MSc Chemistry

Molecular Sciences

Literature Thesis

Transition metal catalyzed electrochemical

functionalization of hydrocarbon bonds

by

Vera Cornelia Deij

10624139

November 2017

12 EC

Period 1

Supervisor/Examiner: Examiner:

Prof. dr. Bas de Bruin Dr. Moniek Tromp

Van ’t Hoff Institute of Molecular Sciences / Homogeneous, Supramolecular and Bio-

Inspired catalysis

2

Abstract In this study, research on transition metal catalyzed electrochemical functionalization reactions of

carbon-hydrogen and carbon-carbon double bonds is summarized. Electrochemical functionalization

methods are examined because these reactions can potentially replace conventional redox reagents

by electrodes. By changing the redox reagent to electrons, less organic byproducts are formed and this

results in an easier separation and less waste, making the reaction more sustainable. The atom

economy will be improved as well as the redox economy since the synthesis of the redox reagents is

no longer required, which reduces the amount of oxidation and reduction steps. Also the required

amount of energy can be reduced as the applied voltage can be tuned, resulting in mild(er) reaction

conditions. However, in an electrochemical cell electrolyte is required and the other electrode may

give an unwanted byproduct, therefore product separation is still needed.

This study shows that methods are present in which C-H halogenation, C-H phosphorylation,

conversion of C-H into C-O bonds, C-H olefination, C-H fluoroalkylation, diazidation of alkenes and

fluoroalkylation of alkenes can be performed electrochemically. These methods give the desired

products in comparable or higher yields than non-electrochemical ones, but without the presence of

additional oxidants. In general, expanding the substrate scope expansion is desirable for these

methods to obtain a method that tolerates (more) substrates. In C-H bond functionalization reactions,

substrates with a nitrogen based directing group are used to facilitate the C-H activation, but this limits

the substrate scope to these compounds. Therefore, it would be promising to examine the possibility

of using substrates without a directing group, to obtain an even broader implementation of the

method. In addition, further research is desirable to understand the mechanisms of the reactions and

to examine the reactions at the other electrode because the byproduct might be useful such as

hydrogen gas. It can be concluded that these electrochemical methods are promising additions to

functionalization reactions in general and that they show advantages in making the reactions more

sustainable.

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Content Abstract ................................................................................................................................................... 2

Introduction ............................................................................................................................................. 4

Methods and techniques ......................................................................................................................... 6

C-H functionalization reactions ............................................................................................................... 8

C-H halogenation ................................................................................................................................. 8

C-H phosphonation ............................................................................................................................ 20

Conversion of C-H to C-O bond ......................................................................................................... 29

C-H olefination and fluoroalkylation ................................................................................................. 35

C=C bond functionalization reactions ................................................................................................... 40

Diazidation of alkenes ....................................................................................................................... 40

Fluoroalkylation of alkenes ............................................................................................................... 43

Conclusion and outlook ......................................................................................................................... 45

References ............................................................................................................................................. 46

4

Introduction An important aspect in chemistry is the formation of carbon-carbon, carbon-heteroatom and carbon-

halogen bonds and possible routes towards these bonds are carbon-hydrogen or C=C bond

functionalization. The functionalization of C-H bonds catalyzed by transition metals has gained lots of

attention in the last decades since functionalizing the C-H bonds has become an important and

promising tool in making carbon-carbon, carbon-heteroatom and carbon-halogen bonds.1,2 Due to

direct molecule transformation, multiple initial functionalization reactions of the substrate have

become avoidable, which decreases the amount of steps in the reaction and this results in less waste

and higher atom economy. In most C-H functionalization reactions stoichiometric oxidants or co-

oxidizing agents, such as silver or other metal salts, are needed to promote the reductive elimination

of the product or to recycle or activate the transition-metals used as catalysts.3–5 The disadvantages of

using such stoichiometric oxidants can be waste formation, the difficult separation of the oxidants or

derived byproducts from the reaction mixture, the use of expensive oxidants which might be toxic or

the insufficient selectivity resulting in low yields and poor atom economy.6,7 Another aspect is the

redox economy which means that it is tried to reduce the oxidation or reduction steps in the overall

synthesis and to select an oxidant that is not stronger than required.8 The oxidant has to be

synthesized, which requires energy and if the oxidant has a higher potential than the substrate, it can

oxidize the substrate but the extra energy is lost since it is not used in the reaction. The amount of

reduction and oxidation steps in the synthesis are also influenced by synthesizing oxidants, for example

the synthesis of a hypervalent iodide includes an oxidation with sodium perioidate.9 The same

disadvantages apply to functionalization reactions of C=C bonds, for example azidation potentially

followed by reduction for amination and fluoroalkylation, both of which may require oxidizing or

reducing agents.10,11

A potential and promising solution to these disadvantages is the use of electrochemistry for

redox transformations. Utilizing electrodes instead of oxidizing or reducing agents can result in an

easier separation due to the absence of stoichiometric redox agents, which reduces the costs and

improves the sustainability. Additional energy and reagents are needed to synthesize the redox agents

so by circumventing the use of these reagents, less energy is required and less waste is generated,

resulting in a better redox economy and making it more sustainable.8,12 Furthermore, the absence of

the reagents in the reaction reduces the amount of needed chemicals and therefore the amount of

waste. Replacing stoichiometric redox agents by electrodes can prevent the use of toxic reagents as

the unstable and dangerous reagents can be formed in situ using clean reagents, making the reaction

safer.6,12 Due to the controllability of the energy of the electrons by the applied voltage, the reactions

can be performed under mild(er) conditions so energy usage could be reduced.12 The transfer of

electrons is potentially specific for an electroactive group and that results in a controllable and

selective electrolysis as the amount of reactive intermediates and chemoselectivity can be tuned by

changing the applied voltage.13,14 This control also allows other functional groups that are labile to

reduction or oxidation to be present in the substrate. No additional steps are therefore required to

protect and deprotect these groups, improving the sustainability of the reaction and by shortening the

synthetic route and reducing the amount of energy and waste. This may result in a better redox

economy if oxidation and reduction steps are used in the protection and because the applied energy

is tuned and specific, no energy is lost due to a stronger oxidizing agent.

5

The advantages of using electrodes instead of redox agents are thus promising to make the

reactions more sustainable and perhaps more selective. This report will therefore summarize research

on C-H and C=C functionalization using electrochemical methods to examine what kind of reactions

can be replaced by transition metal catalyzed electrochemical reactions. Different methods will be

compared in order to form an answer to the following questions: Which C-H or C=C bond

functionalization reactions can be performed using electrodes instead of conventional oxidizing or

reducing agents? Is it possible to synthesize the desired products in yields comparable to methods

using redox agents? Which specific redox agents are replaced and could this be extrapolated to similar

reactions using the same reagent?

6

Methods and techniques Implementation of electrolysis in reactions can occur through the use of a divided cell (two

compartments and a separator) or an undivided cell (one compartment) as shown in Figure 1.12,15 In

general, an electrochemical cell consist of a working electrode, an auxiliary (or counter) electrode,

electrolyte, solvent and an electroactive reagent. Depending on whether the reaction is an oxidation

or a reduction, the working electrode is the anode or the cathode respectively, and the anode is

connected to the positive pole and the cathode to the negative. Furthermore, the electrolyte is mostly

a salt which improves the conductivity of the solution by dissociating in ions and it should be chosen

such that it will not oxidize or reduce under the reaction conditions. In an undivided cell, the anode

and the cathode are present in the same compartment and are linked via a potentiostat that closes

the system.15 It should be taken into account that, when this cell is chosen, the substrates and the

products of both electrodes are present in the same solution which can lead to interference of the

reaction at the other electrode. This potential problem can be solved by using a divided cell in which,

ideally, the separator allows good conductivity by transport of the ions but exchange of substrate or

product molecules is low.12

Figure 1. Schematics of a divided (left) and an undivided (right) electrochemical cell.15

Another aspect of electrocatalysis is the use of a controlled potential or a constant current in

the reaction.15 The controlled potential can be chosen to selectively oxidize or reduce species in the

mixture under a specific potential resulting in less byproducts. In addition to the working and the

counter electrode, a reference electrode is needed to measure the applied potential and to set a

chosen potential in a controlled potential reaction. In a constant potential oxidation or reduction

reaction, the resistance increases as the substrate is consumed and because the potential is kept

constant, the current will drop. This is shown in Equation (1) in which V is the potential, i is the current

and R is the resistance of the cell.15 The drop in current will result in a longer reaction time because

the oxidation or reduction will take longer as the transfer of electrons becomes more difficult with

higher resistance. Another option is performing the reaction with a constant current. The potential will

increase and stay constant whilst the substrate is oxidized and after full oxidation the potential will

increase further where it can oxidize other species of the reaction mixture.15 Under this condition the

potential of the substrate should be known to selectively oxidize or reduce the substrate and not the

solvent, byproducts or the product.

V = 𝑖R (1)

The redox potential of the substrate can be determined by cyclic voltammetry (CV). This

method measures the current response of an electrode immersed in an unstirred solution to a linear

7

potential scan with a triangular waveform.15,16 As the potential increases the molecule at the electrode

will be oxidized, resulting in a positive current, and if the molecules are all oxidized the current will

decrease.15 When the potential is decreased, the molecules get reduced, resulting in a negative

current. As the potential reaches its starting value the measurement is finished and plots such as Figure

2 can be obtained. Next, for a reversible redox couple the redox potential can be determined by

calculating the potential that lies exactly between the potentials of the oxidation and reduction

peaks.16

Figure 2. Cyclic voltammogram of a reversible redox couple with current (mA) on the y-axis and potential (V) on the x-axis.15

The transfer of electrons to the substrate can either occur via direct or indirect (mediated)

electrolysis. In direct electrolysis the electron transfer occurs at the surface of the electrode and that

can be seen as a heterogeneous process.12,17 It is possible that direct electrolysis does not yield the

desired selectivity and this can be solved by using indirect electrolysis utilizing a redox catalyst which

is an electron carrier and is also called a mediator as shown in Figure 3.12,13 To acts as the mediator, a

few requirements must be met, such as the capability of transferring the electrons fast and easy and

of being recycled, good stability in both oxidation states and easily separable from the reaction

mixture.12 Only catalytic amounts are needed of the mediator as a result of the electron transfer from

the electrode to the substrate or vice versa in which the mediator is recycled. In addition, attention

must be paid to the chosen potential since the mediator should be oxidized or reduced by the

electrodes as it should react indirect with the substrate. This results in a mediator with a redox

potential which is higher than the substrate redox potential for indirect reduction and lower for

indirect oxidation of the substrate.17 The same reasoning applies to the functional groups in the

substrate so by choosing the right potential, the reaction could be tolerable for many functional

groups.18 As a result the reaction can be performed under milder conditions and there will be less side

reactions with the substrate since the potential is lower and the reaction proceeds via the mediator.

This will make the reaction more sustainable because the energy use is decreased and formation

byproducts that are considered as waste are reduced.12

Figure 3. General illustration for a redox mediated reaction.17

8

C-H functionalization reactions An important and promising tool in synthesizing molecules is C-H functionalization since there are

often many C-H bonds present in molecules. The C-H bonds are often unreactive but the reaction can

occur if the bond is activated by for example transition metals.2 With the direct transformation of C-H

bonds to C-X, C-P or C-C bonds, prefunctionalization such as protecting and deprotecting other

functional groups has become unnecessary which reduces the amount of steps in the synthesis and

therefore also the waste. These reactions still produce waste as the catalyst is re-oxidized to recycle

the catalyst by using stoichiometric amounts of oxidants. This waste may be avoided when electrolysis

is used to recycle the catalyst as the used electrons do not generate waste. In this chapter, the

transformation of C-H to C-X, C-P, C-O and C-C with the use of transition metal and electrolysis will be

discussed.

C-H halogenation A useful functionalization is the transformation of C-H bonds into C-X bonds since halogenated

molecules can be used as reagents in synthesis in, for example, arylation and for some molecules there

is pharmaceutical interest.19,20 One common way to introduce halogens to arenes is by means of

electrophilic aromatic substitution in which an arene-H bond can be transformed to an arene-X bond

using reagents such as N-halosuccinimides.21 It is also possible to use a transition metal catalyst for C-

H activation which can be used in direct oxidation of the C-H bond. This is shown in research on

palladium catalyzed oxidative functionalization of benzo[h]quinoline resulting in chlorination and

bromination conducted by Sanford et al as shown in Scheme 1.22 This research shows a halogenation

reaction in which first iodobenzene diacetate was used in stoichiometric amounts as oxidant in

combination with Pd(OAc)2 and oxidation in the presence of excess LiCl or LiBr gives only traces of the

desired halogenated product. Then, it was found that the yield could be improved if N-

chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) is used in stoichiometric amounts instead of

iodobenzene resulting in an isolated yield of 95% and 93% after 1-3 days, respectively.

Scheme 1. General halogenation reaction of benzo[h]quinoline by Sanford et al.22

However, research conducted by Kakiuchi et al states that separation of product, byproducts

and remaining oxidant is unavoidable in the above mentioned reactions.23 Therefore, the use of

aqueous HCl an HBr as halogenation reagent for aromatic C-H halogenation was examined in an

electrochemical cell considering organic byproducts will not be formed.23 The reaction is performed in

a divided cell with platinum electrodes and an anion-exchange membrane under constant current with

the halogen source, the arene and PdCl2 or PdBr2 as catalyst at 90 °C as shown in Scheme 2. Depending

on the halogen source being either HCl or HBr the temperature changes and depending

on the substrate the time changes. It is expected that the halogen ions originate from HX that diffuse

through the anion-exchange membrane. The first examined arene was benzo[h]quinoline

and then halogenation of 2-phenylpyridine and substituted arylpyridines were studied.

9

Substrates with electron-donating and electron-withdrawing groups were tested and the reaction

proceeded for all substituents, which shows that the reaction tolerates for both kinds of substituents.

The chlorination method gives the products in yields between 87 and 100% and the bromination gives

the products with R= 2-Me or R= 3-CF3 in 83 and 94% yield. Furthermore, using the same method it

also possible to chlorinated arylpyrimidine, 2-(2-methylphenyl)pyrimidine, naphthylpyridine and

naphthylpyrimidine giving the products in 91, 94, 100 and 95%, respectively.

Scheme 2. The general reactions of the palladium catalyzed chlorination (a) and bromination (b) by electrochemical oxidation by Kakiuchi et al.23

The mechanism of the halogenation includes most likely the Pd(II) and Pd(IV) species as shown

in Scheme 3. First, it is expected that the nitrogen atom in the substrate coordinates to the PdX2

followed by C-H activation resulting in a palladacycle and the loss of HX. Then a halonium ion is

generated by anodic oxidation which will react with the palladacycle leading to a Pd(IV) species. After

reductive elimination and dissociation the ortho-halogenated product and the catalyst are obtained.

The reductive elimination of the product can take place under milder conditions as the reduction from

Pd(IV) is easier than that from Pd(II).3 The proposed mechanism includes the anodic oxidation but not

the reaction at the cathode. However, Scheme 2 shows the reaction conditions and it can be seen that

at the cathode HXaq is present which may result in a transformation of H+ into H2 at the cathode. An

advantage of the performed reaction is the absence of supporting electrolyte because HCl and HBr can

act as electrolyte and therefore the amount of used chemicals can be reduced. Furthermore, the

separation of this process is rather simple as all the arene is converted resulting in a mixture with only

the solvent and product that have to be separated. Another advantage is the use of electrolysis which

allows control over the reactive ions by changing the applied current resulting in a suppression of side

reactions. Furthermore, tuning the electric current can control the regioselectivity and this in

combination with the suppression of the side reactions makes the reaction more selective.

10

Scheme 3. Generalized mechanism of palladium catalyzed halogenation by Kakiuchi et al (adjusted from Jiao et al).3,23

The substrate scope of the halogenation method by Kakiuchi et al covers arylpyridine and

arylpyrimidines and this scope was expanded with benzamide derivatives with a bidentate directing

group by the same group by Kakiuchi et al.20 Prior to expansion of the scope, research had been

conducted by several groups into C-H chlorination of arenes containing bidentate directing groups as

shown in Scheme 4. Research conducted by Stahl et al showed that the ortho C-H chlorination of N-(8-

quinolinyl)- benzamide can be performed using CuCl2 as catalyst, 20 mol% LiOAc, 2 equivalents LiCl

under 1 atm O2 at 100 °C with a yield of 88%.24 In a study by Shi et al the halogenation of benzamides

is performed with a removable auxiliary using a Co(II)-catalyst, 1.4 equivalent N-halosuccinimide (NXS)

and a zinc additive which may participate in activating the NXS reagent.25 The reaction showed

tolerance for a broad substrate scope including electron-donating and electron-withdrawing groups

resulting in moderate to good yield, but poor regioselectivity was found for meta-methoxy- and bromo

substituted benzamides. Another study by Shi et al examined the halogenation of similar substrates

but using Ni(OTf)2 catalyst in combination with a removable directing group for benzamides, three

equivalents LiX as halogen source and two equivalents KMnO4 as oxidant.26 It was found that

bromination and iodination of benzamide proceeded in moderate to good yield for both electron-

withdrawing and electron-donating substituents on the phenylring. Chlorination was performed with

yields of 62, 71 and 82% with the substituents being R= Br, OMe or Cl, respectively. A disadvantage of

these studies is the amount of reagents used in the halogenation such as two or three equivalents

instead of one equivalent LiX and stoichiometric KMnO4 making a reduction of the chemicals desirable.

11

Scheme 4. Halogenation reactions by Stahl et al and by Shi et al.24–26

Kakiuchi et al uses an electrochemical method for the chlorination of the benzamide

derivatives to replace stoichiometric reagents or oxidants by anodic oxidation making the reaction

more clean and possibly less expensive.20 Initially aromatic carbonyl compounds were tested but the

reaction does not proceed with the substrates. According to the researchers, this may be due to low

coordination ability which results in inefficient C-H bond cleavage. Therefore, benzamides with a

bidentate directing group as shown in Scheme 5 were chosen as the coordination ability is higher

resulting in a more efficient C-H bond cleavage. The mechanism was determined by reacting a

benzamide derivative with PdOAc2 making a palladacycle that can react with the generated Cl+ to form

the desired products according to the mechanism shown in Scheme 3. The formed palladacycle is most

likely the result of a directed C-H bond cleavage of the benzamide derivative which is also found in

literature.27 The reaction at the cathode is not mentioned but a solution of 2M HCl is present at the

cathode, which could result in a reduction of H+ to H2. The initial reaction conditions were changed to

10 mol% PdCl2, 5 mA because it was found that a lower electric current increases the yield as product

decomposition is suppressed and acetonitrile because DMF did not give high yield. In addition,

substrates containing a 5,7-dichloro-8-quinolinyl group are chosen as it is preferred to avoid

complicated mixtures and this choice results in a mixture of the mono- and di-chlorinated product as

shown in Scheme 5.

12

Scheme 5. The halogenation of benzamide derivatives by Kakiuchi et al.20

The reaction of the o-methylbenzamide derivative was performed by lowering the electric

current to 2.5 mA and increasing the reaction time to 12 hours instead of 6 hours, which increases the

yield to 86%. Next, meta- and para-substituted benzamide derivatives were examined using the same

electric current but changing reaction times depending on the substituted group. It was found that

electron-withdrawing groups give a higher selectivity for the monochlorination products, providing the

product in 71 and 77% yield for Br- and CF3-substituents but longer reaction times are required.

Furthermore, electron-donating groups are showing higher reactivity and a mixture of mono- and

dichlorination products and for meta-substituted substrates the mixture can consist of 62-84%

monochlorination product and 10% dichlorination product. Although several substituents are

tolerated, the examined scope is limited to benzamide with the specific bidentate directing group so

perhaps additional research can look into other bidentate directing groups to further expand the

substrate scope. The advantage of this method compared to the previous methods is the absence of

the zinc additive and excess of halogen source resulting in a better atom economy.

In the same group, Kakiuchi et al examined the catalytic electrochemical C-H iodination for an

one pot halogenation/ arylation reaction.19 Previous research on the iodination of substituted arenes

was found by Glorius et al using a cationic Rh(III) catalyst.28 This method can both perform bromination

and iodination reactions. The iodination reaction is performed using [RhCp*Cl2]2 as catalyst, 1.1

equivalent NIS as iodine source, AgSbF6, 1.1 equivalent pivalic acid in 1,2-DCE as shown in Scheme 6.

The time and temperature are dependent on the substituent with times of 16-52 hours and

temperatures of 60, 90 or 120 °C. First, diisopropyl-, dimethyl- and n-butyl- benzamide were tested

giving the ortho-iodinated products in 98, 75 and 78% yield, respectively. Then acetanilide was tested

but instead of the ortho-iodinated product the para-substituted product was formed in 82% yield. This

presumably occurs via electrophilic aromatic substitution since the same product is obtained when no

catalyst is used. Phenylpyridine can also be used as substrate and upon addition of 2.2 equivalent of

NIS, the dihalogenated product is formed in 88% yield. For the iodination of tert-butyl phenyl ketone

the NIS should be added in portions and for acetophenone and isopropylphenone the pivalic acid

should be changed in Cu(OAc)2 with higher catalyst loading resulting in the products up to 62% yield.

Looking into the mechanism shows that C-H activation of the substrates is the rate determining step.

It is suggested that C-H activation leads to a rhodacycle and then the halogenation can proceed via an

oxidative addition of NIS forming a Rh(V) species followed by reductive elimination of the product or

via a kind of nucleophilic addition of iodine to the rhodacycle giving directly the product and Rh(III). An

advantage is the versatile substrate scope and the high yields but using NIS gives an organic byproduct

which could be prevented by using I2.

13

Scheme 6. The iodination reaction of substituted arenes, adjusted from Glorius et al.28

Research conducted by Yu et al shows the use of I2 as sole oxidant in the iodination of arenes

containing an amide substituent acting as a directing group.29 In this study the reaction is performed

using Pd(OAc)2 as catalyst, I2, CsOAc and NaHCO3 as coadditive in a mixture of DMF and t-AmylOH at

65 °C for 20 hours as shown in Scheme 7. The reaction was also tested with PdCl2 and PdI2 as catalyst.

This shows that the presence of CsOAc is required as absence of CsOAc result in loss of reactivity. It is

suggested that formation of Pd(OAc)2 or PdI(OAc) via anionic ligand exchange is essential.

Furthermore, the role of CsOAc is to improve the catalytic turnover by regenerating the Pd(OAc)2

catalyst. Previous research by the same group shows that the first step is C-H activation which is easier

as the amide directing group can coordinate to the Pd(II) center. The C-H activation results in AcOH

and the Pd(II) complex which is oxidized by I2. Then after the reductive elimination the product and

Pd(II)-I is obtained. Since it is suggested that CsOAc regenerates the catalyst, Pd(OAc)2 and CsI are most

likely formed. The method shows tolerance for naphthalene and methyl-, methoxy-, chloro-, fluoro-

and trifluoromethyl substituents on the phenylacetic amides giving the products in yields of 87-96%.

Increasing the catalyst loading was required for the strong electron-withdrawing groups. This also

applies to the di-iodination which can even occur for a meta-substituted aryl giving the products in 85-

95% yield. The reaction can also be performed at gram-scale for methoxy-, methyl- and trifluoromethyl

substituents with a catalyst loading of 0.5 mol% giving the product in 71, 75 and 50% yield. If the

solvent is changed to DMSO and 0.2 equivalents of K2S2O8 instead of NaHCO3, ortho-substituted

benzamides with methoxy-, methyl-, chloro- or trifluoro substituents are also allowed obtaining the

products in 89-97% yield. Using the new conditions for the iodination of unsubstituted benzamide

results in the product in 41% yield opposed to the conditions shown in Scheme 7 which results in the

homocoupling product in 48%. The reaction is also performed using pyrazoles, oxazoles, thiazoles and

pyridine substituted isonicotinic amide and 2-methyl-nicotinic amide as substrates using 10 mol%

Pd(OAc)2 and for some substrates K2S2O8 instead of NaHCO3 resulting in the iodinated products in 52-

91% yield. This method shows a broad range of substrates, the products are obtained in moderate to

good yields and I2 is used as iodine source which can result in an easier separation. However, the

reaction requires additives in stoichiometric amounts and this can lead to more waste and a lower

atom economy.

Scheme 7. The palladium catalyzed iodination of phenylacetic amides by Yu et al.29

14

In the research by Kakiuchi et al shown in Scheme 8, the chlorination method was tried for

iodination.19 The chlorination method uses no electrolyte and therefore the separate addition of

electrolyte and an iodine source was examined. If the reaction uses HI as iodine source, the product is

not observed. Using KI and H2SO4 gives the desired product but it was observed that there is an

induction period before the iodination reaction. It is expected that the iodide ion is converted to I2 in

the induction period which is supported by the relation between a longer induction period when more

equivalents KI are used. When I2 is used as iodine source, no induction period is observed and the

researchers suggest that the active species is the iodonium ion generated by electrochemical oxidation

from I2. It is considered that the iodination occurs via the same mechanism as the chlorination depicted

in Scheme 3. Different arylpyridines can be halogenated in a divided electrochemical cell using 2

equivalents I2 at 90 °C and either an electric current of 5 or 10 mA depending on the substrate.

Arylpyridines can be substituted with m- or p-Me, CF3 and p-F giving the product in 61-85% yield.

Furthermore, it is found that to obtain a higher yield a substituent is needed at the 3-position of the

pyridine ring or the ortho-position on the benzene ring. After formation of the iodinated product, the

electric current is switched off in order to stop the formation of the reactive oxidant and then base

and phenyl boronic acid are added to perform the Suzuki−Miyaura coupling. The method allows both

electron-donating as electron-withdrawing substituents on the phenyl boronic acid and gives the

product in yields between 53-84%. The disadvantage of this method is the use of two equivalents I2

which is not preferred as it is an excess. Compared to the aforementioned method no organic

byproduct is formed which may indicate an easier separation and no additives are required. The

substrate scope is limited to arylpyridines so additional research to expand the scope is desirable and

perhaps the amount of used I2 could be reduced to improve atom economy.

Scheme 8. The iodination of pyridine derivatives by Kakiuchi et al.19

Research by Kakiuchi et al on the homocoupling of arenes uses the same iodination method to

some extent with the difference being the amount of I2 that is used.30 In this method the coupling can

be performed in a similar fashion as shown in Scheme 8, using one equivalent I2 and different

substituted phenylpyridines with substituents such as methoxycarbonyl, phenyl, trifluoromethyl,

bromine and methyl giving the product in 56-80% yield. The homocoupling of para-methyl substituted

phenylpyridine gives the product in 66%, but without applying electric current the product is also

formed but less effective and the same applies to phenylpyridine which gives the product in 62% when

electric current is applied. The reaction is also performed for the coupling of 2-(3-

(trifluoromethyl)phenyl)pyridine using I2 in catalytic amounts for 9 hours and this gives the product in

59% yield. Looking at the formal changes in the molecules, no incorporation of I2 occurs and this shows

that I2 probably acts as a redox mediator. The precise mechanism is not mentioned, only that the ortho-

C-H bond of two phenylpyridines are activated and will form a complex with the Pd(II) catalyst. This

complex will be oxidized by I+ which is generated in situ by anodic oxidation of I2 and then reductive

15

elimination occurs of the coupled phenylpyridines as shown in Scheme 9. A possible explanation of the

iodide mediated reaction is that after the reductive elimination in which the product and I-Pd(II)-L are

formed, the catalyst activates an ortho-C-H bond forming HI that is present in ionized form. The proton

will be present at the cathode after a transfer through the membrane. The iodide is present at the

anode and can be oxidized to I+ which subsequently will oxidize the complex. This will be followed by

reductive elimination which closes the catalytic cycle. The transferred proton is reduced at the cathode

resulting in the formation of H2. The formation of H2 is confirmed in this reaction but also in the

chlorination and bromination when the method by Kakiuchi et al is used. The homocoupling using

catalytic I2 is promising since no prefunctionalization is needed but additional research is required to

further examine the scope of this method.

Scheme 9. Suggested mechanism for the iodination with the method of Kakiuchi et al.30 I+ is generated electrochemically from I2 or I- at the anode.

Another halogenation reaction that has been studied is the fluorination of pyridine and

pyridine derivatives. The fluorination of pyridines commonly occurs via nucleophilic substitution at the

2-position with a suitable leaving group for fluoride resulting in fluoroarenes which are more reactive,

making an intermediate that can be used for synthesizing a broad range of 2-pyridyl compounds.31,32

Fluorination can also occur directly at C(sp2)-H bonds replacing a hydrogen by fluorine which is shown

in research conducted by Daugulis et al as shown in Scheme 10.33 This research shows the use of a

Cu(I)-catalyst for the mono- and difluorination of benzamides. The monofluorination is performed

using 10-25% CuI depending on the substituents on the benzylgroup, 3.5-4 equivalents AgF and 4.5-5

equivalents NMO as oxidant at temperatures of 50-125 °C which results in yields between 54 and 80%.

The reaction time varies from 30 to 120 minutes with pyridine added for longer reaction times to

prevent substrate decomposition. The difluorination is performed using 18-30% CuI, two equivalents

pyridine, 5-6 equivalents AgF, 7-8 equivalents NMO at temperatures of 75-105 °C with times varying

from 1.5 to 2 hours obtaining the product in yields of 61-77%. Both reactions tolerate electron-

withdrawing and electron-donating groups and heterocyclic benzyl substituents.

16

Scheme 10. Fluorination of benzamides by Daugulis et al.33

Another method is the electrochemical monofluorination of pyridine found in 1985 by Teare

et al as shown in Scheme 11.34 This research shows the oxidation of pyridine to a cation at a potential

of 2.5 V which is lower than the potential of the used fluoride source to perform controlled

fluorination. Next, the cation reacts with MeNF.2HF in acetonitrile that acts as both electrolyte and

fluoride source to get 2-fluoropyridine. However, a 70-fold excess of dry fluoride is needed to obtain

the product in 22% yield because if water is added the yield decreases to 11%. Over time the current

efficiency decreases as the anode is coated and if an undivided cell is used it is possible that the yield

is low due to reduction of the product at the cathode but this can potentially be solved by placing a

diaphragm in the cell.34 The method allows the fluorination of dilute pyridine, pyridine derivatives and

compounds that are solid under the reaction temperature due to the presence of acetonitrile, but the

fluorination of nicotine was not possible.

Scheme 11. Fluorination of pyridine by Teare et al.34

A disadvantage of these methods is the large amount of chemicals needed to perform the

reactions. Therefore, a new method is desirable and this has been studied for pyridine and 4-

ethylpyridine by Budnikova et al.31 This research shows a monofluorination method using a nickel,

cobalt or silver nitrate catalyst in a divided electrochemical cell in which the catalyst can be

regenerated for the selective fluorination as shown in Scheme 12. The reaction is performed using

K2NiF6 as catalyst, pyridine and two equivalents cesium fluoride (CsF) as fluoride source in acetonitrile

at room temperature, providing 3-fluoropyridine in 43% yield. Furthermore, it can also be performed

using CoF3 both as catalyst and as fluoride ion source in acetonitrile but it suspected that a pyridinium

salt is formed and upon addition of triethylamine 2-fluoropyridine can be obtained in 49% yield. In

addition, the reaction can also be performed using AgNO3 as catalyst, 2 equivalents CsF as fluoride

source in acetonitrile and this gives 2-fluoropyridine in 48% yield. It is also possible to perform the

reaction using 4-ethylpyridine which result in 3-fluoro-4-ethylpyridine and 2-fluoro-4-ethylprydine in

45, 57 and 20% yield, respectively. This research found that the source of fluorine influences the yield

and not the position of the fluorination. It is stated that pyridine does not oxidize at the applied

potentials and it assumed that the fluoride ions oxidize but the mechanism is not elucidated so

clarification is needed. Furthermore, the position of the fluorine by the different catalysts is only

mentioned and no reason for this difference is given.

17

This method is an improvement of the aforementioned methods as the product are obtained

in higher yield and the amount of fluorine source is reduced. However, further research is desirable to

expand the scope of the reaction, to elucidate the mechanism of the different catalyst to potentially

explain the difference in products and to examine further optimization to improve the yields coming

closer to the yields of the method by Daugulis et al. A potential method could be a method that

combines the fluorination of aromatic C-H bonds by Daugulis et al with the electrochemical

halogenation by Kakiuchi et al as both methods are applicable to the halogenation of benzamide.

Furthermore, it is possible for pyridine to coordinate to the palladium center to facilitate C-H

activation. If this can be combined, the fluoride source might be 1 equivalent and no excess of oxidants

is needed. However, this can only happen if a non-dangerous fluoride source can be used and not HF.

Scheme 12. The monofluorination of pyridine catalyzed by (a) nickel, (b) cobalt and (c) silver nitrate by Budnikova et al.31

Not only arenes and pyridines can be halogenated also halogenation of 1,3-dicarbonyl

compounds is performed. A study by Ibrahim et al shows the α-chlorination of 1,3-dicarbonyl

compounds using 0.25 equivalents TiCl4 as catalyst and chlorine source and 1.2 equivalents

(diacetoxyiodo)benzene (DIB) in acetonitrile at room temperature.35 According to the authors, the DIB

is used as oxidant that generates Cl+ by umpolung which reacts with the substrate that formed a

complex with TiCl4 as shown in Scheme 13. Furthermore, the authors argue that the use of 0.25

equivalent TiCl4 indicates that under the conditions TiCl4 can contribute four equivalents of Cl+. Various

1,3-diketones, β-ketoesters, β-ketoamides and a β-ketophosphonate were tested and the mono-

chlorinated products are obtained in high yields in the range 71 to 98%. The reaction time is mostly

two to four minutes with some exceptions of 20, 25 or 50 minutes for substrates containing a phenyl

or NBn2 substituent. Furthermore, the dichlorination of benzyl-3-oxobutanoate is performed in two

minutes with 0.6 equivalents TiCl4 and 2.2 equivalents DIB and this gives the product in 93% yield. A

disadvantage of this method is use of stoichiometric amounts of DIB which result in stoichiometric

amounts of waste as iodobenzene is formed when Cl+ is generated. The waste could be reduced by

replacing the oxidants by an anode to remove electrons directly to generate Cl+ by anodic oxidation.

18

Scheme 13. Mechanism of chlorination of 1,3-dicaronyl compounds by Ibrahim et al.35

Research conducted by Kakiuchi et al continues on the chlorination of aromatic C-H bonds in

which HCl is used as chlorine source as shown in Scheme 2.36 The reaction is performed in a divided

cell with Cu(II) as catalyst, β-keto esters, HCl as chlorine source and acetonitrile as solvent at room

temperature as shown in Scheme 14. No electrolyte is separately added but it is required so it is most

likely that HCl acts as electrolyte as shown in previous research.23 The reaction can give both the mono-

and dichlorination product after extraction but in the optimized reaction gives the dichlorination

product in 6% yield and the monochlorination product in 83% isolated yield. Furthermore, copper(II)

triflate is used as catalyst because it shows good catalytic activity and is easier to handle than copper(II)

tetrafluoroborate hexahydrate. The method tolerates benzoylacetate derivatives with electron-

withdrawing groups such as NO2 and CF3 which gives moderate yields of 56 and 57% and an o- or p-

methoxy substituent gives higher yields of 70 and 82%. Fluoro- and bromobenzoylacete are also

allowed giving the products in 73-84% yield. In addition, the reaction is performed with a β-diketone

and that gives the monochlorination product in 66% yield. The reaction is also performed with a β-

ketoamide and by reducing the reaction time with 1 hour, the monochlorination product is obtained

in 68% and the dichlorination product in 15%. This shows that the method is applicable for multiple

substrates. The mechanism is not clarified but it is believed that a copper enolate reacts with generated

Cl+. This method does not form iodobenzene as byproduct and thus reduces the amount of waste.

However, the products are obtained in lower yields so if further optimization could be examined as it

would improve the potential of the method. Additional research may also lead to broadening of the

substrate scope to more β-diketones and β-ketoamides and possible clarification of the mechanism.

Scheme 14. The chlorination of 1,3-dicarbonycompounds by Kakiuchi et al.36

19

In summary, C-H activation can be used in electrochemical halogenation reactions for

pyridines, pyridines derivatives, benzamides and 1,3-dicarbonyl compounds in moderate to good

yields. In the discussed methods, divided cells are used because it can occur that the product is reduced

at the cathode in an undivided cell as found in fluorination of pyridine by Teare et al. The chlorination

and bromination of substituted arylpyridines and arylpyrimidines and the chlorination of benzamides

containing a bidentate directing group tolerates both electron-withdrawing and electron-donating

groups. Iodination of pyridines derivatives with various substituents can also be performed

electrochemically. These new methods replace N-halosuccinimide or LiX as halogen source by aqueous

HX or I2. Therefore, no organic byproducts are formed which results in an easier separation and a better

atom economy. In addition, the aqueous HX can act as electrolyte which reduces the amount of

chemicals since no additional electrolyte is added. Expansion of the substrate scope for all the methods

and tolerance for more bidentate groups is desirable and for some methods further optimizing is

preferable if it is possible. In addition, the iodination method ca be used for arylation of the iodinated

phenyl derivatives and for the homocoupling of arenes with various substituents. In the homocoupling,

I2 may even react as a redox mediator which is promising for coupling reactions since no

prefunctionalizations are required, but additional research is required to determine the scope of this

method. It is also confirmed that the reactions with aqueous HX produce H2 at the cathode as a result

of the reduction of protons and this may potentially be used in other reactions.

Electrochemical fluorination of pyridine and 4-ethylpyridine is possible which are obtained in

moderate yields. The new method reduces the amount of required chemicals, improving the atom

economy. Direct fluorination of benzamide derivatives is known with oxidants and since the reactions

use similar substrates it could be promising to look into another electrochemical fluorination that uses

a similar method as shown for the chlorination of benzamides. However, it can only contribute to a

more sustainable method if a non-dangerous fluoride source is used.

Moreover, a method shows that 1,3-dicarbonyl compounds with various substrates and

substituents can be chlorinated electrochemically. This method replaces the use of

(diacetoxyiodo)benzene by electrons which result in less byproducts since iodobenzene is not formed.

The method is promising but the yield is lower than in a previous method, so additional research is

desirable to examine if further optimization is feasible. This can be combined with elucidation of the

mechanism and broadening of the substrate scope to increase the possible applications of the method.

20

C-H phosphonation Another useful functionalization is the formation of C-P bonds as these are present in natural

molecules, pesticides and potential drugs and since phosphorus can coordinate to metals molecules

with C-P bonds can act as ligands.37,38 A problem in the formation of C-P bonds is the influence of the

strong coordinating phosphorus reagents which may result in inhibition of the C-H activation.39,40 To

suppress this coordination, the phosphorus reagent is added dropwise to keep the concentration as

low as possible. Furthermore, minimizing the concentration can result in the C-H activation of a less

coordination bond that would not coordinate in the presence of strong coordinating phosphorus

reagents.

In 2013 Yu et al conducted a research on phosphorylation of phenylpyridine derivatives using

Pd(II) as catalyst, H-phosphonates as phosphorus sources, AgOAc as oxidant to recycle the catalyst as

shown in Scheme 15.39 The study shows that NaOAc is used as base to promote the reaction and that

the stronger base K3PO4 inhibits the reaction. In addition, the reaction requires 1,4-benzoquinone (BQ)

because it likely has a promoting role in the reductive elimination of the product. The phosphorylated

2-phenylpyridine was obtained 84% yield when the reaction is performed at 120 °C in tert-amyl alcohol

for 13 hours with Pd(OAc)2 as catalyst, 1 equivalent BQ, 2 equivalents NaOAc as base, 2 equivalents

AgOAc as oxidant and diisopropyl H-phosphonate as phosphorus source. Methyl and methoxy

substituents on both the pyridine and arene ring are tolerated giving the products in moderate to good

yields, 61 to 80%. Chlorine as substituent at the para position at the arene gives the product in 67%

yield and at the meta position the yield reduces to 58%. Furthermore, different strong electron-

withdrawing groups at the para position give lower yields ranging from 58 to 15%. The method also

allows 2-napthalene or phenylpyrimidines as substrates and directed phosphorylation of quinoline and

isoquinoline. It is also possible to change the phosphorus source from H-phosphonate to diaryl

phosphine oxides and this give the product in moderate yield.

Scheme 15. The phosphorylation of arylpyridines by Yu et al.39

The suggested mechanism is depicted in Scheme 16 and shows the forming a palladacycle by

C-H activation of 2-phenylpyridine followed by anionic ligand exchange which results in a complex

containing both the phosphonate and 2-phenylpyridine. Then reductive elimination promoted by 1,4-

benzoquinone gives the product and AgOAc oxidizes the formed Pd(0) to Pd(II) to recycle the catalyst.

The promoting role of BQ could come from oxidation of Pd(II) leading to an easier reductive elimination

or from the stabilization of Pd(0) by BQ.41 Since AgOAc is used to oxidize Pd(0) to Pd(II) it is presumed

that due to stabilization of Pd(0), the reductive elimination occurs more easily. A disadvantage is the

use of both AgOAc and BQ to make the reaction catalytic for palladium.

21

Scheme 16. Proposed mechanism for phosphorylation of 2-pheylpyridine [adjusted from Yu et al].39

Around the same period is Murakami et al performed similar research on phosphonation of 2-

arylpyridines using a palladium catalyst as shown in Scheme 17.40 This study tested both H-

phosphonate and α-hydroxyphosphonate as phosphate source with the latter being a masked

phosphorus source to prevent catalyst deactivation. It was found that α-hydroxyphosphonate gives

the product in 70% yield compared to the 12% yield when H-phosphonate is used. It is suggested that

α-hydroxyphosphonate gives a better result due to gradually supply of H-phosphonate that is

generated when acetone is released from α-hydroxyphosphonate. The reaction is performed using

Pd(OAc)2 as catalyst, 40 mol% N-methylmaleimide (NMMI) to promote reductive elimination, 2.5

equivalents AgOAc as oxidant and 4.5 equivalents K2HPO4 as base in tBuOH at 120 °C for 48 hours. The

method tolerates both ortho- and meta-tolyl pyridine, methoxy and chloro substituents on the phenyl

ring, benzothiophene as well as pyrimidine and quinoline as directing groups giving the products in

good yields between 66 and 84%. Also mechanistic studies are performed with dimeric palladium

complexes and this shows the formation of the phosphorylation palladium complex after a reaction of

α-hydroxyphosphonate and the dimeric complex containing acetate with K2PO4 in dioxane at 120 °C

showing that a ligand exchange occurs prior to the reductive elimination of the product. The suggested

mechanism shows a good resemblance with the mechanism of Yu et al as shown in Scheme 16 with

the difference being the formation of dibutyl H-phosphonate and acetone from an α-

hydroxyphosphonate instead of adding the H-phosphonate directly.

Scheme 17. The phosphonation of 2-phenylpyridine by Murakami et al.40

22

Both methods use the expensive oxidant AgOAc and elevated temperatures. The reaction may

be performed under milder conditions without expensive oxidants using an electrochemical cell. This

is shown in research conducted by the group of Budnikova et al in which the phosphorylation of 2-

phenylpyridine is studied similar to Scheme 15.6,37 The reaction is performed using Pd(OAc)2 as catalyst,

2 equivalents NaOAc as base, 2 equivalents BQ in MeCN at 20 °C with a constant potential. The

phosphorus source is diethyl phosphite and is added dropwise and afterwards the mixture is heated

at 80 °C for 1 hour and that gives the product in 68% yield.37 By changing the amount of NaOAc to 4

equivalents the product can be obtained in 78% yield which the same group published concerning the

same research.6 It is speculated by the authors that the role of AgOAc depicted in Scheme 16 is not the

oxidation of Pd(0) to Pd(II) but rather the oxidation of the palladacycle to release the desired product.

The mechanism is examined using dimeric palladium complexes and the proposed mechanism

of the phosphorylation by Budnikova et al is depicted in Scheme 18. It shows that there are two

complexes present which can both be oxidized at the anode giving either the acetoxylated or

phosphorylated product. Two oxidation steps are possible in both complexes and oxidation of complex

B occurs at higher potentials than that of complex A showing that oxidation of complex B is more

difficult. However, complex B can be electrochemically oxidized at room temperature giving the

desired product at the first oxidation potential which may show that electrochemical oxidation is more

effective for complex B than for complex A. After the oxidation of complex B either Pd(III) or Pd(IV) is

formed depending on the number of electrons that are transferred to the anode, but it is not

mentioned if one specific species is present in the intermediate or that both species are present in the

dimer and participate in the reaction. The use of BQ increases the yield and it is suggested that this is

due to a shift of the oxidation potential leading to the preferred oxidation of complex B resulting in a

more facile reductive elimination of the product. At the cathode a saturated solution of pyridinium

tetrafluoroborate is present but is not mentioned what might occur at the cathode so it is expected

that the reaction is not known. An advantage of this method is the absence of 2-2.5 equivalents AgOAc

as oxidants since this would reduce the amount of waste. However, the disadvantage is the use of

stoichiometric amounts of BQ but it is known in literature that BQ can be recycled by electrons.42 Thus,

a potential improvement of the method is recycling BQ (i.e. use BQ as a redox mediator) to generate

less waste but the applied potential should be thoroughly studied as it can interfere with the reaction

so additional research is required.

23

Scheme 18. The proposed mechanism of the phosphorylation of 2-phenylpyridine, adjusted from Budnikova et al.6

Benzene is also a potential substrate for oxidative phosphorylation although it does not

contain substituents that can facilitate C-H activation.43 In 1985 the electrochemical phosphorylation

of benzene was studied by Effenberger and Kottmann.44 The reaction was performed using triethyl

phosphite as phosphorus source, Bu4NClO4 in acetonitrile at 20 °C giving the product in 38% yield. Also,

chemical oxidation was studied using Na2S2O8 and AgNO3 giving the phosphorylated benzene in 48%

yield. These methods use dangerous reagents and give moderate yield and therefore a catalytic

method was studied by Ishii et al as shown in Scheme 19.38 This research conducted by Ishii et al on

benzene phosphorylation continues on alkene phosphorylation under mild conditions by the same

group.45 The reaction was performed using a Mn(II)/Co(II) catalytic system under O2 (0.5 atm) and N2

(0.5 atm) with diethyl phosphite as phosphorus source and after 5 hours at 45 °C a 62% conversion

with 81% selectivity for the desired product can be obtained.

Scheme 19. Phosphonation of benzene by Ishii et al.38

A reaction with dimethyl phosphite under the same conditions gives 68% conversion and 87%

selectivity but using diisopropyl phosphite gives 30% conversion and 83% selectivity showing that the

phosphorus source influences the conversion. The study shows that upon addition of AcOK the

reaction rate increases and it can be performed at 25 °C but a conversion of 25% and selectivity of 92%

are observed. Then different substituents were tested and this showed a conversion ranging from 56-

71% and p-xylene and mesitylene gave a selectivity of 90 and 82%, respectively. Reaction with electron-

withdrawing substituents as –Cl and –CF3 required longer reaction times (15 hours) giving 89%

selectivity and a difficult to determine isomer ratio. It is suggested that the reaction proceeds via a

24

radical mechanism as the reaction does not run upon addition of 2,6-di-tert-butyl-4-methylphenol and

as the reaction is accelerated by base a hydrogen abstraction is expected. Generation of Mn(III) by Co

and O2 was proposed leading to a one-electron oxidation of diethyl phosphite by in situ generated

Mn(III) which forms a radical cationic phosphite. This is deprotonated by base and can react with

benzene giving the desired product as shown in Scheme 20.

Scheme 20. Phosphonation of benzene by a Mn(II)/Co(II)/O2 system by Ishii et al.38

The conversion of the reagents was low and therefore Budnikova et al examined benzene

phosphorylation.43 This study tried the phosphorylation of benzene using different catalytic systems

containing two metals that can be electrochemically oxidized from M(II) to M(III) such as manganese,

cobalt or nickel. The reaction is performed in with controlled potential in a divided cell under argon

using one equivalent diethyl phosphite as phosphorus source at 20 °C in a mixture of acetonitrile and

acetic acid as the solubility of the manganese salts is increased by acetic acid. It is found that complexes

[MnSO4/CoCl2dmphen] and [MnCl2/CoCl2bipy] are the most efficient with 100% conversion of diethyl

phosphite after passing 2 F electricity and 90% yield of phosphorylated benzene. To examine the metal

complexes cyclic voltammetry was used and this showed that for CoCl2dmphen and CoCl2bipy upon

addition of a mixture of benzene and diethyl phosphite the reaction can be performed catalytically.

Furthermore, a quasi-reversible peak is observed at lower potentials which presumably is a result of

the coordination of diethyl phosphite to the metal forming a metal phosphonate that could be oxidized

at a lower potential than the starting metal complex. It is supposed that in the mechanism a metal

phosphonate is formed after which anodic oxidation of the metals occurs followed by rearrangement

resulting in the metal complex and a phosphonate radical that reacts with benzene as shown in Scheme

21. An advantage of this method is the use of reagents only and no additional additives are used and

in compared to Ishii et al better conversion are obtained.

25

Scheme 21. Proposed mechanism of phosphorylation of benzene under oxidative conditions by Budnikova et al.46

Based on this research the same group performed the phosphorylation of coumarins using a

bimetallic complex as catalyst.47 The phosphorylation of coumarins has been studied by Wu et al

shortly after the research on aryl C-H phosphorylation by Yu et al and Murakami et al.48 The reaction

is performed using PdCl2 as catalyst, 2,2’-bipyridine (bipy) as ligand, 3 equivalents K2S2O8 as oxidant

and diethyl phosphite in acetonitrile at 100 °C for 24 hours and this gives the product in 46% yield as

shown in Scheme 22. The yield can be improved using diisopropyl phosphite or di-sec-butyl phosphite

giving the phosphorylated coumarin in 56 and 59%, respectively. For C-6 methyl substituted coumarin

the yield is 46 or 52% using either diethyl phosphite or diisopropyl phosphite. The method was also

tested for coumarin derivatives giving the products in moderate to good yield with high

regioselectivity. In general, higher yields were obtained with electron-donating groups than with

electron-withdrawing groups. With an electron-donating substituent on C-7 and either diethyl

phosphite or diisopropyl phosphite the product can be obtained in yields ranging from 57 to 74%.

Furthermore, the method also tolerates an OH-group and CHO-group giving the product in 34 and 27%

yield and 1-methyl-2-quinolinone was phosphorylated in 47% yield when diisopropyl phosphite was

used. To investigate if the reaction proceeds via a radical mechanism TEMPO was added but it did not

influence the reaction. Furthermore, the addition of BQ and tert-butyl hydroperoxide instead of K2S2O8

resulted in no reaction, which could be an indication that a radical mechanism is not followed. The

formation of a cationic complex was found and this may be Pd(bipy) connected with one diethyl

phosphite and coordinated to diethyl phosphite giving the positive charge. Then the catalyst is oxidized

by the K2S2O8 to Pd(IV) after which reductive elimination can occur.

26

Scheme 22. Palladium catalyzed phosphorylation of coumarins by Wu et al.48

The phosphorylation of coumarins by Budnikova et al is performed in a divided cell using 1

equivalent diethyl phosphite, 1% [MnCl2bipy/CoCl2bipy] or [MnCl2bipy/Ni(BF4)2bipy] as catalyst in

acetonitrile in at room temperature as shown in Scheme 23.47 When the complex containing nickel is

used the products are obtained in 30-37% yield and when the cobalt complex is used in 50-70%. The

higher yield is obtained when a methyl substituent is present in the coumarin and efficiency is

decreased when a monometallic system is used leading to an inseparable suspension. The electrolysis

in the reaction proceeds at the potential of the metal phosphonate which supports the formation of

the metal phosphonates in the proposed mechanism as shown in Scheme 21. It is also expected that

the high regioselectivity in the coumarin phosphorylation comes from coordination of Mn cations to

the carbonyl group and participation of the cations in the radical generation in directing the reaction

to the C-H next to carbonyl. The advantage of this method is the absence of K2S2O8 as oxidant and the

lower reaction temperature.

Scheme 23. Phosphorylation of coumarins catalyzed by a bimetallic complex by Dudkina et al.47

Further expansion of the substrate scope was performed by the same group using

[MnCl2bipy/Ni(BF4)2bipy] as catalyst and the same method as shown in Scheme 23.46 This study tested

diethyl phosphite, diisopropyl phosphite and dibutyl phosphite as phosphorus source for

phosphorylation of benzene, coumarins and benzene substituted with -CN, -NMe2 and -NO2 at the

meta and para position. When diethyl phosphite is used the products are obtained in 50-71% yield,

with diisopropyl phosphite 46-68% yield and with dibutyl phosphite 48-71% yield. This shows that the

phosphorus source does not greatly influence the yield and both electron-donating and electron-

withdrawing groups are tolerated in this method. The study states that base on the research on

benzene it is shown that higher yields can be obtained for all substrates including benzene and

coumarins if the electrosynthesis is performed a day after mixing the substrates. This can be attributed

to the formation of metal phosphonates which are oxidized at lower potentials than the bimetallic

complexes and corresponds to the used potential for phosphorylation coumarins in which the reaction

proceeds at the metal phosphonate potential. Using cyclic voltammetry, it is observed that the best

catalytic efficiency occurs when a bimetallic complex is used, which is supported by a higher yield for

a bimetallic complex in comparison with a monometallic complex. These findings support the proposed

mechanism of the benzene phosphorylation as shown in Scheme 21. In addition, it is suggested that

the reaction at the cathode is the reduction of protons forming H2 in the process. However, further

research is needed to confirm the mechanism.

27

Budnikova et al also performed a direct phosphorylation on pyridine using the metal

complexes Ni(BF4)2bipy and CoCl2bipy and diethyl phosphite at 20 °C in acetonitrile and this gives the

pyridyl-2-phosphonate in 85-90% yield.49 Prior to this research, different methods for phosphorylation

of pyridine were found as shown in Scheme 24. One method is the reaction of a N-methoxypyridinium

salt with an alkali metal derivative of diethyl phosphonate giving the pyridine-2-phosphonates in 35-

67% yield.50,51 The formation of the N-methoxypyridinium requires dimethyl sulfate and either H2O2

and pyridine or pyridine N-oxide. In another method a pyridine cation is refluxed in benzene followed

by oxidation with tetrachloro-1,4-benzoquinone (chloranil) resulting in pyridine-2-phosphonate, in

unknown yields, which can be converted to phosphonic acid upon heating with HCl.51 Comparing these

methods to the one used by Budnikova et al shows the absence of H2O2 and n-butyl lithium, higher

yield of the desired product, the use of less energy as the reaction is performed at 20 °C instead of

reflux and the replacement of benzene by acetonitrile, making the method more sustainable.

Scheme 24. Different methods for the phosphorylation of pyridine.51

Additional research in the same group shows the phosphorylation of hetaryl-azoles such as

benzoxazoles using Ni(BF4)2bipy as catalyst in acetonitrile at 20 °C in a divided cell as shown in Scheme

25.52 It is found that diethyl phosphite coupling with benzoxazoles gives 67% yield and diethyl

phosphite is the best phosphorus source in this method but no additional information on other

phosphorus sources were given. The reactions are performed in the presence of Ni(BF4)2bipy or

CoCl2bipy as catalyst. However, this seems counterintuitive since a bimetallic system in which the

catalyst is combined with MnCl2bipy is used in similar work by the group on which this research is

based. Furthermore, the authors stated that for coumarins the use of a monometallic system reduces

the efficiency and gives a non-separable suspension. The reason for the formation of this suspension

is not mentioned but according to the proposed catalytic cycle in Scheme 21 the reaction proceeds via

the conversion of a Mn(II)-Mn(II) dimer in a dimer containing Mn(II) and Ni(II). A possible explanation

is the requirement of different metal centers to create asymmetry to form the phosphorus radical. No

reasoning for the low efficiency in coumarin phosphorylation is given so the possible explanation is not

supported. Thus, additional research is needed to determine the role of the different metal centers in

the phosphorylation of coumarins, benzene and its derivatives. Furthermore, it is advised to look into

the mechanism of the phosphorylation of pyridine and hetaryl-azoles to understand why one metal

center is needed instead of two centers and this could be combined with expansion of the substrate

scope of both substituted pyridines as hetaryl-azoles.

28

Scheme 25. The phosphorylation of hetaryl-azoles by Budnikova et al.52

In summary, an electrochemical method for the phosphorylation of 2-phenylpyridine is found

which produces the product in comparable yield to a non-electrochemical method. The reaction time

at elevated temperatures is shortened and the AgOAc as oxidant is absent because it is replaced with

electrodes. This decreases the required amount of energy and improves the atom economy, making it

more sustainable. Nevertheless, benzoquinone is still needed in excess in the reaction to facilitate the

reductive elimination. A potential solution may be the recycling of benzoquinone which could be done

by electrons but this could interfere with the phosphorylation so additional research is required.

In addition, a method is found for the oxidative phosphorylation of benzene and different

substituted benzenes with different phosphite sources. This method reaches higher conversion than

previous ones and a higher yield is obtained. The use of Na2S2O8 as oxidant is prevented by the use of

electrodes which result in a better atom economy. A similar method is used for the phosphorylation

of non-substituted and methyl-substituted coumarins with different phosphite sources. The products

can be obtained in comparable yields with non-electrochemical methods and the reaction

temperature is lower, thus the required amount of energy is reduced. However, the scope is limited

compared to the method that uses K2S2O8 as oxidant. For both new methods, broadening of the scope

is desirable to examine whether they can be made more applicable to obtain a sustainable method

while maintain the functional group tolerance.

The phosphorylation of pyridine and benzoxazoles can be performed electrochemically in high

and moderate yield, respectively. The mechanisms of these reactions are not mentioned and

additional research is desirable since a similar method by the same group uses bimetallic complexes

instead of monometallic complexes as catalyst. In addition to understanding the mechanism,

additional research could broaden the scope of the method to substituted pyridines for example.

29

Conversion of C-H to C-O bond In addition to the formation of carbon-halogen and carbon-phosphorus bonds, the formation of

carbon-oxygen bonds is important since carbon-oxygen bonds are present in a large variety of

molecules, its formation has a great synthetic interest. The formation of these bonds is possible by

means of C-H bond functionalization which is mostly catalyzed by a palladium(II) species. In 1996

Yoneyama and Crabtree performed the acetoxylation of benzene and other arenes using Pd(OAc)2 as

catalyst and PhI(OAc)2 (DIB) as oxidant in acetic acid at 100 °C for 20 hours.53 The acetoxylated arenes

are formed in 9-75% yield with byproducts such as biphenyl coming from a homocoupling or

phenylacetate which most likely comes from the oxidant.

Research by Sanford et al on the oxidative functionalization of C-H bonds showed a method

for the chlorination and bromination of benzo[h]quinoline but this method can also be used for the

oxygenation of benzo[h]quinoline as shown in Scheme 26.22 Performing the reaction using 2 mol%

Pd(OAc)2 as catalyst and 2 equivalents PhI(OAc)2 as oxidant at 75 °C for 12 hours in acetonitrile, results

in a mixture of substituted OAc or OH benzo[h]quinoline in a 11:1 ratio with 86% yield. It is suggested

that the acetoxylated product is hydrolyzed on silica forming the hydroxylated product. By changing

acetonitrile to alcohol solvents the product is no longer acetoxylated but changes to the corresponding

substituted product. This was performed with MeOH, EtOH, HOCH2CF3 and i-PrOH/AcOH giving the

products in 71-95% yield. The substrate is chosen to direct the oxidation via coordinating functional

groups with a chelating effect and this was expanded to azobenzene, 1-phenyl-1H-pyrazole, N,1-

diphenylmethanimine, arylpyridines and 8-methylquinoline, in which C-H activation of methyl occurs,

giving the products in 47-83% yield. The reaction can also be performed with 4-(2-

pyridyl)benzaldehyde as substrate in which the reaction is rather directed by the pyridine than by the

aldehyde giving the product in 58% yield. It is suggested that the first step is the C-H activation directed

by the chelate forming a dimetallic palladacycle. Next the palladacycle to Pd(IV) is oxidized after which

the carbon-oxygen bond is formed via internal or external attack resulting in the desired product. If

benzoquinone or Cu(OAC)2 are used as oxidant no product is formed, supporting that Pd(II) and Pd(IV)

are present in the reaction as both oxidants are used for Pd(0)/Pd(II) catalysis. Comparing this method

with of Yoneyama and Crabtree shows a reduction in the reaction time and temperature and therefore

the required amount of energy showing that this method is an improvement. A disadvantage of this

method is the use of 2 equivalents of (diacetoxyiodo)benzene as oxidant because it will most likely give

iodobenzene as byproduct and thus stoichiometric amounts of waste are generated and separation of

the product and byproducts is needed.

Scheme 26. General palladium catalyzed oxygenation reaction of benzo[h]quinoline by Sanford et al.22

This waste can be reduced when an electrochemical method is used and this is tested for the

2-phenylpyridine in research by Budnikova et al.54 This study shows that the acetoxylation of

2-phenylpyridine can be achieved by using a Pd(II) catalyst, 4 equivalents AcOH in CH2Cl2 and

treatment with the substrate at 40°C for 4 hours as shown in Scheme 27. This study is based on the

perfluoroalkylation of 2-phenylpyridine in the same group which will be discussed later.

30

It is suggested that 2-phenylpyridine and Pd(OAC)2 will form a dimer in CH2Cl2 at 40 °C after the C-H

activation. This complex will be oxidized electrochemically in the presence of acetic acid forming a

Pd(III)-Pd(III) dimer and this is treated with 2-phenylpyridine which results in the product in 61% yield.

This is supported by research by Ritter et al in which the dimer is oxidized by PhI(OAc)2 forming a Pd(III)-

Pd(III) dimer containing two phenylpyridines and four OAc groups of which two bridge the palladium

centers and after reductive elimination the product is obtained.55 The authors state that the product

is formed after treatment with 2-phenylpyridine and it might be due to coordination to the dimer

which facilitates reductive elimination after which the coordination is thus immediately filled but

additional is required to understand the complete mechanism. The reaction can also be performed

using Pd(OAc)2 or Pd(TFA)2 as catalyst in acetonitrile with C6F13COOH or HC4F8COOH as acetate source,

giving the oxygenated products in 65, 62 and 73 and 68% yield, respectively. This shows that the

catalysts are equally efficient and it is suggested that both proceed via a mononuclear fluorinated Pd(II)

complex as the formation of a dimer with Pd(TFA) in acetonitrile is more difficult and a monomer is

easier formed. If the reaction is performed with Pd(OAc)2, HC4F8COOH and CH2Cl2 as solvent the

product is obtained in 14% yield whilst the reaction acetonitrile gives 73% yield. This difference could

stem from the findings that if CH2Cl2 is used the dimer is formed and if acetonitrile is used the monomer

is formed and that the reaction presumably occurs via a mononuclear fluorinated Pd(II) complex. This

method shows that acetoxylation of 2-phenylpyridine can be performed using an electrochemical

method instead of PhI(OAc)2 as oxidant. Furthermore, it shows that the substrate can also be

oxygenated with perfluoroacetate derivatives. However, this method shows only acetoxylation of 2-

phenylpyridine and no other substituted pyridines so additional research could expand the substrate

scope.

Scheme 27. Electrochemical acetoxylation of 2-phenylpyridine by Budnikova et al.54

Sanford et al also studied the oxygenation of unactivated C(sp3)-H bonds in O-methyl oxime

continuing on the study of oxidation of benzo[h]quinoline.56 This substrate was chosen because it is

suggested that ketones or amines can be formed by converting the expected products and it possesses

the chelating functionality. The reaction is performed using Pd(OAc)2 as catalyst and PhI(OAc)2 as

oxidant at 100 °C for 1.5-3.5 hours in a mixture of AcOH/Ac2O (1:1) as shown in Scheme 28. Performing

the reaction with pinacalone O-methyl oxime leads to a mixture of mono-, di- and tri-acetoxylated

product and upon addition of 4.5 equivalents PhI(OAc)2 the tri-acetoxylated product is obtained in 59%

yield. Using 3-methylbutan-2-one, 3—methylpentan-2-one and (Z)-heptan-2-one O-methyl oxime give

the mono-β-acetoxylated product in 74, 78 and 39% yield. It is suggested that the nitrogen

coordinates to the palladium forming a five-membered palladacycle as intermediates followed by

oxidation to Pd(IV) and subsequently reductive elimination of the product. It is presumed that no β-H

elimination occurs due to the rigidity of this intermediate. The high selectivity stems from the

preference of the functionalization of primary over the secondary β-C-H bonds which is most likely

driven by steric preference and the preference of oxidation of β- rather than ɣ-C-H bonds.

31

In addition, α-branching results in higher yields probably due to the conformation in which the oxime

and the C-H bonds are coplanar. Other substrates include substituted pyridines, trans-decalone and

the O-methyl oximes of 2,2-dimethylcyclopentanone, camphor, 2-methyl and 2-methyl-4-tert-butyl

cyclohexanone giving the mono-β-acetoxylated products in 42-86% yield after 5 minutes to 12 hours.

The acetoxylation of 2-methyl-4-tert-butyl cyclohexanone was finished in 5 minutes in 86% yield due

to the coplanarity locked by the tert-butyl group. This supports the assumption made for the α-

branched substrates. The products of trans-decalone gives is obtained as a single diastereomer with

equatorial OAc showing the high stereoselectivity of the C-H activation and oxidative cleavage. The

reactions are performed using 1.1-3.2 equivalents of PhI(OAc)2 to oxidize Pd(II) to Pd(IV) resulting in

stoichiometric amounts of waste.

Scheme 28. General acetoxylation of O-methyl oximes by Sanford et al.56

To reduce this waste Sanford et al studied the same reaction replacing PhI(OAc)2 by NaNO3 as

redox co-catalyst under air or O2 atmosphere.57 The reaction is performed in a similar fashion as shown

in Scheme 28, but it is changed to 25-100 mol% NaNO3 in AcOH/Ac2O at 100-110 °C under air or 1 atm

O2. The substrates contain directing groups being either O-methyl oximes or pyridines and are similar

to the substrates of the previous method and after the acetoxylation the β-acetoxylated products are

obtained in 41-83% yield. The reaction with substrates containing a tert-butyl group close to the

nitrogen, mostly at the β -position, gives the tri-acetoxylated product. Furthermore, the method

tolerates benzylic C-H bonds. It is expected that the first step is the C-H bond activation by the Pd(II)

catalyst and NO2 is formed from NaNO3 as shown in Scheme 29. Then the Pd(II) complex is oxidized by

NO2 and 2 equivalents of AcOH forming the Pd(IV) complex, H2O and NO. The final product is obtained

by reductive elimination and NO is oxidized by O2 to NO2. Labeled 18O shows that the incorporated OAc

groups originates from the solvent and therefore the reaction of 2-tert-butylpyridine with propionic

acid was tested and this gives the product with CO2Et incorporated in 80% yield. A potential problem

could be the safety when performing oxygen-mediated reactions on a large scale.58

Scheme 29. Proposed mechanism for acetoxylation of oximes by Sanford et al.57

32

Mei et al studied the same reaction to create a method that does not require O2 making the

reaction safer.58 The reaction is performed using Pd(OAc)2 as catalyst, NaOAc as acetate source in

acetic acid in a divided cell with constant current for 12 hours as shown in Scheme 30. The reaction

temperature is in general 70 °C but for some substrates it is changed to 50, 90 or 100 °C. Different

substituted oximes such as ester, acetoxy-, OTBS-, chlorine-, amino- and cyano substituted oximes are

tolerated and the products were obtained in a range of 72-92% yield. Furthermore, oxazoline is also a

suitable substrate giving the product in 60% yield. If a substrate contains an acetoxy group at the β-

position or a hydrogen at the α-position the reaction gives the product in 25 and 35% yield,

respectively. The reason for this drop in yield is not explained but it could come from steric hindrance

in the palladacycle forming for the oxime substituted with an OAc group. It is also to perform the

reaction using other carboxylic acids or sodium salts such as propanoic acid and fluorinated acids and

this results in the corresponding oxygenated products in 18-63% yield. According to the authors the

lower yields could come from formation of the acetoxylated product under the reaction conditions in

which AcOH is used as solvent.

Scheme 30. Palladium catalyzed electrochemical oxygenation by Mei et al.58

Mechanistic studies shows that the C-H activation is the limiting step. Furthermore, a recorded

cyclic voltammogram shows that the anode can oxidize the Pd(II) to Pd(IV) which is needed for

reductive elimination under milder conditions as reductive elimination forming a C-O bond of a Pd(II)

center is typically slow.58 It is expected that the substrate coordinated to the Pd(II) with nitrogen

resulting in an easier β-H activation and this is followed by oxidation of the Pd(II) complex to Pd(IV)

complex by the anode as shown in Scheme 31. After reductive elimination the product is obtained and

the catalytic cycle can be closed by ligand exchange. An improvement to the method by Sanford et al

is the absence of O2 making it easier to scale-up this reaction. On the other hand, four equivalents

NaOAc are required instead of catalytically NaNO3, so more chemicals are used.

33

Scheme 31. Proposed mechanism of oxygenation of oximes, adjusted from Mei et al.58

The same group expanded the scope of the method by Mei et al by studying the acetoxylation

of aryl substituted oximes.7 The reaction is performed using Pd(OAc)2 and tetrabutylammonium

acetate in acetic acid in a divided cell at 40 °C under constant current as shown in Scheme 32. This

method tolerates both electron-donating and electron-withdrawing groups on the para-position at the

aryl giving the product in 60-80% yield. The product is obtained in 48 and 49% yield when a nitro- or a

cyano-substituent at the para-position is used. When meta-substituents are used the less steric

crowded ortho C-H bond is acetoxylated in 53-67% yield and it is suggested that this is due to sterics

in the palladacycle that is formed after C-H bond activation. Performing the reaction with a fluoro-

group as ortho-substituent gives the product in 30% yield due to low conversion which presumably

originates from the electronics on the ortho-C-H bond and the statistics of one ortho-C-H bonds

present instead of two. Furthermore, alkylphenone, diarylketone and 1- cyclohexenylethanone O-

methyl oximes were tolerated, giving the products in 70, 70 and 53% yield, respectively. It is expected

that the mechanism is the same as for the oxygenation shown in Scheme 31. These methods allow that

both C(sp3)-H and C(sp2)-H bonds in oximes are acetoxylated without the use of additional oxidants

and therefore reduces the waste as iodobenzene is generated in the method by Sanford et al. This

method is therefore a promising replacement since both methods use oximes as substrates but the

method by Sanford et al tolerates also pyridines which are not tested in the electrochemical methods.

Since the same oximes are acetoxylated whilst changing the method and pyridines contain a nitrogen

atom that can coordinate to the Pd(II) center, additional research for the substrate scope expansion is

preferred including pyridines as substrates to possibly optimize the method for the acetoxylation of

benzo[h]quinoline and derivatives.

34

Scheme 32. Acetoxylation reaction of aryl substituted O-methyl oximes by Mei et al.7

In summary, an electrochemical method was found for the acetoxylation of 2-phenylpyridine

and the oxygenation of 2-phenylpyridine using different perfluoroacetates. This shows a promising

improvement of oxygenation reactions that use (diacetoxyiodo)benzene as oxidant instead of

electrodes and this can reduces the amount of byproducts. The substrate scope is limited to 2-

phenypyridines so expansion of the substrate scope is desirable to make the more sustainable method

more applicable. Oxygenation of benzo[h]quinoline and the acetoxylation of azobenzene, 1-phenyl-

1H-pyrazole, N,1-diphenylmethanimine, arylpyridines and 8-methylquinoline are known and might be

promising substrates to start expansion of the substrate scope.

A redox mediated oxygenation for unactivated C(sp3)-H bonds in O-methyl oximes was found.

The products are obtained in comparable yields and the solvent is incorporated in the final oxygenated

product. The final oxidant is O2 instead of (diacetoxyiodo)benzene, which reduces waste but it could

pose a potential problem on large scale. An electrochemical method was found using electrodes

instead of O2 as terminal oxidant, but this requires more chemicals. The products are obtained in high

yields and other carboxylic acids can also be incorporated in the product in low to moderate yield. The

substrate scope for this method was expanded to aryl substituted oximes with both electron-donating

and electron-withdrawing groups and this provides the products in moderate to good yields. This

method shows that both C(sp3)-H and C(sp2)-H bonds in substituted oximes can be oxygenated,

replacing PhI(OAc)2 for electrodes to prevent formation of iodobenzene. Additional research is

desirable to examine if other substrate are tolerated such as pyridines. Overall, it is observed that

PhI(OAc)2 can successfully be replaced by electrodes to perform electrochemical oxygenation reactions

at substrates containing a directing group or an atom that can coordinate to the catalyst.

35

C-H olefination and fluoroalkylation In synthesis it is important to form C-C bonds and it is possible to achieve this by C-H activation followed

by a coupling using transition metals. An example pioneered by Fujiware et al is the Heck coupling of

an aryl with an olefin in which C-H activation has taken place in the aryl.59 In research conducted by

the group of Fujiwara it was found that the coupling of arenes and olefins can be performed

catalytically.59 In these reactions they found that the arene-H bond can be activated by catalytic

Pd(OAc)+ after which insertion of the alkene occurs as shown in Scheme 33. Then it is most likely that

there is β-H elimination of the product and reductive elimination of AcOH and afterwards by using

oxidants such as Ag(I), Cu(II), O2, t-BuO2H, and PhCO3Bu-t the catalyst can be recycled. Other research

by the same group has shown that in the same reaction using a Pd(OAc)2 catalyst a high turnover

number can be reached if benzoquinone (BQ) is used as cocatalyst in catalytic amounts and tBuOOH

as oxidant.60 The mechanism of the reaction does not change and therefore after the product is formed

Pd-H or Pd(0) species are present in the mixture. The recycling of the catalyst can occur via two routes

which are the direct oxidation of Pd(0) by tBuOOH or via the reduction of BQ to hydroquinone which

is oxidized back by tBuOOH. This method allows a broad range of arene substrates including benzene,

toluene, anisole, furan, methyl furan, benzofuran and indole and different olefins containing a -CO2Et,

-COMe, -CN, -CO2H, -CHO, -Ph substituent on one side and –H, -Me or –Ph on the other side. The

products are obtained in a range from 10-75% isolated yield by performing the reaction in AcOH-Ac2O

at 50-90 °C for 12-15 hours. Since tBuOOH is used stoichiometrically, a stoichiometric amount of waste

is formed.

Scheme 33. Mechanism for the coupling of arenes and olefins catalyzed by palladium.59

De Vries and van Leeuwen et al also performed a similar reaction but under slightly milder

conditions.61 The coupling of substituted acetanilides and n-butyl acrylate is executed using catalytic

amount of Pd(OAc)2, 1 equivalent BQ and 0.5-1 equivalent TsOH in AcOH/toluene at 20 °C for 16 hours

as shown in Scheme 34. Coupling of methyl-, 4-methoxy-, 4-trifluoromethyl substituted acetanilide

with n-butyl acrylate were tested which resulted in the corresponding products in 29-91% yield. Using

formanilide and benzanilide as substrate gives the products in 26 and 55% yield, furthermore, N-

methylacetanilide did not give conversion at all. It is mentioned that if an acid such as CF3COOH is used

the Pd(II) becomes more electrophilic because the AcO-group is replaced and it is stated that a mixture

of TsOH/AcOH shows a similar performance with this replacement. An advantage of this reaction is

that it can be performed at room temperature, but still a stoichiometric amount of oxidant is needed

to recycle the catalyst and therefore stoichiometric amounts of waste are generated.

36

Scheme 34. The coupling of substituted acetanilides and n-butyl acrylate by de Vries and van Leeuwen et al.61

A solution for this problem is the use of electrons as oxidants to recycle either the catalyst or

the cocatalyst as shown in research conducted by Jutand et al.62 The research focused on the use of

electrons to oxidize the hydroquinone back to benzoquinone to reduce the amount of waste from the

cooxidant when benzoquinone is used in catalytic amounts to recycle the catalyst. The recycling of

benzoquinone using electrons is known in literature to be efficient.42 The reaction is performed in

AcOH at room temperature for 4 hours in a divided cell with a nickel cathode and a carbon anode and

using either controlled potential or constant current as shown in Scheme 35. Two alkenes were

examined for the coupling with 3’-methylacetanilide giving around 80% yield with n-butyl acrylate and

36% yield for styrene. It is mentioned that the formation of the palladacycle is more difficult with

styrene than with n-butyl acrylate resulting in a lower hydroquinone turnover. The method shows the

reaction for two substrates so to implement this method additional research is required to expand the

substrate scope and to examine the functional group tolerance of the method. This may eventually

lead to a replacement of the method by Fujiwara et al since both the catalyst and the cocatalyst are

recycled which reduces the amount of waste.

Scheme 35. Pd/Benzoquinone catalyzed olefination of an arene, adjusted from Jutand et al.62

In the studied reaction the arene-H is activated using a side arm on the arene that can

coordinate to the catalyst Pd(OAc)2 after which the C-H activation is facilitated. Then, the alkene is

inserted in the arene-Pd bond via carbopalladation after which the product is obtained by β-H

elimination and after reductive elimination of AcOH Pd(0) is obtained. Benzoquinone oxidizes Pd(0) to

Pd(II) and in the presence of solvent AcOH the catalyst is recycled as shown in Scheme 36. The formed

hydroquinone can be oxidized back to benzoquinone using electrons to reduce the amount of waste.

Considering the oxidation of hydroquinone to benzoquinone uses electrons as oxidant, it is also

possible to start with hydroquinone since it will be oxidized at the anode to benzoquinone. At the

cathode the reduction of H+ to H2 occurs which may be potentially be used for other applications.

Research showed that this reaction cannot be performed in an undivided cell because the

benzoquinone will be reduced at the cathode before the protons and therefore a divided cell is used.

In the study the oxidation potential of hydroquinone and the reduction potential of

benzoquinone are measured in acetic acid at a gold disk electrode giving a value of +1.13 V and -0.08

V vs. SCE, respectively. The difference in values is not discussed but it may originate from a different

order of the formation of semiquinone by oxidizing hydroquinone and reducing benzoquinone. It is

possible that benzoquinone gains an electron and then a proton to form semiquinone but to form

37

benzoquinone semiquinone can also lose first the electron and then the proton so the reversibility is

not completely the same which may result in different potentials.63 The reaction can be performed so

additional research on the origin of the difference is not needed but it could be added to research on

broadening the scope.

Scheme 36. Mechanism of the palladium catalyzed electrochemical arene olefin coupling by Jutand et al.62

Besides the olefination of C-H bonds, it is also possible to perform perfluoroalkylation of C-H

bonds in which also C-C bonds are formed that can be used in pharmaceuticals.64 A method found by

Yu et al shows the ortho-trifluoromethylation of arenes using a Pd(II) catalyst.64 The reaction is

performed using Pd(OAc)2 as catalyst, an electrophilic trifluoromethylating reagent, 10 equivalents

trifluoroacetic acid (TFA), 1 equivalent Cu(OAc)2 in DCE at 110 °C for 48 hours as shown in Scheme 37.

The electrophilic trifluoromethylating reagent is the (trifluoromethyl)dibenzothiophenium salt and

two counter ions were tested and this shows that BF4- gives a higher yield than OTf- and it is suggested

that BF4- shows stronger electrophilicity. The method tolerates methyl-, methoxy- and chloro-

substituents on the arene and naphthalene as substrates giving the products in 54-83% yield. With the

chloro-substituent but the catalyst loading was increased but no explanation is given. Furthermore, 2-

phenylpyrimidines substituted with a methyl- or methoxy group can be fluorinated with a slight lower

yield for the methoxy-substituted arenes giving the products in 88, 75 and 58 and 62% yield. Phenyl

substituted imidazole and thiazole can also be used as substrates in the triflouoromethylation in which

the product are obtained in 53 and 74% yield. Two potential pathways are given with either

nucleophilic attack on CF3+ resulting in the fluorinated product and the catalyst or oxidation by CF3

+

followed by reductive elimination. The nucleophilic attack is most likely the attack of the arene on the

CF3+. In addition to the products a sulfoxide from the electrophilic trifluoromethylating reagent is

detected by GC-MS as byproduct. The formation of this sulfoxide is not discussed but it could originate

either from the Cu(OAc)2 or the trifluoroacetic acid. It is suggested that the Cu(OAc)2 acts as an oxidant

for the Pd-catalyst and Lewis acid for sulfur and that other acids do not work as effective as TFA so

both play an important role but to understand the precise role of these reagents and the mechanism,

additional research is required.

38

Scheme 37. The ortho-trifluoromethylation of substituted 2-phenylpyridines by Yu et al.64

The disadvantage of this method is the use of 1 equivalent Cu(OAc)2, 10 equivalents of TFA and

(trifluoromethyl)dibenzothiophenium tetrafluoroborate which results in stoichiometric amounts of

waste and the formation of a sulfoxide. Research by Budnikova et al shows the ortho-fluoroalkylation

of 2-phenylpyridine using an electrochemical method which could reduce the waste.65 The reaction is

a joint electrochemical oxidation and is performed with 6H-perfluorohexyl bromide in acetonitrile in a

divided cell under a stream of argon as shown in Scheme 38. Different catalysts were tested including

Pd(OAc)2, Pd2(OAc)2(PhPy)2 and [Ni(bipy)3]2+ at different potentials and this resulted selectively in the

ortho-fluoroalkylation in 10, 30 and 62% yield, respectively. Cyclic voltammograms show that the

reaction with nickel is performed at the potential of the Ni(II)/Ni(III) shuttle and that at the applied

potential palladium is in a higher oxidation state. The specific oxidation state is not given but since

nickel and palladium react in a similar fashion it could be Pd(III).

Scheme 38. The perfluoroalkylation of 2-phenylpyridine using 6H-perfluorohexyl bromide, adjusted from Budnikova et al.65

Perfluoroheptanoic acid was also tested as perfluoroalkyl source because it assumed that it is

a useful source of the perfluoroalkyl functional group.65,66 With the different catalysts are the products

obtained in 81 and 85% yield for Pd2(OAc)2(PhPy)2 and [Ni(bipy)3]2+. If Pd(OAc)2 was used the product

is obtained up to 18% but also a palladium complex and ortho-carboxylated phenylpyridine are present

in the reaction mixture. It is suggested that in the reaction with the perfluoroalkyl carboxylic acids the

intermediate is the ortho-carboxylated product, which is confirmed by GC-MS, and that the final

product is obtained after decarboxylation of the intermediate as shown in Scheme 39. In the

intermediate a C-O bond is formed, which was used as a basis for the method for the oxygenation of

2-phenylpyridine using fluorinated acids as discussed before. This method is an improvement on the

method by Yu et al as no additional reagents are needed which reduces the waste. However, it would

be desirable to expand the scope for both substrates as well as perfluoroalkyl sources to potentially

have broader applications and understanding the mechanism may be included in this additional

research. As shown in Scheme 27, a similar method is used for oxygenation of 2-phenylpyridine so

expansion of the substrate scope for both oxygenation and perfluoroalkylation may be combined.

39

Scheme 39. The perfluoroalkylation of 2-phenylpyridine using perfluoroheptanoic acid by Budnikova et al.65

In summary, an electrochemical method for the coupling of N-(m-tolyl)acetamide and olefins

is found in which the products are obtained in similar yields compared to a non-electrochemical

method. Benzoquinone is recycled by electrodes in this method and can replace the use of tBuOOH

and stoichiometric benzoquinone, which lowers the amount of generated byproducts. Reduction of

protons at the other electrode gives H2 as byproduct which potentially may be used in other reactions.

The reaction temperature is lower compared to non-electrochemical methods, which results in a lower

energy requirement. This method is therefore promising in making the reaction more sustainable

because the use of energy and waste formation is reduced. However, the method can be applied to

two substrates and therefore expansion of the substrate scope is desired. This could be combined with

examining the functional group tolerance of this method.

Other research shows that a C-H bond can be used in perfluoroalkylation forming a new C-C

bond. A method was found for the ortho-fluoroalkylation of 2-phenylpyridine using either a

perfluorohalide or a fluorinated acid which gives the product in moderate to good yields. Previous

research uses an electrophilic trifluoromethylating reagent and the method allows different substrates

and substituents, providing the products in moderate to good yield. The reagent generates a

stoichiometric amount of waste which can be prevented by the new method. However, the scope is

limited so additional research is required to expand the scope. Since the mechanism is not completely

understood, perhaps examining the first steps of the mechanism can be combined with substrate

scope expansion. It is suggested that the reaction proceeds via an ortho-carboxylated phenylpyridine

and the same group uses a similar method for the oxygenation so additional research on expansion of

the substrate scope may be combined for oxygenation and perfluoroalkylation.

40

C=C bond functionalization reactions Formation of new bonds can also be obtained by functionalization of carbon-carbon double bonds.

Compared to C-H bonds, C=C bonds are generally less frequently present in molecules and are usually

more reactive and can participate in different coupling reactions.67 Electrochemical functionalization

methods may reduce the synthetic route. For example the Heck reaction in which an arylhalide is

coupled to an alkene.67 To perform this reaction, prefunctionalization of the aryl is required, adding an

additional step to the synthetic route. If the reaction can be changed to an electrochemical route it

may not require the prefunctionalization as the alkene could directly react with the aryl, which results

in a better atom economy. Functionalization of the alkene such as diazidation and fluoroalkylation can

also be performed using metal catalyzed electrochemical reactions which will be discussed in this

chapter.

Diazidation of alkenes One useful functionalization is the formation of a C-N bond for the synthesis of diamines which are

present in natural products, pharmaceuticals and can act as ligands.68 A possible intermediate in

diamine synthesis is a diazide which can easily be reduced to the amine. Organic azides can also act as

intermediates or reagents in other reactions such as the C-H amination.14,69 In 1964 Minisci et al

showed a method for the diazidation of styrene using NaN3 as azide source, Fe(II) and ammonium

peroxydisulfate giving the product in 89% yield but it is only compatible with styrenyl olefins.10,70

Another method is found by Xu et al using Fe(OTf)2 as catalyst, azidoiodinane 1a as azido-transfer

reagent, ligand 1 or 2 and TMSN3 at 22 °C for 1-4 hours as shown in Scheme 40.10 It is suggested that

activation of azidoiodinane by TMSN3 is required to transfer the azido-group. Azidoiodinane formation

occurs via a benziodoxole 1b with an excess of TMSN3 and because benziodoxole is barely soluble

under the conditions, it was tested as transfer agent with different catalysts such as Fe(OTf)2, Fe(NTf2)2

and Fe(OAc)2. The reaction gave the product in around 80% yield for the different catalysts and it is

suggested that azidoiodinane is formed in situ. Since TMSN3 is needed to activate the transfer reagent

and to synthesize azidoiodinane combining the two reduces the overall amount of reaction steps and

therefore probable the required energy.

Scheme 40. Diazidation of indene, adjusted from Xu et al.10

41

Different substrates such as terminal olefins, styrenyl, aliphatic terminal olefins, cyclic olefins,

trans-2-octene, methyl cinnamate, electron-rich enamide and electron-rich olefin were tested with

one of the three catalysts and one of the two ligands that can improve the diastereoselectivy. The

products are obtained in 66-91% yield and can further be converted in the corresponding diaminium

salts in 72-95% yield using PPh3 or PMe3, H2O at 50 °C and then TsOH or Pd/C, H2 at 22 °C and then

TsOH. Furthermore, the diazidation of an acetyl quinine and a glycal were tested resulting in the

products in 82% and 52% yield, respectively. The mechanism was also studied and it is expected that

TMS plays a crucial role in the activation of azidoiodinane which most likely reacts with TMSN3 resulting

in a ring opened product in which iodide contains two azide groups as shown in Scheme 41.

Then in the presence of the Fe(II) catalyst the I-N3 bond is reductively cleaved giving an azido radical

and a high valent iron species. The azido radical reacts with the olefin forming a new radical species

that probably associates to the catalyst which oxidizes this species by azido group transfer resulting in

the diazidated product. In absence of the Fe(II) catalyst, the Z-alkene is converted to the E-alkene and

no diazidation product is observed. Conversion of both the Z- and E-alkene shows the same

diastereomeric ratio and it is therefore suggested that Fe(II) plays a role in the diastereomer

determining step.

Scheme 41. The mechanism of diazidation of (Z)-1,2-diphenyethene, adjusted from Xu et al.10

The aforementioned methods use peroxydisulfated or hypervalent iodines and it is suggested

that this could exclude oxidative labile functionalities in the substrates and that at practical scale

hypervalent iodine sources are difficult to use.14 A new method for the diazidation of alkenes was

found by Lin et al which shows high reactivity and chemoselectivity.14 The reaction is performed using

MnBr2 as catalyst and NaN3 as azide source in a lithium perchlorate/acetonitrile mixture under N2

atmosphere in a one-compartment cell at constant potential for 2-6 hours as shown in Scheme 42. The

substrate scope of this method involves terminal, 1,1- and 1,2-disubstituted and tetra-substituted

alkenes including cyclic and aryl-substituted acyclic alkenes in which less influence is observed for the

electronic properties of the substituted aryl. Furthermore, the method tolerates alcohol, aldehyde,

enolizable ketone, carboxylic acid, amine, sulfide and alkyne as functional groups in the substrates

which are sensitive to oxidation and functional groups sensitive to nucleophilic substitution are

allowed. The reaction is non-stereospecific and the different substituted products can be obtained in

62 to 95% yield of which some have diastereomeric ratios of 2:1, 3:1, 9:1 or 10:1. In addition, the

diazidation product of ferrocene was obtained in 76% yield, showing that although ferrocene is a

stronger reducing agent than Mn(II)-N3, it is tolerated as functional group. It is therefore suggested

that the high chemoselectivity may originate from catalyst induced kinetic control.

42

Converting the diazides to vicinal diamines was tested with different methods with substrates

containing reductively labile groups and this resulted in the diamines in 42 to 96% yield. It is also

possible to perform the diazidation and subsequently the reduction to diamines, making it safer since

isolation of the diazidated alkene is prevented.

Scheme 42. Mn(II) catalyzed electrochemical alkene diazidation by Lin et al.14

Due to the manganese catalyst most of the electricity passed through the cell is consumed

showing a good Faradaic efficiency and the authors state that Mn plays an important role in the

inhibition of side reaction which improves the chemoselectivity and energy efficiency. The mechanism

was examined using voltammetric and spectrophotometric studies and it was found that mixing Mn(II)

and N3- results in Mn(II)-N3 and upon oxidation at the anode Mn(III)-N3 is formed which can transfer

N3· to the alkene as shown in Scheme 43. Transferring the N3-group results in a radical adduct as

intermediate which allows the non-stereospecificity, resulting in diastereomers. Then another Mn(III)-

N3 reacts with the radical adduct forming the diazidated product. The reaction at the cathode is the

reduction of protons to from H2 and these protons originate from the AcOH in the solution that is

either present in a MeCN:AcOH ratio of 9:1 or 4:1. An advantage of this method compared to others is

that only H2 and NaOAc are formed as byproducts.

Scheme 43. Proposed catalytic cycle of diazidation of alkene, adjusted from Lin et al.14

43

Fluoroalkylation of alkenes Functionalization of alkenes can also be used to form new carbon-carbon bonds for example

perfluoroalkylation and the fluorinated products could be used in pharmaceuticals or materials.11,64,71

Research by Budnikova et al shows the fluoroalkylation of α-methylstyrene using a nickel catalyst as

shown in Scheme 44.11 It is stated by the authors that this study is conducted to demonstrate the proof-

in-principle of performing perfluoroalkylation electrochemically. In this reaction α-methylstyrene is

coupled with perfluorohexyliodide or 6H-perfluorohexylbromide by joint electrolysis in DMF at

ambient temperature with controlled potential under argon. The products obtained in 70 and 50%

yield are dimers and it is stated that they are in the meso form because the inversion center and the

molecular center coincides which is confirmed by X-ray analysis. This product is different than, for

example, in the Heck reaction in which only RF is coupled to the alkene and an unsaturated product is

obtained, since an additional C-C bond is formed. This shows that other products can be obtained using

this method. The potential in this reaction is held at -1.2 V vs. SCE to regenerate Ni(0) which means

that Ni(II) is reduced to Ni(0) during the reaction. The reaction was tested with the presence of NaHClO4

to form a monomer as a proton source is present but it did not form the monomer. Furthermore, the

reaction does not proceed without the Ni(II) catalyst present and no perfluoroalkyl dimerization or

olefin addition is observed upon reduction of the perfluoroalkylhalide in the absence of nickel. The

reaction was performed in a divided cell at the Pt cathode and undivided cell with a Pt-cathode and

Mn-anode and it was found that the divided cell is the most efficient.72

Scheme 44. Electrochemical perfluoroalkylation of α-methylstyrene by Budnikova et al.11

The same group proposes another possible mechanism as shown in Scheme 45.73 It is

suggested that Ni(II) is electrochemically reduced to Ni(I) which is followed by oxidative addition of

RFX. Then the radical species RF can add to the alkene making a new radical species which is unstable

and further conversion to the dimeric product occurs. It is suggested that σ-complex RFNibipy is formed

which can add to the alkene but it may also be possible that the radical RF is formed directly.

Regenerating Ni(I) after formation of the radical is achieved by the addition of an electron. Other

research by the group shows that the reduction peak of Ni(II)/Ni(0) decreases upon addition of RFX.74

It is suggested that a comproportionation may occur forming a (bipy)Ni(I)Br species that reacts rapidly

with RFX forming a Ni(III) intermediate species. The next steps are presumed to be reaction with the

olefin and reductive elimination generating the Ni(I) species and a radical intermediate that can react

again which result in a dimer. The formation of a monomer is also possible when tributyltin hydride is

added to the reaction which gives the product in 52% yield.74 Additional research into the precise

mechanism using NiBr2bipy is desirable in which intermediates might be isolated.

44

Scheme 45. Proposed mechanism for perfluoroalkylation of α-methylstyrene, adjusted from Budnikova et al.73

Based on this research, the same group studied the perfluoroalkylation of 2-vinylpyridine using

a similar method and the same perfluoroalkyl sources.75 Performing the reaction as shown in Scheme

44 gives the dimeric product in 61 and 48% yield. A higher yield was obtained in a cell with a Pt-cathode

and a soluble Zn-anode at 4 °C as it was found that the yield depends on the temperature and the

nature of the anode. Furthermore, it is found that a slightly higher yield is obtained in the undivided

cell compared to the divided which seems contradictive as in the previous research the divided cell is

more efficient. If triethylamine is added to the reaction, 1-perfluorohexyl-2-pyridinethylene is formed

in 49% yield. Another substrate is dibenzylideneacetone which was coupled with perfluorohexyliodide

at 60 °C forming the dimeric product in 9% yield and it is suggested that the substrate can form stable

bonds with the metal center which competes with the perfluoroalkylation of the double bond. Overall,

the possibility of performing perfluoroalkylation electrochemically is described but further expansion

of the substrate scope is desirable and this may be combined with examining which electrochemical

cell shows the best potential.

45

Conclusion and outlook Nowadays, methods are present that can functionalize carbon-hydrogen bonds or carbon-carbon

double bonds by means of electrochemical functionalization reactions catalyzed by transition metals.

Research shows that these functionalization reactions include C-H halogenation, C-H phosphorylation,

conversion of C-H into C-O bonds, C-H olefination and C-H fluoroalkylation, diazidation of alkenes and

fluoroalkylation of alkenes. All these discussed electrochemical reactions provide the products in

comparable or even higher yield than methods using conventional redox reagents. In C-H halogenation

methods, halogen sources such as N-halosuccinimides or lithium halide can be replaced by the

corresponding aqueous hydrohalic acid and this reduces the amount of organic byproducts, improving

the overall atom economy. A potential new method for electrochemical fluorination could originate

from expanding an electrochemical chlorination method, if a less-dangerous fluorine source than HF

can be found. The electrochemical phosphorylation of C-H bonds replaces the use of silver acetate or

potassium persulfate by electrodes, which could make the reaction less expensive, since an additional

redox reagent such as a metal salt is not required. In addition, converting C(sp3)-H and C(sp2)-H bonds

to C-O bonds with various oxygen-containing reagents is possible. It is observed that

(diacetoxyiodo)benzene can successfully be replaced by electrodes to perform the oxygenation

electrochemically. Formation of C-C bonds can be achieved by C-H olefination in which benzoquinone

is used as cocatalyst and is regenerated using electrodes, replacing tert-butyl hydroperoxide as

oxidant. Electrochemical fluoroalkylation of C-H bonds can also achieve C-C bond formation and it

replaces an electrophilic trifluoromethylating reagent by fluorinated acids or perfluoroalkylhalides,

which results in less waste and therefore a better atom economy. Formation of C-N bonds can be

achieved by the electrochemical diazidation of alkenes. This method replaces a hypervalent iodide

reagent for sodium azide which presumably improves the redox economy whilst maintaining good

chemoselectivity.

In general, expansion of the substrate scope is desired because methods using conventional

redox reagents show a broader range of applicable substrates and for some methods only a few

substrates were tested. In the functionalization of C-H bonds, a directing group strategy is used in

which the substrates mostly contain a nitrogen based directing group to facilitate the selective C-H

activation and this limits the substrate scope considerably. It could therefore be interesting to examine

substrates without directing groups to potentially apply the new method for a broad range of

substrates and possibly maintaining the selectivity. Elucidation of mechanisms and perhaps reaction

optimization of some methods can be combined in further studies.

An advantage of the electrochemical methodology is that more expensive reagents can be

replaced by electrodes. Energy is still required for the reaction, but this could potentially be cheaper

than the conventional redox reagents. Furthermore, it could result in an easier separation since no

organic byproducts are formed, which also reduces the costs. However, it should be taken into account

that electrolyte is required, so product and electrolyte separation is still demanded. It should also be

considered that it can occur that expensive electrodes may be required which increases the costs. In

addition, it can occur that at the other electrode an unwanted byproduct is formed or that the reaction

is unknown, resulting in an unknown byproduct. On the other hand, the byproduct may be useful in

other reactions, but then potential storage should be considered. Overall, transition metal catalyzed

electrochemical functionalization methods are promising for multiple reactions in which electrodes

can replace conventional redox reagents, making it more sustainable.

46

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