Iridium catalysts for acceptorless dehydrogenation of alcohols to carboxylic acids: Scope and mechanism

Article abstract of DOI:10.1021/acscatal.8b00105

We introduce iridium-based conditions for the conversion of primary alcohols to potassium carboxylates (or carboxylic acids) in the presence of potassium hydroxide and either [Ir(2-PyCH₂(C₄H₅N₂))(COD)]OTf (1) or [Ir(2-PyCH₂PBu₂^t)(COD)]OTf (2). The method provides both aliphatic and benzylic carboxylates in high yield and with outstanding functional group tolerance. We illustrate the application of this method to a diverse variety of primary alcohols, including those involving heterocycles and even free amines. Complex 2 reacts with alcohols to form the crystallographically characterized catalytic intermediates [IrH(η¹,η³-C₈H₁₂)(2-PyCH₂P^tBu₂)] (2a) and [Ir₂H₃(CO)(2-PyCH₂P^tBu₂){μ-(C₅H₃N)CH₂P^tBu₂}] (2c). The unexpected similarities in reactivities of 1 and 2 in this reaction, along with synthetic studies on several of our iridium intermediates, enable us to form a general proposal of the mechanisms of catalyst activation that govern the disparate reactivities of 1 and 2, respectively, in glycerol and formic acid dehydrogenation. Moreover, careful analysis of the organic intermediates in the oxidation sequence enable new insights into the role of Tishchenko and Cannizzaro reactions in the overall oxidation.

Full text of DOI:10.1021/acscatal.8b00105

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Iridium Catalysts for Acceptorless Dehydrogenation of
Alcohols to Carboxylic Acids: Scope and Mechanism
Valeriy Cherepakhin, and Travis J. Williams
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00105 • Publication Date (Web): 26 Mar 2018
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ACS Catalysis
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Iridium Catalysts for Acceptorless Dehydrogenation of Alcohols to
Carboxylic Acids: Scope and Mechanism
Valeriy Cherepakhin and Travis J. Williams*
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Donald P. and Katherine B. Loker Hydrocarbon Institute and Department of Chemistry, University of Southern Cal-
ifornia, Los Angeles, California, 90089-1661, United States.
ABSTRACT: We introduce iridium-based conditions for the conversion of primary alcohols to potassium carboxylates (or
carboxylic acids) in the presence of potassium hydroxide and either [Ir(2-PyCH2(C4H5N2))(COD)]OTf (1) or [Ir(2-
t
PyCH2PBu2 )(COD)]OTf (2). The method provides both aliphatic and benzylic carboxylates in high yield and with out-
standing functional group tolerance. We illustrate the application of this method to a diverse variety of primary alcohols,
including those involving heterocycles and even free amines. Complex 2 reacts with alcohols to form crystallographically-
characterized catalytic intermediates [IrH(η1,η3-C8H12)(2-PyCH2PtBu2)] (2a) and [Ir2H3(CO)(2-PyCH2PtBu2){µ-
(C5H3N)CH2PtBu2}] (2c). The unexpected similarities in reactivities of 1 and 2 in this reaction, along with synthetic studies
on several of our iridium intermediates, enable us to form a general proposal of the mechanisms of catalyst activation that
govern the disparate reactivities of 1 and 2, respectively in glycerol and formic acid dehydrogenation. Moreover, careful
analysis of the organic intermediates in the oxidation sequence enable new insights into the role of Tishchenko and Can-
nizzaro reactions in the overall oxidation.
KEYWORDS Acceptorless dehydrogenation, Iridium, Metal hydride, Alcohol, Carboxylic acid
PNN,15 PNP,16 and NHC-ligands,17 catalyze acceptorless
INTRODUCTION
dehydrogenation. The Cp*IrIII system enables reactions in
neutral water.17a The former reactions take place in boiling
NaOH solutions and give high yields of aliphatic carbox-
ylates and benzoates. Such reactions also are possible in
refluxing toluene18 and neat alcohol (150 oC).19
Oxidation of primary alcohols to carboxylic acids is a
quintessential transformation in organic chemistry, his-
torically accomplished with a stoichiometric portion of a
metal-based oxidant, such as potassium permanganate,1,2
chromium(VI)
oxide,3
pyridinium
dichromate,4
We recently reported very robust catalysts for acceptor-
less dehydrogenation of formic acid (based on 2, Figure
1)20 and glycerol (1, 4),21 with the latter giving an example
of excellent selectivity for primary alcohol oxidation in
the presence of other molecular complexity. In this study
we report that these same iridium-based systems enable a
method for acceptorless dehydrogenation of primary al-
cohols to carboxylic acids. This method gives good yields
of many carboxylates and enables selectivity that is diffi-
cult to achieve with other catalytic systems. We show
broad substrate scope, including reactions of alcohols
with a secondary amino group or aryl halide, and report
unanticipated features of the catalytic mechanism. Par-
ticularly, we show details of catalyst initiation and pro-
vide a unifying proposal of the mechanisms of catalyst
activation that govern the disparate reactivities of 1 and 2,
respectively in glycerol and formic acid dehydrogenation.
RuCl3/NaIO4,5 sodium hypochlorite,6 or the like. These
evolved, ultimately to culminate in Lindgrin (and related)
oxidation of aldehydes, the mild conditions of choice for
complex molecule synthesis. Still, some forcing condi-
tions to dehydrogenate primary alcohols directly to car-
boxylates have been known since the 19th century. For
example, J. B. Dumas (1840) and later E. Reid et al.7 con-
verted primary alcohols to carboxylate salts and H2 by
o
heating with hydroxide at 350 C. This approach has re-
cently advanced to emerge as an elegant 21st-century re-
placement for the stoichiometric oxidant methods, which
is important, because alcohol to carboxylate conversion
remains a frequent operation in complex molecule syn-
thesis.8–11
Carboxylate synthesis by acceptorless dehydrogenation
presents a graceful approach with the recent development
of new catalytic conditions, some enabling the reaction
OTf
X
OTf
o
Mes
under very convenient conditions (25 – 120 C, 1 atm). To
R
R
N
N
P
N
N
CO
CO
date, homogeneous catalysts for this reaction include sys-
tems based on rhodium, ruthenium, and recently one
iridium complex. The former include a diolefin amido
tridentate ligand and catalyze hydrogen transfer from
alcohols to acceptors like cyclohexanone,12 1-hexene,13 or
O2/DMSO.14 Ruthenium complexes featuring tridentate
Cl
Ir
Ir
Ir
Ir
Ir
N
N
N
Cl
1
2
: R = t-Bu, X = OTf
4
5
3: R = Ph, X = Cl
Figure 1. Iridium Complexes 1-5.
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Application of the optimized reaction conditions enabled
RESULTS AND DISCUSSION
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an effective conversion of a variety of primary alcohols to
potassium carboxylates (Table 2). Substrate scope in-
cludes aliphatic alcohols (entries 1 – 5), benzylic alcohols
(entries 6 – 12), and even heteroatom functionalized sys-
tems like thioethers (entry 8), amino alcohols (entries 13
and 14) and heterocycles (entries 16 and 17). This latter
class of substrates is unknown for other catalytic systems
for this reaction, including the one based on iridium.
Alcohol Oxidation
The discovery and optimization of our reaction is out-
lined in Table 1. The material balance of the reaction in-
volves one equivalent of hydroxide. However, any base in
the reaction will cause
a
parallel Guerbet self-
condensation.7 For example,22 neat 1-octanol (6b) con-
verts to potassium octanoate (7b, 72%) and 2-octyl-1-
octanol (8b, 28%) in the presence of 1 eq. of potassium
9
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Several generalizations can be drawn from these data.
Unfunctionalized alkyl systems proceed smoothly (entries
1-3), and an adjacent strained ring is not derivatized in the
reaction (entry 4). Sterically bulky systems can be prob-
lematic. For example, entries 5 and 18 demonstrate that a
1-adamantyl substituent (6e) slows the reaction, ca. half
the rate, although it reaches completion. A doubly-
blocked 2,6-dimethylbenzyl alcohol (6r) is unreactive.
hydroxide and 1 (1 mol%) at 150 C (yields calculated by
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NMR). In order to suppress this side-reaction, we conduct
the dehydrogenation in a solvent of refluxing toluene:
here, 1-octanol gives 99% of octanoate, 1% of Guerbet al-
cohol 8b after 40 h. This solvent choice contrasts many
examples of primary alcohol dehydrogenation in the liter-
ature,15–17 in which reactions are typically run in water.
Complex 1 is less effective in an aqueous medium, and the
yield of octanoate is only 7% after 40 h. The origin of se-
lectivity for carboxylate formation appears to be solubili-
ty: hydroxide’s limited solubility in toluene limits the to-
tal base concentration available for the Guerbet side reac-
tion. In our hands, toluene is useful for most alcohols;
diols and triols have limited solubility, and thus limited
reactivity.
Although aryl bromides and iodides are only moderately
tolerated, entries 10 and 11 give examples of Ar-Br and Ar-I
bonds surviving alcohol dehydrogenation conditions. We
observe reduction (to Ar-H groups) as the major side re-
action in these cases.18 For example, 4-bromobenzyl alco-
hol (6j) undergoes dehydrogenation to form both the
corresponding 4-bromobenzoate (58%) and the reduced
benzoate (9%) product. 4-Iodobenzyl alcohol (6k) afford-
ed a larger amount of dehalogenated benzoate (32%) in
addition to the halogenated product (42%). In contrast to
aryl bromides and iodides, aryl chlorides are well tolerat-
ed (entry 9), and afford access to a growing number of
metal-catalyzed coupling reactions.23
Table 1 shows the performance of our iridium pre-
catalysts in alcohol dehydrogenation in toluene. The most
effective catalyst, typically 1 or 2 in different cases, was
determined among our available iridium(I) complexes
(Figure 1) on the basis of product yield and selectivity. 1-
Butanol (6a), 1-octanol (6b), and 1-hexadecanol (6c) were
used as substrates. The selectivity for carboxylate synthe-
sis decreases with increased molecular weight of the alco-
hol, which we believe to be an effect of base solubility.
Secondary amines and azoles are tolerated. Whereas sev-
eral iridium complexes catalyze alkylation of primary
amines with alcohols,24,25 we were curious how an amino
alcohol would fare in our conditions. We found that we
can convert amino alcohol 6m efficiently to the corre-
sponding amino acid without polymerization or other
side reactions. This presents an unprecedented approach
to amino acid synthesis. We further find that intramolec-
ular oxidative cyclization of amino alcohols is possible:
dehydrogenation of 6n results in cyclization, yielding
indole 7n exclusively.24a
Relative rates of catalysis for complexes 1, 2, and 5 were
evaluated by recording hydrogen evolution in the conver-
sion of benzyl alcohol (6f) to benzoate. Benzyl alcohol
was chosen to avoid a Guerbet reaction. Kinetic profiles of
hydrogen evolution demonstrate that complex 2 has the
highest catalytic activity (Figure 2). Though 2 proved to
be the fastest catalyst among the iridium compounds,
complex 1 was also examined in substrate scope studies.
Table 1. Selectivity Screening of Catalysts 1-5.a
aReaction conditions: a mixture of alcohol (2.1 mmol),
KOH (2.4 mmol), catalyst (2.1 x 10-5 mol, 1 mol%), and
toluene (4 mL) was stirred at reflux for 37 h (oil bath, 120
Figure 2. Hydrogen evolution profiles of 6f dehydrogena-
tion with 1, 2, and 5. Conditions: a mixture of a catalyst (4
x 10-6 mol, 0.2 mol%), KOH (2.2 mmol), 6f (2.0 mmol),
and toluene (10 mL) was actively stirred at reflux (oil
bath, 120 oC).
oC). The yields were derived from H NMR spectra. 0.1
1
b
mol% of 1 was used.
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however, we also observe trace quantities of naphthalene,
Table 2. Substrate Scope for Dehydrogenation of
Primary Alcohols Using Pre-Catalysts 1 and 2.a
1,2-dihydronaphthalene, tetralin, and potassium formate
in the reaction mixture. Quinoline 6q is even more sus-
ceptible to over-reduction, yet we see only a trace of the
corresponding tetrahydroquinoline in the crude product
mixture of 7q. By contrast, an attempt to dehydrogenate
2-(hydroxymethyl)thiophene and 3-phenylpropargyl al-
cohol resulted in product decarboxylation, giving potassi-
um formate. Unfortunately, alkenes and nitro compounds
are incompatible with our conditions and undergo uncon-
trolled reduction.
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We showed that our catalytic systems can be applied to
large-scale synthesis of carboxylic acids. Complexes 1 and
2 convert benzyl alcohol to benzoic acid with turnover
numbers 16400 and 40600 respectively. Pre-catalyst 2
loading can be as low as 50 ppm to give up to 15 g of ben-
zoic acid. Moreover, precipitation of the carboxylate dur-
ing the reaction enables easy separation of the product by
simple filtration. The catalyst-containing toluene solution
can then be reused.
The catalytic method presented here is the second exam-
ple we know for iridium based primary alcohol dehydro-
genation. The previously reported method by Fujita uti-
lizes IrIII pre-catalyst [Cp*Ir(NC)(H2O)](OTf)2 (NC – pyri-
dylcarbene bidentate ligand).17a An advantage of the
method is the possibility to conduct alcohol oxidation
under base-free conditions, whereas our method requires
stoichiometric KOH. Fujita’s method uses high catalyst
loading (2 – 5 mol%) and the reaction scope is confined to
simple benzyl alcohols, with reactions of aliphatic alco-
hols giving yields of <25%. Thus, our method is a useful
complement to the Fujita’s chemistry.
Mechanism
The near-interchangeability of 1 and 2 in the conversions
of 6 to 7 was not anticipated. We observe very different
reactivity of these species respectively in glycerol21 and
formic acid20 dehydrogenation: 1 works only in the former
and 2 only in the latter. Carboxylate synthesis thus pro-
vides us with a platform from which to run comparative
stoichiometric reactions of 1 and 2 (Scheme 1) to gain in-
sight into both the mechanisms of catalyst initiation and
the differences in their reactivities.
Complex 1 reacts with neat alcohol 6g in the presence of
potassium hydroxide to form iridium(I) alkoxide complex
1a, which can be extracted from potassium salts with
C6D6. The structure of 1a was established by NMR, with
the coordination geometry assigned by NOE analysis (see
Supporting Information). The complex retains its biden-
tate N—C ligand without proton loss, and the aryl alkox-
ide ligand exchanges slowly (k ~ 1 s-1) with excess 6g in
solution. Complex 1a is reactive in benzene solution in
the presence of excess 6g, converting it to 4-
methoxybenzyl-4-methoxybenzoate (1b). The iridium-
containing species precipitates from solution leaving cy-
clooctene. These data are consistent with hydrogen trans-
fer from 6g to coordinated 1,5-cyclooctadiene to give re-
duction of one its olefins. We observe the same of 1 in
glycerol dehydrogenation.21 Importantly, we see no evi-
aReaction conditions: a mixture of an alcohol (2.0 mmol),
KOH (2.2 mmol), catalyst, and toluene (10 mL) was stirred
at reflux.
We observe good selectivity for carboxylate synthesis in
cases where arene hydrogenation or reductive decarboxy-
lation can take place. For example, alcohol 6l gives a high
yield (84%, entry 12) of the corresponding carboxylic acid,
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1
dence of an iridium hydride or any other metallic inter-
mediate in this sequence.
(Scheme 2). According to H NMR data, heating the solu-
tion of pure 2c leads to disappearance of the two cis-
hydride signals and reduction of types of tert-butyl
groups from four to two. This indicates that 2c is involved
in a fast dynamic equilibrium with a symmetrical species,
which we propose to be the product of Ir–H–Ir bridge
cleavage 2e. The next step is slow, and the system comes
to equilibrium only after four hours (Keq = [2f]/[2c]=
1
2
3
4
5
6
7
8
Scheme 1. Reactions of Complexes 1 and 2.
0.626; ꢀGo = 360 cal/mol; k1 = 1.4(1) x 10-4 s-1; and k-1 =
383
2.2(1) x 10-4 sꢁ1). The equilibrated mixture at room temper-
9
ature contains chemical shifts of pure 2c and 2f only.
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1
The structure of 2f was established by NMR studies. H
spectrum contains two hydride peaks in the ratio 1 : 2 at -
6.64 (d, JPH = 150.4) and -8.98 (br. s) ppm respectively.
2
Seven aromatic peaks indicate that 2f has two ligands and
one of them is ortho-metalated. Two doublets of the four
tert-butyl groups indicate the presence of a symmetry
plane in the molecule. 1H – 31P HMBC experiment demon-
strates coupling between different hydrides (-6.64, and -
8.98 ppm) and different phosphorus nuclei (63.79, and
88.66 ppm respectively). Hence, the only reasonable mo-
lecular structure must have all three hydrides bound to
one iridium center. We assign this structure as 2f in
scheme 2.
Complex 2 reacts with 6g or isopropanol to give iridi-
um(III) complex 2b (Scheme 1), which can be isolated in
64% yield. The structure of 2b was established by single-
crystal X-ray diffraction (Figure 3). It is analogous to the
structure of [IrH(η1,η3-C8H12)(dppm)], reported by Werner
and co-workers.26 We believe that an intermediate iridi-
um alkoxide is involved in the formation of 2b, but unlike
1a, this converts to a stable iridium hydride species. We
believe that this is the same initiation sequence observed
for 2 in the dehydrogenation of formic acid, because 2b is
easily converted to 2d, a form of the active catalyst of
formic acid dehydrogenation initiating from 2.20
Scheme 2. Reactions of Complex 2c.
Figure 3. Molecular structures of 2b (left) and 2c (right)
shown with 50% probability ellipsoids. Hydrogen atoms
are omitted for clarity, except for localized hydrides.
Complex 2c reacts with 10 eq. of n-hexanal at room tem-
perature. This initially produces a number of unidentified
iridium hydride complexes. After two days at 80 C the
o
Complex 2 reacts with 1-butanol and potassium hydroxide
in boiling toluene to form dinuclear iridium(II) complex
2c (Scheme 1), which is isolated in 63% yield. Its structure,
shown in Figure 3, has two notable features: a single CO
ligand and a bridging ortho-metalated pyridine fragment.
The CO ligand derives from n-butanal,27–30 and several
cases of pyridine ortho-metalation by iridium complexes
have been described.31–33 1H NMR of 2c shows three hy-
dride ligands; their arrangement in the coordination
reaction reaches completion and all the transient iridium
hydrides turn to a single complex, 2g (Scheme 2). Its
structure was determined with NMR and MALDI-MS da-
ta. The 1H NMR spectrum of 2g contains two peaks of the
hydride ligands at ꢁ8.44 (ddd) and ꢁ11.15 (ddd) ppm and six
aromatic peaks, suggesting that both pyridine fragments
are ortho-metalated. No chemical exchange (EXSY) was
observed between the hydride ligands, which is consistent
with their proposed trans configuration. Complex 2g has
two hydrogen atoms fewer than 2c, meaning that it is a
dehydrogenated form of 2c. The identified organic prod-
ucts in this reaction are 1-hexanol and hexyl hexanoate. 1-
Hexanol is the product of hydrogen transfer from 2c to n-
hexanal, and hexyl hexanoate is the product of Tishchen-
1
sphere was confirmed by COSY, NOESY/EXSY, and H –
31P HMBC experiments (see Supporting Information).
Complex 2c is stable in the solid state and in solution at
room temperature in the absence of air, however it un-
o
dergoes reversible isomerization to 2f in toluene at 110 C
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hexanol to return initial 2c, indicating that 2c is more
ko dimerization. Hexanal remains present in the mixture
1
2
3
4
5
6
7
8
after prolonged heating, showing that 2g does not cata-
lyze its disproportionation; this is most likely accessed via
one of the transient iridium hydrides mentioned above.
Reduction of 2g back to 2c by 1-hexanol or H2 (1 atm) at
110 oC in toluene is not detected, even after 12 h.
acidic than t-BuOH, but less acidic than 1-hexanol.
Scheme 3 illustrates the proposed mechanism of catalyst
generation and catalytic alcohol dehydrogenation using
complex 2 as a pre-catalyst. We believe that both 1 and 2
initiate through analogous sequences, but that the hy-
drides of 1 are high energy, and are thus not observed. We
believe that the difference in hydride stabilities is a con-
sequence of the subtle electronic differences between the
respective carbene and phosphine groups of 1 and 2. The
first step involves a nucleophilic attack of an alkoxide
anion on 2, producing iridium(I) alkoxide 2a, which is the
structural analogue of 1a. Species 2a undergoes β-hydride
elimination to give an aldehyde and complex 2b, the
mechanism of this transformation had been studied pre-
viously on a similar iridium complex.26
When 2 reacts with 1-butanol and KOH in boiling toluene
a mixture of iridium hydride complexes is formed, in
which 2c, 2f, and 2g are the major components (Figure 4).
Moreover, we showed that 2c is active in benzyl alcohol
dehydrogenation with an identical kinetic profile to 2.
These facts suggest that 2c, 2f, and 2g are the catalyst
resting states which convert among each other during
alcohol dehydrogenation with pre-catalyst 2.
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Scheme 3. Mechanism of Pre-catalyst 2 Activation.a
1
Figure 4. H NMR spectra (600 MHz, C6D6) demonstrat-
ing IrH peaks: (1) mixture of complexes formed in the
reaction between 2, 1-butanol, and KOH in boiling tolu-
ene; (2) 2c; (3) 2f; (4) 2g.
Whereas the interconversion of 2c and 2f is accessed at
elevated temperature, it is unclear how 2c can convert
reversibly to 2g in the catalytic process. Nevertheless, we
showed this transformation to be involved in the catalytic
mechanism by conducting deuteration experiment.
Treatment of 2c with 1-hexanol-O,1,1-d3 (6s) under dehy-
drogenation conditions (Scheme 2) reveals partial deuter-
ation of all three hydrides and the pyridine ortho-
hydrogen in equal portions. Thus, all three hydrides are
reversibly derivatized under the catalytic conditions.
Since 2g contains two ortho-metalated pyridine fragments
we propose it as the intermediate in the ortho-
deuteration of the free pyridine fragment of 2c.
a. Colored labels on iridium hydride groups are not in-
tended to imply specificity in hydride transfer steps, but
simply to guide the reader. In fact, these hydrides equili-
brate rapidly.
Complex 2b is stable at room temperature, and subse-
quent intermediates were accessed at elevated tempera-
ture. We find that 2b forms complex mixtures of iridium
hydride species when reacted with 1-butanol or n-hexanal
at 80 oC, however, complex 2c was detected after reaction
with n-hexanal. Hence, we conclude that 2b can be con-
verted to 2c by an aldehyde produced in the conversion of
2a. This gives our system access to the 2c/2f equilibrium.
Since we have shown that 2c reacts with n-hexanal rather
than 1-hexanol, we believe that the next step of the mech-
anism involves reversible reaction between 2e and an al-
dehyde, ultimately leading to 2g. We suggest that one of
the intermediates in this reaction is the jumping-off point
for the catalytic process (“Active Catalyst’’, scheme 3). We
expect the catalytic cycle to proceed by a traditional β-
hydride elimination from an intermediate iridium alkox-
ide. We expect this to be irreversible, because toluene
solutions of 2c, 2f, and 2g do not react with H2 (1 atm) at
The linking methylene group of complex 2c has an acidity
comparable to that of alcohols (Scheme 2), but we do not
observe the deprotonated form as a major species in ca-
talysis. For example, we observe that treating yellow solu-
tion of 2c with t-BuOK in benzene gives red-colored
complex 2h (Scheme 2). A 1H NMR spectrum of 2h shows
selective deprotonation of benzylic arm of the metalated
ligand and dearomatization of the corresponding pyridine
system. The hydride ligands remain intact. Similar reac-
tivity of structurally related PNP pincer ligands with simi-
lar colorometric behavior was reported by Milstein.34
Complex 2h undergoes complete protonation by 1-
o
either 25 or 110 C. Although we could not fully character-
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1
ize the chain of all iridium species involved, all of them
that we have are dinuclear, starting from 2c.
mixture by H NMR spectroscopy. These observations
necessitate Cannizzaro reaction, but do not necessitate or
exclude Tishchenko reaction in the sequence.
1
2
3
4
5
6
7
8
Our studies on the organic intermediates involved in the
alcohol dehydrogenation process turned up two unex-
pected observations (Scheme 4). First, formation of ester
by-products rules in the possibility of Tishchenko like
reaction of an intermediate aldehyde. Second, kinetic
evidence necessitates Cannizzaro reaction in the mecha-
nism of oxidation of benzyl alcohols.
SUMMARY
In conclusion, complexes 1 and 2 are efficient pre-
catalysts for the conversion of primary alcohols to potas-
sium carboxylates. Under optimized the reaction condi-
tions the method applicable to a wide range of substrates,
including some (amino alcohols and some heterocycles)
that are unknown for any catalytic conditions in this
class. We show that 1 and 2 are both active in primary
alcohol dehydrogenation, despite their previously investi-
gated difference in catalytic activity towards glycerol and
formic acid dehydrogenation. Upon catalysis initiation,
complex 1 forms observable iridium(I) alkoxide 1a, which
decomposes to relatively reactive iridium hydrides. On
the contrary, complex 2 reacts with alcohols in the pres-
ence of KOH to form a number of stable iridium hydride
complexes 2b, 2c, 2f, and 2g even though 2a is not ob-
served. We propose that the jumping-off point for cataly-
sis to be an intermediate in the equilibration of 2c and 2g.
9
Scheme 4. Mechanisms of Aldehyde and Carboxylate
Formation.
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Taken together with our prior work on glycerol and for-
mic acid dehydrogenation, realized respectively with 1
and 2, these data help to frame a picture that explains the
specify of 1 and 2 for those processes: both proceed
through initiation sequences that are differentiated by the
reactivities of intermediate iridium hydride intermediates
that steer initiation to the respective active species. These
stabilities are apparently governed by differences in met-
al-ligand bonding between NHC carbene and phosphine
groups, thus illustrating dramatic consequences mani-
fested by the subtle differences in these ligating moieties.
More details on this generalization are forthcoming from
our lab.
Synthesis of 1a is illustrated in scheme 1. We find that
upon exposure to our catalytic conditions at 25 C, this
o
material generates 4,4’-dimethoxybenzyl benzoate, which
indicates that Tishchenko like reaction of 4-
methoxybenzaldehyde is faster than its direct conversion
to 7g. Moreover, formation of hexyl hexanoate in the re-
action between 2c and n-hexanal shows that ester genera-
tion is also possible when pre-catalyst 2 is used. In order
to verify our proposed Tishchenko pathway, we showed
that a significant portion of an aldehyde exists in the
hemiacetal form under catalytic conditions: NMR data
show that n-hexanal reacts with an excess of 1-butanol in
the presence of catalytic KOH in toluene to give the cor-
responding hemiacetal (1-butoxyhexan-1-ol). Thus, we
must consider ester formation as a route in the mecha-
nism of carboxylate synthesis (Scheme 4A).
EXPERIMENTAL SECTION
Materials and Methods. Chloroform-d1, dimethyl sulfox-
ide-d6, methanol-d4, D2O, benzene-d6, and toluene-d8
were purchased from Cambridge Isotopes Laboratories.
Benzene-d6, toluene-d8, and toluene were dried and dis-
tilled according to known procedures. Iridium complexes
1, 2, 3, and 4 were synthesized according to described pro-
cedures.20,21 Alcohols 6a – 6r, methanol, isopropanol, di-
chloromethane, ethyl acetate, methyl hexanoate, 18-
crown-6, chloro(1,5-cyclooctadiene)iridium(I) dimer, and
potassium hydroxide were purchased from commercial
sources without further purification. Benzaldehyde was
distilled under reduced pressure prior to use. All air and
water sensitive procedures were carried out in a Vacuum
Atmosphere glove box under nitrogen (2-10 ppm O2 for all
manipulations). 1H, 13C, 31P NMR spectra were recorded on
Varian Mercury 400 and VNMRS 600 spectrometers, and
processed using MestReNova v11.0.2. All chemical shifts
Aromatic aldehydes undergo Cannizzaro reaction in the
presence of KOH to give the corresponding benzyl alco-
hols and carboxylates (Scheme 4B). Such disproportiona-
tion is known under our conditions in the absence of irid-
o
ium (1 h, KOH, toluene, 110 C).18 In our conditions, the
resulting alcohol converts to aldehyde via iridium cata-
lyzed dehydrogenation. We are convinced that Canniz-
zaro reaction must be happening, because when benzal-
dehyde is used instead of an alcohol under typical dehy-
drogenation conditions, it takes ca. 30 min for hydrogen
evolution to begin. If no Cannizzaro reaction was in-
volved, aldehyde oxidation would initiate immediately.
This delay is apparently benzaldehyde disproportionation
that is required to generate a sufficient amount of benzyl
alcohol to form the catalytic species. We expect that it is
required to convert 1 to 1a (and 2 to 2a), and that its C—H
groups are needed to convert on to 1b (or 2b): an alde-
hyde cannot fill this role. After hydrogen formation ceas-
es, traces of benzyl alcohol can be detected in the reaction
1
are reported in ppm and referenced to the residual H or
13C solvent peaks. Following abbreviations are used: (s)
singlet, (bs s) broad singlet, (d) doublet, (t) triplet, (dd)
double doublet, etc. NMR spectra of air-sensitive com-
pounds were taken in 8” J. Young tubes (Wilmad or No-
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Page 7 of 11
ACS Catalysis
13
rell) with Teflon valve plugs. Infrared spectra were rec-
1H, CH2). C NMR (151 MHz, D2O): δ 185.74, 40.92, 25.93,
17.29. IR (PE film, cm-1): 2975, 2941, 2859, 1656, 1553, 1409,
680. GC-MS: m/z calcd. for C5H8O2 [M]+ 100.05, found
100.1.
1
2
3
4
5
6
7
8
orded on Bruker OPUS FTIR spectrometer. Samples of
pure potassium carboxylates were treated with acetic acid
in ethyl acetate followed by GC-MS analysis on Thermo
Scientific Focus DSQ II instrument. MALDI-MS spectra
were acquired on Bruker Autoflex Speed MALDI Mass
Spectrometer. Elemental analyses were conducted on
Flash 2000 CHNS Elemental Analyzer.
1-Adamantanecarboxylic Acid (7e). Isolation by meth-
od A followed by recrystallization from hexane-ethanol
1
mixture gave 7e as colorless crystals (0.34 g, 77%). H
NMR (600 MHz, CDCl3): δ 2.00 – 2.05 (m, 3H, 3CH), 1.88 –
1.94 (m, 6H, 3CH2), 1.67 – 1.77 (m, 6H, 3CH2). 13C NMR (151
MHz, CDCl3): δ 184.45, 40.64, 38.71, 36.57, 27.97. IR (PE
film, cm-1): 2928, 1693, 1450, 1410, 1284, 1085, 951, 744, 670,
531. GC-MS: m/z calcd. for C11H16O2 [M]+ 180.12, found
180.1.
General Procedure for Alcohol Dehydrogenation. An
alcohol (2.0 mmol), iridium complex 1 or 2 (see table 2),
and potassium hydroxide (123 mg, 2.2 mmol) were mixed
with dry toluene (10 mL). The suspension was stirred at
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o
reflux for required period of time (oil bath, 120 C). After
the reaction was over, the solvent was evaporated under
reduced pressure affording crude potassium carboxylate.
Benzoic Acid (7f). Isolation by method A followed by
recrystallization from toluene gave 7f as colorless crystals
1
Isolation method A: Potassium carboxylate was dissolved
in deionized water (40 mL) and the resulting solution was
washed with dichloromethane (2 x 10 mL). Then, the solu-
tion was acidified with 1 M HCl, and extracted with ethyl
acetate (3 x 10 mL). The organic phase was separated,
dried (Na2SO4) and evaporated in vacuum, giving pure
carboxylic acid.
(0.24 g, 98%). H NMR (600 MHz, DMSO-d6): δ 12.93 (br
s, 1H, CO2H), 7.95 (d, J = 7.0 Hz, 2H, 2CH), 7.62 (t, J = 7.4
13
Hz, 1H, CH), 7.50 (t, J = 7.7 Hz, 2H, 2CH). C NMR (151
MHz, DMSO-d6): δ 167.33, 132.88, 130.76, 129.27, 128.58. IR
(PE film, cm-1): 1689, 1455, 1426, 1327, 1294, 936, 709. GC-
MS: m/z calcd. for C7H6O2 [M]+ 122.04, found 122.0.
4-Methoxybenzoic Acid (7g). Isolation by method A
Isolation method B: Potassium carboxylate was dissolved
in DI water (40 mL) and the resulting solution was
washed with dichloromethane (2 x 10 mL). The aqueous
solution was evaporated in vacuum to dryness and the
residue was dissolved in methanol. The methanol solution
was filtered, and the filtrate was evaporated to dryness,
giving pure potassium carboxylate.
followed by recrystallization from toluene-ethanol mix-
1
ture gave 7g as colorless crystals (0.24 g, 79%). H NMR
(600 MHz, DMSO-d6): δ 12.62 (br s, 1H, CO2H), 7.89 (d, J =
8.7 Hz, 2H, 2CH), 7.01 (d, J = 8.7 Hz, 2H, 2CH), 3.81 (s, 3H,
CH3). 13C NMR (151 MHz, DMSO-d6): δ 167.04, 162.86,
131.37, 123.00, 113.83, 55.45. IR (PE film, cm-1): 1683, 1603,
1427, 1301, 1263, 1168, 1026, 927, 844, 773, 617, 550. GC-MS:
m/z calcd. for C8H8O3 [M]+ 152.05, found 152.0.
Potassium Butyrate (7a) was isolated by method B as a
1
white powder (0.24 g, 96%). H NMR (600 MHz, D2O): δ
4-(Methylthio)benzoic Acid (7h). Isolation by method
2.16 (t, J = 7.3 Hz, 2H, CH2), 1.57 (h, J = 7.3 Hz, 2H, CH2),
A followed by recrystallization from toluene-ethanol mix-
13
1
0.90 (t, J = 7.4 Hz, 3H, CH3). C NMR (151 MHz, D2O): δ
ture gave 7h as colorless crystals (0.25 g, 74%). H NMR
184.05, 39.64, 19.35, 13.26. IR (PE film, cm-1): 2956, 2918,
1564, 1412, 1254, 888, 750. GC-MS: m/z calcd. for C4H8O2
[M]+ 88.05, found 88.1.
(500 MHz, CD3OD): δ 7.92 (d, J = 7.9 Hz, 2H, 2CH), 7.30
13
(d, J = 8.1 Hz, 2H, 2CH), 2.52 (s, 3H, CH3). C NMR (126
MHz, CD3OD): δ 169.62, 147.25, 131.07, 127.81, 125.94, 14.66.
IR (KBr, cm-1): 1680, 1595, 1421, 1325, 1192, 757. GC-MS: m/z
calcd. for C8H8O2S [M]+ 168.02, found 168.0.
Potassium Octanoate (7b) was isolated by method B as
a white powder (0.33 g, 90%). 1H NMR (400 MHz, D2O): δ
2.18 (t, J = 7.5 Hz, 2H, CH2), 1.63 – 1.47 (m, 2H, CH2), 1.38 –
4-Chlorobenzoic Acid (7i). Isolation by method A fol-
13
1.20 (m, 8H, 4CH2), 0.88 (t, J = 6.7 Hz, 3H, CH3). C NMR
lowed by recrystallization from toluene-ethanol mixture
1
(100 MHz, D2O): δ 184.13, 37.50, 30.88, 28.55, 28.09, 25.75,
21.83, 13.24. IR (KBr, cm-1): 2954, 2926, 2854, 1563, 1411, 914,
718, 694. GC-MS: m/z calcd. for C8H16O2 [M]+ 144.12, found
144.1.
gave 7i as colorless crystals (0.25 g, 80%). H NMR (400
MHz, DMSO-d6): δ 13.09 (br s, 1H, CO2H), 7.93 (d, J = 8.5
13
Hz, 2H, 2CH), 7.55 (d, J = 8.5 Hz, 2H, 2CH). C NMR (151
MHz, DMSO-d6): δ 166.49, 137.83, 131.16, 129.67, 128.75. IR
(KBr, cm-1): 2924, 2955, 1680, 1322, 1284, 762. GC-MS: m/z
calcd. for C7H5ClO2 [M]+ 156.00, 157.99; found 156.0, 158.0.
Potassium Palmitate (7c). After evaporation of toluene,
crude 7c was washed with hexanes and dried under re-
1
duced pressure. White powder (0.50 g, 85%). H NMR
4-Bromobenzoic Acid (7j). Isolation by method A fol-
(600 MHz, CD3OD): δ 2.15 (t, J = 8.6 Hz, 2H, CH2), 1.63 –
1.55 (m, 2H, CH2), 1.35 – 1.25 (m, 24H, 12CH2), 0.90 (t, J =
7.0 Hz, 3H, CH3). 13C NMR (151 MHz, CD3OD): δ 183.12,
39.38, 33.07, 30.90, 30.79 (6CH2), 30.76, 30.68, 30.47,
27.85, 23.73, 14.45. IR (PE film, cm-1): 2925, 2850, 1561, 1472,
1331, 1104, 716. GC-MS: m/z calcd. for C16H32O2 [M]+ 256.24,
found 256.3.
lowed by recrystallization from toluene-ethanol mixture
1
gave 7j as colorless crystals (0.16 g, 40%). H NMR (600
MHz, DMSO-d6): δ 13.17 (s, 1H, CO2H), 7.86 (d, J = 7.1 Hz,
2H, 2CH), 7.70 (d, J = 7.1 Hz, 2H, 2CH). 13C NMR (151 MHz,
DMSO-d6): δ 166.58, 131.68, 131.27, 130.00, 126.85. IR (PE
film, cm-1): 1676, 1587, 1426, 1320, 1070, 1013, 758. GC-MS:
m/z calcd. for C7H5BrO2 [M]+ 199.95, 201.95; found 199.9,
201.9.
Potassium Cyclobutanecarboxylate (7d) was isolated
1
by method B as a white powder (0.22 g, 81%). H NMR
4-Iodobenzoic Acid (7k). Isolation by method A fol-
(600 MHz, D2O): δ 3.03 (p, J = 8.7 Hz, 1H, CH), 2.15 – 2.05
(m, 4H, 2CH2), 1.89 (h, J = 9.2 Hz, 1H, CH2), 1.78 – 1.70 (m,
lowed by recrystallization from toluene-ethanol mixture
1
gave 7k as colorless crystals (0.21 g, 42%). H NMR (600
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ACS Catalysis
Page 8 of 11
MHz, DMSO-d6): δ 13.12 (s, 1H, CO2H), 7.88 (d, J = 8.1 Hz, 8.5 Hz, 1H, CH), 7.60 (d, J = 8.4 Hz, 1H, CH), 7.50 (t, J = 7.7
2H, 2CH), 7.69 (d, J = 8.0 Hz, 2H, 2CH). 13C NMR (151
MHz, DMSO-d6): δ 166.88, 137.55, 131.04, 130.27, 101.14. IR
(PE film, cm-1): 1675, 1427, 1009, 754. MALDI-MS: m/z
calcd. for C7H5INaO2 [M + Na]+ 270.92, found 270.72.
Hz, 1H, CH), 7.45 (d, J = 8.1 Hz, 1H, CH), 7.28 (t, J = 7.5 Hz,
1H, CH). 13C NMR (151 MHz, D2O): δ 172.84, 154.01, 145.89,
137.75, 130.12, 128.09, 127.96, 127.60, 127.38, 120.13. IR (KBr,
cm-1): 3298, 1615, 1387, 802, 770. GC-MS: m/z calcd. for
C9H7N [M – CO2]+ 129.16, found 129.1.
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1-Naphthoic Acid (7l). Isolation by method A followed
by recrystallization from toluene gave 7l as colorless crys-
1-Hexanol-O,1,1-d3 (6s). In a glovebox, a solution of me-
thyl hexanoate (2.06 g, 15.8 mmol) in 10 mL of dry ether
was added dropwise to a stirred solution of LiAlD4 (0.67 g,
15.8 mmol) in 20 mL of ether. The mixture was stirred at
room temperature for 24 h, and then carefully quenched
with D2O at vigorous stirring till aluminum hydroxide
separated from organic phase. The ethereal solution was
separated, dried (Na2SO4), and evaporated in vacuum.
The product was obtained as a colorless liquid (1.34 g,
81%). 1H NMR (600 MHz, CDCl3): δ 1.52 (t, J = 7.8 Hz, 2H,
CH2), 1.34 – 1.24 (m, 6H, 3CH2), 0.87 (t, J = 7.0 Hz, 3H,
CH3). 13C NMR (151 MHz, CDCl3): δ 62.13 (p, 1JCD = 21.5 Hz),
32.58, 31.76, 25.49, 22.73, 14.10. IR (PE film, cm-1): 3331,
2957, 2859, 1467, 1160, 1127, 967. GC-MS: m/z calcd. for
C6H10D2 [M – HDO]+ 86.11, found 86.1.
[Ir(2-PyCH2(C4H5N2))(η2-COD)(OCH2C6H4OMe)] (1a).
In a glovebox, complex 1 (40.0 mg, 6.4 x 10-5 mol), 6g (18.0
mg, 1.3 x 10-4 mol), potassium hydroxide (7.2 mg, 1.3 x 10-4
mol) and 2 – 3 drops of C6D6 were mixed together till the
slurry turned yellow. Then, C6D6 (0.7 mL) was added re-
sulting in a yellow solution of 1a and potassium triflate
precipitate. The solution was immediately filtered and
transferred to J. Young NMR tube. The structure of 1a was
derived from NMR data. 1H NMR (600 MHz, C6D6): δ 8.33
(dq, J = 5.0, 0.9 Hz, 1H, Py), 7.39 (d, J = 7.8 Hz, 1H, Py),
7.35 (d, J = 8.6 Hz, 2H, C6H4), 7.08 (td, J = 7.7, 1.8 Hz, 1H,
Py), 6.85 (d, J = 8.6 Hz, 2H, C6H4), 6.64 (d, J = 1.9 Hz, 1H,
NHC), 6.58 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H, Py), 5.86 (d, J = 1.9
Hz, 1H, NHC), 5.73 (d, J = 14.7 Hz, 1H, NCH2), 5.42 (d, J =
14.7 Hz, 1H, NCH2), 5.24 (d, J = 13.8 Hz, 1H, OCH2), 5.10
(td, J = 7.7, 3.6 Hz, 1H, =CH), 5.00 – 5.06 (m, 1H, =CH),
4.85 (d, J = 13.7 Hz, 1H, OCH2), 3.40 (s, 3H, OCH3), 3.19 (s,
3H, NCH3), 2.49 (td, J = 7.0, 2.4 Hz, 1H, =CH), 2.41 (td, J =
7.4, 3.0 Hz, 1H, =CH), 2.28 – 2.37 (m, 3H, 2CH2), 2.11 – 2.17
(m, 1H, CH2), 1.62 – 1.83 (m, 4H, 2CH2). 13C NMR (151 MHz,
C6D6, derived from HSQC and HMBC): δ 183.25, 158.69,
156.75, 149.34, 141.45, 136.46, 127.26, 123.17, 122.46, 120.82,
120.56, 113.36, 84.78, 84.04, 75.30, 55.27, 54.66, 45.81, 45.44,
36.38, 34.54, 33.77, 29.90, 29.23. MALDI-MS: m/z calcd. for
C26H32IrN3O2 [M]+ 611.21, found 611.14.
1
tals (0.29 g, 84%). H NMR (600 MHz, DMSO-d6): δ 13.14
(s, 1H, CO2H), 8.87 (d, J = 8.6 Hz, 1H, CH), 8.15 (d, J = 7.4
Hz, 2H, 2CH), 8.01 (d, J = 8.0 Hz, 1H, CH), 7.64 (t, J = 7.7
Hz, 1H, CH), 7.59 (t, J = 7.7 Hz, 2H, 2CH). 13C NMR (151
MHz, DMSO-d6): δ 168.65, 133.46, 132.92, 130.67, 129.84,
128.59, 127.71, 127.55, 126.17, 125.48, 124.87. IR (PE film, cm-
1): 2916, 1674, 1593, 1306, 774. MALDI-MS: m/z calcd. for
C11H8NaO2 [M + Na]+ 195.04, found 194.87.
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Potassium Ethylaminoacetate (7m) isolated by method
1
B as a white powder (0.23 g, 82%). H NMR (600 MHz,
D2O): δ 3.26 (s, 2H, CH2), 2.70 (q, J = 6.8 Hz, 2H, CH2), 1.13
13
(t, J = 7.1 Hz, 3H, CH3). C NMR (151 MHz, D2O): δ 177.81,
51.11, 42.62, 12.90. IR (PE film, cm-1): 1597, 1407, 1383, 1283.
MALDI-MS: m/z calcd. for C4H8K2NO2 [M + K]+ 179.98,
found 180.00.
Indole (7n). Complex 2 (2.7 mg, 4 µmol), 6n (274 mg, 2.0
mmol), and potassium hydroxide (123 mg, 2.2 mmol) were
mixed with dry toluene (10 mL). The suspension was
o
stirred at reflux for 13 hours (oil bath, 120 C). After the
reaction was over, the solvent was evaporated in vacuum,
and the residue was stirred at reflux with hexanes (50 mL)
and charcoal for 1 h. Then, the hexane solution was fil-
tered and evaporated in vacuum giving 7n as a colorless
1
liquid (0.19 g, 80%). H NMR (600 MHz, CDCl3): δ 8.11 (br
s, 1H, NH), 7.68 (dd, J = 7.8, 0.7 Hz, 1H, CH), 7.41 (dd, J =
8.0, 0.7 Hz, 1H, CH), 7.25 – 7.19 (m, 2H, 2CH), 7.17 – 7.12
13
(m, 1H, CH), 6.60 – 6.56 (m, 1H, CH). C NMR (151 MHz,
CDCl3): δ 135.88, 127.95, 124.25, 122.09, 120.84, 119.92, 111.14,
102.71. IR (PE film, cm-1): 3401, 1457, 1353, 1246, 1090, 932,
746, 612, 505, 430. GC-MS: m/z calcd. for C8H7N [M]+
117.06, found 117.1.
3-Phenylpropanoic Acid (7o). Isolation by method A
1
gave 7o as a yellow liquid (0.24 g, 80%). H NMR (600
MHz, CDCl3): δ 11.57 (br s, 1H, CO2H), 7.34 – 7.29 (m, 2H,
2CH), 7.25 – 7.20 (m, 3H, 3CH), 2.99 (t, J = 7.8 Hz, 2H,
CH2), 2.71 (t, J = 7.8 Hz, 2H, CH2). 13C NMR (151 MHz,
CDCl3): δ 179.50, 140.27, 128.70, 128.39, 126.51, 35.77, 30.71.
IR (PE film, cm-1): 3028, 1708, 1496, 1417, 1295, 1215, 936,
748, 699. GC-MS: m/z calcd. for C9H10O2 [M]+ 150.07,
found 150.1.
Decomposition of 1a to 1b and 1c. Complex 1a is unsta-
ble in a solution, and it completely decomposes in two
Potassium Pyridine-2-carboxylate (7p) was isolated by
1
days to 1b, 1c, and iridium-containing precipitate. 1b: H
1
method B as a white powder (0.20 g, 63%). H NMR (500
NMR (600 MHz, C6D6): δ 8.16 (d, J = 9.0 Hz, 2H, 2CH),
7.21 (d, J = 8.8 Hz, 2H, 2CH), 6.73 (d, J = 8.7 Hz, 2H, 2CH),
6.62 (d, J = 9.0 Hz, 2H, 2CH), 5.23 (s, 2H, CH2), 3.26 (s, 3H,
CH3), 3.13 (s, 3H, CH3). GC-MS: m/z calcd. for C16H16O4
MHz, CD3OD): δ 8.58 (d, J = 4.4 Hz, 1H, CH), 8.02 (d, J =
7.7 Hz, 1H, CH), 7.85 (t, J = 8.1 Hz, 1H, CH), 7.46 – 7.32 (m,
13
1H, CH). C NMR (126 MHz, CD3OD): δ 172.94, 156.47,
149.55, 138.17, 125.93, 125.01. IR (KBr, cm-1): 2927, 1640,
1405, 702. GC-MS: m/z calcd. for C6H5NO2 [M]+ 123.03,
found 123.0.
1
[M]+ 272.10, found 272.1. 1c: H NMR (600 MHz, C6D6): δ
5.62 – 6.67 (m, 2H, 2CH), 2.02 – 2.12 (m, 4H, 2CH2), 1.36 –
1.48 (m, 8H, 4CH2). GC-MS: m/z calcd. for C8H14 [M]+
110.11, found 110.1.
Potassium Quinoline-2-carboxylate (7q) was isolated
1
by method B as a white powder (0.27 g, 65%). H NMR
(600 MHz, D2O): δ 7.88 (d, J = 8.5 Hz, 1H, CH), 7.77 (d, J =
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ACS Catalysis
[IrH(η1,η3-C8H12)(2-PyCH2PBu2 )] (2b). In a glovebox,
complex 2 (50.0 mg, 7.3 x 10-5 mol), isopropyl alcohol (20.0
mg, 3.3 x 10-4 mol), and potassium hydroxide (12.0 mg, 2.2
x 10-4 mol) were mixed with dry benzene (1.0 mL) and
stirred at room temperature for two days. Then, the
brown solution was filtered and the solvent was evapo-
rated in vacuum to dryness. The residue was recrystal-
lized twice from benzene affording the product as a pale-
yellow crystalline powder (25.0 mg, 64%). Crystals suita-
ble for X-ray analysis were obtained by slow evaporation
of benzene solution. 1H NMR (600 MHz, C6D6): δ 7.77 (d, J
= 5.6 Hz, 1H, Py), 6.65 (t, J = 7.3 Hz, 1H, Py), 6.44 (d, J = 7.5
Hz, 1H, Py), 6.05 (t, J = 6.4 Hz, 1H, Py), 5.20 – 5.13 (m, 1H,
CH), 4.64 – 4.57 (m, 1H, CH), 3.91 (t, J = 7.8 Hz, 1H, CH),
2.96 – 2.90 (m, 1H, CH), 2.87 (dd, J = 16.6, 9.0 Hz, 1H,
PCH2), 2.68 (dd, J = 16.6, 8.2 Hz, 1H, PCH2), 2.62 – 2.51 (m,
1H, CH2), 2.27 – 2.11 (m, 4H, 3CH2), 2.05 – 1.99 (m, 1H,
CH2), 1.94 – 1.77 (m, 2H, 2CH2), 1.38 (d, J = 12.1 Hz, 9H,
3CH3), 1.10 (d, J = 12.3 Hz, 9H, 3CH3), -9.99 (d, J = 17.6 Hz,
1H, IrH). 13C NMR (151 MHz, C6D6): δ 163.78, 148.87, 133.73,
121.87, 121.10, 96.21, 76.00, 60.79, 56.43, 55.14, 38.75, 36.48,
35.29, 30.34, 29.06, 28.05, 25.33, 14.01. 31P{1H} NMR (243
MHz, C6D6): δ 56.20. IR (KBr, cm-1): 2915, 2871, 2800, 2043,
1472, 821, 762. MALDI-MS: m/z calcd. for C22H37IrNP [M]+
539.23, found 539.31. Anal. calcd for C22H37IrNP: C 49.05,
H 6.92, N 2.60. Found: C 48.11, H 6.96, N 2.76.
133.03 (d, J = 4.6 Hz), 121.93 (d, J = 7.3 Hz), 120.35, 112.56 (d,
J = 9.2 Hz), 39.69 (d, J = 16.1 Hz), 35.21 (d, J = 15.4 Hz),
35.06 (d, J = 13.5 Hz), 34.71 (d, J = 12.0 Hz), 33.14 (d, J = 19.0
Hz), 30.92 (d, J = 23.9 Hz), 30.59 – 30.08 (m), 29.87 (d, J =
t
1
2
3
4
5
6
7
8
31
4.6 Hz), 29.61 – 28.98 (m). P{1H} NMR (243 MHz, C6D6):
δ 89.01, 62.75. IR (KBr, cm-1): 2942, 2896, 2106, 1914, 1582,
1473, 826. MALDI-MS: m/z calcd. for C29H50Ir2N2OP2 [M]+
888.26, found 888.23. Anal. calcd for C29H50Ir2N2OP2: C
39.18, H 5.67, N 3.15. Found: C 39.91, H 5.71, N 3.19.
9
Conversion of 2b to 2d. A solution of 2b (10 mg) and
sodium formate (10 mg) in formic acid (0.7 mL) was
placed in a J. Young NMR tube. The tube was connected
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to eudiometer and heated in an oil bath at 70 C for 30
min. About 15 mL of gas was produced during heating.
The solvent was evaporated in vacuum and the resulting
residue was left under vacuum for 1 h. The residue was
1
then dissolved in formic acid-d2. H NMR spectrum of the
residue contains peaks at -19.39, -25.04, and -27.11 ppm
which were assigned to complex 2d.20
Isomerization of 2c to 2f. A solution of 2c (40 mg) in
toluene-d8 (0.7 mL) was placed in a J. Young NMR tube
o
and heated in an oil bath at 110 C for 4 h. The resulting
solution contained 2c and 2f in a 1.6 : 1 ratio (Keq = 0.626).
1
The structure of 2f was derived from NMR data: H NMR
(600 MHz, toluene-d8): δ 9.41 (d, J = 6.7 Hz, 1H, ArH), 7.26
(d, J = 8.0 Hz, 1H, ArH), 6.74 (td, J = 7.7, 1.6 Hz, 1H, ArH),
6.61 (d, J = 7.8 Hz, 1H, ArH), 6.55 (t, J = 7.3 Hz, 1H, ArH),
6.20 (d, J = 7.3 Hz, 1H, ArH), 5.98 (t, J = 7.2 Hz, 1H, ArH),
3.02 (d, J = 7.8 Hz, 2H, CH2), 2.52 (d, J = 8.7 Hz, 2H, CH2),
1.30 (d, J = 12.2 Hz, 18H, 6CH3), 1.23 (d, J = 13.4 Hz, 18H,
6CH3), -6.64 (d, J = 150.4 Hz, 1H, IrH), -8.98 (br s, 2H,
t
t
[Ir2H3(CO)(2-PyCH2PBu2 ){µ-(C5H3N)CH2PBu2 }] (2c).
In a glovebox, complex 2 (50.0 mg, 7.3 x 10-5 mol), n-
butanol (108.0 mg, 1.46 x 10-3 mol, 20 eq.), and potassium
hydroxide (88.0 mg, 1.57 x 10-3 mol, 21.5 eq.) were mixed
with dry toluene (5 mL) in a 20 mL Straus flask. The flask
was charged with a stirring bar and sealed with a septum.
Outside the glovebox, the flask was placed in an oil bath
o
2IrH, resolves to a doublet at 100 C with J = 46.2 Hz). 13C
NMR (151 MHz, toluene-d8, derived from HSQC and
HMBC): δ 164.19, 163.48, 162.13, 159.87, 140.85, 134.09,
131.10, 121.13, 120.70, 109.83, 39.65, 34.44, 34.03, 31.80.
31P{1H} NMR (243 MHz, toluene-d8): δ 88.66, 63.79.
o
(120 C), and the septum was immediately pierced with a
syringe needle attached to eudiometer. In 15 min hydro-
gen evolution stopped, and the solution color turned
from dark-violet to orange. The flask was brought back to
the glovebox, and the precipitate (potassium butyrate)
was filtered off and washed with toluene. The orange so-
lution was evaporated to dryness under vacuum, and then
hexane (3 mL) was added to the solid to form a yellow
precipitate. The precipitate was filtered and washed with
hexane. After crystallization from benzene-hexane mix-
ture, 2c was obtained as a yellow crystalline powder (20
mg, 63%). Crystals suitable for X-ray analysis were ob-
Deuteration of 2c under Alcohol Dehydrogenation
Conditions. In a glovebox, complex 2c (10.0 mg, 1.13 x 10-5
mol), 1-hexanol-O,1,1-d3 (59.0 mg, 5.62 x 10-4 mol, 50 eq.),
and potassium hydroxide (31.0 mg, 5.62 x 10-4 mol, 50 eq.)
were mixed with dry toluene (5 mL) in a 20 mL Straus
flask. The following manipulations were the same as in
the synthesis of 2c (reaction time was 3 h). Analysis of the
1
recovered 2c-d4 by H NMR spectroscopy showed partial
deuteration (up to 34%) of protons with chemical shifts at
6.62, -7.51, -13.87, and -19.99 ppm.
1
tained by slow addition of hexane to benzene solution. H
NMR (600 MHz, C6D6): δ 8.58 (d, J = 5.6 Hz, 1H, ArH),
7.90 (dd, J = 7.7, 2.1 Hz, 1H, ArH), 6.86 (t, J = 7.6 Hz, 1H,
ArH), 6.78 (td, J = 7.5, 1.3 Hz, 1H, ArH), 6.62 (d, J = 7.8 Hz,
1H, ArH), 6.51 (d, J = 7.4 Hz, 1H, ArH), 6.07 (t, J = 7.1 Hz,
1H, ArH), 3.19 (dd, J = 15.7, 7.7 Hz, 1H, CH2), 3.00 (dd, J =
15.8, 7.3 Hz, 1H, CH2), 2.58 – 2.43 (m, 2H, CH2), 1.50 (d, J =
12.2 Hz, 9H, 3CH3), 1.37 (d, J = 12.1 Hz, 9H, 3CH3), 1.18 (d, J
= 13.6 Hz, 9H, 3CH3), 1.11 (d, J = 13.4 Hz, 9H, 3CH3), -7.51
(dd, J = 67.6, 7.5 Hz, 1H, IrH), -13.87 (ddd, J = 26.7, 13.7, 5.3
Conversion of 2c to 2g. A solution of 2c (20.0 mg, 2.25 x
10-5 mol) and freshly distilled n-hexanal (22.5 mg, 2.25 x 10-
mol, 10 eq.) in C6D6 (0.5 mL) was placed in a J. Young
4
NMR tube and heated in an oil bath at 80 oC for two days.
The resulting solution contained 2g, n-hexanol, hexyl
hexanoate, and unreacted n-hexanal. The solution was
evaporated to dryness under vacuum giving crude 2g as a
dark-yellow oil. The structure of 2g was derived from
NMR data: 1H NMR (600 MHz, toluene-d8): δ 8.18 (dd, J =
4.7, 1.7 Hz, 1H, ArH), 7.43 (dd, J = 7.6, 2.6 Hz, 1H, ArH),
6.81 (t, J = 7.6 Hz, 1H, ArH), 6.76 (dd, J = 7.5, 1.8 Hz, 1H,
ArH), 6.53 (d, J = 7.5 Hz, 1H, ArH), 6.36 (dd, J = 7.5, 4.7
13
Hz, 1H, IrH), -19.99 (dt, J = 12.2, 4.1 Hz, 1H, IrH). C NMR
(151 MHz, C6D6): δ 187.12 (d, J = 8.0 Hz), 178.55 (dd, J =
103.5, 4.4 Hz), 166.04 (d, J = 6.2 Hz), 164.98 (dd, J = 10.8,
6.1 Hz), 153.04 (d, J = 2.5 Hz), 144.85 (d, J = 7.7 Hz), 134.48,
ACS Paragon Plus Environment

ACS Catalysis
Hz, 1H, ArH), 3.76 (dd, J = 16.6, 9.2 Hz, 1H, CH2), 3.60 (dd,
Page 10 of 11
gents for Organic Synthesis, 2001, John Wiley &
1
2
3
4
5
6
7
8
J = 16.6, 9.5 Hz, 1H, CH2), 2.41 (d, J = 8.7 Hz, 2H, CH2), 1.37
(d, J = 13.1 Hz, 9H, 3CH3), 1.20 (d, J = 12.8 Hz, 9H, 3CH3),
1.06 (d, J = 13.9 Hz, 9H, 3CH3), 0.96 (d, J = 14.0 Hz, 9H,
3CH3), -8.44 (ddd, J = 52.5, 7.3, 5.2 Hz, 1H, IrH), -11.15 (ddd,
J = 25.9, 12.6, 5.2 Hz, 1H, IrH). 31P{1H} NMR (243 MHz, tol-
uene-d8): δ 88.18, 44.46. MALDI-MS: m/z calcd. for
C29H48Ir2N2OP2 [M]+ 886.25, found 886.25.
Deprotonation of 2c. t-BuOK (12.6 mg, 1.13 x 10-4 mol, 5
eq.) was added to a solution of 2c (20.0 mg, 2.25 x 10-5
mol) in C6D6 (0.5 mL) which caused formation of 2h and
instant color change from yellow to dark-red. Addition of
n-hexanol (23.0 mg, 2.25 x 10-4 mol, 10 eq.) to the red solu-
tion converted 2h back to 2c. These transformations were
monitored by 1H NMR (see Supporting Information).
Sons, Ltd.
7. Reid, E.E.; Worthington, H.; Larchar, A.W., The
Action of Caustic Alkali and of Alkaline Salts on
Alcohols. J. Am. Chem. Soc. 1939, 61, 99-101.
8. Ciufolini, M.A.; Swaminathan, S., Synthesis of a
Model Depsipeptide Segment of Luzopeptins (BBM
928), Potent Antitumor and Antiretroviral Antibi-
otics. Tetrahedron Lett. 1989, 30, 3027-3028.
9
9. Crimmins, M.T.; DeBaillie, A.C., Enantioselective
Total Synthesis of Bistramide A. J. Am. Chem. Soc.
2006, 128, 4936-4937.
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drate-Based Approach. Tetrahedron Lett. 2009, 50,
2048-2049.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/**.
Experimental procedures, graphical and tabular characteriza-
tion information (PDF)
11. Fuwa, H., Chapter 5 - (−)-Lyngbyaloside B, a Ma-
rine Macrolide Glycoside: Total Synthesis and Ste-
reochemical Revision. Strategies and Tactics in Or-
ganic Synthesis 2016, 12, 143-168.
12. Zweifel, T.; Naubron, J.; Grützmacher, H., Cata-
lyzed Dehydrogenative Coupling of Primary Alco-
hols with Water, Methanol, or Amines. Angew.
Chem. Int. Ed. 2009, 48, 559–563.
AUTHOR INFORMATION
Corresponding Author
*E-mail TJW: travisw@usc.edu
13. Trincado, M.; Grutzmacher, H.; Vizza, F.;
Bianchini, C., Domino Rhodium/Palladium-
Catalyzed Dehydrogenation Reactions of Alcohols
to Acids by Hydrogen Transfer to Inactivated
Alkenes. Chem. Eur. J. 2010, 16, 2751–2757.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
14. Annen, S.; Zweifel, T.; Ricatto, F.; Grutzmacher, H.,
Catalytic Aerobic Dehydrogenative Coupling of
Primary Alcohols and Water to Acids Promoted by
This work is sponsored by the NSF (CHE-1566167), and the
Hydrocarbon Research Foundation. We thank the NSF (DBI-
0821671, CHE-0840366, CHE-1048807) and the NIH (S10
RR25432) for analytical instrumentation. We thank Prof. Ralf
Haiges for help with X-ray crystallography. Fellowship assis-
tance from USC Dornsife College is gratefully acknowledged.
a
Rhodium(I) Amido N-Heterocyclic Carbene
Complex. ChemCatChem 2010, 2, 1286–1295.
15. Balaraman, E.; Khaskin, E.; Leitus, G.; Milstein, D.,
Catalytic Transformation of Alcohols to Carboxylic
Acid Salts and H2 Using Water as the Oxygen Atom
Source. Nature Chemistry 2013, 5, 122-125.
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