DFT Studies Provide Mechanistic Insight into Nickel-Catalyzed Cross-Coupling Involving Organoaluminum-Mediated C-O Bond Cleavage

Article abstract of DOI:10.1055/s-0036-1590863

Density functional theory (DFT) calculations were performed to examine the reaction pathway of Ni-catalyzed cross-coupling with organoaluminum through C-O bond cleavage. The results indicate that the strong Lewis acidity of organoaluminums significantly f

Full text of DOI:10.1055/s-0036-1590863

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DFT Studies Provide Mechanistic Insight into Nickel-Catalyzed
Cross-Coupling Involving Organoaluminum-Mediated C–O Bond
Cleavage
Ze-Kun Yanga,b
Chao Wang*a,b
Masanobu Uchiyama*a,b
a Graduate School of Pharmaceutical Sciences, the University of
Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo-to 113-0033, Japan
chaowang@mol.f.u-tokyo.ac.jp
uchiyama@mol.f.u-tokyo.ac.jp
b Advanced Elements Chemistry Research Team, RIKEN Center for
Sustainable Resource Science, and Elements Chemistry Laboratory
RIKEN, 2-1 Hirosawa, Wako-shi, Saitama-ken 351-0198, Japan
Published as part of the Cluster C–O Activation
Received: 31.05.2017
Accepted after revision: 10.07.2017
Published online: 25.08.2017
role of the aluminum reagent, we carried out a mechanistic
study of organoaluminum-mediated C–O cleavage-type
cross-coupling based on DFT calculations. It has often been
DOI: 10.1055/s-0036-1590863; Art ID: st-2017-s0411-c
Abstract Density functional theory (DFT) calculations were performed
to examine the reaction pathway of Ni-catalyzed cross-coupling with
organoaluminum through C–O bond cleavage. The results indicate that
the strong Lewis acidity of organoaluminums significantly facilitates the
transmetalation step, but not the oxidative addition or reductive elimi-
nation step.
carboxylate
NiCl2(PCy3)2 (5 mol%)
Ph
Ar
Ph
AliBu2
R
O
+
Ar
toluene, r.t., 24 h
(1.2 equiv)
(1.0 equiv)
(yield)
O
O
O
O
Key words cross-coupling, C–O bond cleavage, nickel catalyst, orga-
noaluminum, DFT calculation
O
Ar
O
Ar
O
Ar
O
Ar
tBu
Me
+
Et2N
tBuO
ester (pivalate)
(93%)
ester (acetate)
(64%)
carbamate
(95%)
carbonate
(51%)
Synthetic applications of organoaluminum (C–Al) have
long been of great interest in both academic research and
industry,1 because C–Al reagents offer many advantages, in-
cluding low cost, ready availability, low toxicity, high reac-
tivity, and exceptional Lewis acidity. The initial use of C–Al
in transition-metal (TM) catalyzed cross-coupling reaction
can be traced back to Negishi’s reports as early as in 1976,2
but in subsequent decades, C–Al was largely neglected in fa-
vor of other organometallics (Mg, Zn, B, Sn, etc.).3 Recently,
some cross-coupling reactions of C–Al with organic halides
have been developed,1 but few protocols are available for
coupling of C–Al with phenol derivatives (ArOX).4 Recently,
several Ni-catalyzed alkylation reactions of the C–O bond in
aryl methyl ether (ArOMe) with trialkylaluminum (R3Al)
were reported by Chatani and Tobisu,5a Rueping,5b and
Agapie.5c More recently, we also reported an in-depth ex-
perimental study on Ni-catalyzed cross-coupling between
organoaluminums and various types of C–O electrophiles,
including sulfonates (OMs, OTs, OTf), phosphates, carboxyl-
ates (ester, carbamate, carbonate) and ether, which provide
a useful and versatile toolbox for synthetic utilization of or-
ganoaluminums, as well as for inert bond activation.5d To
further understand the reaction mechanism, as well as the
O
NiCl2(PCy3)2 (5 mol%)
toluene, T (°C), 24 h
Ar1
AliBu2
O
Ar2
Et2N
(1.5 equiv)
(1.0 equiv)
OMe
CF3
95% (r.t.)
93% (70 °C)
91% (50 °C)
Me
O
O
NiPr2
OiPr
Me
Me
98% (50 °C)
65% (70 °C)
N
91%
(110 °C)
MeO
N
N
Me
Me
95% (70 °C)
85% (70 °C)
94% (50 °C)
MeO
N
N
F3C
F
90% (50 °C)
98% (50 °C)
70% (90 °C)
MeO
Scheme 1 Representative results of Ni-catalyzed cross-coupling of aryl
carboxylates with aryl aluminum reagents
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
Z.-K. Yang et al.
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speculated that the Lewis acidity of organoaluminum re-
agents could promote oxidative addition of the C–O bond to
Ni(0); however, the results of our computational study
clearly indicate that the Lewis acidity of aluminum primari-
ly facilitates the transmetalation step, rather than the oxi-
dative addition step.
catalyst takes place via TS1 to generate CP2-1, giving the
C(Aryl)–Ni(II)–O species with a total activation barrier of 24.3
kcal/mol. The OAc moiety on Ni(II) in CP2-1 then coordi-
nates to the aluminum reagent to form CP2-2, which un-
dergoes transmetalation through TS2 → CP3 → TS3 to afford
Ar2Ni(II) species CP4 along the intrinsic reaction coordi-
nate, with release of the Me2AlOAc moiety. Transmetalation
proceeds with a quite low activation barrier (< 12 kcal/mol),
without much energy gain. Finally, reductive elimination
takes place via TS4 (ΔGa = 3.2 kcal/mol), leading to coupling
product PD and regeneration of the Ni(0) catalyst with large
exothermicity. None of the stages in the process involves
any energetically unfavorable CPs/TSs with a large overall
energy gain (Figure 1).
All DFT (B3LYP6 and M067) calculations were performed
with the Gaussian09 program8 and GRRM11 program9 to
clarify the reaction pathway/mechanism. Structure optimi-
zation and frequency calculations were carried out with
B3LYP/6-31G*(H, C, O, Al, P) & LANL2DZ (Ni). Single-point
energy considering the solvent effect of toluene (PCM mod-
el10) was obtained via calculation of the B3LYP geometries
with M06/6-311++G**(H, C, O, Al, P) & SDD (Ni). Gibbs free
energy (kcal/mol) was used as a basis for discussion. PhOAc
and PhAl(OMe2)Me2 were employed as model reactants.
Ni(PCy3)2 was regarded as the active catalyst species based
on recent work,11 from which the initial geometry of PCy3
was also taken. For full citations and details, see the Sup-
porting Information. Natural bond orbital (NBO) analysis
was performed with NBO5.9.12
The results of several examinations indicated that the
reaction pathway of Ni-catalyzed cross-coupling via alumi-
num-mediated C–O cleavage, as illustrated in Scheme 2 and
Figure 1, is the most probable. The cross-coupling basically
proceeds according to a catalytic cycle consisting of three
elementary steps; namely, oxidative addition, transmetala-
tion, and reductive elimination. In the initial step, Ni(0) cat-
alyst forms a π-arene complex with the aromatic substrate,
and then oxidative addition of the C(Aryl)–O bond to Ni(0)
Figure 1 Energy profiles
Having thus clarified the pathway of the present cross-
coupling reaction, we next wished to identify the main con-
tributions of organoaluminum reagents to the excellent re-
activity. It has been widely accepted, and we also anticipat-
Ni(PCy3)2
PhOAc
Ph
Ph
(G = –48.0)
SM
(G = 0.0)
Cy3P
Ni
Cy3P
Cy3P
PCy3
Ni
O
Ni
O
Ni
Me
Me
PCy3
CP4
(G = –14.5)
O
O
Me
Al
CP1
TS1
(G = 8.3)
(G = 24.3)
O
O
TS4
(G = –11.3)
O
Me
Me
Cy3P
Ni
PhAlMe2(THF)
Me
Cy3P
Ni
Cy3P
Ni
O
Me
O
O
Al
Me
O
Me
O
Al
Me
THF
Me
Me
CP2-1
(G = –14.4)
CP2-2 (G = –10.7)
TS3 (G = –3.0)
Cy3P
Ni
Cy3P
Ni
Me
O
Me
O
O
O
Al
Me
Al
Me
Me
Me
CP3 (G = –10.0)
TS2 (G = –4.2)
Scheme 2 Calculated reaction route for Ni-catalyzed cross-coupling between PhOAc and PhAlMe2 (G: kcal/mol)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
Z.-K. Yang et al.
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ed a priori, that the potent Lewis acidity of organoalumi-
nums would promote the oxidative addition of Ni(0)
because of the Lewis acidic activation of C–O bond cleav-
age,5b–c,13 but our DFT calculations do not support this view.
Three plausible modes of action for oxidative addition with
or without O···Al interaction are illustrated in Scheme 3.
Unexpectedly, all three transition states lay at almost the
same energy level (energetic difference <3 kcal/mol), and
the oxidative addition with no assistance of the aluminum
reagent (TS1) showed the lowest energy path. This is proba-
bly because the interaction from the potent Lewis acidic Al
metal center weakens the chelation of the carbonyl group
(OAc) to Ni(0), as seen in TS1Al–OPh and TS1Al–OAc (where the
Ni–O distances are much longer than that in TS1). NBO
analyses of the TSs provides further support for this idea;
that is, the contribution from Ni in the NLMO (natural local-
ized molecular orbital) decreases in the order TS1 > TS1Al–
OPh > TS1Al–OAc. These findings suggest that the coordination
of the OAc moiety to Al decreases electron donation from
the carbonyl oxygen to the Ni center, resulting in a more
electron-deficient Ni(0) character, and offsetting the activa-
tion of C–O by Lewis acid–base interaction.
(1) Ph migration from Al to Ni (CP2-2 → TS2 → CP3), and (2)
elimination of Me2AlOAc (CP3 → TS3 → CP4) (Scheme 1).
The Ph (green) moiety on the Al center in CP2-2 can mi-
grate smoothly to the Ni center (via TS2) to form a dispro-
portionated Ph–Ni(II)–Ph intermediate CP3. This process is
facilitated by push-pull synergy through O···Al interaction,
which weakens the Ni–O bond and polarizes the Ph–Al
bond, as reflected in the bond lengths (a longer Ni–O bond
in CP2-2 than CP2-1), NPA charges (more negative charge at
carbon in Ni–C–Al moiety) and donor (O)-acceptor (Al) in-
teraction energy (ΔE, a stronger Lewis acid–base interac-
tion in CP2-2 than that in PhAl(THF)Me2) (Scheme 4). The
complex CP3 undergoes smooth dissociation with very low
activation energy (7.0 kcal/mol) owing to the potent Lewis
acidity of the aluminum reagent: the Me2AlOAc moiety of
CP3 is easily detached from the Ni(II) center to give an un-
saturated diphenylnickel(II) species, which undergoes rapid
reductive elimination to eject the coupling product and to
regenerate the Ni(0) species. Thus, the present DFT study
has revealed that the potent Lewis acidity of aluminum re-
agents strongly facilitates the transmetalation step both ki-
netically and thermodynamically; this may be the reason
why the present reaction requires only a small excess of the
aluminum reagent and proceeds under mild conditions. It is
worth noting that the calculations are in good accordance
with the experimental observations5d that: (1) the coupling
reaction proceeds much more efficiently in toluene solu-
tion than in a coordinative solvent such as THF, and (2) alu-
minates that have low Lewis acidity, such as [ArAlMe3]– and
[Ar2AliBu2]–, show lower reactivity. Our findings imply that
aluminum reagents may be generally applicable for inert
bond cleavage-type cross-couplings via smooth transmeta-
lation.
O
O
Cy3P
Ni
Me
+
*
Cy3P
Ni
O
ΔE
*
Me
Me
ΔE
O
*Al
THF
+
*
Al
*
C
*
Me
C
CP2-1
O
Me
Scheme 3 Influence of Lewis acidity of aluminum reagent on the oxi-
dative addition process (H atoms are omitted for clarity)
Me
CP2-2
ΔE
(kcal/mol)
62.7
NPA charge
Al*
O*
C*
Several mechanistic investigations of Ni-catalyzed
cross-coupling of C(Aryl)–O substrates, including esters, car-
bamates, and sulfonates, have been reported, in which the
transmetalation steps are usually energetically unfavorable
and rate-determining.11 This is presumably the reason why
an excess (≥3 equiv) amount of organo-boron or -zinc re-
agent is normally needed in such reactions, together with
harsh conditions. In contrast, aluminum reagents were re-
quired only stoichiometrically or in just slight excess (≤1.5
equiv), and the reaction proceeded at room temperature (or
with gentle heating). We speculated that the Lewis acidity
of Al reagents facilitates the transmetalation step, and, in-
deed, this proved to be the case. The energy diagram sug-
gests that the transmetalation step involves two processes,
PhAlMe2(THF)
CP2-2
+1.785 –0.650 –0.596
+1.796 –0.899 –0.661
96.4
Scheme 4 NBO analysis of the transmetalation step (ΔE: sum of sec-
ond-order perturbation energy for O–Al donor–acceptor interaction)
In summary, the present DFT study has revealed the re-
action pathway and mechanism of the Ni-catalyzed cross-
coupling reactions between organoaluminum and phenol
carboxylate derivatives though C–O bond cleavage. In sharp
contrast to the widely accepted view that Lewis acid could
activate the C–O bond to promote a smooth oxidative addi-
tion process, the current theoretical investigations clearly
show that the Lewis acidity of organoaluminum reagents
primarily facilitates the transmetalation step, rather than
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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others such as the C–O bond cleavage or C–C bond-forming
step. These results underline the conclusion that novel and
interesting mechanisms may hide in well-established reac-
tions that are considered to be fully understood. Our find-
ings open up a new approach for designing novel re-
agents/reactions/protocols, and may also have implications
for other organometallic transformations. Further experi-
mental and theoretical studies on the applicability of this
mechanism to other TM-mediated reactions are in prog-
ress.
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Funding Information
This work was supported by JSPS KAKENHI (S) (No. 24229011, No.
17H06173) (to M. U.). This research was also partly supported by
grants from Asahi Glass Foundation, Nagase Science Technology De-
velopment Foundation, Sumitomo Foundation, and Kobayashi Inter-
national Scholarship Foundation (to M. U.), and from YakuGaku
ShinKoKai Foundation (to C. W.)
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Acknowledgment
A generous allotment of computational resources (Projects G16028
and G17022) from RICC (RIKEN Integrated Cluster of Clusters) and
HOKUSAI GreatWave (RIKEN) is gratefully acknowledged.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590863.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D