Aromatic C?H Hydroxylation Reactions with Hydrogen Peroxide Catalyzed by Bulky Manganese Complexes

Article abstract of DOI:10.1002/adsc.202001590

The oxidation of aromatic substrates to phenols with H₂O₂ as a benign oxidant remains an ongoing challenge in synthetic chemistry. Herein, we successfully achieved to catalyze aromatic C?H bond oxidations using a series of biologically inspired manganese catalysts in fluorinated alcohol solvents. While introduction of bulky substituents into the ligand structure of the catalyst favors aromatic C?H oxidations in alkylbenzenes, oxidation occurs at the benzylic position with ligands bearing electron-rich substituents. Therefore, the nature of the ligand is key in controlling the chemoselectivity of these Mn-catalyzed C?H oxidations. We show that introduction of bulky groups into the ligand prevents catalyst inhibition through phenolate-binding, consequently providing higher catalytic turnover numbers for phenol formation. Furthermore, employing halogenated carboxylic acids in the presence of bulky catalysts provides enhanced catalytic activities, which can be attributed to their low pK_a values that reduces catalyst inhibition by phenolate protonation as well as to their electron-withdrawing character that makes the manganese oxo species a more electrophilic oxidant. Moreover, to the best of our knowledge, the new system can accomplish the oxidation of alkylbenzenes with the highest yields so far reported for homogeneous arene hydroxylation catalysts. Overall our data provide a proof-of-concept of how Mn(II)/H₂O₂/RCO₂H oxidation systems are easily tunable by means of the solvent, carboxylic acid additive, and steric demand of the ligand. The chemo- and site-selectivity patterns of the current system, a negligible KIE, the observation of an NIH-shift, and the effectiveness of using ^tBuOOH as oxidant overall suggest that hydroxylation of aromatic C?H bonds proceeds through a metal-based mechanism, with no significant involvement of hydroxyl radicals, and via an arene oxide intermediate. (Figure presented.).

Full text of DOI:10.1002/adsc.202001590

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DOI: 10.1002/adsc.202001590
Very Important Publication
Aromatic CÀ H Hydroxylation Reactions with Hydrogen Peroxide
Catalyzed by Bulky Manganese Complexes
Eduard Masferrer-Rius,a Margarida Borrell,b Martin Lutz,c Miquel Costas,b and
Robertus J. M. Klein Gebbinka,*
a
Organic Chemistry and Catalysis, Debye Institute for Nanomaterials Science, Utrecht University, Universiteitsweg 99, 3584 CG
Utrecht, The Netherlands
Phone: (+31)-30-2531889;
E-mail: r.j.m.kleingebbink@uu.nl
Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de Girona, Campus Montilivi, E-
b
17071 Girona, Catalonia, Spain
Structural Biochemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The
c
Netherlands
Manuscript received: December 22, 2020; Revised manuscript received: February 18, 2021;
Version of record online: ■■■, ■■■■
© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
Abstract: The oxidation of aromatic substrates to phenols with H2O2 as a benign oxidant remains an ongoing
challenge in synthetic chemistry. Herein, we successfully achieved to catalyze aromatic CÀ H bond oxidations
using a series of biologically inspired manganese catalysts in fluorinated alcohol solvents. While introduction
of bulky substituents into the ligand structure of the catalyst favors aromatic CÀ H oxidations in alkylbenzenes,
oxidation occurs at the benzylic position with ligands bearing electron-rich substituents. Therefore, the nature
of the ligand is key in controlling the chemoselectivity of these Mn-catalyzed CÀ H oxidations. We show that
introduction of bulky groups into the ligand prevents catalyst inhibition through phenolate-binding,
consequently providing higher catalytic turnover numbers for phenol formation. Furthermore, employing
halogenated carboxylic acids in the presence of bulky catalysts provides enhanced catalytic activities, which
can be attributed to their low pKa values that reduces catalyst inhibition by phenolate protonation as well as to
their electron-withdrawing character that makes the manganese oxo species a more electrophilic oxidant.
Moreover, to the best of our knowledge, the new system can accomplish the oxidation of alkylbenzenes with
the highest yields so far reported for homogeneous arene hydroxylation catalysts. Overall our data provide a
proof-of-concept of how Mn(II)/H2O2/RCO2H oxidation systems are easily tunable by means of the solvent,
carboxylic acid additive, and steric demand of the ligand. The chemo- and site-selectivity patterns of the
t
current system, a negligible KIE, the observation of an NIH-shift, and the effectiveness of using BuOOH as
oxidant overall suggest that hydroxylation of aromatic CÀ H bonds proceeds through a metal-based mechanism,
with no significant involvement of hydroxyl radicals, and via an arene oxide intermediate.
Keywords: Aromatic CÀ H oxidation; Bioinspired oxidation; Fluorinated alcohol solvents; Halogenated
carboxylic acids; Manganese catalysts; Phenols
chemical industry. The interest mainly arises from the
fact that the oxygenated organic molecules can be
Introduction
Oxidations of organic compounds are essential reac- further used to produce different classes of valuable
tions widely studied in academia as well as in the chemicals, such as pharmaceuticals. Despite many
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research efforts, the selective oxidation of organic supported by a tripodal tetradentate aminopyridine
substrates still represents a critical challenge in ligand in the direct hydroxylation of aromatics using a
synthetic chemistry. For instance, the direct one-step significant excess of oxidant (Figure 1).[4a] High TONs
hydroxylation of aromatic molecules to the corre- were only achieved using extremely low concentra-
sponding phenols could provide easy access to relevant tions of catalyst under long reaction times; yet,
building blocks for more complex molecules, thereby absolute yields of phenol products did not exceed
representing a highly desired reaction.
7.5%. Remarkably though, when the complex was
To date, several bioinspired iron and manganese used at 10 mol% loading with respect to the substrate,
complexes have been shown to perform aliphatic CÀ H 21% phenol yield was formed (2 turnovers per
oxidations[1] as well as olefin oxidation reactions,[2] nickel).[4a,5] Later, Kodera et al. described a dinuclear
whereas hydroxylation of aromatic compounds has copper complex as catalyst for the hydroxylation of
remained an ongoing issue since recent years.[3] In aromatics, showing good selectivities for phenol
earlier studies, an iron complex supported by the tpa products (Figure 1).[4b] Again, an elevated TON
ligand (tpa=tris(2-pyridylmethyl)amine) was found to (12,550) was obtained at a low catalyst concentration,
be capable of stoichiometrically oxidizing ligated with phenol yields up to 21% for benzene oxidation.
perbenzoic acids through the self-hydroxylation of the Di Stefano et al. reported an iminopyridine iron
aromatic
ring,
forming
iron(III)-salicylate complex capable of oxidizing aromatic substrates, as
complexes.[3a] Also, an iron complex based on the well as aromatic amino acids, under mild reaction
bpmen ligand (bpmen=N,N’-dimethyl-N,N’-bis(2-pi- conditions (Figure 1).[3g,6] However, for all these exam-
colyl)ethylenediamine) showed activity for the hydrox- ples, aromatic oxidation of alkylbenzenes is effectively
ylation of aromatic compounds using H2O2, although accompanied by benzylic hydroxylation. In addition,
strong coordination of phenolates to the iron(III) center recently reported nickel, copper and cobalt complexes
prevented efficient catalysis.[3b,d] An iron complex supported by aminopyridine ligands accomplished the
supported by a N-heterocyclic carbene ligand has been oxidation of benzene to phenol in improved yields
shown to be cable of hydroxylating benzene and (29–41%) (Figure 1).[4e–g]
alkylbenzenes with H2O2 as well, albeit at low
Previously, we have shown that bulky iron com-
conversions and yields for phenol products, and with plexes with tips moieties (tips = tris-(isopropyl)silyl)
the formation of benzylic oxidized products from catalyze the site-selective oxidation of alkyl CÀ H
alkylbenzene substrates.[3e,h] Recent research progress bonds with H2O2, affording high product yields and
indicates that iron complexes supported by bpbp-type enhanced preferential oxidation of secondary over
ligands (bpbp=N,N’-bis(2-pyridylmethyl)-2,2’-bipyr- tertiary CÀ H bonds.[1i] Likewise, manganese complexes
rolidine) can hydroxylate aromatic substrates with supported by aminopyridine ligands catalyze chemo-
H2O2.[3i,j,o] However, overoxidation products and mod- and enantioselective aliphatic CÀ H oxidations with
est selectivities for oxidation of the aromatic ring were H2O2.[1f,j,k,o–r,t,7] Recently, White et al. reported that a
observed, resulting in mixtures of products in which
oxidation has taken place on aromatic as well as
aliphatic positions. A manganese complex supported
by the Bn-TPEN ligand (Bn-TPEN=N-benzyl-
N,N’N’-tris(2-pyridylmethyl)-1,2-diaminoethane) has
been found to oxidize naphthalene, among other
substrates, with iodosylbenzene as oxidant.[3p] How-
ever, efficient catalytic turnover numbers (TON) were
not achieved. Later, a manganese tpa complex incorpo-
rated into mesoporous silica-alumina was described to
be active in the selective hydroxylation of benzene
derivatives with H2O2.[3q] Interestingly, incorporation of
the complex into the mesoporous support was neces-
sary to get useful catalytic activities. Very recently,
intramolecular aromatic hydroxylation, as well as
intermolecular hydroxylation of benzene to phenol, has
been demonstrated with an iron complex based on the
Bn-TPEN ligand through OÀ O bond heterolysis of an
Fe(III)À OOH species to form an Fe(V)=O oxidant.[3n]
Other transition-metal complexes have also been
developed as homogeneous catalysts for aromatic CÀ H
oxidations with H2O2 as the oxidant.[4] Itoh et al.
Figure 1. Examples of metal complexes previously employed
in aromatic CÀ H hydroxylation reactions with H2O2.
demonstrated the catalytic ability of a nickel complex
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bulky manganese complex with pendant o-CF3-sub- Results and Discussion
stituted aryl rings can oxidize methylene groups in the
Aliphatic vs Aromatic CÀ H Oxidation
presence of aromatic functionalities.[1u] The authors
also report non-productive aromatic substrate oxidation For our study we have investigated complexes of the
as a side-reaction. Finally, fluorinated alcohols have type [M(OTf)2(L)] based on the bpmcn, bpbp, bpbi and
recently been shown to be suitable solvents for bpmen ligand families (Scheme 1) (bpmcn=N,N’-
oxidation chemistry, preserving the first-formed alco- dimethyl-N,N’-bis(2-picolyl)-cyclohexane-trans-1,2-di-
hol products and, thus, reducing overoxidation amine, bpbi=N,N’-bis(2-picolyl)-2,2’-bis-isoindoline).
reactions.[1o,7a,8]
We have included manganese complexes containing
Herein, we focus on the use of bioinspired electron-rich, as well as bulky pyridines.
manganese complexes for the oxidation of aromatic
Initially, we focused our attention on the hydrox-
substrates. We demonstrate that the application of ylation of propylbenzene as substrate using 1 mol% of
bulky Mn catalysts in the presence of fluorinated Mn(tipsbpmcn), Mn(dMMbpmcn), or Mn(bpmcn) as
alcohol solvents favors oxidation at the aromatic ring catalyst (Table 1). Catalytic oxidation reactions were
over the oxidation of benzylic positions, providing an carried out by mixing the Mn(II) catalyst and AcOH
improved route to produce phenols. On the basis of (2 equiv.) into a solution of propylbenzene (1 equiv.) in
°
previous literature examples which propose that prod- TFE (TFE=2,2,2-trifluoroethanol) at 0 C. A sub-
uct inhibition through metal-phenolate binding pre- stoichiometric amount of aqueous H2O2 (0.5 equiv.,
vents catalytic turnover in aromatic oxidation reac- 35% w/w solution) was added dropwise through a
tions, we rationalized that the presence of bulky tips syringe pump over a period of 30 min. Interestingly,
groups in position 5 of the pyridine rings may help in chemoselectivity was found to be largely dependent on
preventing product inhibition. Our study also shows the catalyst used. The bulky manganese complex
that the yields of the aromatic reactions are further Mn(tipsbpmcn) favors the oxidation at the aromatic
improved by using halogenated carboxylic acids as ring, providing the para-phenol as the major product,
additives, which in part can be attributed to their lower together with ortho-phenol and propyl-p-benzoquinone
pKa values which reduces product inhibition through a as minor products. Some 1-phenyl-1-propanol was also
favorable acid-base equilibrium between the carboxylic detected as minor product in this case, showing a ratio
acid and the (substituted) phenol products. Overall, our of aromatic:aliphatic oxidation of 7.3:1. In contrast,
study has resulted in the development of a selective when the electron-rich catalyst Mn(dMMbpmcn) was
manganese-based catalyst system that performs arene used the chemoselectivity changed completely, and
hydroxylation reactions with H2O2 as a benign oxidant preference for the oxidation at the benzylic position
with improved yields of (substituted) phenol products was observed with a ratio of aromatic:aliphatic
with respect to the previously described homogeneous oxidation products of 1:13.5. This observation is in
catalysts.
agreement with previous reports on the use of electron-
Scheme 1. Manganese and iron complexes employed in this work.
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Table 1. Oxidation of propylbenzene in TFE with different manganese catalysts.
Catalyst
r.s.m[a]
p-Phenol[b]
o-Phenol[b]
Quinone[b]
Alcohol[b]
Ketone[b]
MB[c]
Ratio[d]
Mn(tipsbpmcn)
Mn(dMMbpmcn)
Mn(bpmcn)
68
65
72
9 (18)
1 (2)
3 (6)
1 (3)
n.d.
1 (2)
2 (8)
n.d.
3 (11)
2 (4)
12 (23)
4 (9)
n.d.
1 (4)
n.d.
88
85
89
7.3:1
1:13.5
2.1:1
[a] Remaining starting material (r.s.m) in %.
[b] Yields in % with respect to substrate determined by GC against an internal standard. In parenthesis yields in % with respect to
H2O2. Yields are calculated considering that 2 equiv. of H2O2 are necessary for the formation of the ketone and quinone products.
[c] Mass balance (MB) was calculated considering remaining starting material and all products formed, plus a percentage of substrate
loss calculated with blank experiments (an average of 6% of substrate is lost): MB=(r.s.m %)+(Product Yields %)+(Substrate
loss).
[d] Ratio (aromatic:aliphatic)=[n(p-phenol)+n(o-phenol)+n(quinone)]/[n(alcohol)+n(ketone)]. n.d.=non-detected.
rich manganese complexes for asymmetric benzylic Kodera,[4b] we can conclude that the current system
oxidations, where no aromatic oxidation products were performs the hydroxylation of an alkylbenzene with
detected.[1o,7a,8f] With the parent Mn(bpmcn) complex, yields commensurate to state-of-the-art homogeneous
we observed both oxidation at the aromatic ring as catalysts, at a relatively low catalyst loading. Further-
well as at the benzylic position in a ratio of 2.1:1, more, the nature of the ligand in the current system
respectively, showing a slight preference for aromatic seems key for diverting the chemoselectivity of the
oxidation.
catalyst from oxidation of the more activated benzylic
Worthy of note are the blue colors that progres- position to the hydroxylation of the aromatic ring,
sively form in the reaction mixtures after starting the showing a catalyst dependent selectivity. Yet, overall
addition of H2O2 to the reaction mixture containing the the reactions shown in Table 1 suffer from moderate
substrate and the catalyst (Mn(tipsbpmcn) or Mn- conversions and yields, but do show reasonable mass
(bpmcn)). We hypothesize that these colors are due to balances. Noteworthy is that blank experiments with-
charge transfer bands arising from phenolate binding out catalyst showed that a certain amount of substrate
to the Mn center, which in turn inhibits the catalyst and is lost during the reaction and analysis protocol (~6%).
prevents further catalytic turnover.[9] Consistent with This loss was taken into account to calculate the mass
this hypothesis, ESI-MS analysis of a mixture of balances in Table 1.
Mn(tipsbpmcn) (1 mol%), tert-butylbenzene (1 equiv.),
°
AcOH (2 equiv.) and H2O2 (1 equiv.) at 0 C in TFE
showed a main peak at m/z = 493.8060, which
Screening of Catalysts
corresponds to the formation of a complex ion Based on these results, we selected bulky manganese
composed of a Mn(tipsbpmcn) fragment and a coupled complexes with different amine backbones for further
bis(phenolate) fragment ([Mn(tipsbpmcn)(C6H3OC- screening for the oxidation of aromatic CÀ H bonds
(CH3)3)2]2+, calcd m/z 493.8064) (SI, Section 5.7, (Scheme 1). A bulky iron complex, Fe(tipsbpmcn), was
Figure S11). Importantly, the blue color was observed also included in our study. The parent complexes
immediately after the start of H2O2 addition in the case without any substituents on the pyridines were consid-
of Mn(bpmcn), whereas for the reaction with Mn- ered as well. For all cases, the metal center adopts a
(tipsbpmcn) the blue color appears later in the course of C2-symmetric cis-α topology, with the two pyridines
the reaction. These observations lead us to believe that trans to each other. A new manganese complex
the bulky tips groups help in preventing phenolate supported by a bulky tripodal tetradentate ligand based
binding, and thus allow for higher catalytic turnover on the tpa motif (5À tips3tpa)[2m] was also included.
numbers. A control experiment without an aromatic
substrate did not show the appearance of the blue since it lacks benzylic CÀ H bonds to selectively screen
colors described above. for activity in aromatic oxidation. Using stoichiometric
Tert-butylbenzene was used as a model substrate
Comparing our result on arene hydroxylation amounts of H2O2, crude mixtures were analyzed by
catalyzed by Mn(tipsbpmcn) with previous literature GC, detecting mainly 4-tert-butylphenol as the oxi-
examples, such as the systems described by Itoh[4a] and dized product, next to unreacted substrate. Interest-
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ingly, no ortho-hydroxylation product was observed, which translates in a much lower catalytic efficiency
which is in contrast to, e.g., the oxidation of tert- for the iron catalysts. Accordingly, we focused our
butylbenzene catalyzed by an iminopyridine Fe(II) study exclusively on the use of manganese complexes
complex.[3g] In general, poor mass balances were as catalysts. Complex Mn(5À tips3tpa), which bears a
observed for these reactions. We believe that a side sterically encumbered tripodal tetradentate aminopyr-
reaction might happen, leading to overoxidized by- idine ligand based on the tpa scaffold, also provided a
products, which we have not been able to identify yet. poor 4-tert-butylphenol yield (SI, Table S1, entry 11),
However, interest was focused here on the formation indicating that the use of linear tetradentate amino-
of the phenol product. First, a screening of different pyridine ligands with a cis-α topology seems preferred
solvents was done (Scheme 2). Next to TFE, HFIP over the use of tripodal ligands. Manganese triflate
(HFIP=1,1,1,3,3,3-hexafluoro-2-propanol) was found was also tested as catalyst, showing no reaction.
to be an appropriate solvent as well, allowing similar
Catalyst Mn(tipsbpmcn) was then chosen for further
phenol formation as TFE. Interestingly, acetonitrile is reaction optimization (SI, Table S2) since it showed
not a suitable solvent, showing no formation of the the better selectivity for phenol production. However,
desired phenol product. The positive effect of using at this point yields for phenol product were still modest
fluorinated alcohol solvents may be attributed to their (up to 15% yield).
strong hydrogen donor ability, which decreases the
nucleophilicity of the phenol, thereby allowing higher
catalytic turnover numbers by hampering product
Carboxylic Acid Additives
inhibition. These findings inspired us to use manganese Carboxylic acids have been investigated in detail as
complexes in the presence of fluorinated alcohol additives in H2O2-mediated oxidation catalysis. We
solvents in further investigations.
found that very low phenol product formation was
Next, we proceeded to screen the different com- observed when the oxidation of tert-butylbenzene was
plexes shown in Scheme 1 using TFE as the solvent run without the addition of any carboxylic acid,
(SI, Table S1). Overall, complexes bearing bulky, tips- showing that this additive is crucial for reactivity
appended ligands exhibited a better catalytic activity, (Table 2, entry 1). As previously discussed in the
showing higher conversion and phenol production literature, catalysis might proceed through a “carbox-
compared to their parent complexes. Maximum yields ylic acid-assisted” pathway, in which the acid helps in
for the 4-tert-butyphenol product were obtained using the heterolytic cleavage of the OÀ O bond of a Mn(III)
Mn(tipsbpmcn), Mn(tipsbpbi), and Mn(tipsbpmen) (SI, hydroperoxo intermediate to form a Mn(V) oxo
Table S1, entry 2, 7 and 9), whereas the other com-
plexes show good conversions but lower yields. The
Table 2. Oxidation of tert-butylbenzene using different carbox-
current findings suggest the relevance of steric effects
in aromatic hydroxylation reactions, whereas electronic
effects may play a less important role. We believe that
product inhibition in complexes with bulky ligands
occurs to a lower extent in comparison to complexes
with non-bulky ligands. Besides, iron complex Fe-
(tipsbpmcn), supported by a bulky bpmcn ligand,
provided a poor yield (SI, Table S1, entry 3). Iron
complexes with N4 ligands have been reported as
catalysts for aromatic oxidation by Bryliakov and co-
workers.[3j,k] Yet, we believe that product inhibition in
these catalysts through phenolate-iron coordination is
more prominent than with our manganese complexes,
ylic acids.[a]
Entry
Carboxylic acid
(2 equiv.)
4-tert-butylphenol yield
(%)[b]
1
2
3
–
4
13
6
Acetic acid
Propionic acid
4
Butyric acid
6
5
Isobutyric acid
3
6
Pivalic acid
1
7
8
9
2-ethylhexanoic acid
Chloroacetic acid
Dichloroacetic acid
Trichloroacetic acid
Fluoroacetic acid
Difluoroacetic acid
Trifluoroacetic acid
Iodoacetic acid
5
26
29
2
26
21
n.d.
6
2
23
25
10
11
12
13
14
15
16
17
N,N-dimethylglycine
2-nitrobenzoic acid
3-nitrobenzoic acid
[a]
Reaction conditions: Mn(tipsbpmcn):H2O2:substrate:
°
RCO2H=1:100:100:200, in HFIP at 0 C.
[b] Conversion and yields determined from crude reaction
mixtures by GC. n.d.=non-detected.
Scheme 2. Oxidation of tert-butylbenzene in different solvents.
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species, responsible for the oxidation of the aromatic
substrate.[1m,10] Alternatively, the acid could also help in
CÀ H bond activation, as in acetate-assisted CÀ H
activation with palladium.[11] Since the introduction of
bulky substituents in the ligand has been found to be a
key feature in order to obtain catalytic turnover, several
bulkier carboxylic acids were tested. Carboxylic acids
with longer alkyl chains, i.e. propionic acid and
butyric acid, showed lower phenol formation compared
to acetic acid (Table 2, entries 3 and 4). When bulkier
carboxylic acids such as isobutyric acid, pivalic acid,
and 2-ethylhexanoic acid were tested, yields for the
desired oxidized product also decreased (Table 2,
entries 5, 6 and 7). Therefore, our findings show that
the introduction of bulk into the carboxylic acid
additive decreases product formation. Similar trends
were observed when either HFIP or TFE were used as
solvent (SI, Table S3-S6 and Figure S3-S6).
Figure 2. Effect of pKa of the carboxylic acid additive on the
hydroxylation of tert-butylbenzene. Reaction conditions: Mn-
(
tipsbpmcn):H2O2:substrate:RCO2H=1:100:100:200, in HFIP at
°
0 C.
Next, we considered the use of halogenated
carboxylic acids, which have been used previously in
oxidation reactions.[1u,7d,12] Interestingly, we have found
that chloroacetic acid, dichloroacetic acid, fluoroacetic poor yield for the desired phenol product, as well as
acid, and difluoroacetic acid afford a significant low substrate conversion (Table 2, entry 15). Thus, we
increase in yield for the desired phenol product, with can conclude that steric bulk on the carboxylic acid
up to 29% 4-tert-butylphenol yield (Table 2, entry 9). additive is detrimental for the arene hydroxylation
The reason of this improvement could be related to the reaction, and that there is an optimum pKa of the acid
pKa of the carboxylic acids, which varies significantly additive.
within the series of tested aliphatic carboxylic acids.
While it may be initially regarded as a modest
The role of the lower pKa of these carboxylic acids in value, the 29% yield obtained for 4-tert-butylphenol in
arene hydroxylation reactions could be twofold. First, a completely site selective manner is remarkable when
it keeps the phenol products protonated, which compared with literature precedents; a recently re-
hampers catalyst deactivation by phenolate binding. ported iminopyridine Fe(II) catalyst has been shown to
Second, the electron-withdrawing character of these be capable of oxidizing tert-butylbenzene to 4-tert-
acids makes the proposed Mn(V) oxo species more butylphenol in 23% yield, together with the ortho-
electrophilic, which may result in a more reactive phenol and benzoquinone as minor products, which at
oxidant towards arenes. The use of nitrobenzoic acids that time were the highest numbers reported for tert-
also lead to increased phenol formation compared to butylbenzene oxidation.[3g]
the use of acetic acid. However, in these cases side-
Further investigations on the effect of halogenated
product formation through arene hydroxylation of the carboxylic acids showed that the conversion and yield
nitrobenzoic acid was observed. In the presence of do not drastically change between 0.5 to 8 equiv. of
halogenated carboxylic acids higher catalytic activities acid when Mn(tipsbpmcn) is used as catalyst (SI,
were achieved in HFIP compared to TFE (SI, Table S3 Table S5 and Figure S5). This allows catalysis to be
and S6).
Increasing the acidity has a positive effect, going
performed at a much lower carboxylic acid loading.
Next, bulky manganese complexes with different
from acetic acid (pKa =4.76) to 3-nitrobenzoic acid amine backbones in the ligand structure were tested in
(pKa =3.46), chloroacetic acid (pKa =2.87), fluoro- the aromatic hydroxylation of tert-butylbenzene using
acetic acid (pKa =2.59), 2-nitrobenzoic acid (pKa = optimized chloro- and dichloroacetic acid loadings
2.17) and dichloroacetic acid (pKa =1.35) (Fig- (Figure 3). The use of chloroacetic acid afforded
ure 2).[13] However, the use of trichloroacetic acid similar efficiencies for the four catalysts tested, Mn-
(pKa =0.66) or trifluoroacetic acid (pKa =0.52) lead to (tipsbpmcn) being the one that showed better conver-
a dramatic decrease in catalytic activity, which might sion and yield. For dichloroacetic acid, we observed
be due to protonation of the amine moieties of the that Mn(tipsbpmcn) and Mn(tipsbpbp) performed best,
ligand. Iodoacetic acid (pKa =3.18) provided good with Mn(tipsbpmcn) showing significantly higher con-
conversion but a poor phenol yield, which could be version and yield. In contrast, Mn(tipsbpbi) and Mn-
explained by the weaker C-halogen bond that may lead (tipsbpmen) showed very poor results when using
to side reactions (Table 2, entry 14). N,N-dimeth- dichloroacetic acid. A similar reactivity trend was
ylglycine was also not a suitable additive, showing observed when TFE was used as solvent (SI, Table S7
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Substrate Scope
Aromatic CÀ H hydroxylation of different substrates
has been explored under the optimized experimental
conditions using the manganese complex Mn-
(tipsbpmcn) (Table 3). For comparison purposes, some
of the best results described so far in the literature with
transition-metal complexes are collected in Tables S9
and S10. In general, our current Mn(II)/H2O2/
Cl2CHCOOH catalytic system affords higher yields
and substantially improved selectivities for aromatic
over aliphatic CÀ H oxidation.
At first, we considered benzene as substrate, which
leads to phenol in a remarkable yield of 32%, along
Figure 3. Effect of different amine ligand backbones on the
Mn-catalyzed hydroxylation of tert-butylbenzene. Reaction with para-benzoquinone in 7% yield (Table 3, entry 1).
conditions: Mn-cat.:H2O2:substrate:RCO2H=1:100:100:50, in
Interestingly, when phenol was used as the substrate,
13% yield of para-benzoquinone was observed, show-
ing that the primary oxidation product in benzene
hydroxylation can indeed engage in a second oxidation
step (Table 3, entry 2). Next, we extended our study to
°
HFIP at 0 C (blue bars represent substrate conversion and grey
bars 4-tert-butylphenol yield).
and Figure S9). Therefore, we can conclude that the the oxidation of alkylbenzenes. Oxidized products
amine backbone in the ligand structure of the were obtained in remarkable total product yields
manganese complexes has a considerable impact on ranging from 29 to 37%, with the para-phenol as the
catalytic activity. Besides, we believe that the simpler main product in all cases, which is reminiscent to
ethylene diamine backbone is less stable under acidic reactions proceeding via an electrophilic aromatic
conditions, since with dichloroacetic acid as additive a substitution type of mechanism. Toluene was oxidized
poor 4-tert-butylphenol yield is afforded. Consistent to para-cresol in 22% yield, together with ortho-cresol
with this hypothesis, this complex is more efficient and methyl-para-benzoquinone in 8 and 1% yield,
under low carboxylic acid loadings; hydroxylation of respectively (Table 3, entry 3). Recent studies on
tert-butylbenzene with Mn(tipsbpmen) leads to only aromatic oxidations have shown other complexes to be
6% 4-tert-butylphenol yield when 2 equivalents of capable of oxidizing the aromatic ring of toluene as
chloroacetic acid are used, whereas 15% yield is well, showing however significant amounts of aliphatic
obtained with 0.5 equiv. of the acid.
oxidation towards benzyl alcohol or benzaldehyde
Finally, we have further investigated the role of the products.[3g,4a,b,e,f] Remarkably, Mn(tipsbpmcn) shows an
halogenated carboxylic acid additives by examining excellent selectivity for oxidation of the aromatic ring
the use of dichloroacetic acid with different manganese over the aliphatic site chain. Oxidation of other
complexes for the hydroxylation of propylbenzene, this alkylbenzene derivatives with more reactive benzylic
time at a low H2O2 loading (SI, Table S11). Our earlier CÀ H bonds was also explored. Ethylbenzene provided
findings showed that for Mn(tipsbpmcn) the use of 4-ethylphenol as the major product in 26% yield, along
dichloroacetic acid provides an enhanced catalytic with 2-ethylphenol and ethyl-para-benzoquinone in 8
activity compared to the use of AcOH (compare and 2% yield, respectively (Table 3, entry 4). For the
Tables 1 and S11). On the other hand, for the electron- oxidation of propylbenzene, we observed 4-propylphe-
rich complex Mn(dMMbpmcn) a complete change in nol, 2-propylphenol and propyl-para-benzoquinone in
chemoselectivity from aliphatic to aromatic hydroxyla- 24, 8, and 2% yield, respectively (Table 3, entry 5).
tion was observed when switching to dichloroacetic
Cumene was also considered, which bears a more
acid, albeit at low yields (compare Tables 1 and S11). encumbered isopropyl substituent with a weak 30
For the parent complex Mn(bpmcn) an increased benzylic CÀ H bond. 4-Isopropylphenol and 2-isopro-
activity for aromatic hydroxylation was observed when pylphenol were obtained in 30 and 5% yield,
dichloroacetic acid was employed instead of AcOH. respectively. Minor amounts of isopropyl-para-benzo-
Remarkably, traces of 1-phenyl-1-propanol were de- quinone were detected in 2% yield (Table 3, entry 6).
tected for all these catalysts when dichloroacetic acid To the best of our knowledge, hydroxylation of this
was employed, revealing that the use of a halogenated group of alkylbenzene substrates catalyzed by the
carboxylic acid increases the selectivity towards the current system provides the highest yields reported to
oxidation of aromatic CÀ H bonds for these complexes date with homogeneous catalysts. Remarkably, only
in a general sense, avoiding the generation of products traces of benzylic oxidation products were detected in
originating from oxidation at a more activated benzylic these reactions, suggesting that the current catalytic
position.
system is selective for aromatic hydroxylation reac-
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Table 3. Product analysis in the oxidation of benzene and its derivatives catalyzed by Mn(tipsbpmcn)[a]
Entry Substrate (r.s.m %)[b] p-Phenol (%)[c] o-Phenol (%)[c] Quinone (%)[c] Benzylic oxidation (%)[d] Mass balance (%)[e]
1
44
70
32
–
–
–
7
–
–
88
86
2
3
13
49
34
45
38
22
26
24
30
8
8
8
5
1
2
2
2
traces
traces
traces
traces
80
71
81
75
4
5
6
7
8
32
45
29
8
–
–
5
–
–
–
66
72
14
9
84
6
–
4
–
–
–
94[f]
10
>99
–
>99[f]
[a] Reaction conditions: Mn(tipsbpmcn):H2O2:substrate:Cl2CHCOOH=1:100:100:50, in HFIP at 0 C for 30 min.
[b] Remaining starting material (r.s.m.) determined from crude reaction mixtures by GC.
[c] Product yields determined from crude reaction mixtures by GC.
°
[d] Benzaldehyde or ketone products were not detected.
[e] Mass balance was calculated considering remaining starting material and all products formed, plus a percentage of substrate loss
calculated from blank experiments: MB=(r.s.m %)+(Product Yields %)+(Substrate loss %).
[f] Percentage of substrate loss was not calculated.
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tions. A cautious note must be introduced at this point
because some of these compounds show the lowest
mass balance of all substrates tested in this study,
which raises the possibility that benzylic oxidation
products are also formed but overoxidized to non-
detected products. Important to note is that no
formation of ketone products was observed, i.e.
secondary oxidation of initial benzylic alcohol prod-
ucts does not seem to take place. Blank experiments
Scheme 3. Aromatic CÀ H hydroxylation of a natural product.
without catalyst were done to calculate the amount of in anisole and benzonitrile might also interfere with
substrate loss during the reactions, and were used to catalysis. We believe that the poor catalytic activity for
calculate the mass balances in Table 3.
anisole may be due to strong binding of the first
We observed a correlation between the bulk of the formed hydroxylated product to the metal center
lateral alkyl chain in the aromatic substrate and the (indicated by a strong color change to purple). Indeed,
product profile. Our results clearly show that increas- competitive experiments using equimolar amounts of
ing the bulk of the substituents on the substrate anisole and tert-butylbenzene show only 2% 4-tert-
translates into a decreased formation of ortho-phenol butylphenol yield, demonstrating catalyst deactivation
product, which is likely due to steric effects of both the in the presence of anisole.
catalyst and the substrate. The amounts of ortho-
Amino acid substrates are particularly interesting
phenol were similar for toluene, ethylbenzene, and because of their biological significance and their
propylbenzene. However, when a bulkier substrate, molecular complexity, containing different types of
such as cumene, was used, the yield for the ortho- CÀ H bonds. We therefore examined the catalytic
phenol decreased. More remarkable is the oxidation of hydroxylation of phenylalanine. Our idea was to
tert-butylbenzene, where no ortho-phenol product was extrapolate the reactivity that we have observed using
detected at all, i.e. 4-tert-butylphenol was detected as simple aromatic substrates to the oxidation of more
the only product in 29% yield (Table 3, entry 7). The complex molecules. Interestingly, we found that
current data contrast with the oxidation of cumene oxidation at the para-position of the aromatic ring of a
catalyzed by a Ni(II) complex supported by an amino- protected phenylalanine yields the corresponding tyro-
pyridine ligand, where mixtures of ortho-, meta- and sine as the main product in 7% yield, which represents
para-phenols were obtained together with benzylic 7 catalytic turn-overs per Mn (Scheme 3). The hydrox-
oxidized products, albeit in very low yields.[4a] Thus, ylation of phenylalanine might be further optimized by
our data indicate the importance of steric catalyst variation of reaction conditions and protecting groups.
effects to dictate the regioselectivity of the hydroxyla-
tion reaction.
Mechanistic Considerations
Using bromobenzene as substrate, 2-bromophenol
and 4-bromophenol were obtained in 14 and 8% yield, Finally, our efforts have been devoted to the under-
respectively. 2-Bromo-1,4-benzoquinone was also de- standing of the mechanism of the aromatic hydroxyla-
tected in 5% yield (Table 3, entry 8). The formation of tion reaction. Generally, activation of H2O2 by man-
ortho and para phenols is in agreement with classical ganese or iron complexes supported by aminopyridine
aromatic substitution reactions, halogen and alkyl ligands leads to electrophilic oxidants.[1h,2e,g,10a,b] It is
substituents being ortho and para directing groups. proposed that the starting Mn(II) complex is first
However, of importance is the different selectivity oxidized to a Mn(III) hydroperoxo species, which then
observed for bromobenzene compared to the alkylben- converts to a Mn(V) oxo complex through OÀ O bond
zene substrates; where the ortho-phenol was obtained heterolysis,[1m,10a,b] this last step being assisted by the
as the main oxidized product in the former case, the carboxylic acid additive (Scheme 4). We propose that
para-phenol was the major product in the latter case.
the aromatic hydroxylation reaction occurs via a
An electron-donating substituent was expected to similar oxidizing species, without the involvement of
enhance the reactivity of the arene substrate in our oxygen-centered radicals. It is well-known that free
system. Nonetheless, anisole showed a poor reactivity, radicals, such as hydroxyl radicals generated via a
with 4-methoxyphenol and 2-methoxyphenol being Fenton process, can perform the oxidation of aromatic
produced in only 6 and 4% yield, respectively (Table 3, CÀ H bonds, but show low efficiencies and
entry 9). No benzoquinone was detected in this case. selectivities.[14] The involvement of such radicals
For benzonitrile, bearing an electron-withdrawing would lead to side products through lateral site chain
cyano group, no oxidized products were detected oxidation in alkylbenzene derivatives, because these
(Table 3, entry 10). While the cyano group could oxygen-centered radicals poorly discriminate between
deactivate the aromatic ring towards electrophiles, the CÀ H bonds of different strengths.[3g,15] In addition,
coordinating ability of the methoxy and cyano groups hydroxylation of alkylbenzenes via hydroxyl radicals
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radicals, and consequently point towards the involve-
ment of a metal-based mechanism.
To get further insight in the mechanism, we
considered performing the hydroxylation reaction with
another oxidant than H2O2. Remarkably, we found that
catalytic hydroxylation of tert-butylbenzene by Mn-
(tipsbpmcn) in fluorinated alcohol solvents can also be
t
accomplished employing BuOOH as oxidant, generat-
ing 4-tert-butylphenol as the oxidized product in 9%
t
yield. It is known that oxidations with BuOOH can
proceed through a Fenton-type process, generating
free-diffusing tert-butoxy and tert-butylperoxy radicals
that can engage in hydrogen abstraction reactions with
t
aliphatic CÀ H bonds.[2e,18] However, BuOOH activa-
tion does not produce hydroxyl radicals, and tert-
butoxy radicals, unlike hydroxyl radicals, do not add to
aromatic rings.[19] Another evidence against the in-
volvement of hydroxyl radicals is that the aromatic
hydroxylation reactions catalyzed by Mn(tipsbpmcn)
are not affected by the presence, or absence, of air.
Independent experiments carried out under air and
under a nitrogen atmosphere showed similar efficien-
cies for the generation of 4-tert-butylphenol (SI,
Table S12). In contrast, a significant impact of air on
product yields is observed when oxidations are
mediated by oxygen-centered radicals.[3g,14c,d,20]
Scheme 4. Proposed mechanistic cycle based on the carboxylic
acid assisted OÀ O cleavage of non-heme Fe and Mn
complexes.[1h,m,2e,16]
give a specific distribution of ortho-, meta- and para-
Next, we carried out a kinetic isotope effect (KIE)
phenol isomers.[17] Several of our observations speak experiment using a 1:1 mixture of benzene and
against the involvement of hydroxyl radicals in our perdeuterated benzene as substrate and Mn(tipsbpmcn)
aromatic hydroxylation reaction, and point towards a as catalyst. From the ratio of phenol to phenol-d5, a
metal-based oxidation mechanism.
KIE value of 0.97�0.06 was determined for this
Our catalysis experiments show that oxidation of reaction. This value rules out Fenton-type processes,
electron-rich benzene derivatives leads to the forma- for which a KIE of 1.7 has been reported.[21] Overall,
tion of para and ortho phenol products, with no our combined data suggest that aromatic hydroxylation
formation of the meta isomer. This clearly contrasts reactions catalyzed by Mn(tipsbpmcn) occur through a
with other catalysts capable of performing arene metal-based mechanism with no significant involve-
hydroxylation, such as the systems reported by Itoh,[4a] ment of hydroxyl radicals. Besides, the high bond
Bryliakov[3j] and Di Stefano,[3g] where mixtures of dissociation energy of aromatic CÀ H’s discards a HAT
ortho-, meta- and para-phenols were observed (SI, initiated process. Instead, the data is consistent with an
Table S10); and thus, suggests that the current reaction aromatic hydroxylation mechanism via electrophilic
undergoes through a more selective species. In con- attack of the high valent metal oxo on the aromatic
trast, when switching to electron-poor substrates, no ring. As a first option, the KIE value found in this
aromatic hydroxylation reaction takes place with the study is compatible with the formation of a Wheland
current system. These observations agree with the type of intermediate found in an electrophilic aromatic
proposal of an electrophilic manganese-oxo species, substitution mechanism. Alternatively, an initial arene
with a reactivity sensitive to the electronic nature of epoxidation reaction conducted by the high valent
the substrate.
manganese-oxo species, followed by an acid catalyzed
Previous studies have shown that the oxidation of re-aromatization to form the corresponding phenol
toluene with hydroxyl radicals afford cresols with a could be a plausible mechanism.[22] Both proposed
distribution of 71:9:20 for ortho:meta:para isomers.[17] processes show a negligible KIE, which is consistent
The current work has shown that the bulky Mn- with a change in hybridization from sp2 to sp3 of the
(tipsbpmcn) catalyst is capable of oxidizing toluene aromatic carbon where the oxidation takes place.[3g,23]
with high selectivity, affording a ratio of 27:0:73 for
To get further insight into the arene hydroxylation
the ortho-, meta- and para-cresols, respectively. There- mechanism, we performed a catalytic experiment using
fore, our data clearly show a distinct distribution of 1-tert-butyl-4-deuterobenzene to probe the occurrance
isomers compared with the reaction involving hydroxyl of an NIH shift (Scheme 5). This characteristic feature
of arene hydroxylation reactions based on the migra-
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preventing coordination of the phenolate products to
the manganese center. Remarkably, the use of bulky
manganese complexes favors aromatic oxidation over
(benzylic) aliphatic CÀ H bond oxidation, whereas
electron-rich manganese complexes selectively oxidize
the weaker benzylic CÀ H bonds, demonstrating a
dependency of the chemoselectivity on the catalyst. A
synthetically relevant property of the current Mn
system is that oxidation of a broad range of aromatic
substrates can be accomplished. Notable is the
oxidation of monoalkylbenzenes using Mn(tipsbpmcn)
as the catalyst, which to our knowledge provide the
highest phenol product yields reported to date for
Scheme 5. Deuterium labeling study.
tion of a substituent from the formal hydroxylation site homogeneous catalysts. The overall product profiles of
to an adjacent carbon position can indicate the involve- this system, in combination with a negligible KIE
t
ment of an arene oxide as a reaction intermediate.[24] effect and the effectiveness of using BuOOH as
Based on our previous experiments, we know that oxidant, overall point towards a metal-based mecha-
hydroxylation of tert-butylbenzene only occurs at the nism with no significantly involvement of oxygen-
para-position of the benzene ring. Combined GC and centered radicals. Besides, the observation of a NIH
GC-MS analysis of the reaction with 1-tert-butyl-4- shift indicates that aromatic oxidation with the current
deuterobenzene indeed showed the exclusive formation system is likely to occur via an arene epoxidation
of para-phenol products (26%), with a 4-tert-butyl-2- pathway.
deuterophenol and 4-tert-butylphenol ratio of 47/53,
Future efforts will be focused on the understanding
indicating that an NIH-shift takes place during the of the factors that govern product selectivity, as well as
reaction. On basis of this observation, we suggest that of possible catalyst deactivation pathways that lead to
the aromatic hydroxylation reaction most likely occurs the still moderate product yields observed in this study.
through an arene epoxidation mechanism, involving Additional investigations of the current catalytic
the generation of a cyclohexadienone intermediate system will also focus on a further insight in the
after arene oxide formation.
overall modest mass balances obtained. Overall, our
We propose that the use of an electron-deficient current findings represent a next step in the design of
acid can make the metal oxo species more electro- molecular catalysts for the selective oxidation of
philic, which also reduces catalyst inhibition by aromatic substrates, and provide a stepping stone for
phenolate protonation. These effects, together with a the further development of selective oxidation catalysts
sterically demanding aminopyridine ligand, translate based on manganese.
into an oxidizing agent which is reactive towards the
para-position of the aromatic ring instead of the
Experimental Section
(benzylic) aliphatic CÀ H bonds. Overall, we believe
that there is a synergy between the carboxylic acid and General Procedure for Catalytic Hydroxylation
the manganese complex, as was recently also shown Reaction
for methylene and tertiary CÀ H oxidation catalyzed by
additive.[1u,7d,25] Further investigations into the exact
role of halogenated carboxylic acids are required to
understand how chemoselectivity is governed in these
aromatic hydroxylation reactions.
A 3 mL or 20 mL vial was charged with: substrate (1 equiv.)
and the indicated loading of catalyst and corresponding solvent
(0.5 mL or 2 mL). The carboxylic acid was added with
indicated loading. The vial was cooled on an ice bath or
acetonitrile/dry ice bath, depending on the desired temperature,
other manganese complexes with chloroacetic acid as
with stirring. Subsequently,
a solution of H2O2 in the
corresponding solvent (indicated loading, diluted from a 35%
H2O2 aqueous solution) was delivered by syringe pump over
30 min. After the oxidant addition, the resulting mixture was
brought to room temperature, and at this point, a 0.8 M biphenyl
solution in CH3CN (0.5 equiv.) was added as internal standard.
The solution was filtered through a Celite©, silica and alumina
plug, which was subsequently rinsed with 2×1 mL EtOAc.
Then the sample was submitted to GC analysis to determine the
mass balance, the conversion, and relative ratio of products by
comparison with authentic samples. Yields for ethyl-p-benzo-
quinone, propyl-p-benzoquinone and isopropyl-p-benzoquinone
Conclusion
We have presented a new catalytic procedure for the
direct one-step hydroxylation of aromatic CÀ H bonds
to the corresponding phenol products using manganese
complexes in combination with H2O2. Pivotal to our
findings is the use of sterically encumbered tetraden-
tate aminopyridine ligands in combination with a
halogenated carboxylic acid additive and a fluorinated
alcohol solvent. We have shown that complexes with
bulky ligands perform better in arene oxidations by
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were calculated with the response factor of methyl-p-benzoqui-
none.
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Detailed experimental procedures and characterization data for
all new compounds are described in the supporting information.
CCDC-1994176 contains the supplementary crystallographic
data for (S,S)-Mn(tipsbpbi). These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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Acknowledgements
Funding Sources: The European Commission is acknowledged
for financial support through the NoNoMeCat project (675020-
MSCA-ITN-2015-ETN). We also thank Utrecht University.
Support by the Spanish Ministry of Science (PGC2018-101737-
B-I00 to M.C. and PhD grant to M.B. BES-2016-076349), and
Generalitat de Catalunya (ICREA Academia Award to M.C. and
2017 SGR 00264) is acknowledged. STR of UdG are acknowl-
edged for technical support.
Competing interests: The authors declare no competing
financial interest.
Author contributions: R.K.G and M.C. devised the project and
designed experiments. E.M. performed the experiments and
analyzed the data. M.B. analyzed data. M.L. performed X-ray
analysis. E.M. and R.K.G. wrote the manuscript. All authors
provided comments on the experiments and manuscript during
its preparation.
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Aromatic CÀ H Hydroxylation Reactions with Hydrogen
Peroxide Catalyzed by Bulky Manganese Complexes
Adv. Synth. Catal. 2021, 363, 1–14
E. Masferrer-Rius, M. Borrell, M. Lutz, M. Costas, R. J. M.
Klein Gebbink*