l3 lit. review michael ludden

Michael Ludden Level 3 Literature Review

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Meta C-H Activation: A Pathway to Molecular Development –

Selected Methods and the Chemistry behind them.

Michael Ludden

Department of Chemistry, University of Sheffield, Sheffield S3 7HF, UK.

Email: [email protected]

Abstract

New developments in the field of meta-specific C-H activation by various research groups have

provided methods that allow meta- C-H functionalisation on aromatic rings with great

selectivity, a process not previously known to be possible. New synthetic routes allow the

inclusion of a greater number of starting molecules, along with a wider range of functional

groups on substrates. This review will detail some of the methods that have been reported in

recent years and explain the chemistry behind each method, any advantages/disadvantages of

note and the scope for application of these methods will also be discussed.

Introduction

Building molecules with great selectivity

regardless of pre-attached functional

groups is a challenge that organic chemists

have faced for many years. Until recently,

knowledge of aromatic substitution

allowing selective removal of a hydrogen in

favour of another group was limited by a

lack of well-developed catalysts, reagents

or strategies to functionalising C-H bonds.

Replacing hydrogen atoms on aromatic

rings with other functional groups is an

invaluable method of generating more

complex and synthetically useful molecules,

whether it be for pharmaceutical use or

applications in industry. Traditionally this

could be done through directing groups on

the aromatic ring, allowing aromatic

substitution (SEAr or SNAr) to take place at

either the ortho-, meta-, or para- position,

depending on the nature of the functional

group attached to the aromatic.

This method of functionalisation is not

without its disadvantages, however. The

electron-donating groups (EDG’s) required

for ortho- activation may also induce

functionalisation at the para- position,

yielding the di-substituted product.

Aromatic substitution itself will rarely occur

without an EDG being present, as the ring is

not ‘activated’ and remains stable due to

the delocalisation that is characteristic of

aromatic compounds. The discovery made

independently by both Gilman and Wittig1

was directed ortho- metalation (DoM),

which using a direct metalation group

(DMG), such as a methoxy group or a

tertiary amine, allowed C-H substitution for

a lithium atom ortho- to the DMG. This can

then be substituted for an electrophile

through SEAr, giving the desired product

with high ortho- selectivity, overcoming the

problem associated with EDG’s.

Figure 1 - Reaction schematic of DoM.

mailto:[email protected]


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C-H activation builds upon the foundations

set by the many cross-coupling reactions

reported in the past, such as Suzuki-

Miyaura, Stille or Negishi coupling.2 Whilst

these methods are effective in combining

aromatic substrates with alkyl, allyl or aryl

coupling partners, there are certain

functional groups that are not easily

tolerated. Groups including aryl halides that

are ortho- substituted or contain an

electron-withdrawing group, secondary

alcohols and heterocycles are generally not

compatible with the synthetic methods

listed above.

Another shortcoming of cross-coupling is

selectivity. During molecular construction,

good positional selectivity is a desirable

feature for the chosen synthetic route, but

cross-coupling usually only allows

substitution at one position. As the field of

C-H activation has developed, more and

more possibilities have become apparent,

whether it be in terms of usable substrates,

functional groups tolerated or unexpected

selectivity.

Cross-coupling reactions suffer in general

from large amounts of waste, along with a

general inefficiency in terms of atom- and

step-economy. This is even more prevalent

when meta- substituted products are

attempted, as their synthesis usually takes

a longer, more complex synthetic route.

C-H activation methods are increasingly

becoming the alternative, as they offer

higher yields in fewer steps, and are

generally far more efficient than their cross-

coupling analogues.

With the abundance of aromatic and

heterocyclic rings in organic chemistry,

methods of replacing hydrogen atoms at

the meta- position are sought after in the

pursuit of new organic compounds.

Numerous research groups have recently

brought to light methods allowing C-H

functionalisation at the meta- position,

including use of a directing template,3

addition of a traceless directing group4 and

development of specialised catalysts

enabling direct alkylations.5 This paper will

discuss these methods in detail, focusing on

the catalysts used and applications in the

world of chemistry.

Methods

1. Use of a Nitrile directing template (J-Q.

Yu group)

The first method that will be discussed in

this review is the use of a directing

template, published by Jin-Quan Yu and his

research group as recently as 2012.3

A template was devised that allowed

activation of distal meta- C-H bonds

Figure 3 - A comparison of ortho-metalation using a σ-chelating catalyst and meta-activation using a directing

template.

a) Ortho-type

b) Meta-type

Figure 2 - A general catalytic cycle for a Pd(II) catalyst using organometallic reagents.


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through precise positioning of a Pd(II)

catalyst. The design of the template was

developed with many different interactions

in mind; the reversible attachment of the

template to the target molecule being one

and the linear, ‘end-on’ interaction

between the nitrile group and the

palladium catalyst being another.

The geometry of this co-ordination relieves

the strain commonly observed with the pre-

transition state of larger structures and

overcomes any electronic and steric biases

that may be apparent due to other

functional groups on the aromatic. The

limitations previously known to hinder

meta- C-H activation were primarily

involving creating rigid pre-transition state,

as the structure must be rigid at this stage

of the reaction to ensure delivery of the

catalyst to the desired area of the target

arene. The nitrile group was chosen as it

provides numerous benefits for the

template; not only does it bind weakly and

linearly to the catalyst (due to its sp

hybridised C≡N backbone) but also

increases the electrophilicity of the catalyst.

This relieves steric strain and also increases

the reactivity of the catalyst – a desirable

characteristic for C-H activation. The linear

structure also benefits selectivity as it rules

out the possibility of ortho- selective

substitution due to strain imposed on the

structure.

Replacement of the nitrile group with both

a methyl group and a CF3 group resulted in

either a great reduction or complete loss of

reactivity and selectivity. This points to the

lone pair donation from the nitrogen of the

nitrile group being essential for the

template’s operation – CF3 is an

electronegative group, similar to CN, but

cannot donate linearly. This proves that it is

the ‘end-on’ interaction that makes the

catalyst effective, rather than

electronegative effects.

The nature of both R groups, R1 and R2

affect the efficiency of the template

noticeably. It was suggested that the R1

groups should be bulky to reduce

conformational movement. Experimental

data confirmed this proposition; it was

found that tBu groups were essential for

Table 1 - A comparison of selected substituted aromatics. These results are for the substitution of the meta- C-H with the olefin ethyl acrylate using 10% Pd(OPiv)2 as the catalyst, 3 mol eq. AgOPiv as an additive, 1,2-dichloroethane as the solvent. Reaction was at 90°C for 30-48 h.

STARTING MOLECULE SUBSTITUTIONS (W/ TEMPLATE) % YIELD % META- SELECTIVITY

BENZENE (NO SUBSTITUTIONS) 55 93 METHYL AT META’-POSITION 86 94 FLUORINE AT META’-POSITION 52 75 NITRILE AT META’-POSITION 54 98 METHYL AT ORTHO’-POSITION 89 91 FLUORINE AT ORTHO’-POSITION 70 98 METHYL AT PARA-POSITION 54 96 FLUORINE AT PARA-POSITION 45 95

Figure 4 - The general structure of the template developed. Note how the nitrile group does not allow

activation at the ortho position.


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reactivity, with both Me and H groups

resulting in a much lower yield.

It was also found that increasing steric size

of the R2 groups produced an increase in

meta- selectivity. The reason for this is

credited to the Thorpe-Ingold effect – with

increasing substituent size on a tetrahedral

centre comes an increase in reactivity for

the other two substituents.6 (See Fig. 3 for

relative positions of R1 and R2 on template).

This particular template is easily removable

through simple hydrolysis at room

temperature using LiOH as a base, yielding

the product with a 95% yield and the

template with a 65% return.

Table 1 details how the template approach

tolerates substitutions on the starting

molecule. Excellent levels of meta-

selectivity (>90%) were reported for nearly

all substitutions, with reproducible yields

obtained throughout.

It was found that many starting molecules

were also compatible with the template.

Other papers by Yu et al. report that the

template method has successfully been

applied to phenol and its derivatives,7 along

with aniline-type substrates (eg. 2-

phenylpyrrolidines)8. Further research will

undoubtedly bring to light more

applications of this template to more

diverse starting molecules.

A drawback to the nitrile template was

discovered when the process was

attempted with aromatic heterocycles.

Heterocycles are a common component of

drug molecules due to their ability to

improve solubility and also reduce

lipophilicity.9 However it was found that the

Pd(II) catalyst tended to react directly with

the heteroatom present in the aromatic

ring rather than with the nitrile on the

template. Strongly co-ordinating nitrogen,

sulphur or phosphorous atoms can

overcome the binding to the directing

group, leading to catalyst poisoning or C-H

functionalisation at an undesired position.

As a result of this competition, the scope of

new drug discovery using this method is

narrowed.10

2. Use of a Traceless Directing Group (I.

Larrosa group)

The second method put forward that allows

meta- C-H functionalisation is one utilising

previously known methods of directing

functional groups combined with a special

strategy to add and then subsequently

remove a traceless directing group.4 This

process is reported as being a “one-pot”

synthesis – in other words, can be

completed in one synthetic operation.

Larrosa et al. have reported this traceless

directing group to work on a variety of

substituted aromatics, producing bi-aryl

products, and phenol derivatives. In similar

work, Miura et al. have reported a synthetic

route to direct olefination of benzoic

acids.11

Both strategies detail use of the CO2H group

as a powerful ortho- directing group which

can be easily removed at the end of the

Figure 5 - The general reaction scheme for the results detailed in Table 1, where X is the substituted species.

Figure 6 - Fundamental limitations of directed C-H functionalisation of heterocycles: inaccessibility of meta-

H atoms


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synthesis through decarboxylation leaving

only the desired product (hence the term

“traceless”). Adding the CO2H group to

phenol is a simple process, as the OH group

itself is ortho-, para- directing. Upon

addition of the more powerfully directing

CO2H group, iodoarene coupling partners

are employed to produce the final product

for both substituted aromatics and phenol

starting materials. Miura put forward a

method using substituted styrenes as

reactive substrates, retaining the vinyl

double bond in the product.

There are many advantages to this traceless

directing group method, the first of which is

complete meta- selectivity. Larrosa et al.

reported that no arylation was detected in

either the ortho- or para- positions, and

exclusively mono-arylation being another

beneficial result of this method. This is an

improvement on the template method as

ortho- or para- isomers were also produced

during the synthesis.

Many functional groups are tolerated for

the iodoarene coupling partner, as Table 2

displays. Both electron-donating and

electron-withdrawing groups are allowed

to be present on the substrate without

affecting the overall yield significantly.

Fluorine produced a yield of 46% but the

similar functional groups chlorine and

bromine returned yields of 65% and 61%

respectively. Cl and Br are also useful

functional groups as they act in a similar

manner to the iodine present on the arene

substrates – allowing further

functionalisation on the new aromatic ring.

The initial phenol moiety can also be

modified without variation of the reaction

conditions, allowing a vast number of

potential molecules to be paired in this way.

A downside to this method is that there are

also certain substitutions that do not work.

Ortho- substituted iodoarenes are

incompatible, potentially due to

unfavourable steric crowding between this

ortho- functional group and the CO2H

during the transition state.

Some substitutions on the phenol also

result in a lack of reactivity; NO2, for

example, deactivates the ring to the extent

that the initial carboxylation does not

occur. Substitution at C4 of the ring (para-

to the hydroxyl) also led to either much

lower yields or no product returned.

Iodoarene substrate % yield

65

63

46

56

Table 2 - A comparison of some of the yields of pure isolated product for varying iodoarene substrates

during Larrosa's experiment.4

Figure 7 - Comparison of methods developed by Miura and Larrosa, respectively.


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Finally, this directing group method is

unfortunately optimised using relatively

harsh reaction conditions. The initial

carboxylation (Kolbe-Schmitt type) requires

25 atm of CO2 and a reaction temperature

of 190 °C.

Further work on this method by Larrosa has

produced a more efficient synthetic route

but with little deviance in the

methodology.12 This entails use of an

aldehyde directing group rather than CO2H,

which can be added under milder

conditions through simple formylation and

removed with ease during the final step of

the reaction. The CHO group has not been

used in this way before due to its reactivity

in traditional C-H arylation reactions.

This traceless group mirrors many of the

advantages and disadvantages that CO2H

displays, including a lack of tolerance for

ortho- substituted iodoarenes, for example.

The main improvement is the milder

reaction conditions required to add the

directing group.

3. Use of a specialised transition metal

catalyst (Ackermann, Gaunt, Frost groups)

Transition metal catalysts have been known

to facilitate cross-coupling reactions for

many years with many different

mechanisms reported, such as the Heck

reaction, Suzuki-Miyaura coupling and Stille

coupling. These reactions have traditionally

involved inefficient reagents that may also

generate undesired waste. With an ever-

increasing focus on environmentally

friendly, ‘greener’ chemistry, reduction of

toxic waste chemicals is a goal across

organic chemistry.

The aim of this method is to allow

installation of new alkyl groups onto the

meta- position of aromatic compounds

without excessive waste or numerous

synthetic steps. Different research groups

have reported different methods of C-H

activation, all using individually designed

catalysts specialised with a certain synthetic

route in mind.

As early as 2002, Hartwig et al. reported the

development of an iridium-based catalyst

that allowed meta- selective halogenation

of di-substituted arenes.13 This catalyst

operated on steric grounds rather than

electronic ones, with interactions between

the bulky boronic additive and the groups

already present on the arene promoting

substitution at the meta- position. As the

reaction is based upon steric properties,

both electron-withdrawing and electron-

donating groups are tolerated on the

aromatic substituent.

The catalyst in this instance is

[Ir(COD)(OMe)2] (COD = cyclooctadiene)

and produces 3,5-disubstituted boronic

esters. These are then converted to aryl

halides through interaction with a co-

operative CuX2 salt (where X = Cl, Br).

Another method reporting specifically

meta- C-H functionalisation was published

by Gaunt et al. in 2009 and uses a Cu(III)

catalyst.14 The simple change from a

palladium-based catalyst to a copper-based

one resulted in a higher oxidation state on

the metal. The increased electrophilicity

caused by this results in a stronger

activation of the aromatic ring to which the

catalyst is bound, hence substitution at the

meta- position is favoured. No reaction

occurs in the absence of the Cu catalyst,

Figure 8 - The general synthetic route using CHO as a traceless directing group. Note the similarity to the

scheme seen in Fig. 7


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indicating it is the cupration of the meta- C-

H bond that allows substitution to occur.

This catalyst is functional in mild reaction

conditions, with a reaction temperature of

90 °C and atmospheric pressure in 1,2-

dichloroethane.

The amide group in this case can be

substituted for a carbonyl-containing group

that still allows for meta- direction for the

copper catalyst. In another paper by Gaunt,

it was hypothesised that an interaction

between the carbonyl on the amide group

was contributing to the observed selectivity

of the catalyst.15 By replacing the amide

with exclusively a carbonyl group and

attempting a similar synthesis to the one

detailed above, it was found that the

carbonyl group was correctly identified as

the group responsible for the meta-

selectivity.

A method that precedes yet shares a basis

with the template method is one put

forward by C. G. Frost in 2011.16 This utilises

an interaction between the Ru(II) catalyst

and a pyridine positioned on the aromatic

starting molecule to direct the catalyst to

the bond ortho- to the pyridine. This forms

a Ru-C bond which strongly activates the

ring for para- substitution, meta- to the

original substituent.

As it is the nitrogen that is providing the

direction for the catalyst, the pyridyl group

can be swapped for any that contained a

nitrogen atom. It was reported in a paper by

Ackermann, however, that the pyridyl

substituent was the most effective for this

method of activation, with higher yields

returned for pyridines than azoles and

pyrimidines.5

This catalytic method comes with its

advantages and disadvantages. As it

requires ruthenation ortho- to the nitrogen-

containing substituent, meta- substituted

arenes are strongly unfavoured due to

steric crowding (see Fig. 12). On the other

hand, it also allows groups to be added in

sterically crowded areas of the molecule.

Figure 9 - A comparison of a Pd(II) catalyst compared to a Cu(III) catalyst for arylation of an amide-substituted

aromatic.14

Figure 10 - A similar reaction to the one seen in Fig. 9, also published by Gaunt. Here, the amide group has been replaced by a carbonyl group with no significant change to either the catalyst or other reactants.

Figure 11 - meta-sulphonation of an arene through ortho-ruthenation involving a weak interaction between the

pyridyl substituent and the catalyst.


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The ruthenation step in this method is

reversible, yielding the substituted product

and subsequently returning the catalyst. It

is also highlighted that the process is

completely mono-selective for electron-

rich starting arenes such as azoles, but can

afford di-substituted products for electron-

poor molecules, such as pyrimidines.

This process has been shown to work with

primary alkyl halides, and benzyl halides in

the ortho- position, so development of

meta- substitution for these substrates

looks promising for future work.17,18

Catalysts – advantages and disadvantages

1. Palladium

Palladium has been the transition metal of

choice for many catalysts employed for

cross-coupling reactions and more recently

C-H activation. Pd can exist in many

oxidation states – Pd(0), Pd(II) and Pd(IV) all

commonly found in catalytic cycles.

Palladium is readily available in both Pd(0)

and Pd(II) form in compounds such as

Pd(PPh3)4 or Pd2(dba)3-CHCl3 for Pd(0) and

PdCl2 or Pd(OAc)2 for Pd(II).

Table 3 - Direct comparison of some transition metal catalysts that have been reported to induce meta- C-H functionalisation. As many factors as possible were kept constant when collating data, although each individual study displays certain combinations of starting molecule/substrate pairings. T1 = nitrile template (see section 1 of Methods).

Catalyst Starting molecule Substrate %

yield

[RuCl2(p-cymene)]2

55

[RuCl2(p-cymene)]2

56

Cu(OTf)2

51

[Ir(COD)(OMe)2]

61

[Pd(OPiv)2]

54

Figure 12 - A diagrammatical comparison of a meta-substituted arene (a) vs an ortho-substituted arene

interacting with a ruthenium catalyst. The congested steric areas are highlighted in red.


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Palladium owes its popularity to its ability

to form a range of carbon-carbon bonds on

organic molecules. Pd catalysts and

reagents are tolerated by most functional

groups, including hydroxyl and carbonyl;

other reagents may react with these more

readily. Palladium is relatively stable in

contact with both air and moisture – nickel,

on the other hand, as Ni(0) is extremely air-

sensitive.

Every catalyst has its downsides, however,

and Pd is no exception. As a metal it is very

expensive when compared to ruthenium

and there are concerns over its toxicity.

The template method also suffers due to its

use of palladium as a catalyst. When the

process was attempted with aromatic

heterocycles, it was found the Pd(II) catalyst

tended to react with the heteroatom rather

than the nitrile on the template. Strongly

coordinating nitrogen, sulphur or

phosphorous atoms can overcome the

binding to the directing group, leading to

catalyst poisoning or C-H functionalisation

at an undesired position. As a result of this

competition, the scope of new drug

discovery using heterocycles is narrowed

when using this method.10

2. Copper

Copper has demonstrated its worth in C-H

activation through development by Gaunt

etc.14,15 Being a vastly cheaper option to

palladium and non-toxic, copper

alternatives to already established

palladium catalysts are sought after.

Copper also allows C-H substitution at

positions that Pd cannot. As discussed

earlier (Methods, part 3), the higher

oxidation state of a Cu(III) catalyst of the

same composition as a catalyst including

Pd(II) allows arylation at a different position

of the aromatic in question.

Copper salts, used in catalysis, can be rather

insoluble in many solvents. It is common for

a higher stoichiometric amount of copper

to be needed for reactions, also.19

3. Ruthenium

Ruthenium catalysts are primarily known in

industry as Grubbs catalysts and are used

primarily for olefin metathesis. Ruthenium

can take both Ru(II) and Ru(III) forms

relatively easily, and it is this

interconversion that renders it suitable for

ortho- ruthenation in the methods

developed by Frost and Ackermann. The

catalyst displayed meta- selective C-H

alkylations using water as a non-toxic, non-

flammable solvent and high yielding direct

alkylations in the absence of solvents. This

holds promise for an application in industry,

as water as a solvent is cheap and

abundant, along with the aforementioned

benefits. It was also highlighted that

carboxylate assistance was required when

using the ruthenium catalyst; the chloro-

ruthenacycle without a carboxylic acid

additive did not afford a product.

The ruthenium catalyst binds to the arene

through interaction with a heteroatom on a

functional group. The hindrance with

heterocycles is they are difficult to remove

or modify. The product, therefore, should

contain the heterocycle moiety also to

avoid problems with removal.20

Figure 13 - The structure of PEPPSI-iPr, a specialised Pd catalyst used by Larrosa et al.21 (PEPPSI = Pyridine

enhanced precatalyst preparation stabilization and initiation).


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Applications

The methods detailed in this review all

describe ways of building more complex

aromatics from basic starting molecules.

Areas such as materials science, industrial

chemical production and the

pharmaceutical sector can all benefit from

developments in the field of meta- C-H

functionalisation.

Polycyclic aromatics and heteroarenes are

important classes of organic

semiconductors and due to their low cost of

manufacture are attracting interest in both

materials science and industry.22

Many chemicals widely used in industry are

based around aromatic backbones.

Benzenes, napthalenes, anilines and

phenols are amongst the list of chemicals

produced on large scales by chemical

industries. The methods listed in this paper

are allowing new pathways to C-C bond

formation from inert C-H bonds through

efficient catalysis and are looking to be

implemented in industrial-scale processes.

Fig. 14 shows the potential of phenol-based

modifications.

A large number of drug backbones can be

constructed through aromatic substitution.

Modification of phenols via the template

method can also be applied to α-

phenoxycarboxylic acids found in the drug

molecule fenofibrate, clofibrate and

etofibrate, for example. Biaryl compounds

can be formed with use of a traceless

directing group. Biaryl compounds are a key

structural motif in several drugs as they

allow high binding affinity to several

receptors – a desirable trait for drug

molecules.23 The traceless directing group

method can also be applied to inhibitor-

type molecules. A phenol derivative under

development for the treatment of

Alzheimer’s disease can be produced with a

41% yield via this method, compared to a

previous best in the literature of 6%.24

Figure 14 - The applications of the hydroxy group on a phenol derivative. Many aromatic substitutions can be performed, yielding a myriad of potential products. Selected yields from the literature for these processes are also displayed.


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As well as possessing the ability to construct

large pre-existing drug backbones, meta-

C-H activation also gives the possibility to

add groups as small as methyl or large as a

heterocycle to aromatic structures. The

methyl group is present in many drug

molecules, as it increases binding potency

and therefore the effectiveness of the drug.

In 2011, more than 67% of the top selling

drugs on the market contained a methyl

functional group.25 Heterocycles could be

viewed with equal importance, as their

presence in a drug molecule improves

solubility and reduces lipophilicity.9

Conclusion

With a number of methods for meta- C-H

functionalisation coming to light in recent

years, it can be said that great progress has

been made in this previously challenging

area. Development of individual methods

by each research group is producing more

synthetic routes for an ever-increasing

range of starting molecules with the aim

being complete control over chemical

syntheses in terms of functionality and

selectivity. The scope of utilisation for

meta- C-H functionalisation is vast and

could bring important advances in areas

such as pharmaceutical products and

treatments, industrial applications,

materials science and potentially other

areas in the near-future.

This review aimed to describe the methods

that have been reported in recent years and

highlight any advantages/disadvantages for

each. The advantage of these methods on

the whole is their reduction of synthetic

steps needed to reach a product through

both step and catalyst efficiency. Pairing

this new synthetic tool with traditional

cross-coupling reactions widens the scope

of potential suitable molecules that can be

modified. Given time, this area of chemistry

will develop rapidly as the syntheses

become more popular with organic

chemists and will undoubtedly be the

subject of many further papers and reviews.

References

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l3 lit. review michael ludden

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