Analysis of the palladium-catalyzed (aromatic)C-H bond metalation- deprotonation mechanism spanning the entire spectrum of arenes

Article abstract of DOI:10.1021/jo202342q

A comprehensive understanding of the C-H bond cleavage step by the concerted metalation-deprotonation (CMD) pathway is important in further development of cross-coupling reactions using different catalysts. Distortion-interaction analysis of the C-H bond cleavage over a wide range of (hetero)aromatics has been performed in an attempt to quantify the various contributions to the CMD transition state (TS). The (hetero)aromatics evaluated were divided in different categories to allow an easier understanding of their reactivity and to quantify activation characteristics of different arene substituents. The CMD pathway to the C-H bond cleavage for different classes of arenes is also presented, including the formation of pre-CMD intermediates and the analysis of bonding interactions in TS structures. The effects of remote C2 substituents on the reactivity of thiophenes were evaluated computationally and were corroborated experimentally with competition studies. We show that nucleophilicity of thiophenes, evaluated by Hammett σ_p parameters, correlates with each of the distortion-interaction parameters. In the final part of this manuscript, we set the initial equations that can assist in the development of predictive guidelines for the functionalization of C-H bonds catalyzed by transition metal catalysts.

Full text of DOI:10.1021/jo202342q

Article
pubs.acs.org/joc
Analysis of the Palladium-Catalyzed (Aromatic)C−H Bond
Metalation−Deprotonation Mechanism Spanning the Entire
Spectrum of Arenes
Serge I. Gorelsky,* David Lapointe,* and Keith Fagnou†
Department of Chemistry and Center for Catalysis Research and Innovation, University of Ottawa, 10 Marie Curie, Ottawa, ON,
K1N 6N5 Canada
S
* Supporting Information
ABSTRACT: A comprehensive understanding of the C−H
bond cleavage step by the concerted metalation−deprotona-
tion (CMD) pathway is important in further development of
cross-coupling reactions using different catalysts. Distortion−
interaction analysis of the C−H bond cleavage over a wide
range of (hetero)aromatics has been performed in an attempt
to quantify the various contributions to the CMD transition
state (TS). The (hetero)aromatics evaluated were divided in different categories to allow an easier understanding of their
reactivity and to quantify activation characteristics of different arene substituents. The CMD pathway to the C−H bond cleavage
for different classes of arenes is also presented, including the formation of pre-CMD intermediates and the analysis of bonding
interactions in TS structures. The effects of remote C2 substituents on the reactivity of thiophenes were evaluated
computationally and were corroborated experimentally with competition studies. We show that nucleophilicity of thiophenes,
evaluated by Hammett σp parameters, correlates with each of the distortion−interaction parameters. In the final part of this
manuscript, we set the initial equations that can assist in the development of predictive guidelines for the functionalization of C−
H bonds catalyzed by transition metal catalysts.
Herein, we evaluate parameters that govern the activation
barrier of the C−H bond cleavage via a concerted metalation−
deprotonation (CMD) mechanism (eq 1) with palladium-
carboxylate complexes for a diverse set of (hetero)arenes
covering a wide spectrum of aromatic C−H coupling partners.
We also identify and analyze various parameters that are
common to all of the (hetero)arene C−H bond palladium-
catalyzed reactions. We assess, both experimentally and
computationally, the effect of substituents at a C2 position
on the reactivity of C5−H bond of thiophenes. From this
detailed analysis, we also set the basis of the guidelines that
could eventually lead to a simple method that can be used to
estimate the barriers of activation for a wide range of
(hetero)arenes as well as to accurately predict the regiose-
lectivity for all C−H functionalization reactions.
Mechanistic Work Precedents. Several previous inves-
tigations have focused on the understanding of the C−H bond
cleavage mechanism on a wide range of systems, and from these
studies, several different pathways have been proposed. The
two mechanisms that have received the most attention are the
electrophilic aromatic substitution (SEAr) and the CMD
pathways.10,11 Recently, Studer and Itami proposed a stepwise
1,2-migratory insertion mechanism to support the reversal in
the regioselectivity caused by arylboronic acids in their report
on the C4 arylation of thiophene and thiazole.12 With respect
INTRODUCTION
■
Transition-metal-catalyzed functionalization of (hetero)arene
C−H bonds has emerged over the past few years as a rapidly
growing and increasingly reliable alternative to traditional cross-
coupling reactions. The functionalization of a C−H bond
generally depends on the growing array of compatible directing
groups to access adjacent C−H bonds or relies on the intrinsic
C−H bond reactivity toward catalysts.1 In order to employ this
transformation over a broad range of substrates and as part of
increasingly more complex settings, it will require a more
comprehensive understanding of the governing parameters
influencing the reactivity and selectivity of the C−H bond
cleavage step, especially for the approaches that do not use
directing groups. In line with this objective, functionalities on
aromatic rings such as fluorine,2,3 chlorine,4 trifluoromethyl,
nitro,5,6 nitrile,6 and some ethers6,7 were found over the years
to impart an activating influence on C−H bonds toward
functionalization reactions. Also, it was demonstrated that
remote substituents at the C6 position of 1-methylindoles
moderately affected the C2-arylation reactivity of the C−H
bonds of these substrates.8 Beyond searching for other
activating groups, efforts aimed at better understanding of the
reaction mechanism were made by categorizing the reactivity of
arenes in terms of relative and absolute rates.9
We are interested in developing reactivity guidelines in order
to predict the regioselectivity of C−H bond functionalization
with various arenes by extracting as much information as
possible from previously investigated (hetero)aromatics.
Received: November 16, 2011
Published: December 9, 2011
© 2011 American Chemical Society
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Scheme 1. Distortion−Interaction Analysis for the CMD Transition State; Benzene Is Shown as a Representative Substrate
to the CMD process, the earliest C−H bond cleavage
mechanistic studies by metal-carboxylate complexes began in
the 1980s,13 and the first computational study with palladium
was reported in 2000.14 These studies however were limited to
benzene metalation.
RESULTS AND DISCUSSION
■
To gain a better understanding of how the CMD mechanism
might be applicable to a disparate range of (hetero)arenes, a
distortion−interaction analysis was performed for every C−H
bond of selected aromatics.22 This analysis quantifies different
contributions to the CMD barrier V (Scheme 1). On one hand
there is the energetic cost (distortion energy, ΔEdist) associated
with the distortion of the palladium complex and the arene
from their ground state structures (I and II) to their geometries
(III and IV) in the TS structure V. On the other hand, there is
the energy gain (interaction energy, ΔEint) resulting from the
electronic interaction of fragments III and IV to form the TS
structure V.
To evaluate the parameters governing the palladium-
catalyzed C−H bond cleavage, (hetero)arenes 1−22h were
selected to represent a range of (hetero)arenes spanning the
entire spectrum of C−H coupling partners (Figure 1, Table S1
in Supporting Information). The mechanism of the C−H bond
metalation by a palladium-acetate complex of each arene was
evaluated by density functional theory (DFT) with the
B3LYP23 exchange-correlation functional. Even though some
of the arenes chosen were part of our original computational
study,18 eight additional nonthiophene substrates (2, 3, 4, 6, 9,
10, 18, 19) and nine C2 substituted thiophenes (22a−j) were
included in order to increase the scope of the study. For each
substrate, a lowest-energy transition state corresponding to the
CMD pathway was located. PdII-catalyzed C−H bond
functionalization of arene 4 is the only example on this list
that has not been reported experimentally24 and yet it has been
demonstrated that a chlorine substituent has C−H bond
activating properties similar to those of a fluorine substituent.4
While solvent corrections were not employed, the relative
barriers of activation on each of the (hetero)arenes employed
(1−22h) matched the experimental regioselectivity for all cases
except anisole (6).25 The CMD activation barriers for C−H
bond cleavage of anisole were found to be dependent on the
Recent mechanistic studies on the palladium-catalyzed direct
arylation were conducted on various systems, including
benzene,15,16 tethered diarenes,2,7,17 as well as electron-deficient
arenes, such as fluorobenzenes3 and azine-N-oxides.9 The
results of these studies supported the concerted metalation−
deprotonation mechanism with the participation of an inner- or
outer-sphere base.11 However, until recently it was generally
accepted that electron-rich heteroarenes reacted through a SEAr
mechanism due to their high nucleophilicity. In 2008, we
demonstrated that the C−H bond cleavage for a wide range of
(hetero)arenes, including electron-rich (hetero)arenes, by the
PdII-acetate complex proceed by the CMD pathway.18 The
calculated activation barriers predicted accurately the regiose-
lectivity observed experimentally for the palladium-catalyzed
direct arylation of each (hetero)arene evaluated. For the
oxidative cross-coupling of indole with benzene,19 both C−H
bond cleavages were explained by the same mechanism.20 Tan
and Hartwig recently demonstrated that the C−H bond
cleavage of benzene by the PdII catalyst with a DMA ligand has
a lower CMD activation barrier than the C−H bond cleavage
with the phosphine analogue.16 This finding points to future
opportunities in the development of better PdII catalysts for C−
H bond functionalization. Nonetheless, the phosphine ligand is
used in a majority of the direct coupling reactions reported in
the literature. It was experimentally demonstrated that the
calculated barriers of activation for the CMD mechanism are
also in agreement with the relative reactivity of the various
(hetero)arenes.21 As a result, one can utilize the values of CMD
activation barriers to determine the site-selectivity of direct
coupling reactions where two or more heteroarenes are present
within a single substrate.
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Figure 1. Free energy of activation (ΔG298K, kcal mol−1) for C−H bond functionalization via the CMD pathway with the [Pd(C6H5)(PMe3)(OAc)]
catalyst. Red bonds correspond to the experimentally observed sites of arylation26 except for arene 4.27
inclusion of solvent effects. For example, the CMD activation
barriers for anisole in acetonitrile are 40.9:42.2:40.6 kcal mol−1
for o:m:p C−H bonds, respectively, whereas the corresponding
barriers in the gas phase are 32.7:35.1:34.4 kcal mol−1.
Values of Gibbs free energy barriers show good correlation
with electronic energy barriers (Figure S1 in Supporting
Information). The former are higher than the latter due to the
entropic factor, TΔS (free substrate and catalyst form a
transition state complex reducing the number of species by
one).
The distortion−interaction analysis for CMD TS structures
for each C−H bonds of arenes 1−22h revealed several factors
that influence the regioselectivity of palladium-acetate catalyzed
functionalization reactions. These factors allowed for the
classification of the arenes into three categories (Scheme 1,
Table S1). We have categorized to Class I arenes, for which the
regioselectivity of C−H bond functionalization is controlled by
the difference in the (hetero)arene distortion energies,
ΔEdist(ArH). An example of such an arene is benzothiophene
(7) for which Cα−H bonds are more reactive than Cβ-H bonds
in the CMD process due to lower arene distortion energy at the
Cα site (37.5 kcal mol−1 for Cα arylation vs 39.8 kcal mol−1 for
Cβ arylation, Table S1). In Class II are included the
(hetero)arenes for which interaction energies, ΔEint, are the
determining factor that define the most reactive C−H bond. An
example of such an arene is furan (11) for which Cα−H bonds
are more reactive than Cβ-H bonds in the CMD process due to
more negative interaction energy at the Cα site (−44.8 kcal
mol−1 for Cα arylation vs −40.0 kcal mol−1 for Cβ arylation,
Table S1). The (hetero)arenes in which both the distortion and
interaction energies influence the choice of the C−H bond with
the lowest barrier of activation are part of Class III compounds.
An example of such arene is thiophene 22h for which Cα−H
bonds are more reactive than Cβ-H bonds in the CMD process
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due to lower arene distortion energy at the Cα site (39.9 kcal
mol−1 for Cα arylation vs 41.8 kcal mol−1 for Cβ arylation, Table
S1) and more favorable interaction energy at the Cα site (−41.4
kcal mol−1 for Cα arylation vs −37.8 kcal mol−1 for Cβ arylation,
Table S1). This classification of the (hetero)arenes helps to
better understand arylation regioselectivity for these substrates.
Detailed DFT Analysis of the Process Leading to CMD
(π-Complexes). Previous mechanistic work on C−H bond
functionalization of simple arenes demonstrated the formation
of κ1, η1, or η2 π-complexes between the arene with the metal-
carboxylate complex prior to the cleavage of the C−H
bond.11,14,18,28 Computationally such intermediates are typically
obtained with electron-rich heteroarenes such as thiophene
(Scheme 2, black pathway). Benzene has also previously been
entropic loss. The geometries of arenes are not significantly
perturbed in the structures of the π-complexes, as can be seen
from very low values of the arene distortion energies
I
(ΔEdist (ArH) ≤ 1.4 kcal mol−1). The only factor favoring the
formation of these intermediates is the electronic interaction
between the PdII atom with an open coordination site and the
π-electrons of the arenes. From the pre-CMD intermediate, the
TS can easily be accessed with diminished energetic cost
(ΔEdistII(PdL) and ΔEdistII(ArH) in Table 1).
However, not every arene can form a π-complex
intermediate. When undergoing the PdII-catalyzed C−H bond
cleavage, pentafluorobenzene (1), an electron-deficient arene,
does not go through the formation of the π-complex
intermediate. The analysis of the reaction pathway reveals
that, when this arene approaches the empty coordination site of
the palladium central atom, an interaction with the carbon of
the arene C−H bond and the interaction of the C−H bond
proton with the base ligand lead into the CMD process
(Scheme 2, purple pathway). For this substrate, no potential
energy minimum corresponding to the π-complex intermediate
was detected in the reaction pathway before the C−H bond
cleavage transition state.
Scheme 2. CMD Pathways for C−H Bond Cleavage in
a
Various Arenes
Metalation−Deprotonation: Concerted or Not?
Throughout the mechanistic studies performed in regards to
C−H bond cleavage of various (hetero)arenes by metal-
carboxylate complexes, quite often these studies were proposing
either the stepwise SEAr mechanism or a single-step concerted
process. Sames and co-workers proposed an intermediary
process for the C5 functionalization of N-SEM-imidazoles, the
electrophilic metalation−deprotonation (EMD) mechanism.29
This proposal goes along with the idea of a possible continuum
for the mechanisms of the C−H bond cleavage by transition
metal-carboxylate complexes. At one end of this continuum lies
a “pure” stepwise SEAr pathway in which the metal−carbon
bond is fully formed before the C−H bond cleavage occurs. On
the other end would reside a fully concerted process in which
the metal−carbon bond is formed at the same time as the C−H
bond is cleaved. The mechanism of C−H bond functionaliza-
tion of each (hetero)arene with different transition-metal
catalysts can fall in between these two limiting scenarios. To
verify this proposal, we have prepared a More O’Ferrall−Jencks
diagram,30 in which both the O−H and M−C bond formations
and the C−H bond breaking at the CMD transition state for
(hetero)arenes 1−22h (Figure 2 and Figure S2 in Supporting
Information) are characterized by Mayer bond orders for the
corresponding bonds.
a
C6F5H, purple; C6H6, green; C4H4S, black.
shown to form a π-complex intermediate (Scheme 2, green
pathway).14,28 The distortion-interaction analysis for these π-
complex intermediates (Table 1) reveals that the major energy
cost for the formation of these structures comes from the
distortion of the metal complex (ΔEdistI(PdL)) as well as the
At the transition state with the PdII−acetate catalyst, the
bond orders of the forming O−H bonds are narrowly situated
in the 0.52−0.59 range. The Pd−C and C−H bond orders are
more dependent on the nature of the arene; particularly the
Table 1. Gibbs Free Energies and Electronic Energies of Pre-CMD Intermediates for the Lowest-Energy CMD Pathway with
ArH Substrates and [Pd(C6H5)(PMe3)(OAc)] Catalyst, Catalyst and Substrate Distortion Energies, Difference between
Distortion Energies for CMD Transition States and Pre-CMD Intermediates, and Metal-Arene Interaction Energies (kcal
mol−1)
a
a
a
II
ΔEI
Edist (PdL)
Edist (ArH)
Eint
Edist (PdL)
Edist (ArH)
Eint
I
I
I
II
II
arene
ΔG298K
17
14.0
14.8
14.1
11.7
2.2
3.3
9.4
12.9
13.4
12.3
0.4
1.0
1.4
0.8
−7.6
−10.7
−12.5
−14.2
b
7.0
4.4
4.2
5.5
44.2
38.9
38.2
41.7
−28.3
−30.7
−30.9
−30.6
22h
b
22c
2.3
11
−1.0
a
See Scheme 2 for notations and Table S1 for Edist values for CMD TS structures. 2-Fluorothiophene; see Figure 3.
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the TS structures are also narrow (from 0.32 to 0.41), but
taking into consideration the diversity of the nature of the C−H
bonds and the important proximity to the Pd−C bond
formation process, they all are similar TSs. In general, Class I
arenes exhibited weaker Pd−C bonding interactions in the
CMD TS structures than Class II arenes. This could be
attributed to poor nucleophilicity of Class I arenes relative to
Class II arenes. Thus, quite remarkably, all the CMD TS
structures of the (hetero)arenes investigated fit into a fairly
narrow region in both 2-dimensional representations of the 3-
dimensional More O’Ferrall−Jencks diagram. Thus, fairly small
deviation of data points (O−H bond orders vs M−C bond
orders) from the expected trend for the concerted formation of
the M−C and O−H bonds (the dashed line in Figures 2 and
S2) for different arenes do not provide support for the idea of
significant continuum of mechanisms for the arene C−H bond
cleavage using the PdII-carboxylate catalysts.
To compare the dependence of the CMD process with
respect to the nature of the metal catalyst, the transition states
of arene C−H bond cleavage were calculated for iridium(III),31
rhodium(III),32 and ruthenium(II).33 The CMD TS structure
with the IrIII-carbonate catalyst has a high synchronicity for the
formation of the O−H and Ir−C bonds, although the TS
occurs very early in the progression of the metal−benzene
interaction. Rhodium(III) and ruthenium(II) are known to be
fairly electrophilic, and this is reflected by the increased metal−
carbon bonding interaction over the O−H bond at the CMD
TS structures with the RhIII- and RuII-acetate catalysts. Overall,
the metalation−deprotonation process presents a high level of
synchronicity in the formation of the metal−carbon and O−H
bonds (dashed line in Figure 2), which is in contrast to the
formation of a σ-complex (Wheland intermediate) in a SEAr
process. The Wheland intermediate, a signature of a SEAr
process, would exhibit a fully formed M−C bond with the C−
H bond left intact.
Figure 2. Metal−C(arene), (base ligand)O−H and C−H(arene) bond
orders for the lowest-energy CMD TS structures for arenes 1−22h
with the [Pd(C6H5)(PMe3)(OAc)] catalyst (red triangles for Class I
arenes, blue squares for Class II arenes, and black circles for Class III
arenes) and with the other catalysts (gray circles) [Pd(C6H5)(PF3)-
(OAc)] and [Ir(C5H5)(PMe3)(CO3)] (benzene is the substrate)31
and the intramolecular CMD for the [Rh(C5H5)(X)(OAc)] and
[Ru(C6H6)(X)(OAc)] complexes,32,35 where X is the arene substrate
(phenylpyridine for Ru and N-hydroxybenzamide for Rh) bound to
the central metal through the N atom. The dashed line represents the
expected trend for the perfectly concerted formation of M−C and O−
H bonds.
Pd−C(arene) bond orders spread from 0.36 to 0.62, which is
still fairly narrow. The distribution of the C−H bond orders in
Thiophenes. Previous mechanistic work on the mechanism
of direct arylation has highlighted the effect of a remote
Figure 3. Experimentally observed relative reactivity of C2-substituted thiophenes (except for the substrates inside boxes (22c, 22f, 22g, 22h) for
which competition experiments could not be carried, see main text for clarifications). Values in red correspond to the Gibbs free energy of activation
(ΔG298K, kcal mol−1) for the CMD pathway with the [Pd(C6H5)(PMe3)(OAc)] catalyst. R1 = i-Pr was modeled as Me. R2 = n-Pr was modeled as
Me.
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substituent on the reactivity of C−H bonds.8 The arylation of
thiophenes under standard CMD reaction/catalyst conditions
always results in functionalization of Cα−H bonds (Figure 1).
To gain a better understanding of the effect of substituents, we
chose to focus our attention on the C5 functionalization of C2-
substituted thiophenes. These thiophenes reacted in good
yields under standard direct arylation reaction conditions
without optimizations,26b although we employed a variation of
a precatalyst [2′-Pd(PCy3)Cl-2-aminobiphenyl] (23), devel-
oped by Buchwald and co-workers.34 Competition experiments
(Figure S3 in Supporting Information) provided the data
required for comparison of the experimental reactivity of these
thiophenes with the calculated barriers of C−H bond cleavage
at the C5 position (Figure 3). Considering the limitations of
the DFT calculations and the inherent experimental variability
of the competition reactions, the experimental and theoretical
results are in good agreement. Unfortunately, not every
thiophene in Figure 3 could be tested because of either
reactivity or availability issues. For instance, the competition
reactions with 2-methoxythiophene (22f) could not be taken
into consideration in the reactivity chart, since 22f was
incompatible with the reactions conditions when tested
individually (less than 10% yield). The unsubstituted thiophene
22h could not be employed in the competition reactions
because although it reacted very well under the standard
conditions, the arylation product (22g) was significantly more
reactive than the parent thiophene, and so a substantial quantity
of double arylation product was formed.35
(22c), and nitrile (22b), reduce the energetic penalties for the
arene distortions but also reduce the magnitude of the
interaction energy between the substrate and the catalyst.
A closer examination of the distortion-interaction parameters
revealed a correlation with the nature of the C2 substituent.
Indeed, the expression of −Eint as a function of Hammett σp
constants36 for the substituent highlights the relationship
between the π-nucleophilicity of the arenes and their
interaction with the palladium-acetate catalyst (Figure 4, blue
Figure 4. Distortion−interaction parameters (kcal mol−1) for the PdII-
catalyzed CMD transition states as a function of σp values for C2
substituted thiophenes. The solid lines show the linear correlations.
circles). As mentioned before, the beneficial effects of electron-
donating groups on the Eint values are partially offset by the
increased Edist(ArH) penalties (Figure 4, red squares). Figure 4
puts in contrast these two factors. The third factor is Edist(PdL)
(Figure 4, black squares). The small dependence of Edist(PdL)
on the arene nucleophilicity can be rationalized by the fact that
arenes with high nucleophilicity and, thus, more negative Eint
are expected to cause greater structural distortion of the metal-
acetate catalyst to accommodate the incoming substrate.
Using the linear regression for the distortion−interaction
parameters in Figure 4 we obtain:
The observed reactivity of substituted thiophenes (Figure 3)
is not in agreement with SEAr reactivity. Thiophenes with
electron-withdrawing groups at the C2 position such as nitrile
(22b) and ester (22e) were found (experimentally and
computationally) to be the most reactive substrates along
with thiophene containing the strongly electron-donating N-
pyrrolidine substituent (22a). Thiophene with a weak electron-
donating group such as a propyl chain (22j) was found
experimentally to be the least reactive substrate along with the
thiophene possessing the acetyl substituent (22i).
The distortion-interaction analysis of the CMD TS structures
for thiophenes casts light on the influence of the substituents
on both the distortion energy of the arene and the arene−
catalyst interaction energy (Table 2). Highly π-nucleophilic
E
E
E
(ArH) = 40.0(2) − 7.7(4)σ
p
dist
dist
int
(2)
(3)
(4)
(PdL) = 17.8(2) − 2.0(4)σ
p
Table 2. Distortion-Interaction Analysis (kcal mol−1) for
CMD TS Structures of C2-Substituted Thiophenes with the
[Pd(C6H5)(PMe3)(OAc)] Catalyst
= − 43.2(5) + 11(1)σ
p
Although correlations with Hammett parameters have
previously been employed in the C−H bond cleavage
mechanistic studies with various systems, including simple
arenes,37 indoles,8 and pyridine-N-oxides,9 to the best of our
knowledge this is the first time that Hammett σp constants are
shown to be linked to the Edist(ArH) and Eint factors.
Unfortunately, the current σp model derived from eqs 2−4
for thiophenes 22a−j does not allow accurate evaluation of
CMD activation barriers (Figure S4 in Supporting Information)
due to accumulation of parameter errors.
Efforts toward the Establishment of Predictable
Arene C−H Bond Functionalization Guidelines. As
mentioned in the introduction, we are interested in deriving
general trends from a wide array of (hetero)arenes with a final
objective of developing reactivity guidelines for predicting the
regioselectivity of C−H bond functionalization of various
(hetero)arenes.
a
b
Distortion energy for the [Pd(C6H5)(PMe3)(OAc)] catalyst. R1 = i-
c
Pr was modeled as Me. R2 = n-Pr was modeled as Me.
thiophenes, such as 22a and 22f, benefit from more negative
Eint, although this effect is partially counterbalanced by an
increase in the arene distortion energy, Edist(ArH). Electron-
withdrawing groups, such as acetyl (22i), ester (22e), fluorine
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Arene Distortion Energy. The energy cost associated with
the distortion of the arenes into their CMD transition state
geometry can be separated into two components: (1) the C−H
bond elongation and (2) the out-of-plane bending of the C−H
bond of the arene. Evaluation of the C−H bond elongation and
out-of-plane bending of the C−H bond as contributions to
Edist(ArH) for each arene (Figure 5) demonstrated that the out-
Figure 6. Arene distortion energies for the lowest-energy CMD TS
structures with the [Pd(C6H5)(PMe3)(OAc)] catalyst as a function of
the C−H bond deprotonation energies for substrates 1−22h (Class I
arenes are red triangles, Class II arenes are blue squares, and Class III
arenes are black circles). Linear correlation (red line) for Class I arenes
is shown.
one (indolizine 21) and for three Class II arenes out of six
(indolizine 15, imidazopyrimidine 16 and thiazole-N-oxide 13
show significantly higher distortion energies than those
expected from eq 5).
Figure 5. Arene distortion energies (squares; red for Class I arenes,
blue for Class II arenes, and black for Class III arenes) and the C−H
bond distortion energies (circles) for the lowest-energy CMD TS
structures with the [Pd(C6H5)(PMe3)(OAc)] catalyst as a function of
the C−H bond elongation for different arene substrates.
Metal−Arene Interaction Energy. The evaluation of the
electronic interaction (Eint) when the metal catalyst and the
arene in their CMD transition state geometry are brought
together remains elusive. Generally speaking, the interaction
energy for the CMD process results from two interactions: the
metal−C(arene) interaction and the interaction of the base
ligand with the partially cleaved C−H bond. For C2-substituted
thiophenes, we have shown that the Eint is linked to
nucleophilicity (Figure 4). The principal difficulty resides in
the fact that there is little data available to assess the
nucleophilicity of different carbon sites in (hetero)arene
structures. The solution may be found in the development of
a quantitative method that easily allows the evaluation of
carbon site nucleophilicities.
of-plane bending contribution to the arene distortion energy is,
in fact, fairly constant (the average value 13.2 kcal mol−1 with a
standard deviation of 2.2 kcal mol−1 derived from the distortion
energy values for 22 arenes in Figure 5).
As shown in Figure 2, the C−H bond orders in the CMD TS
structures with the PdII catalyst revealed that for all the arenes
the C−H bond orders are in a narrow range (0.32−0.41, the
mean value is 0.36). This information would simplify the
evaluation of arene distortion energies, if one could take the
energy cost to elongate a C−H bond to a distance that
corresponds to the bond order of ∼0.36 in free arene and add
this value to the out-of-plane bending “constant”, 13.2 kcal
mol−1. Unfortunately, this procedure cannot be applied because
the hydrogen atom of the C−H bond in the TS structure also
interacts with the base ligand (acetate). In the absence of the
interaction with the base ligand, the C−H bond order would be
considerably higher than ∼0.36 for the same bond elongation
and would exhibit significant variation in bond orders (Table
S3).
Nonetheless, the estimation of arene distortion energies can
be made using the deprotonation energies of the C−H bonds
of free arenes (Figure 6). The C−H bond deprotonation
energy, Edeprotonation, could be easily calculated by removing the
proton from the corresponding C−H bond of the arene and
optimizing the structure of the resulting anion. For Class I
substrates, the linear regression analysis of the correlation
between Edist(ArH) and Edeprotonation leads to an approximate
expression:
CONCLUSION
■
Distortion-interaction analysis of the C−H bond cleavage of a
wide range of (hetero)aromatics through the concerted
metalation−deprotonation pathway has been performed in an
attempt to quantify the contributions to the CMD reactivity.
On the basis of this analysis, all (hetero)arene substrates can be
divided into three classes. For Class I arenes, the regioselectivity
of C−H bond functionalization is controlled by the difference
in the arene distortion energies. Class II includes the
(hetero)arenes for which interaction energies with the metal
catalyst are the determining factor in reactivity. Class III arenes
are the (hetero)arenes in which both the distortion and
interaction energies influence the C−H bond functionalization.
This classification of the (hetero)arenes allows for an easier
understanding of their reactivity.
The analysis of the CMD reaction pathway reveals that for
some electron-rich and simple heteroarenes π-complexes are
formed prior to the C−H bond cleavage step. In such
intermediates, the arene fragments undergo only small
distortion, refuting the idea of the formation of a Wheland
intermediate that would possess strong Pd−(hetero)arene
interaction.
E
(ArH) = 0.37(5)E
− 107(21)
dist
deprotonation
(5)
Figure 6 also indicates that the correlation established for
Class I arenes works fairly well for all Class III arenes except
664
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The Journal of Organic Chemistry
Article
significant amount of a gray precipitate in suspension had formed. The
precipitate in suspension was then separated from solid LiCl by
decantation, and the remaining LiCl was washed with dry acetone
once. The acetone suspension was then stored for some time to let the
precipitate settle. Most of the solvent was removed with a pipet and
washed twice with ether (∼5 mL). When most of the solvent was
removed with a pipet, the remaining solvent was removed with a rotary
vacuum evaporator and dried under vacuum. Yield: 850 mg, 1.44
mmol (80%). 31P NMR (121 MHz CDCl3): 36.0, 33.8. (rotamers).
General Procedure for the Direct Arylation of Hetero-
cycles.26b 2′-(PdPCy3Cl)-2-Aminobiphenyl (5 mol %), K2CO3 (1.5
equiv), and PivOH (30 mol %) were weighed in air and placed in a
screw-cap vial equipped with a magnetic stir bar. The heteroarene (1.1
equiv) and the aryl bromide (1.0 equiv), if a solid, were then added.
The vial was purged with argon, and a solution of the coupling
partners, if liquid, in dimethylacetamide (DMA) (0.3 M) was added to
the mixture. The reaction mixture was then stirred vigorously at 100
°C for 4−16 h. The solution was then cooled to ambient temperature
and loaded directly on the column or was diluted with ethyl acetate,
then filtered, and evaporated under reduced pressure. The crude
product was purified by silica gel column chromatography to afford the
corresponding product.
The analysis of the bond interactions in the TS structures
using a More O’Ferrall−Jencks diagram allows for the
assessment of how concerted metalation−deprotonation
depends on the nature of the (hetero)arene and the metal
catalyst.
The effects of remote C2 substituents on the reactivity of
thiophenes were evaluated. The computed trends in the
reactivity were corroborated by experimental competition
studies using six thiophenes. Nucleophilicity of thiphenes
evaluated by the Hammett σp values appears to correlate with
not just the catalyst−substrate interaction energies but also
with the distortion energies of the substrate and of the catalyst.
Initial stepping stones were placed in the development of
predictive guidelines for the activation of C−H bond
functionalization catalyzed by PdII-acetate catalysts. It has
been shown that there is a correlation between the
deprotonation energy of the (hetero)arenes and the distortion
energy of arene in the CMD process. The C−H bond out-of-
plane bending energy penalty for different arenes was found to
have a fairly constant value. The principal remaining challenge
to the development of the guidelines is to quantify the
relationship between the nucleophilicity of (hetero)arenes and
the energy of the interaction of the catalyst and (hetero)arene.
Nevertheless, we believe that the findings in this work will be of
practical use for future reaction development. We have
presented where our conception of the CMD pathway stands
and hope that this work will inspire new ideas and discoveries
in the field of C−H bond functionalization.
General Procedure of the Competition Experiments of
Figure 3, with the Exception of the Competitions Involving 1-
(Thiophene-2-yl)pyrrolidine (22a). 2′-(PdPCy3Cl)-2-Aminobi-
phenyl (23) (3.5 mg, 0.006 mmol, 1 mol %), K2CO3 (83 mg, 0.60
mmol, 1.0 equiv), and PivOH (9.2 mg, 0.09 mmol, 15 mol %) were
weighed in air and placed in a screw-cap vial equipped with a magnetic
stir bar. The heteroarenes (0.30 mmol, 0.50 equiv each), if a solid,
were then added. The vial was purged with argon, and a solution of the
5-bromo-m-xylene (11.1 mg, 0.060 mmol, 10 mol %) and the
heteroarenew (0.30 mmol, 0.5 equiv each), if liquid, in dimethylace-
tamide (2.0 mL, 0.3 M) was added to the mixture. The reaction
mixture was then stirred vigorously at 100 °C overnight. The solution
was then cooled to ambient temperature and then filtered and
evaporated under reduced pressure. The remaining solvent was then
remove under reduce pressure using a Kugelrohr apparatus. The crude
EXPERIMENTAL SECTION
■
Computational Details. Density functional theory (DFT)
calculations have been performed using the Gaussian 03 program.38
In all calculations, the spin-restricted method was employed. Wave
function stability calculations were performed to confirm that the
calculated wave functions corresponded to the electronic ground state.
The structures of all species were optimized using the B3LYP
exchange-correlation (XC) functional39,40 with the mixed double/
triple-ζ basis set (DZVP41 on Pd and Rh, LANL2DZ basis set and
effective-core potential on Ir, and TZVP42 on all other atoms). Tight
SCF convergence criteria (10−8 au) were used for all calculations.
Harmonic frequency calculations with the analytic evaluation of force
gradients were used to determine the nature of the stationary points.
Intrinsic reaction coordinate (IRC)43,44 calculations were used to
confirm the reaction pathways through the CMD transition states
(TSs) for all reactants. Gibbs free energies of species were evaluated at
298 K and 1 atm.
1
mixture was then analyzed by H NMR spectroscopy.
General Procedure of the Competition Experiments of
Figure 3 Involving 1-(Thiophene-2-yl)pyrrolidine (22a). Due to
the instability of 22a, an electron-deficient aryl bromide needed to be
employed to give greater stability to the arylation product. 2′-
(PdPCy3Cl)-2-Aminobiphenyl (23) (3.5 mg, 0.006 mmol, 1 mol %),
K2CO3 (83 mg, 0.60 mmol, 1.0 equiv), and PivOH (9.2 mg, 0.09
mmol, 15 mol %) were weighed in air and placed in a screw-cap vial
equipped with a magnetic stir bar. The heteroarenes (0.30 mmol, 0.50
equiv each), if a solid, were then added. The vial was purged with
argon and a solution of the 1-bromo-4-(trifluoromethyl)benzene (13.5
mg, 0.060 mmol, 10 mol %) and the heteroarenes (0.30 mmol, 0.5
equiv each), if liquid, in dimethylacetamide (2.0 mL, 0.3 M) was added
to the mixture. The reaction mixture was then stirred vigorously at 100
°C overnight. The solution was then cooled to ambient temperature
and then filtered and evaporated under reduced pressure. The
remaining solvent was then remove under reduce pressure using a
Mayer bond orders,45 orbital populations, and compositions were
calculated using Mulliken population analysis (MPA)46 and the
AOMix program.47
Preparation of the 2′-(PdPCy3Cl)-2-Aminobiphenyl (23)
Precatalyst. The preparation of the precatalyst was made following
the procedures reported by Buchwald et al.34 A mixture of Pd(OAc)2
(420 mg, 1.87 mmol, 1.0 equiv) and freshly purified 2-amino-biphenyl
(331 mg, 1.96 mmol, 1.05 equiv) in anhydrous toluene (12 mL, 0.15
M) was heated at 60 °C for 30 min under an argon atmosphere, at
which point the initial red color of the solution faded and a gray
precipitate had formed. After the reaction cooled to room temperature,
toluene was removed with a pipet. The remaining solid was washed
twice with toluene (∼3 mL) and then suspended in dry acetone (12
mL). After addition of lithium chloride (226 mg, 5.34 mmol, 3.0 equiv,
stored in a desiccator), the resulting slurry was stirred at room
temperature under argon for 1 h to give a homogeneous solution.
PCy3 (500 mg, 1.78 mmol, 1.0 equiv) was then added slowly over 5
min. The PCy3 was stored and weighed in the glovebox, although
PCy3 can be stored on benchtop if kept under inert atmosphere. The
mixture was stirred at room temperature for 3−4 h, at which point a
1
Kugelrohr apparatus. The crude mixture was then analyzed by H
NMR spectroscopy.
1-(Thiophene-2-yl)pyrrolidine (22a). Synthesized following a
known procedure from 2-iodothiophene on a 10 mmol scale.48
Variable yield depending on the batch: ∼40−50%, 600−770 mg, ∼4−
5 mmol. Light-sensitive oil; Rf 0.35 (petroleum ether/ethyl acetate 80/
1
20); H NMR (400 MHz, CDCl3) δ ppm 6.78 (ddd, J = 5.2, 3.8, 1.2
Hz, 1H), 6.38 (dd, J = 5.4, 1.2 Hz, 1H), 5.75 (dd, J = 3.7, 1.2 Hz, 1H),
3.25 (dq, J = 6.5, 3.4 Hz, 4H), 2.05−1.97 (m, 4H); 13C NMR (100
MHz, CDCl3) δ ppm 155.9, 126.9, 108.3, 100.0, 51.2, 25.8; IR (νmax
/cm−1) 2966, 2889, 2837, 1533, 1471, 1456, 1362 cm−1; HRMS calcd
for C8H11NS (M+) 153.0612, found 153.0614.
5-(3,5-Dimethylphenyl)thiophene-2-carbonitrile. Synthesized
according to the general procedure for the direct arylation on a 0.50
mmol scale. Yield: 65 mg, 0.31 mmol (62%). Yellow solid, mp 68−70
°C (CHCl3); Rf 0.60 (petroleum ether/ethyl acetate 80/20); 1H NMR
665
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The Journal of Organic Chemistry
Article
(400 MHz, CDCl3) δ ppm 7.57 (d, J = 3.9 Hz, 1H), 7.24 (d, J = 3.9
Hz, 1H), 7.21 (s, 2H), 7.04 (s, 1H), 2.36 (s, 6H); 13C NMR (100
MHz, CDCl3) δ ppm 152.4, 139.1, 138.4, 132.3, 131.3, 129.8, 124.4,
123.2, 114.7, 21.4; IR (νmax /cm−1) 3084, 2961, 2358, 2331, 2219,
1652 cm−1; HRMS calcd for C13H11NS (M+) 213.0612, found
213.0618.
Isopropyl 5-(3,5-Dimethylphenyl)thiophene-2-carboxylate.
Synthesized according to the general procedure for the direct arylation
on a 0.50 mmol scale. Yield: 132 mg, 0.48 mmol (96%). Pale oil; Rf
0.50 (petroleum ether/ethyl acetate 80/20); 1H NMR (400 MHz,
CDCl3) δ ppm 7.73 (d, J = 3.9 Hz, 1H), 7.25 (s, 2H), 7.25 (d, J = 4.1
Hz, 1H), 6.99 (s, 1H), 5.22 (septuplet, J = 6.3 Hz, 1H), 2.35 (s, 6H),
1.36 (d, J = 6.3 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ ppm 162.0,
151.5, 138.8, 134.1, 133.5, 132.8, 130.6, 124.2, 123.4, 68.8, 22.1, 21.4;
IR (νmax /cm−1) 2979, 2926, 2875, 1697, 1276 cm−1; HRMS calcd for
C16H18O2S (M+) 274.1028, found 274.1050.
6H); 13C NMR (100 MHz, CDCl3) δ ppm 161.7, 148.8, 137.0, 134.7,
134.1, 130.5 (q, JC−F = 33.0 Hz), 126.5 (q, JC−F = 3.8 Hz), 126.2,
124.9, 124.2 (q, JC−F = 272.1 Hz), 69.2, 22.1; IR (νmax /cm−1) 3002,
2993, 1679, 1653, 1276 cm−1; HRMS calcd for C15H13F3O2S (M+)
314.0588, found 314.0589.
2-Chloro-5-(4-(trifluoromethyl)phenyl)thiophene. Synthe-
1
sized according to the general procedure for the direct arylation. H
NMR of the final product matched the previously reported spectrum.4
1
Pale yellow solid; Rf 0.60 (petroleum ether/ethyl acetate 95/5); H
NMR (400 MHz, CDCl3) δ ppm 7.64−7.59 (m, 4H), 7.16 (d, J = 3.9
Hz, 1H), 6.93 (d, J = 3.9 Hz, 1H).
1-(5-(4-(Trifluoromethyl)phenyl)thiophen-2-yl)ethanone.
Synthesized according to the general procedure for the direct arylation
on a 0.50 mmol scale. Yield: 68 mg, 0.25 mmol (50%). 1H NMR of the
final product matched the previously reported spectrum.49 White
1
solid; Rf 0.35 (petroleum ether/ethyl acetate 70/30); H NMR (400
MHz, CDCl3) δ ppm 7.76 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 3.9 Hz,
2H), 7.67 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 4.0 Hz, 1H), 2.59 (s, 3H).
2-Propyl-5-(4-(trifluoromethyl)phenyl)thiophene. Synthe-
2-Chloro-5-(3,5-dimethylphenyl)thiophene. Synthesized ac-
cording to the general procedure for the direct arylation. Yield: 109
mg, 0.489 mmol (98%). Green solid, mp 70−71 °C (CHCl3); Rf 0.65
1
1
sized according to the general procedure for the direct arylation. H
(petroleum ether/ethyl acetate 80/20); H NMR (400 MHz, CDCl3)
NMR of the final product matched the previously reported
spectrum.26b 1H NMR (400 MHz, CDCl3) δ ppm 7.64 (d, J = 8.4
Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 3.6 Hz, 1H), 6.78 (d, J
= 3.5 Hz, 1H), 2.81 (t, J = 7.5 Hz, 2H), 1.74 (sext, J = 7.5 Hz, 2H),
1.01 (t, J = 7.3 Hz, 3H).
δ ppm 7.12 (wide s, 2H), 7.02 (d, J = 3.9 Hz, 1H), 6.93 (wide s, 1H),
6.86 (d, J = 3.9 Hz, 1H), 2.33 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
ppm 143.4, 138.7, 133.7, 129.7, 128.8, 127.1, 123.6, 122.1, 21.4; IR
(νmax /cm−1) 2914, 2850, 1598, 1431 cm−1; HRMS calcd for
C12H11ClS (M+) 222.0270, found 222.0254.
1-(5-(3,5-Dimethylphenyl)thiophen-2-yl)ethanone. Synthe-
sized according to the general procedure for the direct arylation on
a 0.30 mmol scale. Yield: 28 mg, 0.12 mmol (40%). Clear oil; Rf 0.30
ASSOCIATED CONTENT
■
1
S
* Supporting Information
(petroleum ether/ethyl acetate 80/20); H NMR (400 MHz, CDCl3)
δ ppm 7.64 (d, J = 4.0 Hz, 1H), 7.28 (d, J = 4.0 Hz, 1H), 7.27 (wide s,
2H), 7.00 (wide s, 1H), 2.55 (s, 3H), 2.35 (d, J = 0.6 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ ppm 153.4, 142.8, 138.8, 133.5, 133.3,
130.9, 127.3, 124.3, 123.8, 26.7, 21.4; IR (νmax /cm−1) 3004, 2921,
2864, 1647, 1436 cm−1; HRMS calcd for C14H14OS (M+) 230.0765,
found 230.0761.
Cartesian coordinates and absolute energies of CMD transition
states, the results of distortion−interaction analysis, and
spectroscopic characterization of the reactants and products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
2-(3,5-Dimethylphenyl)-5-propylthiophene. Synthesized ac-
cording to the general procedure for the direct arylation on a 0.30
mmol scale. Yield: 50.5 mg, 0.22 mmol (73%). Oil; Rf 0.70 (petroleum
ether/ethyl acetate 80/20); 1H NMR (400 MHz, CDCl3) δ ppm 7.18
(s, 2H), 7.09 (d, J = 3.5 Hz, 1H), 6.88 (s, 1H), 6.72 (dd, J = 3.5, 1.9
Hz, 1H), 2.79 (t, J = 7.5 Hz, 2H), 2.33 (s, 6H), 1.72 (sextet, J = 7.4
Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
ppm 145.2, 142.1, 138.4, 134.7, 128.9, 125.1, 123.6, 122.6, 32.5, 25.0,
21.5, 13.8; IR (νmax /cm−1) 2962, 2922, 2870, 1652, 1558 cm−1; HRMS
calcd for C15H18S (M+) 230.1129, found 230.1121.
1-(5-(4-(Trifluoromethyl)phenyl)thiophen-2-yl)pyrrolidine.
Synthesized according to the general procedure for the direct arylation
on a 0.30 mmol scale. Yield: 56.4 mg, 0.19 mmol (63%). Green solid,
mp 142−144 °C (CHCl3); Rf 0.25 (petroleum ether/ethyl acetate 80/
20); 1H NMR (300 MHz, CDCl3) δ ppm 7.53−7.47 (m, 4H), 7.16 (d,
J = 3.9 Hz, 1H), 5.73 (d, J = 4.0 Hz, 1H), 3.34−3.30 (m, 4H), 2.08−
2.03 (m, 4H); 13C NMR (100 MHz, CDCl3) δ ppm 156.2, 139.1,
126.5 (q, JC−F = 32.0 Hz), 125.8 (q, JC−F = 3.9 Hz), 125.1, 124.6 (q,
JC−F = 272.1 Hz), 124.1, 123.6, 101.6, 51.0, 25.9; IR (νmax /cm−1)
3055, 2985, 2856, 1610, 1517, 1481, 1326, 1107 cm−1; HRMS calcd for
C15H14F3NS (M+) 297.0799, found 297.0792.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sgorelsk@uottawa.ca; dlapo063@uottawa.ca.
Notes
†Prof. Keith Fagnou passed away on November 11, 2009.
ACKNOWLEDGMENTS
■
The authors thank Thomas Markiewicz for his help in the
preparation of this manuscript. We thank NSERC, CCRI, and
the University of Ottawa for supporting this work. D.L. thanks
NSERC for a postgraduate scholarship (PGS-D).
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1
a 0.50 mmol scale. Yield: 92 mg, 0.363 mmol (73%). H NMR of the
final product matched the previously reported spectrum.49 Yellow
1
solid; Rf 0.10 (petroleum ether/diethyl ether 95/5); H NMR (400
MHz, CDCl3) δ ppm 7.73−7.68 (m, 4H), 7.63 (d, J = 3.9 Hz, 1H),
7.36 (d, J = 3.9 Hz, 1H).
Isopropyl 5-(4-(Trifluoromethyl)phenyl)thiophene-2-car-
boxylate. Synthesized according to the general procedure for the
direct arylation on a 0.50 mmol scale. Yield: 105 mg, 0.336 mmol
(67%). White solid, mp 96−98 °C (CHCl3); Rf 0.60 (petroleum
ether/ethyl acetate 80/20); 1H NMR (400 MHz, CDCl3) δ ppm 7.77
(d, J = 3.9 Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H),
7.36 (d, J = 3.9 Hz, 1H), 5.24 (7, J = 6.3 Hz, 1H), 1.38 (d, J = 6.3 Hz,
666
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The Journal of Organic Chemistry
Article
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