oxidative quenching, respectively (Scheme 7). The photocatalyst ends up in an electronical ground-state, but with a different oxidation state and to regenerate the active photocatalyst another electron transfer must take place. The redox potentials of the photocatalyst, the acceptor or donor species are the best parameters to predict if the reaction is feasible. To generate alkyl radicals from unactivated alkanes the respective photoredox cycle must be combined with another catalytic system such as a HAT catalyst.

Scheme 7 Mechanistic pathways in photoredox catalysis.25

Atom transfer

The second activation pathway is the direct atom transfer by the excited state photocatalyst. Frequently, a hydrogen atom is transferred instead of the stepwise transfer of an electron and a proton, but other atoms are also transferable. The photocatalyst in the electronically excited state can abstract a hydrogen atom from a substrate, forming two radical species (Scheme 8). The photocatalyst is regenerated by another HAT or a sequential electron/proton transfer. The feasibility of HAT is generally determined by the C-H bond-strength, which makes it difficult with the strong C-H bonds of unactivated alkanes.

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12 Scheme 8 Mechanism of a photoinduced HAT transfer catalyst.

Energy transfer

Energy transfer is the third and last photocatalytic activation pathway. The excited-state energy of the photocatalyst is transferred to a substrate, which results in nonradiative relaxation of the photocatalyst in combination with the generation of an excited state of the substrate (Scheme 9). This process is also known as photosensitization. The feasibility of the reaction is not determined by the electrochemical potentials because there is no net redox change, hence the relative energies of the triple state of the photocatalyst and the substrate are a better predictor.

Scheme 9 General mechanism of photosensitization.

While it is most desirable to use catalytic systems, multiple other pathways to use light to facilitate the reaction are possible. A photomediator can also activate the substrates, but the photomediator is deactivated afterwards (Scheme 10a). The photomediator can activate substrates via the same activation pathways as described previously for photocatalysts but reacts stoichiometrically. A radical chain reaction can also be photo-initiated (Scheme 10b), in which only small amounts of initiator are necessary. The radical species that is generated with the initiation reacts with alkanes forming alkyl radical species. These can in turn generate more free radicals until the chain is terminated by reaction with another radical. However, this type of mechanism is often more difficult to control.

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13 Scheme 10 Activation mechanism of a photomediator (a) and the photo-initiated radical chain mechanism (b). Besides the yield of photochemical reactions, the quantum yield (Φ) is also an important measure of the system, which is the efficiency of the conversion of absorbed light into the desired product. It shows the number of times the desired process occurs per photon absorbed in the system. If the quantum yield exceeds 1, a chain reaction also contributes to the reaction. Another experiment to indicate the contribution of a radical chain mechanism is the light on/off experiment. If the reaction proceeds when the lamp is off, light is not necessary for the reaction and a chain mechanism is most likely contributing.

𝛷 = # 𝑚𝑜𝑙𝑒𝑐𝑢𝑙𝑒𝑠 𝑎𝑐𝑡𝑖𝑣𝑎𝑡𝑒𝑑/𝑓𝑢𝑛𝑐𝑡𝑖𝑜𝑛𝑎𝑙𝑖𝑧𝑒𝑑

# 𝑝ℎ𝑜𝑡𝑜𝑛𝑠 𝑎𝑏𝑠𝑜𝑟𝑏𝑒𝑑

The aforementioned principles will be applied in the following sections on the (catalytic) systems for the activation of unactivated alkanes. The sections will be divided by the nature of the photocatalyst.

Transition metal based photocatalysts

Iridium-based photocatalysts

Among inorganic photocatalysts, iridium-based complexes have dominated the field. A commonly used photocatalyst is an iridium(III) complex, that consists of one bipyridine ligand and two cyclometalated ligands coordinated to iridium(III) (Figure 2). The photophysical and photoredox properties of the complex can be changed by the introduction of functional groups on the ligands. Electron-withdrawing substituents such as fluoride or trifluoromethyl on the cyclometalating ligand

(R3, R4 and R5) cause shorter emission wavelengths and shift the oxidation potential to higher values,

making it harder to oxidize both in the ground-state and in the excited-state.26 They do not affect the

reduction potential significantly, but they lengthen the excited-state lifetime making electron-transfer from the excited-state more competitive with non-radiative relaxation. Electron-donating

substituents such as tert-butyl groups on the bipyridine (R1 and R2) shift the emission wavelengths to

shorter wavelengths and decrease the oxidation potentials in both the ground-state and excited

state to more negative values causing an easier oxidation.27 The photocatalyst can be combined with

different HAT agents or catalysts to form alkyl radicals and can be quenched both reductively and oxidatively depending on the specific reagents.

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14 Figure 2 General structure of a cyclometalated iridium(III) complex.

Huang et al. reported the arylation of different alkanes with heteroarenes by this type of iridium(III)

photocatalyst [Ir(ppy)2(dtbbpy)]PF6 (ppy = 2-phenylpyridine; dtbbpy =

4,4′-di-tert-butyl-2,2′-bipyridine, see Scheme 11) and persulfate as HAT agent precursor.28 The reactions were performed in

acetonitrile in the presence of 0.05 M trifluoroacetic acid (TFA). By irradiation with blue LEDs (λmax =

450 nm), yields up to 92% were obtained in the arylation of cyclohexane (50 equiv.) using isoquionline. Other cycloalkanes (C4, C7-C8) also gave good yields (85 to 89%). Pentane and hexane only gave a yield of 40% and 46%, respectively, which could be caused by the lower stability of the radical species in comparison to the cycloalkyl radicals.

The involvement of radical intermediates was indicated by suppressed product formation after the

addition of a radical scavenger (TEMPO). A significant kinetic isotope effect (kH/kD = 2.5) was found,

which implies the breaking of a C-H bond to be the rate-determining step. With these results of the mechanistic studies a mechanism was proposed (Scheme 11), that starts with irradiation of the

photocatalyst [IrIII] with visible light. This brings the complex into the excited metal-to-ligand charge

transfer (3MLCT) state, which is oxidatively quenched by K

2S2O8. The SET activates the persulfate to

split into a sulfate radical anion and a sulfate anion. The sulfate radical anion performs a HAT on the alkane substrate, resulting in the corresponding alkyl radical species. This species adds to the protonated heteroarene forming an amine radical cation intermediate, which loses a proton to form the α-amino radical. The catalytic cycle is closed by oxidation of the α-amino radical by the oxidized photocatalyst [IrIV] to form the arylation product and the photocatalyst in the ground-state. This is

the only mechanism in this thesis where the iridium photocatalyst is oxidatively quenched instead of reductively.

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15 Scheme 11 Proposed mechanism of arylation of cyclohexane..28

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16 Mukherjee et al reported the trifluoromethylthiolation with a photoredox/HAT dual catalytic system using an iridium-based photoredox catalyst [Ir(dF(CF3)ppy)2(dtbbpy)]PF6; (dF(CF3)ppy) =

2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine) and sodium benzoate as HAT catalyst under irradiation

with 5 W blue LEDs (λmax = 455 nm) at ambient temperature.29 The shelf-stable

N-trifluoromethylthiophthalimide (Phth−SCF3, see Scheme 12) was used as the

trifluoromethylthiolating reagent and everything was dissolved in acetonitrile. Cyclohexane and cycloheptane were the only unactivated alkanes tested and gave reasonable yields of 40% and 70% of the trifluoromethylthiolated product, respectively. This was done using 2 equiv. of substrate, only 1 mol% of the photocatalyst and 5 mol% of HAT catalyst.

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17 No radical trapping experiments were performed to confirm the formation of alkyl radicals, but other experiments were performed to support the proposed mechanism. Quenching studies show that the substrate and the trifluoromethylthiolating reagent do not have significant quenching interactions, which indicates that the benzoate catalyst performs the quenching of the photocatalyst. The quantum yield of 1.76 suggests a contribution of a radical chain process. However, this was measured with 5-methylhexan-2-yl benzoate as substrate instead of an unactivated alkane. By determining the quenching fraction, the average chain length was determined to be 2 or 3, depending on the method. The phthalimide radical is expected to be the chain carrier in a chain propagation step by HAT from the substrate, since the BDE of the O-H bond of benzoic acid (111 kcal

mol-1) is too high for a phthalimide radical to abstract an hydrogen atom from (BDE C-H Phth-H = 89.1

kcal mol-1). All these results are combined, ending up with the proposed mechanism shown in

Scheme 12. The photoredox catalyst [IrIII] is excited to the electronically excited state with visible

light and reductively quenched by the benzoate HAT catalyst forming a benzoyloxy radical and the

reduced [IrII] photocatalyst. A HAT is performed on the cycloalkane by the benzoyloxy radical

producing benzoic acid and the alkyl radical, which reacts with the trifluoromethylthiolating reagent

Phth−SCF3 forming the product and the phthalimide radical (Phth•). The photocatalyst is regenerated

by a SET to Phth•, and the HAT cycle is closed by deprotonation of benzoic acid by Phth-.

The group of Robert Knowles reported in 2016 the alkylation of cyclohexane by a PET mechanism, performed by an [Ir(dF(CF3)ppy)2(4,4′-d(CF3)bpy)]PF6 (4,4′-d(CF3)bpy = 4,4’-bis(trifluoromethyl)

bipyridine) photocatalyst and the tetrabutyl ammonium salt of dibutyl phosphate.30

N-ethyl-4-methoxybenzamide was used as the HAT agent in a solution of trifluorotoluene (PhCF3) under

irradiation of a 34 W blue LED lamp at 60 °C. An isolated yield of 69% was obtained when cyclohexane was alkylated with α-phenyl methacrylate as limiting reagent using 10 equiv. of cyclohexane, 2 mol% of photocatalyst and 5 mol% of phosphate base. The method was originally designed for intramolecular C-H functionalization but could be adapted to show activity in the intermolecular reaction with cyclohexane.

After multiple quenching experiments, an EPT mechanism of N-H bond activation was proposed. The photocatalyst in the excited state and the phosphate base homolyze the N-H bond of N-ethyl-4-methoxybenzamide forming an amidyl radical, the protonated base and the reduced photocatalyst

[IrII] (Scheme 13). This amidyl radical can perform a HAT from cyclohexane to result in the cyclohexyl

radical, which is engaged in a conjugate addition with α-phenyl methacrylate furnishing a new C-C bond and an α-carbonyl radical. The reduced photocatalyst transfers an electron to this radical generating the enolate anion that is readily protonated by the phosphoric acid to form the alkylated product and return both catalysts to their active form. A quantum yield of 0.12 was determined in a model reaction with 4-methoxy-N-(4-methylpentyl)benzamide and methyl vinyl ketone.

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18 Scheme 13 Proposed mechanism for the alkylation of cyclohexane.30

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19 Almost the same photoredox catalyst and phosphate base were used again by the group of Robert Knowles in 2019 to alkylate different cycloalkanes, but surprisingly without the use of an additional

HAT agent.31 Under irradiation of blue LED light cycloalkanes with four to eight carbon atoms were

alkylated with 1,1-bis-(phenylsulfonyl)ethylene in dichloromethane at ambient temperature. Moderate yields of 45-55 % were obtained using the cycloalkane as the limiting reagent with 2 mol%

of photocatalyst ([Ir(dF(CF3)ppy)2(5,5’dCF3bpy)]PF6), 5 mol% of phosphate base (OP(O)(OBu)2) and 3

equiv. of the alkene.

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20 The initial hypothesis for the reaction mechanism involved HAT by an oxygen-centered radical of the phosphate base generated by SET from the excited-state photocatalyst, as described by Nicewicz and

Alexanian in the azidation reaction with an organic photocatalyst.32 However, the half peak potentials

of the dibutyl phosphate base (Ep/2(P−/P•) > 1.6 V vs Fc+/Fc) and the excited state of the Ir

photocatalyst (Ep/2(IrIII*/IrII) = 1.30 V vs Fc+/Fc) show this to be an endergonic process and unlikely to

be accessible during the lifetime of the 3MLCT excited state of the photocatalyst (240 ns). On the

basis of the binding studies the authors propose the formation of a noncovalent complex between the photocatalyst and the phosphate base. When this complex is in the excited state, it is believed to perform a multisite-PCET on the C-H bond of the cycloalkane. The formation of the complex decreases the molecularity of the photo-induced HAT in comparison to the previous system, making a concerted transfer possible. The mechanism begins with the ground-state complex of the photocatalyst and the phosphate base that upon excitation performs a concerted PCET involving the

C-H bond of the substrate and the excited-state of the [IrIII]*-phosphate complex (Scheme 14). The

complex splits into IrII species and the protonated phosphate base and an alkyl radical is formed, that

forms a new C-C bond by the addition to an electron-deficient alkene. A SET from the IrII species to

the new alkyl radical regenerates the photocatalyst and forms the corresponding anion of the alkyl radical. This is protonated by the conjugate acid of the phosphate base and resulting in the alkylated product and the phosphate base that can coordinate again to the photocatalyst.

In 2018 the group of Barriault reported the redox-neutral Giese-type addition of (cyclo)alkyl radicals to activated olefins by using a chlorine atom as HAT agent which was produced by a SET from an iridium catalyst.33 A good yield of 80% was obtained for the addition of cyclohexane (3 equiv.) to

dimethylmaleate (1 equiv.) with 2 mol% of the [Ir(dF(CF3)ppy)2(dtbbpy)]Cl photocatalyst in benzene

under irradiation of blue LED light (λ=465 nm) at temperatures between 60 and 80 °C. The coupling of cyclopentane and cyclooctane with the same alkene gave lower yields of 69% and 53%, respectively.

The chlorine atom radical is believed to be formed by photoredox mediated activation of chloride by reductive quenching of the excited photocatalyst (Scheme 15). Although this step is thermodynamically unfavorable, quenching experiments show that the kinetics are feasible. An explanation for this could be the formation of a charge-transfer complex between the chloride anion and the photocatalyst, which undergoes PET after excitation. Complexation of the generated chlorine atom to a solvent molecule can occur and a HAT can be performed on the cycloalkane substrate. This radical can add to the activated alkene forming a radical intermediate species. SET from the reduced photocatalyst to the radical intermediate regenerates the photocatalyst and forms an anionic intermediate that is protonated by HCl yielding the product. This closed cycle mechanism is confirmed for THF, but it is reasonable that a radical chain mechanism is also in play. The quantum yield was not determined, which would give more insights into this.

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21 Scheme 15 Proposed mechanism of the coupling of dimethylmaleate with cyclohexane.33

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22 The group of Doyle reported the esterification of cyclic alkyl hydrocarbons by chloroformates with a nickel catalyst (dtbbpy)Ni0 and an iridium photocatalyst Ir[dF(CF

3)ppy]2(dtbbpy)PF6.34 Cycloalkanes

with ring sizes from 5 to 15 carbon atoms were functionalized with phenyl chloroformate by using

0.5 mol% of photocatalyst and 4 mol% of Ni and additives of 2 equiv. of K3PO4 and 1 equiv. of sodium

tungstate. Benzene was used as the solvent and under irradiation with blue LED light the reaction was heated to 34-40 °C. Moderate to good yields were obtained (48-70%) and the esterification of acyclic alkanes resulted in regioisomeric products in moderate yields (50-53%) with a statistical distribution based on the BDFE of the different C-H bonds in the molecules.

Overfunctionalization of the products and unproductive consumption by the chlorine radical was avoided by the choice of coupling partner based on their philicity. The chlorine radical is an electrophilic hydrogen atom acceptor that wants to react with a nucleophilic species, hence by choosing an electron-deficient coupling partner these pathways should be avoided. Chloroformates were used in this study to function as the coupling partner.

No mechanistic studies were performed on this catalytic system, but the authors proposed a

mechanism based on previously performed studies on similar systems (Scheme 16).35,36 This starts

with the oxidative addition of a chloroformate to the nickel catalyst (dtbbpy)Ni0. At the same time,

the iridium photocatalyst (IrIII) is brought to the excited state by irradiation with visible light. This

excited state is quenched by a SET from the nickel complex, which performs a photoelimination of a chlorine radical after irradiation with visible light. The free chlorine radical performs a HAT on the aliphatic substrate, generating an alkyl radical species which is added to the NiII complex and

reductive elimination results in the ester product. Both catalysts are regenerated by SET from the

(23)

23 Scheme 16 Proposed mechanism for ester formation.34

(24)

24

Cerium based photocatalyst

Hu et al. reported the selective functionalization of methane, ethane, cyclohexane and other small alkanes with a cerium photocatalyst and simple alcohols as catalyst where HAT and ligand-to-metal

charge transfer (LMCT) are synergistically merged.7 The reactions are performed in a standard

pressure reactor with a sapphire window on top to irradiate with 400 nm LED light. Ethane would already react at atmospheric pressure, but methane needs higher pressures up to 5000 kPa to increase the solubility in acetonitrile, both at ambient temperature. Addition of 40 mol% trifluoracetic acid was necessary in the reaction with methane as substrate, while the other substrates needed addition of tetrabutylammonium chloride (TBACl). Different cerium salts were tested in the amination of methane and yields up to 45% regarding the azo compound were obtained and TONs up to 2900. These low yields are caused mostly by the reduction of the azo compound to the hydrazine. When D3-acetonitrile was used in absence of TBACl and TFA, this pathway was suppressed resulting in a higher yield of the aminated methane and less hydrazine byproduct. Amination of ethane proceeded with a yield of 97% and a TON of 9700 when using an increased pressure of ethane (1000 kPa) with a catalyst loading of only 0.1 mol% of CeCl3. Another way to

increase the yield with ethane, propane and butane is the use of a continuous-flow micro reactor instead of a batch reactor. Unfortunately, the yield of the amination of methane decreased since the pressure limit of the commercially available micro-reactors is too low, but this is promising for reactors with higher pressure limits. Acetonitrile was used as a solvent, but functionalization of this was prevented by the philicity of the species since it is kinetically unfavourable to abstract a hydrogen from the weak, acidic and electron rich C-H bonds of acetonitrile (BDE = 93 kcal/mol). Formation of the HAT agent was achieved by a LMCT photoexcitation mechanism which is possible by transition metal-based coordination complexes if they have an empty valence shell. A mechanism was proposed based on radical trapping and other control experiments. Alkoxy radicals of methanol, trichloroethanol and trifluoroethanol (TFE) could be trapped by styrene, suggesting the involvement in the mechanism. The proposed mechanism starts with in situ generation of a Ce(IV)-alkoxy complex from the alcohol and the Ce(IV) salt, which undergoes photoinduced LMCT causing homolysis of the Ce-O bond and formation of an electrophilic alkoxy radical and reduced Ce(III) species (Scheme 17). A HAT is performed with the alkoxy radical on the alkane to generate the corresponding alkyl radical species, which reacts selectively with azo compounds, electron-deficient alkenes and other double bonds. The newly formed radical-adduct undergoes a single electron reduction by the Ce(III) species to form the desired product and the regenerated cerium catalyst. The quantum yield was determined for the amination of ethane to be only 0.22 after a reaction time of 1h.

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25 Scheme 17 Proposed mechanism of amination.7

Organic photocatalysts

Acridinium-based photocatalyst

Besides the established transition metal based photocatalysts, organic alternatives have drawn significant attention in the field because of the high cost and scarcity of the iridium complexes. Commonly used organo-photoredox catalysts are the mesityl-acridinium-based photocatalysts

(Mes-Acr-R1X; Figure 3).37 They are a good replacement for the earlier mentioned iridium based

photocatalysts because of their solubility in a wide range of solvents, insensitivity to pH and the redox window they cover. The synthesis is easy, since the corresponding triarylamine can be

transformed to the tetra-substituted catalyst in a single step using an acyl chloride.38

Formation of an electron transfer state upon irradiation via a PET from the mesitylene moiety to the singlet excited state of the acridinium ion moiety is suggested by transient absorption spectroscopy

and EPR. 39 This state can be stabilized by the intermolecular formation of a π-dimer radical cation

between the ground-state of Acr+-Mes-R1 and the electron transfer state.40 The question is if in the

catalytic reaction this dimer is formed before the quenching of the electron transfer state by another molecule. For the specific mechanisms the formation of this dimer is not relevant, and it is therefore not depicted. However, the π-dimers could be formed in all the catalytic systems. Another option is the formation of an encounter complex between the photocatalyst and an anion, which after PET generates two radicals.41,42 However, this has not been reported by any of the groups for this

(26)

26 Figure 3 General structure of mesityl-acridinium-based photocatalysts Mes-Acr-R1X.

The group of Nicewicz reported a catalytic system using such an acridinium photocatalyst,

9-mesityl-3,6-di-tert-butyl-10-phenylacridinium tetrafluoroborate (Mes-Acr-PhBF4), in combination with a

phosphate base (K3PO4) under irradiation with 455 nm LED light.32 The azidation of cyclohexane,

cycloheptane and cyclooctane with 3 equiv. of 4-(trifluoromethyl)benzenesulfonyl azide, 5 mol% photocatalyst and 1.1 equiv. of phosphate base in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) provided moderate to good yields (57–72%). Cyclooctane was further tested with different trapping reagents to form C-F, C-Cl, C-Br, C-N, C-C and C-S bonds in yields ranging from 30–76% using dichloroethane as solvent with pH 8 phosphate buffer. This shows that this strategy for the functionalization of aliphatic C-H bonds is not limited to the introduction of one specific functional group but is a more general approach.

In the proposed mechanism of azidation the photocatalyst Mes-Acr+ is brought into the excited-state

by irradiation with 455 nm light and subsequently quenched reductively by the phosphate base forming an centered radical and the reduced photocatalyst (Scheme 18). The oxygen-centered radical performs a HAT on the cycloalkane to generate a carbon-oxygen-centered radical that is trapped by the sulfonyl azide yielding the desired azidation product and a sulfonyl radical. Regeneration of the photocatalyst is achieved by oxidation of Mes-Acr· by the sulfonyl radical. 1H

NMR spectra suggest the formation of an acridinium−phosphate complex in solution, which can imply the formation of an encounter complex. However, this should be confirmed with more experiments. The proposed mechanism is in agreement with the performed quenching studies show that an anionic phosphate base is necessary in quenching the excited state of the acridinium photocatalyst. However, it is questionable that all radical trapping reagents can oxidize the reduced photocatalyst, hence additional electron acceptors will be necessary with some reagents. The involvement of radical intermediates was also not confirmed with any experiment, just like the quantum yield of the system. Free radical chain processes could also play a role in these transformations, but more mechanistic studies should be performed to elucidate on this.

(27)

27 Scheme 18 Proposed mechanism for azidation of cyclohexane.32

The group of Fukuzimi reported the oxygenation of unactivated alkanes using oxygen in the presence

of hydrogen chloride.43 Cyclohexane and cyclooctane were oxygenated to the corresponding alcohol

and ketone with the 9-mesityl-10-methylacridinium perchlorate (Mes-Acr-MeClO4; 2 mol%) and (4

mol%) HCl under visible light irradiation at ambient temperature in acetonitrile in the presence of oxygen. Both substrates had low conversions of only 16% for cyclohexane and 26% for cyclooctane and poor selectivity with alcohol to ketone ratios of 31:50 and 4:30, respectively.

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28 The mechanism of the oxygenation was examined with several techniques and at different concentrations of hydrocarbon substrates. Transient absorption spectroscopy showed an increased decay rate of the Mes•+ moiety of the electron transfer state by higher concentrations of HCl,

indicating that Cl- quenches the photocatalyst. Radical intermediates (Mes-Acr and CyOO) were

detected with EPR. The proposed mechanism for low concentrations of cycloalkane (0-50 mM) starts

with excitation of the photocatalyst Mes-Acr+ to form the electron transfer state (Scheme 19). The

mesityl moiety is reduced by Cl- to form Cl, which can perform a HAT on the C-H bond of the

unactivated alkanes. The generated cycloalkyl radical reacts with oxygen to form the peroxyl radical that further disproportionates to the alcohol or ketone. Oxygen reoxidizes the acridinium moiety

producing a superoxide ion (O2•-) and the ground state photocatalyst. The superoxide ion

disproportionates with a proton to obtain hydrogen peroxide and oxygen. A quantum yield of 0.04 was determined for the oxygenation of cyclohexane using monochromatized light at 430 nm, which does not indicate a radical chain mechanism as the main contribution.

Scheme 19 Oxygenation of hexane with oxygen.43

At high cyclohexane concentrations (0.2-1.0 M) terminal radical chain processes are also involved (Scheme 20). Initiation happens with HAT of the cycloalkane by Cl• forming the cycloalkyl radical.

Addition of O2 produces the peroxyl radical that can react with a new cycloalkane to generate a

cycloalkyl radical and the hydroperoxide, which is are the propagation steps. The chain ends when the peroxy radical disproportionates into the ketone or alcohol.

(29)

29 Scheme 20 Chain propagation mechanism to cyclohexyl peroxide.43

Deng et al. reported C-H alkylation and allylation of multiple unactivated alkanes with the same type

of catalytic system as the group of Fukuzimi.44 The main difference in the reaction conditions was the

use of a stop-flow microtubing (SFMT) reactor or continuous-flow microtubing reactor because of poor reproducibility in conventional batch reactors. Cycloalkanes (C5-C8 and C10) and pentane (2 equiv.) were alkylated with 2-benzylidenemalononitrile in good to excellent yields (75-92%) under

irradiation with blue LEDs in a SMFT reactor with 2 mol% of Mes-Acr-MeClO4 photocatalyst, 5 mol%

HCl in acetonitrile/dichloroethane 7:1 at 50 °C. Ethane could also be alkylated in good yields (45-95%) at 20 bar pressure (ca. 10 equiv.) with different electron-deficient alkenes under the same reaction conditions. The reactions only proceeded effectively when using a strong Michael acceptor with two electron-withdrawing groups as coupling reagent. The radical adducts with other less electrophilic alkenes are probably not oxidizing enough to regenerate the photocatalyst. The alkylation of methane was unsuccessful because it gave a complex mixture of unidentified products. On the other hand, allylation of cyclohexane and cyclooctane with different allyl phenyl sulfones gave moderate to good yields (44-81%).

Radical-trapping experiments with TEMPO indicated the presence of transient alkyl radicals in both the alkylation and allylation reactions. Quenching studies suggest that the excited state of acridinium could only be quenched by HCl and not by the other substrates. Light on/off experiments reveal that light is a necessity in the reaction and thus a radical chain mechanism does not contribute. Another indication for this are the quantum yields of 0.40 and 0.37 that were determined for the alkylation of cyclohexane with 2-benzylidenemalononitrile and the allylation of cyclooctane with methyl 2- ((phenylsulfonyl)methyl)acrylate, respectively. Accordingly, a mechanism was proposed (Scheme 21) where chlorine radical is the HAT agent that is produced by oxidation of the chloride anion by the electron transfer state of the photocatalyst, just like in the previous mechanism of Fukuzumi. The produced alkyl radical adds to the alkene generating a radical adduct species that oxidizes the reduced photocatalyst to regenerate the photocatalyst and form the alkylated product.

(30)

30 Scheme 21 Proposed mechanism for alkylation of cyclohexane.44

Eosin Y

The same alkylation of cyclohexane with 2-benzylidenemalononitrile was performed using the eosin Y HAT catalyst instead of the acridinium type photocatalyst. This reaction was reported by the group

of Wu in 2018.45 They used 5 equiv. of cyclohexane with 1 equiv. of the electron-deficient olefin

2-benzylidenemalononitrile and 2 mol% of the eosin Y photocatalyst in acetone under irradiation with white LED light at 60 °C. The efficiency of the alkylation was quite low with only 32% yield.

The mechanism for the alkylation of THF was studied intensely and this same mechanism could apply for cyclohexane. A quantum yield of 0.40 was determined and light on/off experiments show no activity when the lights were off, both indicating that a radical chain mechanism is not the main contribution in the mechanism but does not rule out it has a small contribution. The addition of TEMPO to the reaction mixture resulted in no product formation, but TEMPO-H was detected. Both THF and the olefin could not quench the excited state of eosin Y and a new long-lived species was formed in the presence of THF, which indicates a HAT step. All these observations were combined in the proposed mechanism depicted in Scheme 22. The alkyl radical is formed by HAT by the excited state of eosin Y and is consequently trapped by the alkene. Reverse HAT from the adduct regenerates the photocatalyst, but this could also happen by a hydrogen atom abstraction from another cyclohexane molecule by the adduct followed by reverse HAT of the photocatalyst on the cyclohexyl radical (not depicted in the scheme).

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31 Scheme 22 Proposed mechanism for the alkylation of cyclohexane with Eosin Y as catalyst.45

Eosin Y can also be employed in the formation of C-Br bonds from unactivated C-H bonds in a SET

mechanism as reported by the group of Kee.46 C5 tot C8 cycloalkanes and n-butane were brominated

in the presence of CBr4 and morpholine in a biphasic system with only 1 mol% Eosin Y disodium salt

under irradiation with a 11 W desktop lamp at 34 °C. Cyclopentane and cyclohexane gave moderate yields of 57% for the monobrominated product, while cycloheptane and cyclooctane gave higher yields of 76% and 74%, respectively. The bromination of n-butane gave a yield of only 31% with the bromo substituent on the 2-position. Although the C-H bonds of dichloromethane have a lower BDE relative to cyclohexane, hydrogen abstraction from dichloromethane is not competitive with abstraction of cyclohexane. The authors provide an explanation that proposes the involvement of hydrogen tunnelling as is suggested by the high kinetic isotope effect of 13, but more experiments should be performed to elucidate on this.

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32 Radical trapping experiments show the involvement of alkyl radicals in the mechanism via a radical

relay process, which is also supported by computational studies. The triple excited state of Eosin Y2- is

oxidatively quenched by CBr4 resulting in the CBr4- anion and Eosin Y- (Scheme 23). The CBr3• radical is

formed by dissociation of the CBr4- anion and the radical reacts with morpholine to generate the

longer-lived N-centered radical of morpholine which abstracts a hydrogen from the alkane producing

the C-centered alkyl radical. This reacts with CBr4 to yield the brominated product. The photocatalyst

is regenerated by oxidation with morpholine. The contribution of the CBr3• radical as HAT agent can

also not be excluded, but radical trapping experiments only trap the N-centered radical of morpholine. Removing the light source during the reaction stops the activity hence no radical chain

mechanism contributes and the reverse reaction from CBr3• and a bromide ion should be fast. The

reactions will predominantly take place in the organic phase of the system due to poor solubility of the substrates and photocatalyst in water. The water phase makes sure that the concentration of

bromide ions is low in the organic phase so the reverse reaction from the CBr3• radical to the CBr4

-anion is not competitive with bromination.

Scheme 23 Proposed mechanism for bromination with dianionic eosin Y.46

Pentacenetetrone

Regio- and stereoselective functionalization of (branched) alkanes and cycloalkanes was performed by the group of Gong with an organic HAT photocatalyst coupled with a chiral catalyst with an

earth-abundant metal.47 The photocatalyst (5,7,12,14-pentacenetetrone, Scheme 29) is one of the few

photocatalysts that perform HAT, while the others have to be coupled to other HAT agents or catalysts. The unactivated alkanes were reacted with a N-sulfonylimines in chloroform with 5 mol% of photocatalyst and 20 mol% of a chiral copper catalyst (BOX) under irradiation of light. Yields up to 81% were obtained for cyclooctane with 69% e.e., while smaller cycloalkanes gave lower yields (31-60%) and lower e.e. (5-60% e.e.). Propane was functionalized with 21 equiv. obtaining a yield of 35% with 39% e.e. and a regioselectivity of >50:1 r.r. for the secondary position. An even lower yield was achieved with pentane (18%) with a preference for the 2-position over the 3-position (2/3 = 2:1).

(33)

33 The proposed mechanism starts by excitation of the photocatalyst by visible light to yield the triple excited state, which is a biradical species (Scheme 29). This excited state performs a HAT on the alkane to form the alkyl radical and the semiquinone species of the photocatalyst. The N-sulfonylimines substrate coordinates to the copper complex and is reduced by the semiquinone-type photocatalyst by a SET regenerating the photocatalyst and yielding a metal-stabilized carbon radical. This radical can cross-couple with the alkyl radical to an intermediate in which the regio- and stereoselectivity are sterically controlled by the copper complex. Protonation of the intermediate and substitution by another N-sulfonylimine yields the functionalized product and regenerates the coordinated imine. A quantum yield of 0.08 was determined, which indicates that the chain radical mechanism is not the predominant mechanism. The replacement of the copper by other metals reveals that the chiral copper complex probably acts as a chiral Lewis acid.

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34

Iodine oxide and chloride

Photo-oxygenation of methane, ethane, propane and cyclohexane to generate alkyl esters was

reported by the group of Gunnoe in 2019 with a IO3-/Cl- system.48 Esterification of methane gave 48%

yield of the methylester of TFA and a selectivity of 95% in respect to methylchloride. The reactions

were performed using NH4IO3 (7.7 mmol), KCl (2.01 mmol) and 3.45 barr methane in 8 mL TFA under

irradiation with a mercury lamp. It is believed that an alkyliodide is an intermediate species that reacts with TFA to form the ester. Functionalization of ethane (1.72 barr) gave a combined yield of 82% of the TFA ester and chloride products and only very low amounts of difunctionalized products were formed. Almost 60% of this yield was for the esterformation. The major product for the functionalization of propane (1.72 barr) was 2-trifluoroacetoxypropane, which was obtained in ~24% yield and a variety of other products was formed including difunctionalized products. Cyclohexane (1

equiv.) gave 12% yield of trifluoroacetoxycyclohexane with 1 equiv. of NH4IO3 and 2.6 equiv. of KCl

and a total product yield of 26%.

The kH/kD values obtained from deuterium labeling studies suggest that the hydrogen atom

abstraction is performed by a chlorine atom as it has the same value as with other chlorine atom sources. The chlorine atom source is not totally clear since ICl, ICl3 and Cl2 are all observed in the

system; hence they could be the chlorine atom source, but more research should be performed to determine this. The chlorine radical thus performs a HAT on the alkyl, generating an alkyl radical that is trapped by iodine (Scheme 24). The origin of the iodine radical is not clear but must originate from iodate. An alkyliodide is formed, which reacts with TFA to the alkylester. The ester functionality protects the mono-oxidized product from overfunctionalization, although it is not completely known for what reasons. The BDE of the C-H bond is reduced, but this is not merely the only explanation. The authors propose the manifestation of the polar effect, where attack of C-H by chlorine atoms is deactivated by electron-withdrawing substituents since chlorine atoms are electron-accepting species. The ester moiety could reduce the polarity of the transition state which increases the transition state barrier towards HAT.

Scheme 25 Proposed mechanism for the oxygenation of methane.48

NaClO

2

Ohkubo et al. reported the aerobic light-driven oxygenation of methane and ethane with the chlorine

dioxide radical.49 In a two-phase system of perfluorohexane (PFH) and water the small hydrocarbons

were oxygenated with molecular oxygen to the corresponding alcohol and acid products. Both gave conversions of 99% based on the hydrocarbons within reaction times as low as 15 min under irradiation of a xenon lamp (500 W) at ambient temperature and pressure. Conversion of methane yielded 14% of methanol and 85% of formic acid and ethane gave yields of 19% of ethanol and 80% of acetic acid.

(35)

35 Quantum yields were measured on the systems and gave 1.30 for methane and 4.00 for ethane. Both systems thus have a radical chain mechanism. A HAT on the small alkanes is believed to be

performed by a chlorine atom which is formed by photoexcitation of ClO2• (Scheme 25a). This

chlorine dioxide reagent is generated from NaClO2 in the presence of acid (HCl) and upon

photoexcitation a bond rearrangement from Cl-O-Cl to Cl-O-O results in Cl•and 1O

2. The afforded

alkyl radical reacts with singlet oxygen yielding a peroxy radical species, which reacts in a bimolecular fashion to the (m)ethoxy radical and the alcohol. The (m)ethoxy radical forms a new alkyl radical upon reaction with an alkane. Another radical chain cycle can occur from the (m)ethoxy radical if a rearrangement happens, but this part is omitted for clarity. Since the oxygenated products and water do not dissolve in PFH, a two-layer system forms. The reaction will occur in the fluorous phase, while the products are transferred to the aqueous phase (Scheme 25b). Transfer of the monofunctionalized product to the aqueous layer protect them from overoxidation.

Scheme 26 Proposed mechanism of the oxygenation of methane (a) and the distribution in the different phases (b).49

NaCl/Oxone

The group of Lu described the monochlorination of different cycloalkanes and hexane with

NaCl/Oxone under irradiation with visible light at room temperature in the presence of H2O.50 When

using 1 equiv. of cycloalkane in combination with 1 equiv. of NaCl and oxone in TFE yields up to 60% were obtained based on NaCl. An excess of cycloalkane (4-6 equiv.) gave yields up to 99%, indicating a very high mass efficiency of NaCl. Chlorination of n-hexane (5 equiv.) only gave 67% yield of an isomer mixture.

A two-phase system was formed with H2O/TFE as the solvents being one layer and the nonpolar

substrate the second one. The polar layer contained most of the product, NaCl and oxone, while chlorine was mostly found in the nonpolar layer. A chlorine atom is believed to do the HAT of the substrate forming an alkyl radical, which reacts towards the chlorinated product (Scheme 26). NaCl is oxidized by oxone to Cl2, which is in turn oxidized by oxone to the chlorine atom. The cycle of

chlorine can be closed by oxidation of HCl which is formed by the HAT to Cl2.

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36

KBr/Air

The only photochemical system that uses bromine atoms for the hydrogen abstraction from alkanes

instead of chlorine is reported by the same group in 2018.51 Catalytic bromination of cycloalkanes

was performed with KBr/air with a NaNO2 catalyst in HCl (aq)/TFE under irradiation of visible light.

Monobromocyclohexane was obtained in 71% yield based on KBr at room temperature with 5 equiv. of cyclohexane. Cyclopentane gave 69% yield of the monobrominated product when 6 equiv. of cyclopentane was used. Cyclooctane showed the most monobrominated product with a yield of 78% with 2 equiv. of substrate and 1 equiv. of TFA and 3 equiv. of HCl instead of 2 equiv. of HCl and TFE. They did not report why this combination of TFA and HCl was not used with the other substrates. Only secondary bromides were formed in the bromination of n-hexane in 47% yield (β/γ=1:1.4).

Control experiments showed the necessity of visible light, O2, NaNO2 and an acidic environment. The

proposed mechanism starts with the formation of NO2 and NO from NaNO2 in HCl (Scheme 27). NO2

reduces the bromide anion from KBr or HBr to obtain Br2 and NO in an acidic medium. The HAT agent

Br• is produced from Br

2 under visible light irradiation and abstracts a hydrogen from the alkanes

forming an alkyl radical and HBr. The monobrominated product is afforded after reaction of the alkyl radical with Br2.

Scheme 28 Proposed mechanism for the bromination of cyclohexane with KBr/air.51

Peroxy species

In 2019 the group of Jin reported the visible-light cross-coupling reaction between unactivated

alkanes and heteroarenes with hydrogen peroxide.52 The reactions proceeded under irradiation with

426 nm LED light in acetonitrile at room temperature with 2 equiv. of H2O2 and HCl with 20 equiv. of

alkane substrate. Cycloalkanes (C4-C8) gave good yields of 68-87% based on the heteroarene (lepidine) and n-hexane showed two regio-isomers with a preference for the C2-position (C2: 28% and C3: 16%).

(37)

37 After addition of TEMPO the activity was completely suppressed, indicating a radical mechanism. Reactions without a light source also did not show any activity, showing the necessity of light for the

reaction to proceed. The authors came to a proposed mechanism were H2O2 is converted into

hydroxyl radicals by irradiation of LED light (Scheme 28). This hydroxyl radical than performs a HAT

on the alkane yielding an alkyl radical and H2O. The alkyl radical adds to the protonated heteroarene,

which is in turn deprotonated and reduced by another hydroxyl radical generating the cross-coupling product.

Scheme 29 Proposed mechanism for the coupling of heteroarenes to cyclohexane with H2O2.52

Amidyl radicals

The stoichiometric bromination and chlorination of cyclo(hexane) with bromo- and chloroamides was

reported by the group of Alexanian.53,54 The bromination of cyclohexane with the electrophilic

bromoamide (1) in benzene at ambient temperature under irradiation of visible light gave 70% yield of the monobrominated product. Dihalogenation was not observed in the reaction and the yield dropped minimally in air. Chlorination with the chloroamide is less selective than the bromination, but the addition of Cs2CO3 as a base and heating to 55 °C improved the selectivity to yield 69% of

monochlorinated product of cyclohexane. N-hexane gave a yield of 66% for the monobrominated product with 58.7% selectivity for the C2-position. Some dihalogenation products were found as well after the reaction. The yield and selectivity were better in monochlorination than the bromination of

n-hexane with 70% combined yield and a selectivity for the C2-position of 65.5%.

A primary kinetic isotope effect of kH/kD = 5.8 was found for the bromination which indicates an

irreversible hydrogen atom abstraction. Br2 and N-bromosuccinimide both did not show any

reactivity under the same reaction conditions suggesting the involvement of an amidyl radical. The chlorination showed a similar primary kinetic isotope effect of kH/kD = 4.9. Hence, both show the

involvement of an amidyl radical which is formed by light-induced homolytic splitting of the nitrogen halogen bond as shown in Scheme 30.

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38

Selectfluor

Selectfluor (see Scheme 31) was identified as a visible-light promoted HAT reagent by the group of Jin in 2019.55 Cyclohexane (20 equiv.) could be coupled to lepidine (1 equiv.) with 2 equiv. of

Selectfluor and 1 equiv. of HCl when irradiated with 427 nm LED light at ambient temperature in 90% yield in the presence of oxygen. The reaction in acetonitrile with 2 equiv. of TFA yielded 92% but was

performed in a N2 atmosphere. Other heteroarenes also worked nicely with yields ranging from 71%

to 89%. Also, other cycloalkanes (C5, C7-C8 and C12) were successfully reacted to yield only one arylation product in good yields from 67-90%). Pentane and hexane afforded multiple products with a more than statistical preference for the C2 position in combined yields of 70% and 61%, respectively.

The addition of 1.5 equiv. of TEMPO shut down the activity of the system, indicating a radical-type mechanism. The radical scavengers were not isolated to determine the formed radicals. Light on/off experiments do not show activity when the light is off which suggests that a radical chain mechanism is not the most prominent mechanism. However, the authors still suggest a light-enabled radical chain process as shown in Scheme 31. An alkyl radical is formed by HAT by the N-radical cation of Selectfluor which is formed by light enabled homolytic cleavage of the nitrogen fluorine bond. This is followed by the coupling of the alkyl radical to the protonated heteroarene.

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