Formation and propagation of well-defined Pd nanoparticles (PdNPs) during C-H bond functionalization of heteroarenes: Are nanoparticles a moribund form of Pd or an active catalytic species?

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Formation and propagation of well-defined Pd nanoparticles (PdNPs) during C-H bond

functionalization of heteroarenes: are nanoparticles a moribund form of Pd or an active catalytic

species?

1

1,2

2

1,2

2

Christoph G. Baumann, Sara De Ornellas, Jonathan P. Reeds, Thomas E. Storr, Thomas J. Williams

2

and Ian J. S. Fairlamb *

1

Department of Biology, University of York, York, United Kingdom, YO10 5DD.

2

Department of Chemistry, University of York, York, United Kingdom, YO10 5DD.

Email: ian.fairlamb@york.ac.uk; Fax: 0044 (0)1904 324091

Abstract

Examination of a series of C-H bond functionalization reactions of heteroarenes (e.g. indole, benzoxazole,

benzthiazole, benzimidazole, and purine derivatives) mediated by Pd(OAc) , a commonly used C-H bond

2

functionalization catalyst, reveals that well-defined Pd nanoparticles (PdNPs) are rapidly formed under

working catalyst conditions. The PdNPs can be characterized ex situ after entrapment in a polymer matrix

(

polyvinylpyrrolidinone, PVP). Independently synthesized Pd(PVP)NPs are catalytically competent species,

exhibiting catalyst activity commensurate with Pd(OAc) in several C-H bond functionalization reactions.

2

Across a range of reactions, Pd concentration is a common variable which can be linked to the propagation

of PdNPs under working catalytic conditions using polar solvents like DMF, DMSO and acetic acid.

Introduction

Pd-catalysed C-H bond activation processes offer great potential when considering the development of

1

modern atom- and step-efficient synthetic methods for the formation of arylated heteroarenes. Traditional

cross-coupling strategies require that both substrates are pre-functionalized. A typical example is the Stille

0

cross-coupling reaction of organostannanes with organohalides catalysed by Pd . The advantage of using

substrates without prefunctionalization is obvious, with the caveat that often a metal-directing group or

neighbouring heteroatom is needed to aid the C-H bond functionalization reaction. Examples include direct

functionalization of arenes/heteroarenes with: (a) aryl halides (requiring base); (b) aryl metals (oxidative); (c)

arenes / heteroarenes (oxidative).1 The mechanisms surrounding the reactions in class (a) have been

examined by a combination of traditional experimental and theoretical approaches; catalytic intermediates

2

are typically presumed to involve one or two Pd atoms, operating in an entirely homogeneous phase. For

example, concerted metalation deprotonation (CMD) mechanism involves one Pd atom with an inner sphere

acetate / carbonate base playing a pivotal role in the deprotonation step. In higher oxidation state Pd

III

IV

3

catalysis, involving Pd /Pd species, dinuclear Pd species have been shown to be important oxidative

4

cross-couplings (e.g. acetoxylation, halogenation etc.), although this can be considered mechanistically

distinct to common arene / heteroarene C-H bond functionalization reactions involving C-C bond formation.

In general terms, many of these transformations can be simplified, particularly in the context of the

homogeneous catalytic cycle, as depicted on the right hand side in Scheme 1. In this case, the active Pd

0

II

III

IV

species (e.g. operating in either a Pd /Pd or higher oxidation Pd /Pd catalytic cycles) are ligand-

5

stabilized. In such a case the ligand plays a critical role in controlling the coordination environment around

the Pd centre, as is necessary for the CMD mechanism, for example. There are distinct advantages in

operating in the higher oxidation states, as Pd agglomeration is significantly less likely to occur (under

0

strongly oxidising conditions vide infra), noting that Pd …Pd binding interactions are significantly stronger

II

6

than Pd ...Pd binding interactions, although bridging halides can allow salt structures to be formed.

For traditional cross-coupling processes several influential studies have shown that the mechanistic picture is

7

far more complex than first proposed. Indeed for many years the active catalyst phase was thought to

involve single Pd species, under apparent homogeneous conditions. Critically, higher order Pd species were

8

9

found to be catalytically competent species in Heck, Negishi and Suzuki-Miyaura cross-couplings. Well-

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defined mononuclear Pd species containing 2-electron donor ligands (e.g. PPh , other phosphines or N-

3

1

0

heterocyclic carbenes) can form Pd nanoparticles (PdNPs). Moreover, PdNPs (~2-5 nm) stabilised by

polymer and polar solvent (usually aprotic, but not exclusively) are effective catalyst systems in their own

11

right. Under carefully controlled conditions PdNPs of similar size can be generated in situ from a variety of

homogeneous Pd precursor sources, especially in the presence of a stabilizing additive such as n-Bu NX

4

1

2

0

(

Jeffery conditions), surfactant or ionic liquid. In the case of Pd (dba) precursors, PdNP formation is a

2 3

significant issue, especially in terms of its preparation and general stability in solution in the absence of other

1

3

supporting ligands.

1

4

15

Much has also been learnt from related Pd-catalysed carbonylation chemistry and aerobic oxidation. In a

landmark study for our group (in collaboration with Lee) we established X-ray absorption spectroscopy

(

XAS) as an ideal spectroscopic tool to probe the local chemical environment and oxidation state of PdNPs

1

6

in operando Suzuki coupling. This study, in tandem with our detailed kinetic studies, proved unequivocally

that polymer-stabilised PdNPs can function as heterogeneous catalysts under specifically-tailored working

conditions, which was a significant breakthrough in mechanistic understanding. Other related work was

1

7

subsequently published by others, most notably on the Heck cross-coupling reaction, where evidence for Pd

leaching was uncovered. Generally speaking there is a considerable body of evidence for Pd leaching under a

variety of reaction conditions.5 In essence, one can surmise that an ensemble of Pd catalyst species are

operational and catalytically relevant in a large number of traditional cross-coupling processes.

Given the extensive body of literature precedent for pseudo-heterogeneous catalyst behaviour in traditional

cross-couplings it is surprising that the field of C-H bond functionalization has been dominated by discussion

1

8

of homogeneous Pd species. A notable example is Glorius’ study, who showed that heterogeneous Pd

catalysts (Pd/C) effect an alternative regioselectivity in benzo[b]thiophene arylation. In addition, Fagnou and

co-workers reported the use of Pearlman’s catalyst, Pd(OH) /C, for direct arylation reactions where Pd

2

1

9

leaching was proposed to occur under the conditions of the reaction.

R X

R H

R' M

R' H

_C_a_t_._P_d0

R R'

base, additives

(oxidant)

III

IV

Pd /Pd

The f ull mechanistic picture is yet to be determined

f or C-H bond activation processes

RX

or RH + [OX]

Homogeneous

catalytic cycle

[OX]

[RED]

Heterogeneous

catalytic cycle

Pd

n

clusters

_P_dII

R'M or R'H

(

n = 3-20)

High [Pd]

RR'

High [Pd]

RX

or RH (+ oxidant)

Pd⁰

RR'

R'M or R'H

Pd CLUSTER PHASE -

STRUCTURE AND

REACTIVITY

Ligand-stabilised Pd complexes

(MECHANISM KNOWN)

Kinetically stable metallic PdNPs (ca. 1-5 nm)

UNKNOWN

Scheme 1. Mechanistic complexity found in catalytic cross-coupling processes.

Our preliminary data shows that well-defined PdNPs are formed in C-H bond activation processes (vide

infra). Catalyst behaviour in C-H bond functionalization / activation is similar to classical cross-coupling in

several ways (i.e. type of additives, solvent and Pd concentration). Many C-H bond functionalization

reactions require high Pd catalyst loadings (typically 5 mol% Pd).

The central aim of this study was to show that PdNPs form from Pd(OAc) , and related precursors, and

2

propagate in several C-H bond functionalization reactions to give well-defined PdNPs. As a consequence,

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intentionally prepared and characterized polymer-stabilized PdNPs of a certain size and shape can be

independently tested in exemplar catalytic reactions.

Results and Discussion

In this study, a series of C-H bond functionalization reactions are examined which have been of specific

interest to our research group. Each class is discussed in its own specific section.

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0

Arylation of benzoxazole and benzthiazole. The reactions of interest, catalyzed by a Pd/Cu catalyst

2

1

22

system in the presence of base, are shown in Scheme 2. Pd(OAc) was tested against Pd(PVP)NPs. The

2

latter Pd species were prepared as previously reported, and characterized principally by Transmission

Electron Microscopy (TEM; ~3 nm – spherical particles, i.e. truncated icosahedra – see Fig. 1 and Table 1

for analysis). Previously, Pd(PVP)NPs have been characterized by Extended X-ray Absorption Spectroscopy

1

6

(

EXAFS) measurements. In this case we employed X-ray photoelectron spectroscopy (XPS) to probe the

2

3

0

II

Pd surface oxidation states, which showed a mixture of Pd and Pd sites in a ratio of ca. 2.5:1 (see

experimental data). The advantage of these PdNPs is that they are easy to prepare, and are air and moisture

stable. The latter characteristic allows them to be handled in solid-form (formed as a black, glass-like solid

which can ground in air to give a convenient black powder) and then subsequently resuspended in the test

reaction of interest. It is imperative that each Pd(PVP)NP batch is independently characterized as size

variations can occur in their synthesis.

Pd Cat. (5 mol%),

CuI (2 eq.), CsF (2.5 eq.),

Schlenk

Yield / %

Pd cat.

Yield / %

o

N

O

DMF, 120 C, 24 h

N

O

Ph

^P^d⁽^O^A^c⁾2

27

79

71

-

I

1

(2 eq.)

2

3

Pd(PVP)NPs (~3 nm)

Schlenk

Yield / %

Pd cat.

Yield / %

N

S

as above

N

S

Ph

Pd(OAc)₂

23

59

53

-

I

4

(2 eq.)

2

5

Pd(PVP)NPs (~3 nm)

Scheme 2. Arylation of benzoxazole and benzthiazole catalyzed by a Pd/Cu catalyst system.

For fair comparison the reactions (1→3 and 4→5) catalyzed by Pd(OAc) and Pd(PVP)NPs were run side-

2

by-side in a reaction carousel under an N atmosphere. Due to the design of the reaction carousel it is not

2

possible to rigorously exclude trace quantities of air. In carrying out these experiments the reactions

mediated by Pd(OAc) were found much more effective when conducted with rigorous exclusion of air on a

2

Schlenk line. The observation was noted for both benzoxazole 1 and benzthiazole 4 arylations. Remarkably,

the reactions mediated by Pd(PVP)NPs were more catalytically active under equivalent conditions (in the

2

4

reaction carousel). In the case of benzoxazole, Miura and co-workers recorded yields of 88% for 3 (after 9

h) and 75% for 5 (after 6 h), using a catalyst system derived from Pd(OAc) / PPh at 140 °C. The results

2

3

presented here demonstrates that similarly good yields can be obtained at lower temperatures using

Pd(PVP)NPs.

We were intrigued to learn more about the active catalyst phase in the reactions catalyzed by Pd(OAc) in the

2

reaction carousel as compared with the completely oxygen-free Schlenk line reaction. Previously, our group

2

5

has developed a method for efficiently trapping-out PdNPs that are generated in situ. The method involves

addition of an exogenous polymer, which acts as a stabilizer for PdNPs. In this case PVP was selected, as

this polymer encapsulates the in situ generated PdNPs well (binding defect atom sites), and improves the

reliability of size distribution analysis without changing the in solvent concentration, which can promote Pd

agglomeration in vacuo.

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Figure 1. Electron micrograph of a sample of PVP (M_W_,_P_V_P= 29,000) stabilised Pd nanoparticles {denoted

Pd(PVP)NPs} by TEM. The histogram of particle diameter (nm) across a sample of nanoparticles (n = 98) is

also shown.

Table 1. Table showing simple statistical measurement for Pd(PVP)NPs (M_W_,_P_V_P= 29000).

SD = Standard Deviation, IQR = Interquartile Range, IQM = Interquartile Mean.

Mean

SD

Median Mode

IQR

IQM

Pd-PVP

3.20 nm 1.01 nm 3.09 nm 3.34 nm 1.17 nm 3.04 nm

Two samples were taken from the arylation of benzothiazole 4 with Pd(OAc) conducted in both the Schlenk

2

and reaction carousel tubes. To one sample was added PVP (M_W_,_P_V_P= 29,000, 10 monomer equivalents per

theoretical quantity of Pd, assuming a homogenous reaction mixture). The solvent was removed from the

samples in vacuo with heating at ca. 50 °C. Transmission electron micrographs were recorded for each of

these samples (Fig. 2 and Fig. 3). In the samples containing PVP polymer, well-defined PdNPs were

observed. The samples without exogenous polymer lacked well-defined particles. Hence, in this case the

addition of exogenous PVP polymer was critical in being able to adequately characterize the in situ

generated PdNPs. This observation suggests that polymer-stabilization of PdNPs may be masking an

intrinsic instability of these particles, i.e. rapid particle growth and dissolution occurs under certain reaction

conditions.

The PdNPs generated from Pd(OAc) in the Schlenk tube are larger than those taken from the reaction

2

carousel tube (∆ꢀꢁ̅ = 1.43ꢀnm; size difference is outside of the estimated error, Table 2). The Schlenk tube

sample exhibits a larger range of particle sizes, as shown by the greater standard deviation and interquartile

range. Further, visual inspection of the histograms reveals a greater number of outlying sizes (at sizes > 10

nm).

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Table 2. Table showing simple statistical measures for nanoparticles isolated from the C-H bond

functionalization of benzothiazole 4 with Pd(OAc) /CuI catalyst systems to give 5. SD = Standard

2

Deviation, IQR = Interquartile Range, IQM = Interquartile Mean.

Mean

SD

Median Mode

IQR

IQM

Carousel-derived 4.64 nm 1.62 nm 3.39 nm 3.39 nm 2.54 nm 4.52 nm

PdNPs

Schlenk-derived 6.07 nm 2.25 nm 6.68 nm 6.03 nm 1.72 nm 5.98 nm

PdNPs

This result was unexpected. The more active (Schlenk tube) in situ generated PdNPs are larger than those

generated in the carousel, and indeed the presynthesized Pd(PVP)NPs. Previously it has been demonstrated

2

6

that oxygen (air) promotes the formation of larger PdNPs. In this case, the rigourous exclusion of air has

led to the formation of larger PdNPs.

Figure 2. Electron micrograph of a sample taken from the C-H bond functionalization of benzothiazole 4

performed in a reaction carousel tube after 2 h, with PVP (10 monomer equivalents per Pd) added before

solvent removal. The histogram of particle diameter (nm) across a sample of nanoparticles (n = 100) is also

shown. The inset shows another region from the TEM grid.

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Figure 3. Electron micrograph of a sample taken from the C-H bond functionalization of benzothiazole 4

performed in a Schlenk tube after 2 h, with PVP (10 monomer equivalents per Pd) added before solvent

removal. The histogram of particle diameter (nm) across a sample of nanoparticles (n = 100) is also shown.

2

7

It is interesting to compare the reaction conditions reported by Chen, Cheng and co-workers with that

2

0

reported above under the Bellina-Rossi conditions. In the former case PhI(OAc) was utilized as the aryl

2

source (Scheme 3). Although hypervalent iodine compounds are found as aryl sources in the C-H bond

functionalisation of indoles (vide infra), PhI(OAc) had not previously been used for this purpose. By

comparison with other functionalisations using hypervalent iodine salts, and considering the strong oxidizing

2

7

II/IV

nature of the reagent, the authors proposed that this reaction proceeds via a Pd

catalytic manifold.

2

Pd(OAc) (5 mol%),

Phen (10 mol%),

PhI(OAc)₂6 (1.25 eq.),

N

O

N

O

Ph

Cs CO (1 eq.)

2

3

o

1

150 C, 20 h

3

Scheme 3. C-H bond functionalization of benzoxazole 1 with PhI(OAc) 6 to give 2-phenylbenzoxazole 3.

2

This reaction is performed at high temperature (150 °C) in polar solvent (DMSO), with carbonate base

(

Cs CO ). These conditions are similar to those previously reported for the functionalisation of benzazoles

2 3

2

8

with aryl iodide. For example, studies by Murai and co-workers use near-identical conditions with PhI, and

DMA as opposed to DMSO.

2

7

The reported reaction works well –a 69% yield of 2-phenylbenzoxazole 3 was recorded. Crucially, almost

immediately on addition of DMSO to the reaction mixture a colour change from orange to dark brown was

observed, indicating the propagation of a colloidal ‘naked’ suspension of PdNPs (Fig. 4). The reaction

2

0

appeared similar to the Bellina-Rossi arylations vide supra. Consequently, two separate aliquots of the

reaction mixture were taken (after 2 h heating). To one of these samples, PVP (10 monomer equivalents per

theoretical amount of Pd, assuming the reaction was a homogenous mixture) was added. Solvent was

removed from both samples in vacuo at 50 °C. Transmission electron micrographs were recorded for each of

these samples (Fig. 4). In both samples, PdNPs were observable by TEM. A random sample of nanoparticles

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was chosen (n = 100) from each sample and measured manually. Statistical data is shown in Table 3 (data is

also represented in a histogram in Fig. 4).

Figure 4. Example electron micrograph of a sample taken from the ‘Chen-Cheng’ reaction (1 + 6→3) after 2

h, with PVP (10 monomer equivalents per Pd) added before solvent removal in vacuo. The histogram of

particle diameter (nm) across a sample of nanoparticles (n = 100) is also shown.

Table 3. Statistical analyses for nanoparticles produced in Chen-Cheng reaction. SD = Standard Deviation,

IQR = Interquartile Range, IQM = Interquartile Mean.

Mean

SD

Median Mode

IQR

IQM

With PVP

2.44 nm 0.58 nm 2.13 nm 2.55 nm 0.638 nm 2.43 nm

2.11 nm 0.46 nm 1.69 nm 1.69 nm 0.636 nm 2.07 nm

Without PVP

PdNPs in both TEM samples were < 5 nm and there is a small difference between these samples that is

within error (∆ꢀꢁ ꢂ 0.3ꢀnm; size difference is within the estimated error).

̅

29

In our preliminary study it was demonstrated that PhI(OAc) 6 rapidly degrades to PhI under the working

2

conditions of the reaction (within 10 mins at 150 ºC). The critical finding came from the reaction of PhI {as a

2

7

substitute for PhI(OAc) } with benzoxazole 1 under the reported reaction conditions, which gave 2-

2

phenylbenzoxazole 3 in 84% yield. Further evidence was gathered in a competition experiment – namely

reaction of benzoxazole 1 in the presence of PhI(OAc) 6 (1.25 eq.) and 4-iodotoluene 7 (1.25 eq.), which

2

gave a mixture of arylated products (3 and 8) which mirrors there reactivities in the oxidative addition step

3

0

(

Scheme 4).

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N

Pd(OAc) (5 mol%),

2

Phen (10 mol%),

3

O

N

O

+

PhI(OAc)₂6 (1.25 eq.),

4-MeC H I 7 (1.25 eq.),

N

O

6

4

1

Cs CO (1 eq.)

Me

2

3

o

1

50 C, 20 h

8

1

Ratio of 3:8 ~1.5:1 (by H NMR)

Scheme 4. Competition experiment between PhI(OAc) 6 and 4-iodotoluene 7 in the arylation of

2

benzoxazole 1.

There is strong evidence that PhI(OAc) 6 is not the aryl source in this reaction. Rather, PhI 2 is formed in

2

0

situ. In light of the presence of Pd nanoparticles, which have now been characterized, we propose that the

aryl halide will functionalise benzoxazole 1 in an electrophilic aromatic substitution mechanism and not via a

II

IV

27

Pd /Pd catalytic manifold, as tentatively postulated originally.

3

1

C8-arylation of adenosine and 2'-deoxyadenosine. The biomolecules, adenosine 9 and 2'-

deoxyadenosine 10, which both contain hydroxyl substituents, a purine ring system containing an amino

substituent and sensitive β-glycosyl bonds (arylation reaction temperatures >120 °C is problematic for

2

5

32

adenosine and >80 °C for 2'-deoxyadenosine ). Using Bellina’s and Rossi’s conditions for the arylation of

imidazoles, benzimidazoles and related heteroaromatics as the starting point, e.g. Pd Cat., CuI

20

(

stoichiometric), Cs CO , DMF, 140-160 °C, we developed new reaction conditions. The C8-arylation of 9

2 3

works well at 120 °C (Scheme 5), and in addition to the reported conditions, new results are provided in

Table 4.

NH₂

N

NH₂

N

Pd Cat. (see table)

CuI (3 eq.),

N

Cs CO (2.5 eq.), DMF,

2

3

o

N

120 C, xx h (see table)

N

HO

O

(2 eq.)

I

OH OH

9

2

OH OH

11

Scheme 5. Arylation of adenosine 9 to give 8-phenyl-adenosine 11.

Table 4. Arylation of adenosine 9 to give 8-phenyladenosine 11 using a Pd-Cu mediated reaction (other

conditions as for Scheme 5).

Entry

Pd Cat.

Cat.

Loading / mol%

Reaction

time / h

Yield / %

Ref.

1

2

3

4

5

6

7

8

9

Pd(OAc)₂

Pd(PVP)NPs (~2 nm)

Pd(PVP)NPs (~3.4 nm)

Pd/C (10 wt%)

5

0.5

5

10

13

15

20

15

20

13

65

51

18

21

64

65

70

82

24

a

this work

Pd(OH) /C (20 wt.%)

this work

2

Pd(acac)₂

PdCl₂

trans-Pd(N-Succ) (SMe )

2

2 2

a

in ref. 20d this catalyst was also examined, without intentionally added base.

The Pd(PVP)NPs (~ 2 nm) are as viable as Pd(OAc) at equivalent Pd catalyst loadings (compare entries 2

2

and 3). Supported Pd catalysts were also examined (entries 5 and 6), which show that Pd(OH) /C is as

2

effective as Pd(OAc) at equivalent catalyst loading (compare entries 1 and 6). Other soluble Pd precatalysts

2

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were found to be as effective as Pd(OAc) , and in one particular case significantly surpassing its activity (e.g.

2

3

trans-Pd(N-Succ) (SMe ) , entry 9), giving 8-phenyladenosine 11 in 82% yield. Each of the Pd precatalysts

2

2 2

mirror the behaviour of Pd(OAc) , in that Pd agglomeration is visible in reaction mixtures.

2

3

2

For the C8-arylation of 2'-deoxyadenosine 10, in the study reported we identified that trace dimethylamine

formed by degradation of DMF) was necessary for effective cross-coupling (vide infra). To enable effective

(

cross-coupling at 80 ºC, piperidine was added as an activating co-ligand, which aids the reduction of the in

situ formed Pd(OAc) (piperidine) complex (which can be independently isolated and characterized). Simply

2

heating this complex in DMF at 80 ºC results in degradation to form Pd(DMF)NPs, which have been

analysed here by TEM measurements (Scheme 6), showing that small PdNPs were formed under these

reaction conditions (ꢁ̅ ꢂ 1.7ꢀnm).

Scheme 6. Piperidine-activated Pd(OAc) , leading to well-defined PdNPs when heated to 80 °C.

2

3

2a

With our best reported conditions, previously conducted at 80 °C, we questioned whether Pd(PVP)NPs

could mediate the arylation reaction (10→12) at lower temperature (Scheme 7). Remarkably, the

Pd(PVP)NPs were found to be active at 60 ºC, affording 8-phenyl-2'-deoxyadenosine 12 in 52% yield. To

place this yield into context it is worth considering that the original Pd-Cu mediated reaction temperatures

2

0

described by Bellina and Rossi for imidazoles were conducted at 140-160 ºC, and that the purine arylation

3

4

reactions reported by Hocek and co-workers were typically run between 125-150 ºC. The breakthrough

3

5

here in the milder conditions paves the way for the site-selective C8-arylation of more sensitive

oligonucleotides.

NH₂

N

NH₂

N

Pd Cat. (5 mol%),

CuI (3 eq.), PhI 2 (2 eq.),

N

^C^s^C^O3 (2.5 eq),

2

HO

N

HO

O

DMF (degassed),

xx ^oC (see table), 15 h

1

0

12

OH

Temp. / ^o

C

Pd Cat.

Yield / % ref.*

Pd(OAc)₂

80

60

68

<10

52

31a

-

Pd(PVP)NPs (~2 nm)

Scheme 7. Arylation of 2'-deoxyadenosine 10 to give 8-phenyl-2'-deoxyadenosine 12.

Four other aryl iodide coupling partners have been examined using the Pd(PVP)NPs as the catalyst (Scheme

8

). For both p-methoxyiodobenzene 13 and p-fluoroiodobenzene 15 reasonable yields of the arylated

products (14 and 16, respectively) are obtained. A slightly lower yield was recorded using p-

methyliodobenzene 17 to give 18.

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NH₂

N

NH

2

ArI

Yield / %

Pd(PVP)NPs (~2 nm, 5 mol%),

CuI (3 eq), ArI (2 eq),

N

Ar

4

-MeO-C H -

55

53

38

6

4

^C^s^C^O3 (2.5 eq),

2

N

HO

N

HO

O

4-F-C H -

6

4

DMF (degassed),

o

60

C, 15 h

4

-CH -C H -

OH

10

OH

4 (Ar = 4-MeO-C H -)

3 6 4

1

6

4

6 (Ar = 4-F-C H -)

6

4

8 (Ar = 4-CH -C H -)

3

6 4

Scheme 8. Arylation of 2'-deoxyadenosine 10 with different aryl iodide coupling partners to give 8-arylated

'-deoxyadenosines 14, 16 and 18.

2

0

It is pertinent to return to the original reactions reported by Bellina and Rossi (Scheme 9). In the presence

of Pd(OAc) the reaction of imidazole 19 with p-methoxyiodobenzene 13 gives 2-phenylimidazole 20 in

2

5

7% yield (53% literature yield). It is important to note that there is no intentionally added base in this

chemistry. However, the temperature is high enough for DMF degradation (to give Me NH and CO), with

2

3

6

the imidazole functioning as the base required to assist in the decomposition process. DMF can also act as a

3

7

hydride source at >120 °C. The vagaries of whether a base is necessary for this transformation aside, we

find that the Pd(PVP)NPs are catalytically competent and more efficient than Pd(OAc) for this reaction

2

under otherwise equivalent reaction conditions.

Pd Cat. (5 mol%),

CuI (2 eq.), DMF,

Pd Cat.

Pd(OAc)₂

Yield / % ref.*

N

o

N

135 C, 48 h

OMe

57 (53)*

67

19c

-

N

H

N

H

I

OMe

13

Pd(PVP)NPs (~2 nm)

1

9

(2 eq.)

20

Scheme 9. C2-Arylation of imidazole 19 by Pd(OAc) or Pd(PVP)NPs.

2

C2-arylation of indole and tryptophan.

3

8

In the final example, Sanford’s C2-arylation of N-methylindole 21, in the presence of PhB(OH) 22 and

2

PhI(OAc) 6 in AcOH at 20 ºC, was examined (Scheme 10). Using Pd(OAc) as the catalyst a yield of 84%

2

was recorded. It was noted that PdNPs were formed in this chemistry within 15 seconds of adding the N-

methylindole 21, which would suggest that their formation is autocatalytic. The finding encouraged us to test

Pd(PVP)NPs as a catalyst. Using the Pd(PVP)NPs (ca. 3 nm) a yield of 59% was recorded, confirming once

again their catalytic viability in C-H bond functionalization chemistry.

Pd Cat. (5 mol%)

Pd cat.

Pd(OAc)₂

Yield / % ref.*

PhB(OH)₂22 /

PhI(OAc)

6 (2 eq.)

2

Ph

84 (80)*

59

37

-

o

AcOH, 20 C

N

Pd(PVP)NPs (~3 nm)

21

Me

23 Me

Scheme 10. C2-Arylation of N-methylindole 21 to give 2-phenyl N-methylindole 23.

Our primary interest in this methodology derived from the need to selectively arylate an N-acetyl protected

3

8

typtophan derivative 24. Sanford’s reaction conditions were applied to 24 to afford 2-phenyltryptophan

3

9

derivative 25 in 56% yield (Scheme 11), which we reported in a recently communication. Since that study

II

we have determined that SIMesPd (OAc) (H O) 26 (see inset in Scheme 11 for structure), a previously used

2

3

8

homogeneous catalyst/precatalyst for the indole arylation, is unable to effect this transformation.

ACCEPTED MANUSCRIPT

Me

Cat. loading / % Yield / % TON

MeO

AcHN

MeO

AcHN

^P^d⁽^O^A^c⁾2 (x mol%)

PhB(OH)₂22/

PhI(OAc)₂6 (2 eq.)

O

10

5

66

56

44

15

44

6.6

11.4

17.6

15

Me

OAc

Pd

N

o

^O^H2

AcOH, 16 h, 40 C

2.5

Ph

25

Me OAc

N

H

1

24

1*

44

Me

26

*

Reaction run for 69 h

Scheme 11. Arylation of an N-acetyl protected tryptophan 24 under mild conditions (TON = catalyst

turnover number). The inset shows the structure of precatalyst 26 also tested in this reaction, which was

found to be inactive.

For Pd(OAc) , optimal turnover numbers and yields were seen between 2.5-5 mol% Pd. Running the reaction

2

for longer (16→69 h), then a modest conversion (44%) can be seen at 1 mol% Pd. The correlation between

Pd concentration (ppm) and catalyst turnover number shows that the reaction with highest catalytic efficacy

is that run with 2.5 mol% Pd(OAc) , correlating with ca. 50 ppm (Fig. 5). It is interesting to make the

2

4

0

comparison to de Vries’ optimized Pd concentration in Heck cross-coupling of acrylates with aryl halides

ca. 40 ppm) and the similar Pd concentrations recorded in optimized Sonogashira cross-coupling of terminal

(

4

1

acetylenes with aryl halides from our group. A recent review highlights homeopathic Pd effects in

4

2

traditional cross-coupling reactions, and the findings detailed herein show that this these effects need to be

4

3

considered in C-H bond functionalization chemistry.

Figure 5. Relationship between catalyst turnover number Pd (ppm) in the C2-arylation of tryptophan

24→25).

(

In-keeping with the observations made above with N-methylindole 21, the rapid propagation of PdNPs

occurred within minutes of the reaction being initiated. The in situ generated PdNPs from reaction 24→25

were characterised in naked colloidal form and encapsulated form by addition of exogenous PVP polymer

stabilizer, which was added to an aliquot of the reaction mixture after 1 h (in a similar manner to that

described earlier). TEM confirmed the presence of the colloidal acetic acid-stabilized PdNPs (denoted

Pd(AcOH)NPs) and the encapsulated Pd(PVP)NPs, which were within the same size region (Fig. 6). PdNPs

in both samples were < 5 nm and well defined, as demonstrated by the small standard deviation. There is a

small difference between the two samples, which is within error (∆ꢀꢁ̅ = 0.3ꢀnm; size difference is within the

estimated error, see Table 5).

ACCEPTED MANUSCRIPT

PhB(OH)₂

PhI(OAc)₂

/

AcOH

PVP polymer

2

4

AcOH

Pd(AcOH)NP

ex situ

Pd(OAc)₂(cat.)

AcOH

AcOH, 1 h,

o

2

5

40

C

Encapsulated

Pd(PVP)NP

in situ

Scheme 12. Sampling PdNPs generated under working reaction conditions in the reaction 24→25, forming

acetic acid stabilised PdNPs and the encapsulated Pd(PVP)NPs.

Figure 6. Electron micrograph of sample taken after 1 h from the arylation of an N-acetyl protected

tryptophan 24 to give 25: A without PVP; B with PVP (10 monomer equivalents per Pd) added prior to

solvent removal in vacuo. The histogram of particle diameter (nm) across a sample of nanoparticles (n =

1

00) is shown for both TEM images.

Table 5. Simple statistical analyses of the Pd nanoparticles isolated from the C-H bond functionalisation of

2

4 using PhI(OAc) 6/PhB(OH) 22 (see Fig. 5). SD = Standard Deviation, IQR = Interquartile Range, IQM

2

=

Interquartile Mean.

Mean

SD

Median

2.20 nm

3.05 nm

Mode

2.40 nm

2.17 nm

IQR

IQM

With PVP

2.52 nm

2.22 nm

0.52 nm

0.32 nm

0.680 nm

0.435 nm

2.46 nm

2.20 nm

Without PVP

The intentionally-synthesized Pd(PVP)NPs (ca. 3 nm) gave a comparable yield to the Pd(OAc) catalysed

2

-

II/IV

38

reactions. Since this reaction on indole substrates has been proposed to proceed via a Pd -catalytic cycle,

0

/II

the result is surprising, suggesting that either the reaction proceeds via a traditional Pd manifold, or that Pd

II

atoms are labilized from the polymer support and oxidised to Pd by solvent, reagents or air, which can then

IV

access the higher oxidation state Pd species, which we have no evidence for at the current time. Moreover,

no evidence for Pd(OAc) formation could be obtained from suspending Pd(PVP)NPs in acetic acid at 40 ºC

2

(

by IR spectroscopic analysis, ReactIR™).

ACCEPTED MANUSCRIPT

Conclusions

In this paper we have brought together several C-H bond functionalization reactions where PdNPs are

formed under working reaction conditions. In some cases the appearance of PdNPs is within seconds (e.g.

2

1→23 and 24→25). For other reactions, e.g. 1→3, 4→5, 9→11 and 10→12, PdNPs are formed within 2 h

of the reaction commencing (i.e. during substrate turnover). The question is whether the PdNPs are

catalytically competent species – this is difficult to assess without further kinetic studies / in operando XAFS

measurements. However, the PdNPs are formed under working catalyst conditions and could be acting as a

reservoir of Pd, akin to that previously reported for Heck arylations.7 It is interesting to note that all the

reactions: 1→3, 4→5, 9→11 and 10→12, operate with Pd catalyst loadings where the Pd concentration is

ca. 700 ppm. At higher temperatures, e.g. >120 °C, PdNPs are formed in DMF and DMSO at this Pd

II

0

concentration. The role of piperidine in the reaction 10→12 serves to assist the Pd to Pd reduction process,

leading to the formation and propagation of PdNPs at lower temperatures (e.g. at 80 °C). For the reactions:

2

1→23 and 24→25, both in acetic acid, the working Pd concentration is ca. 200 ppm (5 mol%), and the

optimum concentration giving highest turnover numbers (not yield) is ca. 100 ppm (2.5 mol%).

It cannot simply be said that PdNPs are a moribund form of the active catalyst phase. For all of the reactions

examined in this paper, the presynthesized Pd(PVP)NPs (ca. 2-3 nm) are active catalyst species. In several

cases, catalyst activity is commensurate with Pd(OAc) . In two cases, the activity of Pd(PVP)NPs was found

2

to be superior to Pd(OAc) (e.g. 10→12 and 19→20). The higher reactivity of Pd(PVP)NPs allows C-H

2

functionalization of 10 to be reduced to 60 °C. Understanding that PdNPs are formed and propagated in this

example has allowed the reaction temperature to be lowered from 140-160 °C (i.e. our starting point back in

2

006) to 60 °C, which is a breakthrough for this particular chemistry.

4

It is pertinent to place into context an intramolecular direct arylation, mediated by Pearlman’s catalyst -

Pd(OH) /C, which was reported by Fagnou and co-workers. It was questioned whether the active catalyst

2

phase was operating in a homogeneous or heterogeneous phase. Use of the three-phase test allowed this to be

45

examined - an aryl halide-anchored to a Wang resin was fully converted to the cyclic product in the

presence of Pd(OH) /C, indicating Pd leaching and a homogeneous process (cf. a heterogeneous reaction

2

should not be possible between a supported substrate and supported catalyst). The experiment did not

confirm whether it is mononuclear Pd species or Pd clusters that are catalytically active. The pore size of

n

Wang resin is significantly large enough to seed and encapsulate Pd clusters. Pd leaching is required, and

n

4

6

whilst the finding is conclusive, the identity of the true catalyst species was not determined. Bellina and

Rossi also showed that Pd/C was an active catalyst for C-H bond functionalization of azoles.

2

0d

We anticipate that more reactive forms of PdNPs could be tested in C-H bond functionalization chemistry,

especially as stabilized Pd(PVP)NPs contain an exogenous PVP polymer which binds to defect sites on the

particle surface (i.e. the likely active catalytic sites).

In summary, we have gathered evidence that PdNPs are formed in a number of C-H bond functionalization

reactions. We hope that the field will now question and probe the involvement of PdNPs in C-H bond

functionalization reactions in the future.

Experimental Section

General details. Reagents were purchased from Sigma-Aldrich®, Alfa Aesar® or Fluorochem® and used as

received unless otherwise stated. Dry DMF was obtained from Acros® and degassed by N bubbling with

2

sonication. Petroleum ether refers to the fraction of petroleum that is collected at 40 – 60 °C. Air sensitive

procedures were performed using standard Schlenk techniques. Nitrogen gas was oxygen free and dried

immediately prior to use by passing through a column of sodium hydroxide pellets and silica. Filtration was

performed under gravity through fluted filter paper unless otherwise stated.

ACCEPTED MANUSCRIPT

TLC analysis was carried out using Merck 5554 aluminium backed silica plates, and visualised using UV

light (254 nm) or an iodine tank. All column chromatography was performed using silica gel 60 and a

solvent system as stated in the text.

1

13

H and C NMR spectra were recorded on a Jeol ECS/ECX400 (400 and 100 MHz respectively).

1

13

Alternatively and where specified, H and C NMR spectra were recorded on a Bruker AV500 (500 and 126

MHz respectively) spectrometer. H Chemical shifts are reported in parts per million and were referenced to

residual non-deuterated/partially-deuterated solvent. Coupling constants have been quoted to ±0.2 Hz. H

NMR chemical shifts are given to two decimal places; C NMR chemical shifts are given to 1 decimal

place. Spectra were typically recorded at 298 K. C spectra were recorded with H decoupling. Spectra were

processed using MestreNova® (version 8 or below).

1

3

1

3

1

IR spectroscopy was performed using a Perkin Elemer Spectrum 2 or a Unicam Research Series FTIR, both

using an ATR attachment. Where indicated, reactions were monitored in situ using a Mettler Toledo

-1

ReactIR™ ic10 with K6 conduit SiComp (silicon) probe and MCT detector. Resolution 4 cm , range 4000-

-1

6

50 cm and gain adjustment at 1x.

UV-Visible spectroscopy was performed on a Jasco® V-560 spectrometer. A baseline in the appropriate

solvent was obtained prior to recording spectra.

Mass spectrometry was performed using a Bruker Daltronics micrOTOF spectrometer, an Agilent series

1

200 LC, or a Thermo LCQ using electrospray ionization (ESI), with less than 5 ppm error for all HRMS.

Liquid induction field desorption ionization (LIFDI) mass spectrometry was performed using a Waters GCT

Premier mass spectrometer.

Melting points were recorded using a Stuart digital SMP3 machine.

Transmission electron microscopy was performed at the University of York, Department of Biology

Technology Facility, by Dr. Meg Stark using a Technai 12 BioTWIN microscope, operated at 120 kV. The

images were enlarged, and particle sizes measured manually. Statistical analyses were performed and

histograms drawn using Microsoft Excel:mac 2010 with AnalystSoft StatPlus:mac LE.2009 (build 5.8.0.0).

Synthesis and characterisation of Pd(PVP)NPs

To a three-necked round-bottomed flask fitted with a mechanical stirrer and reflux condenser was added

PdCl (255 mg, 1.44 mmol), HCl (aq., 0.2 M, 14.4 mL), and water (706 mL). The reaction mixture was

2

stirred for 1 h, after which time PdCl had dissolved to give an orange solution. PVP (3.2 g), water (672 mL)

2

and EtOH (1000 mL) were added and the reaction heated to reflux with stirring for 4.5 h. The mixture was

cooled to room temperature, and the solvent removed under reduced pressure to give 3.367 g of black solid.

Approximately 1 mg of material was suspended in EtOH (with vigorous shaking), which was applied to a

TEM slide, and the solvent evaporated in vacuo. They dried particles were then analyzed by transmission

electron microscopy (see Results and Discussion section, and further analysis below).

X-ray photoelectron spectroscopy (XPS) on this sample provided information on the Pd(PVP)NP surface

0

II

oxidation state. The Pd 3d XP spectrum indicates the presence of Pd and a small amount of Pd . The higher

1

6

oxidation state is probably the result of minor oxidation of surface Pd. The Pd(PVP)NPs exhibit a strong

NR bonding mode in the N 1s XP spectrum, consistent with the structure of the tertiary amide present in the

3

polymer subunit.

ACCEPTED MANUSCRIPT

0

II

A: Pd 3d XP spectral data showing the presence of Pd , and a small quantity of Pd . B: N 1s XP spectral

data showing the NR bonding mode.

3

General procedure for the arylation of benzoxazole 1 and benzthiazole 4

To an oven-dried Schlenk or carousel tube was added CsF (2.5 eq.), Pd catalyst (5 mol% Pd), and CuI (2

eq.). The reaction vessel was evacuated under high vacuum with stirring and refilled with N . This process

2

was repeated twice. To this was added heterocycle (1 eq.), iodobenzene (2 eq.) and DMF (5 mL). The

reaction mixture was then heated to 120 °C with stirring for 24 h. To the reaction mixture was added sat. aq.

NH Cl (20 mL) and the mixture stirred in air for 1 h to give a homogeneous blue solution. If the mixture

4

remained heterogeneous, pyridine (100 ꢀl) was added. The mixture was then extracted into EtOAc (3 x

4

0mL). The organic layers were combined, dried over MgSO , filtered and the solvent removed under

4

reduced pressure. The resulting brown residue was dry-loaded onto silica gel, and purified by flash

chromatography eluting with EtOAc in petroleum ether solvent systems to give the products.

2

-Phenylbenzo[d]oxazole 3. Eluted from silica gel column using 4% EtOAc in petroleum ether 40-60 ºC.

4

7 1

R 0.79 (20% EtOAc/PE); MP 103 – 106 (lit. 102.8 °C) ; H NMR (400 MHz, CDCl ) δ 8.31 – 8.20 (m,

2

F

3

1

3

H), 7.83 – 7.72 (m, 1H), 7.63 – 7.55 (m, 1H), 7.55 – 7.48 (m, 3H), 7.37 – 7.31 (m, 2H); C NMR (101

MHz, CDCl ) δ 163.2, 150.9, 142.2, 131.7, 129.1, 127.8, 127.3, 125.3, 124.7, 120.2, 110.8; ESI-MS m/z 196

3

-1

[

M+H]; ESI-HRMS m/z 196.0855 [M+H] (calc. for C H NO 196.0757); IR (solid-state ATR, cm ) 1617,

13 10

1

552, 1446, 1258, 1241, 1021, 923, 806, 780, 758.

2

-Phenylbenzo[d]thiazole 5. Eluted from silica gel column using 4% EtOAc in petroleum ether 40-60 ºC.

4

7 1

R 0.88 (20% EtOAc/PE); MP 114 – 116 °C (lit. 111 – 112 °C) ; H NMR (400 MHz, CDCl ) δ 8.11 – 8.05

F

3

1

3

(

m, 3H), 7.92 – 7.89 (m, 1H), 7.53 – 7.45 (m, 4H), 7.38 (ddd, J = 8.2, 7.4, 1.1 Hz, 1H); C NMR (101 MHz,

CDCl ) δ 168.2, 154.2, 135.2, 133.7, 131.1, 129.1, 127.7, 126.4, 125.3, 123.3, 121.7; ESI-MS m/z 212

3

-1

[

M+H]; ESI-HRMS m/z 212.0532 [M+H] (calc. for C H NS 212.0528); IR (solid-state ATR, cm ) 1509,

13 10

1

477, 1454, 1432, 1313, 1257, 1225, 1159, 1088, 1070, 1012, 962, 797, 758, 729, 684.

Analysis of PdNPs formed in situ in the arylation of benzthiazole 4

Two reactions were prepared, by the general procedure using benzthiazole: one reaction was conducted in a

Schlenk tube and the second reaction in a reaction carousel tube (Radley’s® system). The reactions were

heated to 120 °C for 2 h. Two aliquots (1 mL) were removed from each reaction mixture via syringe. To one

aliquot per reaction, PVP (M_w_,_P_V_P= 29,000, 22 mg, 10 monomer equivalents per theoretical amount of Pd)

was added. The solvent of all aliquots was removed under reduced pressure. Each analysis sample (ca. 100

µL) was suspended in EtOH, applied to a TEM slide, and the solvent evaporated in vacuo. The dried

particles were then analyzed by transmission electron microscopy. Representative images are shown in the

results and discussion section.

ACCEPTED MANUSCRIPT

General Procedure for the ‘Chen-Cheng’ arylation of benzoxazole 1

To a Schlenk tube was added benzoxazole (119 mg, 1 mmol, 1 eq.), PhI(OAc) (415 mg, 1.25 mmol, 1.25

2

eq.), Cs CO (326 mg, 1 mmol, 1 eq.), 1,10-phenanthroline (18.0 mg, 0.1 mmol, 0.1 eq.) and Pd(OAc) (11.1

2

3

2

mg, 0.05 mmol, 0.05 eq.). The reaction vessel was then placed under vacuum and refilled with N . This

2

process was repeated twice. DMSO (5 mL) was added via syringe, and the reaction heated to 150 °C for 20

h. The reaction mixture was then exposed to air, diluted with EtOAc (15 mL) and washed with water (3 x 20

mL). The organic layer was dried over MgSO , filtered, and the solvent removed under reduced pressure to

4

give a residue. This residue was dry loaded onto silica gel, and purified by flash chromatography (4% EtOAc

in petroleum ether 40-60 °C) to give product as a white solid (135 mg, 69% yield). Analytical data identical

to that reported above.

Analysis of PdNPs formed in situ in the ‘Chen-Cheng’ arylation of benzoxazole 1

To a Schlenk tube was added benzoxazole (119 mg, 1 mmol, 1 eq.), PhI(OAc) (415 mg, 1.25 mmol, 1.25

2

eq.), Cs CO (326 mg, 1 mmol, 1 eq.), 1,10-phenanthroline (18 mg, 0.1 mmol, 0.1 eq.) and Pd(OAc) (11.1

2

3

2

mg, 0.05 mmol, 0.05 eq.). The reaction vessel was then placed under vacuum and refilled with N . This

2

process was repeated twice. DMSO (5 mL) was added via syringe, and the reaction heated to 150 °C for 2 h.

Two aliquots (1 mL) were removed via syringe from the reaction mixture. To one aliquot, PVP (M =

w

2

9,000, 22 mg, 10 monomer equivalents per theoretical amount of Pd) was added. The solvent of both

aliquots was removed under reduced pressure. Each analysis sample was suspended in EtOH and dropped

onto a gold grid, and the solvent evaporated in vacuo. The dried particles were then analyzed by TEM.

Representative images are shown in the Results and Discussion section of the manuscript. The nanoparticle

sizes were measured as outlined earlier.

General procedure for C8-arylation of adenosine 9 at 120 °C

To a vacuum dried Schlenk tube was added adenosine (1.0 eq., 500 mg, 1.88 mmol), Cs CO (2.5 equiv.,

2

3

1

.53 g, 4.68 mmol), CuI (3.0 equiv., 1.07 g, 5.61 mmol), Pd(OAc) (5 mol%, 21 mg, 94 ꢀmol) and the aryl

2

iodide (2.0 equiv., 3.74 mmol). The reaction vessel was evacuated under high vacuum at 25 ºC with stirring,

the vessel was subsequently flushed with N (three cycles). Distilled DMF (10 mL) was then added and the

2

reaction heated in an oil bath at 120 ºC, and stirring continued for 13 h. The mixture was then allowed to

cool to 25 ºC and 1M HCl solution (10 mL) added. The pH was then adjusted to pH 6.5 with 1M NaOH and

the aqueous solution extracted with a iPrOH:EtOAc (1:9, v/v, 5 x 50 mL) mixture. The organic extracts were

combined, dried (MgSO ), filtered and reduced in vacuo to yield a thick gum, which was dried under high

4

vacuum to give a powder. This powder was re-dissolved/suspended in MeOH (20 mL) and reduced in vacuo

to adsorb onto silica-gel (approximately 0.5 g). A short silica-gel column (approximately 10 g) was eluted

using CH OH:CH Cl (2:98 v/v, moving in stepwise increments to 10:90 v/v by gradient elution). The

3

2

fractions containing the product were combined and the solvents removed in vacuo. The final pure product

was isolated and dried under high vacuum (~0.1 mmHg). The characterization data for compound 11 has

2

5

previously been reported.

The Pd pre-catalysts, which were used in this study were added to the reaction with the solid substrates, and

all reactions were performed on a 1.88 mmol scale.

Using palladium black (10 mg, 94 ꢀmol, 5.0 mol%) as the pre-catalyst, the product was obtained as a black

solid (39 mg, 6%).

Using 10 wt% palladium on carbon (100 mg, 94 ꢀmol, 5.0 mol%) as the pre-catalyst, the product was

obtained as a light brown solid (137 mg, 21%).

Using 20 wt% Pearlman’s catalyst (50 mg, 94 ꢀmol, 5.0 mol%) as the pre-catalyst, the product was obtained

as a light orange solid (408 mg, 64%).

Using palladium(II) acetate (2.1 mg, 9.4 ꢀmol, 0.5 mol%) as the pre-catalyst, the product was obtained as a

light orange solid (325 mg, 51%).

ACCEPTED MANUSCRIPT

Using palladium(II) acetylacetonate (29 mg, 94 ꢀmol, 5.0 mol%) as the pre-catalyst, the product was

obtained as a light tan solid (415 mg, 65%).

Using palladium(II) dichloride (16.7 mg, 94 ꢀmol, 5.0 mol%) as the pre-catalyst, the product was obtained as

a dark orange solid (448 mg, 70%).

Using PdII(N-succ) (SMe ) (40 mg, 94 ꢀmol, 5.0 mol%) as the pre-catalyst, the product was obtained as a

2

2 2

brown solid (526 mg, 82%).

General procedure for C8-arylation of 2′-deoxyadenosine 10 at 60 °C

2

′-Deoxyadenosine (251 mg, 1.0 mmol, 1.0 eq), CuI (571 mg, 3.0 mmol, 3 eq), caesium carbonate (815 mg,

.5 mmol, 2.5 eq) and Pd catalyst (mol%) were added to a Schlenk under a N atmosphere. DMF (5.3 ml)

2

and the aryl iodide (2.0 mmol, 2.0 eq) were added and the reaction was stirred at 60 °C for either 24 or 48 h.

The reaction was then cooled to room temperature, and HCl (5.3 ml, 1 M) was added to acidify the crude

mixture. The pH was tested, and NaOH (1 M) was added until the pH reached 6.5. The reaction mixture

i

was then extracted with EtOAc/ PrOH (5 x 25 ml, 9:1 v/v), dried over MgSO and the solvent removed in

4

vacuo. The crude product was redissolved in MeOH/CH Cl (1:1 v/v) and absorbed onto silica. The product

2

was then purified by column chromatography on silica gel, eluting with MeOH/CH Cl (2:98 → 1:9 v/v).

2

The solvent was removed in vacuo to yield the pure product. The characterisation data for compound 12

3

2

(

and 14,16 and 18) has previously been reported by us.

Analysis of PdNPs formed in situ in the C8-arylation of 2′-deoxyadenosine 10 at 60 °C

The arylation reaction was carried out as described above. After 1.5 h, an aliquot (1 mL) was removed and

PVP (M = 29,000; 208 mg, 20 monomer equivalents with respect to Pd) was added and the mixture was

w

stirred for 30 min. Each analysis sample was suspended in EtOH and dropped onto a gold grid, and the

solvent evaporated in vacuo. The dried particles were then analyzed by TEM. The nanoparticle sizes were

measured using the PSA macro for ImageJ.

Arylation of imidazole 19 with p-methoxyiodobenzene 13

2

0c

Based on a protocol reported by Bellina et al.. Imidazole (34.0 mg, 0.500 mmol, 1 equiv.), 4-iodoanisole

234 mg, 1.0 mmol, 2 equiv.), Pd(PVP)NPs (~ 2 nm, 25 ꢀmol, 0.05 equiv) and copper(I) iodide (190 mg,

.00 mmol, 2 equiv.) were added to a Radleys carousel or Schlenk tube under a stream of argon. The flask

was evacuated and filled with argon three times and dry, degassed N,N-dimethylformamide (DMF)

purchased dry from Acros or Fischer) (2.5 mL) was added via syringe. The apparatus was sealed and stirred

(

1

(

at 135 ºC (internal temperature) for 48 h. After cooling to ambient temperature the reaction was diluted with

ethyl acetate (10 mL) and poured into a saturated solution of ammonium chloride (10 mL). This was stirred

(

30 mins) and the organic layer was extracted three times with ethyl acetate. The organic phase was washed

water, 10 mL), dried (MgSO ), filtered and reduced in vacuo to give a brown oil. The crude product was

4

added to a silica-gel Biotage SP4 column, eluting with CH Cl /MeOH/NH 100/0/0 to 90/10/0.05 v/v/v, or

2

3

purified manually by column chromatography on silica-gel. Fractions containing the product by UV

visualisation were combined and the solvent removed in vacuo to give the title compound as a white powder.

2

0c 1

Data for 2-[4-(methyloxy)phenyl]-1H-imidazole 20 : H NMR (400 MHz, MeOD) δ 7.77 (app. d, J = 8.9

Hz, 2H, phenyl CH), 7.07 (s, 2H, imidazole CH), 6.97 (app. d, J = 8.9 Hz, 2H, phenyl CH), 3.80 (s, 3H,

1

3

+

OCH ). C NMR (101 MHz, MeOD) δ 161.6, 148.1, 127.8, 124.1, 123.4, 115.2, 55.7. ESI -MS m/z 174.97

(

3

+

-

100%, [MH] ). ESI -MS m/z 173.01 (100%, [M-H] ).

Arylation of 1-methylindole 21

3

To a microwave tube was added phenylboronic acid (93 mg, 0.763 mmol, 2 eq.), bis(acetyloxy)phenyl-λ -

iodane (246 mg, 0.763 mmol, 2 eq.) and Pd(OAc) (4 mg, 19.1 ꢀmol, 5 mol%) and acetic acid (5 mL). The

2

reaction mixture was stirred at 40 °C for 10 min. To the resulting orange-brown solution was added 1-

methylindole (50 mg, 0.381 mmol, 48 ꢀl, 1 eq.). The reaction was stirred at 40 °C for 16 h. The resulting

black reaction mixture was filtered through Celite®, and the solvent removed under reduced pressure to give

ACCEPTED MANUSCRIPT

a brown solid. This was dissolved in EtOAc (10 mL) and washed with sat. aq. NaHCO . The organic layer

3

was collected and dried (MgSO ), filtered and the solvent removed under reduced pressure to give a solid.

4

This was dry-loaded onto silica gel and purified by flash chromatography eluting with ethyl

acetate:petroleum ether (1:24) to give product as a white solid (66 mg, 84%). Data for compound 22: MP

1

01.1 – 102.9 °C (lit. 99 – 102 °C); H NMR (500 MHz, CDCl ) δ 7.65 (dt, J = 8.1, 1.0 Hz, 1H), 7.55 – 7.51

3

(

1

m, 2H), 7.48 (t, J = 7.5 Hz, 2H), 7.43 – 7.39 (m, 1H), 7.38 (dd, J = 8.1, 1.0 Hz, 1H), 7.26 (ddd, J = 8.1, 7.0,

1

3

.0 Hz, 1H), 7.16 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 6.58 (s, 1H), 3.76 (s, 3H); C NMR (126 MHz, CDCl ) δ

3

41.68, 138.47, 132.97, 129.49, 128.59, 128.09, 127.95, 121.77, 120.58, 119.96, 109.70, 101.77, 31.26; ESI-

+

MS m/z 208 ([M+H] ); ESI-HRMS m/z 208.1120 [M+H] (calc. for C H N 208.1121); IR (CDCl solution,

cm ) ν 3061, 2948, 2365, 2338, 2245, 1470; UV-Vis (cyclohexane, nm) λ

mol dm cm ), 298 (ε = 15334 mol dm cm ).

1

5

14

3

-

1

206 (26304), 222 (ε = 27028

maxima

-3

-1

-3

-1

Arylation of methyl (2S)-2-amino-3-(1H-indol-3-yl)propanoate 24

3

To a microwave tube was added phenylboronic acid (47 mg, 0.384 mmol, 2 eq.), bis(acetyloxy)phenyl-λ -

iodane (123 mg, 0.384 mmol, 2 eq.), Pd(OAc) (2 mg, 9.6 ꢀmol, 5 mol%) and acetic acid (5 mL). The

2

reaction mixture was stirred at 40 °C for 10 min. To the resulting orange-brown solution was added methyl

(

°

2R)-2-acetylamino-3-(1H-indol-3-yl)propioniate (50 mg, 0.192 mmol, 1 eq.). The reaction was stirred at 40

C for 16 h. The resulting black reaction mixture was filtered though Celite®, and the solvent removed under

reduced pressure to give a brown solid. This was dissolved in EtOAc (10 mL) and washed with sat. aq.

NaHCO . The organic layer was collected and dried (MgSO ), filtered and the solvent removed under

3

4

reduced pressure to give a brown solid. This was dry-loaded onto silica gel and purified by flash

chromatography eluting with ethyl acetate:petroleum ether (1:1, v/v) to give product as a white solid (36 mg,

1

5

3

8

6%). Data for compound 25: MP 83–84 °C; H NMR (400 MHz, CDCl ) δ 8.20 (s, 1H), 7.63 – 7.54 (m,

3

H), 7.51 – 7.45 (m, 2H), 7.44 – 7.33 (m, 2H), 7.21 (ddd, J = 8.0, 7.0, 8.0 Hz, 1H), 7.15 (ddd, J = 8.0, 7.0,

.0 Hz, 1H), 5.77 (d, J = 8.0 Hz, 1H), 4.84 (dt, J = 8.0, 5.5 Hz, 1H), 3.56 (dd, J = 15.0, 5.5 Hz, 1H), 3.53 (dd,

J = 15.0, 5.5 Hz, 1H), 3.30 (s, 3H), 1.67 (s, 3H); C NMR (101 MHz, CDCl ) δ 172.6, 170.0 136.4, 136.1,

1

3

1

33.6, 129.9, 129.6, 128.7, 128.6, 123.0, 120.5, 119.4, 111.4, 107.2, 53.2, 52.5 27.0, 23.4.; ESI-MS m/z 337

[

(

M+H], 359 [M+Na], 395 [M+K]; ESI-HRMS m/z 337.1539 [M+H] (calc. for C H N O 337.1547); IR

20

2

3

-1

solid-state ATR, cm ) 3284, 2961, 1735, 1654, 1525, 1434, 1259, 1094, 1013, 795, 741, 697; UV-Vis

-3

-1

DMSO, nm) λ_m_a_x_i_m_a308 (ε = 9120 mol dm cm ).

II

Synthesis of SIMesPd(OAc)(OH ) 26. The Pd complex was synthesized by a slightly different route to that

2

4

8

reported (synthetic route outlined below, which is slightly different to that reported ). The procedures for the

individual steps to give this product are detailed here.

ACCEPTED MANUSCRIPT

3

1

,3-[di(2,4,6-trimethylphenyl)-4,5-dihydroimidazolylidene](η -2-methylpropenyl)chloropalladium(II)

4

9

Following a standard procedure to a related complex: To a round-bottomed flask containing 1,3-di(2,4,6-

trimethylphenyl)-2-(pentafluorophenyl)-2,4,5-trihydroimidazole (200 mg, 0.421 mmol, 2 eq.) and di-ꢀ-

3

chlorobis(η -2-methylpropenyl)dipalladium(II) (82.7 mg, 0.211 mmol) was added toluene (5 mL). The

reaction mixture was stirred at 80 °C for 3 h. Solvent was removed under reduced pressure to give product as

1

a white solid (211 mg, 100%). MP 135 – 136 °C; H NMR (400 MHz, CDCl ) δ 6.92 (d, J = 10.0 Hz, 4H),

3

4

6

4

1

.02 – 3.91 (m, 4H), 3.60 (d, J = 3.1 Hz, 1H), 2.98 (d, J = 2.4 Hz, 1H), 2.62 (s, 1H), 2.46 (s, 6H), 2.39 (s,

13

H), 2.27 (s, 6H), 1.79 (s, 1H), 1.25 (s, 3H); C (101 MHz, CDCl ) δ 138.2, 136.2, 129.5, 129.4, 71.8, 51.1,

3

-

1

9.7, 22.1, 21.0, 18.7, 18.6 (allyl C2 carbon has not observed); IR (solid-state ATR, cm ) 3651, 3238, 2912,

734, 1656, 1607, 1488, 1434, 1403, 1376, 1298, 1265, 1232, 1184, 1098, 1061, 860, 850, 837, 738, 696.

Trans-di-ꢀ-chlorobis{[1,3-di(2,4,6-trimethylphenyl)-4,5-dihydroimidazolylidene]chloropalladium(II)}

3

To a round-bottomed flask containing 1,3-[di(2,4,6-trimethylphenyl)-4,5-dihydroimiazolylidene](η -2-

methylpropenyl)chloropalladium(II) (150 mg, 0.297 mmol) was added hydrogen chloride (6 mL, 1 M in

diethyl ether). The reaction was stirred at ambient temperature for 24 h. The solvent was removed under

50 1

reduced pressure to give product as an orange solid (146 mg, 98%). MP >260 °C (lit. >239 °C) ; H NMR

1

3

(

1

400 MHz, CDCl ) δ 6.99 (s, 4H), 3.85 (s, 4H), 2.49 – 2.18 (m, 18H); C (101 MHz, CDCl ) δ 177.8, 138.4,

3 3

-1

34.4, 129.7, 122.8, 51.3, 21.3, 19.1; IR (solid-state ATR, cm ) 3650, 2967, 1607, 1489, 1452, 1404, 1377,

265, 11847, 1099, 1029. This compound was not observed by ESI-MS or LIFDI-MS, but was carried

forward in the next step.

[

1,3-Di(2,4,6-trimethylphenyl)-4,5-dihydroimidazolylidene]diacetateaquopalladium(II)

To a round-bottomed flask containing trans-di-ꢀ-chlorobis{[1,3-di(2,4,6-trimethylphenyl)-4,5-

dihydroimidazolylidene]chloropalladium(II)} (120 mg, 0.124 mmol, 1 eq.) and CH Cl (6 mL) was added

2

silver acetate (167 mg, 0.510 mmol, 4.1 eq.). The reaction mixture was stirred at ambient temperature for 2

h. The reaction mixture was filtered through Celite® to give a yellow solution. Solvent was removed under

4

8

reduced pressure to give the product (known) as a yellow solid (112 mg, 82%). MP 259 – 261 °C

1

(

decomp.); H NMR (400 MHz, CDCl ) δ 7.04 (s, 4H), 4.00 (d, J = 5.6 Hz, 4H), 2.37 (s, 18H), 1.75 (s, 6H);

3

1

3

C NMR (101 MHz, CDCl ) δ 181.5, 181.3, 139.1, 136.6, 134.4, 129.8, 50.6, 23.7, 21.3, 17.9; ESI-MS m/z

07 [M-Pd-2OAc-H O]; IR (solid-state ATR, cm ) 3438, 3415, 3229, 3310, 3229, 1723, 1444, 1406, 1331,

3

-1

3

2

1

276, 1237, 1119, 1104, 1068, 1008, 918, 738, 651, 638, 506.

Acknowledgements

We thank the EPSRC (T.E.S., J.P.R., T.J.W.) and BBSRC (S.D.O.) for funding. GSK provided an industrial

CASE award in support of J.P.R. We are grateful to following people for assisting us with this study: Dr. K.

Wilson (Cardiff Catalysis Institute, University of Cardiff – currently at the Bioenergy Institute, Aston

University) who performed the XPS analysis on the Pd(PVP)NPs, and Dr. Meg Stark who conducted all of

the TEM measurements. We thank Mr. Thomas Herbert for assistance with characterizing presynthesized

Pd(PVP)NPs.

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ACCEPTED MANUSCRIPT

Graphical Abstract

Formation and propagation of well-defined Pd nanoparticles (PdNPs) during C-H bond

functionalization of heteroarenes: are nanoparticles a moribund form of Pd or an active catalytic

species?

1

1,2

2

1,2

2

Christoph G. Baumann, Sara De Ornellas, Jonathan P. Reeds, Thomas E. Storr, Thomas J. Williams

and Ian J. S. Fairlamb*

,

2

1

Department of Biology, University of York, York, United Kingdom, YO10 5DD.

Department of Chemistry, University of York, York, United Kingdom, YO10 5DD.

2

*

Corresponding author.

Article Doi

Formation and propagation of well-defined Pd nanoparticles (PdNPs) during C-H bond functionalization of heteroarenes: Are nanoparticles a moribund form of Pd or an active catalytic species?

DOI: 10.1016/j.tet.2014.06.002

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Authors:

Article abstract of DOI:10.1016/j.tet.2014.06.002

Full text of DOI:10.1016/j.tet.2014.06.002

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