Mechanistic Insights on Reduction of Carboxamides by Diisobutylaluminum Hydride and Sodium Hydride?Iodide Composite

Article abstract of DOI:10.1002/hlca.201900166

The reaction mechanisms on reduction of tertiary carboxamides by diisobutylaluminum hydride (DIBAL) and sodium hydride (NaH)-sodium iodide (NaI) composite were elucidated by the computational and experimental approaches. Reduction of N,N-dimethyl carboxamides with DIBAL provides the corresponding amines, whereas that with the NaH?NaI composite exclusively forms aldehyde even at high reaction temperature. DFT calculations revealed that dimeric structural nature of DIBAL and Lewis acidity on its Al center play crucial role to decompose the tetrahedral anionic carbinol amine intermediate through C?O bond cleavage. On the other hand, in the reduction with the NaH?NaI composite, the resulting tetrahedral anionic carbinol amine intermediate could be kept stable, thus providing aldehydes as a sole product by the aqueous workup.

Full text of DOI:10.1002/hlca.201900166

HELVETICA
chimica acta
Accepted Article
Title: Mechanistic Insights on Reduction of Carboxamides by
Diisobutylaluminum Hydride and Sodium Hydride-Iodide
Composite
Authors: Derek Yiren Ong, Kohei Watanabe, Ryo Takita, and
Shunsuke Chiba
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Helvetica Chimica Acta
10.1002/hlca.201900166
HELVETICA
Mechanistic Insights on Reduction of Carboxamides by
Diisobutylaluminum Hydride and Sodium Hydride-Iodide Composite
a
b
,b
,a
Derek Yiren Ong, Kohei Watanabe, Ryo Takita* , and Shunsuke Chiba*
a
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371 (Singapore) e-mail: shunsuke@ntu.edu.sg
b
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
e-mail: takita@mol.f.u-tokyo.ac.jp
Dedicated to Professor Philippe Renaud in celebration of his 60th birthday
The reaction mechanisms on reduction of tertiary carboxamides by diisobutylaluminum hydride (DIBAL) and sodium hydride (NaH)-sodium
iodide (NaI) composite were elucidated by the computational and experimental approaches. Reduction of N,N-dimethyl carboxamides with
DIBAL provides the corresponding amines, whereas that with the NaH-NaI composite exclusively forms aldehyde even at high reaction
temperature. DFT calculations revealed that dimeric structural nature of DIBAL and Lewis acidity on its Al center play crucial role to
decompose the tetrahedral anionic carbinol amine intermediate through C-O bond cleavage. On the other hand, in the reduction with the
NaH-NaI composite, the resulting tetrahedral anionic carbinol amine intermediate could be kept stable, thus providing aldehydes as a sole
product by the aqueous workup.
Keywords: Amides • Reduction • Diisobutylaluminum hydride • Sodium hydride • DFT calculation
On the other hand, our group recently disclosed that sodium hydride
Introduction
(
NaH) could act as a hydride donor in the presence of NaI or LiI in
Among a series of metal-based hydride reagents for reduction of π-
THF, capable of performing controlled reduction of tertiary
[
1,2]
[13-18]
polar electrophiles,
diisobutylaluminum hydride (DIBAL) is one of
carboxamides into aldehydes (Scheme 2).
This unique
the most commonly used chemicals in both academics and
controlled feature could be observed even if the reactions are
performed at higher reaction temperature (i.e. reflux in THF),
implying that the resulting anionic carbinol amine intermediate II is
kept extremely stable under the reaction conditions. The protonated
hemiaminal III, formed by the aqueous work-up, should be
immediately decomposed into aldehydes with release of amines.
These totally distinct reactivities of DIBAL and NaH toward reduction
of carboxamides stimulated us to explore their reaction mechanisms
[
3-5]
industries (Scheme 1A).
Its reactivity toward various types of
electrophiles were explored in details and described in the common
[
6]
textbooks in basic organic chemistry. For example, reduction of
[
7-9]
tertiary carboxamides
by DIBAL is known to form the
corresponding amines (Scheme 1B), despite several exceptions
such as reduction of N-methoxy-N-methylamides (the Weinreb
[
10-12]
amides).
However, the reaction mechanism for the amine
formation, especially pertaining to how the process mediates
selective cleavage of the C-O bond from the anionic carbinol amine
intermediate I formed by the 1st hydride transfer, has not clearly
been uncovered.
in detail.
This article describes their elucidation through the
theoretical and experimental approaches.
[
Na]
O
NaH
NaI
H
O
H O
H
OH
2
O
R”
R”
R
N
R
N
R”
R
N
(
work up)
A. Diisobutylaluminum hydride (DIBAL)
R
H
R’
amides
R’
II
R’
aldehydes
III
origin of the stability of II?
H
+
R”
•
•
dimeric form with bridging hydrides
commercially available as a solution
in various aprotic solvents
Al
Al
H
N
•
R’
H
Scheme 2. Controlled reduction of amides into aldehydes by NaH-NaI
B. Reduction of amides by DIBAL
R”
via C-O cleavage
R
N
O
[Al]
R”
R’
amines
Results and Discussion
H
O
DIBAL
R”
R
N
R
N
At the outset of the project, we selected N,N-dimethyl-2-naphthamide
(1a) and aliphatic amide 1b derived from gemfibrozil as the model
R’
R’
via C-N cleavage
amides
I
R
OH
[
19]
alcohols
substrates and examined their reduction by titrated DIBAL and the
NaH-NaI system. Treatment of amide 1a with 2.2 equiv of DIBAL
resulted in smooth double hydride reduction of 1a at room
•
•
mechanism of C-O cleavage?
origin of selectivity?
Scheme 1. Diisobutylaluminum hydride (DIBAL).
1
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Helvetica Chimica Acta
10.1002/hlca.201900166
HELVETICA
temperature to give amine 3a in 97% yield along with a small amount
O
). We found that the reduction by the resulting hydride species
(
<2% yield) of alcohol 4a (Scheme 3A). In the sharp contrast, the
within INT2’dimer/C–O proceeds smoothly and the amine is obtained
with the concomitant formation of an oxo-bridged aluminum dimer
(Al–O–Al). In contrast, in the case of the C–N scission process that
affords the corresponding alcohol (Scheme 5B), only one of the
aluminum centers can be involved in the electrophilic activation of
reaction in the presence of 3 equiv of NaH and 1 equiv of NaI
afforded 2-napthaldehyde (2a) in 93% yield as a sole product
[
15]
(
Scheme 3B).
Exactly the same trend was observed in the
reduction of aliphatic amide 1b (Scheme 4).
‡
the nitrogen atom. This results in high energy (∆G +37.9 kcal/mol)
A. with DIBAL
for the C–N bond cleavage, which unlikely occurs under the
reduction conditions. These theoretical outcomes clearly illustrate the
experimentally observed selectivity in amide reduction with DIBAL. It
O
DIBAL (2.2 equiv)
NMe2
THF
2
5 °C, 2 h
1
a
then H O
2
2
should be noted that the calculations with a monomeric Me AlH led
to an unreasonable pathway (C–O scission, Scheme 5C) or high
activation energy (C–N scission, Scheme 5D). The dimeric structure
of DIBAL with Lewis acidic Al centers is indispensable for the
controlled selectivity in the amide reduction.
O
+
+
Ar =
Ar
NMe2
Ar
OH
Ar
H
2
a 0%
3a 97%
4a <2%
B. with NaH-NaI
O
NaH (3 equiv)
NaI (1 equiv)
A. With Me AlH dimer: C–O bond scission to afford the amine
2
O
H 1.75
1.83
NMe2
1.77
1.83
H
1.79
AlMe
2
H
Ar
H
a 93%
1
.83
AlMe2
THF
Me Al
AlMe2
∆G‡
+13.7
1.78
2
Me
2
Al 1.77
Me Al
O
1.78
1
.88
1.87
O
1.77
2
4
0 °C, 10 h
O
–
1.9
2
1.46
1
.43
2.84
1.29 NMe2
1
a
then H O
2
NMe2
1.29
NMe
2
H
H
1
.10
H
.09
1.09
1
Scheme 3. Reduction of amide 1a.
INT1dimer/C–O
TS1dimer/C–O
INT2dimer/C–O
(0.0)
(13.7)
(11.8)
A. with DIBAL
+0.6
Me
Me
O
DIBAL (2.2 equiv)
THF
Me
Me
Me
1
.71
∆G‡
Al 1.68
Me
O
NMe2
1.11
1.79
Me Al
2
H
Al
H
–35.7
1.70
H
2
+4.7 Me
2
Al 1.70
O
H
1
.70
1.77
2
5 °C, 2 h
O
1.10
.10
1
.46
1.29 NMe
2
1
b
O
NMe2
then H O
1.71
NMe2
2
Me
2
Al
1.09
1.30
AlMe
2
H
H
O
R =
1.09
Me
O
INT3dimer/C–O
TS2dimer/C–O
INT2’dimer/C–O
+
+
R
NMe2
R
OH
(–18.6)
(17.1)
(12.4)
R
H
Me
2
b 0%
3b 96%
4b <3%
2
B. With Me AlH dimer: C–N bond scission to afford the alcohol
1
.64
H
Me
Al
2
Me
Al 2.78
2
H 1.62
AlMe
H1.62
Me
2
Al
1.91
3.04
1.81
∆G‡
+37.9
1.82
3.18
AlMe
2
1.97
B. with NaH-NaI
2
N
1
.88
1.98
AlMe
2.07
2
N
O
–1.3
Me
O
O
Me
NaH (3 equiv)
NaI (1 equiv)
1
.41
1.51
Me
Me 1.26
1.10
Me 1.25
O
O
N
H
1.10
H
1
.10
Me
H
Me
R
H
Me
O
NMe2
THF
0 °C, 14 h
INT1dimer/C–N
TS1dimer/C–N
INT2dimer/C–N
2
b 88%
(–5.9)
(32.0)
(30.7)
4
1
b
then H O
2
2
C. With Me AlH monomer: C–O bond scission
thf
2.06 thf
Scheme 4. Reduction of amide 1b.
2.00
thf
2
.05
2
Me Al
1.70
AlMe
.76
2
G‡
+45.4
1
∆
AlMe
.70
2
O
1.57
O
.39
–4.9
1
1
1
.46
H
1.16
To gain the insights into the detailed molecular mechanisms, we next
performed DFT calculations for the reduction of benzamide as the
model substrate at the ωB97X-D/6-311+G**/SMD(THF)//ωB97X-D/6-
O
H
1.30
NMe
2
NMe2
H
1.10
1.84
1.10
NMe
2
INT1monomer/C–O
TS1monomer/C–O
INT2monomer/C–O
(0.0)
(45.4)
(40.5)
3
1+G*/SMD(THF) level of theory. Scheme 5A and B displayed the
D. With Me
2
AlH monomer: C–N bond scission
thf
calculated reaction pathways by a Me AlH dimer, which is used as a
2
thf
2
.06
3.24
1.96
thf
∆G‡
+30.2
2.00
1
.82
simplified model of DIBAL herein. The C–O bond scission process
starts from the anionic carbinol amine intermediate (INT1dimer/C–O) that
is generated by the first hydride attack to benzamide (Scheme 5A).
The dimeric aluminum complex facilitates the liberation of a dianionic
oxygen atom, through the efficient cooperative activation by the two
aluminum centers having highly Lewis acidic/oxophilic properties
AlMe
2
AlMe
1.89
2
O
1.24
AlMe
1.84
NMe
2
2
O
O
–8.6
1
.38
2.30
1.25
1
.50
2.62
1.10
NMe2
NMe2
H
H
H
1.10
1
.10
INT1monomer/C–O
TS1monomer/C–O
INT2monomer/C–O
(–4.0)
(26.2)
(17.6)
Scheme 5. The calculated reaction pathways for the reduction of benzamide
with the dimer (A,B) or monomer (C,D) of Me AlH. Energy changes and bond
2
(
TS1dimer/C-O). Thus, the C–O bond is cleaved with a reasonable
‡
lengths at the ωB97X-D/6-311+G**/SMD(THF)//ωB97X-D/6-31+G*/SMD(THF)
activation energy (∆G +13.7 kcal/mol) to afford an iminium cation
level of theory are shown in kcal/mol and Å, respectively.
together with an oxo-bridged dinuclear aluminum hydride (INT2dimer/C–
2
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Helvetica Chimica Acta
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The amide reduction by the NaH-NaI composite empirically gave the
corresponding aldehydes (Schemes 3B and 4B). We assume that
counter ion metathesis between NaH and NaI in THF allows for
generation of activated, nanomeric units of NaH, that possesses
enhanced nucleophilic hydridic character to promote the present
intermediate. Energy changes and bond lengths at the ωB97X-D/6-
311+G**/SMD(THF)//ωB97X-D/6-31+G*/SMD(THF) level of theory are shown
in kcal/mol and Å, respectively.
Although the anionic carbinol amine intermediate II is found fairly
stable under the reaction conditions, we wondered why the aqueous
workup can immediately convert it into the corresponding aldehyde.
[
20]
process. Thus, using a NaH dimer as an appropriate model of the
active species, the possibility of the pathways for the C–O and C–N
bonds scission from the anionic carbinol amine intermediate II was
investigated by the same DFT method. In the C–O scission pathway
+
Is it derived from the difference between sodium cation (Na ) and
+
proton (H )? Scheme
7 addressed this question. While the
degradation should not proceed with a simply protonated carbinol
(
(
Scheme 6A), the oxygen atom in the tetrahedral intermediate
2
amine intermediate (Scheme 7A), the presence of a H O molecule
INT1NaH/C–O) coordinates to the two sodium cations, the structure of
‡
markedly accelerates the process (∆G +10.0 kcal/mol) via the
which is analogous to that of INT1dimer/C–O in the DIBAL reduction
Scheme 5A). However, the Na–O–Na moiety in this complex should
formation of 6-membered ring hydrogen-bonding network
(
(
TS1proton/H2O), allowing for the smooth release of aldehyde and
have extremely strong basicity, and the calculation implied an
unusual deprotonation pathway from the methyl group on the
nitrogen atom (TS1NaH/C–O). Its activation barrier is too high, and this
pathway should not be feasible. On the other hand, as shown in
Scheme 6B, the C–N bond scission pathway also requires high
amine (Scheme 7B). The proton relay with the aid of H
the expeditious degradation upon an acidic work-up.
2
O facilitates
A. Proton-promoted degradation of hemiaminal
‡
H
0.97
1.35
∆G‡
26.4
1.35O
O
1.21
activation energy (∆G +30.4 kcal/mol), that should prevent the
O
H 1.22
1.02
H
+
1.57
–23.1
1
.41 1.46
Me
H
N
reaction progress. To detect formation of the anionic carbinol amine
N
H
N
H
Me
Me Me
INT2proton
B. Proton-promoted degradation of hemiaminal in the presence of H O
Me Me
1
3
intermediate, we prepared C-labeled benzamide 1c and reduced it
INT1proton
TS1proton
under the optimized reaction conditions in THF-d (Scheme 6C). The
8
1
13
2
H and C NMR analyses of the resulting crude mixture showed a
1
doublet peak having a coupling constant of 143 Hz at 5.01 ppm ( H
0.98
H
O 2.11
1.94
H
1.15
H
1
.29
H
1.86
0
.98
H
G‡
+10.0
H
∆
1
3
O
O
O
.22
O
.40
O
1.34
–6.2
NMR) and 98.4 ppm (proton-coupled C NMR), clearly indicating the
0.99
1.53
1
1
H
1
.50
1.58
H
1.09
H
1
3
1.87
H
N
N
1.02
presence of 5c having a tetrahedral C-labeled carbon with one
hydrogen atom. These computational and experimental outcomes
implied that the anionic carbinol amine intermediate II would not be
decomposed under the reaction conditions. This is consistent with
the previous observation by Olah and co-workers, in which the
reactions of tertiary formamide with Grignard reagents afforded the
N
H
Me
H
Me
Me Me
INT2proton/H2O
Me
Me
INT1proton/H2O
TS1proton/H2O
Scheme 7. The calculated reaction pathways for the degradation of the
carbinol amine intermediate. Energy changes and bond lengths at the ωB97X-
D/6-311+G**/SMD(water)//ωB97X-D/6-31+G* level of theory are shown in
kcal/mol and Å, respectively.
[
21]
corresponding aldehydes.
The distinct selectivity observed in the reduction with DIBAL or NaH-
NaI composite should be reflected mostly by the difference in Lewis
acidic properties between Al and Na cations. This could also be
ascertained by iterative reduction of amide 1a with the NaH-NaI
system and DIBAL. The anionic carbinol amine intermediate II,
formed by the reaction of amide 1a under the NaH-NaI system, was
subsequently treated with DIBAL, that could induce the
decomposition of II and the second hydride transfer to form amine 3a
as the major product (Table 1). It was interestingly found that the
lower loadings of DIBAL resulted in incomplete reduction, providing a
mixture of aldehyde 2a, amine 3a, and alcohol 4a (entries 1 and 2),
whereas the selective formation of amine 3a was observed in use of
2 equivalents of DIBAL (entries 3 and 4).
A. C–O bond scission
thf
thf
2
.32
2.25 Na 2.20
2
.23
H
O
2.26
2.38
H
0.96
thf
Na
H
2
.14
O
2.20
Na
2.20
Na
2.20
G‡
85.4
Na
H
∆
2.32
H
thf
thf
2.15 O1.72
1.15
+
–51.4
Na
CH
1
.36
thf
2
1
.49
1.4C5 H2
1.32
2
.79
NMe2
1.30N
N
.35
1
H
Me
Me
1
.11
1.09H
1.08H
INT1NaH/C–O
0.0)
TS1NaH/C–O
INT2NaH/C–O
(
(85.4)
(34.0)
B. C–N bond scission
thf
2
.16
thf
2
.15
2
.27
H
2.27
H
2.37 thf
Na
Na
H
2.26
Na 2
.15
2.29
2.31 Na
∆G‡
+30.4
thf
Na
thf
O 2.32
O
.23
O
Na
2.27
–1.7
1
.35
1
.51
2.52
1
2.27
Me
1.23
thf
N
N
N
1.10
1.11
H
Me
Me
INT1NaH/C–O
1.5)
H
Me
1.11H
Me
Me
TS1NaH/C–O
INT2NaH/C–O
(
(31.9)
(30.2)
C. Observation of the carbinol amine intermediate
δ 5.01 ppm (d, J1H-13C = 143 Hz)
O– Na+
C13
O
H
NaH (3 equiv)
NaI (1 equiv)
C13
NMe2
NMe2
THF-d8
0 °C, 25 h
δ 98.4 ppm (d, J1H-13C = 143 Hz)
4
1
c
5
c
Scheme 6. The calculated reaction pathways for the reduction of benzamide
with NaH dimer and the experimental observation of the anionic carbinol amine
3
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Helvetica Chimica Acta
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HELVETICA
Table 1. Iterative reduction of amide 1a by NaH-NaI and DIBAL
with DIBAL is a fundamental reaction in organic chemistry, and the
investigations herein identified that the structural requirement of
dimeric complex as well as Lewis acidic properties of aluminum
centers play a crucial role for the controlled selectivity to afford the
amine formation. On the other hand, anionic carbinol amine
intermediate II formed in the reduction with the NaH-NaI system was
found stable under the reaction conditions, leading to the selective
aldehyde formation with the aqueous workup. These fundamental
mechanistic insights should be beneficial to guide further design and
development of new reductive molecular transformation of amides
and their derivatives in a highly controlled manner.
O
Na+
then
DIBAL
NaH (3 equiv)
NaI (1 equiv)
H
O
NMe2
Ar
NMe2
conditions
2 h
then H O
THF
0 °C, 10 h
4
II
1
a
2
O
+
+
Ar
NMe2
3a
Ar
OH
Ar
H
2
a
4a
(Ar = 2-naphthyl)
Entry
DIBAL
Temp
Conv.
2a
3a
4a
[
b]
[b]
[b]
[b]
(
equiv)
[°C]
[%]
[%]
[%]
[%]
1
2
3
4
1.0
1.5
2.0
2.0
0
0
>99
>99
>99
>99
48
18
2
39
69
94
98
12
11
4
Supplementary Material
0
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/MS-number.
25
0
<1
1
[
a] The reactions were conducted using 0.5 mmol of amide 1a. [b] H NMR
Acknowledgements
yields based on the internal standard.
This work was financially supported by Nanyang Technological
University (NTU), the Singapore Ministry of Education (Academic
Research Fund Tier 1: RG10/17 for S. C.), and JSPS Grant-in-Aid for
Scientific Research (C) (19K0662, for R. T.). R.T. thanks the Takeda
Science Foundation, The FUGAKU Trust for Medicinal Research,
and Uehara Memorial Foundation for financial support. The
computations were performed using Research Center for
Computational Science at Okazaki, Japan.
Similarly, the iterative reduction of aliphatic amide 1b needed 2
equivalents of DIBAL to obtain amine 3b selectively (Scheme 8A).
These results suggested that both of the higher Lewis acidity of
aluminum and the dimeric structure of DIBAL cooperatively assist the
C–O bond scission even from the anionic carbinol amine
intermediate III (Scheme 8).
A. Iterative reduction of amide 1b
Me
NaH (3 equiv)
NaI (1 equiv)
then
DIBAL
O
Author Contribution Statement
Me
O
NMe2
THF
0 °C, 14 h
2
5 °C, 2 h
R.T. and S.C. designed the studies. D.Y.O. performed the
experiments. K.W. and R.T. conducted DFT calculation. R.T. and
S.C. wrote the manuscript.
4
then H O
2
1
b
R =
Me
O
+
R
NMe2
b 98%
R
OH
Me
References
3
4b <1%
[
[
[
1]
2]
3]
M. Hudlicky, ‘Reductions in Organic Chemistry’, Ellis Horwood Ltd.,
Chichester, U.K., 1984.
B. A proposed mechanism
Na+
H
J. Seyden-Penne, ‘Reductions by the Alumino- and Borohydrides in
Organic Synthesis’, Wiley, New York, 1997.
R’
R’ Al
H
H
Na+
H
R
IV
+
NMe2
H
O
DIBAL
R’
Al
R’
O
K. Ziegler, H. Martin, F. Krupp, ‘Metallorganische Verbindungen, XXVII
R
NMe2
C-O
cleavage
R
NMe2
III
Na+
Aluminiumtrialkyle
und
Dialkyl-Aluminiumhydride
Aus
II
R’
R’ Al
H
Aluminiumisobutyl-Verbindungen’, Liebigs Ann. 1960, 629, 14-19.
H
R’
Al
[4]
[5]
P. Galatsis, M. Sollogoub, P. Sinaÿ, ‘Diisobutylaluminum Hydride in
Encyclopedia of Reagents for Organic Synthesis’, John Wiley & Sons,
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O
R’
V
H
H
Na+
E. Winterfeldt, ‘Applications of Diisobutylaluminium Hydride (DIBAH)
and Triisobutylaluminium (TIBA) as Reducing Agents in Organic
Synthesis’, Synthesis 1975, 617-630.
R’
+
H
R’ Al
R
NMe2
a or 3b
R’
R’
Al
O
3
VI
[
6]
N. M. Yoon, Y. S. Gyoung, ‘Reaction of diisobutylaluminum hydride with
selected organic compounds containing representative functional
groups’, J. Org. Chem. 1985, 50, 2443-2450.
Scheme 8. Iterative reduction of amide 1b and a proposed mechanism
[
[
7]
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Conclusions
We have verified the reaction mechanisms on reduction of tertiary
carboxamides by DIBAL and the NaH-NaI composite by the
computational and experimental approaches. The reduction of amide
4
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Helvetica Chimica Acta
10.1002/hlca.201900166
HELVETICA
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[
[
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5
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Helvetica Chimica Acta
10.1002/hlca.201900166
HELVETICA
Entry for the Table of Contents
(
(Insert TOC Graphic here; max. width: 17.5 cm; max. height: 7.0 cm))
H
DIBAL
(
i-Bu) Al
Al(i-Bu)2
2
O
R
NMe2
NMe2
via
• C-O cleavage
R
H
O
–
•
second H reduction
R
NMe2
NaH
NaI
Na
O
H
H O
O
2
NMe2
R
R
H
•
stable before aqueous workup
6
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