Mechanistically Guided Design of Ligands That Significantly Improve the Efficiency of CuH-Catalyzed Hydroamination Reactions

Article abstract of DOI:10.1021/jacs.8b09565

Using a mechanically guided ligand design approach, a new ligand (SEGFAST) for the CuH-catalyzed hydroamination reaction of unactivated terminal olefins has been developed, providing a 62-fold rate increase over reactions compared to DTBM-SEGPHOS, the previous optimal ligand. Combining the respective strengths of computational chemistry and experimental kinetic measurements, we were able to quickly identify potential modifications that lead to more effective ligands, thus avoiding synthesizing and testing a large library of ligands. By optimizing the combination of attractive, noncovalent ligand-substrate interactions and the stability of the catalyst under the reaction conditions, we were able to identify a finely tuned hybrid ligand that greatly enables accelerated hydrocupration rates with unactivated alkenes. Moreover, a modular and robust synthetic sequence was devised, which allowed for the practical, gram-scale synthesis of these novel hybrid ligand structures.

Full text of DOI:10.1021/jacs.8b09565

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Article
Mechanistically Guided Design of Ligands that Significantly
Improve the Efficiency of CuH-Catalyzed Hydroamination Reactions
Andy A Thomas, Klaus Speck, Ilia Kevlishvili, Zhaohong Lu, Peng Liu, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09565 • Publication Date (Web): 23 Sep 2018
Downloaded from http://pubs.acs.org on September 23, 2018
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Mechanistically Guided Design of Ligands that Significantly Improve the
Efficiency of CuH-Catalyzed Hydroamination Reactions
†
§
†§
†‡
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‡
§
Andy A. Thomas, Klaus Speck, Ilia Kevlishvili, Zhaohong Lu, Peng Liu, * and Stephen L. Buchwald *
Submitted to the
Journal of the American Chemical Society
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Address Correspondence to:
Professor Stephen L. Buchwald
1
8-490 Dreyfus Laboratory
Department of Chemistry
Massachusetts Institute of Technology
77 Massachusetts Avenue,
Cambridge, MA 02139
tel: (617) 253-1885
FAX: (617) 253-3297
e-mail: slbuchwald@mit.edu
ABSTRACT
Using a mechanically guided ligand design approach, a new ligand (SEGFAST) for
the CuH-catalyzed hydroamination reaction of unactivated terminal olefins has been
developed, providing a 62-fold rate increase over reactions compared to DTBM-
SEGPHOS, the previous optimal ligand. Combining the respective strengths of
computational chemistry and experimental kinetic measurements, we were able to quickly
identify potential modifications that lead to more effective ligands, thus avoiding
synthesizing and testing a large library of ligands. By optimizing the combination of
attractive, non-covalent ligand-substrate interactions and the stability of the catalyst under
the reaction conditions, we were able to identify a finely-tuned hybrid ligand that greatly
enables accelerated hydrocupration rates with unactivated alkenes. Moreover, a modular
and robust synthetic sequence was devised, which allowed for practical, gram-scale
synthesis of these novel hybrid ligand structures.
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INTRODUCTION
1
2
In 2013, Buchwald, and Miura and Hirano independently demonstrated that copper
hydride complexes (LCuH) can catalyze the chemo- and enantioselective hydroamination
reactions between olefins and hydroxylamine esters (Figure 1a). Since then the generality and
applicability of this approach has been well demonstrated for a variety of substrates such as
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styrenes, vinylsilanes, alkynes and occasionally unactivated olefins, highlighting its enormous
potential. Despite these achievements hydroamination reactions catalyzed by LCuH are not
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without limitations. For example, transformation of coupling partners such as cyclic, internal,
and some unactivated terminal olefins often require elevated temperatures and increased reaction
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times compared to those of activated substrates. In particular, an efficient anti-Markovnikov
hydroamination reaction with unactivated terminal olefins is highly desirable, because the
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products of these reactions are frequently found in bioactive molecules. These compounds are
traditionally prepared by transforming carbonyl compounds, amides or alkyl electrophiles into
1
0
their corresponding amine products. From a strategic standpoint, hydroamination reactions
between olefins and electrophilic amine sources provide one of the most straightforward and
general avenues to access these important motifs, especially since the precursors are typically
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stable, readily available, and easy to handle.
12,13
14
Recently, several experimental
and computational mechanistic investigations have
appeared on both CuH catalyzed hydroamination and hydroboration reactions, revealing the
same basic catalytic cycle, comprised of four elementary steps: hydrocupration (I), oxidative
15
addition (II), reductive elimination (III) and s-bond metathesis (IV) (Figure 1b). These studies
demonstrated that the rate determining step (RDS) can vary between different olefinic substrates.
Specifically, the RDS for activated substrates, such as styrenes, is often the catalyst regeneration
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by s-bond metathesis, whereas it changes to the hydrocupration step for unactivated internal or
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terminal alkenes,
indicating that the lower reactivity observed for unactivated olefins is the
direct result of higher barriers for hydrocupration.
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a)
R
Cu(OAc)
2
, Ligand
R
+
2
Bn NOBz
N
Bn
silane
Bn
R
3
R SiOBz
b)
LCuH
σ-bond
R
3
SiH
metathesis
hydrocupration
IV
I
R
LCuOBz
CuL
R
reductive
oxidative
addition
II
Bn
N
elimination
N
Bn
III
Bn
OBz
Bn
R
L
Bn
Cu
N
OBz
Bn
RDS for activated substrates = σ-bond metathesis
RDS for unactivated substrates = hydrocupration
c)
t-Bu
OMe
O
O
O
O
O
P
P
2
2
P
P
t-Bu
t-Bu
2
2
O
O
O
OMe
t-Bu
SEGPHOS L1
DTBM-SEGPHOS L2
Figure 1. a) LCuH-catalyzed anti-Markovnikov hydroamination reaction. b) Proposed catalytic
cycle for LCuH-catalyzed anti-Markovnikov hydroamination reaction. c) SEGPHOS L1 and
DTBM-SEGPHOS L2 ligands.
Typically, reaction development in this area has relied on empirical observations
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pertaining to which catalytic system provides the fastest reaction rates. For example, reactions
with SEGPHOS L1 supported LCuH catalysts are often found to be slower; whereas, the use of
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sterically more demanding DTBM-SEGPHOS L2 derivative is often key to achieving higher
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reactivity, especially in the reactions of unactivated olefins (Figure 1c).
Beginning last year, our laboratories sought to unravel the theoretical foundations that
lead to favorable hydrocupration events between LCuH (L = L1 and L2) and various unactivated
olefins, by performing the ligand-substrate interaction model analysis on this crucial step (Figure
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a).
Using this approach, the contributions of the different types of catalyst-substrate
‡
interactions to the overall activation energy (∆E ) were split into three categories: (1) the
distortion energy required for the LCuH and the substrate to reach their transition state
geometries (∆Edist); (2) the through-space interactions between the ligand and the substrate (∆Eint-
space); and (3) the through-bond interactions between the CuH moiety and the substrate (∆Eint-
bond). In the hydroamination reactions when SEGPHOS L1 and DTBM-SEGPHOS L2 ligands
were employed, the ∆Edist and ∆Eint-bond terms were not found to correlate with the overall
‡
activation energies (∆E ); however, excellent linear correlations were observed with ∆Eint-space
.
2
This suggested that the t-butyl substituents at the 3- and 5-positions on the P-aryl groups in
DTBM-SEGPHOS L2 promote stabilizing non-covalent interactions (Figure 2b). Indeed,
dissecting the ∆Eint-space term into its individual components revealed that attractive London
2
dispersion forces (∆Edisp) between the 3,5-di-t-butyl substituents on the P-aryl groups and the
substrate were the main contributing factor to achieve high catalyst activity with the DTBM-
SEGPHOS L2 ligand. While the London dispersion interactions are relatively weak (0.5~1.5
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4a,16
kcal/mol for interactions with each t-Bu substituent),
collectively they significantly reduce
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activation barriers via transition state stabilization.
Moreover, these conclusions were
a
experimentally validated through ligand synthesis and subsequent kinetic analysis.14
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Figure 2 a) Ligand-substrate interaction model to study the origin of reactivity in
hydrocupration. b) London dispersion interactions lowering the hydrocupration barrier for
L2CuH.
Building upon this knowledge, we undertook the challenge of designing a new family of
ligands based on SEGPHOS L1 to more efficiently facilitate the copper-hydride catalyzed anti-
Markovnikov hydroamination reaction with terminal olefins. We theorized a more effective
ligand system can be rationally designed by retaining the stabilizing dispersion effects of
DTBM-SEGPHOS L2 while incorporating other types of stabilizing through-bond and/or
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through-space interactions. Specifically, we surmised that other types of weak non-covalent
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interactions with the olefin substrate, may be harnessed by installation of hetero-atom-
containing substituents on the P-aryl groups. In addition, the through-bond stabilization between
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the CuH moiety and the substrate in the hydrocupration transition state can be fine-tuned by
altering the electronic character of the ligands. However, when designing catalysts capable of
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promoting reactivity through an assortment of stabilizing interactions, infinite possibilities are
conceivable. With the unique ability to computationally quantify and experimentally verify these
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interactions, an iterative catalyst design approach was envisioned (Figure 3).
This approach
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comprised of four stages: (1) experimentally identify a suitable class of ligand derivatives; (2)
using computational analysis to understand what key interactions can stabilize the transition
state; (3) using this knowledge to computationally predict a more effective ligand and (4)
experimentally test the ligand providing feedback for the next round of ligand optimization.
Computation
Old
Ligand
New
Ligand
Experiment
Understand
Predict
Figure 3. Project outline.
3.1. Kinetic and computational analysis of SEGPHOS Ligands. 3.1.1. Preliminary
Experimental Investigations with Symmetric SEGPHOS Ligands. As described above, previous
investigations indicated that primarily bulky substituents at the 3 and 5-positions on the P-aryl
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4a
groups were critical in facilitating the hydrocupration event with terminal olefins. This finding
directed our preliminary studies to investigate SEGPHOS derivatives with substituents
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3
possessing different steric (TMS) and electronic (CF ) properties at these positions (Scheme 1).
To kinetically quantify and compare the effects of these ligands on the hydrocupration event 4-
phenyl-1-butene (1) and O-benzoyl-N,N-dibenzylhydroxylamine (2) were selected as model
substrates, because a first order dependence on the olefin had been shown previously for the
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hydroamination reaction with DTBM-SEGPHOS L2. The initial rates were measured for the
reaction with each ligand by monitoring the formation of hydroamination product 3 under typical
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copper hydride hydroamination conditions (1.0 mol% Cu(OAc) , 1.1 mol% ligand, 0.36 M in
THF, 23 °C) utilizing dimethyoxymethylsilane (DMMS, 3.0 equiv/1) as the stoichiometric
reductant. To allow for a straightforward comparison, the rate of hydroamination was measured
−
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first with DTBM-SEGPHOS L2 (8.60 ± 0.05) x 10 M/s so that the rates could be normalized
(Scheme 1).
Scheme 1. Initial kinetic analysis for symmetric ligands L2, L3 and L4.
Cu(OAc)
2
(1.0 mol%)
(
±)-L-(1.1 mol%)
NBn
2
+
Bn
2
NOBz
Ph
O
Ph
DMMS (3.0 equiv)
THF, 23 °C
1
2
3
R
1
kobs, 10-6 M/s
Ligand
k
rel
R
2
L2: R
1
= t-Bu
8
.60 ± 0.05
8.6 ± 0.3
1.0
R
2
= MeO
O
O
P
P
R
R
1
1
2
L3: R
1
= TMS
2
3.3
6.7
R
2
= H
L4: R
1 3
= CF
R2 = H
5
8.4 ± 0.5
O
R
2
R
1
Average of duplicate runs.
2
ꢀ
Following our standard protocol, the reaction employing TMS-SEGPHOS L3 was found to be
.3 times faster than that with DTBM-SEGPHOS L2, suggesting that the larger TMS
substituents, with a Taft value of E ´ = 1.79, have stronger interactions with the olefin substrate
than the t-Bu groups (E ´ = 1.49) in DTBM-SEGPHOS L2 (Scheme 1). Interestingly, the
hydroamination with the CF -SEGPHOS L4 derivative underwent the hydrocupration event 6.7
times faster than L2 and 2.0 times faster than L3 even though the CF groups (E ´ = 0.78) are
3
s
2
5
s
3
3
s
2
6
smaller and presumably less polarizable. This suggested that the fluorine-containing
substituents have additional stabilizing effects that are stronger than simple London dispersion
interactions as observed with L2 and L3. The origin for this significant and unexpected rate
increase for L4 was revealed by computational investigations as detailed below.
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.1.2. Computational Analysis of the Origin of Reactivity with Symmetric SEGPHOS
Derivatives. The preliminary experimental studies revealed promising results with the CF
3
-
SEGPHOS L4 derivative. However, it was unclear what further modifications could lead to
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additional reactivity enhancement.
Although successful predictions of new transition metal
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catalysts from computational results alone are still rare, several examples have recently been
described wherein a combination of computational and experimental evaluations has led to the
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discovery of catalysts with improved reactivity and selectivity.
Such synergetic efforts
effectively utilize the predictive power of computation, while the experimental verification helps
resolve the uncertainty of calculated energies and issues that cannot be readily addressed by
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computations alone, such as catalyst decomposition.
3
.1.2.1 Computational Methods Geometry optimizations and single-point energy calculations
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were carried out using Gaussian 09. Geometries of intermediates and transition states were
3
1
optimized using the B3LYP functional with a mixed basis set of SDD for Cu and 6-31G(d) for
other atoms in the gas phase. Vibrational frequency calculations were performed for all of the
stationary points to confirm if each optimized structure is a local minimum or a transition state
3
2
structure. Truhlar’s quasi-harmonic corrections were applied for entropy calculations using 100
-
1
cm as the frequency cut-off. Solvation energy corrections were calculated in THF solvent with
3
3
the CPCM continuum solvation model based on the gas-phase optimized geometries. The
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ωB97X-D functional with a mixed basis set of SDD for Cu and 6-311+G(d,p) for other atoms
was used for solvation single-point energy calculations. The computed gas-phase activation
‡
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energy (ΔE ) was dissected using the following ligand-substrate interaction model analysis.
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⧧
ΔE = ΔEdist + ΔEint-bond + ΔEint-space
eq.1
3
5
The distortion energy (ΔEdist) is the sum of the energies required to distort the LCuH
catalyst and the substrate into their transition state geometries. ΔEint-space was calculated from the
interaction energy of a supramolecular complex of the phosphine ligand and the olefin substrate
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at the transition state geometry but in the absence of the CuH moiety (ΔEint-space = Elig+sub − Elig
−
⧧
E
sub). Then, the through bond interaction was calculated from ΔEint-bond = ΔE − ΔEdist − ΔEint-
space. The ΔEdist and ΔEint-space were both calculated using the ωB97X-D functional with the SDD
basis set for Cu and 6-311+G(d,p) for other atoms. The ωB97X-D functional was chosen because
36
it has been shown to accurately describe non-covalent interactions, which we expected to be
important in this system. The computed free energy barriers using this method provided very
good agreement with the experimental reaction rate constants (see SI for details and comparison
with results from other functionals and solvation models). The through-space interaction energy
(
ΔEint-space) between the ligand and the substrate is further dissected according to the following
equation:
ΔEint-space = ΔEPauli + ΔEelstat+ ΔEpol + ΔEct + ΔEdisp
eq. 2
In accordance with our previous study, the dispersion energy component (ΔEdisp) was
obtained from the difference of interaction energies calculated using MP2 and HF. The MP2
calculations were performed with Q-Chem 5.0 using the SOS(MI)-MP2 method in combination
3
7
with the dual-basis set approach utilizing the db-cc-pVTZ basis set. The ΔEPauli, ΔEelstat, ΔEdisp
,
ΔEpol, and ΔEct terms in eq 2 were calculated using the second-generation energy decomposition
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analysis based on absolutely localized molecular orbitals (ALMO-EDA) method implemented
3
9
in Q-Chem 5.0. The second generation ALMO-EDA provides further decomposition of the
Pauli and electrostatic interaction (∆Erep) term into Pauli repulsion (∆EPauli) and electrostatic
0
1
2
3
4
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1
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9
0
(
∆Eelstat) energies, which is important in the analysis of through-space electrostatic interactions
with the fluorinated ligands. To avoid double counting of dispersion, HF method with the 6-
3
11G(d,p) basis set was employed in the energy decomposition analysis (EDA) calculations.
3
.1.2.2. Computational Analysis of Symmetric-SEGPHOS Ligands. In order to fully understand
the underlying principles and interactions that lead to the enhanced rate, an in-depth
computational analysis was performed to study the origin of the different hydroamination
3
reactivities between the DTBM-SEGPHOS L2 and CF -SEGPHOS L4-supported CuH catalysts.
The activation energies of the rate-determining hydrocupration transition states were
computed using propene (4) as the model substrate with the method outlined above (Table 1).
The computed barrier of hydrocupration with the CF
3
-SEGPHOS L4CuH complex was in good
agreement with the experimentally observed rate increase with L4 compared to DTBM-
‡
‡
SEGPHOS L2CuH (ΔΔG comp = 1.5 kcal/mol vs ΔΔG exp = 1.1 kcal/mol). In order to quantify
the different factors that lead to the improved reactivity, the ligand-substrate interaction model
analysis was employed to dissect the overall hydrocupration activation energies (Eqs. 1 and 2,
see Computational Methods for details). Energy-decomposition analysis of the hydrocupration
transition state with L4CuH revealed that the increase in the reaction rate was due to
significantly stronger through-bond interactions (ΔEint-bond) resulting in an extra 2.3 kcal/mol
stabilization of TS-4 compared to the DTBM-SEGPHOS-bound TS-2. This is because of the
electron-withdrawing nature of the CF
3
-substitutents which consequently results in enhanced
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Lewis acidity of the CuH catalyst and more favorable binding of the olefin substrate (see SI for
details). While the through-space interaction energies (ΔEint-space) are comparable in TS-2 and
TS-4, the origins are different. Using the second-generation ALMO-EDA methods, the ΔEint-space
term was further dissected into its individual energy components (Eq. 2). While TS-2 is
stabilized by stronger attractive London dispersion (ΔEdisp = –13.3 kcal/mol for TS-2 compared
to –10.7 kcal/mol for TS-4), electrostatic interactions are more favorable in TS-4 (ΔEelstat = 0.3
kcal/mol for TS-2 compared to –1.5 kcal/mol for TS-4). The optimized geometry of TS-4
revealed multiple C–F···H–C contacts, which are responsible for the through-space electrostatic
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
4
4
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4
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4
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5
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5
5
5
5
5
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5
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0
1
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5
6
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8
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1
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5
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9
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1
2
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
‡
interactions between L4 and the olefin substrate thereby lowering ΔE (Figure 4).
Although the use of CF
reactivity, the computational analysis suggested types of modifications that might result in a
more effective ligand. Considering that the CF -SEGPHOS L4 ligated LCuH complex has
weakened dispersion interactions when compared to the L2CuH complex, we hypothesized that
the installation of a larger perfluorinated substituent would be beneficial. Since the i-C group
is sterically more demanding than CF , we assumed that it should increase stabilizing London
3
-SEGPHOS L4 leads to a relatively moderate increase of
3
3 7
F
3
dispersion, while maintaining the favorable through-space electrostatic attractions and through-
bond electronic effects.
Indeed, the calculated hydrocupration transition state TS-5 indicated that the use of i-
3 7
C F -SEGPHOS L5 as the ligand led to an additional 1.5 kcal/mol lower activation energy
compared to the hydrocupration with L4CuH (Table 1).
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 1. Activation free energies of the hydrocupration transition states and energy components
derived from the ligand-substrate interaction model.
a
R
R
O
O
P
P Cu
P
P
Cu H
P
P
O
O
O
O
Me
Cu H
P
P
R 2
R
P
P
R 2
t-Bu
+
H
H
H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
Me
O
O
OMe
LCuH
4
TS-2-TS-6
LCuR
R
t-Bu
L6 R = i-C3F7
2
2
L4 R = CF3
L5 R = i-C3F7
ligand
DTBM (L2)
CF
3
(L4)
i-C
3
F
7
(L5)
DTBM-i-C
3
F7 (L6)
hydrocupration transition
state
TS-2
TS-4
TS-5
TS-6
ΔG‡solv
20.2
–0.1
28.6
18.7
–1.0
29.5
17.2
–3.4
28.8
17.0
–3.0
27.9
ΔE‡
distortion (ΔEdist
)
through-bond interaction
–
23.9
–26.2
–4.3
–26.2
–6.0
–25.4
–5.6
(
ΔEint-bond)
through-space interaction
–
4.8
(
ΔEint-space)
Pauli repulsion (ΔEPauli
electrostatic (ΔEelstat
)
9.0
0.3
8.4
7.9
7.8
–0.3
–13.0
)
–1.5
–1.2
London dispersion (ΔEdisp
)
–13.3
–0.2
–0.6
0.0
–10.7
–0.2
–0.4
–1.5
–1.1
–11.9
–0.1
–0.4
–3.0
charge transfer (ΔEct
)
0.0
polarization (ΔEpol
)
–0.4
–3.2
–2.4
ΔΔG‡comp
ΔΔG‡exp
0.0
–2.4
a
‡
‡
All energies are reported in kcal/mol. The activation energies (ΔG solv and ΔE ) are with respect
‡
to the separated CuH catalyst and propene (4). ΔΔG comp values were calculated by subtracting
ΔG solv-L2 from ΔG solv-LX. ΔΔG exp were derived from the experimental relative rate constants
‡
‡
‡
(krel).
The ligand-substrate interaction model analysis validated our hypothesis, as the ΔEdist and
ΔEint-bond terms of TS-5 remained largely unchanged when compared to TS-4. Meanwhile, the
through-space interaction of TS-5 was 1.7 kcal/mol more stabilizing. Further dissection of the
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through-space interactions revealed that the primary reason for the increased reactivity was due
to the increased London-dispersion interactions (ΔEdisp) in TS-5. To validate this computational
3 7
prediction, we needed to experimentally measure the reactivity of i-C F -SEGPHOS-supported
1
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8
9
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1
2
3
4
5
6
7
8
9
0
CuH catalyst L5CuH.
Figure 4. Optimized geometries of hydrocupration transition states with the DTBM-SEGPHOS
TS-2) and CF -SEGPHOS ligands (TS-4). Distances are in Ångström [Å].
(
3
3
3 7
.1.4. Synthesis and Kinetic Analysis of Hydroamination with the Symmetric i-C F -SEGPHOS
Ligand. Informed by the computational predictions described above, we set out to synthesize
ligand L5. Adopting a closely related report by Yu, we were able to prepare L5 from dibromide
4
0
5
3 7 6 3 2
and bis-(3,5-i-C F -C H ) PBr (6) in a single step (Scheme 2a).
Scheme 2. Synthesis of SEGPHOS derivatives L5 and L6 (see Supporting Information for
details).
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5
6
a)
3 7
i-C F
O
O
O
O
n-BuLi, MgBr
2
O
O
i-C3F7
Br
Br
P
P
2
2
then
3 7
i-C F
Ar PBr 6
2
O
(14%)
O
3 7
i-C F
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0
5
L5
i-C
3
F
7
b)
1
) n-BuLi, MgBr
) CODPd(CH TMS)
Cs CO , Ar P(O)H 7
) Et N, HSiCl
26%, 3 steps)
2 2
, Ar PBr 6
O
2
2
2
,
2
3
2
O
O
3 7
i-C F
P
P
2
5
3
3
3
t-Bu
(
O
OMe
t-Bu
2
L6
When L5 was employed with the standard catalytic conditions, vide supra, the formation
of hydroamination product 3 was observed to be 61 times faster than with L2, indicating that
increased London dispersion interactions were indeed facilitating the hydrocupration event.
However, only a short burst of reactivity was observed under the reaction conditions employing
L5. This suggests that the L5CuH complex, although an active catalyst, was not stable under the
4
1
reaction conditions (Figure 6, red curve). This catalyst decomposition is most likely the
consequence of the diminished Lewis basicity of the phosphorus atoms in L5, due to the
3 7
electron-withdrawing nature of the i-C F substituents which results in weaker binding to the
copper center. In order to exhibit both high reactivity and stability, the Lewis acidity of the
copper center needed to be finely tuned.
3
.1.5. Hybrid-SEGPHOS Ligands To harness the increased reactivity that we observed using the
i-C substituents without sacrificing the stability of the resulting complex, we had two options:
3 7
F
either to synthesize and test various new derivatives with different substituents, in order to find a
suitable ligand that provides a catalyst system that combines high activity and stability, or
exchange one P-aryl
2
substituent for a more electron-donating group in order to stabilize the
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resulting copper complex. To avoid significant structural changes at the 3- and 5-positions of the
3 7
aryl groups, we reasoned that the merger of DTBM-L2 and i-C F -L5, the ligands with higher
catalyst stability and reactivity, might result in the perfect balance of their respective beneficial
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
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3
4
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5
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5
6
0
1
2
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5
6
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9
0
1
2
3
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5
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9
0
1
2
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9
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2
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0
1
2
3
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8
9
0
interactions. This hypothesis found further support in examining the transition-state structure TS-
5
, in which the improved through-space ligand-substrate interactions primarily arise from the C–
st
th
nd
rd
F···H–C interactions in the 1 and 4 quadrants (Figure 5). The i-C
3 7
F groups in the 2 and 3
quadrants are further away from the substrate, and thus are less significant in promoting the
nd
rd
hydrocupration step. Therefore, exchanging the P-aryl
2
groups in the 2 and 3 quadrants was
not expected to significantly impact the enhanced reactivity gained from the i-C
3 7
F
moieties.
3
.1.5.1 Computational Studies of Hydrocupration with Hybrid-SEGPHOS Ligands The
computational investigations showed that the hydrocupration barrier for the hybrid SEGPHOS
derivative L6CuH was similar to that of the symmetric derivative L5CuH (see Table 1). In the
lowest energy transition state structure with L6 (TS-6, Figure 5), the methyl group on propene
st
rd
(
4) prefers to be placed in the i-C
3 7
F -occupied 1 quadrant, rather than the DTBM-occupied 3
quadrant (TS-6a, Figure 5), indicating the C–F···H–C non-covalent interactions with the i-C
3 7
F
group are more favorable than the C–H···H–C interactions with the t-Bu group. Further energy
decomposition analysis showed similar through-space interaction energies (ΔEint-space) in TS-6
and TS-5 (Table 1). While electrostatic interactions in TS-6 were slightly decreased relative to
those in TS-5, London dispersion interactions were increased as a result of the larger t-butyl
nd
rd
substituents in the 2 and 3 quadrants of TS-6. This finding indicated, that a comparable
energy barrier of hydrocupration might be obtained from L6CuH.
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2
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2
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3 7
Figure 5. Optimized geometries of hydrocupration transition states with the i-C F -SEGPHOS
(TS-5) and the hybrid DTBM-i-C
3 7
F -SEGPHOS ligand (TS-6 and TS-6a). Distances are
reported in Ångström [Å].
3.1.5.2 Synthesis of Hybrid-SEGPHOS Ligands To verify our hypothesis, a practical
synthetic sequence had to be developed to prepare this hybrid ligand. After extensive
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experimental effort, a modular three-step sequence was established (Scheme 2b). The installation
of the bis-(3,5-CF
3
-C
6
H
3
)
2
P subunit was achieved by trapping mono-magnesiated 5 with freshly
prepared bis-(3,5-i-C
3
F
7
-C PBr (6). After, the introduction of the DTBM-P(O) moiety, via a
6 3 2
H )
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
4
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5
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5
5
5
5
5
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
palladium catalyzed cross-coupling reaction with DTBM phosphine oxide 7, and subsequent
42
reduction, L6 was obtained in 26% yield over 3 steps.
3
.1.5.3 Kinetic Analysis of Hybrid-SEGPHOS Ligands Following our standard kinetic protocol,
L6 was employed with our usual catalytic conditions and the formation of hydroamination
product 3 was found to be 62 times faster than that when using L2, indicating that the rate
enhancement observed with the symmetric L5CuH complex was maintained (Figure 6, black
curve). We also noted that no detectable catalyst decomposition was observed with L6 under the
reaction conditions, validating our hypothesis that the hybrid system could maintain stability
4
1
without sacrificing reactivity.
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5
5
5
5
5
5
5
5
5
5
6
Figure 6. Combined data for the formation of amination product 3 (see, supplemental material
for details).
3
.1.6. Demonstration of Hybrid-SEGPHOS Ligand L6 under Preparative Conditions. In order
0
1
2
3
4
5
6
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8
9
0
1
2
3
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
for this newly developed ligand to be useful in a synthetic context, the observed rate increase
would need to be maintained at preparatively relevant scales and on substrates bearing functional
groups. After slight optimization of the reaction conditions, the scope of olefins was established
using hydroxylamine ester 2 as the amine source (Table 2). The hydroamination of terminal
olefins that contained various functional groups were surveyed at room temperature. Epoxide 8,
ester 9, silyl ether 10, and ketal 11 all provided the desired tertiary amine product in excellent
yield. Moreover, substrates that contained a variety of heterocycles, such as piperazine 12,
morpholine 13, and thiophene 14 also underwent smooth hydroamination at room temperature.
Stronger Lewis bases found in heterocyclic compounds like indole 15, benzothiazole 16,
pyrimidine 17, and in quinolines 18 and 19 slightly inhibited the reaction, and thus their
reactions required slightly elevated temperatures (40 ºC) to reach full conversion within 3
4
3
hours. To compare our new catalyst to the current state-of-the-art catalyst, L2, epoxide 8 and
4b
ester 9 were subjected to these reaction conditions employing DTBM-L2 as the ligand.
Diminished yields of 17 and 29% were observed compared to 89 and 94% with L6, respectively.
This demonstrates that the rate enhancement using this catalyst system is maintained under
preparative reaction conditions.
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Scheme 3. Isolated yields are reported as the average of two runs. Standard reaction conditions:
2 2
terminal olefin (0.50 mmol), Bn NOBz (2) (0.60 mmol), Cu(OAc) (2.50 mol%), L6 (2.55
a
b
mol%), DMMS (1.50 mmol), THF (1.0 mL), 23 °C, 3h. 40 °C. DTBM-SEGPHOS was used in
place of L6 and NMR yields are provided.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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9
0
1
2
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5
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9
0
1
2
3
4
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8
9
0
1
2
3
4
5
6
7
8
9
0
Cu(OAc)
2
(2.50 mol%), L6 (2.55 mol%)
Bn
2
NOBz 2 (1.20 equiv)
NBn
2
R
R
DMMS (3.00 equiv)
THF (0.5 M), rt, 3h
Me
O
NBn
2
Et
O
O
NBn
2
O
8
(89%)
9 (94%)
(29%)
b
b
(17%)
O
7
TIPSO
NBn
2
Me
Me
O
NBn
2
1
0 (94%)
11 (79%)
BocN
O
N
NBn
2
N
NBn
2
O
1
2 (91%)
13 (90%)
Me
NBn
2
2
Bn N
N
S
O
15 (91%)a
14 (91%)
S
O
N
O
N
NBn2
N
NBn
2
1
6 (96%)a
17 (89%)a
Me
Me
NBn
2
N
O
NBn
2
N
O
8 (89%)a
19 (82%)a
1
CONCLUSION
This study demonstrates how the combination of mechanistic insights, computational
prediction, and experimental verification can successfully benefit ligand development. Using this
synergistic approach we were able to discover a new hybrid ligand L6 that is capable of
promoting the anti-Markovnikov hydroamination of unactivated, terminal olefins with a 62 fold
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rate increase compared to DTBM-SEGPHOS L2. By employing energy decomposition analysis
methods, we were able to deconvolute each individual energy contributions of the steric,
electronic, and dispersion effects that comprise the hydrocupration barrier. During the course of
our investigation we identified that in addition to London dispersion, both electrostatic C–F···H–
0
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C non-covalent interactions and inductive effects of the i-C
lowering the energy barrier for hydrocupration even further. Ultimately, the merger of both
DTBM and i-C substituents was key to success in designing L6 with balanced stability and
3 7
F substituents are capable of
3 7
F
reactivity. Furthermore, a modular and robust synthetic sequence to access these novel hybrid
ligand structures was devised, that allowed for its gram-scale synthesis. In addition, the
effectiveness of the catalyst system employing L6 was proven under preparative conditions. We
anticipate that this rational ligand design approach can be utilized in other catalytic systems
providing accelerated reaction development.
SUPPORTING INFORMATION
The Supporting Information is available free of charge on the ACS Publications website
at DOI: XX. Full computational and experimental procedures along with characterization
1
13
31
19
data and copies of H, C, P, and F, spectra, along with full kinetic data are provided.
AUTHOR INFORMATION
Corresponding Authors
sbuchwal@mit.edu
pengliu@pitt.edu
Author Contributions
†
A.A.T., K.S. and I.K. contributed equally to this work.
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ACKNOWLEDGMENT
ꢀ
This material is based upon work supported by the NIH Postdoctoral Fellowship Program under
Grant No. 1F32GM125163 (A.A.T.), Leopoldina - National Academy of Science under Grant
No. LPDS2017-08 (K.S.) and the NIH (Grant No. GM122483 and R35GM128779). Any
opinions, findings, conclusions, or recommendations expressed in this material are those of the
authors and do not necessarily reflect the views of the NIH. We are grateful to Drs. Peter Müller
and Charlene Tsay for crystallographic analysis, and we acknowledge Richard Liu and Drs.
Christine Nguyen and Scott McCann for assistance in the preparation of this manuscript.
Calculations were performed at the Center for Research Computing at the University of
Pittsburgh and the Extreme Science and Engineering Discovery Environment (XSEDE)
supported by the NSF.
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M.; Richard, R. M.; ́ Rohrdanz, M. A.; Steele, R. P.; Sundstrom, E. J.; Woodcock, H. L.;
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The corresponding diarylchlorophosphine resulted in no product formation; see: Liu, L.;
Wu, H.C.; Yu, J.Q.; Chem. Eur. J. 2011, 17, 10828–10831.
Colloidal copper was observed after a few minutes along with the observation of
unbound L5.
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The structure of L6 was additionally validated by single crystal X-ray analysis (see
supplementary information for details).ꢀ
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The reactions of substrates incorporating an imidazole unit resulted in no product
formation, presumably due to the imidazole’s Lewis basicity.
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