Catalytic deuteration of C(sp2)-H bonds of substituted (Hetero)arenes in a Pt(II) CNN-pincer complex/2,2,2Trifluoroethanol-d1 system: Effect of substituents on the reaction rate and selectivity

Article abstract of DOI:10.1021/acs.organomet.0c00652

Thirty four (hetero)arene derivatives have been tested in catalytic H/D exchange reactions involving their C(sp²)- H bonds and 2,2,2-trifluoroethanol-d₁ (TFE-d₁) in the presence of the homogeneous Pt(II) complex 1 supported by a sulfonated CNN-pincer ligand at 80 °C. The 18 substrates, including one pharmaceutical (naproxen), that are stable in the presence of 1 and are active in the H/D exchange reaction have been characterized by their position-specific extent of deuteration and, in a number of cases, the reaction kinetic selectivity. For the most reactive substrates the extent of deuteration approaches the expected statistical distribution of the exchangeable H and D atoms: e.g., 67-69% for phenol after 23 h and 88% for indole β-CH bonds after 45 min. For a few substrates (N,N-dimethylaniline, indole, nitrobenzene) the H/D exchange is highly position selective. No satisfactory correlation was found between the position-specific (meta, para) H/D exchange rate constants for X-monosubstituted benzenes and Hammett σ_X constants. This observation was proposed to be related to the concerted nature of the CH bond activation, the rate-determining CH bond oxidative addition at a Pt(II) center. A novel scale of Hammett σ^M_X constants was introduced to characterize the reactivity of C(sp²)-H bonds in transition-metal-mediated reactions. The experimentally determined position-specific Gibbs energies of activation of the H/D exchange in substituted benzenes (meta and para positions) as well as in thiophene (α and β positions) were matched satisfactorily using DFT calculations.

Full text of DOI:10.1021/acs.organomet.0c00652

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Article
Catalytic Deuteration of C(sp2)−H Bonds of Substituted
(Hetero)arenes in a Pt(II) CNN-Pincer Complex/2,2,2-
Trifluoroethanol‑d1 System: Effect of Substituents on the Reaction
Rate and Selectivity
Morgan Kramer, David Watts, and Andrei N. Vedernikov*
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ABSTRACT: Thirty four (hetero)arene derivatives have been
tested in catalytic H/D exchange reactions involving their C(sp2)−
H bonds and 2,2,2-trifluoroethanol-d1 (TFE-d1) in the presence of
the homogeneous Pt(II) complex 1 supported by a sulfonated
CNN-pincer ligand at 80 °C. The 18 substrates, including one
pharmaceutical (naproxen), that are stable in the presence of 1 and
are active in the H/D exchange reaction have been characterized
by their position-specific extent of deuteration and, in a number of
cases, the reaction kinetic selectivity. For the most reactive
substrates the extent of deuteration approaches the expected
statistical distribution of the exchangeable H and D atoms: e.g.,
67−69% for phenol after 23 h and 88% for indole β-CH bonds
after 45 min. For a few substrates (N,N-dimethylaniline, indole,
nitrobenzene) the H/D exchange is highly position selective. No satisfactory correlation was found between the position-specific
(meta, para) H/D exchange rate constants for X-monosubstituted benzenes and Hammett σX constants. This observation was
proposed to be related to the concerted nature of the CH bond activation, the rate-determining CH bond oxidative addition at a
Pt(II) center. A novel scale of Hammett σM constants was introduced to characterize the reactivity of C(sp2)−H bonds in
X
transition-metal-mediated reactions. The experimentally determined position-specific Gibbs energies of activation of the H/D
exchange in substituted benzenes (meta and para positions) as well as in thiophene (α and β positions) were matched satisfactorily
using DFT calculations.
Chart 1. Pt(II) Aqua Complexes 1−3 Supported by
Sulfonated CNN-Pincer Ligands
1. INTRODUCTION
Since the discovery of the first homogeneous platinum(II)
complexes capable of hydrocarbon C−H bond activation
observed initially as an H/D exchange between hydrocarbon
substrates and CD3CO2D−D2O,1,2 catalytic H/D exchange
experiments have become a prime and simple tool to probe the
reactivity of various transition-metal species toward C−H
bonds. On the practical side, various homogeneous transition-
metal complexes are now used as catalysts in H/D exchange
reactions.3 Recently, we have reported the preparation of
Pt(II) complexes 1−3 supported by our novel CNN-pincer
ligands (Chart 1) that appeared to be some of the most active
platinum-based homogeneous catalysts for H/D exchange
between C(sp2)−H bonds of arenes (HnSub) and 2,2,2-
trifluoroethanol-d1 (TFE) (eq 1),4,5 in comparison to other
reported Pt-based systems:6,7
catalyst’s turnover frequency reaches 46 h−1 at 80 °C.4 Our
subsequent study of reactivity of complex 1 led us to the
discovery of Pt-mediated stoichiometric CH oxidation with O2
Received: September 28, 2020
HnSub + nCFCH2OD → D Sub + nCFCH2OH
(1)
3
n
3
For instance, reaction 1 with 10 vol %benzene as a substrate
and complex 1 as a catalyst can be observed at 20 °C; the
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Chart 2. Aromatic Substrates HnSub Studied in This Work and the Extent of Their Deuterium Incorporation, x, Observed after
a
the Time Indicated Using ∼1 M Solutions of the Substrates in Wet TFE-d1 with Complex 1 as a Catalyst at 80 °C
a
The values in parentheses show the extent of deuteration x observed in the absence of catalyst 1 after otherwise identical conditions.
of various arenes ArH and complex 1 (eq 2).8 The reaction
produces arene-derived Pt(IV) aryl hydroxo complexes
LPtIVAr(OH) and can involve both electron-rich o- and m-
dialkylbenzenes ArH (alkyl = Me, t-Bu), as well as electron-
poor o-dichloro- and o-difluorobenzenes. Interestingly, except
for o-F2C6H4, these oxidation reactions result in >90% selective
formation of a single isomer of the derived LPtIVAr(OH)
compounds.8
(1) catalyzed by complex 1. We use a wide range of arenes
bearing various electron-donating and electron-withdrawing
functional groups, as well as some heteroarenes, 4−32 (Charts
1
1−3). By using H NMR spectroscopy and measuring the
initial reaction 1 rate, we were able to determine the reaction
kinetic selectivity involving specific types of C(sp2)−H bonds
1
producing well-resolved H NMR signals. Knowledge of the
kinetic (regio)selectivity of the transition-metal complexes
with respect to various arene C(sp2)−H bonds2,6,7,9−12 is
limited, especially for Pt-based systems.2,6,7 We use the rates of
H/D exchange at the meta and para positions of mono-
substituted benzene derivatives in Chart 2 to introduce a new
scale of Hammett constants, σXM, for metal-assisted C−H
bond activation reactions. An additional result of this study of
the reactivity of a wide range of substrates in Charts 2−4 is the
information about the functional group tolerance of complex 1.
Notably, we also tested the performance of catalyst 1 in the
deuteration of two pharmaceuticals, ibuprofen (33) and
naproxen (34) (Chart 4), thus probing the possible application
of Pt-catalyzed H/D exchange for deuterium labeling of
medicinal compounds. A detailed report of these studies is
provided below.
2LPtII(H2O) + ArH + O2 + CFCH2OH
3
→ LPtIVAr(OH) + LPtIV(OCH2CF)(OH) + 2H2O
3
(2)
According to our kinetics study of reaction 2, the arene CH
activation at a Pt(II) center may be responsible for the
selectivity of oxidation of the benzene derivatives above.
Hence, a better understanding of the reactivity of complex 1 in
reaction 1 with respect to various arene C(sp2)−H bonds, as
well as the effect of arene substitution on such reactivity, may
be important for future development of Pt-mediated CH
functionalization chemistry. When complexes 2 and 3 are
considered as the catalysts of the H/D exchange reaction (eq
1), it is worth mentioning that they are more reactive than 1
but they also lose their activity much more rapidly at 80 °C
(complex 2) or already above 20 °C (complex 3)5 due to the
formation of poorly soluble polynuclear platinum species.
Hence, in this work we focus on the H/D exchange reaction
2. RESULTS AND DISCUSSION
2.1. Experimental Setup and Expected Extent of
Substrate Deuteration. The catalytic H/D exchange
between aromatic substrates HnSub and TFE-d1 (eq 1) used
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Chart 3. Aromatic Substrates HnSub That Either Engage in Side Reactions under the Conditions Indicated in Chart 2 or Are
Inactive in the H/D Exchange
Chart 4. Pharmaceuticals 33 and 34 Probed in the H/D Exchange Experiments
as a deuterium source was carried out at 80 °C using, typically,
0.1−0.5 mol % of complex 1 as a catalyst.4,5 In a typical
experiment 0.050 mL of HnSub (or ∼50 mg for solids) was
dissolved in 0.450 mL of wet TFE-d1 containing 0.150 M D2O
and 6−12 μmol of catalyst 1. The water additive was shown
earlier to slow down the catalyst deactivation caused by the
formation of poorly soluble polynuclear species.4 The reactions
compounds, phenol (9), N,N-dimethylaniline (10), and β-
CH bonds of indole (17), by the end of their respective
reaction periods (Chart 2). Not all of the compounds 5−34
tested in this work were deuterated under these conditions.
The substrates active in the H/D exchange (1) are included in
Chart 2 and, in part, Chart 4 (naproxen 34). On the other end
of the reactivity series are the substrates shown in Chart 3, as
well as ibuprofen (33) (Chart 4). These compounds engage in
more or less rapid side reactions or decompose in the presence
of 1 (pyrrole (18), furan (19), iodobenzene (20), styrene
(21), and phenylacetylene (22)), do not change in the
presence of 1 (trifluoromethylbenzene (23), benzenesulfona-
mide (24), o-dichlorobenzene (25), and ibuprofen (33)), or
are able to strongly coordinate to a Pt(II) center in complex 1
thus effectively inhibiting the H/D exchange (e.g., benzonitrile,
pyridine, pyrimidine, and pyrazole, 26−32). In practical terms,
for substrates 23−33 the extent of deuteration did not exceed
∼2%.
1
were monitored by H NMR spectroscopy using the TFE-d1
CH2 group signal as an internal reference. To estimate the
initial reaction rate, the conversion of substrates was checked
more often in the period of time corresponding to no more
than ∼10% substrate conversion and minimal catalyst
deactivation.4 Most of the substrates were used with a
concentration of ∼1 M, which corresponds to an ∼1−6 M
concentration of the arene C(sp2)−H bonds of a specific type.
In none of our experiments were we able to observe H/D
exchange involving C(sp3)−H bonds of alkyl groups. The total
concentration of exchangeable deuterium from TFE-d1 is
∼12.5 M, which translates to the expected extent of the
substrate’s deuteration of ∼68−81% upon reaching a hypo-
thetical statistical distribution of deuterium between solvent
and all reactive CH bonds of the substrate. In fact, a ≥67%
deuteration was observed for the three most reactive
Notably, the use of CD3CO2D as a solvent and a source of
exchangeable deuterium was also attempted and resulted in
slower reaction rates. For example, the extent of deuteration of
benzene in CD3CO2D solution was 14% after 26 h, noticeably
lower than 40% with TFE-d1 after 22 h (Chart 2).
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2.2. Stability of Catalyst 1. Background H/D
Exchange Reactivity with TFE-d1. The potential issues
that may affect our ability to estimate the reactivity of 1 in
reaction 1 with respect to a specific substrate’s CH bonds may
be a strong coordination of a substrate to 1, the catalyst
decomposition under our reaction conditions, and a back-
ground H/D exchange.
only noticeable after 24 h (Chart 2, in parentheses). For indole
the background reaction was not noticeable until after ∼90
min. The reaction (1) of indole catalyzed by 1 is very fast with
3.6% catalyst loading, and a close to statistical 88% extent of
deuteration of indole β-CH bonds is reached after 45 min of
reaction, well before the background reaction becomes
detectable.
For the rest of the substrates in Chart 2 no noticeable H/D
exchange was observed in the absence of the catalyst 1 and no
visible sign of the catalyst decomposition was detected. The
reactivity and selectivity of catalytic deuteration of substrates
shown in Chart 2 are discussed next.
2.3. Reaction 1 Kinetics Model and Initial Rates of CH
Activation. The reaction 1 mechanism with benzene as a
substrate was studied earlier by means of kinetics, mechanistic
tests, the DFT calculations.4,5 It was found that the initial rate
of the reaction in Scheme 1b is first order in both the substrate
CH bond concentration, [C−H], and the catalyst 1
concentration, [1], (eq 3):
Not all Pt(II)-coordinating substrates may be unreactive in
H/D exchange. In particular, N,N-dimethylaniline forms an
adduct with complex 1, but according to our observations
(Chart 2), this substrate is very active in reaction 1, thus
suggesting that the adduct with 1 is weak. In particular, the
dark purple platinum complex 35 could be isolated from a
solution of 1 in a 1/1 (v/v) mixture of N,N-dimethylaniline
and TFE upon precipitation with diethyl ether. The resulting
solid is stable under an argon atmosphere and in methanol-d4
solution for at least 72 h, according to 1H NMR spectroscopy.
1
In the H NMR spectrum of the solution two N−CH3 group
signals of equal intensity are observed, along with signals of a
Pt-coordinated CNN-pincer ligand of matching intensity, thus
suggesting the formation of the adduct LPt(PhNMe2) (35).
The adduct coexists in an apparent equilibrium with an
approximately equimolar amount of free PhNMe2 and,
presumably, a methanol analogue of 1, LPt(MeOH), thus
suggesting that the stability of the adduct 35 is low. Similarly,
the formation of an adduct between complex 1 and thiophene
d[C−D]
= kc[C−H][1] initial rates
(3)
dt
The proposed reaction sequence responsible for the substrate/
TFE-d1 H/D exchange, slightly modified in comparison to the
original proposal,4 is presented in Scheme 2. It involves an
CNN
arene coordination step a to form the σ-arene complex
1
ArX
1
was detected by H NMR but our attempts to isolate the
with a CNN-coordinated pincer ligand, an isomerization step b
CNO
adduct were not successful because of its even lower stability.
Thiophene is also very active in the H/D exchange (reaction
1).
to form an isomer
1
ArX
with a CNO-coordinated pincer
ligand, a rate-limiting CH bond oxidative addition to a Pt(II)
center at step c, via the transition state TSAr‑X, and a redox
isomerization of the resulting Pt(IV) hydrido complex 1(Ar)(X)
at step d via the lower-energy transition state TS3 (Scheme 2)
to form the Pt(II) aryl 1-XAr and a facile H/D exchange of the
latter with TFE-d1 or D2O. The possible involvement of the
Pt(II) aryl 1-XAr and its formation via TS3 was not considered
in the earlier model.4 The details of the DFT calculations
carried out in this work are given in section 2.5 and in the
Supporting Information.
For the purpose of subsequent discussion we assume that
the same rate law (3) and the same general mechanism are
valid for other substrates in Chart 2. We will use the effective
catalytic rate constants kc for each specific type of a substrate’s
C(sp2)−H bond as a measure of the C−H bond reactivity
toward catalyst 1. The kc values are calculated using eq 4:
A catalyst deactivation due to the formation of a light yellow
precipitate that was not identified was observed for benzoic
acid after about 6 h of reaction. Accordingly, the H/D
exchange reactivity of this substrate was only analyzed for the
first 6 h. For a few other substrates such as chloro- and
bromobenzene formation of a red precipitate, presumably the
dinuclear product of the decomposition of catalyst 1
decomposition,4,5 was observed, but only by the end of the
monitored reaction 1 period (∼24 h). Oxidative addition of
the bromobenzene C−Br bond at a Pt(II) center may also be
involved to some extent.
To get a better estimate of the reactivity of catalyst 1, in
addition to considering the catalyst deactivation, the H/D
exchange of all studied substrates in reaction 1 was analyzed in
the absence of 1 (Scheme 1a), as well as in the presence of 1
d[C−D]
dt
1
1
kc =
initial rates
Scheme 1. Background and Pt-Catalyzed H/D Exchange
between a Substrate HnSub and TFE-d1
[C−H] [1]
(4)
In turn, the initial rate of incorporation of deuterium into a
substrate, d[C−D], is determined using the least-squares fitting
dt
procedure during the reaction period corresponding to the
substrate’s conversion not exceeding 10% (see Figure 1 for an
example of initial rate calculations for anisole).
In our experiments involving some monosubstituted
benzene derivatives only their m-C(sp2)−H bond H NMR
1
(Scheme 1b). The contribution of the background reaction to
the deuteration of substrate C−H bonds was considered for
the initial reaction period (<10% deuteration) and by the end
of our experiments (typically, ∼24 h); the latter contribution is
indicated in parentheses in Chart 2.
In fact, the background reaction contribution to the initial
rate of reaction 1 was not detected for any of the substrates in
Chart 2. The background reaction for N,N-dimethylaniline was
signals were resolved well enough to allow for an accurate
integration. Accordingly, the corresponding initial rates and
rate constants for their m-C(sp2)−H bonds, kc,m, were
calculated (Figure 1, right). In turn, the signals produced by
o- and p-CH bonds of these substrates were integrated
together, thus allowing the calculation of the average reaction
rates and the average rate constants, kc,o‑p, for these C(sp2)−H
bonds (Figure 1, left).
D
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Scheme 2. Proposed Reaction Sequence Involved in the H/D Exchange between Arene C(sp2)−H bonds and TFE-d1
a
Catalyzed by Complex 1
a
The standard Gibbs energies for individual reaction steps for TFE solutions at 298 K (blue type) are given for benzene (C6H6) in kcal/mol.4
Figure 1. Concentration of C(sp2)−D bonds of anisole-dx resulting from reaction 1 between anisole and TFE-d1 catalyzed by complex 1, as a
function of time in the reaction’s initial period at 80 °C: a plot for the anisole-dx o- and p-CD bonds (left) and a plot for the product m-CD bonds
(right). The initial concentrations [C6H5OCH3]0 = 0.87 M and [1] = 0.0138 M, and the resulting rate constants are kc,o‑p = 5.1 0.1 M−1 h−1 and
kc,m = 8.6 0.5 M−1 h−1.
Finally, for substrates containing more than one type of
arene C(sp2)−H bond a weighted average value, kc‑all, were
also calculated. These values can be used for the most general
comparison of substrate reactivity. The resulting average
values, kc‑all, and the individual CH bond kc values are given
in Table 1. The kc value for C6H6 will be used as a reference in
the following discussion.
2.4. Reactivity of Benzene Derivatives 5−15. The first
two substrates, p-xylene (5) and mesitylene (6), that follow
benzene in Table 1 contain one or two methyl substituents in
the position ortho to the substrate C(sp2)−H bonds. The
methyl groups make these substrates electron-richer, in
comparison to benzene. Notably, in the transition states
TSAr‑X corresponding to oxidative addition of an o-CH bond to
a Pt(II) center a noticeable steric interference is anticipated
between these substrates’ methyl substituents and the Pt-
coordinated oxygen atom of the pincer ligand of the catalyst 1,
as shown in Figure 2. These steric interactions destabilize the
transition states. Overall, the kc values for benzene (4), p-
xylene (5), and mesitylene (6) (Table 1) decrease in the
sequence benzene > p-xylene ≫ mesitylene, but it is not clear
if the electronic effects of the methyl groups work in the same
or in the opposite direction, in comparison to the steric
interactions in the transition state. The subsequent analysis of
reactivity of monosubstituted benzene derivatives suggests that
the steric and electronic effects change in the opposite
directions (vide infra).
To be able to exclude the substituents’ steric effect from
consideration as the factor affecting the reactivity of
monosubstituted benzene derivatives in Chart 2, and focus
on the substituents’ purely electronic effects, we will consider
reactions involving these substrates’ m- and p-CH bonds.
When considering m- and p-CH bonds of monosubstituted
benzene derivatives 7, 9−12, 14, and 15, first, we wanted to
see if there is a satisfactory correlation between the Gibbs
energies of activation of reaction 1 involving these bonds and a
simple substituent parameter such as the corresponding
Hammett σX constant.13 A plot of the experimentally found
reaction Gibbs energies of activation, ΔG353⧧(exp), vs the
substituent σX values is given in Figure 3. The plot shows the
absence of any good correlation. Still, one can notice that,
overall, reaction 1 tends to be slower for substrates with
electron-withdrawing groups, NO2, CO2H, and halogens F and
Cl (see also σc‑all values for these substrates and bromobenzene
(13) in Table 1), in comparison to benzene. In turn, the rate
constants for the H/D exchange involving m-CH bonds of
phenol (9) and anisole (7) are slightly larger than those for
benzene and the substrates bearing MeO and OH groups.
E
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Table 1. Reaction 1 Rate Constants kc (Eq 3) and the Corresponding Gibbs Energies of Activation for the H/D Exchange
a
between Specific C(sp2)−H Bonds of Substrates 4−16 and TFE-d1 catalyzed by 1 at 80 °C
Gibbs energy of activation, kcal/mol
b
substrate
benzene (4)
p-xylene (51)
mesitylene (6)
anisole (7)
CH bond
all
kc, M−1 h−1
ΔG353⧧(exp), experiment
ΔG298⧧(DFT/gas phase)
ΔG298⧧(DFT/TFE)
6.8 0.4
3.7 0.4
0.52 0.02
5.1 0.1
8.6 0.5
6.5 0.3
6.5 0.9
4.9 0.7
7.3 0.4
5.9 0.6
21
3.1 0.3
14.0 0.9
0.70 0.12
1.3 0.22
1.43 0.06
1.1 0.27
2.2 0.3
25.2 0.1
25.6 0.1
22.5
27.5
22.3
27.0
all C(sp2)−H
all C(sp2)−H
o-CH, p-CH
m-CH
all
c
d
25.0 0.1
22.8
n/a
e
e
benzodioxole (8)
phenol (9)
all C(sp2)−H
o-CH, p-CH
m-CH
all
o-CH, p-CH
m-CH
all C(sp2)−H
o-CH
p-CH
m-CH
all
o-CH
p-CH
c
25.1 0.1
25.7 0.1
23.1
22.4
23.5
e
c
N,N-dimethylaniline (10)
fluorobenzene (11)
1
d
n/a
e
26.8 0.1
26.3 0.1
26.3 0.1
24.6
24.0
24.2
23.6
23.9
24.4
e
chlorobenzene (12)
26.0 0.1
25.8 0.2
25.7 0.1
29.4
23.6
23.6
28.8
23.9
24.0
2.7 0.8
3.2 0.2
2.7 0.1
2.4 0.2
m-CH
all
all
e
e
bromobenzene (13)
nitrobenzene (14)
o-CH
0.00
p-CH
m-CH
all
o-CH, p-CH
m-CH
all
0.9 0.3
0.35 0.06
0.33 0.04
0.78 0.06
2.5 0.8
26.6 0.2
27.3 0.1
25.2
24.8
25.1
25.2
e
benzoic acid (15)
thiophene (16)
d
25.9 0.2
24.4
n/a
e
1.5 0.4
α-CH
β-CH
all
18
10.
14.2 0.6
1
1
24.5 0.1
24.9 0.1
21.1
22.3
20.9
22.2
e
a
ΔG353⧧(exp) are the experimental values, and ΔG298⧧(DFT/gas phase) and ΔG298⧧(DFT/TFE) are calculated by DFT for the gas phase and TFE
b
c
d
solutions, respectively. Calculated using initial reaction rates at <10% substrate conversion. Weighted average for o- and p-CH bonds, kc,o‑p. Not
e
determined due to thedifficulty of locating TSAr‑X in TFE. Weighted-average value for all C(sp2)−H bonds, kc‑all
.
Figure 3. Plot of Gibbs energies of activation of reaction 1 involving
m- and p-CH bonds of monosubstituted benzene derivatives 7, 9−12,
14, and 15 and the substituents’ Hammett σX constants.
Figure 2. DFT-optimized structure of the transition state TSAr‑X for
the oxidative addition of a p-xylene C(sp2)−H bond. The distances
(Å) between the pincer ligand oxygen atom and two hydrogen atoms
of one of the substrate’s methyl groups are shown.
Similarly to phenol and anisole, benzodioxole (8) (Table 1),
containing a methylenedioxo fragment, is more reactive than
F
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benzene. These observations suggest that the catalyst 1 may be
weakly electrophilic overall.
are small. The corresponding higher-temperature values,
ΔG353⧧(DFT/gas phase) and ΔG353⧧(DFT/TFE), have also
been found in our calculations (Tables S1 and S2). These
values follow the same trend (Figure S19), in comparison to
ΔG298⧧(DFT/gas phase) and ΔG298⧧(DFT/TFE) values
discussed next.
The lack of a good correlation in Figure 3 may not be
surprising. The regular σX constants are determined from
proton transfer equilibria (pKa values) of the corresponding X-
substituted benzoic acids, where the electron density change
on the carboxylic group bearing arene carbon atom is
responsible for the reactivity change (“charge control”).14 In
turn, on the basis of the classic mechanistic consideration of
concerted CH oxidative addition to a transition-metal center
such as one involving TSAr‑X (Figure 2), such reactions are
orbital-controlled and, ideally, involve a concerted transfer of
two electrons from the metal d subshell to the σ* orbital of the
substrate C−H bond and a two-electron transfer of the
substrate C−H σ-bond electrons onto a suitable empty metal
orbital.15 Hence, the CH bond oxidative addition to a metal
center represents a substantially different reaction type that
may require the use of a different type of substituent σX
constants (vide infra). The involvement of two oppositely
directed electron flows in C(sp2)−H bond oxidative addition
reactions may result in the absence of a strong dependence
between the reactivity of X-substituted substrates and σX
constants, as observed in Figure 3. Still, in some situations,
the reaction activation energy may be more sensitive to either
“electrophilicity” or “nucleophilicity” of the engaging CH
bond, depending on the nature and the orbital parameters of
the reacting species.
On the basis of the results of our previous work,4 our DFT
calculations of reaction 5 with complex 1 as a reference
compound underestimate the experimental values of the
reaction Gibbs energy of activation by ∼2−3 kcal/mol. This
discrepancy is related to the fact that in neat TFE solutions
complex 1 produces an unknown/not isolable adduct with the
solvent in a slightly exergonic reaction.4 Hence, for more
accurate results, not complex 1 but its TFE adduct should be
viewed as a reference state. This consideration suggests that
the same small correction parameter needs to be added to each
of the DFT-calculated Gibbs energies of activation,
ΔG298⧧(DFT/gas phase) or ΔG298⧧(DFT/TFE), when they
are compared with the experimental values ΔG353⧧(exp). With
this idea in mind, a good match of the Gibbs energies of
activation calculated for the gas-phase reactions, ΔG298⧧(DFT/
gas phase), and the experimental values, ΔG353⧧(exp), can be
obtained when the former values are corrected (increased) by
2.3 kcal/mol (Figure 4a; the solid line with slope 1). Two
types of CH bonds, p-xylene C(sp2)−H bonds and
In this situation, we turned to DFT modeling of the reaction
rate-limiting step and calculations of the Gibbs energy of the
corresponding transition states TSAr‑X to help account for the
available experimental observations.
2.5. DFT Modeling of the Effect of Substituents on
the Kinetics of H/D Exchange Catalyzed by Complex 1.
The Gibbs energies of the formation of the respective
transition states TSAr‑X from 1 and the corresponding
substrates (eq 5) were calculated in this work using the DFT
method employing a PBE16 functional and a relativistic
LACVP** basis set, as implemented in the Jaguar program
package,17 as was done in our previous DFT analysis of
reaction 1 with benzene as a substrate:4
⧧
⧧
1 + Ar−X → {TSAr‐X} + H2O ΔG298
(5)
In addition to the gas phase geometry optimization at the
PBE/LACVP** level of theory with a full frequency analysis
resulting in the corresponding gas phase values ΔG298⧧(DFT/
gas phase), geometry optimizations were also done for TFE
solutions utilizing Poisson−Boltzmann continuum solvation
model (PBF), resulting in the corresponding solution phase
values, ΔG298⧧(DFT/TFE). Due to some difficulties at
geometry optimization of the transition states in TFE, some
conformationally more flexible substrates were not charac-
terized in the liquid phase. The so-produced DFT-calculated
Gibbs energies of activation, ΔG298⧧(DFT/gas phase) and
ΔG298⧧(DFT/TFE), are given in Table 1 for m-CH and p-CH
bonds of monosubstituted benzene derivatives 7, 9−12, 14,
and 15, α- and β-CH bonds of thiophene (16), and o-CH
bonds of fluorobenzene (11), chlorobenzene (12), and p-
xylene (5).
Figure 4. Plot of the DFT-calculated Gibbs energies of activation of
reaction 5 vs the experimental values ΔG353⧧(exp): (a) the gas-phase
calculated ΔG298⧧(DFT/gas phase); (b) the TFE calculated
ΔG298⧧(DFT/TFE). Solid lines are shown for minimal root-mean-
square deviations of the “corrected” DFT-calculated data from the
experimental data with the slope set to 1. Dashed lines are spaced at
the RMS value from the solid lines. Strongly deviating data points for
p-xylene and chlorobenzene o-CH bonds are not shown.
From the calculated gas-phase values, ΔG298⧧(DFT/gas
phase), and the corresponding calculated TFE solution values,
ΔG298⧧(DFT/TFE), given in the last two columns in Table 1,
one can note that in most cases they differ only by 0.1−0.4
kcal/mol. Hence, the calculated solvation effects in reaction 5
G
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chlorobenzene o-CH bonds, are not included in this
correlation, as the steric effects of the substituents in these
substrates, Me and Cl, appear to be overestimated in our DFT
calculations of the reaction 5 Gibbs energy of activation (vide
infra). The 2.3 kcal/mol correction allows us to attain the root-
mean-square deviation (RMS) of the DFT-calculated corrected
values from the experimental values of 0.5 kcal/mol, which is
small, in comparison to some typical accuracies attainable
currently in DFT calculations of organometallic reactions.18 In
turn, the data points for p-xylene and chlorobenzene o-CH
bonds deviate from the solid line on the plot in Figure 4a by
4.2 and 5.7 kcal/mol, respectively, both being greater than
three RMS values. Interestingly, a more “compact” fluorine
substituent does not exhibit such issues. The use of a
dispersion-corrected DFT functional PBE-D319 for single-
point calculations corresponding to the level of theory PBE-
D3/LACVP**//PBE/LACVP** results only in a minor
improvement in this respect (see Tables S3−S6 and Figures
S20 and S21).
With the exception of thiophene α-CH bonds and N,N-
dimethylaniline m-CH bonds, the remaining data in Figure 4a
fall into a relatively narrow range ΔG353⧧(exp) − 2.3 RMS
(RMS = 0.5 kcal/mol); this range is shown in Figure 4a with
two dashed lines with slope 1 each. The point corresponding
to N,N-dimethylaniline may be slightly off of the trend as a
consequence of the ability of this compound to become
involved in an acid−base equilibrium with TFE, so that a
sizable part of N,N-dimethylaniline is converted to the
corresponding cation, which has a different reactivity that is
not accounted for in our DFT modeling. Qualitatively, the
cation derived from N,N-dimethylaniline should be more
electron poor than the aniline itself and, on the basis of the
overall reactivity trend mentioned earlier, be less reactive.
Turning now to the DFT-calculated Gibbs energies of
activation of reaction 5 in TFE solutions, ΔG298⧧(DFT/TFE),
and holding in mind small solvation effects calculated for
reaction 5, as noted earlier, we can obtain an expected good
match of the calculated values and the experimental values,
ΔG353⧧(exp), when the former values are corrected (increased)
by 2.3 kcal/mol (Figure 4b; the solid line with slope 1). The
root-mean-square deviation of the DFT-calculated corrected
values from the experimental values is 0.7 kcal/mol (Figure
4b). Once again, a significant deviation from the solid line in
Figure 4b of the calculated values ΔG298⧧(DFT/TFE) for p-
xylene and chlorobenzene o-CH bonds, by 4.7 and 5.1 kcal/
mol, respectively, may suggest that the DFT model used here
overestimates the steric effects of the Me and Cl fragment in
these substrates in our calculations of the Gibbs energy of
activation of reaction 5.
substituent X, the negative sign is used in front of the
logarithmic function:
σXM = −log(kc(X)/kc(H))
The corresponding σX values are given in Table 2. Except
(6)
M
M
NMe2 group, the series of σX constants in Table 2 is
M
Table 2. Hammett-Type σX Constants for Metal-Assisted
C−H Bond Activation Reactions Based on Rate Constant kc
Data from Table 1
substituent X
OMe
OH
H
Cl
CO2H
0.43
F
NO2
σXM, meta
σXM, para
−0.10
−0.03
0
0
0.33
0.40
0.68
0.72
1.29
0.88
qualitatively similar to that of σX values. An unexpectedly large
positive value was calculated for the NMe2 group, 0.34 (not
shown in Table 2), which may be related to the group’s partial
protonation in TFE solutions, and therefore, this value is not
recommended for general use.
2.7. Regioselectivity of H/D Exchange (Reaction 1).
Notably, the initial regioselectivity of the H/D exchange
observed in reaction 1 typically is low, as follows from an
inspection of the rate constants kc given in Table 1. For
example, for chlorobenzene the kc,o (ortho-CH bonds), kc,m
(meta-CH bonds), and kc,p (para-CH bonds) values fall in a
narrow range of 2.2−3.2 M−1 h−1. For fluorobenzene the
reaction rate constant for o-CH bonds, kc,o = 0.7 M−1 h−1, is
only 2 times lower than the value for its m-CH bonds, kc,m
=
1.3 M−1 h−1, or p-CH bonds, kc,p = 1.43 M−1 h−1, which, in
turn, are very similar.
There are a few notable exceptions from this “low
selectivity” picture. In particular, nitrobenzene o-CH bonds
are virtually unreactive under our reaction conditions,
presumably due to both the electronic and steric effects of
this group, whereas the p-CH bonds, kc,p = 0.9 M−1 h−1, are
somewhat more reactive than the meta-CH bonds, kc,m = 0.35
M−1 h−1.
Two other substrates demonstrating notable positional
selectivity in their CH bond deuteration (1) are N,N-
dimethylaniline and indole. The relatively low reactivity of
m-CH bonds of N,N-dimethylaniline makes it possible to carry
out a selective deuteration of the CH bonds in the ortho and
para positions of this substrate after 27 h of the reaction
(Figure 5). An exclusive deuteration of the indole β-CH bonds
with a virtually statistical 88% degree of deuterium
incorporation was observed in our experiments for indole
(17) after 45 min of reaction.
To illustrate qualitatively some possible reasons behind the
observed (often low) regioselectivity of complex 1 in the H/D
exchange reaction (1) that would be consistent with the
proposed reaction mechanism (Scheme 2), we considered the
following two cases, one involving deuteration of α- vs β-CH
bonds of thiophene (TP) and another involving deuteration of
the m- vs p-CH bonds of nitrobenzene (NB). Experimentally,
the deuteration of thiophene α-CH bonds and the deuteration
of nitrobenzene p-CH bonds is slightly selective (Table 1 and
Chart 2). For thiophene the difference in the reactivity of α-
and β-CH bonds is reproduced qualitatively in our DFT
calculations of the Gibbs energy of activation of reaction 5; for
nitrobenzene the DFT predicts virtually no difference (Table 1
and Figure 4).
2.6. Novel Hammett Constants σXM for Metal-Assisted
C−H Bond Activation Reactions. The inability to describe
substituent effects in the organometallic reaction (5) using
Hammett σX constants and the somewhat limited accuracy of
modern DFT calculations, as demonstrated in Figure 4 and
shown by other researchers,18 prompted us to introduce a new
empirical set of Hammett constants, σXM, for metal-assisted
CH bond activation reactions. Such constants may be useful in
analyzing the reactivity of various metal complexes and
M
substrates in CH activation reactions. Our σX constants are
defined by eq 6. Since reaction 5 is decelerated by electron-
withdrawing groups, for the sake of consistency of the sign of
M
σX values and the sign of classical σX values for the same
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1
Figure 5. H NMR spectra (aromatic region) demonstrating the selectivity of the H/D exchange between N,N-dimethylaniline and wet TFE-d1
catalyzed by complex 1 at 80 °C: (a) before reaction; (b) after 27 h.
To that end, we considered a perturbation molecular orbital
theory approach20 where the two fragments LPt and the
corresponding CH bond of thiophene or nitrobenzene are,
formally, engaged in the interaction in the corresponding
transition states TSAr‑X. First, we consider the difference in the
charges on the atoms of competing CH bonds involved in the
reaction. The DFT-calculated natural charge on the Pt atom in
the LPt fragment is positive, 0.69. Hence, a larger negative
charge on the carbon atom of a reacting CH bond would lead
to a stronger interaction of LPt and the CH bond, a greater
stabilization of the corresponding TSAr‑X, a lower activation
energy, and a higher selectivity with respect to that type of CH
bond. In turn, in the absence of a significant difference in the
charge on the carbon atoms of the competing CH bonds, we
focus on the covalent component of such an interaction. A
stronger interaction of the frontier molecular orbitals (FMOs)
of these fragments, which is proportional to the square of the
FMO resonance integral and inversely proportional to their
energy difference,20 would favor a lower activation barrier.
Considering the natural charges on the carbon atoms of the
thiophene α-CH bond, −0.47, and β-CH bond, −0.30 (the
natural charges on the hydrogen atoms are virtually identical,
+0.26), we can expect a somewhat selective activation of the
substrate’s α-CH bonds. In turn, on qualitative comparison of
the two FMO diagrams in Figure 6, one involving thiophene’s
α-CH bonds (Figure 6a) and one involving thiophene’s β-CH
bonds (Figure 6b), no dramatic difference is expected in terms
of the energy of interactions of the FMOs of the engaged
fragments in these two cases. On the one hand, ΔE2,a (Figure
6a) corresponding to the reaction involving the thiophene α-
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LPt and CH bond fragments in this reaction points to a
somewhat electrophilic character of complex 1.
Considering now the m- and p-CH bonds of free
nitrobenzene, we find virtually identical natural charges on
the H atoms,+0.26, and very similar natural charges on the m-
and p-C atoms, −0.24 and −0.22, respectively. Hence, we can
expect that the Coulombic interactions of the fragments do not
affect the reaction 1 selectivity involving this substrate. In turn,
on qualitative comparison of two FMO diagrams in Figure 7,
Figure 6. Qualitative frontier molecular orbital diagrams illustrating
FMO interactions between frontier orbitals of the LPt fragment and
the corresponding C−H bonds of thiophene: (a) α-CH bonds of
thiophene; (b) β-CH bonds of thiophene.
CH bond is slightly greater than ΔE2,b (Figure 6b)
corresponding to the reaction of the thiophene β-CH bond.
On the other hand, the α-CH HOMO is more localized
between the bonded α-C and H atoms, thus favoring a slightly
stronger interaction of the α-CH HOMO with the LUMO of
the LPt fragment. Therefore, we can speculate that the latter
orbital interactions may favor a lower energy of activation and
a faster α-CH bond cleavage, thus reinforcing the effect of the
Coulombic interactions. Overall, this qualitative perturbation
molecular orbital theory analysis predicts a faster cleavage of
the thiophene’s α-CH bonds, as observed, with kc,α = 18 M−1
h−1 and kc,β = 10 M−1 h−1 (Table 1). Also, the above discussion
of the importance of the Coulombic interactions between the
Figure 7. Qualitative frontier molecular orbital diagrams illustrating
FMO interactions between frontier orbitals of the LPt fragment and
the corresponding C−H bonds of nitrobenzene: (a) m-CH bonds of
nitrobenzene; (b) p-CH bonds of nitrobenzene.
J
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one involving nitrobenzene’s m-CH bonds (Figure 7a) and one
involving nitrobenzene’s p-CH bonds (Figure 7b), two
is distinct from CH bond oxidative addition to a Pt(II) center
in this work.
hypotheses can be made. First, in both cases the LPtLUMO
−
A qualitative comparison of the extent of deuteration x in
Chart 2 with that for identical substrates after 24 h of reaction
reported in ref 9 shows some similarities and some differences.
For example, for one of the more reactive substrates, anisole
(7), after 28 h of reaction the catalyst 1 allows for a lower
extent of o-CH deuteration (31%), in comparison to 36/
AgOTf (77%), whereas the extent of deuteration of m- and p-
CH bonds is about the same, 53−62% in the presence of
complex 1/TFE-d1 and 64% (on average) in the 36/AgOTf/
CF3CO2D system.
For another reactive substrate, phenol (9), after 24 h of
reaction both systems show almost identical performance and
the lack of selectivity with respect to phenol’s o-, m-, or p-CH
bonds: 67% deuteration for o-CH and 69% deuteration, on
average, for m- and p-CH bonds for complex 1/TFE-d1 system
vs 55% (o-CH) and 62% (m- and p-CH bond average) for the
complex 35/AgOTf/CF3CO2D system.
Notably, the reactivity of N,N-dimethylaniline (10, )is
higher when the less acidic system 1/TFE-d1 is employed, in
comparison to the 35/AgOTf/CF3CO2D system.9 In partic-
ular, after 25 h of reaction with 1/TFE-d1 the extent of
deuteration of the substrate’s m-CH bonds is 14%; it is 75% for
o-CH bonds and 77% for p-CH bonds, which corresponds to
51%, on average, for all of the substrate C(sp2)−H bonds. In
turn, a 25% average extent of deuteration was achieved with
35/AgOTf/CF3CO2D. It appears that the protonation of the
basic dimethylamino fragment of 10 transforms it into an
electron-withdrawing ammonium group, thus causing the
reaction to slow.
Interestingly, a higher extent of deuteration by the complex
1/TFE-d1 system, in comparison to 35/AgOTf/CF3CO2D,
was observed after similar reaction times for electron-poor
chlorobenzene. The average degree of deuteration for all arene
C(sp2)−H bonds is 39% in the first system and 2.6% in the
second system.
2.8. Ibuprofen and Naproxen Substrates. Driven by
curiosity as to whether our 1/TFE-d1 system can be used for
deuteration of some pharmaceutical compounds containing
C(sp2)−H bonds, we tested two over the counter medications,
ibuprofen (33) and naproxen (34) (Chart 4). Due to their low
solubility in TFE, a 1/1 (v/v) mixture of wet TFE-d1 and
CDCl3 was used instead. The resulting homogeneous solutions
containing catalyst 1 were subjected to the reaction at 80 °C.
Similar to the reaction involving benzoic acid, a fine yellow
precipitate was observed in ibuprofen-containing solutions
already after 3 h. At this time the reaction was stopped to
reveal a negligible (<2%) deuterium incorporation. The
probable reasons behind this low reactivity are the rapid
catalyst deactivation and some steric interference between the
catalyst and the substituents present in this substrate which are
in a position ortho to the available C(sp2)−H bonds. In the
case of naproxen the catalyst deactivation was also observed
but only after 20 h and the reaction resulted in an average 9%
deuterium incorporation per C(sp2)−H bond with a low
overall selectivity with respect to six distinct types of CH
bonds (Chart 4). This result shows some promise of a future
possible application of the 1/TFE-d1 system for deuteration of
some pharmaceutical compounds containing aromatic CH
bonds.
NBHOMO gap, ΔE2, is smaller than the LPtHOMO−NBLUMO gap,
ΔE1, thus suggesting that the first interaction may be more
important and the LPt fragment is somewhat electrophilic in
its behavior even with respect to electron-poor nitrobenzene.
Second, the HOMO−LUMO energy gap ΔE2,p (Figure 7b)
corresponding to the reaction involving the nitrobenzene p-
CH bond is slightly greater than ΔE2,m (Figure 7a)
corresponding to the cleavage of the nitrobenzene m-CH
bond. At the same time, the p-CH HOMO is more localized
between the bonded p-C and -H atoms, allowing for a better
orbital overlap of the p-CH HOMO with the LPt LUMO.
Hence, we speculate that the latter factor is more important.
Therefore, this qualitative perturbation molecular orbital
theory analysis suggests an “orbital-controlled” slight kinetic
preference of the p-CH bond cleavage, as observed
experimentally: kc,p = 0.9 M−1 h−1 vs kc,m = 0.35 M−1 h−1.
Overall, depending on the type of a CH bond donor and the
nature of a metal fragment engaged in a reaction, one needs to
consider the contributions to the reaction activation energy of
the Coulombic interactions of the fragments (ultimately, a
“charge controlled” reactivity) and/or their FMO interactions
(ultimately, “orbital-controlled” reactivity).20 Driven by this
conclusion, we found that, similar to the case for thiophene, in
reaction 1 involving indole the observed exclusive selectivity
with respect to the substrate’s β-CH vs α-CH bonds is likely a
consequence of the enhanced Coulombic interactions of the
LPt and β-CH bond fragments (“charge control”): the natural
charge on the indole β-C atom is −0.32, in comparison to
−0.06 on its α-C atom, and the natural charges on the
respective hydrogen atoms are almost identical, 0.26 and 0.24.
The results of our analysis of the reaction 1 selectivity
involving complex 1 would be interesting to compare with
those of other transition-metal-based systems. Although it may
be valuable for some practical applications,3 in general, the
kinetic selectivity of H/D exchange in substituted benzenes has
not been systematically analyzed in previous works. In turn, the
practically important extent and selectivity of deuteration of
aromatic substrates at the late stage of the reaction have been
reported for some catalytic systems7,9 and can be compared
with our results included in Chart 2.
In one of the recent works, the anionic rhodium(III)
complex Na[(bpzmc)RhCl3] (36; Chart 5) in combination
Chart 5. Rh(III) Complex 36 Used in Combination with 3
Equiv of AgOTf for Catalytic H/D Exchange between
Substituted Benzene Substrates and CF3CO2D at 100 °C9
with 3 equiv of AgOTf was used as a catalyst in H/D exchange
between a number of aromatic substrates and CF3CO2D at 100
°C.9 The CH activation in this system was proposed to operate
by a concerted metalation−deprotonation mechanism, which
K
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Complete contact information is available at:
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CONCLUSION
■
As a result of this work, a wide range of arene substrates were
tested in catalytic H/D exchange with TFE-d1 solvent
catalyzed by the Pt(II) pincer complex 1 (Charts 2−4).
(Het)arene substrates and their derivatives with relatively
weekly coordinating functional groups can be efficiently
deuterated (Chart 2), whereas substrates that are either not
chemically robust in the presence of 1, or strongly coordinate
1, or too electron poor cannot be deuterated (Chart 3). By
monitoring the initial stage of the H/D exchange, we were able
to measure the corresponding initial reaction rates and, often,
characterize the reaction kinetics selectively for different types
of C(sp2)−H bonds involved (Table 1). A moderate to very
high positional kinetic selectivity was observed for a few
substrates, N,N-dimethylaniline, nitrobenzene, and indole,
whereas for the rest of the substrates the selectivity is low.
An almost “statistical” deuterium distribution between the
substrate reactive C(sp2)−H bonds and TFE-d1 solvent that
corresponds to 67−88% deuterium incorporation could be
achieved for the most active compounds, phenol, indole, and
N,N-dimethylaniline, after 45 min (indole) to 24 h. An attempt
to use the 1/TFE-d1/CDCl3 system for deuteration of the
pharmaceutical compounds ibuprofen and naproxen (Chart 4)
was only successful for the latter, which has relatively
unencumbered C(sp2)−H bonds, albeit with a low 9% average
deuterium incorporation after 20 h, which still may be an
acceptable level in some labeling experiments.3 Notably, our
attempts to correlate the Gibbs energies of activation of the H/
D exchange involving X-monosubstituted benzene derivatives
with the corresponding Hammett meta and para σX constants
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CHE-1800089). The authors thank Dr. Phil DeShong for the
idea of possible applications of complex 1 for the catalytic
deuteration of pharmaceuticals.
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resulted in a lack of good correlation and prompted us to
M
introduce a new set of empirical Hammett constants, σX
,
which may be useful in the future research of metal-assisted
C−H bond activation reactions. Finally, a DFT modeling of
the H/D exchange reaction demonstrates a satisfactory match
of the experimentally found and calculated Gibbs energies of
activation for the reactions involving m- and p-CH bonds of
substituted benzenes, as well as the CH bonds of thiophene.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge on the
ACS Publications Web site at DOI: (PDF and XYZ). The
Supporting Information is available free of charge at https://
pubs.acs.org/doi/10.1021/acs.organomet.0c00652.
NMR spectra and computational details (PDF)
Cartesian coordinates of the calculated structures (XYZ)
AUTHOR INFORMATION
Corresponding Author
■
(10) (a) Jones, W. D. Alkane Activation Processes by Cyclo-
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Palladium-catalyzed ortho-selective C-H deuteration of arenes:
Andrei N. Vedernikov − Department of Chemistry and
Biochemistry, University of Maryland, College Park,
Maryland 20742, United States; orcid.org/0000-0002-
7371-793X; Email: avederni@umd.edu
Authors
Morgan Kramer − Department of Chemistry and
Biochemistry, University of Maryland, College Park,
Maryland 20742, United States
David Watts − Department of Chemistry and Biochemistry,
University of Maryland, College Park, Maryland 20742,
United States
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