Mechanistic insight into the catalytic hydrogenation of nonactivated aldehydes with a Hantzsch ester in the presence of a series of organoboranes: NMR and DFT studies

Article abstract of DOI:10.1039/c9ra01468c

Mechanistic studies on the organoborane-catalyzed transfer hydrogenation of nonactivated aldehydes with a Hantzsch ester (diethyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) as a synthetic NADH analogue were performed by NMR experiments and DFT ca

Full text of DOI:10.1039/c9ra01468c

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Mechanistic insight into the catalytic
hydrogenation of nonactivated aldehydes with
a Hantzsch ester in the presence of a series of
organoboranes: NMR and DFT studies†
Cite this: RSC Adv., 2019, 9, 10201
ab
ab
ab
Go Hamasaka,
Hiroaki Tsuji,
Masahiro Ehara
abc
*
and Yasuhiro Uozumi
Mechanistic studies on the organoborane-catalyzed transfer hydrogenation of nonactivated aldehydes with
a Hantzsch ester (diethyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) as a synthetic NADH
analogue were performed by NMR experiments and DFT calculations. In the reaction of benzaldehyde
with the Hantzsch ester, the catalytic activity of tris[3,5-bis(trifluoromethyl)phenyl]borane was superior to
that of other borane catalysts, such as tris(pentafluorophenyl)borane, trifluoroborane etherate, or
triphenylborane. Stoichiometric NMR experiments demonstrated that the hydrogenation process
proceeds through activation of the aldehyde by the borane catalyst, followed by hydride transfer from
the Hantzsch ester to the resulting activated aldehyde. DFT calculations for the hydrogenation of
benzaldehyde with the Hantzsch ester in the presence of borane catalysts supported the reaction
pathway and showed why the catalytic activity of tris[3,5-bis(trifluoromethyl)phenyl]borane is higher than
that of the other boron catalysts. Association constants and Gibbs free energies in the reaction of boron
catalysts with benzaldehyde or benzyl alcohol, which were investigated by 1H NMR analyses, also
indicated why tris[3,5-bis(trifluoromethyl)phenyl]borane is a superior catalyst to tris(pentafluorophenyl)
borane, trifluoroborane etherate, or triphenylborane in the hydrogenation reaction.
Received 26th February 2019
Accepted 25th March 2019
DOI: 10.1039/c9ra01468c
rsc.li/rsc-advances
keto esters with
a
synthetic NADH analogue.3–7 Despite
Introduction
numerous investigations of Brønsted or Lewis acid-catalyzed
hydrogenations of nonactivated aldehydes with synthetic
NADH analogues, no efficient hydrogenation system was
developed until 2015.8,9 In 2015, we reported the rst example of
an organoborane-catalyzed hydrogenation of nonactivated
aliphatic and aromatic aldehydes with a Hantzsch ester (diethyl-
Biological hydrogenation processes are recognized as important
reactions in nature. These processes are mediated by a combi-
nation of an enzyme and an organic reduction cofactor (e.g.,
NADH or NADPH).1 In particular, the biological hydrogenation
of acetaldehyde is a crucial nal step in the fermentation of
sugars to form ethanol. The reaction proceeds in the presence of
alcohol dehydrogenase and NADH under anaerobic conditions.
The reaction pathway of this process is known to be as follows:
(1) acetaldehyde is activated by coordination of its carbonyl
group to the Zn center of alcohol dehydrogenase; and (2)
hydride is transferred to the activated acetaldehyde from NADH
(Fig. 1).1,2
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate)
as
a synthetic NADH analogue to give the corresponding primary
alcohols (Scheme 1).10 In this reaction, tris[3,5-
bis(triuoromethyl)phenyl]borane showed superior catalytic
In attempts to realize a biomimetic hydrogenation process,
many organic chemists have investigated the catalytic hydro-
genation of imines, a,b-unsaturated carbonyl compounds, or a-
aInstitute for Molecular Science (IMS), Myodaiji, Okazaki 444-8787, Japan. E-mail:
uo@ims.ac.jp
bSOKENDAI (The Graduate University for Advanced Studies), Myodaiji, Okazaki 444-
8787, Japan
cJST-ACCEL, Myodaiji, Okazaki 444-8787, Japan
† Electronic supplementary information (ESI) available: Experimental and
computational details. See DOI: 10.1039/c9ra01468c
Fig. 1 Active site of alcohol dehydrogenase for the reduction of
acetaldehyde with NADH.
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Scheme 1 Organoborane-catalyzed hydrogenation of nonactivated
aldehydes with a Hantzsch ester (our previous work).
activity to other borane catalysts. However, the details of the
reaction mechanism and the origin of the superiority of tris[3,5-
bis(triuoromethyl)phenyl]borane to the other borane catalysts
were not claried.
Because of their high oxophilic Lewis acidities, organo-
borane compounds such as tris(pentauorophenyl)borane have
been used as Lewis acid catalysts in various organic trans-
formations including the Mukaiyama-aldol reaction and the
Hosomi–Sakurai reaction.11,12 These reactions proceed through
coordination of the carbonyl compound to the boron catalyst
(as exemplied by the formation of intermediate Int-I in Fig. 2a)
followed by attack by a nucleophile (silyl enol ether or allyl
silane) on the resulting activated carbonyl compound.
Electron-decient borane compounds have also been used as
partners in frustrated Lewis pair catalysts to promote the
hydrogenation of unsaturated bonds with H2.13–15 In 2010, Ste-
phan, Crudden, and co-workers discovered that borohydride
species such as Int-IV in Fig. 2b are generated by the reaction of
tris(pentauorophenyl)borane with Hantzsch esters.16 However,
catalytic applications of these borohydrides were not investi-
gated. Recently, Oestreich and co-workers reported that tris(-
pentauorophenyl)borane catalyzes the hydrogenation of
imines or related N-heterocycles with cyclohexa-1,4-dienes.17,18
In this reaction, tris(pentauorophenyl)borane abstracts
hydrogen from the cyclohexa-1,4-diene to generate a borohy-
dride species; this reaction is similar to that reported by Ste-
phan and Crudden and co-workers.16 This process is followed by
reaction with the imine or a related N-heterocycle to give the
corresponding hydrogenated product.
On the basis of the reaction pathways reported in the liter-
ature,11–18 we propose two plausible reaction pathways for our
organoborane-catalyzed hydrogenation of aldehydes with
a Hantzsch ester, as shown in Fig. 2. The rst of these proposed
reaction pathways is shown in Fig. 2a. In this pathway, an
aldehyde 1 is activated by a boron catalyst. Hydrogen is trans-
ferred to the activated aldehyde from the Hantzsch ester 2 to
form an alcohol–boron adduct Int-III and the Hantzsch pyridine
4. Int-III then dissociates to give an alcohol 3, with the regen-
eration of the boron catalyst. The second possible reaction
pathway is shown in Fig. 2b. This proceeds through generation
of a borohydride species Int-IV by the reaction of 2 with the
boron catalyst. Int-IV then reacts with 1 to give Int-III. Dissoci-
ation of Int-III to afford 3 is accompanied by regeneration of the
boron catalyst.
Fig. 2 Possible reaction pathways. (a) Lewis acid activation pathway,
(b) borohydride pathway.
calculations. We also discuss why tris[3,5-bis(triuoromethyl)
phenyl]borane shows a superior catalytic activity to that of
other boron catalysts.
Results and discussion
Evaluation of the catalytic activity of borane catalysts in the
hydrogenation of benzaldehyde with a Hantzsch ester
Here, we report an investigation of the mechanism of our
organoborane-catalyzed hydrogenation of aldehydes with
a Hantzsch ester by means of NMR experiments and DFT
To compare the catalytic activity of borane catalysts, we exam-
ined the reaction of benzaldehyde (1) with the Hantzsch ester 2
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in the presence of a catalytic amount of various borane
compounds B-a to B-d (Scheme 2). When tris[3,5-
bis(triuoromethyl)phenyl]borane (B-a) was used as the cata-
lyst, the reaction proceeded efficiently to give benzyl alcohol (3)
quantitatively. Tris(pentauorophenyl)borane (B-b) also
promoted the reaction to give 3 in 88% yield. The catalytic
efficiency of B-a is therefore superior to that of B-b. On the other
hand, only a 7% yield of 3 was obtained from the corresponding
reaction in the presence of triuoroborane etherate (B-c),
whereas triphenylborane (B-d) did not promote the reaction at
all. These results indicate that the order of catalytic activity is as
follows: B-a > B-b > B-c > B-d.
Stoichiometric reaction experiments
To identify the reaction pathway, we examined the stoichio-
metric reactions of B-a with benzaldehyde (1) and with
Hantzsch ester 2 (Scheme 3). In a glove box, B-a, 1, and CD2Cl2
were introduced into a J. Young NMR tube (Scheme 3a), and the
Scheme 3 Stoichiometric experiments on (a) the reaction of benzal-
dehyde (1) with tris[3,5-bis(trifluoromethyl)phenyl]borane (B-a) fol-
lowed by treatment with Hantzsch ester 2; (b) the reaction of
benzaldehyde (1) with Hantzsch ester 2.
1
resulting sample was analyzed by H, 13C, and 11B NMR spec-
troscopy. In the 1H NMR spectrum of this sample, the peak
derived from the aldehyde functionality shied to a higher eld
(1: d ¼ 10.01 ppm; Int-Ia: d ¼ 9.17 ppm), whereas the peaks
derived from the aromatic protons of the benzaldehyde shied
to a lower eld (Fig. 3a–c). In the 13C NMR measurement, the
peak derived from the aldehyde functionality shied to a lower
eld (1: d ¼ 192.6 ppm, Int-Ia: d ¼ 200.2 ppm). These observa-
tions suggest that the electron density of the aldehyde func-
tionality decreased aer reaction with B-a. A high eld shi was
observed in the 11B NMR measurements (B-a: d ¼ 68.6 ppm, Int-
Ia: d ¼ 36.0 ppm), showing that the electron density at the boron
center in the resulting product had increased. These results
indicated that Int-Ia was formed in this reaction. The resulting
mixture was also examined by ESI-MS, and a peak correspond-
ing to Int-Ia (m/z ¼ 779 [M + Na]+) was observed. The addition of
2 to the reaction mixture then led to further reaction (Scheme
3a). The resulting sample was analyzed by 1H NMR spectroscopy
(Fig. 3d). In the 1H NMR spectrum of the resulting mixture, the
peak derived from the aldehyde functionality disappeared and
a peak derived from benzylic protons appeared (Fig. 3d, inset;
d ¼ 4.53 ppm). Int-Ia immediately reacted with 2 to give the
benzyl
alcohol–tris[3,5-bis(triuoromethyl)phenyl]borane
adduct Int-IIIa in 90% NMR yield. GC/MS analysis of the reac-
tion mixture demonstrated the formation of benzyl alcohol (3)
(m/z ¼ 108 [M]+). In contrast, no peaks arising from the boro-
hydride species Int-IVa were observed in the reaction of B-a with
2.19 If the reaction proceeds via a borohydride species (Fig. 2b),
Int-IVa should have been detected. Therefore, the reaction
proceeds through activation of the aldehyde by the boron
catalyst, followed by hydride transfer from the Hantzsch ester
(Fig. 2a).20
DFT calculations for the hydrogenation of benzaldehyde with
a Hantzsch ester catalyzed by various organoboranes
We next performed DFT calculations to elucidate details of our
catalytic reaction. All the calculations were carried out with the
GAUSSIAN 09 (Revision E.01) program.21 Geometry optimiza-
tions and frequency calculations for all molecules were carried
out at the M06-2x22 level of theory with the basis sets 6-31G(d,p)
for C and H and 6-31+G(d,p) for B, N, O, and F. Single-point
energies were obtained by calculations at the M06-2x/6-
311++G(d,p) level of theory using the SMD23 solvation model
(1,4-dioxane). The energies reported here includes the elec-
tronic energy, the zero-point energy, thermal correction at
298.15 K and 1 atm, and solvent-effect correction.
First, we calculated the expected reaction pathway (Scheme
2a). The obtained energy diagram of this catalytic reaction and
the calculated structures of transition states are shown in Fig. 4
and 5, respectively. The energy diagram for the reaction with B-
a is drawn as a red line in Fig. 4. The calculated Gibbs free
energy for coordination of 1 to borane B-a is ꢀ3.7 kcal molꢀ1
,
Scheme 2 Hydrogenation of benzaldehyde (1) with Hantzsch ester 2.
Reaction conditions: 1 (0.25 mmol), 2 (0.38 mmol), [B] cat. (0.013
mmol), 1,4-dioxane (1 mL), 25 ꢁC, 12 h.
showing that this is an energetically downhill step. The activa-
tion energy of the hydride-transfer process is 9.9 kcal molꢀ1
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Fig. 3 1H NMR spectra for (a) tris[3,5-bis(trifluoromethyl)phenyl]borane (B-a), (b) benzaldehyde (1), (c) a mixture of 1 and B-a, and (d) after
addition of Hantzsch ester 2 in CD2Cl2.
relative to the initial state. The energy difference between TSa should be generated (DGInt-IIb ¼ ꢀ17.2 kcal molꢀ1). The ionic
(Fig. 5a) and [Int-Ia + 2] is 13.6 kcal molꢀ1. Aer the hydride intermediate Int-IIb is therefore more stable than Int-Ib
transfer, the ionic pair Int-IIa is generated and the Gibbs free (DDGInt-IIb–Int-Ib ¼ ꢀ8.3 kcal molꢀ1), showing that the reaction
energy is ꢀ8.7 kcal molꢀ1. Ionic pair Int-IIa is more stable than should proceed. The Gibbs free energy of Int-IIIb is
Int-Ia (DDGInt-IIa–Int-Ia ¼ ꢀ5.0 kcal molꢀ1). These results show ꢀ18.2 kcal molꢀ1, whereas that for the formation of Int-IIIb
that the hydride-transfer process should proceed smoothly from 3 and B-b is ꢀ10.1 kcal molꢀ1. This value is comparable to
because this step is energetically downhill and has a low acti- the formation of Int-Ib: the calculated energy difference is only
vation energy. A proton is then moved to the benzyl alcohol 1.2 kcal molꢀ1. These results suggest that the generated 3
moiety from the protonated Hantzsch pyridine (DGInt-IIIa
¼
suppresses regeneration of the catalyst, thereby explaining why
ꢀ9.2 kcal molꢀ1, DDGInt-IIIa–Int-IIa ¼ ꢀ0.5 kcal molꢀ1). Finally, B- the catalytic activity of B-b is lower than that of B-a.
a is liberated from Int-IIIa to give 3. The calculated stabilization
The energy diagram for the reaction with B-c as the catalyst is
energy for the formation of Int-IIIa from B-a and 3 is shown by the green line in Fig. 4. In this calculations, interac-
ꢀ1.1 kcal molꢀ1. The stabilization energy of the formation of tion between diethyl ether and intermediates is not considered.
Int-Ia is therefore lower than that of the formation of Int-IIIa, so The Gibbs free energy for the formation of Int-Ic is
the catalytic reaction should proceed smoothly.
1.9 kcal molꢀ1. Under the calculation conditions, B-c is more
We also examined the hydrogenation with B-b as the catalyst stable than Int-Ic. However, the energy difference is small.
(Fig. 4; blue line). The formation of Int-Ib is a downhill step Therefore, formation of Int-Ic is possible. For the formation of
(stabilization energy ꢀ8.9 kcal molꢀ1). The activation energy of the ionic-pair intermediate Int-IIc, the calculated Gibbs free
the hydride-transfer process from 2 to Int-Ib is 5.3 kcal molꢀ1 energy is ꢀ8.9 kcal molꢀ1. The energy difference between Int-Ic
relative to the initial state. The energy difference between TSb and Int-IIc is therefore ꢀ10.8 kcal molꢀ1, indicating that the
(Fig. 5b) and [Int-Ib + 2] is 14.2 kcal molꢀ1. This value is slightly hydride-transfer process is energetically downhill. The activa-
greater than the value of the energy difference between TSa and tion energy for the hydride-transfer process is as high as
[Int-Ia + 2] (13.6 kcal molꢀ1). Aer the hydride transfer, Int-IIb 16.8 kcal molꢀ1 relative to the initial state, and the energy
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Fig. 4 Energy diagram in the organoborane-catalyzed hydrogenation of benzaldehyde (1) with Hantzsch ester (2). Red: tris[3,5-bis(tri-
fluoromethyl)phenyl]borane (B-a), blue: tris(pentafluorophenyl)borane (B-b), green: trifluoroborane etherate (B-c), black: triphenylborane (B-d).
difference between TSc (Fig. 5c) and [Int-Ic
+ 2] is should not take place. These calculation results suggest that the
14.9 kcal molꢀ1. These results suggest that the hydride-transfer reaction with B-d should not proceed at all.
process should proceed. The activation energy of TSc
In our reaction system, the boron catalysts might also react
(14.9 kcal molꢀ1) is larger than that of TSa (13.6 kcal molꢀ1) and with the Hantzsch ester 2 or with the Hantzsch pyridine 4. To
TSb (14.2 kcal molꢀ1). The ion-pair intermediate Int-IIc should understand the inuence of 2 or 4 on the hydrogenation reac-
undergo proton transfer to give Int-IIIc and 4, because this tion, we performed DFT calculations for the possible interme-
process is slightly energetically uphill (DDGInt-IIIc–Int-IIc
¼
diates Int-IV to Int-VIII (Scheme 4). The results of these
0.7 kcal molꢀ1). The formation of Int-IIIc from B-c and 3 is calculations are summarized in Table 1. In the case of the
energetically downhill (ꢀ0.1 kcal molꢀ1). These results suggest reaction of borane B-a with 2 and 4, the Gibbs free energies are
that the reaction is difficult due to the higher activation energy 10.9 (Int-IVa), 1.0 (Int-Va), 18.7 (Int-VIa), 7.8 (Int-VIIa), and
barrier and the higher stability of the formation of Int-IIIc than 7.9 kcal molꢀ1 (Int-VIIIa), respectively. These reactions should
that of the formation of Int-Ic by 2.0 kcal molꢀ1. Therefore, proceed with difficulty, because they are energetically uphill,
when B-c was used as the catalyst, 3 was obtained in only 7% indicating that 2 and 4 are unlikely to affect the efficiency of the
yield, because the generated 3 inhibited the formation of Int-Ic hydrogenation reaction.
(Scheme 2).
On the other hand, in the reaction of B-b, the Gibbs free
The energy diagram for the hydrogenation reaction with B- energies for the formation of Int-IVb and Int-Vb are ꢀ4.0 and
d is shown as a black line in Fig. 4. The formation of Int-Id is ꢀ2.5 kcal molꢀ1, respectively. These intermediates might,
energetically uphill (DGInt-Id ¼ 4.6 kcal molꢀ1), suggesting that therefore, be formed in the reaction of B-b with 2. The processes
it is difficult for 1 to coordinate to B-d. In the hydride-transfer for the formation of Int-VIb, Int-VIIb, and Int-VIIIb are ener-
process, the energy of the desired intermediate Int-IId is getically uphill. From these results, the formation of Int-IIIb is
higher than that of Int-Id (DDGInt-IId–Int-Id ¼ 6.0 kcal molꢀ1), and the most energetically favored of these processes. Therefore, the
the activation energy is relatively high (24.3 kcal molꢀ1 relative desired hydrogenation process proceeds and the resulting
to the initial state). Therefore, the hydride-transfer process hydrogenated product 3 partially inhibits the desired formation
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Table 1 Summary of the calculated Gibbs free energies for the ex-
pected reactions of boron catalysts (kcal molꢀ1
)
B-a
B-b
B-c
B-d
1
2
Int-Ia (ꢀ3.7)
Int-IVa (10.9)
Int-Va (1.0)
Int-Ib (ꢀ8.9)
Int-IVb (ꢀ4.0)
Int-Vb (ꢀ2.5)
Int-VIb (7.9)
Int-Ic (1.9)
Int-Id (4.6)
Int-IVc (32.8)
Int-Vc (1.2)
Int-VIc (7.0)
Int-IVd (29.9)
Int-Vd (9.1)
Ind-VId (ꢀ)a
Int-VIa (18.7)
3
4
Int-IIIa (ꢀ1.1) Int-IIIb (ꢀ10.1) Int-IIIc (ꢀ0.2) Int-IIId (3.5)
Int-VIIa (7.8)
Int-VIIIa (7.9)
Int-VIIb (4.6)
Int-VIIIb (3.4)
Int-VIIc (7.0)
Int-VIIIc (1.9)
Int-VIId (16.4)
Int-VIIId (15.9)
a
The coordinated structure Int-VId was not obtained in the DFT
calculation.
Determination of association constants between boron
reagents and benzaldehyde or benzyl alcohol
The DFT study indicated that a preferential formation of Int-I
compared with the formation of Int-III is important for the
catalytic hydrogenation reaction to proceed. Therefore, we next
determined the association constants between boron reagents
B-a to B-d and benzaldehyde (1) or benzyl alcohol (3). To obtain
the association constants, boron compounds B-a to B-d and 1 or
3 were dissolved in CD2Cl2 and subjected to 1H NMR
Fig. 5 Calculated structures of transition states TSa (a), TSb (b), TSc (c),
and TSd (d) and selected bond distances (the molecular structures
were drawn with CYLview24).
1
measurements. Variable-temperature (VT) H NMR spectra for
the reaction of B-a with 1 are shown in Fig. 6. The peak derived
from the aldehyde functionality separated into peaks derived
from uncoordinated benzaldehyde and the coordinated benz-
aldehyde Int-Ia below ꢀ40 ꢁC. By using a van't Hoff plot, the
association constant was estimated to be 1.19 ꢂ 104 Mꢀ1
(Fig. 7). The Gibbs free energy for the formation of Int-Ia was
calculated from the association constant to be ꢀ5.6 kcal molꢀ1
(Table 2).
We also recorded VT 1H NMR spectra for a mixture of B-a and
3 in CD2Cl2 (Fig. 8). By using the van't Hoff plot (Fig. 9), the
association constant and the Gibbs free energy for the forma-
tion of the borane–benzyl alcohol adduct Int-IIIa were deter-
mined to be 95.4 Mꢀ1 and ‒2.7 kcal molꢀ1, respectively (Table
2). The Gibbs free energy of the formation of Int-Ia is lower than
that for the formation of Int-IIIa (DDGInt-Ia–Int-IIIa
¼
ꢀ2.9 kcal molꢀ1, Table 2). Therefore, coordination of B-a to 1 is
preferred to that of B-a to 3, and the desired reaction should
proceed smoothly (Scheme 2).
Scheme
4 Possible reactions of boron catalysts in the reaction
system.
1
We also measured the VT H NMR spectra for the reactions
of B-b with 1 or 3.25 The association constants and the Gibbs free
energies for the formation of Int-Ib were 396 Mꢀ1 and ‒
3.5 kcal molꢀ1, respectively, and those of Int-IIIb were 58.3 Mꢀ1
and ‒2.4 kcal molꢀ1, respectively (Table 2).26 In this case, the
difference in the value of the Gibbs free energies for the
formation of Int-Ib and Int-IIIb is ꢀ1.1 kcal molꢀ1 (Table 2), so
the formation of Int-Ib competes with the formation of Int-IIIb.
Consequently, the catalytic activity of B-b should be lower than
that of B-a.
In the case of BF3$OEt2 (B-c), the association constant and
Gibbs free energy for the formation of Int-Ic are 5.51 Mꢀ1 and ‒
1.0 kcal molꢀ1, respectively, and the corresponding values for
Int-IIIc are 263 Mꢀ1 and ‒3.3 kcal molꢀ1, respectively (Table 1).25
of Int-Ib. The formation of Int-IVb and Int-Vb might also disturb
the formation of Int-Ib. Thus, the catalytic activity of B-b is lower
than that of B-a.
In the results of our DFT calculation for the reactions of B-c
with 2 or 4, the Gibbs free energies for the formation of Int-Vc
and Int-VIIIc were 1.2 and 1.9 kcal molꢀ1, respectively. These
values are comparable with the Gibbs free energy for the
formation of Int-Ic (1.9 kcal molꢀ1). Thus, 2, 3, and 4 inhibit the
desired reaction, resulting in a low yield of the desired product.
In the reaction of B-d, the formation of all intermediates is
energetically uphill (by at least 3.5 kcal molꢀ1). Consequently,
the reaction of B-d does not proceed at all.
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Fig. 6 VT 1H NMR spectra of a mixture of 1 and B-a (20 ꢁC to ꢀ90 ꢁC).
Fig. 8 VT 1H NMR spectra for a mixture of 3 and B-a (20 ꢁC to ꢀ90 ꢁC).
Fig. 7 van't Hoff plot for a mixture of 1 and B-a (ꢀ40 ꢁC to ꢀ90 ꢁC).
The Gibbs free energy for the formation of Int-IIIc is therefore
Fig. 9 van't Hoff plot for a mixture of 3 and B-a (ꢀ60 ꢁC to ꢀ90 ꢁC).
the formation of Int-I and Int-III [catalytic activities: B-a > B-b >
B-c (Scheme 2); energy differences between formation of Int-I
and Int-III: B-a < B-b < B-c, (Table 2)].
In the reaction of B-d with 1 or 3, the association constants
were 0.195 and 5.67 ꢂ 10ꢀ3 Mꢀ1, respectively, and the Gibbs
free energies were 1.0 and 3.1 kcal molꢀ1, respectively (Table
1).25 These reactions were energetically uphill. Therefore, the
lower than that for the formation of Int-IIIc (DDGInt-Ic–Int-IIIc
¼
2.3 kcal molꢀ1, Table 2) In the hydrogenation of 1 with 2 with B-
c as the catalyst, the generated 3 should therefore inhibit the
catalytic reaction. Consequently, the reaction does not proceed
efficiently (Scheme 2). The order of the catalytic activities of B-a,
B-b, and B-c is correlated with the energy differences between
Table 2 Summary of the association constants (Ka) and Gibbs free energy (DG) values for the reaction of borane reagents B-a to B-d with
1
benzaldehyde (1) or benzyl alcohol (3), as estimated by H NMR measurements
Benzaldehyde (1)
Ka, Mꢀ1
Benzyl alcohol (3)
Ka, Mꢀ1
DG, kcal molꢀ1
DG, kcal molꢀ1
DDGInt-I–Int-III, kcal molꢀ1
B-a
B-b
B-c
B-d
1.19 ꢂ 104
396
5.51
‒5.6
‒3.5
‒1.0
1.0
95.4
58.3
‒2.7
‒2.4
‒3.3
3.1
‒2.9
‒1.1
2.3
263
0.195
5.67 ꢂ 10ꢀ3
‒2.1
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coordination of 1 to B-d occurs with difficulty, explaining why lower than that for the BF3–benzyl alcohol adduct. The gener-
the hydrogenation of 1 does not proceed at all in this case ation of benzyl alcohol therefore inhibits the hydrogenation of
(Scheme 2).
benzaldehyde when BF3$OEt2 is used as a catalyst. The associ-
ation constants of triphenylborane with benzaldehyde and
benzyl alcohol are low, suggesting the hydrogenation reaction
should not proceed efficiently. These experimental results also
Conclusions
We performed NMR experiments and DFT calculations to demonstrated why tris[3,5-bis(triuoromethyl)phenyl]borane is
elucidate the mechanism of the organoborane-catalyzed a superior catalyst to the other borane catalysts in the hydro-
hydrogenation of benzaldehyde with a Hantzsch ester as genation reaction.
a synthetic NADPH analogue, and to explain the activity or lack
of activity of various borane catalyst in this reaction. The reac-
tions in the presence of tris[3,5-bis(triuoromethyl)phenyl]
Conflicts of interest
borane, tris(pentauorophenyl)borane, BF3$OEt2, and triphe- There are no conicts to declare.
nylborane gave benzyl alcohol in yields of 100, 88, 4, and 0%,
respectively. Tris[3,5-bis(triuoromethyl)phenyl]borane there-
fore showed a superior catalytic activity to the other borane
Acknowledgements
catalysts in this reaction. Stoichiometric NMR experiments This research project was supported by JST-ACCEL program
demonstrated that the hydrogenation process proceeds through (JPMJAC1401). G. H. appreciates funding from the JSPS-
activation of benzaldehyde by the borane catalyst, followed by KAKENHI [Grant-in-Aid for Young Scientists (B) No.
hydride transfer from the Hantzsch ester to the activated 17K14524]. The calculations were performed at the Research
aldehyde.
DFT calculations for the hydrogenation of benzaldehyde
Center for Computational Science, Okazaki, Japan.
with a Hantzsch ester in the presence of borane catalysts were
carried out to elucidate details of the reaction. The activation
energies for the hydrogenations in the presence of tris[3,5-
bis(triuoromethyl)phenyl]borane and tris(pentauorophenyl)
borane are sufficiently low to permit the reaction to proceed.
However, in the case of tris(pentauorophenyl)borane, the
benzyl alcohol–B(C6F5)3 adduct is almost as stable as the
benzaldehyde–B(C6F5)3 adduct, indicating that the generated
benzyl alcohol is likely to inhibit the catalytic cycle. In the case
of BF3$OEt2, the formation of the BF3–benzyl alcohol adduct,
the BF3–Hantzsch ester adduct, and the BF3–Hantzsch pyridine
adduct should retard the formation of the BF3–benzaldehyde
adduct, explaining why the catalytic reaction does not proceed
efficiently. In contrast, the activation energy in the reaction with
triphenylborane is relatively high and the hydrogen-transfer
process is energetically uphill, explaining why the reaction
proceeds with difficulty. These results explain why tris[3,5-
bis(triuoromethyl)phenyl]borane is superior to the other
boron catalysts in this hydrogenation reaction.
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