Origin of the Difference in Reactivity between Ir Catalysts for the Borylation of C-H Bonds

Article abstract of DOI:10.1021/jacs.9b08920

A mechanistic study on the origin of the difference in reactivity between Ir catalysts for C-H borylation reactions is reported. Catalytic reactions of B₂pin₂ with a series of substrates that require high temperatures and long reaction times were conducted. These reactions catalyzed by the combination of [Ir(COD)(OMe)]₂ and 3,4,7,8-tetramethylphenanthroline (tmphen) occur in yields that are substantially higher than those of reactions catalyzed by [Ir(COD)(OMe)]₂ and 4,4′-di-tert-butylbipyridine (dtbpy). The electronic properties of Ir catalysts ligated by dtbpy or tmphen and their stoichiometric reactivity were investigated. It was found that a longer lifetime rather than higher reactivity of the catalyst leads to higher yields of reactions catalyzed by Ir-tmphen. The catalyst ligated by dtbpy decomposes principally by dissociation of the ligand and rapid borylation at the positions alpha to nitrogen. Thus, the greater stability of the catalyst containing tmphen results from its greater binding constant.

Full text of DOI:10.1021/jacs.9b08920

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Article
Origin of the Difference in Reactivity between
Ir Catalysts for the Borylation of C-H Bonds
Raphael J. Oeschger, Matthew Larsen, Alessandro Bismuto, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08920 • Publication Date (Web): 20 Sep 2019
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Origin of the Difference in Reactivity between Ir Catalysts for the
Borylation of C-H Bonds
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Raphael J. Oeschger, Matthew A. Larsen, Alessandro Bismuto, John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California, 94720
ABSTRACT: A mechanistic study on the origin of the difference in reactivity between Ir catalysts for C-H borylation reactions
is reported. Catalytic reactions of B2pin2 with a series of substrates that require high temperatures and long reaction times
were conducted. Reactions catalyzed by the combination of [Ir(COD)(OMe)]2 and 3,4,7,8-tetramethylphenanthroline
(tmphen) occur in yields that are substantially higher yields than those of reactions catalyzed by [Ir(COD)(OMe)]2 and 4,4’-
di-tert-butylbipyridine (dtbpy). The electronic properties of Ir catalysts ligated by dtbpy or tmphen and their stoichiometric
reactivity were investigated. It was found that the longer lifetime, rather than higher reactivity of the catalyst, leads to higher
yields of reactions catalyzed by Ir-tmphen. The catalyst ligated by dtbpy decomposes principally by dissociation of the ligand
and rapid borylation at the positions alpha to nitrogen. Thus, the greater stability of the catalyst containing tmphen results
from its greater binding constant.
secondary alkyl C-H bonds of amines, ethers,16,
silanes18 (Scheme 2d).
and
17
INTRODUCTION
The borylation of C-H bonds has become a widely used
and researched method for the functionalization of C-H
bonds (Scheme 1).1, 2 These reactions occur without direct-
ing groups with regioselectivities that result from steric hin-
drance and, in some cases, the acidity of the C-H bond. This
selectivity complements that of other catalytic and classical
functionalizations of aryl C-H bonds.3 The reaction forms or-
ganoboronate esters that can be transformed to a variety of
C-C and C-heteroatom bonds.4
Scheme 2. Published examples of the borylations of C-H
bonds showing the different yields for reactions catalyzed
by Ir-tmphen and Ir-dtbpy.
Scheme 1. Typical reaction conditions for Ir catalyzed
borylation of arenes.
The ligands used for these iridium-catalyzed functionali-
zations are typically based on nitrogen Lewis bases, and the
catalyst is often generated from the combination of
[Ir(COD)OMe]2 and 4,4’-di-tert-butylbipyridine (dtbpy).5-11
Some of these reactions occur with turnover numbers ap-
proaching 20,00011, 12 and have been used to produce kilo-
grams of active pharmaceutical ingredients (API).13, 14 How-
ever, the borylation of many types of arenes and het-
eroarenes catalyzed by [Ir(COD)OMe]2 and dtbpy occur in
low yields or require high catalyst loadings (Scheme 2a, b).
In these cases, higher yields of the aryl or heteroaryl boronic
esters have been achieved by generating the catalyst from
[Ir(COD)OMe]2 and 3,4,7,8-tetramethylphenanthroline
(tmphen).9, 15 This system even catalyzes the borylation of
aliphatic C-H bonds (Scheme 2c), including primary and
Many catalysts for reactions involving organometallic in-
termediates of noble metals contain phosphines as dative
ligands,19-21 and many studies have revealed the effects of
the properties of phosphines on such catalytic reactions.22-
24 Far fewer catalysts of such metals contain dative ligands
bearing only Lewis-basic nitrogen donors.25-29 Few studies
on the origins of the activity of such metal-ligand complexes
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have been published, and most of these studies focus on the
dimethoxybenzene (3) with Ir complexes (10.5 M) 1
(blue) and 2 (red).
polymerization of alkenes.30-32 Thus, the origins of the dif-
ferences in reactivity of complexes of bipyridine and phe-
nanthroline ligands on the borylation of C-H bonds are dif-
ficult to glean from prior published literature.
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The rates of the stoichiometric reactions of 1 and 2 with
1,3-dimethoxybenzene (3), an arene that forms the product
of borylation in high yield with both catalysts, was studied
first to assess differences in the rate of reaction of aryl C-H
bonds with the two trisboryl complexes containing the dif-
ferent ligands. These data are provided in Figure 1 and
show that the rate of the reaction with dtbpy-complex 1 is
similar to that with tmphen-complex 2. Thus, an inherently
higher reactivity of the complex ligated by tmphen with aryl
C-H bonds than of the complex ligated by dtbpy does not ex-
plain the difference in yields of reactions catalyzed by com-
plexes of the two ligands. Analogous reactions of 1 and 2
with benzene and 2-methoxy-1,3-dimethylbenzene also
showed that the rates of the reactions of complex 1 are sim-
ilar to those of complex 2 with the same arene (see Support-
ing Information).
To reveal the origin of the difference in reactivity be-
tween the combination of [Ir(COD)OMe]2 and dtbpy or
tmphen as ligand for the borylation of C-H bonds, we stud-
ied the relative rates for reaction of the boryl intermediates
with various substrates, the relative rates for catalyst de-
composition, and the origin of catalyst decomposition. We
show that the rates of the reactions catalyzed by the two
types of complexes are similar to each other, but the lifetime
of the catalyst containing tmphen is much longer than that
containing dtbpy, and this longer lifetime, rather than
higher reactivity of the catalytic boryl intermediate, leads to
the higher yields of reactions catalyzed by tmphen than of
those catalyzed by dtbpy. The catalyst lifetime is limited by
the borylation of the free nitrogen-based ligand; the higher
binding constant of phenanthroline ligands and thereby
lower concentration of free ligand, not slower modification
of free, phenanthrolines, accounts for the difference life-
time.
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Scheme 3. C-O Stretching frequencies of iridium-trisboryl
carbonyl complexes 4 and 5.
RESULTS AND DISCUSSIONS
To determine the origins of the difference in reactivity be-
tween catalysts containing 4,4’-di-tert-butylbipyridine
(dtbpy) and 3,4,7,8-tetramethylphenanthroline (tmphen),
we first monitored the rates of reactions of a series of sub-
strates of varying reactivity with the iridium-trisboryl com-
plexes [Ir(Bpin)3(L2)(COE)] (1 and 2) in which L2 is dtbpy
or tmphen and COE (cyclooctene) is derived from the cata-
lyst precursor. Such tris-boryl complexes are known to be
the resting state of the catalyst during the borylation of
arenes,33 and the reaction of such complexes with the C-H
bond of the substrate is known to be rate limiting for reac-
tions of arenes catalyzed by complexes of both ligands.
These complexes react with the substrate after dissociation
of COE.33
Consistent with the similar rates for reactions of com-
plexes of the two ligands, the degree of electron density at
iridium in the trisboryl complex containing dtbpy was sim-
ilar to that containing tmphen. The infrared stretching fre-
quencies of the Ir-bound carbonyl23 ligands in trisboryl
complexes [Ir(Bpin)3(L2)(CO)] (L2=dtbpy: 4;34 and
L2=tmphen: 5) ligated by CO in place of COE (Scheme 3)
were 1972 cm-1 and 1971 cm-1, respectively. These data, to-
gether with the kinetic data for stoichiometric reactions,
show that the origin of the difference in yields of reactions
catalyzed by the two iridium-ligand combinations is more
likely due to factors besides a difference in reactivity result-
ing from a difference in the electronic properties of the two
trisboryl complexes.
Table 1. Yields of borylated product after 24 h, initial rates of
the borylation reactions, and percentage of borylated dtbpy lig-
and for the catalytic reactions of THF (6), Julolidine (8), and
2,4-dimethylbenzimidazole (10).
Product
7
9
11
Yield with 5 mol% Ir-dtbpy
5%
31%
30%
Yield with 5 mol%
Ir-tmphen
103%
91%
88%
Initial rates with 5 mol%
Ir-dtbpy (M s-1)
2.7 10-6 6.6 10-6 4.9 10-6
Figure 1. Reaction profile of stoichiometric borylation of m-
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Initial rates with 5 mol%
Ir-tmphen (M s-1)
5.7 10-6 7.1 10-6 3.7 10-6
80 % 60% 45%
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4
Percentage of dtbpy ligand
borylated after 24 h
To point toward alternative origins of the differences in
yields of reactions catalyzed by complexes of the two lig-
ands, we conducted catalytic reactions of B2pin2 with THF
and with two aromatic compounds that react in higher yield
with the catalyst ligated by tmphen than with that ligated by
dtbpy. (Mes)Ir(Bpin)3 was used as catalyst precursor in-
stead of [Ir(COD)(OMe)]2, which is more typically used for
synthetic purposes, to eliminate the induction period some-
times observed with [Ir(COD)(OMe]2.33 The profiles of the
borylation of with the two catalysts are shown in Figure 2.
The reactions of these arenes with the trisboryl complex li-
gated by tmphen formed the products in high yield (7:
103%, 9: 91%, 11: 88%), whereas the reactions with the
trisboryl complex ligated by dtbpy form the product in
much lower yield (7: 5%, 9: 31%, 11: 30%, Table 1).
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Figure 2. Catalytic borylation of a) THF (6), b) Julolidine (8),
and c) 2,4-Dimethylbenzimidazole (10) with (Mes)Ir(Bpin)3 (5
mol%). Initial rates 6: 5.7 10-6 M s-1 (Ir-tmphen) and 2.7 10-6
M
s-1 (Ir-dtbpy), 8: 7.1 10-6 M s-1 (Ir-tmphen) and 6.6 10-6 M s-1 (Ir-
dtbpy), 10: 3.7 10-6 M s-1 (Ir-tmphen) and 4.9 10-4 M s-1 (Ir-
dtbpy).
The formation of product over time began to reveal the
origin of these differences in yields. These plots showed that
the initial rates (Figure 2 and Table 1) of the reactions cata-
lyzed by Ir-tmphen are similar to those catalyzed by Ir-
dtbpy. However, the reactions catalyzed by Ir-tmphen oc-
curred to high conversion and high yield, whereas the
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reactions catalyzed by Ir-dtbpy stopped after partial con-
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borylation of dtbpy is comparable to that of the borylation
of o-xylene. To determine if the borylation of dtbpy is com-
petitive with the borylation of o-xylene in the same reaction
solution, we conducted the reaction of B2pin2 with 1 equiv
of -xylene and 1 equiv of dtbpy catalyzed by the Ir-dtbpy
system (Scheme 3b). Monoborylated dtbpy (46 %), di-
borylated dtbpy (8%), and monoborylated o-xylene (58%)
all formed. These experiments show that the rate of the
borylation of dtbpy is similar to that of the borylation of
arenes and that it is plausible that dtbpy undergoes boryla-
tion during the catalytic processes, particularly during cat-
alytic reactions of substrates, such as THF, containing less
reactive C-H bonds.
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version. The plots show that the remaining material in these
reactions was starting substrate, and no significant accumu-
lation of side products was observed (see Supporting Infor-
mation). These results show that the lower yields from the
borylations of alkanes, electron-rich arenes, and het-
eroarenes catalyzed by Ir-dtbpy than those from the boryla-
tions catalyzed by Ir-tmphen is due to catalyst lifetime, not
due to a difference in inherent reactivity of the trisboryl in-
termediate with the substrate or formation of side products
from reactions of the catalyst bearing dtbpy.
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To assess whether dtbpy underwent borylation during
reactions of substrates that form borylated products in
higher yields when catalyzed by Ir-tmphen than when cata-
lyzed by Ir-dtbpy, we obtained 1H NMR spectra of crude re-
actions of THF, aminoarene 8, and heteroarene 10 after 12
h of reaction time at 80 °C. These spectra showed that 80%,
60%, and 45% of the dtbpy ligand had converted to the
borylated dtbpy 13 for the reactions of THF, aminoarene 8
and heteroarene 10, respectively (Table 1). These data are
consistent with the conclusion that the ligand undergoes
borylation in competition with the substrate and that this
borylation leads to catalyst deactivation.
To investigate whether the borylation of the ligand inac-
tivates the catalyst, we tested the activity of Ir catalysts con-
taining diborylated ligand 13 for the borylation of Julolidine
(8) and 2,4-dimethylbenzimidazole (10). Consistent with
the borylation of dtbpy leading to catalyst deactivation, the
borylation of 8 and 10 catalyzed by the combination of
(Mes)Ir(Bpin)3 and modified ligand 13 (Scheme 4) gave
only traces of product (< 5%).
Scheme 4. Reactions with Bpin2-tbpy 13 as ligand.
To test whether the longer lifetime of the catalyst con-
taining tmphen is due simply to a difference in rate of the
borylation of the ligand, which could be retarded by the
presence of methyl groups in the 2 and 9 positions ortho to
the nitrogen atoms of the phenanthroline, we conducted the
reaction of 1 equiv of tmphen with 2 equiv of B2pin2 under
the same conditions that led to the borylation of dtbpy. In
contrast to the slower rate of decomposition of the catalyst
containing tmphen than of that containing dtbpy, the reac-
tion of free tmphen with B2pin2 was faster than that of dtbpy
(Figure 4). This reaction of tmphen formed a complex mix-
ture of products. After oxidation of the borylation products
with H2O2 and NaOH, the mixture was analyzed by
HPLC/MS. Several species corresponding to mono and dihy-
droxylated phenanthrolines were detected, suggesting that
tmphen is borylated at both aromatic and benzylic positions
(see Supporting Information).
Figure 3. a) Catalytic borylation of o-xylene and tert-butylbi-
pyridine with [Ir(COD)(OMe)]2 (2.5 mol%). b) Reaction of 1
equiv o-xylene, 1 equiv tert-butylbipyridine and 1 equiv B2pin2.
To reveal the origin of the difference in catalyst lifetime,
the borylation of THF catalyzed by Ir-dtbpy was analyzed by
1H-NMR spectroscopy after 12 h at 100 °C. We observed the
formation of a new species corresponding to signals at 8.70
ppm and 7.82 ppm. A comparison of the NMR spectra of in-
dependently synthesized 2,2’-(pinB)2-4,4’-(tBu)2bpy (13)
matched that of the new species observed during the reac-
tion (see Supporting Information for solid-state structure
by X-ray diffraction).35 To gauge the rate of the borylation of
dtbpy versus that of the borylation of the substrate, the re-
action of a 1:1 molar combination of dtbpy and -xylene was
monitored. The plot in Figure 3a shows that the rate of the
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Because the faster catalytic borylation of free tmphen
Scheme 5. Ligand exchange followed by borylation of
dtbpy.
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than of free dtbpy runs counter to the relative catalyst life-
times, we considered that the differences in binding of the
ligand to iridium and effect of binding on the borylation pro-
cess could account for the difference in catalyst stability. To
determine the relative binding of dtbpy and tmphen to the
trisboryl-iridium fragment and qualitative rate of ligand ex-
change, we conducted ligand substitution reactions
(Scheme
5).
The
reaction
of
1
equiv
of
(dtbpy)Ir(Bpin)3(COE) (1) with 1 equiv of tmphen in THF-
9
1
d8 was monitored by H-NMR spectroscopy. Free tmphen
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fully replaced bound dtbpy within 5 minutes, showing that
tmphen binds substantially more strongly to Ir than does
dtbpy.36 The higher binding constants of phenanthroline lig-
ands than of bipyridine ligands are due to the more favora-
ble orientation of the nitrogen atoms for binding the metal
in free phenanthrolines than in free bipyridines. In contrast
to the orientation of the nitrogen atoms in free phenanthro-
line, the two nitrogen atoms in the most stable confor-
mation of free dtbpy are distal from each other, and the di-
poles are aligned more favorably than they are in the re-
quired orientation of the nitrogen atoms for binding of bpy
ligands.37, 38
The borylation of free bipyridine-based structures has
been observed previously but has not been connected to the
lifetime of the catalyst. For example, the diborylation of
dtbpy catalyzed by Ir-dtbpy was reported by Marder et al.
in a study on C-H borylations of pyridines.35 In related work,
the borylation of a pincer ligand on cobalt was reported by
Chirik et al. and, in this case, the borylation of ligand was
shown to decrease activity of cobalt catalysts for the boryla-
tion of arenes.39 However, the ligand on cobalt is a strongly
bound pincer. Thus, borylation of the pincer ligand presum-
ably occurs directly on the bound ligand, and borylation
process likely imparts unfavorable changes to the electronic
properties of the catalyst that decreases its reactivity.
After this solution was allowed to sit for 5 hours at room
temperature, borylated dtbpy was observed by 1H NMR
spectroscopy (ca. 40%), but no signals corresponding to
borylated tmphen were observed. On the other hand, a so-
lution of 1 equiv of (tmphen)Ir(Bpin)3(COE) (2) and 1 equiv
of dtbpy was unchanged after 5 minutes, and only borylated
dtbpy was observed after 5 hours. These results, together
with the faster borylation of free tmphen than of free dtbpy
imply that dtbpy and tmphen are borylated when they are
unbound from the metal. Thus, the stronger binding of
tmphen than of dtbpy leads to a lower concentration of free
ligand in reactions catalyzed by Ir-tmphen than in those cat-
alyzed by Ir-dtbpy. This lower concentration of free ligand
leads to slower borylation of tmphen and catalyst decompo-
sition.
CONCLUSIONS
A series of experiments on reaction rates, catalyst lifetime
and pathways to catalyst decomposition shows that the ac-
tivity of the iridium catalysts ligated by tmphen and dtbpy
are similar but the yields for reactions catalyzed by Ir-dtbpy
are lower than those catalyzed by Ir-tmphen in many cases
because of catalyst deactivation. Table 1 summarizes our
data on reaction yields, initial rates, and amount of
borylated dtbpy formed in reactions of an aliphatic com-
pound, an electron-rich arene, and a heteroarene: THF (6),
Julolidine (8), and 2,4-dimethylbenzimidazole (10). The
electronic properties of the two catalysts are similar to each
other, and the rates of the stoichiometric reactions of arenes
with the trisboryl complexes ligated by the two ligands are
similar to each other. However, the catalyst containing
dtbpy decomposes during borylations that require higher
temperatures and longer reaction times, such as the boryla-
tion of Csp3-H bonds, electron-rich arenes, and heteroarenes,
and this catalyst decomposition limits reaction yields.
The major decomposition pathway occurs by borylation
of the nitrogen-based ligand when it is unbound from the
metal. Counterintuitively, tmphen, which leads to the more
stable catalyst, reacts in its free form with B2pin2 faster than
free dtbpy reacts with B2pin2. Thus, the longer lifetime of
the Ir-tmphen catalyst than of the Ir-dtbpy catalyst is due to
stronger binding of tmphen to the metal than of dtbpy, as a
result of its more rigid structure. Stronger binding leads to
a lower concentration of free ligand, and thereby slower
borylation of the ligand and catalyst decomposition. These
data predict that catalysts containing other rigid bidentate
ligands should resist catalyst deactivation during the
borylation of C-H bonds, and these findings will guide our
future studies on the development of new catalysts for the
borylation of C-H bonds.
Figure 4. Consumption of dtbpy (blue) and tmphen (red)
over time.
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Borylation of C−H Bonds in N-Containing Heterocycles:
Regioselectivity in the Synthesis of Heteroaryl Boronate Esters.
Angew. Chem. Int. Ed. 2006, 45, 489-491.
ASSOCIATED CONTENT
Supporting Information
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R.; Hartwig, J. F., Mild Iridium-Catalyzed Borylation of Arenes. High
Turnover Numbers, Room Temperature Reactions, and Isolation of
a Potential Intermediate. J. Am. Chem. Soc. 2002, 124, 390-391.
12. Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N., A
Stoichiometric Aromatic C−H Borylation Catalyzed by
Iridium(I)/2,2-Bipyridine Complexes at Room Temperature.
Angew. Chem. Int. Ed. 2002, 41, 3056-3058.
13. Sieser, J. E.; Maloney, M. T.; Chisowa, E.; Brenek, S. J.;
Monfette, S.; Salisbury, J. J.; Do, N. M.; Singer, R. A., Ir-Catalyzed
Borylation as an Efficient Route to a Nicotine Hapten. Org. Process
Res. Dev. 2018, 22, 527-534.
14. Campeau, L.-C.; Chen, Q.; Gauvreau, D.; Girardin, M.; Belyk,
K.; Maligres, P.; Zhou, G.; Gu, C.; Zhang, W.; Tan, L.; O’Shea, P. D., A
Robust Kilo-Scale Synthesis of Doravirine. Org. Process Res. Dev.
2016, 20, 1476-1481.
15. Preshlock, S. M.; Ghaffari, B.; Maligres, P. E.; Krska, S. W.;
Maleczka, R. E.; Smith, M. R., High-Throughput Optimization of Ir-
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Am. Chem. Soc. 2013, 135, 7572-7582.
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18. Ohmura, T.; Torigoe, T.; Suginome, M., Catalytic
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19. Gillespie, J. A., Zuidema, E. , van Leeuwen, P. W. and Kamer,
P. C. Phosphorus Ligand Effects in Homogeneous Catalysis and
Rational Catalyst Design. In Phosphorus(III) Ligands in
Homogeneous Catalysis: Design and Synthesis, P. C. Kamer and P. W.
van Leeuwen, Eds.; John Wiley & Sons, Inc.: Hoboken, New Jersey,
2012.
Experimental procedures, characterization of new com-
pounds, crystallographic information, and CIF files. This
material is available free of charge via the internet at
http://pubs.acs.org
Acknowledgements
We gratefully acknowledge financial support from the
NIH R35GM130387. R.J.O. is a Swiss National Science Foun-
dation postdoctoral fellow. AB thanks the Royal Society of
Chemistry for a Researcher Mobility Grant and EPSRC and
CRITICAT CDT (Ph.D. studentship to A.B.; No.
EP/L016419/1). R.J.O. thanks Caleb Karmel for helpful dis-
cussions and assistance in the preparation of the manu-
script.
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AUTHOR INFORMATION
Corresponding Author
*jhartwig@berkeley.edu
ORCID
Raphael J. Oeschger: 0000-0002-5209-1595
Matthew A. Larsen: 0000-0002-9366-2999
Alex Bismuto: 0000-0002-5840-1144
John F. Hartwig: 0000-0002-4157-468X
Notes
The authors declare no competing financial interest.
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