La[N(SiMe3)2]3-Catalyzed Ester Reductions with Pinacolborane: Scope and Mechanism of Ester Cleavage

Article abstract of DOI:10.1021/acscatal.9b02605

Tris[N,N-bis(trimethylsilyl)amido]lanthanum (La^NTMS) is an efficient, highly active, and selective homogeneous catalyst for ester reduction with pinacolborane (HBpin). Alkyl and aryl esters are cleaved to the corresponding alkoxy- and aryloxy-boronic esters which can then be straightforwardly hydrolyzed to alcohols. Ester reduction is achieved with 1 mol % catalyst loading at 25-60 °C, and most substrates are quantitatively reduced in 1 h. Nitro, halide, and amino functional groups are well tolerated, and ester reduction is completely chemoselective over potentially competing intra- or intermolecular alkene or alkyne hydroboration. Kinetic studies, isotopic labeling, and density functional theory calculations with energetic span analysis argue that ester reduction proceeds through a rate-determining hydride-transfer step that is ligand-centered (hydride is transferred directly from bound HBpin to bound ester) and not through a metal hydride-based intermediate that is often observed in organolanthanide catalysis. The active catalyst is proposed to be a La-hemiacetal, [(Me₃Si)₂N]₂La-OCHR(OR)[HBpin], generated in situ from La^NTMS via hydroboronolysis of a single La-N(SiMe₃)₂ bond. These results add to the growing compendium of selective oxygenate transformations that La^NTMS is competent to catalyze, further underscoring the value and versatility of homoleptic lanthanide complexes in homogeneous catalytic organic synthesis.

Full text of DOI:10.1021/acscatal.9b02605

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Article
La[N(SiMe3)2]3 – Catalyzed Ester Reductions with
Pinacolborane. Scope and Mechanism of Ester Cleavage
Christopher Jeffrey Barger, Alessandro Motta, Victoria L. Weidner, Tracy Lynn Lohr, and Tobin J. Marks
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02605 • Publication Date (Web): 21 Aug 2019
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La[N(SiMe3)2]3 – Catalyzed Ester Reductions with
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Pinacolborane. Scope and Mechanism of Ester Cleavage
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Christopher J. Barger, Alessandro Motta, † Victoria L. Weidner, Tracy L. Lohr,*‡ and Tobin J.
Marks*
Department of Chemistry, Northwestern University, 2145 Sheridan Rd, Evanston, Illinois 60208-
3113, United States
†Dipartimento di Scienze Chimiche, Università di Roma "La Sapienza" and INSTM, UdR Roma,
Piazzale Aldo Moro 5, I-00185 Roma, Italy
Lanthanides, homogeneous catalysis, hydroboration, ester reduction, C-O bond cleavage
Abstract. Tris[N,N-bis(trimethylsilyl)amido]lanthanum (LaNTMS) is an efficient, highly active,
and selective homogeneous catalyst for ester reduction with pinacolborane (HBpin). Alkyl and
aryl esters are cleaved to the corresponding alkoxy- and aryloxy-boronic esters which can then be
straightforwardly hydrolyzed to alcohols. Ester reduction is achieved with 1 mol% catalyst loading
at 25-60°C, and most substrates are quantitatively reduced in 1 hour. Nitro, halide, and amino
functional groups are well-tolerated, and ester reduction is completely chemoselective over
potentially competing intra- or intermolecular alkene or alkyne hydroboration. Kinetic studies,
isotopic labeling, and DFT calculations with energetic span analysis argue that ester reduction
proceeds through a rate-determining hydride transfer step that is ligand-centered (hydride is
transferred directly from bound HBpin to bound ester) and not through a metal hydride-based
intermediate that is often observed in organolanthanide catalysis. The active catalyst is proposed
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to be a La-hemiacetal, [(Me3Si)2N]2La-OCHR(OR)[HBpin], generated in situ from LaNTMS via
hydroboronolysis of a single La-N(SiMe3)2 bond. These results add to the growing compendium
of selective oxygenate transformations that LaNTMS is competent to catalyze, further underscoring
the value and versatility of homoleptic lanthanide complexes in homogeneous catalytic organic
synthesis.
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Introduction
The selective reduction of esters is a topic of great interest to both the academic and industrial
synthetic chemistry communities.1 In addition to being an important transformation in the
synthesis of fine chemicals and pharmaceuticals,2 ester linkages are ubiquitous in lignocellulosic
biomass and plant-based oils, valuable renewable sources of fuels and chemical feedstocks, and
their selective reduction is of great importance.3 Unlike ketones and aldehydes, esters are generally
inert towards mild reductants as typified by NaBH4 and instead require more aggressive reductants
such as BH3 and LiAlH4, reagents which can pose significant handling risks and often suffer from
poor selectivity in the presence of other reducible functionalities.4 Catalytic hydrogenation has
been explored extensively as a more atom-efficient and selective route to ester reduction, however
the high pressures and temperatures required to achieve satisfactory conversions, typically in
excess of 5 bar and 100°C, pose significant safety concerns, and require capital-intensive
equipment.5 The need for safer and more convenient ester reduction methodologies has generated
great interest in recent years in catalytic hydrosilylation, leading to a wealth of reports detailing
the selective reduction of esters and other carbonyl groups at ambient pressures and moderate
temperatures (typically < 100°C).6 Conversely, reports of efficient, selective ester hydroboration
are sparse,7 a surprising observation considering that silanes and boranes often behave similarly in
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other hydrofunctionalization processes,1a, 6b, 8 and that hydroboration is well-developed in the
context of ketone/aldehyde reduction.7c, 9
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Encouraged by recent results from this laboratory on lanthanide triflate-catalyzed ester Calkoxy
-
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O bond tandem hydrogenolysis processes, we turned our focus to kinetically labile and
electrophilic lanthanide complexes with alternative reducing agents to affect Cacyl-O bond
reduction,
specifically
hydroboronolysis
(Figure
1A).10
Tris[N,N-
bis(trimethylsilyl)amido]lanthanide complexes (Ln[N(SiMe3)2]3, abbreviated here as LnNTMS
Figure 1B) are commercially available for many lanthanides, or they can be readily
,
B.
Ln
A.
R
O
O
O
SiMe3
SiMe3
O
X = OTf
H2
X = N(SiMe3)2
(RO)2B-H
R'
B H
N
R'
LnX3
O
O
R
3
LnNTMS
Calkoxy-O Cleavage
Cacyl-O Cleavage
HBpin
Figure 1. A. Comparison of ester Calkoxy-O bond cleavage/hydrogenolysis, previously reported for
lanthanide (Ln) triflates),10 and Ln-catalyzed Cacyl-O bond cleavage/hydroboronolysis pathways
(this work). OTf¯ = CF3SO3¯. B. Structures of tris[N,N-bis(trimethylsilyl)amido]lanthanide
complexes (LnNTMS) where Ln = any lanthanide, and pinacolborane (HBpin).
synthesized/purified, rendering them accessible and of great utility to the synthetic methods
community.11 As such, they are frequently employed as precursors to more elaborate lanthanide
organometallics12 and as homogeneous catalysts, particularly for alkene/alkyne
hydrofunctionalization.13 Recently, we reported that LaNTMS displays remarkable catalytic activity
for ketone and aldehyde hydroboration with HBpin (Figure 1B), with turnover frequencies as high
as 40,000 h-1 at 25°C.9l With this in mind, we sought to explore the catalytic hydroboration activity
of LaNTMS with more complex, less readily-reduced oxygenates. While this investigation was in
progress, Patnaik and Sadow reported that the homoleptic lanthanide tris-hydrocarbyl
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La[C(SiHMe2)3]3 is highly active for the hydroboration of epoxides and esters, raising the
intriguing question of whether commercially available lanthanide amides such as LaNTMS might be
viable ester hydroboration catalysts, and if so, with what scope and reaction mechanism.7a
Here we report that LaNTMS effectively mediates the cleavage of a wide variety of alkyl and
aryl esters to the corresponding alkoxyboranes. This system, which utilizes a commercially
available catalyst, mild reaction conditions, and easily-handled HBpin, represents a significant
advance over traditional ester reduction methods. We discuss the scope and mechanism of this
transformation through combined experiment and DFT-level theory, which is, to the best of our
knowledge, the first attempt to do so in the field of catalytic ester hydroboration. It will be seen
that the reaction, which is selective over nitro functionalities as well as alkene and alkyne
reductions, proceeds through a La-hemiacetal active catalyst/resting state with a very unusual
ligand-centered hydride transfer step.
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Results
Ester catalytic reduction scope
Optimal conditions for ester cleavage (Table 1) are achieved with 1 mol % of LaNTMS catalyst
and a slight excess of HBpin (2.2 equiv vs. ester). Table 1 shows the full scope of esters
investigated. Other LnNTMS complexes (Ln = Ce, Sm, Yb, and Y) were also screened with phenyl
benzoate reduction as the model reaction. These catalysts are found to have similar, though slightly
diminished reduction rates relative to LaNTMS. This, combined with the relative ease with which
NMR spectra of metal-organics containing diamagnetic La3+ can be analyzed, led us to pursue
further studies with LaNTMS exclusively. Catecholborane (“HBcat”) and 9-
borabicyclo[3.3.1]nonane (“9-BBN”) were also explored as alternative reductants to HBpin (also
using phenyl benzoate reduction as a model reaction). HBcat produces negligible product (<5%)
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after 20 hours at 25°C, while 9-BBN affords 46% conversion under the same conditions. These
are both significantly poorer performing than HBpin (97% yield after 16 hours at 25°C; Table 1).
As can be seen in Table 1, all esters are reduced near-quantitatively at 25°C under the
conditions described above, although several require heating at 60°C for more convenient reaction
times (≤ 5 h). Importantly, side-reactions with nitro groups or conjugated alkenes are not observed
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Table 1. Scope of LaNTMS-catalyzed ester reduction/cleavage with pinacolboranea
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1% LaNTMS OBpin
O
R'
+ 2.2 HBpin
+
R'OBpin
T/°C t/h Yield/%b
C6D6
R
O
R
Substrate
Product(s)
#
1
O
9
PhCH2OBpin
+
25
60
16
5
97
99
Ph
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PhOBpin
Ph
O
O
2
3
4
25 0.25 >99
2 EtOBpin
O
O
PhOBpin
+
25
60
5
1
>99
>99
Ph
EtOBpin
O
O
O
CyOBpin
+
>99
25
1
EtOBpin
O
O
tBuOBpin
+
25
60
16
1
>99
>99
5
6
EtOBpin
AdmOBpin
+
O
25
>99
1
EtOBpin
O
O
Cy(OBpin)2
+
2EtOBpin
O
O
98
>99
25
60
48
1
7c
8
O
O
O
iBuOBpin
+
25 0.25
>99
>99
EtOBpin
O
(CH3)3CCH2OBpin
25
0.5
+
9
O
EtOBpin
O
OBpin
OBpin
10
O
25 0.25
>99
O
25
60
16
3
>99
>99
11d
12d
Ph
N
OBpin
OBpin
Ph
N
O
O
O
25
25
16
98
93
OBpin
O
13d
1.5
O
O
OBpin
14d
15d
16d
25
25
1.5
1.5
>99
O
OBpin
OBpin
O
>99
>99
O
F
F
O
25 0.25
O
O2N
O2N
a
Reaction conditions: Ester (0.25 mmol) and HBpin (0.55 mmol, 2.2
equiv) in C6D6 (500 L), and LaNTMS (2.5 mol). b Yields of RCH2OBpin
products calculated by integration of product 1H NMR signals vs
c
d
hexamethylbenzene internal standard. 4.4 equiv. HBpin. Product +
MeOBpin
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(Table 1, entries 16 and 11, respectively), and intermolecular competition experiments indicate
that the esters are preferentially reduced with complete exclusion of added 1-octene or 1-octyne
(Scheme 1). Given the high activity observed for LaNTMS-catalyzed ketone and aldehyde
hydroboration,9l selectivity for ester reduction over these more reactive functional groups would
not be expected. Predictably, reduction of tert-butyl acetoacetate occurs only at the ketone, and the
ester functionality remains intact, even after 16 hours at 25°C (see SI for details). Preparative-scale
(2.5 mmol) reduction of ethyl acetate (entry 2) gives a 94% isolated yield of EtOBpin under
conditions identical to those used in the NMR scale reaction.
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OBpin
O
1% LaNTMS
+
+
+
+
-octyl-Bpin
n
hexyl
n-
O
2 eq HBpin
BpinO
N.D.
0.125 mmol
0.125 mmol
98%
OBpin
O
O
Bpin
+
1% LaNTMS
2 eq HBpin
+
-hexyl
n
-hexyl
n
BpinO
0.125 mmol
0.125 mmol
N.D.
96%
Scheme 1. Competition experiments illustrating the selective reduction of phenyl benzoate in the
presence of 1-octene (top) and 1-octyne (bottom). N.D. = not detected. Conditions: 1.00 mL C6D6,
60°C, 5h.
While all ester substrates are efficiently reduced at 60°C, steric impediments at the alkoxy-
position (R’ in Table 1) significantly depress rates at 25°C, with tert-butyl acetate (Table 1, entry
5) requiring 16 h to reach completion, vs. 1 h for cyclohexyl- and 2-adamantyl acetate (entries 4
and 6, respectively) and only 10 min for ethyl acetate (entry 2). Interestingly, steric impediments
at the acyl position (R in Table 1) have very little effect on the rate of reduction, with ethyl acetate
ethyl isobutyrate, and ethyl pivalate (entries 2, 8, and 9, respectively) all required ≤ 30 min at 25°C
to reach completion. The presence of a phenyl group in the R’ position (entries 1 and 3) likewise
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depresses the rate, suggesting the charge density on the alkoxy oxygen is an important factor in
determining the overall conversion rate, possibly implicating La-O coordination in the turnover-
limiting step (vide infra). Note also that ε-caprolactone (Table 1, entry 10) is reduced
quantitatively to the ring-opened bis-borane at 25°C in ~15 min, with no evidence of potentially
competing polymerization. This is surprising since the analogous SmNTMS and YNTMS complexes
are reported to be highly active catalysts for caprolactone ring-opening polymerization.14 Indeed,
when ε-caprolactone is added to a LaNTMS solution in benzene without HBpin present, rapid
polymerization ensues, as evidenced by solidification of the reaction mixture. Interestingly,
subsequent addition of HBpin to the polycaprolactone results in rapid de-polymerization and
conversion to a non-viscous liquid that is NMR spectroscopically identical to the product of entry
10 in Table 1.
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Experimental kinetic studies
To probe the mechanism of the present ester cleavage process, the rate law for catalytic phenyl
benzoate reduction was determined by a combination of initial rates analysis at various catalyst
concentrations (for the order in LaNTMS concentration) and by monitoring substrate consumption
under pseudo-first order conditions (see SI for details). The reaction rate is observed to have a
first-order dependence on LaNTMS concentration, whereas ester and HBpin concentration variations
over a broad range have no detectable effect on the rate (eq. 1). Activation parameters calculated
for the reduction of phenyl benzoate over the temperature range of 15-35°C reveal a relatively
Rate = k[LaNTMS]1[Ester]0[HBpin]0
(1)
low apparent activation enthalpy (ΔH‡ = 8.2 ± 0.3 kcal/mol) and a very large, negative activation
entropy (ΔS‡ = -53.1 ± 0.9 e.u.). To gauge the impact of electron density at the carbonyl carbon
on the rate of reaction, a Hammett plot (Figure 2) was constructed using a series of para-substituted
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methyl benzoates (Table 1 entries 12-16; see SI for details on rate determination). A significant
increase in turnover is observed for substrates with electron-withdrawing substituents at the R
position, as indicated by a positive value (1.11) for the parameter ρ. Additional mechanistic details
were obtained from isotopic labeling studies. Replacing HBpin with DBpin in the reduction of
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1
methyl 4-(N,N-dimethylamino)benzoate eliminates both methylene protons in the product H
NMR spectra, indicating both hydride equivalents are delivered to the carbonyl carbon (Figure 3).
Comparing these reaction rates yields a kinetic isotope effect (KIE) of 1.49 (see SI for details).
Figure 2. Hammett plot generated for the LaNTMS-catalyzed reduction of para-substituted methyl
benzoates with HBpin.
OBpin
H
H
N
OBpin
D
D
N
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
ppm
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Figure 3. 1H NMR spectra of the LaNTMS-catalyzed reduction of methyl 4-
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(dimethylamino)benzoate with 2 equiv of HBpin (top) and DBpin (bottom). The absence of a
1
signal in the ~δ 5.0 ppm region (outlined in red) for reduction with DBpin shows that both H
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NMR-silent deuteride equivalents are delivered to the carbonyl carbon of the substrate.
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In Situ Stoichiometric 1H, 13C and 11B NMR Spectroscopic Studies
The pathway(s) and species involved in the present ester hydroboration process were probed
in situ by examining the reactivity of LaNTMS with stoichiometric amounts of ester and/or HBpin
at room temperature. No reaction is observed between LaNTMS and phenyl benzoate only, however
the 1H NMR signals of both species shift slightly, suggesting that ester reversibly coordinates to
Lewis acidic LaNTMS 15 In contrast, LaNTMS and HBpin undergo reaction, as evidenced by the
.
1
13
11
appearance of several new signals in the H, C and, B NMR spectra (see SI for spectra and
characterization details). In the 1H NMR, singlets at δ 0.37 and 1.03 ppm (integrating as 18 and 12
H, respectively) are attributable to the known compound pinB-N(SiMe3)2.16 Singlets at δ 1.37 and
1.56 ppm, both integrating to 6 H, as well as a quartet in the 11B NMR at -6.3 ppm, are indicative
of a reaction pathway involving ring-opening of a pinacolborane ring to give the off-cycle borate
complex shown below (AOC, Scheme 2A). A similar complex was reported, by this laboratory, to
be an off-cycle product of lanthanocene-catalyzed pyridine dearomatization with pinacolborane
(Scheme 2B) and characterized by x-ray diffraction.17 Notably, in the present system, the La-O
bond integrity is
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A.
B.
La[N(SiMe3)2]3
4 HBpin
2 pinB-N(SiMe3)2
4 HBpin + PhCO2Ph
Cp*
Cp*
N
H
2 pinB-N(SiMe3)2
+ PhOBpin
La
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2 HBpin
H
H
O
Pyridine
O
B
O
O
N(SiMe3)2
H
H
N(SiMe3)2
La
H
H
B
La
O
BH2
Cp*
Cp*
O
O
O
BH3
La
O
BOC
Bpin
AOC
PhCO2Ph PhOBpin
Scheme 2. A. Catalyst off-cycle products observed in NMR studies of stoichiometric substrate and
LaNTMS. B. Structure of a product similar to AOC isolated from an organolanthanide-catalyzed
pyridine dearomatization/hydroboration process.17 Cp* = η5-pentamethylcyclopentadienyl
maintained, as evidenced by a greater downfield shift in the adjacent C(CH3)2 protons (1.56
ppm),18 whereas with pyridine hydroboration, this bond is broken and replaced by an intact Bpin
moiety (adjacent C(CH3)2 protons appear at 1.30 ppm; Scheme 2B). When ester is added to
complex AOC, or when stoichiometric ester and HBpin are added simultaneously to LaNTMS, the
11B NMR signal at -6.3 ppm disappears and a triplet at 47.4 ppm grows in, indicating a hydride is
ˉ
transferred from the R-BH3 group, yielding R-BH2 and a partially reduced ester (BOC, Scheme
2A). Subsequent addition of excess substrates does not result in turnover, indicating this is, in fact,
an off-cycle pathway that likely results in deactivation. We propose that the true active catalyst
(vide infra) is not detectable by NMR, likely due to the availability of the above deactivation
pathway at low substrate concentrations relative to catalyst concentration (such as those employed
in the above spectroscopic studies). Attempts to more fully characterize these off-cycle products
were unsuccessful due to their decomposition into intractable, white solids over the course of 2
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hours at room temperature. However, DFT analysis argues that these products are energetically
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accessible in the conditions employed above and their formation is highly exergonic (see SI, p.
S17).
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DFT Mechanistic Analysis
To more fully understand the mechanism of LaNTMS-catalyzed ester reduction with
pinacolborane, DFT modeling of the catalyst activation process, catalytic cycle, and potential off-
cycle pathways was performed using methyl benzoate as a model ester (see Experimental Section
for computational details; see SI for DFT analysis and free energy profiles of the catalyst
deactivation pathway). Figure 4 shows the computed catalyst activation process. The LaNTMS pre-
catalyst is activated for ester reduction first by HBpin-mediated cleavage of a La-N(SiMe3)2 bond
(TSact-1), forming complex Iact-2. Direct hydride transfer from the coordinated
[(SiMe3)2NB(H)pin]- molecule of Iact-2 to a coordinated ester molecule (TSact-2) then affords
lanthanide-hemiacetal species Iact-3 and pinB-N(SiMe3)2 as a byproduct. Subsequent coordination
of a second HBpin molecule leads to the active catalyst. The entire process is exergonic (-44.9
kcal/mol) and has an energy barrier of only 9.9 kcal/mol associated with the scission of the La-N
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TSact-1
TSact-2
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6.9
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-1.5
2.4
-3.0
0.0
-8.7
Active
Catalyst
Iact-1
-28.5
Iact-3
Iact-2
-44.9
Figure 4. Gibbs free energy profile (kcal/mol) of the LaNTMS pre-catalyst activation process using
methyl benzoate as a model ester substrate. The occurrence of a La-centered hydride (via the step
denoted by a red “X”) is energetically implausible. La = violet, C = grey, H = cyan, B = yellow,
and N[SiMe3]2 = brown.
bond in TSact-1. The possibility of a [(Me3Si)2N]2La-H active catalyst was also explored due to
the ubiquity of proposed L2Ln-H species as both active catalysts and intermediates in the
organolanthanide literature,17, 19 however the energy required to form such a species in the present
system (> 30kcal/mol) appears to be unlikely.
The proposed catalytic cycle consists of three principal steps (Figure 5): 1) Lewis acidic boron
(of the coordinated HBpin molecule) attack on the hemiacetal oxygen of the active catalyst A
(TS1), leading to formation of a new B-O bond and dissociation of the La-Ohemiacetal bond. This
step, which produces a La-coordinated hemiacetal-pinacolborate species, proceeds with a
computed barrier of 3.1 kcal/mol, and the subsequent coordination of a second ester molecule leads
to an overall stabilization (-12.4 kcal/mol) and generates complex B. 2) Transfer of the ester
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TS1
TS2
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3.1
A
1.7
ester
HBpin
TDTS
0.0
ester
TS3
-12.4
ester
HBpin
-31.3
B
14.7
-46.0
-53.1
I2
C
TDI
A
Figure 5. Gibbs free energy profile (kcal/mol) for the catalytic cleavage of methyl benzoate via
hydroboration. The active catalyst is derived from LaNTMS (Figure 4); TDI = turnover-determining
intermediate, TDTS = turnover-determining transition state. La = violet, C = grey, H = cyan, B =
yellow, and N[SiMe3]2 = brown.
methoxy group to the coordinated HBpin, followed by a rapid hydride transfer from
[HB(OMe)(pin)]– to the La-hydroborate complex (TS2), forms the first reduction product,
MeOBpin. The product of this step (complex C) is highly stabilized by the coordination of both
ester and HBpin molecules, leading to an overall stabilization of -46.0 kcal/mol. 3) Intramolecular
hydride transfer from complex C to the coordinated ester (TS3) leads to formation and subsequent
release of the second reduction product, PhCH2OBpin, restoring the active catalyst A. In the
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transition state structure, HBpin loses its coordination with the La metal center and interacts
weakly with the carbonyl oxygen of the coordinated ester. This step is exergonic (-7.1 kcal/mol)
and represents the rate-determining step with an energy barrier of 14.7 kcal/mol.
Discussion
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Figure 6 presents a plausible scenario that accounts for the experimental mechanistic
observations and DFT calculations discussed above. Note that negligible reaction is observed in
stoichiometric mixtures of LaNTMS and phenyl benzoate, providing evidence that LaNTMS must be
R
R'
R
O
O
H
RCO2R'
H
B
O
O
HBpin
N*- Bpin
*N
*N
O
La N*
i
R'
O
R
*N
*N
La
O
HBpin
O
O
O
HBpin
R'
B
B H
ii
A
R
H
O
O
*N
*N
R'OBpin
La
R'
HBpin
C
O
RCH2OBpin
TDTS
R
R
H
R
H
O
O
H
B
O
O
H
B
O
H
*N
*N
R
H
La
*N
O
La
iii
*N
O
O
O
R'
O
B H
O
B
R'
O
H
O
Figure 6. Catalyst activation and catalytic cycle for LaNTMS-catalyzed ester hydroboration. N* =
N(SiMe3)2. Step iii is proposed to be turnover limiting, and the DFT-computed turnover-
determining transition state (TDTS) is shown.
activated with HBpin to initiate the catalytic reduction cycle. According to the DFT and NMR
results described above, activation of the ester-coordinated precatalyst with HBpin, followed by
coordination of additional HBpin, generates the lanthanide-hemiacetal active catalyst A and
known pinB-N(SiMe3)2 as a by-product. Just as in the stoichiometric studies described above, the
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TMS methyl protons of the aminoborane are also observed in the in situ H NMR spectra of
catalytic reactions (the Bpin methyl protons are obscured by substrate/product signals).16 This
resonance integrates in an approximate 1:2 ratio to the LaNTMS methyl protons (at δ 0.28 ppm),
arguing mono-activation of the pre-catalyst does in fact occur. Furthermore, Sadow and co-
workers recently proposed a similar hemiacetal-based catalytic intermediate, [La]-OCHR(OR), for
La[C(SiHMe2)3]3-catalyzed ester hydroboration based on detailed kinetic studies.7a The
similarities between these homoleptic lanthanide complexes, both in terms of structure and
reactivity, suggest similar species would be active for ester hydroboration. Additionally, the
involvement of both ester and HBpin in catalyst activation is supported in the present work by the
off-cycle reaction observed when HBpin is allowed to react with LaNTMS in the absence of ester
(vide supra). This suggests that without a substantial excess of ester (relative to LaNTMS) to accept
the hydride from La-coordinated HBpin and generate A, an unstable La-hydride/borate species is
formed, opening the pinacolate ring of HBpin and deactivating the La center.17
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Activated by the oxophilic La center, HBpin promotes La-Ohemiacetal bond dissociation and B-
Ohemiacetal bond formation (Figure 6, step i), producing a transient complex that is spontaneously
stabilized by coordination of a new ester molecule, yielding intermediate B. This sterically
congested species then rearranges intramolecularly, yielding R’OBpin. Subsequent, barrierless
coordination of HBpin affords stabilized complex C (step ii). Finally, intramolecular hydride
transfer from the boron atom of the hydroborate-La complex to the coordinated ester (step iii)
restores the active catalyst A for subsequent catalytic cycles. Assignment of this step as turnover-
limiting is supported by several experimental observations. The experimentally derived activation
parameters, consisting of a small, positive ΔH‡ and large, negative ΔS‡, suggest the transition state
is highly organized and sterically congested, and the overall first-order reaction rate requires that
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the turnover-limiting step is intramolecular.20 Notably, the activation parameters reported for this
system (ΔH‡ = 8.2 kcal/mol, ΔS‡ = -53.1 e.u.) are very similar to those reported previously for
aldehyde hydroboration with B-alkyl-9-BBN (ΔH‡ = 9.1 - 9.8 kcal/mol, ΔS‡ = -43 - -49 e.u.).21
The transition state proposed for this reaction is also quite similar to the one proposed above, as it
proceeds through a sterically congested and conformationally constrained transition state and
involves intramolecular hydride transfer to the carbonyl.
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The zero order reaction rate law found experimentally for HBpin and ester concentrations is
supported by the DFT calculations (Figure 5), which find that neither HBpin nor ester enters the
catalytic cycle between the turnover-determining intermediate (TDI, C) and the turnover-
determining transition state (TDTS, TS3).22 The high degree of steric congestion in the transition
state would lead to depressed rates for sterically encumbered substrates, which is observed
experimentally. A small, positive Hammett ρ value (ρ = 1.11, Figure 2) indicates that the transition
state is stabilized by withdrawal of electron density from the carbonyl carbon, but to a much lesser
extent than is observed for typical base-catalyzed ester cleavages (ρ =1.9-2.5).23 This supports the
present assignment that the turnover-limiting step involves nucleophilic hydride attack on a
carbonyl bond that has been activated, in this case by simultaneous C=O coordination to both
HBpin and La, priming the acyl carbon for nucleophilic attack and diminishing ρ.
While the present KIE of 1.49 for ester reduction with DBpin is small for a primary KIE, it is
much larger than typical values for secondary isotope effects, 20 supporting an assignment of B-H
scission in the turnover-limiting step. While the lack of previously reported KIEs for HBpin-based
ester reduction prevents direct comparison, analogous reductions of N-heteroarenes,24 ketones,25
and nitriles26 proceed with somewhat higher KIEs, ranging from 2.3-2.8. However, Hartwig and
co-workers report a similarly small KIE (1.62) for the addition of catecholborane, via σ-bond
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metathesis, to a Ru-alkyl, indicating KIEs this small are not without precedent for B-H bond
scission.27 In this system, it is likely that slight OB interaction in the TDTS likely weakens the
B-H bond prior to scission, contributing to the lower KIE than might be expected for such a
reaction. The terminal location of the borane derived hydrogens is also telling. As noted above,
the deuterium-labelling experiment shows that both hydride equivalents are delivered to the
carbonyl carbon, effectively ruling out the possibility of a reverse-Tishchenko-based mechanism
(Scheme 3). Such a mechanism warrants consideration since the Tishchenko reaction (coupling of
aldehydes to form esters) is catalyzed by LnNTMS complexes,28 and a similar mechanism was
proposed previously for Mg-catalyzed ester hydroboration.7d Note also that a Tishchenko-like pre-
equilibrium could not account for substrates lacking an α-H in the R’ position (i.e., Table 1, entries
1, 3, and 5) since the aldehyde C=O bond cannot form at a fully substituted carbon center.
Bpin
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O
O
O
[La]
O
D
R
[La]
[La]
R'
R
O
R
H
R'
H
DBpin
O
R'
[La]
2 DBpin
Reverse
Tishchenko
DBpin
Hemiacetal
Bpin
D
D
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H
H
Bpin
D
H
Bpin
D
H
O
O
O
O
R
R'
R
R'
OBSERVED
NOT OBSERVED
Scheme 3. Isotopic labelling differentiation of the hemiacetal-based ester hydroboration
mechanism proposed here and the reverse-Tishchenko type mechanism proposed for Mg-catalyzed
ester hydroboration.7d
Conclusions
The scope and mechanism of LaNTMS-catalyzed, pinacolborane-based reduction of a diverse
series of esters is investigated experimentally and by DFT computation. The catalyst shows
complete selectivity for ester reduction over competing nitro groups, alkenes, and alkynes, even at
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temperatures as high as 60°C. Experimental and computation-based mechanistic studies indicate
that the active catalyst is generated from the LaNTMS pre-catalyst by HBpin-mediated La-N bond
scission, generating a La-hemiacetal species that is active for ester reduction. The presence of ester
in the catalyst activation process likely inhibits the formation of a L2La-H species, which could
explain the selectivity of this catalyst over alkene and alkyne hydroboration, reactions which have
previously been proposed to proceed through a L2La-H active catalyst.13k, 19e The turnover-limiting
step is proposed to involve intramolecular, concerted hydride transfer/C-O bond cleavage, leading
to an overall first-order rate law, rate = [LaNTMS]1[ester]0[HBpin]0. This report further demonstrates
the important role that lanthanide catalysis can play in experimental chemical synthesis, and it
represents the first attempt at a combined experimental-theoretical approach to discerning HBpin-
mediated ester reduction. By combining a mild reductant like HBpin with the highly active and
readily accessible catalyst LaNTMS, a safer, more selective, and convenient route to ester reduction
has been realized.
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Experimental Section
Materials and Methods
All manipulations of air-sensitive materials were carried out with rigorous exclusion of O2
and moisture in flame- or oven-dried Schlenk-type glassware on a dual-manifold Schlenk line or
in an argon-filled glovebox with a high capacity recirculator (<0.5 ppm O2). Benzene-d6
(Cambridge Isotope Laboratories; 99+ atom % D) was stored over Na/K alloy and vacuum
transferred prior to use. La[N(SiMe3)2]3 (LaNTMS) and hexamethylbenzene were purchased from
Sigma-Aldrich Co. and sublimed under high-vacuum (10-6 Torr). Pinacolborane (“HBpin”) was
purchased from Sigma-Aldrich Co. and distilled under high-vacuum (10-6 Torr) to remove trace
boronic acid impurities and stored at -35°C in a glovebox.17 Ester substrates were purchased from
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Sigma-Aldrich Co. and dried over 3Å molecular sieves (liquid esters) or under vacuum overnight
(solid esters). The products of ester cleavage (alkoxy boryl esters) were characterized by 1H, 13C,
and 11B NMR. NMR spectra were recorded on a Bruker Avance III (500 MHz, 1H; 125 MHz, 13C),
Varian Inova 500 (500 MHz, 1H; 125 MHz, 13C), Agilent DD MR-400 (400 MHz, 1H; 100 MHz,
13C; 128 MHz, 11B), or Agilent DD2 500 (500 MHz, 1H; 125 MHz, 13C). Chemical shifts (δ) for
1H and 13C are referenced to residual solvent resonances (7.16 and 128.06 ppm, resp., for benzene-
d6). 11B shifts are referenced to an external BF3·OEt2 standard. NMR scale reactions were carried
out either in Teflon-sealed J. Young tubes or rubber septum-sealed tubes.
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General Procedure for NMR-scale, LaNTMS-catalyzed ester reductions with HBpin
For solid esters: In the glovebox, the ester substrate (0.25 mmol) and HBpin (0.55 mmol) were
dissolved in benzene-d6 (total volume 1.0 mL). This solution was then injected into a vial
containing LaNTMS (2.5 μmol) and shaken to dissolve the catalyst. The reaction mixture was next
transferred to a J. Young capped NMR tube and removed from the glovebox, and the ensuing
reaction was monitored by 1H NMR.
For liquid esters: In a glovebox, LaNTMS (2.5 μmol) was placed in a rubber septum-sealed NMR
tube, and the cap was wrapped with Parafilm. HBpin (0.55 mmol) and benzene-d6 were next added
to a septum-sealed vial, and the cap was wrapped with electrical tape. Outside the glovebox, the
liquid ester (0.25 mmol) was then injected into the vial with HBpin and internal standard, the vial
was shaken, and the contents were injected into the NMR tube containing the catalyst, all under
N2. The tube was shaken to dissolve the catalyst, and the ensuing reaction was monitored by 1H
NMR.
DBpin Synthesis
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This synthesis was adapted from literature procedures.29 BD3•SMe2 (Cambridge Isotope
Laboratories, 8.5 mmol, 10 M) was diluted with 10 mL DCM in an addition funnel under N2. This
solution was next added dropwise over 30 min to a 0°C solution of pinacol (8.5 mmol, 1.0 g) in
20 mL DCM. After addition was complete, the solution was brought to room temperature and
stirred until bubbling was no longer observed (1 h). The DBpin was purified by distillation (0°C
at 10 mmHg). 1H NMR (400 MHz, C6D6): 1.00 (s, 12H, DBpin) 11B NMR (128 MHz, C6D6): 28.37
(t, 2JDB=22.8 Hz).
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Computational Details
Geometry optimizations of all reactants, products, intermediates, and transition states were
carried out along the entire catalytic cycle. Calculations were performed adopting the M06 hybrid
meta-GGA functional. The effective core potential of Hay and Wadt30, (LANL2DZ) and the
relative basis set were used for the La and Si atoms. The standard all-electron 6-31G** basis31 was
used for all the remaining atoms. Molecular geometry optimization of stationary points was
carried out without symmetry constraints and used analytical gradient techniques. The transition
states were searched with the “distinguished reaction coordinate procedure” along the emerging
bonds. Step i of Figure 4 was monitored along the emerging C–O bond, whereas the subsequent
bond formation/breaking step induced by the approach of a second HBpin molecule (step ii) was
monitored along the breaking C–O bond. Finally, the hydride transfer of step iii and the catalyst
activation step were monitored along the emerging C-H bond. Methyl benzoate was adopted as
substrate model. Frequency analysis was performed to obtain thermochemical information about
the reaction pathways at 298 K using the harmonic approximation. The difference in translational
and rotational Gibbs free energy when moving from gas to solvent are accounted for by adding an
energy contribution of 8RT to each species as detailed in the literature.32 Moreover, the effect of
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concentration on moving from 1 atm to 1 M is accounted for by adding an energy contribution of
1.89 kcal/mol (RTln(P1M/P1atm)) to each species. All calculations were performed using the G16
code33 on Linux cluster systems.
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AUTHOR INFORMATION
Corresponding Author
t-marks@northwestern.edu, tracy.lohr@shell.com
Present Addresses
‡
Shell Projects & Technology, Shell Technology Center Houston, 3333 Highway 6 South,
Houston, Texas, 77082, United States.
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information. The following file is available free of charge.
Experimental details, kinetic and thermodynamic data, computation details, product
characterization and NMR spectra. (Word)
ACKNOWLEDGMENTS
The authors thank the National Science Foundation (grants CHE-1464488 and CHE-1856619) for
financial support. This work made use of the IMSERC facility at Northwestern University, which
has received support from the NSF (CHE-1048773 and CHE-9871268); Soft and Hybrid
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Nanotechnology Experimental (SHyNE) Resource (NSF NNCI-1542205); the State of Illinois and
International Institute for Nanotechnology. V.L.W. thanks NSF for an NSF Graduate Research
Fellowship. Computational resources were provided by the Northwestern University Quest High
Performance Computing cluster (T.L.L.) and CINECA award N. HP10CP3HMF 2017 under the
ISCRA initiative (A.M.).
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REFERENCES
1. (a) Cornils, B.; Hermann, W. A.; Beller, M.; Paciello, R., Applied Homogeneous Catalysis
with Organometallic Compounds: A Comprehensive Handbook in Four Volumes, Volume 4.
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