Michael Ludden Level 3 Literature Review 1 | Page 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 Wittig 1 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.
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Michael Ludden Level 3 Literature Review
1 | P a g e
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.
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.
Michael Ludden Level 3 Literature Review
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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.
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.
Michael Ludden Level 3 Literature Review
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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.